Stahl's Essential Psychopharmacology - 5th Edition

25th
With this fully revised Fourth Edition, Dr. Stahl returns to the essential
roots of what it means to become a neurobiologically empowered
Stephen M. Stahl is Adjunct
Professor of Psychiatry at the
Stahl Anniversary Stephen M. Stahl
psychopharmacologist, expertly guided in the selection and combination University of California at San
of treatments for individual patients in practice. Diego, California, USA, and Fourth
Embracing the unifying themes of “symptom endophenotypes,” dimensions
Honorary Visiting Senior Fellow
in Psychiatry at the University Edition Fifth Edition
of psychopathology that cut across syndromes, and “symptoms and of Cambridge, Cambridge,
Stahl’s Essential
circuits,” every aspect of the text has been updated to the frontiers of UK. He has conducted various
Stahl’s Essential Psychopharmacology

current knowledge, with the clarity of explanation and illustration that research projects awarded by
only Dr. Stahl can bring. the National Institute of Mental
Health, Veterans Affairs, and
Psychopharmacology
Integrating much of the basic neuroscience into the clinical chapters, and
with major additions in the areas of psychosis, antipsychotics, antidepres- the pharmaceutical industry.
Author of more than 500
sants, impulsivity, compulsivity, and addiction, this is the single most readily
articles and chapters,
readable source of information on disease and drug mechanisms.
Dr. Stahl is the author of the
This remains the essential text for all students and professionals in mental bestseller Stahl’s Essential
health seeking to understand and utilize current therapeutics, and to
anticipate the future for novel medications.
Psychopharmacology and
The Prescriber’s Guide.
Neuroscientific Basis and Practical Applications
Praise for previous editions: “Essential Psychopharmacology offers a wide range

of readers an engaging and comprehensive view of
“… essential reading … I would thoroughly recommend
psychopharmacology. It is highly recommended to both
this book to anyone who works with psychotropic drugs
novice and experienced researchers, who stand to gain
– or who has the task of teaching others about them!”
a new or renewed appreciation for the complexity and
American Journal of Psychiatry
beauty of how the nervous system mediates the
“The clinically orientated chapters do an impressive behavioral effects of drugs.” Contemporary Psychology
job of bringing together the neuropathological basis
“The book is an excellent source of information for the
and psychopharmacological approaches to psychiatric
art of prescribing psychotropic medications. This book
conditions. I would highly recommend this as a concise,
belongs in every clinician’s library and serves as a model
entertaining, and easily accessible source of informa-
of clarity for others.” Acta Psychiatrica Scandinavica
tion.” Addiction Biology
“Medical students, psychiatry residents, and fellows
“If there is one basic psychopharmacology text for a
and experienced clinicians will find the style and content
practitioner or teacher of psychiatric medicine to own,
refreshing … I recommend this text as an extremely
this is it … Cleverly illustrated with simple cartoons, this
useful reference work as we enter the next decade of
book presents complex information in an easily accessi-
discovery in brain neurosciences and its role in clinical
ble manner … Essential Psychopharmacology is a
psychiatry.” Psychological Medicine
first-rate book.” The Lancet
“We highly recommend this book both to general prac-
“… an excellent basic textbook covering the key areas
titioners who may need information on general mecha-
of psychopharmacology. Its concise and structured
nisms of psychotropic drugs and to students who would
approach made reading enjoyable … I would wholeheart-
like to learn more about basic psychopharmacology and
edly recommend this book to all psychiatric trainees.”
its practical applications.” Clinical Neuropsychiatry
Journal of Intellectual Disability Research
“As an MRC psychiatry student I have benefited enor-

mously from studying this book. Stahl has allowed me
to see the light in what I previously found to be a very
complex subject; it has made a fascinating and fulfilling
read.” International Journal of Geriatric Psychiatry
Stahl’s Essential
Psychopharmacology
Neuroscientific Basis and Practical
Applications
Fifth Edition
Since 1996, students and mental health professionals across the world have turned
to Stahl’s Essential Psychopharmacology as the single most readable source of
information on the fundamentals of psychopharmacology, disease and drug
mechanisms. 25 years later, the fifth edition of this bestselling book continues
Dr Stahl’s proud legacy of helping readers to understand and utilize current
therapeutics, and to anticipate the future for novel medications.
Long established as the preeminent source in its field, the eagerly anticipated fifth
edition of Dr. Stahl’s essential textbook of psychopharmacology is here! With its use
of icons and figures that form Dr. Stahl’s unique “visual language,” the book is the
single most readable source of information on disease and drug mechanisms for all
students and mental health professionals seeking to understand and utilize current
therapeutics, and to anticipate the future for novel medications.
Every aspect of the book has been updated, with the clarity of explanation that
only Dr. Stahl can bring. The new edition includes over 500 new or refreshed figures,
an intuitive color scheme, 14 new uses for older drugs and 18 brand new drugs,
coverage of Parkinson’s disease psychosis, behavioral symptoms of dementia, and
mixed features in major depressive episodes, and expanded information on the
medical uses of cannabis and hallucinogen-assisted psychotherapy.
The opportunity to review and comment on Stahl’s though this approach is it does present challenges for
Essential Psychopharmacology, 5th edition, is truly a students, scientists, and clinicians who wish to learn
pleasure. The depth and comprehension of this edition about or keep up with such a diverse, rich, and rapidly
reads like a fresh view of everything we would want to evolving knowledge base. Essential Psychopharmacology
know in the area of psychopharmacology, including admirably meets these needs for all who wish to
the integration of basic and clinical neuroscience learn about or develop their skills and knowledge of
information. The clarity as a teaching tool for any level of psychopharmacology. Written by Dr. Stahl, an author who
education and sophistication is remarkable, just as is the is a most accomplished clinician, scientist, and teacher,
ease of reading and enjoying the unique set of figures and it covers all relevant fields of Psychopharmacology in an
tables. The book represents a departure from the usual expertly informed and accessible way. Previous editions
fare that we are offered as we delve into the mysteries have established Essential Psychopharmacology as a vital
of our body. In short, this 5th edition is not a simple introductory and reference text for the students and
reworking of earlier editions but really a brand new view. practitioners of psychopharmacology as well as for all
It represents a model for the way that we should cover scientists with an interest in the field. The latest edition
other areas of neuroscience. admirably follows its predecessors and will undoubtedly
be a vital resource for all those interested in this
Ellen Frank, PhD, Distinguished Professor
fascinating discipline.
Emeritus of Psychiatry, University of Pittsburgh
School of Medicine Professor Allan Young, Chair of Mood Disorders,
Director of the Centre for Affective Disorders,
Can you improve on a classic psychopharmacology
Department of Psychological Medicine, Institute of
textbook? Yes! Updated, restyled, and with enhanced
Psychiatry, Psychology and Neuroscience King’s College
illustrations, this 5th edition of Stephen Stahl’s “must
London
have” text is comprehensive, readable, and beautifully
presented. This book is a must for anyone who would like to dive
into psychotropics and get a state-of-the-art knowledge in
Professor David Castle, MD, FRANZCP, FRCPsych,
a clear, elegant, and accessible platform.
Scientific Director, Centre for Complex Interventions,
Professor Stahl has managed to provide simple,
Centre for Addictions and Mental Health, Toronto,
yet accurate, cutting-edge concepts using creative
Canada; and Professor, University of Toronto
and innovative graphics and design. In this regard,
This new edition of a classical textbook is superb. it’s presenting the perfect marriage of contemporary
Unlike most other volumes on psychopharmacology, it neuroscience knowledge with outstanding accessibility.
is organized around biological mechanisms, and uses I found this book extremely useful for well-informed
that framework to review the latest research. Another clinicians as well as colleagues who are starting to
unique feature is its use of wonderfully reader-friendly practice psychiatry and recommend it as an essential
illustrations, bringing to life many pathways that addition for all mental health professionals as well as for
would otherwise be difficult for the non-specialist to general practitioners with interest in psychiatry.
understand.
Professor Joseph Zohar, Director of Psychiatry and
Joel Paris, MD, Emeritus Professor of Psychiatry, the Anxiety and Obsessive Compulsive Clinic at the Sheba
McGill University and Author of “Nature and Nurture in Medical Center, Tel HaShomer, Israel and Professor of
Mental Disorders: A Gene-Environment Model” Psychiatry at Tel Aviv University, Israel
Although the effects of drugs on the mind, via the brain, Stahl’s Essential Psychopharmacology is without a
have preoccupied humans since the dawn of history, the doubt the leading textbook on the neuroscientific basis
scientific discipline of Psychopharmacology has only of psychopharmacology. It covers the neuroscience
developed during modern times. From its inception, relevant to understanding psychotropic drugs and
Psychopharmacology has always benefitted from a integrates this with the pharmacology of all the main
virtuous cycle of science informing clinical practice and drugs used in practice. This 5th edition is extensively
clinical questions driving the science. This is now often revised and updated to incorporate the latest advances
called “Translational Medicine,” an approach that has in neuroscience relevant to psychopharmacology. Dr.
always been central to Psychopharmacology. Admirable Stahl has distilled the latest advances in neuroscience
to fully revamp this edition. Dr. Stahl’s talent is to make revised figures, information on 18 new medications, and
complex ideas deceptively easy to grasp. This is no small dozens of other additions or changes. Stahl’s Essential
feat. He does it with pithy explanations, clear diagrams, Psychopharmacology will remain the only pharmacology
and memorable analogies. My favorite is the “Fab Four” textbook I recommend to my trainees.
of cognition but you’ll have to read the book to find
Dr. Richard C. Shelton, Charles Byron Ireland
out where “The Beatles” come into it. There are many
Professor, Director, UAB Depression and Suicide Center,
textbooks in the field, but this stands out in the clarity
Department of Psychiatry and Behavior Neurobiology,
of explanation and cutting-edge neuroscience. True to
Director of Research, UAB Huntsville Regional Medical
its name, it is essential reading for psychiatrists, primary
Campus, School of Medicine, The University of Alabama
care physicians, students, and other professionals treating
at Birmingham
patients with mental illnesses. It will also be useful for
trainees and neuroscientists. In short, Dr. Stahl does it Stahl’s Essential Psychopharmacology is a classic in the
again! field, which is unique in providing not only excellent
teaching about mechanisms of drug action through the
Professor Oliver Howes, MRCPsych, PhD, DM, use of attractive and innovative icons but also a sense
Professor of Molecular Psychiatry, King’s College London of the actual clinical experience of tailoring therapeutic
and Imperial College London drug choices to psychiatric symptom profiles.
Stahl’s Essential Psychopharmacology has lived up Trevor W. Robbins, Professor of Cognitive
to its name as “essential” reading for generations Neuroscience, University of Cambridge
of psychiatrists and other professionals involved
in the prescription of psychotropic medication at Steve Stahl’s “Essential Psychopharmacology” is a
various levels of skill. Its hallmark has always been its classic, used by clinicians, students, and researchers
approachability while maintaining a depth which still throughout the world. For clinicians it’s practical, for
provides important new information for experienced students it’s clear, and for researchers it’s innovative.
clinicians. The current edition is even more remarkable Stahl is an experienced clinician, and his text is filled
than its predecessors for its ability to provide useful with useful pearls. Stahl is an expert on the principles of
and indeed essential information at multiple levels of medical education; these inform the text and figures, and
expertise. It is remarkable that something as readable contribute to their extraordinary impact. Finally, Stahl
and as approachable at a very basic level can still be is a creative researcher, and his framework for thinking
incredibly informative to even the most experienced about psychiatric medications provides the field with
and expert psychopharmacologists. The fully revised an innovative approach. The 5th edition of the volume
diagrams are as ever informative, understandable, and is timely, given ongoing work in the field, and has been
even entertaining. This edition has done what I thought thoroughly updated to reflect recent advances.
would be impossible in significantly improving on past Dan Stein, Professor and Head of the Department of
editions and in producing something that is even more Psychiatry and Mental Health at the University of Cape
readable and informative to people with a vast range of Town
experience.
Stahl’s Essential Psychopharmacology, 5th edition,
Richard J. Porter, Professor of Psychiatry, Head of the is a masterpiece of impeccable scholarship and the
Department Psychological Medicine and Director of the art of education. Signature to Dr. Stahl is this book’s
Mental Health Clinical Research Unit, University of Otago tremendous expanse of knowledge that provides not only
Stahl’s Essential Psychopharmacology, 5th edition, is the science but also clarity in understanding complex
truly the preeminent textbook on the pharmacology concepts of psychiatric psychopharmacology. Dr. Stahl
of psychotropic drugs. It is comprehensive but very has demonstrated yet again that he is the “people’s
readable to both students and practitioners alike. educator.”
Dr. Stahl is not only an excellent scientist but also a Roger S. McIntyre, MD, FRCPC, Professor of
superb educator, providing a deep understanding of Psychiatry and Pharmacology, University of Toronto,
both disease states and drug mechanisms. His unique Canada Head, Mood Disorders Psychopharmacology
combination of visual and verbal material makes even Unit and Chairman and Executive Director, Brain and
the most complex topics approachable. This 5th edition Cognition Discovery Foundation (BCDF), Toronto,
has been extensively revised with hundreds of new or Canada
Since its inception, Stahl’s Essential Psychopharmacology The truth is that this book has a secret: it is obviously a
has been a real treasure for those learning and teaching book on pharmacology, but it hides a second one, a book
psychopharmacology and the neuroscience of mental on neuroscience-based psychopathology.
disorders, and as a clinician and medical teacher I have Going back from the receptors to the
used and warmly recommended each of the four earlier psychopathological dimensions of the disorders Stahl
editions. However, this new 5th edition is the best yet has his own personal style, starting with his use of
in my opinion and resets the bar again for textbooks in the “incipit”: here he makes it clear what he is going
this field. It has been extensively revised and brought to explain to you, and where you have to focus your
completely up to date throughout without a major attention. Concentrate! Then Steve Stahl gives you
expansion in page count, and covers the entire field picture of the determined domain: this time animated
comprehensively while retaining the clarity and ease in sequences to make you figure concretely the matter of
of learning it is famous for. I am pleased to see that psychopharmacology. At the end, just to make sure that
with this edition it has moved to a neuroscience-based you really grasped the concepts, he repeats everything
nomenclature and that many new drugs have been in a convenient summary, which is very useful to
added. A particular strength of this textbook has always consolidate the knowledge.
been its appeal to visual learners as much as text-based
Stefano Pallanti, MD, PhD, Professor of Psychiatry
learners through its wealth of figures and captions.
and Neurosciences, Director of the Institute for
These have been impressively updated with a new color
Neurosciences – Florence (IT)
scheme and many new figures, so that the book is not
only comprehensive and right up to date but is also a real
pleasure to read and learn from.
Peter S. Talbot, MD, FRCPsych, Consultant
Psychiatrist & Honorary Senior Lecturer, Greater
Manchester Mental Health NHS Foundation Trust &
University of Manchester
Stahl’s Essential
Psychopharmacology
Neuroscientific Basis and Practical Applications
Stephen M. Stahl
University of California at Riverside and at San Diego, Riverside and San Diego, California
Editorial Assistant
Meghan M. Grady
With illustrations by
Nancy Muntner
University Printing House, Cambridge CB2 8BS, United Kingdom
One Liberty Plaza, 20th Floor, New York, NY 10006, USA
477 Williamstown Road, Port Melbourne, VIC 3207, Australia
314–321, 3rd Floor, Plot 3, Splendor Forum, Jasola District Centre, New Delhi
– 110025, India
79 Anson Road, #06–04/06, Singapore 079906
Cambridge University Press is part of the University of Cambridge.

It furthers the University’s mission by disseminating knowledge in the pursuit of
education, learning, and research at the highest international levels of
excellence.
www.cambridge.org
Information on this title: www.cambridge.org/9781108838573
DOI: 10.1017/9781108975292
© Stephen M. Stahl 1996, 2000, 2008, 2013, 2021
This publication is in copyright. Subject to statutory exception
and to the provisions of relevant collective licensing agreements,
no reproduction of any part may take place without the written
permission of Cambridge University Press.
First edition published 1996
Second edition published 2000
Third edition published 2008
Fourth edition published 2013
Fifth edition published 2021
Printed in Singapore by Markono Print Media Pte Ltd
A catalogue record for this publication is available from the British Library.
ISBN 978-1-108-83857-3 Hardback
ISBN 978-1-108-97163-8 Paperback
Cambridge University Press has no responsibility for the persistence or accuracy
of URLs for external or third-party internet websites referred to in this publication
and does not guarantee that any content on such websites is, or will remain,
accurate or appropriate.
Every effort has been made in preparing this book to provide accurate and
up-to-date information that is in accord with accepted standards and practice
at the time of publication. Although case histories are drawn from actual cases,
every effort has been made to disguise the identities of the individuals involved.
Nevertheless, the authors, editors, and publishers can make no warranties that
the information contained herein is totally free from error, not least because
clinical standards are constantly changing through research and regulation.
The authors, editors, and publishers therefore disclaim all liability for direct
or consequential damages resulting from the use of material contained in this
book. Readers are strongly advised to pay careful attention to information
provided by the manufacturer of any drugs or equipment that they plan to use.
Contents
Preface to the Fifth Edition ix
CME Information xiii
8 Anxiety, Trauma, and Treatment 359

1 Chemical Neurotransmission 1
9 Chronic Pain and Its Treatment 379
2 Transporters, Receptors, and Enzymes as
Targets of Psychopharmacological Drug 10 Disorders of Sleep and Wakefulness
Action 29 and Their Treatment: Neurotransmitter
Networks for Histamine and Orexin 401
3 Ion Channels as Targets of
Psychopharmacological Drug Action 51 11 Attention Deficit Hyperactivity Disorder
and Its Treatment 449
4 Psychosis, Schizophrenia, and the
Neurotransmitter Networks Dopamine, 12 Dementia: Causes, Symptomatic
Serotonin, and Glutamate 77 Treatments, and the Neurotransmitter
Network Acetylcholine 486
5 Targeting Dopamine and Serotonin
Receptors for Psychosis, Mood, and 13 Impulsivity, Compulsivity, and
Beyond: So-Called “Antipsychotics” 159 Addiction 538
6 Mood Disorders and the Neurotransmitter
Networks Norepinephrine and
γ-Aminobutyric Acid (GABA) 244
7 Treatments for Mood Disorders: So- Suggested Reading and Selected References 579
Called “Antidepressants” and “Mood Index 615
Stabilizers” 283
vii
Preface to the Fifth Edition
WHAT’S NEW IN THE FIFTH • describes five new drugs for psychosis: lumateperone
EDITION? approved, and xanomeline, pimavanserin, trace
amine-associated receptor type 1 (TAAR1) agonists,
For this fifth edition of Stahl’s Essential and roluperidone in development
Psychopharmacology you will notice that every figure in the • updated receptor binding data for all drugs
book has been revised, refreshed, and updated with new • new coverage of tardive dyskinesia and new drug
colors, shading, and outlining. About half the figures are treatments: deutetrabenazine and valbenazine
entirely new. The number of chapters has decreased by one, • new coverage of uses of serotonin–dopamine
with merger of mood stabilizers into treatments for mood drugs for psychosis that are now used even more
disorders; the text itself and the total number of figures and frequently for depression
tables are all approximately the same in length and number, • The chapters on mood disorders have:
although all chapters have been edited, most of them • new coverage of mixed mood states
extensively, with the details of what has changed listed • new coverage of GABAA (γ-aminobutyric acid A)
below. The number of references has now been doubled. receptor subtypes and neurosteroid binding sites
Overall, 14 drugs have new uses and indications presented, • new coverage of neurotrophic growth factors and
and 18 brand new drugs are introduced and discussed. neuroplasticity in depression
Highlights of what has been added or changed since • new coverage of inflammation in depression
the fourth edition include: • mood stabilizers redefined
• New coverage of interference RNA (iRNA) in basic • new/expanded coverage of levomilnacipran,
neuroscience chapters vortioxetine
• Restructuring all chapters to reflect neuroscience- • new coverage of treating cognition in depression
based nomenclature, that is, drugs named for their • new drugs: neuroactive steroids, ketamine/
mechanism of action rather than use esketamine, dextromethorphan combinations,
• Thus, drugs for depression are not “antidepressants” dextromethadone
but “monoamine reuptake inhibitors with • expanded coverage of treatment resistance
antidepressant action”; drugs for psychosis are not and augmentation treatments for monoamine
“antipsychotics” but “serotonin/dopamine antagonists reuptake inhibitors including brexpiprazole,
with antipsychotic actions,” etc. ketamine, esketamine, and trials with cariprazine,
• The psychosis chapter has: pimavanserin
• new coverage of the direct and indirect striatal • expanded coverage of new hypotheses of
dopamine pathways neuroplastic downstream changes following
• new coverage of trace amines, receptors, and NMDA (N-methyl-D-aspartate) antagonist therapy
pharmacology with ketamine, esketamine, and others
• revision of the classic dopamine theory of psychosis • expanded coverage of treating bipolar depression
• two new theories of psychosis (serotonin and with new indications and new drugs lurasidone,
glutamate) cariprazine
• coverage of dementia-related psychosis and Parkinson • The anxiety chapter has:
psychosis in addition to schizophrenia psychosis • removal of obsessive–complusive disorder (OCD)
• updated coverage of new indications for drugs to the impulsivity chapter
previously approved, including lurasidone, • coverage of posttraumatic stress disorder (PTSD) as
cariprazine, and brexpiprazole a traumatic disorder rather than anxiety disorder
ix
• emphasis on anxiety symptoms rather than anxiety • The final chapter on impulsivity, compulsivity, and
disorders substance abuse has:
• GABA moved to mood chapter • new coverage of novel combinations of
• revised discussions on treatments of individual psychotherapy and hallucinogenic/dissociative
anxiety disorders drugs for treatment-resistant depression
• renewed emphasis on combining psychotherapy • updated and expanded coverage of opioid use
with psychopharmacology for symptoms of anxiety disorder and its treatment
• The pain chapter has: • updated and expanded coverage of the
• new criteria for fibromyalgia diagnosis endocannabinoid neurotransmitter system
• The sleep chapter has: and cannabis use for recreation, abuse, and
• much expanded coverage of orexin neuroscience therapeutics
• expanded coverage of histamine neuroscience • update on Ecstasy and psilocybin
• much expanded coverage of neurotransmitters • update on impulsive–compulsive disorders
across the sleep/wake cycle
• presentation of concept of different threshold
WHAT HAS NOT CHANGED IN
levels of drugs of different mechanisms in order to
induce sleep
THE FIFTH EDITION?
• expanded coverage of dual orexin receptor What has not changed in this new fifth edition is
antagonists including a new agent lemborexant the didactic style of the first four editions: namely,
• discussion of new H3 histamine antagonist, this text attempts to present the fundamentals of
pitolisant, for narcolepsy psychopharmacology in simplified and readily readable
• discussion of a new wake-promoting form. We emphasize current formulations of disease
norepinephrine–dopamine reuptake inhibitor mechanisms and also drug mechanisms. As in previous
(NDRI), solriamfetol editions, although the total number of references has
• expanded circadian rhythm discussion been doubled from the fourth edition, the text is not
• The attention deficit hyperactivity disorder (ADHD) extensively referenced to original papers, but rather
chapter has: to textbooks and reviews and a few selected original
• coverage of multiple new dosage formulations of papers, with only a limited reading list for each chapter,
methylphenidate and amphetamine but preparing the reader to consult more sophisticated
• discussion of new drugs on the horizon: viloxazine, textbooks as well as the professional literature.
and others The organization of information continues to apply
• a presentation of concept of threshold levels the principles of programmed learning for the reader,
necessary for efficacy of stimulants in ADHD namely repetition and interaction, which has been shown
• expanded coverage of neurodevelopment in ADHD to enhance retention. Therefore, it is suggested that
• The dementia chapter has: novices first approach this text by going through it from
• new coverage of acetylcholine and cholinergic beginning to end by reviewing only the color graphics
receptors and the legends for these graphics. Virtually everything
• introduction of theories for the circuits of memory covered in the text is also covered in the graphics and
versus psychosis versus agitation in dementia icons. Once having gone through all the color graphics
• de-emphasis of the amyloid cascade hypothesis in these chapters, it is recommended that the reader
• new emphasis on new treatments emerging for then go back to the beginning of the book, and read the
the behavioral symptoms of dementia, including entire text, reviewing the graphics at the same time. After
pimavanserin for psychosis in all-cause dementia, the text has been read, the entire book can be rapidly
and brexpiprazole and dextromethorphan/ reviewed again merely by referring to the various color
bupropion for agitation in Alzheimer disease graphics in the book. This mechanism of using the
• expanded coverage of Alzheimer disease and new materials will create a certain amount of programmed
coverage of vascular dementia, dementia with Lewy learning by incorporating the elements of repetition, as
bodies, frontotemporal dementia, and Parkinson well as interaction with visual learning through graphics.
dementia, clinical characteristics, and neuropathology Hopefully, the visual concepts learned via graphics will
x
reinforce abstract concepts learned from the written • Case Studies, 2nd edition, with cases from Tom
text, especially for those of you who are primarily Schwartz’s practice at State University of New York
“visual learners” (i.e., those who retain information Syracuse
better from visualizing concepts than from reading • Case Studies, 3rd edition, with cases from the
about them). For those of you who are already familiar University of California Riverside Department
with psychopharmacology, this book should provide of Psychiatry (with Takesha Cooper and Gerald
easy reading from beginning to end. Going back and Maguire)
forth between the text and the graphics should provide For those teachers and students wanting to assess
interaction. Following review of the complete text, it objectively their expertise, to pursue maintenance
should be simple to review the entire book by going of certification credits for board recertification
through the graphics once again. in psychiatry in the US, and for background on
instructional design and how to teach, there are two
HOW HAS THE ESSENTIAL books:
PSYCHOPHARMACOLOGY • Stahl’s Self Assessment Examination in Psychiatry:
FAMILY OF BOOKS AND Multiple Choice Questions for Clinicians, now in its
EDUCATIONAL SERVICES third edition
GROWN? • Best Practices in Medical Teaching
Expansion of Essential Psychopharmacology Books For those interested in expanded visual coverage of
specialty topics in psychopharmacology, there is the
The fifth edition of Essential Psychopharmacology is the
Stahl’s Illustrated series:
flagship of this book series, but not the entire fleet, as the
• Antidepressants
Essential Psychopharmacology Series has further expanded.
• Antipsychotics: Treating Psychosis, Mania and
For those of you interested, there is an entire suite of
Depression, 2nd edition
dozens of books and extensive online information now
• Mood Stabilizers
available that accompany Essential Psychopharmacology,
• Anxiety, Stress, and PTSD
Fifth Edition. There are now six prescriber’s guides:
• Attention Deficit Hyperactivity Disorder
• for psychotropic drugs, Stahl’s Essential
• Chronic Pain and Fibromyalgia
Psychopharmacology: the Prescriber’s Guide, now in its
• Substance Abuse and Impulsive Disorders
seventh edition
• Violence: Neural Circuits, Genetics, and Treatment
• for psychotropic drugs specifically for use in children
• Sleep and Sleep Wake Disorders
and adolescents, Stahl’s Essential Psychopharmacology
• Dementia
Prescribers Guide: Children and Adolescents
• for neurology drugs, Essential Neuropharmacology: the For practical and in-depth management tips and
Prescriber’s Guide, second edition. guidance, a newly introduced Handbook series:
• for pain drugs: Essential Pain Pharmacology: the • The Clozapine Handbook (with Jonathan Meyer)
Prescriber’s Guide • Handbook of Psychotropic Drug Levels (with Jonathan
• for drugs to treat serious mental illnesses particularly Meyer)
in forensic settings, a new book, Management of • Suicide Prevention Handbook (with Christine Moutier
Complex Treatment Resistant Psychotic Disorders (with and Anthony Pisani)
Michael Cummings) Finally, there is an ever-growing edited series of
• for the UK, there will soon be published a subspecialty topics:
Cambridge Prescribers Guide for psychotropic drugs • Practical Psychopharmacology (applying evidence-
to fit into UK practice patterns (with Sep Hafizi and based studies to treatment, with Joe Goldberg)
Peter Jones) • Violence in Psychiatry (with Katherine Warburton)
For those interested in how the textbook and • Decriminalizing Mental Illness (with Katherine
prescriber’s guides get applied in clinical practice there Warburton)
are now three books of case studies: • Evil, Terrorism and Psychiatry (with Donatella
• Case Studies: Stahl’s Essential Psychopharmacology, Marazitti)
covering 40 cases from my own clinical practice • Next Generation Antidepressants
xi
• Essential Evidence-Based Psychopharmacology, 2nd The NEI Website, www.neiglobal.com

edition • Access CME credits for this and other books in the
• Essential CNS Drug Development Stahl series
• Cambridge Textbook of Neuroscience for Psychiatrists • Access the Master Psychopharmacology Program, an
(with Mary-Ellen Lynall and Peter Jones) assessment-based certificate program that covers all of
the content in Stahl’s Essential Psychopharmacology
Online Options • Purchase downloadable PowerPoint slides of all the
Essential Psychopharmacology Online figures in this book
Now, you also have the option of accessing all these books Hopefully the reader can appreciate that this is an
plus additional features online by going to Essential incredibly exciting time for the fields of neuroscience
Psychopharmacology Online at www.stahlonline.org. and mental health, creating fascinating opportunities for
In addition, www.stahlonline.org is now linked to: clinicians to utilize current therapeutics and to anticipate
• the journal CNS Spectrums, www.journals.Cambridge. future medications that are likely to transform the field
org/CNS, of psychopharmacology. Best wishes for your first step on
of which I am the editor-in-chief, and which is the this fascinating journey.
official journal of the Neuroscience Education Institute
(NEI), free online to NEI members. This journal Stephen M. Stahl, MD, PhD, DSc (Hon.)
features readable and illustrated reviews of current In memory of Daniel X. Freedman, mentor,
topics in psychiatry, mental health, neurology, and the colleague, and scientific father
neurosciences as well as psychopharmacology To Shakila
xii
CME Information
Release/expiration dates Questions? call 888-535-5600, or email

Released: May 1, 2021 [email protected]
CME credit expires: May 1, 2024
Peer review
Learning objectives The content was peer-reviewed by an MD, PsyD, or PhD
After completing this activity, you should be better able specializing in psychiatry to ensure the scientific accuracy
to: and medical relevance of information presented and its
• Describe the neuropathology underlying mental independence from bias. NEI takes responsibility for
health disorders the content, quality, and scientific integrity of this CME
• Describe the differential neurobiological targets for activity.
psychotropic medications
• Link the mechanisms of psychotropic medications to Disclosures
their clinical targets All individuals in a position to influence or control
content are required to disclose any relevant financial
Accreditation and credit designation statements relationships. Although potential conflicts of interest
The Neuroscience Education Institute (NEI) is accredited are identified and resolved prior to the activity being
by the Accreditation Council for Continuing Medical presented, it remains for the participant to determine
Education (ACCME) to provide continuing medical whether outside interests reflect a possible bias in either
education for physicians. the exposition or the conclusions presented.
NEI designates this enduring material for a maximum
of 61.5 AMA PRA Category 1 Credits TM. Physicians Author
should claim only the credit commensurate with the Stephen M. Stahl, MD, PhD, DSc (Hon.)
extent of their participation in the activity. Clinical Professor, Department of Psychiatry and
Nurses and Physician Assistants: for your CE Neuroscience, University of California, Riverside School of
requirements, the ANCC and NCCPA will accept AMA Medicine, Riverside, CA
PRA Category 1 Credits TM from organizations accredited Adjunct Professor, Department of Psychiatry, University
by the ACCME. The content in this activity pertains to of California, San Diego School of Medicine, La Jolla, CA
pharmacology and is worth 61.5 continuing education Honorary Visiting Senior Fellow, University of
hours of pharmacotherapeutics. Cambridge, Cambridge, UK
Director of Psychopharmacology Services, California
Optional posttests and CME credit instructions Department of State Hospitals, Sacramento, CA
Optional posttests and certificates of CME credit are Grant/Research: Acadia, Avanir, Braeburn,
available for each topical section of the book (total of Intra-Cellular, Ironshore, Lilly, Neurocrine, Otsuka,
nine sections). There is a fee for each posttest (varies per Sunovion
section) which is waived for NEI members. Consultant/Advisor: Acadia, Alkermes, Allergan,
1. Read the desired topical section Arbor, Axovant, Axsome, Celgene, ClearView, Concert,
2. Pass the related posttest (70% score or higher), EMD Serono, Eisai, Ferring, Impel, Intra-Cellular,
available only online at www.neiglobal.com/CME Ironshore, Janssen, Lilly, Lundbeck, Merck, Otsuka,
(under “Book”) Pfizer, Sage, Servier, Sunovion, Takeda, Taliaz, Teva,
3. Print your certificate Tonix, Tris, Vifor
xiii
CME Information
Speakers Bureau: Acadia, Lundbeck, Otsuka, Perrigo, Donna M. Wilcock, PhD

Servier, Sunovion, Takeda, Vertex Assistant Dean of Biomedicine; Associate Director, Outreach
Board Member: Genomind and Partnerships; Sanders-Brown Center on Aging; Sweeney-
Nelms Professor in Alzheimer’s Disease Research, Alzheimer’s
Content Editor Disease Center; Associate Professor, Department of Physiology;
Meghan M. Grady, BA University of Kentucky College of Medicine, Lexington, KY
Vice President, Content Development, Neuroscience Consultant/Advisor: AC Immune, Alector, AvroBio
Education Institute, Carlsbad, CA
The Planning Committee, Editorial, and Design
No financial relationships to disclose.
Staff, and remaining Peer Reviewers have no financial
relationships to disclose.
Editorial Staff
Gabriela Alarcón, PhD Disclosure of Off-Label Use
Medical Writer, Neuroscience Education Institute, This educational activity may include discussion of unlabeled
Carlsbad, CA and/or investigational uses of agents that are not currently
All of Dr. Alarcón’s financial relationships are through labeled for such use by the FDA. Please consult the product
her spouse/partner. prescribing information for full disclosure of labeled uses.
Employee (spouse/partner): Ashfield Healthcare
Communications Cultural and Linguistic Competency
A variety of resources addressing cultural and
Peer Reviewers linguistic competency can be found at this link:
William M. Sauvé, MD www.neiglobal.com/go/cmeregs.
Regional Medical Director, Greenbrook TMS NeuroHealth
Centers, Virginia Support
Speakers Bureau: Avanir This activity is supported solely by the provider, NEI.
xiv
1 Chemical
Neurotransmission
Anatomical versus Chemical Basis of Beyond the Second Messenger to a
Neurotransmission 1 Phosphoprotein Cascade Triggering Gene
General Structure of a Neuron 2 Expression 15
Principles of Chemical Neurotransmission 5 How Neurotransmission Triggers Gene
Neurotransmitters 5 Expression 18
Neurotransmission: Classic, Retrograde, and Molecular Mechanism of Gene Expression 18
Volume 6 Epigenetics 23
Excitation–Secretion Coupling 8 What Are the Molecular Mechanisms of
Signal Transduction Cascades 9 Epigenetics? 23
Overview 9 How Epigenetics Maintains or Changes the Status
Quo 24
Forming a Second Messenger 11
A Brief Word about RNA 26
Beyond the Second Messenger to Phosphoprotein
Messengers 13 Alternative Splicing 26
RNA Interference 26
Summary 28
Modern psychopharmacology is largely the story of is thus a complex wiring diagram, ferrying electrical
chemical neurotransmission. To understand the actions impulses to wherever the “wire” is plugged in (i.e., at a
of drugs on the brain, to grasp the impact of diseases synapse). Synapses can form on many parts of a neuron,
upon the central nervous system, and to interpret the not just from the axon of one neuron to the dendrite of
behavioral consequences of psychiatric medicines, one another neuron as axodendritic synapses, but also from
must be fluent in the language and principles of chemical the axon of one neuron to the soma of another neuron as
neurotransmission. The importance of this fact cannot be axosomatic synapses, and even from one neuron’s axon
overstated for the student of psychopharmacology. This to another neuron’s axon, especially at the beginning and
chapter forms the foundation for the entire book, and at the end of the receiving neuron’s axons (axoaxonic
the roadmap for one’s journey through one of the most synapses) (Figure 1-2). Such synapses are said to be
exciting topics in science today, namely the neuroscience “asymmetric” since communication is structurally
of how disorders and drugs act upon the central nervous designed to be in one direction, i.e., anterograde from
system. the axon of the first neuron to the dendrite, soma, or
axon of the second neuron (Figures 1-2 and 1-3). This
ANATOMICAL VERSUS means that there are presynaptic elements that differ
CHEMICAL BASIS OF from postsynaptic elements (Figure 1-4). Specifically, a
NEUROTRANSMISSION neurotransmitter is packaged in the presynaptic nerve
terminal like ammunition in a loaded gun, and then fired
What is neurotransmission? Neurotransmission can at the postsynaptic neuron to target its receptors.
be described in many ways: anatomically, chemically, Neurons are the cells of chemical communication
electrically. The anatomical basis of neurotransmission is in the brain. Human brains are comprised of tens of
neurons (Figures 1-1 to 1-3) and the connections between billions of neurons, and each is linked to thousands of
them, called synapses (Figure 1-4), sometimes also called other neurons. Thus, the brain has trillions of specialized
the anatomically addressed nervous system, a complex of connections known as synapses. Neurons have many
“hard-wired” synaptic connections between neurons, not sizes, lengths, and shapes that determine their functions.
unlike millions of telephone wires within thousands upon Localization within the brain also determines function.
thousands of cables. The anatomically addressed brain When neurons malfunction, behavioral symptoms may
1
STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY
Figure 1-1 General structure of a

neuron. This is an artist’s conception
dendrites of the generic structure of a neuron.
All neurons have a cell body known
as the soma, which is the command
center of the nerve and contains the
nucleus of the cell. All neurons are also
set up structurally to both send and
receive information. Neurons send
information via an axon that forms
presynaptic terminals as the axon
dendritic spines passes by (en passant) or as the axon
cell body (soma) ends.
en passant
axon presynaptic
axon terminals
presynaptic axon
terminals
occur. When drugs alter neuronal function, behavioral (Figure 1-2). Neurons are also set up structurally to send
symptoms may be relieved, worsened, or produced. information to other neurons via an axon that forms
presynaptic terminals as the axon passes by (en passant,
General Structure of a Neuron
Figure 1-1) or as the axon ends (presynaptic axon
Although this textbook will often portray neurons with a terminals, Figures 1-1 through 1-4).
generic structure (such as that shown in Figures 1-1 to 1-3), Neurotransmission has an anatomical infrastructure,
the truth is that many neurons have unique structures but it is fundamentally a very elegant chemical
depending upon where in the brain they are located and operation. Complementary to the anatomically
what their function is. On the one hand, all neurons have addressed nervous system is thus the chemically
a cell body known as the soma, and are set up structurally addressed nervous system, which forms the chemical
to receive information from other neurons through basis of neurotransmission: namely, how chemical
dendrites, sometimes via spines on the dendrites and signals are coded, decoded, transduced, and sent along
often through an elaborately branching “tree” of dendrites the way. Understanding the principles of chemical
2
Chapter 1: Chemical Neurotransmission
1
Figure 1-2 Axodendritic,
dendritic axosomatic, and axoaxonic
spines connections. After neurons migrate,
they form synapses. As shown in
this figure, synaptic connections
can form not just between the
axon and dendrites of two neurons
(axodendritic) but also between the
axon and the soma (axosomatic)
or the axons of the two neurons
dendritic (axoaxonic). Communication is
tree anterograde from the axon of the
first neuron to the dendrite, soma, or
axon of the second neuron.
synaptic
vesicles
spine
axodendritic
synapse
axosomatic
synapse
axoaxonic
(initial segment)
synapse
axon
axoaxonic
(terminal)
synapse
postsynaptic
dendrite
neurotransmission is a fundamental requirement for Understanding the chemically addressed

grasping how psychopharmacological agents work, nervous system is also a prerequisite for becoming a
because these agents target key molecules involved in “neurobiologically informed” clinician: that is, being
neurotransmission. Drug targeting of specific chemical able to translate exciting new findings on brain circuitry,
sites that influence neurotransmission is discussed in functional neuroimaging, and genetics into clinical
Chapters 2 and 3. practice, and potentially improving the manner in which
3
Classic Synaptic Neurotransmission
reception
hormone
drug
light
integration A
chemical
encoding
nerve impulse
electrical neurotransmitter
encoding
signal
propagation
signal
transduction
neurotransmitter
Figure 1-3 Classic synaptic neurotransmission. In classic synaptic neurotransmission, stimulation of a presynaptic neuron (e.g., by
neurotransmitters, light, drugs, hormones, nerve impulses) causes electrical impulses to be sent to its axon terminal. These electrical
impulses are then converted into chemical messengers and released to stimulate the receptors of a postsynaptic neuron. Thus, although
communication within a neuron can be electrical, communication between neurons is chemical.
4
presynaptic
neuron
mitochondrion
synaptic
vesicles
vesicles
synaptic cleft
releasing
neurotransmitter
postsynaptic
neuron
Figure 1-4 Enlarged synapse. The synapse is enlarged conceptually here showing the specialized structures that enable chemical
neurotransmission to occur. Specifically, a presynaptic neuron sends its axon terminal to form a synapse with a postsynaptic neuron.
Energy for neurotransmission from the presynaptic neuron is provided by mitochondria there. Chemical neurotransmitters are stored
in small vesicles, ready for release upon firing of the presynaptic neuron. The synaptic cleft is the gap between the presynaptic neuron
and the postsynaptic neuron; it contains proteins and scaffolding and molecular forms of “synaptic glue” to reinforce the connection
between the neurons. Receptors are present on both sides of this cleft and are key elements of chemical neurotransmission.
psychiatric disorders and their symptoms are diagnosed acetylcholine

and treated. The chemistry of neurotransmission in glutamate
specific brain regions and how these principles are GABA (γ-aminobutyric acid)
applied to various specific psychiatric disorders, treated Each is discussed in detail in the clinical chapters related
with various specific psychotropic drugs, are discussed to the specific drugs that target them.
throughout the rest of the book. Other neurotransmitters that are also important
neurotransmitters and neuromodulators, such as
PRINCIPLES OF CHEMICAL histamine and various neuropeptides and hormones,
NEUROTRANSMISSION are mentioned in brief throughout the relevant clinical
Neurotransmitters chapters in this textbook.
There are more than a dozen known or Some neurotransmitters are very similar to drugs
suspected neurotransmitters in the brain. For and have been called “God’s pharmacopeia.” For
psychopharmacologists, it is particularly important to example, it is well known that the brain makes its own
know the six key neurotransmitter systems targeted by morphine (i.e., β-endorphin) and its own marijuana (i.e.,
psychotropic drugs: endocannabinoids). The brain may even make its own
serotonin Prozac, its own Xanax, and and its own hallucinogens!
norepinephrine Drugs often mimic the brain’s natural neurotransmitters
dopamine and some drugs have been discovered prior to the natural
neurotransmitter. Thus, morphine was used in clinical
5
practice before the discovery of β-endorphin; marijuana in the first neuron is converted to a chemical signal at
was smoked before the discovery of cannabinoid the synapse between it and a second neuron, in a process
receptors and endocannabinoids; the benzodiazepines known as excitation–secretion coupling, the first stage of
Valium (diazepam) and Xanax (alprazolam) were chemical neurotransmission. This occurs predominantly
prescribed before the discovery of benzodiazepine but not exclusively in one direction, from the presynaptic
receptors; and the antidepressants Elavil (amitriptyline) axon terminal to a second postsynaptic neuron (Figures
and Prozac (fluoxetine) entered clinical practice before 1-2 and 1-3). Finally, neurotransmission continues in
molecular clarification of the serotonin transporter the second neuron either by converting the chemical
site. This underscores the point that the great majority information from the first neuron back into an electrical
of drugs that act in the central nervous system act impulse in the second neuron, or, perhaps more elegantly,
upon the process of neurotransmission. Indeed, this by the chemical information from the first neuron
apparently occurs at times in a manner that can mimic triggering a cascade of further chemical messages within
the actions of the brain itself, when the brain uses its the second neuron to change that neuron’s molecular and
own chemicals. genetic functioning (Figure 1-3).
Input to any neuron can involve many different An interesting twist to chemical neurotransmission
neurotransmitters coming from many different neuronal is the discovery that postsynaptic neurons can also
circuits. Understanding these inputs to neurons within “talk back” to their presynaptic neurons. They can do
functioning circuits can provide a rational basis for this via retrograde neurotransmission from the second
selecting and combining therapeutic agents. This neuron to the first at the synapse between them (Figure
theme is discussed extensively in each chapter on the 1-5, right panel). Chemicals produced specifically as
various psychiatric disorders. The idea is that for the retrograde neurotransmitters at some synapses include
modern psychopharmacologist to influence abnormal the endocannabinoids (EC, also known as “endogenous
neurotransmission in patients with psychiatric disorders, marijuana”), which are synthesized in the postsynaptic
it may be necessary to target neurons in specific circuits. neuron. They are then released and diffuse to presynaptic
Since these networks of neurons send and receive cannabinoid receptors such as the CB1 or cannabinoid
information via a variety of neurotransmitters, it may 1 receptor (Figure 1-5, right panel). Another retrograde
therefore be not only rational but necessary to use neurotransmitter is the gaseous neurotransmitter nitric
multiple drugs with multiple neurotransmitter actions oxide (NO), which is synthesized postsynaptically and
for patients with psychiatric disorders, especially if single then diffuses out of the postsynaptic membrane and
agents with single neurotransmitter mechanisms are not into the presynaptic membrane to interact with cyclic
effective in relieving symptoms. guanosine monophosphate (cGMP)-sensitive targets
there (Figure 1-5, right panel). A third type of retrograde
Neurotransmission: Classic, Retrograde, and Volume
neurotransmitter are neurotrophic factors such as nerve
Classic neurotransmission begins with an electrical growth factor (NGF), which is released from postsynaptic
process by which neurons send electrical impulses from sites, and then diffuses to the presynaptic neuron,
one part of the cell to another part of the same cell via where it is taken up into vesicles, and transported all
their axons (see neuron A of Figure 1-3). However, the way back to the cell nucleus via retrograde transport
these electrical impulses do not jump directly to other systems to interact with the genome there (Figure 1-5,
neurons. Classic neurotransmission between neurons right panel). What these retrograde neurotransmitters
involves one neuron hurling a chemical messenger, or have to say to the presynaptic neuron and how this
neurotransmitter, at the receptors of a second neuron modifies or regulates the communication between pre
(see the synapse between neuron A and neuron B in and postsynaptic neuron are subjects of intense active
Figure 1-3). This happens frequently but not exclusively investigation.
at the sites of synaptic connections. In the human brain, In addition to “reverse” or retrograde
a hundred billion neurons each make thousands of neurotransmission at synapses, some neurotransmission
synapses with other neurons for an estimated trillion does not need a synapse at all! Neurotransmission
chemically neurotransmitting synapses. without a synapse is called volume neurotransmission, or
Communication between all these neurons at synapses nonsynaptic diffusion neurotransmission (examples are
is chemical, not electrical. That is, an electrical impulse shown in Figures 1-6 through 1-8). Chemical messengers
6
1
Classic Neurotransmission versus Retrograde Neurotransmission Figure 1-5 Retrograde
neurotransmission. Not all
neurotransmission is classic or
anterograde or from top to bottom –
namely, presynaptic to postsynaptic
(left). Postsynaptic neurons may
NGF
also communicate with presynaptic
neurons from the bottom to the top
via retrograde neurotransmission, from
postsynaptic neuron to presynaptic
neuron (right). Some neurotransmitters
produced specifically as retrograde
NGF
neurotransmitters at some synapses
A
include the endocannabinoids (ECs,
or endogenous marijuana), which
cGMP are synthesized in the postsynaptic
sensitive neuron, released, and diffuse to
targets NGF presynaptic cannabinoid receptors
CB1
receptor such as the cannabinoid 1 receptor
NGF (CB1); the gaseous neurotransmitter
nitric oxide (NO), which is synthesized
postsynaptically and then diffuses both
out of the postsynaptic membrane
EC and into the presynaptic membrane
to interact with cyclic guanosine
monophosphate (cGMP)-sensitive
NO NGF targets there; and neurotrophic factors
(nitric oxide) (nerve growth such as nerve growth factor (NGF),
which is released from postsynaptic sites
A
EC factor)
and diffuses to the presynaptic neuron,
where it is taken up into vesicles and
transported all the way back to the cell
nucleus via retrograde transport systems
Classic Retrograde to interact with the genome there.
A Figure 1-6 Volume neurotransmission. Neurotransmission

can also occur without a synapse; this is called volume
neurotransmission or nonsynaptic diffusion. In this figure,
two anatomically addressed synapses (neurons A and B) are
1 2 shown communicating with their corresponding postsynaptic
receptors (a and b; 1). However, there are also receptors for
neurotransmitter A, neurotransmitter B, and neurotransmitter
C, which are distant from the synaptic connections of the
anatomically addressed nervous system. If neurotransmitter A
a c a or B can diffuse away from its synapse before it is destroyed, it
will be able to interact with other matching receptor sites distant
3
from its own synapse (2). If neurotransmitter A or B encounters
a different receptor not capable of recognizing it (receptor c),
it will not interact with that receptor even if it diffuses there (3).
B Thus, a chemical messenger sent by one neuron to another

can spill over by diffusion to sites distant from its own synapse.
c a Neurotransmission can occur at a compatible receptor within
the diffusion radius of the matched neurotransmitter. This is
analogous to modern communication with cellular telephones,
1 which function within the transmitting radius of a given cell. This
2 concept is called the chemically addressed nervous system, in
2 which neurotransmission occurs in chemical “puffs.” The brain
is thus not only a collection of wires but also a sophisticated
“chemical soup.”
b b b
sent by one neuron to another can spill over to sites given cell tower (Figure 1-6). This concept is part of
distant to the synapse by diffusion (Figure 1-6). Thus, the chemically addressed nervous system, and here
neurotransmission can occur at any compatible receptor neurotransmission occurs in chemical “puffs” (Figures
within the diffusion radius of the neurotransmitter, not 1–6 through 1–8). The brain is thus not only a collection
unlike modern communication with cellular telephones, of wires, but also a sophisticated “chemical soup.” The
which function within the transmitting radius of a chemically addressed nervous system is particularly
7
Volume Neurotransmission Figure 1-7 Volume neurotransmission:

dopamine. An example of volume
neurotransmission would be that
DA
of dopamine (DA) in the prefrontal
neuron
cortex. Since there are few dopamine
reuptake pumps in the prefrontal cortex,
D1 dopamine is available to diffuse to
receptors nearby receptor sites. Thus, dopamine
released from a synapse (arrow 1)
targeting postsynaptic neuron A is
free to diffuse further in the absence
of a reuptake pump and can reach
1
dopamine receptors on that same
neuron but outside of the synapse from
which it was released, on neighboring
2 dendrites (arrow 2). Shown here is
A B dopamine also reaching extrasynaptic
receptors on a neighboring neuron
3
(arrow 3).
Synaptic neurotransmission at 1 and diffusion to 2 and 3
important in mediating the actions of drugs that act at end of the neuron (top of the neurons in Figure 1-8) are
various neurotransmitter receptors, since such drugs will autoreceptors that inhibit the release of neurotransmitter
act wherever there are relevant receptors, and not just from the axonal end of the neuron (bottom of the
where such receptors are innervated with synapses by neurons in Figure 1-8). Although some recurrent axon
the anatomically addressed nervous system. Modifying collaterals and other monoamine neurons may directly
volume neurotransmission may indeed be a major way in innervate somatodendritic receptors, these so-called
which several psychotropic drugs work in the brain. somatodendritic autoreceptors also apparently receive
A good example of volume neurotransmission is neurotransmitter from dendritic release (Figure 1-8,
dopamine action in the prefrontal cortex. Here there middle and right panels). There is no synapse here,
are very few dopamine reuptake transport pumps no synaptic vesicles, just neurotransmitter apparently
(dopamine transporters or DATs) to terminate the action “leaked” from the neuron’s dendrites upon its own
of dopamine released in the prefrontal cortex during receptors in a mechanism that is still being clarified. The
neurotransmission. This is much different from other nature of a neuron’s regulation by its somatodendritic
brain areas, such as the striatum, where dopamine autoreceptors is a subject of intense interest, and is
reuptake pumps are present in abundance. Thus, when theoretically linked to the mechanism of action of many
dopamine neurotransmission occurs at a synapse in the antidepressants, as will be explained later in Chapter 7.
prefrontal cortex, dopamine is free to spill over from that The take-home point here is that not all chemical
synapse and diffuse to neighboring dopamine receptors neurotransmission occurs at synapses.
and stimulate them, even though there is no synapse at
Excitation—Secretion Coupling
these “spillover” sites (Figure 1-7).
Another important example of volume An electrical impulse in the first – or presynaptic – neuron
neurotransmission is at the sites of autoreceptors on is converted into a chemical signal at the synapse by a
monoamine neurons (Figure 1-8). At the somatodendritic process known as excitation–secretion coupling. Once an
8
1
autoreceptor
synaptic vesicles
dendritic monoamine
Figure 1-8 Volume neurotransmission: monoamine autoreceptors. Another example of volume neurotransmission could involve
autoreceptors on monoamine neurons. Autoreceptors located on the dendrites and soma of a neuron (at the top of the neuron in the left
panel) normally inhibit release of neurotransmitter from the axon of that neuron (at the bottom of the neuron in the left panel), and thus
inhibit impulse flow through that neuron from top to bottom. Monoamines released from the dendrites of this neuron (at the top of the
neuron in the middle panel), then bind to these autoreceptors (at the top of the neuron in the right panel) and would inhibit neuronal
impulse flow in that neuron (from the bottom of the neuron in the right panel). This action occurs due to volume neurotransmission and
despite the absence of synaptic neurotransmission in the somatodendritic areas of these neurons.
electrical impulse invades the presynaptic axon terminal, electrical impulse enters the presynaptic neuron. It is
it causes the release of chemical neurotransmitter stored also possible for the neuron to transduce a chemical
there (Figures 1-3 and 1-4). Electrical impulses open ion message from a presynaptic neuron back into an
channels – both voltage-sensitive sodium channels (VSSCs) electrical chemical message in the postsynaptic neuron
and voltage-sensitive calcium channels (VSCCs) – by by opening ion channels linked to neurotransmitters
changing the ionic charge across neuronal membranes. As there. This also happens very quickly when chemical
sodium flows into the presynaptic nerve through sodium neurotransmitters open ion channels that change the
channels in the axon membrane, the electrical charge of flow of charge into the neuron, and ultimately, action
the action potential moves along the axon until it reaches potentials in the postsynaptic neuron. Thus, the process
the presynaptic nerve terminal where it also opens of neurotransmission is constantly transducing chemical
calcium channels. As calcium flows into the presynaptic signals into electrical signals, and electrical signals back
nerve terminal, it causes synaptic vesicles anchored to the into chemical signals.
inner membrane to spill their chemical contents into the
synapse. The way is paved for chemical communication SIGNAL TRANSDUCTION
by previous synthesis of neurotransmitter and storage of CASCADES
neurotransmitter in the first neuron’s presynaptic axon Overview
terminal. Neurotransmission can be seen as part of a much larger
Excitation–secretion coupling is thus the way that process than just the communication of a presynaptic
the neuron transduces an electrical stimulus into a axon with a postsynaptic neuron at the synapse between
chemical event. This happens very quickly once the them. That is, neurotransmission can also be seen as
9
first 1 first
1
messenger messenger
2
++
second fourth Ca
2 second
messenger messenger
P
messenger
3
3
third third
messenger messenger
kinase phosphatase
activation/inactivation
of fourth messenger phosphoprotein
diverse biological responses

Figure 1-9 Signal transduction cascade. The cascade of events that occurs following stimulation of a postsynaptic receptor is known as
signal transduction. Signal transduction cascades can activate third-messenger enzymes known as kinases, which add phosphate groups
to proteins to create phosphoproteins (on the left). Other signal transduction cascades can activate third-messenger enzymes known as
phosphatases, which remove phosphates from phosphoproteins (on the right). The balance between kinase and phosphatase activity,
signaled by the balance between the two neurotransmitters that activate each of them, determines the degree of downstream chemical
activity that gets translated into diverse biological responses, such as gene expression and synaptogenesis.
communication from the genome of the presynaptic activation of otherwise “sleeping” and inactive molecules
neuron (neuron A of Figure 1-3) to the genome of the (see for example, Figures 1-9 through 1-19).
postsynaptic neuron (neuron B of Figure 1-3), and then An overview of such a molecular “pony express,”
back from the genome of the postsynaptic neuron to from first-messenger neurotransmitter through several
the genome of the presynaptic neuron via retrograde “molecular riders” to the production of diverse biological
neurotransmission (right panel of Figure 1-5). Such a responses, is shown in Figure 1-9. Specifically, a first-
process involves long strings of chemical messages within messenger neurotransmitter on the left activates the
both presynaptic and postsynaptic neurons, called signal production of a chemical second messenger that in turn
transduction cascades. activates a third messenger, namely an enzyme known as
Signal transduction cascades triggered by chemical a kinase that adds phosphate groups to fourth-messenger
neurotransmission thus involve numerous molecules, proteins to create phosphoproteins (Figure 1-9, left).
starting with neurotransmitter first messenger, and Another signal transduction cascade is shown on the
proceeding to second, third, fourth, and more messengers right with a first-messenger neurotransmitter opening
(Figures 1-9 through 1-30). The initial events occur in an ion channel that allows calcium to enter the neuron
less than a second, but the long-term consequences are and act as the second messenger for this cascade system
mediated by downstream messengers that take hours to (Figure 1-9, right). Calcium then activates a different
days to activate, yet can last for many days or even for third messenger on the right, namely an enzyme known
the lifetime of a synapse or neuron (Figure 1-10). Signal as a phosphatase that removes phosphate groups from
transduction cascades are somewhat akin to a molecular fourth-messenger phosphoproteins and thus reverses the
“pony express” with specialized molecules acting as a actions of the third messenger on the left. The balance
sequence of riders, handing off the message to the next between kinase and phosphatase activity, signaled by the
specialized molecule, until the message has reached balance between the two neurotransmitters that activate
a functional destination, such as gene expression or each of them, determines the degree of downstream
10
Time Course of Signal Transduction Figure 1-10 Time course of signal

transduction. The time course of
signal transduction is shown here. The
long-term effects process begins with binding of a first
of late gene products messenger (bottom), which leads to
activation of ion channels or enzymatic
formation of second messengers. This,
activation of in turn, can cause activation of third
late genes and fourth messengers, which are
often phosphoproteins. If genes are
subsequently activated, this leads to the
activation of synthesis of new proteins, which can alter
early genes
the neuron’s functions. Once initiated,
the functional changes due to protein
activation of third activation or new protein synthesis can
response
and fourth messengers last for at least many days and possibly
much longer. Thus, the ultimate effects of
enzymatic formation of signal transduction cascades triggered
second messengers by chemical neurotransmission are not
only delayed but also long-lasting.
activation of ion channels
binding of first messenger
1 hr 1 day 10 days
time
chemical activity that gets translated into active fourth In the case of G-protein-linked systems, the second
messengers able to trigger diverse biological responses, messenger is a chemical, but in the case of an ion-
such as gene expression and synaptogenesis (Figure 1-9). channel-linked system, the second messenger can be an
Each molecular site within the cascade of transduction of ion such as calcium (Figure 1-11). For some hormone-
chemical and electrical messages is a potential location linked systems, a second messenger is formed when the
for a malfunction associated with a mental illness; it is hormone finds its receptor in the cytoplasm and binds to
also a potential target for a psychotropic drug. Thus, the it to form a hormone–nuclear receptor complex (Figure
various elements of multiple signal transduction cascades 1-11). For neurotrophins, a complex set of various second
play very important roles in psychopharmacology. messengers exist (Figure 1-11), including proteins that
Four of the most important signal transduction are kinase enzymes with an alphabet soup of complicated
cascades in the brain are shown in Figure 1-11. These names.
include G-protein-linked systems, ion-channel-linked The transduction of an extracellular first
systems, hormone-linked systems, and neurotrophin- neurotransmitter from the presynaptic neuron into
linked systems. There are many chemical messengers for an intracellular second messenger in the postsynaptic
each of these four critical signal transduction cascades; neuron is known in detail for some second-messenger
the G-protein-linked and the ion-channel-linked cascades systems, such as for those that are linked to G proteins
are triggered by neurotransmitters (Figure 1-11). Many (Figures 1-12 through 1-15). There are four key elements
of the psychotropic drugs used in clinical practice today to this second-messenger system:
target one of these two signal transduction cascades. • the first-messenger neurotransmitter
Drugs that target the G-protein-linked system are • a receptor for the neurotransmitter that belongs to the
discussed in Chapter 2; drugs that target the ion channel- receptor superfamily in which all have the structure
linked system are discussed in Chapter 3. of seven transmembrane regions (designated by the
number 7 on the receptor in Figures 1-12 to 1-15)
Forming a Second Messenger
• a G protein capable of binding both to certain
Each of the four signal transduction cascades conformations of the neurotransmitter receptor (7)
(Figure 1-11) passes its message from an extracellular and to an enzyme system (E) that can synthesize the
first messenger to an intracellular second messenger. second messenger
11
G-protein-linked ion-channel-linked
neurotrophin
neurotransmitter neurotransmitter hormone
NT
NT1
First Messenger
membrane
Ca++
cAMP 2 Ras/Raf/MEK
Second Messenger
hormone
nuclear
receptor
complex
A
Third Messenger ERK/RSK/
CaMK
MAPK/GSK-3
PO4
HRE
Fourth Messenger/ CREB genes
Gene Expression
cell nucleus
Figure 1-11 Different signal transduction cascades. Four of the most important signal transduction cascades in the brain are
shown here. These include G-protein-linked systems, ion-channel-linked systems, hormone-linked systems, and neurotrophin-linked
systems. Each begins with a different first messenger binding to a unique receptor, leading to activation of very different downstream
second, third, and subsequent chemical messengers. Having many different signal transduction cascades allows neurons to respond
in amazingly diverse biological ways to a whole array of chemical messaging systems. Neurotransmitters (NTs) activate both the
G-protein-linked system and the ion-channel-linked system on the left, and both of these systems activate genes in the cell nucleus by
phosphorylating a protein there called cAMP response element-binding protein (CREB). The G-protein-linked system works through
a cascade involving cAMP (adenosine monophosphate) and protein kinase A, whereas the ion-channel-linked system works through
calcium and its ability to activate a different kinase called calcium/calmodulin kinase (CaMK). Certain hormones, such as estrogen and
other steroids, can enter the neuron, find their receptors in the cytoplasm, and bind them to form a hormone–nuclear receptor complex.
This complex can then enter the cell nucleus to interact with hormone-response elements (HREs) there to trigger activation of specific
genes. Finally, the neurotrophin system on the far right activates a series of kinase enzymes, with a confusing alphabet soup of names,
to trigger gene expression, which may control such functions as synaptogenesis and neuronal survival. Ras is a G protein, Raf is a kinase,
and the other elements in this cascade are proteins as well (MEK stands for mitogen-activated protein kinase/extracellular signal-
regulated kinase; ERK stands for extracellular signal-regulated kinase itself; RSK is ribosomal S6 kinase; MAPK is MAP kinase itself, and
GSK-3 is glycogen synthase kinase 3).
• and finally the enzyme system itself for the second two receptors cooperate with each other: namely, the
messenger (Figures 1-12 through 1-15) neurotransmitter receptor itself, and the G protein, which
The first step is the neurotransmitter binding to its can be thought of as another type of receptor associated
receptor (Figure 1-13). This changes the conformation with the inner membrane of the cell. This cooperation is
of the receptor so it can now fit with the G protein, indicated in Figure 1-14 by the G protein turning green
as indicated by the receptor (7) turning green and its and its conformation changing on the right so it is now
shape changing at the bottom. Next comes the binding capable of binding to an enzyme (E) that synthesizes
of the G protein to this new conformation of the the second messenger. Finally, the enzyme, in this case
receptor–neurotransmitter complex (Figure 1-14). The adenylate cyclase, binds to the G protein and synthesizes
12
first messenger
The first messenger

7
causes the receptor to
change
receptor
7
E
G protein can now bind to the receptor
E Figure 1-13 First messenger. In this figure, the

neurotransmitter has docked into its receptor. The first
messenger does its job by transforming the conformation of
G protein the receptor so that the receptor can bind to the G protein,
indicated here by the receptor turning the same color as the
neurotransmitter and changing its shape at the bottom in order
to make it capable of binding to the G protein.
and subsequent chemical messengers. Having many

Figure 1-12 Elements of G-protein-linked system. Shown here different signal transduction cascades allows neurons to
are the four elements of a G-protein-linked second-messenger respond in amazingly diverse biological ways to a whole
system. The first element is the neurotransmitter itself,
sometimes also referred to as the first messenger. The second array of chemical messaging systems.
element is the G-protein-linked neurotransmitter receptor, What is the ultimate target of signal transduction?
which is a protein with seven transmembrane regions. The third
element, a G protein, is a connecting protein. The fourth element There are two major targets of signal transduction:
of the second-messenger system is an enzyme, which can phosphoproteins and genes. Many of the intermediate
synthesize a second messenger when activated.
targets along the way to the gene are phosphoproteins,
such as the fourth-messenger phosphoproteins shown
cAMP (cyclic adenosine monophosphate), which serves in Figures 1-18 and 1-19 that lie dormant in the neuron
as second messenger (Figure 1-15). This is indicated in until signal transduction wakes them up and they can
Figure 1-15 by the enzyme turning green and generating spring into action.
cAMP (the icon with number 2 on it). The actions shown in Figure 1-9 on fourth-messenger
phosphoproteins as targets of signal transduction can
Beyond the Second Messenger to Phosphoprotein be seen in more detail in Figures 1-16 through 1–19.
Messengers Thus, one signal transduction pathway can activate a
Recent research has begun to clarify the complex third-messenger kinase through the second-messenger
molecular links between the second messenger and its cAMP (Figure 1-16), whereas another signal transduction
ultimate effects upon cellular functions. These links are pathway can activate a third-messenger phosphatase
specifically the third, fourth, and subsequent chemical through the second-messenger calcium (Figure 1-17).
messengers in the signal transduction cascades shown in In the case of kinase activation, two copies of the second
Figures 1-9, 1-11, 1-16 through 1-30). Each of the four messenger target each regulatory unit of dormant or
classes of signal transduction cascades shown in Figure “sleeping” protein kinase (Figure 1-16). When some
1-11 not only begins with a different first messenger protein kinases are inactive, they exist in dimers (two
binding to a unique receptor, but this also leads to copies of the enzyme) while binding to a regulatory unit,
activation of very different downstream second, third, thus rendering them in a conformation that is not active.
13
7
7
E
E
Once bound to the receptor, the G protein Once this binding takes place, the second
changes shape so it can bind to an enzyme capable messenger will be released. 2
of synthesizing a second messenger.
Figure 1-14 G protein. The next stage in producing a second

messenger is for the transformed neurotransmitter receptor to Figure 1-15 Second messenger. The final step in formation
bind to the G protein, depicted here by the G protein turning of the second messenger is for the ternary complex
the same color as the neurotransmitter and its receptor. Binding neurotransmitter–receptor–G protein to bind to a messenger-
of the binary neurotransmitter–receptor complex to the G synthesizing enzyme, depicted here by the enzyme turning the
protein causes yet another conformational change, this time in same color as the ternary complex. Once the enzyme binds
the G protein, represented here as a change in the shape of the to this ternary complex, it becomes activated and capable of
right-hand side of the G protein. This prepares the G protein synthesizing the second messenger. Thus, it is the cooperation of
to bind to the enzyme capable of synthesizing the second all four elements, wrapped together as a quaternary complex, that
messenger. leads to the production of the second messenger. Information
from the first messenger thus passes to the second messenger
through use of receptor–G protein–enzyme intermediaries.
Activating a Third-Messenger Kinase through Cyclic AMP

first messenger -
neurotransmitter
1
E E
2
second
messenger
2 2
2 2 2 R R 2
R R 2 R R 2
P P
3 3
inactive activation third messenger -

protein kinase active protein kinase
Figure 1-16 Third-messenger protein kinase. This figure illustrates activation of a third-messenger protein kinase through the second-
messenger cAMP. Neurotransmitters begin the process of activating genes by producing a second messenger (cAMP), as shown
previously in Figures 1-12 through 1-15. Some second messengers activate intracellular enzymes known as protein kinases. This enzyme
is shown here as inactive when it is paired with another copy of the enzyme plus two regulatory units (R). In this case, two copies of the
second messenger interact with the regulatory units, dissociating them from the protein kinase dimer. This dissociation activates each
protein kinase, readying this enzyme to phosphorylate other proteins.
14
1
Figure 1-17 Third-messenger
Activating a Third-Messenger Phosphatase through Calcium phosphatase. This figure illustrates
activation of a third-messenger
first messenger - phosphatase through the second-
neurotransmitter messenger calcium. Shown here
is calcium binding to an inactive
1 phosphatase known as calcineurin,
thereby activating it and thus readying
it to remove phosphates from fourth-
messenger phosphoproteins.
++
Ca
2 second
messenger
2 inactive
calcineurin
3
third messenger -
active calcineurin
(phosphatase)
In this example, when two copies of cAMP bind to each a dormant phosphoprotein; for other phosphoproteins,
regulatory unit, the regulatory unit dissociates from the dephosphorylation can be activating. Activation of
enzyme, and the dimer dissociates into two copies of the fourth-messenger phosphoproteins can change the
enzyme, and the protein kinase is now activated, shown synthesis of neurotransmitters, alter neurotransmitter
with a bow and arrow ready to shoot phosphate groups release, change the conductance of ions, and generally
into unsuspecting fourth-messenger phosphoproteins maintain the chemical neurotransmission apparatus
(Figure 1-16). in either a state of readiness or dormancy. The balance
Meanwhile, the nemesis of protein kinase is also between phosphorylation and dephosphorylation of
forming in Figure 1-17, namely a protein phosphatase. fourth-messenger kinases and phosphatases plays a vital
Another first messenger is opening an ion channel here, role in regulating many molecules critical to the chemical
allowing the second-messenger calcium to enter, which neurotransmission process.
activates the phosphatase enzyme calcineurin. In the
presence of calcium, calcineurin becomes activated, Beyond the Second Messenger to a Phosphoprotein
shown with scissors ready to rip phosphate groups off Cascade Triggering Gene Expression
fourth-messenger phosphoproteins (Figure 1-17). The ultimate cellular function that neurotransmission
The clash between kinase and phosphatase can often seeks to modify is gene expression, either turning a
be seen by comparing what happens in Figures 1-18 gene on or turning a gene off. All four signal transduction
and 1-19. In Figure 1-18, the third-messenger kinase cascades shown in Figure 1-11 end with the last molecule
is putting phosphates onto various fourth-messenger influencing gene transcription. Both cascades triggered
phosphoproteins such as ligand-gated ion channels, by neurotransmitters are shown acting upon the CREB
voltage-gated ion channels, and enzymes. In Figure system, which is responsive to phosphorylation of its
1-19, the third-messenger phosphatase is taking those regulatory units (Figure 1-11, left). CREB is cAMP
phosphates off. Sometimes phosphorylation activates response element-binding protein, a transcription factor
15
Third-Messenger Kinases Put Phosphates on Critical Proteins Figure 1-18 Third-messenger

kinase puts phosphates on critical
proteins. Here the activation of a third-
messenger kinase adds phosphates
first 1 to a variety of phosphoproteins,
messenger P such as ligand-gated ion channels,
voltage-gated ion channels, and
various regulatory enzymes.
Adding a phosphate group to some
phosphoproteins activates them; for
second 2 other proteins, this inactivates them.
4
messenger
ligand-gated
ion channel
third
P P
messenger -
4
kinase 3
regulatory enzymes
voltage-gated
ion channel
Third-Messenger Phosphatases Undo What Kinases Create - Take Phosphates Off Critical Proteins
first messenger -
neurotransmitter
1
P
4
Ca++
ligand-gated ion channel 2 second
messenger
regulatory enzymes 2
inactive
calcineurin
3 3
P
third messenger -
active calcineurin
4
(phosphatase)
voltage-gated ion channel
Figure 1-19 Third-messenger phosphatase removes phosphates from critical proteins. In contrast to the previous figure, the third
messenger here is a phosphatase; this enzyme removes phosphate groups from phosphoproteins such as ligand-gated ion channels,
voltage-gated ion channels, and various regulatory enzymes. Removing a phosphate group from some phosphoproteins activates them;
for others, it inactivates them.
16
1
in the cell nucleus capable of activating expression of signal cascade messengers is activated by neurotrophins
genes, especially a type of gene known as immediate and related molecules. Activating this system by first-
genes or immediate early genes. When G-protein- messenger neurotrophins leads to activation of enzymes
linked receptors activate protein kinase A, this activated that are mostly kinases, one kinase activating another
enzyme can translocate or move into the cell nucleus until finally one of them phosphorylates a transcription
and stick a phosphate group on CREB, thus activating factor in the cell nucleus and starts transcribing genes
this transcription factor and causing the nearby gene to (Figure 1-11). Ras is a G protein that activates a cascade
become activated. This leads to gene expression, first as of kinases with confusing names. For those who are
RNA and then as the protein coded by the gene. good sports with an interest in the specifics, this cascade
Interestingly, it is also possible for ion-channel-linked starts with Ras activating Raf, which phosphorylates
receptors that enhance intracellular second-messenger and activates MEK (MAPK kinase/ERK kinase or
calcium levels to activate CREB by phosphorylating mitogen-activated protein kinase kinase/extracellular
it. A protein known as calmodulin, which interacts signal regulated kinase kinase), which activates ERK
with calcium, can lead to activation of certain kinases kinase (extracellular signal-regulated kinase itself), RSK
called calcium/calmodulin-dependent protein kinases (ribosomal S6 kinase), MAPK (MAP kinase itself), or
(Figure 1-11). This is an entirely different enzyme than GSK-3 (glycogen synthase kinase), leading ultimately to
the phosphatase shown in Figures 1-9, 1-17, and 1-19. changes in gene expression. Confused? It is actually not
Here, a kinase and not a phosphatase is activated. When important to know the names, but to remember the take-
activated, this kinase can translocate into the cell nucleus away point that neurotrophins trigger an important signal
and, just like the kinase activated by the G-protein transduction pathway that activates kinase enzyme after
system, add a phosphate group to CREB and activate this kinase enzyme, ultimately changing gene expression.
transcription factor so that gene expression is triggered. This is worth knowing because this signal transduction
It is important to bear in mind that calcium is thus pathway may be responsible for the expression of genes
able to activate both kinases and phosphatases. There that regulate many critical functions of the neuron, such
is a very rich and sometimes confusing array of kinases as synaptogenesis and cell survival, as well as the plastic
and phosphatases, and the net result of calcium action is changes that are necessary for learning, memory, and
dependent upon what substrates are activated, because even disease expression in various brain circuits. Both
different phosphatases and kinases target very different drugs and the environment target gene expression in
substrates. Thus, it is important to keep in mind the ways that are just beginning to be understood, including
specific signal transduction cascade under discussion and how such actions contribute to the cause of mental
the specific phosphoproteins acting as messengers in the illnesses and to the mechanism of action of effective
cascade in order to understand the net effect of various treatments for mental illnesses.
signal transduction cascades. In the case illustrated in In the meantime, it is mostly important to realize that
Figure 1-11, the G-protein system and the ion-channel a very wide variety of genes are targeted by all four of
system are working together to produce more activated these signal transduction pathways. These range from the
kinases and thus more activation of CREB. However, in genes that make synthetic enzymes for neurotransmitters,
Figures 1-9 and 1-16 through 1-19, they are working in to growth factors, cytoskeleton proteins, cellular adhesion
opposition. proteins, ion channels, receptors, and the intracellular
Genes are also the ultimate target of the hormone signaling proteins themselves, among many others. When
signal transduction cascade in Figure 1-11. Some genes are expressed by any of the signal transduction
hormones, such as estrogen, thyroid, and cortisol, act pathways shown in Figure 1-11, this can lead to making
at cytoplasmic receptors, bind them, and produce a more or fewer copies of any of these proteins. Synthesis
hormone–nuclear receptor complex that translocates of such proteins is obviously a critical aspect of the
to the cell nucleus, finds elements in the gene that it neuron performing its many and varied functions.
can influence (called hormone-response elements, or Numerous diverse biological actions are effected within
HREs), and then acts as a transcription factor to trigger neurons that alter behaviors in individuals due to gene
activation of nearby genes (Figure 1-11). expression that is triggered by the four major signal
Finally, a very complicated signal transduction system transduction cascades. These range widely from neuronal
with terrible sounding names for their downstream responses such as synaptogenesis, strengthening of
17
a synapse, neurogenesis, apoptosis, increasing or are expressed that seems to be the important factor in
decreasing the efficiency of information processing in regulating neuronal function. These same factors of gene
cortical circuits to behavioral responses such as learning, expression are now thought to also underlie the actions
memory, antidepressant responses to antidepressant of psychopharmacological drugs and the mechanisms of
administration, symptom reduction by psychotherapy, psychiatric disorders within the central nervous system.
and possibly even the production of a mental illness.
Molecular Mechanism of Gene Expression
How Neurotransmission Triggers Gene Expression Chemical neurotransmission converts receptor
How does the gene express the protein it codes? The occupancy by a neurotransmitter into the creation of
discussion above has shown how the molecular “pony third, fourth, and subsequent messengers that eventually
express” of signal transduction has a message encoded activate transcription factors that turn on genes (Figures
with chemical information from the neurotransmitter– 1-20 through 1-30). Most genes have two regions, a
receptor complex that is passed along from molecular coding region and a regulatory region with enhancers
rider to molecular rider until the message is delivered to and promoters of gene transcription (i.e., DNA being
the appropriate phosphoprotein mailbox (Figures 1-9 and transcribed into RNA) (Figure 1-20). The coding
1-16 through 1-19) or DNA mailbox in the postsynaptic region of DNA is the direct template for making its
neuron’s genome (Figures 1-11 and 1-20 through 1-30). corresponding RNA. This DNA is “transcribed” into its
Since the most powerful way for a neuron to alter its RNA with the help of an enzyme called RNA polymerase.
function is to change which genes are being turned However, RNA polymerase must be activated, or it won’t
on or off, it is important to understand the molecular work.
mechanisms by which neurotransmission regulates gene Luckily, the regulatory region of the gene can make
expression. this happen. It has an enhancer element and a promotor
How many potential genes can neurotransmission element (Figure 1-20), which can initiate gene expression
target? It is estimated that the human genome contains with the help of transcription factors (Figure 1-21).
approximately 20,000 genes located within 3 million base Transcription factors themselves can be activated
pairs of DNA on 23 chromosomes. Incredibly, however, when they are phosphorylated, which allows them to
genes only occupy a few percent of this DNA. The other bind to the regulatory region of the gene (Figure 1-21).
96% used to be called “junk” DNA since it does not This in turn activates RNA polymerase and off we go
code proteins, but it is now known that these sections with the coding part of the gene transcribing itself
of DNA are critical for structure and for regulating into its messenger RNA (mRNA) (Figure 1-22). Once
whether or not a gene is expressed or is silent. It is not transcribed, of course, this messenger RNA goes on to
just the number of genes we have, it is whether and when translate itself into the corresponding protein (Figure
and how often and under which circumstances they 1-22). However, there is a great deal of RNA that never
gets translated into proteins and instead exerts regulatory
functions as explained below.
cell nucleus
Figure 1-20 Activation of a gene, part 1: gene

is off. The elements of gene activation shown
here include the enzyme protein kinase; a
P transcription factor transcription factor, a type of protein that can
(inactive) activate a gene; RNA polymerase, the enzyme
3
TF that synthesizes RNA from DNA when the gene
protein kinase is transcribed; the regulatory regions of DNA,
such as enhancer and promoter areas; and
finally the gene itself. This particular gene is
RNA polymerase off because the transcription factor has not yet
gene
(inactive) been activated. The DNA for this gene contains
both a regulatory region and a coding region.
enhancer promoter coding The regulatory region has both an enhancer
element and a promoter element, which can
initiate gene expression when they interact with
gene is off activated transcription factors. The coding region
is directly transcribed into its corresponding RNA
once the gene is activated.
18
1
Figure 1-21 Activation of a gene, part 2:
cell nucleus gene turns on. The transcription factor is now
activated because it has been phosphorylated
by protein kinase, allowing it to bind to the
regulatory region of the gene.
P
P
3 activated
TF
4
transcription factor
P
gene
TF
4
enhancer promoter coding
transcription factor is activated;

gene is turning on
Figure 1-22 Activation of a gene, part 3:

cell nucleus gene product. The gene itself is now activated
because the transcription factor has bound
to the regulatory region of the gene, in turn
activating the enzyme RNA polymerase. Thus,
the gene is transcribed into messenger RNA
(mRNA), which in turn is translated into its
corresponding protein. This protein is thus the
product of activation of this particular gene.
4
TF
P
RNA polymerase
activated
DNA gene is activated
mRNA
protein
Third Messenger Activating a Transcription Factor for an Early Gene Figure 1-23 Immediate early
gene. Some genes are known as
immediate early genes. Shown here
is a third-messenger protein kinase
enzyme activating a transcription
P factor, or fourth messenger, capable of
activating, in turn, an early gene.
P TF TF
3 4
inactive activated "early"

transcription factor transcription factor
Some genes are known as immediate early genes immediate early genes function as rapid responders to
(Figure 1-23). They have weird names such as cJun the neurotransmitter’s input, like the special ops troops
and cFos (Figures 1-24 and 1-25) and belong to a sent into combat quickly and ahead of the full army.
family called “leucine zippers” (Figure 1-25). These Such rapid deployment forces of immediate early genes
19
Figure 1-24 Early genes activate

late genes, part 1. In the top panel,
a transcription factor is activating
the immediate early gene cFos and
P producing the protein product Fos.
While the cFos gene is being activated,
another immediate early gene, cJun,
cFOS is being simultaneously activated and
producing its protein, Jun, as shown in
the bottom panel. Fos and Jun can be
5 thought of as fifth messengers.
FOS -
fifth messenger
nucleus
5 cJUN
JUN - P
fifth messenger nucleus
Figure 1-25 Early genes activate late

genes, part 2. Once Fos and Jun proteins
ZIPPER
are synthesized, they can collaborate as
partners and produce a Fos–Jun combination
inactive protein, which now acts as a sixth-messenger
5 FOS JUN 5 transcription factor transcription factor for late genes.
nucleus
FOS - JUN -
fifth messenger fifth messenger
6
sixth messenger
late gene
late gene product
mRNA mRNA
mRNA
nucleus
mRNA
Figure 1-26 Early genes activate late genes, part 3. The Fos–
Jun transcription factor belongs to a family of proteins called
leucine zippers. The leucine zipper transcription factor formed E
by the products of the activated early genes cFos and cJun now
returns to the genome and finds another gene. Since this gene
is being activated later than the others, it is called a late gene. Figure 1-27 Examples of late gene activation. A receptor, an
Thus, early genes activate late genes when the products of enzyme, a neurotrophic growth factor, and an ion channel are all
early genes are themselves transcription factors. The product of being expressed owing to activation of their respective genes.
the late gene can be any protein the neuron needs, such as an Such gene products go on to modify neuronal function for many
enzyme, a transport factor, or a growth factor. hours or days.
20
first messenger -
neurotransmitter
1 1
1 1
E E
2 second
messenger
2
2 2
2 2 2 R R 2
R R 2 R R 2
P P
3 3
inactive activation third messenger -

protein kinase active protein kinase
P P
TF
3
TF
4
inactive fourth messenger -

transcription factor activated "early"
transcription factor
nucleus FOS -
P fifth messenger
TF
4
Figure 1-28 Gene regulation by neurotransmitters. This figure summarizes gene regulation by neurotransmitters, from first-messenger
extracellular neurotransmitter to intracellular second messenger, to third-messenger protein kinase, to fourth-messenger transcription
factor, to fifth-messenger protein, which is the gene product of an early gene.
are thus the first to respond to the neurotransmission When Jun and Fos team up, they form a leucine zipper
signal by making the proteins they encode. In this type of transcription factor (Figure 1-25), which in turn
example, it is Jun and Fos proteins coming from activates many kinds of later-onset genes (Figures 1-26,
cJun and cFos genes (Figure 1-24). These are nuclear 1-27, 1-29). Thus, Fos and Jun serve to wake up the much
proteins; that is, they live and work in the nucleus. larger army of inactive genes. Which individual “late”
They get started within 15 minutes of receiving a soldier genes are so drafted to active gene duty depends
neurotransmission, but only last for a half hour to an upon a number of factors, not the least of which is which
hour (Figure 1-10). neurotransmitter is sending the message, how frequently
21
cFOS
5
cJUN FOS -
nucleus fifth messenger
5
JUN -
fifth messenger
ZIPPER
FOS JUN
sixth messenger
late gene
late gene product and

nucleus biological response
Figure 1-29 Activating a late gene. This figure summarizes the process of activating a late gene. At the top, immediate early genes
cFos and cJun are expressed and their fifth-messenger protein products Fos and Jun are formed. Next, a transcription factor, namely a
leucine zipper, is created by the cooperation of Fos and Jun together, combining to form the sixth messenger. Finally, this transcription
factor goes on to activate a late gene, resulting in the expression of its own gene product and the biological response triggered by that
late gene product.
it is sending the message, and whether it is working in In summary, one can trace the events from the
concert or in opposition with other neurotransmitters neurotransmitting first messenger, through gene
talking to other parts of the same neuron at the same transcription (Figures 1-9, 1-11, 1-28, and 1-29). Once
time. When Fos and Jun partner together to form a the second-messenger cAMP is formed from its first-
leucine zipper type of transcription factor, this can lead messenger neurotransmitter (Figure 1-28), it can interact
to the activation of genes to make anything you can think with a protein kinase third messenger. cAMP binds to
of, from enzymes to receptors to structural proteins (see the inactive or sleeping version of this enzyme, wakes it
Figure 1-27). up, and thereby activates protein kinase. Once awakened,
22
1
the protein kinase third messenger’s job is to activate EPIGENETICS
transcription factors by phosphorylating them (Figure
1-28). It does this by traveling straight to the cell nucleus Genetics is the DNA code for what a cell can transcribe
and finding a sleeping transcription factor. By sticking a into specific types of RNA or translate into specific
phosphate onto the transcription factor, protein kinase proteins. However, just because there are about 20,000
is able to “wake up” that transcription factor and form genes in the human genome, it does not mean that every
a fourth messenger (Figure 1-28). Once a transcription gene is expressed, even in the brain. Epigenetics is a
factor is aroused, it will bind to genes and cause protein parallel system that determines whether any given gene
synthesis, in this case, the product of an immediate is actually made into its specific RNA and protein, or if it
early gene, and this functions as a fifth messenger. Two is instead ignored or silenced. If the genome is a lexicon
such gene products bind together to form yet another of all protein “words,” then the epigenome is a “story”
activated transcription factor, and this is the sixth resulting from arranging the “words” into a coherent tale.
messenger (Figure 1-29). Finally, the sixth messenger The genomic lexicon of all potential proteins is the same
causes the expression of a late gene product, which could in every one of the 100+ billion neurons in the brain,
be thought of as a seventh-messenger protein product of and indeed is the same in all of the 200+ types of cells in
the activated gene. This late gene product then mediates the body. So, the plot of how a normal neuron becomes
some biological response important to the functioning of a malfunctioning neuron in a psychiatric disorder, as
the neuron. well as how a neuron becomes a neuron instead of a liver
Of course, neurotransmitter-induced molecular cell, is the selection of which specific genes are expressed
cascades into the cell nucleus lead to changes not only or silenced. In addition, malfunctioning neurons
in the synthesis of its own receptors, but also in that of are impacted by inherited genes that have abnormal
many other important postsynaptic proteins, including nucleotide sequences, which if expressed contribute to
enzymes and receptors for other neurotransmitters. If mental disorders. Thus, the story of the brain depends
such changes in genetic expression lead to changes in not only upon which genes are inherited but also
connections and in the functions that these connections whether any abnormal genes are expressed or even
perform, it is easy to understand how genes can modify whether normal genes are expressed when they should
behavior. The details of nerve functioning – and thus be silent or silenced when they should be expressed.
the behavior derived from this nerve functioning – are Neurotransmission, genes themselves, drugs, and the
controlled by genes and the products they produce. environment all regulate which genes are expressed or
Since mental processes and the behaviors they cause silenced, and thus all affect whether the story of the brain
come from the connections between neurons in the is a compelling narrative such as learning and memory, a
brain, genes therefore exert significant control over regrettable tragedy such as drug abuse, stress reactions,
behavior. But can behavior modify genes? Learning and psychiatric disorders, or therapeutic improvement of
as well as experiences from the environment can a psychiatric disorder by medications or psychotherapy.
indeed alter which genes are expressed and thus What Are the Molecular Mechanisms of Epigenetics?
can give rise to changes in neuronal connections. In
this way, human experiences, education, and even Epigenetic mechanisms turn genes on and off by
psychotherapy may change the expression of genes that modifying the structure of chromatin in the cell nucleus
alter the distribution and “strength” of specific synaptic (Figure 1-30). The character of a cell is fundamentally
connections. This in turn may produce long-term determined by its chromatin, a substance composed of
changes in behavior caused by the original experience nucleosomes (Figure 1-30). Nucleosomes are an octet of
and mediated by the genetic changes triggered by that proteins called histones around which DNA is wrapped
original experience. Thus, genes modify behavior and (Figure 1-30). Epigenetic control over whether a gene
behavior modifies genes. Genes do not directly regulate is read (i.e., expressed) or is not read (i.e., silenced),
neuronal functioning. Rather, they directly regulate the is done by modifying the structure of chromatin.
proteins which create neuronal functioning. Changes Chemical modifications that can do this include not
in function have to wait until the changes in protein only methylation, but also acetylation, phosphorylation,
synthesis occur, and the events which they cause start and others, and these processes are regulated by
to happen. neurotransmission, drugs, and the environment
(Figure 1-30). For example, when DNA or histones are
23
methylated, this compacts the chromatin and acts to It used to be thought that, once a cell differentiated,
close off access of molecular transcription factors to the the epigenetic pattern of gene activation and gene
promoter regions of DNA, with the consequence that the silencing remained stable for the lifetime of that
gene in this region is silenced, and not expressed, so no cell. Now, however, it is known that there are various
RNA or protein is manufactured (Figure 1-30). Silenced circumstances in which epigenetics may change in
DNA means molecular features that are not part of a mature, differentiated neurons. Although the initial
given cell’s personality. epigenetic pattern of a neuron is indeed set during
Histones are methylated by enzymes called histone neurodevelopment to give each neuron its own lifelong
methyltransferases, and this is reversed by enzymes “personality,” it now appears that the storyline of
called histone demethylases (Figure 1-30). Methylation some neurons is that they respond to their narrative
of histones can silence genes whereas demethylation experiences throughout life with a changing character
of histones can thus activate genes. DNA can also be arc, thus causing de novo alterations in their epigenome.
methylated and this, too, silences genes. Demethylation Depending upon what happens to a neuron (such
of DNA reverses this. Methylation of DNA is regulated as experiencing child abuse, adult stress, dietary
by DNA methyltransferase (DNMT) enzymes, and deficiencies, productive new encounters, psychotherapy,
demethylation of DNA by DNA demethylase enzymes drugs of abuse, or psychotropic therapeutic medications),
(Figure 1-30). There are many forms of methyltransferase it now seems that previously silenced genes can become
enzymes, and they all tag their substrates with activated and/or previously active genes can become
methyl groups donated from L-methylfolate via silenced (Figure 1-30). When this happens, both favorable
S-adenosyl-methionine (SAMe) (Figure 1-30). When and unfavorable developments can occur in the character
neurotransmission, drugs, or the environment impact of neurons. Favorable epigenetic mechanisms may be
methylation, for example, this regulates whether genes triggered in order for one to learn (e.g., spatial memory
are epigenetically silenced or expressed. formation) or to experience the therapeutic actions
Methylation of DNA can eventually lead to of psychopharmacological agents. On the other hand,
deacetylation of histones as well, by activating enzymes unfavorable epigenetic mechanisms may be triggered in
called histone deacetylases (HDACs). Deacetylation of order for one to become addicted to drugs of abuse, or to
histones also has a silencing action on gene expression experience various forms of “abnormal learning,” such as
(Figure 1-30). Methylation and deacetylation compress when one develops fear conditioning, an anxiety disorder,
chromatin, as though a molecular gate has been closed, or a chronic pain condition.
and thus transcription factors that activate genes How these epigenetic mechanisms arrive at the scene
cannot get access to their promoter regions, and thus of the crime remains a compelling neurobiological and
the genes are silenced and not transcribed into RNA or psychiatric mystery. Nevertheless, a legion of scientific
translated into proteins (Figure 1-30). On the other hand, detectives is working these cases and is beginning to show
demethylation and acetylation do just the opposite: they how epigenetic mechanisms are mediators of psychiatric
decompress chromatin as though a molecular gate has disorders. There is also the possibility that epigenetic
been opened, and thus transcription factors can get to the mechanisms can be harnessed to treat addictions,
promoter regions of genes, and do activate them (Figure extinguish fear, prevent the development of chronic pain
1-30). Activated genes thus become part of the molecular states, and maybe even prevent disease progression of
personality of a given cell. psychiatric disorders such as schizophrenia by identifying
high-risk individuals before the “plot thickens” and
How Epigenetics Maintains or Changes the Status Quo
the disorder is irreversibly established and relentlessly
Some enzymes try to maintain the status quo of a cell, marches on to an unwanted destiny.
enzymes such as DNMT1 (DNA methyltransferase 1), One of the mechanisms for changing the status quo
which maintain the methylation of specific areas of DNA of epigenomic patterns in a mature cell is via de novo
and keep various genes quiet for a lifetime. For example, DNA methylation by a type of DNMT enzyme known
this process keeps a neuron always a neuron, and a liver as DNMT2 or DNMT3 (Figure 1-30). These enzymes
cell always a liver cell, including when a cell divides into target neuronal genes for silencing that were previously
another one. Presumably methylation is maintained at active in a mature neuron. Of course, deacetylation
genes that one cell does not need, even though another of histones near previously active genes would do the
cell type might. same thing, namely silence them, and this is mediated
24
Gene Activation and Silencing

Gene Activating
histone acetyl transferase
DNA demethylase
histone demethylase
TF Me
Me
Ac Ac
gates
open neurotransmission/
drugs/ gates
environment close
TF
Gene Silencing
histone deacetylase
DNMT
DNMT
histone
methyltransferase
Me
RNA RNA
SAMe
CH3
H H
L-MF
Gene gene
H H product
Product
activated gene silenced gene
Key
Me
CH3
Me Me Me Me H H Me
TF
L-MF methyl group
H H
Ac
transcription chromatin methylated DNA L-methylfolate methylated acetyl group
factor (histone + DNA) histone core
Figure 1-30 Gene activation and silencing. Molecular gates are opened by acetylation and/or demethylation of histones, allowing
transcription factors access to genes, thus activating them. Molecular gates are closed by deacetylation and/or methylation provided
by the methyl donor SAMe derived from L-methylfolate. This prevents access of transcription factors to genes, thus silencing them. Ac =
acetyl; Me = methyl; DNMT = DNA methyltransferase; TF = transcription factor; SAMe = S-adenosyl-methionine; L-MF = L-methylfolate.
by HDACs. In reverse, demethylation or acetylation of develops? This part of the story remains a twisted mystery
genes both activate genes that were previously silent. The but some very interesting detective work has already been
real question is how does a neuron know which genes done by various investigators who hope to understand
among its thousands to silence or activate in response how some neuronal stories evolve into psychiatric
to the environment, including stress, drugs, and diet? tragedies. These investigations may set the stage for
How might this go wrong when a psychiatric disorder rewriting the narrative of various psychiatric disorders by
25
DNA Gene
5’ 3’
Exon 1 Exon 2 Intron Exon 3 Exon 4
Transcription
RNA
Primary Transcript
RNA Splicing
mRNA (splice variant 1) mRNA (splice variant 2)
Protein 1 Protein 2
Figure 1-31 Alternative splicing. When DNA is transcribed into messenger RNA (mRNA), this is called the primary transcript. The
primary transcript can then be translated into a protein; however, sometimes an intermediary step occurs in which the mRNA is spliced,
with certain sections reorganized or removed outright. This means that one gene can give rise to more than one protein.
therapeutically altering the epigenetics of key neuronal not “translated” directly into a motion picture, in many
characters so that the story has a happy ending. cases, the “raw” mRNA is also not immediately translated
into a protein. Now comes the interesting part: editing. It
A BRIEF WORD ABOUT RNA turns out that mRNA can be “spliced,” much like a movie
producer edits and splices movie film once the live shoot
Alternative Splicing
is over, organizing the splices into different sequences
As mentioned above, the RNA that encodes our 20,000 and leaving some on the cutting-room floor. For spliced
genes is called messenger RNA (mRNA) and serves as mRNA, these sections won’t be translated into protein
an intermediate between DNA and protein. Although (Figure 1-31). This “alternative splicing” means that one
it might seem as if our 20,000 genes would make only gene can give rise to many proteins (Figure 1-31), just
20,000 proteins, that is not so. It turns out that developing like a movie can have different endings or be edited into a
mRNA into protein is a similar process as when an short trailer. Thus, thanks in part to RNA editing, the true
old-fashioned movie producer makes cinema. That is, molecular diversity of the brain is notably greater than
mRNA records the action from DNA just as the movie our 20,000 genes.
studio faithfully develops the film exactly as initially
recorded. In the case of DNA transcription, this “first RNA Interference
draft” is called the primary transcript (Figure 1-31). There are forms of RNA other than mRNA that are
However, just as the raw footage from a movie shoot is now known to exist and that do not code for protein
26
1
Figure 1–32 RNA
DNA interference. Some forms of
RNA do not code for protein
synthesis, and instead have
regulatory functions. As
shown here, small hairpin RNA
(shRNA) is transcribed from
DNA but is not translated into
protein. Instead, it forms hairpin
RNA loops and is exported into
the cytoplasm by the enzyme
exportin, where it is then
chopped into pieces by the
enzyme dicer. The small pieces
nucleus bind to a protein complex
called RISC, which in turn binds
shRNA to mRNA and inhibits protein
synthesis.
Exportin
Dicer
mRNA undergoing
translation
RISC
ribosome
RISC
ribosome
no translation
RNA interference
synthesis; instead they have direct regulatory functions. go on to be translated into proteins. Instead, they form
These include ribosomal RNA (rRNA), transfer RNA hairpin loops and are then exported to the cytoplasm
(tRNA), and small nuclear RNA (snRNA), along with by the enzyme exportin, where they are chopped into
a large number of other noncoding RNAs (e.g., small pieces by an enzyme called “dicer” (Figure 1-32). Small
hairpin RNAs because they are shaped like a hairpin, pieces of iRNA then bind to a protein complex called
sometimes also called microRNA [miRNA]; interference RISC, which binds in turn to mRNA to inhibit protein
RNA [iRNA]; and small interfering RNA [siRNA]. synthesis (Figure 1-32). So, forms of RNA can lead both
When miRNAs are transcribed from DNA, they do not to protein synthesis and to blocking protein synthesis.
27
Future therapeutics may be able to utilize iRNAs to or even when ion flows have been altered or second
inhibit protein synthesis in genetic disorders, such as messengers have been created. Events such as these all
Huntington’s disease. start and end within milliseconds to seconds following
release of presynaptic neurotransmitter. The ultimate
SUMMARY goal of neurotransmission is to alter the biochemical
The reader should now appreciate that chemical activities of the postsynaptic target neuron in a profound
neurotransmission is the foundation of and enduring manner. Since the postsynaptic DNA
psychopharmacology. There are many neurotransmitters, has to wait until molecular pony express messengers
and all neurons receive input from a multitude of make their way from the postsynaptic receptors, often
neurotransmitters in classic presynaptic to postsynaptic located on dendrites, to phosphoproteins within the
asymmetrical neurotransmission. Presynaptic to neuron, or to transcription factors and genes in the
postsynaptic neurotransmissions at the brain’s trillion postsynaptic neuron’s cell nucleus, it can take a while for
synapses are key to chemical neurotransmission, but neurotransmission to begin influencing the postsynaptic
some neurotransmission is retrograde from postsynaptic target neuron’s biochemical processes. The time it takes
neuron to presynaptic neuron, and other types of from receptor occupancy by neurotransmitter to gene
neurotransmission, such as volume neurotransmission, expression is usually hours. Furthermore, since the last
do not require a synapse at all. messenger triggered by neurotransmission – called a
The reader should also have an appreciation for transcription factor – only initiates the very beginning of
elegant if complex molecular cascades precipitated by a gene action, it takes even longer for the gene activation to
neurotransmitter, with molecule-by-molecule transfer of be fully implemented via the series of biochemical events
that transmitted message inside the neuron receiving that it triggers. These biochemical events can begin many
message, eventually altering the biochemical machinery hours to days after the neurotransmission occurred, and
of that cell in order to carry out the message that was sent can last days or weeks once they are put in motion.
to it. Thus, the function of chemical neurotransmission Thus, a brief puff of chemical neurotransmission
is not so much to have a presynaptic neurotransmitter from a presynaptic neuron can trigger a profound
communicate with its postsynaptic receptors, but to postsynaptic reaction that takes hours to days to develop
have a presynaptic genome converse with a postsynaptic and that can last days to weeks or even a lifetime. Every
genome: DNA to DNA, presynaptic “command center” to conceivable component of this entire process of chemical
postsynaptic “command center” and back. neurotransmission is a candidate for modification by
The message of chemical neurotransmission is drugs. Most psychotropic drugs act upon the processes
transferred via three sequential “molecular pony express” that control chemical neurotransmission at the level of
routes: (1) a presynaptic neurotransmitter synthesis the neurotransmitters themselves or their enzymes and
route from presynaptic genome to the synthesis and especially their receptors. Future psychotropic drugs
packaging of neurotransmitter and supporting enzymes will undoubtedly act directly upon the biochemical
and receptors; (2) a postsynaptic route from receptor cascades, particularly upon those elements that
occupancy through second messengers all the way to control the expression of pre- and postsynaptic genes.
the genome, which turns on postsynaptic genes; and Also, mental and neurological illnesses are known
(3) another postsynaptic route starting from the newly or suspected to affect these same aspects of chemical
expressed postsynaptic genes transferring information neurotransmission. The neuron is dynamically modifying
as a molecular cascade of biochemical consequences its synaptic connections throughout its life, in response
throughout the postsynaptic neuron. to learning, life experiences, genetic programming,
It should now be clear that neurotransmission does epigenetic changes, drugs, and diseases, with chemical
not end when a neurotransmitter binds to a receptor neurotransmission being the key aspect underlying the
regulation of all these important processes.
28
Transporters, Receptors,
2
and Enzymes as Targets of
Psychopharmacological Drug
Action
Neurotransmitter Transporters as Targets of Drug Vesicular Transporters (SLC18 Gene Family) as
Action 29 Targets of Psychotropic Drugs 35
Classification and Structure 29 G-Protein-Linked Receptors 36
Monoamine Transporters (SLC6 Gene Family) as Structure and Function 36
Targets of Psychotropic Drugs 31 G-Protein-Linked Receptors as Targets of
Other Neurotransmitter Transporters (SLC6 and Psychotropic Drugs 36
SLC1 Gene Families) as Targets of Psychotropic Enzymes as Sites of Psychopharmacological Drug
Drugs 34 Action 45
Where Are the Transporters for Histamine and Cytochrome P450 Drug Metabolizing Enzymes as
Neuropeptides? 35 Targets of Psychotropic Drugs 49
Vesicular Transporters: Subtypes and Function 35 Summary 50
Psychotropic drugs have many mechanisms of action, but drugs are used for indications far beyond their original
they all target specific molecular sites that have profound use (e.g., so-called antipsychotics that are used for
effects upon neurotransmission. It is thus necessary to depression). Thus, throughout this textbook we will use
understand the anatomical infrastructure and chemical the new nomenclature for drugs (neuroscience-based
substrates of neurotransmission (Chapter 1) in order to nomenclature), which is based upon mechanism of action
grasp how psychotropic drugs work. Although there are and not therapeutic indication, wherever possible. This
over 100 essential psychotropic drugs utilized in clinical chapter and the next will explain all known mechanisms
practice today (see Stahl’s Essential Psychopharmacology: targeted by psychotropic drugs that form the basis for
the Prescriber’s Guide), there are only a few sites of action how they are named.
for all these therapeutic agents (Figure 2-1). Specifically, Finally, since there are genetic variants known
about a third of psychotropic drugs target one of the for many targets of psychotropic drugs, there is an
transporters for a neurotransmitter; another third target ongoing effort to determine to what extent such genetic
receptors coupled to G proteins; and perhaps only 10% variants may increase or decrease the odds that a
target enzymes. All three of these sites of action will be patient will have a good clinical response or side effects
discussed in this chapter. The balance of psychotropic to drugs that engage that target, in a process called
drugs target various types of ion channels, which pharmacogenomics. The scientific foundation for
will be discussed in Chapter 3. Thus, mastering how clinical application of genetic variants of psychotropic
just a few molecular sites regulate neurotransmission drug targets is still evolving, but current insights will be
allows the psychopharmacologist to understand the mentioned briefly when the specific target is described
theories about the mechanisms of action of virtually all throughout this textbook.
psychopharmacological agents.
In fact, these molecular targets form the basis of NEUROTRANSMITTER
how psychotropic drugs are now named. That is, there TRANSPORTERS AS TARGETS OF
is a modern movement afoot to name psychotropic DRUG ACTION
drugs for their pharmacological mechanism of action
Classification and Structure
(e.g., serotonin transport inhibitor, dopamine D2,
and serotonin 5HT2A antagonist) rather than for Neuronal membranes normally serve to keep the internal
their therapeutic indication (e.g., antidepressant, milieu of the neuron constant by acting as barriers to
antipsychotic, etc.). Naming drugs for therapeutic the intrusion of outside molecules and to the leakage
indication has led to endless confusion, because many of internal molecules. However, selective permeability
29
The Five Molecular Targets of Psychotropic Drugs
= =
12
7
A B
12 transmembrane 7 transmembrane region
region transporter G-protein linked
~ 30% of psychotropic drugs ~ 30% of psychotropic drugs
C D E
Enzyme 4 transmembrane region 6 transmembrane region

~ 10% of psychotropic drugs ligand-gated ion channel voltage-gated ion channel
~ 20% of psychotropic drugs ~ 10% of psychotropic drugs
Figure 2-1 The molecular targets of psychotropic drugs. There are only a few major sites of action for the wide expanse of
psychotropic drugs utilized in clinical practice. Approximately one-third of psychotropic drugs target one of the twelve-transmembrane-
region transporters for a neurotransmitter (A), while another third target seven-transmembrane-region receptors coupled to G proteins
(B). The sites of action for the remaining third of psychotropic drugs include enzymes (C), four-transmembrane-region ligand-gated ion
channels (D), and six-transmembrane-region voltage-sensitive ion channels (E).
of the membrane is required to allow discharge as well in common the structure of going in and out of the
as uptake of specific molecules to respond to the needs membrane 12 times (Figure 2-1A). These transporters
of cellular functioning. Good examples of this are are a type of receptor that binds to the neurotransmitter
neurotransmitters, which are released from neurons prior to transporting that neurotransmitter across the
during neurotransmission, and in many cases are also membrane.
transported back into presynaptic neurons as a recapture Recently, details of the structures of neurotransmitter
mechanism following their release. This recapture – or transporters have been determined and this has led
reuptake – is done in order for neurotransmitter to to a proposed subclassification of neurotransmitter
be reused in a subsequent neurotransmission. Also, transporters. That is, there are two major subclasses of
once inside the neuron, most neurotransmitters are plasma membrane transporters for neurotransmitters
transported again into synaptic vesicles for storage, (Tables 2-1 and 2-2). Some of these transporters are
protection from metabolism, and immediate use during a presynaptic and others are on glial membranes. The
volley of future neurotransmission. first subclass is comprised of sodium/chloride-coupled
Both types of neurotransmitter transport – transporters, called the solute carrier SLC6 gene
presynaptic reuptake as well as vesicular storage – utilize family, and includes transporters for the monoamines
a molecular transporter belonging to a “superfamily” serotonin, norepinephrine, and dopamine (Table 2-1 and
of 12-transmembrane-region proteins (Figures 2-1A Figure 2-2A) as well as for the neurotransmitter GABA
and 2-2). That is, neurotransmitter transporters have (γ-aminobutyric acid) and the amino acid glycine (Table
30
Chapter 2: Transporters, Receptors, and Enzymes
Table 2-1 Presynaptic monamine transporters
Transporter Common abbreviation Gene family Endogenous substrate False substrate

Serotonin transporter SERT SLC6 Serotonin Ecstasy (MDMA) 2
Norepinephrine transporter NET SLC6 Norepinephrine Dopamine
Epinephrine
Amphetamine
Dopamine transporter DAT SLC6 Dopamine Norepinephrine
Epinephrine
Amphetamine
MDMA = 3.4-methylenedioxymethamphetamine
Table 2-2 Neuronal and glial GABA and amino acid transporters
Transporter Common Gene Endogenous

abbreviation family substrate
GABA transporter 1 (neuronal and glial) GAT1 SLC6 GABA
GABA transporter 2 (neuronal and glial) GAT2 SLC6 GABA beta-alanine
GABA transporter 3 (mostly glial) GAT3 SLC6 GABA beta-alanine
GABA transporter 4 also called betaine transporter GAT4 SLC6 GABA betaine
(neuronal and glial) BGT1
Glycine transporter 1 (mostly glial) GlyT1 SLC6 Glycine
Glycine tranporter 2 (neuronal) GlyT2 SLC6 Glycine
Excitatory amino acid transporters 1–5 EAAT1–5 SLC1 L-glutamate
L-aspartate
2-2 and Figure 2-2A). The second subclass is comprised is, the unique presynaptic transporter for the monoamine
of high-affinity glutamate transporters, also called the serotonin is known as SERT, for norepinephrine is
solute carrier SLC1 gene family (Table 2-2 and Figure known as NET, and for dopamine, DAT (Table 2-1 and
2-2A). Figure 2-2A). All three of these monoamines are then
In addition, there are three subclasses of intracellular transported into synaptic vesicles of their respective
synaptic vesicle transporters for neurotransmitters: neurons by the same vesicular transporter, known
the SLC18 gene family comprised both of vesicular as VMAT2 (vesicular monoamine transporter 2)
monoamine transporters (VMATs) for serotonin, (Figure 2-2B and Table 2-3).
norepinephrine, dopamine, and histamine and the Although the presynaptic transporters for these three
vesicular acetylcholine transporter (VAChT); the SLC32 neurotransmitters – SERT, NET, and DAT – are unique
gene family and their vesicular inhibitory amino acid in their amino acid sequences and binding affinities for
transporters (VIAATs); and finally the SLC17 gene family monoamines, each presynaptic monoamine transporter
and their vesicular glutamate transporters, such as nevertheless has appreciable affinity for amines other
vGluT1–3 (Table 2-3 and Figure 2-2B). than the one matched to its own neuron (Table 2-1).
Thus, if other transportable neurotransmitters or drugs
Monoamine Transporters (SLC6 Gene Family) as are in the vicinity of a given monoamine transporter, they
Targets of Psychotropic Drugs may also be transported into the presynaptic neuron by
Reuptake mechanisms for monoamines utilize unique hitchhiking a ride on certain transporters that can carry
presynaptic transporters (Figure 2-2A) in each different them into the neuron.
monoamine neuron but the same vesicular transporter For example, the norepinephrine transporter NET
(Figure 2-2B) in the synaptic vesicle membranes of all has high affinity for the transport of dopamine as well as
three monoamine neurons plus histamine neurons. That for norepinephrine; the dopamine transporter DAT has
31
+ -
Na Cl
AT
+ -
Na Cl
VM
VMA
H+
T
proton pump
T
SER
SERT
AT
VM
VM
ATPase
AT
H+
H+
T
SER
SE
RT
VMAT2 VIAAT
+
K
vesicular monoamine transporter vesicular inhibitory
+ (5HT, NE, DA, HA) amino acid transporter
K
(GABA)
SERT GAT VAChT VGluT
serotonin transporter GABA transporter vesicular acetylcholine vesicular glutamate

transporter (ACh) transporter (glutamate)
Figure 2-2B Vesicular transporters. Vesicular transporters
NET GlyT package neurotransmitters into synaptic vesicles through the use
of a proton ATPase, or proton pump. The proton pump utilizes
energy to pump positively charged protons continuously out of
norepinephrine transporter glycine transporter the synaptic vesicle. Neurotransmitter can then be transported
into the synaptic vesicle, keeping the charge inside the vesicle
constant. Examples of vesicular transporters include the vesicular
monoamine transporter (VMAT2), which transports serotonin
DAT EAAT (5HT), norepinephrine (NE), dopamine (DA), and histamine (HA);
the vesicular acetylcholine transporter (VAChT), which transports
acetylcholine; the vesicular inhibitory amino acid transporter
dopamine transporter excitatory amino acid (VIAAT), which transports GABA; and the vesicular glutamate
transporter (VGluT), which transports glutamate.
transporter
Figure 2-2A Sodium–potassium ATPase. Transport of many
neurotransmitters into the presynaptic neuron is not passive,
but rather requires energy. This energy is supplied by sodium–
potassium ATPase, an enzyme that is also sometimes referred to high affinity for the transport of amphetamines as well as
as the sodium pump. Sodium–potassium ATPase continuously for dopamine; the serotonin transporter SERT has high
pumps sodium out of the neuron, creating a downhill
gradient. The “downhill” transport of sodium is coupled to affinity for the transport of “Ecstasy” (the drug of abuse
the “uphill” transport of the neurotransmitter. In many cases MDMA or 3,4-methylenedioxymethamphetamine) as
this also involves cotransport of chloride and in some cases
countertransport of potassium. Examples of neurotransmitter well as for serotonin (Table 2-1).
transporters include the serotonin transporter (SERT), the How are neurotransmitters transported? Monoamines
norepinephrine transporter (NET), the dopamine transporter
(DAT), the GABA transporter (GAT), the glycine transporter are not passively shuttled into the presynaptic neuron,
(GlyT), and the excitatory amino acid transporter (EAAT).
32
Table 2-3 Vesicular neurotransmitter transporters
Transporter Common abbreviation Gene family Endogenous substrate

Vesicular monoamine VMAT1 SLC18 Serotonin 2
transporters 1 and 2 VMAT2 Dopamine
Histamine
Norepinephrine
Vesicular acetylcholine transporter VAChT SLC18 Acetylcholine
Vesicular inhibitory VIAAT SLC32 GABA
amino acid transporter
Vesicular glutamate vGluT1–3 SLC17 Glutamate
transporters 1–3
because it requires energy to concentrate monoamines and in this case, there is binding of neither sodium
into a presynaptic neuron. That energy is provided nor monoamine. An example of this is shown for the
by transporters in the SLC6 gene family coupling the serotonin transporter SERT in Figure 2-2A where the
“downhill” transport of sodium (down a concentration transport “wagon” has flat tires indicating no binding
gradient) with the “uphill” transport of the monoamine of sodium, as well as absence of binding of serotonin
(up a concentration gradient) (Figure 2-2A). Thus, to its substrate binding site since the transporter has
the monoamine transporters are really sodium- low affinity for serotonin in the absence of sodium. The
dependent cotransporters; in most cases, this involves allosteric site for a drug that inhibits this transporter is
the additional cotransport of chloride, and in some also empty (the front seat in Figure 2-2A). However, in
cases the countertransport of potassium. All of this is Figure 2-2A in the presence of sodium ions, the tires are
made possible by coupling monoamine transport to now “inflated” by sodium binding and serotonin can
the activity of a sodium–potassium ATPase (adenosine now also bind to its substrate site on SERT. The situation
triphosphatase), an enzyme sometimes called the is now primed for serotonin transport back into the
“sodium pump” that creates the downhill gradient for serotonergic neuron, along with cotransport of sodium
sodium by continuously pumping sodium out of the and chloride down the gradient and into the neuron
neuron (Figure 2-2A). and countertransport of potassium out of the neuron
The structure of a monoamine neurotransmitter (Figure 2-2A). If a drug binds to an inhibitory allosteric
transporter from the SLC6 family has recently been site, namely the front seat on the SERT transporter wagon
proposed to have binding sites not only for the in Figure 2-2A (i.e., drugs such as the selective serotonin
monoamine, but also for two sodium ions (Figure 2-2A). reuptake inhibitor fluoxetine [Prozac]), this reduces the
In addition, these transporters may exist as dimers, affinity of the serotonin transporter SERT for its substrate
or two copies working together with each other, but serotonin, and serotonin binding is prevented.
the manner in which they cooperate is not yet well Why does this matter? Blocking the presynaptic
understood and is not shown in the figures. There monoamine transporter has a huge impact on
are other binding sites on this transporter – not well neurotransmission at any synapse that utilizes
defined – for several drugs such as the many selective that neurotransmitter. The normal recapture of
serotonin reuptake inhibitors (known as SSRIs) and neurotransmitter by the presynaptic neurotransmitter
other related agents used to treat unipolar depression. transporter in Figure 2-2A keeps the levels of this
When these drugs bind to the transporter, they inhibit neurotransmitter from accumulating in the synapse.
reuptake of monoamines. These drugs do not bind to the Normally, following release from the presynaptic
substrate site (where the monoamine itself binds to the neuron, neurotransmitters only have time for a brief
transporter) and are not transported into the neuron, and dance on their synaptic receptors, and the party is soon
thus are said to be allosteric (i.e., “other site”). over because the monoamines climb back into the
In the absence of sodium, there is low affinity of the presynaptic neuron on their transporters (Figure 2-2A).
monoamine transporter for its monoamine substrate, If one wants to enhance normal synaptic activity of
33
these neurotransmitters, or restore their diminished Other Neurotransmitter Transporters (SLC6 and SLC1
synaptic activity, this can be accomplished by blocking Gene Families) as Targets of Psychotropic Drugs
these transporters in Figure 2-2A. Although this In addition to the three transporters for monoamines
might not seem to be a very dramatic thing, the fact is discussed in detail above, there are several other
that this alteration in chemical neurotransmission – transporters for various different neurotransmitters or
namely the enhancement of synaptic monoamine their precursors. Although this includes a dozen additional
action – is thought to underlie the clinical effects of transporters, there is only one psychotropic drug used
all the agents that block monoamine transporters, clinically that is known to bind to any of these transporters.
including most drugs that treat ADHD (attention Thus, there is a presynaptic transporter for choline, the
deficit hyperactivity disorder). “Stimulants” for ADHD, precursor to the neurotransmitter acetylcholine, but no
such as methylphenidate and amphetamine, as well known drugs target this transporter. There are also several
as the drug of abuse cocaine, all act on DAT and NET. transporters for the ubiquitous inhibitory neurotransmitter
Also, most drugs that treat unipolar depression act GABA, known as GAT1–4 (Table 2-2). Although debate
at SERT, NET, DAT, or some combination of these continues about the exact localization of these subtypes
transporters. However, it is a misnomer to call these to presynaptic neurons, neighboring glia, or even
agents simply “antidepressants,” since they are not first- postsynaptic neurons, it is clear that a key presynaptic
line treatments for all forms of depression, and they are transporter of GABA is the GAT1 transporter, which is
used for many, many other indications in addition to selectively blocked by the anticonvulsant tiagabine, thereby
unipolar depression. Specifically, many drugs that block increasing synaptic GABA concentrations. In addition to
monoamine transporters are not only effective in the anticonvulsant actions, this increase in synaptic GABA
treatment of unipolar depression. They are also used to may have therapeutic actions in anxiety, sleep disorders,
treat many forms of anxiety, from generalized anxiety and pain. No other inhibitors of this transporter are
disorder to social anxiety disorder to panic disorder; for available for clinical use.
reducing neuropathic pain in fibromyalgia, postherpetic Finally, there are multiple transporters for two amino
neuralgia, diabetic peripheral neuropathic pain, and acid neurotransmitters, glycine and glutamate (Table
other pain conditions; for improving eating disorders, 2-2). There are no drugs utilized in clinical practice that
impulsive–compulsive disorders, obsessive–compulsive are known to block glycine transporters although new
disorder, and trauma- and stress-related disorders such agents are in clinical trials for treating schizophrenia
as posttraumatic stress disorder. They have additional and other disorders. The glycine transporters, along
therapeutic actions as well. Furthermore, some forms of with the choline and GABA transporters, are all
depression, notably bipolar depression and depression members of the SLC6 gene family, the same family to
with mixed features, are not treated first-line with drugs which the monoamine transporters belong and have a
that block monoamine transporters. No wonder we don’t similar structure (Figure 2-2A and Tables 2-1 and 2-2).
call agents that block monoamine transporters simply However, the glutamate transporters belong to a unique
“antidepressants” anymore! family, SLC1, and have a somewhat unique structure
Given the high prevalence of disorders that inhibitors and somewhat different functions compared to those
of monoamine transporters treat, it may come as no transporters of the SLC6 family (Table 2-2).
surprise that these drugs are among the most frequently Specifically, there are several transporters for
prescribed psychotropic drugs. In fact, some estimates glutamate, known as excitatory amino acid transporters
are that a monoamine transport inhibitor is prescribed 1–5 (EAAT1–5; Table 2-2). The exact localization of these
every second of every minute of every hour of every day various transporters to presynaptic neurons, postsynaptic
in the US alone (many millions of prescriptions a year)! neurons, or glia is still under investigation, but the uptake
Also, about a third of the currently prescribed essential of glutamate into glia is well known to be a key system
100 psychotropic drugs act by targeting one or more of for recapturing glutamate for re-use once it has been
the three monoamine transporters. Thus, the reader can released. Transport into glia results in conversion of
see why understanding monoamine transporters and how glutamate into glutamine, and then glutamine enters the
various drugs act at these transporters is so important presynaptic neuron for reconversion back into glutamate.
to grasping how one of the critical classes of agents in No drugs utilized in clinical practice are known to block
psychopharmacology works. glutamate transporters.
34
One difference between transport of neurotransmitters Figure 2-2B and Table 2-3). Finally, vesicular transporters
by the SLC6 gene family and transport of glutamate for glutamate, called vGluT1–3 (vesicular glutamate
by the SLC1 gene family is that glutamate does not transporters 1, 2, and 3), are members of the SLC17 gene 2
seem to cotransport chloride with sodium when it also family and are also shown in Figure 2-2B and listed in
cotransports glutamate. Also, glutamate transport is Table 2-3. A novel 12-transmembrane-region synaptic
almost always characterized by the countertransport of vesicle transporter of uncertain mechanism and with
potassium, whereas this is not always the case with SLC6 unclear substrates, called the SV2A transporter and
gene family transporters. Glutamate transporters may localized within the synaptic vesicle membrane, binds the
work together as trimers rather than dimers, as the SLC6 anticonvulsant levetiracetam, perhaps interfering with
transporters seem to do. The functional significance neurotransmitter release and thereby reducing seizures.
of these differences remains obscure, but may become How do neurotransmitters get inside synaptic
more apparent if clinically useful psychopharmacological vesicles? In the case of vesicular transporters, storage
agents that target glutamate transporters are discovered. of neurotransmitters is facilitated by a proton ATPase,
Since it may often be desirable to diminish rather than known as the “proton pump” that utilizes energy to
enhance glutamate neurotransmission, the future utility pump positively charged protons continuously out of the
of glutamate transporters as therapeutic targets is also synaptic vesicle (Figure 2-2B). The neurotransmitters can
unclear. then be concentrated against a gradient by substituting
their own positive charge inside the vesicle for the
Where Are the Transporters for Histamine and
positive charge of the proton being pumped out. Thus,
Neuropeptides?
neurotransmitters are not so much transported as they
It is an interesting observation that apparently not all are “antiported” – i.e., they go in while the protons
neurotransmitters are regulated by reuptake transporters. are actively transported out, keeping charge inside the
The central neurotransmitter histamine apparently does vesicle constant. This concept is shown in Figure 2-2B
not have a transporter for it presynaptically (although for the VMAT transporting dopamine, in exchange
it is transported into synaptic vesicles by VMAT2, for protons. Contrast this with Figure 2-2A where a
the same transporter used by the monoamines – see monoamine transporter on the presynaptic membrane
Figure 2-2B). Histamine’s inactivation is thus thought is cotransporting a monoamine along with sodium
to be entirely enzymatic. The same can be said for and chloride, but with the help of a sodium–potassium
neuropeptides, since reuptake pumps and presynaptic ATPase (sodium pump) rather than a proton pump.
transporters have not been found for them, and are thus
thought to be lacking for this class of neurotransmitter. Vesicular Transporters (SLC18 Gene Family) as Targets
Inactivation of neuropeptides is apparently by diffusion, of Psychotropic Drugs
sequestration, and enzymatic destruction, but not Vesicular transporters for acetylcholine (SLC18 gene
by presynaptic transport. It is always possible that a family), GABA (SLC32 gene family), and glutamate
transporter will be discovered in the future for some of (SLC17 gene family) are not known to be targeted
these neurotransmitters, but at the present time there are by any drug utilized by humans. However, vesicular
no known presynaptic transporters for either histamine transporters for monoamines in the SLC18 gene family
or neuropeptides. (VMATs), particularly those in dopamine neurons,
are targeted by several drugs, including amphetamine
Vesicular Transporters: Subtypes and Function
(as a transported substrate) and tetrabenazine and
Vesicular transporters for the monoamines (VMATs) its derivatives deutetrabenazine and valbenazine (as
are members of the SLC18 gene family and have already inhibitors, see Chapter 5) . Amphetamine thus has
been discussed above. They are shown in Figure 2-2B two targets: monoamine transporters discussed above
and listed in Table 2-3. The vesicular transporter for as well as VMATs discussed here. In contrast, other
acetylcholine – also a member of the SLC18 gene family drugs for ADHD, such as methylphenidate, and the
but known as VAChT – is shown in Figure 2-2B and so-called “stimulant” drug of abuse cocaine, target
listed in Table 2-3. The GABA vesicular transporter is a only the monoamine transporters, and in much the
member of the SLC32 gene family and is called VIAAT same manner as described for SSRIs at the serotonin
(vesicular inhibitory amino acid transporter; shown in transporter.
35
G-PROTEIN-LINKED RECEPTORS function of G-protein-linked receptors and their role

in signal transduction from specific neurotransmitters
Structure and Function
as described in Chapter 1 in order to understand how
Another major target of psychotropic drugs is the class drugs acting at G-protein-linked receptors modify the
of receptors linked to G proteins. These receptors all signal transduction that arises from these receptors.
have the structure of seven-transmembrane regions, This is important to understand because such drug-
meaning that they span the membrane seven times induced modifications in signal transduction from
(Figure 2-1). Each of the transmembrane regions G-protein-linked receptors can have profound actions on
clusters around a central core that contains a binding psychiatric symptoms. In fact, the single most common
site for a neurotransmitter. Drugs can interact at this action of psychotropic drugs utilized in clinical practice
neurotransmitter binding site or at other sites (allosteric is to modify the actions of one or more G-protein-linked
sites) on the receptor. This can lead to a wide range of receptors, resulting in either therapeutic actions or side
modifications of receptor actions due to mimicking effects. More than a dozen G-protein-linked receptors
or blocking, partially or fully, the neurotransmitter as targets of various drugs are discussed in the various
function that normally occurs at this receptor. Drug clinical chapters that follow. Here we will describe
actions at G-protein-linked receptors can thus change how various drugs stimulate or block these receptors
downstream molecular events – e.g., determining in general, and throughout the textbook we will show
which phosphoproteins are activated or inactivated and how particular drugs acting at specific G-protein-linked
therefore which enzymes, receptors, or ion channels receptors have unique actions on improving distinct
are modified by neurotransmission. Drug actions at psychiatric symptoms as well as causing characteristic
G-protein-linked receptors can also determine whether side effects.
a downstream gene is expressed or silenced, and thus
which proteins are synthesized and which neuronal G-Protein-Linked Receptors as Targets of Psychotropic
Drugs
functions are amplified, from synaptogenesis, to
receptor and enzyme synthesis, to communication with G-protein-linked receptors are a large superfamily of
downstream neurons innervated by the neuron with the receptors that interact with many neurotransmitters
G-protein-linked receptor. and with many psychotropic drugs (Figure 2-1B).
These actions on neurotransmission at G-protein- There are many ways to subtype these receptors,
linked receptors are described in detail in Chapter 1 on but pharmacological subtypes are perhaps the most
signal transduction and chemical neurotransmission. important to understand for clinicians who wish to target
The reader should have a good command of the specific receptors with psychotropic drugs utilized in
The Agonist Spectrum
antagonist
partial
agonist
agonist
inverse
agonist
Figure 2-3 Agonist spectrum. Shown here is the agonist spectrum. Naturally occurring neurotransmitters stimulate receptors and are
thus agonists. Some drugs also stimulate receptors and are therefore agonists as well. It is possible for drugs to stimulate receptors
to a lesser degree than the natural neurotransmitter; these are called partial agonists or stabilizers. It is a common misconception that
antagonists are the opposite of agonists because they block the actions of agonists. However, although antagonists prevent the actions
of agonists, they have no activity of their own in the absence of the agonist. For this reason, antagonists are sometimes called “silent.”
Inverse agonists, on the other hand, do have opposite actions compared to agonists. That is, they not only block agonists but can also
reduce activity below the baseline level when no agonist is present. Thus, the agonist spectrum reaches from full agonists to partial
agonists through to “silent” antagonists and finally inverse agonists.
36
No Agonist: Constitutive Activity Figure 2-4 Constitutive activity. The

absence of agonist does not mean that
there is no activity related to G-protein-
linked receptors. Rather, in the absence
of agonist, the receptor’s conformation 2
is such that it leads to a low level of
activity, or constitutive activity. Thus,
signal transduction still occurs, but
at a low frequency. Whether this
constitutive activity leads to detectable
E signal transduction is affected by the
receptor density in that brain region.
3 P
clinical practice. That is, the natural neurotransmitter number of receptors, it can still produce detectable signal
interacts at all of its receptor subtypes, but many drugs transduction output. This is represented as a small – but
are more selective than the neurotransmitter itself not absent – amount of signal transduction in Figure 2-4.
for just certain receptor subtypes and thus define a
Agonists
pharmacological subtype of receptor at which they
specifically interact. This is not unlike the concept of An agonist produces a conformational change in the
the neurotransmitter being a master key that opens G-protein-linked receptor that turns on the synthesis of
all the doors, and selective drugs that interact at second messenger to the greatest extent possible (i.e.,
pharmacologically specific receptor subtypes functioning the action of a full agonist) (Figure 2-5). The full agonist
as a specific key opening only one door. Here we will is generally represented by the naturally occurring
develop the concept that drugs have many ways of neurotransmitter itself, although some drugs can also
interacting at pharmacological subtypes of G-protein- act in as full a manner as the natural neurotransmitter
linked receptors, across what is called an “agonist itself. What this means from the perspective of chemical
spectrum” (Figure 2-3). neurotransmission is that the full array of downstream
signal transduction is triggered by a full agonist
No Agonist (Figure 2-5). Thus, downstream proteins are maximally
An important concept for the “agonist spectrum” is that phosphorylated, and genes are maximally impacted. Loss
the absence of agonist does not necessarily mean that of the agonist actions of a neurotransmitter at G-protein-
nothing at all is happening with signal transduction linked receptors, due to deficient neurotransmission of
at G-protein-linked receptors. Agonists are thought to any cause, would lead to the loss of this rich downstream
produce a conformational change in G-protein-linked chemical tour de force. Thus, agonists that restore this
receptors that leads to full receptor activation, and thus natural action would be potentially useful in states where
full signal transduction. In the absence of agonist, this reduced signal transduction leads to undesirable symptoms.
same conformational change may still be occurring at There are two major ways to stimulate G-protein-
some receptor systems, but only at very low frequency. linked receptors with full agonist action. Firstly, several
This is referred to as constitutive activity, which may be drugs directly bind to the neurotransmitter site on the
present especially in receptor systems and brain areas G-protein-linked receptor itself and can produce the
where there is a high density of receptors. Thus, when same full array of signal transduction effects as a full
something occurs at very low frequency but among a high agonist (see Table 2-4). These are called direct-acting
37
Full Agonist: Maximum Signal Transduction
agonist
E
P
3 P
P P
3 P
P P
3 P
P P
3 P
Figure 2-5 Full agonist: maximum signal transduction. When a full agonist binds to G-protein-linked receptors, it causes
conformational changes that lead to maximum signal transduction. Thus, all the downstream effects of signal transduction, such as
phosphorylation of proteins and gene activation, are maximized.
38
Table 2-4 Key G-protein-linked receptors directly targeted by psychotropic drugs
Neurotransmitter G-protein Pharmacological Therapeutic

receptor and action action 2
pharmacological
subtype directly
targeted
Dopamine D2 Antagonist or Antipsychotic; antimanic
partial agonist
Serotonin 5HT2A Antagonist or Antipsychotic actions in Parkinson’s disease
inverse agonist psychosis
Antipsychotic actions in dementia-related psychosis
Reduced drug-induced parkinsonism
Possible reduction of negative symptoms in
schizophrenia
Possible mood stabilizing and antidepressant
actions in bipolar disorder
Improve insomnia and anxiety
Agonist Psychotomimetic actions
Experimental treatment of refractory depression
and other disorders, especially accompanying
psychotherapy
5HT1B/1D Antagonist or Possible pro-cognitive and antidepressant actions
partial agonist
5HT2C Antagonist Antidepressant
5HT6 ? ?
5HT7 Antagonist Possible pro-cognitive and antidepressant actions
5HT1A Partial agonist Reduced drug-induced parkinsonism
Anxiolytic
Booster of antidepressant actions of SSRIs/SNRIs
Norepinephrine Alpha 2 Antagonist Antidepressant actions
Agonist Improved cognition and behavioral disturbance in
ADHD
Alpha 1 Antagonist Improved sleep (nightmares)
Improved agitation in Alzheimer disease
Side effects of orthostatic hypotension and possibly
sedation
GABA GABA-B Agonist Cataplexy
Sleepiness in narcolepsy
Possible enhanced slow-wave sleep
Pain reduction in chronic pain and fibromyalgia
Possible utility for alcohol use disorder and alcohol
withdrawal
Melatonin MT1 Agonist Improvement of insomnia and circadian rhythms
MT2 Agonist Improvement of insomnia and circadian rhythms
39
Table 2-4 (cont.)
Neurotransmitter G-protein Pharmacological Therapeutic

receptor and action action
pharmacological
subtype directly
targeted
Histamine H1 Antagonist Therapeutic effect for anxiety and insomnia
Side effect of sedation and weight gain
H3 Antagonist/ Improvement of daytime sleepiness
inverse agonist
Acetylcholine M1 Agonist Procognitive and antipsychotic
Antagonist Side effect of sedation and memory disturbance
M4 Agonist Antipsychotic
M2/3 Antagonist Dry mouth, blurred vision, constipation, urinary
retention
May contribute to metabolic dysregulation
(dyslipidemia and diabetes)
M5 ? ?
Orexin A, B Ox1,2 Antagonist Hypnotic for insomnia
Table 2-5 Key G-protein-linked receptors indirectly targeted by psychotropic drugs
Neurotransmitter G-protein receptor and Pharmacological action Therapeutic action

pharmacological subtype
indirectly targeted
Dopamine D1,2,3,4,5 agonist actions Dopamine reuptake Improvement of ADHD,
inhibition/release by depression, wakefulness
methylphenidate/
amphetamine
Serotonin 5HT1A agonist (presynaptic Serotonin reuptake Antidepressant,
somatodendritic inhibition by SSRIs/SNRIs anxiolytic
autoreceptors)
5HT2A agonist (postsynaptic
receptors; possibly 5HT1A,
5HT2C, 5HT6, 5HT7 postsynaptic
receptors)
5HT2A/2C agonist Serotonin release by MDMA “Empathogen” experimental
treatment of PTSD especially
with psychotherapy
Norepinephrine All norepinephrine receptors Norepinephrine reuptake Antidepressant; neuropathic
agonist inhibition pain; ADHD
Acetylcholine M1 (possibly M2–M5) Agonist via increasing Cognition in
acetylcholine itself at all Alzheimer disease
acetylcholine receptors
via acetylcholinesterase
inhibition
ADHD, attention deficit hyperactivity disorder; SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin norepinephrine reuptake inhibitors; PTSD,
posttraumatic stress disorder; MDMA, 3.4-methylenedioxymethamphetamine.
40
agonists. Secondly, many drugs can indirectly act to boost produce a conformational change in the G-protein-linked
the levels of the natural full agonist neurotransmitter receptor that causes no change in signal transduction –
itself (Table 2-5) and then this increased amount of including no change in whatever amount of any 2
natural agonist binds to the neurotransmitter site on “constitutive” activity that may have been present in the
the G-protein-linked receptor. Enhanced amounts of absence of agonist (compare Figure 2-4 with Figure 2-6).
full agonist happen when neurotransmitter inactivation Thus, true antagonists are “neutral” and, since they have
mechanisms are blocked. The most prominent examples no actions of their own, are also called “silent.”
of indirect full agonist actions have already been There are many more examples of important antagonists
discussed above, namely inhibition of the monoamine of G-protein-linked receptors than there are of direct-acting
transporters SERT, NET, and DAT and the GABA full agonists in clinical practice (see Table 2-4). Antagonists
transporter GAT1. Another way to accomplish indirect are well known both as the mediators of therapeutic actions
full agonist action is to block the enzymatic destruction in psychiatric disorders and as the cause of undesirable side
of neurotransmitters (Table 2-5). Two examples of this effects (Table 2-4). Some of these may prove to be inverse
are inhibition of the enzymes monoamine oxidase (MAO) agonists (see below), but most antagonists utilized in
and acetylcholinesterase which will be explained in more clinical practice are characterized simply as “antagonists.”
detail in later chapters. Antagonists block the actions of everything in
the agonist spectrum (Figure 2-3). In the presence
Antagonists
of an agonist, an antagonist will block the actions of
On the other hand, it also is possible that full agonist that agonist but do nothing itself (Figure 2-6). The
action can be too much of a good thing and that maximal antagonist simply returns the receptor conformation
activation of the signal transduction cascade may not back to the same state as exists when no agonist is
always be desirable, as in states of overstimulation by present (Figure 2-4). Interestingly, an antagonist will
neurotransmitters. In such cases, blocking the action of also block the actions of a partial agonist (explained
the natural neurotransmitter agonist may be desirable. below in more detail). Partial agonists are thought to
This is the property of an antagonist. Antagonists produce a conformational change in the G-protein-
“Silent” Antagonist: Back to Baseline, Figure 2-6 “Silent” antagonist. An

antagonist blocks agonists (both full
Constitutive Activity Only, Same as No Agonist and partial) from binding to G-protein-
linked receptors, thus preventing
agonists from causing maximum signal
transduction and instead changing
the receptor’s conformation back
antagonist to the same state as exists when no
agonist is present. Antagonists also
reverse the effects of inverse agonists,
again by blocking the inverse agonists
from binding and then returning the
receptor conformation to the baseline
GE
state. Antagonists do not have any
impact on signal transduction in the
absence of an agonist.
3 P
41
linked receptor that is intermediate between a full removes the baseline constitutive activity (Figure 2-9).
agonist and the baseline conformation of the receptor An antagonist reverses this back to the baseline state
in the absence of agonist (Figures 2-7 and 2-8). An that allows constitutive activity (Figure 2-6), the
antagonist reverses the action of a partial agonist by same as exists for the receptor in the absence of the
returning the G-protein-linked receptor to that same neurotransmitter agonist (Figure 2-4).
conformation as exists when no agonist is present By themselves, therefore, it is easy to see that true
(Figure 2-4). Finally, an antagonist reverses an inverse antagonists have no activity and why they are sometimes
agonist (also explained below in more detail). Inverse referred to as “silent.” Silent antagonists return the entire
agonists are thought to produce a conformational spectrum of drug-induced conformational changes in
state of the receptor that totally inactivates it and even the G-protein-linked receptor (Figures 2-3 and 2-10) to
Partial Agonist: Partially Enhanced Signal Transduction
partial
agonist
GE
P
3 P
P P
3 P
Figure 2-7 Partial agonist. Partial agonists stimulate G-protein-linked receptors to enhance signal transduction but do not lead to
maximum signal transduction the way full agonists do. Thus, in the absence of a full agonist, partial agonists increase signal transduction.
However, in the presence of a full agonist, the partial agonist will actually turn down the strength of various downstream signals. For this
reason, partial agonists are sometimes referred to as stabilizers.
42
the same place (Figure 2-6) – i.e., the conformation that stabilizes G-protein-linked receptor output somewhere
exists in the absence of agonist (Figure 2-4). between too much and too little downstream action. For
this reason, partial agonists are also called “stabilizers” 2
Partial Agonists
since they have the theoretical capacity to find a stable
It is possible to produce signal transduction that is solution between the extremes of too much full agonist
something more than an antagonist yet something less action and no agonist action at all (Figure 2-7).
than a full agonist. Turning down the gain a bit from full Since partial agonists exert an effect less than that
agonist actions, but not all the way to zero, is the property of a full agonist, they are also sometimes called “weak,”
of a partial agonist (Figure 2-7). This action can also be with the implication that partial agonism means partial
seen as turning up the gain a bit from silent antagonist clinical efficacy. That is certainly possible in some
actions, but not all the way to a full agonist. Depending cases, but it is more sophisticated to understand the
upon how close this partial agonist is to a full agonist potential stabilizing and “tuning” actions of this class
or to a silent antagonist on the agonist spectrum will of therapeutic agents, and not to use terms that imply
determine the impact of a partial agonist on downstream clinical actions for the entire class of drugs that may only
signal transduction events. apply to some individual agents. Several partial agonists
The amount of “partiality” that is desired between are utilized in clinical practice (Table 2-4) and more are
agonist and antagonist – that is, where a partial agonist in clinical development.
should sit on the agonist spectrum – is both a matter of
debate as well as trial and error. The ideal therapeutic Light and Dark as an Analogy for Partial Agonists
agent may have signal transduction through G-protein- It was originally conceived that a neurotransmitter could
linked receptors that is not too “hot,” yet not too “cold,” but only act at receptors like a light switch, turning things on
“just right,” sometimes called the “Goldilocks” solution when the neurotransmitter is present and turning things
(Figure 2-7). Such an ideal state may vary from one clinical off when the neurotransmitter is absent. We now know
situation to another, depending upon the balance between that many receptors, including the G-protein-linked
full agonism and silent antagonism that is desired. receptor family, can function rather more like a rheostat.
In cases where there is unstable neurotransmission That is, a full agonist will turn the lights all the way on
throughout the brain, such as when “out-of-tune” neurons (Figure 2-8A), but a partial agonist will only turn the
are theoretically mediating psychiatric symptoms, it may light on partially (Figure 2-8B). If neither full agonist nor
be desirable to find a state of signal transduction that partial agonist is present, the room is dark (Figure 2-8C).
FULL AGONIST -- PARTIAL AGONIST -- NO AGONIST --

light is at its brightest light is dimmed but still shining light is off
A B C
Figure 2-8 Agonist spectrum: rheostat. A useful analogy for the agonist spectrum is a light controlled by a rheostat. The light will be
brightest after a full agonist turns the light switch fully on (left panel). A partial agonist will also act as a net agonist and turn the light on,
but only partially, according to the level preset in the partial agonist’s rheostat (middle panel). If the light is already on, a partial agonist
will “dim” the lights, thus acting as a net antagonist. When no full or partial agonist is present, the situation is analogous to the light
being switched off (right panel).
43
Each partial agonist has its own set point engineered that are theoretically with an excess of full agonist. An
into the molecule, such that it cannot turn the lights on agent such as a partial agonist may even be able to treat
brighter even with a higher dose. No matter how much simultaneously states which are mixtures of both excess
partial agonist is given, only a certain degree of brightness and deficiency in neurotransmitter activity.
will result. A series of partial agonists will differ one from
Inverse Agonists
the other in the degree of partiality, so that theoretically
all degrees of brightness can be covered within the range Inverse agonists are more than simple antagonists, and
from “off ” to “on,” but each partial agonist has its own are neither neutral nor silent. These agents have an action
unique degree of brightness associated with it. that is thought to produce a conformational change in
What is so interesting about partial agonists is that the G-protein-linked receptor that stabilizes it in a totally
they can appear as a net agonist, or as a net antagonist, inactive form (Figure 2-9). Thus, this conformation produces
depending upon the amount of naturally occurring full a functional reduction in signal transduction (Figure 2-9)
agonist neurotransmitter that is present. Thus, when a full that is even less than that produced when there is either no
agonist neurotransmitter is absent, a partial agonist will be agonist present (Figure 2-4), or a silent antagonist present
a net agonist. That is, from the resting state, a partial agonist (Figure 2-6). The result of an inverse agonist is to shut
initiates somewhat of an increase in the signal transduction down even the constitutive activity of the G-protein-linked
cascade from the G-protein-linked second-messenger receptor system. Of course, if a given receptor system has
system. However, when full agonist neurotransmitter no constitutive activity, perhaps in cases when receptors are
is present, the same partial agonist will become a net present in low density, there will be no reduction in activity
antagonist. That is, it will decrease the level of full signal and the inverse agonist will look like an antagonist.
output to a lesser level, but not to zero. Thus, a partial In many ways, therefore, inverse agonists do the
agonist can simultaneously boost deficient neurotransmitter opposite of agonists. If an agonist increases signal
activity yet block excessive neurotransmitter activity, transduction from baseline, an inverse agonist decreases
another reason that partial agonists are called stabilizers. it, even below baseline levels. In contrast to agonists
Returning to the light-switch analogy, a room will and antagonists, therefore, an inverse agonist neither
be dark when agonist is missing and the light switch is increases signal transduction like an agonist (Figure 2-5)
off (Figure 2-8C). A room will be brightly lit when it is nor merely blocks the agonist from increasing signal
full of natural full agonist and the light switch is fully on transduction like an antagonist (Figure 2-6); rather,
(Figure 2-8A). Adding partial agonist to the dark room an inverse agonist binds the receptor in a fashion so
where there is no natural full agonist neurotransmitter as to provoke an action opposite to that of the agonist,
will turn the lights up, but only as far as the partial namely causing the receptor to decrease its baseline
agonist works on the rheostat (Figure 2-8B). Relative to signal transduction level (Figure 2-9). It is unclear from
the dark room as a starting point, a partial agonist acts
Inverse Agonist: Beyond Antagonism;
therefore as a net agonist. On the other hand, adding a Even the Constitutive Activity Is Blocked
partial agonist to the fully lit room will have the effect
of turning the lights down to the intermediate level of inverse
agonist
lower brightness on the rheostat (Figure 2-8B). This is a
net antagonistic effect relative to the fully lit room. Thus,
after adding partial agonist to the dark room and to the
brightly lit room, both rooms will be equally lit. The E
degree of brightness is that of being partially turned on as
dictated by the properties of the partial agonist. However, 2
in the dark room, the partial agonist has acted as a net

agonist, whereas in the brightly lit room, the partial Figure 2-9 Inverse agonist. Inverse agonists produce
conformational change in the G-protein-linked receptor that
agonist has acted as a net antagonist. renders it inactive. This leads to reduced signal transduction
Having an agonist and an antagonist in the as compared not only to that associated with agonists but also
that associated with antagonists or the absence of an agonist.
same molecule is quite an interesting dimension to The impact of an inverse agonist is dependent on the receptor
therapeutics. This concept has led to proposals that density in that brain region. That is, if the receptor density is so
low that constitutive activity does not lead to detectable signal
partial agonists could treat not only states which are transduction, then reducing the constitutive activity would not
theoretically deficient in full agonist, but also states have any appreciable effect.
44
a clinical point of view what the relevant differences are ENZYMES AS SITES OF
between an inverse agonist and a silent antagonist. In PSYCHOPHARMACOLOGICAL
fact, some drugs that have long been considered to be
silent antagonists, such as serotonin 2A antagonists and
DRUG ACTION 2
histamine 1 antagonists/antihistamines, may turn out in Enzymes are involved in multiple aspects of chemical
some areas of the brain actually to be inverse agonists. neurotransmission, as discussed extensively in Chapter
Thus, the concept of an inverse agonist as clinically 1 on signal transduction. Every enzyme is the theoretical
distinguishable from a silent antagonist is still evolving target for a drug acting as an enzyme inhibitor. However,
and the clinical differentiation between antagonist and in practice, only a minority of currently known drugs
inverse agonist remains to be clarified. utilized in the clinical practice of psychopharmacology
In summary, G-protein-linked receptors act along an are enzyme inhibitors.
agonist spectrum, and drugs have been described that Enzyme activity is the conversion of one molecule
can produce conformational changes in these receptors into another, namely a substrate into a product (Figure
to create any state from full agonist, to partial agonist, to 2-11). The substrates for each enzyme are very unique
silent antagonist, to inverse agonist (Figure 2-10). When and selective, as are the products. A substrate (Figure
one considers the spectrum of signal transduction along 2-11A) comes to the enzyme to bind at the enzyme’s
this spectrum (Figure 2-10), it is easy to understand why active site (Figure 2-11B), and departs as a changed
agents at each point along the agonist spectrum differ so molecular entity called the product (Figure 2-11C).
much from each other, and why their clinical actions are The inhibitors of an enzyme are also very unique and
so different. selective for one enzyme compared to another. In the
Agonist Spectrum
no agonist or silent antagonist
partial
agonist
GE G inverse
2 2 agonist
agonist GE P
3 3
P
P
GE
GE
3
3
P
Figure 2-10 Agonist spectrum. This figure summarizes the implications of the agonist spectrum. Full agonists cause maximum signal
transduction, while partial agonists increase signal transduction compared to no agonist but decrease it compared to full agonist.
Antagonists lead to constitutive activity and thus, in the absence of an agonist, have no effects; in the presence of an agonist, they
lead to reduced signal transduction. Inverse agonists are the functional opposites of agonists and actually reduce signal transduction
beyond that produced in the absence of an agonist.
45
presence of an enzyme inhibitor, the enzyme cannot bind by the substrate (Figure 2-12B). The irreversible type of
to its substrates. The binding of inhibitors can be either enzyme inhibitor is sometimes called a “suicide inhibitor”
irreversible (Figure 2-12) or reversible (Figure 2-13). because it covalently and irreversibly binds to the enzyme
When an irreversible inhibitor binds to the enzyme, it protein, permanently inhibiting it and therefore essentially
cannot be displaced by the substrate; thus, that inhibitor “killing” it by thus making the enzyme nonfunctional
binds irreversibly (Figure 2-12). This is depicted as binding forever (Figure 2-12). Enzyme activity in this case is only
with chains (Figure 2-12A) that cannot be cut with scissors restored when new enzyme molecules are synthesized.
After a Substrate Binds to an Enzyme, It Is Figure 2-11 Enzyme activity. Enzyme

Turned into a Product Which is Then Released activity is conversion of one molecule
into another. Thus, a substrate is said to
from the Enzyme. be turned into a product by enzymatic
modification of the substrate molecule.
The enzyme has an active site at which
the substrate can bind specifically (A).
The substrate then finds the active site
of the enzyme and binds to it (B) so
that a molecular transformation can
occur, changing the substrate into the
product (C).
E E E
A B C
Irreversible Substrate Irreversible

inhibitor inhibitor
A B
Figure 2-12 Irreversible enzyme inhibitors. Some drugs are inhibitors of enzymes. Shown here is an irreversible inhibitor of an enzyme,
depicted as binding to the enzyme with chains (A). A competing substrate cannot remove an irreversible inhibitor from the enzyme,
depicted as scissors unsuccessfully attempting to cut the chains off the inhibitor (B). The binding is locked so permanently that such
irreversible enzyme inhibition is sometimes called the work of a “suicide inhibitor,” since the enzyme essentially commits suicide by binding
to the irreversible inhibitor. Enzyme activity cannot be restored unless another molecule of enzyme is synthesized by the cell’s DNA.
46
However, in the case of reversible enzyme inhibitors, the substrate or the inhibitor “wins” or predominates
an enzyme’s substrate is able to compete with that depends upon which one has the greater affinity for the
reversible inhibitor for binding to the enzyme, and enzyme and/or is present in the greater concentration. 2
literally shove it off the enzyme (Figure 2-13). Whether Such binding is called “reversible.” Reversible enzyme
Substrate
Reversible Reversible
inhibitor inhibitor
A B
Reversible
inhibitor
Substrate
C
Figure 2-13 Reversible enzyme inhibitors. Other drugs are reversible enzyme inhibitors, depicted as binding to the enzyme with a
string (A). A reversible inhibitor can be challenged by a competing substrate for the same enzyme. In the case of a reversible inhibitor,
the molecular properties of the substrate are such that it can get rid of the reversible inhibitor, depicted as scissors cutting the string
that binds the reversible inhibitor to the enzyme (B). The consequence of a substrate competing successfully for reversal of enzyme
inhibition is that the substrate displaces the inhibitor and shoves it off (C). Because the substrate has this capability, the inhibition is said
to be reversible.
47
inhibition is depicted as binding with strings (Figure important enzyme in the signal transduction
2-13A), such that the substrate can cut them with pathway of neurotrophic factors (Figure 2-14). That
scissors (Figure 2-13B) and displace the enzyme is, some neurotrophins, growth factors, and other
inhibitor, and bind the enzyme itself with its own strings signaling pathways act through a specific downstream
(Figure 2-13C). phosphoprotein, an enzyme called GSK-3 (glycogen
These concepts can be applied potentially to any synthase kinase), to promote cell death (so-called
enzyme system. Several enzymes are involved in proapoptotic actions). Lithium has the capacity to
neurotransmission, including in the synthesis and inhibit this enzyme (Figure 2-14B). It is possible
destruction of neurotransmitters, as well as in signal that inhibition of GSK-3 is physiologically relevant,
transduction. Only a few enzymes are known to be because this action could lead to neuroprotective
targeted by psychotropic drugs currently used in actions, long-term plasticity, and may contribute to
clinical practice, namely monoamine oxidase (MAO), the antimanic and mood-stabilizing actions known to
acetylcholinesterase, and glycogen synthase kinase be associated with lithium. It is also possible that the
(GSK). MAO inhibitors are discussed in more detail antimanic agent valproate and the neurostimulatory
in Chapter 7 on treatments for mood disorders and treatment for depression ECT (electroconvulsive
acetylcholinesterase inhibitors are discussed in more therapy) may have actions on GSK-3 as well (Figure
detail in Chapter 12 on dementia. Briefly, regarding 2-14B). The development of novel GSK-3 inhibitors is
GSK, the antimanic agent lithium may target this in progress.
GSK-3 (Glycogen Synthase Kinase):

Possible Target for Lithium and Other Mood Stabilizers
insulin
insulin
IGF-1 Wnt
IGF-1 Wnt neurotrophin
neurotrophin glycoproteins glycoproteins
membrane
lithium
? valproate
P P
? ECT
GSK-3 GSK-3
proapoptotic
neuroprotective
long-term plasticity
antimanic / mood stabilizer
Figure 2-14 Receptor tyrosine kinases. Receptor tyrosine kinases are potential targets for novel psychotropic drugs. Left: Some
neurotrophins, growth factors, and other signaling pathways act through a downstream phosphoprotein, an enzyme called GSK-3
(glycogen synthase kinase), to promote cell death (proapoptotic actions). Right: Lithium and possibly some other mood stabilizers
may inhibit this enzyme, which could lead to neuroprotective actions and long-term plasticity as well as possibly contribute to mood-
stabilizing actions.
48
CYTOCHROME P450 DRUG metabolism are shown in Figure 2-16. There are over
METABOLIZING ENZYMES AS 30 known CYP450 enzymes, and probably many more
awaiting discovery and classification. Not all individuals
TARGETS OF PSYCHOTROPIC have all the same genetic form of the CYP450 enzymes
2
DRUGS and types of enzyme for any individual can now be
Pharmacokinetic actions are mediated through the readily determined with pharmacogenetic testing.
hepatic and gut drug metabolizing system known These enzymes are collectively responsible for the
as the cytochrome P450 (CYP450) enzyme system. degradation of a large number of psychotropic drugs,
Pharmacokinetics is the study of how the body acts and variations in the genes encoding for the different
upon drugs, especially to absorb, distribute, metabolize, CYP450 enzymes can alter the activity of these enzymes,
and excrete them. The CYP450 enzymes and the resulting in alterations of drug levels at standard doses.
pharmacokinetic actions they represent must be contrasted Most individuals have “normal” rates of drug metabolism
with the pharmacodynamic actions of drugs, the latter from the major CYP450 enzymes and are said to be
being the major emphasis of this book. Pharmacodynamic “extensive metabolizers”; most drug doses are set for
actions at the specific drug targets discussed earlier these individuals. However, some individuals have
in this chapter and also in Chapter 3 are known as the genetic variants of these enzymes and may be either
mechanism of action of psychotropic drugs, and account intermediate metabolizers or poor metabolizers, with
for the therapeutic effects and side effects of drugs. reduced enzyme activity that can result in increased risk
However, most psychotropic drugs also target the CYP450 for elevated drug levels, drug–drug interactions, and
drug metabolizing enzymes either as a substrate, inhibitor,
and/or inducer, and a brief overview of these enzymes and gut bloodstream
their interactions with psychotropic drugs is in order. drug
unchanged
CYP450 enzymes follow the same principles of drug
enzymes transforming substrates into products as
illustrated in Figures 2-11 through 2-13. Figure 2-15 biotransformed
depicts the concept of a psychotropic drug being drug
absorbed through the gut wall on the left and then sent
to the big blue enzyme in the liver to be biotransformed
so that the drug can be sent back into the bloodstream
to be excreted from the body via the kidney. Specifically,
CYP450 enzymes in the gut wall or liver convert the
CYP450
drug substrate into a biotransformed product in the
bloodstream. After passing through the gut wall and
liver, the drug will exist partially as unchanged drug and Figure 2-15 CYP450. The cytochrome P450 (CYP450) enzyme
system mediates how the body metabolizes many drugs,
partially as biotransformed product in the bloodstream including antipsychotics. The CYP450 enzyme in the gut wall
(Figure 2-15). or liver converts the drug into a biotransformed product in
the bloodstream. After passing through the gut wall and liver
There are several known CYP450 systems. Six of (left), the drug will exist partly as unchanged drug and partly as
the most important enzymes for psychotropic drug biotransformed drug (right).
Figure 2-16 Six CYP450

enzymes. There are many cytochrome
P450 (CYP450) systems; these are
classified according to family, subtype,
and gene product. Five of the most
important are shown here, and include
1A2 2B6 2D6 2C9 2C19 3A4 CYP450 1A2, 2B6, 2D6, 2C9, 2C19,
and 3A4.
1 = family
A = subtype
1 = gene product
49
reduced amounts of active metabolites. Such patients may for serotonin, NET for norepinephrine, and DAT for
require less than standard doses of drugs metabolized dopamine) are key targets for most of the known drugs
by their variant CYP450 enzymes. On the other hand, that treat unipolar depression, ADHD, and numerous
some patients can also be ultra-rapid metabolizers, with other disorders ranging from anxiety to pain. The
elevated enzyme activity, subtherapeutic drug levels, vesicular transporter for all three of these monoamines
and poor efficacy with standard doses. When genetic is known as VMAT2 (vesicular monoamine transporter
variations are unknown, it can lead to altered efficacy 2), which not only stores monoamines and histamine in
and side effects of psychotropic drugs. Since the genes for synaptic vesicles, but is also inhibited by drugs recently
these CYP450 enzymes can now be readily measured and introduced to treat movement disorders such as tardive
used to predict which patients might need to have dosage dyskinesia.
adjustments of certain drugs up or down, the practice G-protein receptors are the most common targets of
of psychopharmacology is increasingly moving to the psychotropic drugs, and their actions can lead to both
measurement of genes for drug metabolism, especially in therapeutic effects and side effects. Drug actions at
patients who do not respond or do not tolerate standard these receptors occur in a spectrum, from full agonist
doses of psychotropic drugs. This is called genotyping actions, to partial agonist actions, to antagonism, and
the patient for pharmacogenomic use. Sometimes it even to inverse agonism. Natural neurotransmitters
is useful to couple genotyping with therapeutic drug are full agonists, and so are some drugs used in clinical
monitoring that can detect the actual levels of drug in practice. However, most drugs that act directly on
the blood and thus confirm the predictions from genetic G-protein-linked receptors act as antagonists. A few act
testing of which CYP450 enzyme type has been shown as partial agonists, and some as inverse agonists. Each
to be present. The use of pharmacogenomic testing drug interacting at a G-protein-linked receptor causes
in combination with therapeutic drug monitoring a conformational change in that receptor that defines
(sometimes also called phenotyping) can help in the where on the agonist spectrum it will act. Thus, a full
management particularly of treatment-resistant patients. agonist produces a conformational change that turns on
Drug interactions mediated by CYP450 enzymes and signal transduction and second-messenger formation
their genetic variants are constantly being discovered, to the maximum extent. One novel concept is that of a
and the active clinician who combines drugs must be partial agonist, which acts somewhat like an agonist, but
alert to these, and thus be continually updated on what to a lesser extent. An antagonist causes a conformational
drug interactions are important. Here we present only change that stabilizes the receptor in the baseline state
the general concepts of drug interactions at CYP450 and thus is “silent.” In the presence of agonists or partial
enzyme systems, but the specifics should be found in a agonists, an antagonist causes the receptor to return to
comprehensive and up-to-date comprehensive reference this baseline state as well, and thus reverses their actions.
source (such as Stahl’s Essential Psychopharmacology: the A novel receptor action is that of an inverse agonist,
Prescriber’s Guide, a companion to this textbook) before which leads to a conformation of the receptor that stops
prescribing. all activity, even baseline actions. Understanding the
agonist spectrum can lead to prediction of downstream
consequences on signal transduction, including clinical
SUMMARY actions.
Nearly a third of psychotropic drugs in clinical practice Finally, a minority of psychotropic drugs target
bind to a neurotransmitter transporter, and another third enyzmes for their therapeutic effects. Several enzymes are
of psychotropic drugs bind to G-protein-linked receptors. involved in neurotransmission, including in the synthesis
These two molecular sites of action, their impact upon and destruction of neurotransmitters as well as in signal
neurotransmission, and various specific drugs that act at transduction, but in practice only three are known to
these sites have all been reviewed in this chapter. be targeted by psychotropic drugs. A larger portion
Specifically, there are two subclasses of plasma of psychotropic drugs target the cytochrome P450
membrane transporters for neurotransmitters and three drug metabolizing enzymes, which is relevant to their
subclasses of intracellular synaptic vesicle transporters for pharmacokinetic profiles but not their pharmacodynamic
neurotransmitters. The monoamine transporters (SERT profiles.
50
3 Ion Channels as Targets
of Psychopharmacological
Drug Action
Ligand-Gated Ion Channels as Targets of Different States of Ligand-Gated Ion Channels 63
Psychopharmacological Drug Action 51 Allosteric Modulation: PAMs and NAMs 64
Ligand-Gated Ion Channels, Ionotropic Receptors, Voltage-Sensitive Ion Channels as Targets of
and Ion-Channel-Linked Receptors 51 Psychopharmacological Drug Action 66
Ligand-Gated Ion Channels: Structure and Structure and Function 66
Function 53 VSSCs (Voltage-Sensitive Sodium Channels) 67
Pentameric Subtypes 53 VSCCs (Voltage-Sensitive Calcium Channels) 70
Tetrameric Subtypes 54 Ion Channels and Neurotransmission 73
The Agonist Spectrum 56 Summary 76
Many important psychopharmacological drugs target ion ligand-gated ion channels, ionotropic receptors, and
channels. The role of ion channels as important regulators ion-channel-linked receptors. These channels and their
of synaptic neurotransmission has been covered in associated receptors will be discussed next. The other
Chapter 1. Here we discuss how targeting these molecular major class of ion channel is opened by the charge or
sites causes alterations in synaptic neurotransmission that voltage across the membrane and is called either a
are linked in turn to the therapeutic actions of various voltage-gated or a voltage-sensitive ion channel, and these
psychotropic drugs. Specifically, we will cover ligand- will be discussed later in this chapter.
gated ion channels and voltage-sensitive ion channels as Ion channels that are opened and closed by actions
targets of psychopharmacological drug action. of neurotransmitter ligands at receptors acting as
gatekeepers are shown conceptually in Figure 3-1. When a
LIGAND-GATED ION neurotransmitter binds to a gatekeeper receptor on an ion
CHANNELS AS TARGETS OF channel, that neurotransmitter causes a conformational
PSYCHOPHARMACOLOGICAL change in the receptor that opens the ion channel (Figure
DRUG ACTION 3-1A). A neurotransmitter, drug, or hormone that binds to
a receptor is sometimes called a ligand (literally, “tying”).
Ligand-Gated Ion Channels, Ionotropic Receptors, and
Thus, ion channels linked to receptors that regulate their
Ion-Channel-Linked Receptors
opening and closing are often called ligand-gated ion
The terms ligand-gated ion channels, ionotropic receptors, channels. Since these ion channels are also receptors,
and ion-channel-linked receptors are in fact different they are also sometimes also called ionotropic receptors
terms for the same receptor/ion-channel complex. Ions or ion-channel linked receptors. These terms will be used
normally cannot penetrate membranes because of their interchangeably with ligand-gated ion channels here.
charge. In order to selectively control access of ions into Numerous drugs act at many sites around such
and out of neurons, their membranes are decorated with receptor/ion-channel complexes, leading to a wide
all sorts of ion channels. The most important ion channels variety of modifications of receptor/ion-channel actions.
in psychopharmacology regulate calcium, sodium, These modifications not only immediately alter the
chloride, and potassium. Many can be modified by various flow of ions through the channels, but with a delay can
drugs, and this will be discussed throughout this chapter. also change the downstream events that result from
There are two major classes of ion channels, and transduction of the signal that begins at these receptors.
each class has several names. One class of ion channels The downstream actions have been extensively discussed
is opened by neurotransmitters and goes by the names in Chapter 1 and include both activation and inactivation
51
Figure 3-1 Ligand-gated ion-channel

gatekeeper. This schematic shows a
ligand-gated ion channel. In panel A,
a receptor is serving as a molecular
gatekeeper that acts on instruction
ENTER from neurotransmission to open the
channel and allow ions to travel into
the cell. In panel B, the gatekeeper is
keeping the channel closed so that
ions cannot get into the cell. Ligand-
gated ion channels are a type of
receptor that forms an ion channel and
are thus also called ion-channel-linked
receptors or ionotropic receptors.
A
EN NO
Y
TR
52
Chapter 3: Ion Channels
of phosphoproteins, shifting the activity of enzymes, are also multiple binding sites for everything from
the sensitivity of receptors, and the conductivity of ion neurotransmitters to ions to drugs. That is, these
channels. Other downstream actions include changes complex proteins have several sites where some ions
in gene expression and thus changes in which proteins travel through a channel and others also bind to the
are synthesized and which functions are amplified. Such channel; where one neurotransmitter or even two
functions can range from synaptogenesis, to receptor and cotransmitters act at separate and distinct binding sites;
enzyme synthesis, to communication with downstream where numerous allosteric modulators – i.e., natural
3
neurons innervated by the neuron with the ionotropic substances or drugs that bind to a site different than
receptor, and many more. The reader should have a good where the neurotransmitter binds – increase or decrease
command of the function of signal transduction pathways the sensitivity of channel opening.
described in Chapter 1 in order to understand how drugs
Pentameric Subtypes
acting at ligand-gated ion channels modify the signal
transduction that arises from these receptors. Many ligand-gated ion channels are assembled from
Drug-induced modifications in signal transduction five protein subunits, and that is why they are called
from ionotropic (sometimes called ionotrophic) receptors pentameric. The subunits for pentameric subtypes of
can have profound actions on psychiatric symptoms. ligand-gated ion channels each have four transmembrane
About a fifth of psychotropic drugs currently utilized in regions (Figure 3-2A). These membrane proteins go in
clinical practice, including many drugs for the treatment and out of the membrane four times (Figure 3-2A). When
of anxiety and insomnia such as the benzodiazepines, five copies of these subunits are selected (Figure 3-2B),
are known to act at these receptors. Because ionotropic they come together in space to form a fully functional
receptors immediately change the flow of ions, drugs pentameric receptor with the ion channel in the middle
that act on these receptors can have an almost immediate (Figure 3-2C). The receptor sites are in various locations
effect, which is why many drugs for anxiety and for sleep on each of the subunits; some binding sites are in the
that act at these receptors may have immediate clinical channel, but many are present at different locations
onset. This is in contrast to the actions of many drugs at outside the channel. This pentameric structure is typical
G-protein-linked receptors described in Chapter 2, some for GABAA receptors, nicotinic cholinergic receptors,
of which have clinical effects – such as actions on mood – serotonin 5HT3 receptors, and certain glycine receptors
that may occur with a delay necessitated by awaiting (Table 3-1). Drugs that act directly on pentameric ligand-
initiation of changes in cellular functions activated gated ion channels are listed in Table 3-2.
through the signal transduction cascade. Here we will If this structure were not complicated enough,
describe how various drugs stimulate or block various pentameric ionotropic receptors actually have many
molecular sites around the receptor/ion-channel complex. different subtypes. Subtypes of pentameric ionotropic
Throughout the textbook we will show how specific receptors are defined based upon which forms of each
drugs acting at specific ionotropic receptors have specific of the five subunits are chosen for assembly into a fully
actions on specific psychiatric disorders.
Ligand-Gated Ion Channels: Structure and Function
Table 3-1 Pentameric ligand-gated ion channels
Are ligand-gated ion channels receptors or ion channels?
The answer is “yes” – ligand-gated ion channels are both Four transmembrane regions
Five subunits
a type of receptor and they also form an ion channel. That
is why they are called not only a channel (ligand-gated Neurotransmitter Receptor subtype
ion channel) but also a receptor (ionotropic receptor and Acetylcholine Nicotinic receptors
ion-channel-linked receptor). These terms try to capture (e.g. α7 nicotinic receptors;
the dual function of these ion channels/receptors and α4β2 nicotinic receptors)
may explain why there is more than one term for this GABA GABAA receptors (e.g. α1
receptor/ion-channel complex. subunits; γ subunits; δ subunits)
Ligand-gated ion channels are comprised of several Glycine Strychnine-sensitive glycine
long strings of amino acids assembled as subunits receptors
around an ion channel. Decorated on these subunits
Serotonin 5HT3 receptors
53
Figure 3-2 Ligand-gated ion channel

structure. The four transmembrane
regions of a single subunit of a
pentameric ligand-gated ion channel
form a cluster, as shown in panel A.
An icon for this subunit is shown on
= the right in panel A. Five copies of the
subunits come together in space (panel
B) to form a functional ion channel in
the middle (panel C). Ligand-gated ion
channels have receptor binding sites
A located on all five subunits, both inside
and outside the channel.
constituted receptor. That is, there are several subtypes Tetrameric Subtypes
for each of the four transmembrane subunits, making it Ionotropic glutamate receptors have a different
possible to piece together several different constellations structure from the pentameric ionotropic receptors
of fully constituted receptors. Although the natural just discussed. The ligand-gated ion channels for
neurotransmitter binds to every subtype of ionotropic glutamate are comprised of subunits that have three full
receptor, some drugs used in clinical practice, and many transmembrane regions and a fourth re-entrant loop
more in clinical trials, are able to bind selectively to (Figure 3-3A), rather than four full transmembrane
one or more of these subtypes, but not to others. This regions as shown in Figure 3-2A. When four copies of
may have functional and clinical consequences. Specific these subunits are selected (Figure 3-3B), they come
receptor subtypes and the specific drugs that bind to together in space to form a fully functional ion channel
them selectively are discussed in chapters that cover their in the middle with the four re-entrant loops lining the
specific clinical use. ion channel (Figure 3-3C). Thus, tetrameric subtypes of
54
Table 3-2 Key ligand-gated ion channels directly targeted by psychotropic drugs
Neurotransmitter Ligand-gated ion Pharmacological Drug class Therapeutic

channel receptor action action
subtype directly
targeted
Acetylcholine Alpha4 Beta2 Partial agonist Nicotinic receptor Smoking cessation
nicotinic partial agonist (NRPA) 3
(varenicline)
GABA GABAA Full agonist, Benzodiazepines Anxiolytic
benzodiazepine phasic inhibition
receptors
GABAA non- Full agonist, “Z DRUGS”/hypnotics Improves insomnia
benzodiazepine phasic inhibition (zolpidem, zaleplon,
PAM sites zopiclone, eszopiclone)
GABAA neurosteroid Full agonist, Neuroactive steroids Postpartum depression
sites tonic inhibition (allopregnanolone) Rapid-acting
(benzodiazepine antidepressant
insensitive) Anesthetic
Glutamate NMDA Antagonist NMDA glutamate Pro-cognitive in
NAM channel sites/ antagonist (memantine) Alzheimer disease
Mg++ sites
NMDA open- Antagonist PCP/phencyclidine Dissociative
channel sites Ketamine hallucinogen
Dextromethorphan Anesthetic
Dextromethadone Pseudobulbar affect
Agitation in Alzheimer
disease
Rapid-acting
antidepressant
Treatment-resistant
depression
Serotonin 5HT3 Antagonist Mirtazapine Pro-cognitive
Vortioxetine Antidepressant
5HT3 Antagonist Anti-emetic Reduce
chemotherapy-
induced emesis
PAM, positive allosteric modulator; NAM, negative allosteric modulator; NMDA, N-methyl-D-aspartate; Mg, magnesium.
ion channels (Figure 3-3) are analogous to pentameric and NMDA (N-methyl-D-aspartate) subtypes (Table 3-3).
subtypes of ion channels (Figure 3-2A), but just have four Drugs that act directly at tetrameric ionotropic glutamate
subunits rather than five. Receptor sites are in various receptors are listed in Table 3-2. Receptor subtypes for
locations on each of the subunits; some binding sites are glutamate according to the selective agonist acting at that
in the channel, but many are present at different locations receptor as well as the specific molecular subunits that
outside the channel. comprise that subtype are listed in Table 3-3. Subtype
This tetrameric structure is typical of the ionotropic selective drugs for ionotropic glutamate receptors are
glutamate receptors known as AMPA (α-amino-3- under investigation but not currently used in clinical
hydroxy-5-methyl-4-isoxazole-propionic acid), kainate, practice.
55
Table 3-3 Tetrameric ligand-gated ion channels The Agonist Spectrum
Three transmembrane regions and one re-entrant The concept of an agonist spectrum for G-protein-linked
loop receptors discussed extensively in Chapter 2 can also be
Four subunits applied to ligand-gated ion channels (Figure 3-4). Thus,
Neurotransmitter Receptor subtype full agonists change the conformation of the receptor to
open the ion channel the maximal frequency allowed
Glutamate AMPA (e.g. GluR1–4 subunits)
by that binding site (Figure 3-5). This then triggers the
KAINATE (e.g. GluR5–7, maximal amount of downstream signal transduction
KA1–2 subunits)
possible to be mediated by this binding site. The ion
NMDA (e.g. NMDAR1, channel can open to an even greater extent (i.e., more
NMDAR2A–D, NMDAR3A frequently) than with a full agonist alone, but this requires
subunits) the help of a second receptor site, that of a positive
AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; NMDA, N-methyl-D-aspartate.
allosteric modulator (PAM) as will be shown later.
Figure 3-3 Tetrameric ligand-gated ion

channel structure. A single subunit of a
tetrameric ligand-gated ion channel is
shown to form a cluster in panel A, with
an icon for this subunit shown on the
= right in panel A. Four copies of these
subunits come together in space (panel
B) to form a functional ion channel in
the middle (panel C). Ligand-gated ion
channels have receptor binding sites
A located on all four subunits, both inside
and outside the channel.
56
The Agonist Spectrum Antagonists stabilize the receptor in the resting state
(Figure 3-6B), which is the same as the state of the
antagonist receptor in the absence of agonist (Figure 3-6A). Since
partial
agonist there is no difference between the presence and absence
of the antagonist, the antagonist is said to be neutral or
agonist
silent. The resting state is not a fully closed ion channel,
inverse so there is some degree of ion flow through the channel
agonist 3
even in the absence of agonist (Figure 3-6A) and even
in the presence of antagonist (Figure 3-6B). This is due
to occasional and infrequent opening of the channel
even when an agonist is not present and even when an
antagonist is present. This is called constitutive activity
Figure 3-4 Agonist spectrum. The agonist spectrum and its
and is also discussed in Chapter 2 for G-protein-linked
corresponding effects on the ion channel are shown here. This receptors. Antagonists of ion-channel-linked receptors
spectrum ranges from agonists (on the far left), which open the reverse the action of agonists (Figure 3-7) and bring the
channel the maximal frequency allowed by that binding site
(depicted for simplicity’s sake with a wider opening), through receptor conformation back to the resting baseline state,
antagonists (middle of the spectrum), which retain the resting but do not block any constitutive activity.
state with infrequent opening of the channel, to inverse agonists
(on the far right), which put the ion channel into a closed and Partial agonists produce a change in receptor
inactive state. Between the extremes of agonist and antagonist conformation such that the ion channel opens to a greater
are partial agonists, which increase the degree and frequency of
ion-channel opening as compared to the resting state, but not extent and more frequently than in its resting state but
as much as a full agonist. Antagonists can block anything in the less than in the presence of a full agonist (Figures 3-8
agonist spectrum, returning the ion channel to the resting state
in each instance. and 3-9). An antagonist reverses a partial agonist, just
like it reverses a full agonist, returning the receptor to its
resting state (Figure 3-10). Partial agonists thus produce
Figure 3-5 Actions of an agonist. In

nis t panel A, the ion channel is in its resting
ago state, during which the channel opens
agonist infrequently (constitutive activity). In
panel B, the agonist occupies its binding
site on the ligand-gated ion channel,
increasing the frequency at which the
channel opens. This is represented as
the red agonist turning the receptor red
and opening the ion channel.
agonist
channel in its resting state in the absence agonist binds to the receptor and the
of agonist channel is more frequently open
A B
57
anta Figure 3-6 Antagonists acting alone. In

t gonis
antagonis t panel A, the ion channel is in its resting
state, during which the channel opens
infrequently. In panel B, the antagonist
occupies the binding site normally
occupied by the agonist on the ligand-
gated ion channel. However, there is
no consequence to this, and the ion
channel does not affect the degree or
antagonist frequency of opening of the channel
compared to the resting state. This is
represented as the yellow antagonist
docking into the binding site and
turning the receptor yellow but not
affecting the state of the ion channel.
channel in its resting state antagonist binds to the receptor, not affecting
the frequency of opening of the channel
compared to the resting
A B
state of no agonist
Figure 3-7 Antagonist acting in the

st ist presence of agonist. In panel A, the
antagoni gon ion channel is bound by an agonist,
a
which causes it to open at a greater
frequency than in the resting state. This
is represented as the red agonist turning
the receptor red and opening the ion
channel as it docks into its binding
site. In panel B, the yellow antagonist
prevails and shoves the red agonist off
agonist antagonist the binding site, reversing the agonist’s
actions and restoring the resting state.
Thus, the ion channel has returned to its
status before the agonist acted.
the agonist causes the channel to become the antagonist takes over and puts
open more frequently the channel back into the resting state
A B
58
ial
Figure 3-8 Actions of a partial agonist. In
part ist part panel A, the ion channel is in its resting
agon agon ial
ist state and opens infrequently. In panel B, the
partial agonist occupies its binding site on
the ligand-gated ion channel and produces
a conformational change such that the ion
channel opens to a greater extent and at a
greater frequency than in the resting state,
though less than in the presence of a full
partial agonist. This is depicted by the orange partial
agonist agonist turning the receptor orange and 3
partially but not fully opening the ion channel.
channel in its resting state partial agonist binds to the receptor and
causes it to open more frequently than
A
the resting state but less frequently B
than with a full agonist
partial
agonist
agonist
1 the partial agonist 2 the partial agonist

causes the causes the
channel to open channel to open
more frequently; less frequently;
in this case the in this case
partial agonist is the partial agonist
1 2
having a net is having a net
channel in its resting state agonist action antagonistic action the full agonist opens
the channel maximally
and frequently
Figure 3-9 Net effect of partial agonist. Partial agonists act either as net agonists or as net antagonists, depending on the amount of
agonist present. When full agonist is absent (on the far left), a partial agonist causes the channel to open more frequently as compared
to the resting state; thus, the partial agonist is having a net agonist action (moving from left to right). However, in the presence of a full
agonist (on the far right), a partial agonist decreases the frequency of channel opening in comparison to the full agonist and thus acts as
a net antagonist (moving from right to left).
59
Figure 3-10 Antagonist acting in

antagonist pa presence of partial agonist. In panel A,
agorntial
ist a partial agonist occupies its binding
site and causes the ion channel to
open more frequently than the resting
state. This is represented as the orange
partial agonist docking to its binding
site, turning the receptor orange, and
partial partially opening the ion channel. In
agonist antagonist panel B, the yellow antagonist prevails
and shoves the orange partial agonist
off the binding site, reversing the partial
agonist’s actions. Thus the ion channel is
returned to its resting state.
partial agonist binds to the receptor and the antagonist causes the channel
causes it to open more frequently than to return to baseline
the resting state A B
ion flow and downstream signal transduction that is appear as net agonists, or as net antagonists, depending
something more than the resting state in the absence of upon the amount of naturally occurring full agonist
agonist, yet something less than a full agonist. Just as is neurotransmitter which is present. Thus, when a full
the case for G-protein-linked receptors, depending upon agonist neurotransmitter is absent, a partial agonist
how close this partial agonist is to a full agonist or to a will be a net agonist (Figure 3-9). That is, from the
silent antagonist on the agonist spectrum will determine resting state, a partial agonist initiates somewhat of
the impact of a partial agonist on downstream signal an increase in the ion flow and downstream signal
transduction events. transduction cascade from the ion-channel-linked
The ideal therapeutic agent should have ion flow receptor. However, when full agonist neurotransmitter
and signal transduction that is not too hot, yet not too agonist is present, the same partial agonist will become
cold, but just right, called the “Goldilocks” solution in a net antagonist (Figure 3-9). That is, it will decrease
Chapter 2, a concept that can apply here to ligand-gated the level of full signal output to a lesser level, but not to
ion channels as well. Such an ideal state may vary from zero. Thus, a partial agonist can simultaneously boost
one clinical situation to another, depending upon the deficient neurotransmitter activity yet block excessive
balance between full agonism and silent antagonism neurotransmitter activity, another reason that partial
that is desired. In cases where there is unstable agonists are called stabilizers. An agonist and an
neurotransmission throughout the brain, finding such antagonist in the same molecule acting at ligand-gated
a balance may stabilize receptor output somewhere ion channels is quite an interesting new dimension to
between too much and too little downstream action. For therapeutics. This concept has led to proposals that
this reason, partial agonists are also called “stabilizers,” partial agonists could treat not only states which are
since they have the theoretical capacity to find the stable theoretically deficient in full agonist, but also states that
solution between the extremes of too much full agonist are theoretically in excess of full agonist. As mentioned in
action and no agonist action at all (Figure 3-9). the discussion of G-protein-linked receptors in Chapter 2,
Just as is the case for G-protein-linked receptors, a partial agonist at ligand-gated ion channels could
partial agonists at ligand-gated ion channels can also theoretically treat states that are mixtures of both
60
Figure 3-11 Actions of an inverse

inverse agonist. In panel A, the ion channel
agonist is in its resting state and opens
infrequently. In panel B, the inverse
agonist occupies the binding site
on the ligand-gated ion channel
and causes it to close. This is the
opposite of what an agonist does and
is represented by the purple inverse
agonist turning the receptor purple 3
and closing the ion channel. Eventually,
the inverse agonist stabilizes the
ion channel in an inactive state,
represented by the padlock on the
channel itself.
channel closed channel closed

and inactivated
channel in its resting state the inverse agonist causes the channel
to open very infrequently
and eventually stabilizes it
in an inactive state
A
B
Figure 3-12 Antagonist acting in the

st
antagoni presence of inverse agonist. In panel A,
the ion channel has been stabilized in
inverse
agonist an inactive form by the inverse agonist
occupying its binding site on the ligand-
gated ion channel. This is represented
as the purple inverse agonist turning
the receptor purple and closing and
antagonist padlocking the ion channel. In panel
B, the yellow antagonist prevails and
shoves the purple inverse agonist
off the binding site, returning the ion
channel to its resting state. In this way,
the antagonist’s effects on an inverse
agonist’s actions are similar to its
effects on an agonist’s actions; namely,
it returns the ion channel to its resting
state. However, in the presence of an
inverse agonist, the antagonist increases
the frequency of channel opening,
whereas in the presence of an agonist,
the antagonist decreases the frequency
of channel opening. Thus an antagonist
can reverse the actions of either an
agonist or an inverse agonist despite
the inverse agonist causes the channel the antagonist returns the channel the fact that it does nothing on its own.
to stabilize in an inactive form to the resting state
A B
excessive and deficient neurotransmitter activity. Partial agonists at ligand-gated ion channels are thought to
agonists at ligand-gated ion channels are just beginning produce a conformational change in these receptors that
to enter into use in clinical practice (Table 3-2), and first closes the channel and then stabilizes it in an inactive
several more are in clinical development. form (Figure 3-11). Thus, this inactive conformation
Inverse agonists at ligand-gated ion channels are (Figure 3-11B) produces a functional reduction in ion
different from simple antagonists, and are neither neutral flow and in consequent signal transduction compared to
nor silent. Inverse agonists are explained in Chapter 2 the resting state (Figure 3-11A) that is even less than that
in relationship to G-protein-linked receptors. Inverse produced when there is either no agonist present or when
61
a silent antagonist is present. Antagonists reverse this the meantime, inverse agonists remain an interesting
inactive state caused by inverse agonists, returning the pharmacological concept.
channel to the resting state (Figure 3-12). In summary, ion-channel-linked receptors act along
In many ways, therefore, an inverse agonist does an agonist spectrum, and drugs have been described that
the opposite of an agonist. If an agonist increases signal can produce conformational changes in these receptors
transduction from baseline, an inverse agonist decreases to create any state from full agonist, to partial agonist, to
it, even below baseline levels. Also, in contrast to silent antagonist, to inverse agonist (Figure 3-4). When
antagonists, which stabilize the resting state, inverse one considers the spectrum of signal transduction along
agonists stabilize an inactivated state (Figures 3-11 and 3- this spectrum, it is easy to understand why agents at
13). It is not yet clear if the inactivated state of the inverse each point along the agonist spectrum differ so much
agonist can be distinguished clinically from the resting from each other, and why their clinical actions are so
state of the silent antagonist at ionotropic receptors. In different.
Figure 3-13 Inverse agonist actions

reversed by antagonist. Antagonists
cause conformational change in ligand-
gated ion channels that stabilizes the
receptors in the resting state (top left),
the same state they are in when no
antagonist agonist or inverse agonist is present
(top right). Inverse agonists cause
conformational change that closes the
ion channel (bottom right). When an
inverse agonist is bound over time, it
may eventually stabilize the ion channel
in an inactive conformation (bottom
left). This stabilized conformation of
an inactive ion channel can be quickly
reversed by an antagonist, which
restabilizes it in the resting state (top
left).
resting state stabilized resting state

by antagonist
inactivated state possibly reversed closed state caused

immediately by an antagonist by inverse agonist
62
Different States of Ligand-Gated Ion Channels receptor desensitization can be caused by prolonged
There are even more states of ligand-gated ion channels exposure to agonists, and may be a way for receptors to
than those determined by the agonist spectrum discussed protect themselves from overstimulation. An agonist
above and shown in Figures 3-4 through 3-13. The states acting at a ligand-gated ion channel first induces a
discussed so far are those that occur predominantly change in receptor conformation that opens the channel,
with acute administration of agents that work across but with the continuous presence of the agonist, over
the agonist spectrum. These range from the maximal time leads to another conformational change where the
3
opening of the ion channel from conformational changes receptor essentially stops responding to the agonist even
caused by a full agonist to the maximal closing of the ion though the agonist is still present. This receptor is then
channel caused by an inverse agonist. Such changes in considered to be desensitized (Figures 3-14 and 3-15).
conformation caused by the acute action of agents across This state of desensitization can at first be reversed
this spectrum are subject to change over time since these relatively quickly by removal of the agonist (Figure 3-15).
receptors have the capacity to adapt, particularly when However, if the agonist stays much longer, on the order
there is chronic or excessive exposure to such agents. of hours, the receptor converts from a state of simple
We have already discussed the resting state, the open desensitization to one of inactivation (Figure 3-15). This
state, and the closed state shown in Figure 3-14. The state does not reverse simply upon removal of the agonist,
best-known adaptive states are those of desensitization since it also takes hours in the absence of agonist to
and inactivation, also shown in Figure 3-14. We have also revert back to the resting state where the receptor is again
briefly discussed inactivation as a state that can be caused sensitive to new exposure to agonist (Figure 3-15).
by acute administration of an inverse agonist, beginning The state of inactivation may be best characterized
with a rapid conformational change in the ion channel for nicotinic cholinergic receptors, ligand-gated ion
that first closes it, but over time stabilizes the channel in channels that are normally responsive to the endogenous
an inactive conformation that can relatively quickly be neurotransmitter acetylcholine. Acetylcholine is
reversed by an antagonist, which then restabilizes the ion quickly hydrolyzed by an abundance of the enzyme
channel in the resting state (Figures 3-11 through 3-13). acetylcholinesterase, so it rarely gets the chance to
Desensitization is yet another state of the ligand-gated desensitize and inactivate its nicotinic receptors.
ion channel shown in Figure 3-14. Ion-channel-linked However, the drug nicotine is not hydrolyzed by
channel in channel open channel closed channel channel

resting state desensitized inactivated
Figure 3-14 Five states of ligand-gated ion channels. Summarized here are five well-known states of ligand-gated ion channels. In the
resting state, ligand-gated ion channels open infrequently, with consequent constitutive activity that may or may not lead to detectable
signal transduction. In the open state, ligand-gated ion channels open to allow ion conductance through the channel, leading to
signal transduction. In the closed state, ligand-gated ion channels are closed, allowing no ion flow to occur and thus reducing signal
transduction to even less than is produced in the resting state. Channel desensitization is an adaptive state in which the receptor stops
responding to agonist even if it is still bound. Channel inactivation is a state in which a closed ion channel over time becomes stabilized
in an inactive conformation.
63
agonist agonist
open state desensitized state

resting state activated by activated by prolonged agonist
acute agonist order of hours
order of hours
inactivated state
not immediately reversed by
removal of agonist
Figure 3-15 Opening, desensitizing, and inactivating by agonists. Agonists cause ligand-gated ion channels to open more frequently,
increasing ion conductance in comparison to the resting state. Prolonged exposure to agonists can cause a ligand-gated ion channel
to enter a desensitized state in which it no longer responds to the agonist even if it is still bound. Prompt removal of the agonist can
reverse this state fairly quickly. However, if the agonist stays longer, it can cause a conformational change that leads to inactivation of the
ion channel. This state is not immediately reversed when the agonist is removed.
acetylcholinesterase, and is famous for stimulating receptors described here. Addiction to nicotine and other
nicotinic cholinergic receptors so profoundly and substances is described in more detail in Chapter 13
so enduringly that the receptors are not only rapidly on impulsivity and substance abuse. These transitions
desensitized in about the time it takes to smoke a single among various receptor states induced by agonists are
cigarette, but enduringly inactivated for about the time shown in Figure 3-15.
most smokers take between cigarettes. Ever wonder why
Allosteric Modulation: PAMs and NAMs
cigarettes are the length they are and why most smokers
smoke about a pack a day (20 cigarettes) in about 16 Ligand-gated ion channels are regulated by more than
waking hours? It all has to do with adjusting the dosing the neurotransmitter(s) that bind to them. That is, there
of nicotine to the nature of receptor action of nicotinic are other molecules that are not neurotransmitters but
64
PAM
+
NT1
NT1 NT1 3
binding site
within
membrane
PAM
+
When a neurotransmitter binds to receptors making up an ion channel, the channel
opens more frequently. However, when BOTH the neurotransmitter and
a positive allosteric modulator (PAM) are bound to the receptor,
the channel opens much more frequently,
allowing more ions into the cell.
Figure 3-16 Positive allosteric modulators. Allosteric modulators are ligands that bind to sites other than the neurotransmitter site on
an ion-channel-linked receptor. Allosteric modulators have no activity of their own but rather enhance (positive allosteric modulators, or
PAMs) or block (negative allosteric modulators, or NAMs) the actions of neurotransmitters. When a PAM binds to its site while an agonist
is also bound, the channel opens more frequently than when only the agonist is bound, therefore allowing more ions into the cell.
can bind to the receptor/ion channel complex at different than happens with a full agonist by itself (Figure 3-16).
sites from where neurotransmitter(s) bind. These sites That is why the PAM is called “positive.” Good examples
are called allosteric (literally, “other site”) and ligands that of PAMs are benzodiazepines. These ligands boost
bind there are called allosteric modulators. These ligands the action of GABA (γ-aminobutyric acid) at GABAA
are modulators rather than neurotransmitters because types of ligand-gated chloride ion channels. GABA
they have little or no activity on their own in the absence binding to GABAA sites increases chloride ion flux by
of the neurotransmitter. Allosteric modulators thus only opening the ion channel, and benzodiazepines acting as
work in the presence of the neurotransmitter. agonists at benzodiazepine receptors elsewhere on the
There are two forms of allosteric modulators – those GABAA receptor complex cause the effect of GABA to be
that boost what the neurotransmitter does and are thus amplified in terms of chloride ion flux by opening the ion
called positive allosteric modulators (PAMs), and those channel to a greater degree or more frequently. Clinically,
that block what the neurotransmitter does and are thus this is exhibited as reducing anxiety, inducing sleep,
called negative allosteric modulators (NAMs). blocking convulsions, blocking short-term memory, and
Specifically, when PAMs or NAMs bind to their relaxing muscles. In this example, benzodiazepines are
allosteric sites while the neurotransmitter is not binding acting as full agonists at the PAM site.
to its site, the PAM and the NAM do nothing. However, On the other hand, when a NAM binds to its allosteric
when a PAM binds to its allosteric site while the site while the neurotransmitter resides at its agonist
neurotransmitter is sitting in its site, the PAM causes binding site, the NAM causes conformational changes
conformational changes in the ligand-gated ion channel in the ligand-gated ion channel that block or reduce the
that open the channel even further and more frequently actions that normally occur when the neurotransmitter
65
neurotransmitter
M
NA-
NAM
-
When a neurotransmitter binds to receptors making up an ion channel, the channel
opens more frequently. However, when BOTH the neurotransmitter and
a negative allosteric modulator (NAM) are bound to the receptor,
the channel opens much less frequently,
allowing fewer ions into the cell.
Figure 3-17 Negative allosteric modulators. Allosteric modulators are ligands that bind to sites other than the neurotransmitter site on
an ion-channel-linked receptor. Allosteric modulators have no activity of their own but rather enhance (positive allosteric modulators,
or PAMs) or block (negative allosteric modulators, or NAMs) the actions of neurotransmitters. When a NAM binds to its site while an
agonist is also bound, the channel opens less frequently than when only the agonist is bound, therefore allowing fewer ions into the cell.
acts alone (Figure 3-17). That is why the NAM is called When either PCP or ketamine bind to their NAM site,
“negative.” One example of a NAM is a benzodiazepine they prevent glutamate/glycine cotransmission from
inverse agonist. Although these are only experimental, opening the channel.
as expected, they have the opposite actions of
benzodiazepine full agonists and thus diminish chloride VOLTAGE-SENSITIVE ION
conductance through the ion channel so much that they CHANNELS AS TARGETS OF
cause panic attacks, seizures, and some improvement PSYCHOPHARMACOLOGICAL
in memory – the opposite clinical effects of a DRUG ACTION
benzodiazepine full agonist. Thus, the same allosteric site
can either have NAM or PAM actions, depending upon Structure and Function
whether the ligand is a full agonist or an inverse agonist. Not all ion channels are regulated by neurotransmitter
NAMs for NMDA receptors include phencyclidine (PCP, ligands. Indeed, critical aspects of nerve conduction,
also called “angel dust”) and its structurally related action potentials, and neurotransmitter release are all
anesthetic agent ketamine, also used as a treatment for mediated by another class of ion channels, known as
resistant depression and suicidal thoughts. These agents voltage-sensitive or voltage-gated ion channels because
bind to a site inside the calcium channel, but can get into their opening and closing are regulated by the ionic
the channel to block it only when the channel is open. charge or voltage potential across the membrane in
66
Ionic Components of an Action Potential
Na+ Ca++
K+
3
A B C
Figure 3-18 Ionic components of an action potential. The ionic components of an action potential are shown graphically here. First,
voltage-sensitive sodium channels open to allow an influx of “downhill” sodium into the negatively charged internal milieu of the
neuron (A). The change of voltage potential caused by the influx of sodium triggers voltage-sensitive calcium channels to open and
allow calcium influx (B). Finally, after the action potential is gone, potassium enters the cell while sodium is pumped out, restoring the
neuron’s baseline internal electrical milieu (C).
which they reside. An electrical impulse in a neuron, also associated with the four subunits, and these appear to
known as the action potential, is triggered by summation have regulatory functions.
of the various neurochemical and electrical events of Let us now build a voltage-sensitive ion channel from
neurotransmission. These are discussed extensively scratch, and describe the known functions for each part of
in Chapter 1, which covers the chemical basis of the proteins that make up these channels. The subunit of
neurotransmission and signal transduction. a pore-forming protein has six transmembrane segments
Electrically, the action potential is shown in (Figure 3-19). Transmembrane segment 4 can detect the
Figure 3-18. The first phase is sodium rushing “downhill” difference in charge across the membrane, and is thus
into the sodium deficient, negatively charged internal the most electrically sensitive part of the voltage-sensitive
milieu of the neuron (Figure 3-18A). This is made possible channel. Transmembrane segment 4 thus functions like a
when voltage-gated sodium channels open the gates and voltmeter, and when it detects a change in ion charge across
let the sodium in. A few milliseconds later, the calcium the membrane, it can alert the rest of the protein, and begin
channels get the same idea, with their voltage-gated ion conformational changes of the ion channel, and either open
channels opened by the change in voltage potential caused it or close it. This same general structure exists for both
by the sodium rushing in (Figure 3-18B). Finally, after the VSSCs (Figure 3-19A) and for VSCCs (Figure 3-19B), but
action potential is gone, during recovery of the neuron’s the exact amino acid sequence of the protein subunits are
baseline internal electrical milieu, potassium makes its obviously different for VSSCs compared to VSCCs.
way back into the cell through potassium channels as Each subunit of a voltage-sensitive ion channel has an
sodium is again pumped out (Figure 3-18C). It is now extracellular amino acid loop between transmembrane
known or suspected that several psychotropic drugs segments 5 and 6 (Figure 3-19). This section of amino
work on voltage-sensitive sodium channels (VSSCs) and acids serves as an “ionic filter” and is located in a position
voltage-sensitive calcium channels (VSCCs). These classes so that it can cover the outside opening of the pore.
of ion channels will be discussed here. Potassium channels This is illustrated as a colander configured molecularly
are less well known to be targeted by psychotropic drugs to allow only sodium ions to filter through the sodium
and will thus not be emphasized. channel on the left and only calcium ions to filter through
the calcium channel on the right (Figure 3-19).
VSSCs (Voltage-Sensitive Sodium Channels) Four copies of the sodium-channel version of this
Many dimensions of ion-channel structure are similar protein are strung together to form one complete ion
for VSSCs and VSCCs. Both have a “pore” that is the channel pore of a VSSC (Figure 3-20A). The cytoplasmic
channel itself, allowing ions to travel from one side of loops of amino acids that tie these four subunits together
the membrane to the other. However, voltage-gated ion are sites that regulate various functions of the sodium
channels have a more complicated structure than just a channel. For example, on the connector loop between
hole or pore in the membrane. These channels are long the third and fourth subunits of a VSSC, there are amino
strings of amino acids, comprising subunits, and four acids that act as a “plug” to close the channel. Like a ball
different subunits are connected to form the critical pore, on an amino acid chain, this “pore inactivator” stops up
known as an α subunit. In addition, other proteins are the channel on the inner membrane surface of the pore
67
voltage-sensitive sodium voltage-sensitive calcium

channel (VSSC) channel (VSCC)
outside the cell
1 2 3 4 5 6 1 2 3 4 5 6
Na+ Ca++
inside the cell
A B
Figure 3-19 Ionic filter of voltage-sensitive sodium and calcium channels. The extracellular loop between transmembrane segments
5 and 6 of an α pore unit acts as an ionic filter (illustrated here as a colander). (A) Shown here is an α pore unit of a voltage-sensitive
sodium channel, with the ionic filter allowing only sodium ions to enter the cell. (B) Shown here is an α pore unit of a voltage-sensitive
calcium channel, with the ionic filter allowing only calcium ions to enter the cell.
(Figure 3-20A and B). This is a physical blocking of the Indeed, the α unit itself may also be a phosphoprotein,
hole in the pore, and reminiscent of an old-fashioned with the possibility that its own phosphorylation state
bathtub plug stopping up the drain in a bathtub. The could be regulated by signal transduction cascades and
pore-forming unit of the VSSC is also shown as an icon in thus increase or decrease the sensitivity of the ion channel
Figure 3-20B with a hole in the middle of the pore, and a to changes in the ionic environment. This is discussed in
pore inactivator ready to plug the hole from the inside. Chapter 1 as part of the signal transduction cascade, and
Many figures in textbooks represent voltage-gated ion ion channels in some cases may act as third, fourth, or
channels with the outside of the cell on the top of a figure subsequent messengers triggered by neurotransmission.
and this is the way the ion channel is shown in Figure Both β subunits and the α subunit itself may have various
3-20A and B. Here, we also show what the channel looks sites where various psychotropic drugs act, especially
like when the inside of the cell is at the top of the figure, anticonvulsants, some of which are also useful as mood
since throughout this book these channels will often be stabilizers or as treatments for chronic pain. Specific
shown on presynaptic membranes where the inside of drugs will be discussed in further detail in the chapters
the neuron is up and the outside of the neuron, namely on mood stabilizers and pain.
its synapse, is down, like that orientation represented in Three different states of a VSSC are shown in Figure
Figure 3-20C). In either case, the sodium is kept out of 3-21. The channel can be open and active, a state allowing
the neuron when the channel is closed or inactivated, and maximum ion flow through the α unit (Figure 3-21A).
the direction of sodium flow is into the neuron when the When a sodium channel needs to stop ion flow, it has two
channel is open, activated, and the pore is not plugged up states that can do this. One state acts very quickly to flip the
with the pore-inactivating amino acid loops. pore inactivator into place, stopping ion flow so fast that the
Voltage-sensitive sodium channels may have one or channel has not yet even closed (Figure 3-21B). Another
more regulatory proteins, some called β units, located state of inactivation actually closes the channel with
in the transmembrane area and flanking the α pore conformational changes in the ion channel’s shape (Figure
forming unit (Figure 3-20C). The function of these β 3-21C). The pore inactivation mechanism may be for fast
subunits is not clearly established, but they may modify inactivation, and the channel closing mechanism may be for
the actions of the α unit and thereby indirectly influence a more stable state of inactivation, but it is not entirely clear.
the opening and closing of the channel. It is possible that There are many subtypes of sodium channels, but the
β units may be phosphoproteins, and that their state of details of how they are differentiated from each other by
phosphorylation or dephosphorylation could regulate differential location in the brain, by differential functions,
how much influence they exert on ion-channel regulation. and by differential drug actions are only beginning to
68
Four Subunits Combine to Form the Alpha Pore Subunit, or Channel,

for Sodium of a VSSC (Voltage-Sensitive Sodium Channel)
outside the cell Na+
outside the cell
I II III IV
3
=
pore
inside the cell inactivation
A
pore
inactivation
inside the cell
inside the cell
pore
inactivation
= ß ß
C
outside the cell
Na+
Figure 3-20 Alpha pore of voltage-sensitive sodium channel. The α pore of a voltage-sensitive sodium channel comprises four
subunits (A). Amino acids in the intracellular loop between the third and fourth subunits act as a pore inactivator, “plugging” the channel.
An iconic version of the α unit is shown here, with the extracellular portion on top (B) and with the intracellular portion on top (C).
Figure 3-21 States of voltage-sensitive sodium

channel. Such channels can be in the open
state, in which the ion channel is open and
active and ions flow through the α unit (A).
Three States of a Voltage-Sensitive Sodium Channel (VSSC) Voltage-sensitive sodium channels may also be
in an inactivated state, in which the channel is
not yet closed but has been “plugged” by the
pore inactivator, preventing ion flow (B). Finally,
conformational changes in the ion channel can
cause it to close, the third state (C).
A B C
open inactivated closed and inactivated
69
be clarified. For the psychopharmacologist, what is now extracellular amino acids connecting segments 5 and 6
of interest is the fact that various sodium channels may acting as an ionic filter (Figure 3-19) – only this time as
be the sites of action of several anticonvulsants, some a colander allowing calcium to come into the cell, not
of which have mood-stabilizing and pain-reducing sodium (see Figure 3-19B). Obviously, the exact sequence
properties. Most currently available anticonvulsants of amino acids differs between a sodium channel and
probably have multiple sites of action, including multiple a calcium channel, but they have a very similar overall
sites of action at multiple types of ion channels. The organization and structure.
specific actions of specific drugs will be discussed in the Just like voltage-gated sodium channels, VSCCs
chapters that cover specific disorders. also string together four of their subunits to form a
pore, called in the case of a calcium channel, an α1 unit
VSCCs (Voltage-Sensitive Calcium Channels)
(Figure 3-22A and B). The connecting string of amino
Many aspects of VSCCs and VSSCs are similar – not acids also has functional activities that can regulate
just their names. Like their sodium-channel cousins, calcium-channel functioning, but in this case the
the VSCCs also have subunits with six transmembrane functions are different from that for sodium channels.
segments, with segment 4 a voltmeter, and with the That is, there is no pore inactivator working as a plug for
Four Subunits Combine to Form the Alpha1 Pore Subunit, or Channel,

for Calcium of a VSCC (Voltage-Sensitive Calcium Channel)
Ca++
outside the cell
outside the cell
I II III IV
=
inside the cell snare
A
inside the cell
inside the cell
C 2 outside the cell
Figure 3-22 Alpha1 pore of voltage-sensitive calcium channel. The α pore of a voltage-sensitive calcium channel, termed an α1 unit,
comprises four subunits (A). Amino acids in the cytoplasmic loop between the second and third subunits act as a snare to connect with
synaptic vesicles, thereby controlling neurotransmitter release (A). An iconic version of the α1 unit is shown here, with the extracellular
portion on top (B) and with the intracellular portion on top (C).
70
Opening a Presynaptic Voltage-Sensitive N or P/Q

Calcium Channel: Triggers Neurotransmitter Release
glutamate
3
ß vesicle ß
snare
N N
P/Q P/Q
2
A B
Ca++
Figure 3-23 N and P/Q voltage-sensitive calcium channels. Voltage-sensitive calcium channels that are most relevant to
psychopharmacology are termed N and P/Q channels. These ion channels are presynaptic and involved in the regulation of
neurotransmitter release. The intracellular amino acids linking the second and third subunits of the α1 unit form a snare that hooks onto
synaptic vesicles (A). When a nerve impulse arrives, the snare “fires,” leading to neurotransmitter release (B).
the VSCC, as was described above for the VSSC; instead, As would be expected, there are several subtypes of
the amino acids connecting the second and third subunits VSCCs (Table 3-4). The vast array of VSCCs indicates
of the VSCC work as a “snare” to hook up with synaptic that the term “calcium channel” is much too general, and
vesicles and regulate the release of neurotransmitter in fact can be confusing. For example, calcium channels
into the synapse during synaptic neurotransmission associated with the ligand-gated ion channels discussed
(Figure 3-22A and Figure 3-23). The orientation of the in the previous section, especially those associated
calcium channel in Figure 3-22B is with the outside of the with glutamate and nicotinic cholinergic ionotropic
cell at the top of the page, and this is switched in Figure receptors, are members of an entirely different class of
3-22C so that the inside of the cell is now at the top of ion channels from the VSCCs under discussion here. As
the page, so the reader can see how these channels might we have mentioned, calcium channels associated with
look in various configurations in space. In all cases, the this previously discussed class of ion channels are called
direction of ion flow is from outside the cell to the inside ligand-gated ion channels, ionotropic receptors, or ion-
when that channel opens to allow ion flow to occur. channel-linked receptors, to distinguish them from VSCCs.
Several proteins flank the α1 pore-forming unit of a The specific subtypes of VSCCs of most interest to
VSCC, called γ, β, and α2δ (Figure 3-22C). Shown here psychopharmacology are those that are presynaptic, that
are γ units that span the membrane, cytoplasmic β units, regulate neurotransmitter release, and that are targeted
and a curious protein called α2δ, because it has two parts: by certain psychotropic drugs. This subtype designation
a δ part that is transmembrane, and an α2 part that is of VSCC is shown in Table 3-4 and such channels are
extracellular (Figure 3-22C). The functions of all these known as N or P/Q channels.
proteins associated with the α1 pore-forming unit of a Another well-known subtype of VSCC is the L channel.
VSCC are just beginning to be understood, but already This channel exists not only in the central nervous system,
it is known that the α2δ protein is the target of certain where its functions are still being clarified, but also on
psychotropic drugs, such as the anticonvulsants pregabalin vascular smooth muscle where it regulates blood pressure
and gabapentin, and that this α2δ protein may be involved and where a group of drugs known as dihydropyridine
in regulating conformational changes of the ion channel to “calcium channel blockers” interact as therapeutic
change the way the ion channel opens and closes. antihypertensives to lower blood pressure. R and T
71
Table 3-4 Subtypes of voltage-sensitive calcium channels (VSCCs)
Type Pore-forming Location Function

L Cav1.2, 1.3 Cell bodies, dendrites Gene expression, synaptic integration
N Cav 2.2 Nerve terminals Transmitter release
Dendrites, cell bodies Synaptic integration
P/Q Cav, 2.1 Nerve terminals Transmitter release
Dendrites, cell bodies Synaptic integration
R Cav, 2.3 Nerve terminals Transmitter release
Cell bodies, dendrites Repetitive firing, synaptic integration
T Cav, 3.1, 3.2, 3.3 Cell bodies, dendrites Pacemaking, repetitive firing, synaptic
integration
Docking of Synaptic Vesicle with Presynaptic Membrane,

VSCC (Voltage-Sensitive Calcium Channel), and Snare Proteins
VMAT synaptobrevin synaptotagmin

synaptic vesicle
membrane
SV2A
syntaxin
SNAP 25
N
P/Q
presynaptic membrane
++
Ca
Figure 3-24 Snare proteins. Proteins that link the voltage-sensitive calcium channel to the synaptic vesicle, called snare proteins,
are shown here; they include SNAP 25 (synaptosomal-associated protein 25), synaptobrevin, syntaxin, and synaptotagmin. A VMAT
(vesicular monoamine transporter) is shown on the left. Another transporter, SV2A, is shown on the right. The mechanism of this
transporter is not yet clear, but the anticonvulsant levetiracetam is known to bind to this site.
72
channels are also of interest, and some anticonvulsants ion channels are well orchestrated, brain communication
and psychotropic drugs may also interact there, but the becomes a magical mix of electrical and chemical
exact roles of these channels are still being clarified. messages made possible by ion channels. The coordinated
Presynaptic N and P/Q VSCCs have a specialized acts of ion channels during neurotransmission are
role in regulating neurotransmitter release because they illustrated in the Figures 3-25 and 3-26.
are linked by molecular “snares” to synaptic vesicles The initiation of chemical neurotransmission by a
(Figure 3-23). That is, these channels are literally hooked neuron’s ability to integrate all of its inputs, and then
3
to synaptic vesicles. Some experts think of this as a translate them into an electrical impulse is presented in
cocked gun – loaded with neurotransmitters packed in Chapter 1. We now show how ion channels are involved
a synaptic vesicle bullet (Figure 3-23A) ready to be fired in this process (Figure 3-26). After a neuron receives and
at the postsynaptic neuron as soon as a nerve impulse integrates its inputs from other neurons, it then encodes
arrives (Figure 3-23B). Some of the structural details of them into an action potential, and that nerve impulse
the molecular links – namely, with snare proteins – that is next sent along the axon via VSSCs that line the axon
connect the N, P/Q VSCC with the synaptic vesicle are (Figure 3-25).
shown in Figure 3-24. If a drug interferes with the ability The action potential could be described as lighting a
of the channel to open and let in calcium, the synaptic fuse, with the fuse burning from the initial segment of
vesicle stays tethered to the voltage-gated calcium channel. the axon to the axon terminal. Movement of the burning
Neurotransmission can thus be prevented, and this may edge of the fuse is carried out by a sequence of VSSCs that
be desirable in states of excessive neurotransmission, such open one after the other, allowing sodium to pass into
as pain, seizures, mania, or anxiety. This may explain the the neuron, and then carrying the electrical impulse so
action of certain anticonvulsants. generated along to the next VSSC in line (Figure 3-25).
Indeed, it is neurotransmitter release that is the raison When the electrical impulse reaches the axon terminal,
d’etre for presynaptic voltage-sensitive N and P/Q channels. it meets VSCCs in the presynaptic neuronal membrane,
When a nerve impulse invades the presynaptic area, this already loaded with synaptic vesicles and ready to fire
causes the charge across the membrane to change, in (see axon terminal of neuron A in Figure 3-25).
turn opening the VSCC, allowing calcium to enter, and When the electrical impulse is detected by
this makes the synaptic vesicle dock into and merge with the voltmeter in the VSCC, it opens the calcium
the presynaptic membrane, spewing its neurotransmitter channel, allowing calcium to enter, and bang!, the
contents into the synapse to effect neurotransmission neurotransmitter is released in a cloud of synaptic
(Figures 3-25 and 3-26). This conversion of an electrical chemicals from the presynaptic axon terminal via
impulse into a chemical message is triggered by calcium excitation–secretion coupling (see axon terminal of
and sometimes called excitation–secretion coupling. neuron A in Figure 3-25 and enlarged illustrations
Anticonvulsants are thought to act at various VSSCs of this in Figure 3-26). Details of this process of
and VSCCs and will be discussed in further detail in the excitation–secretion coupling are shown in Figure 3-26,
relevant clinical chapters. Many of these anticonvulsants beginning with the action potential about to invade the
have several uses in psychopharmacology, from chronic presynaptic terminal, and with a closed VSSC sitting
pain to migraine, from bipolar mania to bipolar next to a closed but poised VSCC snared to its synaptic
depression to bipolar maintenance, and possibly as agents vesicle (Figure 3-26A). As the nerve impulse arrives
for anxiety and sleep aids. These specific applications and in the axon terminal, it first hits the VSSC as a wave
more details about hypothetical mechanisms of action are of positive sodium charges delivered by the openings
explored in depth in the clinical chapters dealing with the of upstream sodium channels, which are detected by
various psychiatric disorders. the sodium channel’s voltmeter (Figure 3-26B). This
opens the last sodium channel shown, allowing sodium
ION CHANNELS AND to enter (Figure 3-26C). The consequence of this
NEUROTRANSMISSION sodium entry is to change the electrical charge nearby
the calcium channel, and then this is detected by the
Although the various subtypes of ligand-gated ion
VSCC’s voltmeter (Figure 3-26D). Next, the calcium
channels and voltage-gated ion channels are presented
channel opens (Figure 3-26E). At this point, chemical
separately, the reality is that they work cooperatively
neurotransmission has now been irreversibly triggered,
during neurotransmission. When the actions of all these
73
and the translation of an electrical message into a presynaptic membrane, then merge with it, spewing its
chemical message has begun. Calcium entry from the neurotransmitter contents out of the membrane and into
VSCC now increases the local concentrations of this ion the synapse (Figure 3-26G). This amazing process occurs
in the vicinity of the VSCC, the synaptic vesicle, and the almost instantaneously and simultaneously from many
neurotransmitter release machinery (Figure 3-26F). This VSCCs releasing neurotransmitter from many synaptic
causes the synaptic vesicle to dock into the inside of the vesicles.
Summary: From Presynaptic to Postsynaptic Signal Propagation
reception
integration A
chemical
encoding
electrical
encoding
signal
propagation
presynaptic
signal
transduction
postsynaptic glutamate
signal B
transduction
reception
integration
chemical
encoding
electrical
encoding
signal
propagation
presynaptic
signal
transduction
Figure 3-25 Signal propagation. Summary of signal propagation from presynaptic to postsynaptic neuron. A nerve impulse is
generated in neuron A, and the action potential is sent along the axon via voltage-sensitive sodium channels until it reaches voltage-
sensitive calcium channels linked to synaptic vesicles full of neurotransmitters in the axon terminal. Opening of the voltage-sensitive
calcium channel and consequent calcium influx causes neurotransmitter release into the synapse. Arrival of neurotransmitter at
postsynaptic receptors on the dendrite of neuron B triggers depolarization of the membrane in that neuron and, consequently,
postsynaptic signal propagation.
74
Action
Potential
neurotransmitter
vesicle 3
VSSC VSCC
A
Na+
VSSC VSCC VSSC VSCC

B C
Ca++
VSSC VSCC VSSC VSCC
D E
Ca++ Ca ++
VSSC VSCC VSSC VSCC
F G
Figure 3-26 Excitation–secretion coupling. Details of excitation–secretion coupling are shown here. An action potential is encoded
by the neuron and sent to the axon terminal via voltage-sensitive sodium channels along the axon (A). The sodium released by those
channels triggers a voltage-sensitive sodium channel at the axon terminal to open (B), allowing sodium influx into the presynaptic
neuron (C). Sodium influx changes the electrical charge of the voltage-sensitive calcium channel (D), causing it to open and allow
calcium influx (E). As the intraneuronal concentration of calcium increases (F), the synaptic vesicle is caused to dock and merge with the
presynaptic membrane, leading to neurotransmitter release (G).
75
By now, only about half of the sequential phenomena Ligand-gated ion channels are both ion channels and
of chemical neurotransmission have been described. The receptors. They are also commonly called ionotropic
other half occurs on the other side of the synapse. That receptors as well as ion-channel-linked receptors. One
is, reception of the released neurotransmitter now occurs subclass of ligand-gated ion channels has a pentameric
in neuron B (Figure 3-25), which can set up another structure, and includes GABAA receptors, nicotinic
nerve impulse in neuron B. This whole process, from cholinergic receptors, 5HT3 receptors, and certain glycine
nerve impulse generation and propagation of it along receptors. The other subclass of ligand-gated ion channels
neuron A to its nerve terminal, then sending chemical has a tetrameric structure, and includes many glutamate
neurotransmission to neuron B, and finally propagating receptors, including the AMPA, kainate, and NMDA
this second nerve impulse along neuron B, is summarized subtypes.
in Figure 3-25. VSSCs in presynaptic neuron A propagate Ligands act at ligand-gated ion channels across an
the impulse there, and then VSCCs in presynaptic neuron agonist spectrum, from full agonist, to partial agonist,
A release the neurotransmitter glutamate. Ligand-gated to antagonist, to inverse agonist. Ligand-gated ion
ion channels on dendrites in postsynaptic neuron B channels can be regulated not only by neurotransmitters
next receive this chemical input, and translate this acting as agonists, but also by molecules interacting at
chemical message back into a nerve impulse propagated other sites on the receptor, either boosting the action
in neuron B by VSSCs in that neuron. Also, ligand-gated of neurotransmitter agonists as positive allosteric
ion channels in postsynaptic neuron B translate the modulators (PAMs), or diminishing the action of
glutamate chemical signal into another type of electrical neurotransmitter agonists as negative allosteric
phenomenon called long-term potentiation, to cause modulators (NAMs). In addition, these receptors exist
changes in the function of neuron B. in several states, from open, to resting, to closed, to
inactivated, to desensitized.
The second major class of ion channels is called
SUMMARY either voltage-sensitive ion channels or voltage-gated
Ion channels are key targets of many psychotropic drugs. ion channels, since they are opened and closed by the
This is not surprising because these targets are key voltage charge across the membrane. The major channels
regulators of chemical neurotransmission and the signal from this class of interest to psychopharmacologists are
transduction cascade. the voltage-sensitive sodium channels (VSSCs) and the
There are two major classes of ion channels: ligand- voltage-sensitive calcium channels (VSCCs). Numerous
gated ion channels and voltage-sensitive ion channels. anticonvulsants bind to various sites on these channels,
The opening of ligand-gated ion channels is regulated and may exert their anticonvulsant actions by this
by neurotransmitters whereas the opening of voltage- mechanism, as well as their actions as mood stabilizers,
gated ion channels is regulated by the charge across the treatments for chronic pain, drugs for anxiety, and sleep
membrane in which they reside. effects.
76
Psychosis, Schizophrenia, and
4
the Neurotransmitter Networks
Dopamine, Serotonin, and
Glutamate
Symptoms of Psychosis 77 The Serotonin Hypothesis of Psychosis and
The Three Major Hypotheses of Psychosis and Their Schizophrenia 111
Neurotransmitter Networks 78 The Serotonin Neurotransmitter Network 113
The Classic Dopamine Hypothesis of Psychosis and The Serotonin Hyperfunction Hypothesis of
Schizophrenia 79 Psychosis 131
The Dopamine Neurotransmitter Network 79 Summary and Conclusions Regarding Dopamine,
The Classic Dopamine Hypothesis of the NMDA, and Serotonin Neurotransmission in
Positive Symptoms of Psychosis: Mesolimbic Psychosis 141
HyperDopaminergia 90 Schizophrenia as the Prototypical Psychotic
Corollary to the Classic Dopamine Hypothesis of Disorder 141
Schizophrenia: Mesocortical HypoDopaminergia Beyond the Positive and Negative Symptoms of
and the Cognitive, Negative, and Affective Schizophrenia 143
Symptoms of Schizophrenia 95 What Is the Cause of Schizophrenia? 148
The Glutamate Hypothesis of Psychosis and Other Psychotic Illnesses 156
Schizophrenia 95 Mood-Related Psychosis, Psychotic Depression,
The Glutamate Neurotransmitter Network 96 Psychotic Mania 157
The NMDA Glutamate Hypofunction Hypothesis Parkinson’s Disease Psychosis 157
of Psychosis: Faulty NMDA Neurotransmission at Dementia-Related Psychosis 157
Glutamate Synapses on GABA Interneurons in
Summary 158
Prefrontal Cortex 105
Psychosis is a difficult term to define and is frequently SYMPTOMS OF PSYCHOSIS

misused not only in the media, but unfortunately among
mental health professionals as well. Stigma and fear Psychosis is a syndrome – that is, a mixture of
surround the concept of psychosis, sometimes using symptoms – that can be associated with many different
the pejorative term “crazy.” This chapter gives a general psychiatric disorders, but is not a specific disorder itself
description of psychotic symptoms and explores the in diagnostic schemes such as the DSM or ICD. At a
major theories of how all forms of psychosis are linked to minimum, psychosis means delusions and hallucinations.
the neurotransmitter systems dopamine, serotonin, and Delusions are fixed beliefs – often bizarre – that have
glutamate. An overview of specific psychotic disorders, an inadequate rational basis and can’t be changed
with an emphasis on schizophrenia, is presented here by rational arguments or evidence to the contrary.
but does not list the diagnostic criteria for all the Hallucinations are perceptual experiences of any sensory
disorders in which psychosis is either a defining feature modality – especially auditory – that occur without a
or an associated feature. The reader is referred to real external stimulus, yet are vivid and clear, just like
standard reference sources such as the DSM (Diagnostic normal perceptions, but not under voluntary control.
and Statistical Manual of the American Psychiatric Delusions and hallucinations are the hallmarks of
Association) and the ICD (International Classification of psychosis and are often called the “positive symptoms”
Diseases) for that information. Although schizophrenia of psychosis. Psychosis can also include other symptoms
is emphasized here, we will approach psychosis as a such as disorganized speech, disorganized behavior, gross
syndrome associated with a variety of disorders that are distortions of reality testing, and so-called “negative
all targets for the various drugs that treat psychosis and symptoms” of psychosis, such as diminished emotional
that will be discussed in Chapter 5. expression and decreased motivation.
77
Psychosis itself, whether part of schizophrenia or manifesting loud and boisterous speech; exhibiting
another disorder, can be paranoid, disorganized/excited, overactivity or restlessness; and exhibiting excess of
or depressive. In addition, perceptual distortions and speech. Excitement can be especially characteristic of
motor disturbances can be associated with any type of mania or schizophrenia.
psychosis. Perceptual distortions include being distressed Depressive psychosis is characterized by psychomotor
by hallucinatory voices; hearing voices that accuse, retardation, apathy, and anxious self-punishment
blame, or threaten punishment; seeing visions; reporting and blame. Psychomotor retardation and apathy are
hallucinations of touch, taste, or odor; or reporting manifested by slowed speech; indifference to one’s future;
that familiar things and people seem changed. Motor fixed facial expression; slowed movements; deficiencies in
disturbances are peculiar, rigid postures; overt signs of recent memory; manifesting blocking in speech; apathy
tension; inappropriate grins or giggles; peculiar repetitive toward oneself or one’s problems; slovenly appearance;
gestures; talking, muttering, or mumbling to oneself; or low or whispered speech; and failure to answer questions.
glancing around as if hearing voices. It can be hard to distinguish from negative symptoms
In paranoid psychosis, the patient has paranoid of psychosis. Anxious self-punishment and blame is the
projections, hostile belligerence, and grandiose tendency to blame or condemn oneself; anxiety about
expansiveness. This type of psychosis often occurs in specific matters; apprehensiveness regarding vague
schizophrenia and in many drug-induced psychoses. future events; an attitude of self-deprecation, manifesting
Paranoid projection includes preoccupation with delusional depressed mood; expressing feelings of guilt and remorse;
beliefs; believing that people are talking about oneself; preoccupation with suicidal thoughts, unwanted ideas,
believing one is being persecuted, or being conspired and specific fears; and feeling unworthy or sinful, seen
against; and believing people or external forces control often in psychotic depression
one’s actions. A particular type of paranoid delusion may In summary, the term “psychosis” can be considered
be seen in Parkinson’s disease psychosis; namely, the belief to be a set of symptoms in which a person’s mental
that one’s spouse is being unfaithful or that one’s spouse capacity, affective response, and capacity to recognize
or loved ones are stealing from them. Hostile belligerence reality, communicate, and relate to others is impaired.
is verbal expression of feelings of hostility; expressing an This brief discussion of clusters of psychotic symptoms
attitude of disdain; manifesting a hostile, sullen attitude; does not constitute diagnostic criteria for any psychotic
manifesting irritability and grouchiness; tending to blame disorder. It is given merely as a description of several
others for problems; expressing feelings of resentment; types of symptoms that can occur as a part of many
complaining and finding fault; as well as expressing different types and causes of psychosis in order to give
suspicion of people. This, too may be seen especially in the reader an overview of the nature of behavioral
schizophrenia and drug-induced psychoses. Grandiose disturbances associated with the various psychotic
expansiveness is exhibiting an attitude of superiority; illnesses.
hearing voices that praise and extol; believing one has
unusual powers or is a well-known personality, or that one THE THREE MAJOR
has a divine mission, which is often seen in schizophrenia HYPOTHESES OF
and in manic psychosis PSYCHOSIS AND THEIR
In a disorganized/excited psychosis, there is conceptual NEUROTRANSMITTER
disorganization, disorientation, and excitement. NETWORKS
Conceptual disorganization can be characterized by
giving answers that are irrelevant, or incoherent; drifting The dopamine (DA) hypothesis of psychosis is well
off the subject; using neologisms; or repeating certain known and has in fact become a classic, and one of
words or phrases. Any psychotic disorder may exhibit the most enduring ideas in psychopharmacology.
disorganization. Disorientation is not knowing where However, DA is not the only neurotransmitter linked
one is, the season of the year, the calendar year, or one’s to psychosis. Increasing evidence implicates both
own age and is common in psychoses associated with glutamate and serotonin neuronal networks as well in the
dementias and in drug-induced states. Excitement is pathophysiology and treatment of some forms of psychosis,
expressing feelings without restraint; manifesting speech not only schizophrenia, but psychoses associated with
that is hurried; exhibiting an elevated mood; an attitude Parkinson’s disease, with various forms of dementia, and
of superiority; dramatizing oneself or one’s symptoms; with numerous psychotomimetic drugs. Thus, there are
78
Chapter 4: Psychosis, Schizophrenia, and Neurotransmitter Networks
Table 4-1 Pharmacological models link dopamine and serotonin receptor agonists and NMDA glutamate receptor antagonists to
psychosis symptoms
Psychostimulants Dissociative anesthetics Psychedelics (LSD,

(cocaine, amphetamine) (PCP, ketamine) psilocybin)
Proposed mechanism Dopamine D2 agonist NMDA antagonist Serotonin 5HT2A agonist
(and to a lesser extent 5HT2C)
Main type of hallucinations Auditory Visual Visual
Most frequently associated Paranoid Paranoid Mystical
delusions
Insightfulness No No Yes
D2, dopamine 2; PCP, phencyclidine NMDA, N-methyl-D-aspartate; LSD, lysergic acid diethylamide; 5HT, 5-hydroxytryptamine (serotonin). 4
Three Neurotransmitter Pathways Linked to Psychosis Figure 4-1 Neurotransmitter pathways linked to
psychosis. Psychosis has been theoretically linked
to three major neurotransmitter pathways. The
longstanding dopamine theory centers around the
Dopamine Theory concept of hyperactive dopamine 2 (D2) receptors
Hyperactive dopamine at D2 receptors in the mesolimbic pathway in the mesolimbic pathway. The glutamate theory
proposes that N-methyl-D-aspartate (NMDA)
receptors are hypoactive at critical synapses in the
prefrontal cortex, which could lead to downstream
Glutamate Theory hyperactivity in the mesolimbic dopamine pathway.
NMDA receptor hypofunction The serotonin theory posits that there is serotonergic
hyperactivity particularly at serotonin 2A (5HT2A)
receptors in the cortex, which also could result in
hyperactivity in the mesolimbic dopamine pathway.
Serotonin Theory It is likely that one or more of these three pathways is
5HT2A receptor hyperfunction in the cortex involved in the development of psychosis.
now three major neurotransmitter systems hypothetically DA in the mesolimbic pathway and that all treatments
linked to psychosis (Figure 4-1 and Table 4-1). What must therefore block DA D2 receptors in this pathway. As
follows is a discussion of each of these three hypotheses it turns out, however, there is much more to psychosis
accompanied by an extensive presentation of the neuronal than mesolimbic DA, and much more to the treatment
pathways and receptors for the three neurotransmitter of psychosis than D2 antagonists, as will be discussed in
networks for DA, glutamate, and serotonin. Chapter 5. Before reviewing the classic and the updated
DA hypothesis, not only of psychosis but of drugs that
THE CLASSIC DOPAMINE treat psychosis, it is important to understand fully DA
HYPOTHESIS OF PSYCHOSIS neurotransmission, so we will begin with a discussion of
AND SCHIZOPHRENIA DA receptors and brain circuits.
If one had asked any mental health clinician or researcher The Dopamine Neurotransmitter Network
over the past 50 years what neurotransmitter was linked To understand the potential role of DA in schizophrenia,
to psychosis, the resounding answer would have been DA, we will first review how DA is synthesized, metabolized,
and specifically DA hyperactivity at D2 DA receptors in and regulated, then show the functions of DA
the mesolimbic pathway. This so-called DA hypothesis receptors, and finally show the localization of key DA
of psychosis makes sense because release of DA by pathways in the brain.
amphetamine causes a paranoid psychosis similar to the
psychosis in schizophrenia (see Table 4-1), and drugs Synthesis and Inactivation of Dopamine in
that block DA D2 receptors have been the mainstay of Dopaminergic Neurons
treatment for essentially all forms of psychosis for over Dopaminergic neurons utilize the neurotransmitter DA,
50 years. Furthermore, this DA theory has proven so which is synthesized in dopaminergic nerve terminals
powerful that some may still assume (wrongly) that all from the amino acid tyrosine after it is taken up into the
positive symptoms of psychosis are caused by excessive neuron from the extracellular space and bloodstream by
79
a tyrosine pump, or transporter (Figure 4-2). Tyrosine tyrosine hydroxylase (TOH) and then by the enzyme
is converted into DA first by the rate-limiting enzyme DOPA decarboxylase (DDC) (Figure 4-2). DA is then
taken up into synaptic vesicles by a vesicular monoamine
Dopamine is Produced transporter (VMAT2) and stored there until it is used
during neurotransmission. Excess DA that escapes
tyrosine storage in synaptic vesicles can be destroyed within the
transporter neuron by the enzymes monoamine oxidase A (MAO-A)
or monoamine oxidase B (MAO-B) (Figure 4-3A).
In the striatum and some other brain regions, DA
terminals have a presynaptic transporter (reuptake
pump) called DAT (DA transporter), which is unique
DDC for DA and which terminates DA’s synaptic action
by whisking it out of the synapse back into the
E presynaptic nerve terminal where it can be re-stored
E in synaptic vesicles for subsequent reuse in another
TYR
DOPA
neurotransmission (Figure 4-3A). DATs are the principle
TOH
pathway of inactivation for DA at synapses where DATs
are present, with secondary inactivation extracellularly by
VMAT2
catechol-O-methyltransferase (COMT).
DATs are not in high density at the axon terminals of all
DA neurons (Figure 4-3B). For example, in the prefrontal
cortex, DATs are relatively sparse, and thus DA is inactivated
DA (dopamine)
in these synapses by other mechanisms, principally COMT
(Figure 4-3B). When DATs are not present, DA can also
Figure 4-2 Dopamine synthesis. Tyrosine (TYR), a precursor
to dopamine, is taken up into dopamine nerve terminals via a diffuse away from synapses where it is released until it
tyrosine transporter and converted into DOPA by the enzyme eventually reaches a neighboring norepinephrine (NE)
tyrosine hydroxylase (TOH). DOPA is then converted into
dopamine by the enzyme DOPA decarboxylase (DDC). After neuron and confronts its NE transporters (NETs) that then
synthesis, dopamine is packaged into synaptic vesicles via the inactivate this DA by transporting it into NE neurons as a
vesicular monoamine transporter (VMAT2) and stored there until
its release into the synapse during neurotransmission.
“false” substrate (Figure 4-3B).
Dopamine Action Is Terminated
E
E
dopamine MAO A or B MAO A or B

transporter destroys DA destroys DA
(DAT)
E
E
norepinephrine
COMT transporter DA COMT
DA
destroys DA (NET) destroys DA
A Striatal dopamine terminal B Cortical dopamine terminal

Figure 4-3 Dopamine’s action is terminated. Dopamine’s action can be terminated through multiple mechanisms. (A) Dopamine can
be transported out of the synaptic cleft and back into the presynaptic neuron via the dopamine transporter (DAT), where it may be
repackaged for future use. Alternatively, dopamine may be broken down extracellularly via the enzyme catechol-O-methyltransferase
(COMT). Other enzymes that break down dopamine are monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), which
are present in mitochondria within the presynaptic neuron and in other cells such as glia. (B) In the prefrontal cortex, DATs are relatively
sparse; thus, the predominant method of dopamine inactivation is via MAO-A or MAO-B intracellularly, and COMT extracellularly.
Dopamine can also diffuse away from the synapses and be taken up by the norepinephrine transporter (NET) at neighboring neurons.
80
Dopamine Receptors DA receptors are divided into two groups. The first
Receptors for DA are the key regulators of dopaminergic group is the D1-like receptors, including both D1 and D5
neurotransmission (Figure 4-4). We have already receptors. D1-like receptors are excitatory, and positively
mentioned the DA transporter DAT and the vesicular linked to adenylate cyclase (Figure 4-4, left). The second
monoamine transporter VMAT2, which are both types group is the D2-like receptors, including D2, D3, and D4
of receptors. A plethora of additional DA receptors exist, receptors. D2-like receptors are inhibitory and negatively
including at least five pharmacological subtypes and linked to adenylate cyclase (Figure 4-4, right). Thus,
several more molecular isoforms (Figure 4-4). Currently, the neurotransmitter DA can be either excitatory or
Postsynaptic Dopamine Receptors

4
D1 D2 D3 D4 D5
D1-Like Receptors D2-Like Receptors
DAT
Excitatory and Inhibit
stimulate postsynaptic
D1 D5 postsynaptic D2 D3 D4 neuron
neuron
Figure 4-4 Postsynaptic dopamine receptors. There are two groups of postsynaptic dopamine receptors. D1-like receptors, which
include both D1 and D5 receptors, are excitatory and thus stimulate the postsynaptic neuron. D2-like receptors, which include D2, D3, and
D4, are inhibitory and thus inhibit the postsynaptic neuron.
Presynaptic Dopamine Receptors Figure 4-5 Presynaptic dopamine

receptors. Dopamine 2 and 3 are also
located presynaptically, where, due to their
inhibitory actions, they act as autoreceptors
to inhibit further dopamine release. The D2
autoreceptor is less sensitive to dopamine
than the D3 autoreceptor and thus it takes a
higher concentration of synaptic dopamine
for the D2 autoreceptor to become activated
(left) than it does for the D3 autoreceptor to
D2 D3 become activated (right).
DAT
D1 D2 D3 D4 D5 D1 D2 D3 D4 D5
81
inhibitory, depending upon which DA receptor subtype has accumulated in the synapse with a D2 presynaptic
it binds. autoreceptor (on the left) than in the synapse with
All five DA receptors can be located postsynaptically a D3 presynaptic autoreceptor (on the right). This is
(Figure 4-4), but D2 and D3 receptors can also both be because the D3 receptor is more sensitive to DA and
located presynaptically, where, due to their inhibitory thus it takes a lesser concentration of synaptic DA to
actions, they act as autoreceptors to inhibit further DA activate the D3 receptor and turn off further DA release
release (Figure 4-5). Note in Figure 4-5 that more DA compared to neurons having the D2 presynaptic receptor.
Figure 4-6 Presynaptic dopamine

autoreceptors. Presynaptic D2 and
D3 autoreceptors are “gatekeepers”
for dopamine. (A) When dopamine
autoreceptors are not bound by
dopamine (no dopamine in the
gatekeeper’s hand), the molecular gate
presynaptic is open and allows dopamine release. (B)
autoreceptor (D2 or D3) When dopamine binds to the dopamine
“gatekeeper” - open autoreceptor (now the gatekeeper has
dopamine in his hand), the molecular
gate closes and prevents dopamine from
being released.
dopamine
presynaptic
autoreceptor (D2 or D3)
“gatekeeper” - closed
82
Presynaptic D2/D3 receptors act as “gatekeepers” either different manner than synapses with D2 presynaptic
allowing DA release when they are not occupied by autoreceptors (Figure 4-5), but also when comparing
DA (Figure 4-6A) or inhibiting DA release when DA mesocortical DA neurons with mesolimbic and
builds up in the synapse and occupies the gatekeeping nigrostriatal (mesostriatal) neurons side by side (Figure
presynaptic autoreceptor (Figure 4-6B). Such receptors 4-9). Mesocortical DA neurons arising from the ventral
are located either on the axon terminal (Figure 4-7) or tegmental area (VTA) in the brainstem and projecting
on the other end of the neuron in the somatodendritic to prefrontal cortex have either D2 or D3 autoreceptors
area of the DA neuron (Figure 4-8). In both cases, they on their cell bodies in the VTA, but there are only
are considered presynaptic and occupancy of these D2 sparse D2/D3 receptors in the prefrontal cortex pre- or
or D3 autoreceptors provides negative feedback input, postsynaptically (Figure 4-9A). Without autoreceptors
or a braking action upon the release of DA from the DA on axon terminals in the prefrontal cortex, DA release
4
neuron (Figures 4-7B and 4-8B). is not shut off by this mechanism and thus is freer to
Thus, DA neurons can be regulated quite differently diffuse away from the synapse where it is released,
depending upon which DA receptors are present. This as shown by the large blue cloud of DA. Moreover, as
is exemplified not only by synapses with D3 presynaptic already mentioned, mesocortical DA neurons have few
autoreceptors having their DA release regulated in a if any DATs on their presynaptic nerve terminals in the
Figure 4-7 Presynaptic dopamine

autoreceptors. Presynaptic D2 and
D3 autoreceptors can be located on
the axon terminal, as shown here.
When dopamine builds up in the
DA synapse (A), it is available to bind to
the autoreceptor, which then inhibits
dopamine release (B).
presynaptic
83
Figure 4-8 Somatodendritic

dopamine autoreceptors. D2 and D3
autoreceptors can also be located in
the somatodendritic area, as shown
somatodendritic
here. When dopamine binds to the
receptor here, it shuts off neuronal
impulse flow in the dopamine neuron
(see loss of lightning bolts in the
neuron in B), and this stops further
dopamine release.
prefrontal cortex. Without DATs to whisk synaptic DA thus beyond the synapse from where it was released. On
back into the presynaptic neuron, or D2/D3 presynaptic the other hand, mesostriatal DA neurons have either
autoreceptors to turn off DA release as synaptic DA presynaptic D2 or D3 receptors present, not only on the
accumulates, this allows a larger diffusion radius of DA cell bodies in the VTA and substantia nigra, but also on
away from presynaptic terminals (Figure 4-9A) compared presynaptic nerve terminals and postsynaptic sites in the
to terminals that have DATs and D2/D3 autoreceptors striatum (Figure 4-9B). Furthermore, DATs are present on
present (Figure 4-9B – note the sizes of the blue clouds presynaptic nerve terminals in the striatum of these DA
in these figures). That is a good thing perhaps, since the neurons. As mentioned, neurons with D2 autoreceptors
predominant postsynaptic receptor in the prefrontal have a wider diffusion radius compared to those with
cortex is the D1 receptor, and the D1 receptor is the least D3 autoreceptors, providing a range of possibilities for
sensitive to DA and thus requires a higher concentration regulation of DA release in the striatum (Figure 4-9B).
of DA to be present to be activated compared to D2 or
D3 receptors. Greater diffusion of DA also means the Classic Dopamine Pathways and Key Brain Regions
possibility of volume neurotransmission (see Chapter 1 The five classic DA pathways in the brain are shown in
and Figures 1-6 and 1-7) so that DA from one presynaptic Figure 4-10. They include the tuberoinfundibular DA
terminal can communicate with D1 receptors anywhere pathway, a thalamic DA pathway, the nigrostriatal DA
within its diffusion radius in the prefrontal cortex and pathway, and most importantly for the DA hypothesis,
84
PFC PFC striatum striatum
D1 D1 D1 D1 D1 D1 D1 D2 D3 D1 D2 D3
D3 D3 D2
D2
DAT D
DAT
D3 D2 D3 D2
D3 D2 D3 D2
D3 D3 D2 D2 D3 D3 D2 D2
VTA VTA and SN
mesocortical mesostriatal
A B (mesolimbic and nigrostriatal)
Figure 4-9 Mesocortical vs. mesostriatal neurons. (A) Mesocortical neurons project from the ventral tegmental area (VTA) to the
prefrontal cortex (PFC). In the VTA, dopamine release is regulated by somatodendritic D2 and D3 autoreceptors. In the PFC, however,
there are few D2 or D3 presynaptic autoreceptors to inhibit dopamine release, as well as few dopamine transporters (DATs) to
remove dopamine from the synapse. Thus, dopamine is more freely able to diffuse away from the synapse (indicated by the large
blue cloud). Postsynaptically, the predominant dopamine receptor is D1, which is excitatory. (B) Dopamine release from mesolimbic
neurons (projecting from the VTA to the striatum) is regulated by somatodendritic D3 autoreceptors in the VTA and by presynaptic D3
autoreceptors and DATs in the striatum (left). Dopamine release from nigrostriatal neurons (projecting from the substantia nigra [SN] to
the striatum) is regulated by somatodendritic D2 autoreceptors in the SN and by presynaptic D2 autoreceptors and DATs in the striatum
(right). D2 autoreceptors are less sensitive to dopamine than D3 autoreceptors, thus allowing for a wider diffusion radius (indicated by
the comparative sizes of the blue clouds). Postsynaptically, D1, D2, and D3 receptors are all present in the striatum.
the mesocortical and the mesolimbic DA pathways. by lesions or drugs, prolactin levels can also rise. Elevated
Advances in neuroscience propose some more recent and prolactin levels are associated with galactorrhea (breast
sophisticated ways to view these pathways in schizophrenia, secretions), gynecomastia (enlarged breasts especially
but first we will consider the classic approach. in men), amenorrhea (loss of ovulation and menstrual
periods), and possibly other problems such as sexual
Tuberoinfundibular Dopamine Pathway dysfunction. Such problems can occur after treatment
The DA neurons that project from hypothalamus to anterior with many drugs for psychosis that block DA D2 receptors,
pituitary gland are known as the tuberoinfundibular and will be discussed further in Chapter 5. In untreated
DA pathway (Figure 4-11). Normally, these neurons schizophrenia, the function of the tuberoinfundibular
are tonically active and inhibit prolactin release. In the pathway may be relatively preserved (Figure 4-11).
postpartum state, however, the activity of these DA
Thalamic Dopamine Pathway
neurons is decreased. Prolactin levels can therefore rise
during breast feeding so that lactation will occur. If the Recently, a DA pathway that innervates the thalamus in
functioning of tuberoinfundibular DA neurons is disrupted primates has been described. It arises from multiple sites,
85
Classic Dopamine Pathways and Key Brain Regions
DLPFC
striatum
nucleus
thalamus accumbens
a b
c
substantia
nigra e
hypothalamus VMPFC
pituitary
tegmentum
Figure 4-10 Five dopamine pathways in the brain. (a) The nigrostriatal dopamine pathway, which projects from the substantia nigra
to the basal ganglia or striatum, is part of the extrapyramidal nervous system and controls motor function and movement. (b) The
mesolimbic dopamine pathway projects from the midbrain ventral tegmental area (VTA) to the nucleus accumbens, a part of the limbic
system of the brain thought to be involved in many behaviors such as pleasurable sensations, the powerful euphoria of drugs of abuse,
and delusions and hallucinations of psychosis. (c) The mesocortical dopamine pathway also projects from the midbrain VTA but sends
its axons to areas of the prefrontal cortex, where they may have a role in mediating cognitive symptoms (dorsolateral prefrontal cortex
or DLPFC) and affective symptoms (ventromedial prefrontal cortex or VMPFC) of schizophrenia. (d) The tuberoinfundibular dopamine
pathway projects from the hypothalamus to the anterior pituitary gland and controls prolactin secretion. (e) The fifth dopamine pathway
arises from multiple sites, including the periaqueductal gray, ventral mesencephalon, hypothalamic nuclei, and lateral parabrachial
nucleus, and projects to the thalamus. Its function is not currently well known.
Figure 4-11 Tuberoinfundibular dopamine pathway. The

Tuberoinfundibular Pathway tuberoinfundibular dopamine pathway from the hypothalamus to
the anterior pituitary gland regulates prolactin secretion into the
circulation. Dopamine inhibits prolactin secretion. In untreated
schizophrenia, activation of this pathway is believed to be
“normal.”
normal
NORMAL
86
including the periaqueductal gray matter, the ventral 4-13F as the “direct” and “indirect” DA pathways. The
mesencephalon, from various hypothalamic nuclei, and so-called direct pathway (shown in Figure 4-13B on
from the lateral parabrachial nucleus (Figure 4-10). the left and in Figures 4-13C and 4-13E) is populated
Its function is still under investigation, but may be with D1 dopamine receptors that are excitatory (Figure
involved in sleep and arousal mechanisms by gating 4-13E; see also Figure 4-4, left) and projects directly from
information passing through the thalamus to the cortex the striatum to the globus pallidus interna to stimulate
and other brain areas. There is no evidence at this movements (“go” pathway) (Figure 4-13C). The so-called
point for abnormal functioning of this DA pathway in indirect pathway (shown in Figure 4-13B on the right
schizophrenia. and in Figures 4-13D and 4-13F) is populated with D2
dopamine receptors that are inhibitory (Figure 4-13F;
Nigrostriatal Dopamine Pathway
see also Figure 4-4, right) and projects indirectly to the
Another key DA pathway is the nigrostriatal DA pathway, 4
globus pallidus interna via the globus pallidus externa
which projects from DA cell bodies in the brainstem and subthalamic nucleus. Normally, this pathway blocks
substantia nigra via axons terminating in the striatum motor movements (“stop” pathway) (see Figure 4-13D).
(Figure 4-12). Classically, the nigrostriatal DA pathway Dopamine inhibits this action at D2 receptors in the
has been considered to be part of the extrapyramidal indirect pathway (Figure 4-13F) and this says “don’t stop”
nervous system, and to control motor movements to the stop pathway, or “go more.” The bottom line is that
via its connections with the thalamus and cortex in dopamine stimulates motor movements in both the direct
cortico-striato-thalamo-cortical (CSTC) circuits or loops and indirect motor pathways. Synchronizing the outputs
(Figure 4-13A). A more sophisticated anatomical model of these pathways is thought to lead to the smooth
of how DA regulates CSTC loops and motor movements execution of motor movements.
in the striatum is shown in Figures 4-13B through Figure
Nigrostriatal Pathway
Classic CSTC (Cortico-Striato-Thalamo-Cortical) Loop
normal C
NORMAL
T
DA
SN
Figure 4-12 Nigrostriatal dopamine pathway. The nigrostriatal C = cortex

T = thalamus
dopamine pathway projects from the substantia nigra to
S = striatum
the basal ganglia or striatum. It is part of the extrapyramidal SN = substantia nigra
nervous system and plays a key role in regulating movements.
When dopamine is deficient, it can cause parkinsonism with Figure 4-13A Cortico-striato-thalamo-cortical (CSTC) loop. In
tremor, rigidity, and akinesia/bradykinesia. When dopamine the most simple terms, the nigrostriatal dopamine pathway is
is in excess, it can cause hyperkinetic movements such as tics considered to control motor movements via its connections with
and dyskinesias. In untreated schizophrenia, activation of this the thalamus and cortex in a circuit known as the cortico-striato-
pathway is believed to be “normal.” thalamo-cortical loop.
87
Dopamine Regulation of Direct (D1) and Indirect (D2) Pathways:

Stop and Go Signals for Motor Movement
motor output
+ glu
Cortex
GABA
-
Thalamus
+ glu
GABA
GABA -
-
STN
GPi /SN r
GABA
direct pathway - indirect pathway
“go” GPe “stop”
D1 D2
+ -
DA DA
Striatum
STN= subthalamic nucleus

SNr = substantia nigra reticulata
SNc= substantia nigra compacta
GPe = globus pallidus externa
GP i = globus pallidus interna
glu = glutamate
GABA = γ-aminobutyric acid
DA = dopamine SN c
D1 = dopamine 1 receptor
Figure 4-13B Direct and indirect dopamine pathways for motor control. Populated with excitatory D1 receptors, the direct pathway for
dopamine regulation of motor movements (left) projects from the striatum to the globus pallidus interna and results in the stimulation
of movement. The indirect pathway for dopamine regulation of motor movements (right) projects to the globus pallidus interna via
the globus pallidus externa and subthalamic nuclei. This pathway is populated with inhibitory D2 receptors and normally blocks motor
movements.
Although there is no evidence at this point akinesia/bradykinesia (i.e., lack of movement or slowing
for abnormal functioning of this DA pathway in of movement), and tremor. DA deficiency in the striatum
schizophrenia (Figures 4-12 and 4-13), deficiencies of can hypothetically also be involved in the mechanism
DA in these motor pathways cause movement disorders that produces akathisia (a type of restlessness) and
including Parkinson’s disease, characterized by rigidity, dystonia (twisting movements especially of the face and
88
Go - Direct Pathway Activated Stop - Indirect Pathway Activated
STOP:
GO don’t go
+ glu
Cortex Cortex
GABA
G
-
Thalamus Thalamus
+ glu
4
GABA
BA
-
STN STN
GPi /SN r GPi /SN r
activation of
direct pathway G
GABA
-
“GO” activation of
GPe GPe
indirect pathway
“STOP”
“don’t go”
STN= subthalamic nucleus

SNr = substantia nigra reticulata Striatum Striatum
SNc = substantia nigra compacta
GPi = globus pallidus interna STN= subthalamic nucleus
glu = glutamate SNr = substantia nigra reticulata
GABA = γ-aminobutyric acid SNc= substantia nigra compacta
glu = glutamate
SNc GABA = γ-aminobutyric acid SN c
Figure 4-13C Activation of the direct (go) dopamine

pathway. A γ-aminobutyric acid (GABA) neuron projecting Figure 4-13D Activation of the indirect (stop) dopamine
from the striatum to the globus pallidus interna is activated. The pathway. A γ-aminobutyric acid (GABA) neuron projecting from
released GABA inhibits activity of another GABAergic neuron the striatum to the globus pallidus externa is activated. The
that projects to the thalamus. In the absence of GABA release in released GABA inhibits activity of another GABAergic neuron
the thalamus, a glutamatergic neuron is activated and releases that projects to the subthalamic nucleus (STN). In the absence
glutamate into the cortex, stimulating movement. of GABA release in the STN, a glutamatergic neuron is activated
and releases glutamate into the globus pallidus interna, which
in turn stimulates a GABAergic neuron to release GABA into
the thalamus. GABA then binds to a glutamatergic neuron,
inhibiting it from releasing glutamate into the cortex and thus
neck). These same movement disorders can be replicated inhibiting movement.
by drugs that block D2 DA receptors in this pathway,
causing drug-induced parkinsonism (sometimes called
by its better-known but much less accurate name levodopa-induced dyskinesias or LID). Chronic blockade
extrapyramidal symptoms or EPS). This will be discussed of these same D2 DA receptors in the nigrostriatal
in more detail in Chapter 5 on drugs for the treatment of pathway is hypothesized to cause another hyperkinetic
psychosis. movement disorder known as tardive dyskinesia. Tardive
Not only can too little DA activity cause movement dyskinesia and its treatment will be discussed further in
disorders, so can too much. Thus, hyperactivity of Chapter 5 on drugs for psychosis.
DA in the nigrostriatal pathway is thought to underlie
various hyperkinetic movement disorders such as chorea, The Mesolimbic Dopamine Pathway
dyskinesias, and tics (in conditions such as Huntington’s The mesolimbic DA pathway projects from DA cell
disease, Tourette syndrome, and others). Chronic bodies in the VTA of the brainstem (i.e., mesencephalon)
stimulation of D2 DA receptors in the nigrostriatal to the nucleus accumbens in the ventral striatum,
pathway by treatment of Parkinson’s disease with which is part of the limbic system (thus, mesolimbic)
levodopa is hypothesized to underlie the emergence of (Figures 4-10 and 4-14 A–D). DA release from this
abnormal hyperkinetic and dyskinetic movements (called pathway is thought to have an important role in several
89
D1 Stimulation of Go Pathway D2 Inhibition of Stop Pathway
GO Inhibition of stop
or “GO”
+
+ glu glu
g
Cortex
Cortex
Thalamus
Thalamus
-
GABA
BA
- GABA
G
STN
GPi /SN r STN
GPi /SN r
GPe
GPe
D1 stimulation of
+ D2
“GO” pathway - DA
-
“go more” DA
STN= subthalamic nucleus Striatum STN= subthalamic nucleus
SNr = substantia nigra reticulata SNr = substantia nigra reticulata Striatum
SNc= substantia nigra compacta SNc= substantia nigra compacta
GPe = globus pallidus externa GPe = globus pallidus externa D2 inhibition of
GP i = globus pallidus interna GP i = globus pallidus interna “STOP” pathway -
glu = glutamate glu = glutamate “don’t stop,
GABA = γ-aminobutyric acid GABA = γ-aminobutyric acid
so go more”
DA = dopamine DA = dopamine
D1 = dopamine 1 receptor D2 = dopamine 2 receptor
SN c
SN c
Figure 4-13E Dopamine-1 receptor stimulation of the go
pathway. Dopamine released from the nigrostriatal pathway Figure 4-13F Dopamine-2 receptor inhibition of the stop
binds to postsynaptic D1 receptors on a γ-aminobutyric acid pathway. Dopamine released from the nigrostriatal pathway
(GABA) neuron projecting to the globus pallidus interna. This binds to postsynaptic D2 receptors on a γ-aminobutyric acid
causes phasic activation of the direct (go) pathway, essentially (GABA) neuron projecting to the globus pallidus externa. This
telling it to “go more.” causes inhibition of the indirect (stop) pathway, thus instead
telling it to “go.”
normal emotional behaviors, including motivation, The Classic Dopamine Hypothesis of the
pleasure, and reward (Figure 4-14A). Although this may Positive Symptoms of Psychosis: Mesolimbic
be an oversimplification, the mesolimbic dopamine HyperDopaminergia
pathway may in fact be the final common pathway As mentioned above, hyperactivity of this mesolimbic
of all reward and reinforcement, including not only DA pathway (“hyperdopaminergia”) hypothetically
normal reward (such as the pleasure of eating good accounts for positive psychotic symptoms (that is,
food, orgasm, listening to music) (Figure 4-14A), but delusions and hallucinations) as a final common pathway
also emotions experienced when rewards are too high for psychosis, whether those symptoms are part of the
(Figures 4-14B and C) or too low (Figure 4-14D). Too illness of schizophrenia, of drug-induced psychosis, or
much DA in this pathway classically is thought to cause whether positive psychotic symptoms accompany mania,
the positive symptoms of psychosis (Figure 4-14C) as depression, Parkinson’s disease, or dementia. Hyperactivity
well as the artificial reward (drug-induced “high”) of of mesolimbic DA neurons may also play a role in causing
substance abuse (Figure 4-14B) (see also discussion impulsive, agitated, aggressive, and hostile symptoms in
on drugs of abuse in Chapter 13). On the other hand, any of the illnesses associated with positive symptoms
too little DA in this pathway hypothetically causes the of psychosis (Figure 4-15). Although mesolimbic
symptoms of anhedonia, apathy, and lack of energy seen DA hyperactivity can be a direct pharmacological
in conditions such as unipolar and bipolar depression consequence of psychostimulants such as cocaine and
and in the negative symptoms of schizophrenia (Figure methamphetamine, mesolimbic DA hyperactivity
4-14D). in psychosis associated with schizophrenia, mania,
90
Classic Mesolimbic Pathway
normal
HIGH
4
overactivation
B
drug-induced high
normal
HIGH
DA
neuron
A
C
positive
symptoms
motivation reward
normal
LOW
affective
Figure 4-14 Mesolimbic dopamine pathway. (A) The
symptoms
mesolimbic dopamine pathway, which projects from the
ventral tegmental area (VTA) in the brainstem to the nucleus D
accumbens in the ventral striatum, is involved in regulation of
motivation and reward. Classically, hyperactivity of this pathway (SIGH)
negative
is associated with drug-induced highs (B) and is believed to
symptoms
account for the positive symptoms of psychosis (C), while anhedonia
hypoactivity is associated with symptoms of anhedonia, apathy,
and lack of energy as well as with the negative symptoms of apathy
schizophrenia. lack of energy
91
The Classic Mesolimbic Dopamine Hypothesis of

Positive Symptoms of Schizophrenia
haircuts
impulsivity
agitation
mesolimbic overactivity = violence/

positive symptoms of schizophrenia aggression
*#%!
hostility
positive symptoms
Figure 4-15 Mesolimbic dopamine hypothesis. Hyperactivity of dopamine neurons in the mesolimbic dopamine pathway theoretically
mediates the positive symptoms of psychosis such as delusions and hallucinations. Mesolimbic overactivity may also be associated with
impulsivity, agitation, violence/aggression, and hostility.
depression, Parkinson’s disease, or Alzheimer disease striatum for motor movements (the “neurologists’
and other dementias may be the indirect consequence of striatum”) and a ventral or “lower” striatum for emotions
dysregulation in prefrontal circuits and their glutamate (the “psychiatrists’ striatum”) (Figure 4-16A). These
and serotonin neurons as well as dopamine neurons. concepts have been derived largely from anatomical
These brain circuits are discussed in detail in the following and pharmacological studies in rodents combined
sections on glutamate and serotonin. with drug studies in humans. Although heuristically
valuable, recent results from human neuroimaging
New Developments in the Dopamine Hypothesis of studies show that the idea of separate dedicated pathways
Positive Symptoms of Psychosis in Schizophrenia where anatomical differences correlate with function
Classically, DA projections from the substantia nigra to (motor vs. emotion) may need to be modified. That is,
the dorsal striatum (Figure 4-12) have been considered neuroimaging of DA activity in the striatum of living,
to regulate motor movements and to be in parallel with unmedicated patients with schizophrenia does not
pathways from the VTA to the ventral striatum (nucleus show the expected hyperdopaminergia uniquely in the
accumbens) that regulate emotions (Figure 4-14A). ventral striatum. Instead, the hyperdopaminergia may be
A simplistic notion is that there is a dorsal or “upper” especially present in an intermediate part of the striatum
92
called the associative striatum, which receives input from and lateral substantia nigra may also be important in
the substantia nigra but not from the VTA (Figure 4-16B). mediating the positive symptoms of schizophrenia
These findings suggest that a more sophisticated (Figure 4-16B). These findings indicate a remarkable
formulation of DA pathways may be necessary in order development in thinking about the dorsal striatum and
to understand the hyperdopaminergia of schizophrenia. nigrostriatal pathways as having emotional as well as
That is, hyperdopaminergia in projections not only motor components. Compulsions and habits are also
from the VTA but perhaps especially from the medial theoretically localized to the dorsal striatum (discussed
Classic Mesolimbic Hyperdopaminergia

dorsal dorsal 4
striatum striatum
ventral ventral
striatum striatum
SN SN
VTA VTA
normal schizophrenia
overactivation
A
New Concept:
Integrative Hub Mesostriatal Hyperdopaminergia
sensorimotor sensorimotor
associative associative
ventral ventral
SN(L) SN(M) SN(L) SN(M)

VTA VTA
B
normal schizophrenia
SN(L) substantia nigra lateral

SN(M) substantia nigra medial
VTA ventral tegmental area
Figure 4-16 Integrative hub mesostriatal hyperdopaminergia. (A) A classic understanding of striatal functioning has been that the
dorsal striatum regulates motor movement and the ventral striatum regulates emotions, with overactivity of dopamine in the ventral
striatum associated with the positive symptoms of schizophrenia. (B) Neuroimaging data in unmedicated patients with schizophrenia
suggest that dopaminergic activity may be unaltered in the ventral striatum, but may instead be overactive in an intermediate part of
the striatum called the associative striatum, which receives input from the substantia nigra rather than the ventral tegmental area (VTA).
Rather than separate nigrostriatal and mesolimbic projections, a better conception may be that of a mesostriatal pathway.
93
Classic Mesocortical Pathway to DLPFC
normal
LOW
(SIGH)
A B
negative cognitive
symptoms symptoms
Figure 4-17 Mesocortical pathway to the dorsolateral prefrontal cortex (DLPFC). The mesocortical dopamine pathway projects
from the ventral tegmental area (VTA) to the prefrontal cortex. Projections specifically to the DLPFC are associated with cognitive and
executive functioning (A), with hypoactivity in this pathway classically believed to be involved in the cognitive and some negative
symptoms of schizophrenia (B).
Classic Mesocortical Pathway to VMPFC
normal
LOW
(SIGH)
A B
negative affective
symptoms symptoms
Figure 4-18 Mesocortical pathway to the ventromedial prefrontal cortex (VMPFC). The mesocortical dopamine pathway projects from
the ventral tegmental area (VTA) to the prefrontal cortex. Projections specifically to the VMPFC are associated with emotions and affect
(A), with hypoactivity in this pathway classically believed to be involved in the negative and affective symptoms of schizophrenia (B).
in Chapter 13). Thus, the dorsal striatum may not be all bottom line is that rather than thinking of the projections
motor and only the neurologists’ striatum! It may also from the midbrain to the striatum as parallel pathways
have an important role in emotional regulation. The with separate and distinct functions (as in Figure
94
The Classic Mesocortical Dopamine Hypothesis of Cognitive, Negative,

and Affective Symptoms of Schizophrenia
cognitive
symptoms 4
(SIGH)
negative
symptoms
affective
symptoms
Figure 4-19 Mesocortical dopamine hypothesis. Hypoactivity of dopamine neurons in the mesocortical dopamine pathway
theoretically mediates the cognitive, negative, and affective symptoms of schizophrenia.
4-16A), the new notion from neuroimaging is that the dorsolateral prefrontal cortex (Figure 4-17) whereas
VTA–substantia nigra complex is instead an integrative affective and other negative symptoms of schizophrenia
hub and its pathways can be thought of as mesostriatal may be due to a deficit of DA activity in mesocortical
rather than nigrostriatal/mesolimbic (Figure 4-16B). projections to ventromedial prefrontal cortex (Figure
Hyperdopaminergia of schizophrenia in this sense is 4-18). The behavioral deficit state suggested by negative
mesostriatal rather than purely mesolimbic. symptoms certainly implies underactivity or lack of
proper functioning of mesocortical DA projections,
Corollary to the Classic Dopamine Hypothesis of
and a leading theory is that this is the consequence of
Schizophrenia: Mesocortical HypoDopaminergia and
the Cognitive, Negative, and Affective Symptoms of
neurodevelopmental abnormalities in the N-methyl-D-
Schizophrenia aspartate (NMDA) glutamate system, as described in the
following section on glutamate.
Another DA pathway also arising from cell bodies
in the VTA but projecting to areas of the prefrontal
THE GLUTAMATE HYPOTHESIS
cortex is known as the mesocortical DA pathway
(Figures 4-17 through 4-19). Branches of this pathway
OF PSYCHOSIS AND
into the dorsolateral prefrontal cortex are hypothesized SCHIZOPHRENIA
to regulate cognition and executive functions (Figure The glutamate theory of psychosis proposes that the
4-17), whereas branches of this pathway into the NMDA (N-methyl-D-aspartate) subtype of glutamate
ventromedial parts of prefrontal cortex are hypothesized receptor is hypofunctional at critical synapses in the
to regulate emotions and affect (Figure 4-18). The prefrontal cortex (Table 4-1 and Figure 4-1). Disruption of
exact role of the mesocortical DA pathway in mediating NMDA glutamate functioning can be hypothetically due to
symptoms of schizophrenia is still a matter of debate, the neurodevelopmental abnormalities in schizophrenia, to
but many researchers believe that cognitive and some the neurodegenerative abnormalities in Alzheimer disease
negative symptoms of schizophrenia may be due to a and other dementias, and to the NMDA receptor blocking
deficit of DA activity in mesocortical projections to the actions of drugs such as the dissociative anesthetics
95
ketamine and phencyclidine (PCP) (Figure 4-1 and Table neurotransmitter, but as an amino acid building block for
4-1). In order to understand how glutamate dysfunction protein biosynthesis. When used as a neurotransmitter,
could lead to the positive, negative, and cognitive it is synthesized from glutamine in glia, which also assist
symptoms of psychosis in various disorders, and also in the recycling and regeneration of more glutamate
how glutamate dysfunction might cause the downstream following glutamate release during neurotransmission.
hyperdopaminergia discussed in the previous section, we When glutamate is released from synaptic vesicles of
will first review glutamate and its receptors and pathways. glutamate neurons, it interacts with receptors in the
synapse and is then transported into neighboring glia
The Glutamate Neurotransmitter Network
by a reuptake pump known as an excitatory amino acid
Glutamate is the major excitatory neurotransmitter in transporter (EAAT) (Figure 4-20A). The presynaptic
the central nervous system and is sometimes considered glutamate neuron and the postsynaptic site of glutamate
to be the “master switch” of the brain, since it can neurotransmission may also have EAATs (not shown in
excite and turn on virtually all central nervous system the figures) but these EAATs do not appear to play as
neurons. In recent years, glutamate has attained a key important a role in glutamate recycling and regeneration
theoretical role in the hypothesized pathophysiology as the EAATs in glia (Figure 4-20A).
of schizophrenia, of positive symptoms of psychosis After reuptake into glia, glutamate is converted
in general, and also in a number of other psychiatric into glutamine inside the glia by an enzyme known
disorders, including depression. It is also now a key target as glutamine synthetase (arrow 3 in Figure 4-20B).
of novel psychopharmacological agents for the treatment It is possible that glutamate is not simply reused but
of schizophrenia and depression. The synthesis, rather converted into glutamine, to keep it in a pool for
metabolism, receptor regulation, and key pathways of neurotransmitter use, rather than being lost into the pool
glutamate are therefore critical to the functioning of the for protein synthesis. Glutamine is released from glia by
brain and will be reviewed here. reverse transport via a pump or transporter known as a
specific neutral amino acid transporter (SNAT, arrow 4
Glutamate Synthesis
in Figure 4-20C). Glutamine may also be transported out
Glutamate, or glutamic acid, is a neurotransmitter of glia by a second transporter known as a glial alanine–
that is an amino acid. Its predominant use is not as a serine–cysteine transporter or ASC-T (not shown). When
Figure 4-20A Glutamate is recycled and

Glutamate Is Recycled and Regenerated: Part 1 regenerated, part 1. After release of glutamate
from the presynaptic neuron (1), it is taken up into
glial cells via the excitatory amino acid transporter
(EAAT) (2).
glial cell
2 glutamate
2
1
EAAT
GLU (glutamate)
96
Figure 4-20B Glutamate is recycled and

Glutamate Is Recycled and Regenerated: Part 2 regenerated, part 2. Once inside the glial cell,
glutamate is converted into glutamine by the
enzyme glutamine synthetase (3).
glial cell
glutamine
3
glutamine
E synthetase 4
glutamate
Figure 4-20C Glutamate is recycled and

Glutamate Is Recycled and Regenerated: Part 3 regenerated, part 3. Glutamine is released from
glial cells by a specific glial neutral amino acid
transporter (SNAT) through the process of reverse
transport (4), and then taken up by SNATs on
SNAT
glutamine glutamate neurons (5).
5
5
reversed
SNAT 4 glial cell
glutamine
glial SNATs and ASC-Ts operate in the inward direction, for subsequent release during neurotransmission.
they transport glutamine and other amino acids into Once released, glutamate’s actions are stopped not by
glia. Here, they are reversed so that glutamine can get enzymatic breakdown, as in other neurotransmitter
out of the glia and hop a ride into a neuron via a different systems, but by removal by EAATs on neurons or glia, and
type of neuronal SNAT, operating inwardly in a reuptake the whole cycle is started again (Figures 4-20A–D).
manner (arrow 5 in Figure 4-20C).
Synthesis of Glutamate Cotransmitters Glycine and
Once inside the neuron, glutamine is converted
D-Serine
back into glutamate for use as a neurotransmitter by
an enzyme in mitochondria called glutaminase (arrow Glutamate systems are curious in that one of the
6 in Figure 4-20D). Glutamate is then transported into key receptors for glutamate requires a cotransmitter
synaptic vesicles via a vesicular glutamate transporter in addition to glutamate in order to function. That
(vGluT, arrow 7 in Figure 4-20D), where it is stored receptor is the NMDA receptor, described below, and
97
Figure 4-20D Glutamate is recycled and

Glutamate Is Recycled and Regenerated: Part 4 regenerated, part 4. Glutamine is converted
into glutamate within the presynaptic glutamate
neuron by the enzyme glutaminase (6) and
taken up into synaptic vesicles by the vesicular
glutamine glutamate transporter (vGluT), where it is stored
for future release.
6
glutaminase glial cell

6 glutamate
vGluT
7
the cotransmitter is either the amino acid glycine main mechanism responsible for terminating the action
(Figure 4-21), or another amino acid, closely related to of synaptic glycine (Figure 4-21). GlyT1 transporters
glycine, known as D-serine (Figure 4-22). are probably also located on the glutamate neuron, but
Glycine is not known to be synthesized by glutamate any release or storage from the glutamate neuron is
neurons, so glutamate neurons must get the glycine not well characterized (Figure 4-21). Glycine can also
they need for their NMDA receptors either from glycine be synthesized from the amino acid L-serine, derived
neurons or from glia (Figure 4-21). Glycine neurons from the extracellular space, bloodstream, and diet,
contribute only a small amount of glycine to glutamate transported into glia by an L-serine transporter (L-
synapses, since much of the glycine they release is taken SER-T), and converted from L-serine into glycine by the
back up into those neurons by a type of glycine reuptake glial enzyme serine hydroxymethyl-transferase (SHMT)
pump known as the type 2 glycine transporter (GlyT2) (Figure 4-21). This enzyme works in both directions,
(Figure 4-21). either converting L-serine into glycine, or glycine into
Thus, neighboring glia are thought to be the source L-serine.
of most of the glycine available for glutamate synapses. How is the cotransmitter D-serine produced? D-serine
Glycine itself can be taken up into glia as well as into is unusual in that it is a D-amino acid, whereas the 20
glutamate neurons from the synapse by a type 1 glycine known essential amino acids are all L-amino acids,
transporter (GlyT1) (Figure 4-21). Glycine can also including D-serine’s mirror image amino acid L-serine.
be taken up into glia by a glial SNAT (specific neutral It just so happens that D-serine has high affinity for
amino acid transporter). Glycine is not known to be the glycine site on NMDA receptors, and that glia are
stored within synaptic vesicles of glia, but as we will equipped with an enzyme that can convert regular L-
learn below, the companion neurotransmitter D-serine serine into the neurotransmitting amino acid D-serine by
is thought possibly to be stored within some type of means of an enzyme that can go back and forth between
storage vesicle within glia. Glycine in the cytoplasm of D- and L-serine known as D-serine racemase (Figure
glia is nevertheless somehow available for release into 4-22). Thus, D-serine can be derived either from glycine
synapses, and it escapes from glial cells by riding outside or from L-serine, both of which can be transported
them and into the glutamate synapse on a reversed into glia by their own transporters, and then glycine
GlyT1 transporter (Figure 4-21). Once outside, glycine converted to L-serine by the enzyme SHMT, and finally
can get right back into the glia by an inwardly directed L-serine converted into D-serine by the enzyme D-serine
GlyT1, which functions as a reuptake pump and is the racemase (Figure 4-22). Interestingly, the D-serine so
98
NMDA Receptor Cotransmitter Glycine Is Produced
glutamate
neuron
L-serine
L
glycine L-SER-T
glial cell
neuron
L
SHMT GlyT1
E 4
SNAT
GlyT2
reversed
GlyT1 GlyT1
(release) (reuptake)
glycine
NMDA receptors
Figure 4-21 NMDA receptor cotransmitter glycine is produced. Glutamate’s actions at NMDA receptors are dependent in part upon
the presence of a cotransmitter, either glycine or D-serine. Glycine can be derived directly from dietary amino acids and transported into
glial cells either by a glycine transporter (GlyT1) or by a specific neutral amino acid transporter (SNAT). Glycine can also be produced
both in glycine neurons and in glial cells. Glycine neurons provide only a small amount of the glycine at glutamate synapses, because
most of the glycine released by glycine neurons is used only at glycine synapses and then taken back up into presynaptic glycine
neurons via the glycine 2 transporter (GlyT2) before much glycine can diffuse to glutamate synapses. Glycine produced by glial cells
plays a larger role at glutamate synapses. Glycine is produced in glial cells when the amino acid L-serine is taken up into glial cells via
the L-serine transporter (L-SER-T), and then converted into glycine by the enzyme serine hydroxymethyl-transferase (SHMT). Glycine from
glial cells is released into the glutamate synapse through reverse transport by GlyT1. Extracellular glycine is then transported back into
glial cells via GlyT1.
produced may be stored in some sort of vesicle in glia of DAO, known not surprisingly as D-amino acid oxidase
for subsequent release on a reversed glial D-serine activator or DAOA.
transporter (D-SER-T) for neurotransmitting purposes
Glutamate Receptors
at glutamate synapses containing NMDA receptors.
D-serine’s actions are not only terminated by synaptic There are several types of glutamate receptors (Figure
reuptake via the inwardly acting glial D-SER-T, but also 4-23 and Table 4-2), including the neuronal presynaptic
by an enzyme D-amino acid oxidase (DAO) that converts reuptake pump (EAAT) and the vesicular transporter for
D-serine into inactive hydroxypyruvate (Figure 4-22). glutamate into synaptic vesicles (vGluT), both of which
Below, we will discuss how the brain makes an activator are types of receptors. The general pharmacological
99
NMDA Receptor Cotransmitter D-Serine Is Produced
glutamate
neuron
GlyT1
SHMT
L SNAT
D-serine racemase L-SER-T
L
L
D DAO
OH-pyruvate
D D
glutamate reversed
glial D-SER-T glial D-SER-T
D D-serine (release)
D
(reuptake)
L L-serine
glycine D
Figure 4-22 NMDA receptor cotransmitter D-serine is produced. Glutamate requires the presence of either glycine or D-serine at
NMDA receptors in order to exert some of its effects there. In glial cells, the enzyme serine racemase converts L-serine into D-serine,
which is then released into the glutamate synapse via reverse transport on the glial D-serine transporter (glial D-SER-T). L-serine’s
presence in glial cells is a result of either its transport there via the L-serine transporter (L-SER-T) or its conversion into L-serine from
glycine via the enzyme serine hydroxymethyl-transferase (SHMT). Once D-serine is released into the synapse, it is taken back up into the
glial cell by a reuptake pump called D-SER-T. Excess D-serine within the glial cell can be destroyed by the enzyme D-amino acid oxidase
(DAO), which converts D-serine into hydroxypyruvate (OH-pyruvate).
properties of various transporters are discussed in Chapter presynaptically, where they function as autoreceptors
2. Shown also on the presynaptic neuron as well as the to block glutamate release (Figures 4-23 and 4-24).
postsynaptic neuron are metabotropic glutamate receptors Drugs that stimulate these presynaptic autoreceptors as
(Figure 4-23). Metabotropic glutamate receptors are those agonists may therefore reduce glutamate release. Group I
glutamate receptors that are linked to G proteins. The metabotropic glutamate receptors on the other hand may
general pharmacological properties of G-protein-linked be located predominantly postsynaptically, where they
receptors are also discussed in Chapter 2. hypothetically interact with other postsynaptic glutamate
There are at least eight subtypes of metabotropic receptors to facilitate and strengthen responses mediated
glutamate receptors, organized into three separate by ligand-gated ion-channel receptors for glutamate
groups (Table 4-2). Research suggests that Group during excitatory glutamatergic neurotransmission
II and Group III metabotropic receptors can occur (Figure 4-23).
100
Glutamate Receptors
Figure 4-23 Glutamate receptors. Shown
here are receptors for glutamate that
regulate its neurotransmission. The excitatory
amino acid transporter (EAAT) exists
presynaptically and is responsible for clearing
excess glutamate out of the synapse. The
vesicular transporter for glutamate (vGluT)
transports glutamate into synaptic vesicles,
where it is stored until used in a future
neurotransmission. Metabotropic glutamate
receptors (linked to G proteins) can occur
either pre- or postsynaptically. Three types of
postsynaptic glutamate receptors are linked to
ion channels, and are known as ligand-gated
ion channels: N-methyl-D-aspartate (NMDA)
receptors, α-amino-3-hydroxy-5-methyl-4-
isoxazole-propionic acid (AMPA) receptors, 4
vGluT presynaptic and kainate receptors, all named for the
metabotropic agonists that bind to them.
receptor
EAAT
NMDA AMPA kainate postsynaptic

receptor receptor receptor metabotropic
receptor
NMDA (N-methyl-D-asparate), AMPA (α-amino- which plugs its calcium channel (Figure 4-26). NMDA
3-hydroxy-5-methyl-4-isoxazole-propionic acid), receptors are an interesting type of “coincidence detector”
and kainate receptors for glutamate, named after the that can open to let calcium into the neuron to trigger
agonists that selectively bind to them, are all members postsynaptic actions from glutamate neurotransmission
of the ligand-gated ion-channel family of receptors only when three things occur at the same time (Figures
(Figure 4-23 and Table 4-2). These ligand-gated ion 4-26 and 4-27):
channels are also known as ionotropic receptors and (1) glutamate occupies its binding site on the NMDA
also as ion-channel-linked receptors. The general receptor
pharmacological properties of ligand-gated ion channels (2) glycine or D-serine binds to its site on the NMDA
are discussed in Chapter 3. They tend to be postsynaptic receptor
and work together to modulate excitatory postsynaptic (3) depolarization occurs, allowing the magnesium plug
neurotransmission triggered by glutamate. Specifically, to be removed
AMPA and kainate receptors may mediate fast, excitatory Some of the many important signals by NMDA receptors
neurotransmission, allowing sodium to enter the neuron that are activated when NMDA calcium channels are
to depolarize it (Figure 4-25). NMDA receptors in the opened include long-term potentiation and synaptic
resting state are normally blocked by magnesium, plasticity, as will be explained later in this chapter.
101
Table 4-2 Glutamate receptors
Metabotropic
Group I mGluR1
mGluR5
Group II mGluR2
mGluR3
Group III mGluR4
mGluR6
mGluR7
mGluR8
Ionotropic (ligand-gated ion channels; ion-channel-linked receptors)

Functional class Gene family Agonists Antagonists
AMPA GluR1 Glutamate
GluR2 AMPA
GluR3 Kainate
GluR4
Kainate GluR5 Glutamate
GluR6 Kainate
GluR7
KA1
KA2
NMDA NR1 Glutamate
NR2A Aspartate
NR2B NMDA MK801
NR2C Ketamine
NR2D PCP (phencyclidine)
Key Glutamate Pathways in the Brain (a) Cortico-brainstem glutamate pathways. A very
Glutamate is a ubiquitous excitatory neurotransmitter important descending glutamatergic pathway projects
that seems to be able to excite nearly any neuron in the from glutamatergic cortical pyramidal neurons
brain. That is why it is sometimes called the “master to brainstem neurotransmitter centers, including
switch.” Nevertheless, there are about a half-dozen the raphe for serotonin, the ventral tegmental area
specific glutamatergic pathways that are of particular (VTA) and substantia nigra for dopamine, and
relevance to psychopharmacology and especially to the the locus coeruleus for norepinephrine (pathway
pathophysiology of schizophrenia (Figure 4-28). They are: a in Figure 4-28). This pathway is the cortico-
(a) Cortico-brainstem brainstem glutamate pathway, and is a key regulator
(b) Cortico-striatal of neurotransmitter release. Direct innervation
(c) Hippocampal-striatal of monoamine neurons in the brainstem by these
(d) Thalamo-cortical excitatory cortico-brainstem glutamate neurons
(e) Cortico-thalamic stimulates neurotransmitter release, whereas
(f) Cortico-cortical (direct) indirect innervation of monoamine neurons by
(g) Cortico-cortical (indirect)
102
Figure 4-24 Metabotropic glutamate

autoreceptors. Groups II and III
metabotropic glutamate receptors can
exist presynaptically as autoreceptors to
regulate the release of glutamate. When
glutamate builds up in the synapse (A), it
is available to bind to the autoreceptor,
which then inhibits glutamate release (B).
mGluR type II/III

presynaptic
autoreceptor
mGluR type II/III

presynaptic
autoreceptor
103
Na+ K+ closed &

desensitized
glutamate
prolonged
agonist
AMPA, kainate
receptors agonist desensitized
resting open
&
depolarized
fast excitatory neurotransmission
Figure 4-25 Glutamate at AMPA and kainate receptors. When glutamate binds to AMPA and kainate receptors, this leads to
fast excitatory neurotransmission and membrane depolarization. Sustained binding of the agonist glutamate will lead to receptor
desensitization, causing the channel to close and be transiently unresponsive to agonist.
Na+ Ca++
Mg++
Mg++
glutamate
glycine
NMDA
receptors
co-agonists depolarization
& other mechanisms
resting but blocked by Mg++ co-agonists open the channel, open

but it is blocked by Mg++ &
- not depolarized unblocked
Figure 4-26 Magnesium as a negative allosteric modulator. Magnesium is a negative allosteric modulator at NMDA glutamate
receptors. Opening of NMDA glutamate receptors requires the presence of both glutamate and glycine, each of which bind to a
different site on the receptor. When magnesium is also bound and the membrane is not depolarized, it prevents the effects of glutamate
and glycine and thus does not allow the ion channel to open. In order for the channel to open, depolarization must remove magnesium
while both glutamate and glycine are bound to their sites on the ligand-gated ion-channel complex.
these excitatory cortico-glutamate neurons via (c) Hippocampal-accumbens glutamate pathway.

γ-aminobutyric acid (GABA) interneurons in the Another key glutamate pathway projects from the
brainstem blocks neurotransmitter release. hippocampus to the nucleus accumbens and is
(b) Cortico-striatal glutamate pathways. A second known as the hippocampal-accumbens glutamate
descending glutamatergic output from cortical pathway (c in Figure 4-28). Specific theories link this
pyramidal neurons projects to the striatal complex particular pathway to schizophrenia (see below). Like
(pathway b in Figure 4-28). This pathway is the cortico-striatal glutamate pathway (b in Figure
known as the cortico-striatal glutamate pathway. 4-28), the hippocampal glutamate projection to the
This descending glutamate pathway terminates nucleus accumbens (c in Figure 4-28) also terminates
on GABA neurons destined for a relay station in on GABA neurons there that in turn project to a relay
another part of the striatal complex called the station in the globus pallidus.
globus pallidus. (d) Thalamo-cortical glutamate pathway. The thalamo-
cortical glutamate pathway (d in Figure 4-28) brings
104
Na+ Mg++
K+
glycine
resting but
resting blocked by Mg++
glutamate Na+
glutamate Ca++
activated resting but activated activated

blocked by Mg++
depolarization
B C
long-term
potentiation
Figure 4-27 Signal propagation via glutamate receptors. (A) On the left is an AMPA receptor with its sodium channel in the resting
state, allowing minimal sodium to enter the cell in exchange for potassium. On the right is an NMDA receptor in the resting state, with
magnesium blocking the calcium channel and glycine bound to its site. (B) When glutamate arrives, it binds to the AMPA receptor,
causing the sodium channel to open, thus increasing the flow of sodium into the dendrite and potassium out of the dendrite. This
causes the membrane to depolarize and triggers a postsynaptic nerve impulse. (C) Depolarization of the membrane removes
magnesium from the calcium channel. This, coupled with glutamate binding to the NMDA receptor in the presence of glycine, causes
the NMDA receptor to open and allow calcium influx. Calcium influx through NMDA receptors contributes to long-term potentiation, a
phenomenon that may be involved in long-term learning, synaptogenesis, and other neuronal functions.
information from the thalamus back into the cortex, their own neurotransmitter glutamate (f in Figure
often to process sensory information. 4-28).
(e) Cortico-thalamic glutamate pathway. A fifth glutamate (g) Indirect cortico-cortical glutamate pathways. On
pathway, known as the cortico-thalamic glutamate the other hand, one pyramidal neuron can inhibit
pathway, projects directly back to the thalamus, where another via indirect input, namely via interneurons
it may direct the manner in which neurons react to that release GABA (g in Figure 4-28).
sensory information (pathway e in Figure 4-28).
(f ) Direct cortico-cortical glutamate pathways. The NMDA Glutamate Hypofunction Hypothesis
Finally, a complex of many cortico-cortical of Psychosis: Faulty NMDA Neurotransmission
glutamate pathways is present within the cortex at Glutamate Synapses on GABA Interneurons in
(Figure 4-28, pathways f and g). On the one hand, Prefrontal Cortex
pyramidal neurons can excite each other within Although NMDA receptors and synapses are ubiquitous
the cerebral cortex via direct synaptic input from throughout the brain, the NMDA glutamate hypofunction
105
Key Glutamate Pathways
d g
f
striatum
b
nucleus
accumbens
e
thalamus
brainstem
neurotransmitter
centers
Figure 4-28 Glutamate pathways in the brain. Although glutamate can have actions at virtually all neurons in the brain, there are key
glutamate pathways particularly relevant to schizophrenia. (a) The cortico-brainstem glutamate projection is a descending pathway
that projects from cortical pyramidal neurons in the prefrontal cortex to brainstem neurotransmitter centers (raphe nucleus, locus
coeruleus, ventral tegmental area, substantia nigra) and regulates neurotransmitter release. (b) Another descending glutamatergic
pathway projects from the prefrontal cortex to the striatal complex (cortico-striatal glutamate pathway). (c) There is also a glutamatergic
projection from the ventral hippocampus to the nucleus accumbens. (d) Thalamo-cortical glutamate pathways ascend from the thalamus
and innervate pyramidal neurons in the cortex. (e) Cortico-thalamic glutamate pathways descend from the prefrontal cortex to the
thalamus. (f) Intracortical pyramidal neurons can communicate directly with each other via the neurotransmitter glutamate; these
pathways are known as direct cortico-cortical glutamatergic pathways and are excitatory. (g) Intracortical pyramidal neurons can also
communicate via GABAergic interneurons; these indirect cortico-cortical glutamate pathways are therefore inhibitory.
theory of psychosis suggests that psychosis may be caused they also have deficits in the enzyme that makes their
by dysfunction of glutamate synapses at a specific site: own neurotransmitter GABA (namely, decreased activity
namely, at certain GABA interneurons in the prefrontal of GAD67 [glutamic acid decarboxylase]), causing a
cortex (see g in Figure 4-28 and Figures 4-29A, 4-29B, compensatory increase in the postsynaptic amount
and 4-29C). Dysfunction hypothetically can be caused of the α2 subunit-containing GABAA receptors in the
by neurodevelopmental problems in schizophrenia postsynaptic axon initial segment of the pyramidal
(Figure 4-29B, box 1A), by drug toxicity in ketamine/ neurons they innervate (Figure 4-29B, box 2; compare
phencyclidine abuse (Figure 4-29B, box 1B), or by with Figure 4-29A, box 2).
neurodegenerative problems in dementia (Figure 4-29C). Both ketamine and phencyclidine (PCP) can cause
First, interference with normal neurotransmission psychosis with some of the same clinical characteristics
at these sites between glutamate and GABA neurons as the psychosis of schizophrenia (Table 4-1). Both
could hypothetically be due to neurodevelopmental agents also block NMDA receptors as antagonists at a
abnormalities genetically and environmentally site inside the ion channel (Figure 4-30). The mechanism
programmed in schizophrenia (compare Figure 4-29A, of their psychotomimetic actions is hypothesized to be
box 1 with Figure 4-29B, box 1A). The loss of function blocking NMDA receptors at the same sites on GABA
of these inhibitory GABA interneurons (Figure 4-29B, interneurons as hypothesized for the neurodevelopmental
box 2) causes glutamate neurons that they innervate abnormalities in schizophrenia (compare Figure 4-29B,
downstream to become “disinhibited” and thus boxes 1A and 1B). In the case of schizophrenia, the
hyperactive (see Figure 4-29B, box 3). Other problems NMDA hypofunction is hypothesized to be caused
with these GABA neurons in schizophrenia may be that neurodevelopmentally by genetic and environmental
106
1
Glu
2 GABA
GAD67 α2
NMDA
receptor GABA R
Glu
GAT1
Figure 4-29A Hypothetical site of glutamate dysfunction in psychosis, part 1. Shown here is a close-up of intracortical pyramidal
neurons communicating via GABAergic interneurons. (1) Glutamate is released from an intracortical pyramidal neuron and binds to an
NMDA receptor on a GABAergic interneuron. (2) GABA is then released from the interneuron and binds to GABA receptors of the α2
subtype that are located on the axon of another glutamate pyramidal neuron. (3) This inhibits the pyramidal neuron, thus reducing the
release of cortical glutamate.
107
1A
Glu
2
GABA
GAD67
α2
GABA R
3
neurodevelopmental Glu
hypofunctional NMDA
receptor and synapse
in schizophrenia
1B
Glu GAT1
ketamine
hypofunctional NMDA
after ketamine
Figure 4-29B Hypothetical site of glutamate dysfunction in psychosis, part 2. Shown here is a close-up of intracortical pyramidal
neurons communicating via GABAergic interneurons in the presence of hypofunctional NMDA receptors. (1) Glutamate is released from
an intracortical pyramidal neuron. However, the NMDA receptor that it would normally bind to is hypofunctional, preventing glutamate
from exerting its effects at the receptor. This could be due to neurodevelopmental abnormalities (1A) or to drug toxicity resulting from
ketamine or phencyclidine abuse (1B). (2) This prevents GABA release from the interneuron; thus, stimulation of α2 GABA receptors
on the axon of another glutamate neuron does not occur. (3) When GABA does not bind to the α2 GABA receptors on its axon, the
pyramidal neuron is no longer inhibited. Instead, it is disinhibited and overactive, releasing excessive glutamate into the cortex.
108
loss of cortical neurons 4

from neurodegeneration
3
Glu
Lewy
plaque tangle
stroke body
Figure 4-29C Hypothetical site of glutamate dysfunction in psychosis, part 3. Shown here is a close-up of intracortical pyramidal
neurons communicating via GABAergic interneurons in the presence of neurodegeneration associated with dementia. Not all patients
with dementia develop symptoms of psychosis. It may be that, in those that do, the neurodegeneration associated with the accumulation
of amyloid plaques, tau tangles, and/or Lewy bodies, as well as the damage caused by strokes, may destroy some glutamatergic
pyramidal neurons and GABAergic interneurons while leaving others intact, at least temporarily. The end result may be excessive
glutamate activity in the cortex, as in schizophrenia (see Figure 4-29B, box 1A) or in ketamine abuse (see Figure 4-29B, box 1B).
input (Figure 4-29B, box 1A), whereas in ketamine/PCP In neurodegenerative disorders that cause Alzheimer
psychosis, the NMDA hypofunction is hypothesized to be disease and other types of dementia, the accumulation
caused by acute and reversible pharmacological actions of amyloid plaques, tau tangles, Lewy bodies, and/or
directly at NMDA receptors (Figure 4-29B, box 1B). strokes progressively knocks out neurons as the disease
109
progresses (Figure 4-29C). Up to half of patients with of preserving these particular glutamate neurons is
dementia may at some point in their clinical course explained further below. Knocking out some neurons
experience psychosis (see Chapter 12 for a more while preserving some others could explain why only
extensive discussion on the behavioral symptoms of certain patients develop psychosis as neurodegeneration
dementia). Why do some dementia patients experience in dementia progresses.
psychosis and others not? One hypothesis is that
Linking the NMDA Glutamate Hypofunction
in patients with dementia-related psychosis, the
Hypothesis of Psychosis to the Dopamine Hypothesis
neurodegeneration has progressed in such a way as to of Psychosis
knock out some glutamatergic pyramidal neurons and
GABAergic interneurons in the prefrontal cortex while What are the consequences to dopamine activity of the
leaving other glutamatergic pyramidal neurons intact, hypothetical dysconnectivity of glutamatergic pyramidal
at least temporarily (Figure 4-29C). This theoretically neurons with these particular GABAergic interneurons
creates the same dysconnectivity (Figure 4-29C), in schizophrenia, ketamine/PCP toxicity, and dementia
but by a different mechanism, that occurs in both (Figures 4-29A, 4-29B, and 4-29C)? The short answer
schizophrenia (Figure 4-29B, box 1A) and in ketamine/ is that it theoretically leads to the very same dopamine
PCP psychosis (Figure 4-29B, box 1B). Hypothetically hyperactivity already discussed above for the dopamine
this occurs in only some patients with dementia and hypothesis of psychosis.
specifically only in those whose pattern of neuronal Certain glutamate neurons directly innervate VTA/
degeneration leaves glutamate neurons that drive mesostriatal dopamine neurons, and when they lose
dopamine neurons downstream intact. The significance their GABA inhibition from any cause they become
Site of Action of PCP and Ketamine: Bind to Open Channel

at PCP Site to Block NMDA Receptor
PCP site
(in the ion ketamine
channel) or PCP
A B
Figure 4-30 Site of action of PCP and ketamine. The anesthetic ketamine binds as an antagonist to the open channel conformation of
the NMDA receptor. Specifically, it binds to a site within the calcium channel of this receptor, which is often termed the PCP site because
it is also where phencyclidine (PCP) binds as an antagonist.
110
hyperactive and stimulate too much dopamine release disease as well as in Alzheimer disease and other dementias,
from the mesostriatal projections of those dopamine and to drugs such as LSD, mescaline, and psilocybin (Figure
neurons (Figures 4-31 through 4-34). As discussed in the 4-1 and Table 4-1). Interestingly, psychoses associated
previous section, neurodevelopmentally deficient NMDA with serotonin imbalance tend to have more visual
synapses (Figure 4-29B, box 1A) hypothetically cause this
downstream glutamate hyperactivity in schizophrenia
(Figures 4-31 and 4-32). In PCP/ketamine abuse, the
drug acting directly at these synapses (Figure 4-29B,
box 1B) causes the downstream glutamate hyperactivity
(Figure 4-33), and in dementia, neurodegeneration
knocks out cortical neurons (Figure 4-29C) to cause this DA
neuron 4
glutamate hyperactivity (Figure 4-34). In turn, glutamate
hyperactivity from any cause (Figures 4-31 through 4-34)
theoretically results in dopamine hyperactivity and the
positive symptoms of psychosis.
Hyperactive glutamate output from the prefrontal
cortex can hypothetically not only potentially explain
positive symptoms, but also negative symptoms in the A
case of schizophrenia. When the cascade from NMDA
hypofunction to glutamate hyperactivity enhances
dopamine release (Figure 4-31), it hypothetically causes Psychosis in Schizophrenia
positive symptoms of psychosis; however, there is
hypothetically a second population of glutamate neurons hypofunctional NMDA
that project to a different set of VTA neurons, namely, glutamate synapse normal
those that are mesocortical rather than mesostriatal/ in schizophrenia
mesolimbic (Figure 4-35). This circuit actually inhibits HIGH
dopamine release, due to the presence of a key GABA

interneuron in VTA for mesocortical dopamine projections
to the prefrontal cortex that is hypothetically lacking
for mesostriatal/mesolimbic projection to the striatum
(compare Figures 4-31B and 4-35B). Hyperactivity of
these specific glutamate neurons innervating mesocortical
dopamine neurons in Figure 4-35B would lead to the
opposite effects of those discussed for the population of
glutamate neurons innervating mesostriatal dopamine
neurons: namely, reduced dopamine release, and this
hypothetically causes the negative, cognitive, and affective
direct innervation so
symptoms of psychosis (Figure 4-35B). B
excitatory glu causes positive
DA hyperactivity symptoms
THE SEROTONIN HYPOTHESIS overactivation

OF PSYCHOSIS AND
SCHIZOPHRENIA Figure 4-31 NMDA receptor hypofunction and psychosis in
schizophrenia, part 1. (A) The cortical brainstem glutamate
projection communicates with the mesolimbic dopamine
The serotonin theory of psychosis proposes pathway in the ventral tegmental area (VTA) to regulate
that hyperactivity/imbalance of serotonin dopamine release in the nucleus accumbens. (B) If NMDA
receptors on cortical GABA interneurons are hypoactive,
(5-hydroxytryptamine, 5HT) activity, particularly at then GABA release is inhibited and the cortical brainstem
serotonin 5HT2A receptors, can result in psychosis (Table pathway to the VTA will be overactivated, leading to excessive
release of glutamate in the VTA. This will lead to excessive
4-1 and Figure 4-1). Disruption of 5HT functioning, leading stimulation of the mesolimbic dopamine pathway and thus
to positive symptoms of psychosis, can be hypothetically excessive dopamine release in the nucleus accumbens. This is
the theoretical biological basis for the mesolimbic dopamine
due to the neurodevelopmental abnormalities in hyperactivity thought to be associated with the positive
schizophrenia, to the neurodegeneration in Parkinson’s symptoms of psychosis.
111
striatum
globus
pallidus
nucleus
accumbens
VTA
ventral
hippocampus
Psychosis in Schizophrenia
striatum
globus
pallidus
nucleus
accumbens
VTA
ventral
B
hypofunctional NMDA hippocampus
glutamate synapse
Figure 4-32 NMDA receptor hypofunction and psychosis in schizophrenia, part 2. Hypofunctional NMDA receptors at glutamatergic
synapses in the ventral hippocampus can also contribute to mesolimbic dopamine hyperactivity. (A) Glutamate released in the ventral
hippocampus binds to NMDA receptors on a GABAergic interneuron, stimulating the release of GABA. The GABA binds at receptors
on a pyramidal glutamate neuron that projects to the nucleus accumbens; this prevents excessive glutamate release there. The normal
release of glutamate in the nucleus accumbens allows for normal activation of a GABAergic neuron projecting to the globus pallidus,
which in turn allows for normal activation of a GABAergic neuron projecting to the ventral tegmental area (VTA). This leads to normal
activation of the mesolimbic dopamine pathway from the VTA to the nucleus accumbens. (B) If NMDA receptors on ventral hippocampal
GABA interneurons are hypoactive, then the glutamatergic pathway to the nucleus accumbens will be overactivated, leading to
excessive release of glutamate in the nucleus accumbens. This will lead to excessive stimulation of GABAergic neurons projecting to
the globus pallidus, which in turn will inhibit release of GABA from the globus pallidus into the VTA. This will lead to disinhibition of the
mesolimbic dopamine pathway and thus excessive dopamine release in the nucleus accumbens.
112
DA DA
neuron neuron
4
A
A
Psychosis in Ketamine/PCP
Psychosis in Dementia
NMDA glutamate
receptor blocked by normal Neurodegeneration of
ketamine/PCP glutamate/GABA
connections normal
Lewy
HIGH plaque tangle body
stroke
HIGH
ketamine
delusions and
auditory
hallucinations
visual hallucinations
direct innervation so
B
excitatory glu causes positive
DA hyperactivity symptoms
B
overactivation
overactivation positive
symptoms
Figure 4-33 NMDA receptor blockade and psychosis in
ketamine abuse. (A) The cortical brainstem glutamate Figure 4-34 Neurodegeneration and psychosis in
projection communicates with the mesolimbic dopamine dementia. (A) The cortical brainstem glutamate projection
pathway in the ventral tegmental area (VTA) to regulate communicates with the mesolimbic dopamine pathway in the
dopamine release in the nucleus accumbens. (B) If ketamine ventral tegmental area (VTA) to regulate dopamine release
blocks NMDA receptors on cortical GABA interneurons, then in the nucleus accumbens. (B) If neurodegeneration leads
GABA release is inhibited and the cortical brainstem pathway to the destruction of some glutamatergic neurons and some
to the VTA will be overactivated, leading to excessive release GABAergic interneurons, but not others, then this could lead to
of glutamate in the VTA. This will lead to excessive stimulation excessive release of glutamate in various brain regions. In the
of the mesolimbic dopamine pathway and thus excessive VTA, this could lead to excessive stimulation of the mesolimbic
dopamine release in the nucleus accumbens. dopamine pathway and thus excessive dopamine release in
the nucleus accumbens, resulting in delusions and auditory
hallucinations. In the visual cortex, excessive glutamatergic
hallucinations, whereas those associated principally with activity could result in visual hallucinations.
dopamine have more auditory hallucinations. In order

to understand how hyperactivity of serotonin at 5HT2A The Serotonin Neurotransmitter Network
receptors could lead to the positive symptoms of psychosis Serotonin, better known as 5HT (5-hydroxytryptamine),
in various disorders, we will first review serotonin and its is a monoamine neurotransmitter which regulates a brain
extensive set of receptors and pathways. network that is one of the most targeted by psychotropic
113
Mesocortical Pathway serotonin neurotransmission is critical in order to grasp

some of the most important principles across the breadth
of psychopharmacology, from psychosis to mood and
beyond.
Serotonin Synthesis and Termination of Action
Synthesis of 5HT begins with the amino acid tryptophan,
which is transported into the brain from the plasma to
serve as the 5HT precursor (Figure 4-36). Two synthetic
enzymes then convert tryptophan into serotonin: firstly,
tryptophan hydroxylase (TRY-OH) converts tryptophan into
5-hydroxytryptophan (5HTP), and then aromatic amino
acid decarboxylase (AAADC) converts 5HTP into 5HT
A (Figure 4-36). After synthesis, 5HT is taken up into synaptic
vesicles by a vesicular monoamine transporter (VMAT2)
Negative and Cognitive and stored there until it is used during neurotransmission.
Symptoms in Schizophrenia
5HT action is terminated when it is enzymatically
hypofunctional NMDA
destroyed by monoamine oxidase (MAO) and converted
normal
glutamate synapse in schizophrenia
into an inactive metabolite (Figure 4-37). Serotonergic
LOW
neurons themselves contain monoamine oxidase B
(MAO-B), but it has low affinity for 5HT, so 5HT is
only enzymatically degraded when its intracellular
concentrations are high. The 5HT neuron also has a
presynaptic transport pump for serotonin called the
serotonin transporter (SERT) that is unique for 5HT
and that terminates serotonin’s actions by pumping it
out of the synapse and back into the presynaptic nerve
terminal where it can be re-stored in synaptic vesicles
for subsequent use in another neurotransmission
(Figure 4-37). Unlike dopamine neurons, some of which
do not contain their dopamine transporter (DAT), all
(SIGH)
B
glutamate hyperactivity 5HT neurons are thought to contain SERTs. Also, there
causes key GABA interneurons
negative cognitive
are functional polymorphisms in the gene that codes for
to inhibit DA release
symptoms symptoms
SERT, which have become of intense interest since they
alter the amount of synaptic serotonin and may help
predict which patients are less likely to respond as well
as more likely to have side effects when given drugs for
affective
symptoms depression that block SERT. This will be discussed in more
Figure 4-35 NMDA receptor hypofunction and negative detail in Chapter 7 on treatments for mood disorders.
symptoms of schizophrenia. (A) The cortical brainstem
glutamate projection communicates with the mesocortical 5HT Receptors: Overview
dopamine pathway in the ventral tegmental area (VTA) via
GABAergic interneurons, thus regulating dopamine release in Serotonin has more than a dozen receptors, and at least
the prefrontal cortex. (B) If NMDA receptors on cortical GABA half of them have known clinical relevance (Figure 4-38).
interneurons are hypoactive, then the cortical brainstem pathway
to the VTA will be overactivated, leading to excessive release Only a few 5HT receptors are located on the serotonin
of glutamate in the VTA. This will lead to excessive stimulation neuron itself (5HT1A, 5HT1B/D, 5HT2B) (Figures 4-38
of the brainstem GABA interneurons, which in turn leads to
inhibition of mesocortical dopamine neurons. This reduces through 4-41), and their purpose is to regulate the
dopamine release in the prefrontal cortex and is the theoretical presynaptic serotonin neuron directly, especially its firing
biological basis for the negative symptoms of psychosis.
and how it releases and stores its own serotonin. Just to
drugs. For example, many if not most drugs that treat be confusing, these same receptors can also be located
psychosis and mood target, in one way or another, the postsynaptically, as can all known 5HT receptors. First,
serotonin network. Thus, a thorough understanding of we describe how those 5HT receptors that are presynaptic
114
Serotonin Is Produced Serotonin Is Destroyed
tryptophan
transporter
AAADC
TRY-OH serotonin
E transporter
E
(SERT)
E
5HTP
tryptophan MAO-B destroys 5HT 4
at high concentrations
VMAT2
5HT (serotonin)
Figure 4-36 Serotonin is produced. Serotonin Figure 4-37 Serotonin’s action is terminated. Serotonin’s

(5-hydroxytryptamine [5HT]) is produced from enzymes after (5HT) action is terminated enzymatically by monoamine
the amino acid precursor tryptophan is transported into oxidase B (MAO-B) within the neuron when it is present in
the serotonin neuron. Once transported into the serotonin high concentrations. These enzymes convert serotonin into an
neuron, tryptophan is converted by the enzyme tryptophan inactive metabolite. There is also a presynaptic transport pump
hydroxylase (TRY-OH) into 5-hydroxytryptophan (5HTP), which selective for serotonin, called the serotonin transporter (SERT),
is then converted into 5HT by the enzyme aromatic amino which clears serotonin out of the synapse and back into the
acid decarboxylase (AAADC). Serotonin is then taken up into presynaptic neuron.
synaptic vesicles via the vesicular monoamine transporter
(VMAT2), where it stays until released by a neuronal impulse.
Serotonin Receptor Subtypes
1A
2B
+
7 +
6 +
4 + regulate other
3 + neurotransmitters
1B/D in downstream
2C +
circuits
2B +
2A +
1B/D
1A
Figure 4-38 Serotonin receptors. Presynaptic serotonin (5HT) receptors include 5HT1A, 5HT1B/D, and 5HT2B, all
of which act as autoreceptors. There are also numerous postsynaptic serotonin receptors, which regulate other
neurotransmitters in downstream circuits.
(located on the serotonin neuron itself) regulate Presynaptic Receptors: Serotonin Regulating
serotonin, and then we discuss how postsynaptic 5HT Serotonin
receptors regulate essentially every other neurotransmitter As for all monoamine neurons, the serotonin neuron
in a network of downstream brain circuits. has receptors both on its axon terminals (axon-
115
terminal autoreceptors) and on its dendrites and soma considered to be presynaptic. Whereas the dopamine
(somatodendritic autoreceptors), both to help regulate (earlier in this chapter and Figures 4-5 through 4-8)
serotonin release (Figures 4-38 through 4-41). Both are and norepinephrine (Chapter 6 and Figures 6-14
5HT1A
somatodendritic
autoreceptor
1A
1A
Figure 4-39 Serotonin (5HT) 1A autoreceptors. (A) Presynaptic 5HT1A receptors are autoreceptors located on the cell body and
dendrites, and are therefore called somatodendritic autoreceptors. (B) When serotonin is released somatodendritically, it binds to these
5HT1A receptors and causes a shutdown of 5HT neuronal impulse flow, depicted here as decreased electrical activity and a reduction in
the release of 5HT from the synapse on the right.
116
through 6-16) neurons have the same receptors at both and 4-41) are different from the somatodendritic
ends, for the serotonin neuron, the axon-terminal receptors (with 5HT1A and 5HT2B pharmacology)
receptors (with 5HT1B/D pharmacology) (Figures 4-38 (Figures 4-38 through 4-40).
5HT2B
somatodendritic
autoreceptor
2B
4
2B
Figure 4-40 Serotonin (5HT) 2B autoreceptors. (A) Presynaptic 5HT2B receptors are autoreceptors located on the cell body and
dendrites, and are therefore called somatodendritic autoreceptors. (B) When 5HT is released somatodendritically, it binds to these 5HT2B
receptors and causes increased 5HT neuronal impulse flow, depicted here as increased electrical activity and increased release of 5HT
from the synapse on the right.
117
Presynaptic 5HT1A Receptors still not yet fully understood, but this appears to be
Located on the dendrites and cell bodies of serotonin an important process for how the serotonin neuron
neurons in the midbrain raphe (Figure 4-39A), these regulates release at the presynaptic end. When 5HT is
presynaptic somatodendritic 5HT1A receptors detect released somatodendritically, it activates these 5HT1A
serotonin released from dendrites. How serotonin is autoreceptors and this causes a slowing of neuronal
released at the opposite end of the neuron from where impulse flow through the serotonin neuron and a
its classic presynaptic nerve terminals are located is reduction of serotonin release from its axon terminal
5HT1B/D
axon terminal
autoreceptor
5HT1B/D
axon terminal
autoreceptor
Figure 4-41 Serotonin (5HT) 1B/D autoreceptors. Presynaptic 5HT1B/D receptors are autoreceptors located on the presynaptic axon
terminal. They act by detecting the presence of 5HT in the synapse and causing a shutdown of further 5HT release. When 5HT builds up
in the synapse (A), it is available to bind to the autoreceptor, which then inhibits serotonin release (B).
118
(Figure 4-39B). Downregulation and desensitization of are we supposed to figure out what is the net effect of a
these presynaptic 5HT1A somatodendritic autoreceptors drug acting at a receptor if these receptors are all over
are thought to be critical to the antidepressant actions of the place and if they do different things at different
drugs that block serotonin reuptake (discussed in Chapter sites? Furthermore, how can we possibly understand
7 on treatments for mood disorders). psychiatric illnesses involving serotonin if this same
neurotransmitter does quite different things in different
Presynaptic 5HT2B receptors
circuits and in different synapses?
Recently, it has been discovered that the somatodendritic The answer in part is to step back and appreciate the
area of 5HT neurons is regulated by a second receptor, wonderful complexity of the brain’s neurotransmitter
the 5HT2B receptor (Figure 4-40), which acts in opposition systems, and that we are only beginning to scratch
to the 5HT1A receptor. That is, 5HT2B receptors activate the surface of how these neurotransmitter systems
the serotonin neuron to cause more impulse flow and 4
theoretically work as the substrates of normal
increased serotonin release from presynaptic nerve feelings and emotions as well as the symptoms of
terminals. Thus, it appears at this point in time that the mental illnesses. Here we will hazard a mere glimpse
5HT2B receptors are “feed forward” receptors whereas of how neurotransmitters regulate each other’s
5HT1A receptors are “negative feedback” receptors. It is neurotransmission by acting through networks of
not yet clear which 5HT neurons in the midbrain raphe neurons communicating with each other, not only with
contain 5HT1A receptors, which contain 5HT2B receptors, different neurotransmitters at different nodes in the
and which contain both. Clearly, much more is yet to be various neuronal networks, but with different receptor
learned about 5HT2B receptors and the drugs that act subtypes for the same neurotransmitters at nodes or
upon them. However, it already appears likely that the connecting points within these neuronal networks.
balance between actions at presynaptic somatodendritic Hypothetically, when neural networks are experiencing
5HT1A versus 5HT2B receptors is important in regulating inefficient information processing (i.e., one could
how much serotonin activity and serotonin release is say they are “out of tune”), this in part mediates the
occurring at serotonin presynaptic nerve terminals symptoms of mental illnesses. A corollary to this notion
throughout the brain. is that when our drugs “tune” these neuronal networks
by their actions at specific receptor subtypes, they have
Presynaptic 5HT1B/D Receptors
the potential for improving the efficiency of information
Presynaptic 5HT receptors on the axon terminal have processing in these neuronal networks, thereby
the 5HT1B/D subtype and act as negative-feedback reducing the symptoms of mental illnesses. Although
autoreceptors to detect the presence of 5HT, causing oversimplified and perhaps a bit naïvely reductionistic in
a shutdown of further 5HT release and 5HT neuronal presentation, this discussion is the next step past the now
impulse flow (Figure 4-41). When 5HT is detected in the dated notion that mental illnesses and drugs that treat
synapse by presynaptic 5HT receptors on axon terminals, them are simply “chemical imbalances” at synapses. In
it occurs via a 5HT1B/D receptor, which is also called a considering the modern neurobiology of mental illnesses
terminal autoreceptor (Figure 4-41). In the case of the and their treatments, one would be well advised to
5HT1B/D terminal autoreceptor, 5HT occupancy of this remain humble about what we know and perhaps recall
receptor causes a blockade of 5HT release (Figure 4-41B). how The Devil’s Dictionary (by Ambrose Bierce) defined
Postsynaptic Serotonin Regulates Other the mind in the nineteenth century:
Neurotransmitters in Downstream Brain Circuits MIND, n. A mysterious form of matter secreted by
It turns out that each neurotransmitter not only controls the brain. Its chief activity consists in the endeavor
its own synthesis and release from presynaptic sites; to ascertain its own nature, the futility of the attempt
each neurotransmitter also controls the actions of the being due to the fact that it has nothing but itself to
other neurotransmitters via postsynaptic actions and know itself with.
networks of brain circuits. So, if every neurotransmitter
Constructing the 5HT Network
regulates every other neurotransmitter, it’s complicated!
No longer can we think of a neurotransmitter acting only Serotonin, as do all neurotransmitters, interacts
synaptically; neurotransmitters also act trans-synaptically downstream with other neurons and the
in brain circuits that both control other neurotransmitters neurotransmitters these neurons release (Figures 4-42
and are controlled by other neurotransmitters. So, how and 4-43). Thus, what happens after serotonin is released
119
depends not only upon what receptor it interacts with serotonin receptor subtype where it is interacting, and
(see nine different serotonin receptors in Figure 4-42), but upon whether the postsynaptic neuron itself releases
also very much upon what neuron it is communicating the excitatory neurotransmitter glutamate or the
with and the neurotransmitter that neuron releases (see inhibitory neurotransmitter GABA. When serotonin has
interactions with glutamate and GABA neurons in Figure neurotransmission simultaneously in both excitatory and
4-42 and with glutamate, GABA, norepinephrine (NE), inhibitory situations, which predominates? The short
dopamine (DA), histamine (HA), and acetylcholine (ACh) answer is that it seems to depend upon whether a specific
in Figure 4-43). Note all the options that serotonin has receptor is expressed in a specific location; the density
for control: it can excite or inhibit depending upon the of that receptor, with response more likely with densely
5HT Receptors Regulate Glutamate Release

Directly and Indirectly Through GABA
2C +
4 +
5 -
GABA
1A -
6 + -
2A +
7 + +
3
SERT
-
2 +
2A
SERT
GABA
PFC 1A -
PFC
Glu 5HT 1B -
+
-
SERT
R
2A Glu
G
5HT Raphe
1A
1 -
Raphe -
1
1B -
Regulation of
Regulation of downstream
downstream release of DA,
release of DA, NE, ACh, HA, 5HT
NE, ACh, HA, 5HT
- inhibitory non-parvalbumin positive, parvalbumin positive,

regular-spiking, late- fast-spiking GABA
+ excitatory
spiking, or bursting interneurons
GABA interneurons
Figure 4-42 Serotonin (5HT) regulates glutamate release directly and indirectly. Most 5HT receptor subtypes are postsynaptic
heteroreceptors and reside on the neurons that release any of a number of neurotransmitters; thus, serotonin (like all neurotransmitters)
can regulate downstream release of numerous neurotransmitters. Left: 5HT’s direct influence on glutamate pyramidal neurons can be
both excitatory (e.g., at 5HT2A, 5HT2C, 5HT4, 5HT6, and 5HT7 receptors) and inhibitory (at 5HT1A, 5HT5, and possibly postsynaptic 5HT1B
heteroreceptors). Glutamate neurons, in turn, synapse with the neurons of most other neurotransmitters to regulate their downstream
release. Right: Glutamate output can also be controlled indirectly by 5HT receptors on inhibitory GABAergic interneurons. With so many
ways to stimulate and to inhibit the glutamate neurons, and with some 5HT receptors having opposing actions on glutamate release due
to their presence on both glutamate neurons and GABA interneurons (e.g., 5HT2A), it seems that the coordinated actions of 5HT at its
various receptors may serve to “tune” glutamate output and keep it in balance. The net effects of 5HT upon glutamate release depend on
the regional and cellular expression patterns of 5HT receptor subtypes, the density of 5HT receptors, and the local concentration of 5HT.
120
5HT Interacts in a Neuronal Network to Regulate Figure 4-43 Serotonin (5HT) interacts in
a neuronal network to regulate all major
All Major Neurotransmitter Systems neurotransmitter systems. 5HT circuits
arise from discrete brainstem nuclei,
including the dorsal and median raphe
PFC nuclei. These circuits project to a wide
range of cortical and subcortical brain areas,
= GABA including the prefrontal cortex (PFC) and
the loci for the cell bodies of neurons of
other neurotransmitters, such as the locus
coeruleus (LC) for norepinephrine, the
ventral tegmental area (VTA) for dopamine,
the tuberomammillary nucleus of the
hypothalamus (TMN) for histamine, and
the basal forebrain (BF) for acetylcholine.
Through these connections, the 5HT
network may both modulate itself and 4
directly and indirectly influence virtually
Glu all other neurotransmitter networks. Thus,
it is not surprising that the 5HT network is
5HT thought to regulate a variety of behaviors,
including mood, sleep, and appetite, or that
dysregulation of the 5HT network has been
implicated in many psychiatric disorders.
ACh
BF
HA
TMN
DA
VTA
NE
LC
versus sparsely populated receptors; the sensitivity of a first and directly at a particular receptor of a particular
receptor to serotonin; and the amount of release and the neurotransmitter can have profound net effects on all
firing rate of the serotonin neuron, with some receptors sorts of neurotransmitters. Understanding a bit about
more sensitive to low levels of serotonin than others. neural networks can also be the foundation for beginning
Finally, it depends upon whether the interaction is direct to grasp why the frequent practice of giving drugs with
(e.g., serotonin directly acting at a glutamate neuron – two or more mechanisms of action (or two different
Figure 4-42, left – or a GABA neuron – Figure 4-42, right) agents with two or more different actions) can have either
or indirect (e.g., serotonin indirectly acting at glutamate additive/synergistic effects or canceling/antagonistic
neurons via a GABA neuron that itself innervates a effects. This is reflected in the corresponding effects on
glutamate neuron – Figure 4-42, right). Norepinephrine, drug efficacy and side effects.
dopamine, histamine, and acetylcholine can also receive
5HT1A Receptors
input directly from serotonin neurons, especially at their
cell bodies, or indirectly via glutamate and/or GABA 5HT1A receptors can promote the release of other
neurons as intermediaries (Figure 4-43). Thus, it can neurotransmitters (Figure 4-44). 5HT1A receptors are
readily be seen that a drug acting directly on serotonin always inhibitory, but they are very frequently localized
neurons and their receptors not only can affect serotonin upon postsynaptic GABA neurons, which means that the
itself, but can have profound downstream effects on all net downstream effect in this case is actually excitatory
the other neurotransmitters. Which ones are affected, in (Figure 4-44). For example, 5HT1A receptors are located
what priority, and at which sites are currently the subject on GABA interneurons in the prefrontal cortex and these
of intense investigation. However, these networks and GABA interneurons in turn act to inhibit neurotransmitter
how they are organized can explain why a drug that acts release from glutamate neurons (see Figure 4-42B). 5HT1A
121
Figure 4-44 Serotonin (5HT) 1A stimulation

GABA Inhibiting Norepinephrine, Dopamine, indirectly increases release of other
and Acetylcholine Release neurotransmitters. (A) 5HT1A heteroreceptors
on GABA interneurons in the prefrontal
cortex can indirectly regulate the release
of norepinephrine (NE), dopamine (DA),
and acetylcholine (ACh). (B) Stimulation of
1A Prefrontal Cortex 5HT1A receptors is inhibitory; thus, serotonin
GABA binding at these receptors could reduce GABA
GABA output and in turn disinhibit norepinephrine,
5HT dopamine, and acetylcholine release.
Raphe 1A
NE
GABA GABA
DA 1A
GABA
GABA
ACh
ACh
BF DA
VTA
NE
A LC
5HT1A Stimulation Increases Release of

Norepinephrine, Dopamine, and Acetylcholine
1
1A Prefrontal Cortex
GABA
5HT
5HT
Raphe 1A
A
NE GABA
5HT
1A
DA 5HT GABA
ACh
ACh
BF DA
BF = Basal Forebrain VTA

VTA = Ventral Tegmental Area
NE
B LC = Locus Coeruleus
LC
122
Figure 4-45 Serotonin (5HT) 1B

5HT1B Presynaptic Regulation of NE, DA, HA, stimulation decreases release of other
and ACh in Prefrontal Cortex neurotransmitters. (A) 5HT1B receptors on the
presynaptic nerve terminals of norepinephrine
(NE), dopamine (DA), acetylcholine
Baseline Neurotransmitter Release (ACh), and histamine (HA) neurons can
theoretically regulate the release of these
neurotransmitters. (B) Stimulation of 5HT1B
heteroreceptors on ACh, HA, DA, and NE
Prefrontal Cortex neurons is inhibitory; thus, serotonin binding at
these receptors could potentially decrease the
release of these neurotransmitters.
5HT
1B
Raphe 4
NE
1B
DA
1B
HA
1B
ACh
A ACh
BF HA
TMN DA
VTA NE
LC
5HT1B Inhibits Neurotransmitter Release
Prefrontal Cortex
5HT
5HT
1
1B
Raphe
5HT
1
1B
5HT
1B
5HT
1B
BF = Basal Forebrain
TMN = Tuberomammillary Nucleus
ACh
LC = Locus Coeruleus BF HA
TMN DA
VTA NE
B LC
123
Figure 4-46 Serotonin (5HT) 2A

5HT2A Receptors Regulate Glutamate Release – stimulation both promotes and inhibits
But It’s Complicated glutamate release. 5HT2A receptors are
always excitatory, but depending on
their localization can either stimulate
GABA
or inhibit glutamate release. (A) 5HT2A
2A receptors are located on glutamate
pyramidal neurons, and through
the stimulation of these receptors
can increase glutamate release. (B)
2A
A + However, 5HT2A receptors are also
present on GABA interneurons and
when stimulated cause GABAergic
5HT inhibition of glutamate. Thus, the net
Glu Prefrontal Cortex effects of 5HT2A stimulation – or of
5HT2A antagonism – on glutamate
neurotransmission will depend
on multiple factors, including the
Raphe density of the receptors and the local
concentration of 5HT.
release of DA, NE, ACh, HA
A
GABA
2A
A+
-
2A
5HT
Glu Prefrontal Cortex
Raphe
non-parvalbumin positive,
regular-spiking, late-
spiking, or bursting Opposite effect on downstream
GABA interneurons release of DA, NE, ACh, HA
receptors located on other GABA interneurons also inhibit Shown in Figure 4-44A is the baseline condition where
neurotransmitter release from presynaptic terminals of a low tonic GABA release allows only a correspondingly
norepinephrine, dopamine, and acetylcholine neurons. low baseline of norepinephrine, dopamine, and
124
acetylcholine release. However, when serotonin is released the GABA interneuron leads to GABA release, and this
at 5HT1A receptors localized on GABA interneurons GABA is inhibitory to the glutamate neuron it innervates,
(Figure 4-44B), this receptor action inhibits the GABA with opposite effects on neurons downstream to glutamate
interneurons, reducing their inhibitory GABA release neurons (Figure 4-46B). Many drugs that treat psychosis
and allowing an increase in the release of downstream and mood have 5HT2A antagonist properties and will be
norepinephrine, dopamine, and acetylcholine. Thus, discussed extensively in Chapter 5 on drugs for psychosis
serotonin action at these 5HT1A receptors facilitates and in Chapter 7 on drugs for mood disorders. Additionally,
downstream norepinephrine, dopamine, and acetylcholine most hallucinogens have 5HT2A agonist properties and this
release. As will be explained in subsequent chapters, will be discussed in Chapter 13 on drug abuse.
many psychotropic drugs that treat psychosis, mood, and
5HT2C Receptors
anxiety are 5HT1A agonists or partial agonists.
5HT2C receptors generally inhibit the release of downstream 4
5HT1B Receptors neurotransmitters. 5HT2C receptors are excitatory,
5HT1B receptors are inhibitory and can specifically postsynaptic, and are mostly present upon GABA
inhibit neurotransmitter release from norepinephrine, interneurons (Figures 4-47A and 4-47B). This means that
dopamine, histamine, and acetylcholine neurons when 5HT2C receptors have net inhibitory effects wherever their
these receptors are localized upon presynaptic nerve GABA interneurons go. For example, when those GABA
terminals of these neurons (Figure 4-45). When a interneurons with 5HT2C receptors on them innervate
receptor for a neurotransmitter other than the one the downstream norepinephrine or dopamine neurons, the net
neuron uses as its own neurotransmitter is present, it is effect of 5HT is to inhibit norepinephrine and dopamine
called a “heteroreceptor” (literally, other receptor). In release (compare baseline levels of norepinephrine and
the case of 5HT1B receptors present on non-serotonin dopamine in the prefrontal cortex in Figure 4-47A with
presynaptic nerve terminals, they are inhibitory and act to the levels of norepinephrine and dopamine after serotonin
prevent release of those other neurotransmitters (Figure release at 5HT2C receptors in Figure 4-47B). Agonists of
4-45A). At baseline, some amount of neurotransmitter is 5HT2C receptors can treat obesity and antagonists of 5HT2C
shown being released from four different neurons in the receptors treat psychosis and mood disorders.
prefrontal cortex: norepinephrine, dopamine, histamine,
5HT3 Receptors
and acetylcholine (Figure 4-45A). However, when
serotonin is released upon their presynaptic inhibitory 5HT3 receptors located in the brainstem chemoreceptor
5HT1B heteroreceptors, this reduces the release of these trigger zone outside of the blood–brain barrier are well
four neurotransmitters (Figure 4-45B). Thus, serotonin known for their role in centrally mediated nausea and
inhibits norepinephrine, dopamine, histamine, and vomiting. However, elsewhere in the central nervous
acetylcholine release at 5HT1B receptors. A few agents system, especially in the prefrontal cortex, 5HT3 receptors
known to be 5HT1B antagonists that may thus enhance are localized on a particular type of GABA interneuron
the release of these four neurotransmitters are used to (specifically that with the properties of not binding to
treat depression and are discussed in Chapter 7 on drug a calcium dye called parvalbumin, and also having a
treatments for mood disorders. characteristic GABA interneuron firing pattern that is
regular-spiking, late-spiking, or bursting, see Figure
5HT2A Receptors 4-42, right). Just like 5HT2C receptors, 5HT3 receptors
5HT2A receptors can both promote and inhibit the release are excitatory upon the GABA neurons they innervate,
of other neurotransmitters. That is, although 5HT2A meaning 5HT3 receptors also exert net inhibitory effects
receptors are always excitatory, the variability of their wherever their GABA interneurons go.
location in the brain means that these receptors can both 5HT3 receptors specifically inhibit the release
facilitate and inhibit the release of various downstream of acetylcholine and norepinephrine at the cortical
neurotransmitters. For example, when 5HT2A receptors level (Figure 4-48). That is, interneurons containing
are localized on glutamate neurons, generally upon the 5HT3 receptors terminate upon the nerve endings of
apical dendrites of glutamate neurons, they are excitatory, presynaptic acetylcholine and norepinephrine neurons
leading to excitatory glutamate release on downstream to inhibit them (see baseline state with a low level of
targets (Figure 4-46A). On the other hand, when 5HT2A GABA release allowing a low level of acetylcholine
receptors are localized on GABA interneurons that and norepinephrine release in Figure 4-48A).
innervate glutamate neurons, excitatory 5HT2A input to Acetylcholine and norepinephrine release are reduced
125
NE release DA release
prefrontal cortex
overactivation
DA
NE neuron
neuron locus coeruleus VTA
GABA
interneurons
5HT2C
receptors
5HT
neuron
raphe
brainstem neurotransmitter centers

A
Figure 4-47A Serotonin (5HT) 2C stimulation, part 1. Excitatory 5HT2C receptors are mostly present on GABA interneurons. When
serotonin is absent, the GABA receptors are not stimulated, and thus downstream neurons, in this case norepinephrine (NE) and
dopamine (DA) neurons projecting to the prefrontal cortex, are active.
when GABA release is increased by serotonin exciting One of the more important regulatory controls upon
the interneuron at excitatory 5HT3 receptors (Figure excitatory glutamate output from the prefrontal cortex
4-48B). Thus, serotonin acting at 5HT3 receptors is tonic inhibition by GABA interneurons receiving 5HT
inhibits both acetylcholine and norepinephrine release. input upon their 5HT3 receptors (Figure 4-49A). When
5HT3 antagonists, including some drugs that treat 5HT input onto these 5HT3 receptors is increased, the
depression, would be expected to have the opposite firing rate of the glutamatergic pyramidal neuron is
effect, namely enhancing the release of acetylcholine and diminished (Figure 4-49B). Not only does this reduce
norepinephrine (discussed further in Chapter 7). the excitatory effects of glutamate on a plethora of
126
prefrontal cortex
overactivation
4
DA
NE neuron
neuron locus coeruleus VTA
GABA
interneurons
5HT2C
receptors
5HT 5HT
5HT
neuron
raphe

B
Figure 4-47B Serotonin (5HT) 2C stimulation, part 2. Serotonin binding at 5HT2C receptors on GABA
interneurons inhibits norepinephrine (NE) and dopamine (DA) release in the prefrontal cortex.
downstream sites it innervates, it also specifically glutamate reciprocally regulates serotonin (i.e., in a
reduces the excitatory feedback loop of glutamate feedback loop that normally excites serotonin release
upon serotonin neurons at the level of the midbrain from glutamate actions on serotonin cell bodies in the
raphe (Figure 4-49B). So, not only does this circuit raphe, but now is diminished due to the inhibition of
show serotonin regulating glutamate (i.e., reducing glutamate release by serotonin). This is but one simple
glutamate release by 5HT3 receptor actions at GABA example of reciprocal regulations of neurotransmitters
interneurons), it demonstrates one way in which by each other.
127
Baseline Neurotransmitter Release Figure 4-48 Serotonin (5HT) 3 stimulation

inhibits norepinephrine and acetylcholine
release. Excitatory 5HT3 receptors located
on the terminals of GABA interneurons in the
5HT
prefrontal cortex can regulate the release of
3 norepinephrine (NE) and acetylcholine (ACh).
+ (A) At baseline, tonic GABA release allows for
GABA
a low level of NE and ACh release. (B) When
GABA 5HT is released, it binds to 5HT3 receptors on
5HT
GABAergic neurons, causing phasic release
-
Prefrontal of GABA onto noradrenergic and cholinergic
5HT neurons, thus reducing the release of NE and
Cortex
Raphe
NE ACh, respectively.
3
GABA
GABA
ACh
Basal
ACh
Forebrain
NE
Locus
Coeruleus
A
5HT3 Receptors Inhibit

Norepinephrine and Acetylcholine Release
5HT
3
+
GABA
GA
5HT GABA
- Prefrontal
5HT
Cortex
Raphe
3
+
GABA
GABA
-
Basal
ACh
Forebrain
spiking, or bursting
GABA interneurons
3 5HT3 receptor stimulated NE
Locus
Coeruleus
B
128
Figure 4-49 Serotonin (5HT)

Serotonin and Glutamate Regulate Each Other 3 stimulation inhibits serotonin
release. Excitatory 5HT3 receptors
located on the terminals of GABA
GABA interneurons in the prefrontal
cortex can regulate the release of
3 + - glutamate, and glutamate in turn
can regulate release of serotonin.
(A) At baseline, low-level serotonin
release stimulates 5HT3 receptors on
GABA interneurons, which synapse
with pyramidal glutamate neurons.
5HT Glutamate release downstream
Glu regulates release of downstream
Prefrontal Cortex
+ dopamine (DA), norepinephrine
(NE), acetylcholine (ACh), and
histamine (HA). Glutamate also 4
Raphe regulates 5HT release in the raphe.
(B) When concentrations of 5HT
are higher, the stimulation at 5HT3
receptors on GABA interneurons
increases GABA release. GABA, in
turn, inhibits glutamate pyramidal
neurons, reducing glutamate output.
Decreased release of excitatory
glutamate means that there may be
a resultant decrease in downstream
release of neurotransmitters,
including 5HT.
spiking, or bursting
GABA interneurons release of DA, NE, ACh, HA
A
Serotonin Actions at 5HT3 Receptors

Reduces Its Own Release
GABA
3 + -
5HT
+
Raphe
3 5HT3 receptor stimulated Regulation of downstream

129
5HT6 Receptors GABA interneurons, 5HT7 receptors generally inhibit the

5HT6 receptors are postsynaptic and may be key release of downstream neurotransmitters. 5HT7 receptors
regulators of the release of acetylcholine release and of specifically inhibit the release of glutamate at the cortical
control of cognitive processes. Blocking this receptor level (Figure 4-50B). That is, cortical interneurons
improves learning and memory in experimental animals, containing 5HT7 receptors terminate on apical dendrites of
so 5HT6 antagonists have been proposed as novel glutamatergic pyramidal neurons (see baseline state with
pro-cognitive agents for the cognitive symptoms of a normal level of glutamate release in the absence of 5HT7
schizophrenia, Alzheimer disease, and other disorders. receptor activation in Figure 4-50A). When serotonin binds
to 5HT7 receptors on these cortical GABA interneurons,
5HT7 Receptors this inhibits glutamate output (Figure 4-50B).
5HT7 receptors are postsynaptic, excitatory, and 5HT7 receptors also regulate serotonin release at the
frequently localized on inhibitory GABA interneurons, level of the brainstem raphe (Figures 4-51A and 4-51B).
same as discussed above for the 5HT1A, 5HT2C, and 5HT3 That is, a recurrent collateral from the serotonin neuron
receptors. Just like these other receptors localized on loops backwards to innervate a GABA neuron that
Figure 4-50A Serotonin (5HT) 7

Baseline Glutamate Release stimulation inhibits glutamate release, part
1. 5HT7 receptors are located on GABA
interneurons that synapse with glutamate
pyramidal neurons. In the absence of
serotonin, tonic GABA release results in
pyramidal normal glutamate release downstream.
neuron
GABA neuron
5HT7
receptor
PFC
baseline
glutamate release
overactivation
5HT
neuron
raphe
130
Figure 4-50B Serotonin (5HT) 7

5HT7 Inhibits Glutamate Release stimulation inhibits glutamate release, part
2. When serotonin binds to 5HT7 receptors
on GABA interneurons, the phasic GABA
release leads to inhibition of glutamate
release.
pyramidal
neuron
GABA neuron
5HT7
receptor
4
PFC
reduced
glutamate release
overactivation
5HT
neuron
raphe
B
innervates the serotonin cell body. At baseline, serotonin psychosis secondary to Parkinson’s disease or Alzheimer
release is not affected by this inhibitory feedback system disease, since treatment with D2 blockers causes harm
(Figure 4-51A). However, when serotonin release to these patients, worsening movements in Parkinson’s
gets high, this activates serotonin release from the disease and increasing the risk of stroke and death in
recurrent collateral, stimulating the 5HT7 receptor there Alzheimer disease. Until recently, dogma dictated that all
(Figure 4-51B). This activates GABA release, which in turn psychoses were due to excessive mesolimbic dopamine
inhibits further serotonin release by its inhibitory actions and all treatments needed to block D2 receptors there.
at the cell body of the serotonin neuron (Figure 4-51B). While this characterization worked well for patients with
5HT7 antagonists are used for the treatment of psychosis schizophrenia, it obviously was not ideal for patients with
and mood and are discussed in more detail in Chapter 7. psychosis in Parkinson’s disease or in dementia, since it
meant that the only available drugs for psychosis were
The Serotonin Hyperfunction Hypothesis of Psychosis
relatively contraindicated for them.
If the glare of the dopamine hypothesis blinded some Although serotonin receptors and synapses are
of us to the possibility of alternate explanations for ubiquitous throughout the brain, the serotonin
psychosis, it created a dilemma for patients with hyperfunction hypothesis of psychosis suggests that
131
Figure 4-51A Serotonin (5HT) 7

Baseline Serotonin Release stimulation inhibits serotonin release,
part 1. Excitatory 5HT7 receptors
located on the terminals of GABA
interneurons in the raphe can regulate
serotonin release. When 5HT7 receptors
are not occupied, serotonin is released
into the prefrontal cortex (PFC).
baseline
5HT release
PFC
overactivation
5HT7
receptor
GABA neuron 5HT

neuron
raphe
A
psychosis may be caused by an imbalance in excitatory have long been known to induce psychosis, dissociative
5HT2A receptor stimulation of those glutamate pyramidal experiences, and especially visual hallucinations by
neurons discussed above, which directly innervate VTA/ overstimulating prefrontal and visual cortex 5HT2A
mesostriatal integrated hub dopamine neurons and receptors (compare Figure 4-52A and 4-52B; see also
visual cortex neurons (Figures 4-52A–D and Figures Figure 4-53). These symptoms can be blocked by 5HT2A
4-53 through 4-55). The hallucinogens LSD, mescaline, antagonists, demonstrating that hallucinogens cause
and psilocybin, which are all powerful 5HT2A agonists, psychosis by 5HT2A stimulation.
132
Figure 4-51B Serotonin (5HT) 7

5HT7 Inhibits Serotonin Release stimulation inhibits serotonin release,
part 2. When serotonin binds to 5HT7
receptors that innervate GABA neurons
in the raphe nucleus, this causes the
release of inhibitory GABA, which then
turns off further serotonin release.
reduced 4
5HT release
PFC
overactivation
5HT7
receptor
Stimulation of 5HT7 Receptors
in the Raphe Reduces
GABA neuron 5HT Serotonin Release
neuron
raphe
B
The next link in the serotonin hyperfunction loss of serotonin and serotonin nerve terminals leads to
hypothesis of 5HT2A overstimulation causing psychosis upregulation and too many 5HT2A receptors in the cortex,
comes from work in Parkinson’s disease psychosis (PDP), perhaps a futile attempt to overcome serotonin loss
affecting up to half of Parkinson’s patients, especially (Figure 4-52C). The overabundance of 5HT2A receptors
later in the disease. Postmortem examinations as well leads to an imbalance in their excitatory actions on
as neuroimaging in living patients with PDP have glutamate dendrites from the remaining serotonin in
demonstrated not only loss of dopamine nerve terminals the cortex, and consequently, the symptoms of psychosis
in the motor striatum of the nigrostriatal pathway (Figures 4-52C and 4-54). Drugs with 5HT2A antagonist
that causes the classic motor symptoms of Parkinson’s actions can block these symptoms of PDP, as will be
disease, but also loss of serotonin nerve terminals in explained in further detail in Chapter 5 on drugs for
the prefrontal and visual cortex (Figure 4-52C). This psychosis. These observations support the serotonin
133
Baseline
PFC
5HT2A
5HT2A
5HT2A
Visual
cortex
Striatum
VTA SN Raphe
Figure 4-52A Serotonin (5HT) 2A receptors and psychosis, baseline. Glutamatergic pyramidal neurons in the prefrontal cortex (PFC)
project to the ventral tegmental area (VTA) and to the visual cortex. Activity of the glutamatergic pyramidal neurons is regulated by
serotonergic neurons that project from the raphe nucleus as well as by GABA interneurons in the PFC. At baseline, when excitatory
5HT2A receptors are not stimulated and GABA neurotransmission is tonic, the glutamatergic neurons are not active.
hyperfunction hypothesis of psychosis by demonstrating Psychosis in dementia and its link to serotonin
that PDP is related to serotonin hyperfunction at 5HT2A hyperfunction at 5HT2A receptors appears to be
receptors that results from the malfunctioning and different from what is happening with hallucinogen
upregulation of 5HT2A receptors by the disease process of psychosis or PDP, where there is postulated
Parkinson’s disease. overstimulation of 5HT2A receptors. In dementia-
134
Hallucinogen Psychosis
PFC
1
hallucinogen
(LSD, psilocybin,
mescaline) stimulate 4
5HT2A receptors
and excitate glutamate
5HT2A receptors
5HT2A
5HT2A
Visual
cortex
delusions and
auditory
hallucinations
Striatum
overactivation VTA SN Raphe
2
5HT2A excitation of
glutamate by hallucinogens
causes mesolimbic DA
hyperactivity and psychosis
Figure 4-52B Serotonin (5HT) 2A receptors and psychosis, hallucinogens. Hallucinogens such as LSD, psilocybin, and mescaline are
5HT2A agonists. (1) When these agents stimulate 5HT2A receptors on glutamatergic pyramidal neurons in the prefrontal cortex (PFC),
this causes overactivation of the glutamate neuron. (2) The resultant release of glutamate into the ventral tegmental area (VTA) causes
hyperactivity of the mesolimbic dopamine (DA) pathway, resulting in delusions and auditory hallucinations. Excessive glutamate release
in the visual cortex can cause visual hallucinations.
related psychosis there is no consistent evidence plaques, tangles, and Lewy bodies, as well as the
for upregulation of 5HT2A receptors like there is damage from strokes, hypothetically knocks out
in PDP. Instead, in dementia, the accumulation of cortical neurons and leads to a lack of inhibition of
135
Parkinson's Disease Psychosis
PFC
5HT2A
5HT2A
5HT2A
A
5HT2A
A 3
5HT2A Normal or even low
5HT release now over-
5HT2A
stimulates upregulated
5HT2A receptors
Visual
cortex
akinesia Loss of
rigidity
nigrostriatal DA 2
tremor
causes motor Loss of raphe 5HT
symptoms causes upregulated
5HT2A receptors
delusions and 1
auditory Striatum in PFC
hallucinations
4
Upregulated
5HT2A receptors
cause glutamate excitation,
VTA SN Raphe
mesolimbic DA
hyperactivity, and
psychosis
Figure 4-52C Serotonin (5HT) 2A receptors and psychosis, Parkinson’s disease psychosis. (1) Loss of nigrostriatal dopamine neurons
causes the motor symptoms of Parkinson’s disease, such as akinesia, rigidity, and tremor. (2) Parkinson’s disease also causes loss of
serotonergic neurons that project from the raphe to the prefrontal cortex (PFC). (3) This leads to upregulation of 5HT2A receptors,
in which case normal or even low serotonin release can overstimulate these receptors, causing overactivation of the glutamatergic
pyramidal neuron. (4) Excessive glutamate release into the ventral tegmental area (VTA) causes hyperactivity of the mesolimbic
dopamine pathway, resulting in delusions and auditory hallucinations. Excessive glutamate release in the visual cortex can cause visual
hallucinations.
the surviving glutamate neurons (Figure 4-29C and mesostriatum integrated hub and to the visual cortex,
Figure 4-52D). If there is not enough GABA inhibition this enhanced output theoretically causes psychosis in
to counter the normal 5HT2A stimulation coming to these dementia patients (Figure 4-52D and 4-55). It is
surviving glutamate neurons projecting to the VTA/ now known that selective 5HT2A antagonism reduces
136
Lewy
plaque tangle
stroke body
PFC
2 sustained 5HT2A
excitation no longer
balanced
by GABA inhibition
5HT2A
5HT2A
5HT2A
1 loss of normal GABA

inhibition by
neurodegeneration
Visual
cortex
delusions and
auditory
hallucinations Striatum
3 imbalance between 5HT2A excitation

and GABA inhibition causes VTA SN Raphe
glutamate excitation, mesolimbic
DA hyperactivity, and psychosis
Figure 4-52D Serotonin (5HT) 2A receptors and psychosis, dementia. (1) Accumulation of amyloid plaques, tau tangles, and/or Lewy
bodies, as well as the damage caused by strokes, may destroy some glutamatergic pyramidal neurons and GABAergic interneurons
while leaving others intact. The loss of GABA inhibition upsets the balance of control over glutamatergic pyramidal neurons. (2) When
the effects of stimulation of excitatory 5HT2A receptors are not countered by GABA inhibition, there is a net increase in glutamatergic
neurotransmission. (3) Excessive glutamate release into the ventral tegmental area (VTA) causes hyperactivity of the mesolimbic
dopamine pathway, resulting in delusions and auditory hallucinations. Excessive glutamate release in the visual cortex can cause visual
hallucinations.
137
5HT2A Figure 4-53 Serotonin (5HT) 2A receptors

and psychosis, hallucinogens. (A) Shown
receptors here is a cortico-brainstem glutamatergic
pathway projecting from the prefrontal
cortex to the ventral tegmental area (VTA),
and an indirect cortico-cortical glutamatergic
pathway in the visual cortex. Activity of
both pathways is regulated by serotonergic
neurons that project from the raphe nucleus
as well as by GABA interneurons in the
prefrontal cortex. At baseline, normal
stimulation of excitatory 5HT2A receptors
on the glutamate neurons is balanced by
tonic stimulation of GABA receptors on the
same neurons; the net effect is thus normal
activation of the glutamatergic neurons.
(B) Hallucinogens such as LSD, psilocybin,
and mescaline are 5HT2A agonists. When
mesolimbic DA neuron these agents stimulate 5HT2A receptors on
glutamatergic pyramidal neurons in the
prefrontal cortex, this causes overactivation
of the glutamate neurons. Excessive
glutamate release into the VTA causes
hyperactivity of the mesolimbic dopamine
(DA) pathway, resulting in delusions and
auditory hallucinations. Excessive glutamate
release in the visual cortex can cause visual
hallucinations.
Hallucinogen Psychosis
stimulated
5HT2A receptors normal
by hallucinogen
HIGH
delusions and
auditory
hallucinations
overactivation
138
5HT2A
receptor
5HT2A
receptor
nigrostriatal DA neuron
mesolimbic DA neuron
Psychosis in Parkinson’s Disease
upregulated normal
5HT2A receptors
HIGH
akinesia
rigidity
visual hallucinations degeneration of tremor delusions and
nigrostriatal DA auditory
neuron hallucinations
degeneration of
raphe 5HT neuron
overactivation
Figure 4-54 Serotonin (5HT) 2A receptors and psychosis, Parkinson’s disease psychosis. (A) Shown here is a cortico-brainstem
glutamatergic pathway projecting from the prefrontal cortex to the ventral tegmental area (VTA), and an indirect cortico-cortical
glutamatergic pathway in the visual cortex. Activity of both pathways is regulated by serotonergic neurons that project from the raphe
nucleus as well as by GABA interneurons in the prefrontal cortex. At baseline, normal stimulation of excitatory 5HT2A receptors on the
glutamate neurons is balanced by tonic stimulation of GABA receptors on the same neurons; the net effect is thus normal activation
of the glutamatergic neurons. (B) Loss of nigrostriatal dopamine neurons causes the motor symptoms of Parkinson’s disease, such as
akinesia, rigidity, and tremor. Parkinson’s disease also causes loss of serotonergic neurons that project from the raphe to the prefrontal
cortex and to the visual cortex. This leads to upregulation of 5HT2A receptors on glutamatergic pyramidal neurons in the prefrontal
cortex, in which case normal or even low serotonin release can overstimulate these receptors. Excessive glutamate release into the VTA
causes hyperactivity of the mesolimbic dopamine (DA) pathway, resulting in delusions and auditory hallucinations. Excessive glutamate
release in the visual cortex can cause visual hallucinations.
139
5HT2A
receptor
mesolimbic DA neuron
loss of GABA inhibition normal

normal 5HT2A
excitation
now out of balance
HIGH
delusions and
visual hallucinations auditory
hallucinations
overactivation
B
Lewy
plaque tangle body
stroke
Figure 4-55 Serotonin (5HT) 2A receptors and psychosis, dementia. (A) Shown here is a cortico-brainstem glutamatergic pathway
projecting from the prefrontal cortex to the ventral tegmental area (VTA), and an indirect cortico-cortical glutamatergic pathway in
the visual cortex. Activity of both pathways is regulated by serotonergic neurons that project from the raphe nucleus as well as by
GABA interneurons in the prefrontal cortex. At baseline, normal stimulation of excitatory 5HT2A receptors on the glutamate neurons
is balanced by tonic stimulation of GABA receptors on the same neurons; the net effect is thus normal activation of the glutamatergic
neurons. (B) Accumulation of amyloid plaques, tau tangles, and/or Lewy bodies, as well as the damage caused by strokes, may destroy
some glutamatergic pyramidal neurons and GABA interneurons while leaving others intact. When the effects of stimulation of excitatory
5HT2A receptors are not countered by GABA inhibition, there is a net increase in glutamatergic neurotransmission. Excessive glutamate
release into the VTA causes hyperactivity of the mesolimbic dopamine pathway, resulting in delusions and auditory hallucinations.
Excessive glutamate release in the visual cortex can cause visual hallucinations.
140
the psychosis associated with dementia. Presumably at any node in this dysfunctional psychosis circuit could
this is due to lowering the normal 5HT2A stimulation to theoretically be therapeutic for psychosis of many causes.
surviving glutamate neurons that have lost their GABA
inhibition by neurodegeneration. This hypothetically SCHIZOPHRENIA AS THE
could rebalance the output of the surviving glutamate PROTOTYPICAL PSYCHOTIC
neurons so that 5HT2A antagonism and its reduction of DISORDER
neuronal stimulation compensates for the loss of GABA
inhibition. 5HT2A antagonist treatment of dementia- Schizophrenia is the prototypical psychotic disorder since
related psychosis will be discussed in further detail in it is the most common and best known and expresses
Chapter 5 and in Chapter 12 on the treatment of the prototypical psychotic symptoms. Schizophrenia affects
behavioral symptoms of dementia. about 1% of the population anywhere in the world and
is one of the most devastating illnesses in medicine. Its 4
Linking the Psychosis Hypothesis of Serotonin onset during adolescence and early adulthood coincides
Hyperfunction at 5HT2A Receptors to the Dopamine with the years of life that should be the most dynamic
Hypothesis of Psychosis and formative. Instead, this illness has a chronic course,
What are the consequences to dopamine activity of the with marked and lifelong functional disability, decreased
hypothetical excessive or imbalanced 5HT2A stimulation lifespan of 25 to 30 years, and an alarming mortality rate
at glutamatergic pyramidal neurons? The short that is three to four times that of the general population.
answer is that it theoretically leads to the very same On top of all of this misfortune is the fact that 5% of
dopamine hyperactivity already discussed above for the patients with schizophrenia complete suicide. Although
dopamine hypothesis of psychosis and for the NMDA the treatments described in this book do improve
hypofunction hypothesis of psychosis (Figures 4-52 symptoms, they do not return most patients to normal
through 4-55). functioning, nor do they necessarily adequately reduce
That is, when those glutamate neurons that directly the anguish that patients and their families feel from the
innervate VTA dopamine neurons lose either their ravages of this illness.
serotonin input due to neurodegeneration of serotonin Schizophrenia by definition is a disturbance that must
neurons in Parkinson’s disease or their GABA inhibition last for 6 months or longer, including at least one month
from neurodegeneration of any cause, they become of positive symptoms (i.e., delusions, hallucinations,
hyperactive and stimulate too much dopamine release disorganized speech, grossly disorganized or catatonic
from the mesostriatal projections of those dopamine behavior) or negative symptoms.
neurons (Figure 4-52 through 4-55), just as happens in Positive symptoms are listed in Table 4-3 and shown
schizophrenia. in Figure 4-56. These symptoms of schizophrenia are
often emphasized since they can be dramatic, can erupt
Summary and Conclusions Regarding Dopamine,
suddenly when a patient decompensates into a psychotic
NMDA, and Serotonin Neurotransmission in Psychosis
episode (often called a psychotic “break,” as in break
In summary, there are three interconnected pathways from reality), and are the symptoms most effectively
theoretically linked to hallucinations and delusions: treated by medications. Delusions are one type of positive
(1) Dopamine hyperactivity at D2 receptors in the symptom, and these usually involve a misinterpretation
mesolimbic/mesostriatal pathway, which extends of perceptions or experiences. The most common
from the VTA/mesostriatum integrated hub to the content of a delusion in schizophrenia is persecutory,
ventral striatum but may include a variety of other themes including
(2) NMDA receptor hypoactivity at GABAergic referential (i.e., erroneously thinking that something
interneurons with loss of GABAergic inhibition in the refers to oneself), somatic, religious, or grandiose.
prefrontal cortex Hallucinations are also a type of positive symptom
(3) Serotonin hyperactivity/imbalance at 5HT2A receptors (Table 4-3) and may occur in any sensory modality (e.g.,
on glutamate neurons in the cerebral cortex auditory, visual, olfactory, gustatory, and tactile) but
All three neuronal networks and neurotransmitters auditory hallucinations are by far the most common and
are linked together, and both 5HT2A and NMDA receptor characteristic hallucinations in schizophrenia. Positive
actions can hypothetically result in hyperactivity of the symptoms generally reflect an excess of normal functions,
downstream mesolimbic dopamine pathway. Targeting and in addition to delusions and hallucinations may
141
also include distortions or exaggerations in language Table 4-3 Positive symptoms of psychosis and schizophrenia
and communication (disorganized speech) as well as in Delusions
behavioral monitoring (grossly disorganized or catatonic
Hallucinations
or agitated behavior). Positive symptoms are well known
because they are dramatic, are often the cause of bringing Distortions or exaggerations in language and
a patient to the attention of medical professionals and law communication
enforcement, and are the major target of drug treatments Disorganized speech
for schizophrenia. Disorganized behavior
Negative symptoms of schizophrenia are listed in
Catatonic behavior
Tables 4-4 and 4-5 and shown in Figure 4-56. Classically,
there are at least five types of negative symptoms all Agitation
starting with the letter A (Table 4-5):
alogia – dysfunction of communication; restrictions Table 4-4 Negative symptoms of schizophrenia
in the fluency and productivity of thought and
Blunted affect
speech
affective blunting or flattening – restrictions in the Emotional withdrawal
range and intensity of emotional expression Poor rapport
asociality – reduced social drive and interaction Passivity
anhedonia – reduced ability to experience pleasure
Apathetic social withdrawal
avolition – reduced desire, motivation, or persistence;
restrictions in the initiation of goal-directed Difficulty in abstract thinking
behavior Lack of spontaneity
Negative symptoms in schizophrenia commonly Stereotyped thinking
are considered a reduction in normal functions, such
Alogia: restrictions in fluency and productivity of
as blunted affect, emotional withdrawal, poor rapport,
thought and speech
passivity and apathetic social withdrawal, difficulty
in abstract thinking, stereotyped thinking, and lack of Avolition: restrictions in initiation of goal-directed
spontaneity. Negative symptoms in schizophrenia are behavior
associated with long periods of hospitalization and poor Anhedonia: lack of pleasure
social functioning. As will be discussed below, it can be Attentional impairment
Schizophrenia: The Phenotype Figure 4-56 Positive and negative

symptoms. The syndrome of
schizophrenia consists of a mixture of
symptoms that are commonly divided
into two major categories, positive and
negative. Positive symptoms, such as
delusions and hallucinations, reflect
the development of the symptoms of
schizophrenia psychosis; they can be dramatic and
may reflect loss of touch with reality.
deconstruct the syndrome...
Negative symptoms reflect the loss of
normal functions and feelings, such as
losing interest in things and not being
able to experience pleasure.
positive symptoms
-delusions
-hallucinations
...into symptoms
negative symptoms
-apathy
-anhedonia
-cognitive blunting
-neuroleptic dysphoria
142
Table 4-5 What are negative symptoms?
Domain Descriptive term Translation

Dysfunction of Alogia Poverty of speech; e.g., talks little, uses few words
communication
Dysfunction of affect Blunted affect Reduced range of emotions (perception, experience, and
expression); e.g., feels numb or empty inside, recalls few emotional
experiences, good or bad
Dysfunction of Asociality Reduced social drive and interaction; e.g., little sexual interest, few
socialization friends, little interest in spending time with (or little time spent with)
friends
Dysfunction of Anhedonia Reduced ability to experience pleasure; e.g., finds previous hobbies or 4
capacity for pleasure interests unpleasurable
Dysfunction of Avolition Reduced desire, motivation, persistence; e.g., reduced ability to
motivation undertake and complete everyday tasks; may have poor personal
hygiene
quite difficult to tell the difference between the negative diagnostic criteria of schizophrenia and occur before the
symptoms of schizophrenia, the cognitive symptoms onset of the full syndrome of schizophrenia. Prodromal
of schizophrenia, the affective/mood symptoms of negative symptoms are important to detect and monitor
schizophrenia, particularly depression, and the side over time in high-risk patients so that treatment can
effects of drugs that treat psychosis (discussed in be initiated at the first signs of psychosis. Negative
Chapter 5). Although formal rating scales can be used to symptoms can also persist between psychotic episodes
measure negative symptoms versus cognitive symptoms once schizophrenia has begun and reduce social and
versus affective symptoms for research studies, in occupational functioning in the absence of positive
clinical practice it may be more practical to identify symptoms.
and monitor mostly negative symptoms and to do this
Beyond the Positive and Negative Symptoms of
quickly by observation alone (Figure 4-57) or by some
Schizophrenia
simple questioning (Figure 4-58). Negative symptoms
are not just part of the syndrome of schizophrenia; Although not recognized formally as part of the
they can also be part of a “prodrome” that begins with diagnostic criteria for schizophrenia, numerous studies
subsyndromal symptoms that do not meet the full subcategorize the symptoms of this illness into five
Key Negative Symptoms Identified Solely on Observation Figure 4-57 Negative symptoms
identified by observation. Some
negative symptoms of schizophrenia
– such as reduced speech, poor
grooming, and limited eye contact – can
Reduced speech: Patient has restricted speech quantity, uses be identified solely by observing the
few words and nonverbal responses. May also have impoverished patient.
content of speech, when words convey little meaning*
A
Poor grooming: Patient has poor grooming and hygiene, clothes are
dirty or stained, or subject has an odor*
Limited eye contact: Patient rarely makes eye contact with the
interviewer*
C
*symptoms are described for patients at the more severe end of the spectrum
143
Key Negative Symptoms Identified with Some Questioning Figure 4-58 Negative symptoms
identified by questioning. Other
negative symptoms of schizophrenia can
be identified by simple questioning. For
Reduced emotional responsiveness: Patient exhibits example, brief questioning can reveal
few emotions or changes in facial expression, and when questioned the degree of emotional responsiveness,
can recall few occasions of emotional experience* interest level in hobbies or pursuing life
goals, and desire to initiate and maintain
A
social contacts.
(SIGH)
Reduced interest: Reduced interests and hobbies, little or nothing

stimulates interest, limited life goals and inability to proceed with them*
Reduced social drive: Patient has reduced desire to initiate social

contacts and may have few or no friends or close relationships*
C
*symptoms are described for patients at the more severe end of the spectrum
Figure 4-59 Localization of symptom

Match Each Symptom to Hypothetically domains. The different symptom
Malfunctioning Brain Circuits domains of schizophrenia may best be
subcategorized into five dimensions:
positive, negative, cognitive, affective,
and aggressive. Each of these symptom
mesocortical/ domains may hypothetically be
prefrontal cortex mediated by unique brain regions.
mesolimbic
nucleus accumbens
positive negative reward circuits
symptoms symptoms
affective aggressive
symptoms symptoms cognitive
symptoms dorsolateral
prefrontal cortex
ventromedial
prefrontal cortex
orbitofrontal amygdala
cortex
dimensions: not just positive and negative symptoms, prioritizing, and modulating behavior based upon social
but also cognitive symptoms, affective symptoms, and cues). Important cognitive symptoms of schizophrenia
aggressive symptoms (Figure 4-59). This is perhaps a are listed in Table 4-6. Cognitive symptoms begin before
more sophisticated if complicated manner of describing the onset of the first psychotic illness and manifest
the symptoms of schizophrenia. as lower than expected IQ scores. IQ and cognition
Cognitive symptoms of schizophrenia include impaired then worsen during the prodrome before the onset of
attention and information processing, manifesting as full-blown psychosis, and then progressively worsen
difficulties with verbal fluency (i.e., the ability to produce throughout the course of schizophrenia. Cognitive
spontaneous speech), problems with serial learning (of symptoms in schizophrenia do not include the same
a list of items or a sequence of events), and impairment symptoms commonly seen in dementia, such as short-
in vigilance for executive functioning (i.e., problems term memory disturbance; instead, cognitive symptoms
with sustaining and focusing attention, concentrating, of schizophrenia emphasize “executive dysfunction,”
144
Table 4-6 Cognitive symptoms of schizophrenia schizophrenia. Thus, whenever possible, consideration
Problems representing and maintaining goals should be given to treat the affective symptoms of
schizophrenia even if they do not reach full criteria for
Problems allocating attentional resources
a comorbid mood or anxiety disorder. Even though
Problems focusing attention affective symptoms in a patient with schizophrenia may
Problems sustaining attention very well respond to drug treatments for depression or
Problems evaluating functions anxiety, these same treatments are not very effective if at
all for true negative symptoms.
Problems monitoring performance
Aggressive symptoms, such as overt hostility,
Problems prioritizing assaultiveness and physical abuse, frank violence, verbally
Problems modulating behavior based upon social abusive behaviors, sexually acting-out behaviors, self-
4
cues injurious behaviors including suicide, and arson and
Problems with serial learning other property damage can all occur in schizophrenia.
Aggression is different from agitation in that aggression
Impaired verbal fluency
tends to refer to intentional harm, while agitation is
Difficulty with problem solving a more nonspecific and often nondirected state of
heightened psychomotor or verbal activity, accompanied
which includes problems representing and maintaining by an unpleasant state of tension and irritability. In
goals, allocating attentional resources, evaluating and schizophrenia, both can occur alongside positive
monitoring performance, and utilizing these skills to symptoms, particularly when positive symptoms are
solve problems. out of control, and both agitation and aggression often
Affective symptoms are frequently associated with improve when positive symptoms are reduced by drugs
schizophrenia, but this does not necessarily mean that that treat psychosis.
they fulfill the full diagnostic criteria for a comorbid Both agitation and aggression can also occur in
anxiety or affective disorder. Nevertheless, depressed patients with dementia but must be distinguished from
mood, anxious mood, guilt, tension, irritability, and worry positive psychotic symptoms, since new treatments
frequently accompany schizophrenia. These various are evolving for agitation in dementia that differ from
symptoms are also prominent features of major depressive treatments for psychosis in dementia and these also
disorder, numerous anxiety disorders, psychotic differ from treatments for psychosis in schizophrenia.
depression, bipolar disorder, schizoaffective disorder, Treatments of agitation and aggression are discussed
organic dementias, childhood psychotic disorders, and in more detail in Chapter 5 on treatments for psychosis
treatment-resistant cases of depression, bipolar disorder, and in Chapter 12 on treatments for the behavioral
and schizophrenia, among many others. Affective symptoms of dementia. Aggressive symptoms can also
symptoms of schizophrenia, particularly symptoms of occur in numerous other disorders that exhibit problems
depressed mood, anhedonia, lack of motivation, and with impulse control such as bipolar disorder, childhood
lack of pleasure, can also be quite difficult to distinguish psychosis, borderline personality disorder, antisocial
from the negative symptoms of schizophrenia and from a personality disorder, drug abuse, attention deficit
comorbid mood or anxiety disorder. hyperactivity disorder, conduct disorders in children, and
Wherever encountered, affective symptoms need many others.
to be treated. In the case of schizophrenia, when For schizophrenia, the topic of violence – a type
affective symptoms are not sufficiently improved by of aggression – is controversial. The stereotype of
traditional drugs for the positive symptoms of psychosis, schizophrenia patients as frequent violent perpetrators
consideration can be given to adding drugs used to of mass shootings is an unfortunate exaggeration
treat anxiety and/or depression (e.g., selective serotonin contributing to the stigma of this illness. Most patients
reuptake inhibitors, SSRIs), not only to relieve the with schizophrenia in fact are not violent, and patients
current affective symptoms, but also to prevent suicide, are more likely to be a victim of violence than a
which is unfortunately very common in patients with perpetrator. However, some studies do suggest that
schizophrenia. There is no drug treatment for the schizophrenia patients commit violence more often than
disorder of schizophrenia itself, only for the symptoms of the general population, although the increased rate is
145
not large, and the violence is often linked to a lack of approximately 40,000 of them) have a serious mental
adequate medication treatment as well as to concomitant illness requiring treatment with drugs for psychosis,
substance abuse. this would mean that perhaps 10% of all patients with
Not surprisingly, schizophrenia patients who commit schizophrenia in California are in prison or jail – again
violence often become involved in the criminal justice probably those who are the most likely to engage in
system. This may be a sorry reflection of the lack of violence when unmedicated and/or abusing drugs.
adequate outpatient treatment as well as the lack of An even smaller subpopulation of patients with
short-term crisis and inpatient beds in the community schizophrenia are those who commit a violent felony
for treating patients with schizophrenia. It is a shocking and are judged either incompetent to stand trial
fact that in the United States we have “criminalized” or insane, and sent to one of the five state forensic
serious mental illnesses such as schizophrenia, since hospitals in California. This population is only a few
our largest “mental health institutions” are now jails thousand patients, or perhaps only 1% of all patients
and prisons. For example, the twin towers of the Los with schizophrenia in California. Unfortunately, they
Angeles County Jail, the New York City jail at Rikers are the most violent subset of schizophrenia patients:
Island, and the Cook County Chicago jail are the largest not surprising, as a violent felony put them in the
mental health facilities in the country. Up to a quarter state forensic hospital in the first place. Studies show
of the 2 million inmates in jails and prisons throughout that violence in this setting is actually associated with
the country have serious mental illnesses. Although criminogenic risk, suggesting that it is the process of
patients with schizophrenia do get treatment in jail criminalization from living in an institutional setting,
and prison, this treatment is widely acknowledged to and not the positive symptoms of psychosis, that are
be substandard in correctional environments and the driving a lot of this violence. Once in the state forensic
correctional environment itself is inherently counter- hospitals they often continue to commit violent acts,
therapeutic. Furthermore, when released, patients often even when treated and medicated. But not all patients
do not take medication, are homeless, and eventually with schizophrenia even in state forensic hospitals are
are re-arrested for another violent offense. In California, violent; only about a third of them commit a violent act
the numbers of patients with serious mental illnesses during hospitalization, usually a single event within the
who are arrested for a felony and found incompetent to first 120 days. Actually, about 3% of state forensic patients
stand trial because of their illness and who have had 15 (a few hundred at most or fewer than 1 per 100,000
or more prior arrests have been increasing; half of them patients with schizophrenia in California) commit about
have not accessed reimbursable mental health services 40% of the violence within the state forensic hospital,
including medication for the six months prior to their about half against staff and about half against other
arrest and half are in an unsheltered homeless condition. patients. Thus, only a tiny fraction of patients with
Fortunately, innovative treatment programs modeled schizophrenia commit a lot of violence, and the number
on a successful program in Miami, Florida seek to of patients with violence is frequently exaggerated by
decriminalize the treatment of schizophrenia by diversion media. Nevertheless, working in a state forensic hospital
programs sending patients to treatment with housing can be very dangerous, as can living as a patient in these
rather than to jail and prison. settings. Treating violence in patients with schizophrenia
Nevertheless, once sent to jail, prison, or state forensic can be very important in state forensic hospitals, jails,
hospitals, patients with schizophrenia can frequently and prisons, as can preventing violence in these patients
experience and cause violence. Some of this is due to the when they leave these settings.
fact that institutions have violent environments and some Rather than lumping all forms of violence together,
of this is due to the fact that those with serious mental experts parse violence in institutionalized patients with
illnesses who find themselves in institutions are a small schizophrenia into three types: impulsive, predatory, and
subset of all patients, specifically those most likely to psychotic (Figure 4-60). Psychotic violence, associated
commit violence. If schizophrenia is roughly 1% of the with positive symptoms of psychosis, which typically
population, there are an estimated 400,000 patients with command hallucinations and/or delusions, is actually
this illness in the State of California, whose population the least common type of violence in institutional
is about 40 million. If up to 200,000 individuals are settings, despite the fact that these patients have a
incarcerated in California and perhaps 25% of them (or psychotic illness (Figure 4-60). This is presumably
146
Organized - 29%
Planned behavior not typically associated with Psychotic - 17%
frustration or response to immediate threat Associated with positive symptoms of psychosis
Might not be accompanied by autonomic arousal – typically command hallucinations and/or delusions
Planned with clear goals in mind
Also called predatory, instrumental, proactive,
or premeditated aggression
Impulsive - 54%
Characterized by high levels of autonomic arousal
Precipitated by provocation
Associated with negative emotions, such as anger or fear
Usually represents response to perceived stress
Also called reactive, affective, or hostile aggression
Figure 4-60 Three types of violence. There are at least three different types of violence: psychotic, impulsive, and
organized/psychopathic. Psychotic violence is associated with positive symptoms of psychosis. The most common
form of violence is impulsive; it is associated with autonomic arousal and often precipitated by stress, anger, or fear.
Organized or psychopathic violence is planned and is not accompanied by autonomic arousal.
because treatment in institutional settings is often psychotic symptoms. Nevertheless, psychotic patients
effective for positive symptoms. However, treating in institutional settings can also have psychopathic
positive symptoms does not quell all violence, since the tendencies and commit organized violence, which may
most common form of violence in institutional settings require forms of confinement rather than drugs in
is actually impulsive violence – often precipitated by order to manage. Certain treatments, such as clozapine
provocation as a response to stress and associated with or high doses of standard drugs for schizophrenia,
negative emotions such as anger or fear (Figure 4-60). may also be useful for psychotic or impulsive violence
For these reasons, impulsive violence is also called in patients with underlying psychotic disorders, but
reactive, affective, or hostile aggression. The third behavioral interventions may be particularly helpful to
form of violence, also more common than psychotic prevent violence linked to poor impulsivity associated
violence, is psychopathic or organized and is planned with violence (i.e., by reducing provocations from the
behavior not typically associated with frustration or environment). Impulsive and organized violence in
response to immediate threat (Figure 4-60). If psychotic schizophrenia are not as clearly related to dopamine
violence and impulsive violence are “hot-blooded” D2 overactivity as psychotic violence when positive
with emotional arousal, organized violence is “cold- symptoms of schizophrenia are out of control, especially
blooded” and not accompanied by autonomic arousal in the small population of frequent aggressors. In
as it is planned with clear goals in mind (Figure 4-60). California state forensic hospitals, these frequent
Organized violence is what is commonly seen in patients aggressors that can be so difficult to manage have
with psychopathic or antisocial personalities and is an underlying psychotic illness, exhibit psychotic or
associated with criminogenic behaviors more than with impulsive violence rather than organized violence, and
147
have a cognitive deficiency beyond that usually associated mental illnesses (Figure 4-61). Genes do not code
with schizophrenia. Aggression and violence are directly for mental illnesses or for psychiatric symptoms,
discussed in further detail in Chapter 13 on impulsivity behaviors, personalities, or temperaments. Instead,
and compulsivity and are also differentiated from genes code directly for proteins and epigenetic regulators
agitation and from positive symptoms or psychosis in (see Figures 1-31 and 1-32). It is thought that the actions
dementia in Chapter 12. of genes must “conspire” amongst themselves (Figure
4-62, upper left) and amongst environmental stressors
What is the Cause of Schizophrenia?
(Figure 4-62, upper right) in order to produce a mental
What causes schizophrenia: nature (i.e., genetics) illness (Figure 4-62, bottom). Thus, current theories
or nurture (i.e., the environment or epigenetics)? state that inheriting many risk genes for a mental illness
Is schizophrenia neurodevelopmental or sets the stage for a mental illness, but does not cause a
neurodegenerative? The modern answer indeed may be mental illness per se. More properly, individuals inherit
“yes” in part to all of these. risk for mental illness, but they do not inherit mental
illness. Whether this risk evolves into a manifest mental
Genetics and Schizophrenia
disorder is hypothesized to be dependent upon what
Modern theories of mental illness have long abandoned happens in the environment to an individual who has
the notion that single genes cause any of the major risk genes.
Figure 4-61 Classic theory of

Classic Theory: inherited disease. According to the
Genes Cause Mental Illness classic theory of inherited disease, a
single abnormal gene can also cause
a mental illness. That is, an abnormal
gene would produce an abnormal
gene product, which, in turn, would
lead to neuronal malfunction that
directly causes a mental illness.
However, no such gene has been
hypothetical mental identified, and there is no longer any
illness gene expectation that such a discovery
might be made. This is indicated
by the red cross-out sign over this
theory.
abnormal gene
product causes
neuronal malfunction
mental illness
148
Nature Nurture
virus or toxin
abusive marijuana
cognition neurotoxicity of childhood
!! # @
neuroplasticity psychosis @ # !! traumatic

experience
obstetric (e.g., combat)
synaptogenesis events
a few hundred stress

neurotransmitter vulnerability
risk genes multiple life bullying
systems events
4
cumulative
polygenic risk score environmental
stress factors
abnormal
competitive
dysconnectivity elimination of
synapses
abnormal LTP
dysregulation of
abnormal synaptic inadequate glutamate,
plasticity and synaptic dopamine,
connectivity strength serotonin
thought
hallucinations delusions
disorder
schizophrenia
Figure 4-62 The nature and nurture of schizophrenia. Schizophrenia may occur as the result of both genetic (nature) and epigenetic
(nurture) factors. That is, an individual with multiple genetic risk factors, combined with multiple stressors causing epigenetic changes,
may have abnormal information processing in the form of dysconnectivity, abnormal long-term potentiation (LTP), reduced synaptic
plasticity, inadequate synapse strength, dysregulated neurotransmission, and abnormal competitive elimination of synapses. The result
may be psychiatric symptoms such as hallucinations, delusions, and thought disorder.
Recent evidence suggests that a portfolio of a few synaptogenesis, neuroplasticity, neurodevelopment,

hundred specific genes – each with a small contribution cognition, the neurotoxicity of psychosis, and stress
of less than 1% – may together confer risk for vulnerability, amongst other functions (Figure 4-62,
schizophrenia (Table 4-7). The function of all of these upper left). One way to deal with this complexity is to add
risk genes is not fully known, but may be to regulate such up all the abnormal genes any individual has amongst
key aspects of the brain as neurotransmitter systems, the known few hundred risk genes, and compute what is
149
called a “polygenic risk score” suggesting how much risk synaptogenesis (Figure 4-62, bottom). How can that be?
there might be for developing schizophrenia. Even with Normal genes causing mental illness? Hypothetically,
this simplification, the known contribution of all risk yes, when environmental stressors (Figure 4-62,
genes added together only confers a portion of the risk upper right) cause various critical normal genes to be
for schizophrenia. What comprises the remaining risk? expressed when they should be silenced, or silenced
In schizophrenia, it is various environmental stressors, when they should be expressed, in a process called
specifically, cannabis use, emotionally traumatic epigenetics (Figure 1-30). Some of the best evidence
experiences such as early childhood adversity, bullying, that environmental stressors and normal genes are
obstetric events, sleep deprivation, being a migrant, also involved with abnormal genes in the causation
and others (Figure 4-62, upper right). For example, the of schizophrenia is that only half of identical twins of
incidence of psychosis has been shown to be higher in patients with schizophrenia also have schizophrenia.
cities with a lot of migrants; in one such city, London, the Having identical genes is thus not enough to cause
incidence of psychosis falls by one-third if migrants and schizophrenia and instead epigenetics is also in play,
their children are excluded from the population studied. such that the affected twin not only expresses some
Other studies show that there is a high correlation abnormal genes that the unaffected co-twin might not
between the frequency of cannabis use and the rate of express, but also expresses some normal genes at the
psychosis across European cities, and that if nobody wrong time or silences other normal genes at the wrong
smoked high-potency cannabis, 12% of all cases of first- time; together these factors may cause schizophrenia in
episode psychosis across Europe would be prevented. one co-twin but not the other.
In particular cities, the estimated reduction in first- In summary, mental illnesses such as schizophrenia
episode psychosis would be 32% in London and 50% in are now thought to be due not only to the summed
Amsterdam. biological action of abnormal genes with flawed DNA
How does the environment unmask schizophrenia causing flaws in the structure and function of the proteins
in those who have genetic risk for it? The answer is that and regulators they code (Figure 4–62, upper left), but
the environment hypothetically puts a load on the neural are also due to the environment, which plays upon both
circuits where the risk genes are expressed and causes abnormal genes and normal genes that make normal
these circuits to malfunction under pressure (Figure functioning proteins and regulators but are activated or
4-62, bottom). Furthermore, these same stressors silenced at the wrong times (Figure 4-62, upper right). In
can even cause normal genes to malfunction and other words, schizophrenia results from both nature and
together all of this causes aberrant neuroplasticity and nurture (Figure 4-62, bottom).
Table 4-7 Some candidate susceptibility risk genes involved in biological functions implicated in schizophrenia
Genes Description
Glutamate neurotransmission and synaptic plasticity
GRIA1 Ionotropic glutamate receptor mediating fast synaptic neurotransmission
GRIN2A Glutamate gated-ion-channel protein and key mediator of synaptic plasticity
GRM3 Encodes glutamate metabotropic receptor 3, one of the major excitatory neurotransmitter
receptors, extensively explored as a potential drug target in schizophrenia
Calcium channel and signaling
CACNA1C Encodes an α1 subunit of voltage-sensitive calcium channels
CACNB2 One of the voltage-sensitive calcium channels
Neurogenesis
SOX2 Transcription factor essential for neurogenesis

SATB2 Essential for cognitive development and involved in long-term plasticity
150
Schizophrenia: Problems with Neurodevelopment, areas throughout life. After birth, differentiation and
Neurodegeneration, or Both? myelination of neurons as well as synaptogenesis also
In the case of schizophrenia, two major questions always continue throughout a lifetime. All along the way, not
arise: just prenatally or even just in childhood but throughout
(1) How does the scheming of nature and nurture lead adult life, disruption of this neurodevelopmental process
to the full onset of this illness around the time of (Figure 4-63) can hypothetically result in various
adolescence? psychiatric symptoms and illnesses.
(2) What kind of neurobiological processes underlie this In the case of schizophrenia, the suspicion is that
disorder such that the results of nature and nurture the neurodevelopmental process of synaptogenesis
can appear to be neurodevelopmental at the onset of and brain restructuring has gone awry. Synapses are
schizophrenia yet neurodegenerative over the lifetime normally formed at a furious rate between birth and age
4
course of this illness? 6 (Figure 4-64). Although brain restructuring occurs
Both the neurodevelopmental and the throughout life, it is most active during late childhood
neurodegenerative theories of schizophrenia are and adolescence in a process known as competitive
discussed next. elimination (Figures 4-63 and 4-64). Competitive
elimination and restructuring of synapses peak during
Neurodevelopment and Schizophrenia pubescence and adolescence, normally leaving only
Modern research findings strongly suggest that about half to two-thirds of the synapses that were
something is amiss in the way the brain makes, retains, present in childhood to survive into adulthood (Figures
and revises its synaptic connections in schizophrenia, 4-63 and 4-64). Since the onset of positive symptoms
starting from birth. Telltale signs of this include of psychosis (psychotic “breaks”) follows this critical
the cognitive deficits, lowering of IQ, oddness, and neurodevelopmental period of peak competitive
social deficits of patients before the overt onset of a elimination and restructuring of synapses, it has thrown
psychotic break that signals the full diagnostic criteria suspicion on possible abnormalities in these processes as
of schizophrenia. In order to grasp what might be underlying in part the onset of schizophrenia.
going wrong with neurodevelopment in schizophrenia, In order to understand how aberrant competitive
it is important to first have an understanding of elimination could contribute to the onset and worsening
normal neurodevelopment. An overview of normal of schizophrenia, it is important to consider how the
neurodevelopment is shown in Figure 4-63. After brain decides which synapses to keep and which ones
conception, stem cells differentiate into immature to eliminate. Normally, when glutamate synapses are
neurons. Only a minority of neurons that are formed are active, their N-methyl-D-aspartate (NMDA) receptors
selected for inclusion in the developing brain. The others trigger an electrical phenomenon known as long-term
die off naturally in a process called apoptosis. It remains potentiation (LTP) (shown in Figure 4-65). With the
a mystery why the brain makes so many more neurons help of gene products that converge upon glutamate
than it needs, and how it decides which neurons to select synapses and receptors, ion channels, and the processes
for inclusion in the developing brain, but it is certainly of neuroplasticity and synaptogenesis, LTP normally
feasible that abnormalities in the process of neuronal leads to structural and functional changes of the synapse
selection could be a factor in neurodevelopmental that make neurotransmission more efficient, sometimes
disorders, from autism to intellectual disability (formerly called “strengthening” of synapses (Figure 4-65, top).
known as mental retardation) to schizophrenia on the This includes changes in synaptic structure such as an
severe end of the spectrum, and ADHD (attention deficit increase in the number of AMPA (α-amino-3-hydroxy-
hyperactivity disorder) and dyslexia on the mild to 5-methyl-4-isoxazole-propionic acid) receptors for
moderate end of the spectrum. At any rate, those neurons glutamate. AMPA receptors are important for mediating
that are selected migrate and then differentiate into excitatory neurotransmission and depolarization at
different types of neurons, after which synaptogenesis glutamate synapses. Thus, more AMPA receptors can
(making of synaptic connections) occurs (Figure 4-63). mean a “strengthened” synapse. Synaptic connections
Most neurogenesis (i.e., birth of new neurons), neuronal that are frequently used develop frequent LTP and
selection, and neuronal migration occur before birth, consequential robust neuroplastic influences, thus
although new neurons continue to form in some brain strengthening them according to the old saying “nerves
151
Overview of Neurodevelopment
ErbB4 NRG
NRG dysbinden
DISC1 NRG
dysbinden
DISC1
immature
neurons RGS4
ErbB4 DAOA
eliminated NRG NRG
DISC1 AMPA
DISC1
stem cell
eliminated
differentia- Synapto- Synapto- Competitive

neurogenesis selection migration tion and genesis genesis elimination of
myelination (presynaptic; (postsynaptic; synapses
axonal dendritic (loss of dendritic
growth & arborization) arborization)
connections)
conception birth death conception birth conception birth death conception birth 6 16 death
years years
Figure 4-63 Overview of neurodevelopment. The process of brain development is shown here. After conception, stem cells
differentiate into immature neurons. Those that are selected migrate and then differentiate into different types of neurons, after
which synaptogenesis occurs. Most neurogenesis, neuronal selection, and neuronal migration occur before birth, although new
neurons can form in some brain areas even in adults. After birth, differentiation and myelination of neurons as well as synaptogenesis
continue throughout a lifetime. Brain restructuring also occurs throughout life, but is most active during childhood and adolescence
in a process known as competitive elimination. Key genes involved in the process of neurodevelopment include DISC1 (disrupted
in schizophrenia-1), ErbB4, neuregulin (NRG), dysbindin, regulator of G-protein signaling 4 (RGS4), D-amino acid oxidase activator
(DAOA), and genes for α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA).
Figure 4-64 Synapse formation

by age. Synapses are formed at
a furious rate between birth and
age 6. Competitive elimination and
restructuring of synapses peaks
during pubescence and adolescence,
leaving about half to two-thirds of
the synapses present in childhood to
survive into adulthood.
Birth Age 6 Age 14-60
152
that fire together wire together” (Figure 4-65, top). to ineffective LTP and fewer AMPA receptors trafficking
However, if something is wrong with the genes that into the postsynaptic neuron (Figure 4-65, bottom).
regulate synaptic strengthening, it is possible that this Such a synapse would be “weak,” theoretically causing
causes less effective use of these synapses, makes the inefficient information processing in its circuit and
NMDA receptors hypoactive (Figure 4-29B), and leads possibly also causing symptoms of schizophrenia.
Neurodevelopmental Hypothesis of Schizophrenia: Key Susceptibility

Genes Causing Abnormal Synaptogenesis
4
glutamate
in din
dysb
synapse survives
NMDA
receptor competitive elimination
lin
gu
ure
ne
C1
DIS
AMPA
receptors
normal
synaptic strengthening
ep m
ig ult
en ip
et le
ics fla
/fl we
aw d
NMDA ed ge
ne
receptor en s
vir
on
m
en
t
LTP
NMDA
receptor
AMPA
receptor
abnormal
synaptic strengthening weak synapse
and dysconnectivity competitively eliminated
Figure 4-65 Neurodevelopmental hypothesis of schizophrenia. Dysbindin, DISC1 (disrupted in schizophrenia-1), and neuregulin are
all involved in “strengthening” of glutamate synapses. Under normal circumstances, N-methyl-D-aspartate (NMDA) receptors in active
glutamate synapses trigger long-term potentiation (LTP), which leads to structural and functional changes of the synapse to make it
more efficient, or “strengthened.” In particular, this process leads to an increased number of α-amino-3-hydroxy-5-methyl-4-isoxazole-
propionic acid (AMPA) receptors, which are important for mediating glutamatergic neurotransmission. Normal synaptic strengthening
means that the synapse will survive during competitive elimination. If the genes that regulate strengthening of glutamate synapses are
abnormal, combined with environmental insults, then this could cause hypofunctioning of NMDA receptors, with a resultant decrease
in LTP and fewer AMPA receptors. This abnormal synaptic strengthening and dysconnectivity would lead to weak synapses that would
not survive competitive elimination. This would theoretically lead to increased risk of developing schizophrenia, and these abnormal
synapses could mediate the symptoms of schizophrenia.
153
Another important aspect of synaptic strength is it can seemingly appear that as it progresses, it is
that this likely determines whether a given synapse neurodegenerative. In other words, if the manner in
is eliminated or maintained. Specifically, “strong” which synapses are made and revised dramatically
synapses with efficient NMDA neurotransmission during adolescence potentially explains how the
and many AMPA receptors survive, whereas “weak” full onset of schizophrenia can be conceptualized as
synapses with few AMPA receptors may be targets for neurodevelopmental, then the manner in which synapses
elimination (Figure 4-65). This normally shapes the are made and revised in a more methodical manner
brain’s circuits so that the most critical synapses are not throughout adult life could potentially explain how the
only strengthened but also survive the ongoing selection long-term course of schizophrenia can be conceptualized
process, keeping the most efficient and most frequently as neurodegenerative.
utilized synapses while eliminating inefficient and rarely As stated earlier, normally, almost half of the brain’s
utilized synapses. However, if critical synapses are not synapses are eliminated in adolescence (Figure 4-64).
adequately strengthened in schizophrenia, it could lead to However, what is often not appreciated as well is that,
their wrongful elimination, causing dysconnectivity that in adulthood, you may lose (and replace elsewhere)
disrupts information flow from circuits now deprived about 7% of the synapses in your cortex every week!
of synaptic connections where communication needs You can imagine if this process in adulthood runs
to be efficient (Figure 4-65). Sudden and catastrophic amok over a long period of time that this could have
competitive elimination of “weak” but critical pervasive cumulative consequences on adult brain
synapses during adolescence could even explain why development – or lack thereof – and be manifest as a
schizophrenia has onset at this time. If abnormalities in progressively declining clinical course and even brain
genes converging upon the processes of neuroplasticity atrophy (Figure 4-66). That is, the strengthening or
and synaptogenesis lead to the lack of critical synapses weakening of synapses occurs not only when these
being strengthened, these critical synapses may be synapses first form, but continues throughout life
mistakenly eliminated during adolescence, with as a sort of ongoing remodeling in response to what
disastrous consequences, namely the onset of symptoms experiences the individual has, and thus how often
of schizophrenia. This could explain why genetically that synapse is used or neglected. The strengthening
programmed dysconnectivity present from birth is or weakening of glutamate synapses in particular is an
masked by the presence of many additional weak example of “activity dependent” or “use dependent” or
connections prior to adolescence, acting with exuberance “experience dependent” regulation of NMDA receptors
to compensate for defective connectivity, and when that and functionality at glutamate synapses. The old saying
compensation is destroyed by the normal competitive is, “use it or lose it.” In schizophrenia, it is possible that
elimination of synapses in adolescence, schizophrenia abnormal synaptogenesis prevents normal synapses from
emerges. Thus, aberrant neurodevelopment of both strengthening even if the patient is “using” that synapse.
not forming adequate synapses and competitively It is also possible that the “wrong” synapses are “used”
and erroneously removing critical synapses during and strengthened, while the critical synapses for full
adolescence may provide partial answers both to why functioning are not used and therefore lost along with
schizophrenia has its full catastrophic onset at this critical the function those connections would have provided,
stage of neurodevelopment, and why schizophrenia has yielding a progressive downhill course. Evidence is
aspects of a neurodevelopmental disorder, especially accumulating that allowing the positive symptoms of
around the time of full onset of the disorder. psychosis to persist unabated hastens the progressive
loss of brain tissue associated with recurrent episodes of
Neurodegeneration and Schizophrenia
psychotic breaks (usually with repeated hospitalizations)
Many patients with schizophrenia have a progressive, in schizophrenia (Figure 4-66).
downhill course, especially when available treatments Abnormalities in these continuing dynamics at NMDA
are not used consistently and there are long durations receptors and glutamate synapses in particular may
of untreated psychosis (Figure 4-66). Such observations explain why the course of schizophrenia is progressive
have led to the notion that this illness may thus be and changes over time for most patients; namely,
neurodegenerative in nature. If schizophrenia looks from an asymptomatic period to a prodrome (maybe
as though it begins as aberrant neurodevelopment, due to laying down deficient synapses initially in the
154
Course of Illness in Schizophrenia

Prodrome
100
90
Response
Level of functioning (%)
80
70
60
Chronic relapsing/residual symptoms
50
First episode
40
Progressive brain tissue loss
30
First Second Third Fourth Treatment resistance 4
20 episode episode episode episode
10
0
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Age (years)
Figure 4-66 Course of illness in schizophrenia. Although schizophrenia may begin as a neurodevelopmental disorder, its progressive
nature suggests that it may also be a neurodegenerative disorder. Strengthening and weakening of synapses occurs throughout the
lifetime. In schizophrenia, it is possible that abnormal synaptogenesis prevents normal synapses from strengthening even if they are
being “used,” and/or allows the “wrong” synapses to strengthen and be retained. There is evidence that recurrent episodes of psychotic
breaks are associated with progressive loss of brain tissue in schizophrenia and loss of treatment responsiveness.
young brain) to a first-break psychosis (when synaptic altogether. In fact, there is an emerging concept in
remodeling dramatically accelerates and perhaps the psychopharmacology in general that treatments that
wrong synapses are eliminated) (Figure 4-66). One reduce symptoms can also be disease modifying.
powerful indication of a downhill course in schizophrenia Whether or not the same agents that treat the symptoms
is what happens over time to treatment responsiveness of schizophrenia could also prevent the emergence of
and to the brain’s structure. At the time of a first-break schizophrenia when given to high-risk individuals who
psychosis, there is often robust treatment responsiveness are either presymptomatic or in a state with only mild
to medicines for psychosis, and the brain can appear prodromal symptoms remains speculative. However, it
grossly normal (see first episode brain in Figure 4-66). already seems quite clear that continuous treatment of
However, as the number of psychotic episodes mounts, patients with schizophrenia once it has begun is now
often due to medication discontinuation, this can often the standard of care in treatment of schizophrenia in
be accompanied by declining treatment responsiveness order to maximize the chances of preventing or slowing
to medications for psychosis and progressive loss of a deteriorating course, brain-tissue loss, a tripling of
brain tissue observable on structural neuroimaging (see suicide attempts, and treatment resistance with repetitive
second, third, and fourth episodes and accompanying relapses after the first episode.
brain scans in Figure 4-66). Finally, the patient too often Is the neurodevelopmental onset and
can progress to a state of pervasive negative and cognitive neurodegenerative progression of schizophrenia the
symptoms without recovery and with relative resistance case for any psychotic illness? Fortunately not. As will
to treatment with drugs for psychosis and with even be briefly discussed in the following section of this
more dramatic signs of brain degeneration observed with chapter, although schizophrenia is the commonest and
neuroimaging. best known psychotic illness, it is not synonymous with
The good news is that there is evidence that psychosis, but is just one of many causes of psychosis and
reducing the period of untreated psychosis may slow each has its own unique onset and course of illness. The
the progression of schizophrenia, and there is even hope natural history and course of illness for schizophrenia
that presymptomatic or prodromal treatments prior to are not generally the same for every other psychotic
the onset of full psychotic symptoms in schizophrenia illness, although severe forms of bipolar psychosis
may some day prevent or slow the onset of the illness are sometimes lumped together with severe forms of
155
schizophrenia and referred to together as “serious mental Table 4-8 Disorders in which psychosis is a defining feature
illness” or SMI. These forms of psychosis can all have Schizophrenia
a dismal functional outcome, including homelessness,
Substance/medication-induced psychotic disorders
premature death, and even confinement in the criminal
justice system. Schizophrenia affects approximately 1% Schizophreniform disorder
of the population, and in the United States there are Schizoaffective disorder
over 300,000 acute schizophrenic episodes annually. Delusional disorder
Between 25% and 50% of schizophrenia patients attempt
Brief psychotic disorder
suicide, and up to 10% eventually succeed, contributing
to a mortality rate eight times greater than that of the Shared psychotic disorder
general population. Life expectancy of a schizophrenia Psychotic disorder due to another medical condition
patient may be 20 to 30 years shorter than the general Childhood psychotic disorder
population, not only due to suicide, but also due to
premature cardiovascular disease. Accelerated mortality
from premature cardiovascular disease in schizophrenia Table 4-9 Disorders in which psychosis is an associated feature
patients is caused by genetic and lifestyle factors, such as
smoking, unhealthy diet, and lack of exercise, leading to Mania
obesity and diabetes, but also – sorrily – from treatment Depression
with some antipsychotic drugs that themselves cause Cognitive disorders
an increased incidence of obesity and diabetes and thus
Alzheimer disease and other dementias
increased cardiac risk. In the United States, over 20% of
all social security benefit days are used for the care of Parkinson’s disease
schizophrenia patients. The direct and indirect costs
of schizophrenia in the US alone are estimated to be in
the tens of billions of dollars every year. Many of these another medical condition, and childhood psychotic
costs in the US are borne by the criminal justice system disorder (Table 4-8). Disorders that may or may not have
of courts, jails, prisons, and state and forensic hospitals psychotic symptoms as an associated feature include
that provide housing and treatment for patients with mood disorders (both bipolar mania and many types of
schizophrenia due to the lack of adequate outpatient depression), Parkinson’s disease (known as Parkinson’s
treatment or long-term hospitals, as has already been disease psychosis or PDP), and several cognitive disorders
discussed. This may be changing due to innovative such as Alzheimer disease and other forms of dementia
outpatient diversion programs that are beginning to (Table 4-9).
divert patients from the criminal justice system to Symptoms of schizophrenia are not necessarily unique
community housing and treatment, which is far less to schizophrenia. It is important to recognize that several
expensive and possibly more humane and effective illnesses other than schizophrenia can share some of
than alternating homelessness and no treatment with the same five symptom dimensions described here for
incarceration in a revolving-door fashion. schizophrenia and shown in Figure 4-59. Thus, numerous
disorders in addition to schizophrenia can have positive
OTHER PSYCHOTIC ILLNESSES symptoms (delusions and hallucinations), including
Parkinson’s disease, bipolar disorder, schizoaffective
Psychotic disorders have psychotic symptoms as their disorder, psychotic depression, Alzheimer disease and
defining features, but there are several other disorders other organic dementias, childhood psychotic illnesses,
in which psychotic symptoms may be present but are drug-induced psychoses, and others. Negative symptoms
not necessary for the diagnosis. Those disorders that can also occur in disorders other than schizophrenia,
require the presence of psychosis as a defining feature especially mood disorders and dementias where
of the diagnosis include schizophrenia, substance/ it can be difficult to distinguish between negative
medication-induced (i.e., drug-induced) psychotic symptoms such as reduced speech, poor eye contact,
disorder, schizophreniform disorder, schizoaffective diminished emotional responsiveness, reduction of
disorder, delusional disorder, brief psychotic disorder, interest, and reduced social drive and the cognitive and
shared psychotic disorder, psychotic disorder due to affective symptoms that occur in these other disorders.
156
Schizophrenia is certainly not the only disorder with retained, which is not characteristic of psychosis in
cognitive symptoms. Autism, post-stroke (vascular or psychiatric disorders. PDP is conceptualized as an
multi-infarct) dementia, Alzheimer disease, and many imbalance in serotonin and dopamine with upregulation
other organic dementias (Parkinsonian/Lewy body of 5HT2A receptors and treatable with 5HT2A antagonists
dementia; frontotemporal/Pick’s dementia, etc.), and (Figure 4-52C and Figure 4-54).
mood disorders including major depression and bipolar
Dementia-Related Psychosis
depression can also be associated with various forms of
cognitive dysfunction. As the world’s population ages, and without a known
disease-modifying target to prevent the relentless march
Mood-Related Psychosis, Psychotic Depression, of dementia, the behavioral symptoms of dementia are
Psychotic Mania
attaining more and more attention, as dementia patients
Mood disorders, from unipolar depression to bipolar are surviving longer and as their dementia progresses. 4
disorder, can have symptoms of psychosis that accompany Agitation and psychosis are particularly important,
their mood symptoms. We have already discussed how common, and disabling behavioral symptoms of
schizophrenia can have symptoms of depressed mood, dementia and can be difficult to distinguish from each
anxious mood, guilt, tension, irritability, and worry. other in dementia. However, it is important to do so
Thus, schizophrenia can have affective symptoms and whenever possible, as the neuronal pathways for these
mood disorders can have psychotic symptoms. The point different behaviors are also different, and so are their
is, whenever psychotic symptoms are encountered, they evolving treatments. Agitation in dementia is discussed in
need to be treated, and whenever affective symptoms detail in Chapter 12 on dementia. In this chapter we have
are encountered, they too need to be treated, not only only briefly covered psychosis in dementia. Although
to relieve the current affective symptoms, but to prevent we have discussed how psychosis is generally defined
suicide, which is unfortunately common in patients with as the presence of delusions and/or hallucinations,
schizophrenia. it is delusions that are often more common in many
dementias, especially Alzheimer disease, where there
Parkinson’s Disease Psychosis
is a 5-year-period prevalence of delusions of over 50%.
Parkinson’s disease begins of course with prominent However, in Lewy body dementia, patients often have the
motor symptoms. Motor symptoms are believed to same visual hallucinations and delusions characteristic
be caused by deposition of Lewy bodies containing of PDP, not surprising since Lewy body deposition in the
α-synuclein in the substantia nigra. However, Parkinson’s cerebral cortex is thought to be a contributing cause of
disease progresses in over half the cases, especially in psychosis in both conditions.
those with concomitant dementia, to psychosis with From a pharmacological point of view, it may matter
delusions and hallucinations, called Parkinson’s disease little what causes the disruption of brain pathways that
psychosis (PDP). Several causes are proposed for PDP, the brings on the symptoms of psychosis. It may matter
most prominent theory being the accumulation of Lewy far more where the pathways are disrupted and which
bodies in the cerebral cortex as well as in serotonin cell pathways are disrupted. That is, whether an amyloid
bodies in the midbrain raphe (Figures 4-52C and 4-54). plaque, a tau tangle, a small stroke, or a Lewy body
Psychosis in Parkinson’s disease is a big risk factor for disrupts the glutamate–GABA connections or the
hospital admissions, for nursing-home placement, and for serotonin–glutamate connections in the cerebral cortex,
mortality, with mortality after 3 years of about 40% for it may not matter as long as the disruption leads to
Parkinson’s patients after onset of psychosis. downstream dopamine hyperactivity and the symptoms
PDP is not simply schizophrenia in a Parkinson’s of delusions and hallucinations (Figure 4-52D and 4-55).
patient. First, the hallucinations in PDP tend to be visual When those same pathological conditions occur in other
rather than auditory (e.g., seeing people, animals). pathways, presumably those patients do not experience
Second, the delusions tend to be a particular type of psychosis, but perhaps the other symptoms of dementia,
persecutory belief (e.g., the impression that someone, such as memory disturbances and agitation.
particularly a loved one, is trying to harm, steal from, Alzheimer disease dementia patients may have a
or deceive), or jealousy (e.g., the impression that your serotonin component to their psychosis, since serotonin
partner is cheating on you). Third, insight into the false in presubiculum of the cerebral cortex is reported
nature of these hallucinations and delusions is initially
157
to be low in patients with psychotic compared with hypofunctioning NMDA receptors at different GABA
nonpsychotic dementia. Furthermore, the C102 allele interneurons. Imbalance in serotonin neurotransmission,
of the 5HT2A receptor gene may also be associated with particularly excessive activity at 5HT2A receptors
psychosis in Alzheimer disease. In addition, Alzheimer in the cortex, may explain psychosis in Parkinson’s
patients with psychosis have significantly more plaques disease. Imbalance between serotonin and GABA
and tangles in the medial temporal-presubicular area neurotransmission at glutamate neurons in the cerebral
and middle frontal cortex and five times higher levels cortex due to neurodegenerative processes knocking
of abnormal paired helical filament-tau protein in out GABA inhibition may lead to excessive excitation of
entorhinal and temporal cortices. If these lesions disrupt glutamate neurons by serotonin acting at 5HT2A receptors
regulation of glutamate–GABA–serotonin–dopamine and that can be relieved by 5HT2A antagonists.
circuits, they would be expected to be the cause of The synthesis, metabolism, reuptake, and receptors
psychosis (Figure 4-52D and 4-55). for dopamine, glutamate, and serotonin are all described
in this chapter. D2 receptors are targets for drugs that
treat psychosis, as are 5HT2A receptors specifically
SUMMARY for the psychosis associated with Parkinson’s disease
This chapter has provided a brief description of psychosis and with dementias. NMDA glutamate receptors
and an extensive explanation of the three principal require interaction not only with the neurotransmitter
theories of psychosis, namely those linked to dopamine, glutamate, but also with the cotransmitters glycine or
glutamate, and serotonin (5HT). The major dopamine, D-serine.
glutamate, and serotonin pathways in the brain have Dysconnectivity of NMDA-receptor-containing
all been described. Overactivity of the mesolimbic synapses caused by genetic and environmental/
dopamine system may mediate the positive symptoms of epigenetic influences is a major hypothesis for the cause
psychosis and may be linked to hypofunctioning NMDA of schizophrenia, including its upstream glutamate
glutamate receptors in parvalbumin-containing GABA hyperactivity and NMDA receptor hypofunction, as well
interneurons in the prefrontal cortex and hippocampus as its downstream increases in mesolimbic dopamine
in some psychotic disorders such as schizophrenia. but decreases in mesocortical dopamine. A whole host of
Underactivity of the mesocortical dopamine system susceptibility genes that regulate neuronal connectivity
may mediate the negative, cognitive, and affective and synapse formation may represent a hypothetical
symptoms of schizophrenia and could also be linked to central biological flaw in schizophrenia.
158
5
Targeting Dopamine and Serotonin
Receptors for Psychosis, Mood, and
Beyond: So-Called “Antipsychotics”
Targeting Mesolimbic/Mesostriatal Dopamine D2 Mania 195
Receptors Causes Antipsychotic Actions 161 Antidepressant Actions in Bipolar and Unipolar
Targeting Dopamine D2 Receptors in Mesolimbic/ Depression 195
Mesostriatal and Mesocortical Pathways Causes Anxiolytic Actions 196
Secondary Negative Symptoms 162 Agitation in Dementia 197
Secondary Negative Symptoms Due to Targeting Sedative Hypnotic and Sedating Actions 197
Mesolimbic Dopamine D2 Receptors 162
Cardiometabolic Actions 198
Secondary Negative Symptoms Due to Targeting
Pharmacological Properties of Selected Individual
Mesocortical Dopamine D2 Receptors 163
First-Generation D2 Antagonists 201
Targeting Tuberoinfundibular Dopamine D2
Chlorpromazine 201
Receptors Causes Elevation of Prolactin 164
Fluphenazine 202
Targeting Nigrostriatal Dopamine D2 Receptors
Haloperidol 202
Causes Motor Side Effects 165
Sulpiride 202
Drug-Induced Parkinsonism 166
Amisulpride 203
Drug-Induced Acute Dystonia 169
An Overview of the Pharmacological Properties
Akathisia 169
of Individual 5HT2A/ D2 Antagonists and D2/5HT1A
Neuroleptic Malignant Syndrome 169
Partial Agonists: The Pines (Peens), Many Dones
Tardive Dyskinesia 170 and a Rone, Two Pips and a Rip 204
Drugs Targeting Dopamine D2 Receptors: The Pines (Peens) 222
So-Called First Generation or Conventional
Many Dones and a Rone 234
“Antipsychotics” 179
Two Pips and a Rip 239
Drugs Targeting Serotonin 2A Receptors with or
Selective 5HT2A Antagonist 240
without Simultaneously Targeting Dopamine D2
Receptors 183 The Others 240
5HT2A Receptor Regulation of Dopamine Release in Future Treatments for Schizophrenia 241
Three Downstream Pathways 184 Roluperidone (MIN-101) 241
Drugs Targeting Serotonin 1A Receptors and D3 Antagonists 241
Dopamine D2 Receptors as Partial Agonists 189 Trace Amine Receptor Agonists and SEP-
D2 Partial Agonism 189 363856 241
How Does D2 Partial Agonism Cause Fewer Motor Cholinergic Agonists 242
Side Effects than D2 Antagonism? 192 A Few Other Ideas 242
5HT1A Partial Agonism 193 Summary 242
Links between Receptor Binding Properties
of Drugs Used to Treat Psychosis and Other
Therapeutic Actions and Side Effects 195
This chapter explores drugs that target dopamine mood disorders than for psychosis, yet are not classified
receptors, serotonin receptors, or both, for the treatment as “antidepressants.” As mentioned earlier, throughout
of psychosis, mania, and depression. It also explores this textbook we strive to utilize modern neuroscience-
myriad additional neurotransmitter receptors that based nomenclature, where drugs are named for their
these agents engage. The drugs covered in this chapter pharmacological mechanism of action and not for
have classically been called “antipsychotics,” but this their clinical indication. Thus, drugs discussed in this
terminology is now considered out of date and confusing chapter have “antipsychotic action” but are not called
since these same agents are used even more frequently for “antipsychotics”; they also have “antidepressant action”
159
but are not called “antidepressants.” Instead, this chapter not practical issues such as how to prescribe these drugs
reviews one of the most extensively prescribed classes (for that information, see, for example, Stahl’s Essential
of psychotropic agents in psychiatry today, namely, Psychopharmacology: the Prescriber’s Guide, which is a
those that target dopamine and serotonin receptors, and companion to this textbook).
that began as drugs for psychosis, and later extended The pharmacological concepts developed here
their use even more frequently as drugs for mania, should help the reader understand the rationale for
bipolar depression, and treatment-resistant unipolar how to use each of the different agents, based first and
depression. On the horizon is the use of at least some of foremost upon their interactions with the dopamine and
these agents in PTSD (posttraumatic stress disorder), serotonin receptor systems, and secondarily with other
agitation in dementia, and beyond. We discuss how the neurotransmitter systems. Such interactions can often
pharmacological properties of these agents form not only explain both the therapeutic actions and the side effects
a single large class of many agents, but in many ways, of the various drugs in this group. Understanding the
how each individual agent has binding properties that full range of receptor interactions for each individual
render every agent unique from all the others. The reader drug also sets the stage for differentiating one drug from
is referred to standard reference manuals and textbooks another, and thus for tailoring the selection of a drug
for practical prescribing information because this chapter treatment by matching the pharmacological mechanisms
on drugs for psychosis and mood emphasizes basic of a specific drug to the therapeutic and tolerability needs
pharmacological concepts of mechanism of action and of an individual patient.
Therapeutic Mechanisms of Drugs for Psychosis
D2
D2 antagonist
5HT2A 5HT2A
PA
T1A
5H
D2
5HT2A antagonist
D2
5HT2A/D2 antagonist
PA
D2/5HT1A partial agonist

Figure 5-1 Therapeutic mechanisms of drugs for psychosis. The first mechanism identified to treat psychosis was dopamine-2 (D2)
antagonism, and for several decades all available medications to treat psychosis were D2 antagonists. Today, there are many agents
available with additional mechanisms, including D2 antagonism combined with serotonin (5HT) 2A (5HT2A) antagonism, D2 partial
agonism (PA) combined with serotonin 1A (5HT1A) partial agonism, and 5HT2A antagonism alone.
160
Chapter 5: Targeting for Psychosis
Mesolimbic/Mesostriatal Pathway -
Untreated Schizophrenia
normal
HIGH
positive
symptoms
A
Mesolimbic/Mesostriatal Pathway - 5
D2 Antagonist/Partial Agonist
normal
therapeutic NORMAL
reduced positive
symptoms
(SIGH)
side effect
overactivation
= D2 antagonist/
partial agonist
secondary negative
symptoms
(apathy, anhedonia)
B
Figure 5-2 Mesolimbic/mesostriatal dopamine pathway and D2 antagonists. (A) In untreated schizophrenia, the mesolimbic/
mesostriatal dopamine pathway is hypothesized to be hyperactive, indicated here by the pathway appearing red as well as by the
excess dopamine in the synapse. This leads to positive symptoms such as delusions and hallucinations. (B) Administration of a D2
antagonist or partial agonist blocks dopamine from binding to the D2 receptor, which reduces hyperactivity in this pathway and thereby
reduces positive symptoms as well. However, because the mesolimbic/mesostriatal dopamine pathway also plays a role in regulating
motivation and reward, blockade of D2 receptors can cause secondary negative symptoms such as apathy and anhedonia.
TARGETING MESOLIMBIC/ discovered by accident in the 1950s when a drug with

MESOSTRIATAL DOPAMINE antihistamine properties (chlorpromazine) was observed
to improve psychosis when this putative antihistamine was
D2 RECEPTORS CAUSES
tested in schizophrenia patients. Chlorpromazine indeed
ANTIPSYCHOTIC ACTIONS has antihistaminic activity, but its therapeutic actions in
How do the drugs approved for treating psychosis, schizophrenia are not mediated by this property. Once
especially in schizophrenia, work? The earliest effective chlorpromazine was observed to be an effective drug
treatments for schizophrenia and other psychotic for treating psychosis out of proportion to its ability to
illnesses arose from serendipitous clinical observations cause sedation, it was tested experimentally to uncover its
approximately 70 years ago, rather than from scientific mechanism of antipsychotic action, which was identified
knowledge of the neurobiological basis of psychosis, or of as dopamine D2 receptor antagonism (Figures 5-1 and 5-2).
the mechanism of action of effective drugs that empirically Early in the testing process, chlorpromazine and other
treated psychosis. Thus, the first truly effective drugs drugs for psychosis of this era were all found to cause
for psychosis other than sedating tranquilizers were “neurolepsis,” known as an extreme form of slowness
161
or absence of motor movements as well as behavioral positive symptoms of psychosis from excessive release
indifference in experimental animals. The original drugs of dopamine in the pathway (see Figures 4-14, 4-15,
for psychosis in fact were first discovered largely by their and 5-2A), but also to have a major role in regulating
ability to produce this effect in experimental animals, and motivation and reward (Figures 4-14 and 5-2B). In fact,
thus sometimes drugs with antipsychotic properties are the nucleus accumbens, a major target of mesolimbic/
called “neuroleptics.” A human counterpart of neurolepsis mesostriatal dopamine neurons in the ventral emotional
is also caused by these drugs and is characterized by striatum, is widely considered to be the “pleasure center”
psychomotor slowing, emotional quieting, and affective of the brain. The mesolimbic dopamine pathway to the
indifference, sometimes also called “secondary” negative nucleus accumbens is often considered the final common
symptoms because they mimic the primary negative pathway of all reward and reinforcement (even if this is
symptoms associated with the untreated illness itself an oversimplification), including not only normal reward
(see Figures 4-56 through 4-59 and Tables 4-4 and 4-5). (such as the pleasure of eating good food, orgasm, listening
We know today that neurolepsis and secondary negative to music) but also the artificial reward of substance abuse
symptoms are likely caused at least in part by blocking D2 (see the discussion on drugs of abuse in Chapter 13).
receptors that normally mediate motivation and reward If normal mesolimbic D2 receptor stimulation is
(Figure 5-2B) as an undesired “cost of doing business” associated with the experience of pleasure (Figure 4-14)
in order to simultaneously block D2 receptors that are and excessive mesolimbic D2 receptor stimulation is
thought to mediate the positive symptoms of psychosis associated with the positive symptoms of psychosis
due to excessive release of dopamine (see Figure 5-2A). (Figure 5-2A), D2 antagonism/partial agonism may not
By the 1970s it was widely recognized that the key only reduce the positive symptoms of schizophrenia,
pharmacological property of all “neuroleptics” with but at the same time block reward mechanisms (both
antipsychotic properties was their ability to block D2 shown in Figure 5-2B). When this happens, it can
receptors (Figure 5-1 and Figure 5-2B), specifically those leave patients feeling apathetic, anhedonic, and lacking
in the mesolimbic/mesostriatal dopamine pathway (Figure motivation, interest, or joy from social interactions,
5-2B; see also Figure 4-15). This pharmacological property a state very similar to that of negative symptoms of
has been retained by many of the newer agents, some of schizophrenia. However, these negative symptoms are
which add highly potent serotonin 2A (5HT2A) antagonism caused by the drug, not the illness and thus are termed
and/or 5HT1A partial agonism to D2 antagonism, others “secondary” negative symptoms. When D2 blockers are
of which substitute D2 partial agonism for D2 antagonism, administered, as has already been mentioned above,
and, most recently, still others which only have 5HT2A an adverse behavioral state can thus be simultaneously
antagonism and drop the D2 targeting entirely (Figure produced by D2 antagonist/partial agonists, sometimes
5-1). The effects of serotonin-receptor-targeting of the called the “neuroleptic-induced deficit syndrome”
newer agents and of partial agonism are discussed in detail because it looks so much like the negative symptoms
below. Also explained in the following sections are how produced by schizophrenia itself, and this is reminiscent
targeting serotonin and dopamine receptors in various of “neurolepsis” in animals. The near shut-down of the
brain circuits mediates not only therapeutic effects in mesolimbic dopamine pathway, sometimes necessary
psychosis and other conditions, but also side effects. These to improve the positive symptoms of psychosis (Figure
drugs are first classified into several general groups and 5-2A), may exact a heavy “cost of doing business” to the
then each individual drug is discussed. patient by causing a worsening of anhedonia, apathy,
and other negative symptoms (Figure 5-2B). Worsening
TARGETING DOPAMINE D2 negative symptoms with loss of pleasure caused by
RECEPTORS IN MESOLIMBIC/ treatment with drugs for psychosis is a plausible partial
MESOSTRIATAL AND explanation for the high incidence of smoking and
MESOCORTICAL PATHWAYS drug abuse in schizophrenia as patients may attempt
CAUSES SECONDARY NEGATIVE to overcome this anhedonia and lack of pleasurable
experiences. The emotional flattening and worsening of
SYMPTOMS negative symptoms may contribute to patients stopping
Secondary Negative Symptoms Due to Targeting their given D2 blockers.
Mesolimbic Dopamine D2 Receptors Treatment of negative symptoms includes reducing the
Dopamine 2 (D2) receptors in the mesolimbic/mesostriatal dose of the D2 blocker or switching to a D2 blocker that is
dopamine pathway are postulated not only to mediate the better tolerated; some adjunct medications can be helpful
162
in reducing negative symptoms, including drugs that treat Secondary Negative Symptoms Due to Targeting
depression. Several other agents are in various stages of Mesocortical Dopamine D2 Receptors
development for negative symptoms and include 5HT2A Negative symptoms (Figure 5-3A) can also be
antagonists as well as dopamine 3 (D3) partial agonists, as worsened by D2 antagonist/partial agonist actions in
discussed below in the section on individual agents. the mesocortical dopamine pathway (Figure 5-3B).
normal
Mesocortical Pathway -
Untreated Schizophrenia LOW
(SIGH)
5
negative
symptoms
affective
symptoms
normal
symptoms
Mesocortical Pathway - worsen
D2 Antagonist/Partial Agonist LOW
cognitive
symptoms (SIGH)
negative
symptoms
symptoms
worsen
= D2 antagonist/ affective
partial agonist symptoms
Figure 5-3 Mesocortical dopamine pathway and D2 antagonists. (A) In untreated schizophrenia, the mesocortical dopamine pathways
to the dorsolateral prefrontal cortex (DLPFC) and to the ventromedial prefrontal cortex (VMPFC) are hypothesized to be hypoactive,
indicated here by the dotted outlines of the pathway. This hypoactivity is related to cognitive symptoms (in the DLPFC), negative
symptoms (in the DLPFC and VMPFC), and affective symptoms of schizophrenia (in the VMPFC). (B) Administration of a D2 antagonist or
partial agonist could further reduce activity in this pathway and thus potentially worsen these symptoms.
163
Drugs for psychosis also block those D2 receptors TARGETING

that are present in the mesocortical dopamine TUBEROINFUNDIBULAR
pathway (Figure 5-3B) where dopamine is already
hypothetically deficient in schizophrenia (see Figures
DOPAMINE D2 RECEPTORS
4-17 through 4-19). This can cause or worsen not only CAUSES ELEVATION OF
negative symptoms of schizophrenia, but also cognitive PROLACTIN
and affective symptoms related to dopamine action Dopamine 2 receptors in the tuberoinfundibular
in the mesocortical dopamine pathway, even though dopamine pathway are also blocked when D2
there is only a low density of D2 receptors in the cortex antagonists are administered and this causes plasma
(Figure 5-3B). prolactin concentrations to rise, a condition called
Tuberoinfundibular Pathway -
Untreated Schizophrenia
normal
NORMAL
Tuberoinfundibular Pathway -
D2 Antagonist
normal
LOW
prolactin
levels
= pure D2 antagonist
rise
B
Figure 5-4 Tuberoinfundibular dopamine pathway and D2 antagonists. (A) The tuberoinfundibular dopamine pathway, which projects
from the hypothalamus to the pituitary gland, is theoretically “normal” in untreated schizophrenia. (B) D2 antagonists reduce activity in
this pathway by preventing dopamine from binding to D2 receptors. This causes prolactin levels to rise, which is associated with side
effects such as galactorrhea (breast secretions) and amenorrhea (irregular menstrual periods).
164
hyperprolactinemia (Figure 5-4). This can be TARGETING NIGROSTRIATAL

associated with a condition called gynecomastia, DOPAMINE D2 RECEPTORS
or enlargement of the breasts, in men as well as
women, and another condition called galactorrhea
CAUSES MOTOR SIDE EFFECTS
(i.e., breast secretions) and amenorrhea (i.e., Motor side effects are caused by D2 antagonists/partial
irregular or lack of menstrual periods) in women. agonists blocking D2 receptors in the nigrostriatal motor
Hyperprolactinemia may thus interfere with fertility, pathway (Figure 5-5). When D2 receptors are blocked
especially in women. Hyperprolactinemia might lead acutely in the nigrostriatal pathway – the same pathway
to more rapid demineralization of bones, especially in that degenerates in Parkinson’s disease – this can cause
postmenopausal women who are not taking estrogen a condition known as drug-induced parkinsonism (DIP)
replacement therapy. Other possible problems because it looks similar to Parkinson’s disease with
associated with elevated prolactin levels may include tremor, muscular rigidity, and slowing of movements
sexual dysfunction and weight gain, although the role of (bradykinesia) or loss of movement (akinesia) (Figure
prolactin in causing such problems is not clear. 5-5B). Often, any abnormal motor symptoms caused
Nigrostriatal Pathway - Untreated Schizophrenia 5
normal
NORMAL
Nigrostriatal Pathway - D2 Antagonist/Partial Agonist

normal
LOW
dystonia
= D2 antagonist/
partial agonist
DIP
drug-induced
parkinsonism
akathisia
Figure 5-5 Nigrostriatal dopamine pathway and D2 antagonists. (A) The nigrostriatal dopamine pathway is theoretically unaffected
in untreated schizophrenia. (B) Blockade of D2 receptors prevents dopamine from binding there and can cause motor side effects
such as drug-induced parkinsonism (tremor, muscle rigidity, slowing or loss of movement), akathisia (motor restlessness), and dystonia
(involuntary twisting and contractions).
165
by D2 receptor blockers are lumped together and called such as constant chewing, tongue protrusions, facial
collectively extrapyramidal symptoms (EPS), but EPS grimacing, but also limb movements that can be quick,
is an old-fashioned and relatively imprecise term for jerky, or choreiform (dancing). Unfortunately, DIP and
describing the motor side effects of D2 antagonists/ TD are often lumped together as EPS, leading to the
partial agonists. A practical consequence of lumping all failure to differentiate one versus the other despite the
D2-blocker-induced movements together as EPS is to fact that they have essentially opposite pharmacologies
miss the fact that different motor symptoms can have and vastly different treatments, as discussed below. Now
different clinical manifestations and – importantly – that treatments exist for both DIP and TD, it is more
vastly different treatments. More precise terms than important than ever to make this differentiation so that
EPS include not only DIP but also akathisia (motor proper treatment can be given. Inadequate relief of motor
restlessness) and dystonia (involuntary twisting and side effects of D2 blockers is a major reason why patients
contractions), which can also be caused by the acute stop their medication.
administration of D2 antagonists/partial agonists and are
Drug-Induced Parkinsonism
discussed below.
Yet another abnormal involuntary movement disorder The most common side effect of drugs that target D2
can be caused by the chronic blockade of D2 receptors receptors for psychosis is drug-induced parkinsonism,
in the nigrostriatal dopamine pathway, namely tardive explained above as the presence of tremor, muscular
dyskinesia (TD) (“tardive” because, unlike the other rigidity, and slowing of movements (bradykinesia)
motor symptoms caused by D2 blockade, these abnormal or loss of movement (akinesia). Classic treatment for
involuntary movements are late and delayed in onset, DIP is the use of “anticholinergics,” namely drugs that
often after months to years of treatment) (Figure 5-6). TD block muscarinic cholinergic receptors, especially the
emerges only after chronic treatment with D2 blockers, postsynaptic M1 receptor. This approach exploits the
and can be irreversible. It consists of involuntary normal reciprocal balance between dopamine and
continuous movements, often about the face and tongue, acetylcholine in the striatum (Figure 5-7A). Dopamine
chronic
treatment
A B
tardive
dyskinesia
Figure 5-6 Tardive dyskinesia. (A) Dopamine binds to D2 receptors in the nigrostriatal pathway. (B) Chronic blockade of D2 receptors
in the nigrostriatal dopamine pathway can cause upregulation of those receptors, which can lead to a hyperkinetic motor condition
known as tardive dyskinesia, characterized by facial and tongue movements (e.g., tongue protrusions, facial grimaces, chewing) as well
as quick, jerky limb movements.
166
neurons in the nigrostriatal motor pathway make the other hand, there are many potential problems with
postsynaptic connections on cholinergic interneurons administering anticholinergics (such as the commonly
(Figure 5-7A). Dopamine acting at D2 receptors used benztropine); namely, peripheral side effects, such
normally inhibits acetylcholine release from postsynaptic as dry mouth, blurred vision, urinary retention, and
nigrostriatal cholinergic neurons (Figure 5-7A). When constipation, as well as central side effects including
D2 blockers are given, dopamine can no longer suppress drowsiness and cognitive dysfunction, such as problems
acetylcholine release, thus disinhibiting acetylcholine with memory, concentration, and slowing of cognitive
release from cholinergic neurons (see enhanced processing (Figure 5-8). To compound matters, many
acetylcholine release in Figure 5-7B). This in turn leads drugs for psychosis themselves have anticholinergic
to more excitation of postsynaptic muscarinic cholinergic properties as will be discussed below for each individual
receptors on medium spiny GABAergic neurons, which agent. Furthermore, many patients are on concomitant
hypothetically leads in part to inhibition of movements psychotropic and nonpsychotropic medications that
and to the symptoms of DIP (akinesia, bradykinesia, have anticholinergic properties. Thus, the clinician
rigidity, and tremor). However, when the enhanced must be alert to the total anticholinergic burden for a
downstream release of acetylcholine is blocked by given patient and also be wary of the side effects that
5
anticholinergics at muscarinic cholinergic receptors, can interfere with normal cognitive functioning and
this hypothetically restores in part the normal balance can lead to life-threatening decrease in bowel motility
between dopamine and acetylcholine in the striatum, and called paralytic ileus. On balance, today many patients
DIP is reduced (Figure 5-7C). administered D2 blockers are overmedicated with total
Empirically, anticholinergics do work in clinical anticholinergic burden. Alternatives to using these
practice to reduce DIP, especially the DIP caused by some agents should often be sought, such as use of a different
of the older D2 blockers that lack serotonergic actions. On drug for psychosis that lacks anticholinergic properties,
= acetylcholine (ACh)
= dopamine (DA)
M1 receptor
cholinergic
interneuron
D2 receptor
ACh release
inhibited
DA inhibiting
ACh release
A
nigrostriatal DA neuron striatum
Figure 5-7A Reciprocal relationship of dopamine and acetylcholine. Dopamine and acetylcholine have a reciprocal relationship in
the nigrostriatal dopamine pathway. Dopamine neurons here make postsynaptic connections with the dendrite of a cholinergic neuron.
Normally, dopamine binding at D2 receptors suppresses acetylcholine activity (no acetylcholine being released from the cholinergic
axon on the right).
167
= D2 antagonist/
partial agonist
enhanced
ACh release
D2 blocker
reversing DA
inhibition striatum
B
Figure 5-7B Dopamine, acetylcholine, and D2 antagonism. Since dopamine normally suppresses acetylcholine activity, removal of
dopamine inhibition causes an increase in acetylcholine activity. As shown here, if D2 receptors are blocked on the cholinergic dendrite
on the left, then acetylcholine release from the cholinergic axon on the right is enhanced. This is associated with the production of drug-
induced parkinsonism.
= anticholinergic
blockade of
enhanced ACh action
at M1 receptors
C
striatum
Figure 5-7C D2 antagonism and anticholinergic agents. One compensation for the overactivity that occurs when D2 receptors are
blocked is to block the muscarinic cholinergic receptors with an anticholinergic agent (M1 receptors being blocked by an anticholinergic
on the far right). This hypothetically restores in part the normal balance between dopamine and acetylcholine and can reduce symptoms
of drug-induced parkinsonism.
168
M1 Inserted
cholinergic neuron
ACh LAXATIVE
E
E
P Q
P Q
constipation
blurred
vision
M1 cognitive
receptor dysfunction
dry mouth
drowsiness
5
Figure 5-8 Side effects of muscarinic cholinergic receptor blockade. Blockade of muscarinic cholinergic receptors can reduce drug-
induced parkinsonism, but can also induce side effects such as constipation, blurred vision, dry mouth, drowsiness, and cognitive
dysfunction (problems with memory and concentration, slowed cognitive processing).
or stopping anticholinergic medications, or use of this condition and can even make this form of dystonia
amantadine, which lacks anticholinergic properties but worse.
can mitigate the symptoms of DIP.
Akathisia
Amantadine’s mechanism of action is thought to be
weak antagonism of NMDA (N-methyl-D-aspartate) Akathisia is a syndrome of motor restlessness seen
glutamate receptors, possibly leading to downstream commonly after treatment with D2 blockers. Akathisia
changes in the activity of dopamine in both the direct has both subjective and objective features. Subjectively,
and indirect striatal motor pathways. No matter what its there is a sense of inner restlessness, mental unease, or
actual mechanism of action, amantadine can be useful dysphoria. Objectively, there are restless movements,
for improving DIP and also has some evidence of being most typical being lower-limb movements such as
useful in TD and levodopa-induced dyskinesias caused by rocking from foot to foot, walking or marching in place
levodopa treatment of Parkinson’s disease. when standing, or pacing. Sometimes drug-induced
akathisia can be difficult to distinguish from the
Drug-Induced Acute Dystonia agitation and repetitive restless movements that are
Occasionally, exposure to D2 blockers, especially those part of the underlying psychiatric disorder. Akathisia is
with neither serotonergic nor anticholinergic properties, not particularly effectively treated with anticholinergic
can cause a condition called dystonia, often upon first medication, but instead is often more effectively treated
exposure to the D2 blocker. Dystonia is intermittent with either β-adrenergic blockers or benzodiazepines.
spasmodic or sustained involuntary contraction of the Serotonin 2A antagonists can also be helpful.
muscles in the face, neck, trunk, pelvis, extremities,
Neuroleptic Malignant Syndrome
or even the eyes. Drug-induced dystonias can be
frightening and severe; fortunately, administration of an A rare but potentially fatal complication can occur with
intramuscular injection of an anticholinergic is nearly D2 receptor blockade, possibly due in part to D2 receptor
always effective within 20 minutes. The cause and the blockade specifically in the nigrostriatal motor pathway.
treatment of this condition are other examples of the This is called the “neuroleptic malignant syndrome,”
clinical significance of the balance between dopamine associated with extreme muscular rigidity, high fevers,
and acetylcholine in the motor striatum for the regulation coma, and even death. Some consider neuroleptic
of movements (Figures 5-7A, 5-7B, and 5-7C). malignant syndrome to be the most extreme form of
Chronic treatment with D2 blockers can also cause DIP; others theorize that this is a toxic complication
late-onset dystonia as a manifestation of tardive of D2 blocking drugs on cell membranes, including
dyskinesia, sometimes also called tardive dystonia. This muscle. It constitutes a medical emergency that requires
requires TD treatment, as anticholinergics rarely work for withdrawal of the D2 blocker, muscle-relaxing agents such
169
as dantrolene and dopamine agonists, as well as intensive schizophrenia. That is, chronic levodopa administration
supportive medical treatment. in Parkinson’s disease can lead to levodopa-induced
dyskinesias that look very similar to TD, and may share a
Tardive Dyskinesia
similar pathophysiology of aberrant striatal plasticity and
Pathophysiology abnormal neuronal “learning.” Perhaps the lesson here is
Overall, about 5% of patients maintained on D2 not to mess with your dopamine receptors in the motor
antagonists that have little or no serotonin receptor striatum or consequences may ensue!
action will develop TD every year (i.e., about 25% of A more detailed view of D2 antagonist/partial agonist
patients by 5 years), not a very encouraging prospect effects in the nigrostriatal dopamine system is shown in
for an illness starting in the early 20s and requiring Figures 5-9A, 5-9B, and 5-9C. This view was introduced
lifelong treatment. The risk of developing TD in elderly in Chapter 4 and illustrated in Figures 4-13B, 4-13C,
subjects may be as high as 25% within the first year of 4-13D, 4-13E, and 4-13F. Some fibers of the nigrostriatal
exposure to D2 antagonists. Estimates for the newer D2 dopamine pathway, particularly those projecting medially
drugs for psychosis that have serotonergic receptor action to the associative striatum, may be hyperactive as part
are more difficult to obtain since many patients taking of the limbic (emotional) system and contribute to the
them have taken the older drugs as well in the past. positive symptoms of psychosis (see Figure 4-16B).
Nevertheless, for those likely to have taken only newer Other nigrostriatal dopamine projections, particularly
D2 antagonists/5HT2A antagonists or D2/5HT1A partial those projecting to the sensorimotor striatum, are part
agonists, the rate of TD may be about half the rate of the of the extrapyramidal nervous system and control motor
older drugs. These newer agents may mitigate DIP as movements and those are the nigrostriatal dopaminergic
well by the mechanisms discussed in detail below. Those neurons depicted in Figures 5-9A, 5-9B, and 5-9C.
mechanisms are both 5HT2A antagonism and 5HT1A Normally, dopamine acts at D2 receptors in the
partial agonism. Perhaps these mechanisms by which indirect motor pathway, which is the receptor subtype
they mitigate DIP serve also to mitigate the chances of present in this pathway. The so-called indirect pathway
getting TD. is also the pathway for “stop” actions (Figures 4-13F and
Who amongst all those who receive drugs for 5-9A). Since D2 receptors are inhibitory, dopamine causes
psychosis will get TD and how does this happen? Some inhibition of the stop pathway; a fancy way for dopamine
evidence suggests that those who are most vulnerable to say “go” in this pathway (Figures 4-13B and 5-9A).
to having DIP with acute D2 blockade may also be Thus, dopamine at D2 receptors in the indirect pathway
those who are the most vulnerable to getting TD with triggers a “go” signal.
chronic D2 blockade. One theory is that nigrostriatal What happens when this action of dopamine is
D2 receptors most sensitive to blockade trigger a form blocked? When acute D2 antagonists/partial agonists
of undesirable neuroplasticity called supersensitivity are administered, this blocks the ability of dopamine to
in reaction to D2 receptor blockade (Figures 5-6). If D2 say “go” because these drugs inhibit dopamine’s action
receptor blockade is removed early enough, TD may in the “stop” pathway. Another way to say this is that D2
reverse. This reversal is theoretically due to a “resetting” antagonists say “stop” in the indirect pathway (Figure
of supersensitive D2 receptors by an appropriate return 5-9B). If there is too much “stop,” this can result in DIP
to normal in the number or sensitivity of D2 receptors in (Figure 5-9B). In technical terms, when “stop” is not
the nigrostriatal pathway once the antipsychotic drug that inhibited by dopamine action at D2 receptors in the
had been blocking these receptors is removed. However, indirect pathway because of the presence of a D2 blocker,
after long-term treatment, sometimes the D2 receptors then movements are “stopped” – sometimes so much
apparently cannot reset back to normal, even when D2 so that the slow, rigid movements of DIP are produced
blocking drugs are discontinued. This leads to TD that (Figure 5-9B).
is irreversible, persisting whether or not D2 blockers are If this situation is allowed to persist, D2 receptors in
administered. the indirect pathway of the motor striatum hypothetically
Interestingly, D2 receptors in the motor striatum react to the acute D2 receptor blockade shown in Figure
also appear to react in much the same way to chronic 5-9B by “learning” to have TD when D2 blockade
stimulation by levodopa in Parkinson’s disease as they do becomes chronic (Figure 5-9C). The theoretical
to chronic blockade by D2 antagonists/partial agonists in mechanism for this is a proliferation of excess numbers
170
D2 Inhibition of Stop Pathway
Inhibition of stop
or “GO” normally
+ STN= subthalamic nucleus

glu
g
SNr = substantia nigra reticulata
SNc= substantia nigra compacta
Cortex GPe = globus pallidus externa
glu = glutamate 5
GABA = γ-aminobutyric acid
DA = dopamine
Thalamus
-
G
GABA
STN
GP i /SNr
D2
GPe
D22
-
DA
Striatum dopamine
inhibiting the
“STOP” pathway
makes you “GO”
SN c normally
Figure 5-9A D2 receptor inhibition of the stop pathway. Dopamine released from the nigrostriatal pathway binds to postsynaptic D2
receptors on a γ-aminobutyric acid (GABA) neuron projecting to the globus pallidus externa. This causes inhibition of the indirect (stop)
pathway, thus instead telling it to “go.”
of D2 receptors in the indirect motor pathway (Figure is supersensitivity of the indirect pathway to dopamine.
5-9C). Perhaps the dopamine system becomes engaged It has been difficult to prove, but animal models and
in a futile attempt to overcome drug-induced blockade positron emission tomography (PET) scans in patients
by making more D2 receptors (Figure 5-9C). The result with schizophrenia do indeed suggest that chronic D2
171
D2 Blocker Activates “STOP” Pathway

and Causes Drug-Induced Parkinsonism
STOP:
don’t go
Cortex
-
G
GABA
Thalamus
+ D2 antagonist/
glu partial agonist
STN
GP i /SNr
-
GABA
G
GPe
D2 antagonist blocks
Striatum DA from inhibiting the
“stop” pathway -
makes you stop -
i.e. DIP
SN c
Figure 5-9B D2 receptor blockade activates the stop pathway. Dopamine released from the nigrostriatal pathway is blocked from
binding to postsynaptic D2 receptors on a γ-aminobutyric acid (GABA) neuron projecting to the globus pallidus externa. This prevents
inhibition of the indirect (stop) pathway; in other words, D2 antagonists activate the indirect (stop) pathway. Too much stop can result in
drug-induced parkinsonism.
blockade in the motor striatum causes upregulated, happening, it leads to the opposite situation (Figure
supersensitive D2 receptors, and this happens to 5-9C) to what was just described for acute blockade of D2
the greatest extent in patients with TD. Whatever is receptors (Figure 5-9B). Namely, instead of not enough
172
Chronic D2 Blockade Causes Upregulation of D2 Receptors,

Enhanced Inhibition of “STOP” Pathway, and Tardive Dyskinesia
Major Inhibition of stop

or “GO” “GO” “GO”
+
glu
Cortex
Thalamus
-
GABA D2 antagonist/ upregulated supersensitive
partial agonist D2 receptors
STN
ST
GP i /SNr
D2
GPe
D2
upregulated D2 receptors
- DA
from chronic blockade
Striatum cause major inhibition of
the “stop” pathway
and tardive dyskinesia
SN c
Figure 5-9C Chronic D2 receptor blockade and overinhibition of the stop pathway. Dopamine released from the nigrostriatal pathway
is blocked from binding to postsynaptic D2 receptors on a γ-aminobutyric acid (GABA) neuron projecting to the globus pallidus
externa. Chronic blockade of these receptors can lead to their upregulation; the upregulated receptors may also be “supersensitive” to
dopamine. Dopamine can now exert its inhibitory effects in the indirect (stop) pathway, and in fact cause so much inhibition of the “stop”
signal that the “go” signal is overactive, leading to the hyperkinetic involuntary movements of tardive dyskinesia.
inhibition of stop signals from acute D2 blockade (Figure has flipped from slow rigid movements of DIP (Figure
5-9B), there is now too much inhibition of stop signals 5-9B) to rapid hyperkinetic involuntary movements of
from chronic D2 blockade (Figure 5-9C). The situation TD (Figure 5-9C).
173
What is the mechanism that causes the indirect who discontinue D2 blockade soon after the onset of their
pathway to flip from too much stop to too much go? The TD movements – will likely enjoy reversal of their TD. In
answer may be abnormal neuronal plasticity causing the fact, most patients experience an immediate worsening
proliferation of too many and too sensitive D2 receptors of their movements when D2 blockade is eliminated,
in the indirect pathway (Figure 5-9C). Now, all of a due to the completely unblocked actions of dopamine in
sudden, instead of not enough dopamine at D2 receptors the absence of any D2 antagonist therapy at all. Thus, D2
(Figure 5-9B), there is too much dopamine at too many antagonist drug discontinuation is often not an option in
D2 receptors (Figure 5-9C). The motor striatum translates the treatment of TD.
this into excessive inhibition of the “stop” signal; thus, Recent developments show that TD can now
“not enough stop” and “too much go.” Therefore, be successfully treated by inhibiting the vesicular
neuronal impulse traffic out of the striatum no longer monoamine transporter type 2 (VMAT2). Presynaptic
has an enforced speed limit, and thus, the involuntary transporters for neurotransmitters released into the
hyperkinetic movements of TD emerge. synapse were discussed in Chapter 2 (see Table 2-3
The emergence of abnormal involuntary movements and Figures 2-2A and 2-2B). These transporters are
of TD should be specifically monitored, using a localized on the presynaptic axon terminal and are well
neurological examination and a rating scale such as known as “reuptake pumps” targeted by many drugs for
the AIMS (Abnormal Involuntary Movement scale) depression (Figures 2-2A and 2-2B; see also discussion of
periodically. Best practices are to monitor movements monoamine reuptake blockers in Chapter 6 on drugs for
in anyone taking any of these drugs, although it is depression). Transporters also exist for neurotransmitters
frequently not done, and especially not done in patients that are inside neurons; these intraneuronal transporters
being treated for depression, unfortunately. If anything, are located on synaptic vesicles and called vesicular
patients with mood disorders may be at greater risk for transporters. Several types of vesicular transporters
TD. Remember, these are the same drugs no matter in have been identified, including different ones for
whom they are used. GABA (γ-aminobutyric acid), glutamate, glycine,
acetylcholine, monoamines, and others (see Chapter 2
Treatment and Figures 2-2A and 2-2B). The specific transporter
If the brain has literally “learned” to have TD in known as VMAT2 is located on synaptic vesicles
an aberrant attempt to compensate for chronic D2 inside dopamine, norepinephrine, serotonin, and
blockade and this has resulted in unwanted dopamine histamine neurons. VMAT2 acts to store intraneuronal
overstimulation in the indirect pathway, then TD would neurotransmitters until they are needed for release
seem to be a disorder ideally set up to respond to during neurotransmission (Figure 5-10A). VMAT2 can
interventions that lower dopamine neurotransmission. also transport certain drugs as “false” substrates, such
How can this be done? as amphetamine and “Ecstasy” (MDMA; 3,4-methylene-
One way is to raise the dose of D2 antagonist to block dioxymethamphetamine), and these false substrates can
those numerous new upregulated and supersensitive D2 compete with the “true” natural neurotransmitter and
receptors. Although this might work short-term in some block it from being transported. This is discussed in
patients, it is done at the expense of more immediate further detail in Chapter 11 on stimulant treatment for
side effects and the prospects of making TD even worse attention deficit hyperactivity disorder, and in Chapter
down the road. Another treatment possibility is to stop 13 on substance abuse. Synaptic vesicles create low pH in
the offending D2 antagonist with the hope that the motor their lumens (interiors) with an energy-requiring proton
system will readjust back to normal on its own and that pump there (Chapter 2 and Figures 2-2A and 2-2B).
the movement disorder will reverse. Many patients who Low pH in turn serves as the driving force to sequester
do not have an underlying psychotic disorder may be neurotransmitter in synaptic vesicles.
able to tolerate the discontinuation of their D2 antagonist/ There are actually two types of VMATs: VMAT1
partial agonist, but most patients with psychosis may localized on synaptic vesicles of neurons in both the
not be able to tolerate D2 antagonist/partial agonist peripheral and central nervous system, and VMAT2,
discontinuation. Furthermore, it does not seem that the located only on synaptic vesicles within central nervous
TD brain can “forget” its aberrant neuroplastic learning system neurons. There are also two known types of
very well, and only some patients – particularly those VMAT inhibitors: reserpine, which irreversibly inhibits
174
Storage of Dopamine by VMAT2 Dopamine Depletion by VMAT2 Inhibition
E E
E E
VMAT2 VMAT2
VMAT2 VMAT2
VMAT2 VMAT2 5
VMAT2 inhibitor
DA release DA depletion
Figure 5-10B Dopamine depletion by VMAT2

inhibition. Inhibition of VMAT2 prevents dopamine from being
Figure 5-10A Vesicular monoamine transporter 2 (VMAT2) and
taken up into synaptic vesicles. The intraneuronal dopamine is
dopamine. The VMAT2 is an intraneuronal transporter located
therefore metabolized, leading to depletion of dopamine stores.
on synaptic vesicles. VMAT2 takes intraneuronal monoamines,
including dopamine, up into the synaptic vesicles so that
they can be stored until they are needed for release during
neurotransmission. +β-dihydro enantiomer because it has the greatest
potency for VMAT2 of those metabolites that inhibit
VMAT2 (Figure 5-11A). Tetrabenazine is not approved
both VMAT1 and VMAT2; and tetrabenazine-related for the treatment of TD, but is approved for the treatment
drugs, which reversibly inhibit only VMAT2. That is of a related hyperkinetic movement disorder, namely,
why reserpine, but not tetrabenazine-related drugs, is the chorea of Huntington’s disease. Tetrabenazine’s
associated with frequent peripheral side effects, such as disadvantages are its short half-life and thus need for
orthostatic hypotension (reserpine was once used for three times a day dosing; its peak-dose side effects,
hypertension), stuffy nose, itching, and gastrointestinal including sedation and drug-induced parkinsonism;
side effects. Although VMAT2 transports multiple the need to do genetic testing for poor metabolizers
neurotransmitters into synaptic vesicles (dopamine, of CYP450 2D6 in order to go to higher doses; and the
norepinephrine, serotonin, and histamine), risk of depression and even suicide when used to treat
tetrabenazine preferentially affects dopamine transport Huntington’s disease.
at clinical doses (Figure 5-10B). When tetrabenazine- A clever trick called deuteration has recently been
related drugs block the transport of dopamine into discovered that converts a drug that is a good substrate
presynaptic vesicles, dopamine is rapidly degraded by for CYP450 2D6 into a poorer substrate for CYP450
monoamine oxidase (MAO) within the presynaptic 2D6; this allows for a longer half-life, less frequent
neuron, leading to depletion of presynaptic dopamine dosing, and lower peak plasma levels. Deuteration is
proportional to the degree of VMAT2 inhibition the process of substituting some of the hydrogen atoms
(Figure 5-10B). in a drug with deuterium, also called heavy hydrogen.
Tetrabenazine itself is actually an inactive prodrug Deuterium is a stable isotope of hydrogen with a nucleus
converted into four active dihydro metabolites by the consisting of one proton and one neutron, which is
enzyme carbonyl reductase, and all four are inactivated double the mass of the nucleus of ordinary hydrogen
by CYP450 2D6 (Figure 5-11A). Most of the inhibition that contains only one proton. This substitution causes
of VMAT2 by tetrabenazine is ultimately done by the the drug to be a less favorable substrate for CYP450 2D6,
175
resulting in the predicted increased half-life, decreased have substantial concentrations of the –α- and the
dosing frequency (twice rather than three times a day), –β-dihydro enantiomers, which carry additional receptor
and reduced peak-dose side effects, all problems with actions, especially antagonism of 5HT7 receptors and to a
non-deuterated tetrabenazine mentioned above. For lesser extent antagonism of D2 receptors (Figures 5-11A
commercial considerations, deuteration can also restart and 5-11B).
the patent life of the non-deuterated drug, creating Another form of tetrabenazine is called valbenazine,
incentives for drug development. Other advantages of named because the amino acid valine is linked
deuterated tetrabenazine, also called deutetrabenazine, to the +α enantiomer of tetrabenazine. When
are specific regulatory approval for the treatment of TD swallowed, valbenazine is hydrolyzed into valine
as well as Huntington’s disease, no longer needing to and +α-tetrabenazine, which is rapidly converted by
do genetic testing in order to administer the full dose carbonyl reductase to just the +α dihydro enantiomer
range, and the lack of a suicide warning for treatment of tetrabenazine, the most selective and potent inhibitor
of TD. Disadvantages include need for twice daily of VMAT2 amongst the four active enantiomers (Figure
administration and dosing with food. 5-11C). The slow hydrolysis of valbenazine results in a
The metabolites of deutetrabenazine (Figure 5-11B) long half-life and once-daily administration. Valbenazine
are the same as those of nondeuterated tetrabenazine is approved for the treatment of TD, has no need for
(Figure 5-11A). In addition to the +β-dihydro genetic testing, no need for dosing with food, once-daily
enantiomer, both tetrabenazine and deutetrabenazine dosing, and no suicide warning.
T7
5H
VMAT2
-α
D2
VMAT2
+ß
tetrabenazine
E E inactive metabolites
7
5HT
c2D6
carbonyl
reductase
tetrabenazine - -ß VMAT2
inactive prodrug
D2
+α VMAT2
dihydro active
metabolites
Figure 5-11A Tetrabenazine potency. Tetrabenazine is an inactive prodrug; its metabolism by carbonyl reductase results in four active
dihyro metabolites, all of which are converted into inactive metabolites by CYP450 2D6. Of the four active metabolites, the +β-dihydro
enantiomer has the greatest potency for VMAT2 and thus is responsible for most of tetrabenazine’s therapeutic effects. The other active
metabolites have additional receptor actions, as shown.
176
D T7
5H
VMAT2
Deu -α
D2
D
VMAT2
D Deu +ß
Deutetrabenazine
E D
E 5
inactive metabolites
7
5 HT c2D6
carbonyl D
D reductase
Deuterated Deu -ß
VMAT2
tetrabenazine -
inactive prodrug D
D2
Deu +α
VMAT2
D
dihydro
deuterated
active metabolites
Figure 5-11B Deutetrabenazine potency. Deuteration is the process of substituting some of the hydrogen atoms in a drug with
deuterium. Deuterium has one proton and one neutron and is thus double the mass of hydrogen. The substitution of deuterium for
hydrogen makes it a less favorable substrate for CYP450 2D6 (shown with the smaller c2D6 enzyme compared to Figure 5-11A). This
allows for a longer half-life, decreased dosing frequency, and reduced peak-dose side effects.
valine VMAT2
valine
+α
tetrabenazine
E E +α
dihydro
E inactive
tetrabenazine
metabolites
hydrolysis 2D6
carbonyl
+α reductase
tetrabenazine
Figure 5-11C Valbenazine potency. Valbenazine is tetrabenazine with the amino acid valine linked to the +α enantiomer of
tetrabenazine. When swallowed, valbenazine is hydrolyzed into valine and +α tetrabenazine and then rapidly converted by carbonyl
reductase into +α-dihydrotetrabenazine. The slow hydrolysis results in a long half-life and once-daily dosing.
A more detailed explanation of the mechanism of pathways. The state of normal movements condition
action of VMAT2 inhibition on TD is shown in Figures is shown in Figure 5-12A, where dopamine at the
5-12A through 5-12D within both the direct and indirect bottom left is enhancing “go” in the direct pathway at
177
D1 receptors and at the bottom right where dopamine is of tetrabenazine is chosen to block VMAT2 in order to
inhibiting “stop” in the indirect pathway at D2 receptors. treat TD, it appears that a high degree, perhaps >90%,
The striatum regulates normal motor movements by of VMAT2 inhibition may often be required for the best
facilitating or diminishing dopamine release at the balance between efficacy for TD and tolerability. VMAT2
direct and indirect pathways as it orchestrates the inhibition is a mechanism that reduces dopamine
smooth execution of movements and postures that stimulation without blocking D2 receptors. Thus, this
require muscles to go or to stop, often in sequence and in action reduces the overstimulation of D2 receptors in
changing ways over time (Figure 5-12A). the indirect pathway (bottom right in Figure 5-12C),
Figure 5-12B shows the situation when TD develops, resulting in less inhibition of the stop signal there.
with the upregulation of D2 receptors on the bottom However, there is also a benefit of VMAT2 inhibition
right in the indirect pathway causing far too much in the direct pathway, where “go” signals are being
inhibition of stop, and thus the message “go, go, go,” with amplified normally by dopamine at D1 receptors (Figure
the result being the hyperkinetic involuntary movements 5-12A). Even though these D1 receptors and this direct
of TD. This was also explained above and shown in extrapyramidal pathway (Figure 5-12A) may not be the
Figure 5-9C. site of pathology in TD (see Figures 5-9C and 5-12B),
Figures 5-12C and 5-12D show the mechanism of they do drive “go” signals for movement normally
action of VMAT2 inhibition in TD. No matter what form (Figure 5-12A), and thus lowering dopamine there by
Normal Regulation of Motor Movements by Dopamine: Figure 5-12A Normal regulation

of motor movements by
Enhancing “Go” at D1 Receptors in the Direct Pathway dopamine. Dopamine regulates motor
and Inhibiting “Stop” at D2 Receptors in the Indirect Pathway movements through both the direct
(go) and indirect (stop) pathways. In
the direct pathway (shown on the left),
motor output dopamine released into the striatum
binds to D1 receptors on GABA neurons.
This stimulates GABA release, which
ultimately leads to glutamate release
+ glu in the cortex and thus enhances motor
output. In the indirect pathway (shown
Cortex on the right), dopamine released into
the striatum binds to D2 receptors on
GABA neurons. This inhibits GABA
release, thus inhibiting the “stop”
pathway, and therefore also enhancing
GABA motor output.
-
Thalamus
+ glu
GABA
GABA -
-
STN
GPi /SN r
GABA
direct pathway - indirect pathway
“go” GPe “stop”
D1 D2
+ -
DA DA
Striatum
enhancing inhibiting
“go” “stop”
SN c
178
Tardive Dyskinesia: Upregulated D2 Receptors in the Figure 5-12B Upregulation of

dopamine 2 receptors in the indirect
Indirect Pathway and Too Much “GO” pathway. Chronic blockade of D2
receptors can lead to their upregulation;
the upregulated receptors may also
be supersensitive to dopamine. In the
motor output indirect (stop) pathway, this can lead
to so much inhibition of the “stop”
signal that the “go” signal is overactive,
leading to the hyperkinetic involuntary
movements of tardive dyskinesia.
+ glu
Cortex
Thalamus
5
GABA
GABA -
-
STN
GPi /SN r
D2
GPe
D1 D2
+ -
DA DA
Striatum
too much inhibition
of “stop” causing
tardive dyskinesia
SN c
VMAT2 inhibition would be expected to lower the “go” symptomatically, must be determined by long-term
signals arising from the direct pathway (Figure 5-12D). studies of VMAT2 inhibition in TD.
Combined with more “stop” signals from the indirect
pathway (Figure 5-12C), motor output to drive abnormal DRUGS TARGETING DOPAMINE
involuntary hyperkinetic movements is therefore robustly D2 RECEPTORS: SO-
reduced by this combination of effects of dopamine CALLED FIRST GENERATION
depletion in both pathways (Figures 5-12C and 5-12D). OR CONVENTIONAL
So, it appears that VMAT2 inhibition “trims” the “go” “ANTIPSYCHOTICS”
drives of dopamine in both direct and indirect motor
pathways (Figures 5-12C and 5-12D) to compensate for A list of many of the earliest agents used to treat
the abnormal “learning” just in the indirect pathway psychosis is given in Table 5-1. Several of these remain
after chronic D2 receptor blockade (Figures 5-9C and in clinical use today. Although not generally used first
5-12B). Whether this will be disease modifying in the line, conventional D2 antagonists are still used in patients
long run, and reverse rather than only treat movements who do not respond to the newer drugs for psychosis and
179
VMAT2 Inhibition in the Indirect Pathway Causes Less Figure 5-12C VMAT2 inhibition in
the indirect (stop) pathway. VMAT2
D2 Inhibition of “Stop,” so TD Movements are Stopped inhibition reduces dopaminergic output;
thus, it can reduce the overstimulation
of inhibitory D2 receptors in the indirect
(stop) pathway. This disinhibits the
motor output indirect (stop) pathway and therefore
can reduce the hyperkinetic movements
of tardive dyskinesia.
+ glu
Cortex
GABA
-
Thalamus
+ glu
GABA
-
STN
GPi /SN r
GABA
-
GPe
D1
+
DA
Striatum
SN c VMAT2 inhibition in aberrant

indirect pathway reduces “go”
in patients requiring injections, both immediate-onset and even for gastrointestinal problems including
and long-acting injections. Several of the first-generation gastroesophageal reflux, gastroparesis from diabetes,
drugs for psychosis are available both orally and as and to prevent/treat nausea and vomiting including from
injections and many clinicians still have experience cancer chemotherapy. So, not just antipsychotic actions!
with them, even preferring them in treatment-resistant Modern nomenclature for the drugs in this group of
and difficult cases. Although these original drugs for original agents for psychosis is “D2 antagonists” because
psychosis (Table 5-1) are often called “conventional,” this is the common pharmacological mechanism for all
“classic,” or “first-generation” antipsychotics, we will uses, not just for antipsychotic actions.
continue to refer to drugs as “having antipsychotic D2 antagonists have various other pharmacological
actions” and not as “antipsychotics,” to reduce confusion, properties, including muscarinic cholinergic antagonism
since many of these same agents are used to treat many (discussed above, see Figure 5-8), antihistaminic
other conditions, including bipolar mania, psychotic actions (H1 antagonism), and α1-adrenergic antagonism
mania, psychotic depression, Tourette syndrome, (Figure 5-13). These additional pharmacological
180
VMAT2 Inhibition in the Direct Pathway Causes Less Figure 5-12D VMAT2 inhibition in the
D1 Stimulation of “GO,” so TD Movements are Stopped direct (go) pathway. VMAT2 inhibition
reduces dopaminergic output; thus, it
can reduce activation of excitatory D1
receptors in the direct (go) pathway.
motor output This inhibits the direct (go) pathway and
therefore can reduce the hyperkinetic
movements of tardive dyskinesia.
+ glu
Cortex
GABA
-
Thalamus
+ glu GABA 5
GABA -
-
STN
GPi /SN r
GABA
-
GPe
VMAT2 inhibited
D1
+
DA
Striatum
VMAT2 inhibition in normal SN c

direct pathway also reduces “go”
properties are linked much more to side effects than to is needed in some clinical situations, it is not always
therapeutic effects. Blockade of muscarinic cholinergic desirable. Conventional D2 antagonists (Table 5-1) differ
receptors is associated with dry mouth, blurred vision, in terms of their ability to block muscarinic, histaminic,
and risk of paralytic ileus as discussed earlier (Figure and α1-adrenergic receptors. For example, the popular
5-8); blocking H1 histamine receptors is associated with conventional antipsychotic haloperidol has relatively
weight gain and sedation (Figure 5-13A); and blockade little anticholinergic or antihistaminic binding activity.
of α1-adrenergic receptors is associated with sedation Because of this, conventional D2 antagonists differ
as well as cardiovascular side effects such as orthostatic somewhat in their side-effect profiles, even if they do not
hypotension (Figure 5-13B). As many D2 antagonists differ overall in their therapeutic profiles. That is, some
have all three actions, anticholinergic, antihistaminic, D2 blockers are more sedating than others; some have
and α1 antagonist, they can combine to contribute to more ability to cause cardiovascular side effects than
a great deal of sedation by simultaneously blocking others, some have more ability to cause DIP and other
several of the neurotransmitters in the arousal pathway; movement disorders than others. Differing degrees of
namely, acetylcholine, histamine, and norepinephrine muscarinic cholinergic blockade may explain why some
(Figure 5-14). Agents with particularly strong binding D2 antagonists have a lesser propensity to produce DIP
at these three receptors (such as chlorpromazine) are than others. That is, those D2 antagonists that are more
sometimes administered when sedation is needed on likely to cause DIP are generally the agents that have
top of antipsychotic action. However, even if sedation only weak anticholinergic properties, whereas those D2
181
H1 Inserted Figure 5-13 Blockade of histamine

1 and α1-adrenergic receptors. The
majority of D2 antagonists have
histamine neuron additional pharmacological properties;
the specific receptor profiles differ for
HA each agent and contribute to divergent
side-effect profiles. Many of the early
D2 antagonists also block H1 receptors
250 (A), which can contribute to weight gain
and drowsiness, and/or α1-adrenergic
receptors (B), which can contribute to
dizziness, drowsiness, and decreased
blood pressure.
weight gain drowsiness
H1
receptor
α1 Inserted
norepinephrine
neuron
NE
dizziness
decreased
α1 blood pressure
receptor
drowsiness
Figure 5-14 Neurotransmitters of cortical

Cortical Arousal arousal. The neurotransmitters acetylcholine
(ACh), histamine (HA), and norepinephrine (NE)
are all involved in arousal pathways connecting
neurotransmitter centers with the thalamus (T),
hypothalamus (Hy), basal forebrain (BF), and cortex.
Thus, pharmacological actions at their receptors
could influence arousal. In particular, antagonism
of muscarinic M1, histamine H1, and α1-adrenergic
receptors are all associated with sedating effects.
HA BF
ACh
NE
Hy
alpha1 receptors
M1 receptors
H1 receptors
182
Table 5-1 Earliest agents used to treat psychosis

DRUGS TARGETING SEROTONIN
Generic name Trade name Comment 2A RECEPTORS WITH OR
Chlorpromazine Thorazine Low potency WITHOUT SIMULTANEOUSLY
Cyamemazine Tercian Popular in France; TARGETING DOPAMINE D2
not available in RECEPTORS
the US
In an attempt to improve the efficacy and the tolerability
Flupenthixol Depixol Depot; not of the first-generation classic drugs for psychosis with
available in the US
D2 antagonist properties, a newer class of drugs with
Fluphenazine Prolixin High potency; antipsychotic action combines D2 antagonism
depot with serotonin (5HT) 2A antagonism, so-called second-
Haloperidol Haldol High potency; generation antipsychotics or atypical antipsychotics.
depot We will refer to them as 5HT2A antagonists/D2
Loxapine Loxitane antagonists with antipsychotic properties, and not as
“antipsychotics” or “atypical antipsychotics.” An even 5
Mesoridazine Serentil Low potency;
newer class of drugs with antipsychotic properties
QTc issues;
are agents with 5HT2A antagonism without any D2
discontinued
antagonism. Some preclinical studies suggest that all
Perphenazine Trilafon High potency known 5HT2A antagonists may actually be inverse
Pimozide Orap High potency; agonists (see Chapter 2 and Figures 2-9 and 2-10) rather
Tourette syndrome; than antagonists at 5HT2A receptors (Figure 5-15). Since
QTc issues; second it is not clear what clinical distinction there is between
line
an inverse agonist (Chapter 2 and Figures 2-9 and 2-10)
Pipothiazine Piportil Depot; not and an antagonist (Figures 2-6 and 2-10) at 5HT2A
available in the US receptors, we will continue to refer to these agents using
Sulpiride Dolmatil Not available in the simpler term “antagonist.”
the US Antagonism of serotonin 5HT2A receptors appears
Thioridazine Mellaril Low potency; QTc to improve both the efficacy and the side effects of D2
issues; antagonism:
second line Schizophrenia. Clinical trials show that adding
Thiothixene Navane High potency selective 5HT2A antagonists to drugs with D2
antagonism/partial agonism may improve positive
Trifluoperazine Stelazine High potency
symptoms of psychosis in schizophrenia. Also,
Zuclopenthixol Clopixol Depot; not there is some indication that the more potent
available in the US
a 5HT2A/D2 antagonist is for 5HT2A receptors
compared to potency for D2 receptors, the lower
blockers that cause DIP less frequently are the agents the degree of D2 antagonism that may be necessary
that have stronger anticholinergic properties. These latter to treat positive symptoms, and also the better
agents have a sort of “inbuilt” anticholinergic property tolerated the drug might be. More research is
that accompanies their D2 antagonist property. Although necessary on this possibility.
DIP may occur less frequently with such agents, the Parkinson’s disease psychosis and dementia-
risk of constipation and potential for life-threatening related psychosis. Antagonism of serotonin 5HT2A
paralytic ileus is higher, especially when combined receptors alone appears to provide sufficient
with other drugs with anticholinergic properties, and antipsychotic action to be useful as monotherapy
requires more monitoring of gastrointestinal status and for other causes of psychosis, such as Parkinson’s
bowel movements. A few selected agents from the first- disease psychosis and dementia-related psychosis,
generation class of D2 antagonists are discussed in more allowing D2 antagonism and its side effects to be
detail below. avoided entirely.
183
Where on the Agonist Spectrum Do Drugs for Psychosis Lie?
antagonist
partial
agonist
D2 partial agonists
for psychosis
D2 antagonist
D2 partial agonists 5HT2A antagonist

for Parkinson’s disease inverse agonist
5HT1A partial agonists
full inverse
neurotransmitters
agonist agonist
Figure 5-15 Agonist spectrum for drugs to treat psychosis. Drugs used to treat psychosis may fall along a spectrum, with some having
actions closer to a silent antagonist and others having actions closer to a full agonist. For dopamine 2 (D2) binding, agents with too
much agonism may be psychotomimetic and thus not ideal for treating psychosis, but may be useful within Parkinson’s disease. D2
partial agonists that are closer to the antagonist end of the spectrum may be preferred for treating psychosis, as are D2 antagonists.
Many drugs used to treat psychosis are serotonin 5HT2A antagonists, either in conjunction with D2 binding or without D2 binding. Some
preclinical data suggest that they may actually be inverse agonists, but the clinical significance of this distinction is unclear. 5HT1A partial
agonism is also a common property of many drugs used to treat psychosis, in particular many D2 partial agonists.
Negative symptoms of psychosis in schizophrenia. with reduced side-effect burden is to grasp the
Clinical trials show that administering selective pharmacology of 5HT2A receptors, where they are located,
5HT2A antagonists by themselves, or adding and what happens to dopamine when 5HT2A receptors
selective 5HT2A antagonists to drugs with D2 are blocked. All 5HT2A receptors are postsynaptic and
antagonism/partial agonism, may improve negative excitatory. The 5HT2A receptors critical to this discussion
symptoms in schizophrenia. are the ones located on three separate populations of
Motor side effects. Adding 5HT2A antagonist actions cortical glutamatergic pyramidal neurons that are all
to D2 antagonism has also proven to lessen naturally stimulated by serotonin at their 5HT2A receptors
unwanted motor side effects such as drug-induced to release glutamate downstream. These three separate
parkinsonism. populations of descending glutamate neurons regulate
Hyperprolactinemia. Adding 5HT2A antagonist three distinct dopamine pathways (Figure 5-16).
actions to D2 antagonism lessens the elevation of One population of glutamatergic pyramidal neurons
prolactin caused by D2 receptor blockade. directly innervates mesolimbic/mesostriatal dopamine
Why would adding 5HT2A antagonism improve side effects neurons projecting to the emotional striatum that
of D2 blockade and enhance the antipsychotic efficacy of D2 mediates the positive symptoms of psychosis (Figure
blockade? The short answer may be that 5HT2A antagonism 5-16A). This very same pathway was discussed
opposes D2 antagonism in some pathways by causing more extensively in Chapter 4 and illustrated in Figures
dopamine release in these sites and thus reversing some 4-29A–C through 4-45. The glutamate neuron depicted
of the unwanted D2 antagonism that causes side effects. in Figure 5-16A is that same glutamate neuron in
On the other hand, because of the differing configuration the final common pathway of positive symptoms of
of other brain circuits, 5HT2A antagonism can enhance psychosis (Figures 4-29B, 4-52C, 4-52D, 4-54, and
the efficacy of D2 antagonism in another circuit and thus 4-55). Specifically, this neuron is the hypothetical final
improve positive symptoms. Let’s now explain this. common pathway downstream from all causes of positive
symptoms of psychosis, whether in schizophrenia
5HT2A Receptor Regulation of Dopamine Release in from hypofunctioning glutamate receptors on GABA
Three Downstream Pathways interneurons (Figure 4-29B), in dementia-related
The key to understanding why adding 5HT2A antagonism psychosis from loss of these same GABA interneurons
creates entirely new classes of drugs to treat psychosis (Figure 4-52D and Figure 4-55), in Parkinson’s disease
184
5HT2A
5HT
PFC
DA
Glu
lu
SN m /VTA emotional striatum hallucinations

A
5HT2A
5HT 5
PFC
Glu
u ABA
GABA
low DA
SN l motor striatum
DIP
B
5HT2A low DA
5HT
PFC
emotional blunting,
flattening of affect
GABA
Glu
VTA
lack of mental sharpness

C
Figure 5-16 5HT2A receptor regulation of downstream dopamine (DA) release. 5HT2A receptors, which are postsynaptic and excitatory,
are relevant to the treatment of psychosis because of their presence on three separate populations of descending glutamate neurons.
(A) 5HT2A receptors are located on descending glutamatergic pyramidal neurons that directly innervate mesolimbic/mesostriatal
dopamine neurons projecting to the emotional striatum. Excessive activity in this pathway can lead to the positive symptoms of
psychosis. (B) 5HT2A receptors are located on descending glutamatergic pyramidal neurons that indirectly innervate nigrostriatal
dopamine neurons via a GABAergic interneuron in the substantia nigra. Excessive stimulation of these 5HT2A receptors leads to a
reduction in dopamine release in the motor striatum and can cause side effects such as drug-induced parkinsonism. (C) 5HT2A receptors
are located on descending glutamatergic pyramidal neurons that indirectly innervate mesocortical dopamine neurons via a GABAergic
interneuron in the ventral tegmental area. Excessive stimulation of these 5HT2A receptors leads to a reduction in dopamine release in
the prefrontal cortex (PFC), which could lead to cognitive dysfunction as well as negative symptoms such as emotional blunting and
flattened affect. SNm, medial substantia nigra; VTA, ventral tegmental area; SNl, lateral substantia nigra.
185
psychosis from excessive actions of serotonin (Figure neurons to cause the positive symptoms of psychosis
4-52C and Figure 4-54), or in hallucinogen psychosis (Figure 5-16A).
from excessive stimulation of serotonin receptors (Figure The most common treatment of course is to block
4-52B and Figure 4-53). In all cases, anything that excessive dopamine release at the end of this circuit,
increases the activity of this population of glutamate namely at D2 receptors in the emotional striatum.
neurons will hypothetically lead to downstream release However, one can also reduce the excitatory tone
of dopamine from mesolimbic/mesostriatal dopamine of serotonin at 5HT2A receptors at the beginning of
5HT2A
5HT2A antagonist
5HT2A antagonist PFC
SN m /VTA emotional striatum decreased

A positive
symptoms
5HT2A
5HT2A antagonist
PFC
SN l motor striatum
reduction in DIP
B
5HT2A
5HT2A antagonist
PFC
emotional blunting,
flattening of affect
VTA
lack of mental sharpness
Figure 5-17 5HT2A receptor antagonism and downstream dopamine release. 5HT2A antagonism can modulate downstream dopamine
release via three key pathways. (A) 5HT2A antagonism reduces glutamatergic output from a descending neuron that directly innervates
mesolimbic/mesostriatal dopamine neurons. This in turn reduces dopamine output in the emotional striatum and can therefore decrease
the positive symptoms of psychosis. (B) 5HT2A antagonism reduces glutamatergic output in the substantia nigra, leading to reduced
activity of the GABA interneuron and therefore disinhibition of the nigrostriatal dopamine pathway. The increased dopamine release in
the motor striatum can reduce motor side effects caused by D2 antagonism because there is more dopamine to compete with the D2
antagonist. (C) 5HT2A antagonism reduces glutamatergic output in the ventral tegmental area, leading to reduced activity of the GABA
interneuron and therefore disinhibition of the mesocortical dopamine pathway. Increased dopamine release in the prefrontal cortex
(PFC) can potentially reduce cognitive and negative symptoms of psychosis. SNm, medial substantia nigra; VTA, ventral tegmental area;
SNl, lateral substantia nigra.
186
this circuit (Figure 5-17A, top left) by blocking them (Figure 5-17B, right). That is precisely what is needed
here with a 5HT2A antagonist, using either an agent to reduce motor side effects! Namely, more dopamine
having both D2 and 5HT2A antagonist properties is available to compete with a D2 antagonist in the
or an agent selective for just 5HT2A antagonist motor striatum that otherwise would cause motor side
properties (Figure 5-1). When this happens at the effects. And that is exactly what is observed with 5HT2A
specific glutamate neurons shown in Figure 5-16A, antagonist/D2 antagonist drugs: i.e., fewer motor side
this theoretically reduces release of dopamine in effects compared to D2 antagonists without 5HT2A
the emotional striatum (Figure 5-17A, right) and antagonism. This has indeed been repeatedly observed
this in turn causes a mechanistically independent for 5HT2A/D2 antagonists, and has reduced the need for
antipsychotic action, different from direct D2 receptor anticholinergic medication administration to treat motor
blocking. side effects compared to D2 antagonists without 5HT2A
In the case of schizophrenia being treated with antagonist actions (see Figure 5-1 and compare icons on
agents that have combined 5HT2A/D2 antagonism, any the top with the bottom left).
simultaneous D2 antagonism would theoretically become A third population of glutamatergic pyramidal
even more effective in treating positive symptoms of neurons indirectly innervate those mesocortical dopamine
5
psychosis. Clinical trials are in progress adding a selective neurons that project to the prefrontal cortex and mediate
5HT2A antagonist to the other agents with antipsychotic in part the negative, cognitive, and affective symptoms of
properties to determine if ramping up 5HT2A antagonism schizophrenia (Figure 5-16C). This is yet another parallel
will consistently improve positive symptoms of pathway to the pathways just discussed, and involves
psychosis or if it will allow reduction of dose, to lower yet different glutamate neurons that project indirectly
D2 antagonism, in order to improve side effects without via a GABA interneuron to those dopamine neurons in
losing therapeutic effects. There are indeed suggestions the VTA destined to innervate the prefrontal cortex. As
that drugs with very potent 5HT2A antagonism might discussed above for the nigrostriatal pathway (Figure
require less D2 antagonism to treat positive symptoms 5-16B), this arrangement in Figure 5-16B also has the
of psychosis (see discussion of lumateperone, clozapine, effect of upstream glutamate release leading to inhibiting
quetiapine, and others below). dopamine release downstream (see Figure 5-16C). Thus,
In the case of psychosis in dementia or in Parkinson’s blocking 5HT2A receptors on these specific glutamate
disease, where D2 antagonism can cause problematic side neurons (Figure 5-17C, top left) will lead to disinhibiting
effects or even be dangerous, 5HT2A antagonist action (i.e., increasing) dopamine release in the prefrontal
alone can produce a sufficiently robust antipsychotic cortex (Figure 5-17C, top right). This is just what you
effect even in the absence of any D2 antagonism. need to improve negative symptoms of schizophrenia,
A second population of glutamatergic pyramidal and that is what has been observed in trials of 5HT2A
neurons indirectly innervate those nigrostriatal dopamine selective agents, either alone or augmenting other D2
neurons that project to the motor striatum and mediate antagonist and 5HT2A/D2 antagonist drugs. Increasing
the motor side effects of D2 antagonism (Figure 5-16B). dopamine release in the prefrontal cortex also has the
This is a parallel pathway to the pathway just discussed potential of improving cognitive and affective/depressive
in Figure 5-16A, and involves a different population of symptoms (Figure 5-17C). This effect is not consistent
glutamate neurons that not only project to the substantia or robust across all 5HT2A/D2 antagonist drugs that treat
nigra rather than to the ventral tegmental area (VTA)/ psychosis, in part because of different potencies of 5HT2A
mesostriatum/integrative hub, but do so indirectly, antagonism compared to D2 antagonism, and because of
namely, first to a GABA interneuron in the substantia the presence of additional interfering pharmacological
nigra and then to the nigrostriatal dopamine motor properties in some agents, such as anticholinergic and
pathway (compare Figure 5-16A and B). This has the antihistaminic actions. A better approach may ultimately
effect of changing the polarity of upstream glutamate prove to be adding a selective 5HT2A antagonist to drugs
release from stimulating dopamine release (Figure with D2 antagonist action.
5-16A) to inhibiting dopamine release downstream
How Do 5HT2A Antagonist Actions Reduce
(Figure 5-16B). Therefore, blocking 5HT2A receptors on
Hyperprolactinemia?
the specific glutamate neurons shown in Figure 5-16B
(upper left) leads to disinhibiting (i.e., increasing) The pituitary lactotroph is responsible for secretion of
dopamine release downstream in the motor striatum prolactin and both D2 receptors and 5HT2A receptors
187
are located on the membranes of these cells. Serotonin both D2 antagonism and 5HT2A antagonism, there is
and dopamine have reciprocal roles in the regulation of simultaneous inhibition of 5HT2A receptors, so serotonin
prolactin secretion, with dopamine inhibiting prolactin can no longer stimulate prolactin release (Figure 5-18D).
release via stimulation of D2 receptors (Figure 5-18A) and This mitigates the hyperprolactinemia of D2 receptor
serotonin promoting prolactin release via stimulation of blockade. Although this is interesting theoretical
5HT2A receptors (Figure 5-18B). Thus, when D2 receptors pharmacology, in practice, not all 5HT2A/D2 antagonists
alone are blocked by D2 antagonism, dopamine can no reduce prolactin secretion to the same extent, and others
longer inhibit prolactin release, so prolactin levels rise do not reduce prolactin elevations at all, possibly due to
(Figure 5-18C). However, in the case of a drug that has other off-target receptor properties.
Figure 5-18A, B Dopamine and

serotonin regulate prolactin release,
5HT2A part 1. (A) Dopamine binding at
receptor inhibitory D2 receptors (red circle)
prevents prolactin release from
pituitary lactotroph cells in the pituitary
pituitary gland. (B) Serotonin (5HT) binding at
lactotroph excitatory 5HT2A receptors (red circle)
stimulates prolactin release from
pituitary lactotroph cells in the pituitary
gland. Thus, dopamine and serotonin
have a reciprocal regulatory action on
prolactin prolactin release.
D2
receptor
dopamine
A serotonin
serotonin
5HT2A
receptor
pituitary
lactotroph
prolactin
188
Figure 5-18C, D Dopamine and

serotonin regulate prolactin release,
part 2. (C) D2 antagonism (red circle)
blocks dopamine’s inhibitory effect
on prolactin secretion from pituitary
lactotrophs. Thus, these drugs increase
pituitary
lactotroph prolactin levels. (D) As dopamine and
serotonin have reciprocal regulatory
roles in the control of prolactin
secretion, one cancels the other. Thus,
p 5HT2A antagonism reverses the ability
of D2 antagonism to increase prolactin
secretion.
D2 antagonist 5
pituitary
lactotroph
5HT2A/D2 antagonist
D
D2 Partial Agonism
DRUGS TARGETING SEROTONIN
1A RECEPTORS AND DOPAMINE Some antipsychotics act to stabilize dopamine
neurotransmission at D2 receptors in a state between
D2 RECEPTORS AS PARTIAL
complete silent antagonism (see Chapter 2, Figures 2-6
AGONISTS and 2-10) and full stimulation/agonist action (Chapter
Another attempt to improve first-generation drugs for 2, Figures 2-5 and 2-10). This intermediate position is
psychosis with D2 antagonist properties substitutes D2 illustrated here in Figures 5-19 through 5-22 and is called
partial agonism for D2 antagonism, and adds serotonin partial agonism. This was also discussed and illustrated
5HT1A partial agonism. in Chapter 2 (see Figures 2-7 and 2-10).
189
full D2 antagonist:
prolactin deficiency of agonist
too cold
antipsychotic DIP
dopamine stimulant
excess of full agonist
too hot
psychosis
dopamine partial agonist

dopamine stabilizer:
balance between agonist and antagonist actions
just right
prolactin antipsychotic
DIP
Figure 5-19 Spectrum of dopamine neurotransmission. Simplified explanation of actions on dopamine. (A) Full D2 antagonists
bind to the D2 receptor in a manner that is “too cold”; that is, they have powerful antagonist actions while preventing agonist actions
and thus can reduce positive symptoms of psychosis but also cause drug-induced parkinsonism (DIP) and prolactin elevation. (B) D2
receptor agonists, such as dopamine itself, are “too hot” and can therefore lead to positive symptoms. (C) D2 partial agonists bind in an
intermediary manner to the D2 receptor and are therefore “just right,” with antipsychotic actions but without DIP or prolactin elevation.
190
An oversimplified explanation of partial agonist action each drug in the D2 partial agonist class and there is no
at the D2 receptor is illustrated in Figure 5-19. Namely, perfect “Goldilocks” solution.
D2 antagonist action is “too cold,” with antipsychotic A more sophisticated explanation is that partial
actions but elevated prolactin and motor symptoms such agonists have the intrinsic ability to bind to receptors
as DIP (Figure 5-19A). On the other hand, maximally in a manner that causes signal transduction from
stimulating full agonist actions of dopamine itself (or the receptor to be intermediate between full output
amphetamine, which releases dopamine) are “too hot” and no output (Figure 5-20). The naturally occurring
with positive symptoms of psychosis (Figure 5-19B). neurotransmitter generally functions as a full agonist,
Instead, a partial agonist binds in an intermediary and causes maximum signal transduction from the
manner, hopefully “just right,” with antipsychotic receptor it occupies (volume blaring in Figure 5-20, top),
actions but lower DIP and lesser prolactin elevations whereas antagonists essentially shut down all output
(Figure 5-19C). For this reason, partial agonists are from the receptor they occupy and make them “silent”
sometimes called “Goldilocks” drugs if they get the in terms of communicating with downstream signal
balance “just right” between full agonism and complete transduction cascades (volume essentially turned off in
antagonism. However, as we shall see, this explanation is Figure 5-20, middle). By contrast, partial agonists (Figure
5
an oversimplification; the balance is slightly different for 5-20, bottom) cause receptor output that is more than
Figure 5-20 Dopamine receptor

output. Dopamine (DA) itself is a full
D2R receptor output agonist and causes full receptor output
(top). D2 antagonists allow little if any
DA receptor output (middle). However, D2
partial agonists can partially activate
dopamine receptor output and cause a
stabilizing balance between stimulation
and blockade of dopamine receptors
(bottom).
D2 antagonist
D2 partial agonist
191
the silent antagonist (Figure 5-20, middle), but less than very close to the agonist end of the spectrum (Figure
the full agonist (Figure 5-20, top). Thus, many degrees of 5-15). They are almost full agonists. Using these agents at
partial agonism are possible between these two extremes. the full agonist end of the spectrum for the treatment of
Full agonists, silent antagonists, and partial agonists may psychosis would make the psychosis worse, just as using
all cause different changes in receptor conformation that agents at the other end of the spectrum near to antagonist
lead to a corresponding range of signal transduction for the treatment of Parkinson’s disease would make
output from the receptor (Figure 5-21). their motor movements worse. Thus, it is important not
Where on the agonist spectrum do D2 partial agonists to lump all partial agonists together and to understand
for psychosis lie? This is illustrated in Figure 5-15, where on the spectrum a given agent lies in order to
showing that the D2 partial agonists under discussion understand its pharmacological mechanism of action
here for the treatment of psychosis are very close to because very small changes in the amount of partial
the antagonist end of the spectrum, where all the D2 agonism and placement on this spectrum (Figure 5-15)
antagonists discussed so far lie (Figure 5-15). That is can have profound clinical effects.
because these D2 partial agonists for the treatment of
How Does D2 Partial Agonism Cause Fewer Motor Side
psychosis are “almost” antagonists with just a whiff of
Effects than D2 Antagonism?
intrinsic agonist activity. By contrast, other dopamine
partial agonists useful for the treatment of Parkinson’s It seems that it takes only a very small amount of signal
disease and classified as dopamine partial agonists lie transduction through D2 receptors in the striatum in
antagonist D2 partial agonist
full agonist
Figure 5-21 Agonist spectrum and receptor conformation. This figure shows an artist’s depiction of changes in receptor conformation
in response to full agonists versus antagonists versus partial agonists. With full agonists, the receptor conformation is such that there
is robust signal transduction through the G-protein-linked second-messenger system of D2 receptors (left). Antagonists, on the other
hand, bind to the D2 receptor in a manner that produces a receptor conformation that is not capable of any signal transduction (middle).
Partial agonists, such as a dopamine partial agonist, cause a receptor conformation such that there is an intermediate amount of signal
transduction (right). However, the partial agonist does not induce as much signal transduction (right) as a full agonist (left).
192
order for a D2 partial agonist to have reduced propensity spectrum to aripiprazole, have antipsychotic efficacy
to cause motor side effects, especially drug-induced and low motor side effects but some akathisia, and differ
parkinsonism. Thus, a very slight degree of agonism, mostly in secondary binding properties of receptors other
sometimes called “intrinsic activity,” can have a very than the D2 receptor, as will be discussed in detail in the
different set of clinical consequences compared to a fully section on individual drugs below.
silent and completely blocked D2 receptor, which is what
How Does D2 Partial Agonist Action Reduce
D2 antagonists and 5HT2A/D2 antagonists do. D2 partial
Hyperprolactinemia?
agonists capable of treating psychosis lie very close to
antagonists on the agonist spectrum (Figure 5-15), as The pituitary lactotrophs’ D2 receptors have proven to
more dopamine antagonism than agonist action is what is be more sensitive to the intrinsic activity of D2 partial
needed for the treatment of psychosis. agonists than the other dopamine pathways and targets.
What is so interesting is how very small movements Specifically, the three partial agonists in clinical use all
up and down the partial agonist spectrum (Figure actually reduce prolactin levels, rather than raise them.
5-15) can have profound effects upon the clinical It is hypothesized that this is due to the D2 receptors on
properties. Just slightly too close to a pure agonist and the lactotrophs detecting these drugs more as agonists
than as antagonists, and thus these drugs shut down 5
such agents may have reduced motor side effects and
prolactin elevations and be sufficiently activating to prolactin secretion rather than stimulate it. In fact,
improve negative symptoms but be too activating so co-administration of one of the D2 partial agonists to a
that there is lessened efficacy for positive symptoms, patient who is experiencing hyperprolactinemia while
or even worsening of positive symptoms, as well as taking one of the D2 antagonists can actually reverse that
nausea and vomiting. Fairly extensive testing has been hyperprolactinemia.
made of several D2 partial agonists in schizophrenia and 5HT1A Partial Agonism
three of these are approved. OPC4392 (structurally
and pharmacologically related to both aripiprazole Why would adding 5HT1A partial agonism to D2 partial
and brexpiprazole, which were tested later) turned agonism improve the side effects and enhance efficacy
out to be too much of an agonist; it had relatively little for affective and negative symptoms compared to D2
intrinsic activity and improved negative symptoms blockade? There is a simple answer, easy to understand if
of schizophrenia, with little in the way of motor side you have grasped the reason why 5HT2A antagonism does
effects, but its intrinsic activity was nevertheless too much the same thing. That is, 5HT1A partial agonism,
great because this drug also activated and worsened especially if closer to full agonism than to antagonism
positive symptoms of schizophrenia, so it was never on the partial agonist spectrum (Figure 5-15), has
marketed. Another D2 partial agonist, bifeprunox, is less similar effects to those of 5HT2A antagonism. Just like
of an agonist than OPC4392 but turned out to be still too 5HT2A antagonism shown in Figure 5-17, 5HT1A partial
much of an agonist since it caused nausea and vomiting; agonism/full agonism also opposes D2 antagonism in
although it did have some efficacy for positive symptoms side-effect pathways by causing more dopamine release in
and did not cause motor side effects, it was less robust in these sites, reversing some of the unwanted effects of D2
improving positive symptoms than other agents and also antagonism/partial agonism and improving negative and
had more gastrointestinal side effects, so the US Food affective symptoms (Figure 5-22).
and Drug Administration (FDA) did not approve it. Next, How does this happen? 5HT1A receptors are always
investigators threw another dart closer to the antagonist inhibitory and they can be both presynaptic on serotonin
end of the spectrum and it landed as aripiprazole (the neurons and postsynaptic on many neurons, including
original “pip” – see below). This agent indeed improves the same glutamatergic pyramidal neurons that have
positive symptoms without severe motor side effects, but 5HT2A receptors (compare the glutamate neurons upper
does cause some akathisia and some clinicians question if left in both Figure 5-16A and 5-22A). One can think
it is as efficacious as D2 antagonists for the most severely of the situation as the pyramidal neuron having both
psychotic patients, although this has never been proven. an accelerator (5HT2A receptors) and a brake (5HT1A
Finally, two more D2 partial agonists have been approved: receptors). Taking your foot off the accelerator (5HT2A
a second “pip” called brexpiprazole and a “rip” called antagonism) should have a similar effect as stepping
cariprazine. Both are similar on the D2 partial agonist on the brake (5HT1A partial agonism), especially if they
are done at the same time. Thus, 5HT1A partial agonism
193
5HT1A agonist
5HT1A PFC
SN motor striatum reduction in DIP
improved negative,
5HT1A agonist cognitive, and
PFC affective symptoms
(SIGH)
B
VTA
Figure 5-22 5HT1A receptor partial agonism and downstream dopamine release. 5HT1A receptors are inhibitory and can be located
both presynaptically on serotonin neurons and postsynaptically on other neurons. (A) 5HT1A receptors are located on descending
glutamatergic pyramidal neurons that indirectly innervate nigrostriatal dopamine neurons via a GABAergic interneuron in the substantia
nigra (SN). Partial agonism of these 5HT1A receptors reduces glutamatergic output in the substantia nigra, leading to reduced activity
of the GABA interneuron and therefore disinhibition of the nigrostriatal dopamine pathway. The increased dopamine release in the
motor striatum can reduce motor side effects caused by D2 antagonism/partial agonism because there is more dopamine to compete
with the D2 binding agents. (B) 5HT1A receptors are located on descending glutamatergic pyramidal neurons that indirectly innervate
mesocortical dopamine neurons via a GABAergic interneuron in the ventral tegmental area (VTA). 5HT1A partial agonism reduces
glutamatergic output in the VTA, leading to reduced activity of the GABA interneuron and therefore disinhibition of the mesocortical
dopamine pathway. Increased dopamine release in the prefrontal cortex (PFC) can potentially reduce cognitive, negative, and affective
symptoms of psychosis.
has many of the same effects on dopamine release as partial agonism could potentially reduce motor side effects
5HT2A antagonism. As will be discussed later, some and improve mood, affective, negative, and cognitive
drugs used to treat psychosis and mood have both 5HT2A symptoms by enhancing downstream release of dopamine.
antagonist and 5HT1A partial agonist properties, which
5HT1A partial agonist has actions at glutamatergic
should theoretically enhance the actions on downstream
neurons indirectly innervating nigrostriatal dopamine
dopamine even further compared to either of these neurons projecting to the motor striatum (Figure 5-22A).
mechanisms alone. So, just as explained above for
5HT2A antagonism, 5HT1A partial agonism opposes D2 Recall that blocking 5HT2A receptors on these same
antagonism/partial agonism in some pathways by causing glutamate neurons disinhibits dopamine release to
more dopamine release in these sites and thus reversing reduce motor side effects (Figure 5-17B). That is exactly
some of the unwanted D2 antagonism/partial agonism what happens with 5HT1A partial agonism at these same
that causes motor side effects. There is less evidence neurons, namely disinhibition of dopamine release and
that 5HT1A partial agonism can enhance the efficacy improvement in motor side effects (Figure 5-22A). As
of D2 antagonism/partial agonism to improve positive explained above, more dopamine release competes with
symptoms of psychosis. Let’s now explain how 5HT1A D2 blocking agents for the receptors in the motor striatum
194
to reverse motor side effects. Since D2 partial agonists get mania treatment for free.” That is, essentially any drug
are also 5HT1A partial agonists, these two properties can that can treat the positive symptoms of psychosis can
combine to reduce many motor side effects, although probably also treat the symptoms of mania. That could be
akathisia can still commonly occur. because mania is thought to be due to excessive dopamine
release from mesolimbic/mesostriatal neurons, just as for
5HT1A partial agonist also has actions at glutamatergic
the positive symptoms of schizophrenia (Figures 4-15 and
neurons indirectly innervating mesocortical
dopamine neurons projecting to the prefrontal cortex
4-16). Thus, it is not surprising that agents that reduce
(Figure 5-22B). dopamine overactivity in this pathway are effective when
the patient is in a manic state as well as in a psychotic
Recall that blocking 5HT2A receptors on these specific
state. Further discussion of mania will follow in Chapter 6
glutamate neurons disinhibits dopamine release in
and of treatments for mania in Chapter 7.
the prefrontal cortex (Figure 5-17C). This is just what
you need to improve negative, cognitive, and affective/ Antidepressant Actions in Bipolar and Unipolar
depressive symptoms. That is also what happens with Depression
5HT1A partial agonism at these same neurons (Figure The most common use for 5HT2A/D2 antagonists
5-22B). These clinical actions may be particularly robust and D2/5HT1A partial agonists is not the treatment of 5
in bipolar and unipolar depression where these serotonin/ psychosis in schizophrenia or mania in bipolar disorder.
dopamine partial agonists are frequently used. Rather, the treatment of unipolar major depressive
disorder and bipolar depression is where these agents are
LINKS BETWEEN RECEPTOR most commonly prescribed and at lower doses, especially
BINDING PROPERTIES OF the newer agents with fewer side effects but higher costs.
DRUGS USED TO TREAT Almost all drugs treating psychosis have to be dosed so
PSYCHOSIS AND OTHER that 80% or so of D2 receptors are blocked in the emotional
THERAPEUTIC ACTIONS AND striatum, whereas the doses of these same drugs for
SIDE EFFECTS depression are lower and likely insufficient to robustly
block D2 receptors. So, how do they work in depression?
So far in this chapter we have discussed the antipsychotic 5HT2A antagonism and 5HT1A partial agonism, and the
mechanisms and side effects of drugs for psychosis that resultant increase in dopamine release in the prefrontal
are hypothetically linked to interactions at dopamine cortex, are thought to be potentially key antidepressant
D2, serotonin 5HT2A, and serotonin 5HT1A receptors. mechanisms. Looking over the vast panoply of receptor
The reality is that these same drugs bind to many other actions of the individual drugs in this class (see discussion
neurotransmitter receptors, and are used for many other below and Figures 5-27 through 5-62), one can readily see
therapeutic applications. In fact, many more prescriptions many additional potential antidepressant mechanisms.
for D2 blockers are written for indications other than These will be discussed and illustrated in detail in
psychosis than are written for psychosis, a key reason Chapters 6 and 7 on mood disorders and their treatments;
why they are not called “antipsychotics” here and in here we will just mention several of those key mechanisms.
international nomenclature. These additional receptor Binding properties accompanying D2 blockade that are
actions are likely relevant to other therapeutic actions candidates for explaining antidepressant actions are shown
and side effects (Figures 5-23 through 5-26). The entire for all the individual D2 blockers in the many figures in the
known panoply of receptors that are bound by drugs in sections that follow in this chapter and include:
this class are discussed in the sections below. monoamine reuptake blocking properties
Mania
α2 antagonism
D3 partial agonism
Essentially all drugs with D2 antagonist/partial agonist 5HT2C antagonism
properties are effective in the treatment of acute bipolar 5HT3 antagonism
mania and in preventing recurrences of mania. Some 5HT7 antagonism
agents are better studied than others, and the therapeutic others including possibly 5HT1B/D antagonism
effects in acute bipolar mania are present whether the
mania is psychotic or nonpsychotic. There is an old saying No two agents in this group have exactly the same
about drugs that treat psychosis in schizophrenia: “you binding characteristics and maybe that explains in part
195
Where on the Metabolic Highway Should Figure 5-23 Monitoring on the

metabolic highway. Monitoring
Psychopharmacologists Monitor Antipsychotics? for cardiometabolic side effects is
necessary for any patient taking
premature death and a medication to treat psychosis,
loss of 20-30 although risk can vary by individual
years of normal RIP agent. First, increased appetite and
life span weight gain can lead to elevated
body mass index (BMI) and ultimately
obesity. Thus, weight and BMI should
be monitored here. Second, some
agents can cause insulin resistance
by an unknown mechanism; this can
metabolic be detected by measuring fasting
highway diabetes cardiovascular events plasma triglyceride levels. Finally,
>25 monitor hyperinsulinemia may advance to
antipsychotic pancreatic β-cell failure, prediabetes,
action
and then diabetes. Diabetes increases
the risk for cardiovascular events and
premature death.
sugar
prediabetes
beta cell failure
insulin
muscle
adipose liver
pancreas
insulin resistance
hyperinsulinemia
monitor
antipsychotic
action obesity and O
C O
O
H
C H
increased C O
O
C O
C H
C H
BMI H
triglycerides monitor
antipsychotic
action
increased
appetite
BEWARE:
cardiometabolic
risk ahead
weight gain
why some patients can have an antidepressant response anxiety disorders. Some studies suggest efficacy of
to one agent in this group and not another. Please see these agents as monotherapy for generalized anxiety
the discussion of individual drugs below for which of disorder and to augment other agents for other anxiety
these actions are part of the mechanisms of those specific disorders. Another controversial use of these agents is for
drugs. posttraumatic stress disorder (PTSD). It is possible that
the antihistamine and anticholinergic sedative properties
Anxiolytic Actions of some of these agents are calming in some patients
A somewhat controversial use of drugs normally and responsible for anxiolytic/anti-PTSD action in them.
used to treat psychosis is for the treatment of various If so, why are these uses controversial? There are both
196
Insulin Resistance / Elevated Triglycerides and Drugs for Psychosis:

Caused by Tissue Actions at an Unknown Receptor?
X
serotonin- 5
dopamine A
blocker
insulin
adipose
liver
skeletal X
muscle
X
X
receptor X
Figure 5-24 Insulin resistance and elevated triglycerides: caused by tissue actions at an unknown receptor? Some drugs used to treat
psychosis may lead to insulin resistance and elevated triglycerides, independently of weight gain, although the mechanism is not yet
established. This figure depicts a hypothesized mechanism in which an agent binds to receptor X at adipose tissue, liver, and skeletal
muscle to cause insulin resistance.
positive and negative studies of efficacy for anxiety and signal in most studies, and also because there is a
PTSD indications; also, given the side effects of many safety warning for cardiovascular complications and
agents used to treat psychosis, the risk:benefit ratio is not deaths in elderly dementia patients taking these drugs.
necessarily favorable compared to alternative treatments Although there is promise for drugs acting by different
for anxiety and PTSD. A promising exception may be a mechanisms and currently in testing (see Chapter 12 on
positive study of one of these agents (brexpiprazole) in dementia), there are also positive results for agitation in
combination with a selective serotonin reuptake inhibitor dementia for one agent that is in the class of drugs for
(SSRI), specifically sertraline. This is also mentioned in psychosis, namely brexpiprazole, and it may be that it
Chapter 8 on anxiety and traumatic disorders. has a satisfactory risk:benefit profile. This is discussed in
further detail in Chapter 12 on dementia.
Agitation in Dementia
Treating a problematic condition known as agitation in Sedative Hypnotic and Sedating Actions
patients with dementia is another controversial use of A long debate exists as to whether sedation is a good or a
drugs for psychosis because there is no clear efficacy bad property for antipsychotic action. The answer seems
197
to be that sedation is both good and bad in the treatment H1 histamine receptor and the 5HT2C serotonin receptor.
of psychosis. In some cases, particularly for short-term When these receptors are blocked, particularly at the
treatment, sedation is a desired therapeutic effect, same time, patients can experience weight gain. Since
especially early in treatment, during hospitalization, weight gain can lead to obesity, and obesity to diabetes,
and when patients are aggressive, agitated, or needing and diabetes to cardiac disease along the metabolic
sleep induction. In other cases, particularly for long- highway (Figure 5-23), it seemed feasible at first that
term treatment, sedation is generally a side effect to weight gain might explain all the other cardiometabolic
be avoided because diminished arousal, sedation, complications associated with treatment with those
and somnolence can lead to cognitive impairment. drugs used for psychosis that cause moderate or high
When cognition is impaired, functional outcomes are amounts of weight gain. This may be true, but only in
compromised. The pharmacology of sedation is discussed part, and perhaps mostly for those agents that have both
above and illustrated in Figures 5-8, 5-13, and 5-14 for potent antihistamine properties as well as potent 5HT2C
anticholinergic, antihistamine, and α1 antagonist actions. antagonist properties; notably, clozapine, olanzapine,
Sedative hypnotics are discussed in Chapter 10 on sleep, and quetiapine, as well as the antidepressant mirtazapine
and aggression and violence are discussed in Chapter 13 (discussed in Chapter 7).
on impulsivity. However, it now appears that the cardiometabolic
risk cannot simply be explained by increased appetite
Cardiometabolic Actions and weight gain, nor by antagonist actions at these
Although all D2/5HT2A/5HT1A drugs for treating two receptors, even though they certainly do represent
psychosis share a class warning for causing weight gain the first steps down the slippery slope towards
and risks for obesity, dyslipidemia, and hyperglycemia/ cardiometabolic complications for some of the higher-risk
diabetes mellitus, there is actually a spectrum of risk agents. However, many drugs that block one or another
among the various agents: of these two receptors do not have a great deal of appetite
high metabolic risk: clozapine, olanzapine or weight gain associated with use, and many other drugs
moderate metabolic risk: risperidone, paliperidone, that cause weight gain lack actions at these two receptors.
quetiapine, asenapine, iloperidone It appears that there may be a second mechanism
low metabolic risk: lurasidone, cariprazine, acting to cause weight gain, dyslipidemia, and diabetes;
lumateperone, ziprasidone, pimavanserin, namely, immediate increase in insulin resistance.
aripiprazole, brexpiprazole This can be measured in part by elevation of fasting
The “metabolic highway” shown schematically in triglyceride levels and cannot be explained by weight gain
Figure 5-23 passes by weight gain, dyslipidemia, and alone, because this occurs prior to gaining significant
hyperglycemia/diabetes mellitus and ends with the sad weight; it is as if there is an acute receptor-mediated
destination of premature death. The point of discussing action of these drugs on insulin regulation. We still do not
the metabolic highway is to monitor the patient along their know what that receptor might be, but it is hypothesized
journey of taking one of the moderate- or high-risk agents, as receptor “X” on the drug icon in Figure 5-24.
and to intervene when possible to prevent predictable So, there appears to be a second mechanism of
adverse outcomes. The onramp to the metabolic highway metabolic dysfunction other than that which causes
is increased appetite and weight gain, with progression increased appetite and weight gain of the H1/5HT2C-
to obesity, insulin resistance, and dyslipidemia with mediated mechanism. This outcome was unexpected
increases in fasting triglyceride levels (Figure 5-23). when these drugs were all developed, and some drugs
Ultimately, hyperinsulinemia advances to pancreatic β-cell seem to have this second mechanism (high- and
failure, prediabetes, and then diabetes. Once diabetes moderate-risk agents) while others seem to lack it (low-
is established, risk for cardiovascular events is further risk agents). To date, the mechanism of this increased
increased, as is the risk of premature death (Figure 5-23). insulin resistance and elevation of fasting triglycerides
The pharmacological mechanisms for what propels a has been vigorously pursued but has not yet been
patient taking a drug with antipsychotic properties along identified. The rapid elevation of fasting triglycerides
the metabolic highway to these risks and beyond are upon initiation of some D2/5HT2A antagonists, and the
only beginning to be understood. Increased weight gain rapid fall of fasting triglycerides upon discontinuation
associated with some agents may be due to actions at the of such drugs, is highly suggestive that an unknown
198
pharmacological mechanism causes these changes, Psychopharmacologist’s

although this remains speculative. The hypothetical
actions of agents with this postulated receptor action are
Metabolic Monitoring Tool Kit
shown in Figure 5-24, where adipose tissue, liver, and
skeletal muscle all develop insulin resistance in response
to administration of certain drugs (e.g., high-risk drugs
but not “metabolically friendly” low-risk drugs), at least
in certain patients. Whatever the mechanism of this
effect, it is clear that fasting plasma triglycerides and
insulin resistance can be elevated significantly in some
patients taking certain D2/5HT2A antagonists, that this
enhances cardiometabolic risk and moves such patients
along the metabolic highway (Figure 5–23), and that
this functions as another step down the slippery slope 250
towards the diabolical destination of cardiovascular
+ BMI chart 5
events and premature death. This does not happen
in all patients taking any D2/5HT2A antagonist, but
the development of this problem can be detected by scale
monitoring (Figure 5-25) and it can be managed when it
does occur (Figure 5-26).
Another rare but life-threatening cardiometabolic fasting TGs + fasting glu
problem is known to be associated with serotonin/
dopamine agents that treat psychosis: namely, an
association with the sudden occurrence of diabetic
ketoacidosis (DKA) or the related condition
hyperglycemic hyperosmolar syndrome (HHS). The
mechanism of this complication is under intense
investigation, and is probably complex and multifactorial.
In some cases, it may be that patients with undiagnosed
insulin resistance, prediabetes, or diabetes, who are in a BP
state of compensated hyperinsulinemia on the metabolic
FLOW CHART
highway (Figure 5-23), when given certain serotonin/ John Doe
dopamine antagonists, become decompensated because
of some unknown pharmacological action. Because baseline visit 1 visit 2
of the risk of DKA/HHS, it is important to know the wt/BMI
patient’s location along the metabolic highway prior to fasting TGs
prescribing drugs for psychosis, particularly if the patient fasting glu
has hyperinsulinemia, prediabetes, or diabetes. It is BP
thus important to monitor (Figures 5-23 and 5-25) and
Figure 5-25 Metabolic monitoring tool kit. The
manage (Figure 5-26) these risk factors. psychopharmacologist’s metabolic monitoring tool kit includes
Specifically, there are at least three stops along the items for tracking four major parameters: weight/body mass
index (BMI), fasting triglycerides (TGs), fasting glucose (glu),
metabolic highway where a psychopharmacologist should and blood pressure (BP). These items are simply a flowchart that
monitor a patient taking a drug for psychosis (or using can appear at the beginning of a patient’s chart, with entries for
each visit.
these same drugs for other indications, particularly
depression) and manage their cardiometabolic risks
(Figure 5-23). This starts with monitoring weight, diabetes. The second action to monitor is whether or
body mass index, and fasting glucose to detect the not these drugs are causing dyslipidemia and increased
development of diabetes (Figures 5-23 and 5-25). It also insulin resistance by measuring fasting triglyceride levels
means getting a baseline of fasting triglyceride levels before and after starting a serotonin/dopamine agent
and determining whether there is a family history of (Figure 5-25). If body mass index or fasting triglycerides
199
Figure 5-26 Insulin resistance: what can a

Insulin Resistance: psychopharmacologist do? Several factors
What Can a Psychopharmacologist Do? influence whether or not an individual
develops insulin resistance, some of which
are manageable by a psychopharmacologist
and some of which are not. Unmanageable
factors include genetic makeup and age,
psychopharmacologist while items that are modestly manageable
include lifestyle (e.g., diet, exercise, smoking).
Psychopharmacologists exert their greatest
influence on managing insulin resistance
through the selection of medication treatments
that either do or do not cause insulin resistance.
modest most
no options chance manageable
of option
success
genes/aging choice of
drug for
psychosis
lifestyle/diet
insulin resistance
increase significantly, a switch to a different drug in this monitored one way when used for psychosis, frequently in
class, especially a low-metabolic-risk drug, should be inpatient settings, and another way, much less rigorously,
considered. In patients who are obese, with dyslipidemia, when used for depression, often in outpatient settings.
and either in a prediabetic or diabetic state, it is especially Guess what? These are the same drugs no matter
important to monitor blood pressure, fasting glucose, where or in whom they are used.
and waist circumference before and after initiating a In high-risk patients, it is especially important
serotonin/dopamine agent. Best practices are to monitor to be vigilant for DKA/HHS, and possibly to reduce
these parameters in anyone taking any of these drugs, that risk by maintaining the patient on a drug for
although it is frequently not done, especially not in psychosis (or mood) with lower cardiometabolic risk.
patients being treated for depression, unfortunately. Too In high-risk patients, especially those with pending
often these same patients are not monitored for other or actual pancreatic β-cell failure, as manifested by
side effects in this class either, such as tardive dyskinesia. hyperinsulinemia, prediabetes, or diabetes, fasting
If there is one lesson to be learned about knowing the glucose and other chemical and clinical parameters can
pharmacology of drugs it is that the mechanism dictates be monitored to detect early signs of rare but potentially
not only efficacy but also safety. Too often these drugs are fatal DKA/HHS.
200
The psychopharmacologist’s metabolic toolkit is quite for individual discussion here. To characterize all the
simple (Figure 5-25). It involves a flow chart that tracks receptor binding properties of all the various drugs
perhaps as few as four parameters over time, especially that treat psychosis, we show these properties both by
before and after switches from one agent to another, or simplified icons and by binding strips that represent
as new risk factors evolve. These four parameters are all the known receptors that drug binds as one box per
weight (as body mass index), fasting triglycerides, fasting receptor, in rank order from most potent on the far left
glucose, and blood pressure. to least potent on the far right (see Figures 5-27 through
The management of patients at risk for 5-31 for some of the original D2 antagonists, and see
cardiometabolic disease can be quite simple as subsequent figures for the other drugs to treat psychosis).
well, although patients who already have developed Specifically, the pharmacological binding properties
dyslipidemia, hypertension, diabetes, and heart disease of each drug can be represented as a row of semi-
will likely require management of these problems by a quantitative and rank-order relative binding potencies at
medical specialist. However, the psychopharmacologist numerous neurotransmitter receptors. These figures are
is left with a very simple set of options for managing conceptual and not precisely quantitative, can differ from
patients with cardiometabolic risk who are prescribed one laboratory to another, species to species, method to
5
one of these drugs with any amount of metabolic risk method, and the consensus values for binding properties
(Figure 5-26). The major factors that determine whether evolve over time. More potent binding (higher affinity) is
a patient progresses along the metabolic highway to shown to the left of the value for the D2 receptor, which
premature death include: is indicated by a vertical dotted line; less potent binding
those that are unmanageable (genetic makeup and age) (lower affinity) is shown to the right.
those that are modestly manageable (change in Drugs used to treat psychosis are arguably the most
lifestyle such as diet, exercise, and stopping complicated medicines in psychopharmacology, if
smoking) not indeed in all of medicine, and this method should
those that are most manageable, namely the selection hopefully give the reader a rapid semi-quantitative grasp
of medication and perhaps switching from one of the individual pharmacological properties of two
that is causing increased risk in a particular dozen different drugs used to treat psychosis, and how
patient, to one that monitoring demonstrates these compare to all the other drugs that treat psychosis,
reduces that risk and to do it in a glance.
Other options for managing the metabolic syndrome Dopamine 2 antagonists/partial agonists are generally
and dyslipidemia in patients taking serotonin/dopamine dosed for antipsychotic action so that at least 60–80% of
antagonists is the promising possibility that co-therapy D2 receptors are occupied. Thus, all receptors to the left
with other agents may prevent weight gain and possibly of D2 in the various figures of these drugs are occupied
dyslipidemia. That is, the anti-diabetes drug metformin at the level of 60% or more at antipsychotic dosing levels.
has been shown in several studies to cause weight loss The receptors shown to the right of D2 in these individual
after drug-induced weight gain and, perhaps even more drug figures are occupied at a level of less than 60% at
impressively, to reduce weight gain when starting a antipsychotic dosing levels. Only those receptors that are
high- or moderate-metabolic-risk agent. Less consistent bound by a drug within an order of magnitude of potency
results have also been reported for the anticonvulsant of D2 affinity are likely to have clinically relevant actions
topiramate. A new agent on the horizon that can reduce at antipsychotic doses, and maybe no relevant actions at
olanzapine-induced weight gain is the combination of the lower doses such as doses used to treat depression.
μ-opioid antagonist samidorphan with olanzapine. Chlorpromazine
PHARMACOLOGICAL One of the very first agents with D2 antagonist properties

used to treat psychosis is chlorpromazine, in the chemical
PROPERTIES OF SELECTED
class of phenothiazine. It was originally branded as
INDIVIDUAL FIRST-GENERATION “Largactil” meaning it had a large number of actions, but
D2 ANTAGONISTS none of its actions were known to be linked to any specific
The original D2 antagonists launched approximately receptor at that time. Those “large actions” are shown in
70 years ago are still used to treat psychosis and a few Figure 5-27, and in addition to therapeutic D2 antagonism,
of the most commonly prescribed agents are selected chlorpromazine has numerous receptor actions
201
M1 M3
M4
5HT2A
M
5
H
1
α1
chlorpromazine
5HT2C
D1
D2
T6
5H
D4 D3
7
5HT
α1 D3 H1 D2
5HT2A D4 5HT2C 5HT6 5HT7 M5 M1 M3 M4 D1
+++ +++ +++ +++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ 5HT5A D5 H2 M2 5HT1E 5HT1D α2
+ + + + + + +
Figure 5-27 Chlorpromazine’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking
about the binding properties of chlorpromazine. In addition to the D2 receptor, chlorpromazine binds potently to α1-adrenergic
receptors, D3 receptors, and H1 receptors, and also has actions at numerous other receptors as shown. As with all agents discussed in
this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and
updated.
associated with sedation (muscarinic, α1, and histamine formulations for convenient use, and it is one of the agents
antagonism), as well as other side effects (see Figures 5-8 for which monitoring plasma drug levels may be useful.
and 5-13). Chlorpromazine is often prescribed to exploit
Haloperidol
its sedation in patients who do well with sedation,
particularly short-term orally or as a short-acting Haloperidol (Figure 5-29) is one of the most potent
intramuscular injection when needed to treat agitation or D2 antagonists, and less sedating than some others. It
a sudden worsening in psychosis, often administered on also has both short- and long-acting formulations for
top of another drug in the same class that is given daily. convenient use and it, too, is one of the agents for which
monitoring plasma drug levels may be useful.
Fluphenazine
Sulpiride
This agent is another phenothiazine, although
more potent than chlorpromazine and less sedating Sulpiride (Figure 5-30) has D2 antagonist properties
(Figure 5-28). It has both short-acting and long-acting and, as expected, generally causes motor side effects
202
5HT2A
H
1
α1
α2B
fluphenazine
α2C
D1
T6 5
5H
D2
T7
5H
D5 D3
D4
D2 D3
5HT7 α1
++++ ++++ +++ D5 5HT2A α2C
+++ ++ ++ ++ ++ ++ ++ ++ ++
H1 5HT6 D4 D1 α2B
α2A 5HT1B 5HT1D M5 5HT1E H2 5HT1A 5HT2C
+ + + + + + + +
Figure 5-28 Fluphenazine’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about
the binding properties of fluphenazine. Along with D2 antagonism, fluphenazine has potent actions at D3, 5HT7, and α1-adrenergic
receptors, and binds at numerous other receptors as well. As with all agents discussed in this chapter, binding properties vary greatly
with technique and from one laboratory to another; they are constantly being revised and updated.
and prolactin elevation at usual antipsychotic doses. outside the US. Some early preclinical data suggest that
However, particularly at lower doses, it may be a bit it might be more selective for mesolimbic/mesostriatal
activating, and have efficacy for negative symptoms of dopamine receptors than for nigrostriatal dopamine
schizophrenia and for depression for unclear reasons. receptors, and thus might have a lower propensity for
Dopamine 3 antagonist/partial agonist actions in motor side effects at antipsychotic doses. There are reports
depression are discussed in Chapter 7 on treatments of amisulpride’s efficacy for the negative symptoms of
for mood disorders, and this is a candidate explanation schizophrenia and for depression at doses lower than
(see Figure 5-30). Sulpiride remains a popular option for those used to treat positive symptoms of psychosis.
treating psychosis in countries outside the US such as the Amisulpride has some D3 antagonist actions and some
UK, as it may be better tolerated than some of the other weak 5HT7 antagonist actions, which may explain some of
original D2 agents. its negative symptom and antidepressant actions (Figure
5-31). Antidepressant actions of D3 antagonism/partial
Amisulpride
agonism and 5HT7 antagonism are discussed in Chapter 7.
Amisulpride (Figure 5-31) is structurally related to The active isomer of amisulpride is in early clinical testing
sulpiride (Figure 5-30) and was developed and marketed for possible development in the US.
203
5HT2A
α1
haloperidol D2
D4 D3
D2 σ D3 α1
D4
+++ +++ +++ +++ ++ 5HT2A D1 5HT1B α2C α2B M5 5HT7 α2A
+ + + + + + + +
Figure 5-29 Haloperidol’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about
the binding properties of haloperidol. Haloperidol binds potently to D2 receptors as well as to omega, D3, and α1-adrenergic receptors.
As with all agents discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are
constantly being revised and updated.
used to treat psychosis. The 5HT2A antagonist and/or

AN OVERVIEW OF THE 5HT1A partial agonist properties can help to explain the
PHARMACOLOGICAL reduced propensity for motor side effects and prolactin
PROPERTIES OF INDIVIDUAL elevation and potential therapeutic enhancement of
5HT2A/D2 ANTAGONISTS AND positive, negative, depressive, and cognitive symptoms.
D2/5HT1A PARTIAL AGONISTS: However, the contributions of these properties to each
THE PINES (PEENS), MANY individual agent used to treat psychosis are quite variable.
DONES AND A RONE, TWO PIPS As mentioned above for the original D2 antagonists, we
AND A RIP also characterize all the receptor binding properties of the
D2/5HT2A/5HT1A drugs by binding strips that represent
We have established that D2 antagonist/partial agonist all the known receptors that each drug binds to as one
properties can explain the antipsychotic efficacy for box per receptor, in rank order from most potent on the
positive symptoms as well as many side effects of drugs far left to least potent on the far right (see Figures 5-32
204
Figure 5-30 Sulpiride’s pharmacological and
binding profile. This figure portrays a qualitative
consensus of current thinking about the binding
properties of sulpiride. At usual antipsychotic
doses, sulpiride is a D2 antagonist and also has
D3 antagonist/partial agonist actions. As with
all agents discussed in this chapter, binding
properties vary greatly with technique and from
one laboratory to another; they are constantly
being revised and updated.
sulpiride
D2
D3
D3 D2
++ ++
Figure 5-31 Amisulpride’s pharmacological and

binding profile. This figure portrays a qualitative
consensus of current thinking about the binding
properties of amisulpride. In addition to its
actions at D2 receptors, amisulpride has some
D3 antagonist actions and some weak 5HT7
antagonist actions. As with all agents discussed in
this chapter, binding properties vary greatly with
technique and from one laboratory to another;
they are constantly being revised and updated.
amisulpride
D2
D3
D2 D3
5HT2B
+++ +++ ++ 5HT7
205
5HT2A binding by pines Figure 5-32 5HT2A binding

by drugs used to treat
5HT2A psychosis. Shown here is a visual
depiction of the binding profiles of
drugs used to treat psychosis. Each
clozapine 5HT2A colored box represents a different
binding property, with the size and
positioning of the box reflecting
olanzapine the binding potency of the property
5HT2A
(i.e., size indicates potency relative
to a standard Ki scale, while position
reflects potency relative to the
other binding properties of that
quetiapine drug). The vertical dotted line cuts
5HT2A
through the D2 receptor binding
box, with binding properties that
are more potent than D2 on the
asenapine left and those that are less potent
5HT2A than D2 on the right. Interestingly,
D2 binding is not the most potent
property for any of the agents
A zotepine shown here. (A) The “pines” (i.e.,
clozapine, olanzapine, quetiapine,
5HT2A binding by dones and a rone
asenapine, and zotepine) all bind
5HT2A much more potently to the 5HT2A
receptor than they do to the D2
receptor. (B) The “dones” and “rone”
risperidone (i.e., risperidone, paliperidone,
5HT2A
ziprasidone, iloperidone, lurasidone,
and lumateperone) also bind more
or as potently to the 5HT2A receptor
paliperidone as they do to the D2 receptor.
5HT2A
(C) Aripiprazole and cariprazine
both bind more potently to the D2
receptor than to the 5HT2A receptor,
ziprasidone while brexpiprazole has similar
5HT2A potency at both receptors.
iloperidone
5HT2A
lurasidone
5HT2A
lumateperone
B
5HT2A binding by two pips and a rip

5HT2A
aripiprazole
5HT2A
brexpiprazole
5HT2A
cariprazine
C
more potent than D2 less potent than D2
206
5HT1A binding by pines Figure 5-33 5HT1A binding

5HT1A psychosis. Shown here is a visual
depiction of the binding profiles
of drugs used to treat psychosis.
clozapine (A) Clozapine and quetiapine both
bind more potently to the 5HT1A
receptor than they do to the D2
olanzapine receptor, while asenapine and
zotepine bind less potently to the
5HT1A
5HT1A receptor and olanzapine
does not bind to it at all. (B) All
of the “dones” (i.e., risperidone,
quetiapine paliperidone, ziprasidone,
5HT1A
iloperidone, and lurasidone) bind to
the 5HT1A receptor with less potency
than they do to the D2 receptor;
asenapine lumateperone does not bind the
5HT1A 5HT1A receptor. (C) Aripiprazole,
brexpiprazole, and cariprazine
each have similar relative potency
A zotepine for the D2 and 5HT1A receptors.
5HT1A binding is actually the most 5
5HT1A binding by dones and a rone
potent property of brexpiprazole.
Description of graphic: Each
5HT1A
colored box represents a different
risperidone positioning of the box reflecting
5HT1A the binding potency of the property
paliperidone reflects potency relative to the other
5HT1A binding properties of that drug).
The vertical dotted line cuts through
the D2 receptor binding box, with
ziprasidone binding properties that are more
potent than D2 on the left and those
5HT1A
that are less potent than D2 on the
right. Binding at 5HT2A (see Figure
iloperidone 5-32) is indicated by an orange
5HT1A
outline around the box.
lurasidone
lumateperone
B
5HT1A binding by two pips and a rip

5HT1A
aripiprazole
5HT1A
brexpiprazole
5HT1A
cariprazine
C
207
Monoamine reuptake inhibition by pines Figure 5-34 Monoamine

transporter binding by drugs
used to treat psychosis. Shown
here is a visual depiction of the
binding profiles of drugs used to
clozapine treat psychosis. (A) Of the “pines,”
quetiapine is the only one with
any relevant monoamine reuptake
olanzapine inhibition. Specifically, it binds to
the norepinephrine transporter
NET
(NET) with similar potency as it does
to the 5HT2A receptor, and greater
potency than to the D2 receptor.
quetiapine (B) Ziprasidone binds to NET and
the serotonin transporter (SERT),
though with less potency than to the
D2 receptor. Lumateperone binds
asenapine to SERT with similar potency as to
NET SERT the D2 receptor. (C) Aripiprazole,
brexpiprazole, and cariprazine do
not bind to any of the monoamine
A zotepine transporters. Description of graphic:
Each colored box represents a
Monoamine reuptake inhibition by dones and a rone
different binding property, with
the size and positioning of the box
reflecting the binding potency of the
property (i.e., size indicates potency
risperidone relative to a standard Ki scale, while
position reflects potency relative
to the other binding properties of
that drug). The vertical dotted line
paliperidone cuts through the dopamine 2 (D2)
NET
SERT
receptor binding box, with binding
properties that are more potent
than D2 on the left and those that
ziprasidone are less potent than D2 on the right.
Binding at 5HT2A (see Figure 5-32)
is indicated by an orange outline
around the box.
iloperidone
lurasidone
SERT
lumateperone
B
Monoamine reuptake inhibition by two pips and a rip
aripiprazole
brexpiprazole
cariprazine
C
208
Alpha2 binding by pines Figure 5-35 Alpha-2 binding

α2C α2B
α2A psychosis. Shown here is a visual
drugs used to treat psychosis. (A)
clozapine α2C
All of the “pines” (i.e., clozapine,
α2B α2A
olanzapine, quetiapine, asenapine,
zotepine) bind to α2 receptors to
olanzapine varying degrees. Clozapine and
quetiapine in particular bind to
α2C α2A α2B some α2 receptor subtypes with
greater potency than they do to the
D2 receptor. (B) All of the “dones”
quetiapine (i.e., risperidone, paliperidone,
α2B α2A α2C
ziprasidone, iloperidone,
lurasidone) bind to α2 receptors
to varying degrees. Risperidone
asenapine and paliperidone bind to the α2C
α2 receptor with similar potency as to
the D2 receptor. Lumateperone does
not bind to any α2 receptors. (C)
A zotepine Aripiprazole binds to α2 receptors
with less potency than it does to the 5
Alpha2 binding by dones and a rone
D2 receptor. Brexpiprazole binds
α2C
α2B α2A to α2C receptors, and cariprazine
has some affinity for α2A receptors.
risperidone colored box represents a different
α2C α2A α2B binding property, with the size and
the binding potency of the property
paliperidone (i.e., size indicates potency relative
α2B α2C
α2A to a standard Ki scale, while position
reflects potency relative to the other
binding properties of that drug). The
ziprasidone vertical dotted line cuts through the
dopamine 2 (D2) receptor binding
α2C
α2A α2B box, with binding properties that
are more potent than D2 on the left
iloperidone and those that are less potent than
D2 on the right. Binding at 5HT2A
α2C α2A
(see Figure 5-32) is indicated by an
orange outline around the box.
lurasidone
lumateperone
B
Alpha2 binding by two pips and a rip

α2C α2A α2B
aripiprazole
α2C
brexpiprazole
α2A
cariprazine
C
209
D3 binding by pines Figure 5-36 D3 binding by drugs

used to treat psychosis. Shown here
D3 is a visual depiction of the binding
profiles of drugs used to treat
psychosis. (A) All of the “pines” bind
clozapine D3
to D3 receptors, but with varying
degrees of potency. (B) Likewise, all
of the “dones” bind to D3 receptors,
olanzapine again with varying degrees of
potency. Lumateperone, however,
D3 does not bind to D3 receptors at
all. (C) D3 receptor partial agonism
is actually the most potent binding
quetiapine property of cariprazine. Aripiprazole
D3
and brexpiprazole also bind to D3
receptors, less potently than they
do to D2 receptors. Description
asenapine of graphic: Each colored box
D3
represents a different binding
property, with the size and
A zotepine the binding potency of the property
D3 binding by dones and a rone
D3 reflects potency relative to the other
vertical dotted line cuts through the
risperidone dopamine 2 (D2) receptor binding
D3
and those that are less potent than
paliperidone D2 on the right. Binding at 5HT2A
D3
ziprasidone
D3
iloperidone
D3
lurasidone
lumateperone
B
D3 binding by two pips and a rip

D3
aripiprazole
D3
brexpiprazole
D3
cariprazine
C
210
5HT2C binding by pines Figure 5-37 5HT2C binding

5HT2C psychosis. Shown here is a visual
clozapine 5HT2C
All of the “pines” (i.e., clozapine,
olanzapine, quetiapine, asenapine,
zotepine) bind more potently to the
olanzapine 5HT2C receptor than they do to the
D2 receptor. (B) All of the “dones”
5HT2C (i.e., risperidone, paliperidone,
ziprasidone, iloperidone, lurasidone)
as well as lumateperone have some
quetiapine affinity for the 5HT2C receptor,
5HT2C
although only ziprasidone binds
with comparable potency as at
the D2 receptor. (C) Aripiprazole,
asenapine brexpiprazole, and cariprazine all
5HT2C
have relatively weak affinity for
the 5HT2C receptor. Description
of graphic: Each colored box
A zotepine represents a different binding
property, with the size and 5
5HT2C binding by dones and a rone
5HT2C
risperidone reflects potency relative to the other
5HT2C binding properties of that drug). The
paliperidone box, with binding properties that
5HT2C
ziprasidone (see Figure 5-32) is indicated by an
5HT2C
iloperidone
5HT2C
lurasidone
5HT2C
lumateperone
B
5HT2C binding by two pips and a rip

5HT2C
aripiprazole
5HT2C
brexpiprazole
5HT2C
cariprazine
C
211
5HT3 binding by pines Figure 5-38 5HT3 binding by drugs

used to treat psychosis. Shown
5HT3 here is a visual depiction of the
binding profiles of drugs used
to treat psychosis. (A) All of the
clozapine “pines” bind to 5HT3 with less
5HT3
affinity than they have for the D2
receptor. (B) None of the “dones”
olanzapine or “rone” have any binding activity
at 5HT3 receptors. (C) Aripiprazole
5HT3 binds weakly to 5HT3 receptors.
quetiapine binding property, with the size and
5HT3 positioning of the box reflecting
asenapine to a standard Ki scale, while position
5HT3 reflects potency relative to the other
A zotepine dopamine 2 (D2) receptor binding
5HT3 binding by dones and a rone
risperidone orange outline around the box.
paliperidone
ziprasidone
iloperidone
lurasidone
lumateperone
B
5HT3 binding by two pips and a rip

5HT3
aripiprazole
brexpiprazole
cariprazine
C
212
5HT6 and 5HT7 binding by pines Figure 5-39 5HT6 and 5HT7

binding by drugs used to treat
5HT6 5HT7 psychosis. Shown here is a visual
clozapine (A) Clozapine, quetiapine,
5HT6 5HT7
asenapine, and zotepine each
have greater or similar potency for
olanzapine the 5HT7 receptor compared to
the D2 receptor, while clozapine,
5HT7 5HT6 olanzapine, asenapine, and zotepine
each have greater or similar potency
for the 5HT6 receptor compared to
quetiapine the D2 receptor. (B) Risperidone,
5HT7 5HT6
paliperidone, ziprasidone, and
lurasidone all bind potently to the
5HT7 receptor. In fact, lurasidone has
asenapine greater affinity for the 5HT7 receptor
5HT6 5HT7 than for the D2 receptor. Ziprasidone
and iloperidone also bind to the
5HT6 receptor. (C) Aripiprazole,
A zotepine brexpiprazole, and cariprazine all
bind to the 5HT7 receptor, though 5
5HT6 and 5HT7 binding by dones and a rone
none with more potency than for the
5HT7 D2 receptor. Description of graphic:
risperidone the size and positioning of the box
5HT7
reflecting the binding potency of the
relative to a standard Ki scale, while
paliperidone position reflects potency relative
5HT7 5HT6 to the other binding properties of
cuts through the dopamine 2 (D2)
ziprasidone receptor binding box, with binding
5HT6
5HT7 than D2 on the left and those that
are less potent than D2 on the right.
iloperidone Binding at 5HT2A (see Figure 5-32)
5HT7 is indicated by an orange outline
around the box.
lurasidone
lumateperone
B
5HT6 and 5HT7 binding by two pips and a rip

5HT7 5HT6
aripiprazole
5HT7 5HT6
brexpiprazole
5HT7
cariprazine
C
213
5HT1B/D binding by pines Figure 5-40 5HT1B/D binding

5HT1B 5HT1D psychosis. Shown here is a visual
clozapine Clozapine, olanzapine, asenapine,
5HT1B 5HT1D and zotepine all bind relatively
weakly to the 5HT1B and 5HT1D
olanzapine receptors, while quetiapine binds
relatively weakly only to the
5HT1D 5HT1D receptor. (B) Risperidone,
paliperidone, ziprasidone, and
iloperidone all have some affinity
quetiapine for the 5HT1B and 5HT1D receptors.
5HT1B 5HT1D
In particular, ziprasidone binds
with similar potency to these
two receptors as it does to the
asenapine D2 receptor. Lurasidone and
5HT1B
5HT1D lumateperone do not bind to
5HT1B/D receptors. (C) Aripiprazole
and brexpiprazole each bind weakly
A zotepine to the 5HT1B receptor; aripiprazole
also binds to the 5HT1D receptor.
5HT1B/D binding by dones and a rone
Cariprazine does not bind to 5HT1B/D
5HT1B 5HT1D
receptors. Description of graphic:
risperidone the size and positioning of the box
5HT1B 5HT1D reflecting the binding potency of the
paliperidone position reflects potency relative
5HT1B 5HT1D to the other binding properties of
ziprasidone receptor binding box, with binding
5HT1D 5HT1B
iloperidone Binding at 5HT2A (see Figure 5-32)
is indicated by an orange outline
around the box.
lurasidone
lumateperone
B
5HT1 B/D binding by two pips and a rip

5HT1D 5HT1B
aripiprazole
5HT1B
brexpiprazole
cariprazine
C
214
Antihistamine/Anticholinergic binding by pines Figure 5-41 Antihistamine/

anticholinergic binding by drugs
M1 H1 M4 M3
M2 used to treat psychosis. Shown here
is a visual depiction of the binding
profiles of drugs used to treat
clozapine H1
psychosis. (A) Clozapine, olanzapine,
M1 M3
M2 M4 quetiapine, and zotepine all have
strong potency for histamine 1
olanzapine receptors; clozapine, olanzapine,
and quetiapine also have strong
H1 M3 M1
M4 M2 potency for muscarinic receptors.
Asenapine has some affinity for
histamine H1 receptors and weak
quetiapine
affinity for muscarinic receptors.
H1
M1 M2 (B) None of the “dones” or “rones”
have anticholinergic properties.
Risperidone, paliperidone,
asenapine ziprasidone, and iloperidone all
H1 M1
M2 H2 have some potency for H1 receptors.
(C) Aripiprazole, brexpiprazole,
and cariprazine all bind at the H1
A zotepine
receptor with less potency than
Antihistamine/Anticholinergic binding by dones and a rone they do to the D2 receptor, and do 5
not bind to muscarinic receptors.
H1 Description of graphic: Each
risperidone positioning of the box reflecting
H1
paliperidone
reflects potency relative to the other
H1
ziprasidone box, with binding properties that
H1 are more potent than D2 on the left
iloperidone (see Figure 5-32) is indicated by an
lurasidone
lumateperone
B
Antihistamine/Anticholinergic binding by two pips and a rip

H1
aripiprazole
H1
brexpiprazole
H1
cariprazine
C
215
Alpha1 binding by pines Figure 5-42 Alpha-1 binding

α1A α1B
psychosis. Shown here is a visual
clozapine (A) Clozapine, quetiapine, and
α1A α1B zotepine each have greater potency
for α1 receptors than for the D2
olanzapine receptor, while asenapine binds with
similar potency to the α2 and the
α1A α1B
D2 receptors. (B) All of the “dones”
(i.e., risperidone, paliperidone,
ziprasidone, iloperidone, lurasidone)
quetiapine as well as lumateperone bind
α1B α1A
to the α1 receptor. In particular,
paliperidone and iloperidone bind
with greater potency than they do
asenapine to the D2 receptor. (C) Aripiprazole,
α1 brexpiprazole, and cariprazine each
have some binding potency at α1
receptors. Description of graphic:
A zotepine Each colored box represents a
Alpha1 binding by dones and a rone
the size and positioning of the box
α1A α1B reflecting the binding potency of the
α1B risperidone position reflects potency relative
α1A
to the other binding properties of
paliperidone receptor binding box, with binding
α1B α1A properties that are more potent
ziprasidone Binding at 5HT2A (see Figure 5-32)
α1 is indicated by an orange outline
around the box.
iloperidone
α1
lurasidone
α1
lumateperone
B
Alpha1 binding by two pips and a rip

α1A α1B
aripiprazole
α1B α1A
α1D
brexpiprazole
α1B α1D α1A
cariprazine
C
216
M1
M2
M3
5H
T1
M4
A
5HT2A
H
1
α
1A
α
5HT2B 1B
clozapine α
2A
5HT2C
α
2B
α 5
2C
D2
T6
D4
5H
7
5HT
α1A α1B 5HT2B M1

H1 5HT2A 5HT6 5HT2C M4 α2C α2B D4 M3 5HT7
+++ +++ +++ +++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ M2 α2A 5HT1A D2 5HT3 D1 D3 5HT1B 5HT1E 5HT1D
+ + + + + + + + + +
Figure 5-43 Clozapine’s pharmacological icon and binding profile. This figure portrays a qualitative consensus of current thinking
about the binding properties of clozapine. In addition to 5HT2A/D2 antagonism, numerous other binding properties have been identified
for clozapine, most of which are more potent than its binding at the D2 receptor. It is unknown which of these contribute to clozapine’s
special efficacy or to its unique side effects. As with all agents discussed in this chapter, binding properties vary greatly with technique
and from one laboratory to another; they are constantly being revised and updated.
through 5-63). These pharmacological binding properties he was once asked if he and his son were a lot the same.
are again represented as a row of semi-quantitative He paused, pondered for a bit, then answered, “Yes, but
and rank-order relative binding potencies at numerous our similarities are different.” The same could be said for
neurotransmitter receptors, with each figure highlighting all these drugs used to treat psychosis (and mood, see
a specific receptor so the relative binding potencies of all Chapter 7). In some ways they are a lot the same, but in
these drugs can be compared at a glance. More potent many ways their similarities are different!
binding (higher affinity) is shown to the left of the value So, how are they similar? Beginning with the relative
for the D2 receptor, which itself is indicated by a vertical potencies of each of these agents for 5HT2A receptors
dotted line; less potent binding (lower affinity) is shown compared to D2 receptors, the reader can see at a glance
to the right. in Figure 5-32 that almost all agents show 5HT2A binding
Determining whether all drugs for psychosis should to the left of D2 binding, meaning these drugs with 5HT2A
be in a single class, or a small number of classes, or to the left all have higher affinity for 5HT2A receptors
whether each drug should be treated uniquely, is a bit than for D2 receptors and would be expected to bind
like the famous quote of baseball great Yogi Berra, when even more to 5HT2A receptors than to D2 receptors. The
217
M1
M3
5HT2A
H
1
α2C
5HT2B
5HT2C
olanzapine
D1
D2
D3
T6
D4
5H
H1 5HT2A
5HT6 5HT2B 5HT2C M1 D4 D2 D3 D1 M3 α2C
+++ +++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ α1A α2B 5HT3 M2 M4 5HT7 α2A α1B 5HT1B 5HT1D
+ + + + + + + + + +
Figure 5-44 Olanzapine’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about
the binding properties of olanzapine. Olanzapine binds at several receptors more potently than it does at the D2 receptor; in fact, it has
strongest potency for the H1 and 5HT2A receptors. Olanzapine’s 5HT2C antagonist properties may contribute to its efficacy for mood and
cognitive symptoms, although together with its H1 antihistamine properties they could also contribute to its propensity to cause weight
gain. As with all agents discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another;
they are constantly being revised and updated.
exceptions are the D2 partial agonists, but these drugs and 5-22). Yet, no two drugs are exactly the same and it
all show comparable potency for 5HT1A receptors and can be expected that their clinical properties linked to
D2 receptors (Figure 5-33). However, D2 antagonists 5HT2A and 5HT1A receptors may also differ, even though
with potent 5HT2A properties generally do not have high essentially all drugs listed have 5HT2A antagonism,
affinity for 5HT1A receptors (compare drugs in Figure 5HT1A partial agonism, or both, at least to some degree.
5-32 with the same drugs in Figure 5-33 for their 5HT2A One example of how drugs that all have potent 5HT2A
versus their 5HT1A properties). Maybe that does not antagonist properties nevertheless differ from each other
really matter. Recall that many of the same downstream is the observation that the greater the separation of 5HT2A
actions of 5HT2A antagonism are also caused by 5HT1A binding from D2 binding (i.e., the further 5HT2A is to
partial agonism (see discussion above and Figures 5-17 the left of D2), the less D2 receptor occupancy may be
218
M1
M3
5H
M4
T
1A
5HT2A H
1
α
1A
α
1B
quetiapine 5HT2B α
2A
α
2C
5HT2C
NET
1E
5HT
5
D1
D2
5HT7
H1*
5HT2B* M3* α1A M1* α1B 5HT2A* NET* 5HT7*
+++ ++ 5HT1E* 5HT2C* D1* M4* 5HT1A* α2C α2A* D2* 5HT1D* α2B* 5HT3* 5HT6* M2* D3* 5HT5*
++ ++ ++ ++ ++ ++ ++
+ + + + + + + + + + + + + + +
* Binding primarily due to norquetiapine (a metabolite of quetiapine)
Figure 5-45 Quetiapine’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about
the binding properties of quetiapine. Quetiapine does not actually have particularly potent binding at D2 receptors. Quetiapine’s
prominent H1 antagonist properties probably contribute to its ability to enhance sleep, and this may contribute as well to its ability to
improve sleep disturbances in bipolar and unipolar depression as well as in anxiety disorders. However, this property can also contribute
to daytime sedation, especially combined with M1 antimuscarinic and α1-adrenergic antagonist properties. A potentially important active
metabolite of quetiapine, norquetiapine, may contribute additional actions at receptors, as noted in the binding profile with an asterisk.
5HT1A partial agonist actions, norepinephrine transporter (NET) inhibition, and 5HT2C, α2, and 5HT7 antagonist actions may all contribute
to mood-improving properties of quetiapine. However, 5HT2C antagonist actions combined with H1 antagonist actions may contribute
to weight gain. As with all agents discussed in this chapter, binding properties vary greatly with technique and from one laboratory to
another; they are constantly being revised and updated.
needed for an antipsychotic effect, explaining why studies various agents have many, many pharmacological
show that those with the widest separation (namely, properties other than just dopamine and serotonin
lumateperone, quetiapine, and clozapine) also have the receptor binding, and these additional pharmacological
lowest D2 occupancy at antipsychotic doses, in fact lower properties are shown in the next nine figures (Figures
than 60%. Perhaps all this discussion is just a fancy way 5-34 through 5-42). The first seven of these allow visual
of saying that the drugs to treat psychosis are all the same comparisons of putative antidepressant mechanisms
but their similarities are different. mentioned above and that will be discussed in detail in
If what is the same about these drugs is D2 binding Chapter 7. For example, the various receptor properties
and some degree of binding to either 5HT2A or 5HT1A linked to postulated antidepressant actions are shown in
receptors, that is where the similarities stop. These the following figures:
219
Papa Bear
Mama Bear
M1
M3
5H
M4
Baby Bear
T
1A
5HT2A H
1
M1
α M3
5H
1A M4
T1
α
A
1B 5HT2A H
1
α
5HT2B α 1A
2A α
1B
α
2C α
5HT2C 5HT2B 2A H1
α
NET 2C
1E 5HT2C
5HT
NET
D1 E
5HT1
D1
D2
D2
5HT7
5HT7
800 mg 300 mg 50 mg
antipsychotic antidepressant hypnotic
Figure 5-46 Binding profile of quetiapine at different doses. The binding properties of quetiapine vary depending on the dose used.
At antipsychotic doses (i.e., up to 800 mg/day), quetiapine has a relatively wide binding profile, with actions at multiple serotonergic,
muscarinic, and α-adrenergic receptors. Histamine 1 receptor blockade is also present. At antidepressant doses (i.e., approximately
300 mg/day), the binding profile of quetiapine is more selective and includes norepinephrine reuptake inhibition, 5HT1A partial
agonism, and 5HT2A, α2, 5HT2C, and 5HT7 antagonism. At sedative hypnotic doses (i.e., 50 mg/day), the most prominent pharmacological
property of quetiapine is H1 antagonism.
5HT2A
5HT H
1B α
1
1A
5HT α
1D 1B
α
2A
5HT2B
α
2B
asenapine
5HT2C
D1
T5
5H
D2
T6
D3
5H
5HT7
D4
5HT2C 5HT2A 5HT7

5HT6 D2 D3 D4 D1 α1B 5HT5 α1A 5HT1B H1 5HT2B α2B α2A 5HT1D
α2C 5HT1E 5HT1A
++++ ++++ ++++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ 5HT3 M1 M2
++ ++ ++
+ + +
Figure 5-47 Asenapine’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about
the binding properties of asenapine. Asenapine has a complex binding profile, with potent binding at multiple serotonergic and
dopaminergic receptors, α1 and α2 receptors, and H1 histamine receptors. In particular, 5HT2C antagonist properties may contribute to
its efficacy for mood and cognitive symptoms, while 5HT7 antagonist properties may contribute to its efficacy for mood, cognitive, and
sleep symptoms. As with all agents discussed in this chapter, binding properties vary greatly with technique and from one laboratory to
M1
5HT2A
H
1
α
1
5HT1B
zotepine
5HT2C
D1
D2
T6
5H
5HT7
D4 D3
5HT2A H1 D3 5HT2C 5HT6 α1 5HT7

D2 M1 D4 D1 5HT1B
+++ +++ +++ +++ +++ +++ +++ ++ ++ ++ ++ ++ 5HT1D M2 α2 5HT1A 5HT3 H2 NET SERT 5HT1E
+ + + + + + + + +
Figure 5-48 Zotepine’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about
the binding properties of zotepine. Zotepine is a 5HT2C antagonist, an α2 antagonist, and a 5HT7 antagonist, suggesting potential
antidepressant effects. As with all agents discussed in this chapter, binding properties vary greatly with technique and from one
laboratory to another; they are constantly being revised and updated.
monoamine reuptake blocking properties (Figure α1 antagonism (Figure 5-42).

5-34) The point of these figures showing all these binding
α2 antagonism (Figure 5-35) properties is to be able to see the differences amongst
D3 partial antagonism/partial agonism (Figure 5-36) these drugs as well as the similarities. Individual agents
5HT2C antagonism (Figure 5-37) have quite different mechanisms theoretically linked to
5HT3 antagonism (Figure 5-38) antidepressant actions that may help explain why some
5HT6 and 5HT7 antagonism (Figure 5-39) are indicated for unipolar or bipolar depression and
5HT1B/D antagonism (Figure 5-40) others are not, and also why one patient’s depression may
Also, the various receptor binding properties theoretically respond to one drug in this group but not to another.
linked to side effects are shown in these figures: Another way to help the reader take this tour de force
antihistamine and anticholinergic (Figure 5-41), through two dozen complicated drugs a bit more easily,
221
5HT2A
α
1A
α
1B
α
2C
risperidone
D2
5HT7
D3
D4
5HT2A D2 5HT7 α2C α1A D3 D4 α1B

H1 5HT2C 5HT1B 5HT2B 5HT1D α2B α2A
+++ +++ +++ +++ +++ +++ +++ +++ ++ ++ ++ ++ ++ ++ ++ 5HT5 D1 5HT1A
+ + +
Figure 5-49 Risperidone’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking
about the binding properties of risperidone. Alpha-2 antagonist properties may contribute to efficacy for depression, but this can be
diminished by simultaneous α1 antagonist properties, which can also contribute to orthostatic hypotension and sedation. As with all
agents discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly
being revised and updated.
and for a bit of fun, is to organize all of them into three agent clustered into each of these three groups to try to
whimsical groups: make learning their distinctions easier and memorable.
the pines (peens)
many dones and a rone The Pines (Peens)
two pips and a rip Clozapine
The members of each of the three groups have already Clozapine (Figure 5-43) is widely recognized as being
been organized this way in Figures 5-32 through 5-42 particularly effective when other drugs for psychosis
and now we provide a brief description of each individual fail, and is thus the “gold standard” for efficacy in
222
α
1A
α
5HT2A 1B
paliperidone
α
2C
D2
D3
5HT7
α1B
5HT2A α1A D3 5HT7 D2 α2C
++++ H1 α2A α2B D1 5HT1B 5HT2C D4 5HT2B 5HT1D
+++ +++ +++ +++ +++ +++ ++ ++ ++ ++ ++ ++ ++ ++ ++
5HT5 5HT1A
+ +
Figure 5-50 Paliperidone’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about
the binding properties of paliperidone, the active metabolite of risperidone. Paliperidone shares many pharmacological properties
with risperidone. As with all agents discussed in this chapter, binding properties vary greatly with technique and from one laboratory to
schizophrenia. Clozapine is also the only antipsychotic functioning, and not just significant improvement in
that has been documented to reduce the risk of suicide positive symptoms of psychosis, but this is unfortunately
in schizophrenia and may have a particular niche in rare. The fact that awakenings can be observed at all,
treating aggression and violence in psychotic patients. It however, gives hope to the possibility that a state of
is unknown what pharmacological property accounts for wellness might some day be achieved in schizophrenia by
this gold standard enhanced efficacy of clozapine, but it is the right mix of pharmacological mechanisms.
unlikely to be D2 antagonism since at therapeutic doses, In terms of side effects, clozapine causes little in the
clozapine occupies fewer D2 receptors than the other way of motor symptoms, does not seem to cause tardive
drugs that treat psychosis. Likely, it works by an unknown dyskinesia and may even be effective in treating tardive
but non-D2 mechanism. Patients treated with clozapine dyskinesia, and also does not elevate prolactin. That’s
may occasionally experience an “awakening” (in the the good news. The bad news is that clozapine has some
Oliver Sachs sense), characterized by a return to a near- unique side effects (Table 5-2), and prescribing clozapine
normal level of cognitive, interpersonal, and vocational effectively means the ability to manage these side effects
223
5HT2A
5H α1B
T1
B
5HT1D
ziprasidone
C
5HT2
D2
5HT7 D3
5HT2A α1B
5HT1B 5HT2C D2 5HT1D 5HT7 D3
++++ α1A 5HT1A 5HT2B NET H1 α2B 5HT6 α2C D1
+++ +++ +++ +++ +++ +++ +++ ++ ++ ++ ++ ++ ++ ++ ++ ++ α2A D4 5HT5 SERT 5HT1E
+ + + + +
Figure 5-51 Ziprasidone’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about
the binding properties of ziprasidone. This compound seems to lack the pharmacological actions associated with weight gain and
increased cardiometabolic risk such as increasing fasting plasma triglyceride levels or increasing insulin resistance. Ziprasidone also
lacks many of the pharmacological properties associated with significant sedation. As with all agents discussed in this chapter, binding
properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.
if they arise. One life-threatening and occasionally fatal

complication of clozapine treatment is neutropenia,
requiring patients to have their blood counts monitored
Table 5-2 Side effects of clozapine requiring expert management
for as long as they are treated.
Clozapine also has an increased risk of seizures, Neutropenia
especially at high doses (Table 5-2). It can be very Constipation/paralytic ileus
sedating, has an increased risk of myocarditis, and is
Sedation, orthostasis, tachycardia
associated with the greatest degree of weight gain and
possibly the greatest cardiometabolic risk among the Sialorrhea
drugs for psychosis. Clozapine can also cause excessive Seizures
salivation, which can be mitigated by pro-cholinergic Weight gain, dyslipidemia, hyperglycemia
treatment or even by localized botulinum toxin injections
Myocarditis, cardiomyopathy, interstitial nephritis
for severe cases. Thus, clozapine may have the greatest
efficacy but also the most side effects among the atypical DRESS (drug reaction with eosinophilia and systemic
symptoms), serositis
antipsychotics.
224
Figure 5-52 Iloperidone’s
5H pharmacological and binding
T1 α1A profile. This figure portrays a qualitative
B
consensus of current thinking about
the binding properties of iloperidone.
Among the medications discussed here,
iloperidone has one of the simplest
pharmacological profiles and comes
closest to a serotonin dopamine
antagonist (SDA). Its other prominent
pharmacological property is potent α1
antagonism, which may be responsible
for the risk of orthostatic hypotension
iloperidone but also may contribute to its low risk
of drug-induced parkinsonism (DIP). As
with all agents discussed in this chapter,
binding properties vary greatly with
technique and from one laboratory
to another; they are constantly being
revised and updated.
5
D2
α1
5HT2A D2
++++ D3 H1 D4 5HT1D α2C 5HT6 5HT1A 5HT1B
+++ +++ ++ ++ ++ ++ ++ ++ ++ ++ 5HT2C 5HT7 D1 α2A α2B
+ + + + +
Because of these side-effect risks, clozapine is not care blood-count-monitoring system is now available
considered to be a first-line treatment, but is used when with a finger stick rather than a blood draw and local
other antipsychotics fail. The mechanisms of clozapine’s assay rather than sending away to a distant laboratory.
ability to cause neutropenia and myocarditis are entirely It is important not to lose the art of how to prescribe
unknown; its weight gain may be partially associated clozapine and for whom, and how to mitigate and
with its potent blockade of both H1 histamine and 5HT2C manage side effects, as clozapine remains a powerful and
receptors (Figure 5-43). Sedation is probably linked to unfortunately underutilized therapeutic intervention for
clozapine’s potent antagonism of muscarinic M1, H1, and many patients. Therapeutic drug monitoring of plasma
α1-adrenergic receptors (Figures 5-8, 5-14, and 5-43). drug levels can be of great assistance in finding the
Profound muscarinic blockade can also cause excessive right dose of clozapine. This specific drug is a subject
salivation, especially at higher doses, as well as severe all to itself and for this reason the author has co-written
constipation that can lead to bowel obstruction, especially a handbook on how to use clozapine that the reader
if administered concomitantly with other anticholinergic may wish to consult for details (Meyer and Stahl, The
agents, such as benztropine, or other drugs for Clozapine Handbook).
psychosis with potent anticholinergic properties, such as
Olanzapine
chlorpromazine.
Because of these side effects and the hassle of Olanzapine (Figure 5-44) is an antagonist at both 5HT2A
arranging for blood counts, the use of clozapine is low and D2 receptors, and although not proven as effective
in clinical practice, and probably too low given the as clozapine for psychosis, it is widely considered (by
great number of patients with inadequate responses to clinical experience rather than by definitive clinical
the other drugs for psychosis. To reduce one logistical trials) to be the next most effective agent, with at least
and pragmatic barrier to clozapine use, a point-of- a bit more efficacy than the others in this class except
225
Figure 5-53 Lurasidone’s
pharmacological and binding
profile. This figure portrays a qualitative
5H
T1
the binding properties of lurasidone.
A
5H
T2 Lurasidone has a relatively simple
A pharmacological profile. It binds most
potently to the D4 receptor, the effects
of which are not well understood,
and to the 5HT7 receptor, which
may contribute to efficacy for mood,
cognitive, and sleep symptoms. As with
all agents discussed in this chapter,
revised and updated.
lurasidone
D2
T7
5H
D4
D4 5HT7
D2 5HT2A 5HT1A
++++ ++++ α2C D3 α2A α1
+++ +++ +++ ++ ++ ++ ++ 5HT2C
+
clozapine. It also has a higher risk for metabolic side Perhaps the 5HT2C antagonist properties, with weaker
effects. Olanzapine tends to be used in higher doses than α2 antagonist properties (see Figures 5-35 and 5-37
originally studied and approved for marketing, especially and also Figure 5-44), especially when combined with
when guided by plasma drug levels, since clinical use the 5HT2C antagonist properties of the antidepressant
suggests that higher doses may have greater efficacy, fluoxetine (see Chapter 7 on treatments for mood
especially in patients who have not responded to other disorders), may explain some aspects of olanzapine’s
drugs for psychosis or to olanzapine at lower doses. apparent efficacy in unipolar and bipolar depression.
Olanzapine is approved for schizophrenia and for Olanzapine is available as an oral disintegrating tablet,
maintaining response in schizophrenia (age 13 or older), as an acute intramuscular injection, and as a long acting
for agitation associated with schizophrenia or with 4-week intramuscular depot. An inhaled formulation
bipolar mania (intramuscular), acute bipolar mania/ for rapid onset use is in late clinical development. As
mixed mania and maintenance (age 13 or older), and in mentioned earlier, olanzapine is also in late-stage clinical
combination with fluoxetine for both bipolar depression testing with the μ-opioid antagonist samidorphan to
and treatment-resistant unipolar depression (in the US). mitigate weight gain and metabolic disturbances.
226
Figure 5-54 Lumateperone’s
α1
consensus of current thinking about the
5HT2A binding properties of lumateperone.
Lumateperone has very high affinity
for the 5HT2A receptor and moderate
affinity for the D2, D1, and α1 receptor.
It also has moderate affinity for the
serotonin transporter. As with all agents
discussed in this chapter, binding
properties vary greatly with technique
and from one laboratory to another;
they are constantly being revised and
lumateperone updated.
SERT
D1
5
D2
5HT2A
++++ D2 D1 SERT α1
5HT2C
++ ++ ++ ++
+
Quetiapine drug for psychosis. In fact, like the others in this class,
Quetiapine (Figure 5-45) is an antagonist at both quetiapine is far more often prescribed for indications
serotonin 5HT2A and dopamine D2 receptors, but has other than psychosis, including frequently as a hypnotic
several differentiating pharmacological properties, for insomnia, a drug for depression, for anxiety, for
especially at different doses. The net pharmacological Parkinson’s disease psychosis, or as an adjunct for
actions of quetiapine are actually due to the combined psychosis with other 5HT2A/5HT1A/D2 drugs.
pharmacological actions not only of quetiapine
itself, but also of its active metabolite, norquetiapine Different Drug at Different Doses?
(Figure 5-45 adds together the net actions of quetiapine The story of quetiapine dosing can be told as
and norquetiapine). Norquetiapine has unique Goldilocks and the three bears (Figure 5-46).
pharmacological properties compared to quetiapine, For psychosis, quetiapine is an 800 mg Papa Bear. For
especially norepinephrine transporter (NET) inhibition depression, quetiapine is a 300 mg Mama Bear. For
(i.e., norepinephrine reuptake inhibition) (Figure 5-34), insomnia, quetiapine is a 50 mg Baby Bear. Starting with
but also, combined with the parent drug quetiapine, Baby Bear, only the most potent binding properties of
it has 5HT7 (Figure 5-39), 5HT2C (Figure 5-37), and α2 quetiapine to the far left in the strip at the bottom of
antagonism (Figure 5-35), and 5HT1A partial agonist Figure 5-45 are relevant, especially H1 antihistamine
actions (Figure 5-33), all of which may contribute properties (see also Figure 5-41). Baby Bear doses are not
to quetiapine’s overall clinical profile, especially its approved for use as a hypnotic, and this can be an option
robust antidepressant effects. Thus, quetiapine has an with metabolic risks, so is not considered a first-line
overall very complex set of binding properties to many option for sleep. At this dose, hypothetically there are
neurotransmitter receptors, many of which have higher insufficient numbers of 5HT2C receptors or NETs blocked
potency than to the D2 receptor, and this may account for antidepressant efficacy; also, there is insufficient
for why this drug appears to be far more than simply a occupancy of D2 receptors for antipsychotic efficacy.
227
Normal Psychosis
D2
D2 D2 D2 D2 D2 D2 D2
A B
D2 presynaptic and D2 presynaptic agonist and

postsynaptic antagonist postsynaptic antagonist
D2 presynaptic
D2 presynaptic agonist
antagonist
D2 postsynaptic
antagonist
D2 postsynaptic
antagonist
C D
Figure 5-55 Pre- and postsynaptic dopamine 2 receptor binding. (A) D2 receptors are present both pre- and postsynaptically;
dopamine binding at these receptors is inhibitory. (B) In psychosis, dopamine synthesis and release are enhanced, leading to
excessive stimulation of postsynaptic D2 receptors. (C) Most D2 antagonists block both pre- and postsynaptic D2 receptors. Blockade
of presynaptic D2 receptors disinhibits presynaptic dopamine release, thus further enhancing dopamine release. Full blockade of
postsynaptic D2 receptors, however, can counter the effect of presynaptic D2 blockade. (D) Lumateperone is unusual among D2
antagonists in that it seems to be an antagonist at postsynaptic D2 receptors but a partial agonist at presynaptic D2 receptors. This would
mean that less postsynaptic D2 antagonism would be necessary to achieve an antipsychotic effect, because dopamine release would
already be diminished.
228
5H
T
1A
5HT2A H
1
α
5H 1A
T1
D α
1B
α
5HT2B 2A
α
2C
5
aripiprazole
C
T2
5H
D2
D3
5HT7
5HT2B
D2 5HT1A
++++ D3 5HT7 α1A 5HT2C α1B H1 α2C 5HT2A5HT1D α2A
+++ +++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ α2B D4 5HT6 5HT3 5HT1B
+ + + + +
Figure 5-56 Aripiprazole’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about
the binding properties of aripiprazole. Aripiprazole is a partial agonist at D2 receptors rather than an antagonist. Additional important
pharmacological properties that may contribute to its clinical profile include 5HT2A antagonist actions, 5HT1A partial agonist actions,
5HT7 antagonist actions, and 5HT2C antagonist actions. Aripiprazole lacks or has weak binding potency at receptors usually associated
with significant sedation. Aripiprazole also seems to lack the pharmacological actions associated with weight gain and increased
cardiometabolic risk, such as increasing fasting plasma triglyceride levels or increasing insulin resistance. As with all agents discussed in
this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and
updated.
Mama Bear at 300 mg range has robust reuptake inhibition, 5HT1A partial agonism, and
antidepressant effects in depression by combining 5HT2A, α2, and 5HT2C antagonism) and serotonin
several simultaneous known antidepressant mechanisms release (by 5HT7 antagonism) (see Chapter 7 for
discussed above. Thus, the combination of these explanation and illustrations for all these antidepressant
antidepressant mechanisms would enhance dopamine mechanisms). Especially when combined with selective
and norepinephrine release (via norepinephrine serotonin reuptake inhibitors (SSRIs)/serotonin–
229
5HT1A
5HT2A
α
1B
α
2C
brexpiprazole
D2
5HT1A α1B D2 5HT2A α2C

D3 5HT2B α1D 5HT7 α1A D4
++++ ++++ ++++ ++++ ++++ 5HT2C H1 5HT1B 5HT6
+++ +++ +++ +++ +++ +++ ++ ++ ++ ++ D1
+
Figure 5-57 Brexpiprazole’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking
about the binding properties of brexpiprazole. Brexpiprazole is a partial agonist at D2 receptors rather than an antagonist, and
also binds potently to 5HT2A, 5HT1A, and α1 receptors. Brexpiprazole also seems to lack actions at receptors usually associated with
significant sedation, weight gain, and increased cardiometabolic risk, although it is too early to evaluate the clinical profile of this
medication. As with all agents discussed in this chapter, binding properties vary greatly with technique and from one laboratory to
norepinephrine reuptake inhibitors (SNRIs) there Finally, Papa Bear is 800 mg quetiapine, which
would be triple monoamine actions of increasing completely saturates both H1 histamine and 5HT2A receptors
serotonin as well as norepinephrine and dopamine continuously in both cases, but has more inconsistent
while simultaneously treating symptoms of insomnia occupancy above 60% for D2 receptors, especially between
and anxiety by antihistaminic action (Figure 5-45). doses. Quetiapine is approved both for schizophrenia/
Quetiapine is approved both for bipolar depression and schizophrenia maintenance (ages 13 and above) and
as an augmenting agent to SSRIs/SNRIs in unipolar for mania/mixed mania and maintenance (ages 10 and
depression that fails to respond sufficiently to those above). The pharmacology of quetiapine suggests why it
agents (in the US). is used more often in depression and insomnia than in
230
Figure 5-58 Cariprazine’s
5H
T1A
the binding properties of cariprazine.
α
1A Cariprazine has potent actions at D3,
5HT2A
5HT2B, D2, and 5HT1A receptors, with
α relatively weaker affinity for 5HT2A and
1B H1 receptors. Cariprazine actually has
higher affinity for the D3 receptor than
α dopamine does. As with all agents
1D
5HT2B discussed in this chapter, binding
α
2A and from one laboratory to another;
updated.
cariprazine
D2
5
D3
D3 D2
5HT2B
5HT1A α1B α2A α1D α1A
+++++ ++++ ++++ 5HT2A H1
+++ +++ +++ +++ +++ 5HT7 5HT2C
++ ++
+ +
Figure 5-59 Pimavanserin’s
5HT2A consensus of current thinking about the
binding properties of pimavanserin.
Pimavanserin is the only known drug
with proven antipsychotic efficacy
that does not bind to D2 receptors.
Instead, it has potent 5HT2A antagonism
(sometimes called inverse agonism)
with lesser 5HT2C antagonist actions. As
5HT2C
with all agents discussed in this chapter,
pimavanserin revised and updated.
5HT2A
5HT2C
++++
+++
231
5HT2A
α1
sertindole
C
5HT2
D2
5HT6
5HT2A
5HT2C D2 5HT6 α1
++++ D4 D1 5HT7 5HT1D 5HT1B
+++ +++ +++ +++ ++ ++ ++ ++ ++ DAT 5HT1F 5HT1E α2B α2C 5HT1A M1 α2A
+ + + + + + + +
Figure 5-60 Sertindole’s pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about
the binding properties of sertindole. Potent antagonist actions at α1 receptors may account for some of sertindole’s side effects. As
with all agents discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are
constantly being revised and updated.
psychosis. Quetiapine causes virtually no motor side effects additional serotonin receptor subtypes (Figure 5-47).
nor prolactin elevations. However, quetiapine has at least This suggests that asenapine would have antidepressant
moderate risk for weight gain and metabolic disturbances. actions, but only antipsychotic/antimanic actions have
been proven. Asenapine is unusual in that it is given as
Asenapine a sublingual formulation, because it is not absorbed if
Asenapine (Figure 5-47) has a chemical structure related it is swallowed. The surface area of the oral cavity for
to the antidepressant mirtazapine and shares several oral absorption limits the size of the dose, so asenapine
of mirtazapine’s pharmacological binding properties, is generally taken twice a day despite a long half-life.
especially 5HT2A, 5HT2C, H1, and α2 antagonism, plus Since asenapine is rapidly absorbed sublingually with
many other properties that mirtazapine does not have, rapid peak drug levels, unlike other formulations that
especially D2 antagonism, as well as actions upon many simply dissolve rapidly in the mouth but are followed
232
Figure 5-61 Perospirone’s
5HT1A consensus of current thinking about
the binding properties of perospirone.
5HT1A partial agonist actions may
5HT2A contribute to efficacy for mood and
cognitive symptoms. As with all agents
updated.
perospirone
D2
D4
D4 D2 5HT2A
5HT1A
++++ ++++ ++++ α1 D1
+++ ++ ++ α2
+
by delayed absorption (e.g., orally dissolving olanzapine in the US for bipolar mania (ages 10 or older). It is also
preparations), asenapine can be used as rapid-acting available in a transdermal formulation.
oral PRN (as needed) antipsychotic to “top up” patients
without resorting to an injection. One side effect of Zotepine
sublingual administration in some patients is oral Zotepine (Figure 5-48) is available in Japan and Europe,
hypoesthesia; also, patients may not eat or drink for 10 but not the US. Zotepine has 5HT2A and D2 antagonist
minutes following sublingual administration to avoid the properties and is not as popular as other drugs for
drug being washed into the stomach where it will not be psychosis because it has to be administered three times a
absorbed. Asenapine can be sedating, especially upon day. There may be an elevated risk of seizures. Zotepine is
first dosing, and has a moderate propensity for weight a 5HT2C antagonist, an α1 antagonist, a 5HT7 antagonist,
gain, metabolic disturbances, or motor side effects. It is and a weak partial agonist of 5HT1A receptors as well
approved for schizophrenia/maintenance in adults and as a weak inhibitor of norepinephrine reuptake (NET),
233
Figure 5-62 Blonanserin’s
profile. This figure portrays a
qualitative consensus of current
5HT2A thinking about the binding properties
of blonanserin. Blonanserin has high
affinity for D3 receptors; in fact, it has
higher affinity for D3 receptors than
does dopamine itself. As with all agents
updated.
blonanserin
D2
D3
D3 D2 5HT2A
++++ ++++ ++++
suggesting potential antidepressant effects that have not irritability associated with autistic disorder, including
been well established yet in clinical trials. symptoms of aggression towards others, deliberate
self-injury, tantrums, and quickly changing moods
Many Dones and a Rone
(ages 5–16). Low-dose risperidone is occasionally used
Risperidone
“off-label” for the controversial – due to a “black box”
Risperidone (Figure 5-49) is the original “done” and safety warning – treatment of agitation and psychosis
has a different chemical structure and a different associated with dementia. This practice may lessen
pharmacological profile than the pines (compare pines as other drugs in the pipeline get approved for this
and dones in Figure 5-32). Risperidone has favored indication. Risperidone is available in long-term depot
uses in schizophrenia/maintenance (age 13 and older) injectable formulations lasting for 2 or 4 weeks and it can
and bipolar mania/maintenance (ages 10 and older). be useful to monitor plasma drug levels of risperidone
Some prefer this agent for children and adolescents in and its active metabolite paliperidone, especially to
particular where it is also approved for treatment of guide dosing for patients receiving long-term depot
234
Figure 5-63 Roluperidone’s
5HT2A the binding properties of roluperidone.
Still in clinical testing, roluperidone
is a 5HT2A antagonist with additional
σ2 antagonism. As with all agents
updated.
σ2
roluperidone 5
σ2 5HT2A
++++ ++++
injections and who are treatment-resistant. There is also always well recognized and can lead to underdosing of
an orally disintegrating tablet and liquid formulation of oral paliperidone. Oral sustained release means that
risperidone. paliperidone only needs to be administered once a
Although risperidone does have somewhat reduced day, whereas risperidone, especially when treatment
motor side effects at lower doses, it raises prolactin levels is initiated, and especially in children or the elderly,
even at low doses. Risperidone has a moderate amount of may need to be given twice daily to avoid sedation and
risk for weight gain and dyslipidemia. Weight gain can be orthostasis. Side effects of risperidone may be related in
particularly a problem in children. part to the rapid rate of absorption and higher peak doses
with greater drug-level fluctuation leading to shorter
Paliperidone duration of action, properties that are eliminated by the
Paliperidone, the active metabolite of risperidone, is also controlled release formulation of paliperidone.
known as 9-hydroxy-risperidone and like risperidone Despite the similar receptor binding characteristics
has 5HT2A and D2 receptor antagonism (Figure 5-50). of paliperidone and risperidone, paliperidone tends to
One pharmacokinetic difference, however, between be more tolerable, with less sedation, less orthostasis,
risperidone and paliperidone is that paliperidone, and fewer motor side effects, although this is based upon
unlike risperidone, is not hepatically metabolized, but anecdotal clinical experience and not head-to-head clinical
its elimination is based upon urinary excretion and studies. Paliperidone has moderate risk for weight gain and
thus it has few pharmacokinetic drug interactions. metabolic problems. Paliperidone is approved specifically
Another pharmacokinetic difference is that the oral for schizophrenia/maintenance (ages 12 and older).The
form of paliperidone is provided in a sustained-release main advantage of paliperidone over risperidone is that
oral formulation, which risperidone is not, and this the long-acting injectable for paliperidone is easier to load,
actually changes some of the clinical characteristics of easier to dose, and has both a 1-month and a 3-month
paliperidone compared to risperidone, a fact that is not formulation, with studies in progress for a 6-month
235
TAAR1
bed nucleus stria terminalis
prefrontal cortex
dorsal raphe nucleus hypothalamus

pituitary
amygdala
hippocampus
ventral tegmental area
Figure 5-64 Localization of trace amine-associated receptor type 1 (TAAR1). A new potential mechanism of antipsychotic action
is agonism of the trace amine-associated receptor type 1 (TAAR1). TAAR1 is widely expressed throughout the brain, including in
monoamine brainstem centers (dorsal raphe nucleus, ventral tegmental area) and in monoamine projection areas.
formulation. It can be useful to monitor plasma drug levels orthostatic hypotension and sedation, especially if rapidly
to guide dosing, especially for patients receiving long-term dosed. Although iloperidone has an 18- to 33-hour
depot injections and who are treatment-resistant. half-life that theoretically supports once daily dosing, it
is generally dosed twice daily and titrated over several
Ziprasidone
days when initiated in order to avoid both orthostasis and
Ziprasidone (Figure 5-51) is a 5HT2A/D2 antagonist with sedation. Slow dosing can delay onset of antipsychotic
the major differentiating feature being that it has little or effects, so iloperidone is often used as a switch agent
no propensity for weight gain or metabolic disturbances. in non-urgent situations. It is approved in the US for
However, it is short acting, requires more than once a day schizophrenia/maintenance.
dosing, and must be taken with food. Earlier concerns
about dangerous QTc prolongation by ziprasidone now Lurasidone
appear to be exaggerated. Unlike iloperidone, zotepine, Lurasidone is a 5HT2A/D2 antagonist (Figure 5-53)
sertindole, and amisulpride, ziprasidone does not cause approved for use in schizophrenia and much more
dose-dependent QTc prolongation, and few drugs have popular for use in bipolar depression. This compound
the potential to increase ziprasidone’s plasma levels. exhibits high affinity for both 5HT7 receptors (Figure
Ziprasidone has an intramuscular dosage formulation for 5-39) and 5HT2A receptors (Figure 5-32), moderate
rapid use in urgent circumstances. Ziprasidone is approved affinity for 5HT1A (Figure 5-33) and α2 receptors (Figure
in schizophrenia/maintenance and in bipolar mania/ 5-35), yet minimal affinity for H1 histamine and M1
maintenance. cholinergic receptors (Figure 5-41), properties that may
explain some of lurasidone’s antidepressant profile, with
Iloperidone
low risk of weight gain or metabolic dysfunction. Risk of
Iloperidone (Figure 5-52) also has 5HT2A/D2 antagonist motor side effects or sedation are reduced if lurasidone
properties. Its most distinguishing clinical properties is dosed at night. Due perhaps to the synergism
include a very low level of motor side effects, low amongst the several potential antidepressant properties
level of dyslipidemia, and moderate level of weight accompanied by good tolerability, especially lack of
gain associated with its use. Its most distinguishing weight gain, it is a highly effective agent for bipolar
pharmacological property is its potent α1 antagonism depression (ages 10 and older) and one of the preferred
(Figure 5-52). As discussed earlier in this chapter, α1 agents for this use in the countries where it is approved
antagonism is generally associated with the potential for for this use such as in the US. Lurasidone is approved
236
TAAR1
agonist
TYR TYR
E E E E
TYR TYR
DOPA DA DOPA DA
TOH TOH
Gi
TAAR1 TAAR1
Gi
-arrestin -arrestin
D2 D2
receptor
dimerization
5
receptor
dimerization
D2 D2
Gi -arrestin -arrestin
Gi
TAAR1 TAAR1
GSK-3
overstimulation
and psychosis
A B
Figure 5-65 Agonism of trace amine-associated receptor type 1 (TAAR1). Trace amines are formed from amino acids when either
the tyrosine hydroxylase (TYR) step or the tryptophan hydroxylase (TOH) step is omitted during production of dopamine or serotonin,
respectively. (A) Dopamine is produced and packaged into synaptic vesicles, then released into the synapse. Dopamine binding at both
pre- and postsynaptic D2 receptors can either trigger the inhibitory G (Gi) protein signal transduction cascade or the β-arrestin 2 signal
transduction cascade. The β-arrestin 2 cascade leads to production of glycogen synthase kinase 3 (GSK-3); too much GSK-3 activation
may be associated with mania or psychosis. (B) When TAAR1 receptors are bound by an agonist, they translocate to the synaptic
membrane and couple with D2 receptors (heterodimerization). This biases the D2 receptor toward activating the Gi signal transduction
cascade instead of the β-arrestin cascade. Presynaptically, amplification of the Gi pathway leads to inhibition of the synthesis and release
of dopamine, which would be beneficial in cases of psychosis. Postsynaptically, amplification of the Gi pathway can lead to reduced
production of GSK-3.
worldwide for schizophrenia/maintenance (ages 10 and and moderate affinity for D2, D1 (Figure 5-54), and α1
higher) and because of its good tolerability it is often receptors (Figure 5-42), and low affinity for histamine
preferred for the treatment of children. H1 receptors (Figure 5-41). Unusually, lumateperone
A glutamate modulator D-cycloserine combined also has moderate affinity for the serotonin transporter
with lurasidone, called NRX101 (Cyclurad), combines (Figure 5-34). Early clinical experience suggests
antagonism of the glycine site of the NMDA receptor (see efficacy for schizophrenia without dose titration
Figures 4-21, 4-22, 4-26, 4-27) with lurasidone, for the and good tolerability in terms of little or no weight
potential treatment of acute suicidal ideation and behavior, gain or metabolic disturbances. Two key points on
as well as for bipolar depression, with early positive findings. its mechanism of action include a wide separation
between its 5HT2A antagonist and its D2 antagonist
Lumateperone
binding, perhaps explaining why it has antipsychotic
Lumateperone (Figure 5-54) is a more recently approved actions at doses that have relatively low occupancy of
5HT2A/D2 antagonist for schizophrenia. It has very D2 receptors, and maybe also why there are low D2-type
high affinity for the 5HT2A receptor (Figure 5-32) side effects (e.g., little or no drug-induced parkinsonism
237
Figure 5-66 SEP-363856’s
5H
T1
A
thinking about the binding
5H properties of SEP-363856. A
T1D
new potential mechanism of
antipsychotic action is agonism
of the trace amine-associated
receptor type 1 (TAAR1). SEP-
363856 is an agonist at TAAR1
receptors; it also has 5HT1D,
5HT1A, and 5HT7 receptor
SEP-363856 binding properties. As with all
agents discussed in this chapter,
binding properties vary greatly
with technique and from one
laboratory to another; they are
constantly being revised and
updated.
T7
5H
TAAR1
TAAR1 5HT1D
5HT1A 5HT7
Figure 5-67 Xanomeline’s
5HT1A

5HT2A M1 thinking about the binding
properties of xanomeline.
5H
Xanomeline is being studied

T1
M3
B
for its potential use in psychosis

because of its agonism at
5H central muscarinic cholinergic
T1
D M4 receptors; specifically, the M4
and M1 receptors. Xanomeline
also binds to multiple serotonin
receptor subtypes. As with all
agents discussed in this chapter,
5HT2B binding properties vary greatly
with technique and from one
xanomeline laboratory to another; they are
constantly being revised and
updated.
5HT2C
5HT1D
M4 5HT2B M3 5HT2C 5HT1B 5HT1A M1
+++ 5HT2A 5HT7 M2 5HT4 5HT1E D3
++ ++ ++ ++ ++ ++ ++
+ + + + + +
238
or akathisia). The presence of moderate affinity for Two Pips and a Rip
serotonin reuptake inhibition suggests antidepressant Aripiprazole
potential and indeed early studies in bipolar depression Aripiprazole is the original “pip” and is a D2/5HT1A partial
show promising efficacy. agonist (see Figure 5-56). Because of its D2 partial agonist
Although not yet clarified completely, preclinical actions, aripiprazole has relatively low motor side effects,
evidence suggests a novel mechanism of action of mostly akathisia, and actually reduces prolactin rather
lumateperone at D2 receptors. Recall that PET findings than elevating it. It has only moderate affinity for 5HT2A
show enhanced presynaptic dopamine synthesis and receptors (Figure 5-32), but higher affinity for 5HT1A
release (Figures 4-15 and 4-16; also compare Figure receptors (Figure 5-33). Aripiprazole is effective in treating
5-55A and B). Dopamine 2 blockers generally do not schizophrenia/maintenance (age 13 and older) and also
discriminate between presynaptic D2 receptors and agitation (intramuscular) and bipolar mania/maintenance
postsynaptic D2 receptors (Figure 5-55C). When these (ages 10 and older), and is also approved for use in various
D2 blockers are administered, they block presynaptic D2 other child and adolescent groups, including autism-
receptors, causing disinhibition of presynaptic dopamine related irritability (ages 5 to 17) and Tourette syndrome
release, making things worse! Although that might (ages 6 to 18). It is approved for adjunctive treatment 5
be the last thing you want in treating schizophrenia to SSRIs/SNRIs for major depressive disorder, and this
psychosis, the solution is to so fully block the D2 is by far its major use in clinical practice in the US. It is
receptors postsynaptically that this extra dopamine not approved for bipolar depression but commonly used
release does not matter (Figure 5-55C). However, in off-label for that. How aripiprazole works in depression
the case of lumateperone, preclinical evidence suggests compared to how it works in schizophrenia is of course
that it may have presynaptic agonist actions and unknown, but its potent 5HT1A partial agonist (Figure
postsynaptic antagonist actions, a unique combination 5-33) and 5HT2C and 5HT7 antagonist properties (Figures
of mechanisms. How this may occur as an action 5-37 and 5-39) are theoretical explanations for potential
potentially differentiating it from other D2 blocking antidepressant actions, as these would be active at the
drugs for psychosis is suggested by preclinical data low doses generally used to treat depression. Aripiprazole
showing potentially unique actions to reduce dopamine lacks the pharmacological properties normally associated
synthesis by either presynaptic tyrosine hydroxylase and with sedation, namely, muscarinic cholinergic and H1
other presynaptic protein phosphorylation or changes histamine antagonist properties (Figure 5-41), and thus is
in glutamate-mediated ionic currents (Figure 5-55D). not generally sedating. A major differentiating feature of
Whatever the mechanism, if presynaptic D2 agonism aripiprazole is that it has, like ziprasidone and lurasidone,
is caused by lumateperone rather than presynaptic little or no propensity for weight gain, although weight
antagonism characteristic of the other drugs in this class, gain can be a problem for some, including some children
lumateperone would theoretically turn off dopamine and adolescents.
synthesis presynaptically to reduce the oversupply of An intramuscular dosage formulation of aripiprazole
dopamine present in presynaptic dopamine synapses for short-term use is available as an orally disintegrating
in psychosis (Figure 5-55D). That would mean less tablet and a liquid formulation. One long-acting 4-week
postsynaptic D2 antagonism would be necessary to have injectable and another 4- to 6- to 8-week long-acting
an antipsychotic effect because dopamine release is injectable, the latter with a loading injection on the first
already diminished. If lumateperone can be proven to day not requiring continuing oral loading, are available.
have such a mechanism of presynaptic partial agonism These formulations are commonly used options for
of D2 receptors, combined with its well-established assuring compliance, especially in early-onset psychosis
highly potent 5HT2A antagonism, this could account where aripiprazole’s favorable tolerability profile may be
for why lumateperone has antipsychotic efficacy in particularly well received.
schizophrenia with low amounts of postsynaptic D2
antagonism compared to most other drugs in this class Brexpiprazole
(and low amounts of motor and metabolic side effects). The second “pip” is brexpiprazole (Figure 5-57). Just
Further investigations are needed to clarify this possible as its name suggests, brexpiprazole is chemically and
explanation. Lumateperone is also in clinical trials for pharmacologically related to aripiprazole. However, it
bipolar depression. does differ pharmacologically from aripiprazole in that
239
it has more potent 5HT2A antagonism (Figure 5-32), potent D3 partial agonist actions that are perhaps
5HT1A partial agonism (Figure 5-33), and α1 antagonism the most distinguishing and novel pharmacological
(Figure 5-42) relative to its D2 partial agonism (Figure characteristics. The role of D3 receptors is just now
5-57) than aripiprazole (Figure 5-56), which should being clarified in humans since preclinical studies
theoretically reduce its propensity to cause motor side suggest therapeutic potential of D3 partial agonism
effects and akathisia. There is some indication that for cognition, mood, emotions, and reward/substance
there may be reduced akathisia with brexpiprazole abuse, as well as negative symptoms. In fact,
compared to aripiprazole, but this has not been proven cariprazine has been shown to be superior to D2/5HT2A
in head-to-head trials. Like aripiprazole, brexpiprazole is antagonist treatment for the improvement of negative
approved for the treatment of schizophrenia, but unlike symptoms in schizophrenia.
aripiprazole, is not indicated for the treatment of acute The mechanism of action of D3 partial agonism will be
bipolar mania. illustrated and explained in further detail in Chapter 7 on
Brexpiprazole (Figure 5-57) has 5HT1A partial treatments for mood disorders. In brief, D3 antagonist/
agonist (Figure 5-33) and relatively higher potency partial agonist action may block key postsynaptic D3
for α1 (Figure 5-42) and α2 (Figure 5-35) binding than receptors in limbic areas to reduce dopamine overactivity
aripiprazole. These properties could theoretically in emotional striatum and key somatodendritic
contribute to antidepressant actions (mechanisms further presynaptic D3 receptors in the ventral tegmental area/
explained and illustrated in Chapter 7 on treatments for mesostriatal/integrative hub to increase dopamine release
mood disorders). Alpha-1 actions in particular could in the prefrontal cortex and improve negative, affective,
theoretically help explain the efficacy brexpiprazole has and cognitive symptoms. For this reason, clinical
demonstrated in some of its potential novel indications. trials and clinical experience suggest robust efficacy of
Specifically, brexpiprazole is in late-stage clinical cariprazine across the mood-disorder spectrum for all
development with positive studies for the treatment of mixtures of mania and depression, as will be illustrated
agitation in dementia (discussed further in Chapter 12 on and described in Chapter 7.
dementia). There are also promising preliminary data for
Selective 5HT2A Antagonist
brexpiprazole when combined with the SSRI sertraline
for the treatment of PTSD. Pimavanserin
Pimavanserin (Figure 5-59) is the only known drug
Cariprazine
with proven antipsychotic efficacy that does not have D2
Cariprazine (Figure 5-58) is the “rip” of this group antagonist/partial agonist actions. This agent has potent
and is another D2/5HT1A partial agonist approved 5HT2A antagonist with lesser 5HT2C antagonist actions,
for schizophrenia and also for acute bipolar mania. sometimes called inverse agonism, as explained earlier in
Cariprazine with its potent 5HT1A partial agonist this chapter and as illustrated in Figure 5-15. The role if
actions (Figure 5-33) despite lesser 5HT2A antagonism any of 5HT2C antagonism in the treatment of psychosis is
(Figure 5-32) exhibits low incidence of drug-induced not clear but 5HT2C antagonist actions would theoretically
parkinsonism, but some akathisia, which can be much improve dopamine release in both depression and
reduced by slow-dose titration. Cariprazine has two long- in the negative symptoms of schizophrenia. Indeed,
to very long-lasting active metabolites with the novel pimavanserin is in testing as an augmenting agent to
and interesting potential for development as a weekly SSRIs/SNRIs, with some positive preliminary results in
or biweekly or even monthly “oral depot,” which takes major depressive disorder, and as an augmenting agent
longer to reach steady state but has less reduction in to D2/5HT2A/5HT1A agents in negative symptoms of
plasma drug levels as a dose is skipped. schizophrenia, also with positive results from early trials.
Cariprazine has proven to be a highly effective It is approved for the treatment of psychosis in Parkinson’s
and well-tolerated agent for the treatment of bipolar disease and in late-stage testing for psychosis in dementia.
depression in lower doses. Like lurasidone, which
is also approved for bipolar depression, cariprazine The Others
has a very low propensity for weight gain or Sertindole
metabolic disturbance. Like other drugs in this class, Sertindole (Figure 5-60) is a 5HT2A/D2 receptor
cariprazine has both 5HT1A and α1 and α2 actions, antagonist originally approved in some European
suggesting antidepressant efficacy, but it is the very countries, then withdrawn for further testing of its
240
cardiac safety and QTc-prolonging potential, and then amines in humans and six human trace amine-associated
reintroduced into certain countries as a second-line receptors, but the most important receptor is TAAR1
agent. It may be useful for some patients in whom other (Table 5-3). Trace amines are formed from amino acids
antipsychotics have failed, and who can have close when the tyrosine hydroxylase (see Figure 4-2) step
monitoring of their cardiac status and drug interactions. is omitted or the tryptophan hydroxylase (see Figure
4-36) step is omitted. Trace amines have long been a
Perospirone
mystery as they are only present in trace amounts, are
Perospirone (Figure 5-61) is another 5HT2A and D2 not stored in synaptic vesicles, and are not released
antagonist available in Asia to treat schizophrenia. upon nerve firing. The fact that TAAR1 receptors are
5HT1A partial agonist actions may contribute to its localized in monoamine brainstem centers and in
efficacy and/or tolerability. Its ability to cause weight monoamine projection areas (Figure 5-64) has long
gain, dyslipidemia, insulin resistance, and diabetes is made psychopharmacologists think that trace amines
not well investigated. It is generally administered three might be involved in regulating monoamine action
times a day, with more experience in the treatment of even though trace amines are not neurotransmitters in
schizophrenia than in the treatment of mania. their own right. Instead, trace amines have been called
5
“the rheostat of dopaminergic, glutamatergic, and
Blonanserin
serotonergic neurotransmission,” maintaining central
Blonanserin (Figure 5-62) is also a 5HT2A/D2 antagonist, neurotransmission within defined physiological limits.
available in Asia to treat schizophrenia, and is The current hypothesized mechanism of antipsychotic
administered twice a day. Blonanserin has the unique action for TAAR1 agonists is that they act tonically both
property of higher affinity for the D3 receptor than presynaptically and postsynaptically to prevent the
dopamine has for the D3 receptor (like cariprazine), dopaminergic hyperactivity of psychosis and mania (Figures
suggesting possible utility for the negative symptoms of 4-15 and 4-16). Thus, TAAR1 agonists are potentially a
schizophrenia and for bipolar depression, but it is not yet novel way to prevent dopamine overactivity at D2 receptors.
well studied in these indications. How do they do this? TAAR1 receptors theoretically
prevent dopamine overactivity after occupancy by
FUTURE TREATMENTS FOR an agonist through translocation to the synaptic
SCHIZOPHRENIA membrane, where they couple with D2 receptors (called
heterodimerization), which makes the second-messenger
Roluperidone (MIN-101) system decide to go with the inhibitory G (Gi) protein
Roluperidone (Figure 5-63) is a 5HT2A antagonist with
additional σ2 antagonist actions, which is in study for
Table 5-3 Trace amines and their receptors
schizophrenia. Early studies suggest possibly efficacy for
negative symptoms, and trials are ongoing. Five principal trace amines in humans
D3 Antagonists β-Phenylethylamine (PEA)
In addition to cariprazine and blonanserin (both of p-Tyramine

which are unique in their highly potent D3 antagonist/ Tryptamine
partial agonist properties), other D3 antagonists/partial p-Octopamine
agonists are in clinical trials. One is F17464, which has
p-Synephrine
higher selectivity for D3 than for D2 or 5HT1A receptors,
and which has shown efficacy in schizophrenia in early Six human trace amine-associated receptors (TAARs)
studies. TAAR1 (main TAAR in humans)
Trace Amine Receptor Agonists and SEP-363856 TAAR2
An exciting new potential mechanism of antipsychotic TAAR5

action is trace amine agonism specifically acting at the TAAR6
trace amine-associated receptor type 1 (TAAR1). What TAAR8
is a trace amine and why would targeting its receptors
TAAR9
have antipsychotic action? There are five principal trace
241
signal transduction cascade rather than the β-arrestin 2 alterations may be key to the pathophysiology of
pathway (Figure 5-65A, B). TAAR1 receptors can be said schizophrenia. M4 receptor agonism may reduce
to “bias” D2 receptors away from β-arrestin 2 and towards psychotic symptoms whereas M1 receptor agonism may
Gi-protein-regulated second messengering (Figure be most relevant to improving the cognitive deficits of
5-65B). schizophrenia. Xanomeline (Figure 5-67), as an M4/M1
Why does this matter? When heterodimerization central agonist, decreases dopamine cell firing in the
with TAAR1 happens to presynaptic D2 receptors, ventral tegmental area. This would theoretically reduce
the downstream consequences of the Gi pathway are positive psychotic symptoms. Xanomeline also increases
amplified and those include inhibiting the synthesis extracellular levels of dopamine in the prefrontal cortex,
and release of dopamine (presynaptic area of Figure which theoretically would improve cognitive, negative,
5-65B). That would be a good thing if dopamine is in and affective symptoms. Xanomeline combined with
excess presynaptically, as it seems to be in psychosis and tropsium, an anticholinergic that does not penetrate into
in mania. When D2 receptor signaling postsynaptically the brain and that blocks M2 and M3 activated side effects
is also shunted away from the β-arrestin 2 pathway in the periphery, has shown promising efficacy and
to the Gi pathway by “biased” and heterodimerized tolerability for the psychotic symptoms of schizophrenia
postsynaptic D2 receptors, this theoretically mitigates with improved side effects and is progressing as a
the consequences of excessive signals through β-arrestin potential breakthrough into advanced clinical trials.
to excessive GSK-3 (glycogen synthase kinase 3) The known binding profile of xanomeline at muscarinic
activation that results from postsynaptic D2 receptor cholinergic receptors as well as serotonin receptors is
overstimulation (postsynaptic area of Figure 5-65B). shown in Figure 5-67.
The bottom line of all this is that TAAR1 agonists may
A Few Other Ideas
enhance presynaptic D2 autoreceptors (thus turning off
dopamine synthesis and release) while simultaneously Although several agents targeting glutamate
reducing some of the unwanted downstream functions of neurotransmission have been studied in
overly active postsynaptic D2 receptors (thus mitigating schizophrenia, most have not had consistently positive
the effects of excessive dopamine release in psychosis or robust efficacy findings. A novel idea still being
and mania). Furthermore, TAAR1 agonism does both pursued is to inhibit the enzyme DAO (D-amino acid
pre- and postsynaptic actions without actually directly oxidase) as a way to boost glutamate function (see
pharmacologically blocking the D2 receptor! (Figure Figure 4-22).
5-65B). Another novel approach to blocking the effects
SEP-363856 (Figure 5-66) is an example of a TAAR1 of hyperactive dopamine is to block the action of the
agonist with weak affinity for the TAAR1 receptor as well enzyme phosphodiesterase type 9/10; several potential
as weaker affinities for the 5HT1D and 5HT7 receptors as drugs are in clinical development. This mechanism
antagonist and for the 5HT1A receptor as agonist. This alters the second-messenger signal transduction cascade
drug surprisingly showed preclinical behavioral evidence of dopamine at D1 and D2 receptors and may have
of efficacy serendipitously for psychosis, and only then downstream effects similar to blocking D2 receptors, and
did its pharmacological and molecular mechanism of do it more selectively in the dopamine neurons thought
action on TAAR1 receptors get discovered. Already, an to be hyperactive in schizophrenia.
early study in patients with schizophrenia has confirmed
antipsychotic action with few side effects, and the drug SUMMARY
has been given breakthrough status by regulators. Further
trials are ongoing. This chapter reviews drugs used to treat psychosis, but
has avoided the term “antipsychotics,” since these same
Cholinergic Agonists agents are used more frequently for other indications
Activation of central muscarinic cholinergic receptors, such as unipolar and bipolar depression. Instead, the
either directly or by allosteric modulation, is under hypothetical mechanism of “antipsychotic action” is
investigation as a novel antipsychotic mechanism. explored in detail. Specifically, this chapter reviews the
Preclinical and postmortem studies in patients with pharmacology of drugs that treat psychosis, including
schizophrenia suggest that central cholinergic receptor those with predominantly D2 antagonist properties, those
242
with 5HT2A antagonist/D2 antagonist properties, those actions of these agents, especially to their antidepressant
with D2/5HT1A partial agonist properties, and those with actions, are presented and discussed. Still other receptor
5HT2A selective antagonist properties. These agents are actions hypothetically linked to additional side effects
compared and contrasted across these various dopamine are also presented. The pharmacological and clinical
and serotonin receptor subtypes and their receptor properties of two dozen specific drugs either marketed
actions linked to hypothetical therapeutic actions as or in late-stage clinical trials are discussed in detail,
well as side effects. Multiple additional receptor binding including exciting new potential mechanisms of action
properties at other neurotransmitter receptor sites that at trace amine-associated receptors and at muscarinic
are hypothesized to be linked to additional clinical cholinergic receptors.
243
Mood Disorders and the
6
Neurotransmitter Networks
Norepinephrine and
γ-Aminobutyric Acid (GABA)
Description of Mood Disorders 244 The Monoamine Hypothesis of Depression 264
Mood Spectrum 244 The Monoamine Receptor Hypothesis and
Distinguishing Unipolar Depression from Bipolar Neurotrophic Factors 264
Depression 249 Beyond Monoamines: The Neuroplasticity and
Mixed Features: Are Mood Disorders Neuroprogression Hypothesis of Depression 266
Progressive? 251 Symptoms and Circuits in Mood Disorders 277
Neurobiology of Mood Disorders 252 Symptom-Based Treatment Selections 279
Neurotransmitters 252 Summary 282
This chapter discusses disorders characterized by action and how to select specific drug treatments in
abnormalities of mood: namely, depression, mania, or Chapter 7.
mixtures of both. Included here are descriptions of a wide
variety of mood disorders that occur over a broad clinical DESCRIPTION OF MOOD
spectrum. Clinical descriptions and criteria for how to DISORDERS
diagnose disorders of mood will only be mentioned in
passing. The reader should consult standard reference Mood Spectrum
sources for this material. Also included in this chapter is Disorders of mood are often called affective disorders,
an analysis of how monoamine neurotransmitter systems since affect is the external display of mood, an emotion
have long been hypothetically linked to the biological that is, however, felt internally and called mood. Mood
basis of mood disorders. We will also cover more recent disorders are not just about mood. The diagnosis of a
advances in neurobiology that link mood disorders to major depressive episode requires the presence of at
glutamate, GABA (γ-aminobutyric acid), neurotrophic least five symptoms, only one of which is depressed
factors, neuroinflammation, and stress. mood (Figure 6-1). Similarly, a manic episode requires
Mood disorders have many symptoms and more than just an elevated, expansive, or irritable mood;
approaching them clinically involves first constructing there must be at least three or four additional symptoms
a diagnosis from a given patient’s symptom profile, (Figure 6-2).
but then deconstructing that patient’s mood disorder Classically, the mood symptoms of mania and
into its component symptoms so each symptom can be depression are “poles” apart (Figures 6-3 through
individually targeted therapeutically. We will discuss 6-6). This concept has generated the terms “unipolar”
how to combine this clinical approach to diagnosis with a depression (i.e., patients who experience just the down
neurobiological approach to treatment by first matching or depressed pole) (Figures 6-3 and 6-4) and “bipolar”
every symptom to its hypothetically malfunctioning brain (i.e., patients who at different times experience the up
circuit, regulated by one or more neurotransmitters. The pole, or mania (Figures 6-3 and 6-5) or hypomania
strategy is next to select drugs that target the specific (Figures 6-3 and 6-6) and the down pole, i.e., depressed
neurotransmitters in the specific symptomatic brain pole (Figures 6-3, 6-5, and 6-6). Bipolar I patients
circuits in a given patient. The goal is to improve the have full-blown manic episodes usually followed by
efficiency of information processing in those brain depressive episodes (Figure 6-5). Bipolar II disorder is
circuits and thereby reduce symptoms. Covering the characterized by at least one hypomanic episode and
neurobiological basis of mood disorders in this chapter one major depressive episode (Figure 6-6). Depression
sets the stage for understanding the mechanisms of and mania may even occur simultaneously, which is
244
Chapter 6: Mood Disorders
Symptom Dimensions of a Major Depressive Episode
apathy/
depressed mood
loss of interest
one of these required
sleep disturbances psychomotor fatigue

250
250
weight/
appetite or
changes
four more
of these
guilt required
suicidal
ideation
executive dysfunction 6
worthlessness
Figure 6-1 DSM-5 symptoms of a major depressive episode. According to the Diagnostic and Statistical Manual of Mental Disorders,
fifth edition (DSM-5), a major depressive episode consists of either depressed mood or loss of interest and at least four of the following:
weight/appetite changes, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of guilt or worthlessness,
executive dysfunction, and suicidal ideation.
Symptom Dimensions of a Manic Episode
symptoms necessary
for diagnosis
elevated/expansive irritable mood
mood
increased goal-directed decreased need for

activity or sleep
agitation risk
inflated
self- taking plus
esteem/ three or
grandiosity more of
these
and then I went there and then the next (four if
place and so on and then over to there
and then the market and then a dog was
barking and then I saw a kitty and then
mood is
the dog started chasing the kitty and
then I went into the market and I only
bought some cheese and some
salad and dressing and irritable)
distractible/
concentration
more talkative flight of ideas/
pressured speech racing thoughts
Figure 6-2 DSM-5 symptoms of a manic episode. According to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition
(DSM-5), a manic episode consists of either elevated/expansive mood or irritable mood. In addition, at least three of the following must
be present (four if mood is irritable): inflated self-esteem/grandiosity, increased goal-directed activity or agitation, risk taking, decreased
need for sleep, distractibility, pressured speech, and racing thoughts.
245
mania
hypomania
HYPOMANIA
mixed features
of mania
MIXED FEATURES OF MANIA
MIXED FEATURES OF DEPRESSION

mixed features
of depression
depression
Figure 6-3 Mood episodes. Mood symptoms exist along a spectrum, with the polar ends being pure mania or hypomania (”up” pole)
and pure depression (”down” pole). Patients can also experience mood episodes that include symptoms of both poles; such episodes
can be described as mania/hypomania with mixed features of depression or depression with mixed features of mania. A patient may
have any combination of these episodes over the course of illness; subsyndromal manic or depressive episodes also occur during the
course of illness, in which case there are not enough symptoms or the symptoms are not severe enough to meet the diagnostic criteria
for one of these episodes. Thus the presentation of mood disorders can vary widely.
Major Depressive Disorder

Single Episode or Recurrent Unipolar
HYPOMANIA
single episode recurrent
Figure 6-4 Major depressive disorder. Major depressive disorder is defined by the occurrence of at least a single major depressive
episode, although most patients will experience recurrent episodes.
246
Bipolar I Disorder
Manic Episode +/– Major Depressive Episode
HYPOMANIA
manic manic with
mixed
depressive
features
(after
MIXED FEATURES OF DEPRESSION manic
episode)
Figure 6-5 Bipolar I disorder. Bipolar I disorder is defined as the occurrence of at least one manic episode. Patients with bipolar I
disorder typically experience major depressive episodes as well, although this is not necessary for the bipolar I diagnosis. It is also
common for patients to experience manic episodes with mixed features of depression.
Bipolar II Disorder
Major Depressive and Hypomanic Episodes
HYPOMANIA
Figure 6-6 Bipolar II disorder. Bipolar II disorder is defined as an illness course consisting of one or more major depressive episodes
and at least one hypomanic episode.
247
called a “mixed” mood state or, in DSM-5, “mixed and towards the concept that they are opposite ends
features” (Figure 6-7; Table 6-1). Introduction of the of a spectrum, with all degrees of mixtures in between
mixed-features modifier has moved the field away from (Figure 6-7). Many real patients are neither purely
considering depression and mania as distinct categories depressed nor purely manic, but some mixture of both,
Table 6-1 Mixed features (DSM-5) of manic, hypomanic, and major depressive episodes
Manic or hypomanic episode, with mixed features

Full criteria for manic or hypomanic episode
At least three of the following symptoms of depression:
Depressed mood
Loss of interest or pleasure
Psychomotor retardation
Fatigue or loss of energy
Feelings of worthlessness or excessive or inappropriate guilt
Recurrent thoughts of death or suicidal ideation/actions
Depressive episode, with mixed features
Full criteria for a major depressive episode
At least three of the following manic/hypomanic symptoms:
Elevated, expansive mood (e.g., feeling high, excited, or hyper)
Inflated self-esteem or grandiosity
More talkative than usual or feeling pressured to keep talking
Flight of ideas or subjective experience that thoughts are racing
Increase in energy or goal-directed activity
Increased or excessive involvement in activities that have a high potential for painful consequences
Decreased need for sleep
(*Not included: psychomotor agitation)
(*Not included: irritability)
(*Not included: distractibility)
Mood Disorder Spectrums

depression mania
with mixed features with mixed features
Figure 6-7 Mood-disorder spectrums. Depressive symptoms and manic symptoms can occur as part of the
same episode; this is termed “mixed features” and can be defined as depression with mixed features, in which
depressive symptoms dominate, or as mania with mixed features, in which manic symptoms dominate. Thus
mood disorders are best understood as a spectrum, rather than as discrete categorial diagnoses.
248
with the specific mix of symptoms changing along Distinguishing Unipolar Depression from Bipolar
the mood spectrum over the course of illness. This Depression
is similar to the evolution in the conceptualization Other than a history of a prior manic/hypomanic episode,
of schizophrenia versus bipolar disorder, where the patients with unipolar depressive episodes (Figure 6-4)
old dichotomous model (Figure 6-8) has been largely are diagnosed using the same symptom criteria (Figure
replaced with a continuous disease model spectrum, 6-1) as patients with bipolar depressive episodes (Figures
ranging from pure psychotic disorder to pure mood 6-5 and 6-6). Despite similar symptoms, patients with
disorder (Figure 6-9).
Schizophrenia and Bipolar Disorder Figure 6-8 Schizophrenia and bipolar

disorder: dichotomous disease
Dichotomous Disease Model model. Schizophrenia and bipolar
disorder have been conceptualized
both as dichotomous disorders
and as belonging to a continuum.
In the dichotomous disease model,
Schizoaffective Bipolar schizophrenia consists of chronic,
Schizophrenia Disorder Disorder unremitting psychosis, with poor
outcomes expected. Bipolar
• psychosis • psychosis • mania disorder consists of cyclical manic
and other mood episodes and has
better expected outcomes than
• chronic, unremitting • mood disorder • mood disorder schizophrenia. A third distinct disorder
is schizoaffective disorder, characterized
6
by both psychosis and a mood disorder.
• poor outcome • cyclical
• “even a trace of • good outcome

schizophrenia
is schizophrenia” • “even a trace of a
mood disturbance
is a mood disorder”
Schizophrenia and Bipolar Disorder

Continuum Disease Model
schizoaffective disorder
n
ssio
av
epre
oid
sch an
t
tic d
izo
par id
ano
cho
sch id
izo
psy
ion
ultra typ
al ress
high dep ion
subs risk a r tum e p ress
psyc tp / d ion
yndro
mal hosis pos d mania depress
share prod mix e ton ic
d psy rom c a ta c lia
h o
delusio
chotic
disord
e melan
nal diso
rder
er ct iv e disorder
l affe
schizoph
reniform seasona pre ssion
disorder atypic al de
brief psychotic diso depression
rder
schizophrenia mood disorder
Figure 6-9 Schizophrenia and bipolar disorder: continuum disease model. Schizophrenia and bipolar disorder have been
conceptualized both as dichotomous disorders and as belonging to a continuum. In the continuum disease model, schizophrenia
and mood disorders fall along a continuum in which psychosis, delusions, and paranoid avoidant behavior are on one extreme and
depression and other mood symptoms are on the other extreme. Falling in the middle are psychotic depression and schizoaffective
disorder.
249
unipolar versus bipolar depression have different long- may lead to worse quality of life due to giving the wrong
term outcomes and should generally receive different treatment (for unipolar depression rather than for
treatments. Unfortunately, missed diagnosis or delayed bipolar depression) and this may be ineffective or even
diagnosis of bipolar depression is all too common. dangerous. That is, delay of appropriate treatment in
Over a third of patients with unipolar depression are bipolar depression can increase the risk of mood cycling,
eventually re-diagnosed as having bipolar disorder and relapse, and suicide, and even decrease the chances of
maybe as many as 60% of depressed patients with bipolar responding to appropriate bipolar treatments once they
II disorder are initially diagnosed as having unipolar are given later.
depression. In some cases, this is because the patient had Thus, it is important to tell unipolar from bipolar
depressive episodes before they had manic or hypomanic depression. Is there any way to do this when the patient
episodes, and a bipolar diagnosis could not be made. In is in the depressed state other than to find a prior history
other cases, the diagnosis of a past manic or hypomanic of mania/hypomania? The short answer is no. The long
episode is missed because patients with bipolar disorder answer is that there are certain clinical characteristics
often present in the depressed phase and past hypomania that favor the likelihood of a bipolar depressive episode
is often pleasant for patients and may not be mentioned. instead of a unipolar depressive episode, and these factors
Why do you want to make an early accurate diagnosis can be clues to the diagnosis of a bipolar depressive
of bipolar disorder? Although unipolar versus bipolar episode when the past history of a manic/hypomanic
depression cannot be readily distinguished on the basis episode is unclear (Figure 6-10). Some additional tips
of a patient’s current symptomatology, there are some about how to determine whether a depressed patient
hints that can raise suspicion of a bipolar depressive is unipolar or bipolar might be to ask two questions
episode rather than a unipolar depressive episode (Figure (Table 6-2):
6-10). Missing the diagnosis of bipolar depression early “Who’s your daddy?” and “Where’s your mama?”
Identifying Bipolar Depression
BIPOLAR DEPRESSION
More:
Family history of bipolar disorder
Family history of substance abuse
Comorbid substance abuse
HYPOMANIA Suicide attempts
Early age of onset <25 years
Irritability
Psychotic symptoms
Mood reactivity
Restlessness
Psychomotor agitation (BPII)
Psychomotor retardation (BPI)
Shorter depressive episodes
More previous depressive episodes
Guilt
Melancholia
Figure 6-10 Identifying bipolar depression. Although all symptoms of a major depressive episode can occur in either
unipolar or bipolar depression, some factors can provide hints if not diagnostic certainty that the patient has a bipolar
spectrum disorder. These can include a family history of bipolar disorder, family history of substance abuse, comorbid
substance abuse, history of suicide attempts, earlier age of onset, and shorter but more frequent depressive episodes.
Some symptoms may also be more common as part of a bipolar illness, including irritability, psychotic symptoms, mood
reactivity, restlessness, psychomotor agitation or retardation, guilt, and melancholia.
250
Table 6-2 Is it unipolar or bipolar depression? Questions to ask For one thing, there is evidence that unipolar depression
Who’s your daddy? can progress to mixed features, mixed features progress
to bipolar disorder, and bipolar disorder progress to
What is your family history of:
treatment resistance (Figure 6-11). The presence of even
• mood disorder? subthreshold manic symptoms is strongly associated with
• psychiatric hospitalizations? conversion to bipolar disorder, with each manic symptom
• suicide? increasing risk by 30%. We don’t know if we can halt this
march towards a bad outcome, but the best chance may
• anyone who took lithium, mood stabilizers, drugs
be early recognition and effective treatment that reduces
for psychosis or depression?
or eliminates all symptoms, whether manic or depressed,
• anyone who received ECT? and to do this as early in the course of illness as possible.
These can be indications of a unipolar or bipolar How many depressed patients have mixed features?
spectrum disorder in relatives. The estimates are about a quarter of all patients with
Where’s your mama? unipolar depression and a third of all patients with
I need to get additional history about you from
bipolar I or II depression have subsyndromal symptoms
someone close to you, such as your mother or your of mania. Estimates of mixed features in unipolar
spouse. depression in children and adolescents are even higher.
Compared to those with “pure” depression, those with
Patients may especially lack insight about their manic
symptoms and under-report them. depression plus some manic symptoms may have a more
complex illness and less favorable course and outcome.
6
For example, mixed features may compound the already
“Who’s your daddy?” means more precisely, “what is high risk of suicide in depressed patients. Non-euphoric
your family history?” since a first-degree relative with a manic symptoms such as psychomotor agitation,
bipolar spectrum disorder can give a strong hint that the impulsivity, irritability, and racing/crowded thoughts
patient also has a bipolar spectrum disorder rather than combined with depressive symptoms are a recipe for
unipolar depression. Although the majority of patients suicidality. Suicide rates are twice as high in bipolar
with bipolar depression do not have a family history of than in unipolar depression and up to 20 times higher
bipolar disorder, when it is present, it is arguably the most in bipolar disorder compared to the general population.
robust and reliable risk factor for bipolar depression. Sadly, up to a third of bipolar patients attempt suicide at
Individuals with a first-degree relative with bipolar least once in their life, and 10–20% of them succeed.
disorder are at an 8–10-fold greater risk of developing What about those subsyndromal manic symptoms
bipolar disorder compared to the general population. and suicide? In the presence of mixed features there is a
The second question, “Where’s your mama?,” really fourfold increased risk of suicidality in both unipolar and
means “I need to get additional history from someone bipolar depression. Studies show specifically a worrisome
else close to you,” since patients tend to under-report association of mixed episodes with suicide attempts, so it
their manic symptoms. The insight and observations of is not only important to identify who has mixed features,
an outside informant such as a mother or spouse who but also to treat appropriately. Treatment for mixed
can give past history might indeed prove to be quite features is discussed in Chapter 7 and surprisingly is NOT
different from the one the patient is reporting, and thus the same as the treatment for unipolar depression without
help establish a bipolar spectrum diagnosis that patients mixed features. That is, neither unipolar nor bipolar
themselves deny or do not perceive. depression with mixed features are treated first-line with
standard monoamine reuptake inhibiting drugs used
Mixed Features: Are Mood Disorders Progressive? widely in unipolar depression and discussed in Chapter 7,
In addition to the importance of distinguishing unipolar but rather with serotonin/dopamine antagonists/partial
depression from bipolar depression, it is also very agonists used widely for the treatment of psychosis and
important to look for mixed features in your depressed discussed in Chapter 5. Thus, it cannot be emphasized
patients, whether those patients have a unipolar or too strongly that major depressive episodes need to
bipolar illness. This is because there are big differences be correctly diagnosed as part of a unipolar or bipolar
in the outcome for patients if mixed features are present. illness and as having or lacking mixed features, and that
251
Is Major Depressive Disorder Progressive?
HYPOMANIA
recurrent unipolar mania or treatment

depression mixed features hypomania resistance
Figure 6-11 Is major depressive disorder progressive? There is evidence that mood disorders may be progressive. Unipolar
depression with recurrent episodes may progress to depression with mixed features, which may ultimately progress to a bipolar
spectrum condition and finally treatment resistance.
the correct treatment be given (details of treatment of mood disorders are hypothesized to involve dysfunction of
mood disorders are given in Chapter 7). The hope is that various combinations of these neurotransmitters and ion
recognition and appropriate treatment of both unipolar channels, and all known treatments for mood disorders
and bipolar depression – whether that depressive episode act upon one or more of them. We have extensively
has mixed features or not – will cause all symptoms to discussed the dopamine system (Chapter 4; Figures 4-2
remit for long periods of time and that this might prevent through 4-13), the serotonin system (Chapter 4; Figures
progression to more difficult states (Figure 6-11). This is 4-36 through 4-51), the glutamate system (Chapter 4;
not proven, but is a major hypothesis in the field at the Figures 4-20 through 4-28), and ion channels (Chapter
present time. 3; Figures 3-19 through 3-26). Here, we add two other
neurotransmitter systems: norepinephrine and GABA.
NEUROBIOLOGY OF MOOD Before discussing how these various neurotransmitters
DISORDERS and ion channels are thought to be involved in mood
disorders, we will begin with a general discussion of
Neurotransmitters
norepinephrine, GABA, and their receptors and pathways.
Dysfunctional neurotransmission in various brain
circuits is implicated in both the pathophysiology and Norepinephrine
treatment of mood disorders. Classically, this has included The noradrenergic neuron utilizes norepinephrine
the monoamine neurotransmitters norepinephrine, (noradrenaline) as its neurotransmitter.
dopamine, and serotonin, and more recently the Norepinephrine is synthesized, or produced, from the
neurotransmitters glutamate and GABA (γ-aminobutyric precursor amino acid tyrosine, which is transported
acid) and their associated ion channels. Symptoms of into the nervous system from the blood by means of
252
an active transport pump (Figure 6-12). Once inside synthetic enzyme, dopamine β-hydroxylase (DBH),
the neuron, tyrosine is acted upon by three enzymes converts DA into NE. Norepinephrine is then stored
in sequence: first, tyrosine hydroxylase (TOH), the in synaptic packages called vesicles until released by a
rate-limiting and most important enzyme in the nerve impulse (Figure 6-12).
regulation of norepinephrine (NE) synthesis. Tyrosine Norepinephrine action is terminated by two principal
hydroxylase converts the amino acid tyrosine into destructive or catabolic enzymes that turn NE into
DOPA. The second enzyme then acts, namely, DOPA inactive metabolites. The first is monoamine oxidase
decarboxylase (DDC), which converts DOPA into (MAO) A or B, which is located in mitochondria in the
dopamine (DA). Dopamine itself is a neurotransmitter presynaptic neuron and elsewhere (Figure 6-13). The
in DA neurons as discussed in Chapter 4 and illustrated second is catechol-O-methyltransferase (COMT), which
in Figure 4-2. However, for NE neurons, DA is just is thought to be located largely outside of the presynaptic
a precursor of NE. In fact, the third and final NE nerve terminal (Figure 6-13). The action of NE can be
Norepinephrine Is Produced
tyrosine
transporter 6
DDC
E
E
TYR
DOPA
E
TOH
VMAT2 DBH
NE (norepinephrine)
Figure 6-12 Norepinephrine is produced. Tyrosine (TYR), a precursor to norepinephrine (NE), is taken up into NE nerve terminals via a
tyrosine transporter and converted into DOPA by the enzyme tyrosine hydroxylase (TOH). DOPA is then converted into dopamine (DA)
by the enzyme DOPA decarboxylase (DDC). Finally, DA is converted into NE by dopamine β-hydroxylase (DBH). After synthesis, NE is
packaged into synaptic vesicles via the vesicular monoamine transporter 2 (VMAT2) and stored there until its release into the synapse
during neurotransmission.
253
terminated not only by enzymes which destroy NE, but is the vesicular monoamine transporter 2 (VMAT2),
also by a transport pump for NE that removes it from which transports NE in the cytoplasm of the presynaptic
acting in the synapse without destroying it (Figure 6-14). neuron into storage vesicles (Figure 6-14). The VMAT2
In fact, such inactivated NE can be restored for reuse in transporter was extensively discussed in Chapter 5, as
a later neurotransmitting nerve impulse. The transport the VMAT2 transporter in dopamine nerve terminals is
pump that terminates synaptic action of NE is sometimes the target of treatments for tardive dyskinesia (Figures
called the “NE transporter” or “NET” and sometimes the 5-10 through 5-12). Other NE receptors are classified
“NE reuptake pump.” This NE reuptake pump is located as α1, α2A, α2B, or α2C, or as β1, β2, or β3 (Figure 6-14).
on the presynaptic noradrenergic nerve terminal as part All can be postsynaptic, but only α2 receptors can act
of the presynaptic machinery of the neuron, where it acts as presynaptic autoreceptors (Figures 6-14 through
as a vacuum cleaner whisking NE out of the synapse, off 6-16). Postsynaptic receptors convert their occupancy
the synaptic receptors, and stopping its synaptic actions. by NE into physiological functions, and ultimately, into
Once inside the presynaptic nerve terminal, NE can either changes in signal transduction and gene expression in the
be stored again for subsequent reuse when another nerve postsynaptic neuron (Figure 6-14).
impulse arrives, or it can be destroyed by NE-destroying Presynaptic α2 receptors regulate NE release, so
enzymes (Figure 6-13). they are called “autoreceptors” (Figures 6-14 and 6-15).
The noradrenergic neuron is regulated by a Presynaptic α2 autoreceptors are located both on the axon
multiplicity of receptors for NE (Figure 6-14). The terminal (i.e., terminal α2 receptors; Figures 6-14 and
norepinephrine transporter is one type of receptor, as 6-15) and at the cell body (soma) and nearby dendrites;
Norepinephrine Action Is Terminated
MAO A or B
norepinephrine destroys NE
transporter
(NET)
COMT
NE destroys NE
Figure 6-13 Norepinephrine’s action is terminated. Norepinephrine’s action can be terminated through multiple mechanisms.
Norepinephrine can be transported out of the synaptic cleft and back into the presynaptic neuron via the norepinephrine transporter
(NET), where it may be repackaged for future use. Alternatively, norepinephrine may be broken down extracellularly via the enzyme
catechol-O-methyltransferase (COMT). Other enzymes that break down norepinephrine are monoamine oxidase A (MAO-A) and
monoamine oxidase B (MAO-B), which are present in mitochondria, both within the presynaptic neuron and in other cells, including
neurons and glia.
254
Norepinephrine Receptors
VMAT2
presynaptic
alpha-2
autoreceptor
6
norepinephrine
transporter
(NET)
alpha-1 postsynaptic beta-1 beta-3
receptor alpha-2B receptor receptor
receptor
postsynaptic postsynaptic beta-2
alpha-2A alpha-2C receptor
receptor receptor
Figure 6-14 Norepinephrine receptors. Shown here are receptors for norepinephrine that regulate its neurotransmission. The
norepinephrine transporter (NET) exists presynaptically and is responsible for clearing excess norepinephrine out of the synapse. The
vesicular monoamine transporter 2 (VMAT2) takes norepinephrine up into synaptic vesicles and stores it for future neurotransmission.
There is also a presynaptic α2 autoreceptor, which regulates release of norepinephrine from the presynaptic neuron. In addition, there
are several postsynaptic receptors. These include α1, α2A, α2B, α2C, β1, β2, and β3 receptors.
thus, these latter α2 presynaptic receptors are called stimulating the presynaptic α2 neuron, but other drugs
somatodendritic α2 receptors (Figure 6-16). Presynaptic that antagonize this same receptor will have the effect of
α2 receptors are important because both the terminal cutting the brake cable, thus enhancing release of NE.
and the somatodendritic α2 receptors are autoreceptors.
That is, when presynaptic α2 receptors recognize NE, they GABA (γ-Aminobutyric Acid)
turn off further release of NE (Figures 6-14 and 6-15). GABA is the principle inhibitory neurotransmitter in the
Thus, presynaptic α2 autoreceptors act as a brake for the brain, and normally serves an important regulatory role
NE neuron, and also cause what is known as a negative in reducing the activity of many neurons. Specifically,
feedback regulatory signal. Stimulating this receptor (i.e., GABA is produced, or synthesized, from the amino acid
stepping on the brake) stops the neuron from firing. This glutamate (glutamic acid) via the actions of the enzyme
probably occurs physiologically to prevent over-firing glutamic acid decarboxylase (GAD) (Figure 6-17). Once
of the NE neuron, since it can shut itself off once the formed in presynaptic neurons, GABA is transported
firing rate gets too high and the autoreceptor becomes into synaptic vesicles by vesicular inhibitory amino acid
stimulated. It is worthy to note that some drugs can not transporters (VIAATs), where it is stored until released
only mimic the natural functioning of the NE neuron by into the synapse during inhibitory neurotransmission
255
alpha-2
adrenergic
presynaptic
autoreceptor
NE
A
NE occupying alpha-2 adrenergic

presynaptic autoreceptor halts
release of NE
B
Figure 6-15 Alpha-2 receptors on axon terminal. Shown here are presynaptic α2-adrenergic autoreceptors located on the axon
terminal of the norepinephrine (NE) neuron. These autoreceptors are “gatekeepers” for norepinephrine. (A) When they are not bound
by norepinephrine, they are open, allowing norepinephrine release. (B) When norepinephrine binds to the gatekeeping receptors, they
close the molecular gate and prevent norepinephrine from being released.
256
somatodendritic
alpha-2
adrenergic
autoreceptor
A
6
NE occupying somatodendritic
alpha-2 adrenergic autoreceptor causes a
decrease in firing and a decrease of NE release
Figure 6-16 Somatodendritic α2 receptors. Shown here are presynaptic α2-adrenergic autoreceptors located in the somatodendritic
area of the norepinephrine neuron. (A) When they are not bound by norepinephrine, there is normal neuronal impulse flow, with
resultant release of norepinephrine. (B) When norepinephrine binds to these α2 receptors, it shuts off neuronal impulse flow (see loss of
lightning bolts in the neuron), and this stops further norepinephrine release.
257
(Figure 6-17). GABA’s synaptic actions are terminated by GABA Is Produced

the presynaptic GABA transporter (GAT), also known
as the GABA reuptake pump (Figure 6-18), analogous
to similar transporters for other neurotransmitters
discussed throughout this text. GABA action can also glutamate
be terminated by the enzyme GABA transaminase
(GABA-T), which converts GABA into an inactive
substance (Figure 6-18).
There are three major types of GABA receptors and
numerous subtypes of GABA receptors. The major types
are GABAA, GABAB, and GABAC receptors (Figure 6-19).
GABAA and GABAC receptors are both ligand-gated GABA
ion channels, whereas GABAB receptors are linked to G E
proteins and not to ion channels (Figure 6–19).
GABAA Receptor Subtypes GAD
The molecular structure of GABAA receptors is shown
VIAAT
in Figure 6-20. Each subunit of a GABAA receptor has
four transmembrane regions (Figure 6-20A). When
five subunits cluster together, they form an intact
GABAA receptor with a chloride channel in the center
(Figure 6-20B). There are many different subtypes of
GABA
GABA Action Is Terminated Figure 6-17 Gamma-aminobutyric acid (GABA)

is produced. The amino acid glutamate, a
precursor to GABA, is converted to GABA by
the enzyme glutamic acid decarboxylase (GAD).
After synthesis, GABA is transported into synaptic
vesicles via vesicular inhibitory amino acid
transporters (VIAATs) and stored until its release
into the synapse during neurotransmission.
GABA-T
destroys GABA
E
Figure 6-18 Gamma-aminobutyric acid

(GABA) action is terminated. GABA’s
action can be terminated through
GABA multiple mechanisms. GABA can be
transporter transported out of the synaptic cleft
and back into the presynaptic neuron
(GAT) via the GABA transporter (GAT), where
it may be repackaged for future use.
Alternatively, once GABA has been
transported back into the cell, it may be
converted into an inactive substance
via the enzyme GABA transaminase
GABA (GABA-T).
258
Figure 6-19 Gamma-aminobutyric
GABA Receptors acid (GABA) receptors. Shown here
are receptors for GABA that regulate
its neurotransmission. These include
the GABA transporter (GAT) as well as
three major types of postsynaptic GABA
receptors: GABAA, GABAB, and GABAC.
GABAA and GABAC receptors are
ligand-gated ion channels; they are part
of a macromolecular complex that forms
an inhibitory chloride channel. GABAB
receptors are G-protein-linked receptors
that may be coupled with calcium or
potassium channels.
GABA
transporter
(GAT)
GABA
6
GABA B
GABAA receptor GABA C
receptor receptor
complex complex
GABAA receptors, depending upon which subunits are receptors containing a γ subunit tend to be synaptic, to
present (Figure 6-20C). Subunits of GABAA receptors mediate phasic neurotransmission, and to be sensitive to
are sometimes also called isoforms, and include α (with benzodiazepines. On the other hand, GABAA receptors
six isoforms α1 to α6), β (with three isoforms β1 to β3), γ containing a δ subunit tend to be extrasynaptic, to
(with three isoforms γ1 to γ3), δ, ε, π, θ, and ρ (with three mediate tonic neurotransmission, and to be insensitive to
isoforms ρ1 to ρ3) (Figure 6-20C). What is important for benzodiazepines.
this discussion is that depending upon which subunits are Benzodiazepine-sensitive GABAA receptors have
present, the functions of a GABAA receptor can vary quite several structural and functional features that make
significantly. Thus, GABAA receptors can be classified by them distinct from benzodiazepine-insensitive GABAA
the specific isoform subunits that they contain. receptors. For a GABAA receptor to be sensitive to
GABAA receptors can also be categorized into other benzodiazepines, there must be two β units plus a γ unit
subtypes: those that are synaptic and hypothetically of either the γ2 or γ3 subtype, plus two α units of either
mediate phasic neurotransmission, and those that the α1, α2, or α3 subtype (Figure 6-20C). Benzodiazepines
are extrasynaptic and hypothetically mediate tonic appear to bind to the region of the receptor between
neurotransmission (Figure 6-21). Other classification the γ2/γ3 subunit and the α1/α2/α3 subunit, one
systems are whether GABA receptors are sensitive to benzodiazepine molecule per receptor complex (Figure
the well-known benzodiazepines or insensitive to them. 6-20C). GABA itself binds with two molecules of GABA
Some of these classifications overlap, since GABAA per receptor complex, to the GABA agonist sites in the
259
Structure of GABAA Receptors
four transmembrane regions make up one subunit

extracellular amino
acid chains
transmembrane
region
A cytoplasmic loop
the chloride channel

five substructures form the receptor complex is at the center
B inhibition
Major Subtypes of GABAA Receptors
GABA GABA GABA GABA

binding site BZ binding site BZ binding site BZ binding site
binding site binding site binding site
1 3 6
ß 1 2 2 2 ß 4
ß
neuroactive
steroids
-alcohol
-general
anesthetics
(1-6) (1-3) 2, 1 2, ( 2, 3) ( 4, 6)
( 1-3 or ) -sedative -anxiolytic -tonic inhibition
-phasic inhibition -phasic inhibition -extrasynaptic
-synaptic
C
Figure 6-20 Gamma-aminobutyric acid A (GABAA) receptors. (A) Shown here are the four transmembrane regions that make up one
subunit of a GABAA receptor. (B) There are five copies of these subunits in a fully constituted GABAA receptor, at the center of which is a
chloride channel. (C) Different types of subunits (also called isoforms or subtypes) can combine to form a GABAA receptor. These include
six different α isoforms, three different β isoforms, three different γ isoforms, δ, ε, π, θ, and three different ρ isoforms. The ultimate type
and function of each GABAA receptor subtype will depend on which subunits it contains. Benzodiazepine (BZ)-sensitive GABAA receptors
(middle two) contain two β units, plus either γ2 or γ3, plus two α (α1 through α3) subunits. They generally mediate phasic inhibition
triggered by peak concentrations of synaptically released GABA. Benzodiazepine-sensitive GABAA receptors containing α1 subunits are
involved in sleep (second from left), while those that contain α2 and/or α3 subunits are involved in anxiety (second from right). GABAA
receptors containing α4, α6, or δ subunits (far right) are benzodiazepine-insensitive, are located extrasynaptically, and regulate tonic
inhibition. They are bound by naturally occurring neuroactive steroids and possibly to alcohol and some general anesthetics.
260
regions of the receptor between the α and the β units, of an agonist at their positive allosteric sites, because
sometimes also referred to as the GABA orthosteric site their actions can be reversed by the neutral antagonist
(Figures 6-20C and 6-22). flumazenil (Figure 6-23), which is sometimes used to
Acting alone, GABA acting at its agonist sites can reverse anesthesia with benzodiazepines or overdoses of
increase the frequency of opening of the chloride channel benzodiazepines.
formed inside all its subunits (see Figure 6-20), but only As mentioned above, benzodiazepine-sensitive
to a limited extent (compare Figure 6-22A and 6-22B). GABAA receptor subtypes (with γ subunits and α1 to α3
Since the site for benzodiazepines is in a different subunits) are thought to be postsynaptic and to mediate
location from the agonist sites for GABA (see Figure a type of inhibition at the postsynaptic neuron that is
6-20C and 6-22D), the modulatory site is often called phasic, occurring in bursts of inhibition that are triggered
allosteric (literally “other site”), and the agents that bind by peak concentrations of synaptically released GABA
there “allosteric modulators.” Since the modulation is (Figure 6-21). Theoretically, benzodiazepines acting at
“positive” in the sense that it makes GABA more effective these receptors, particularly the α2/3 subtypes clustered
at GABAA receptors, enhancing the frequency of opening at postsynaptic GABA sites, should exert an anxiolytic
of inhibitory chloride channels (Figure 6-22D), the effect due to enhancement of phasic postsynaptic
action is called “positive allosteric modulation,” and inhibition. However, not all benzodiazepine-sensitive
benzodiazepines are called GABAA positive allosteric GABAA receptors are the same. Notably, on the one
modulators (PAMs). Interestingly, GABA must be present hand, those benzodiazepine-sensitive GABAA receptors
for the PAM to work (compare Figure 6-22C and 6-22D). with α1 subunits may be most important for regulating
The actions of benzodiazepines at benzodiazepine- sleep and are the presumed targets of numerous sedative
6
sensitive GABAA receptors are essentially the actions hypnotic agents, including both benzodiazepine and
Figure 6-21 GABAA
Two Types of GABAA Mediated Inhibition mediation of tonic and phasic
inhibition. Benzodiazepine-sensitive
GABAA receptors (those that contain
GABA γ and α1 through α3 subunits)
are postsynaptic receptors that
neuron glial cell mediate phasic inhibition, which
occurs in bursts triggered by peak
cholesterol mitochondria concentrations of synaptically released
GABA. Benzodiazepine-insensitive
GABAA receptors (those containing
δ subunits and α4 or α6 subunits)
pregnenolone are extrasynaptic and capture GABA
that diffuses away from the synapse
as well as neuroactive steroids that
GABA are synthesized and released by glia.
neuroactive These receptors mediate inhibition
steroid that is tonic (i.e., mediated by ambient
levels of extracellular GABA that has
escaped from the synapse).
GABAA
GABA A ( 4, 6)
( 1, 3)
postsynaptic extrasynaptic
tonic
inhibition
phasic
inhibition
261
Figure 6-22 Positive allosteric

modulation of GABA-A receptors. (A)
chloride Benzodiazepine (BZ)-sensitive GABAA
GABA A channel receptors, like the one shown here,
binding site consist of five subunits with a central
BZ chloride channel and have binding
binding site sites not only for GABA but also for
positive allosteric modulators (e.g.,
benzodiazepines). (B) When GABA
binds to its sites on the GABAA
receptor, it increases the frequency
of opening of the chloride channel
and thus allows more chloride to pass
through. (C) When a positive allosteric
modulator such as a benzodiazepine
binds to the GABAA receptor in the
absence of GABA, it has no effect
on the chloride channel. (D) When a
positive allosteric modulator such as a
benzodiazepine binds to the GABAA
receptor in the presence of GABA, it
causes the channel to open even more
frequently than when GABA alone is
present.
A B
C D
= GABA
= benzodiazepine
non-benzodiazepine PAMs of the GABAA receptor sedative hypnotic benzodiazepines (discussed in Chapter
(Figure 6-21C). The α1 subtype of GABAA receptors and 8 on anxiety and in Chapter 10) (Figure 6-20C). Currently
the drugs that bind to it are discussed further in Chapter available benzodiazepines are nonselective for GABAA
10 on disorders of sleep. Some of these agents (i.e., receptors with different α subunits. Abnormal expression
some Z drugs that also bind to benzodiazepine-sensitive of γ2, α2, or δ subunits have all been associated with
GABAA receptors; see Chapter 10) are selective for only different types of epilepsy. Receptor subtype expression
the α1 subtype of GABAA receptor. On the other hand, can change in response to chronic benzodiazepine
benzodiazepine-sensitive GABAA receptors with α2 and/ administration and withdrawal, and could theoretically
or α3 subunits may be most important for regulating be altered in patients with various psychiatric disorders,
anxiety and are the presumed targets of the anxiolytic and including different subpopulations of depression.
262
Figure 6-23 Flumazenil. The
benzodiazepine receptor antagonist
flumazenil is able to reverse a full
agonist benzodiazepine acting at its
site on the GABAA receptor. This may
be helpful in reversing the sedative
effects of full agonist benzodiazepines
when administered for anesthetic
purposes or when taken in overdose
by a patient.
flumazenil
= GABA
= benzodiazepine
6
= flumazenil
Benzodiazepine-insensitive GABAA receptors are benzodiazepine-sensitive GABAA receptors (Figure

those with α4, α6, γ1, or δ subunits (Figure 6-20C). 6-21). Tonic inhibition may be regulated by the ambient
GABAA receptors with a δ subunit rather than a γ levels of extracellular GABA molecules that have escaped
subunit, plus either α4 or α6 subunits, do not bind to presynaptic reuptake and enzymatic destruction and
benzodiazepines. Benzodiazepine-insensitive GABAA persist between neurotransmissions and is boosted by
receptors bind instead to the naturally occurring allosteric modulation at these sites.
neuroactive steroids, and possibly to alcohol and to Thus, tonic inhibition is thought to set the overall
some general anesthetics (Figure 6-20C). The binding tone and excitability of the postsynaptic neuron, and
site for these non-benzodiazepine modulators is located to be important for certain regulatory events such
between the α and the δ subunits, one site per receptor as the frequency of neuronal discharge in response
complex (Figure 6-20C). Two molecules of GABA bind to excitatory inputs. Since neuroactive steroids have
per receptor complex of benzodiazepine-insensitive antidepressant properties (see Chapter 7), this has led
GABAA receptors at the GABA agonist (orthosteric) sites to the proposal that some depressed patients may have
located between the α and the β subunits (Figure 6-20C), a lack of normal tonic inhibition, and thus too much
just as they do at the benzodiazepine-sensitive GABAA excitability in some brain circuits. Hypothetically this
receptors. could be calmed by neuroactive steroid administration,
As already mentioned, benzodiazepine-insensitive causing more efficiency of information processing in
GABAA receptor subtypes (with δ subunits and α4 or α6 those brain circuits and reduction of the symptoms
subunits) are thought to be located extrasynaptically, of depression. It is possible that neuroactive steroids
where they capture not only GABA that diffuses could also have important anxiolytic actions. Why
away from the synapse, but also neuroactive steroids would more tonic and supposedly sustained opening
synthesized and released by glia (Figure 6-21). of chloride channels be a good thing for depression? In
Extrasynaptic benzodiazepine-insensitive GABAA the case of postpartum depression, it may be potentially
receptors are thought to mediate a type of inhibition explainable on the basis that pregnant women have high
at the postsynaptic neuron that is tonic, in contrast to circulating and presumably brain levels of neuroactive
the phasic type of inhibition mediated by postsynaptic steroids. When they deliver, there is a precipitous decline
263
in circulating neuroactive steroid levels, hypothetically and of the potential link between monoamines and mood
triggering the sudden onset of a major depressive episode disorders in particular.
when tonic inhibition is lost. Restoring neuroactive
steroid levels – and tonic inhibition – for 60 hours of The Monoamine Receptor Hypothesis and
Neurotrophic Factors
intravenous infusion may be enough for the patient
to respond by reversing their depression and then Because of these and other difficulties with the
having some additional time to accommodate to the monoamine hypothesis, the focus of hypotheses for
lower levels of neuroactive steroids postpartum. This the etiology of mood disorders shifted next from the
is a reasonable but not yet proven theory. It may be a monoamine neurotransmitters themselves to their
bit more difficult to understand why positive allosteric receptors and then to the downstream molecular events
modulation by a neuroactive steroid would treat that these receptors trigger, including the regulation of
other forms of depression, and treat quickly. However gene expression and the production of growth factors.
neuroactive steroids exert their antidepressant effects, Currently, there is also great interest in the influence
clearly extrasynaptic benzodiazepine-insensitive GABAA of nature (genes) and nurture (environment and
sites are the targets, because benzodiazepines acting at epigenetics) on brain circuits regulated by monoamines,
the synaptic benzodiazepine-sensitive GABAA sites do especially what happens when epigenetic changes from
not have robust antidepressant action. It may be worth stressful life experiences are combined with inheriting
noting that neuroactive steroids actually work at both various risk genes that can make an individual vulnerable
benzodiazepine-sensitive GABAA receptors as well as at to those environmental stressors.
benzodiazepine-insensitive GABAA receptors. However, The neurotransmitter receptor hypothesis of
their unique action is at the benzodiazepine-insensitive depression posits that an abnormality in the receptors
sites and it is this action that is the focus of much interest for monoamine neurotransmitters leads to depression
in how neuroactive steroids hypothetically mediate their (Figure 6-24B). Thus, if depletion of monoamine
antidepressant actions. neurotransmitters is the central theme of the
monoamine hypothesis of depression (Figure 6-24B),
The Monoamine Hypothesis of Depression the neurotransmitter receptor hypothesis of depression
The classic theory about the biological etiology of takes this theme one step further: namely, that the
depression hypothesizes that depression is due to a depletion of neurotransmitter causes compensatory
deficiency of monoamine neurotransmission. Mania upregulation of postsynaptic neurotransmitter receptors
may be the opposite, due to an excess of monoamine (Figure 6-24C). Direct evidence for this hypothesis is
neurotransmission. This original conceptualization also generally lacking. However, postmortem studies
was a rather simplistic “chemical imbalance” notion do consistently show increased numbers of serotonin
that is now considered relatively unsophisticated 2 receptors in the frontal cortex of patients who die by
and based mainly on observations that certain drugs suicide. Also, some neuroimaging studies have identified
that depleted monoamines could induce depression, abnormalities in serotonin receptors of depressed
and that all effective drugs for depression in the past patients, but this approach has not yet been successful
acted by boosting one or more of three monoamine in identifying consistent and replicable molecular
neurotransmitters: norepinephrine, serotonin, or lesions in receptors for monoamines in depression.
dopamine. Thus, the idea was born that the “normal” Thus, there is no clear and convincing evidence that
amount of monoamine neurotransmitters (Figure monoamine deficiency accounts for depression: i.e.,
6-24A) somehow became depleted by an unknown there is no “real” monoamine deficit. Likewise, there
disease process, stress, or drugs (Figure 6-24B), leading is no clear and convincing evidence that abnormalities
to the symptoms of depression. Direct evidence for the in monoamine receptors account for depression
monoamine hypothesis is still largely lacking. A good even though all the classic drugs to treat depression
deal of effort was expended especially in the 1970s and raise monoamine levels. Although the monoamine
1980s to identify the theoretically predicted deficiencies hypothesis is obviously an overly simplified notion about
of monoamine neurotransmitters in depression and mood disorders, it has been very valuable in focusing
excess in mania. This effort to date has unfortunately attention upon the three monoamine neurotransmitters
yielded mixed results, prompting a search for better norepinephrine, dopamine, and serotonin. This has led
explanations of the etiology of mood disorders in general to a much better understanding of the physiological
264
Figure 6-24 Monoamine receptor hypothesis

Monoamine Receptor Hypothesis of Depression of depression. (A) According to the classic
monoamine hypothesis of depression, when
there is a “normal” amount of monoamine
neurotransmitter activity, there is no depression
present. (B) The monoamine hypothesis of
NE depression posits that if the “normal” amount
of monoamine neurotransmitter activity
becomes reduced, depleted, or dysfunctional
5HT for some reason, depression may ensue. (C) The
monoamine receptor hypothesis of depression
DA extends the classic monoamine hypothesis
of depression, positing that deficient activity
of monoamine neurotransmitters causes
upregulation of postsynaptic monoamine
neurotransmitter receptors, and that this leads to
depression.
normal state - no depression

A
depression - caused by
monoamine deficiency
B
receptors upregulate
due to lack of monoamines
C
265
functioning of these three neurotransmitters, and for a administration of drugs for depression include the
while led to more and more pharmacological treatment downstream synthesis of growth factors such as BDNF
options for depression, with many therapeutic variants (brain-derived neurotrophic factor) (Figure 6-27). One
upon the theme of monoamine targeting. These many notable current hypothesis is that stress, inflammation,
therapeutic approaches and drugs are discussed in detail and other genetic and environmental factors (such as
in Chapter 7. early life adversity, the microbiome, and chronic medical
illnesses) lead to loss of growth factors (Figure 6-28) and
Beyond Monoamines: The Neuroplasticity and this leads in turn to neuroprogression, starting with lack
Neuroprogression Hypothesis of Depression of synaptic maintenance and then loss of synapses and
One of the hints that depression is not simply due to dendritic arborization, and then ultimately leading to loss
deficient monoamines and that drugs for depression of neurons themselves (Figure 6-29, left), at which point
simply restored those deficient monoamines is the neuroprogression becomes irreversible. The effect of the
observation that the classic drugs for depression increased loss of growth factors on maintaining synaptic integrity
monoamines almost immediately, yet the clinical and connectivity is shown in the microscopic inserts in
improvement in depression is delayed for weeks (Figure Figure 6-30 (see loss of dendritic spines indicating loss
6-25). This led to a search for molecular events that of synapses on the right). Ominously, copious degrees of
correlated in time with the onset of clinical antidepressant synaptic and neuronal loss can be observed on structural
effects. Some of the earliest findings showed that delayed magnetic resonance imaging brain scans (Figure
downregulation of neurotransmitter receptors following 6-30). Abnormal functional neuroimaging studies of
immediate elevation of monoamines after administration connectivity of brain circuits have also been reported in
of drugs for depression correlates in time with the onset depression.
of clinical antidepressant effects (Figures 6-25 and 6-26). The hypothetical neurobiology of neuroprogression
Downregulation of neurotransmitter receptors also in depression is multifactorial (Figure 6-31). In addition
correlates in time with the onset of tolerance to some of to possibly deficient production of growth factors
the side effects of drugs used to treat depression. (Figures 6-27 through 6-29; 6-31), there is also the
Other molecular events that correlate with the timing longstanding theory of hypothalamic-pituitary-adrenal
of onset of clinical antidepressant effects following (HPA) axis dysregulation in depression, and it, too,
amount of NT
receptor
sensitivity
clinical effect
Medication introduced
Figure 6-25 Time course of effects of drugs for depression. This figure depicts the different time courses for three effects of most drugs
used to treat depression – namely, clinical changes, neurotransmitter (NT) changes, and receptor-sensitivity changes. Specifically, the
amount of neurotransmitters changes relatively rapidly after a drug for depression is introduced. However, the clinical effect is delayed,
as is the desensitization, or downregulation, of neurotransmitter receptors. This temporal correlation of clinical effects with changes
in receptor sensitivity has given rise to the hypothesis that changes in neurotransmitter receptor sensitivity may actually mediate the
clinical effects of drugs used for depression. These clinical effects include not only antidepressant and anxiolytic actions but also the
development of tolerance to the acute side effects.
266
Neurotransmitter Receptor Hypothesis

of Antidepressant Action
E E
A B
Figure 6-26 Neurotransmitter receptor hypothesis of antidepressant action. Although drugs for depression cause an immediate
increase in monoamines, they do not have immediate therapeutic effects. This may be explained by the monoamine receptor hypothesis
of depression, which states that depression is caused by upregulation of monoamine receptors; thus, clinical antidepressant effects
would be related to downregulation of those receptors, as shown here. (A) When the monoamine reuptake pump is blocked, this causes
more neurotransmitter (in this case, norepinephrine) to accumulate in the synapse. (B) The increased availability of neurotransmitter
ultimately causes receptors to downregulate. The time course of receptor adaptation is consistent both with the delayed clinical effects
of drugs for depression and with development of tolerance to side effects.
Monoamine Signaling Increases BDNF Release, Which Figure 6-27 Monoamine signaling and brain-
derived neurotrophic factor (BDNF) release. The
Modifies Monoamine Innervation neuroprogression hypothesis of depression
states that depression may be caused by reduced
synthesis of proteins involved in neurogenesis and
monoamine synaptic plasticity. BDNF promotes the growth
and development of immature neurons, including
monoaminergic neurons, enhances the survival
and function of adult neurons, and helps maintain
synaptic connections. Because BDNF is important
for neuronal survival, decreased levels may
GE contribute to cell atrophy. In some cases, low levels
of BDNF may even cause cell loss. Monoamines
can increase the availability of BDNF by initiating
2 signal transduction cascades that lead to its release.
Thus, increased synaptic availability of monoamines
by reuptake inhibitors may lead to downstream
increases in neurotrophic factors, a molecular effect
synaptogenesis
neuroplasticity that would correlate in timing with the clinical
CaMK effects.
PKA
BDNF cell
survival
CREB neurogenesis
267
chronic clinical Figure 6-28 Genetic and environmental factors may
illness lead to loss of neurotrophic factors. Neurotrophic
inflammation factors such as brain-derived neurotrophic factor
sleep
(BDNF) play a role in the proper growth and
early life adversity maintenance of neurons and neuronal connections.
stress Multiple environmental factors, including chronic
microbiome
stress, inflammation, chronic illness, early life adversity,
changes in the microbiome, and altered sleep could
contribute to neuroprogression in depression by
causing epigenetic changes that turn the genes for
BDNF off, potentially reducing its production.
BDNF
gene
BDNF
Figure 6-29 Suppression of brain-

derived neurotrophic factor (BDNF)
production. BDNF plays a role in the
proper growth and maintenance of
neurons and neuronal connections (right).
If the genes for BDNF are turned off (left),
the resultant decrease in BDNF could
compromise the brain’s ability to create and
BDNF BDNF maintain neurons and their connections.
This could lead to loss of synapses or even
whole neurons by apoptosis.
apoptosis
268
coronal plane coronal plane
normal depression
Figure 6-30 Loss of dendritic spines in depression. Reduction in neurotrophic factors compromises the maintenance of synaptic
integrity and connectivity and can ultimately lead to synapse loss. This has been shown in structural magnetic resonance imaging
studies of hippocampal volume, in which patients with depression have fewer dendritic spines.
Symptomatic Brain Network Neuroprogression
Vulnerability to relapse
inflammation Treatment resistance
epigenetic
change Functional brain abnormalities
oxidative
stress
neurotrophic Damage to synapses
dysregulation
HPA and neurons
dysregulation
Structural brain abnormalities
Cognitive decline
Figure 6-31 Neuroprogression in depression is multifactorial. Neuroprogression in depression may be related to multiple factors that
may themselves interact. Inflammation, oxidative stress, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may all
contribute to neurotrophic dysregulation, which may lead to epigenetic changes, which may further exacerbate inflammation, oxidative
stress, and HPA axis dysfunction. All these factors may ultimately contribute to damage to synapses and neurons, which may lead to
both functional and structural brain abnormalities.
269
may contribute to neurodegeneration (Figures 6-31, Yet another factor potentially contributing to
6-32A, and 6-32B). Neurons from the hippocampal area neurodegeneration in at least a subset of patients with
and amygdala normally suppress the HPA axis (Figure depression is neuroinflammation (Figure 6-33). That
6-32A), so if stress causes hippocampal and amygdala is, a number of conditions and factors contribute to
neurons to atrophy, with loss of their inhibitory input to inflammation invading the central nervous system in
the hypothalamus, this could lead to overactivity of the a number of psychiatric disorders, maybe especially
HPA axis (Figure 6-32B). In depression, abnormalities in depression (Figure 6-33). Those factors include not
of the HPA axis have long been reported, including only chronic stress, but also obesity, early life/childhood
elevated glucocorticoid and insensitivity of the HPA axis adversity, disruption of the microbiome, and numerous
to feedback inhibition (Figure 6-32B). Some evidence chronic inflammatory medical illnesses (Figure 6-33A).
suggests that glucocorticoids at high levels could even be In such patients, it is hypothesized that these factors
toxic to neurons and contribute to their atrophy under activate microglia in the brain to release proinflammatory
chronic stress (Figure 6-32B). Novel antidepressant molecules (Figure 6-33B), which in turn attract immune
treatments are in testing that target CRF (corticotropin- cells such as monocytes and macrophages into the brain
releasing factor) receptors, vasopressin 1B receptors, and (Figure 6-33C) where they disrupt neurotransmission
glucocorticoid receptors (Figure 6-32B), in an attempt (Figure 6-33D), cause oxidative chemical stress,
to halt and even reverse these HPA abnormalities in mitochondrial dysfunction, HPA-axis dysfunction,
depression and other stress-related psychiatric illnesses. reduction of neurotrophic factor availability, and
The Hypothalamic-Pituitary-Adrenal (HPA) Axis
hypothalamus
corticotropin-
ds releasing
i coi factor
ort
coc
glu
amygdala
hippocampus
pituitary
adrenal ACTH
gland
Figure 6-32A Hypothalamic-pituitary-adrenal (HPA) axis. The normal stress response involves activation of the hypothalamus and a
resultant increase in corticotropin-releasing factor (CRF), which in turn stimulates the release of adrenocorticotropic hormone (ACTH)
from the pituitary. ACTH causes glucocorticoid release from the adrenal gland, which feeds back to the hypothalamus and inhibits CRF
release, terminating the stress response. The amygdala and hippocampus also provide input to the hypothalamus, to suppress activation
of the HPA axis.
270
Hippocampal Atrophy and Hyperactive HPA in Depression
glucocorticoid CRF
antagonist antagonist
hypothalamus
corticotropin-
oids releasing
rtic factor
co
co
glu amygdala
hippocampus 6
adrenal pituitary
gland ACTH
vasopressin 1B
antagonist
Figure 6-32B Hippocampal atrophy and hyperactive HPA axis in depression. In situations of chronic stress, hyperactivity of the HPA
axis leads to excessive glucocorticoid release, which may eventually cause hippocampal atrophy. Because the hippocampus inhibits
the HPA axis, atrophy in this region may lead to chronic activation of the HPA axis, which may increase risk of developing a psychiatric
illness. Because the HPA axis is central to stress processing, it may be that novel targets for treating stress-induced disorders lie within
the axis. Mechanisms being examined include antagonism of glucocorticoid receptors, corticotropin-releasing factor (CRF) receptors,
and vasopressin 1B receptors.
epigenetic changes to unwanted gene expression (Figure discussed above, and these normally peak at night.
6-31), leading ultimately to loss of synapses and death of Desynchronization of biological processes can be so
neurons (Figure 6-31 and 6-33D). pervasive in depression that it is possible to characterize
Another hypothesis for the neurobiological basis depression as fundamentally a circadian illness. It is
at least for some patients with depression is that it is a possible, at least for some patients, that depression is due
circadian rhythm disorder casing a phase delay in the to a “broken” circadian clock. Numerous genes operate in
sleep–wakefulness cycle (Figure 6-34). The degree of this a circadian manner, sensitive to light–dark rhythms and
phase delay correlates with the severity of depression. called clock genes. Abnormalities in various clock genes
Numerous physiological measurements of circadian have been linked to mood disorders and for these patients
rhythms are also altered in depression, from flattening with a circadian rhythm disorder (Figure 6-34), circadian
of the daily body-temperature cycle, elevation of rhythm treatments such as bright light (Figure 6-36A),
cortisol secretion throughout the day, and also reducing melatonin (Figure 6-36B), phase advance, phase delay,
melatonin secretion that also normally peaks at night and even sleep deprivation can have therapeutic effects.
and in the dark (Figure 6-35). Elevations of cortisol Not only do all of these various factors triggered by
secretion and abnormalities of the HPA axis in depression neuroinflammation, stress, genetics, and the environment
are discussed above (Figures 6-32A and B). Other (Figures 6-28, 6-30, 6-31, and 6-33) contribute to
circadian rhythms that may be disrupted in depression synaptic dysfunction and structural brain abnormalities
include a reduction in BDNF and neurogenesis, also with functional decline, theoretically they ultimately
271
Early life
childhood
Chronic stress Microbiome adversity
Blood Brain
Chronic
mental illness
monocyte
resting
Obesity microglia
macrophage
A
Sleep Genes
Blood Brain
cytokines
monocyte
activated
microglia
macrophage
B
Figure 6-33 Neuroinflammation in depression. Neurodegeneration in depression could be related to the development of
neuroinflammation in some patients. (A) Chronic stress, obesity, early life adversity, disruption of the microbiome, chronic sleep issues,
and chronic inflammatory diseases may all contribute to the development of neuroinflammation. Shown here are immune factors in the
blood and resting microglia in the brain. (B) If microglia in the brain are activated due to chronic stress, obesity, etc., they can release
proinflammatory cytokines.
lead to at least three very unwanted clinical outcomes in Major depressive episodes of course are named for their
depression: mood symptom of sadness and depression, and indeed
enduring cognitive decline sad mood has the strongest association with overall
increased vulnerability for further episodes of depression impairment of functioning, but the second strongest
resistance to treatment with monoamine drugs for association with impaired overall functioning is cognitive
depression symptoms, perhaps a bit surprising for something
272
Blood Brain
Blood Brain 6
synaptic and
neuronal damage
Figure 6-33 (cont.) (C) Proinflammatory cytokines attract immune cells, such as monocytes and macrophages, into the brain. (D)
Monocytes and macrophages can disrupt neurotransmission, cause oxidative stress and mitochondrial dysfunction, affect HPA-axis
function, reduce availability of neurotrophic factors, and lead to epigenetic changes, which ultimately can lead to synaptic loss and
neuronal death.
called a “mood disorder” and not a “cognitive disorder.” Depressed patients with smaller hippocampal volumes
Functional neuroimaging studies suggest that cognitive have worse outcomes. A grim statistic is that memory
decline may manifest in the need for more effortful in depression worsens as a function of the number of
thinking because depressed patients show greater previous depressive episodes as though such episodes
activation of brain regions involved in cognitive control, are damaging to the brain and the damage is cumulative.
such as the dorsolateral prefrontal cortex and anterior Interestingly, to support this haunting possibility is the
cingulate cortex. Hippocampal decline in depression observation that cognitive dysfunction in depression may
is discussed above and illustrated in Figure 6-30, and be related to the number of past episodes of depression
is correlated with duration of untreated depression. and to the duration of those episodes, and not to the
273
Depression Causes Phase Delay in the Circadian Rhythms Figure 6-34 Depression can cause
phase delay in circadian rhythms
of Sleep-Wake Cycles of sleep/wake cycles. Circadian
rhythms describe events that occur
on a 24-hour cycle. Many biological
“phase delay” systems follow a circadian rhythm; in
particular, circadian rhythms are key to
the regulation of sleep/wake cycles. In
patients with depression, the circadian
rhythm is often “phase delayed,” which
Healthy Control means that because wakefulness is
not promoted in the morning, such
patients tend to sleep later. They also
have trouble falling asleep at night,
Depression which further promotes feelings of
sleepiness during the day.
sleep sleep
7 am 11 pm 7 am 11 pm 7 am
Figure 6-35 Physiological
Physiological Measurements of Circadian Rhythms measurements of circadian rhythms
Are Altered in Depression are altered in some patients with
depression. Circadian rhythms
are evident in multiple biological
Body Temperature
37.2 functions, including body temperature,

37.0
Healthy Control hormone levels, blood pressure,
metabolism, cellular regeneration,
( C)
36.8 sleep/wake cycles, and DNA

36.6
Depression transcription and translation. The
36.4 internal coordination ordered by
the circadian rhythm is essential to
optimal health. In depression, there are
220
Cortisol (ng/ml)
altered physiological measurements

170 of circadian rhythms, including less
120
fluctuation in body temperature over
the course of a 24-hour cycle, the same
70 pattern but elevated cortisol levels
20 over 24 hours, and the absence of a
spike in melatonin levels at night.
Melatonin (pg/ml)
100
80
60
40
20
6 am noon 6 pm midnight 6 am noon
severity of the symptoms in a current episode, again a high dose of a benzodiazepine or antihistamine.
suggesting past damage. Cognitive symptoms are one of Can you imagine living all day long, every day, with
the most – if not the most – common residual symptom this degree of cognitive impairment? Cognitive
between depressive episodes once sadness and other dysfunction of this degree is not specific for patients
symptoms recover. Thus, cognitive symptoms can with depression, but is very common across many
endure longer than mood symptoms in major depressive psychiatric disorders, from unipolar to bipolar
disorder. disorder, schizophrenia, anxiety/trauma/impulsive
How bad is the cognitive dysfunction? Some disorders, ADHD (attention deficit hyperactivity
estimate that it is about the same degree of impairment disorder), and beyond. Targeting cognitive symptoms
as one has after a night of sleep deprivation, or after with current treatments across psychiatric disorders
being legally intoxicated with alcohol, or after taking is therefore an important therapeutic strategy, and
274
retinohypothalamic
tract pineal
SCN gland
Figure 6-36A The setting of circadian rhythms, part 1. Although various factors can affect the setting of circadian rhythms, light is the
most powerful synchronizer. When light enters through the eye it is translated via the retinohypothalamic tract to the suprachiasmatic
nucleus (SCN) within the hypothalamus. The SCN, in turn, signals the pineal gland to turn off melatonin production. For individuals with
depression who have dysregulation of circadian rhythms, bright-light therapy in the early morning may help to reset the circadian rhythm.
Figure 6-36B Melatonin and

circadian rhythms. During
darkness, there is no input from
the retinohypothalamic tract to
the suprachiasmatic nucleus (SCN)
within the hypothalamus. Thus,
darkness signals the pineal gland
melatonin to produce melatonin. Melatonin,
in turn, can act on the SCN to reset
circadian rhythms. For individuals
with depression who have
dysregulated circadian rhythms,
melatonin in the early evening may
help to reset the circadian rhythm.
retinohypothalamic
tract pineal
SCN gland
275
a critical need for better drugs for cognition exists. may also be occurring with the novel GABAergic drugs
In the meantime, perhaps the best chance to prevent currently being developed. If so, these newer agents have
adverse cognitive and functional outcomes in the potential for rapid onset of an antidepressant effect
depression is to treat early and completely, whenever since their molecular effects (Figure 6-37) can reverse
possible. synaptic loss and show new synapse formation within
Changes in structural and functional outcomes in minutes to hours (reversal of synapse loss is shown in
depression in fact may be potentially reversible when depression in Figure 6-30; see also Chapter 7). It is also
captured at the stage of loss of synapses without loss possible that agents targeting glutamate, GABA, and
of neurons, and that is what rapid-acting drugs for other non-monoaminergic targets will hold promise for
depression, which act on glutamate and GABA systems, treating patients who do not respond to monoaminergic
hold promise for doing: namely, triggering the formation therapeutics. Restoration of neurotransmitter-
of new synapses. These drugs are discussed in Chapter 7. related signal transduction cascades by drugs of any
Here we will just mention that downstream improvement mechanism that can successfully treat depression can
in neuroplasticity may be possible for monoamine- also hypothetically increase BDNF and other trophic
targeting drugs when those drugs are effective. More factors and therefore potentially restore lost synapses.
recently it has been discovered that improvements in In some brain areas, such as the hippocampus, not only
animal models of neuroplasticity can be observed after can synapses potentially be restored, but it is possible
boosting glutamatergic neurotransmission with novel that some lost neurons might even be replaced by
drugs for depression (Figure 6-37). It is possible that this neurogenesis.
Downstream Improvement in Neuroplasticity Figure 6-37 Downstream effects on

neuroplasticity. In depression, there
with Novel Drugs for Depression may be a deficiency in downstream
signal transduction, leading to reduced
synthesis of proteins involved in
Glutamate Monoamine neurogenesis and synaptic plasticity,
GABA
such as brain-derived neurotrophic
regulation regulation DA 5HT NE regulation factor (BDNF). Treatment with drugs
for depression, both traditional
monoamine reuptake inhibitors as well
as novel agents that affect glutamate
Signaling cascades or GABA, can stimulate a variety
of signaling cascades. Each of the
signaling cascades depicted is capable
of activating cAMP response element
binding protein (CREB), which can elicit
the expression of numerous genes
MAPK RSK cAMP PKC Wnt/Frz GSK-3 CaMK involved in neuroplasticity, including
BDNF. Another form of synaptic
plasticity, long-term potentiation
(LTP), involves the strengthening of
Activation of cAMP response element synapses through the modulation of
binding protein (CREB) glutamate receptors. The activation
of CREB increases the expression
of α-amino-3-hydroxy-5-methyl-4-
isoxazole-propionic acid (AMPA)
receptor subunits and downregulates
Genes turned on N-methyl-D-aspartate (NMDA)
BDNF BDNF receptors. Modifying the AMPA:NMDA
receptor ratio by increasing AMPA while
BDNF BDNF
reducing NMDA input may restore
Increased Increased glutamate homeostasis and facilitate
Downregulation neuroplasticity in the depressed brain.
expression of proteins
of NMDA
AMPA receptor involved in
receptors
subunits neuroplasticity
Increased neuroplasticity and restored neurotransmission
276
SYMPTOMS AND CIRCUITS IN psychiatric disorders. That strategy also involves rational
MOOD DISORDERS use of the available drugs that are known to target
the regulation of those same neurotransmitters, and,
Currently, a major hypothesis in psychiatry is that therefore, to target improvement of the symptoms those
psychiatric symptoms are linked to inefficient neurotransmitters regulate.
information processing in specific brain circuits, with Let’s now explain how this strategy works. Each of
different circuits mediating different symptoms according the nine symptoms listed for the diagnosis of a major
to an evolving understanding of the topographical depressive episode can be mapped onto brain circuits
distribution of different functions across different brain whose inefficient information processing theoretically
regions, sometimes called nodes, and across different mediates these symptoms (compare Figure 6-1 and
brain circuits, with connections forming networks. If Figure 6-38). Each of the symptoms listed for the
possibly reductionistic and oversimplified, the theoretical diagnosis of a manic episode can similarly be mapped
notion is to associate specific nodes in the network with onto some of these same but also some different brain
specific psychiatric symptoms. Here we will discuss how circuits (compare Figure 6-2 and 6-39). Note the
this idea might apply to doing this for the nine symptoms innervation of these various brain areas by the three
of a major depressive episode (Figure 6-1) and the nine monoamine neurotransmitter systems (Figure 6-40).
symptoms of a manic episode (Figure 6-2). Glutamate and GABA are ubiquitous throughout
Why do this if our information is still incomplete essentially every area of the brain. This pattern of
and evolving about domains of psychopathology and the monoamine innervation provides the opportunity to
circuits underlying them? It is because it helps us better target various neurotransmitters in order to improve the
6
understand the presenting symptoms of our patients as efficiency of information processing in these brain areas,
well as their symptoms that persist after treatment. The and thus, reduce symptoms. Each node in the networks
goal of this approach is to have a strategy for relieving regulating psychiatric symptoms has neurotransmitters
all symptoms in order to get to complete remission, and distributed to it in a unique if partially overlapping
to do so as rationally as possible based upon how those pattern that regulates each specific hypothetically
specific circuits are currently thought to be regulated malfunctioning brain region (see Figures 6-38 through
by neurotransmitters in normal functioning and in 6-40). Targeting each region with drugs which act on
Match Each Diagnostic Symptom for a Major Depressive Figure 6-38 Matching depression
symptoms to circuits. Alterations in
Episode to Hypothetically Malfunctioning Brain Circuits neuronal activity and in the efficiency
of information processing within
psychomotor each of the brain regions shown here
pleasure fatigue (physical) can lead to symptoms of a major
interests depressive episode. Functionality in
concentration fatigue/ each brain region is hypothetically
interest/pleasure energy
associated with a different constellation
psychomotor of symptoms. PFC, prefrontal cortex;
fatigue (mental) BF, basal forebrain; S, striatum; NA,
nucleus accumbens; T, thalamus;
Hy, hypothalamus; A, amygdala;
H, hippocampus; NT, brainstem
neurotransmitter centers; SC, spinal
PFC S cord; C, cerebellum.
T
NA
BF
guilt Hy
suicidality
worthlessness C
NT
A
H psychomotor
mood
guilt SC fatigue (physical)
suicidality
worthlessness sleep
mood appetite
277
Match Each Diagnostic Symptom for a Manic Episode Figure 6-39 Matching mania
symptoms to circuits. Alterations
to Hypothetically Malfunctioning Brain Circuits in neurotransmission within each of
the brain regions shown here can be
racing thoughts motor/agitation hypothetically linked to the various
goal-directed symptoms of a manic episode.
racing thoughts grandiosity decreased sleep/arousal Functionality in each brain region
grandiosity may be associated with a different
distractibility constellation of symptoms. PFC,
talkative/pressured speech prefrontal cortex; BF, basal forebrain;
S, striatum; NA, nucleus accumbens;
T, thalamus; Hy, hypothalamus; A,
amygdala; H, hippocampus; NT,
brainstem neurotransmitter centers; SC,
spinal cord; C, cerebellum.
PFC S T
decreased
NA
sleep/arousal
BF
Hy
C
mood NT
A
risks H
grandiosity
talkative/pressured speech SC
racing thoughts mood
decreased sleep/arousal
the relevant neurotransmitters that regulate those brain fear, anxiety, hostility, irritability, and loneliness (Figure
regions potentially leads to reduction of each individual 6-41, right). Enhancing serotonin function, and possibly
symptom. The idea is that whenever adjustment of also norepinephrine function, may improve information
specific neurotransmitter-mediated neurotransmission processing in the circuits that hypothetically mediate this
can enhance the efficiency of information processing cluster of symptoms. For patients with symptoms of both
in the hypothetically malfunctioning circuits for each clusters, they may require triple-action treatments that
specific symptom, it will relieve that symptom. If boost all three of the monoamines.
successful, this targeting of neurotransmitters in specific The same general paradigm of neurotransmitter
brain areas could even eliminate all symptoms and cause regulation of the efficiency of information processing
a major depressive episode to go into remission. in specific brain circuits can be applied to mania and to
Many of the mood-related symptoms of depression mixed states as well as depression. Although a simplistic
can be categorized as having either too little positive notion is that the circuit problem in mania may be the
affect or too much negative affect (Figure 6-41). This opposite of that for depression, namely too much in
idea is linked to the fact that there are diffuse anatomic mania versus too little neurotransmitter and neuronal
connections of monoamines throughout the brain, with activity in depression, the reality is that you can have
diffuse dopamine dysfunction in this system driving manic and depressive symptoms at the same time,
predominantly the reduction of positive affect, diffuse and can traverse the entire mood spectrum from full
serotonin dysfunction driving predominantly the increase depression, with increasing amounts of mania, until
in negative affect, and norepinephrine dysfunction arriving at pure mania (Figure 6-7). A more sophisticated
being involved in both. Thus, reduced positive affect and modern notion of mood disorder is that neuronal
includes such symptoms as depressed mood but also transmission in inefficient brain circuits may be chaotic
loss of happiness, joy, interest, pleasure, alertness, and not just too high or too low. The illustrations drawn
energy, enthusiasm, and self-confidence (Figure 6-41, in this chapter sometimes imply there is a single neuron
left). Enhancing dopamine function and possibly also going from one node to another in the network (see for
norepinephrine function may improve information example Figure 6-40), but the reality is that each node
processing in the circuits mediating this cluster of in the network is connected by a vast bundle of neurons,
symptoms. On the other hand, increased negative affect and not all of them are hypothetically functioning
includes not only depressed mood but guilt, disgust, the same way in a mood disorder. Some may have
278
Figure 6-40 Major monoamine projections. (A) Dopamine has

widespread ascending projections that originate predominantly
in the brainstem (particularly the ventral tegmental area and
substantia nigra) and extend via the hypothalamus to the prefrontal
cortex, basal forebrain, striatum, nucleus accumbens, and other
regions. Dopaminergic neurotransmission is associated with
movement, pleasure and reward, cognition, psychosis, and other
functions. In addition, there are direct projections from other
PFC S T sites to the thalamus, creating the “thalamic dopamine system,”
NA which may be involved in arousal and sleep. (B) Norepinephrine
BF has both ascending and descending projections. Ascending
Hy noradrenergic projections originate mainly in the locus coeruleus
of the brainstem; they extend to multiple brain regions, as shown
C
here, and regulate mood, arousal, cognition, and other functions.
Descending noradrenergic projections extend down the spinal
A NT cord and regulate pain pathways. (C) Like norepinephrine,
H serotonin has both ascending and descending projections.
A Ascending serotonergic projections originate mainly in the raphe
SC
nucleus in the brainstem and extend to many of the same regions
as noradrenergic projections. These ascending projections may
regulate mood, anxiety, sleep, and other functions. Descending
serotonergic projections extend down the brainstem and through
the spinal cord; they may regulate pain. PFC, prefrontal cortex; BF,
basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus;
Hy, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem
neurotransmitter centers; SC, spinal cord; C, cerebellum.
6
PFC S T
NA
BF
Hy
C next, but even within an episode over time. This situation
NT
presents a challenge to find treatments that can stabilize
A
H
rather than simply increase or reduce neurotransmitter
action. Treatments for mood disorders are discussed in
SC
detail in Chapter 7.
B
Symptom-Based Treatment Selections
The neurobiologically informed psychopharmacologist
may opt for a symptom-based approach to selecting or
combining a series of drugs for treatment of depression,
mania, and mixed states (Figures 6-42 through 6-44).
This strategy leads to the construction of a portfolio of
PFC
multiple psychopharmacological mechanisms in order
S T
NA
to treat all residual symptoms of a mood disorder until
BF the patient achieves sustained remission. Specific drugs
Hy and treatment choices are discussed in Chapter 7. Here
C we cover the rationale for thinking in neurobiological
A NT terms, namely, the anatomy of brain circuits regulating
H specific symptoms (Figures 6-38 and 6-39) and the
SC neurotransmitters that regulate the circuits (Figure 6-40).
C
The purpose of this approach is to apply understanding
of how a given drug works on neurotransmitters, so a
neurotransmission that is perhaps up, others down, clinician can make rational treatment choices. Using
others normal, and still others vacillating chaotically from this approach, those treatment choices are based upon
up to down in activity. No wonder a patient can appear to addressing those specific symptoms of a given patient
have varying symptoms of concomitant mania during a by targeting the unique collection of hypothetically
full depressive episode, not only from one episode to the malfunctioning brain circuits. This “tailored” approach
279
normal
mood
reduced increased
positive affect negative affect
+++ + - ----
+
NE
NE
depressed mood depressed mood
loss of happiness (joy) guilt/disgust
loss of interest/pleasure fear/anxiety
loss of energy/enthusiasm hostility
decreased alertness irritability
decreased self-confidence loneliness
n
tio
NE
nc
dy
sfu
sfu
DA 5HT
dy
nc
NE
DA d on
tio
ysfun
dysf uncti
n
ction 5HT
Figure 6-41 Positive and negative affect. Mood-related symptoms of depression can be characterized by their affective expression –
that is, whether they cause a reduction in positive affect or an increase in negative affect. Symptoms related to reduced positive affect
include depressed mood; loss of happiness, interest, or pleasure; loss of energy or enthusiasm; decreased alertness; and decreased self-
confidence. Reduced positive affect may be hypothetically related to dopaminergic dysfunction, with a possible role of noradrenergic
dysfunction as well. Symptoms associated with increased negative affect include depressed mood, guilt, disgust, fear, anxiety, hostility,
irritability, and loneliness. Increased negative affect may be linked hypothetically to serotonergic dysfunction and perhaps also
noradrenergic dysfunction.
Figure 6-42 Symptom-based
Symptom-Based Algorithm for Treating Depression Part One: algorithm for treating depression,
Deconstructing Most Common Residual Diagnostic Symptoms part 1. Shown here is the diagnosis
of major depressive disorder
deconstructed into its symptoms
(as defined by the Diagnostic and
major depressive Statistical Manual of Mental Disorders,
disorder
fifth edition [DSM-5]). Of these, sleep
disturbances, problems concentrating,
fatigue and fatigue are the most common
residual symptoms.
concentration
psychomotor
depressed
mood interest/
pleasure guilt/
sleep worthlessness
suicidality appetite/
weight
280
attempts to address the individual patient’s needs and a list of specific symptoms that the individual patient
thereby provide relief of the specific symptoms of that is experiencing (Figure 6-42). Next, these symptoms
individual patient rather than treating all patients with a are matched with the brain circuits that hypothetically
given diagnosis the same. mediate these symptoms (Figure 6-43) and then with the
How is this approach implemented? First, symptoms known neuropharmacological regulation of these circuits
are evaluated and a diagnosis constructed by putting them by neurotransmitters (Figure 6-44). Finally, available
all together, but then that diagnosis is deconstructed into treatment options that target these neuropharmacological
Symptom-Based Algorithm for algorithm for treating depression,
Treating Depression Part Two: part 2. In this figure the most
common residual symptoms of major
Match Most Common Residual Symptoms to depression are linked to hypothetically
Hypothetically Malfunctioning Brain Circuits malfunctioning brain circuits. Insomnia
maybe linked to the hypothalamus
(Hy), problems concentrating to the
interests fatigue (physical) dorsolateral prefrontal cortex (PFC),
fatigue/energy
reduced interest to the PFC and
concentration nucleus accumbens (NA), and fatigue
interest to the PFC, striatum (S), NA, and spinal
cord (SC).
fatigue (mental)
PFC S
NA
Hy
SC
insomnia
fatigue (physical)
Symptom-Based Algorithm for Treating Depression Part Three: algorithm for treating depression,
Target Regulatory Neurotransmitters with Selected Pharmacological Mechanisms part 3. Residual symptoms of
depression can be linked to the
neurotransmitters that regulate them
and then, in turn, to pharmacological
fatigue
mechanisms. Fatigue and
concentration are regulated in large
concentration NE/DA part by norepinephrine (NE) and
dopamine (DA), and therefore may be
treated by agents that boost NE and/
or DA. Sleep disturbance is regulated
NE/DA by serotonin (5HT), γ-aminobutyric
acid (GABA), and histamine (HA) and
sleep can be treated with agents that boost
GABA or block 5HT or HA.
Boost NE or DA
5HT/GABA/
histamine
Boost GABA
Block 5HT, HA
281
mechanisms are chosen to eliminate symptoms one by one approaches (see Chapter 9 on chronic pain and its
(Figure 6-44). When symptoms persist despite treatment, treatment).
another treatment with a different mechanism is added In conclusion, the symptom-based algorithm for
or switched. No evidence proves that this is a superior selecting and combining treatments of mood disorders,
approach, but it appeals not only to clinical intuition but and using them to build a portfolio of mechanisms until
also to neurobiological reasoning as well as to the goal of each symptom of a mood disorder is abolished, is the
individualizing psychopharmacological treatment rather modern psychopharmacologist’s approach to mental
than treating all patients with the same diagnosis the same illnesses in general and to mood disorders in particular.
way in the hope that this will lead to a better outcome. This approach follows contemporary notions of
For example, for the symptoms of “problems neurobiological disease and drug mechanisms, with the
concentrating” and “fatigue,” this approach suggests goal of treatment being sustained remission.
targeting both NE and DA (Figure 6-44). This can also
call for stopping the use of a serotonergic medication if
this is partially the cause of these symptoms. On the other
SUMMARY
hand, for “insomnia,” this symptom is hypothetically This chapter has described the mood disorders across
associated with an entirely different malfunctioning a spectrum from depression to mania with many
circuit regulated by different neurotransmitters (Figure mixed states in between. For prognostic and treatment
6-43); therefore, the treatments for this symptom call for considerations, it is important not only to distinguish
a different approach, namely the use of agents that act unipolar depression from bipolar depression, but also to
on the GABA system or that work to block rather than detect mixed states of subsyndromal mania or depression
boost the serotonin or histamine system (Figure 6-44). It whenever they exist. Although mood disorders are indeed
is possible that any of the symptoms shown in Figure 6-44 disorders of mood, they are much more, and several
would respond to whatever drug is administered, but different symptoms in addition to a mood symptom are
this symptom-based approach can tailor the treatment required to make a diagnosis of a major depressive episode
portfolio to each individual patient, possibly finding or a manic episode. The classic monoamine hypothesis
a faster way of reducing specific symptoms with more of depression, suggesting that dysfunction of one or more
tolerable treatment selections for that patient than a of the three monoamines dopamine, norepinephrine, or
purely random approach. serotonin, or their receptors, may be linked to symptoms
The symptom-based approach for selecting treatments in major depression, has been updated and expanded
for depression can also be applied to treating common to include the notion of abnormalities in neurotrophic
associated symptoms of depression that are not factors, sleep, circadian rhythms, neuroinflammation,
components of the formal diagnostic criteria, such as stress, genes, and the environment in the complex etiology
anxiety and pain. Sometimes it is said that for a good of mood disorders. Also discussed is the troubling notion
clinician to get patients into remission, it requires targeting that mood disorders may be progressive, especially
at least a dozen of the nine symptoms of a mood disorder! if not adequately treated. Finally, each symptom of
Fortunately, psychiatric drug treatments do not a mood disorder can be matched to a hypothetically
respect psychiatric disorders. Treatments that target malfunctioning neuronal circuit. Targeting one or
pharmacological mechanisms in specific brain circuits do more of the neurotransmitters in specific brain regions
so no matter what psychiatric disorder is associated with may improve the efficiency of information processing
the symptom linked to that circuit. Thus, symptoms of there and reduce the symptom caused by that area’s
one psychiatric disorder may be treatable with a proven malfunctioning. Other brain areas associated with the
agent that is known to treat the same symptom in another symptoms of a manic episode can similarly be mapped
psychiatric disorder. For example, anxiety can be reduced to various hypothetically malfunctioning brain circuits.
in patients with major depression who do not have a Understanding the localization of symptoms in circuits, as
full-criteria anxiety disorder with the same serotonin and well as the neurotransmitters that regulate these circuits
GABA mechanisms proven to work in anxiety disorders in different brain regions, can set the stage for choosing
(see Chapter 8 on anxiety disorders and their treatments). and combining treatments for each individual symptom
Painful physical symptoms can be treated with serotonin– of a mood disorder, with the goal being to reduce all
norepinephrine reuptake inhibitors (SNRIs) and other symptoms and lead to remission.
282
7
Treatments for Mood Disorders:
So-Called “Antidepressants” and
“Mood Stabilizers”
Definitions of Clinical Effects of Treatment in Choosing Treatment for Treatment Resistance in
Depression 284 Depression on the Basis of Genetic Testing 323
How Well Do Classic Monoamine Reuptake Augmenting Strategies for Unipolar
Blockers Work in Unipolar Depression? 285 Depression 325
Redefining “Mood Stabilizers”: A Labile Label 288 Second-Line Monotherapies Used for Treatment-
Drugs for Unipolar Depression 289 Resistant Depression 333
Selective Serotonin Reuptake Inhibitors Drugs for Bipolar Disorder Spectrum 338
(SSRIs) 289 Serotonin/Dopamine Blockers: Not Just for
Serotonin Partial Agonist Reuptake Inhibitors Psychosis and Psychotic Mania 338
(SPARIs) 296 Lithium, the Classic “Antimanic” and “Mood
Serotonin–Norepinephrine Reuptake Inhibitors Stabilizer” 345
(SNRIs) 298 Anticonvulsants as “Mood Stabilizers” 346
Norepinephrine–Dopamine Reuptake Inhibitors Anticonvulsants with Proven Efficacy in Bipolar
(NDRIs): Bupropion 303 Disorder 347
Agomelatine 306 Combinations are the Standard for Treating Bipolar
Mirtazapine 308 Disorder 353
Serotonin Antagonist/Reuptake Inhibitors Future Treatments for Mood Disorders 353
(SARIs) 311 Dextromethorphan–Bupropion and
Vortioxetine 315 Dextromethorphan–Quinidine 353
Neuroactive Steroids 320 Dextromethadone 355
Treatment Resistance in Unipolar Hallucinogen-Assisted Psychotherapy 355
Depression 323 Summary 358
In this chapter, we will review pharmacological although they are certainly “drugs for depression.” To
concepts underlying the use of drugs used to treat eliminate confusion about how to discuss categories
mood disorders, from depression, to mixed states, of drugs, throughout this textbook we strive to utilize
to mania. These agents have classically been called modern neuroscience-based nomenclature, where drugs
“antidepressants” and “mood stabilizers” but this are named for their pharmacological mechanism of
terminology is now considered out of date and confusing action and not for their clinical indication.
since not all drugs classically called “antidepressants” Thus, drugs discussed in this chapter have
are used to treat all forms of depression – especially “antidepressant action” but are not called
not bipolar depression or depression with mixed “antidepressants.” Other drugs have mood-stabilizing and
features. Furthermore, many of the classic so-called antimanic action but are not called “mood stabilizers.”
“antidepressants” are also used to treat a whole range of What is a “mood stabilizer”? Originally, a mood stabilizer
disorders from anxiety disorders, to eating disorders, was a drug that treated mania and prevented recurrence
traumatic disorders, obsessive compulsive and impulsive of mania, thus “stabilizing” the manic pole of bipolar
disorders, pain, and beyond. Finally, many of the drugs disorder. Others use this term for a drug that treats
used for psychosis and discussed extensively in Chapter depression and recurrence of depression in bipolar
5 are used even more commonly to treat depression, disorder thus stabilizing the depressed pole of bipolar
unipolar, bipolar, and mixed depression, as well as disorder. Rather than use the term for stabilizing either
mania, yet are not generally classed as “antidepressants” mania or depression, here we will use terms to describe
283
and categorize agents that treat bipolar disorder based symptomatology may be only 20% to 30% reduction of
upon presumed mechanism of therapeutic action. symptoms, with few, if any, patients with schizophrenia
This chapter will review some of the most extensively becoming truly asymptomatic. By contrast, in mood
prescribed psychotropic agents in psychiatry today, disorders there is a greater chance to reach a genuine
namely those that target neurotransmitter transporters, state of sustained and asymptomatic remission and the
receptors, and ion channels. The goal of this chapter is to challenge for those who treat these patients is to help
acquaint the reader with current and evolving ideas about them attain this best outcome whenever possible. That
how the various drugs used to treat disorders of mood is the reason for learning the mechanisms of action of
work. We will explain the mechanisms of action of these so many drugs, the complex biological rationale for
drugs by building upon general pharmacological concepts combining specific sets of drugs, and the practical tactics
introduced in earlier chapters. We will also discuss for tailoring a unique drug treatment portfolio to fit the
concepts about how to use these drugs in clinical practice, needs of an individual patient.
including strategies for what to do if initial treatments
fail and how to rationally combine one drug with another. DEFINITIONS OF CLINICAL
Finally, we will introduce the reader to several new agents EFFECTS OF TREATMENT IN
targeting mood disorders, which have recently been DEPRESSION
approved or are in clinical development.
Our discussion of drugs for the treatment of mood For patients who have a major depressive episode,
disorders in this chapter is at the conceptual level, and unipolar, bipolar, or mixed, and who receive treatment
not at the pragmatic level. The reader should consult and improve to the level 50% reduction of symptoms
standard drug handbooks (such as the companion Stahl’s or more, this outcome is called a response (Figure 7-1).
Essential Psychopharmacology: the Prescriber’s Guide) This used to be the goal of treatment with drugs for
for details of doses, side effects, drug interactions, and depression: namely, reduce symptoms substantially, and
other issues relevant to the prescribing of these drugs in by at least 50%. However, the paradigm for depression
clinical practice. Here we will discuss putting together a treatment has shifted dramatically in recent years so
“portfolio” of two or more mechanisms of action, often that now the goal is complete remission of symptoms
requiring more than one drug, as a strategy for patients (Figure 7-2), and maintaining that level of improvement
who have not responded to single pharmacological so that the patient’s major depressive episode does not
mechanisms. This treatment strategy for mood disorders relapse shortly after remission, nor does the patient have
is very different than that for schizophrenia, discussed a recurrent episode in the future (Figure 7-3). Given the
in Chapter 5, where single antipsychotic drugs as known limits to the efficacy of available drugs to treat
treatments are the rule and the expected improvement in depression, especially when multiple treatment options
Figure 7-1 Response in

depression. When treatment of a
major depressive episode results in at
least 50% improvement in symptoms,
it is called a response. Such patients
are better but not well. Previously, this
was considered the goal of depression
treatment.
HYPOMANIA
response
50% response
medication treatment
284
Chapter 7: Treatments for Mood Disorders
Figure 7-2 Remission in

depression. When treatment of major
depressive episode results in removal
of essentially all symptoms, it is called
remission for the first several months
and then recovery if it is sustained
for longer than several months. Such
patients are not just better – they are
HYPOMANIA well. However, they are not cured, since
remission recovery depression can still recur. Remission
MIXED FEATURES OF MANIA and recovery are now the goals when
100% treating patients with depression.
medication acute
treatment 6-12 continuation maintenance
time weeks 4-9 months 1 or more years
Figure 7-3 Relapse and recurrence

in depression. When depression
returns before there is a full remission
of symptoms or within the first
several months following remission of
symptoms, it is called a relapse. When
depression returns after a patient has
recovered, it is called a recurrence.
HYPOMANIA 7
relapse recurrence
medication acute
treatment 6-12 continuation maintenance
time weeks 4-9 months 1 or more years
are not deployed aggressively and early in the course third of patients with unipolar depression remit on their
of this illness, the goal of sustained remission can be first treatment with a drug from this class, and even after
difficult to reach. Unfortunately, remission is usually not about a year of total treatment with a sequence of four
reached with the first agent chosen to treat depression. different drugs for unipolar depression, each given for 12
weeks, only about two-thirds of patients with unipolar
HOW WELL DO CLASSIC depression ever achieve remission of their symptoms
MONOAMINE REUPTAKE (Figure 7-4).
BLOCKERS WORK IN UNIPOLAR If patients do not fully remit after treatment, what
DEPRESSION? are the most common symptoms that persist? The
answer is shown in Figure 7-5, and the symptoms
The mechanism of action of drugs for unipolar include insomnia, fatigue, multiple painful physical
depression is predominantly inhibition of monoamine complaints (even though these are not part of the formal
reuptake as explained in detail in the following several diagnostic criteria for depression), cognitive problems
sections. Before tackling the mechanism, we can ask, how including difficulty concentrating, and lack of interest or
well do they work? Real-world trials suggest that only a motivation. Drugs for unipolar depression often appear
285
Figure 7-4 Remission rates in unipolar

What Proportion of Unipolar Major Depressive Episodes Remit? depression. Approximately one-third
of patients with unipolar depression
will remit during treatment with any
treatment initially. Unfortunately, for
those who fail to remit, the likelihood
of remission with another monotherapy
goes down with each successive trial.
HYPOMANIA Thus, after a year of treatment with four
67% remission sequential monotherapies taken for 12
MIXED FEATURES OF MANIA after 4 weeks each, only two-thirds of patients
33% 20% 6-7% 6-7% treatments will have achieved remission.
33% nonremitters
67% 47% 40% after 4 treatments
3 months 3 months 3 months

treatment #1 treatment #2 treatment #3 treatment #4
Figure 7-5 Common residual

What Are the Most Common Residual Symptoms in Nonremitters? symptoms. In patients who do not
achieve remission, the most common
residual symptoms are insomnia,
fatigue, painful physical complaints,
problems concentrating, and lack of
interest. The least common residual
symptoms are depressed mood,
HYPOMANIA suicidal ideation, and psychomotor
retardation.
complete
remission 33%
residual OF DEPRESSION
MIXED FEATURES depressed mood
symptoms 67%
least suicidal ideation
common psychomotor
retardation
most insomnia
common fatigue/pain
concentration/
interest
treatment
to work better in improving depressed mood, suicidal was given at all. On the other hand, the bad news is that
ideation, and psychomotor retardation (Figure 7-5). there are still very frequent relapses in the remitters, and
Why should we care whether a patient is in remission these relapse rates are more frequent and come quicker
from major depression or has just a few persistent the more treatments the patient needs in order to get into
symptoms? Part of the answer can be found in Chapter remission (Figure 7-6).
6 in the discussion of neuroprogression from persisting Data like these have galvanized researchers and
symptoms to loss of synapses, loss of neurons, and clinicians alike to treat patients to the point of remission of
treatment resistance (Figures 6-11, 6-28 through 6-33). all symptoms whenever possible, and to try to intervene as
The other part of the answer can be found in Figure 7-6, early as possible in this illness of unipolar major depression,
which illustrates the evolution of treatment resistance not only to be merciful in trying to relieve current
over time, mostly because symptoms persist or return. On suffering from all depressive symptoms, but also because
the one hand, Figure 7-6 shows that if a drug for unipolar of the possibility that aggressive treatment may prevent
depression gets your patient into remission, that patient disease progression (see Chapter 6 and Figures 6-11, 6-28
has a significantly lower relapse rate than if no treatment through 6-33). The concept of disease progression in
286
What Proportion of Unipolar Major Depressive Episodes Relapse?
after 1 treatment after 2 treatments

0% 0%
in remission
33% in remission
not not
relapse
relapse
in remission 50%
rate
rate
in remission
60%
67%
100% 100%
3 6 12 3 6 12
months months months months months months
7
after 3 treatments after 4 treatments
0% 0%
in remission
30%
in remission
relapse
relapse
50% 50%
rate
rate
not
in remission not
70% in remission 70%
100% 100%
3 6 12 3 6 12
months months months months months months
Figure 7-6 Relapse rates. The rate of relapse of major depression is significantly less for patients who achieve remission. However,
there is still a risk of relapse even in remitters, and the likelihood increases with the number of treatments it takes to get the patient to
remit. Thus, the relapse rate for patients who do not remit ranges from 60% at 12 months after one treatment to 70% at 6 months after
four treatments. For those who do remit, the relapse rate ranges from only 33% at 12 months after one treatment all the way to 70% at
6 months after four treatments. In other words, the protective nature of remission virtually disappears once it takes four treatments to
achieve remission.
287
mood disorders is unproven and provocative, but makes “Long live the mood stabilizers.”
a good deal of sense intuitively to many clinicians and – Prescribers
investigators. The idea is that chronicity of a mood disorder,
What is a “mood stabilizer?” As mentioned above,
relapses of a mood disorder, and development of treatment
originally, a mood stabilizer was a drug that treated
resistance could all be reduced, with a better overall
mania and prevented recurrence of mania, thus
outcome in patients with aggressive treatment that leads to
“stabilizing” the manic pole of bipolar disorder. More
remission of all symptoms, thus potentially modifiying the
recently, the concept of mood stabilizer has been defined
course of this illness.
in a wide-ranging manner, from “something that acts
like lithium,” to “an anticonvulsant used to treat bipolar
REDEFINING “MOOD
disorder,” to “an antipsychotic used to treat bipolar
STABILIZERS”: A LABILE LABEL disorder,” to “stabilizing both mania and depression
“There is no such thing as a mood stabilizer.” in bipolar disorder.” Rather than using the term mood
stabilizers, regulatory authorities consider that there
– US FDA
are drugs that can treat any or all of four distinct phases
Figure 7-7 Mania-minded
What Is a “Mood Stabilizer”: treatments. Although the ideal
Mania-Minded Treatments “mood stabilizer” would treat both
treat from above mania and bipolar depression while
also preventing episodes of either
pole, in reality different agents may
be efficacious for different phases of
bipolar disorder. Some agents may be
“mania-minded” and thus able to “treat
HYPOMANIA from above” and/or “stabilize from
stabilize from above above” – in other words, to reduce and/
MIXED FEATURES OF MANIA or prevent symptoms of mania.
Figure 7-8 Depression-minded
What Is a “Mood Stabilizer”: treatments. Although the ideal
Depression-Minded Treatments “mood stabilizer” would treat both
mania and bipolar depression while
also preventing episodes of either
pole, in reality different agents may
be efficacious for different phases of
bipolar disorder. Some agents may be
“depression-minded” and thus able
HYPOMANIA to “treat from below” and/or “stabilize
from below” – in other words, to reduce
MIXED FEATURES OF MANIA and/or prevent symptoms of bipolar
depression.

stabilize from below
treat from below
288
of the illness (Figures 7-7 and 7-8). Thus, a drug can others. There are six principal agents in this group,
be “mania-minded” and “treat from above” to reduce described below, and all share the common property of
symptoms of mania, and/or “stabilize from above” to serotonin reuptake inhibition; thus, they all belong to the
prevent relapse and recurrence of mania (Figure 7-7). same drug class, known as SSRIs. However, each of these
Furthermore, drugs can be “depression-minded” and six drugs also has additional unique pharmacological
“treat from below” to reduce symptoms of bipolar properties that allow them to be distinguished from each
depression, and/or “stabilize from below” to prevent other. First, we will discuss what these six drugs share
relapse and recurrence of depression (Figure 7-8). in common, and then we will explore their distinctive
Not all drugs proven to work in bipolar disorder have individual properties that allow sophisticated prescribers
all four therapeutic actions. In this chapter, we will to match specific drug profiles to individual patient
discuss agents that have one or more of these actions in symptom profiles.
bipolar disorder, but will not refer to any of these agents
What the Six SSRIs Have in Common
as “mood stabilizers” but instead to their presumed
pharmacological mechanism of action. All the six SSRIs have the same major pharmacological
feature in common: selective and potent inhibition of
DRUGS FOR UNIPOLAR serotonin reuptake, also known as inhibition of the
DEPRESSION serotonin transporter (SERT). This simple concept is
shown in Figures 7-9 and 7-10. Although the action of
Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs at the presynaptic axon terminal has classically
Rarely has a class of drugs transformed a field as been emphasized (Figure 7-10), it now appears that
dramatically as the SSRIs have transformed clinical events occurring at the somatodendritic end of the
psychopharmacology. Some estimate that SSRI serotonin neuron (near the cell body) may be more
prescriptions in the US alone occur at the rate of 7 important in explaining the therapeutic actions of
prescriptions per second: over 225 million a year. the SSRIs (Figures 7-11 through 7-15). That is, in the 7
Clinical indications for use of SSRIs range far beyond
unipolar major depressive disorder, to a number of
anxiety disorders, posttraumatic stress disorder (PTSD),
SSRI Action
obsessive–compulsive disorder (OCD), and also to
premenstrual dysphoric disorder, eating disorders, and
SSRI
SERT
Figure 7-9 Selective serotonin reuptake inhibitors. Shown

here is an icon depicting the core feature of selective serotonin
reuptake inhibitors (SSRIs), namely serotonin reuptake inhibition. Figure 7-10 SSRI action. The serotonin reuptake inhibitor (SRI)
Although the agents in this class have unique pharmacological portion of the SSRI molecule is shown inserted into the serotonin
profiles, they all share the common property of serotonin reuptake pump (the serotonin transporter, or SERT), blocking it,
transporter (SERT) inhibition. and causing increased synaptic availability of serotonin.
289
5HT1A Figure 7-11 Mechanism of action of

1A
autoreceptor selective serotonin reuptake inhibitors
(SSRIs), part 1. According to the
5HT postsynaptic monoamine hypothesis of depression,
receptor
there is a relative deficiency of serotonin
(5HT) (see levels of 5HT both in the
SERT synapse near the axon terminal [right]
1A
1A
1A and at somatodendritic areas [left].
1A 1A According to the neurotransmitter
1A
receptor hypothesis of depression,
the number of 5HT receptors is
upregulated, including presynaptic
E 5HT1A autoreceptors as well as
1A
postsynaptic 5HT receptors.

1A
1A
1A
1A
1A
1A
Depressed state: low 5HT, upregulated receptors, low number

of signals in the neuron to release more 5HT
5HT1A Figure 7-12 Mechanism of action of

1A
autoreceptor selective serotonin reuptake inhibitors
(SSRIs), part 2. When an SSRI is
5HT postsynaptic
receptor administered, it immediately blocks the
serotonin reuptake pump or transporter
SERT (SERT) (see icon of an SSRI blocking
1A SERT). However, this causes serotonin
1A
1A
(5HT) to increase initially only in the
1A 1A SSRI somatodendritic area of the 5HT neuron
1A
(left) and not very much in the areas of
the brain where the axons terminate
E
(right). When 5HT levels rise in the
somatodendritic area, this stimulates
1A
1A
1A
nearby 5HT1A autoreceptors.

1A
1A
1A
1A
Antidepressant action: SSRI blocks 5HT reuptake both

at the dendrites and at the axon
depressed state, the monoamine hypothesis of depression for this neuron may also be dysregulated in depression,
states that serotonin may be deficient, both at presynaptic contributing to regional abnormalities in information
somatodendritic areas near the cell body (Figure 7-11, processing, and the development of specific symptoms,
left) and in the synapse itself, near the axon terminal depending upon the region affected, as discussed in
(Figure 7-11, right). The neurotransmitter receptor Chapter 6 and shown in Figure 6-38.
hypothesis proposes that monoamine receptors may be When an SSRI is given acutely, it is well known that
upregulated, as shown in Figure 7-11, representing the serotonin (5HT) rises due to blockade of SERT. What
depressed state before treatment. Neuronal firing rates is somewhat surprising, however, is that blocking the
290
Figure 7-13 Mechanism of action of

selective serotonin reuptake inhibitors
(SSRIs), part 3. The consequence of
increased serotonergic binding at
1A
somatodendritic 5HT1A autoreceptors is
1A that they desensitize or downregulate
(red circle, compare to Figure 7-12).
E
1A
1A
1A
The increase in 5HT causes the autoreceptors to desensitize/downregulate
presynaptic SERT does not immediately lead to a great Once the 5HT1A somatodendritic autoreceptors are
deal of serotonin in many synapses. In fact, when SSRI desensitized, 5HT can no longer effectively turn off its
treatment is initiated, 5HT rises immediately at the own release. Since 5HT is no longer inhibiting its own
somatodendritic area located in the midbrain raphe release, the serotonin neuron is therefore disinhibited
(Figure 7-12, left) due to blockade of SERTs there, rather (Figure 7-14). This results in a flurry of 5HT release from
than in the areas of the brain where the axons terminate axons and an increase in neuronal impulse flow (shown 7
(Figure 7-12, right). as lightning in Figure 7-14 and release of serotonin from
The somatodendritic area of the serotonin neuron the axon terminal on the right). This is just another
is therefore where 5HT increases first (Figure 7-12, way of saying the serotonin release is “turned on” at the
left). Serotonin receptors in this brain area have 5HT1A axon terminals. The serotonin that now pours out of the
pharmacology, as discussed in Chapter 4 and illustrated various projections of serotonin pathways in the brain
in Figure 4-39. When serotonin levels rise in the is what theoretically mediates the various therapeutic
somatodendritic area, this stimulates nearby 5HT1A actions of the SSRIs.
autoreceptors (also on the left in Figure 7-12). These While the presynaptic somatodendritic 5HT1A
immediate pharmacological actions obviously cannot autoreceptors are desensitizing (Figure 7-13), 5HT is
explain the delayed therapeutic actions of the SSRIs. building up in synapses (Figure 7-14), and causes the
However, these immediate actions may explain the postsynaptic 5HT receptors to desensitize as well (Figure
immediate side effects that are caused by the SSRIs when 7-15, right). These various postsynaptic 5HT receptors in
treatment is initiated. turn send information to the cell nucleus of the postsynaptic
Over time, the increased 5HT levels acting at the neuron that serotonin is targeting (on the far right of Figure
somatodendritic 5HT1A autoreceptors causes them to 7-15). The reaction of the genome in the postsynaptic
downregulate and become desensitized (Figure 7-13, neuron is also to issue instructions to downregulate or
left). This desensitization occurs because the increase desensitize some of these receptors as well. The time course
in serotonin is recognized by these presynaptic of this desensitization correlates with the onset of tolerance
5HT1A receptors, and this information is sent to the to the side effects of the SSRIs (Figure 7-15).
cell nucleus of the serotonin neuron. The genome’s This theory thus suggests a pharmacological cascading
reaction to this information is to issue instructions mechanism whereby the SSRIs exert their therapeutic
that cause these same receptors to become desensitized actions: namely, powerful but delayed disinhibition of
over time. The time course of this desensitization serotonin release in key pathways throughout the brain.
correlates with the onset of therapeutic actions of the Furthermore, side effects are hypothetically caused by
SSRIs (Figure 6-25). the acute actions of serotonin at undesirable receptors in
291
Figure 7-14 Mechanism of action

of selective serotonin reuptake
inhibitors (SSRIs), part 4. Once the
somatodendritic 5HT1A receptors
1A
downregulate, there is no longer
1A inhibition of impulse flow in the
serotonin (5HT) neuron. Thus, neuronal
impulse flow is turned on. The
consequence of this is release of 5HT
E in the axon terminal (red circle). This
increase is delayed compared with the
1A
increase of 5HT in the somatodendritic

areas of the 5HT neuron; the delay
is the result of the time it takes for
somatodendritic 5HT to downregulate
the 5HT1A autoreceptors and turn
on neuronal impulse flow in the
1A
5HT neuron. This delay may explain

why SSRIs do not relieve depression
immediately. It is also the reason why
1A the mechanism of action of SSRIs
may be linked to increasing neuronal
impulse flow in 5HT neurons, with 5HT
levels increasing at axon terminals
The downregulation of the autoreceptors causes the neuron to before an SSRI can exert its therapeutic
release more 5HT at the axon effects.

selective serotonin reuptake inhibitors
(SSRIs), part 5. Finally, once the SSRIs
have blocked the reuptake pump (or
1A
serotonin transporter [SERT]), increased
1A somatodendritic serotonin (5HT),
desensitized somatodendritic 5HT1A
autoreceptors, turned on neuronal
impulse flow, and increased release
E of 5HT from axon terminals, the final
step may be the desensitization of
1A
postsynaptic 5HT receptors (red circle).

This desensitization may mediate the
reduction of side effects of SSRIs as
tolerance develops.
1A
1A
The increase of 5HT at the axon causes the postsynaptic receptors to

desensitize/downregulate, reducing side effects
undesirable pathways. Finally, side effects may attenuate to one SSRI versus another. This is not generally observed
over time by desensitization of the very receptors that in large clinical trials where mean group differences
mediate them. between two SSRIs either in efficacy or side effects are
very difficult to document. Rather, such differences are
Unique Properties of Each SSRI: The Not-So-Selective seen by prescribers treating patients one at a time, with
Serotonin Reuptake Inhibitors some patients experiencing a therapeutic response to one
Although the six SSRIs clearly share the same mechanism SSRI and not another, and other patients tolerating one
of action, individual patients often react very differently SSRI and not another.
292
If blockade of SERT explains the shared clinical and depression with 5HT2C antagonist properties include
pharmacological actions of SSRIs, what explains their trazodone, mirtazapine, agomelatine, and some tricyclic
differences? Although there is no generally accepted antidepressants, and these will be described below.
explanation that accounts for the commonly observed Finally, two serotonin 2A/dopamine 2 antagonists,
clinical phenomena of different efficacy and tolerability quetiapine (Figure 5-45) and olanzapine (Figure 5-44),
of various SSRIs in individual patients, it makes sense to also have potent 5HT2C antagonist properties. Both
consider those unique pharmacological characteristics agents are used to treat psychosis (see Chapter 5) but are
of the six SSRIs that are not shared with each other as also approved for augmenting other drugs for unipolar
candidates to explain the broad range of individual depression, treatment-resistant unipolar depression,
patient reactions to different SSRIs (Figures 7-16 through and bipolar depression. Blocking serotonin action at
7-21). Each SSRI has secondary pharmacological actions 5HT2C receptors disinhibits (i.e., enhances) release of
other than SERT blockade, and no two SSRIs have both norepinephrine and dopamine, actions theoretically
identical secondary pharmacological characteristics. beneficial for the treatment of depression (see Chapter
Whether these secondary binding profiles can account for 6 and Figure 6-24B and also the discussion below on
the differences in efficacy and tolerability in individual agomelatine).
patients remains to be proven. However, it does lead to The good news about 5HT2C antagonism may be
provocative hypothesis generation and gives a rational that it is generally activating, and the reason why
basis for psychopharmacologists trying more than one of many patients, even from the first dose, detect an
these agents rather than thinking “they are all the same.” energizing and fatigue-reducing effect of fluoxetine, with
Sometimes only an empiric trial of different SSRIs will improvement in concentration and attention as well. This
lead to the best match of drug to an individual patient. mechanism is perhaps best matched to depressed patients
with reduced positive affect (Figure 6-41), hypersomnia,
Fluoxetine: An SSRI with 5HT2C Antagonist Properties
psychomotor retardation, apathy, and fatigue. Fluoxetine
In addition to serotonin reuptake inhibition, fluoxetine is also approved in some countries in combination with 7
also has 5HT2C antagonist actions that may explain olanzapine for treatment-resistant unipolar depression
many of its unique clinical properties (Figure 7-16). and for bipolar depression. Since olanzapine also has
5HT2C antagonism may contribute to its antidepressant 5HT2C antagonist actions (Figure 5-44), it may be that
actions and also to its efficacy in other disorders, adding the 5HT2C antagonist actions of olanzapine to
especially in eating disorders. Other drugs for unipolar those of fluoxetine could theoretically lead to further
enhanced dopamine and norepinephrine release in
the cortex to mediate the antidepressant actions of this
fluoxetine combination. 5HT2C antagonism may also contribute
to the anti-bulimia effect of higher doses of fluoxetine,
5HT2C
the only SSRI approved for the treatment of this eating
NET disorder. The bad news could be that 5HT2C antagonist
actions of fluoxetine may contribute to this agent being
sometimes less well matched to patients with agitation,
SERT
insomnia, and anxiety, who may experience unwanted
SERT
activation and even a panic attack if given an agent that
further activates them.
Fluoxetine also has weak norepinephrine reuptake
blocking properties (Figure 7-16), which may become
clinically relevant at very high doses. Fluoxetine has
a long half-life (2–3 days), and its active metabolite
Figure 7-16 Fluoxetine. In addition to serotonin reuptake an even longer half-life (2 weeks). The long half-
inhibition, fluoxetine has norepinephrine reuptake inhibition life is advantageous in that it seems to reduce the
(NRI) and serotonin 2C antagonist actions (5HT2C). 5HT2C
antagonism can lead to disinhibition of norepinephrine and withdrawal reactions that are characteristic of sudden
dopamine; this action may be responsible for fluoxetine’s discontinuation of some SSRIs, but it also means that
activating effects. NRI may be clinically relevant only at very high
doses. it takes a long time to clear the drug and its active
293
metabolite after discontinuing fluoxetine, and prior Anecdotally, clinicians have observed the mild and
to starting other agents such as a monoamine oxidase desirable activating actions of sertraline in some patients
(MAO) inhibitor. Fluoxetine is not only available as a with “atypical depression,” improving symptoms of
once-daily formulation, but also as a once-weekly oral hypersomnia, low energy, and mood reactivity. A favorite
dosage formulation. combination of some clinicians for depressed patients is
to add bupropion to sertraline (i.e., Wellbutrin to Zoloft,
Sertraline: An SSRI with Dopamine Transporter (DAT)
sometimes called “Well-oft”), adding together the weak
Inhibition and σ1 Binding
DAT inhibitory properties of each agent. Clinicians have
This SSRI has two candidate mechanisms that also observed the overactivation of some patients with
distinguish it: dopamine transporter (DAT) inhibition panic disorder by sertraline, thus requiring slower dose
and σ1 receptor binding (Figure 7-17). The DAT titration in some patients with anxiety symptoms. All of
inhibitory actions are controversial since they are these actions of sertraline are consistent with weak DAT
weaker than the SERT inhibitory actions, thus leading inhibitory actions contributing to its clinical portfolio of
some experts to suggest that there is not sufficient actions.
DAT occupancy by sertraline to be clinically relevant. The σ1 actions of sertraline are not well understood,
However, as will be discussed later in the section on but might contribute to its anxiolytic effects and
norepinephrine–dopamine reuptake inhibitors (NDRIs), especially to its effects in psychotic and delusional
it is not clear that high degrees of DAT occupancy depression, where sertraline may have advantageous
are necessary or even desirable in order to contribute therapeutic effects compared to some other SSRIs.
to antidepressant actions. That is, perhaps only a
small amount of DAT inhibition is sufficient to cause Paroxetine: An SSRI with Muscarinic Anticholinergic and
improvement in energy, motivation, and concentration, Norepinephrine Transporter (NET) Inhibitory Actions
especially when added to another action such as SERT This SSRI tends to be more calming, even sedating, early
inhibition. In fact, high-impact DAT inhibition is the in treatment compared to the more activating actions of
property of reinforcing stimulants, including cocaine both fluoxetine and sertraline discussed above. Perhaps
and methamphetamine, and would not generally be the mild anticholinergic actions of paroxetine contribute
desired in a drug for depression (see discussion of DAT to this clinical profile (Figure 7-18). Paroxetine also
inhibitors in Chapter 11 on ADHD and Chapter 13 on has weak norepinephrine transporter (NET) inhibitory
impulsivity, compulsivity, and addiction). properties, which could contribute to its efficacy in
depression, especially at high doses. The advantages of
sertraline
paroxetine
DAT
M1
NET
SERT
SERT SERT
SERT
NOS
Figure 7-17 Sertraline. Sertraline has dopamine transporter Figure 7-18 Paroxetine. In addition to serotonin reuptake
(DAT) inhibition and σ1 receptor binding in addition to serotonin inhibition, paroxetine has mild anticholinergic actions
reuptake inhibition (SRI). The clinical relevance of sertraline’s (M1), which can be calming or possibly sedating; weak
DAT inhibition is unknown, although it may improve energy, norepinephrine transporter (NET) inhibition, which may
motivation, and concentration. Its sigma properties may contribute to further antidepressant actions; and inhibition of
contribute to anxiolytic actions and may also be helpful in the enzyme nitric oxide synthase (NOS), which may contribute to
patients with psychotic depression. sexual dysfunction.
294
dual serotonin plus norepinephrine reuptake inhibiting may be an agonist at σ1 receptors, and that this property
properties, or SNRI actions, are discussed below in the may contribute an additional pharmacological action
section on SNRIs. It is possible that weak to moderate to help explain fluvoxamine’s well-known anxiolytic
NET inhibition of paroxetine may contribute importantly properties. Fluvoxamine also has shown therapeutic
to its antidepressant actions. activity in both psychotic and delusional depression,
Paroxetine also inhibits the enzyme nitric oxide where it, like sertraline, may have advantages over other
synthase, which could theoretically contribute to SSRIs.
sexual dysfunction, especially in men. Paroxetine Fluvoxamine is now available as a controlled-release
is also notorious for causing withdrawal reactions formulation, which makes once-daily administration
upon sudden discontinuation, with symptoms such possible, unlike immediate-release fluvoxamine, whose
as akathisia, restlessness, gastrointestinal symptoms, shorter half-life often requires twice-daily administration.
dizziness, and tingling, especially when suddenly In addition, recent trials of controlled-release
discontinued from long-term high-dose treatment. This fluvoxamine show impressive remission rates in both
is possibly due not only to SERT inhibition properties, OCD and social anxiety disorder, as well as possibly less
since all SSRIs can cause discontinuation reactions, peak-dose sedation.
but also to anticholinergic rebound when paroxetine
Citalopram: An SSRI with a “Good” and a “Bad”
is rapidly discontinued. Paroxetine is available in a
Enantiomer
controlled-release formulation, which may mitigate
some of its side effects, including discontinuation This SSRI is comprised of two enantiomers, R and S,
reactions. which are mirror images of each other (Figure 7-20).
The mixture of these enantiomers is known as racemic
Fluvoxamine: An SSRI with σ1 Receptor Binding citalopram, or commonly just as citalopram, and has
Properties mild antihistamine properties that reside in the R
This SSRI was among the first to be launched for the enantiomer. Racemic citalopram is generally one of 7
treatment of depression worldwide, but was never the better-tolerated SSRIs, and has favorable findings
officially approved for depression in the US, so it has been in the treatment of depression in the elderly, but has a
considered more of an agent for the treatment of OCD somewhat inconsistent therapeutic action at the lowest
in the US. Like sertraline, fluvoxamine binds at σ1 sites, dose, often requiring dose increase to optimize treatment.
but this action is more potent for fluvoxamine than for
sertraline (Figure 7-19). The physiological function of citalopram: R+S citalopram
σ1 sites is still a mystery, and thus sometimes called the
“sigma enigma,” but has been linked both to anxiety and
psychosis. Preclinical studies suggest that fluvoxamine
fluvoxamine
1H
S ma R
ram rpo
lop lat
i
cita c
SERT
Figure 7-20 Citalopram. Citalopram consists of two

enantiomers, R and S. Some pharmacological evidence suggests
that the R enantiomer may be pharmacologically active at SERTs
Figure 7-19 Fluvoxamine. Fluvoxamine’s secondary properties in a manner that does not inhibit SERTs but actually interferes
include actions at σ1 receptors, which may be anxiolytic as well with the ability of the active S enantiomer to inhibit SERTs. The R
as beneficial for psychotic depression. enantiomer also has weak antihistamine properties.
295
escitalopram vilazodone
5HT1A
SERT
S-citalopram
SERT
SERT
Figure 7-21 Escitalopram The R and S enantiomers of

citalopram are mirror images of each other but have slightly
different clinical properties. The R enantiomer is the one with
weak antihistamine properties; the R and S enantiomers may
also differ in their effects at the serotonin transporter. The S
enantiomer of citalopram has been developed and marketed as Figure 7-22 Vilazodone. Vilazodone is a partial agonist at the
escitalopram. serotonin 1A receptor and also inhibits serotonin reuptake; thus,
it is referred to as a serotonin partial agonist reuptake inhibitor
(SPARI).
However, dose increase is limited due to the potential
of QTc prolongation at higher doses. These findings all
suggest that it is not favorable for citalopram to contain a SPARI (serotonin partial agonist reuptake inhibitor)
the R enantiomer. In fact, some pharmacological evidence (Figure 7-22). The combination of serotonin reuptake
suggests that the R enantiomer may be pharmacologically inhibition with 5HT1A partial agonism has long
active at SERTs in a manner that does not inhibit SERTs been known by clinicians to enhance the unipolar
but actually interferes with the ability of the active S antidepressant properties and tolerability of SSRIs/SNRIs
enantiomer to inhibit SERTs. This could lead to reduced in some patients (e.g., adding the 5HT1A partial agonist
SERT inhibition, reduced synaptic 5HT, and possibly buspirone [Chapter 8 on anxiety]; the serotonin 1A/
reduced net therapeutic actions, especially at low doses. dopamine 2 partial agonists aripiprazole, brexpiprazole,
or cariprazine [Chapter 5]; or the serotonin/dopamine
Escitalopram: The Quintessential SSRI
antagonist with 5HT1A partial agonist properties,
The solution to improving the properties of racemic quetiapine). With vilazodone this combination
citalopram is to remove the unwanted R enantiomer. mechanism is achieved with only one drug, avoiding drug
The resulting drug is known as escitalopram, as it interactions and various off-target receptor actions that
is comprised of only the pure active S enantiomer may be undesired with the other drugs listed.
(Figure 7-21). This maneuver appears to remove the In animal models, adding 5HT1A partial agonism to
antihistaminic properties and there are no higher dose SSRIs causes more immediate and robust elevations of
restrictions to avoid QTc prolongation. In addition, brain 5HT levels than SSRIs do alone. This is thought to
removal of the potentially interfering R enantiomer be due to the fact that 5HT1A partial agonists are a type of
makes the lowest dose of escitalopram more predictably “artificial serotonin,” selective especially for presynaptic
efficacious. Escitalopram is therefore the SSRI for which somatodendritic 5HT1A autoreceptors, and that 5HT1A
pure SERT inhibition is most likely to explain almost all partial agonist action occurs immediately after the drug
of its pharmacological actions. Escitalopram is considered is given (Figure 7-23). Thus, 5HT1A immediate partial
perhaps the best-tolerated SSRI, with the fewest agonist actions are theoretically additive or synergistic
cytochrome P450 (CYP450)-mediated drug interactions. with simultaneous SERT inhibition (Figure 7-23) since
this leads to faster and more robust actions at 5HT1A
Serotonin Partial Agonist Reuptake Inhibitors (SPARIs)
somatodendritic autoreceptors (Figure 7-24) than with
Vilazodone combines SERT inhibition with 5HT1A SERT inhibition alone (Figure 7-12), including their
partial agonism. For this reason, vilazodone is called downregulation (Figure 7-25). This hypothetically
296
5HT1A Figure 7-23 Mechanism of action

1A
autoreceptor of serotonin partial agonist reuptake
inhibitors (SPARIs), part 1. When a
SERT
SPARI is administered, about half of
serotonin transporters (SERTs) and half
of serotonin 1A (5HT1A) receptors are
1A SPARI occupied immediately.
1A
1A
1A 1A
1A
1A
E
1A
1A
1A
1A
1A
1A
1A
2A
2C
3
6
7
1A
1A
1A
1A
SPARI action: first, about half of SERTs and half of 5HT1A receptors are
occupied immediately

of serotonin partial agonist reuptake
inhibitors (SPARIs), part 2. Blockade of
7
the serotonin transporter (SERT) causes
serotonin to increase initially in the
somatodendritic area of the serotonin
1A neuron (left).
1A
1A
1A 1A
1A
1A
E
1A
1A
1A
1A
1A
1A
1A
2A
2C
3
6
7
1A
1A
1A
1A
SPARI action: second, 5HT increases at 5HT1A somatodendritic

receptors on the left
causes faster and more robust elevation of synaptic 5HT serotonin itself when increased by SERT inhibition alone
(Figure 7-26) than possible with SSRIs alone (Figure 7-14). (Figure 7-14). The downstream actions of 5HT1A receptors
In addition, 5HT1A partial agonism with vilazodone’s that lead to enhanced dopamine release (Figure 7-27) may
SPARI mechanism occurs immediately at postsynaptic be hypothetically responsible for enhanced antidepressant
5HT1A receptors (Figure 7-26), with actions at these and precognitive effects (see Chapter 5 and Figure 5-22).
receptors that are thus faster and with a different type of The addition of 5HT1A partial agonist actions to SERT
stimulation compared to the delayed full agonist actions of inhibition may also account for the observed reduction
297

inhibitors (SPARIs), part 3. The
consequence of serotonin increasing
in the somatodendritic area of the
serotonin (5HT) neuron is that the
1A somatodendritic 5HT1A autoreceptors
1A
desensitize or downregulate (red circle).
1A
E
1A
1A
1A
1A
1A
2A
2C
3
6
7
1A
1A
SPARI action: third, 5HT actions on the left cause 5HT1A autoreceptors
to desensitize/downregulate

inhibitors (SPARIs), part 4. Once
the somatodendritic receptors
downregulate, there is no longer
inhibition of impulse flow in the
1A
1A
serotonin (5HT) neuron. Thus, neuronal
impulse flow is turned on. The
consequence of this is release of 5HT in
the axon terminal (red circle).
1A
1A
E
1A
1A
1A
1A
2A
2C
3
6
7
1A
1A
SPARI action: fourth, neuronal firing and serotonin release are disinhibited at
the synapse on the right
in sexual dysfunction and the relative lack of weight gain Theoretically, there should be some therapeutic advantage
seen in patients treated with vilazodone. of adding NET inhibition to SERT inhibition, since one
mechanism may add efficacy to the other mechanism by
Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs) widening the reach of these drugs to both the serotonin
SNRIs combine the robust SERT inhibition of the SSRIs and the norepinephrine monoamine neurotransmitter
with various degrees of inhibition of the norepinephrine systems throughout more brain regions (see Chapter 6
transporter (NET) (Figures 7-28 through 7-32). and Figures 6-38 and 6-40). A practical indication that
298
5HT1A Figure 7-27 Mechanism of action

1A
autoreceptor of serotonin partial agonist reuptake
inhibitors (SPARIs), part 5. Finally,
SERT once the SPARIs have blocked the
serotonin transporter (SERT), increased
1A
SPARI somatodendritic serotonin (5HT),
1A
desensitized somatodendritic 5HT1A
autoreceptors, turned on neuronal
impulse flow, and increased release
of 5HT from axon terminals, the final
1A
1A step (shown here, red circle) may be
1A
1A the desensitization of postsynaptic 5HT

1A
2A receptors. This timeframe correlates
2C
3 DA with antidepressant action. In addition,
6 the addition of 5HT1A partial agonism
7
may lead to downstream enhancement
of dopamine (DA) release, which may
1A
mitigate sexual dysfunction.
1A
SPARI action: finally, antidepressant actions begin, and downstream enhancement

of DA release may mitigate sexual dysfunction
SERT
SERT
venlafaxine
CYP
2D6 SERT
SERT
NET
desvenlafaxine 7
NET
Figure 7-28 Venlafaxine and desvenlafaxine. Venlafaxine inhibits both the serotonin transporter (SERT) and the norepinephrine
transporter (NET), thus combining two therapeutic mechanisms in one agent. Venlafaxine’s serotonergic actions are present at
low doses, while its noradrenergic actions are progressively enhanced as dose increases. Venlafaxine is converted to its active
metabolite, desvenlafaxine, by CYP450 2D6. Like venlafaxine, desvenlafaxine inhibits reuptake of serotonin and norepinephrine, but
its NET actions are greater relative to its SERT actions compared to venlafaxine. Venlafaxine administration usually results in plasma
levels of venlafaxine that are about half those of desvenlafaxine; however, this can vary depending on genetic polymorphisms of
CYP450 2D6 and if patients are taking drugs that are inhibitors or inducers of CYP450 2D6. Thus, the degree of NET inhibition with
venlafaxine administration may be unpredictable. Desvenlafaxine has now been developed as a separate drug. It has relatively greater
norepinephrine reuptake inhibition than venlafaxine but is still more potent at the SERT.
duloxetine dual monoamine mechanisms may lead to more efficacy is

the finding that the SNRI venlafaxine frequently seems to
have greater unipolar antidepressant efficacy as the dose
increases, theoretically due to recruiting more and more
NET inhibition as the dose is raised (i.e., the noradrenergic
“boost”). Clinicians and experts currently debate whether
SERT remission rates are higher with SNRIs compared to SSRIs
SERT or whether SNRIs are more helpful in depressed patients
who fail to respond to SSRIs than are other options. One
area where SNRIs have established clear efficacy but SSRIs
have not is in the treatment of pain.
NET
NET Inhibition Increases Dopamine in the Prefrontal
Cortex
Figure 7-29 Duloxetine. Duloxetine inhibits both the serotonin
transporter (SERT) and the norepinephrine transporter (NET). Although SNRIs are commonly called “dual action”
Its noradrenergic actions may contribute to efficacy for painful
physical symptoms.
serotonin–norepinephrine agents, they actually have
299
milnacipran: R+S milnacipran levomilnacipran: S-milnacipran
S-milnacipran
SERT
SERT
(levo)
S-milnacipran SERT
SERT TRES R-milnacipran
(levo) (dextro)
NET TEN
NET
Figure 7-31 Levomilnacipran. The R and S enantiomers of

milnacipran are mirror images of each other; the S enantiomer
Figure 7-30 Milnacipran. Milnacipran inhibits both the
is the active enantiomer. The S enantiomer of milnacipran has
serotonin transporter (SERT) and the norepinephrine transporter
been developed and marketed as levomilnacipran.
(NET) but is a more potent inhibitor of NET than SERT. Its robust
NET inhibition may contribute to efficacy for painful physical
symptoms. Milnacipran consists of two enantiomers: S (levo)
and R (dextro), with S as the more active enantiomer.
SNRI Action
Figure 7-32 SNRI actions. The acute dual actions of the serotonin–norepinephrine reuptake inhibitors (SNRIs) are shown. Both the
serotonin reuptake inhibitor portion of the SNRI molecule (left panel) and the norepinephrine reuptake inhibitor portion of the SNRI
molecule (right panel) are inserted into their respective reuptake pumps. Consequently, both pumps are blocked, and synaptic serotonin
and norepinephrine are increased.
300
a third action on dopamine (DA) in the prefrontal Normal DA Release in PFC:

cortex, but not elsewhere in the brain. Thus, they are No DAT, Diffuses to NET
not “full” triple action agents since they do not inhibit
NE
the DA transporter (DAT) except at doses beyond the neuron
clinical range, but SNRIs can perhaps be considered to
have “two-and-a-half actions,” and not just two. That is,
SNRIs not only boost serotonin and norepinephrine (NE)
NET
throughout the brain (Figure 7-32), but they also boost
DA specifically in the prefrontal cortex (Figure 7-33).
This third mechanism of boosting DA in an important
area of the brain associated with several symptoms of DA
neuron
depression should add another theoretical advantage to “normal”
DA diffusion
the pharmacology of SNRIs and to their efficacy in the A
treatment of major depression.

NET Blocked in PFC: “normal”
How does NET inhibition boost DA in the prefrontal NE increases NE diffusion
cortex? The answer is illustrated in Figure 7-33. In
the prefrontal cortex, SERTs and NETs are present
in abundance on serotonin and NE nerve terminals,
respectively, but there are very few DATs on DA nerve
terminals in this part of the brain (Figure 7-33, see also
Chapter 4 and Figure 4-9A). The consequence of this
NET block
lack of DATs in the prefrontal cortex is that once DA is increases NE
released there, it is free to cruise away from the synapse diffusion
(Figure 7-33A). The diffusion radius of DA is thus wider 7
(Figure 7-33A) than the diffusion radius of NE in the
prefrontal cortex (Figure 7-33B) since there are NETs B
at the NE synapse (Figure 7-33B) but no DAT at the DA
NET Blocked in PFC:
synapse (Figure 7-33A). This arrangement may enhance DA increases
the regulatory importance of DA in the prefrontal cortex
functioning, since DA in this part of the brain can NE
neuron
interact with DA receptors not only at its own synapse,
but at a distance, perhaps enhancing the ability of DA to
regulate cognition in an entire area within its diffusion
radius, not just at a single synapse.
Dopamine action is therefore not terminated by DAT “normal”
DA diffusion
in the prefrontal cortex to any significant extent, but by
two other mechanisms. That is, DA diffuses away from NET block
DA increases
the DA synapse until it either encounters the enzyme neuron
DA diffusion
COMT (catechol-O-methyltransferase), which degrades C
it (see Chapter 4 and Figure 4-3) or until it encounters
a NET, which transports it into the NE neuron (Figure Figure 7-33 Norepinephrine transporter blockade and
dopamine in the prefrontal cortex. (A) Although there are
7-33A). NETs in fact have a greater affinity for DA than abundant serotonin transporters (SERTs) and norepinephrine
they do for NE, so they will pump DA as well as NE into transporters (NETs) in the prefrontal cortex (PFC), there are very
few dopamine transporters (DATs). This means that dopamine
NE nerve terminals, halting the action of either. (DA) can diffuse away from the synapse and therefore exert its
What is interesting is to see what happens when there actions within a larger radius. Dopamine’s actions are terminated
at norepinephrine (NE) axon terminals, because DA is taken up
is NET inhibition in the prefrontal cortex. As expected, by NETs. (B) NET blockade in the PFC leads to an increase in
NET inhibition enhances synaptic NE levels and increases synaptic NE, thus increasing NE’s diffusion radius. (C) Because
the diffusion radius of NE (Figure 7-33B). Somewhat NET takes up DA as well as NE, NET blockade also leads to an
increase in synaptic DA, further increasing its diffusion radius.
surprising may be that NET inhibition also enhances Thus, agents that block NET increase NE throughout the brain
DA levels and increases DA’s diffusion radius (Figure and both NE and DA in the PFC.
301
7-33C). The bottom line is that NET inhibition increases the patient is taking another drug that is a CYP450 2D6
both NE and DA in the prefrontal cortex. Thus, SNRIs inhibitor, which shifts the plasma levels towards more
have two-and-a-half mechanisms: boosting serotonin venlafaxine and less desvenlafaxine, also reducing the
throughout the brain, boosting NE throughout the brain, relative amount of NET inhibition. Variability in plasma
and boosting DA in the prefrontal cortex (but not in other levels of venlafaxine versus desvenlafaxine is also due
DA projection areas). to genetic polymorphisms for CYP450 2D6, such that
poor metabolizers will shift the ratio of these two drugs
Venlafaxine
towards more parent venlafaxine and away from the
Depending upon the dose, venlafaxine has different active metabolite desvenlafaxine, and thus reduce the
degrees of inhibition of serotonin reuptake (most potent relative amount of NET inhibition. As a result of these
and robust even at low doses) versus NE reuptake considerations, it can be somewhat unpredictable
(moderate potency and robust only at higher doses) how much NET inhibition a given dose of venlafaxine
(Figure 7-28). However, there are no significant actions will have in a given patient at a given time, whereas
on other receptors. It remains controversial whether this is more predictable for desvenlafaxine. Expert
venlafaxine or other SNRIs have greater efficacy in clinicians have learned to solve this problem with skilled
unipolar major depression than SSRIs, either in terms dose titration of venlafaxine, but the development of
of enhanced remission rates, more robust sustained desvenlafaxine as a separate drug may also solve this
remission over long-term treatment, or greater efficacy problem, with less need for dose titration and more
for treatment-resistant unipolar depression, but this does consistent NET inhibition at a given dose across all
seem plausible given two mechanisms and the boosting patients.
of two monoamines. Venlafaxine is approved and widely
used for several anxiety disorders as well. Adding Duloxetine
NET inhibition likely accounts for two side effects of This SNRI, characterized pharmacologically by slightly
venlafaxine in some patients: sweating and elevated blood more potent SERT than NET inhibition (Figure 7-29), has
pressure. transformed how we think about depression and pain.
Venlafaxine is available as an extended-release Classic teaching was that depression caused pain that was
formulation, which not only allows for once-daily psychic (as in “I feel your pain”) and not somatic (as in
administration but also significantly reduces side “ouch”), and that psychic pain was secondary to emotional
effects, especially nausea. In contrast to several other suffering in depression; therefore, it was thought,
psychotropic drugs available in controlled-release anything that made depression better would make psychic
formulations, extended-release venlafaxine is a pain better nonspecifically. Somatic pain was thus not
considerable improvement over the immediate-release thought to be caused by depression, although depression
formulation, which has fallen into little or no use because could supposedly make it worse, and classically somatic
of unacceptable nausea and other side effects, especially pain was not treated with drugs for depression.
when immediate-release venlafaxine is started or when Studies with duloxetine have changed all this. Not
it is stopped. However, venlafaxine even in controlled- only does this SNRI relieve unipolar depression in the
release formulation can cause withdrawal reactions, absence of pain, but it also relieves pain in the absence
sometimes quite bothersome, especially after sudden of depression. All sorts of pain are improved by this
discontinuation from high-dose long-term treatment. SNRI, from diabetic peripheral neuropathic pain, to
Nevertheless, the controlled-release formulation is highly fibromyalgia, to chronic musculoskeletal pain such
preferred because of enhanced tolerability. as that associated with osteoarthritis and low back
problems, and more. These findings of the efficacy
Desvenlafaxine
of duloxetine for multiple pain syndromes have also
Venlafaxine is a substrate for CYP450 2D6, which validated that painful physical (somatic) symptoms
converts it to an active metabolite desvenlafaxine (Figure are a legitimate set of symptoms that accompany
7-28). Desvenlafaxine has greater NET inhibition relative depression and are not just a form of emotional pain.
to SERT inhibition compared to venlafaxine. Normally, The use of SNRIs such as duloxetine in pain syndromes
after venlafaxine administration, the plasma levels of is discussed in Chapter 9. So, duloxetine has established
venlafaxine are about half of those for desvenlafaxine. efficacy not only in unipolar depression and in chronic
However, this is highly variable, depending upon whether pain, but also in patients with chronic painful physical
302
symptoms of unipolar depression. Painful physical robust NET inhibition of milnacipran suggests that it may
symptoms are frequently ignored or missed by patients be particularly useful in chronic pain related conditions,
and clinicians alike in the setting of unipolar major not just fibromyalgia where it is approved, but possibly
depression, and until recently, the link of these symptoms as well for the painful physical symptoms associated with
to major depression was not well appreciated, in part unipolar depression and chronic neuropathic pain.
because painful physical symptoms are not included Milnacipran’s potent NET inhibition also suggests
in the list of symptoms for the formal diagnostic a potentially favorable pharmacological profile for the
criteria for depression (see Chapter 6 and Figure 6-1). treatment of cognitive symptoms, including cognitive
Nevertheless, it is now widely appreciated that painful symptoms of unipolar depression as well as cognitive
physical symptoms are frequently associated with a symptoms frequently associated with fibromyalgia,
major depressive episode, and are also one of the leading sometimes called “fibro-fog.” Other clinical observations
residual symptoms after initial treatment with drugs for possibly linked to milnacipran’s robust NET inhibition
depression (Figure 7-5). It appears that the dual SNRI are that it can be more energizing and activating than
actions of duloxetine and other SNRIs are superior to other SNRIs. Common residual symptoms after treatment
the selective serotonergic actions of SSRIs for treatment with an SSRI include not only cognitive symptoms, but
of conditions such as neuropathic pain of diabetes and also fatigue, lack of energy, and lack of interest, among
chronic painful physical symptoms associated with other symptoms (Figure 7-5). NET inhibition may be
depression. The role of NET inhibition seems to be related to observations that milnacipran may cause
critical for the treatment not only of painful conditions more sweating and urinary hesitancy than some other
without depression, but also for painful physical SNRIs. For patients with urinary hesitancy, generally
symptoms associated with depression. Duloxetine due theoretically to robust pro-noradrenergic actions at
has also shown efficacy in the treatment of cognitive bladder α1 receptors, an α1 antagonist can reduce these
symptoms of depression that are prominent in geriatric symptoms. Milnacipran must generally be given twice
depression, possibly exploiting the pro-noradrenergic and daily due to its shorter half-life. 7
pro-dopaminergic consequences of NET inhibition in the
Levomilnacipran
prefrontal cortex (see Figure 7-33).
Duloxetine can be given once a day, but this is usually Milnacipran is actually a racemic mixture of two
only a good idea after the patient has had a chance to enantiomers (Figure 7-30). The S or levo enantiomer
become tolerant to it after initiating it at twice-daily is the active enantiomer (Figure 7-31) and has been
dosing, especially during titration to higher doses. independently developed for unipolar major depressive
Duloxetine may have a lower incidence of hypertension disorder in the US, where it is mostly available. Like
and milder withdrawal reactions than venlafaxine. racemic milnacipran, levomilnacipran has greater NET
inhibition than SERT inhibition and may target fatigue
Milnacipran and lack of energy as potential clinical advantages. Also,
Milnacipran is the first SNRI marketed in Japan and many it is dosed in a controlled-release formulation, so, unlike
European countries such as France, where it is currently racemic milnacipran, can be given only once a day.
marketed as a drug for unipolar depression. In the US,
Norepinephrine–Dopamine Reuptake Inhibitors
milnacipran is not approved for unipolar depression,
(NDRIs): Bupropion
but is approved for fibromyalgia. Interestingly, it is the
other way around in Europe: milnacipran is approved for For many years, the mechanism of action of bupropion
unipolar depression but not approved for the treatment has been unclear and still remains somewhat
of fibromyalgia. Milnacipran is a bit different from other controversial. Bupropion itself only has weak reuptake
SNRIs in that it is a relatively more potent NET than blocking properties for dopamine (DAT inhibition),
SERT inhibitor (Figure 7-30), whereas the others are and for norepinephrine (NET inhibition) (Figures 7-34
more potent SERT than NET inhibitors (Figures 7-28 and 7-35). No other specific or potent pharmacological
and 7-29). This unique pharmacological profile may actions have been consistently identified for this
explain milnacipran’s somewhat different clinical profile agent. Bupropion’s actions both as a drug for unipolar
compared to other SNRIs. Since noradrenergic actions depression and upon norepinephrine and dopamine
may be equally or more important for treatment of pain- neurotransmission, however, have always appeared to be
related conditions compared to serotonergic actions, the more powerful than these weak properties could explain,
303
leading to proposals that bupropion acts rather vaguely as

NDRI an adrenergic modulator of some type.
Bupropion is metabolized to a number of active
metabolites, some of which are not only more potent
DAT NET inhibitors than bupropion itself and equally potent
DAT inhibitors, but are also concentrated in the brain. In
some ways, therefore, bupropion is both an active drug
and a precursor for other active drugs (i.e., a prodrug
for multiple active metabolites). The most potent of
these is the + enantiomer of the 6-hydroxy metabolite of
bupropion, also known as radafaxine.
Can the net effects of bupropion on NETs (Figure 7-36A
NET and 7-36B) and DATs (Figure 7-36C) account for its clinical
actions in depressed patients at therapeutic doses? If one
believes that 90% transporter occupancy of DATs and
NETs are required for drugs for antidepressant actions,
Figure 7-34 Norepinephrine–dopamine reuptake inhibitor the answer would be “no.” Human positron emission
(NDRI). The prototypical norepinephrine–dopamine reuptake
inhibitor (NDRI) is bupropion. Bupropion has weak blocking tomography (PET) scans suggest that as little as 10–15%
properties for the dopamine transporter (DAT) and for the and perhaps no more than 20–30% of striatal DATs may
norepinephrine transporter (NET). Its antidepressant actions may
be explained in part by the more potent inhibitory properties of be occupied at therapeutic doses of bupropion. NET
its metabolites. occupancy would be expected to be in this same range. Is
this enough to explain bupropion’s antidepressant actions?
NDRI Action
Figure 7-35 NDRI actions. The norepinephrine reuptake inhibitor portion of the NDRI molecule (left panel) and the dopamine reuptake
inhibitor portion of the NDRI molecule (right panel) are inserted into their respective reuptake pumps. Consequently, both pumps are
blocked, and synaptic norepinephrine and dopamine are increased.
304
NDRI action in prefrontal cortex: NET blockade increases NE and DA

“normal”
NE diffusion
NE
neuron
NET blockade “normal”

increases NE DA diffusion
diffusion
NET blockade
DA increases
neuron DA diffusion
A B
NDRI action in striatum:

DAT blockade increases DA
DAT blockade
increases
DA diffusion 7
“normal”
DA diffusion
DA
neuron
DAT C
Figure 7-36 NDRI actions in prefrontal cortex and striatum. Norepinephrine–dopamine reuptake inhibitors (NDRIs) block the
transporters for both norepinephrine (NETs) and dopamine (DATs). (A) NET blockade in the prefrontal cortex leads to an increase in
synaptic norepinephrine (NE), thus increasing NE’s diffusion radius. (B) Because the prefrontal cortex lacks DATs, and NETs transport
dopamine (DA) as well as NE, NET blockade also leads to an increase in synaptic DA in the prefrontal cortex, further increasing DA’s
diffusion radius. Thus, despite the absence of DAT in the prefrontal cortex, NDRIs still increase DA there. (C) DAT is present in the
striatum, and thus DAT inhibition increases DA diffusion there.
Whereas it is clear from many research studies that Furthermore, there appears to be such a thing as
SSRIs must be dosed to occupy a substantial fraction of “too much DAT occupancy.” That is, when 50% or more
SERTs, perhaps up to 80% or 90% of these transporters, in of DATs are occupied rapidly and briefly, this can lead
order to be effective drugs for depressions, this is far less to unwanted clinical actions, such as euphoria and
clear for NET or DAT occupancy, particularly in the case reinforcement (see discussion of the mysterious DATs
of drugs with an additional pharmacological mechanism in Chapter 11 on attention deficit hyperactivity disorder
that may be synergistic with NET or DAT inhibition. [ADHD] treatment). In fact, rapid, short-lasting, and
That is, when most SNRIs are given in doses that occupy high degrees of DAT occupancy are the pharmacological
80–90% of SERTs, substantially fewer NETs are occupied, characteristics of abusable stimulants such as cocaine
yet there is evidence of both additional therapeutic (discussed in Chapter 13 on drug abuse and reward).
actions and NE-mediated side effects of these agents with When 50% or more of DATs are occupied more slowly
perhaps as little as 50% NET occupancy. and in a more long-lasting manner, especially with
305
controlled-release formulations, DAT inhibitors are less symptoms of reduced positive affect following treatment
abusable and more useful for ADHD (see Chapter 11). with an SSRI or an SNRI, or who develop these symptoms
The issue to be considered here is whether a low level as a side effect of an SSRI or SNRI, frequently benefit from
of slow-onset and long-lasting DAT occupancy is the switching to bupropion or from augmenting their SSRI
desirable solution for the DAT mechanism to be useful or SNRI treatment with bupropion. The combination
as a drug for unipolar depression: thus, not too much or of bupropion with an SSRI or an SNRI has a theoretical
too fast DAT inhibition and therefore abusable; not too rationale as a strategy for covering the entire symptom
little DAT inhibition and therefore ineffective; but just portfolio from symptoms of reduced positive affect to
enough DAT inhibition with slow enough onset and long symptoms of increased negative affect (Figure 6-41).
enough duration of action to make it an effective drug for Bupropion combined with the μ-opioid antagonist
unipolar depression. naltrexone is approved for the treatment of obesity and
The fact that bupropion is not known to be mentioned in Chapter 13 on impulsivity/compulsivity
particularly abusable, is not a scheduled substance, yet syndromes. Bupropion combined with the NMDA (N-
is proven effective for treating nicotine addiction, is methyl-D-aspartate) antagonist dextromethorphan is in
consistent with the possibility that it is occupying DATs late-stage clinical trials both for depression (mentioned
in the striatum and nucleus accumbens in a manner below) and for agitation in Alzheimer disease (discussed
sufficient to mitigate craving but not sufficient to in Chapter 12 on dementia).
cause abuse (Figure 7-36C). This use of bupropion for
Agomelatine
smoking cessation is discussed further in Chapter 13 on
drug abuse and reward. Perhaps this low level of DAT Agomelatine (Figure 7-37) is approved to treat unipolar
occupancy (Figure 7-36C) is also how bupropion works in depression in many countries outside of the US. It has
unipolar depression, combined with an equally low action agonist actions at melatonin 1 (MT1) and melatonin
on NETs (Figure 7-36A and 7-36B). 2 (MT2) receptors and antagonist actions at 5HT2C
Bupropion was originally marketed only in the receptors (Figure 7-37). As discussed above in the section
US as an immediate-release dosage formulation for
three-times-daily administration as a drug for unipolar
depression. Development of a twice-daily formulation agomelatine
(bupropion SR) and then a once-daily formulation
(bupropion XL) have not only reduced the frequency
of seizures at peak plasma drug levels, but have also
5H
increased convenience and enhanced compliance as well.

T2
B
Thus, the use of immediate-release bupropion is all but 5H

T2
abandoned in favor of once-daily administration. C
Bupropion is generally activating or even stimulating.
Bupropion does not appear to cause the bothersome sexual
dysfunction that frequently occurs with many drugs for
unipolar depression that act by SERT inhibition, probably
because bupropion lacks a significant serotonergic
component to its mechanism of action. Thus, bupropion
has proven to be a useful drug for unipolar depression not
only for patients who cannot tolerate the serotonergic side
effects of SSRIs, but also for patients whose depression MT1 MT2
does not respond to serotonergic boosting by SSRIs.
Consistent with its pharmacological profile, bupropion Figure 7-37 Agomelatine. Endogenous melatonin is secreted
is especially targeted at the symptoms of the “dopamine by the pineal gland and mainly acts in the suprachiasmatic
nucleus to regulate circadian rhythms. There are three types
deficiency syndrome” and “reduced positive affect” (see of receptors for melatonin: 1 and 2 (MT1 and MT2), which are
Figure 6-41), including improvement in the symptoms both involved in sleep, and 3, which is actually the enzyme
NRH–quinine oxidoreductase 2 and not thought to be involved
of loss of happiness, joy, interest, pleasure, energy, in sleep physiology. Agomelatine is not only a melatonin 1
enthusiasm, alertness, and self-confidence. Almost every and 2 receptor agonist, but is also a 5HT2C and 5HT2B receptor
antagonist, and is available to treat depression in countries
active clinician knows that patients who have residual outside of the US.
306
Agomelatine Releases Norepinephrine and Dopamine in the Frontal Cortex
250 350
agomelatine
vehicle 300
DA change from Basal (%)

NE change from Basal (%)
200 250
200
150
150
100 100
0 60 120 180 0 60 120 180

time (min) time (min)
NE release DA release
prefrontal cortex
overactivation
DA
NE
locus coeruleus VTA
neuron 7
neuron
GABA
interneurons
5HT2C
agomelatine agomelatine
5HT
neuron
raphe

Figure 7-38 Agomelatine releases norepinephrine and dopamine in the prefrontal cortex. Normally, serotonin binding at 5HT2C
receptors on γ-aminobutyric acid (GABA) interneurons in the brainstem inhibits norepinephrine (NE) and dopamine (DA) release in the
prefrontal cortex. When a 5HT2C antagonist such as agomelatine binds to 5HT2C receptors on GABA interneurons (bottom red circle), it
prevents serotonin (5HT) from binding there and thus prevents inhibition of NE and DA release in the prefrontal cortex; in other words, it
disinhibits their release (top red circles).
on fluoxetine, 5HT2C antagonist actions are a property localized in the suprachiasmatic nucleus (SCN) of the
of several drugs used to treat unipolar depression hypothalamus, the brain’s “pacemaker,” where they
(agomelatine, fluoxetine, trazodone, mirtazapine, interact with melatonin receptors also located there
some tricyclic antidepressants) and bipolar depression (Figure 7-39). Light is detected by the retina during
(olanzapine and quetiapine). 5HT2C receptors are the day, and this information travels to the SCN via the
located in the midbrain raphe and prefrontal cortex retinohypothalamic tract (Figure 7-39; see also Chapter
where they regulate the release of dopamine and 6 and Figures 6-36A and 6-36B), which normally
norepinephrine, an action thought to improve depressive synchronizes many circadian rhythms downstream from
symptoms (see Figure 7-38). 5HT2C receptors are also the SCN. For example, both melatonin receptors and
307
5HT2C receptors fluctuate in a circadian manner in the as well, appears to resynchronize circadian rhythms,
SCN, with high receptor expression at night/dark and low reverse the phase delay of depression, and thereby exert
receptor expression in the day/light. That makes sense an antidepressant effect (Figure 7-39).
since melatonin is only secreted at night in the dark (see
Mirtazapine
Chapter 6 and Figures 6-35 and 6-36B). In some patients
with unipolar depression, however, circadian rhythms Mirtazapine (Figure 7-40) is marketed worldwide and, unlike
are “out of synch,” including low melatonin secretion at almost every other drug for unipolar depression, it
night among numerous other changes. Theoretically, does not block any monoamine transporter. Instead,
agomelatine, by stimulating melatonin receptors in the mirtazapine is a multifunctional drug with five principal
SCN and simultaneously blocking 5HT2C receptors there mechanisms of action: 5HT2A, 5HT2C, 5HT3, α2-adrenergic,
NE
DA
agomelatine
VTA LC
retinohypothalamic
tract pineal
SCN gland
Healthy Control
Depression
sleep sleep
7 am 11 pm 7 am 11 pm 7 am
Figure 7-39 Agomelatine may resynchronize circadian rhythms. Agomelatine, which acts as an agonist at melatonin 1 and 2 receptors,
may resynchronize circadian rhythms by acting as “substitute melatonin.” Thus, even in the absence of melatonin production in the
pineal gland, agomelatine can stimulate melatonin 1 and 2 receptors in the suprachiasmatic nucleus (SCN) to reset circadian rhythms.
5HT2C receptors are also present in the SCN and blocked by agomelatine. In addition, by blocking 5HT2C receptors in the ventral
tegmental area (VTA) and locus coeruleus (LC), agomelatine promotes dopamine (DA) and norepinephrine (NE) release in the prefrontal
cortex.
Figure 7-40 Mirtazapine and

α α α
1 mianserin. Mirtazapine’s primary
2A 2A
therapeutic action is α2 antagonism.
It also blocks three serotonin (5HT)
receptors: 5HT2A, 5HT2C, and 5HT3.
H H Finally, it blocks histamine 1 (H1)
1 1
receptors. Mianserin has a similar
binding profile to mirtazapine, the only
difference being additional effects at α1
mirtazapine receptors. NaSSA: noradrenergic and
5HT2A
(NaSSA) 5HT2A mianserin
mianserin
specific serotonergic antidepressant.
2C 2C
5HT 5HT
T3
T3
5H
5H
308
and H1 histamine antagonism. Two other α2 antagonists the left) has already been discussed and is illustrated
are marketed as drugs for depression in some countries again here. However, there are also α2 “hetero” receptors
(but not the US), namely mianserin (worldwide except US) on serotonin neurons (Figure 7-41A, B, C on the left).
and setiptiline (Japan). Unlike mirtazapine, mianserin also There are many cases where neurotransmitter release is
has potent α1 antagonist properties, which tend to mitigate controlled not only by their “own” autoreceptor, but also
its ability to enhance serotonergic neurotransmission so by presynaptic receptors for “another” neurotransmitter
that this drug enhances predominantly noradrenergic at heteroreceptors (Figure 7-41A; see also Figure 4-45
neurotransmission, yet with associated 5HT2A, 5HT2C, and discussion of presynaptic 5HT1B heteroreceptors on
5HT3, and H1 antagonist properties (Figure 7-40). norepinephrine, dopamine, histamine, and acetylcholine
Clinical consequences of blocking H1 receptors neurons). The same phenomenon is shown in Figure
have been discussed in Chapter 5 and illustrated in 7-41B where not only is serotonin turning off serotonin
Figure 5-13A, showing that H1 antagonist actions are release at its own 5HT1B presynaptic autoreceptor on
associated with sedation and weight gain. 5HT2A antagonist the left hand part of the serotonin neuron, but also
properties also have been discussed in Chapter 5 and norepinephrine migrating from a norepinephrine
illustrated in Figures 5-16 and 5-17, showing increases in terminal is turning off serotonin release via an α2
downstream release of dopamine in the prefrontal cortex, presynaptic heteroreceptor on the right hand part of the
potentially associated with antidepressant actions. 5HT2A serotonin neuron. Norepinephrine is also turning off its
antagonism also improves sleep, especially slow-wave sleep, own release via an α2 presynaptic receptor (Figure 7-41B
which can be helpful in many depressed patients. 5HT2C on the right at the norepinephrine neuron). This sets up
antagonist actions were just explained in the preceding the situation whereby an α2 antagonist can have a dual
section and illustrated in Figure 7-38, showing enhanced effect, facilitating the release of both norepinephrine and
release of norepinephrine and dopamine in the prefrontal serotonin (Figure 7-41C). Not only does α2 antagonism
cortex, which would theoretically improve depression. disinhibit norepinephrine release (Figure 7-41C on the
Here we explain the other actions of mirtazapine, notably right), it also disinhibits serotonin release (Figure 7-41C 7
α2 antagonist actions and 5HT3 antagonist actions. Some on the left). Thus, α2 antagonism causes dual 5HT–NE
other drugs for unipolar depression also have potent α2 action. This is something like the same net outcome as
antagonist actions (Figure 5-35), including brexpiprazole an SNRI but by an entirely different mechanism. Rather
(Figure 5-57) and quetiapine (Figure 5-45). Some other than blocking serotonin and norepinephrine presynaptic
drugs for bipolar depression also have α2 antagonist transporters, α2 antagonism “cuts the brake cable” of
actions, including quetiapine (Figure 5-45) and lurasidone noradrenergic inhibition (NE stepping on the brake to
(Figure 5-53). Another agent for treatment of unipolar prevent 5HT and NE release shown in Figure 7-41B is
depression that has potent 5HT3 antagonist properties is blocked in Figure 7-41C).
vortioxetine, discussed below. These two mechanisms, monoamine transport
blockade and α2 antagonism, are synergistic, so
Alpha-2 Antagonist Action
that blocking them simultaneously gives a much
Alpha-2 antagonism is another way to enhance the more powerful disinhibitory signal to these two
release of monoamines and exert an antidepressant neurotransmitters than if only one mechanism is blocked.
action in unipolar depression. Recall that norepinephrine For this reason, the α2 antagonist mirtazapine is often
turns off its own release by interacting with presynaptic combined with SNRIs for treatment of cases that do
α2 autoreceptors on noradrenergic neurons (discussed in not respond to an SNRI alone. This combination of
Chapter 6 and illustrated in Figures 6-14 through 6-16; mirtazapine with an SNRI is sometimes called “California
see also Figure 7-41A and B on the right). Therefore, rocket fuel” because of the potentially powerful drugs
when an α2 antagonist is administered, norepinephrine for depression blasting the patient out of the depths of
can no longer turn off its own release and noradrenergic depression.
neurons are thus disinhibited from their axon terminals,
such as those in the raphe and in the cortex as shown in 5HT3 Antagonist Action
Figure 7-41C on the right. The 5HT3 receptors best known to clinicians are perhaps
The general principle of serotonin turning off those localized in the chemoreceptor trigger zone of the
serotonin release at serotonin 5HT1B autoreceptors brainstem, where they mediate nausea and vomiting,
(Figure 4-41 and Figure 7-41A compared to 7-41B on especially in response to cancer chemotherapy, and
309
5HT neuron NE neuron
5HT1
B/D α2
α2
5HT1
B/D α2
α2
= α2 antagonist
5HT1
B/D α2
α2
Figure 7-41 Alpha-2 antagonism increases serotonin and norepinephrine release in raphe and cortex. (A) On the left, a serotonergic
neuron is shown with 5HT1B/D autoreceptors and α2-adrenergic heteroreceptors. On the right, a noradrenergic neuron is shown with
presynaptic α2 autoreceptors. (B) 5HT1B/D autoreceptors and α2-adrenergic heteroreceptors on serotonergic neurons both function as
“brakes” to shut off serotonin release when bound by their respective neurotransmitters (left). Likewise, when norepinephrine binds
to α2 autoreceptors on the norepinephrine neuron, this shuts off further norepinephrine release (right). (C) Alpha-2 antagonists “cut
the serotonin brake cable” when they block α2 presynaptic heteroreceptors, thus leading to enhanced serotonin release (left). Alpha-2
antagonists also “cut the norepinephrine brake cable” by blocking presynaptic α2 autoreceptors, leading to enhanced norepinephrine
release (right).
also those localized in the gastrointestinal tract itself, it means that trazodone will act predominantly via its
where they mediate nausea, vomiting, and diarrhea/ highest-affinity receptor interactions at low doses, and
bowel motility when stimulated by serotonin, including will recruit its lower-affinity receptor actions at higher
when stimulated by serotonin that is a side effect of doses.
peripherally increased serotonin by SSRIs/SNRIs.
Different Drug at Different Doses and at Different
Blocking these 5HT3 receptors can therefore protect
Delivery Rates?
against chemotherapy-induced nausea and vomiting
as well as against serotonin-induced gastrointestinal Trazodone is famous for its effectiveness and utility at
side effects that can accompany agents that increase low doses as a hypnotic (Figure 7-46). That is, doses of
serotonin. trazodone lower than those effective for antidepressant
More important to the mechanism of action of central action are quite frequently used for insomnia. Hypnotic
5HT3 antagonists such as mirtazapine and vortioxetine doses engage the receptors for which trazodone has
in the treatment of unipolar depression are the 5HT3 the highest affinity and, amongst these, blockade is
receptors in the brain that regulate the release of hypothetically linked to hypnotic actions (i.e., 5HT2A,
various neurotransmitters downstream in some brain α1 subtypes, and H1). Blocking 5HT2A receptors
circuits that mediate the symptoms of depression. 5HT3 enhances slow-wave sleep, and blocking α1 subtypes
receptors in the brain are usually localized on GABA and H1 receptors interferes with monoamine arousal
(γ-aminobutyric acid) interneurons, and they are always mechanisms (discussed in Chapter 5 and illustrated in
excitatory. This means that when serotonin stimulates a Figures 5-13 and 5-14). The best way to deliver a hypnotic
5HT3 receptor, it causes GABA to inhibit whatever neuron is with a standard oral formulation that is immediate in
is downstream from it. This was shown for 5HT3–GABA onset, peaks quickly, and is out of the system by morning.
interactions at glutamate neurons (Figure 4-49) and Since insomnia is one of the most frequent residual
at acetylcholine and norepinephrine neurons (Figure symptoms of depression after treatment with an SSRI/
4-48). 5HT3 antagonism is a powerful disinhibitor of SNRI (discussed earlier in this chapter and illustrated in 7
glutamate release (Figure 7-42) and of acetylcholine and Figure 7-5), addition of a hypnotic is often necessary in
norepinephrine (Figure 7-43), actions that theoretically treating patients with a major depressive episode. Not
release neurotransmitters downstream to have only can addition of a hypnotic potentially relieve the
antidepressant action. insomnia itself, it may also increase remission rates due
to improvement of other symptoms such as loss of energy
Serotonin Antagonist/Reuptake Inhibitors (SARIs) and depressed mood (Figure 7-5). Thus, the ability of low
The prototype drug that blocks serotonin 2A and 2C doses of trazodone to improve sleep in depressed patients
receptors as well as serotonin reuptake is trazodone, has led to its popular use at low doses as an augmenting
classified as a serotonin antagonist/reuptake inhibitor option for residual insomnia that persists after treatment
(SARI) (Figure 7-44). Nefazodone is another SARI with with SSRIs/SNRIs.
robust 5HT2A antagonist actions and weaker 5HT2C The original oral formulation of trazodone used for
antagonism and SERT inhibition, but is no longer depression was short in duration, required multiple daily
commonly used because of rare liver toxicity (Figure doses higher than hypnotic doses (Figure 7-47), and was
7-44). Trazodone is a very interesting agent, since it acts associated with peak dose sedation after daytime doses,
like two different drugs, depending upon the dose and not an ideal profile for a drug for unipolar depression.
the formulation. We discussed a very similar situation in Although trazodone’s antidepressant actions at higher
Chapter 5 for quetiapine (Figure 5-46). doses are undisputed as well as its lack of causing sexual
A more complete picture of trazodone’s binding dysfunction or weight gain, the presence of daytime
properties has emerged from recent studies (Figures 7-44 sedation makes using trazodone at antidepressant doses
and 7-45) and reflects that it is a serotonin antagonist in the standard oral formulation difficult in clinical
not just at 5HT2A and 5HT2C receptors, but also at 5HT1D, practice. However, a once-daily controlled-release
5HT2B, and 5HT7 receptors. In addition, trazodone has formulation with higher doses of trazodone is available
potent antagonist properties at α1B, α1A, α2C, and α2B for use in depression, which blunts peak plasma drug
receptors, H1 histamine receptors, and agonist actions at levels to reduce daytime sedation. These higher doses
5HT1A receptors (Figure 7-45). Because of these various recruit additional known antidepressant receptor actions,
pharmacological actions occur with varying potencies, including serotonin reuptake inhibition (Figures 7-10
311
Serotonin at 5HT3 Receptors Regulates Glutamate
Release and Downstream Neurotransmitters
GABA
3+ -
5HT
Raphe
regular spiking, late
spiking or bursting
GABA interneuron
- inhibitory
+ excitatory Regulation of downstream

3 5HT3 receptor
5HT3 Antagonists Disinhibit Glutamate Release and Enhance the Release

of Downstream Neurotransmitters to Improve Depression
GABA
3 + -
5HT3
antagonist
5HT
Raphe
Figure 7-42 5HT3 receptors regulate glutamate and downstream neurotransmitters. Serotonin (5HT) binding at 5HT3 receptors on
GABA interneurons is stimulatory; thus, it increases GABA release. GABA, in turn, inhibits glutamate pyramidal neurons, reducing
glutamate output. Decreased release of excitatory glutamate means that there may be a resultant decrease in downstream release of
neurotransmitters, since pyramidal neurons synapse with the neurons of most other neurotransmitters. Antagonism at the 5HT3 receptor
removes GABA inhibition and thus disinhibits pyramidal neurons. The increase in glutamate neurotransmission may in turn increase the
downstream release of neurotransmitters.
5HT3 Receptors Cause Inhibition of Norepinephrine and

Acetylcholine Release
5HT
3
+
GABA
GABA inhibits
5HT NE release
- Prefrontal
5HT
Cortex
Raphe inhibition of NE release
3
+
GABA
GABA inhibits
ACh release
inhibition of ACh release

non-parvalbumin positive, Basal
regular spiking, late ACh Forebrain
spiking or bursting
GABA interneuron
- inhibitory
+ excitatory
3 5HT3 receptor NE
Locus
Coeruleus
5HT3 Antagonists Enhance Norepinephrine and

7
Acetylcholine Release
3
+
5HT3 GABA
antagonist
5HT
Prefrontal
Cortex
Raphe
NE release 3
+
5HT3 GABA
antagonist
ACh release
Basal
ACh Forebrain
NE
Locus
Coeruleus
Figure 7-43 5HT3 receptors regulate norepinephrine and acetylcholine release. When serotonin (5HT) is released, it binds to
5HT3 receptors on GABAergic neurons, which release GABA onto noradrenergic and cholinergic neurons, thus reducing release of
norepinephrine (NE) and acetylcholine (ACh), respectively. Antagonism at the 5HT3 receptor removes GABA inhibition and disinhibits
noradrenergic and cholinergic neurons, leading to release of norepinephrine and acetylcholine.
313
α α α
1 2 1
5H
T
1A
5H H T
T2
A 1 NE
5HT1D
SERT SERT
trazodone
mianserin mianserin
nefazodone
2B 2A
5HT 5HT
C
T2
C
5H
T2
5H
5HT7
Figure 7-44 Serotonin antagonist/reuptake inhibitors (SARIs). Shown here are icons for two serotonin antagonist/reuptake inhibitors
(SARIs): trazodone and nefazodone. These agents have a dual action, but the two mechanisms are different from the dual action of
the serotonin–norepinephrine reuptake inhibitors (SNRIs). The SARIs act by potent blockade of serotonin 2A (5HT2A) receptors as well
as dose-dependent blockade of serotonin 2C (5HT2C) receptors and the serotonin transporter (SERT). SARIs also block α1-adrenergic
receptors. Trazodone has the unique properties of histamine 1 (H1) receptor antagonism and antagonism at multiple additional
serotonin receptors.
1000
higher affinity lower affinity
800
target affinity Ki (nM)
600
400
200
0
2C
1A
1B
2B
D
e)
A
A
B
t)
C
T7
1
B
RT
H
T2
T1
T2
T1
ra
D
tiv
T2
T1
5H
a
a
SE
l(
5H
5H
5H
5H
ph
ph
ph
ph
ec
5H
5H
ne
el
al
al
al
al
an
-s
on
ch
a-
(n
N
a
m
sig
Figure 7-45 Trazodone affinity for different receptors. Trazodone has binding affinity for numerous receptor subtypes, but the potency
varies. Thus, at low doses, trazodone may act predominantly via its highest-affinity receptor actions, with other properties becoming
relevant only at higher doses.
through 7-15) and antagonist action at 5HT1D, 5HT2C, levels to act at all serotonin receptors, stimulating 5HT1A
5HT7, and α2 receptors, as well as 5HT1A agonist actions. receptors for therapeutic actions while concomitantly
The bottom line is that there are numerous potential stimulating 5HT2A receptors and 5HT2C receptors that
mechanisms to cause monoamine neurotransmitter theoretically cause the side effects of SSRIs including
release and antidepressant actions at higher doses. sexual dysfunction, insomnia, and activation/anxiety
Furthermore, with first-dose hypnotic actions, trazodone (Figure 7-48A). However, trazodone blocks the actions of
can exert its antidepressant actions with rapid onset and serotonin at 5HT2A and 5HT2C receptors, accounting for
enhanced tolerability for some side effects compared its profile of lack of sexual dysfunction and reduction of
to SSRIs/SNRIs. That is, SSRIs/SNRIs raise serotonin anxiety and insomnia.
314
Trazodone for Depression: Trazodone for Insomnia: Figure 7-46 Trazodone at different doses. (Left)
Serotonin Antagonist/ Multifunctional Neurotransmitter High doses that recruit saturation of the
Reuptake Inhibitor (SARI) Antagonist serotonin transporter (i.e., 150–600 mg) are
required for trazodone to have therapeutic
α α
2
actions in depression. At this high dose,
1
trazodone is a multifunctional serotonergic
5H
agent with antagonist actions at 5HT2A and

T1
A
5H α1 5HT2C receptors as well as additional serotonin

H
T2
A 1
H1 receptors. Trazodone is also an α1 and histamine
1 (H1) antagonist at these doses. (Right) At lower
5HT1D
SERT
doses of trazodone (i.e., 25–150 mg), it does
trazodone
mianserin 5HT2A
not saturate the serotonin transporter; it does,
B
however, retain antagonist actions at 5HT2A, α1,
5HT2 and H1 receptors, with corresponding efficacy for
insomnia.
C
T2
5H
5HT7
dose for depression dose for insomnia

(150-600 mg) (25-150 mg)
Trazodone IR vs. XR Given Once Nightly Figure 7-47 Trazodone IR versus XR

given once nightly. Shown here are
steady-state estimates of the plasma
2.2 trazodone levels from the hypnotic dosing
2 of 50, 75, or 100 mg once nightly of
trazodone immediate release (IR). Peak
1.8 drug concentrations are reached rapidly
with a similarly rapid fall off overnight.
1.6 The minimum levels estimated for 7
antidepressant actions of trazodone are
1.4 reached transiently, if at all, by hypnotic
dosing. By contrast, 300 mg of trazodone
1.2 300 mg XR qhs extended release (XR) given once
nightly generates plasma levels that rise
mg/L
1 100 mg IR qhs slowly and never fall below minimum

minimum antidepressant concentrations. Peak levels
0.8 antidepressant of trazodone XR at 300 mg are about the
concentration
same as the peak levels of trazodone IR
0.65 at 100 mg.
75 mg IR qhs
0.5
0.3 50 mg IR qhs
0.1
0
23:30 4:00 8:00 12:00 16:00 20:00 23:30
hours
Vortioxetine cognitive actions, especially improving processing speed.

Vortioxetine is a drug approved for treating unipolar The importance of cognitive symptoms in unipolar
depression and which causes SERT inhibition as well as depression is discussed in Chapter 6 as the possible
having antagonist actions at 5HT3 and 5HT7 receptors, clinical consequence of loss of neurotrophic factors,
with agonist actions at 5HT1A receptors and weak synapses, and neurons (Figures 6-27 through 6-31).
partial agonist to antagonist actions at 5HT1B/D receptors What is cognitive processing speed and what could
(Figure 7-49). This unique blend of pharmacological be the mechanism by which vortioxetine improves this
actions leads to downstream release of many different more than other antidepressants? “Cognition” is not a
neurotransmitters as will be explained here, and these single, simple brain function and “cognitive dysfunction”
actions hypothetically lead to antidepressant effects is not a single, simple symptom. Cognitive impairment
in unipolar depression, characterized by robust pro- that can be measured as part of the symptom profile
315
SSRI Action SARI Action at 5HT Synapses
SARI
SSRI
5HT2A 5HT1A 5HT2C 5HT2A 5HT1A 5HT2C
antidepressant antidepressant
sexual dysfunction sexual dysfunction

insomnia insomnia
anxiety anxiety
A B
Figure 7-48 SSRI vs. SARI. (A) Inhibition of the serotonin transporter (SERT) by a selective serotonin reuptake inhibitor (SSRI) at
the presynaptic neuron increases serotonin at all receptors, with 5HT1A-mediated antidepressant actions but also 5HT2A- and 5HT2C-
mediated sexual dysfunction, insomnia, and anxiety. (B) SERT inhibition by a serotonin 2A antagonist/reuptake inhibitor (SARI) at the
presynaptic neuron increases serotonin at 5HT1A receptors, where it leads to antidepressant actions. However, SARI action also blocks
serotonin actions at 5HT2A and 5HT2C receptors, thus failing to cause sexual dysfunction, insomnia, or anxiety. In fact, these blocking
actions at 5HT2A and 5HT2C receptors can improve insomnia and anxiety, and theoretically can exert antidepressant actions of their own.
of a psychiatric disorder, and that can be targeted improve cognition across all these various disorders.
for improvement with drug treatment, is the type “Memory difficulties” are the hallmark of dementia
of cognition most relevant to psychopharmacology. and discussed in Chapter 12. “Memory difficulties” in
Intellectual impairments as measured by IQ are not mood disorders are discussed in Chapter 6 and may be
particularly amenable to improvement with drug a component of chronic depression and PTSD, when
treatment and, other than with schizophrenia, are not loss of synapses and neurons in a major node in the
generally associated with psychiatric disorders treated neuronal network of memory, namely the hippocampus,
in psychopharmacology. On the other hand, “problems occurs. If early loss of neurotrophic factors in mood
concentrating” and “difficulty paying attention” are disorders hypothetically causes potentially reversible loss
seen in many psychiatric disorders and are treatable of synapses, it is important to treat cognitive symptoms
in a range of conditions, including mood disorders in depression soon after they emerge so effective
(Chapter 6), anxiety disorders (Chapter 8), schizophrenia treatments for depression can trigger the release of
and psychotic disorders (Chapter 4), ADHD (Chapter growth factors and restore synaptogenesis (Figures 6-27
11), sleep disorders (Chapter 10), and beyond. Such through 6-31), before neurons are lost and the changes
cognitive symptoms are a great example of a domain of become irreversible. Thus, recognizing and targeting
psychopathology that cuts across many, many psychiatric cognitive symptoms is becoming more important as new
disorders and implies that the same circuits and neuronal treatments emerge.
networks are impaired across all these various disorders. But how can we recognize and monitor cognitive
It also implies that the same treatments may work to symptoms in psychopharmacology? A simple if
316
vortioxetine
5H
T 1A
5H
T1B
5HT1D
SERT
T3
5H
5HT7
Figure 7-49 Vortioxetine. Vortioxetine is a serotonin reuptake

inhibitor and also has actions at several serotonin receptors,
including 5HT1A, 5HT1B, 5HT1D, 5HT3, and 5HT7.
somewhat whimsical way to categorize cognitive

dysfunction and to understand the role of improving
7
individual domains of cognition applicable to
psychopharmacology is illustrated in Figure 7-50 as the Figure 7-50 The “Fab Four” of cognition. Cognition is not
a single, simple brain function. Rather, there are four major
“Fab Four” of cognition. Remember the original Fab cognitive domains, represented here by the four members
Four, the Beatles? Each musician can represent one of the of the Beatles: attention or concentration (John), executive
function or problem solving (Paul), memory (George), and
Fab Four of cognition as well. John, arguably the leader, processing speed (Ringo). All four domains work in concert to
wanted all the attention, so he represents “attention,” keep cognition playing at its best; if any one of these domains
dysfunctions, then cognitive impairment can occur.
which some also refer to as concentration. Paul, perhaps
the brains of the operation and the writer of many of
the songs, is “executive function,” also called “problem calibrating the objective decline in cognitive performance
solving.” The quiet culture carrier of the group, George, of patients with subjective cognitive complaints, and in
represents memory, of which there are many kinds, tracking their improvement on treatment. Vortioxetine
short-term, long-term, verbal, and more. And finally, the improves cognition better than other antidepressants in
drummer, Ringo, represents processing speed, or pace. unipolar major depression, as demonstrated by superior
You can imagine if any of these four is out of synch with performance on the DSST measuring processing speed.
the other three, the music would be a disaster. All four How does vortioxetine work as an antidepressant and
can potentially be compromised in psychiatric disorders. specifically how does it exert its superior pro-cognitive
It turns out that for depression, a test that measures a bit effects?
of all these dimensions of cognition, but arguably most SERT Inhibition and 5HT1A Agonism
prominently measures processing speed, is the DSST
To begin, vortioxetine is a SERT inhibitor and a 5HT1A
(digital symbol substitution test). When processing speed
agonist, thus combining the actions already discussed
is slowed, just like an offbeat drummer in a band, overall
for SSRIs (Figures 7-10 through 7-15) and for combining
cognitive functioning can also feel like a disaster for a
SERT inhibition with 5HT1A agonists (see Chapter 5 and
depressed patient, lagging in cognitive performance,
Figures 7-23 through 7-27). These mechanisms alone
with mental effort now becoming exhausting and
are sufficient for antidepressant action since they raise
work productivity greatly reduced, all causing great
both serotonin levels (SERT inhibition) and the pro-
frustration. This simple, quick DSST can be useful in
317
5HT neuron
5HT1B/D
axon terminal SSRI
autoreceptor
SERT
5HT1B/D
antagonist
A B C
Figure 7-51 SERT inhibition and 5HT1B/D presynaptic antagonism. (A) 5HT1B/D autoreceptors and serotonin transporters (SERTs) are
both present on the axon terminal of a serotonin (5HT) neuron. (B) When SERT is inhibited, synaptic availability of serotonin is increased.
However, serotonin binding at the 5HT1B/D receptor prevents further serotonin release. (C) When both SERTs and the 5HT1B/D receptors
are blocked, increased synaptic serotonin via SERT inhibition is combined with ongoing serotonin release via 5HT1B/D antagonism,
further increasing the availability of serotonin in the synapse.
cognitive neurotransmitter dopamine, acetylcholine, this enhances the release of the antidepressant and pro-
and norepinephrine levels (5HT1A agonism) (see also cognitive neurotransmitters dopamine, norepinephrine,
discussion in Chapter 4, Figure 4-44). histamine, and acetylcholine (Figure 7-52B).
SERT Inhibition and 5HT1B/D Presynaptic Antagonism SERT Inhibition and 5HT3 Antagonism
An additional receptor action that theoretically Another mechanism whereby 5HT3 antagonists enhance
raises serotonin levels even further than by SERT the release of the pro-cognitive neurotransmitters
inhibition alone is inhibition of the 5HT1B/D presynaptic acetylcholine, dopamine, and norepinephrine is
autoreceptor (Figure 7-51). That is, when SERT is illustrated in the earlier discussion of 5HT3- antagonism
inhibited, the amount of synaptic serotonin that (Figure 7-43) and is one of the most potent of
accumulates is blunted because the build-up of serotonin vortioxetine’s several pharmacological actions.
stimulates presynaptic 5HT1B/D autoreceptors, and this
SERT Inhibition and 5HT7 Antagonism
turns off further serotonin release (compare Figure
7-51A and B). However, when 5HT1B/D presynaptic Serotonin inhibits its own release by actions at 5HT7
autoreceptors are simultaneously inhibited, negative receptors (compare Figures 7-53A and 7-53B). Thus,
feedback to serotonin release cannot occur, so serotonin antagonism at 5HT7 receptors enhances serotonin release,
release increases even more (Figure 7-51C). especially in the presence of SERT inhibition (Figure
7-53C). Blocking 5HT7 receptors on GABA neurons in
5HT1B Partial Agonism/Antagonism at the brainstem raphe prevents the downstream inhibition
Heteroreceptors
of serotonin release by GABA, especially in the presence
Another putative mechanism of antidepressant and of SERT inhibition, and leads instead to increased
pro-cognitive actions of vortioxetine is antagonist/partial downstream release of serotonin (Figure 7-53C).
agonist actions on 5HT1B receptors located on presynaptic 5HT7 receptors also regulate glutamate release
nerve terminals of acetylcholine, dopamine, histamine, downstream in the prefrontal cortex (Figure 7-54A).
and norepinephrine neurons in the prefrontal cortex. Blocking these 5HT7 receptors on GABA interneurons
These receptors were discussed earlier in Chapter 4 and enhances the release of glutamate and of downstream
illustrated in Figure 4-45, showing how serotonin acting monoamine neurotransmitters (compare Figures 7-54A
at these receptors inhibits the release of acetylcholine, and 7-54B), which may have both antidepressant and
histamine, dopamine, and norepinephrine. These pro-cognitive actions. Indeed, in experimental animals,
receptors are shown again in Figure 7-52A and when selective 5HT7 antagonists do have pro-cognitive and
they are blocked by a 5HT1B partial agonist/antagonist, antidepressant actions. Also, numerous agents with
318
Figure 7-52 5HT1B heteroreceptors

5HT1B Heteroreceptor Regulation of NE, DA, HA, regulate neurotransmitter release. (A)
and ACh in Prefrontal Cortex 5HT1B receptors on the presynaptic
nerve terminals of norepinephrine
(NE), dopamine (DA), acetylcholine
Baseline Neurotransmitter Release (ACh), and histamine (HA) neurons can
theoretically regulate the release of these
neurotransmitters. Serotonin (5HT) acting
at these receptors would be inhibitory.
Prefrontal Cortex
(B) Antagonism or partial agonism of
5HT1B heteroreceptors on ACh, HA, DA,
and NE neurons would prevent serotonin
from exerting its inhibitory effects, thus
5HT potentially increasing the release of these
1B
neurotransmitters.
Raphe
NE
1B
DA
1B
HA
1B
ACh
A ACh
BF HA
TMN DA
VTA NE
LC 7
5HT1B Antagonist/Partial Agonist Enhances Neurotransmitter Release
Prefrontal Cortex
5HT
1B
Raphe 5HT1B
antagonist/
partial agonist
1B
5HT1B
antagonist/
partial agonist
1B
5HT1B
antagonist/
partial agonist
1B
5HT1B
BF = Basal Forebrain
antagonist/
TMN = Tuberomammillary Nucleus
partial agonist ACh
LC = Locus Coeruleus BF HA
TMN DA
VTA NE
B LC
5HT7 antagonism are effective drugs for depression and Putting it all together, vortioxetine’s pharmacological
possibly for improving cognition, including not only mechanism of action is multimodal, with numerous
vortioxetine, but also trazodone (Figures 7-44 and 7-45), synergistic mechanisms not only leading to the release of
quetiapine, brexpiprazole, aripiprazole, and lurasidone serotonin and to potentiating the release of serotonin (i.e.,
(see Chapter 5 and Figure 5-39). via SERT, 5HT1B/D presynaptic, and 5HT7 blockade), but
319
Figure 7-53A 5HT7 receptors regulate

Baseline Serotonin Release serotonin release, part 1. 5HT7
receptors are located on GABA
interneurons in the raphe nucleus. At
baseline, when these receptors are not
bound, serotonin is released into the
prefrontal cortex.
baseline
5HT release
PFC
overactivation
5HT7
receptor
GABA neuron 5HT

neuron
raphe
also leading to the release of four further antidepressant Neuroactive Steroids

and pro-cognitive neurotransmitters, namely dopamine, Another rapid-onset mood treatment is the neuroactive
norepinephrine, acetylcholine, and histamine (i.e., via steroid brexanolone, a cyclodextrin-based intravenous
5HT1A agonism, 5HT1B heteroreceptor partial agonism/ formulation of the naturally occurring neuroactive
antagonism, and 5HT3 antagonism). This unique steroid allopregnanolone (Figure 7-55). Administered
combination of mechanisms may account for the unique by a 60-hour intravenous infusion for postpartum
pro-cognitive actions of vortioxetine in unipolar major depression, brexanolone has a rapid-onset and sustained
depression. antidepressant effect. As briefly mentioned in Chapter 6,
320
Figure 7-53B 5HT7 receptors

5HT7 Inhibits Serotonin Release regulate serotonin release, part
2. When serotonin binds to 5HT7
receptors on GABA interneurons in
the raphe nucleus, this stimulates
GABA release. GABA in turn inhibits
serotonin release in the prefrontal
cortex.
reduced
5HT release
PFC
overactivation
5HT7
receptor
Stimulation of 5HT7 Receptors
in the Raphe Reduces
GABA neuron 5HT Serotonin Release
neuron
raphe
pregnant women have high circulating and presumably of neuroactive steroids without relapsing, following the
brain levels of naturally occurring allopregnanolone. infusion.
After delivery of the baby, there is a precipitous decline Neuroactive steroids bind to GABAA receptors at
in circulating and presumably brain levels of neuroactive a specific allosteric site called the neuroactive steroid
steroids, hypothetically triggering the sudden onset of a site, which enhances the inhibitory action of GABA
major depressive episode in vulnerable women. Rapidly at GABAA receptors (Figure 7-56; see also discussion
restoring neuroactive steroid levels over a 60-hour period in Chapter 6 and Figures 6-20 and 6-21). Neuroactive
of continuous intravenous infusion with brexanolone steroids target the benzodiazepine-sensitive GABAA
rapidly reverses depression, and the 60-hour duration of receptors, just like benzodiazepines (Figure 7-56A)
administration seems to provide the time necessary for but also the benzodiazepine-insensitive GABAA
postpartum patients to accommodate to their lower levels receptors, unlike benzodiazepines (Figure 7-56B).
321
Figure 7-53C 5HT7 receptors

5HT7 Antagonist Enhances Serotonin Release regulate serotonin release,
part 3. Antagonism at
5HT7 receptors on GABA
interneurons in the raphe
nucleus turns off GABA release.
This prevents the downstream
inhibition of serotonin release
by GABA, thus increasing
serotonin in the prefrontal
cortex.
increased
5HT release
PFC
overactivation
5HT7
antagonist
GABA neuron 5HT

neuron
raphe
Certain general anesthetics (e.g., propofol, etomidate,

the treatment of depression come from observations that
alphaxolone, alfadalone) also bind at the same sites as
GABA levels are reduced in the plasma, spinal fluid, and
neuroactive steroids, but are dosed much higher. Since
brains of depressed patients; GABA interneurons are
benzodiazepines do not have antidepressant actions, it is
reduced in brains of depressed patients; and mRNA levels
the targeting of the benzodiazepine-insensitive GABAA
for the specific GABAA receptor subunits that encode the
receptors (Figure 7-56B) that is thought to be the primary
benzodiazepine-insensitive GABAA receptor subtypes are
mechanism of antidepressant action of neuroactive
also deficient in brains of depressed patients who died
steroids.
by suicide. Perhaps neuroactive steroids compensate for
The benzodiazepine-insensitive GABAA receptors
these GABA-related defects and this is how they mediate
are extrasynaptic and mediate tonic inhibition (see
their rapid-onset antidepressant actions.
discussion in Chapter 6 and Figure 6-20). The way in
SAGE-217 (Figure 7-57) is a synthetic orally active
which engaging their allosteric neuroactive steroid sites
allopregnanolone analogue in clinical testing as a rapid-
results in a rapid and possibly enduring treatment for
onset antidepressant for major depressive disorder, with
major depression is unknown. Hints as to why boosting
some promising preliminary results.
GABA action may be effective for a novel approach to
322
Figure 7-54A 5HT7 receptors

Baseline Glutamate Release regulate glutamate release, part
1. 5HT7 receptors are located on
GABA interneurons in the prefrontal
cortex, which themselves synapse
with glutamate neurons. At baseline,
pyramidal when these receptors are not bound,
glutamate is released.
neuron
GABA neuron
5HT7
receptor
PFC
baseline
glutamate release
overactivation
7
5HT
neuron
raphe
records. In the meantime, it is possible to obtain from

TREATMENT RESISTANCE IN various laboratories genetic variants for a number of
UNIPOLAR DEPRESSION genes that regulate drug metabolism (pharmacokinetic
genes) and that hypothetically regulate efficacy and
Choosing Treatment for Treatment Resistance in side effects of drugs in depression (pharmacodynamic
Depression on the Basis of Genetic Testing genes). For example, several genetic forms of numerous
Genetic testing has the potential of assisting the selection cytochrome P450 (CYP450) drug metabolizing enzymes
of psychotropic drug treatment for depression, especially can be obtained to predict high or low levels of drug, and
when several first-line treatments have failed to work therefore lack of efficacy (low drug levels) or side effects
or to be tolerated. Genotyping has already entered other (high drug levels). These findings can also be coupled
specialties in medicine, and is poised to enter mental with phenotyping, namely obtaining the actual plasma
health practice. In the not-too-distant future, experts drug level itself. CYP450 genotypes and the actual plasma
foresee that most patients will have their entire genomes drug levels together can thus potentially help explain side
entered as part of their permanent electronic medical effects and lack of therapeutic effects in some patients.
323
Figure 7-54B 5HT7 receptors regulate

5HT7 Antagonist Enhances Glutamate Release glutamate release, part 2. Antagonism
at 5HT7 receptors on GABA interneurons
in the prefrontal cortex turns off GABA
release. This prevents inhibition of
glutamate release by GABA, thus
pyramidal increasing glutamate downstream.
neuron
GABA neuron
5HT7
antagonist
PFC
enhanced
glutamate release
overactivation
5HT
neuron
raphe
CH2OH CH2OH CH2OH

H
O O O
H H
OH OH OH
O O
OH OH
HO
OH OH OH H
dextrin allopregnanolone
Figure 7-55 Brexanolone. Brexanolone is a cyclodextrin-based intravenous formulation of the naturally occurring neuroactive steroid
allopregnanolone.
324
chloride chloride
GABA channel GABA channel
binding site binding site
benzodiazepine and neuroactive steroid

neuroactive steroid binding site
binding site
α ß α4,6 ß
γ ß α4,6
ß α
= GABA
= benzodiazepine
= neuroactive steroid
A B
Figure 7-56 Neuroactive steroid binding site on GABAA neurons. Neuroactive steroids bind to GABAA receptors at a specific allosteric
site called the neuroactive steroid site to enhance the inhibitory action of GABA at these receptors. Neuroactive steroids bind to both
benzodiazepine-sensitive (A) and benzodiazepine-insensitive (B) GABAA receptors.
Neuroactive Steroid whether the patient is “biased” towards responding or

allopregnanolone analogue not, tolerating or not, and, along with past treatment
SAGE-217 response, help the clinician make a future treatment
7
recommendation that has a higher chance of success
but is not guaranteed to be effective and tolerated. Some
call this process the “weight of the evidence” and others
“equipoise,” where the genetic information will enrich the
prescribing decision, but not necessarily dictate a single
compelling choice. Genetic testing makes the prescriber
think about, and develop feasible neurobiologically based
hypotheses for, the next choices in treatment, rather than
mere random selection from amongst treatments that
have not yet been attempted.
Augmenting Strategies for Unipolar Depression
As discussed above and illustrated in Figures 7-4 and
7-6, there are diminishing returns of efficacy for unipolar
depression, the more drugs for depression that are tried.
Figure 7-57 SAGE-217. SAGE-217 is a synthetic orally active
allopregnanolone analogue in clinical testing as a rapid onset This has led to earlier use of antidepressant combinations
antidepressant for major depressive disorder. for patients who do not respond well to a single agent, in
an attempt to add together synergistic mechanisms that
Treatment responses are not “all or none” phenomena, could help the patient attain remission.
and genetic markers in psychopharmacology will, in
all likelihood, explain a greater or lesser likelihood of Serotonin/Dopamine Antagonists/Partial Agonists as
response, nonresponse, or side effects, but will not tell Augmenting Agents for Treatment-Resistant Unipolar
a clinician with certainty what drug to prescribe for a Depression
specific individual to guarantee a clinical response or Serotonin/dopamine blocking agents originally developed
avoid a side effect. So far, and for the foreseeable future, for psychosis are now some of the most common
in the practice of psychopharmacology, the information adjunctive treatments to SSRIs/SNRIs in patients with
obtained from pharmacogenomics will likely tell unipolar depression who fail to respond adequately to one
325
or more trials of the various first-line monoamine agents Its efficacy as an augmenting agent to SSRIs/SNRIs for
discussed so far in this chapter. depression is likely linked to the combined actions of
quetiapine and its active metabolite norquetiapine at both
Olanzapine–Fluoxetine Combination
5HT2C receptors (Figure 7-38) and at the norepinephrine
Dopamine 2 (D2) antagonist actions likely account for transporter (NET) (Figure 5-34; also described in Chapter
olanzapine’s approval in schizophrenia, bipolar mania, 5 and illustrated in Figure 5-45). In addition, quetiapine
and bipolar maintenance. 5HT2A antagonist actions acts at other candidate receptors for antidepressant
likely account for some of olanzapine’s ability to improve efficacy including as an antagonist at 5HT2A (Chapter 5
symptoms of depression (5HT2A actions on mood are and Figure 5-17C), 5HT7 (Figure 7-53C) and α2A receptors
discussed in Chapter 5 and illustrated in Figure 5-17C). (Figure 5-35), as well as an agonist at 5HT1A receptors
However, the fact that olanzapine works much better for (Chapter 5 and Figure 5-22). All of these receptor actions
unipolar (or bipolar) depression when combined with are hypothetically associated with antidepressant efficacy
fluoxetine suggests that not only are serotonin reuptake and, added together, could make a theoretically powerful
blocking properties a component of the antidepressant synergy of antidepressant mechanisms (Table 7-1).
effect of olanzapine–fluoxetine combination therapy, However, quetiapine can cause a great deal of sedation
but also 5HT2C antagonist actions (Figure 7-38). Both and moderate weight gain and metabolic disturbance due
olanzapine and fluoxetine are 5HT2C antagonists, and, in to its other receptor actions. Quetiapine is also approved
combination, the net 5HT2C antagonism is greater than for bipolar depression and discussed in the section on
with either drug alone. So, this olanzapine–fluoxetine bipolar depression below.
combination for depression could be considered a potent
SERT/5HT2C inhibitor. Although highly efficacious for Aripiprazole
treatment-resistant unipolar depression (Table 7-1), This D2/5HT1A partial agonist (Chapter 5 and Figure
the combination of olanzapine with fluoxetine is often 5-56) is approved for schizophrenia, acute bipolar
associated with unacceptable weight gain and metabolic mania, and bipolar maintenance and is one of the most
disturbances. Olanzapine–fluoxetine combination is also extensively prescribed augmenting agents to SSRIs/
approved for bipolar depression and is discussed in the SNRIs in unipolar major depression (in the US) (Table
section on bipolar depression below. 7-1). It likely acts in schizophrenia and bipolar mania
as a D2 partial agonist, whereas its prominent 5HT1A
Quetiapine
partial agonist actions (Chapter 5 and Figure 5-22)
Quetiapine (see Chapter 5 and Figure 5-45) is approved likely contribute to its antidepressant actions. Secondary
for schizophrenia, acute bipolar mania, and bipolar properties with potential antidepressant action may
maintenance, likely due to its D2 antagonist actions. also be contributory including D3, 5HT7, 5HT2C, and α2
Table 7-1 Serotonin/dopamine blockers for bipolar spectrum
Evidence of FDA-approved for FDA-approved FDA-approved FDA-approved for

efficacy in bipolar depression for bipolar for bipolar major depressive
mixed features mania maintenance disorder
Aripiprazole Yes Yes Yes (adjunct)
Asenapine Yes, MMX Yes Yes
Brexpiprazole Yes (adjunct)
Cariprazine Yes, MMX, DMX Yes Yes
Lurasidone Yes, DMX* Yes
Olanzapine Yes, MMX Yes (with fluoxetine) Yes Yes Yes (with fluoxetine)
Quetiapine Yes, MMX Yes Yes Yes Yes (adjunct)
Risperidone Yes Yes
Ziprasidone Yes, MMX Yes Yes
MMX, mania with mixed features; DMX, depression with mixed features.
*unipolar and bipolar depression.
326
antagonist actions. Aripiprazole is generally well tolerated 5-22A), and α1 (Figure 7-58A) binding of brexpiprazole
with little weight gain but some patients experience compared to aripiprazole (compare the binding strips of
akathisia. Aripiprazole is not approved for the treatment aripiprazole in Figure 5-56 and brexpiprazole in Figure
of bipolar depression. 5-57). As can be seen in these figures, brexpiprazole
also has more potent α2 antagonist, 5HT7 antagonist,
Brexpiprazole
and D3 partial agonist binding than aripiprazole. These
Another D2/5HT1A partial agonist (see Chapter 5 and various differences in receptor binding profiles could
Figure 5-57) is approved for schizophrenia and also theoretically contribute to different mechanisms of
for adjunctive treatment in unipolar depression (Table therapeutic action and side effects for brexpiprazole
7-1). Brexpiprazole is not approved for the treatment of compared to aripiprazole.
bipolar depression. As mentioned earlier in discussion Alpha-1 antagonist actions have been discussed
of brexpiprazole for psychosis in Chapter 5, there is in Chapter 5 and illustrated in Figure 5-13B showing
some indication of reduced akathisia with brexpiprazole how α1 antagonism, particularly in the thalamus, could
compared to aripiprazole, but this has not been proven contribute to sedation when coupled with simultaneous
in head-to-head trials. Reduced akathisia would be blockade of muscarinic cholinergic and histamine
consistent with the binding profile of enhanced 5HT2A receptors in the reticular activating arousal system
(Chapter 5, Figure 5-17B), 5HT1A (Chapter 5, Figure (Chapter 5, Figures 5-13A and 5-8). However, particularly
α1 α1
receptor antagonist
PFC
7
SN motor striatum reduction in DIP
α1 α1
receptor antagonist improved mood,
affective symptoms,
PFC and cognitive symptoms
(SIGH)
B VTA
Figure 7-58 Alpha-1 antagonism and downstream dopamine release. Alpha-1 antagonism can modulate downstream dopamine
release via two key pathways. (A) Alpha-1 antagonism decreases glutamatergic output in the substantia nigra (SN), leading to reduced
activity of the GABA interneuron and therefore disinhibition of the nigrostriatal dopamine pathway. The increased dopamine release
in the motor striatum can reduce motor side effects caused by D2 antagonism because there is more dopamine to compete with the
D2 antagonist. (B) Alpha-1 antagonism reduces glutamatergic output in the ventral tegmental area (VTA), leading to reduced activity of
the GABA interneuron and therefore disinhibition of the mesocortical dopamine pathway. Increased dopamine release in the prefrontal
cortex (PFC) can potentially improve mood and reduce affective and cognitive symptoms.
327
without simultaneous muscarinic and histaminic to the prefrontal cortex (Figure 7-58B and Chapter 5,
antagonism, α1 antagonist action in the prefrontal cortex Figure 5-17C). What this means is that α1 antagonists
could hypothetically also contribute both to the reduced would theoretically have the same effect as 5HT2A
motor side effects and to the known antidepressant antagonists in this circuit, and the two working together
effects seen with potent α1 antagonists, particularly those would exert a more powerful control of the prefrontal
with simultaneous 5HT2A antagonist properties. Alpha-1 cortex and its downstream projections, to further
antagonist actions of brexpiprazole could also potentially facilitate dopamine release in the prefrontal cortex and
contribute to its evidence of efficacy for agitation in to cause antidepressant action. In fact, this synergy is
Alzheimer disease and in PTSD (as augmentation of likely to be an important component of the mechanism
sertraline). of antidepressant action for those agents that are both
How does this happen and what circuits regulate α1 and 5HT2A antagonists, including brexpiprazole,
α1 antagonist action? The answer is that the reader is quetiapine, and trazodone. The enhancement
already familiar with the circuitry to explain the actions of dopamine release in the prefrontal cortex by
of α1 antagonists, since it is the same circuitry already simultaneous α1 and 5HT2A blockade may theoretically
discussed for 5HT2A receptors and illustrated in Chapter contribute as well to improving “top-down” control of
5 in Figures 5-16 and 5-17. It is now known that α1 agitation in Alzheimer disease and PTSD symptoms,
receptors (illustrated here in Figure 7-58) are colocalized which are seen in ongoing studies of brexpiprazole.
on the same pyramidal neurons with 5HT2A receptors
Cariprazine
(discussed in Chapter 5 and illustrated in Figures 5-16
and 5-17). Since both α1 receptors and 5HT2A receptors Carpirazine (Chapter 5 and Figure 5-58) is a D3/D2/5HT1A
are excitatory and postsynaptic, norepinephrine partial agonist as well as a 5HT2A/α1/α2 antagonist,
and serotonin acting together exert a more powerful approved for the treatment of acute bipolar mania and
excitatory control of prefrontal cortex function through bipolar depression; it also has evidence of efficacy as
their simultaneous action than either neurotransmitter an adjunct to SSRI/SNRIs in unipolar depression (Table
acting alone. 7-1). Cariprazine’s antidepressant mechanism of action
Furthermore, the actions of an α1 antagonist would is discussed below in the section on treating bipolar
be expected to have the same functional effects as a depression.
5HT2A antagonist, the two actions acting together to have
Ketamine
a more powerful downstream inhibitory control of the
prefrontal cortex output than blockade of either receptor Observations that the intravenous infusion of
alone. Figure 7-58A shows the α1 receptors on those subanesthetic doses of ketamine could rapidly improve
specific pyramidal neurons projecting to the substantia depression in patients inadequately responsive to
nigra (same pyramidal neurons and circuitry as shown monoamine-targeting drugs has set forth a bit of a
in Chapter 5, Figure 5-17B). When this glutamatergic revolution in the treatment of depression. Ketamine is
neuron is inhibited by an α1 antagonist, its innervation of an approved anesthetic but used off-label for treatment-
the substantia nigra reduces GABA tone there, allowing resistant depression. Whereas serotonin/dopamine
disinhibition of dopamine release into the motor striatum blockers tend to be used after just one or two failures of
and reduction of drug-induced parkinsonism (Figure an SSRI/SNRI, ketamine tends to be given to patients
7-58A; just as shown in Chapter 5 and Figure 5-17B). with multiple failures on various drugs for depression.
Thus, drug-induced parkinsonism caused by D2 blockers Intravenous ketamine is a racemic mixture of R- and
will be maximally reduced by those D2 blockers that have S-ketamine, each with overlapping binding properties
both 5HT2A and α1 antagonist actions. Indeed, the lowest at the NMDA subtype of glutamate receptor, its putative
frequency and severity of drug-induced parkinsonism mechanism of antidepressant action, and at the σ1
induced by dopamine blockers is for those that also receptor (Figure 7-59). Actions at other sites, including
have robust α1 and 5HT2A antagonist actions, namely, μ-opioid and other neurotransmitter sites, are proposed
brexpiprazole, quetiapine, clozapine, and iloperidone. but disputed, especially the possibility that ketamine’s
Synergy of α1 antagonism with 5HT2A antagonism antidepressant actions may be linked in some way to
can theoretically also enhance antidepressant action, this μ-opioid as well as NMDA action. Thus, a debate exists
time in the circuit of pyramidal neurons innervating the as to how ketamine exerts its rapid-onset antidepressant
ventral tegmental area dopamine neurons that project effects, but NMDA antagonism – specifically at the
328
ketamine: R+S ketamine
NMDA ADMN
σ S-ketamine R-ketamine σ
NMDA σ NMDA σ
+ + + + 7
Figure 7-59 Ketamine. Ketamine is used off-label and is being studied for its potential therapeutic utility in treatment-resistant
depression. Ketamine is an NMDA (N-methyl-D-aspartate) receptor antagonist, with additional weak actions at σ1 receptors, the
norepinephrine transporter (NET), μ-opioid receptors, and the serotonin transporter (SERT). Ketamine consists of two enantiomers, R and S.
open-channel phencyclidine (PCP) site (see discussion in is based on evidence that deficiencies in neurotrophic
Chapter 4 and Figure 4-30) – is the leading hypothesized factors such as BDNF (brain-derived neurotrophic factor)
target for explaining ketamine’s antidepressant and possibly other growth factors such as VEGF (vascular
effects. What is unique about ketamine infusions is endothelial growth factor) occur with chronic stress
the rapid, almost immediate onset of antidepressant and major depression and that when monoaminergic
effects, sometimes accompanied by specific anti- drugs for depression are effective, they restore these
suicidal ideation effects, in patients who seem to have growth factors, but with a delay of weeks after drug
“nonmonoaminergic” depressions since they have failed administration. On the other hand, when monoaminergic
numerous standard monoamine-targeted antidepressant drugs for depression are not effective, it is assumed that
therapies. Unfortunately, the antidepressant effects of for unknown reasons monoamines cannot restore the
ketamine are usually not long lasting, but generally fade necessary growth factors. Loss of BDNF and VEGF are
over a few days. In some cases, the antidepressant effects both linked to neuronal atrophy in brain regions such as
can be re-triggered by repeated infusions over time, or the prefrontal cortex and hippocampus in chronic stress
enhanced by monoaminergic antidepressant treatments models in animals as well as in unipolar major depressive
following infusions. disorder. Chronic stress and depression are also thought
Most interesting perhaps is the possibility that to decrease the receptors for BDNF and VEGF, namely
ketamine causes immediate improvement in neuronal TRKB (tyrosine kinase 2) and FLK1 (fetal liver kinase
plasticity as its downstream mechanism of immediately 1), respectively. Ketamine increases both of these growth
improving depression. Loss of neurotrophic factors in factors.
depression is discussed in Chapter 6 and illustrated in So, how does ketamine induce its rapid antidepressant
Figures 6-27 through 6-33). Recall that the neurotrophic response and rapid reversal of synaptic atrophy in
hypothesis of depression and antidepressant response depression? This is thought to occur because ketamine
329

ketamine. Shown here are two cortical
glutamatergic pyramidal neurons and
a GABAergic interneuron. (1) If an N-
methyl-D-aspartate (NMDA) receptor on
a GABAergic interneuron is blocked by
ketamine, this prevents the excitatory
actions of glutamate (Glu) there. Thus,
the GABA neuron is inactivated and
does not release GABA (indicated by
the dotted outline of the neuron). (2)
GABA binding at the second cortical
glutamatergic pyramidal neuron
normally inhibits glutamate release;
thus, the absence of GABA there means
that the neuron is disinhibited and
glutamate release is increased.
1
Glu
2
Glu
NMDA
blocked by subanesthetic burst of Glu release
infusion of ketamine from upstream NMDA
antagonism
causes an immediate burst of downstream glutamate AMPA receptors while ketamine is blocking NMDA
release after blocking NMDA receptors (discussed receptors (Figures 7-61 and 7-62). One hypothesis for
in Chapter 4 and illustrated in Figure 4-33; see also why ketamine has antidepressant actions proposes that
Figure 7-60). Ketamine’s actions at NMDA receptors this stimulation of AMPA receptors first activates the
are not unlike what is hypothesized to occur due ERK, AKT signal transduction cascade (Figures 7-61A).
to neurodevelopmental abnormalities at NMDA This then triggers the mTOR (mammalian target of
synapses in schizophrenia (also discussed in Chapter rapamycin) pathway (Figures 7-61) and that causes the
4 and illustrated in Figures 4-29B and 4-31 through expression of synaptic proteins, leading to an increased
4-33). This is not surprising given that ketamine can density of dendritic spines (Figures 7-61B). Dendritic
produce a schizophrenia-like syndrome in humans spine proliferation indicating new synaptogenesis
especially at high doses and acute drug administration can be seen within minutes to hours after ketamine is
(Figure 4-33). However, when infused over time and at administered in animals. Hypothetically, it is this increase
subanesthetic doses in the study of depressed patients, in dendritic spines and synaptogenesis that causes the
ketamine does not induce psychosis, but is thought rapid-onset antidepressant effect. Another hypothesis
to produce downstream release in glutamate (Figure for why ketamine has antidepressant actions proposes
7-60). Glutamate that is released in this burst stimulates that the stimulation of AMPA receptors from the burst
330
Figure 7-61 Ketamine, AMPA

receptors, and mTOR. Glutamate
activity heavily modulates synaptic
potentiation; this is specifically
modulated through NMDA
(N-methyl-D-aspartate) and AMPA
(α-amino-3-hydroxy-5-methyl-4-
isoxazole-propionic acid) receptors.
Ketamine is an NMDA receptor
antagonist; however, its rapid
burst of Glu release antidepressant effects may also be
Glu from upstream NMDA related to indirect effects on AMPA
antagonism receptor signaling. (A) One hypothesis
is that blockade of the NMDA receptor
leads to rapid activation of AMPA,
AMPA NMDA which triggers the ERK, AKT signal
receptor receptor transduction cascade, which then
stimulated blocked by triggers the mammalian target of
by Glu rapamycin (mTOR) pathway. (B) This
ketamine
in turn would lead to rapid AMPA-
mediated synaptic potentiation and
increase in dendritic spine formation.
Traditional antidepressants also
ERK, AKT cause synaptic potentiation; however,
they do so via downstream changes
in intracellular signaling. This may
mTOR therefore explain the difference
in onset of antidepressant action
A between ketamine and traditional
antidepressants.
Glu
AMPA
receptor NMDA
receptor
blocked by
ketamine
dendritic spine dendritic spine
formation formation
ERK, AKT
mTOR
B
of glutamate release (Figure 7-62A) activates another Esketamine

signal transduction pathway, namely voltage-sensitive The S enantiomer of ketamine is approved for treatment-
calcium channels, which allow calcium influx that in resistant depression in an intranasal formulation for
turn activates BDNF and VEGF release to induce synaptic administration, and is called esketamine (Figure 7-63).
formation (Figure 7-62B). Thus, ketamine hypothetically The exact pharmacology of R- versus S-ketamine and
reverses the atrophy caused by depression, and does this their active metabolites is still being determined in terms
within minutes. of neurotrophic actions. However, esketamine is indeed
331
Figure 7-62 Ketamine, AMPA

receptors, and BDNF/VEGF
release. Glutamate activity heavily
modulates synaptic potentiation; this
TRKB is specifically modulated through
FLK1 NMDA (N-methyl-D-aspartate)
vesicle with and AMPA (α-amino-3-hydroxy-5-
VEGF methyl-4-isoxazole-propionic acid)
vesicle with receptors. Ketamine is an NMDA
BDNF receptor antagonist; however, its
rapid antidepressant effects may
Ca++ also be related to indirect effects
Glu on AMPA receptor signaling. (A) A
second hypothesis is that blockade
AMPA
of the NMDA receptor leads to rapid
receptor
activation of AMPA, which activates
voltage-sensitive calcium channels
VSCC (VSCCs) to allow calcium influx. (B) This
in turn would lead to activation of brain-
NMDA derived neurotrophic factor (BDNF)
receptor and VEGF (vascular endothelial growth
blocked by factor) release, which bind to TRKB and
ketamine FLK1 receptors, respectively, triggering
A
cascades that induce dendritic spine
formation.
BDNF VEGF
dendritic
PLC /PI3K spine
formation
AKT
active as an acute rapid-onset antidepressant, and it is (e.g., lithium, buspirone, and thyroid), as well as the
administered intranasally and rapidly, so that longer very popular and often effective strategy of combining
intravenous infusions are not necessary. After twice- two monoamine drugs, each approved for unipolar
weekly initiation, esketamine can be given intranasally depression, to create pharmacological synergy. However,
in weekly or biweekly dosing as an augmenting agent none of these strategies are specifically approved.
to standard drugs for depression. A long-term study for
Lithium
up to a year of esketamine nasal spray plus a switch to
an oral monoamine antidepressant not previously tried, Lithium is discussed below as a treatment for mania, but
showed sustained improvements in depression and has been used as well for unipolar depressed patients who
acceptable safety. fail to respond to treatment. Lithium augmentation of
monoamine reuptake inhibitors, particularly the classic
Other Drug Combinations for Treatment-Resistant tricyclic antidepressants also discussed below, has been
Depression used in the past to boost treatment response in unipolar
Other options to augment monoamine treatments for depression. As augmentation for treatment-resistant
unipolar depression include agents that do not have unipolar depression, lithium is administered in doses
robust antidepressant actions as monotherapies but lower than those used for mania, but it has fallen out of
can improve the action of the monoamine treatments favor in recent years.
332
known abilities to regulate neuronal organization,

esketamine arborization, and synapse formation may have the
downstream consequence of boosting monoamine
neurotransmitters, and this may account for how thyroid
NMDA hormones enhance antidepressant action in some patients.
Augmentation of treatments for either unipolar or bipolar
depression with thyroid hormones has also fallen out of
favor in recent years.
Triple-Action Combo: SSRI/SNRI + NDRI

If boosting one neurotransmitter is good, and two is
σ S-ketamine better, maybe three boosted neurotransmitters is best
(Figures 7-64). Triple action (i.e, serotonin, dopamine,
and norepinephrine) drugs for depression therapy with
modulation of all three monoamines would be predicted
to occur by combining either an SSRI with an NDRI or
combining an SNRI with an NDRI, providing even more
noradrenergic and dopaminergic action (Figure 7-64).
These are perhaps some of the most popular combinations
of two drugs for depression utilized in the US.
NMDA σ
California Rocket Fuel: SNRI plus Mirtazapine
+ + This potentially powerful combination exploits the
pharmacological synergy attained by adding the enhanced 7
Figure 7-63 Esketamine. The R and S enantiomers of ketamine
are mirror images of each other; the exact pharmacology of the serotonin and norepinephrine release from inhibition of both
R and S enantiomers and their active metabolites is still being serotonin and norepinephrine reuptake by an SNRI to the
determined. The S enantiomer of ketamine has been developed
and marketed as esketamine. disinhibition of both serotonin and norepinephrine release
by the α2 antagonist actions of mirtazapine (Figure 7-65). It
Buspirone is even possible that additional pro-dopaminergic actions
Buspirone is a 5HT1A partial agonist, so putting it result from the combination of norepinephrine reuptake
together with an SSRI/SNRI is very much similar to the blockade in the prefrontal cortex due to SNRIs with 5HT2C
use of vilazodone (Figure 7-22 through Figure 7-27) actions of mirtazapine disinhibiting dopamine release. This
or vortioxetine (Figure 7-49) discussed above. Indeed, combination can provide very powerful antidepressant action
most of the serotonin/dopamine agents used to augment for some patients with unipolar major depressive episodes.
monoamine antidepressants have 5HT1A properties (e.g.,
Arousal Combos
quetiapine, aripiprazole, brexpiprazole, and cariprazine).
Administering drugs that have 5HT1A agonist actions is a The frequent complaints of residual fatigue; loss of
favored approach for augmenting SSRI/SNRIs, but using energy, motivation, and sex drive; and problems
buspirone for this is less common today than using other concentrating/problems with alertness may be
agents with 5HT1A properties. approached by combining either a stimulant (dopamine
transport inhibitor or DAT inhibitor) with an SNRI,
Thyroid Hormones or modafinil (another DAT inhibitor) with an SNRI
Thyroid hormones act by binding to nuclear ligand (Figure 7-66), to recruit triple monoamine action and
receptors to form a nuclear ligand-activated transcription especially enhancement of dopamine.
factor. Abnormalities in thyroid hormone levels have
long been associated with depression, and various forms Second-Line Monotherapies Used for Treatment-
Resistant Depression
and doses of thyroid hormones have for many years been
utilized as augmenting agents to drugs for depression Tricyclic Antidepressants
either to boost their efficacy in patients with inadequate The tricyclic antidepressants (TCAs) (Table 7-2;
response or to speed up their onset of action. Thyroid’s Figure 7-67) were so-named because their chemical
333
Triple-Action Combos
SSRI + NDRI
= SSRI
5HT NE DA
= NDRI
single boost single boost single boost
SERT NET DAT
SSRI NDRI NDRI

A
SNRI + NDRI
= SNRI
5HT NE DA
= NDRI
single boost double boost single boost
SERT NET DAT
B SNRI NDRI SNRI NDRI
Figure 7-64 Triple-action combo: SSRI/SNRI plus NDRI. (A) Selective serotonin reuptake inhibitor (SSRI) plus a norepinephrine–
dopamine reuptake inhibitor (NDRI) leads to a single boost for serotonin (5HT), norepinephrine (NE), and dopamine (DA). (B) Serotonin–
norepinephrine reuptake inhibitor (SNRI) plus a norepinephrine–dopamine reuptake inhibitor (NDRI) leads to a single boost for
serotonin (5HT), a double boost for norepinephrine (NE), and a single boost for dopamine (DA).
California Rocket Fuel

SNRI + mirtazapine
= SNRI
5HT NE DA
= mirtazapine
quadruple quadruple 5HT double boost
boost boost 5HT 2C 5HT
2C
α2 α2 2A 5HT
2A
SERT NET
mirtazapine
SNRI mirtazapine mirtazapine
SNRI
5HT 5HT
2A 2C
Figure 7-65 California rocket fuel: SNRI plus mirtazapine. Combining a serotonin–norepinephrine reuptake inhibitor (SNRI) with
mirtazapine is a combination that has a great degree of theoretical synergy: serotonin (5HT) is quadruple-boosted (with reuptake
blockade, α2 antagonism, 5HT2A antagonism, and 5HT2C antagonism), norepinephrine (NE) is quadruple-boosted (with reuptake
blockade, α2 antagonism, 5HT2A antagonism, and 5HT2C antagonism), and there may even be a double boost of dopamine (DA) (with
5HT2A and 5HT2C antagonism).
334
Arousal Combos
SNRI + stimulant
= SNRI
5HT NE DA
= stimulant
single boost double boost single boost
SERT NET DAT
SNRI SNRI stimulant stimulant

A
SNRI + modafinil
= SNRI
5HT NE DA
= modafinil
single boost single boost single boost
SERT NET DAT

7
B SNRI SNRI modafinil
Figure 7-66 Arousal combo: SNRI plus stimulant/modafinil. (A) Serotonin (5HT) and dopamine (DA) are single-boosted and
norepinephrine (NE) is double-boosted when a serotonin–norepinephrine reuptake inhibitor (SNRI) is combined with a stimulant. (B)
Serotonin (5HT) and norepinephrine (NE) are single-boosted by the serotonin–norepinephrine reuptake inhibitor (SNRI) while dopamine
(DA) is single-boosted by modafinil.
Table 7-2 Some tricyclic antidepressants still in use structure contains three rings. The TCAs were
synthesized about the same time that other three-
Generic name Trade name
ringed phenothiazine molecules were shown to be
Clomipramine Anafranil effective tranquilizers for schizophrenia (i.e., the early
Imipramine Tofranil D2 antagonist drugs such as chlorpromazine) but were
Amitriptyline Elavil; Endep; Tryptizol; a disappointment when tested as drugs for psychosis.
Laroxyl However, during testing for schizophrenia, they were
Nortriptyline Pamelor; Aventyl serendipitously discovered to be effective in unipolar
depression. Tricyclic antidepressants are not merely drugs
Protriptyline Vivactil
for depression since one of them (clomipramine) has
Maprotiline Ludiomil anti-obsessive–compulsive disorder; many of them have
Amoxapine Asendin anti-panic effects at antidepressant doses and efficacy for
Doxepin Sinequan; Adapin
neuropathic and low back pain at low doses.
Long after their antidepressant properties were
Desipramine Norpramin; Pertofran
observed, the TCAs were discovered to block the reuptake
Trimipramine Surmontil pumps for norepinephrine (i.e., NET), or for both
Dothiepin Prothiaden norepinephrine and serotonin (i.e., SERT) (see Figure
Lofepramine Deprimyl; Gamanil
7-67A). Some tricyclics have equal or greater potency for
SERT inhibition (e.g., clomipramine); others are more
Tianeptine Coaxil; Stablon
selective for NET inhibition (e.g., desipramine, maprotiline,
335
TCA nortriptyline, protriptyline) (Figure 7-67B). Most, however,

block both serotonin and norepinephrine reuptake to
sodium channel some extent (Figure 7-67A). In addition, some TCAs have
blocker antagonist actions at 5HT2A and 5HT2C receptors, which
H1 Na+
could contribute to the therapeutic profile of those tricyclics
α1 that have such pharmacological actions (Figure 7-67C).
The major limitation to the TCAs has never been their
efficacy: these are quite effective agents. The problem
SERT
with drugs in this class is the fact that all of them share
at least four other unwanted pharmacological actions,
namely, blockade of muscarinic cholinergic receptors, H1
histamine receptors, α1-adrenergic receptors, and voltage-
M1 NET
sensitive sodium channels (Figure 7-67). As already
discussed, blockade of H1 receptors causes sedation and
A may cause weight gain (see Chapter 5 and Figure 5-13A).
Blockade of muscarinic cholinergic receptors, also known
as anticholinergic actions, causes dry mouth, blurred
sodium channel vision, urinary retention, and constipation (Figure 5-8).
blocker Blockade of α1-adrenergic receptors may be therapeutic
H1 Na+
but also causes orthostatic hypotension and dizziness
α1 (Figure 5-13B). Tricyclic antidepressants also weakly
block voltage-sensitive sodium channels in the heart
and brain at therapeutic doses; in overdose, this action
is thought to be the cause of coma and seizures due to
central nervous system actions, and cardiac arrhythmias
and cardiac arrest and death due to peripheral cardiac
NET actions (Figure 7-68). The lethal dose of a TCA is only
M1
about a 30-day supply of drug. For this reason, it has
been said that each time you are giving the patient a
B
1-month’s prescription for a TCA, you are handing them a
loaded gun. Obviously, this is often not a good idea in the
sodium channel treatment of a disorder associated with so much suicide;
H1
blocker thus, TCAs have largely fallen out of favor except for
Na+
patients who fail to respond to the various first-line drugs
α1 for depression discussed up to this point in this chapter.
Monoamine Oxidase Inhibitors (MAOIs)
5HT2A SERT
The first clinically effective drugs for depression ever
discovered were inhibitors of the enzyme monoamine
C
T2 oxidase (MAO). They were found by accident when an
5H
NET
anti-tuberculosis drug was observed to help depression
M1 that coexisted in some of the patients who had
tuberculosis. This anti-tuberculosis drug, iproniazid, was
eventually found to work in depression by inhibiting the
C
enzyme MAO. However, inhibition of MAO was unrelated
Figure 7-67 Icons of tricyclic antidepressants (TCAs). All
tricyclic antidepressants block reuptake of norepinephrine
to its anti-tubercular actions. Although best known as
and are antagonists at histamine 1 (H1), α1-adrenergic, and powerful drugs to treat depression, the monoamine
muscarinic cholinergic receptors; they also block voltage-
sensitive sodium channels (A, B, and C). Some TCAs are also
oxidase inhibitors (MAOIs) are also highly effective
potent inhibitors of the serotonin reuptake pump (A, C), and therapeutic agents for certain anxiety disorders such
some may additionally be antagonists at serotonin 2A and 2C as panic disorder and social anxiety disorder. MAOIs
receptors (C).
336
Figure 7-68 Tricyclic antidepressants

Overdose and overdose. Tricyclic
antidepressants block voltage-
sensitive sodium channels in the brain
(top) and heart (bottom). In overdose,
this action can lead to coma, seizures,
arrhythmia, and even death.
H1
coma
sodium
channel
seizures
arrhythmia
H1
sodium death
channel
7
are barely prescribed any more today. Only about one inhibitors, and thus enzyme activity returns only after
in every 3,000 to 5,000 prescriptions for a drug to treat new enzyme is synthesized about 2–3 weeks later.
depression is a MAOI and only a few hundred experts Amphetamine is also a weak but reversible MAOI; some
prescribe MAOIs out of the hundreds of thousands MAOIs have properties related to amphetamine. For
who prescribe other drugs for depression in the US. example, tranylcypromine has a chemical structure
Prescribing MAOIs is beginning to become a lost art modeled on amphetamine, and thus in addition to MAOI
in psychopharmacology as many familiar with them properties, it also has amphetamine-like dopamine-
learned to use MAOIs before the 1990s when SSRIs were releasing properties. The MAOI selegiline itself does not
introduced and largely replaced MAOIs. Most of these have amphetamine-like properties, but is metabolized
prescribers of MAOIs are now retiring from practice. to both l-amphetamine and l-methamphetamine. Thus,
Nevertheless, MAOIs are a most powerful drug class there is a close mechanistic link between some MAOIs and
for unipolar depression and those who prescribe them additional amphetamine-like dopamine-releasing actions.
have seen many patients who respond to nothing else
MAO Subtypes
get better on MAOIs. The reader who is an advanced
psychopharmacologist should gain familiarity and MAO exists in two subtypes, A and B. The A form
experience with these agents so that patients who still preferentially metabolizes the monoamines most closely
need them can get them. The reader is referred to specific linked to depression (i.e., serotonin and norepinephrine)
reviews on MAOIs including some of the author, to help whereas the B form preferentially metabolizes trace
navigate dietary restrictions and drug interactions. amines such as phenethylamine (see Chapter 5 and
The MAOIs phenelzine, tranylcypromine, Figures 5-64 through 5-66 for further discussion on
isocarboxazid, and selegiline are all irreversible enzyme trace amines). Both MAO-A and MAO-B metabolize
337
dopamine and tyramine, another trace amine. Both Normally, the release of norepinephrine by tyramine
MAO-A and MAO-B are in the brain. Noradrenergic is inconsequential because MAO-A safely destroys this
neurons (Figure 6-13) and dopaminergic neurons (Figure released norepinephrine. However, tyramine in the
4-3) are thought to contain both MAO-A and MAO-B, presence of MAO-A inhibition can elevate blood pressure
with MAO-A activity perhaps predominant, whereas because norepinephrine is not safely destroyed. Every
serotonergic neurons are thought to contain only MAO-B prescriber of MAOIs should counsel patients taking the
(Figure 4-37). MAO-A is the major form of this enzyme classic MAOIs about diet and keep up to date with the
outside of the brain, with the exception of platelets and tyramine content of foods their patients wish to eat.
lymphocytes, which have MAO-B.
Drug–Drug Interactions for MAOIs
Brain MAO-A must be substantially inhibited
for antidepressant efficacy to occur (Figure 7-69). While MAOIs are famous for their tyramine reactions,
This is not surprising, since this is the form of drug–drug interactions are potentially more important
MAO that preferentially metabolizes serotonin and clinically. Drug–drug interactions may not only be
norepinephrine, two of the three monoamines linked more common than dietary interactions with tyramine,
to depression and to antidepressant actions, both of but some drug interactions can be dangerous or even
which demonstrate increased brain levels after MAO-A lethal. Drug interactions with MAOIs are often poorly
inhibition (Figure 7-69). MAO-A, along with MAO-B, understood by many practitioners. Since most candidates
also metabolizes dopamine, but inhibition of MAO-A for MAOI treatment will require treatment with many
alone does not appear to lead to robust increases in concomitant drugs over time, including treatment
brain dopamine levels since MAO-B can still metabolize for coughs and colds and for pain, this can prevent
dopamine (Figure 7-69). psychopharmacologists from prescribing a MAOI if they
Inhibition of MAO-B is not effective as an do not know which drugs are safe to give and which
antidepressant, as there is no direct effect on either ones must be avoided. There are two general types of
serotonin or norepinephrine metabolism, and little potentially dangerous drug interactions with MAOIs for a
or no dopamine accumulates due to the continued practitioner to understand and avoid: those that can raise
action of MAO-A (Figure 7-70). What therefore is the blood pressure by sympathomimetic actions and those
therapeutic value of MAO-B inhibition? When this that can cause a potentially fatal serotonin syndrome by
enzyme is selectively inhibited, it can boost the action serotonin reuptake inhibition. Every prescriber of MAOIs
of concomitantly administered levodopa in Parkinson’s should counsel patients taking the classic MAOIs about
disease and reduce on/off motor fluctuations. Three drug interactions and keep up to date with the latest
MAO-B inhibitors selegiline, rasagiline, and safinamide warnings about drug interactions of MAOIs with drugs
are approved for use in patients with Parkinson’s disease, their patients are concomitantly prescribed. Several
but are not effective at selective MAO-B doses for the reviews on these details are available, including some of
treatment of depression. the author’s, and are referenced at the end of the book.
When MAO-B is inhibited simultaneously with
MAO-A, there is robust elevation of dopamine as well as DRUGS FOR BIPOLAR DISORDER
serotonin and norepinephrine (Figure 7-71). This would SPECTRUM
theoretically provide the most powerful antidepressant
efficacy across the range of depressive symptoms, from Serotonin/Dopamine Blockers: Not Just for Psychosis
and Psychotic Mania
diminished positive affect to increased negative affect
(see Figure 6-41). Thus, MAO-A plus MAO-B inhibition When D2 blockers were approved for schizophrenia,
is one of the few therapeutic strategies available to it was not surprising that these agents would work for
increase dopamine in depression, and therefore to treat psychotic symptoms associated with mania, since the
refractory symptoms of diminished positive affect. D2 antagonist actions predict efficacy for psychosis
in general (discussed in Chapter 5). However, it was
The Dietary Tyramine Interaction somewhat surprising when these dopamine/serotonin
One of the biggest barriers to using MAOIs has blockers proved effective for the core nonpsychotic
traditionally been the concern that a patient taking symptoms of mania (Figure 6-2) and for maintenance
a MAOI may develop a hypertensive crisis after treatment to prevent the recurrence of mania. These latter
ingesting tyramine in the diet, classically from cheese. actions are similar to the antimanic therapeutic actions of
338
MAO-A Is Inhibited
Antidepressant Action
5HT neuron 5HT neuron
5HT boosted to
high concentrations
B B
MAO-B destroys 5HT only MAO-B destroys 5HT only

at high concentrations at high concentrations
MAO-A
inhibition
A A
MAO-A
B destroys 5HT B
MAO-B MAO-B
destroys 5HT destroys 5HT
only at high only at high
concentrations concentrations
NE neuron NE neuron
NE boosted to
high concentrations
A A
MAO-A 7
inhibition
A A
MAO-A MAO-A
B destroys NE B destroys NE
MAO-B MAO-B
destroys NE destroys 5HT
only at high only at high
concentrations concentrations
DA neuron DA neuron
DA boosted
moderately
A A
MAO-A
MAO-A MAO-A
destroys DA inhibition destroys DA
A A
MAO-A MAO-A
B destroys DA B destroys DA
MAO-B MAO-B
destroys DA destroys DA
Figure 7-69 Monoamine oxidase A (MAO-A) inhibition. The enzyme MAO-A metabolizes serotonin (5HT) and norepinephrine (NE) as
well as dopamine (DA) (left panels). Monoamine oxidase B (MAO-B) also metabolizes DA, but it metabolizes 5HT and NE only at high
concentrations (left panels). This means that MAO-A inhibition increases 5HT, NE, and DA (right panels) but that the increase in DA is not
as great as that of 5HT and NE because MAO-B can continue to destroy DA (bottom right panel). Inhibition of MAO-A is an efficacious
antidepressant strategy.
339
MAO-B Is Inhibited
No Antidepressant Action
B B
MAO-B destroys 5HT only

MAO-B
inhibition
A A
MAO-A MAO-A
B destroys 5HT B destroys 5HT
MAO-B MAO-B
destroys 5HT inhibition
only at high irrelevant
concentrations
NE neuron NE neuron
A A
MAO-B
inhibition
A A
MAO-A MAO-A
B destroys NE B destroys NE
MAO-B MAO-B
destroys NE inhibition
only at high irrelevant
concentrations
DA neuron DA neuron
DA boosted
moderately
A A
MAO-B
MAO-A
destroys DA inhibition MAO-A
destroys DA
A A
MAO-A MAO-A
B destroys DA B destroys DA
MAO-B MAO-B
destroys DA destroys DA
Figure 7-70 Monoamine oxidase B (MAO-B) inhibition. Selective inhibitors of MAO-B do not have antidepressant efficacy. This is
because MAO-B metabolizes serotonin (5HT) and norepinephrine (NE) only at high concentrations (top two left panels). Since MAO-B’s
role in destroying 5HT and NE is small, its inhibition is not likely to be relevant to the concentrations of these neurotransmitters (top
two right panels). Selective inhibition of MAO-B also has somewhat limited effects on dopamine (DA) concentrations, because MAO-A
continues to destroy DA. However, inhibition of MAO-B does increase DA to some extent, which can be therapeutic in other disease
states, such as Parkinson’s disease.
340
MAO-A and MAO-B Are Inhibited
Robust Antidepressant Action

Including Dopamine Action
5HT boosted to very
high concentrations
B B
MAO-B destroys 5HT only

MAO-A+B
inhibition
A A
MAO-A
B destroys 5HT B
MAO-B
destroys 5HT
only at high
concentrations
NE neuron NE neuron
NE boosted to very
high concentrations
A A
MAO-A+B 7
inhibition
A A
MAO-A
B destroys NE B
MAO-B
destroys NE
only at high
concentrations
DA neuron DA neuron
DA boosted to very
high concentrations
A A
MAO-A+B
MAO-A
destroys DA inhibition MAO-A
destroys DA
A A
MAO-A
B destroys DA B
MAO-B
destroys DA
Figure 7-71 Combined inhibition of monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). Combined inhibition of
MAO-A and MAO-B may have robust antidepressant actions owing to increases not only in serotonin (5HT) and norepinephrine (NE) but
also dopamine (DA). Inhibition of both MAO-A, which metabolizes 5HT, NE, and DA, and MAO-B, which metabolizes primarily DA (left
panels), leads to greater increases in each of these neurotransmitters than inhibition of either enzyme alone (right panels).
341
lithium and various anticonvulsant ion channel blockers blockers approved for the treatment of mania, but this is
that act by very different mechanisms (described below). not done for the treatment of schizophrenia, as lithium
More surprising yet is that some of these same serotonin/ and valproate do not clearly augment the efficacy of
dopamine antagonists/partial agonists are effective for serotonin/dopamine blockers in schizophrenia.
bipolar depression, albeit by mechanisms likely distinct
Serotonin/Dopamine Antagonists/Partial Agonists
from D2 antagonism/partial agonism. The questions
across the Depression Spectrum: Bipolar Depression,
that arise are how serotonin 2/dopamine 2 antagonists Depression with Mixed Features, and as Adjuncts to
and dopamine 2/serotonin 1A partial agonists work in SSRIs/SNRIs in Unipolar Major Depression
both the manic and depressed poles of bipolar disorder.
The serotonin/dopamine antagonists/partial agonists
More recently, some of these same serotonin/dopamine
have proven to be quite versatile therapeutics: from
drugs have evidence of efficacy in unipolar depression
schizophrenia, to mania, to adjuncts for SSRIs/SNRIs in
as augmenting agents to SSRIs/SNRIs when there is
unipolar depression, as we have discussed in this chapter
inadequate response, as discussed above. Furthermore,
so far. Here we consider the extension of therapeutic use
some of these same serotonin/dopamine drugs now
of at least some of the agents in this class to the treatment
have additional evidence of efficacy in unipolar and
of bipolar depression and the closely related state of
bipolar depression with mixed features of mania. Do they
major depressive episodes with mixed features of mania.
work by the same mechanisms across the entire bipolar
A major paradigm shift is afoot in the treatment of
spectrum (Figure 6-7)? Is this a class effect of these drugs
bipolar depression and depression with mixed features.
or do specific drugs work in some but not all parts of the
We used to ask: “Don’t we treat all forms of depression
bipolar spectrum?
with so-called antidepressants, drugs that inhibit the
Putative Pharmacological Mechanism of Serotonin/ reuptake of monoamines?” Although most patients with
Dopamine Antagonists/Partial Agonists in Mania depression, including those with bipolar depression and
The short answer to the question of how serotonin/ depression with mixed features, do receive monoamine
dopamine blockers work in mania is that we do not reuptake inhibiting drugs, the modern answer to
really know. On the one hand, PET scans of patients this question is increasingly becoming a resounding
with mania show the same excessive presynaptic “No!!” Practice guidelines and US FDA approvals are
dopamine levels and release in mesostriatal dopamine moving away from the treatment of bipolar depression
neurons in acute bipolar mania as for acute psychosis in or depression with mixed features with the standard
schizophrenia, described extensively in Chapter 4 and monoamine reuptake inhibiting agents that are so
illustrated in Figures 4-15, 4-16, and Figure 5-2. Thus, commonly used for the treatment of unipolar depression.
blocking the excessive dopamine at D2 receptors should Reuptake inhibitors are increasingly reserved to treat
have as much of an antimanic effect in bipolar mania as patients with unipolar depression only if they do not
it has an antipsychotic effect in schizophrenia. Indeed, have mixed features, and patients with bipolar depression
acute bipolar mania is treated with serotonin/dopamine only as second-line agents to augment other agents. Best
blockers in much the same manner as acute psychosis is practice is evolving for bipolar depression or depression
treated in schizophrenia, including dosing and expected with mixed features, so now first-line treatment is one of
onset of action within minutes to hours. However, not all the specifically approved serotonin/dopamine blockers,
agents in the serotonin/dopamine blocker class approved not a monoamine reuptake inhibitor. However, there
to treat schizophrenia are also approved to treat acute is plenty of controversy over this recommendation, as
bipolar mania, and not all of those approved for acute many prescribers and some experts still advocate for
bipolar mania are approved for bipolar maintenance (see monoamine reuptake inhibitors in some patients with
Table 7-1). Differences in receptor binding profiles could bipolar depression. But more and more studies are
explain why some agents are approved in mania and showing failure of the monoamine reuptake inhibiting
others not; commercial considerations could also explain drugs to work consistently in bipolar depression or in
why some agents are not approved in mania. To enhance mixed features, and, furthermore, monoamine reuptake
antimanic response and to prevent relapse into another inhibitors can induce intolerable activating side effects
episode of mania, lithium and valproate are commonly and even manic episodes and suicidality in patients
used in conjunction with those dopamine/serotonin with bipolar/mixed depression. Other studies do show
342
some benefits of monoamine reuptake blockers in quetiapine treatment of mania with mixed features of
bipolar depression, and in fact fluoxetine combined with depression also suggest efficacy, although depression with
olanzapine is approved for bipolar depression (Table mixed features of mania has not been studied (Table 7-1).
7-1). However, no agent at all is approved for depression 5HT2A antagonist actions combined with 5HT2C and α2
with mixed features. The studies that do exist suggest antagonism, as well as agonist actions at 5HT1A receptors,
poor responses of mixed features to the well-known are likely candidates to be linked to antidepressant
monoamine reuptake inhibitors and an expanding action in bipolar depression (treatment from below).
evidence base for the use of certain serotonin/dopamine Like olanzapine, D2 antagonism by quetiapine could
blockers, particularly those already approved for bipolar theoretically help keep the lid on treatment from below so
depression, as the preferred treatment for mixed features it doesn’t spill over into activation and mania.
as well (see Table 7-1).
Lurasidone
We do not know whether any and all drugs with
serotonin/dopamine blocking properties that are Although approved for the treatment of schizophrenia,
normally used to treat psychosis would be effective lurasidone (Figure 5-53) was never tested nor approved
for bipolar depression, as some have not been for the treatment of mania (Table 7-1). Lurasidone has
studied and others have failed in clinical trials; nor several hypothetical antidepressant receptor binding
are we certain of the antidepressant mechanism of properties: blockade of 5HT2A (Figure 5-17C), 5HT7
action of those that are approved. However, each of (7-53C), and α2 receptors (Figure 7-41), with agonist
the serotonin/dopamine agents now approved to actions at 5HT1A receptors (Figure 5-22). It is one of
treat bipolar depression was originally developed to the only agents to show on post hoc analysis of bipolar
treat psychosis, and their proposed mechanism of depression that those with bipolar depression and mixed
antidepressant therapeutic action in bipolar depression features respond as well to lurasidone as patients with
and depression with mixed features is presented in the bipolar depression without mixed features. Perhaps more
following sections. importantly, lurasidone is the only agent to be studied 7
in a large, randomized multicenter trial of unipolar
Olanzapine–Fluoxetine depression with mixed features and to demonstrate
As previously mentioned, olanzapine–fluoxetine robust antidepressant efficacy in this group without
combination (Figures 5-44 and 7-16) is approved for induction of mania. Lurasidone is prescribed for bipolar
schizophrenia, bipolar mania, treatment-resistant depression and for mixed features at doses lower than
unipolar depression, and bipolar depression. Post hoc those generally used for the treatment of psychosis in
analyses of mania with mixed features of depression schizophrenia, and is generally well tolerated with little
also suggest efficacy of olanzapine for mania with mixed propensity for weight gain or metabolic disturbances and
features of depression, although the counterpart to this is one of the most widely prescribed agents for bipolar
condition at the other end of the spectrum, depression depression.
with mixed features of mania (Figures 6-3 through 6-7),
Cariprazine
has not been studied (Table 7-1).
5HT2A antagonist actions combined with 5HT2C Cariprazine (Figure 5-58) is a D3/D2/5HT1A partial
antagonism are likely candidates to be linked to agonist approved for the treatment of acute bipolar mania
antidepressant action in bipolar depression (“treatment and for bipolar depression, with ongoing trials as an
from below”; see Figure 7-8). D2 antagonism could adjunct to SSRI/SNRIs in unipolar depression (Table 7-1).
theoretically help keep the lid on treatment from below so Cariprazine has 5HT1A partial agonist actions as well as
it doesn’t spill over into activation and mania. α1 (Figure 7-58) and α2 (Figure 7-41) antagonist actions,
each with potential antidepressant mechanisms. What
Quetiapine sets cariprazine apart from other agents in this group of
As previously mentioned, quetiapine (Figure 5-45) is serotonin/dopamine antagonists/partial agonists is its
approved for schizophrenia, bipolar mania, and for unique highly potent action at D3 dopamine receptors as
augmentation of SSRIs/SNRIs in treatment-resistant a partial agonist. Cariprazine is the most potent of any
unipolar depression. It is also approved in bipolar available agent and much more potent than dopamine
depression. Like olanzapine, post hoc analyses of itself for the D3 receptor. How is D3 antagonism/partial
343
Three orders of Two orders of One order of One order of Two orders of Three orders of
magnitude higher magnitude higher magnitude higher magnitude lower magnitude lower magnitude lower
affinity than DA affinity than DA affinity than DA affinity than DA affinity than DA affinity than DA
DA
binding
affinity for D3
(Ki=60nm)
Cariprazine Blonanserin Brexpiprazole Iloperidone Clozapine

binding affinity binding affinity binding affinity binding affinity binding affinity
for D3 for D3 for D3 for D3 for D3
(0.09nM) (0.28nM) (1.1nM) (10.5nM) (304.6nM)
Asenapine Lurasidone Quetiapine
binding affinity binding affinity binding affinity
for D3 for D3 for D3
(1.8nM) (15.7nM) (800nM)
Paliperidone Aripiprazole
binding affinity binding affinity
for D3 for D3
(2.6nM) (17.7nM)
Ziprasidone Olanzapine
binding affinity binding affinity
for D3 for D3
(7.3nM) (39.5nM)
Risperidone
binding affinity
for D3
(8.0nM)
Figure 7-72 Dopamine 3 binding affinity: dopamine versus serotonin/dopamine antagonists/partial agonists. Dopamine 3
antagonism/partial agonism may confer therapeutic benefit in bipolar depression with or without mixed features. Although many
agents may bind to the D3 receptor, only two – cariprazine and blonanserin – have multiple orders of magnitude higher affinity for the D3
receptor than does dopamine (DA) itself, thus allowing them to compete successfully with dopamine for receptor occupancy.
agonism linked to therapeutic efficacy in bipolar What happens when you block a D3 receptor? Recall
depression with or without mixed features? that dopamine has five receptor subtypes (see discussion
We extensively discussed drugs that are antagonists in Chapter 4 and Figure 4-5) in two different groups
or partial agonists at D2 receptors in Chapter 5 and how (Figure 4-4). D3 receptors can be presynaptic and
they are used for psychotic illnesses. The same agents postsynaptic (Figures 4-4 through 4-9). Postsynaptic
also act at D3 receptors, but at clinical doses only two of blockade of D3 receptors in limbic regions may contribute
them – cariprazine and blonanserin (Chapter 5, Figure to antipsychotic actions but it is the presynaptic actions of
5-62) – can highly successfully compete with dopamine D3 antagonism/partial agonism in the ventral tegmental
itself for the D3 receptor (Figure 7-72). That is, in the area (VTA) that are of most interest for explaining
brain, drugs compete with dopamine itself for the D3 cariprazine’s antidepressant actions (Figure 7-73).
receptor and only those drugs with an affinity for the D3 So, what is the consequence of blocking D3 receptors in
receptor significantly higher than dopamine’s affinity the VTA and why might this contribute to antidepressant
for the D3 receptor will actually block the D3 receptor. actions of cariprazine? Recall also that dopamine
Several agents have somewhat higher affinity for the D3 input to the cortex is thought to be deficient in mood,
receptor than dopamine, and may have some net effect motivation, and cognitive symptoms of depression and
blocking the D3 receptor, but cariprazine clearly has also in the negative symptoms of schizophrenia, due
the most potent action at the D3 receptor and would be in part to hypothetically deficient dopamine release
expected to block D3 receptors substantially at clinical from mesocortical dopamine neurons. These neurons
dosing (Figure 7-72). are depicted in Figure 7-73A and show D3 presynaptic
344
Mesocortical Dopamine Pathway
D1
D3 antagonist/
partial agonist
D3 D1
(SIGH) (SIGH)
A negative affective B negative affective

symptoms symptoms symptoms symptoms
Figure 7-73 Dopamine 3 antagonism/partial agonism in the ventral tegmental area (VTA). (A) Presynaptic D3 receptors detect
dopamine and inhibit further dopamine release. These receptors are present in the VTA but not in the prefrontal cortex. There are,
however, postsynaptic D2 receptors in the prefrontal cortex, which are stimulated by dopamine. Shown here is the mesocortical
dopamine pathway, with stimulation of D3 receptors resulting in reduced dopamine release in the prefrontal cortex. Low levels of
dopamine in the prefrontal cortex is hypothesized to contribute to depressed mood, reduced motivation, and cognitive symptoms, all of
which occur in mood disorders, as well as to negative symptoms in schizophrenia. (B) Antagonism/partial agonism of D3 receptors in the
VTA can increase dopamine release in the prefrontal cortex. Because there are no D3 receptors in the prefrontal cortex, D3 antagonists/
partial agonists have no effect there. Dopamine is free to stimulate D1 receptors, hypothetically improving symptoms of depression. 7
Cariprazine is approved for acute bipolar mania and

autoreceptors in the VTA on dopamine cell bodies for a
for acute bipolar depression (Table 7-1). Post hoc analyses
population of mesocortical neurons. The function of these
show significant clinical improvement both in mania
D3 receptors is to detect dopamine and inhibit further
with mixed features of depression and bipolar depression
dopamine release (Figure 7-73A). However, these same
with mixed features of mania. Studies as adjunctive
neurons projecting to the prefrontal cortex do not have
treatment for patients with unipolar depression on
presynaptic autoreceptors on their axon terminals (see
SSRIs/SNRIs have early indications of efficacy reported.
Chapter 4 discussion and Figure 4-9; see also Figure 7-73).
Thus, cariprazine has some of the most robust and
D3 antagonists will have no effect in the prefrontal cortex
wide-ranging efficacy known across the entire bipolar
since there are few D3 receptors there. In Chapter 4 we
spectrum (Figure 6-7).
discussed how most of the dopamine receptors in prefrontal
cortex are postsynaptic and D1 (Figure 4-9). What this Lithium, the Classic “Antimanic” and “Mood
means is that when D3 antagonists/partial agonists act Stabilizer”
in the VTA to block them, this disinhibits the dopamine Bipolar mania has classically been treated with lithium
neurons projecting to prefrontal cortex and they release for more than 50 years. Lithium is an ion whose
dopamine onto D1 receptors (Figure 7-73B). This action mechanism of action is not certain. Candidates for its
hypothetically improves symptoms of depression and is one mechanism of action are various signal transduction sites
explanation for why cariprazine has antidepressant actions, beyond neurotransmitter receptors (Figure 7-74). This
and also why it has more robust improvement of negative includes second messengers such as the phosphatidyl
symptoms of schizophrenia than other drugs for psychosis. inositol system, where lithium inhibits the enzyme
Improvement in energy, motivation, and “brightening” inositol monophosphatase; modulation of G proteins;
are observed after D3 antagonism in patients with both and, most recently, regulation of gene expression for
mood disorders and schizophrenia, and animal models growth factors and neuronal plasticity by interaction
demonstrate precognitive actions and also improvements in with downstream signal transduction cascades, including
substance abuse.
345
Possible Mechanism of Lithium Action on Downstream Figure 7-74 Lithium’s mechanism

of action. Although lithium is
Signal Transduction Cascades the oldest treatment for bipolar
disorder, its mechanism of action
neurotrophin is still not well understood. Several
possible mechanisms exist and
are shown here. Lithium may work
NT1 by affecting signal transduction,
NT perhaps through its inhibition of
second-messenger enzymes such as
inositol monophosphatase (right), by
modulation of G proteins (middle), or
by interaction at various sites within
downstream signal transduction
GE
cascades, including glycogen
++ ++
synthase kinase 3 (GSK-3) (left).
GSK-3
= lithium
promotes neuroprotection
inhibition of GSK-3 (glycogen synthase kinase 3) and adverse effects upon the thyroid and kidney. Lithium has
protein kinase C (Figure 7-74). a narrow therapeutic window, requiring monitoring of
However lithium works, it is proven effective in manic plasma drug levels.
episodes, and in maintenance of recurrence, especially
Anticonvulsants as “Mood Stabilizers”
for manic episodes and, perhaps to a lesser extent, for
depressive episodes. Lithium is well established to help Based upon theories that mania may “kindle” further
prevent suicide in patients with mood disorders. It is episodes of mania, a logical parallel with seizure disorders
also used to treat depressive episodes in bipolar disorder was drawn, since seizures can “kindle” more seizures.
and as an augmenting agent to drugs for depression Several anticonvulsants (Table 7-3) are categorized on the
in treatment-resistant unipolar depression, but is not basis of whether they are “mania-minded,” i.e., treat from
formally approved for these uses. above and stabilize from above (Figure 7-7); “depression-
A number of factors have led to an unfortunate minded,” i.e., treat from below and stabilize from below
decline in the use of lithium in recent years, including (Figure 7-8); or both. Because the known anticonvulsants
the entry of multiple new treatment options into the carbamazepine and valproate proved effective in treating
therapeutic armamentarium for bipolar disorder, the the manic phase of bipolar disorder, this has led to the
side effects of lithium, and the monitoring burden that is idea that any anticonvulsant would be a mood stabilizer,
part of prescribing lithium. The modern use of lithium especially for mania. However, this has not proven to be
by experts departs from its classic use as a high-dose the case (Table 7-3) since anticonvulsants do not all act
monotherapy for euphoric mania, with lithium often by the same pharmacological mechanisms, as discussed
utilized now as one member of a portfolio of treatments, below. These agents for mania or bipolar depression are
often allowing once-daily administration and at lower better classified for their pharmacological mechanism of
doses when combined with other mood stabilizers. action at ion channels rather than as “mood stabilizers”
Well-known side effects of lithium include or “anticonvulsants.” Numerous mood stabilizers that
gastrointestinal symptoms such as dyspepsia, nausea, are also anticonvulsants are discussed below, including
vomiting, and diarrhea, as well as weight gain, hair not only those with proven efficacy in different phases of
loss, acne, tremor, sedation, decreased cognition, and bipolar disorder, but also those with dubious efficacy in
incoordination. There are also potential long-term bipolar disorder (Table 7-3).
346
Table 7-3 Anticonvulsant mood stabilizers
Agent Putative clinical actions

Epilepsy Mania-minded Depression-minded
Treat from Stabilize Treat from Stabilize from
above from above below below
Valproate ++++ ++++ ++ + +/−
Carbamazepine ++++ ++++ ++ + +/−
Lamotrigine ++++ +/− ++++ +++ ++++
Oxcarbazepine/licarbazepine ++++ ++ + +/− +/−
Riluzole + + +/−
Topiramate ++++ +/− +/−
Gabapentin ++++ +/− +/−
Pregabalin ++++ +/− +/−
Anticonvulsants with Proven Efficacy in Bipolar Disorder

Valproic Acid (Valproate, Sodium Valproate)
As for all anticonvulsants, the exact mechanism of action
of valproic acid (also, sodium valproate, valproate) is
uncertain; however, even less may be known about the valproic acid 7
mechanism of valproate than for other anticonvulsants.
Various hypotheses are discussed here, and summarized in
Figures 7-75 through 7-78. At least three possibilities exist
for how valproic acid works: inhibiting voltage-sensitive Na+
sodium channels (Figure 7-76), boosting the actions of the
neurotransmitter GABA (γ-aminobutyric acid) (Figure ++
Ca
7-77), and regulating downstream signal transduction
cascades (Figure 7-78). It is not known whether these
actions explain the mood-stabilizing actions, the
anticonvulsant actions, the anti-migraine actions, or the
side effects of valproic acid. Obviously, this simple molecule
has multiple and complex clinical effects, and research
is trying to determine which of the various possibilities
explain the “mood-stabilizing” antimanic effects of valproic
acid so that new agents with more efficacy and fewer Glu
side effects can be developed by targeting the relevant
pharmacological mechanism for bipolar disorder. GABA
One hypothesis to explain mood-stabilizing antimanic
actions is the possibility that valproate acts to diminish
Figure 7-75 Valproic acid. Shown here is an icon of the
excessive neurotransmission by diminishing the flow of pharmacological actions of valproic acid, an anticonvulsant
ions through voltage-sensitive sodium channels (VSSCs) used in the treatment of bipolar disorder. Valproic acid (also
valproate) may work by interfering with voltage-sensitive sodium
(Figure 7-76). VSSCs are discussed in Chapter 3 and channels, enhancing the inhibitory actions of γ-aminobutyric
illustrated in Figures 3-19 through 3-21. No specific acid (GABA), and regulating downstream signal transduction
cascades, although which of these actions may be related to
molecular site of action for valproate has been identified, mood stabilization is not clear. Valproate may also interact with
but it is possible that valproate may change the sensitivity other ion channels, such as voltage-sensitive calcium channels,
of sodium channels by altering phosphorylation of and also indirectly block glutamate (Glu) actions.
347
Possible Sites of Action of Valproate on VSSCs
= valproate
P
2 2
P0
GE GE
4
Figure 7-76 Possible sites of action of valproate on voltage-sensitive sodium channels (VSSCs). Valproate may exert antimanic
effects by changing the sensitivity of VSSCs, perhaps by directly binding to channel subunits or inhibiting phosphorylating enzymes
that regulate the sensitivity of these ion channels. Inhibition of VSSCs would lead to reduced sodium influx and, in turn, potentially to
reduced glutamate excitatory neurotransmission, which is a possible mechanism for mania efficacy.
Figure 7-77 Possible sites of action of valproate on

Possible Sites of Action of Valproate on GABA γ-aminobutyric acid (GABA). Valproate’s antimanic effects
may be due to enhancement of GABA neurotransmission,
perhaps by inhibiting GABA reuptake, enhancing GABA
GABA neuron release, or interfering with the metabolism of GABA by
= valproate GABA-T (GABA transaminase).
? ?
E
inactive
GABA-T substance
GABA
348
sodium channels, either by binding directly to the VSSC plasticity such as ERK (extracellular signal-regulated
or its regulatory units, or by inhibiting phosphorylating kinase) kinase, BCL2 (cytoprotective protein B-cell
enzymes (Figure 7-76). If less sodium is able to pass into lymphoma/leukemia-2 gene), GAP43 (growth associated
neurons, this may lead to diminished release of glutamate protein 43), and others (Figure 7-78). The effects of these
and therefore less excitatory neurotransmission, but signal transduction cascades are only now being clarified,
this is only a theory. There may be additional effects of and which of these possible effects of valproate might be
valproate on other voltage-sensitive ion channels, but relevant to mood-stabilizing actions are not yet understood.
these are poorly characterized and may relate to side Valproate is proven effective for the acute manic phase
effects as well as to therapeutic effects. of bipolar disorder, and is commonly used long-term to
Another idea is that valproate enhances the actions prevent recurrence of mania, although its prophylactic
of GABA, either by increasing its release, decreasing its effects have not been as well established as its acute
reuptake, or slowing its metabolic inactivation (Figure effects in mania (Table 7-3). Antidepressant actions of
7-77). The direct site of action of valproate that causes the valproate have also not been well established, nor has it
enhancement of GABA remains unknown, but there is good been shown to convincingly stabilize against recurrent
evidence that the downstream effect of valproate ultimately depressive episodes, but there may be some efficacy for
does result in more GABA activity, and thus more inhibitory the depressed phase of bipolar disorder in some patients.
neurotransmission, possibly explaining antimanic actions. Some experts believe valproic acid is more effective than
Finally, a number of downstream actions on complex lithium for rapid cycling and mixed episodes of mania.
signal transduction cascades have been described (Figure In reality, such episodes are very difficult to treat, and
7-78). Like lithium, valproate may inhibit GSK-3, but it may combinations of two or more mood stabilizers, including
also target many other downstream sites, from blockade lithium plus valproate plus serotonin/dopamine blockers,
of phosphokinase C (PKC) and MARCKS (myristoylated are usually in order. For optimum efficacy, it may be
alanine-rich C kinase substrate), to activating various ideal to push the dose of valproate, but no drug works
signals that promote neuroprotection and long-term if your patient refuses to take it, and valproic acid often 7
Figure 7-78 Possible sites of action

Possible Sites of Action of Valproate on Downstream of valproate on downstream signal
Signal Transduction Cascades transduction cascades. Valproate
has been shown to have multiple
neurotrophin downstream effects on signal
transduction cascades, which may
be involved in its antimanic effects.
NT1 Valproate inhibits glycogen synthase
kinase 3 (GSK-3), phosphokinase C
(PKC), and myristoylated alanine-
rich C kinase substrate (MARCKS).
In addition, valproate activates
signals that promote neuroprotection
and long-term plasticity, such as
GE
extracellular signal-regulated kinase
(ERK), cytoprotective protein B-cell
lymphoma/leukemia-2 gene (BCL2),
Ras/Raf/MEK and growth associated protein 43
2 (GAP43).
P ERK
activation
GSK-3 PKC
promotes neuroprotection
= valproate
MARCKS
BCL2 GAP43
activation activation
neuronal genome
349
has unacceptable side effects such as hair loss, weight 7-3), they appear to have different pharmacological
gain, and sedation. Certain problems can be avoided by mechanisms of action, including different side-effect
lowering the dose, but this will generally lower efficacy, profiles. Thus, carbamazepine is hypothesized to act by
and thus there may be the requirement to combine blocking voltage-sensitive sodium channels (VSSCs)
valproate with other mood stabilizers, especially when (Figure 7-80), perhaps at a site within the channel itself,
valproate is given in lower doses. Some side effects may also known as the α subunit of VSSCs. As mentioned
be related more to chronicity of exposure rather than earlier, VSSCs are discussed in Chapter 3 and illustrated
to dose and thus may not be avoidable by reducing the in Figures 3-19 through 3-21. The hypothesized action
dose. This includes warnings for bone marrow, liver, of carbamazepine upon the α subunit of VSSCs (Figure
pancreatic, and fetal toxicities such as neural-tube 7-80) is different from the hypothesized actions of
defects, as well as concerns about weight gain, metabolic valproate on these sodium channels (Figure 7-76), but
complications, and possible risk of amenorrhea and may be similar to how the anticonvulsants oxcarbazepine
polycystic ovaries in women of child-bearing potential. A and its active metabolite eslicarbazepine also act.
syndrome of menstrual disturbances, polycystic ovaries, Although both carbamazepine and valproate are
hyperandrogenism, obesity, and insulin resistance may be anticonvulsants and both treat mania from above, there
associated with valproic acid therapy in such women. are differences between these two “anticonvulsants”
beyond their presumed pharmacological mechanisms
Carbamazepine
of therapeutic action in mania. For example, valproate
Carbamazepine (Figure 7-79) was actually the first to is proven effective in migraine, but carbamazepine is
be shown to be effective in the manic phase of bipolar proven effective in neuropathic pain. Furthermore,
disorder, but did not receive US FDA approval until carbamazepine has a different side-effect profile
recently as a once-daily controlled-release formulation. than valproate, including more profound immediate
Although carbamazepine and valproate both act suppressant effects upon the bone marrow, requiring
effectively on the manic phase of bipolar disorder (Table initial monitoring of blood counts (blood counts
including platelets should also be periodically monitored
on valproate), and notable induction of the cytochrome
carbamazepine P450 enzyme 3A4. Both carbamazepine and valproate are
sedating and can cause fetal toxicity such as neural-tube
Ca ++ defects.
Lamotrigine
Lamotrigine (Figure 7-81) is approved as a “mood
K+ stabilizer” for entirely different clinical indications
than the anticonvulsant mood stabilizers valproate and
carbamazepine, making the point that anticonvulsants
do not all have the same therapeutic actions in bipolar
disorder. Lamotrigine is not approved to treat mania
or depression in bipolar disorder, but is approved to
prevent recurrence of both mania and depression in
bipolar disorder. There are many curious things about
GABA lamotrigine as a “mood stabilizer.” First, the US FDA
has not approved its use for acute bipolar depression,
Na+ channel yet most experts believe that lamotrigine is effective for
unit bipolar depression. A second interesting thing about
Figure 7-79 Carbamazepine. Shown here is an icon of the lamotrigine is that even though it has some overlapping
pharmacological actions of carbamazepine, an anticonvulsant
used in the treatment of bipolar disorder. Carbamazepine may
mechanistic actions with carbamazepine, namely binding
work by binding to the α subunit of voltage-sensitive sodium to the open-channel conformation of VSSCs (Figure
channels (VSSCs) and could perhaps have actions at other ion 7-82), lamotrigine is not approved for bipolar mania.
channels for calcium and potassium. By interfering with voltage-
sensitive channels, carbamazepine may enhance the inhibitory Perhaps lamotrigine’s pharmacological actions are not
actions of γ-aminobutyric acid (GABA). potent enough at sodium channels, or perhaps the long
350
Figure 7-80 Binding site of

carbamazepine. Carbamazepine
is believed to bind to a site
located within the open-channel
conformation of the voltage-
sensitive sodium channel (VSSC) α
subunit.
carbamazepine
lamotrigine
Ca++ Possible Sites of Action of Lamotrigine
+ on Glutamate Release
K
glutamate
neuron
Na+channel
unit Glu lamotrigine
lamotrigine
Figure 7-81 Lamotrigine. Shown here is an icon of the
pharmacological actions of lamotrigine, an anticonvulsant used
in the treatment of bipolar disorder. Lamotrigine may work by Figure 7-82 Possible site of action of lamotrigine on glutamate
blocking the alpha subunit of voltage-sensitive sodium channels release. It is possible that lamotrigine reduces glutamate
(VSSCs) and could perhaps also have actions at other ion channels release through its blockade of voltage-sensitive sodium
for calcium and potassium. Lamotrigine is also thought to reduce channels (VSSCs). Alternatively, lamotrigine may have this effect
the release of the excitatory neurotransmitter glutamate. via an additional synaptic action that has not yet been identified.
351
titration period required when starting lamotrigine making it a more tolerable agent that is easier to dose. On
makes it difficult to show any useful effectiveness for the other hand, oxcarbazepine has never been proven to
mania, which generally requires treatment with drugs work in acute bipolar mania or depression. Nevertheless,
that can work quickly. A third aspect of lamotrigine because of a similar postulated mechanism of action
is that it is generally well tolerated, with one glaring but a better tolerability profile, oxcarbazepine and more
exception: a propensity to cause rashes, including (rarely) recently eslicarbazepine have been utilized “off-label” by
the life-threatening Stevens Johnson syndrome (toxic many clinicians especially for the manic phase of bipolar
epidermal necrolysis). Rashes caused by lamotrigine disorder.
can be minimized by very slow up-titration of the drug
Topiramate
during initiation of therapy, avoiding or managing drug
interactions, such as those with valproate that raise Topiramate is another compound approved as an
lamotrigine levels, and by understanding how to identify anticonvulsant and for migraine, and recently, in
and manage serious rashes, including being able to combination with bupropion, for weight loss in obesity.
distinguish them from benign rashes (see discussion of Topiramate has been tested in bipolar disorder, but
lamotrigine in Stahl’s Essential Psychopharmacology: the with ambiguous results (Table 7-3). It does seem to be
Prescriber’s Guide). Finally, lamotrigine seems to have associated with weight loss and is sometimes given as an
some unique aspects to its mechanism of action (Figure adjunct to drugs for psychosis or to mood stabilizers that
7-82), namely to reduce the release of the excitatory cause weight gain, but can cause unacceptable sedation
neurotransmitter glutamate. It is not clear whether this in some patients. Topiramate is also being tested in
action is secondary to blocking the activation of VSSCs various substance abuse disorders, including stimulant
(Figure 7-82) or to some additional synaptic action. abuse and alcoholism. However, topiramate is not clearly
Reducing excitatory glutamatergic neurotransmission, effective as a mood stabilizer, either from evidence-based
especially if excessive during bipolar depression, may be randomized controlled trials (which are not consistently
a unique mechanism of action of lamotrigine and explain positive) or from clinical practice.
why it has such a different clinical profile as a treatment
Gabapentin and Pregabalin
from below and a stabilizer from below for bipolar
depression. These anticonvulsants seem to have little or no action as
mood stabilizers, yet are robust treatments for various
Anticonvulsants with Uncertain or Doubtful Efficacy in pain conditions, from neuropathic pain to fibromyalgia,
Bipolar Disorder and for various anxiety disorders, and are discussed in
more detail in Chapter 8 on anxiety and Chapter 9 on
Oxcarbazepine/Eslicarbazepine
pain.
Oxcarbazepine is structurally related to carbamazepine,
but is not a metabolite of carbamazepine. Oxcarbazepine Calcium Channel Blockers (L-Type)
is actually not the active form of the drug, but a prodrug There are several types of calcium channels, not
that is immediately converted into a 10-hydroxy only the N or P/Q channels linked to secretion of
derivative, also called the monohydroxy derivative, neurotransmitters, targeted by α2δ ligands and discussed
and most recently has been named licarbazepine. The in Chapter 3 (see Figures 3-23 and 3-24), but also L
active form of licarbazepine is the S enantiomer, known channels localized on vascular smooth muscle and
as eslicarbazepine. Thus, oxcarbazepine really works which are targeted by various antihypertensive and
via conversion to eslicarbazepine, which is itself now antiarrhythmic drugs, commonly called “calcium channel
available as an anticonvulsant. blockers.” L-type channels are located on neurons where
Oxcarbazepine has a presumed mechanism of their function is still being debated, and some anecdotal
anticonvulsant action the same as that for carbamazepine, evidence suggests that calcium channel blockers,
namely, binding to the open-channel conformation of the especially dihydropyridine-type calcium channel blockers,
VSSC at a site within the channel itself on the α subunit may be useful for some patients with bipolar disorder.
(as in Figure 7-80). However, oxcarbazepine seems to
Riluzole
have some important differences from carbamazepine,
including being less sedating, having less bone marrow This agent has anticonvulsant actions in preclinical
toxicity, and also having less CYP450 3A4 interactions, models, but was developed to slow the progression
352
of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s remission of symptoms: treat from above and stabilize
disease). Theoretically, riluzole binds to VSSCs and from above (Figure 7-7) and treat from below and
prevents glutamate release, in an action similar to that stabilize from below (Figure 7-8).
postulated for lamotrigine (see Figure 7-82). The idea is
that diminishing glutamate release in ALS would prevent FUTURE TREATMENTS FOR
the postulated excitotoxicity that may be causing death MOOD DISORDERS
of motor neurons in ALS. Excessive glutamate activity Dextromethorphan–Bupropion and
may be occurring not only in ALS, but also in bipolar Dextromethorphan–Quinidine
depression, although this is not necessarily so severe as to
As discussed above, one of the most interesting
cause widespread neuronal loss.
developments in the treatment of resistant unipolar
Combinations are the Standard for Treating Bipolar depression in recent years has been the observation that
Disorder infusions of subanesthetic doses of ketamine or intranasal
Given the disappointing number of patients who administration of esketamine can exert an immediate
attain satisfactory response in bipolar disorder from antidepressant effect and can often immediately reduce
monotherapy, it is more the rule than the exception suicidal thoughts. Since the effects are often not sustained
that bipolar patients receive combination treatments. for more than a few days, investigators have searched for
Although first-line treatment may be one of the oral ketamine-like agents that could have rapid onset,
serotonin/dopamine agents, if this fails to adequately sustained efficacy, greater ease of administration, and better
control mania, another treatment for mania such as tolerability in patients with treatment-resistant illness.
valproate or lithium may be added (Figure 7-83). On Several such possibilities are in development, namely
the other hand, if serotonin/dopamine agents fail to various NMDA antagonists with additional pharmacological
adequately control depression, lamotrigine may be added properties. One agent combines the NMDA antagonist
or, controversially, a monoamine reuptake inhibitor dextromethorphan with the CYP450 2D6 inhibitor and 7
(Figure 7-83). The goal is four treatments for fullest NDRI bupropion (also known as AXS-05), and the other
Figure 7-83 Bipolar disorder

Combos for Bipolar Disorder combinations. Most patients
with bipolar disorder will require
Evidence-Based Bipolar Combos for Mania treatment with two or more agents.
The combinations with the most
evidence for mania include addition
of a serotonin/dopamine antagonist
+ to either lithium or valproate.
Combinations that are not well
5HT/DA blocker-lithium 5HT/DA blocker lithium studied in controlled trials but that
combo
have some practice-based evidence
for depression include a serotonin/
+ dopamine antagonist plus lamotrigine.
Although controversial, some clinicians
5HT/DA blocker- valproate add a monoamine reuptake inhibitor to
5HT/DA blocker
valproate combo a serotonin/dopamine antagonist for
bipolar depression.
Practice-Based Bipolar Combos for Depression
+
5HT/DA blocker- Lamictal/
Lamictal combo 5HT/DA blocker lamotrigine
Careful Combo
+ +
5HT/DA blocker- Lamictal/ monoamine
Lamictal combo 5HT/DA blocker lamotrigine reuptake
blocker
353
combines dextromethorphan with the CYP450 2D6 concomitant administration of a CYP450 2D6 inhibitor.
inhibitor quinidine (Figure 7-84). The latter combination Each combination product adds a 2D6 inhibitor
has already been approved to treat pathological laughing (Figure 7-84). Quinidine is a 2D6 inhibitor at doses
and crying in pseudobulbar affect. A newer version of the below its cardiovascular actions, and bupropion is
latter combination has deuterated the dextromethorphan not only an NDRI (Figures 7-34 and 7-35) but also
molecule and altered the dose of quinidine (Figure 7-85). a 2D6 inhibitor. For bupropion, as discussed above
Deuteration extends the half-life of a compound and allows and illustrated in Figures 7-34 and 7-35, in addition
re-patenting for commercial development (deuteration of to 2D6 inhibition there is the monoamine-associated
tetrabenazine was previously discussed in Chapter 5 in the antidepressant mechanism of NRDIs (Figure 7-84)
section on treatment of tardive dyskinesia and illustrated in with the potential for synergy with the NMDA
Figure 5-11B). Although it is clear that dextromethorphan antagonist mechanism of dextromethorphan. Both
has clinically relevant affinity for the NMDA receptor, combination products are in trials for treatment-
other binding properties are less well characterized, resistant depression with some promising initial results,
including σ1 receptor binding, SERT inhibition, and weak especially for dextromethorphan–bupropion, which
μ-opioid binding (Figure 7-84). As for all NMDA receptor has been awarded breakthrough therapy status by the
antagonists studied for treatment-resistant depression, it is US FDA for major depressive disorder and fast-track
unclear which subtypes of NMDA receptor are engaged by designation for treatment-resistant depression. Both
dextromethorphan, which are most important, and what combination products are also in trials for agitation
the role of σ1 or μ-opioid binding is in rapid antidepressant in Alzheimer disease and show some promising initial
action. results, especially for dextromethorphan–bupropion,
Dextromethorphan is rapidly metabolized by wh ich was given fast-track designation by the FDA.
CYP450 2D6 making it difficult to achieve therapeutic Dextromethorphan–bupropion treatment of agitation in
blood levels following oral administration without dementia is discussed further in Chapter 12 on dementia.
dextromethorphan Figure 7-84 Dextromethorphan–

bupropion and dextromethorphan–
(DXM) quinidine. Dextromethorphan is a
weak N-methyl-D-aspartate (NMDA)
NMDA receptor antagonist, with stronger
binding affinity for the serotonin
transporter (SERT) and σ1 receptors. It
α1D
is rapidly metabolized by CYP450 2D6,
making it difficult to achieve therapeutic
σ1 blood levels without concomitant
SERT administration of a CYP450 2D6
inhibitor. Dextromethorphan is being
studied in combination with the
norepinephrine–dopamine reuptake
inhibitor (NDRI) bupropion, which
also inhibits CYP450 2D6, and in
combination with the CYP450 2D6
SERT inhibitor quinidine.
σ1 NMDA α1D
++
+ + +
+ +
bupropion quinidine
DAT
2D6 2D6
NET
NDRI quinidine
354
deuterated dextromethorphan
Figure 7-85 Deuterated dextromethorphan. A
deuterated formulation of dextromethorphan in
combination with quinidine is in development.
(Deu-DXM) Deuteration extends the half-life of dextromethorphan,
which in turn affects the required dose of quinidine.
NMDA
α1D
σ1
Deu-DXM SERT
SERT 7
σ1 NMDA α1D
++
+ + +
Dextromethadone dextromethadone, are less well characterized, such as σ1

Methadone is a racemic mixture of dextro- and receptor binding, SERT inhibition, and weak μ-opioid
levomethadone and is given orally as a μ-opioid binding (Figure 7-86). It is possible that these agents
agonist for medication-assisted treatment of opioid use do not act simply as NMDA antagonists, but that some
disorder. The μ-opioid activity resides mostly in the levo degree of μ-opioid agonist activity may shepherd dimers
enantiomer, and the dextro enantiomer has relatively of NMDA and μ receptors by exploiting their natural
more potent NMDA antagonist activity, without as oppositional actions, to create a greater NMDA effect in
potent μ-opioid agonist activity. The dextro enantiomer the presence of μ stimulation than in the absence of it.
(Figure 7-86) is in clinical development as a rapid-onset This is the subject of much further research as the field
treatment of major depression with some promising attempts to clarify the mechanism of rapid antidepressant
early clinical results. Just as for all NMDA antagonists response associated with NMDA antagonism, and which
for treatment-resistant depression (i.e., ketamine, portfolio of receptor actions is optimal.
esketamine, and dextromethorphan), the relative
importance of NMDA antagonism, the specific NMDA Hallucinogen-Assisted Psychotherapy
receptors targeted, and the downstream consequences Psychotherapy has traditionally competed with
of NMDA antagonism are just now being clarified, psychopharmacology. More recently, psychotherapy
including the potential differences amongst these and psychopharmacology have come to be seen as
various NMDA antagonists. Furthermore, the additional complementary and most good mental health prescribers
binding properties of each of these agents, including also practice psychotherapy. It has long been recognized
355
dextromethadone MDMA
NMDA
3,4-methylene-dioxymethamphetamine
5H
T2A
VMAT
σ SERT
SERT
µ δ Figure 7-87 3,4-Methylene-dioxymethamphetamine
(MDMA). MDMA is an amphetamine derivative. Amphetamine
is a norepinephrine–dopamine reuptake inhibitor (NDRI) with
additional inhibition of VMAT2 causing enhanced dopamine
release. MDMA is a serotonin inhibitor, with additional
inhibition of VMAT2 causing enhanced serotonin release.
µ 5HT
MDMA is intesting for PTSD, anxiety, and treatment-resistant
depression.
2A NMDA δ SERT σ
++
+ + + + +
resurrection in the use of hallucinogens to induce a
state of dissociation in which the patient may be more
amenable to psychotherapeutic input. One idea is to
provide more insight and clarity to underlying suppressed
memories. Another idea is to use psychotherapy-guided
Figure 7-86 Dextromethadone. Methadone consists of two
enantiomers, dextro and levo. The levo enantiomer is a potent re-experiencing of memories, coupled with techniques to
μ-opioid receptor agonist, while the dextro enantiomer has less interfere with reconsolidation of traumatic memories so
potent μ-opioid agonism and is also an antagonist at N-methyl-
D-aspartate (NMDA) receptors. The dextro enantiomer of they are “forgotten.” Animal studies show that memories
methadone, dextromethadone, is in clinical development as a are initially consolidated into relatively permanent
rapid-onset treatment for major depressive disorder.
memory files, but become labile when reactivated, and
if not reconsolidated after having or modifying that
memory, it can theoretically be erased. That is the goal
that using both psychotherapy and medication can be of some types of hallucinogen-assisted psychotherapies:
synergistic for many patients in terms of therapeutic to prevent the reconsolidation of painful traumatic
efficacy and favorable long-term outcomes, perhaps memories. Numerous agents have been tested in this
by sharing some common neurobiological links since paradigm of dissociation-assisted psychotherapy, from
both can change brain circuits. Preclinical research ketamine to the hallucinogens MDMA and psilocybin,
increasingly documents psychotherapy as a form described below.
of learning which can induce epigenetic changes in
brain circuits, which can enhance the efficiency of 3,4-Methylene-dioxymethamphetamine (MDMA)
information processing in malfunctioning neurons to 3,4-Methylene-dioxymethamphetamine (MDMA)
improve symptoms in psychiatric disorders, just like (Figure 7-87) is an amphetamine derivative that
drugs. A recent clinical exploitation of the combination transforms amphetamine itself from being predominantly
of psychotherapy with psychopharmacology is a a norepinephrine–dopamine reuptake inhibitor with
356
psilocybin
4-phosphoryloxy-N,N-dimethyltryptamine
5H
T
2A
5HT2
B
5HT2A 5HT2B
+++
++
5HT1E 5HT6 5HT7 E dephosphorylation
+ + +
psilocin
N,N-dimethyltryptamine DMT
7
5H
T2
A
5HT2B
5HT7
5HT7 5HT2B
5HT2A
5HT
+++ +++ 5HT1D 1E 5HT2C 5HT6 5HT5 5HT1B 5HT1A
++
+ + + + + + +
Figure 7-88 Psilocybin. The hallucinogen psilocybin is predominantly a 5HT2A agonist, with actions at some additional serotonin
receptors. It is rapidly converted by dephosphorylation to its active metabolite, psilocin. Psilocybin is being studied in depression,
anxiety, and PTSD.
vesicular monoamine transporter 2 (VMAT2) inhibition serotonin is free to act at all serotonin receptors but
causing enhanced dopamine release (see Chapter 11 seems to have profound actions in stimulating the 5HT2A
and Figures 11-30 through 11-32) into a more powerful receptor, not unlike other hallucinogens.
serotonin reuptake inhibitor with VMAT2 inhibition The reason MDMA may be helpful in psychotherapy is
causing enhanced serotonin release as well. The released that it can produce feelings of increased energy, pleasure,
357
and emotional warmth, and it can promote trust and receptors (Figure 7-88), since 5HT2A antagonists (but not
closeness but cause distortions and hallucinations of selective dopamine D2 antagonists) reverse the effects of
sensory and time perception. MDMA, also known as psilocybin in humans. Hallucinogen-mediated 5HT2A-
“Ecstasy” or “Molly” (slang for Molecular), was once stimulated psychosis was discussed in Chapter 4 as one
popular in the nightclub scene and at “raves” (all-night of the three major theories of psychosis and illustrated
dance parties). Its agonist actions at 5HT2A receptors in Figure 4-52B. Psilocybin has been designated a
may be responsible for the spike in body temperature breakthrough therapy by the US FDA for treatment of
that can occur after taking MDMA, with organ damage depression. Psilocybin is also being widely investigated
and even death, especially when dancing all night and for anxiety and existential distress in terminally ill
when dehydrated. MDMA obtained on the street is often patients, substance abuse, PTSD, and several other
contaminated with “bath salts” (synthetic cathinones), conditions.
methamphetamine, dextromethorphan, ketamine, and/
or cocaine, and is often taken along with marijuana and SUMMARY
alcohol. Pure MDMA is obviously what is studied in
hallucinogen-assisted psychotherapy. MDMA is in testing In this extensive chapter, we have summarized the
for PTSD, anxiety and existential distress in terminally pharmacological mechanisms of actions of the many
ill patients, social anxiety in autism, treatment refractory agents used to treat unipolar major depression, especially
depression, substance abuse, and more. those acting on monoamine systems. More recently
introduced have been agents working outside the
Psilocybin monoamine system, namely on glutamate and GABA
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) neurotransmission. Combining drugs for treatment
(Figure 7-88), also known as an hallucinogen in “magic resistance in unipolar depression is also discussed. Not
mushrooms,” has a structure similar to LSD (lysergic only is the treatment of unipolar depression presented,
acid diethylamide) and has been used and abused for its but this is compared and contrasted with the treatment
ability to cause hallucinogenic, psychedelic, and euphoric of bipolar disorder, from mania, to bipolar depression, to
“trips.” Psilocybin is rapidly converted to its active depression with mixed features. The specific agents for
metabolite psilocin (N,N-dimethyltryptamine or DMT) these conditions, which are mostly different from those for
by dephosphorylation. Both agents bind to a number of the treatment of unipolar depression, are discussed. Many
serotonin receptor subtypes (5HT1A, 5HT2A, 5HT2C, and of these same agents are used in the treatment of psychosis
others), but the hallucinogenic actions of both agents and that use is discussed in Chapter 5. A brief synopsis of
are linked most closely with agonist actions on 5HT2A future treatments for mood disorders is also presented.
358
8 Anxiety, Trauma,
and Treatment
Symptom Dimensions in Anxiety Disorders 359 Serotonin and Anxiety 368
When Is Anxiety an Anxiety Disorder? 359 Noradrenergic Hyperactivity in Anxiety 370
Overlapping Symptoms of Major Depression and Fear Conditioning versus Fear Extinction 370
Anxiety Disorders 360 Novel Approaches to the Treatment of Anxiety
Overlapping Symptoms of Different Anxiety Disorders 374
Disorders 362 Treatments for Anxiety Disorder Subtypes 377
The Amygdala and the Neurobiology of Fear 364 Generalized Anxiety Disorder 377
Cortico-Striato-Thalamo-Cortical (CSTC) Loops and Panic Disorder 377
the Neurobiology of Worry 365 Social Anxiety Disorder 377
Benzodiazepines as Drugs for Anxiety 366 PTSD 377
Alpha-2-Delta Ligands as Anxiolytics 366 Summary 378
This chapter will provide a brief overview of anxiety and its treatment. Although all psychiatric disorders
disorders, traumatic disorders, and their symptoms and can benefit from psychotherapy, anxiety/traumatic
their treatments. Included here are descriptions of how disorders may be especially effectively treated with
the symptoms of anxiety disorders overlap with each psychotherapy. In many cases, psychotherapy for
other, and also with the symptoms of major depressive anxiety disorders can be even more effective than drug
disorder and with the symptoms of trauma and stress- treatment or can enhance the efficacy of anxiolytic
related disorders. Clinical descriptions and formal agents. Novel psychotherapies aiming to prevent or
diagnostic criteria are mentioned here only in passing. reverse fear conditioning and fear reconsolidation
The reader should consult standard reference sources are mentioned briefly here but for more details of
for this material. The discussion here will emphasize psychotherapy for anxiety, the reader is referred
how the functioning of various brain circuits and to general psychiatry and clinical psychology texts
neurotransmitters – especially those centered on the as well as to books by the author that cover both
amygdala – impact our understanding of the symptoms psychopharmacology and psychotherapy (see reference
of fear, worry, and traumatic memories. list). The discussion of anxiety and its disorders in
The goal of this chapter is to acquaint the reader this chapter emphasizes the neurobiology of anxiety
with ideas about the clinical and biological aspects of and the mechanism of action of drugs for anxiety.
anxiety/traumatic symptoms in order to understand The reader should consult standard drug handbooks
the mechanisms of action of the various treatments. (such as Stahl’s Essential Psychopharmacology: the
Many of the psychopharmacological treatments are Prescriber’s Guide) for details of doses, side effects,
extensively discussed in other chapters. For details drug interactions, and other issues relevant to the
of mechanisms of the many agents used to treat prescribing of these drugs in clinical practice.
anxiety that are also used to treat unipolar depression
(monoamine reuptake inhibitors), the reader is referred SYMPTOM DIMENSIONS IN
to Chapter 7 on mood disorders and their treatments; ANXIETY DISORDERS
for those agents used to treat anxiety and traumatic
disorders that are also used to treat chronic pain When Is Anxiety an Anxiety Disorder?
(i.e., certain ion-channel-inhibiting anticonvulsants), Anxiety is a normal emotion under circumstances of
the reader is referred to Chapter 9 on chronic pain threat and is thought to be part of the evolutionary “fight
359
or flight” reaction of survival. Whereas it may be normal attention deficit hyperactivity disorder (ADHD), bipolar
or even adaptive to be anxious when a saber-tooth tiger disorder, pain disorders, sleep disorders, and more.
(or its modern-day equivalent) is attacking, there are So, what is an anxiety disorder? These disorders
many circumstances in which the presence of anxiety is all seem to maintain the core features of some form
maladaptive or excessive and constitutes a psychiatric of anxiety or fear coupled with some form of worry,
disorder. The idea of anxiety as a psychiatric disorder is but their natural history over time shows them to
evolving rapidly, and is characterized by the concept of morph from one into another, to evolve into full
core symptoms of excessive fear and worry (symptoms syndrome expression of anxiety-disorder symptoms
at the center of anxiety disorders in Figure 8-1), (Figure 8-1) and then to recede into subsyndromal levels
compared to major depression, which is characterized of symptoms, only to reappear again as the original
by core symptoms of depressed mood or loss of interest anxiety disorder, a different anxiety disorder (Figures
(symptoms at the center of major depressive disorder 8-2 through 8-5), or major depression (Figure 8-1). If
in Figure 8-1). Some disorders associated with the anxiety disorders all share core symptoms of fear and
symptoms of anxiety such as obsessive–compulsive worry (Figures 8-1 and 8-6) – and as we shall see later
disorder (OCD) are no longer classified as anxiety in this chapter, are all basically treated with the same
disorders in some diagnostic manuals, and here OCD is drugs, including many of the same drugs that treat major
discussed in Chapter 13 on impulsive and compulsive depression – the question now arises as to what the
disorders. Other disorders associated with the symptoms difference is between one anxiety disorder and another.
of anxiety such as posttraumatic stress disorder (PTSD) Also, one could ask what the difference is between major
are also no longer classified as anxiety disorders in depression and anxiety disorders. Are all these entities
certain diagnostic manuals, but are discussed here in really different disorders or are they instead different
this chapter. aspects of the same illness?
Anxiety disorders have considerable symptom
overlap with major depression (see those symptoms Overlapping Symptoms of Major Depression and
Anxiety Disorders
surrounding core features shown in Figure 8-1),
particularly sleep disturbance, problems concentrating, Although the core symptoms of major depression
and fatigue and psychomotor/arousal symptoms. Each (depressed mood or loss of interest) differ from the
anxiety disorder also has a great deal of symptom core symptoms of anxiety disorders (fear and worry),
overlap with other anxiety disorders (Figures 8-2 there is a great deal of overlap with the other symptoms
through 8-5; see also Figure 13-30). Anxiety disorders considered diagnostic for both a major depression
are also extensively comorbid, not only with major episode and for several different anxiety disorders (Figure
depression, but also with each other, since many 8-1). These overlapping symptoms include problems with
patients qualify over time for a second or even third sleep, concentration, and fatigue as well as psychomotor/
concomitant anxiety disorder (Figures 8-2 through arousal symptoms (Figure 8-1). It is thus easy to see
8-5). Finally, anxiety disorders are frequently comorbid how the gain or loss of just a few additional symptoms
with many other conditions such as substance abuse, can morph a major depressive episode into an anxiety
Overlap of Major Depressive Disorder and Anxiety Disorders Figure 8-1 Overlap of major
depressive disorder and anxiety
disorders. Although the core
symptoms of anxiety disorders
fatigue fatigue (anxiety and worry) differ from the core
concentration psychomotor concentration arousal symptoms of major depression (loss of
interest and depressed mood), there
is considerable overlap among the
depressed anxiety rest of the symptoms associated with
mood interest/ worry panic attacks
sleep pleasure guilt/ sleep these disorders (compare the “anxiety
worthlessness phobic
avoidance
disorders” puzzle on the right to the
“major depressive disorder” puzzle on
suicidality appetite/ irritability
weight muscle
compulsions the left). For example, fatigue, sleep
tension difficulties, problems concentrating,
and psychomotor/arousal symptoms
major depressive anxiety disorders are common to both types of disorders.
disorder
360
Chapter 8: Anxiety, Trauma, and Treatment
Figure 8-2 Generalized anxiety

generalized disorder. The symptoms typically
associated with generalized anxiety
anxiety disorder are shown here. These include
disorder the core symptoms of generalized
anxiety and worry as well as increased
arousal, fatigue, difficulty concentrating,
fatigue sleep problems, irritability, and muscle
tension. Many of these symptoms,
concentration including the core symptoms, are
arousal present in other anxiety disorders as
well.
generalized
anxiety/ generalized
fear worry
sleep
irritability
muscle
tension
Figure 8-3 Panic disorder. The

characteristic symptoms of panic
panic disorder are shown here and include
disorder the core symptoms of anticipatory
anxiety as well as worry about panic
attacks; associated symptoms are the
unexpected panic attacks themselves
and phobic avoidance or other
behavioral changes associated with
concern over panic attacks.
anticipatory unexpected
8
worry
anxiety/ about panic panic attacks
fear attacks
phobic
avoidance/
behavioral
change
disorder (Figure 8-1) or one anxiety disorder into another the emphasis from a psychopharmacological point
(Figures 8-2 through 8-5). of view is increasingly to take a symptom-based
From a therapeutic point of view, it may matter therapeutic strategy for patients with any of these
little what the specific diagnosis is across this spectrum disorders because the brain is not organized according
of disorders (Figures 8-1 through 8-5). That is, to the DSM, but according to brain circuits with
psychopharmacological treatments may not be much topographical localization of function. That is, specific
different for a patient who currently qualifies for a treatments can be tailored to the individual patient
major depressive episode plus the symptom of anxiety by deconstructing whatever disorder the patient has
(but not an anxiety disorder) versus a patient who into a list of the specific symptoms a given patient
currently qualifies for a major depressive episode plus is experiencing (see Figures 8-2 through 8-5). These
a comorbid anxiety disorder. Although it can be useful symptoms are then matched to hypothetically
to make specific diagnoses for following patients over malfunctioning brain circuits, regulated by specific
time and for documenting the evolution of symptoms, neurotransmitters, in order to rationally select and
361
Figure 8-4 Social anxiety disorder.

Symptoms of social anxiety disorder,
social anxiety shown here, include the core
disorder symptoms of anxiety or fear over social
performance plus worry about social
exposure. Associated symptoms are
panic attacks that are predictable and
fatigue expected in certain social situations
as well as phobic avoidance of those
concentration situations.
arousal
social/
performance worry expected
anxiety/ about panic attacks
fear exposure
sleep
phobic
avoidance/
behavioral
change
Figure 8-5 Posttraumatic stress

disorder (PTSD). The characteristic
PTSD symptoms of PTSD are shown here.
These include the core symptoms of
anxiety while the traumatic event is
being re-experienced as well as worry
about having the other symptoms of
PTSD, such as increased arousal and
startle responses, sleep difficulties
including nightmares, and avoidance
arousal behaviors. PTSD is now categorized as
a stress-related disorder rather than as
anxiety/ an anxiety disorder, and is considered a
re- disorder of hyperarousal.
experiencing worry
sleep
avoidance
combine psychopharmacological treatments to fear coupled with worry (Figure 8-6). Remarkable
eliminate symptoms by increasing the efficiency of progress has been made in understanding the circuitry
information processing in the malfunctioning brain underlying the core symptom of anxiety/fear based upon
circuits, and thereby get the patient into remission. an explosion of neurobiological research on the amygdala
This was discussed extensively in Chapter 6 on mood (Figures 8-7 through 8-14). The links between the
disorders and illustrated in Figures 6-42 through 6-44. amygdala, fear circuits, and treatments for the symptom
of anxiety/fear across the spectrum of anxiety, trauma,
Overlapping Symptoms of Different Anxiety Disorders and stress disorders are discussed throughout the rest of
Although there are different diagnostic criteria for this chapter.
different anxiety disorders (Figures 8-2 through 8-5), Worry is the second core symptom shared across
these are constantly changing and many do not even the spectrum of anxiety disorders (Figure 8-7). This
consider OCD or PTSD to be anxiety disorders any longer symptom is hypothetically linked to the functioning
(OCD is discussed in Chapter 13 on impulsivity). All of cortico-striato-thalamo-cortical(CSTC) loops. The
anxiety disorders have overlapping symptoms of anxiety/ links between the CSTC “worry loops” and treatments
362
Figure 8-6 Anxiety: the phenotype.

Anxiety: The Phenotype Anxiety can be deconstructed, or broken
down, into the two core symptoms of
fear and worry. These symptoms are
present in all anxiety disorders, although
what triggers them may differ from one
disorder to the next.
deconstruct the syndrome...

anxiety
fear
- panic
- phobia
worry
...into symptoms - anxious misery
- apprehensive
expectation
- obsessions
Figure 8-7 Linking anxiety symptoms

Associate Symptoms of Anxiety with Brain Regions to circuits. Anxiety and fear symptoms
and Circuits That Regulate Them (e.g., panic, phobias) are regulated
by an amygdala-centered circuit.
Worry, on the other hand, is regulated
amygdala-centered by a cortico-striato-thalamo-cortical
circuit (CSTC) circuit. These circuits may be
involved in all anxiety disorders, with
8
the different phenotypes reflecting not
fear
unique circuitry but rather divergent
- panic malfunctioning within those circuits.
- phobia
worry
- anxious misery
- apprehensive
expectation
- obsessions
cortico-striato-
thalamo-cortical
circuit
for the symptom of worry across the spectrum of anxiety disorder, malfunctioning in the amygdala and
anxiety disorders are discussed later in this chapter CSTC worry loops may be hypothetically persistent,
(see also Figures 8-15 through 8-20). We shall see and unremitting, yet not severe (Figure 8-2), whereas
that what differentiates one anxiety disorder from malfunctioning may be theoretically intermittent
another may not be the anatomical localization or the but catastrophic in an unexpected manner for panic
neurotransmitters regulating fear and worry in each of disorder (Figure 8-3) or in an expected manner for
these disorders (Figures 8-6 and 8-7), but the specific social anxiety (Figure 8-4). Circuit malfunctioning may
nature of malfunctioning within these same circuits be traumatic in origin and conditioned in PTSD (Figure
in various anxiety disorders. That is, in generalized 8-5).
363
THE AMYGDALA AND THE threat. However, chronic and persistent activation of this
NEUROBIOLOGY OF FEAR aspect of the fear response can lead to increased medical
comorbidity, including increased rates of coronary artery
The amygdala, an almond-shaped brain center located disease, type 2 diabetes, and stroke (Figure 8-10), and
near the hippocampus, has important anatomical also potentially to hippocampal atrophy, as discussed in
connections that allow it to integrate sensory and Chapter 6 and shown in Figure 6-30. Breathing can also
cognitive information, and then determine whether there change during a fear response, regulated in part by the
will be a fear response. Specifically, the affect or feeling of connections between the amygdala and the parabrachial
fear may be regulated via the reciprocal connections the nucleus in the brainstem (Figure 8-11). An adaptive
amygdala shares with key areas of prefrontal cortex that response to fear is to accelerate respiratory rate when
regulate emotions, namely the orbitofrontal cortex and the having a fight/flight reaction to enhance survival, but, in
anterior cingulate cortex (Figure 8-8). However, fear is not excess, this can lead to unwanted symptoms of shortness
just a feeling. The fear response can also include motor of breath, exacerbation of asthma, or a false sense of
responses. Depending upon the circumstances and one’s being smothered (Figure 8-11), all symptoms common
temperament, those motor responses could be fight, flight, during anxiety, and especially during attacks of anxiety
or freezing in place. Motor responses of fear are regulated such as panic attacks.
in part by connections between the amygdala and the The autonomic nervous system is attuned to fear,
periaqueductal gray area of the brainstem (Figure 8-9). and is able to trigger responses from the cardiovascular
There are also endocrine reactions that accompany system, such as increased pulse and blood pressure for
fear, in part due to connections between the amygdala fight/flight reactions and survival during real threats.
and the hypothalamus, causing changes in the HPA These autonomic and cardiovascular responses are
(hypothalamic-pituitary-adrenal) axis, and thus of mediated by connections between the amygdala and the
cortisol levels. A quick boost of cortisol may enhance locus coeruleus, home of the noradrenergic cell bodies
survival when encountering a real, but short-term, (Figure 8-12; noradrenergic neurons are discussed in
Avoidance
Affect of Fear
PAG
ACC
amygdala
d
OFC fear response

amygdala
d
overactivation motor responses

periaqueductal gray
overactivation fight/flight
or
freeze
fear Figure 8-9 Motor responses of fear. Feelings of fear may be

expressed through behaviors such as avoidance, which is partly
Figure 8-8 Affect of fear. Feelings of fear are regulated by regulated by reciprocal connections between the amygdala
reciprocal connections between the amygdala and the anterior and the periaqueductal gray (PAG). Avoidance in this sense is a
cingulate cortex (ACC) and the amygdala and the orbitofrontal motor response and may be analogous to freezing under threat.
cortex (OFC). Specifically, it may be that overactivation of these Other motor responses are to fight or to run away (flight) in
circuits produces feelings of fear. order to survive threats from the environment.
364
Endocrine Output of Fear Breathing Output
hypothalamus
amygdala
d amygdala
d
PBN
fear response fear response
overactivation endocrine overactivation respiratory

hypothalamus parabrachial nucleus
cortisol respiratory rate
coronary artery disease
shortness of breath
type 2 diabetes
asthma
stroke
Figure 8-11 Breathing output. Changes in respiration may
Figure 8-10 Endocrine output of fear. The fear response may
occur during a fear response; these changes are regulated by
be characterized in part by endocrine effects such as increases
activation of the parabrachial nucleus (PBN) via the amygdala.
in cortisol, which occur because of amygdala activation of the
Inappropriate or excessive activation of the PBN can lead not
hypothalamic-pituitary-adrenal (HPA) axis. Prolonged HPA
only to increases in the rate of respiration but also to symptoms
activation and cortisol release can have significant health
such as shortness of breath, exacerbation of asthma, or a sense
implications, such as increased risk of coronary artery disease,
of being smothered.
type 2 diabetes, and stroke.
Chapter 6 and noradrenergic pathways and neurons include the neurotransmitters GABA, serotonin, and 8
are illustrated in Figures 6-12 through 6-16). When norepinephrine, and the voltage-gated calcium channels.
autonomic responses are repetitive, inappropriately or Not surprisingly, known anxiolytics act upon these same
chronically triggered as part of an anxiety disorder, this neurotransmitters hypothetically in order to mediate
can lead to increases in atherosclerosis, cardiac ischemia, their therapeutic actions.
hypertension, myocardial infarction, and even sudden
death (Figure 8-12). “Scared to death” may not always be CORTICO-STRIATO-THALAMO-
an exaggeration or a figure of speech! Finally, anxiety can CORTICAL (CSTC) LOOPS
be triggered internally from traumatic memories stored AND THE NEUROBIOLOGY OF
in the hippocampus and activated by connections with
the amygdala (Figure 8-13), especially in conditions such
WORRY
as PTSD. The second core symptom of anxiety disorders, namely,
The processing of the fear response is regulated worry, hypothetically involves another unique circuit
by the numerous neuronal connections flowing into (Figure 8-15). Worry, which can include anxious misery,
and out of the amygdala. Each connection utilizes apprehensive expectations, catastrophic thinking, and
specific neurotransmitters acting at specific receptors obsessions, is hypothetically linked to CSTC feedback
(Figure 8-14). What is known about these connections loops from the prefrontal cortex (Figure 8-15 and Figure
is not only that several neurotransmitters are involved 8-16). Some experts theorize that similar CSTC feedback
in the production of symptoms of anxiety at the level of loops regulate the related symptoms of ruminations,
the amygdala, but that numerous anxiolytic drugs have obsessions, and delusions, all of these symptoms being
actions upon these specific neurotransmitter systems to types of recurrent thoughts. Several neurotransmitters
relieve the symptoms of anxiety and fear (Figure 8-14). and regulators are known to modulate these circuits,
The known neurobiological regulators of the amygdala including serotonin, GABA, dopamine, norepinephrine,
365
Autonomic Output of Fear The Hippocampus:

An Internal Fearmonger
LC
C
amygdala
d
fear response
amygdala
hippocampus
overactivation cardiovascular
locus coeruleus
Figure 8-13 The hippocampus and re-experiencing. Anxiety
atherosclerosis can be triggered not only by an external stimulus but also by
cardiac ischemia an individual’s memories. Traumatic memories stored in the
BP hippocampus can activate the amygdala, causing the amygdala,
HR variability in turn, to activate other brain regions and generate a fear
MI response. This is termed re-experiencing and is a particular
sudden death feature of posttraumatic stress disorder.
Figure 8-12 Autonomic output of fear. Autonomic responses

are typically associated with feelings of fear. These include
increases in heart rate (HR) and blood pressure (BP), which are
benzodiazepines hypothetically blunt fear-associated
regulated by reciprocal connections between the amygdala outputs, thereby reducing the symptom of fear (Figure
and the locus coeruleus (LC). Long-term activation of this circuit 8-17B). Benzodiazepines interacting at subtypes of
may lead to increased risk of atherosclerosis, cardiac ischemia,
change in BP, decreased HR variability, myocardial infarction GABAA receptors are discussed in Chapter 6 and
(MI), or even sudden death. illustrated in Figures 6-19 through 6-23. Benzodiazepines
also theoretically modulate excessive output from
glutamate, and voltage-gated ion channels (Figure worry loops (Figure 8-18A) by enhancing the actions of
8-15), greatly overlapping with many of the same inhibitory interneurons in CSTC circuits (Figure 8-18B),
neurotransmitters and regulators known to modulate the thereby reducing the symptom of worry.
amygdala (Figure 8-14).
ALPHA-2-DELTA LIGANDS AS
BENZODIAZEPINES AS DRUGS ANXIOLYTICS
FOR ANXIETY We have discussed voltage-sensitive calcium channels
A simplified notion of how benzodiazepines might (VSCCs) in Chapter 3 and have illustrated presynaptic N
modulate excessive output from the amygdala during and P/Q subtypes of VSCCs and their role in excitatory
fear responses in anxiety disorders is shown in Figure neurotransmitter release (see Figures 3-18 and 3-22
8-18. Excessive amygdala activity (shown in Figures through 3-24). Gabapentin and pregabalin, also known
8-8 through Figure 8-12 and in Figure 8-17A) is as α2δ ligands since they bind to the α2δ subunit of
theoretically reduced by benzodiazepines. These agents presynaptic N and P/Q VSCCs, block the release of
enhance phasic inhibition of GABA (γ-aminobutyric excitatory neurotransmitters such as glutamate that occurs
acid) by positive allosteric modulation of postsynaptic when neurotransmission is excessive, as postulated in
GABAA receptors (see Chapter 6 for explanation of the amygdala to cause fear (Figure 8-17A) and in CSTC
positive allosteric modulation by benzodiazepines at circuits to cause worry (Figure 8-18A). Hypothetically, α2δ
GABAA receptors and Figures 6-20 through 6-23). The ligands bind to open, overly active VSCCs in the amygdala
anxiolytic actions of benzodiazepines are hypothetically (Figure 8-17C) to reduce fear, and in CSTC circuits (Figure
at GABAA receptors localized within the amygdala, where 8-18C) to reduce worry. The α2δ ligands pregabalin and
366
Figure 8-14 Linking anxiety symptoms

Associate Symptoms with Brain Regions, Circuits, and to circuits to neurotransmitters.
Neurotransmitters That Regulate Them Symptoms of anxiety/fear are
associated with malfunctioning of
amygdala-centered circuits; the
5HT neurotransmitters that regulate these
GABA circuits include serotonin (5HT),
γ-aminobutyric acid (GABA), glutamate,
glutamate corticotropin releasing factor (CRF), and
norepinephrine (NE), among others. In
addition, voltage-gated ion channels
are involved in neurotransmission
amygdala-centered within these circuits.
CRF/HPA
circuit
fear
- panic
- phobia NE
voltage-gated
ion channels
Figure 8-15 Linking worry symptoms

Associate Symptoms with Brain Regions, Circuits, and to circuits to neurotransmitters.
Neurotransmitters That Regulate Them Symptoms of worry, such as anxious
misery, apprehensive expectations,
catastrophic thinking, and obsessions,
5HT are associated with malfunctioning of
GABA cortico-striato-thalamo-cortical loops,
which are regulated by serotonin (5HT),
DA γ-aminobutyric acid (GABA), dopamine
(DA), norepinephrine (NE), glutamate,
and voltage-gated ion channels.
cortico-striato-
NE
thalamo-cortical circuit
“worry loop”
worry 8
- anxious misery
- apprehensive glutamate
expectation
- obsessions
voltage-gated
ion channels
Affect of Fear
Figure 8-16 Worry/obsessions
Worry/Obsessions
$ circuit. Shown here is a cortico-striato-
thalamo-cortical loop originating and
ending in the dorsolateral prefrontal
cortex (DLPFC). Overactivation of this
circuit may lead to worry or obsessions.
DLPFC
FC
worry
thalamus striatum
overactivation
367
Hyperactive Amygdala and Fear Figure 8-17 Potential therapeutic

actions of medications on anxiety/
fear. (A) Pathological anxiety/fear
may be caused by overactivation of
amygdala circuits. (B) GABAergic
PAG hypothalamus
agents such as benzodiazepines may
ACC alleviate anxiety/fear by enhancing
LC phasic inhibitory actions at postsynaptic
GABAA receptors within the amygdala.
OFC areas of overactivation (C) Agents that bind to the α2δ subunit
PBN d
amygdala of presynaptic N and P/Q voltage-
A sensitive calcium channels can block
FEAR
the excessive release of glutamate in
Therapeutic Actions of Benzodiazepines Therapeutic Actions of Alpha-2-Delta Ligands the amygdala and thereby reduce the
α 2 δ action symptoms of anxiety. (D) The amygdala
receives input from serotonergic
neurons, which can have an inhibitory
effect on some of its outputs. Thus,
serotonergic agents may alleviate
anxiety/fear by enhancing serotonin
areas of input to the amygdala.
areas of normalized
normalized activation
GABA action activation
GABA = 2 ligand
B neuron C α 2 δ action FEAR
FEAR
Therapeutic Actions of Serotonergic Agents
5HT
neuron
areas of
normalized
5HT action activation
FEAR
D
gabapentin have demonstrated anxiolytic actions in social proven to be effective treatments for anxiety disorders.
anxiety disorder and panic disorder, are approved for Indeed, the leading treatments
the treatment of anxiety in some countries, and are also for anxiety disorders today are increasingly drugs
proven to be effective for the treatment of epilepsy and originally developed as drugs for depression. Serotonin is a
certain pain conditions, including neuropathic pain and key neurotransmitter that innervates the amygdala as well
fibromyalgia. The actions of α2δ ligands on VSCCs are as all the elements of CSTC circuits, namely, the prefrontal
discussed and illustrated in Chapter 9 on pain. Alpha-2- cortex, striatum, and thalamus, and thus is poised to
delta ligands clearly have different mechanisms of action regulate both the symptoms of fear and worry (serotonin
compared to selective serotonin reuptake inhibitors pathways are discussed in Chapters 5 and 6 and illustrated
(SSRIs) or benzodiazepines, and thus can be useful for in Figure 6-40). Most of the drugs for depression that
patients who do not do well on SSRIs/SNRIs (serotonin– can increase serotonin output by blocking the serotonin
norepinephrine reuptake inhibitors) or benzodiazepines. transporter (SERT) are also effective in reducing symptoms
Also, α2δ ligands can be useful to combine with SSRIs/ of anxiety and fear in one or another of the anxiety/trauma
SNRIs or benzodiazepines in patients who are partial disorders illustrated in Figures 8-2 through 8-5, namely,
responders and are not in remission. generalized anxiety disorder, panic disorder, social anxiety
disorder, and PTSD (and also OCD in Figure 13-30).
Such agents include the well-known SSRIs (in Chapter
SEROTONIN AND ANXIETY
7, with their mechanism of action illustrated in Figures
Since the symptoms, circuits, and neurotransmitters linked 7-11 through 7-15), as well as the SNRIs (serotonin–
to anxiety disorders overlap extensively with those for norepinephrine reuptake inhibitors; also discussed in
major depressive disorder (Figure 8-1), it is not surprising Chapter 7, with their mechanism of action illustrated in
that many drugs developed as drugs for depression have Figure 7-32 and Figures 7-11 through 7-15).
368
Hyperactive CSTC
AffectCircuits
of Fear and Worry
worry
Therapeutic Actions of Therapeutic Actions of

Benzodiazepines Alpha-2-Delta Ligands
worry
worry
GABA
neuron
B C
2 action 8
Therapeutic Actions of
Serotonergic Agents
worry
D
5HT
neuron
Figure 8-18 Potential therapeutic actions of medications on worry. (A) Pathological worry may be caused by overactivation of cortico-
striato-thalamo-cortical (CSTC) circuits. (B) GABAergic agents such as benzodiazepines may alleviate worry by enhancing the actions of
inhibitory GABA interneurons within the prefrontal cortex. (C) Agents that bind to the α2δ subunit of presynaptic N and P/Q voltage-
sensitive calcium channels can block the excessive release of glutamate in CSTC circuits and thereby reduce the symptoms of worry. (D)
The prefrontal cortex, striatum, and thalamus receive input from serotonergic neurons, which can have an inhibitory effect on output.
Thus, serotonergic agents may alleviate worry by enhancing serotonin (5HT) input within CSTC circuits.
369
A serotonin 1A (5HT1A) partial agonist, buspirone, is Figures 8-8 through 8-12, but also can trigger numerous
recognized as a drug for generalized anxiety disorder, but central symptoms of anxiety and fear, such as nightmares,
not for treatment of the other anxiety/trauma disorder hyperarousal states, flashbacks, and panic attacks
subtypes. 5HT1A partial agonists as augmenting agents (Figure 8-19A). Excessive noradrenergic activity can
to drugs for depressions are mentioned also in Chapter also reduce the efficiency of information processing
7, as are drugs for depression that combine 5HT1A in the prefrontal cortex and thus in CSTC circuits, and
partial agonism with serotonin reuptake inhibition (i.e., theoretically cause worry (Figure 8-20A). Hypothetically,
serotonin partial agonist reuptake inhibitors [SPARIs] these symptoms may be mediated in part by excessive
and vilazodone, see Figures 7-23 through 7-27), which noradrenergic input onto α1- and β1-adrenergic
should theoretically have anxiolytic actions as well as postsynaptic receptors in the amygdala (Figure 8-19A)
antidepressant action. The 5HT1A partial agonist properties or prefrontal cortex (Figure 8-20A). Symptoms of
of numerous drugs for psychosis are also discussed in hyperarousal like nightmares can be reduced in some
Chapter 5 and illustrated in Figures 5-22 and 5-23, and patients with α1-adrenergic blockers such as prazocin
the downstream actions of 5HT1A receptor stimulation are (Figure 8-19B), and symptoms of fear (Figure 8-19C) and
discussed in Chapter 4 and illustrated in Figure 4-44. worry (Figure 8-20B) can be reduced by norepinephrine
The potential anxiolytic actions of buspirone reuptake inhibitors (also called norepinephrine
could theoretically be due to 5HT1A partial agonist transporter [NET] inhibitors). The clinical effects of NET
actions at both presynaptic and postsynaptic 5HT1A inhibitors can be confusing because symptoms of anxiety
receptors (Figures 7-23 through 7-27), actions at both can actually be made transiently worse immediately
sites resulting in enhanced serotonergic activity in following initiation of an SNRI or selective NET inhibitor,
projections to the amygdala (Figure 8-17D), prefrontal when noradrenergic activity is initially increased but the
cortex, striatum, and thalamus (Figure 8-18D), and thus postsynaptic receptors have not yet adapted. However,
reduce fear and worry, as well as other symptoms of these same NET inhibitory actions, if sustained over
both generalized anxiety disorder and major depression time, will downregulate and desensitize postsynaptic
(Figure 8-1). SSRIs and SNRIs theoretically do the same norepinephrine receptors such as β1 receptors, and
thing (Figures 8-17D and 8-18D). Since the onset of hypothetically lead to the delayed reduction in symptoms
anxiolytic action for buspirone is delayed, just as it is of fear and worry long term (Figure 8-20B).
for drugs for depressions, this has led to the belief that
5HT1A agonists exert their therapeutic effects by virtue FEAR CONDITIONING VERSUS
of adaptive neuronal events and receptor events (Figures FEAR EXTINCTION
7-10 through 7-15 and Figures 7-23 through 7-27), rather
Fear conditioning is a concept as old as Pavlov’s dogs. If
than simply by the acute occupancy of 5HT1A receptors.
an aversive stimulus such as footshock is coupled with
In this way, the presumed mechanism of action of
a neutral stimulus such as a bell, the animal learns to
5HT1A partial agonists is analogous to the use of various
associate the two, and will develop fear when it hears a
drugs for depression, including SSRIs and SNRIs. These
bell. In humans, fear can be “learned” during stressful
actions are quite different in timing from the use of
experiences associated with emotional trauma, and is
benzodiazepines for anxiety – since benzodiazepines act
influenced by an individual’s genetic predisposition as
acutely by occupancy of benzodiazepine receptors and
well as by an individual’s prior exposure to environmental
not with a delay due to adaptation of the receptors.
stressors that can cause stress sensitization of brain
circuits (e.g., child abuse; see Chapter 6 and Figures
NORADRENERGIC
6-28 and 6-33). Often, fearful situations are managed
HYPERACTIVITY IN ANXIETY successfully and then forgotten. Some fears are crucial
Norepinephrine is another neurotransmitter with for survival, such as appropriately fearing dangerous
important regulatory input to the amygdala (Figure situations, and thus the mechanism of learned fear,
8-19A) and to the prefrontal cortex and thalamus in called fear conditioning, has been extremely well
CSTC circuits (Figure 8-20A). Excessive noradrenergic conserved across species, including humans. However,
output from the locus coeruleus can result not only other fears that are “learned” and, if not “forgotten,” may
in numerous peripheral manifestations of autonomic hypothetically progress to anxiety disorders or a major
overdrive, as discussed above and as illustrated in depressive episode. This is a big problem since almost
370
Noradrenergic Hyperactivity in Anxiety,

Fear, and Autonomic Hyperarousal
locus
coeruleus
ß1 receptor
NE
1 receptor
amygdala
fear/panic attacks
tremor
sweating
tachycardia
hyperarousal
A nightmares
Therapeutic Actions of Alpha-1 Antagonists Therapeutic Actions of NET Inhibitors

on Nightmares and Hyperarousal on Anxiety, Fear, and Hyperarousal
NET inhibitor
locus locus downregulated

coeruleus coeruleus ß1 receptors
ß1 receptor
NE NE
1 receptor 1 receptor
1 blocker amygdala
amygdala
fear/panic attacks fear/panic attacks

tremor tremor
sweating sweating
tachycardia tachycardia
hyperarousal hyperarousal
nightmares nightmares
B C
Figure 8-19 Noradrenergic hyperactivity in anxiety/fear. (A) Norepinephrine provides input not only to the amygdala but also to many
regions to which the amygdala projects; thus it plays an important role in the fear response. Noradrenergic hyperactivation can lead
to anxiety, panic attacks, tremors, sweating, tachycardia, hyperarousal, and nightmares. Alpha-1 and β1-adrenergic receptors may be
specifically involved in these reactions. (B) Noradrenergic hyperactivity may be blocked by the administration of α1-adrenergic antagonists,
which can lead to the alleviation of anxiety and other stress-related symptoms. (C) Noradrenergic hyperactivity may also be blocked by the
administration of a norepinephrine transporter (NET) inhibitor, which can have the downstream effect of downregulating β1-adrenergic
receptors. Reduced stimulation via β1-adrenergic receptors could therefore lead to the alleviation of anxiety and stress-related symptoms.
371
Affect of Fear or seeing an explosion, smelling burning rubber, seeing

Hyperactive CSTC Circuits and Worry a picture of a wounded civilian, seeing or hearing
flood waters, can trigger traumatic re-experiencing
worry and generalized hyperarousal and fear in emotionally
traumatized patients with PTSD. Panic associated with
social situations will “teach” the patient to panic in social
situations in social anxiety disorder. Panic randomly
associated with an attack that happens to occur in a
crowd, on a bridge, or in shopping centers will also
trigger another panic attack when the same environment
is encountered in panic disorder. These and other
symptoms of anxiety disorders are all forms of learning
known as fear conditioning (Figure 8-21).
A
The amygdala is theoretically involved in
“remembering” the various stimuli associated with a
given fearful situation. Hypothetically, the amygdala does
this by increasing the efficiency of neurotransmission at
Delayed Therapeutic Actions of glutamatergic synapses in the lateral amygdala as sensory
NET Inhibitors input about those stimuli comes in from the thalamus
worry or sensory cortex (Figure 8-21). This input is then
relayed to the central amygdala, where fear conditioning
also improves the efficiency of neurotransmission at
another glutamate synapse there (Figure 8-21). Both
synapses are hypothetically restructured and potentially
permanent learning is embedded into this circuit by
NMDA receptors, triggering long-term potentiation
and synaptic plasticity so that subsequent input from
B
the sensory cortex and thalamus is very efficiently
NE processed to trigger the same fear response caused by the
locus neuron original experience, since output occurs from the central
coeruleus
amygdala every time there is the re-experiencing of the
Figure 8-20 Noradrenergic hyperactivity in worry. (A) same sensory input associated with the original fearful
Pathological worry may be caused by overactivation of cortico-
striato-thalamo-cortical (CSTC) circuits. Specifically, excessive event (Figure 8-21; see also Figures 8-8 through 8-13).
noradrenergic activity within these circuits can reduce the Input to the lateral amygdala is modulated by the
efficiency of information processing and theoretically cause
worry. (B) Noradrenergic hyperactivity in CSTC circuits may be prefrontal cortex, especially the ventromedial prefrontal
blocked by the administration of a norepinephrine transporter cortex (VMPFC), and by the hippocampus. If the
(NET) inhibitor, which can have the downstream effect of
downregulating β1-adrenergic receptors. Reduced stimulation
VMPFC is unable to suppress the fear response before
via β1-adrenergic receptors could therefore lead to the it arrives at the level of the amygdala, fear conditioning
alleviation of worry.
is thought to proceed. The hippocampus hypothetically
“remembers” the context of the fear conditioning, and
30% of the population will develop an anxiety disorder, makes sure fear is triggered when the fearful stimulus
due in large part to stressful environments, including and all its associated stimuli are encountered again.
exposure to fearful events during normal activities in Most contemporary psychopharmacological treatments
twenty-first-century society, but in particular during for anxiety and fear act by suppressing the fear output
early life, if experiencing abuse or adversity as a child, from the amygdala (see Figure 8-17) and therefore are
and during war and natural disasters, and abusive not cures since the fundamental neuronal learning
relationships, as an adult. underlying fear conditioning in these patients remains in
Repetition of a sensory experience associated with place. On the other hand, psychotherapeutic approaches
an earlier exposure to a fearful event, such as hearing perhaps enhanced by drugs targeting the “unlearning”
372
Fear Conditioning vs. Fear Extinction

VMPFC
VMPFC
hippocampus
hippocampus
sensory cortex
thalamus
lateral
amygdala
intercalated
cell mass
central
amygdala
no fear response
= glutamate
ing
ion
= GABA
dit
on
rc
fea
fear
conditioning
fear
extinction
fear extinction
renewal
no fear response
fear response!!!
Figure 8-21 Fear conditioning versus fear extinction. When an individual encounters a stressful or fearful experience, the sensory
input is relayed to the amygdala, where it is integrated with input from the ventromedial prefrontal cortex (VMPFC) and hippocampus,
so that a fear response can be either generated or suppressed. The amygdala may “remember” stimuli associated with that experience
by increasing the efficiency of glutamate neurotransmission, so that on future exposure to stimuli, a fear response is more efficiently
triggered. If this is not countered by input from the VMPFC to suppress the fear response, fear conditioning proceeds. Fear conditioning
is not readily reversed, but it can be inhibited through new learning. This new learning is termed fear extinction and is the progressive
reduction of the response to a feared stimulus that is repeatedly presented without adverse consequences. Thus the VMPFC and
hippocampus learn a new context for the feared stimulus and send input to the amygdala to suppress the fear response. The “memory”
of the conditioned fear is still present, however.
373
of fear conditioning provide hope for a more long-lasting within the central amygdala, with fear output occurring
solution to symptoms of anxiety. if the fear-conditioning circuit predominates, and no
fear output occurring if the fear-extinction circuit
Novel Approaches to the Treatment of Anxiety predominates.
Disorders
Modern research thus suggests that fear extinction
Once fear conditioning is in place, it can be very theoretically predominates over fear conditioning when
difficult to reverse. Nevertheless, there may be two ways synaptic strengthening and long-term potentiation in the
to neutralize fear conditioning: either by facilitating new circuit are able to produce an inhibitory GABAergic
a process called extinction or by blocking a process drive that can overcome the excitatory glutamatergic
called reconsolidation. Research on extinction and drive produced by the pre-existing fear-conditioning
reconsolidation are leading the way in order to find circuitry (Figure 8-21). When fear extinction exists
novel, more robust, and more long-lasting treatments simultaneously with fear conditioning, memory for both
for anxiety symptoms, especially in patients who do are present, but the output hypothetically depends upon
not respond to standard treatment with serotonergic, which system is “stronger” and “better-remembered,”
benzodiazepine, and α2δ drug therapies or to standard and which has the most robust synaptic efficiency.
psychotherapies such as exposure treatment or cognitive These factors will hypothetically determine which gate
behavioral therapy. Preventing or minimizing “stress” – will open, the one with the fear response or the one
especially early life adversity in young children, and that keeps the fear response in check. Unfortunately,
chronic stress and catastrophic stress in adults – is also over time, fear conditioning in experimental models
under investigation but difficult to implement. and in clinical practice may have the upper hand over
fear extinction. Fear extinction appears to be more
Fear Extinction
labile than fear conditioning, and tends to reverse over
Fear extinction is the progressive reduction of the time. Also, fear conditioning can return if the old fear is
response to a feared stimulus, and occurs when the presented in a context different from the one “learned”
stimulus is repeatedly presented without any adverse to suppress the fear during fear extinction, a process
consequence. When fear extinction occurs, it appears termed “renewal.”
that the original fear conditioning is not really “forgotten”
even though the fear response can be profoundly reduced Therapeutic Facilitation of Fear Extinction
over time by the active process of fear extinction. Rather A novel treatment approach to reducing anxiety
than reversing the synaptic changes described above for symptoms is to facilitate fear extinction with a
fear conditioning, leading theories propose that a new combination of psychotherapy and drugs directed
form of learning with additional synaptic changes in the at facilitating synapse formation. This approach
amygdala occurs during fear extinction. These changes contrasts with how current effective anxiolytic drugs
hypothetically suppress symptoms of anxiety and fear by act, namely by pharmacologically suppressing the
inhibiting the original learning but not by removing it fear response (Figures 8-17 through 8-20). Among
(Figure 8-21). Specifically, if activation of the amygdala currently effective psychotherapies for anxiety used in
by the VMPFC occurs again and again without any fear clinical practice today, cognitive behavioral therapies
being triggered, such as during exposure therapy, the that employ exposure techniques and that require
hippocampus hypothetically begins to “remember” the patient to confront the fear-inducing stimuli in a
this new context in which the feared stimulus did not safe environment may come closest to facilitating fear
have any adverse consequences and fear is no longer extinction, hypothetically because when these therapies
activated (Figure 8-21). Over time, the original stimulus are effective, they are able to trigger the learning of fear
no longer activates fear due to this process of progressive extinction in the amygdala (Figure 8-21). Unfortunately,
desensitization called fear extinction. Such fear extinction because the hippocampus “remembers” the context of
hypothetically occurs when inputs from the VMPFC this extinction, such therapies are often context-specific
and hippocampus now “learn” to activate glutamatergic and do not always generalize once the patient is outside
neurons in the lateral amygdala that synapse upon the safe therapeutic environment of a therapist’s office,
inhibitory GABAergic interneurons, located within the and thus fear and worry may be “renewed” in the real
intercalated cell mass of the amygdala (Figure 8-21). world. Current psychotherapy research is investigating
According to this theory, such an action sets up a gate how contextual cues can be used to strengthen extinction
374
learning so that the therapeutic learning generalizes studies support this possibility and early clinical studies
to other environments. Current psychopharmacology are encouraging but not always robust or consistent, to
research is investigating how specific drugs might also date. In the meantime, prudent psychopharmacologists
strengthen extinction learning by pharmacologically are increasingly leveraging their current anxiolytic drug
strengthening the synapses on the fear-extinction side portfolio with concomitant psychotherapy, since many
of the amygdala gate disproportionately to the synapses patients already receive enhanced therapeutic benefit
on the fear-conditioned side of the amygdala gate. How from this combination.
could this be done?
Blocking Fear Conditioning and Fear Memories
Based on successful animal experiments of
extinction learning, one idea shown in Figure 8-22 is to Blocking either consolidation or reconsolidation of fear
pharmacologically boost N-methyl-D-aspartate (NMDA) memories is another approach to developing novel
receptor activation at the very time when a patient treatments for anxiety symptoms. When fear is first
receives systematic exposure to feared stimuli during conditioned, that memory is said to be “consolidated”
cognitive behavioral therapy sessions. The idea is that via a molecular process that some have thought was
as psychotherapy progresses, learning occurs, because essentially permanent. Hints at the mechanism of the
glutamate release is provoked in the lateral amygdala initial consolidation of fear conditioning come from
and in the intercalated cell mass at inhibitory GABA observations that both β blockers and opioids can
neurons by the psychotherapy. If NMDA receptors at potentially mitigate the conditioning of the original
these two glutamate synapses could be pharmacologically traumatic memory, even in humans, and some studies
boosted to trigger disproportionately robust long-term show that these agents can potentially reduce the chances
potentiation and synaptic plasticity, timed to occur at the of getting PTSD after a traumatic injury (Figure 8-23).
exact time this learning and therapy is taking place and This therapeutic approach is to treat the acutely exposed
thus exactly when these synapses are selectively activated, patient immediately after a traumatic experience in order
it could theoretically result in the predominance of the to block the initial fear from ever becoming conditioned
extinction pathway over the conditioned pathway. Animal or consolidated.
fear Figure 8-22 Facilitating fear

extin extinction with NMDA receptor 8
ction activation. Strengthening of synapses
involved in fear extinction could help
enhance the development of fear-
extinction learning in the amygdala
glial and reduce symptoms of anxiety
cell disorders. Administration of an agent
that enhances N-methyl-D-aspartate
(NMDA) action while an individual
is receiving exposure therapy could
increase the efficiency of glutamate
(Glu) neurotransmission at synapses
Glu involved in fear extinction. If this leads
glycine to long-term potentiation (LTP) and
synaptic plasticity while the synapses
are activated by exposure therapy,
enhancing NMDA it could result in structural changes
LTP action in the amygdala associated with the
fear-extinction pathway and thus
the predominance of the extinction
pathway over the conditioned pathway.
no fear response
no fear response
375
Figure 8-23 Blocking fear conditioning

Beta Blockers and Opiates Prevent Fear Conditioning and reconsolidation. When fear is
and Reconsolidation of Fear first conditioned, the memory is said
to be “consolidated” via a molecular
process that once was thought to be
ß1 blocker
traumatic permanent. However, there is some
experience research to suggest that administration
of either β-adrenergic blockers or
VMPFC opiates can potentially mitigate the
fear traumatic conditioning of the original traumatic
conditioning hippocampus experience memory. Furthermore, research also
opiates retrieved now shows that even when emotional
memories have been consolidated
ß1 blocker as fear conditioning, they can
change when they are retrieved.
Reconsolidation is the state in which
reactivation of a consolidated fear
ß1 blocker memory makes it labile. This requires
protein synthesis to keep the memory
intact and, like fear conditioning, may
reconsolidation also be disrupted by β blockers.
no fear response
locus coeruleus
Although, classically, emotional memories that have experiments suggest, and can change when they are
already been “fear conditioned” were thought to last retrieved, the idea is to use both psychotherapeutic
forever, recent animal experiments show that emotional and psychopharmacological approaches to block
memories can in fact be weakened or even erased at reconsolidation of the fear memory. Blocking
the time they are re-experienced. Current theories reconsolidation would hypothetically allow the patient to
now suggest that at the time emotional memories are “forget” their emotional memory.
re-experienced, they are in a labile state capable of Early studies of β blockers suggest that they may
being modified, and then, once the re-experiencing also disrupt reconsolidation of fear memories as
of the emotion and any modification of it is complete, well as formation of fear conditioning (Figure 8-23).
the memory is restored or “reconsolidated” with those More recently, hallucinogens, dissociatives, and
modifications. Reconsolidation is the state in which entactogens such as psilocybin, MDMA (3,4-methylene-
reactivation of a consolidated fear memory makes dioxymethamphetamine), and ketamine have been
it labile, and requires protein synthesis to keep the employed in an attempt to block reconsolidation of
memory intact. activated memories during psychotherapy sessions.
If emotional memories consolidated as fear These are discussed in more detail in Chapter 13 on
conditioning are not permanent, as animal substance abuse; psilocybin and MDMA are discussed
376
briefly in Chapter 7 and illustrated in Figures 7-87 and Panic Disorder

7-88. Ketamine is more extensively discussed in Chapter Panic attacks occur in many conditions, not just panic
7 as well. Future research is trying to determine how disorder, and panic disorder is frequently comorbid with
to use psychotherapy to provoke emotional memories the other anxiety disorders and with major depression.
and reactivate them by producing a state where a It is thus not surprising that contemporary treatments
pharmacological agent such as a hallucinogen producing for panic disorder overlap significantly with those for
a dissociative state, including ketamine as well as the other anxiety disorders and with those for major
psilocybin or MDMA, could be administered to disrupt depression. Treatments include SSRIs and SNRIs, as
reconsolidation of these emotional memories and thereby well as benzodiazepines, and α2δ ligands. “Off-label”
relieve symptoms of anxiety, trauma, re-experiencing treatments of panic attacks in anxiety disorders can also
and other emotional memories of PTSD and anxiety include mirtazapine and trazodone. The monoamine
disorders, and existential distress in terminally ill patients. oxidase inhibitors (MAOIs), discussed in Chapter 7, are
These are early days in terms of applying this concept much neglected in psychopharmacology in general and
in clinical settings, but this notion supports the growing for the treatment of treatment-resistant panic disorder in
idea that psychotherapy and psychopharmacology can be particular. However, MAOIs can have powerful efficacy
synergistic. Much more needs to be learned as to how to in panic and should be considered when other agents
exploit this theoretical synergy. fail. Cognitive behavioral psychotherapy is both an
alternative or an augmentation to psychopharmacological
TREATMENTS FOR ANXIETY approaches, and can help modify cognitive distortions,
DISORDER SUBTYPES and, through exposure, diminish phobic avoidance
behaviors.
Generalized Anxiety Disorder
Psychopharmacological treatments for generalized Social Anxiety Disorder
anxiety disorder overlap greatly with those for The treatment options for this anxiety disorder are
other anxiety disorders and depression and include very similar to those for panic disorder with a few
SSRIs, SNRIs, benzodiazepines, buspirone, and α2δ noteworthy differences. The SSRIs and SNRIs and α2δ
ligands such as pregabalin and gabapentin. While ligands are certainly useful treatments, but the utility
benzodiazepines should not be prescribed to a patient of benzodiazepine is not as widely accepted as it might 8
with generalized anxiety disorder who is abusing other be for generalized anxiety disorder and panic disorder.
substances, particularly alcohol, benzodiazepines can There is also less evidence for the utility of older drugs for
be useful in patients who are not substance abusers depression for use in social anxiety disorder. Beta blockers,
for short terms when initiating an SSRI or SNRI, since sometimes with benzodiazepines, can be useful for some
these serotonergic agents are often activating, difficult patients with very discrete types of social anxiety, such
to tolerate early in dosing, and have a delayed onset as performance anxiety. One drug that is (unfortunately)
of action. In other patients, benzodiazepines can be quite effective but obviously should not be used is alcohol
useful to “top up” an SSRI or SNRI for patients who for the treatment of social anxiety symptoms. Many
have experienced only partial relief of symptoms and patients of course are aware of this and abuse alcohol
have stabilized on SSRI/SNRI therapy. Benzodiazepines before they seek safer and more effective treatment.
can also be useful for occasional intermittent use when Cognitive behavioral psychotherapy can be a powerful
symptoms surge and sudden relief is needed. Alpha-2- intervention, sometimes better than drugs for certain
delta ligands are a good alternative to benzodiazepines patients, and often helpful in combination with drugs.
in some patients. These ligands are approved for the
treatment of anxiety in Europe and other countries PTSD
but not in the US, yet can be useful “off-label” as Although some treatments such as certain SSRIs are
augmenting agents. approved for PTSD, psychopharmacological treatments
Other “off-label” treatments for anxiety can for PTSD are not as effective as these same treatments are
include mirtazapine, trazodone, vilazodone, tricyclic in anxiety disorders. Also, PTSD is so highly comorbid
antidepressants, or even sedating antihistamines such as that many of the psychopharmacological treatments
hydroxyzine. are more effectively aimed at comorbidities such as
377
depression, insomnia, substance abuse, and pain, than SUMMARY

at core symptoms of PTSD. SSRIs often leave the patient
with residual symptoms, including sleep problems. Thus, Anxiety/trauma disorders have core features of fear and
most patients with PTSD do not take monotherapy. worry that cut across the entire spectrum of anxiety
Benzodiazepines are to be used with caution, not only disorder subtypes, from generalized anxiety disorder to
because of limited evidence from clinical trials for panic disorder, social anxiety disorder, and posttraumatic
efficacy in PTSD, but also because many PTSD patients stress disorder. The amygdala hypothetically plays a
abuse alcohol and other substances. A unique treatment central role in the fear response in these conditions,
for PTSD is the administration of α1 antagonists at night and cortico-striato-thalamo-cortical (CSTC) circuits are
to prevent nightmares. Much more effective medication thought to play a key role in mediating the symptom
treatments for PTSD are greatly needed. Much of the of worry. Numerous neurotransmitters are involved in
advance in treatment of PTSD has been in using drugs regulating the circuits that underlie the anxiety disorders.
to treat comorbidities and psychotherapies to treat core Serotonin, norepinephrine, α2δ ligands and GABA are
symptoms. Exposure therapy is perhaps most effective all key modulators of the hypothetical fear and worry
among psychotherapies, but many forms of cognitive circuits. Known effective drug treatments all target these
behavioral therapy are being investigated and used in neurotransmitters. The concept of opposing actions of
clinical practice, depending upon the training of the fear conditioning versus fear extinction within amygdala
therapist and the specific needs of the individual. Use circuits hypothetically is linked to the production and
of techniques to block reconsolidation of emotional maintenance of symptoms in anxiety disorder and
memories with the combination of psychotherapy and provides a substrate for potential novel therapeutics
drugs (especially MDMA) are in testing now for PTSD. combining psychotherapy and drugs. The concept of
Brexpiprazole, discussed in Chapter 5 as a drug for disruption of the reconsolidation of fear memories is
psychosis, is in testing along with the SSRI sertraline for undergoing testing at this time as a novel therapeutic
PTSD, with promising initial findings. approach to anxiety symptoms.
378
9 Chronic Pain and
Its Treatment
What is Pain? 379 Fibromyalgia 387
“Normal” Pain and the Activation of Nociceptive Decreased Gray Matter in Chronic Pain
Nerve Fibers 381 Syndromes? 387
Nociceptive Pathway to the Spinal Cord 381 Descending Spinal Synapses in the Dorsal Horn
Nociceptive Pathway from the Spinal Cord to the and the Treatment of Chronic Pain 390
Brain 382 Targeting Sensitized Circuits in Chronic Pain
Neuropathic Pain 382 Conditions 395
Peripheral Mechanisms in Neuropathic Pain 382 Targeting Ancillary Symptoms in
Central Mechanisms in Neuropathic Pain 382 Fibromyalgia 399
The Spectrum of Mood and Anxiety Disorders with Summary 400
Pain Disorders 387
This chapter will provide a brief overview of chronic pain WHAT IS PAIN?
conditions associated with different psychiatric disorders
and treated with psychotropic drugs. Included here are No experience rivals pain for its ability to capture our
discussions of the symptomatic and pathophysiological attention, focus our actions, and cause suffering (see
overlap between disorders with pain and many other Table 9-1 for some useful definitions regarding pain). The
disorders treated in psychopharmacology, especially powerful experience of pain, especially acute pain, can
depression and anxiety. Clinical descriptions and formal serve a vital function – to make us aware of damage to
criteria for how to diagnose painful conditions are only our bodies, and to rest the injured part until it has healed.
mentioned here in passing. The reader should consult When acute pain is peripheral in origin (i.e., originating
standard reference sources for this material. The discussion outside of the central nervous system) but continues as
here will emphasize how discoveries about the functioning chronic pain, it can cause changes in central nervous
of various brain circuits and neurotransmitters – especially system pain mechanisms that enhance or perpetuate the
those acting upon the central processing of pain – have original peripheral pain. For example, osteoarthritis, low
impacted our understanding of the pathophysiology and back pain, and diabetic peripheral neuropathic pain all
treatment of many painful conditions that may occur begin as peripheral pain, but over time these conditions
with or without various psychiatric disorders. The goal can trigger central pain mechanisms that amplify
of this chapter is to acquaint the reader with ideas about peripheral pain and generate additional pain centrally.
the clinical and biological aspects of the symptom of This may explain why research has recently shown that
pain, how it can hypothetically be caused by alterations chronic pain conditions of peripheral origin can be
of pain processing within the central nervous system, successfully targeted for relief by psychotropic drugs that
how it can be associated with many of the symptoms of work on central pain mechanisms.
depression and anxiety, and finally, how it can be treated Many other chronic pain conditions may start
with several of the same agents that can treat depression centrally and never have a peripheral causation to the
and anxiety. The discussion in this chapter is at the pain, especially conditions associated with multiple
conceptual level, and not at the pragmatic level. The reader unexplained painful physical symptoms such as
should consult standard drug handbooks (such as Stahl’s depression, anxiety, and fibromyalgia. Because these
Essential Psychopharmacology: the Prescriber’s Guide) for centrally mediated pain conditions are associated
details of doses, side effects, drug interactions, and other with emotional symptoms, that type of pain has until
issues relevant to the prescribing of these drugs in clinical recently often not been considered “real” but rather
practice. a nonspecific outcome of unresolved psychological
379
Table 9-1 Pain: some useful definitions
Pain An unpleasant sensory and emotional experience associated with actual or potential
tissue damage, or described in terms of such damage
Acute pain Pain that is of short duration and resolves; usually directly related to the resolution or
healing of tissue damage
Chronic pain Pain that persists for longer than would be expected; an artificial threshold for chronicity
(e.g., 1 month) is not appropriate
Neuropathic pain Pain that arises from damage to, or dysfunction of, any part of the peripheral or central
nervous system
Nociception The process by which noxious stimuli produce activity in the sensory pathways that convey
“painful” information
Allodynia Pain caused by a stimulus that does not normally provoke pain
Hyperalgesia An increased response to a stimulus that is not normally painful
Analgesia Any process that reduces the sensation of pain, while not affecting normal touch
Local anesthesia Blockade of all sensation (innocuous and painful) from a local area
Noxious stimulus Stimulus that inflicts damage, or would potentially inflict damage, on tissues of the body
Primary afferent The first neuron in the somatosensory pathway; detects mechanical, thermal, or chemical
neuron (PAN) stimuli at its peripheral terminals and transmits action potentials to its central terminals in
the spinal cord; all PANs have a cell body in the dorsal root ganglion
Nociceptor A primary afferent (sensory) neuron that is only activated by a noxious stimulus
Nociception The process by which a nociceptor detects a noxious stimulus and generates a signal
(action potentials) that is propagated towards higher centers in the nociceptive pathway
Dorsal root ganglion Contains the cell bodies of PANs; proteins, including transmitters, receptors, and structural
(DRG) proteins, are synthesized here and transported to peripheral and central terminals
Interneuron Neuron with its cell body, axon, and dendrites within the spinal cord; can be excitatory
(e.g., containing glutamate) or inhibitory (e.g., containing GABA)
Projection neurons Neuron in the dorsal horn that receives input from PANs and/or interneurons, and
projects up the spinal cord to higher processing centers
Spinothalamic tract Tract of neurons that project from the spinal cord to the thalmus
Spinobulbar tracts Several different tracts of neurons that project from the spinal cord to brainstem nuclei
Somatosensory cortex Region of the cerebral cortex that receives input mainly from cutaneous sensory nerves;
the cortex is topographically arranged, with adjacent areas receiving input from adjacent
body areas; stimulation of the somatosensory cortex creates sensations from the body
part that projects to it
conflicts that would improve when the associated (serotonin–norepinephrine reuptake inhibitors, discussed
psychiatric condition improved, and therefore that this in Chapter 7 on treatment for mood disorders [Figures
type of pain did not need to be targeted specifically for 7-28 through 7-33]) and the α2δ ligands (anticonvulsants
treatment. Today, however, many painful conditions that block voltage-gated calcium channels or VSCCs,
without identifiable peripheral lesions that were once discussed in Chapter 8 on anxiety disorders [Figures
linked only to psychiatric disorders are now hypothesized 8-17 and 8-18]). Additional psychotropic agents acting
to be forms of chronic neuropathic pain syndromes and centrally at various other sites are also used to treat a
can be treated with the same agents that successfully treat variety of chronic pain conditions and will be mentioned
neuropathic pain syndromes that are not associated with below. Many additional drugs are being tested as
psychiatric disorders. These treatments include the SNRIs potential novel pain treatments as well.
380
Chapter 9: Chronic Pain and Its Treatment
Since pain is clearly associated with some psychiatric (Figure 9-1). Nociception begins with transduction – the
disorders, and psychotropic drugs that treat various process by which specialized membrane proteins located
psychiatric conditions are also effective for a wide on the peripheral projections of these neurons detect a
variety of pain conditions, the detection, quantification, stimulus and generate a voltage change at their peripheral
and treatment of pain are rapidly becoming neuronal membranes. A sufficiently strong stimulus will
standardized parts of a psychiatric evaluation. Modern lower the voltage at the membrane (i.e., depolarize the
psychopharmacologists increasingly consider pain to be a membrane) enough to activate voltage-sensitive sodium
psychiatric “vital sign,” thus requiring routine evaluation channels (VSSCs) and trigger an action potential that will
and symptomatic treatment. In fact, elimination of pain be propagated along the length of the axon to the central
is increasingly recognized as necessary in order to have terminals of the neuron in the spinal cord (Figure 9-1).
full symptomatic remission not only of chronic pain VSSCs are introduced in Chapter 3 and illustrated in
conditions, but also of many psychiatric disorders. Figures 3-19 and 3-20. Nociceptive impulse flow from
primary afferent neurons into the central nervous system
“Normal” Pain and the Activation of Nociceptive can be reduced or stopped when VSSCs are blocked
Nerve Fibers by peripherally administered local anesthetics such as
The nociceptive pain pathway is the series of neurons lidocaine.
that begins with detection of a noxious stimulus and ends The specific response characteristics of primary
with the subjective perception of pain. This so-called afferent neurons are determined by the specific
“nociceptive pathway” starts from the periphery, enters receptors and channels expressed by that neuron in the
the spinal cord, and projects to the brain (Figure 9-1). periphery (Figure 9-1). For example, primary afferent
It is important to understand the processes by which neurons that express a stretch-activated ion channel are
incoming information can be modulated to increase or mechanosensitive; those that express the vanillinoid
decrease the perception of pain associated with a given receptor 1 (VR1) ion channel are activated by capsaicin,
stimulus because these processes can explain not only the pungent ingredient in chili peppers, and also by
why maladaptive pain states arise but also why drugs that noxious heat, leading to the burning sensation that both
work in psychiatric conditions such as depression and these stimuli evoke. These functional response properties
anxiety can also be effective in reducing pain. are used to classify primary afferent neurons into three
types: Aβ-, Aδ-, and C-fiber neurons (Figure 9-1).
Nociceptive Pathway to the Spinal Cord Aβ fibers detect small movements, light touch, hair
Primary afferent neurons detect sensory inputs movement, and vibrations; C-fiber peripheral terminals
including pain (Figure 9-1). They have their cell bodies are bare nerve endings that are only activated by noxious
in the dorsal root ganglion located along the spinal mechanical, thermal, or chemical stimuli; Aδ fibers fall 9
column outside the central nervous system and thus somewhere in between, sensing noxious mechanical
are considered peripheral and not central neurons stimuli and sub-noxious thermal stimuli (Figure 9-1).
primary afferent dorsal root Figure 9-1 Activation of nociceptive

periphery neurons ganglion spinal cord nerve fibers. Detection of a noxious
stimulus occurs at the peripheral
non-noxious
to higher terminals of primary afferent neurons and
mechanical stimulus
centers leads to generation of action potentials
Aß fiber that propagate along the axon to the
central terminals. Aβ fibers respond only
dorsal
noxious horn
to non-noxious stimuli, Aδ fibers respond
mechanical stimulus to noxious mechanical stimuli and sub-
noxious thermal stimuli, and C fibers
PN respond only to noxious mechanical,
heat, and chemical stimuli. Primary
dorsal root afferent neurons have their cell bodies
projection in the dorsal root ganglion and send
noxious heat
and chemical stimuli C fiber neurons terminals into that spinal cord segment
as well as sending less dense collaterals
up the spinal cord for a short distance.
gray matter Primary afferent neurons synapse onto
several different classes of dorsal horn
white matter projection neurons (PN), which project
via different tracts to higher centers.
381
Nociceptive input and pain can thus be caused by and its intensity. In the emotional/motivational pathway,
activating primary afferent neurons peripherally, such as other dorsal horn neurons project to brainstem nuclei,
from a sprained ankle or a tooth extraction. Nonsteroidal and from there to limbic regions (Figure 9-3). This
anti-inflammatory drugs (NSAIDs) can reduce painful second pain pathway is thought to convey the affective
input from these primary afferent neurons, presumably component that nociceptive stimuli evoke. Only when
via their peripheral actions. Opiates can also reduce such these two aspects of sensory discrimination and emotions
pain, but from central actions as explained below. come together and the final, subjective perception of pain
is created, can we use the word “pain” to describe the
Nociceptive Pathway from the Spinal Cord to the Brain modality (see “ouch” in Figure 9-3). Before this point, we
The central terminals of peripheral nociceptive are simply discussing activity in neural pathways, which
neurons synapse in the dorsal horn of the spinal should be described as noxious-evoked or nociceptive
cord onto the next cells in the pathway – dorsal neuronal activity but not necessarily as pain.
horn neurons, which receive input from many
primary afferent neurons and then project to higher NEUROPATHIC PAIN
centers (Figures 9-2 and 9-3). For this reason, they The term neuropathic pain describes pain that arises from
are sometimes also called dorsal horn projection damage to, or dysfunction of, any part of the peripheral
neurons (PN in Figures 9-1 through 9-3). Dorsal horn or central nervous system, whereas “normal” pain
neurons are thus the first neurons of the nociceptive (so-called nociceptive pain just discussed in the section
pathway that are located entirely within the central above) is caused by activation of nociceptive nerve fibers.
nervous system and thus a key site for modulation
of nociceptive neuronal activity as it comes into Peripheral Mechanisms in Neuropathic Pain
the central nervous system. A vast number of Normal transduction and conduction in peripheral
neurotransmitters have been identified in the dorsal afferent neurons can be hijacked in certain neuropathic
horn, some of which are shown in Figure 9-2. pain states to maintain nociceptive signaling in the
Neurotransmitters in the dorsal horn are synthesized absence of a relevant noxious stimulus. Neuronal
not only by primary afferent neurons, but also by the damage by disease or trauma can alter electrical activity
other neurons in the dorsal horn, including descending of neurons, allow cross-talk between neurons, and
neurons and various interneurons (Figure 9-2). Some initiate inflammatory processes to cause “peripheral
neurotransmitter systems in the dorsal horn are sensitization.” In this chapter, we will not emphasize
successfully targeted by known pain-relieving drugs, peripheral sensitization disorders and mechanisms, but
especially opiates, serotonin and norepinephrine boosting rather central sensitization disorders and mechanisms.
SNRIs, and α2δ ligands acting at VSCCs. All of the
neurotransmitter systems acting in the dorsal horn are Central Mechanisms in Neuropathic Pain
potential targets for novel pain-relieving drugs (Figure At each major relay point in the pain pathway
9-2) and a plethora of such novel agents is currently in (Figure 9-3), the nociceptive pain signal is susceptible to
clinical and preclinical development. modulation by endogenous processes to either dampen
There are several classes of dorsal horn neurons: some down the signal or to amplify it. This happens not only
receive input directly from primary sensory neurons, peripherally at primary afferent neurons, as has just been
some are interneurons, and some project up the spinal discussed, but also at central neurons in the dorsal horn
cord to higher centers (Figure 9-3). There are several of the spinal cord as well as in numerous brain regions.
different tracts in which these projection neurons can The events in the dorsal horn of the spinal cord are better
ascend, which can be crudely divided into two functions: understood than those in brain regions of nociceptive
the sensory/discriminatory pathway and the emotional/ pathways, but pain processing in the brain may be the
motivational pathway (Figure 9-3). key to understanding the generation and amplification
In the sensory/discriminatory pathway, dorsal horn of pain centrally in disorders of chronic peripheral
neurons ascend in the spinothalamic tract; then, thalamic pain, such as osteoarthritis, low back pain, and diabetic
neurons project to the primary somatosensory cortex peripheral neuropathic pain, as well as painful physical
(Figure 9-3). This particular pain pathway is thought to symptoms in affective and anxiety disorders and in
convey the precise location of the nociceptive stimulus fibromyalgia.
382
Multiple Neurotransmitters Modulate Pain Processing

in the Spinal Cord
descending
neurons to higher
dorsal horn centers
projection neuron
primary afferent neuron
interneuron
5HT
opioid
opioid
5HT NE
5HT
3
5HT
1/B/D
2
2
5H
T3
VIP VIPR
somato SR
statin
CGRP CGRP-R PN
Sub P
NKA ,2,3
NKB NK1
,B
GABA BA A
GA -R
glu PA
AM
-R
B
A,
9
DA
BA
,B
CCK-A
NM
GA
glycine
CCK NO
opioid
GABA
Figure 9-2 Multiple neurotransmitters modulate pain processing in the spinal cord. There are many neurotransmitters and their
corresponding receptors in the dorsal horn. Neurotransmitters in the dorsal horn may be released by primary afferent neurons, by
descending regulatory neurons, by dorsal horn projection neurons (PN), and by interneurons. Neurotransmitters present in the dorsal
horn that have been best studied in terms of pain transmission include substance P (NK1, 2, and 3 receptors), endorphins (μ-opioid
receptors), norepinephrine (α2 adrenoceptors), and serotonin (5HT1B/D and 5HT3 receptors). Several other neurotransmitters are also
represented, including vasopressin inhibitory protein (VIP) and its receptor VIPR; somatostatin and its receptor SR; calcitonin G-related
peptide (CGRP) and its receptors CGRP-R; GABA and its receptors GABAA and GABAB; glutamate and its receptors AMPA-R (α-amino-3-
hydroxy-5-methyl-4-isoxazole propionic acid receptor) and NMDA-R (N-methyl-D-aspartate receptor); nitric oxide (NO); cholecystokinin
(CCK) and its receptors CCK-A and CCK-B; and glycine and its receptor NMDA-R.
383
Figure 9-3 From nociception

somatosensory to pain. Dorsal horn neurons in
cortex the spinothalamic tract project
to the thalamus and then to the
primary somatosensory cortex.
This pathway carries information
thalamus about the intensity and location
subjective of the painful stimuli and is
experience termed the sensory/discriminatory
of pain pathway. Neurons ascending in
the spinobulbar tract project to
PN
OUCH! brainstem nuclei and then to both
limbic the thalamus and limbic structures.
structures
These pathways convey the
spinothalamic emotional and motivational aspects
brainstem
tract of the pain experience. Only when
information from the sensory/
discriminatory (thalamocortical)
spinobulbar and emotional/motivational
tract
(limbic) pathways combine is the
human subjective experience of
pain formed (“ouch”).
“Segmental” central sensitization is a process neuropathic pain, and painful cutaneous eruptions of
thought to be caused when plastic changes occur herpes zoster (shingles) (Figure 9-4A).
in the dorsal horn, classically in conditions such as “Suprasegmental” central sensitization is hypothesized
phantom pain after limb amputation. Specifically, to be linked to plastic changes that occur in brain sites
this type of neuronal plasticity in the dorsal horn is within the nociceptive pathway, especially the thalamus
called activity-dependent or use-dependent because and cortex, in the presence of known peripheral causes
it requires constant firing of the pain pathway in the (Figure 9-5A) or even in the absence of identifiable
dorsal horn. The consequence of this constant input of triggering events (Figure 9-5B). In the case of peripherally
pain is eventually to cause exaggerated (hyperalgesic) activated suprasegmental central sensitization, it is as
or prolonged responses to any noxious input – a though the brain “learns” from its experience of pain,
phenomenon sometimes called “wind-up” – as well as and decides not only to keep the process going, but also
painful responses to normally innocuous inputs (called to enhance it and make it permanent. In the case of pain
allodynia). Phosphorylation of key membrane receptors that originates centrally without peripheral input, it is as
and channels in the dorsal horn appears to increase though the brain has figured out how to spontaneously
synaptic efficiency and thus to trip a master switch activate its pain pathways. Interrupting this process of
opening the gate to the pain pathway and turning on sensitized brain pathways for pain and getting the central
central sensitization, which acts to amplify or create nervous system to “forget” its molecular memories
the perception of pain even if there is no pain input may be one of the greatest therapeutic opportunities in
actually coming from the periphery. The gate can also psychopharmacology today, not only because this may
close, as conceptualized in the classic “gate theory” of be a therapeutic strategy for various chronic neuropathic
pain, in order to explain how innocuous stimulation pain conditions as discussed here, but also because it
(e.g., acupuncture, vibration, rubbing) away from the may be a viable approach to treating the hypothesized
site of an injury can close the pain gate and reduce the molecular changes that may underlie disease progression
perception of the injury pain. in a wide variety of disorders, from schizophrenia,
In segmental central sensitization, a definite to stress-induced anxiety and affective disorders,
peripheral injury (Figure 9-4A) is combined with to addictive disorders. Conditions hypothesized to
central sensitization at the spinal cord segment receiving be caused by suprasegmental central sensitization
nociceptive input from the damaged area of the body syndromes of pain originating in the brain without
(Figure 9-4B). Segmental central sensitization syndromes peripheral pain input include fibromyalgia, the syndrome
are thus “mixed” states where the insult of central of chronic widespread pain, and painful physical
segmental changes (Figure 9-4B) are added to peripheral symptoms of depression and anxiety disorders, especially
injuries such as low back pain, diabetic peripheral posttraumatic stress disorder (PTSD) (Figure 9-5B).
384
Onset of Acute Pain from Painful Peripheral Conditions Figure 9-4 Acute pain and
development of segmental central
sensitization. (A) When peripheral
injury occurs, nociceptive impulse
OUCH! flow from primary afferent neurons is
transmitted via dorsal horn neurons
to higher brain centers, where it can
ultimately be interpreted as pain
(represented by the “ouch”). (B) In
some cases, injury or disease directly
affecting the nervous system may
result in plastic changes that lead to
sensitization within the central nervous
system, such that the experience
of pain continues even after tissue
damage is resolved. Impulses may be
generated at abnormal locations either
joint affected by spontaneously or via mechanical forces.
osteoarthritis At the level of the spinal cord, this
process is termed segmental central
sensitization. This mechanism underlies
diabetic peripheral conditions such as diabetic peripheral
neuropathic pain neuropathic pain and shingles.
low back pain
shingles
Development of Segmental Central Sensitization and Increased Pain
OUCH!
joint affected by
osteoarthritis
diabetic peripheral
neuropathic pain
segmental central
sensitization
low back pain
B
shingles
385
Chronic Pain with Suprasegmental Central Sensitization

from Peripheral Injury
OUCH!
suprasegmental
central sensitization
joint affected by
osteoarthritis
diabetic peripheral
neuropathic pain
low back pain
A
shingles
Suprasegmental Central Sensitization Originating in the Brain
OUCH!
fibromyalgia
chronic widespread
pain
painful physical symptoms

B
of depression/anxiety
Figure 9-5 Suprasegmental central sensitization. Plastic changes in brain sites within the nociceptive pathway, especially the thalamus
and cortex, can cause sensitization. This process within the brain is termed suprasegmental central sensitization. This can occur following
peripheral injury (A) or even in the absence of identifiable triggering events (B). This mechanism is believed to underlie conditions such
as fibromyalgia, chronic widespread pain, and painful symptoms in depression and anxiety disorders.
386
The Spectrum of Mood and Anxiety Disorders with Fibromyalgia

Pain Disorders
Fibromyalgia has emerged as a diagnosable and treatable
A large group of overlapping disorders can have pain syndrome, with tenderness but no structural
emotional symptoms, painful physical symptoms, pathology in muscles, ligaments, or joints. Fibromyalgia
or both (Figure 9-6). Although pain in the absence is recognized as a chronic, widespread pain syndrome
of emotional symptoms has long been seen as a associated with fatigue and nonrestorative sleep. It is
neurological disorder, and pain in the presence of diagnosed based on the number of body areas in which
emotional symptoms as a psychiatric disorder, it is the patient experiences pain (widespread pain index, or
now clear that pain is a symptom that can be mapped WPI) combined with the severity of associated symptoms
onto inefficient information processing within the pain (fatigue, waking unrefreshed, cognitive symptoms, and
circuit, and is largely considered the same symptom with other somatic symptoms) (Figure 9-7). It is the second
the same treatments, whether occurring by itself or as most common diagnosis in rheumatology clinics, and
part of any number of syndromes (Figure 9-6). Thus, may affect 2–4% of the general population. Although
pain (Figure 9-6, right) can occur not only by itself, symptoms of fibromyalgia are chronic and debilitating,
but also concomitantly with the emotional symptoms they are not necessarily progressive. There is no known
of depressed mood and anxiety (Figure 9-6, left), and cause and there is no known pathology identifiable in the
with the physical symptoms of fatigue, insomnia, muscles or joints. This syndrome can be deconstructed
and problems concentrating (Figure 9-6, middle). No into its component symptoms (Figure 9-8), and then
matter whether pain occurs by itself or with additional matched with hypothetically malfunctioning brain
concomitant emotional or physical symptoms, or in the circuits (Figure 9-9).
presence of full syndromal psychiatric disorders such as
major depressive disorder, generalized anxiety disorder, Decreased Gray Matter in Chronic Pain Syndromes?
or PTSD (Figure 9-6, left), it must be treated and the Some very troubling preliminary reports suggest that
treatments are the same across the spectrum (Figure 9-6), chronic pain may even “shrink the brain” in the DLPFC
namely SNRIs and α2δ ligands as will be explained below. (dorsolateral prefrontal cortex) (Figure 9-9) and thereby
The Spectrum from Mood and Anxiety Disorders to Chronic

Neuropathic Pain Syndromes
anxiety and mixed chronic neuropathic
mood disorders
painful physical symptoms
pain syndromes 9
of depression/anxiety
chronic widespread
anxiety pain
disorder
subtypes
$ fatigue
fibromyalgia
worry
Z
sleep shingles
PTSD Z
Z
diabetic peripheral
general neuropathic pain
anxiety
disorder
osteoarthritis
cognition
major
depressive
disorder low back pain
mood/anxiety pain
Figure 9-6 The spectrum from mood and anxiety disorders to chronic neuropathic pain syndromes. Pain, though not a formal
diagnostic feature of depression or anxiety disorders, is nonetheless frequently present in patients with these disorders. Similarly,
depressed mood, anxiety, and other symptoms identified as part of depression and anxiety disorders are now recognized as being
common in pain disorders.
387
Figure 9-7 Widespread pain index

Widespread Pain Index (WPI) (WPI). Fibromyalgia is a chronic
for Diagnosis of Fibromyalgia widespread pain syndrome, formerly
diagnosed based on the number
of body areas in which the patient
experiences pain (widespread pain
jaw index, or WPI) combined with the
neck severity of associated symptoms
(fatigue, waking unrefreshed, cognitive
symptoms, and other somatic
shoulder symptoms.
girdle
upper back
upper chest
arm
lower abdomen
arm
lower back
upper
leg
hip (buttock)
lower
leg
Figure 9-8 Symptoms of

fibromyalgia. In addition to pain as a
central feature of fibromyalgia, many
fibromyalgia patients experience fatigue, anxiety,
depression, disturbed sleep, and
problems concentrating.
fatigue
concentration
anxiety
pain
sleep
depression
contribute to cognitive dysfunction in certain pain states all be involved in causing brain atrophy and/or cognitive
such as fibromyalgia (Figure 9-8) and low back pain. dysfunction in fibromyalgia and other chronic pain states.
Brain atrophy is discussed in relationship to stress and Chronic back pain, for example, has also been reported
anxiety disorders in Chapter 6 and illustrated in Figure to be associated with decreased prefrontal and thalamic
6-30. It would not be surprising if stressful conditions gray-matter density (Figure 9-10). Some experts have
that cause pain, as well as pain that causes distress, may hypothesized that in fibromyalgia and other chronic
388
Match Each Symptom of Fibromyalgia Figure 9-9 Symptom-based algorithm

for fibromyalgia. A symptom-based
to Hypothetically Malfunctioning Brain Circuits approach to treatment selection for
fibromyalgia follows the theory that
psychomotor each of a patient’s symptoms can
fatigue (physical) be matched with malfunctioning
pleasure brain circuits and neurotransmitters
-“fibro-fog”
interests pain that hypothetically mediate those
- problems concentrating
- lack of interest/pleasure
fatigue/ symptoms; this information is then
energy used to select a corresponding
psychomotor pharmacological mechanism for
fatigue (mental) treatment. Pain is linked to transmission
pain of information via the thalamus (T),
while physical fatigue is linked to
the striatum (S) and spinal cord (SC).
Problems concentrating and lack of
PFC S interest (termed “fibro-fog”) as well
T
NA as mental fatigue are linked to the
BF
prefrontal cortex (PFC), specifically the
Hy dorsolateral PFC. Fatigue, low energy,
and lack of interest may all also be
C related to the nucleus accumbens (NA).
NT Disturbances in sleep and appetite are
A associated with the hypothalamus (Hy),
H depressed mood with the amygdala (A)
and orbital frontal cortex, and anxiety
mood SC
fatigue (physical) with the amygdala.
depressed mood sleep pain
anxiety appetite
Figure 9-10 Gray-matter loss in chronic

Gray-matter loss in chronic pain pain. Research suggests that chronic pain,
like anxiety and stress-related disorders,
may lead to brain atrophy. Specifically, there
are data showing gray-matter loss in the
dorsolateral prefrontal cortex (DLPFC), the
thalamus, and the temporal cortex in patients
with chronic pain conditions.
DLPFC
thalamus
temporal
cortex
neuropathic pain syndromes, the persistent perception of the cortico-thalamic “brake” on nociceptive pathways.
of pain could lead to overuse of DLPFC neurons, Such an outcome could cause not only increased pain
excitotoxic cell death in this brain region, and reduction perception, but diminished executive functioning,
389
sometimes called “fibro-fog” in fibromyalgia. In Chapter release endorphins, which act via mostly presynaptic
6 we discussed how stress-related HPA (hypothalamic- μ-opioid receptors to inhibit neurotransmission from
pituitary-adrenal) axis abnormalities in CRF–ACTH– nociceptive primary afferent neurons (Figure 9-2). Spinal
cortisol regulation may be linked to hippocampal atrophy μ-opioid receptors are one target of opioid analgesics;
(see Figure 6-32), possibly linked to reduced availability so are μ-opioid receptors in the periaqueductal gray
of growth factors (Figures 6-27 and 6-29). Alterations in itself (Figure 9-11). Interestingly, since Aβ fibers (Figure
growth factors may be linked to the reports of reduction 9-1) do not express μ-opioid receptors, this may explain
in gray-matter volume in chronic pain syndromes why opioid analgesics spare normal sensory input.
(fibromyalgia and low back pain), but in different Enkephalins, which also act via δ-opioid receptors, are
brain regions (DLPFC, temporal cortex, and thalamus) also antinociceptive, whereas dynorphins, acting at
(Figure 9-10) than reported for depression (Figure 6-30). κ-opioid receptors, can be either anti- or pronociceptive.
Gray matter may actually be increased in other brain It is also interesting that opiates in general are no more
regions in chronic pain. effective for chronic neuropathic pain states than SNRIs
Although still preliminary, these findings suggest or α2δ ligands, but in many cases, such as in fibromyalgia,
a possible structural consequence to suprasegmental opiates are not proven to be effective at all.
central sensitization (Figure 9-10), not unlike that Two other important descending inhibitory pathways
suspected for depression and stress (Figure 6-30). are also shown in Figure 9-2. One is the descending spinal
Abnormal pain processing, exaggerated pain responses, norepinephrine pathway (Figure 9-12A), which originates
and perpetual pain could hypothetically be linked to in the locus coeruleus, and especially from noradrenergic
deficiencies in the DLPFC circuit and its regulation cell bodies in the lower (caudal) parts of the brainstem
by dopamine, and provide a potential explanation neurotransmitter center (lateral tegmental norepinephrine
for the cognitive difficulties associated with chronic cell system). The other important descending pathway
pain, especially fibro-fog in fibromyalgia (Figure 9-8). is the descending spinal serotonergic pathway (Figure
Thalamic abnormalities could hypothetically be linked 9-13A), which originates in the nucleus raphe magnus of
to problems sleeping as well as nonrestorative sleep seen the rostroventromedial medulla and especially the lower
in chronic pain syndromes (Figure 9-8). Thus, chronic (caudal) serotonin nuclei (raphe magnus, raphe pallidus,
pain syndromes not only cause pain, but also problems and raphe obscuris). Descending noradrenergic neurons
with fatigue, mental concentration, sleep, depression, inhibit neurotransmitter release from primary afferents
and anxiety (Figure 9-8). Structural brain abnormalities directly via inhibitory α2 adrenoceptors (Figure 9-2),
associated with inefficient information processing in explaining why direct-acting α2 agonists such as clonidine
brain areas that mediate these symptoms (Figure 9-9) can be useful in relieving pain in some patients. Serotonin
may explain why these various symptoms (Figure 9-8) are inhibits primary afferent terminals via postsynaptic
frequently associated with chronic pain syndromes. 5HT1B/D receptors (Figure 9-2). These inhibitory receptors
are G-protein-coupled, and indirectly influence ion
DESCENDING SPINAL SYNAPSES channels to hyperpolarize the nerve terminal and inhibit
nociceptive neurotransmitter release. However, serotonin
IN THE DORSAL HORN AND THE
is also a major transmitter in descending facilitation
TREATMENT OF CHRONIC PAIN pathways to the spinal cord. Serotonin released onto some
The periaqueductal gray is the site of origin and primary afferent neuron terminals in certain areas of
regulation of much of the descending inhibition that the dorsal horn acts predominantly via excitatory 5HT3
projects down the spinal cord to the dorsal horn receptors to enhance neurotransmitter release from these
(Figure 9-2). The periaqueductal gray is discussed in primary afferent neurons (Figure 9-2). The combination
relationship to its connections with the amygdala and of both inhibitory and facilitatory actions of serotonin
the motor component of the fear response in Chapter may explain why SSRIs (selective serotonin reuptake
8 and illustrated in Figure 8-9. The periaqueductal inhibitors), with actions that increase only serotonin
gray also integrates inputs from nociceptive pathways levels, are not consistently useful in the treatment of
and limbic structures such as the amygdala and limbic pain, whereas SNRIs, with actions on both serotonin and
cortex, and sends outputs to brainstem nuclei and norepinephrine, are now proven to be effective in various
the rostroventromedial medulla to drive descending neuropathic pain states, including diabetic peripheral
inhibitory pathways. Some of these descending pathways neuropathic pain and fibromyalgia.
390
Acute Nociceptive Pain
OUCH!
descending
opioid
projections
periaqueductal sprain
gray broken bone
dental extraction
A
Anatomic Site of Action of Opioids
OUCH!
opioid
opioid sprain
broken bone
dental extraction
B
Figure 9-11 Acute nociceptive pain and opioids. The periaqueductal gray integrates inputs from nociceptive pathways and limbic
structures and sends outputs to drive descending inhibitory pathways, including descending opioid projections. (A) Shown here is
nociceptive input from a peripheral injury being transmitted to the brain and interpreted as pain. The descending opioid projection is
not activated and thus is not inhibiting the nociceptive input. (B) Endogenous opioid release in the descending opioid projection, or
exogenous administration of an opioid, can cause inhibition of nociceptive neurotransmission in the dorsal horn or in the periaqueductal
gray and thus prevent or reduce the experience of pain.
391
Descending NE Inhibition of Pain
back stomach muscle/

pain pain joint
pain
descending
NE
projections
normal
NE release
back posture
A muscle/joint movement
digestion
Deficient NE Inhibition Leads to Pain

pain pain joint
pain
deficient
NE release
back posture
muscle/joint movement
B digestion
Figure 9-12A, B Descending noradrenergic neurons and pain. (A) The descending spinal norepinephrine (NE) pathway originates
in the locus coeruleus. Descending NE neurons inhibit neurotransmitter release from primary afferent neurons via presynaptic α2
adrenoceptors, and inhibit activity of dorsal horn neurons via postsynaptic α2 adrenoceptors. This suppresses bodily input (e.g.,
regarding muscles/joints or digestion) from reaching the brain and thus prevents it from being interpreted as painful. (B) If descending
NE inhibition is deficient, then it may not be sufficient to mask irrelevant nociceptive input, potentially leading to perception of pain
from input that is normally ignored. This may be a contributing factor for painful somatic symptoms in fibromyalgia, depression, irritable
bowel syndrome, and anxiety disorders.
392
SNRI Action Boosts NE Inhibition of Pain

pain pain joint
pain
descending
NE
projections
= SNRI
SNRI
boosts NE
back posture
C digestion
Figure 9-12C Enhancement of descending noradrenergic inhibition. A serotonin–norepinephrine reuptake inhibitor (SNRI) can
increase noradrenergic neurotransmission in the descending spinal pathway to the dorsal horn, and thus may enhance inhibition of
bodily input so that it does not reach the brain and get interpreted as pain.
Descending inhibition, mostly via serotonin and Descending inhibition is also activated during severe
noradrenergic pathways, is normally active at rest and injury by incoming nociceptive input, and in dangerous
is thought to act physiologically to mask perception “conflict” situations via limbic structures, causing the
of irrelevant nociceptive input (e.g., from digestion, release of endogenous opioid peptides (Figure 9-11B),
joint movement, etc.) (Figures 9-12A and 9-13A). serotonin (Figure 9-13A), and norepinephrine (Figure 9
One hypothesis for why patients with depression or 9-12A). When this happens, this reduces not only the
fibromyalgia or related chronic pain disorders perceive release of nociceptive neurotransmitters in the dorsal
pain when there is no obvious sign of peripheral horn (Figure 9-2) but also the transmission of nociceptive
trauma is that descending inhibition may not be acting impulses up the spinal cord into the brain (Figure 9-3),
adequately to mask irrelevant nociceptive input. This thereby reducing the perception of pain, dulling it to
leads to the perception of pain from what is actually allow escape from the situation without the injury
normal input that is ordinarily ignored (Figures 9-12B compromising physical performance in the short run
and 9-13B). If this descending monoaminergic inhibition (reduction of “ouch” in Figure 9-3). On return to safety,
is enhanced with an SNRI, irrelevant nociceptive inputs descending facilitation replaces the inhibition to redress
from joints, muscles, and the back in fibromyalgia and the balance, increase awareness of the injury, and force
depression, and from digestion and the gastrointestinal rest of the injured part (lots of “ouch” in Figure 9-3).
tract in irritable bowel syndrome, depression, and anxiety The power of this system can be seen in humans
disorders, are hypothetically once again ignored and persevering through severe injury on the sports
thus are no longer perceived as painful (Figures 9-12C field and on the battle field. The placebo effect may
and 9-13C). SNRIs include duloxetine, milnacipran, also involve endogenous opioid release from these
levomilnacipran, venlafaxine, desvenlafaxine, and some descending inhibitory neurons (Figure 9-11B), since
tricyclic antidepressants (TCAs). SNRIs and TCAs are activation of a placebo response to pain is reversible by
discussed extensively in Chapter 7. the μ-opioid antagonist naloxone. These are adaptive
393
Descending 5HT Inhibition of Pain

pain pain joint
pain
descending
5HT
projections
normal
5HT release
back posture
A muscle/joint movement
digestion
Deficient 5HT Inhibition Leads to Pain

pain pain joint
pain
deficient
5HT release
back posture
B digestion
Figure 9-13A, B Descending serotonergic neurons and pain. (A) The descending spinal serotonin (5HT) pathway originates in the
raphe nucleus. Descending serotonergic (5HT) neurons directly inhibit activity of dorsal horn neurons, predominantly via 5HT1B/D
receptors. This suppresses bodily input (e.g., regarding muscles/joints or digestion) from reaching the brain and thus prevents it from
being interpreted as painful. (B) If descending 5HT inhibition is deficient, it may not be sufficient to mask irrelevant nociceptive input,
potentially leading to perception of pain from input that is normally ignored. This may be a contributing factor for painful somatic
symptoms in fibromyalgia, depression, irritable bowel syndrome, and anxiety disorders.
394
SNRI Action Boosts 5HT Inhibition of Pain

pain pain joint
pain
descending
5HT
projections
= SNRI
SNRI
boosts 5HT
back posture
digestion
C
Figure 9-13C Enhancement of descending serotonergic inhibition. A serotonin–norepinephrine reuptake inhibitor (SNRI) can increase
serotonergic neurotransmission in the descending spinal pathway to the dorsal horn, and thus may enhance inhibition of bodily input
so that it does not reach the brain and get interpreted as pain. However, the noradrenergic effects of SNRIs may be more relevant to
suppression of nociceptive input.
changes within the pain pathways that facilitate voltage-sensitive calcium channels (VSCCs; Figure 9-14),
survival and enhance function for the individual. which is often coupled to the release of glutamate, but also
However, maladaptive changes can also hijack these to aspartate, substance P (SP), calcitonin-gene-related
same mechanisms to inappropriately maintain pain peptide (CGRP), and other neurotransmitters (Figure 9-2). 9
without relevant tissue injury, as may occur in various When this occurs at suprasegmental levels in the thalamus
forms of neuropathic pain, ranging from diabetes to and cortex, it is likely linked to release mostly of glutamate
fibromyalgia and beyond. via the same N-type and P/Q-type VSCCs (Figures 9-14
and 9-15). The idea is that low release of neurotransmitter
TARGETING SENSITIZED creates no pain response because there is insufficient
neurotransmitter release to stimulate the postsynaptic
CIRCUITS IN CHRONIC PAIN
receptors (Figure 9-14A). However, normal amounts of
CONDITIONS neurotransmitter release cause a full nociceptive pain
Chronic pain perpetuated as a marker of an irreversible response and acute pain (Figure 9-14B). Hypothetically,
sensitization process within the central nervous system in states of central sensitization, there is excessive
has already been discussed as a disorder triggered by and unnecessary ongoing nociceptive activity causing
progressive molecular changes due to abnormal neuronal neuropathic pain (Figure 9-15A). Blocking VSCCs with the
activity within the pain pathway, sometimes called α2δ ligands gabapentin or pregabalin (Figures 9-15B and
central sensitization. When this occurs at the spinal 9-16) inhibits release of various neurotransmitters in the
or segmental level, it is likely linked to the multiple dorsal horn (Figures 9-2, 9-15B, and 9-17A) or in thalamus
different neurotransmitters released there, with each and cortex (Figures 9-15B and 9-17B) and has indeed
neurotransmitter’s release mechanism requiring presynaptic proven to be an effective treatment for various disorders
depolarization and activation of N-type and P/Q-type causing neuropathic pain. Gabapentin and pregabalin
395
Subthreshold Pain Response
N
P/Q
N
Q
P/
no pain
A
Full Nociceptive Activity
N
P/Q
P/Q
N
B acute pain
Figure 9-14 Activity-dependent nociception in pain pathways, part 1: acute pain. The degree of nociceptive neuronal activity in pain
pathways determines whether one experiences acute pain. An action potential on a presynaptic neuron triggers sodium influx, which
in turn leads to calcium influx, and ultimately release of neurotransmitter. (A) In some cases, the action potential generated at the
presynaptic neuron causes minimal neurotransmitter release; thus the postsynaptic neuron is not notably stimulated and the nociceptive
input does not reach the brain (in other words, there is no pain). (B) In other cases, a stronger action potential at the presynaptic neuron
may cause voltage-sensitive calcium channels (VSCCs) to remain open longer, allowing more neurotransmitter release and more
stimulation of the postsynaptic neuron. Thus, the nociceptive input is transmitted to the brain and acute pain occurs.
396
Central Sensitization and

Excessive Nociceptive Activity
N
Q
P/
P/Q
N
neuropathic pain
A dorsal horn, thalamus,
or cortex
Relief of Painful Excessive Nociceptive = alpha-2-

delta ligand
Activity in Central Sensitization
N
Q
P/
9
P/Q
N
B neuropathic pain
Figure 9-15 Activity-dependent nociception in pain pathways, part 2: neuropathic pain. The degree of nociceptive neuronal activity
in pain pathways determines whether one experiences acute pain. An action potential on a presynaptic neuron triggers sodium
influx, which in turn leads to calcium influx, and ultimately release of neurotransmitter. (A) Strong or repetitive action potentials can
cause prolonged opening of calcium channels, which may lead to excessive release of neurotransmitter into the synaptic cleft, and
consequently to excessive stimulation of postsynaptic neurons. Ultimately this may induce molecular, synaptic, and structural changes,
including sprouting, which are the theoretical substrates for central sensitization syndromes. In other words, this can lead to neuropathic
pain. (B) Alpha-2-delta ligands such as gabapentin or pregabalin bind to the α2δ subunit of voltage-sensitive calcium channels (VSCCs),
changing their conformation to reduce calcium influx and therefore reduce excessive stimulation of postsynaptic receptors.
397
gabapentin pregabalin Figure 9-16 Gabapentin and

pregabalin. Shown here are icons
of the pharmacological actions of
gabapentin and pregabalin. These
agents bind to the α2δ subunit of
voltage-sensitive calcium channels
(VSCCs).
VSCC VSCC
2 site 2 site
Figure 9-17 Anatomic actions of α2δ

ligands. (A) Alpha-2-delta ligands
may bind to voltage-sensitive calcium
channels in the dorsal horn to reduce
OUCH! excitatory neurotransmission and
alleviate pain. (B) Alpha-2-delta ligands
may also bind to voltage-sensitive
calcium channels in the thalamus
and cortex to reduce excitatory
neurotransmission and alleviate pain.
OUCH!
(Figure 9-16) may more selectively bind the “open-channel” (Figures 9-17B and 9-18B). This molecular action predicts
conformation of VSCCs (Figures 9-17 and 9-18), and thus more affinity for centrally sensitized VSCCs that are actively
be particularly effective in blocking those channels that are conducting neuronal impulses within the pain pathway.
the most active, with a “use-dependent” form of inhibition Thus, they have a selective action on those VSCCs causing
398
Molecular Action of Alpha-2-Delta Ligands in advance, or at least early in the game. The hope is
that early treatment of pain could interfere with the
A. Open conformation of VSCC
inside the cell
development of chronic persistent painful conditions
by blocking the ability of painful experiences to imprint
themselves upon the central nervous system by not
ß allowing triggering of central sensitization. Thus, the
mechanisms whereby symptomatic suffering of chronic
neuropathic pain is relieved, such as with SNRIs or α2δ
N
P/Q ligands, may also be the same mechanisms that could
prevent disease progression to chronic persistent pain
states. This notion calls for aggressive treatment of
outside the cell
painful symptoms in these conditions that theoretically
Ca
++
have their origin within the central nervous system, thus
B. Alpha-2-delta ligand binding to open
“intercepting” the central sensitization process before
conformation and inhibiting VSCC it is durably imprinted into angry circuits. Thus, major
depression and anxiety disorders and fibromyalgia can
all be treated with SNRIs and/or α2δ ligands to eliminate
ß painful physical symptoms and thereby improve the
chances of reaching full symptomatic remission. The
opportunity to prevent permanent pain syndromes
N
P/Q or progressive worsening of pain is one reason why
pain is increasingly being considered a psychiatric
“vital sign” that must be assessed routinely in the
evaluation and treatment of psychiatric disorders by
psychopharmacologists. Future testing of agents capable
C. Closed conformation of VSCC
of reducing pain should be done to determine whether
eliminating painful symptoms early in the course of
psychiatric and functional somatic illnesses will improve
ß
outcomes, including preventing symptomatic relapses,
the development of treatment resistance or even brain
atrophy from stress in pain states (Figure 9-9), and
N hippocampal atrophy from stress in anxiety and affective 9
P/Q
disorders (Figure 6-30). Pre-emptively treating pain
before it occurs, or at least rescuing centrally mediated
2 and sensitizing pain by intercepting such pain before it
becomes permanent, may be some of the most promising
therapeutic applications of dual reuptake inhibitors and
Figure 9-18 Binding of α2δ ligands. (A) Calcium influx occurs α2δ ligands and deserves careful clinical evaluation.
when voltage-sensitive calcium channels (VSCCs) are in the
open-channel conformation. (B) Alpha-2-delta ligands such as
gabapentin and pregabalin have greatest affinity for the open- TARGETING ANCILLARY
channel conformation and thus block those channels that are
most active. (C) When VSCCs are in the closed conformation
SYMPTOMS IN FIBROMYALGIA
α2δ ligands do not bind and thus do not disrupt normal We have repeatedly mentioned the proven usefulness
neurotransmission.
of the α2δ ligands gabapentin and pregabalin and
neuropathic pain, ignoring other VSCCs that are not open, the SNRIs duloxetine, milnacipran, venlafaxine, and
and thus not interfering with normal neurotransmission in desvenlafaxine for treating the painful symptoms of
central neurons uninvolved in mediating the pathological fibromyalgia, yet these two classes have not been studied
pain state. extensively in combination. Nevertheless, they are
Treatment of pain, including neuropathic pain frequently used together in clinical practice on an empiric
conditions, may be less costly when you “pay” for it basis and anecdotally have been shown to give additive
399
improvement in relieving pain. Each class of drug may mirtazapine and tricyclic antidepressants, as well as
also help different ancillary symptoms in fibromyalgia, the tricyclic muscle relaxant cyclobenzapine. Other
so the combination of α2δ ligands with SNRIs may lead to sleep aids such as benzodiazepines, hypnotics, and
broader symptom relief than using either alone, although trazodone can be helpful in relieving sleep disturbance
both are effective for pain in fibromyalgia. That is, α2δ in fibromyalgia. Evidence is also accumulating for the
ligands may reduce symptoms of anxiety in fibromyalgia efficacy of γ-hydroxybutyrate (GHB or sodium oxybate)
(see discussion of α2δ ligands in anxiety in Chapter 8 and in fibromyalgia (use with extreme caution because of
illustrated in Figures 8-17C and 8-18C) and for improving diversion and abuse potential). GHB is approved for
the slow-wave sleep disorder of fibromyalgia (sleep narcolepsy, enhances slow-wave sleep, and is discussed
disorders and their treatment are discussed in further in Chapter 10 on sleep (see Figures 10-67 and 10-68). In
detail in Chapter 10). SNRIs can be useful in reducing heroic cases the use of GHB by experts for the treatment
symptoms of depression and anxiety in fibromyalgia of severe and treatment-resistant cases of fibromyalgia
(see Chapter 7 on treatment for mood disorders) and may be justified. A number of anticonvulsants other than
for treating fatigue as well as the cognitive symptoms the α2δ ligands (Figure 9-16) are also used second-line for
associated with fibromyalgia, sometimes also called fibro- chronic neuropathic pain states, including fibromyalgia.
fog (see Figures 9-8 and 9-9). Problems with executive These agents are thought to target voltage-gated sodium
functioning in a wide variety of clinical conditions are channels rather than voltage-gated calcium channels
generally linked to inefficient information processing and thus seem to have a different mechanism of action
in the dorsolateral prefrontal cortex (DLPFC) where than α2δ ligands and may be effective in patients with
dopamine neurotransmission is important in regulating inadequate response to α2δ ligands.
brain circuits (see Chapter 4 on cognition in schizophrenia
and Figure 4-17). This concept of dopaminergic
SUMMARY
regulation of cognition in the DLPFC and the role of
boosting dopamine neurotransmission to improve This chapter has defined pain, and has explained
executive dysfunction is also discussed in Chapter 11 the processing of nociceptive neuronal activity into
on attention deficit hyperactivity disorder. Since SNRIs the perception of pain by pathways that lead to the
increase dopamine concentrations in the DLPFC (see spinal cord, and then up the spinal cord to the brain.
Figure 7-33C), SNRI agents can also potentially improve Neuropathic pain is discussed extensively, including
symptoms of fibro-fog in fibromyalgia patients. This both peripheral and central mechanisms, and the
may be particularly so for the SNRIs milnacipran and concept of central sensitization. The key role of
levomilnacipran, which have potent norepinephrine descending inhibitory pathways that reduce the activity
reuptake binding properties at all clinically effective doses of nociceptive pain neurons with the release of serotonin
(Figures 7-30 and 7-31), or for higher doses of the SNRIs and norepinephrine is explained, and shown to be
duloxetine (Figure 7-29), venlafaxine, and desvenlafaxine the basis for the actions of serotonin–norepinephrine
(Figure 7-28), which act to increase norepinephrine reuptake inhibitors (SNRIs) as agents that reduce the
reuptake blocking properties of these agents and thus act perception of pain in conditions ranging from major
to increase concentrations of dopamine in the DLPFC depression to fibromyalgia to diabetic peripheral
(Figure 7-33C). Other strategies for improving fibro-fog neuropathic pain, low back pain, osteoarthritis, and
in fibromyalgia patients include the same ones used to related conditions. The critical role of voltage-sensitive
treat cognitive dysfunction in depression, and include calcium channels (VSCCs) is also explained, providing
modafinil, armodafinil, selective norepinephrine reuptake the basis for the actions of α2δ ligands as agents that
inhibitors (NRIs) such as atomoxetine, norepinephrine– also reduce the perception of pain in diabetic peripheral
dopamine reuptake inhibitors (NDRIs) such as bupropion, neuropathic pain, fibromyalgia, painful physical
and with caution, stimulants. SNRIs, sometimes symptoms of depression and anxiety disorders, shingles,
augmented with modafinil, stimulants, or bupropion can and other neuropathic pain conditions. Finally, the
also be useful for symptoms of physical fatigue as well as spectrum of conditions from affective disorders to
mental fatigue in fibromyalgia patients. chronic neuropathic pain disorders is introduced, with
Second-line treatments for pain in fibromyalgia emphasis on the condition of fibromyalgia and its newly
can include sedating drugs for depression including evolving psychopharmacological treatments.
400
Disorders of Sleep and
Wakefulness and Their
10
Treatment: Neurotransmitter
Networks for Histamine
and Orexin
Neurobiology of Sleep and Wakefulness 402 Serotonergic Hypnotics 424
The Arousal Spectrum 402 Histamine 1 Antagonists as Hypnotics 425
Histamine 402 Anticonvulsants as Hypnotics 426
Orexins/Hypocretins 406 Hypnotic Actions and Pharmacokinetics: Your Sleep
Pathways of Arousal and Sleep for the Sleep/Wake Is at the Mercy of Your Drug Levels! 426
Cycle 408 Behavioral Treatments of Insomnia 430
Ultradian Cycles 413 Excessive Daytime Sleepiness 430
Neurotransmitters and the Ultradian Sleep What Is Sleepiness? 430
Cycle 414 Causes of Hypersomnia 431
Why Do We Sleep? Can’t I Sleep When I Die? 414 Circadian Rhythm Disorders 435
Insomnia 418 Wake-Promoting Agents and Treatment of
What Is Insomnia? 418 Excessive Daytime Sleepiness 440
Diagnosis and Comorbidities 418 Caffeine 440
Treating Insomnia: Drugs with Hypnotic Amphetamine and Methylphenidate 441
Actions 421 Modafinil/Armodafinil 442
Benzodiazepines (GABAA Positive Allosteric Solriamfetol, a Wake-Promoting NDRI 444
Modulators) 421 Pitolisant, H3 Presynaptic Antagonist 444
Z Drugs (GABAA Positive Allosteric Modulators) 422 Sodium Oxybate and Narcolepsy/Cataplexy 446
Dual Orexin Receptor Antagonists (DORAs) 423 Summary 448
This chapter will provide a brief overview of the sign,” thus requiring routine evaluation and symptomatic
psychopharmacology of disorders of sleep and wakefulness. treatment whenever encountered. This is similar to
Included here are short discussions of the symptoms, the earlier discussion in Chapter 9, where pain is also
diagnostic criteria, and treatments for disorders that cause increasingly being considered as another psychiatric
insomnia, excessive daytime sleepiness, or both. Clinical “vital sign.” That is, disorders of sleep (and pain) are so
descriptions and formal criteria for how to diagnose sleep important, so pervasive, and cut across so many psychiatric
disorders are mentioned here only in passing. The reader conditions that the elimination of these symptoms – no
should consult standard reference sources for this material. matter what psychiatric disorder may be present – is
The discussion here will emphasize the links between increasingly recognized as necessary in order to achieve
various brain circuits and their neurotransmitters with full symptomatic and functional remission for the patient.
disorders that cause insomnia or sleepiness. The goal of Many of the treatments discussed in this chapter
this chapter is to acquaint the reader with ideas about the are covered in previous chapters. For details of
clinical and biological aspects of sleep and wakefulness, mechanisms of insomnia treatments that are also used
how various disorders can alter sleep and wakefulness, and for the treatment of depression, the reader is referred
how many new and evolving treatments can resolve the to Chapter 7; for those insomnia treatments that are
symptoms of insomnia and sleepiness. benzodiazepines, the reader is also referred to Chapter
The detection, assessment, and treatment of sleep/ 7. For various hypersomnia treatments, especially
wake disorders are rapidly becoming standardized parts of stimulants, the reader is referred to Chapter 11 on
a psychiatric evaluation. Modern psychopharmacologists attention deficit hyperactivity disorder (ADHD) and to
increasingly consider sleep to be a psychiatric “vital Chapter 13 on impulsivity, compulsivity, and addiction
401
for additional information. The discussion in this chapter the ascending reticular activating system, because they
is at the conceptual level, and not at the pragmatic level. are known to work together to regulate arousal. This
The reader should consult standard drug handbooks was discussed in Chapter 5 and illustrated for histamine,
(such as Stahl’s Essential Psychopharmacology: the dopamine, and norepinephrine in Figure 5-14. This same
Prescriber’s Guide) for details of doses, side effects, drug ascending neurotransmitter system is blocked at several
interactions, and other issues relevant to the prescribing sites by many agents that cause sedation (see Chapter 5
of these drugs in clinical practice. and Figures 5-8 and 5-13). Figure 10-1 also shows that
excessive arousal can extend past insomnia to panic,
NEUROBIOLOGY OF SLEEP AND hallucinations, and all the way to frank psychosis (far
WAKEFULNESS right-hand side of the spectrum).
The Arousal Spectrum Histamine
Although many experts approach insomnia and sleepiness Histamine is one of the key neurotransmitters regulating
by emphasizing the separate and distinct disorders that wakefulness, and is the ultimate target of many wake-
cause them, many pragmatic psychopharmacologists promoting drugs (via enhancement of histamine release)
approach insomnia or excessive daytime sleepiness as and sleep-promoting drugs (antihistamines that block
important symptoms that cut across many conditions and histamine at H1 receptors). Histamine is produced
that occur along a spectrum from deficient arousal to from the amino acid histidine, which is taken up into
excessive arousal (Figure 10-1). In this conceptualization, histamine neurons and converted into histamine by
an awake, alert, creative, and problem-solving person has the enzyme histidine decarboxylase (Figure 10-2).
the right balance between too much and too little arousal Histamine’s action is terminated by two enzymes
(baseline brain functioning in the middle of the spectrum working in sequence: histamine N-methyltransferase,
in Figure 10-1). As arousal increases beyond normal, which converts histamine to N-methylhistamine, and
during the day there is hypervigilance (Figure 10-1); if monoamine oxidase B (MAO-B), which converts N-
this increased arousal occurs at night, there is insomnia methylhistamine into N-MIAA (N-methylindoleacetic
(Figure 10-1, overactivation of the brain). From a acid), an inactive substance (Figure 10-3). Additional
treatment perspective, insomnia can be conceptualized as enzymes such as diamine oxidase can also terminate
a disorder of excessive arousal, with drugs having hypnotic histamine action outside the brain. Note that there is no
actions moving the patient from too much arousal to sleep apparent reuptake pump for histamine. Thus, histamine
(specific drugs with hypnotic actions discussed below). is likely to diffuse widely away from its synapse, just like
On the other hand, as arousal diminishes, symptoms dopamine does in the prefrontal cortex.
crescendo from mere inattentiveness to more severe forms There are a number of histamine receptors
of cognitive disturbances until the patient has excessive (Figures 10-4 through 10-7). The postsynaptic histamine
daytime sleepiness with sleep attacks (Figure 10-1, 1 (H1) receptor is best known (Figure 10-5) because it is
hypoactivation of the brain). From a treatment perspective, the target of “antihistamines” (i.e., H1 antagonists) (see
sleepiness can be conceptualized as a disorder of deficient below). When histamine itself acts at H1 receptors, it
arousal, with wake-promoting agents moving the patient activates a G-protein-linked second-messenger system
from too little arousal to awake with normal alertness that activates phosphatidylinositol, and the transcription
(specific wake-promoting agents are discussed below). factor cFOS, and results in wakefulness, normal alertness,
Note in Figure 10-1 that cognitive disturbance and pro-cognitive actions (Figure 10-5). When these H1
is the product of both too little as well as too much receptors are blocked in the brain, this interferes with the
arousal, consistent with the need for cortical pyramidal wake-promoting actions of histamine, and thus can cause
neurons to be optimally “tuned,” with too much activity sedation, drowsiness, or sleep (see below).
making them just as out of tune as too little. Note also Histamine 2 (H2) receptors, best known for their
in Figure 10-1 that the arousal spectrum is linked to actions in gastric acid secretion and the target of a
the actions of several neurotransmitters that will be number of anti-ulcer drugs, also exist in the brain
explained in detail in the following paragraphs (i.e., (Figure 10-6). These postsynaptic receptors also activate
histamine, orexin, dopamine, norepinephrine, serotonin, a G-protein second-messenger system with cyclic
acetylcholine, and γ-aminobutyric acid [GABA]). Several adenosine monophosphate (cAMP), phosphokinase A
of these neurotransmitter circuits as a group are called (PKA), and the gene product CREB. The function of H2
402
Chapter 10: Disorders of Sleep and Wakefulness and Their Treatment
Arousal Spectrum of Sleep and Wakefulness
awake
alert
inattentive creative hypervigilant/
problem solving insomnia
cognitive dysfunction cognitive dysfunction

(understimulation) (overstimulation)
excessive daytime panic/fear

sleepiness/
drowsiness/ HA
sedation
DA
ACh
asleep hallucinations/
5HT
NE psychosis
deficient arousal excessive arousal
overactivation
normal
baseline
hypoactivation
10
Figure 10-1 Arousal spectrum of sleep and wakefulness. One’s state of arousal is more complicated than simply being “awake” or
“asleep.” Rather, arousal exists as if on a dimmer switch, with many phases along the spectrum. Where on the spectrum one lies is
influenced by several key neurotransmitters: histamine (HA), dopamine (DA), norepinephrine (NE), serotonin (5HT), and acetylcholine
(ACh) (all shown) as well as GABA (γ-aminobutyric acid) and orexin (not shown). When there is good balance between too much and
too little arousal – depicted by the gray (baseline) color of the brain – one is awake, alert, and able to function well. As the dial shifts to
the right there is too much arousal, which may cause hypervigilance and consequently insomnia at night. As arousal further increases
this can cause cognitive dysfunction, panic, and in extreme cases perhaps even hallucinations. On the other hand, as arousal diminishes
individuals may experience inattentiveness, cognitive dysfunction, sleepiness, and ultimately sleep.
receptors in brain is still being clarified, but apparently is binds to these receptors, it turns off further release of
not linked directly to wakefulness. histamine (Figure 10-7B). One novel approach to new
A third histamine receptor is present in brain, wake-promoting and pro-cognitive drugs is to block
namely the H3 receptor (Figure 10-7). Histamine H3 these receptors, thus facilitating the release of histamine,
receptors are presynaptic (Figure 10-7A) and function as allowing histamine to act at H1 receptors to produce the
autoreceptors (Figure 10-7B). That is, when histamine desired effects (see below).
403
Histamine Is Produced Histamine Action Is Terminated

histidine
transporter
N-MIAA
(inactive)
E MAO-B
HA HA E
HIS HDC E
Me
N-methyl
HA histamine
Me
NMT
Figure 10-3 Histamine’s action is terminated. Histamine

can be broken down intracellularly by two enzymes.
HA (histamine) Histamine N-methyltransferase (HA NMT) converts histamine
into N-methylhistamine, which is then converted by
Figure 10-2 Histamine is produced. Histidine (HIS), a precursor monoamine oxidase B (MAO-B) into the inactive substance
to histamine, is taken up into histamine nerve terminals N-methylindoleacetic acid (N-MIAA). Note that there is no
via a histidine transporter and converted into histamine by apparent reuptake transporter for histamine; thus, histamine that
the enzyme histidine decarboxylase (HDC). After synthesis, is released into the synapse can diffuse widely.
histamine (HA) is packaged into synaptic vesicles and stored
until its release into the synapse during neurotransmission.
Histamine Receptors
H3
autoreceptor
glu
HA
H1 H2
polyamine site
NMDA (allosteric
receptor modulator
site)
Figure 10-4 Histamine receptors. Shown here are receptors for histamine that regulate its neurotransmission. Histamine 1 and histamine
2 receptors are postsynaptic, while histamine 3 receptors are presynaptic autoreceptors. There is also a binding site for histamine on
glutamatergic NMDA (N-methyl-D-aspartate) receptors – it can act at the polyamine site, which is an allosteric modulatory site.
404
HA HA
H1 H2
GE GE
cFOS CREB
PI cAMP
PKA
other
CNS actions
Figure 10-6 Histamine 2 receptors. Histamine 2 (H2) receptors

are present both in the body and in the brain. When histamine
binds to postsynaptic H2 receptors it activates a G-protein-
awake linked second-messenger system with cyclic adenosine
pro-cognitive monophosphate (cAMP), phosphokinase A (PKA), and the gene
alert product CREB. The function of H2 receptors in the brain is not
yet elucidated but does not appear to be directly linked to
wakefulness.
Figure 10-5 Histamine 1 receptors. When histamine binds

to postsynaptic histamine 1 (H1) receptors, it activates a
G-protein-linked second-messenger system that activates
phosphatidylinositol (PI) and the transcription factor cFOS. This
results in wakefulness and normal alertness.
10
H3
autoreceptor Figure 10-7 Histamine 3
receptors. Histamine 3 (H3) receptors
are presynaptic autoreceptors and
H3 binding by HA function as gatekeepers for histamine.
HA inhibits HA release (A) When H3 receptors are not bound
by histamine, the molecular gate is
open and allows histamine release.
(B) When histamine binds to the H3
receptor, the molecular gate closes
A B and prevents histamine from being
released.
405
There is a fourth type of histamine receptor, H4, discovered them, and named them differently. One
but these are not known to occur in the brain. Finally, group reported the discovery of neurotransmitters in the
histamine acts also at NMDA (N-methyl-D-aspartate) lateral hypothalamus that were oddly similar to the gut
receptors (Figure 10-4). Interestingly, when histamine hormone secretin, a member of the incretin family, so
diffuses away from its synapse to a glutamate synapse they named it “hypocretin” to stand for a hypothalamic
containing NMDA receptors, it can act at an allosteric member of the incretin family. At the same time, another
modulatory site called the polyamine site, to alter the group reported the discovery of the “orexins” to reflect
actions of glutamate at NMDA receptors (Figure 10-4). the orexigenic (appetite-simulating) activity of these
The role of histamine and function of this action are not neurotransmitter peptides. Soon it was realized that these
well clarified. were the same neurotransmitters: excitatory neuropeptides
Histamine neurons all arise from a single small area with approximately 50% sequence identity produced by
of the hypothalamus known as the tuberomammillary cleavage of a single precursor protein to form orexin A
nucleus (TMN) (Figure 10-8), which regulates arousal. with 33 amino acids and orexin B with 28 amino acids.
Thus, histamine plays an important role in arousal, This nomenclature can certainly be confusing but many
wakefulness, and sleep. The TMN is a small bilateral now recognize the history of the discovery of hypocretin by
nucleus that provides histaminergic input to most brain using “hypocretin” to refer to the gene or genetic products
regions and to the spinal cord (Figure 10-8). and “orexins” to refer to the peptide neurotransmitters
themselves. The use of both terms remains a practical
Orexins/Hypocretins
necessity because “HCRT” is the standard gene symbol in
These are peptide neurotransmitters with two names databases and “OX” is used to refer to the pharmacology of
because two different groups of scientists simultaneously the peptide system by international societies.
Figure 10-8 Histamine projections

The Wake Circuit: Histamine and wakefulness. In the brain,
histamine is produced solely by
cells in the tuberomamillary nucleus
(TMN) of the hypothalamus. From
the TMN, histaminergic neurons
project to most brain regions; those
relevant for wakefulness include
the prefrontal cortex, the basal
forebrain, the thalamus, and brainstem
neurotransmitter centers, as well as the
ventrolateral preoptic area and lateral
hypothalamus.
thalamus
basal
forebrain
VLPO LH PPT/
VTA
LDT
TMN RN LC
LC: locus coeruleus

histamine
LH: lateral hypothalamus
PPT/LDT: pedunculopontine and laterodorsal tegmental nuclei
RN: raphe nuclei
TMN: tuberomammillary nucleus
VLPO: ventrolateral preoptic area
VTA: ventral tegmental area
406
Orexin/hypocretin neurons are localized exclusively to orexin 2 receptors leads to increased expression of N-
in certain hypothalamic areas (lateral hypothalamic methyl-D-aspartate (NMDA) glutamate receptors as well
area, perifornical area, and posterior hypothalamus) as inactivation of G-protein-regulated inwardly rectifying
(Figure 10-9). These hypothalamic neurons degenerate potassium (GIRK) channels (Figure 10-11).
in a condition called narcolepsy, characterized by the In addition to their role in stabilizing wakefulness,
inability to stabilize wakefulness and thus sleep attacks orexins also are thought to regulate feeding behavior,
in the daytime. Loss of these neurons causes the inability reward, and other behaviors (Figure 10-12). During
of orexin to be produced and released downstream on periods of wakefulness, orexin/hypocretin neurons
wake-promoting neurotransmitter centers and thus lack are active and fire with tonic frequency to maintain
of stabilizing wakefulness. Treatment of narcolepsy is arousal, but when presented with a stimulus – either
discussed below. external, such as an escapable stressor, or internal, such
Orexin/hypocretin neurons in the hypothalamus make as elevated blood CO2 levels – orexin neurons exhibit a
two neurotransmitters: orexin A and orexin B, which are more rapid phasic burst firing pattern (Figure 10-12).
released from their neuronal projections all over the brain This excitement of hypocretin/orexin neurons leads to
(Figures 10-9 and 10-10), but especially in the monoamine increased activation not only of orexin but of all the other
neurotransmitter centers in the brainstem (Figure 10-9). brain areas that orexin stimulates, hypothetically leading
The postsynaptic actions of the orexins are mediated by in turn to execution of appropriate behavioral responses
two receptors called orexin 1 and orexin 2 (Figure 10-11). such as attainment of reward or the avoidance of potential
Orexin A is capable of interacting with both receptors, danger. In this way, the hypocretin/orexin system not only
whereas the neurotransmitter orexin B binds selectively to mediates wakefulness, but also allows for the facilitation
the orexin 2 receptor (Figure 10-11). The binding of orexin of goal-directed, motivated behaviors, including increased
A to the orexin 1 receptor leads to increased intracellular food intake in response to hunger (Figure 10-12).
calcium as well as activation of the sodium/calcium Orexin 1 receptors are highly expressed in the
exchanger (Figure 10-11). The binding of orexin A or B noradrenergic locus coeruleus, whereas orexin 2
Figure 10-9 Orexin/hypocretin
The Wake Circuit: Orexin projections and wakefulness. The
neurotransmitter orexin (also called
hypocretin) is made by cells located
in the hypothalamus, specifically
in the lateral hypothalamic area as
well as the perifornical and posterior
hypothalamus. From the hypothalamus,
orexinergic neurons project to various
brain areas, including the hypothalamic
tuberomammillary nucleus (TMN),
the basal forebrain, the thalamus, and
brainstem neurotransmitter centers.
10
thalamus
basal
forebrain
VLPO LH PPT/
VTA
LDT
TMN RN LC
LC: locus coeruleus

orexin/hypocretin
RN: raphe nuclei
407
Figure 10-10 Orexin/hypocretin
Orexin/Hypocretin Projections projections interact with arousal
neurotransmitters. Orexin/hypocretin is
released widely in the brain, interacting with
Wakefulness Attention all the arousal neurotransmitters to stabilize
wakefulness and regulate attention.
Orexin is also involved in other behaviors,
serotonin including feeding, motivation, and reward.
norepinephrine LH/PH, lateral hypothalamus/posterior
hypothalamus; PPT/LDT, pedunculopontine
raphe histamine and laterodorsal tegmental nuclei; LC,
LC TMN locus coeruleus; TMN, tuberomammillary
nucleus; PFC, prefrontal cortex; VTA, ventral
tegmental area; NAc, nucleus accumbens.
basal
PFC
forebrain
glutamate
acetylcholine
PPT/LDT LH/PH thalamus

orexin/
hypocretin
NAc VTA
striatum dopamine
GABA
Feeding Motivation Reward
receptors are highly expressed in the histaminergic When circadian drives, homeostatic drives, and
tuberomammillary nucleus (TMN). It is believed that darkness all act together at the end of the day and in
the effect of orexin/hypocretins on wakefulness is the dark, orexin levels are low, wakefulness is no longer
largely mediated by activation of the TMN histaminergic stabilized, and sleep is promoted from the ventrolateral
neurons that express orexin 2 receptors. However, preoptic area (VLPO) with GABA (γ-aminobutryric
orexin receptors and orexin projections to all the arousal acid) neurotransmission enhanced (Figure 10-17), thus
neurotransmitter centers make orexins ideally situated inhibiting all the wake-promoting neurotransmitter
to regulate wakefulness indirectly by effects on the centers (Figures 10-8, 10-13 through 10-16).
multitude of arousal neurotransmitters (see Figures 10-13
through 10-16). Thus, orexins may be not so much arousal Pathways of Arousal and Sleep for the Sleep/Wake
neurotransmitters themselves to cause wakefulness, but Cycle
rather serve to stabilize wakefulness by interacting with We have indicated that a multitude of neurotransmitters
all the arousal neurotransmitters (Figures 10-10 and are involved in the regulation of arousal and have
10-13 through 10-16). For example, orexin’s actions to illustrated their pathways in Figures 10-8, 10-9, and 10-
maintain wakefulness and attention may be mediated 13 through 10-17. This regulation results in a daily cycle
by stimulation of acetylcholine from the basal forebrain of sleep and wakefulness mediated by two opposing
and the pedunculopontine and laterodorsal tegmental drives: the homeostatic sleep drive and the circadian
(PPT/LDT) nuclei (Figure 10-13); dopamine release wake drive (Figure 10-18). The homeostatic sleep drive
from the ventral tegmental area (VTA) (Figure 10-14); accumulates throughout periods of wakefulness and
norepinephrine release from the locus coeruleus (LC) light and is opposed by the circadian wake drive.
(Figure 10-15); serotonin release from the raphe nuclei The longer an individual is awake, the greater the
(RN) (Figure 10-16) and histamine release from the homeostatic drive to sleep. The homeostatic sleep drive
tuberomammillary nucleus (TMN) (Figure 10-8). Wow! is dependent upon the accumulation of adenosine, which
408
from hypothalamus Figure 10-11 Orexin/hypocretin

receptors. Orexin/hypocretin neurons
(LH/PH)
make two neurotransmitters: orexin A
and orexin B. Orexin neurotransmission
is mediated by two types of
postsynaptic G-protein-coupled
receptors, orexin 1 (OX1R) and orexin
2 (OX2R). Orexin A is capable of
interacting with both OX1R and OX2R,
whereas orexin B binds selectively to
OX2R. Binding of orexin A to OX1R
B leads to increased intracellular calcium
as well as activation of the sodium/
calcium exchanger. Binding of orexin
A and B to OX2R leads to increased
expression of NMDA (N-methyl-D-
aspartate) glutamate receptors as well
as inactivation of G-protein-regulated
B
A inward rectifying potassium channels
A B (GIRK). OX1R are particularly expressed
in the noradrenergic locus coeruleus
whereas OX2R are highly expressed in
the histaminergic tuberomammillary
orexin A orexin B nucleus (TMN).
A B
Ca++
Na +
A A B
GIRK
G G G
OX1R OX2R OX2R
Ca++ NMDA
10
awake
increases as the person tires with fatigue throughout wakefulness by enhancing the release of several other
the day, and ultimately leads to the disinhibition of the wake-promoting neurotransmitters. During periods of
ventrolateral preoptic (VLPO) nucleus and the release of light, histamine is released from the tuberomammillary
GABA in the sleep circuit (Figure 10-17), facilitating onset nucleus onto neurons throughout the cortex and in the
of sleep. ventrolateral preoptic area, inhibiting the release of GABA
The circadian wake drive, mediated by light acting (Figure 10-8). Histamine from the tuberomammillary
upon the suprachiasmatic nucleus, stimulates the nucleus also stimulates the release of orexin from the
release of orexin as part of the wake circuit to stabilize lateral hypothalamus as well as the perifornical area and
409
Tonic Firing of Phasic Burst Firing of Figure 10-12 Orexin/hypocretin

Hypocretin/Orexin Hypocretin/Orexin regulation of adaptive behavior.
Neurons to Promote Neurons During periods of wakefulness,
orexin/hypocretin neurons fire
Wakefulness with tonic frequency to maintain
arousal. When presented with a
stimulus, whether internal (e.g.,
hunger) or external (e.g., an
escapable stressor), orexin neurons
exhibit a phasic pattern of firing,
which leads not only to increased
STIMULUS ADAPTIVE BEHAVIOR orexin neurotransmission but
also to increased activation in
Hunger Increased food intake brain areas that orexin stimulates.
Thus orexin not only mediates
wakefulness but also allows for
the facilitation of goal-directed
Drug withdrawal Drug seeking behaviors.
Cold Peripheral thermogenesis
Elevated
Increased respiration
blood CO2
Hypothalamic-pituitary-
Escapable stress adrenal axis activation
Emotional/motivational Promotion of attention,

stimulus cognition, and learning
Figure 10-13 Acetylcholine
The Wake Circuit: Acetylcholine projections and wakefulness. Release
of acetylcholine from the basal
forebrain into cortical areas and from
the pedunculopontine and laterodorsal
tegmental nuclei (PPT/LDT) onto
the thalamus are associated with
wakefulness. Orexin/hypocretin may
thus stabilize wakefulness through its
regulation of acetylcholine (and other
arousal neurotransmitters).
thalamus
basal
forebrain
VLLPO
VLP
V PO
O PPT/
VTA
LDT
TMN RN LC
acetylcholine
LC: locus coeruleus

RN: raphe nuclei
410
Figure 10-14 Dopamine projections

The Wake Circuit: Dopamine and wakefulness. Release of dopamine
from the ventral tegmental area (VTA)
into cortical areas is associated with
wakefulness. Orexin/hypocretin may
thus stabilize wakefulness through its
regulation of dopamine (and other
arousal neurotransmitters).
thalamus
basal
forebrain
VL
VLP
VLPO
PO
O PPT/
VTA
LDT
TMN RN LC
dopamine
LC: locus coeruleus

RN: raphe nuclei
Figure 10-15 Norepinephrine
The Wake Circuit: Norepinephrine projections and wakefulness. Release
of norepinephrine from the locus
coeruleus (LC) into cortical areas
is associated with wakefulness.
Orexin/hypocretin may thus stabilize
wakefulness through its regulation of
norepinephrine (and other arousal
neurotransmitters).
10
thalamus
basal
forebrain
VLLPO
VLP
V PO
O PPT/
VTA
LDT
TMN RN LC
norepinephrine
LC: locus coeruleus

RN: raphe nuclei
VTA: ventral tegmental area 411
Figure 10-16 Serotonin projections

The Wake Circuit: Serotonin and wakefulness. Release of serotonin
from the raphe nucleus (RN) onto
the basal forebrain and the thalamus
is associated with wakefulness.
Orexin/hypocretin may thus stabilize
wakefulness through its regulation
of serotonin (and other arousal
neurotransmitters).
thalamus
basal
forebrain
VL
VLP
VLPO
PO
O PPT/
VTA
LDT
TMN RN LC
serotonin
LC: locus coeruleus
RN: raphe nuclei
Figure 10-17 GABA projections and

The Sleep Circuit sleep. GABA (γ-aminobutyric acid) is
released from the ventrolateral preoptic
nucleus (VLPO) of the hypothalamus
onto the tuberomammillary nucleus
(TMN), the lateral hypothalamus
(LH), the basal forebrain, and
neurotransmitter centers. By inhibiting
activity in these wake-promoting brain
regions, GABA can induce sleep.
thalamus
basal
bas
sal
f b i
forebrain
VLPO PPT/
LH V A
VTA
LD
LDT
TMN RN LC
LC: locus coeruleus

GABA
RN: raphe nuclei
412
Processes Regulating Sleep

awake
REM
ultradian stage 1
(sleep cycle) stage 2
stage 3
stage 4
homeostatic
(sleep drive)
circadian
(wake drive)
sleep sleep
7 am 11 pm 7 am 11 pm 7 am
Figure 10-18 Processes regulating sleep. The sleep/wake cycle is mediated by two opposing drives: homeostatic sleep drive
and circadian wake drive. The circadian wake drive is a result of input (light, melatonin, activity) to the suprachiasmatic nucleus of
the hypothalamus, which stimulates the release of orexin to stabilize wakefulness. Homeostatic sleep drive is dependent on the
accumulation of adenosine, which increases the longer one is awake and decreases with sleep. Accumulated adenosine leads to
disinhibition of the ventrolateral preoptic nucleus and thus the release of GABA in the tuberomammillary nucleus to inhibit wakefulness.
As the day progresses, circadian wake drive diminishes and homeostatic sleep drive increases until a tipping point is reached. Sleep
itself consists of multiple phases that recur in a cyclical manner; this process is known as the ultradian cycle and depicted at the top of
this figure.
the posterior hypothalamus. Then, orexin has a number of rest restores homeostatic sleep drive and light initiates
knock-on effects: wakefulness neurotransmitters.
• Orexin induces the release of acetylcholine from
the basal forebrain in cortical areas and from the Ultradian Cycles
pedunculopontine and laterodorsal tegmental nuclei In addition to the daily sleep/wake cycle (Figure 10-18),
onto the thalamus (Figure 10-13) there is also an ultradian sleep cycle (see inset of Figure
• Orexin also causes the release of dopamine from the 10-18; this cycle occurs faster [ultra] than a day [dian]
ventral tegmental area onto cortical areas (Figure 10-14) and is thus called ultradian). A complete ultradian sleep 10
• Orexin stimulates the release of norepinephrine from cycle (non-REM [rapid eye movement] and REM) lasts
the locus coeruleus onto cortical areas (Figure 10-15) approximately 90 minutes and occurs four to five times a
• Finally, orexin also instigates the release of serotonin night (Figure 10-18, inset). Stages 1 and 2 of sleep make
from the raphe nuclei onto both the basal forebrain up non-REM sleep, whereas stages 3 and 4 of the sleep
and the thalamus (Figure 10-16) cycle are part of deeper, slow-wave sleep. During the
Then, as light fades, norepinephrine from the locus normal sleep period, the duration of non-REM sleep is
coeruleus and serotonin from the raphe nuclei build gradually reduced during the night while the duration
up and are released onto neurons in the lateral of REM sleep is increased. REM sleep is characterized
hypothalamus, causing negative feedback inhibiting by faster activity on an electroencephalogram (EEG) –
the release of orexin. Without orexin, wakefulness is no similar to that seen during periods of wakefulness – as
longer stabilized, and the VLPO and GABA take charge well as distinct eye movements, and peripheral muscle
and suppress all the arousal neurotransmitters (Figure paralysis and loss of muscle tone called atonia. It is during
10-17). Thus, sleep is facilitated and melatonin is secreted REM sleep that dreaming occurs, and positron emission
at night in the dark. Then the cycle repeats itself as tomography (PET) studies have shown activation of
413
the thalamus, the visual cortex, and limbic regions act together to peak during stage 2 sleep and are at their
accompanied by reduced metabolism in other regions, lowest during REM sleep (Figure 10-22).
such as the dorsolateral prefrontal cortex and the parietal
Why Do We Sleep? Can’t I Sleep When I Die?
cortex during REM sleep. In contrast, there is overall
reduced brain activity during non-REM sleep. There is still much debate over the purpose of sleep.
Some propose that sleep is essential for synaptic growth,
Neurotransmitters and the Ultradian Sleep Cycle while others argue that sleep is necessary for synaptic
Neurotransmitters (Figures 10-8, 10-9, and 10-13 through pruning (Figure 10-23). Regardless of which hypothesis –
10-17) not only have a role in regulating the daily sleep/ or some combination of both – is more accurate, it has
wake cycle (Figure 10-18), but also in regulating the become increasingly evident that disturbances of the
various phases of sleep with the ultradian sleep cycle sleep/wake cycle have a detrimental effect on a myriad
(see inset of Figure 10-18). Thus, neurotransmitters of physiological and psychiatric functions. Aside from
fluctuate not only on a circadian (24-hour) basis, but also the economic costs of sleep/wake disorders, the risk of
throughout the various phases of the sleep cycle every cardiometabolic disease, cancer, mental illness, and overall
night (Figures 10-19 through 10-22). Not surprisingly, poorer quality of life are all increased when the sleep/wake
GABA is “on” all night, rising steadily during the first few cycle is disturbed (Figure 10-23). Disturbances in the
hours of sleep, plateaus, and then steadily declines before sleep/wake cycle can have profound effects on cognitive
one wakens (Figure 10-19). Also, not surprisingly, the functioning, including impairments in attention, memory
pattern for orexin is exactly the opposite: namely, orexin deficits, and an inability to process new information
levels steadily decrease during the first few hours of sleep, (Figure 10-24). In fact, 24 hours of sleep deprivation or
plateau, and then steadily increase before one wakens chronic short sleep duration (i.e., 4–5 hours per night)
(Figure 10-20). The pattern of the other neurotransmitters results in cognitive impairments equivalent to those
is sleep-phase dependent (Figures 10-21 and 10-22). That seen when legally intoxicated with alcohol. Both REM
is, acetylcholine levels fluctuate throughout the sleep and non-REM sleep appear to be essential for optimal
cycle, reaching their lowest levels during stage 4 sleep and cognitive functioning, with REM sleep modulating
peaking during REM sleep, tracing the ups and downs affective memory consolidation and non-REM sleep being
between stage 4 and REM every cycle (Figure 10-21). On critical for declarative and procedural memory. At the
the other hand, dopamine, norepinephrine, serotonin, and neurobiological level, there is evidence that disruption of
histamine levels demonstrate a different trend. They all the sleep/wake cycle impairs hippocampal neurogenesis,
Figure 10-19 GABA levels throughout

Neurotransmitter Levels Throughout the the sleep cycle. Neurotransmitter
Sleep Cycle: GABA levels fluctuate throughout the sleep
cycle. GABA levels rise steadily during
the first couple of hours of sleep,
Awake plateau, and then steadily decline
before one wakes.
Stage 1 REM REM REM REM
Stage 2
Stage 3
Stage 4
0 1 2 3 4 5 6 7 8
Time of Sleep (hrs)
414
Figure 10-20 Orexin/hypocretin levels

Neurotransmitter Levels Throughout the throughout the sleep cycle.
Sleep Cycle: Orexin/Hypocretin Neurotransmitter levels fluctuate
throughout the sleep cycle. Orexin/
hypocretin levels drop rapidly during
Awake the first hour of sleep, plateau, and then
steadily rise before one wakes.
Stage 2
Stage 3
Stage 4
0 1 2 3 4 5 6 7 8
Time of Sleep (hrs)
Figure 10-21 Acetylcholine levels

Neurotransmitter Levels Throughout the throughout the sleep cycle.
Sleep Cycle: Acetylcholine Neurotransmitter levels fluctuate
throughout the sleep cycle.
Acetylcholine levels are sleep-phase
Awake dependent: they are lowest during
stage 4 sleep and at their peak during
rapid eye movement (REM) sleep.
Stage 2
Stage 3
10
Stage 4
0 1 2 3 4 5 6 7 8
Time of Sleep (hrs)
which may partly explain the behavioral effects of sleep/ hormone leptin and the orexigenic (appetite-stimulating)
wake cycle disturbances on cognition. hormone ghrelin (Figure 10-25). These changes lead to
In recent years, much interest in the relationship dysfunctional insulin, glucose, and lipid metabolism;
between sleep and cardiometabolic issues such as type 2 in turn, this may increase the risk of obesity, type 2
diabetes and obesity has been expressed (Figure 10-25). diabetes, and cardiovascular disease. Additionally, an
Although much remains unknown, an impaired sleep/ altered sleep/wake cycle has been shown to disturb the
wake cycle has been shown to disrupt the circulating natural fluctuations in gut microbiota, perhaps further
levels of both the anorectic (appetite-inhibiting) promoting glucose intolerance and obesity.
415
Figure 10-22 Monoamine levels

Neurotransmitter Levels Throughout the Sleep Cycle: throughout the sleep cycle.
Dopamine, Norepinephrine, Serotonin, and Histamine Neurotransmitter levels fluctuate
throughout the sleep cycle.
The monoamines dopamine,
Awake norepinephrine, serotonin, and
histamine are at their lowest levels
during rapid eye movement (REM)
Stage 1 REM REM REM REM sleep and peak during Stage 2
sleep.
Stage 2
Stage 3
Stage 4
0 1 2 3 4 5 6 7 8
Time of Sleep (hrs)
Figure 10-23 Costs of sleep/

Epidemiology and Costs of Sleep/Wake Disorders wake disorders. Disturbances in
the sleep/wake cycle can have
profound influences on both
physical and mental health. From
a neuropathological perspective,
disruption in sleep may affect
synaptic potentiation and/or
synaptic pruning. Chronically
Psychiatric disorders, e.g.
disturbed sleep can increase
Depression Immunity Neurological disorders, e.g. the risk of mental illness,
Anxiety cardiometabolic disorders, and
Alzheimer disease
Chronic pain cancer, as well as disrupt immune
and endocrine function. HPA Axis:
hypothalamic-pituitary-adrenal
axis.
The purpose of sleep
Synaptic potentiation or synaptic pruning?
$ Economic costs, e.g.

Sickness absence
Lost productivity
Vehicular/mechanical accidents
HPA
Cardiometabolic
250 Axis
disorders, e.g.
Diabetes
Heart disease
Stroke Endocrine dysfunction
Cancer
416
Figure 10-24 Sleep and

Sleep and Cognition cognition. Disturbances in the sleep/
wake cycle have been shown to impair
hippocampal neurogenesis, which may
partially explain the profound effects of
sleep deprivation on cognitive functioning,
including impairments in attention, memory
deficits, and an inability to process new
information.
Sleep/wake cycle
disturbance
Impaired hippocampal
neurogenesis
Cognitive dysfunction
Figure 10-25 Sleep and

Sleep and Obesity obesity. Disturbances in the sleep/wake
cycle can decrease circulating levels of the
appetite-inhibiting hormone leptin and
increase circulating levels of the appetite-
L
stimulating hormone ghrelin, as well as
Decreased leptin contribute to gut microbiota dysbiosis.
These changes may lead to increased risk of
obesity, type 2 diabetes, and cardiovascular
disease.
10
G G G
Increased ghrelin
Impaired
sleep/wake Increased risk of obesity,
cycle type 2 diabetes, and
cardiovascular disease
Gut microbiota
dysbiosis
417
INSOMNIA million suffer from episodic insomnia. However, as many

as 70% of individuals with insomnia may not report it
What Is Insomnia?
to their clinician. Many conditions are associated with
One way to conceptualize insomnia is being hyperaroused insomnia, including improper sleep hygiene; medical
at night (Figure 10-26). It is not well established why illness; other sleep/wake disorders, including circadian
some of those with insomnia have hyperarousal at night rhythm disorders, restless legs syndrome, and sleep
or how it is mediated, but the most recent evidence from apnea; effects from medications or substances of abuse;
human neuroimaging studies suggests that in insomnia and psychiatric disorders (Figure 10-27). Insomnia
there is not so much an inability of the brain to switch on may be self-perpetuating in that repeated episodes of
sleep-related circuits from the VLPO (shown in Figure wakefulness in bed may become associated with anxiety
10-17) but instead, the inability to switch off arousal- and sleeplessness. Several biological factors have been
related circuits (shown in Figures 10-8, 10-9, 10-13 associated with insomnia, including increased activation
through 10-16). Some patients with insomnia at night of the autonomic nervous system, abnormal glucose
are also hyperaroused and even anxious in the daytime metabolism, decreased GABA levels, reduced nocturnal
and despite poor sleep do not necessarily feel sleepy in melatonin secretion, systemic inflammation, and reduced
the daytime. Whatever causes this hyperarousal, whether brain volume (Figure 10-28). There are also several
it is cortical hyperactivity keeping the wake-promoting genetic factors that have been linked to an increased risk
arousal neurotransmitters from dimming at night, or for insomnia (Figure 10-28). Insomnia may be a risk
even an excess of wake-stabilizing orexin keeping them factor for, or a prodromal symptom of, various psychiatric
awake, is still under active investigation. disorders, including depression, anxiety, and substance
use disorders (Figure 10-29). Additionally, insomnia
Diagnosis and Comorbidities due to psychiatric illness, especially depression, may be
Approximately 40 million individuals in the United more likely to persist than insomnia due to other causes.
States suffer from chronic insomnia, and an additional 20 Conversely, patients with depression who complain
Figure 10-26 Insomnia: excessive

Insomnia: Excessive Nighttime Arousal nighttime arousal? Insomnia is
conceptualized as being related
to hyperarousal at night. Recent
neuroimaging data suggest that
insomnia is the result of an inability
to switch off arousal-related circuits,
rather than an inability to switch on
sleep-related circuits. Some patients
with insomnia experience hyperarousal
during the day as well.
awake
alert
creative insomnia
problem solving
418
Conditions Associated with Insomnia Figure 10-27 Conditions associated with

insomnia. Numerous conditions are associated
with insomnia, including medical conditions,
Medical Conditions Substance Abuse psychiatric disorders, other sleep/wake disorders,
and substance use. Insomnia may also be related to
medication side effects.
Behavioral/
Psychiatric Conditions Psychological Causes
(SIGH)
Medication Side Effects Sleep/Wake Disorders
Figure 10-28 Biology of insomnia.

Biology of Insomnia Numerous neuroanatomical,
neurobiological, and autonomic
abnormalities have been
Neuroanatomical Abnormalities associated with insomnia. There
Reduced gray matter in left orbitofrontal are also several genetic factors that
cortex and hippocampus have been linked to an increased
risk for insomnia.
GABA
Neurobiological Abnormalities
Decreased GABA levels in occipital and anterior cingulate cortices
Reduced nocturnal melatonin secretion
Increased glucose metabolism melatonin
Attenuated sleep-related reduction in glucose metabolism
in wake-promoting regions BDNF 10
Decreased serum BDNF
Autonomic Nervous System Abnormalities

Heart rate elevations and variability HPA
Increased metabolic rate Axis
Increased body temp
HPA axis activation
Increased NE
Systemic Inflammation IL-6
Genetic Factors
CLOCK gene polymorphisms
GABA-A receptor gene polymorphisms
Serotonin reuptake transporter (SERT) gene polymorphisms
Human leukocyte antigen (HLA) gene polymorphisms
Epigenetic modifications affecting genes involved
in the response to stress
419
Insomnia and Psychiatric Illness
3-5 years 2x more likely to develop anxiety
JUNE
Insomnia
4x more likely to develop depression
7x more likely to develop

substance use disorders
Figure 10-29 Insomnia and psychiatric illness. Individuals with insomnia are at increased risk of developing anxiety, depression, and
substance use disorders. Whether this reflects insomnia as a risk factor or as a prodromal symptom is unknown.
of insomnia (approximately 70% of individuals with with insomnia often complain of poor sleep quality
depression) show worse treatment response, increased or duration, difficulty falling asleep, nighttime
depressive episodes, and a worse overall long-term awakenings, or wake times that are earlier than
outcome. desired (Figure 10-31). Many patients also report poor
Insomnia has traditionally been categorized as restoration from their sleep and thus daytime fatigue,
either “secondary” (i.e., a symptom of a psychiatric cognitive impairments, and mood disturbances.
or medical illness) or “primary” (i.e., neither Polysomnography is not generally indicated for the
associated with a psychiatric or medical illness nor diagnosis of insomnia but may be useful for ruling out
a result of substance abuse or withdrawal) (Figure narcolepsy, restless legs syndrome (RLS), or obstructive
10-30). However, it is now more fully understood sleep apnea (OSA). Although subjective measures of sleep
that insomnia is often a comorbidity rather than duration often do not correlate with objective measures,
a symptom of psychiatric and medical illnesses. subjective assessments of sleep are nevertheless
The most recent revised DSM-5 diagnostic criteria important since complaints of short sleep duration are
for insomnia seek to do away with the concepts strongly associated with persistent insomnia and can be
of secondary and primary insomnia and instead quite difficult to treat (Figure 10-31). Thus, insomnia
recognize the intricate two-way, perpetuating can be treated both as a subjective symptom and as an
relationship between insomnia and psychiatric objective disorder of arousal for best outcomes as well as
and medical conditions (Figure 10-30). Patients patient satisfaction.
420
TREATING INSOMNIA: DRUGS

DSM-5 Diagnostic WITH HYPNOTIC ACTIONS
Criteria for Insomnia Agents that treat insomnia come in two categories. The
first are drugs that reduce brain activation by enhancing
Old Diagnostic Criteria: “Secondary Insomnia”
sleep drive via activation of GABA in the hypothalamic
sleep center (VLPO illustrated in Figure 10-17). All
drugs in this category are positive allosteric modulators
(PAMs) of GABAA receptors (GABAA PAMs), i.e., the
benzodiazepines and the “Z drugs”.
psychiatric illness insomnia If insomnia is too much arousal drive rather than not
enough sleep drive, one wonders if enhancing the sleep
New Diagnostic Criteria: Insomnia as a Comorbidity drive with the popular benzodiazepine and Z drugs is the
best way to go for the treatment of insomnia. Thus, one
can also treat insomnia by reducing arousal; drugs that
do this form the second category of agents for insomnia.
Arousal can be reduced by many mechanisms with
psychiatric illness drugs from this category: namely, by blocking orexins
(with dual orexin receptor antagonists or DORAs), by
blocking histamine (with H1 antagonists), by blocking
serotonin (with 5HT2A antagonists), and by blocking
norepinephrine (with α1 antagonists). No matter what
strategy is taken to treat insomnia, the idea is to shift
insomnia
one’s abnormal and unwanted arousal state at bedtime
Figure 10-30 DSM-5 criteria for insomnia. Insomnia has from hyperactive to asleep (Figure 10-32).
previously been conceptualized as primary (not related to
another condition) or secondary (a symptom of another Benzodiazepines (GABAA Positive Allosteric
condition). However, insomnia may more often be comorbid
Modulators)
with rather than a symptom of another disorder, a concept that
is recognized in the DSM-5. There are at least five benzodiazepines approved
specifically for insomnia in the US (Figure 10-33),
although there are several others approved in different
Diagnosing Insomnia countries. Various benzodiazepines approved for the
treatment of anxiety disorders are also frequently used to
treat insomnia. Use of benzodiazepines for the treatment
of anxiety is discussed in Chapter 8 on anxiety disorders.
The mechanism of action of benzodiazepines at GABAA 10
receptors as positive allosteric modulators (PAMs) is
discussed in Chapter 6 and illustrated in Figures 6-17
insomnia through 6-23. These drugs presumably act to treat
insomnia by facilitating GABA neurotransmission in
Suggested criteria for defining insomnia: inhibitory sleep circuits arising from the hypothalamic
Average sleep latency > 30 min
Wakefulness after sleep onset (WASO) > 30 min
VLPO (Figure 10-17).
Sleep efficiency < 85% Benzodiazepines bind to only some GABAA receptors.
Total sleep time < 6.5 hours GABAA receptors are classified by the specific isoform
subunits that they contain, by their sensitivity or
Figure 10-31 Suggested criteria for identifying insomnia. Most insensitivity to benzodiazepines, by whether they mediate
often, insomnia is diagnosed using subjective measures. This tonic or phasic inhibitory neurotransmission, and by
may reflect difficulty falling asleep (sleep latency), wakefulness
after sleep onset, poor quality of sleep, and overall reduced
whether they are synaptic or extrasynaptic (see Chapter 6
duration of sleep. and Figures 6-17 through 6-23). Benzodiazepines,
421
Figure 10-32 Promoting sleep. To

Promoting Sleep treat insomnia, one can administer
medications that enhance the
sleep drive, such as the GABAergic
To Promote Sleep benzodiazepines or Z drugs.
Alternatively, one can administer
Enhance
medications that reduce arousal
GABA by inhibiting neurotransmission
involved in wakefulness; notably,
Inhibit
with antagonists at orexin, histamine,
hypocretin/orexin serotonin, or norepinephrine receptors.
acetylcholine
dopamine insomnia
norepinephrine
serotonin
histamine
asleep
as well as the related Z drugs discussed below, target particularly for severe and treatment-resistant insomnia
those GABAA receptors that contain a γ subunit, are associated with various psychiatric and medical illnesses.
localized in postsynaptic areas, and mediate phasic
inhibitory neurotransmission. For a GABAA receptor Z Drugs (GABAA Positive Allosteric Modulators)
to be sensitive to benzodiazepines or to a Z drug, there Another group of GABAA positive allosteric modulating
must be two β units plus a γ unit of either the γ2 or γ3 drugs, sometimes called “Z drugs” (because they all
subtype, plus two α units of either the α1, α2, or α3 subtype start with the letter Z: zaleplon, zolpidem, zopiclone),
(see Chapter 6 and Figure 6-20C). Benzodiazepines are also prescribed for their hypnotic effects (Figure 10-
and Z drugs bind to a molecular site on the GABAA 34). There is debate as to whether Z drugs bind to an
receptor that is different from where GABA itself binds allosteric site different from that of benzodiazepines,
(thus allosteric or “other site”). Currently available or whether they bind to the same site but perhaps in
benzodiazepines are nonselective for GABAA receptors a different molecular manner that might produce less
with different α subunits (Figure 10-33). As discussed in tolerance and dependence. Whether or not Z-drug
Chapter 6, GABAA receptors containing a δ subunit are binding differs from benzodiazepine binding at the
extrasynaptic, mediate tonic neurotransmission, and are allosteric site of so-called benzodiazepine-sensitive
insensitive to benzodiazepines and Z drugs. GABAA receptors, some Z drugs do bind selectively to α1
Because benzodiazepines can cause long-term subunits of benzodiazepine-sensitive GABAA receptors
problems such as loss of efficacy over time (tolerance) (e.g., zaleplon and zolpidem) (Figure 10-34). By contrast,
and withdrawal effects, including rebound insomnia in benzodiazepines (and zopiclone/eszopiclone) bind to
some patients that is worse than their original insomnia, four α subunits (α1, α2, α3, and α5) (Figures 10-33 and
they are generally considered second-line agents for use 10-34). The functional significance of α1 selectivity is not
as hypnotic drugs. However, when first-line hypnotic yet proven, but may contribute to lower risk of tolerance
agents (either Z drugs or blockers of various other and dependence. The α1 subtype is known to be critical
neurotransmitter receptors) fail to work, benzodiazepines for producing sedation and thus is targeted by every
still have a place in the treatment of insomnia, effective GABAA PAM hypnotic, both benzodiazepines
422
Benzo Hypnotics patients who have middle insomnia. For zopiclone, there
is a racemic mixture of both R- and S-zopiclone, available
outside the US, and the single S enantiomer, eszopiclone,
2-6 2-5
days days available in the US (Figure 10-34). Clinically meaningful
differences between the active enantiomer and the
α5 α5
α1 α1 racemic mixture are debated.
α2 α3 α2 α3
Dual Orexin Receptor Antagonists (DORAs)
flurazepam (Dalmane) quazepam (Doral)
Orexins/hypocretins, their receptors, and their pathways
have been discussed above and are illustrated in Figures
1-2 10-9 through 10-12. Pharmacological blockade of orexin
hours
receptors has hypnotic actions but not by enhancing
α5 inhibitory GABA action in the sleep-promoting center
α1
(VLPO) as do the benzodiazepines and Z drugs (Figure
α2 α3
10-17). Instead, dual orexin receptor antagonists
triazolam (Halcion) (DORAs) (at both orexin 1 and 2 receptors) block the
wake-stabilizing effects of the orexins, especially at orexin
2 receptors (Figures 10-35, 10-36). DORAs inhibit the
12-30 4-20
hours hours ability of naturally occurring orexins from promoting
the release of other wake-promoting neurotransmitters
α5 α5
α1 α1 such as histamine, acetylcholine, norepinephrine,
α2 α3 α2 α3 dopamine, and serotonin (as shown in Figure 10-37).
estazolam (ProSom) temazepam (Restoril) After administration of a DORA, arousal is no longer
enhanced and wakefulness is no longer stabilized by
Figure 10-33 Benzodiazepine hypnotics. Five benzodiazepines orexins, and the patient goes to sleep. Both suvorexant
that are approved in the United States for insomnia are shown
here. These include flurazepam and quazepam, which have and lemborexant (Figure 10-35) improve not only the
ultra-long half-lives; triazolam, which has an ultra-short half-life; initiation but also the maintenance of sleep and do so
and estazolam and temazepam, which have moderate half-lives.
These benzodiazepines are nonselective for GABAA receptors without the side effects expected of a benzodiazepine
with different α subunits. or Z-drug hypnotic, namely lacking dependence,
withdrawal, rebound, unsteady gait, falls, confusion,
amnesia, or respiratory depression.
and Z drugs. The α1 subtype is also linked to daytime Both suvorexant and lemborexant (Figure 10-35) are
sedation, anticonvulsant actions, and possibly to amnesia. reversible inhibitors, which means that as endogenous
Adaptations of this receptor with chronic hypnotic orexins build up in the morning, the inhibitory action
treatments that target it are thought to lead to tolerance of the DORAs are reversed. Thus, at night, DORAs have
and withdrawal. The α2 receptor and α3 receptor subtypes more effect since there is a higher ratio of drug to orexin. 10
are linked to anti-anxiety, muscle relaxant, and alcohol- As daylight begins, orexin levels rise just as DORA levels
potentiating actions. Finally, the α5 subtype, mostly in are falling, and there is less drug relative to the amount
the hippocampus, may be linked to cognition and other of orexin present, (i.e., lower ratio of drug to orexin).
functions. When a threshold of blockade of orexin receptors is
Multiple versions for two of the Z drugs, zolpidem no longer present, the patient awakens. Suvorexant
and zopiclone, are available for clinical use. For zolpidem, has comparable affinity for orexin 1 and orexin 2
a controlled-release formulation known as zolpidem receptors, and lemborexant has higher affinity for orexin
CR (Figure 10-34) extends the duration of action of 2 receptors than orexin 1 receptors (Figure 10-35).
zolpidem immediate release from about 2–4 hours to Lemborexant reportedly exhibits much faster association
a more optimized duration of 6–8 hours, improving and dissociation kinetics at orexin 2 receptors than
sleep maintenance. An alternative dosage formulation of suvorexant. The clinical significance of this is uncertain
zolpidem for sublingual administration with faster onset but may imply a faster reversibility of lemborexant
and given at a fraction of the usual nighttime dose is than suvorexant in the morning as endogenous orexin
also available for middle-of-the-night administration for levels rise to compete for binding at orexin receptors.
423
Figure 10-34 Z drugs: GABAA positive

GABA A PAMs - “Z Drugs” allosteric modulators (PAMs). Several
Z drugs are shown here. These include
racemic zopiclone (not available
in the United States), eszopiclone,
zaleplon, zolpidem, and zolpidem CR.
Zaleplon, zolpidem, and zolpidem
CR are selective for GABAA receptors
that contain the α1 subunit; however,
12 12 12 it does not appear that zopiclone or
9 3 9 3 9 3 eszopiclone have this same selectivity.
6 6 6
α5 α5 α1 α5
α1 α1
α2 α3 α2 α3 α2 α3
R,S-zopiclone eszopiclone
(Stilnox - not in US) (Lunesta)
12 12 12
9 3 9 3 9 3
6 6 6
α1 α1 α1
zaleplon zolpidem zolpidem CR

(Sonata) (Ambien) (Ambien CR)
Figure 10-35 Orexin receptor antagonists. The

OX1 OX1 dual orexin receptor antagonists suvorexant and
R R
lemborexant are shown here. Suvorexant has
comparable affinity for orexin 1 (OX1R) and orexin
2 (OX2R) receptors, while lemborexant has higher
affinity for OX2R than for OX1R.
suvorexant lemborexant
OX2R OX2R
Other DORAs (such as daridorexant) and also selective insomnia (see Chapter 7 for discussion of trazodone’s use
orexin 2 and selective orexin 1 antagonists are currently in depression and Figures 7-45 through 7-47). Trazodone,
in development as well. Competition of endogenous like the DORAs, is another agent that works to reduce
neurotransmitter with drug for the same receptor is arousal in insomnia rather than by enhancing sleep drive.
a concept also discussed in Chapter 7 regarding D3 Trazodone’s hypnotic mechanism is via blockade of the
antagonists/partial agonists and dopamine itself at the D3 arousal neurotransmitters serotonin, norepinephrine,
receptor (see Figure 7-72). and histamine (Figure 7-46). Blockade of α1-adrenergic
and H1 histaminergic pathways is discussed as a side
Serotonergic Hypnotics effect of some drugs for psychosis in Chapter 5 and
One of the most popular hypnotics is the 5HT2A/ α1/H1 illustrated in Figures 5-13 and 5-14. Indeed, one does
antagonist trazodone (Figure 7-46), even though this not want blockade of all these arousal neurotransmitters
agent is not specifically approved for the treatment of in the daytime. However, when α1 blockade is combined
424
from hypothalamus sleep, which can correlate with restorative sleep and even
(LH/PH)
improvement in daytime pain and fatigue.
Trazodone was initially studied for depression at high
doses that also block serotonin reuptake (Figure 7-45),
and given in a short-acting immediate-release
formulation two or three times a day. Although effective
B as an antidepressant, it also caused daytime sedation. It
was serendipitously discovered that lowering the dose
of immediate-release trazodone and giving it at night
made for a very effective hypnotic, which wore off before
A
B morning, and thus a new hypnotic agent was born and
A B has continued to be the most commonly prescribed
agent for sleep in the world. In order for trazodone to
have optimum antidepressant actions, the dose has to be
increased, and for it to be tolerated, it has to be given in a
once-daily controlled-release formulation that generates
DORA DORA blood levels above those needed for antidepressant action
yet below those needed for sedative hypnotic action
(Figure 7-47). Trazodone has not been associated with
GIRK
tolerance, withdrawal, dependence, or rebound.
G G
OX1R OX2R
Histamine 1 Antagonists as Hypnotics

It is widely appreciated that antihistamines are sedating.
Ca++
Antihistamines are popular as over-the-counter sleep aids
NMDA
(especially those containing diphenhydramine/Benadryl
or doxylamine) (Figure 10-38). Because antihistamines
have been widely used for many years not only as
hypnotic agents but also for the treatment of allergies,
there is the common misperception that the properties
of classic agents such as diphenhydramine apply to any
drug with antihistaminic properties. This includes the
idea that all antihistamines have “anticholinergic” side
effects such as blurred vision, constipation, memory
problems, dry mouth; that they cause next-day hangover
asleep
effects when used as hypnotics at night; that tolerance
Figure 10-36 Blockade of orexin receptors. Orexin develops to their hypnotic actions; and that they cause 10
neurotransmission is mediated by two types of postsynaptic
G-protein-coupled receptors, orexin 1 (OX1R) and orexin 2 weight gain. It now seems that some of these ideas about
(OX2R). OX1R are particularly expressed in the noradrenergic antihistamines are due to the fact that most agents with
locus coeruleus whereas OX2R are highly expressed in the
histaminergic tuberomammillary nucleus (TMN). Blockade of potent antihistamine properties have anticholinergic
orexin receptors by dual orexin receptor antagonists (DORAs) actions as well (Figures 10-38 and 10-39). This applies
prevents the excitatory effects of orexin neurotransmitters. In
particular, blockade of OX2R leads to decreased expression
not only to antihistamines used for allergy, but also to
of NMDA (N-methyl-D-aspartate) glutamate receptors and drugs approved for use in psychosis (e.g., chlorpromazine
prevents inactivation of G-protein-regulated inward rectifying
potassium channels (GIRK). LH/PH: lateral hypothalamus/
Figure 5-27 and quetiapine Figure 5-45) and depression
posterior hypothalamus. (such as doxepin Figure 10-39 and other tricyclic
antidepressants Figure 7-67) but also used at low doses as
with H1 blockade (described below and illustrated in hypnotic agents.
Figures 10-38 through 10-40), and these actions are The tricyclic antidepressant doxepin is an interesting
further combined with 5HT2A antagonism, a powerful case because of its very high affinity for the H1 receptor.
hypnotic effect results. 5HT2A antagonism (Figures 7-45 At low to very low doses, far lower than needed for the
and 7-46) specifically enhances slow-wave sleep/deep treatment of depression, it is a relatively selective H1
425
Hypothetical Actions Figure 10-37 Hypothetical actions

of dual orexin receptor antagonists
of DORAs (DORAs). By blocking orexin receptors,
and particularly orexin 2 receptors,
DORAs prevent orexin from promoting
Wakefulness the release of other wake-promoting
= DORA neurotransmitters.
norepinephrine serotonin
raphe histamine
LC TMN
basal
PFC
forebrain
glutamate
acetylcholine
PPT/LDT LH/PH thalamus
What Is Diphenhydramine’s (Benadryl’s) H1 antagonists have only been anecdotally associated

Mechanism as a Hypnotic? with tolerance, but not with withdrawal, dependence, or
rebound.
M1 Anticonvulsants as Hypnotics
H
1
Anticonvulsants are not approved for the treatment of
insomnia but some are prescribed off-label in order to
diphenhydramine promote sleep, especially gabapentin and pregabalin. The
mechanism of action of these agents as open-channel,
N and P/Q voltage-gated ion-channel inhibitors, also
called α2δ ligands, is explained in Chapter 9 on pain and
Figure 10-38 Diphenhydramine. Diphenhydramine is a illustrated in Figures 9-15 through 9-18. These α2δ ligands
histamine 1 (H1) receptor antagonist commonly used as a are approved not only for pain and epilepsy, but in some
hypnotic. However, this agent is not selective for H1 receptors
and thus can also have additional effects. Specifically, countries for anxiety, and their anxiolytic actions are
diphenhydramine is also a muscarinic 1 (M1) receptor antagonist explained in Chapter 8 on anxiety and illustrated in Figures
and thus can have anticholinergic effects (blurred vision,
constipation, memory problems, dry mouth). 8-17 and 8-18. Although not particularly sedating, the α2δ
ligands pregabalin and gabapentin can enhance slow-wave
antagonist (Figure 10-39), without either unwanted sleep, restorative sleep, and assist in the improvement of
anticholinergic properties, or the serotonin and pain.
norepinephrine reuptake blocking properties that make
it a drug for depression at high doses (Figure 10-39). In Hypnotic Actions and Pharmacokinetics: Your Sleep Is
fact, doxepin is so selective at low doses that it is even at the Mercy of Your Drug Levels!
being used in trace doses as a PET ligand to label central So far in this chapter, we have discussed the
nervous system H1 receptors selectively. At clinical doses pharmacodynamic properties of drugs to treat insomnia;
much smaller than those necessary for its antidepressant that is, their pharmacological mechanism of action. Many
actions, doxepin occupies a substantial number of central areas of psychopharmacology involve drugs classified
nervous system H1 receptors (Figures 10-39 and 10-40) by their immediate molecular actions, but that have
and has proven hypnotic actions. Blocking one of the important delayed molecular events that are more clearly
most important arousal neurotransmitters histamine and linked to their therapeutic effects, which are also often
its actions at H1 receptors is clearly an effective way to delayed. This is not so for drugs with hypnotic actions. For
induce sleep. sleep-inducing agents, their immediate pharmacological
426
Figure 10-39 Doxepin. Doxepin
What Is the Mechanism of Doxepin as a Hypnotic? is a tricyclic antidepressant (TCA)
that, at antidepressant doses (150–
300 mg/day), inhibits serotonin
and norepinephrine reuptake
and is an antagonist at histamine
1 (H1), muscarinic 1 (M1), and α1-
H1 adrenergic receptors. At low doses
(1–6 mg/day), however, doxepin is
α1 Na+ quite selective for H1 receptors and
thus may be used as a hypnotic.
doxepin SERT
NET
M1
antidepressant dose (150-300 mg) hypnotic dose (1-6 mg)
Figure 10-40 Histamine 1

antagonism. (A) When histamine
(HA) binds to postsynaptic
histamine 1 (H1) receptors, it
activates a G-protein-linked
second-messenger system that
activates phosphatidyl inositol
(PI) and the transcription factor
cFOS. This results in wakefulness
and normal alertness. (B) H1
antagonists prevent activation of
this second messenger and thus
can cause sleepiness.
HA H1 HA
antagonist
H1 H1
GE GE
cFOS cFOS
PI PI
A B 10
asleep
awake
pro-cognitive
alert
action causes their immediate therapeutic actions. In 10-41A). For antagonists of serotonin and histamine,
fact, your sleep induction is theoretically at the “mercy” the threshold is not as well investigated but is likely to be
of your drug being above a critical threshold of receptor around 80% for a single receptor blocked, or less if more
occupancy! For GABAA drugs, that threshold based on than one receptor is simultaneously blocked. Whatever
preclinical studies is around 25–30% receptor occupancy the exact thresholds, the concept is clear: as soon as a
(Figure 10-41A). For DORAs, it is around 65% (Figure hypnotic drug rises above its sleep-inducing threshold,
427
you go to sleep, and as soon as the drug falls below this concept of too long a half-life, but more importantly too
threshold, you awaken. In practice, these effects may not long above the threshold, is shown: “too hot” and the
be immediate, and being near the threshold may mean result is next-day residual effects. Finally, the concept
sleepiness but not sleep. Nevertheless, this is an important of too short a half-life, but more importantly not long
concept because it is not so much the pharmacokinetic enough above the threshold, is shown (Figure 10-41D):
half-life that is important for a hypnotic drug (i.e., how “too cold” and the result is early morning awakenings
long until half the drug is gone), it is its duration of time before the desired time of rising. These same concepts of
above the sleep threshold. These concepts are illustrated a drug needing to pierce a threshold, and sustain its level
in Figure 10-41A–D; the ideal profile for a hypnotic is above that threshold to be effective, apply to another area
shown in Figure 10-41A: neither too short a time above of psychopharmacology: namely, the use of stimulants for
the threshold nor too long a time, but “just right”: the the treatment of ADHD (attention deficit hyperactivity
Goldilocks solution. In Figure 10-41B and 10-41C, the disorder). This will be discussed in Chapter 11 on ADHD.
The Goldilocks Solution: Figure 10-41A, B Pharmacokinetics

of hypnotics, part 1. (A) For GABAA
The Ideal Hypnotic Agent
medications, the critical threshold
of receptor occupancy for onset of
hypnotic effects is 25–30%, for dual
5 orexin receptor antagonists (DORAs)
it is 65%, and for serotonin and
4
histamine antagonists it is thought to
sleep maintenance be 80%. Both the onset to achieving
drug the threshold, and the duration of
concentration 3 sleep time above the sleep threshold,
onset no hangover are important for efficacy. The ideal
hypnotic agent would have a duration
2
above the threshold of approximately
serotonin histamine antagonist
threshold (80%) 8 hours. (B) Hypnotics with ultra-long
1 half-lives (greater than 24 hours; for
DORA threshold (65%) example, flurazepam and quazepam)
can cause drug accumulation with
GABAA threshold (25%) chronic use. This can result in too long
0 24 48 72 96 120 144 a duration of time above the sleep
hours (taken nightly) threshold, and can cause impairment
duration above threshold: 8 hours
A examples: eszopiclone (Lunesta) that has been associated with increased
zolpidem CR (Ambien CR) risk of falls, particularly in the elderly.
low-dose trazodone (Desyrel)
low-dose doxepin antihistamines
survorexant (Belsomra)
lemborexant (Dayvigo)
Way Too Hot:

Ultralong Half-Life Hypnotics Can
Cause Drug Accumulation (Toxicity)
night day
toxicity
drug
concentration 3
2
relevant threshold
0 24 48 72 96 120 144
hours (taken nightly)
duration above threshold: 24-150 hours
examples: flurazepam (Dalmane)
B quazepam (Doral)
428
Still Too Hot: Figure 10-41C, D Pharmacokinetics

of hypnotics, part 2. (C) For hypnotics
Moderately Long Half-Life Hypnotics
with moderately long half-lives (15–30
Do Not Wear Off Until After hours), receptor occupancies above the
Time to Awaken (Hangover) sleep threshold may not wear off until
after the individual needs to awaken,
potentially leading to “hangover”
5 effects (sedation, memory problems).
(D) For hypnotics with ultra-short half-
lives (1–3 hours), receptor occupancies
4 above the sleep threshold may not
last long enough, causing loss of sleep
drug maintenance.
concentration 3
hangover, levels high after
time to awaken
2
relevant threshold
0 24 48 72 96 120 144
hours (taken nightly)
duration above threshold: 15-30 hours
examples: estazolam (ProSom)
C temazepam (Restoril)
most TCAs
mirtazapine (Remeron)
chlorpromazine (Thorazine)
Too Cold:
Short Half-Life Hypnotics Wear Off
Before Time to Awaken
(Loss of Sleep Maintenance)
drug
concentration 3
loss of sleep maintenance
low levels before time
2
to awaken
relevant threshold
10
0 24 48 72 96 120 144
hours (taken nightly) half-lives: 1-3 hours
examples: triazolam (Halcion)
zaleplon (Sonata)
zolpidem (Ambien)
D melatonin
ramelteon (Rozerem)
The reason these concepts are important to the the evening, or don’t take with food (food can delay the
prescriber is not so much the precision of the estimates absorption of some agents), or raise the dose, or change
of thresholds, as these may vary from patient to the mechanism. If the patient is not sleeping long enough
patient. Instead, these concepts inform the prescriber (Figure 10-41D), theoretically threshold levels are lost too
about what to do to get the Goldilocks solution for early, so either raise the dose or switch to a drug with a
individual patients. If the patient is not falling asleep longer duration of action above the threshold (generally,
quickly enough, theoretically the patient does not reach this would be drugs with a longer pharmacokinetic
threshold fast enough, so either give the drug earlier in half-life; see Figures 10-41A and 10-41C). If the patient
429
is groggy in the morning, theoretically drug levels are respond optimally to one of these agents, the other might
continuing near or above threshold levels when it is time be better. Neither agent is associated with tolerance,
to arise, so lower the dose, give the drug earlier in the withdrawal, dependence, or rebound.
evening, or switch to an agent with a shorter duration
of action (generally, this would be drugs with a shorter Behavioral Treatments of Insomnia
pharmacokinetic half-life; see Figures 10-41A and Good sleep hygiene (Figure 10-42) may allow a patient
10-41D). with insomnia to avoid medication treatment altogether.
One last word on how all this applies to the DORAs. Other treatments for insomnia that avoid medication
Recall that inhibition of the GABAA receptor, serotonin use include relaxation training, stimulus control therapy,
receptor, noradrenergic receptor, and histamine receptor sleep restriction therapy, intensive sleep retraining,
are not effectively competitive. There is no known and cognitive behavioral therapy (Figure 10-43). These
endogenous ligand linked to the sleep/wake cycle that various interventions have been shown to have beneficial
acts at the GABA PAM site that could compete cyclically effects on several sleep parameters, including sleep
with Z-drug hypnotics and benzodiazepines. Endogenous efficiency and sleep quality, and can be very effective,
levels of the neurotransmitters serotonin, norepinephrine, and thus should often be considered before the use of
and histamine are not likely to be in the range to reverse hypnotic agents. In addition, behavioral approaches can
antagonist binding by hypnotic drugs. However, the be useful adjunctive treatments with hypnotic agents for
affinity of orexin A for orexin 1 and 2 receptors is in patients who do not respond adequately to drugs alone.
the same range as the affinity of the DORAs suvorexant
and lemborexant for these very same receptors. What EXCESSIVE DAYTIME
this means is that during the middle of the night, when SLEEPINESS
orexin levels are low, a given concentration of DORA will
have a greater blockade of orexin receptors than later What Is Sleepiness?
in the night and morning, when orexin levels rise and The most common cause of sleepiness (Figure 10-44) is
compete with DORAs for orexin receptors and reverse sleep deprivation and the treatment is sleep. However,
their blockade just as DORA levels are falling. How this there are also many other causes of sleepiness that require
applies in practice could depend upon whether orexin evaluation and specific treatment. These other causes of
levels are abnormally high in certain cases of insomnia excessive daytime sleepiness are hypersomnias including
or comorbid conditions, in which case a higher dose of narcolepsy (Figures 10-45 through 10-48), various
a DORA would be necessary. Also, a higher dose of a medical disorders including obstructive sleep apnea
DORA would possibly be what is needed if the patient (Figures 10-45 and 10-49), circadian rhythm disorders
experiences early morning awakenings. On the other (Figures 10-45 and 10-50 through 10-55), and others
hand, a lower dose of a DORA may be needed if the (Figure 10-45). Although society often devalues sleep and
patient experiences carryover effects the next morning, can often imply that only wimps complain of sleepiness,
something that has been noted sometimes in clinical it is clear that excessive daytime sleepiness is not benign,
practice. With the variables of both drug levels and and in fact can even be lethal. That is, loss of sleep causes
orexin levels determining net receptor blockade and performance decrements equivalent to that of legal
thus duration of time above the threshold for sleep, the levels of intoxication with alcohol, and not surprisingly
pharmacokinetic half-lives of DORAs are not particularly therefore, traffic accidents and fatalities. Thus, sleepiness
clinically relevant. There are no head-to-head studies is important to assess even though patients often do not
to definitively demonstrate potential advantages of complain about it when they have it. Comprehensive
lemborexant versus suvorexant. However, the binding assessment of patients with sleepiness requires that
characteristics (affinities for orexin 1 and 2 receptors, additional information is obtained from the patient’s
association/dissociation kinetics, plasma drug levels and partner, particularly the bed partner. Most conditions
thus orexin receptor blockade for the first 8 hours after can be evaluated by patient and partner interviews,
ingestion, and especially during the critical early morning but sometimes augmented with subjective ratings of
hours) are sufficiently different between lemborexant sleepiness such as the Epworth Sleepiness Scale, as well
and suvorexant to suggest that if a given patient does not as objective evaluations of sleepiness such as overnight
430
Sleep Hygiene Figure 10-42 Sleep hygiene.

Good sleep hygiene involves
using the bed exclusively for sleep
as opposed to activities such as
sleep time wake time reading or watching television;
avoiding stimulants such as
alcohol, caffeine, and nicotine as
well as strenuous exercise before
bed; limiting time spent awake
in bed (if not asleep within 20
minutes, one should get up and
return to bed when sleepy); not
watching the clock; adopting
regular sleep habits; and avoiding
no stimulants light at night.
before bed
activity
dark room
cool environment
bright light
no disturbances
Non-pharmacological Treatments polysomnograms, plus next-day multiple sleep-latency

for Insomnia testing and/or maintenance of wakefulness testing.
RELAXATION TRAINING
Aimed to reduce somatic tension and intrusive thoughts that Causes of Hypersomnia
interfere with sleep
Hypersomnia is present in as much as 6% of the
STIMULUS CONTROL THERAPY population. As many as 25% of individuals with
Get out of bed if not sleepy; use bed only for sleeping;
no napping
hypersomnia may have a mood disorder. In treating
various causes of hypersomnia, it is important to first
SLEEP RESTRICTION THERAPY eliminate and treat secondary causes of hypersomnia 10
Limit time spent in bed to produce mild sleep deprivation;
results in more consolidated sleep (Figure 10-45), such as obstructive sleep apnea (OSA)
(Figure 10-49), psychiatric illnesses, and medication side
INTENSIVE SLEEP RETRAINING
25-hour sleep deprivation period in which the patient is given effects. This can be accomplished by first conducting
50 sleep onset trials but awoken following 3 minutes of sleep a full clinical interview and collecting data from a
COGNITIVE BEHAVIORAL THERAPY sleep/wake diary. If necessary, this information can be
Reduce negative attitudes and misconceptions about sleep supplemented with 1–2 weeks’ worth of actigraphy, a
polysomnogram (sleep EEG), and administering the
Figure 10-43 Non-pharmacological treatments for Multiple Sleep Latency Test (MSLT). One of the most
insomnia. Non-pharmacological treatment options for patients common secondary causes of hypersomnia is OSA
with insomnia include relaxation training, stimulus control
therapy, sleep restriction therapy, intensive sleep retraining, and (Figure 10-49). Approximately one out of 15 adults suffer
cognitive behavioral therapy. with moderate OSA, and as many as 75% of individuals
with insomnia have a sleep-related breathing disorder.
431
Excessive Daytime Sleepiness: Figure 10-44 Excessive daytime

sleepiness: deficient daytime arousal?
Deficient Daytime Arousal? Excessive daytime sleepiness is
conceptualized as being related to
hypoarousal during the day and is a
symptom not only of sleep deprivation
but also of narcolepsy, obstructive
sleep apnea, and circadian rhythm
disorders.
awake
alert
excessive daytime creative
sleepiness problem solving
Hypersomnia So, OSA can cause insomnia at night and hypersomnia in

the day. Having OSA can nearly double general medical
Central Disorders of Hypersomnolence expenses, mainly due to the association of OSA with
cardiovascular disease. Features of OSA include episodes
- Idiopathic hypersomnia of complete (apnea) or partial (hypopnea) upper airway
- Recurrent hypersomnia
- Narcolepsy with cataplexy
obstruction that result in decreased blood oxygen
- Narcolepsy without cataplexy saturation; these episodes are terminated by arousal.
There are also several disorders of hypersomnia
that are thought to arise as a primary consequence
Other Causes of Hypersomnia of neuropathology in the sleep/wake circuitry of the
brain (Figures 10-45 through 10-47). Such disorders
- Medical conditions are known as “central disorders of hypersomnolence”
and include idiopathic hypersomnia (Figure 10-46),
recurrent hypersomnia, and narcolepsy (Figure 10-
- Medication side effects
47). With the exception of narcolepsy with cataplexy
due to a profound loss of orexin/hypocretin neurons
- Substance abuse
in the lateral hypothalamus (Figure 10-48), the
underlying neuropathology of the central disorders of
hypersomnolence is largely unknown.
- Psychiatric conditions depression Idiopathic hypersomnia (Figure 10-46) is
characterized by either long or normal sleep duration
accompanied by constant excessive daytime sleepiness,
Figure 10-45 Conditions associated with hypersomnia. Central
disorders of hypersomnia include idiopathic hypersomnia, short sleep-onset latency, and complaints of non-
recurrent hypersomnia, and narcolepsy with or without refreshing sleep. Patients with idiopathic hypersomnia
cataplexy. Other causes of hypersomnia can include medical
conditions, medication side effects, substance abuse, and may also report sleep drunkenness and somnolence
psychiatric conditions. following sleep, as well as memory and attention deficits,
432
Idiopathic Hypersomnia Figure 10-46 Idiopathic hypersomnia.

Idiopathic hypersomnia is a central
disorder of hypersomnolence – that is,
it is thought to arise as a consequence
*YAWN* of neuropathology in the sleep/wake
circuitry of the brain. It is characterized
by either long or normal sleep duration
accompanied by excessive daytime
sleepiness and complaints of non-
refreshing sleep.
Excessive daytime sleepiness
Idiopathic hypersomnia
Long (>10 hr) or

normal sleep duration
Non-refreshing sleep
Figure 10-47 Narcolepsy.
Narcolepsy Narcolepsy is a central disorder
of hypersomnolence – that is, it is
*YAWN* thought to arise as a consequence
of neuropathology in the sleep/
wake circuitry of the brain. It
is characterized by excessive
daytime sleepiness, intrusion of
sleep during wake times, and
abnormal rapid eye movement
(REM), including sleep-onset REM
periods. Narcolepsy can occur
with or without cataplexy (loss of
muscle tone triggered by emotion). 10
Excessive daytime sleepiness With or without cataplexy
Narcolepsy
Z
ZZ
Abnormal REM manifestations

Intrusion of sleep during wake times
433
Figure 10-48 Neurobiology of

Neurobiology of Narcolepsy with Cataplexy narcolepsy with cataplexy. In
addition to its role in wakefulness
and motivated behaviors, orexin is
also involved in stabilizing motor
movements, allowing normal
movement in the day (when orexin
levels are high) and facilitating
inhibition of motor movements
at night (when orexin levels are
low). When orexin levels are low
due to the degeneration of orexin
neurons, this allows intrusion
of motor inhibition and loss of
muscle tone during wakefulness, a
condition known as cataplexy.
thalamus
basal
forebrain
LH
VLPO
PPT/
LDT
TMN VTA
LC
RN
Obstructive Sleep Apnea
ZZ
Z
Clinical Features Pathophysiology

• Loud snoring • Partial/full collapse of upper airway
• Obesity • Narrowing may occur at different levels
• Hypertension • Muscle tone, airway reflexes
• Neck >17" • Metabolic abnormalities in frontal
• Enlarged tonsils lobe white matter and hippocampus Figure 10-49 Obstructive sleep apnea. Obstructive
• Loss of interest sleep apnea is a common cause of hypersomnia. It
• Excessive daytime sleepiness is characterized by episodes of complete (apnea)
• Fatigue or partial (hypopnea) upper airway obstruction that
• Depression results in decreased blood oxygen saturation.
434
digestive system problems, depression, and anxiety. The Circadian Rhythm Disorders
diagnosis of idiopathic hypersomnia includes excessive Circadian rhythm disorders (Figure 10-50) arise when
daytime sleepiness lasting at least 3 months; short sleep there is dyssynchrony between your internal circadian
latency, and fewer than two periods of REM occurring at clock and external cues that signal “daytime” and
the onset of sleep (SOREMPs; sleep onset REM periods) “nighttime.” This dyssynchrony leads to difficulty
on polysomnographic investigation. Cerebrospinal fluid maintaining a sleep/wake cycle within the typical 24-hour
(CSF) levels of histamine may be low; however, CSF period. There are several circadian rhythm disorders,
orexin levels are not typically affected. including shift work disorder (Figure 10-51), advanced
Narcolepsy (Figure 10-47) is characterized by sleep phase disorder (Figure 10-52), delayed sleep phase
excessive daytime sleepiness, the intrusion of sleep disorder (Figure 10-53), and non-24-hour sleep–wake
during periods of wakefulness, and abnormal REM disorder (Figure 10-54).
sleep, including SOREMPs. Cataplexy, or loss of muscle Shift work is defined as work occurring between
tone triggered by emotions, may also be present (Figure 6 pm and 7 am (outside the standard daytime working
10-48). Hypnagogic hallucinations, which are present hours). Shift workers include those who work night
upon waking, are also often present. As mentioned, a shifts, evening shifts, or rotating shifts, and they make
clear neuropathological substrate has been identified up approximately 15–25% of the workforce in the
for narcolepsy with cataplexy, namely profound loss of United States. Shift workers’ sleep/wake schedules
orexin neurons in the lateral hypothalamus. We have are often out of sync with their endogenous circadian
discussed extensively above how orexin neurons are rhythms, and many (but not all) individuals who work
involved in stabilizing wakefulness through stimulating non-standard or rotating schedules develop shift work
release of wake-promoting neurotransmitters (serotonin, disorder (SWD). In fact, it is estimated that as many
norepinephrine, dopamine, acetylcholine, and as 10–32% of shift workers develop SWD and as many
histamine). Thus, it is not surprising that when orexin as 9.1% of shift workers develop a severe form of the
neurons are lost in narcolepsy, wakefulness is no longer disorder. Younger age and a natural biological clock
stabilized and patients have intrusion of sleep during aligned more to “eveningness” may provide some
periods of wakefulness. protection from the development of SWD. However, for
Orexin also stabilizes motor movements, allowing those who do develop SWD, there may be physical and
normal movement in the day when orexin levels are high psychiatric consequences that extend far beyond sleep/
and facilitating inhibition of motor movements at night, wake disturbances, such as excessive sleepiness during
especially during REM sleep, when orexin levels are low. the work shift and insomnia during periods of sleep.
When orexin levels are low in the daytime due to loss of Individuals with SWD have a dramatically increased
orexin neurons (Figure 10-48), this destabilizes motor risk of cardiometabolic issues, cancer, gastrointestinal
movements during the daytime, allowing intrusions diseases, and mood disorders.
of motor inhibition and loss of muscle tone, known as Advanced sleep phase disorder (ASPD) (Figure 10-
cataplexy, during periods of wakefulness. 52) patients go to bed earlier and awaken earlier than
For those suspected of having narcolepsy or narcolepsy desired, often by 6 hours outside of the typical sleep/ 10
with cataplexy, a CSF orexin level of <110 pg/mL is wake cycle even though they have adequate total sleep
diagnostic for narcolepsy; however, orexin levels are time and quality of sleep. Polymorphisms in the PER2
often within the normal range in narcolepsy, especially gene (an essential component of the molecular clock)
without cataplexy, as well as in idiopathic and recurrent have been associated with ASPD; in fact, there is an
hypersomnia. Even in the absence of low orexin levels, autosomal-dominant form of the disorder called familial
patients with narcolepsy with or without cataplexy advanced sleep phase syndrome (FASPS) in which a PER2
demonstrate ≥2 SOREMPs on the MSLT or 1 SOREMP on mutation is present. In addition to ruling out other sleep/
polysomnographic investigation as well as a short sleep wake disorders, such as insomnia, diagnosing ASPD may
latency (≤8 minutes) on the MSLT; thus, these measures include the use of a sleep diary and/or actigraphy for at
are also considered diagnostic for narcolepsy. Additionally, least a week and the administration of the Morningness–
the majority (90%) of patients with narcolepsy, Eveningness Questionnaire (MEQ). Normal elderly
particularly those with cataplexy, are positive for the HLA people often have a mild or moderate form of ASPD.
DQB1-0602 polymorphism compared to only 20% of the In delayed sleep phase disorder (DSPD) (Figure
general population. 10-53), individuals are unable to fall asleep until early
435
Circadian Rhythm Disorders Figure 10-50 Circadian rhythm

disorders. Circadian rhythm disorders
occur when the internal circadian clock
is out of sync with external cues that
signal daytime and nighttime. Shift
work disorder, advanced sleep phase
Circadian Rhythm Disorders: disorder, delayed sleep phase disorder,
• Persistent or recurring patterns of sleep disturbance and non-24-hour sleep–wake disorder
primarily attributed to circadian disruption and are all circadian rhythm disorders.
circadian misalignment
• Circadian-related sleep disruption resulting in insomnia,

excessive daytime sleepiness, or both
• Sleep disturbance that is associated with impairment in

social, occupational, or other areas of function
Delayed Sleep Advanced Sleep

Phase Disorder
Phase Disorder
Shift Work Disorder

Non-24
Figure 10-51 Shift work disorder.

Shift Work Disorder Shift work is defined as work occurring
between the hours of 6pm and 7am.
Shift workers’ sleep/wake schedules are
often out of sync with their endogenous
circadian rhythms. Some shift workers
therefore develop shift work disorder,
Z in which insomnia or excessive
Z sleepiness is temporarily associated
Z
with their recurring work schedule that
overlaps with the usual time for sleep.
• Insomnia or excessive sleepiness temporarily associated with a recurring work

schedule that overlaps with the usual time for sleep
• Symptoms associated with shift work schedule are present for at least 1 month
• Sleep log or actigraphy monitoring (with sleep diaries) for at least 7 days demonstrates
disturbed sleep (insomnia) and circadian and sleep-time misalignment
• Sleep disturbance is not due to another current sleep disorder, medical disorder,
mental disorder, substance use disorder, or medication use
436
Figure 10-52 Advanced sleep

Advanced Sleep Phase Disorder phase disorder. Patients with
advanced sleep phase disorder
Typical Sleep/Wake Schedule Advanced Sleep Phase Disorder become sleepy and thus go to bed
earlier than desired and also wake
up earlier than desired. These
Bedtime 12am 12am individuals have adequate total
sleep time and quality of sleep.
9pm 3am 9pm 3am
Waketime
Waketime Bedtime
6pm 6am 6pm 6am
3pm 9am 3pm 9am

12pm 12pm
Figure 10-53 Delayed sleep

Delayed Sleep Phase Disorder phase disorder. Patients with
delayed sleep phase disorder are
Typical Sleep/Wake Schedule Delayed Sleep Phase Disorder unable to fall asleep until the early
morning hours and have difficulty
waking until late morning/early
afternoon. These individuals have
Bedtime 12am 12am adequate total sleep time and
quality of sleep; however, the
9pm 3am 9pm 3am shifted sleep schedule can often
interfere with activities of daily
Waketime Bedtime functioning.
6pm 6am 6pm 6am
3pm 9am 3pm 9am

Waketime
12pm 12pm
Figure 10-54 Non-24-hour
Non-24-Hour Sleep−Wake Disorder sleep–wake disorder. Individuals
who are visually impaired are
unable to entrain the internal
SCN circadian clock with light acting
on the suprachiasmatic nucleus
(SCN) via the retinohypothalamic
tract. This free-running internal
clock can cause non-24-hour 10
sleep–wake disorder, characterized
by irregular sleep/wake patterns
and potentially both insomnia and
excessive daytime sleepiness.
retinohypothalamic
tract
437
Figure 10-55 Resetting circadian

Resetting Circadian Rhythms rhythms. Circadian treatments, such as
bright light and melatonergic agents,
Offset Circadian Rhythm in Offset Circadian Rhythm in can be used to reset circadian rhythms
Advanced Sleep Disorder Delayed Sleep Disorder in both advanced and delayed sleep
phase disorders. For advanced sleep
phase disorder, early evening bright
12am 12am
light and early morning melatonin can
9pm 3am 9pm 3am be useful. For delayed sleep phase
Waketime disorder, morning bright light and
Bedtime
Bedtime Adjustment using evening melatonin can be useful.
6pm 6am pharmacological 6pm 6am
and/or non-
pharmacological
treatment
3pm 9am 3pm 9am
12pm Waketime 12pm
Desired Sleep/Wake Schedule
Bedtime 12am
9pm 3am
Waketime
6pm 6am
3pm 9am
12pm
morning hours and awaken in the late morning/early
afternoon. DSPD is the most common of the circadian
Bright Light Therapy rhythm disorders and has been associated with
polymorphisms in the CLOCK gene (another essential
element of the molecular clock). Similarly to advanced
sleep phase disorder (ASPD), sleep duration and quality
of sleep are normal; however, the shift in the sleep/wake
schedule interferes with daily functioning. Many normal
teens have a mild to moderate form of ASPD, as do many
patients with depression.
Non-24-hour sleep–wake disorder (Figure 10-54)
is a circadian rhythm disorder that primarily affects
individuals who are blind. Those who are visually
impaired lack the ability to entrain the internal circadian
clock with light acting on the suprachiasmatic nucleus via
the retinohypothalamic tract. This free-running internal
clock leads to irregular sleep/wake patterns that may
cause both insomnia and excessive daytime sleepiness.
Circadian Treatments
Circadian treatments can be helpful in resetting the offset
circadian rhythms of both advanced sleep phase disorder
Figure 10-56 Bright light therapy. Bright light therapy is and delayed sleep phase disorder (Figure 10-55). This
a circadian treatment. Morning bright light can be used for includes both bright light (Figure 10-56) and melatonergic
patients with delayed sleep phase disorders and may also be
beneficial for patients with shift work sleep disorder. Bright light agents (Figure 10-57). These same circadian treatments
therapy is also used as a treatment for depression. can be used adjunctively to drugs for depression in the
438
treatment of mood disorders or adjunctively to modafinil/ for depressed patients, those who have delayed phase sleep
armodafinil for shift work disorder. disorder, and many normal teenagers, but also for many
Morning light and evening melatonin can help experiencing jet lag from travel-induced shifts in circadian
depression, delayed sleep phase disorder, and shift work rhythms. In all cases, melatonin can facilitate sleep onset.
disorder. On the other hand, early evening light and Melatonin acts at three different sites, not only
early morning melatonin can help advanced sleep phase melatonin 1 (MT1) and melatonin 2 (MT2) receptors, but
disorder. Non-24-hour sleep–wake disorder benefits from also at a third site, sometimes called the melatonin 3 site,
synchronization of circadian rhythms by the powerful which is now known to be the enzyme NRH–quinone
melatonergic agent tasimelteon (Figure 10-57). These oxidoreductase 2, and which is probably not involved in
various circadian treatments can also be beneficial in sleep physiology (Figure 10-57). MT1-mediated inhibition
resetting the biological clock in normal elderly people of neurons in the suprachiasmatic nucleus (SCN) could
(morning melatonin and evening light) and normal teens help to promote sleep by decreasing the wake-promoting
(morning light and evening melatonin). Parents have actions of the circadian “clock” or “pacemaker” that
long recognized the benefits of letting in early morning functions there, perhaps by attenuating the SCN’s alerting
sunlight by opening the shades to get hibernating teens signals, allowing sleep signals to predominate, and thus
up and going in time for school. inducing sleep. Phase shifting and circadian rhythm
effects of the normal sleep/wake cycle are thought to
Melatonergic Hypnotics
be primarily mediated by MT2 receptors, which entrain
Melatonin is the neurotransmitter secreted by the pineal these signals in the SCN.
gland, and acts especially in the suprachiasmatic nucleus Ramelteon is a MT1/MT2 agonist marketed for
to regulate circadian rhythms (discussed in Chapter 6 insomnia, and tasimelteon, another MT1/MT2 agonist,
and illustrated in Figures 6-34 to 6-36). Melatonin shifts is marketed for non-24-hour sleep–wake disorder
circadian rhythms, especially in those with phase delay (Figure 10-57). These agents improve sleep onset,
when taken at the desired appropriate bedtime, not only sometimes better when used for several days in a row.
Figure 10-57 Melatonergic
Melatonergic Agents agents. Endogenous melatonin is
secreted by the pineal gland and
mainly acts in the suprachiasmatic
nucleus to regulate circadian
rhythms. There are three types
of receptors for melatonin: MT1
and MT2, which are both involved
in sleep, and MT3, which is
ramelteon actually the enzyme NRH–quinine
melatonin tasimelteon oxidoreductase 2 and not thought
to be involved in sleep physiology.
MT3 There are several different agents
that act at melatonin receptors.
Melatonin itself, available over
the counter, acts at MT1 and MT2
10
MT2 MT2 receptors as well as at the MT3 site.
MT1 MT1 Both ramelteon and tasimelteon
are MT1 and MT2 receptor agonists
and seem to provide sleep onset
though not necessarily sleep
maintenance. Agomelatine is
not only a MT1 and MT2 receptor
agonist, but is also a serotonin
5HT2B
5HT2C and 5HT2B receptor
antagonist and is available as an
agomelatine antidepressant outside the US.
5HT2C
MT1 MT2
439
They are not known to help sleep maintenance, but will Caffeine
induce natural sleep in those subjects who suffer mostly Caffeine is the world’s most widely consumed
from initial insomnia. The actions of tasimelteon at MT2 psychoactive drug. How does it work? The answer is that
receptors are thought to underlie its effectiveness at it is an antagonist of the neurotransmitter adenosine
retraining the circadian clock. (Figure 10-59). Adenosine was first mentioned in
this chapter as the chemical known to be linked to
WAKE-PROMOTING AGENTS the homeostatic sleep drive (illustrated in Figure 10-
AND TREATMENT OF EXCESSIVE 18). Since adenosine accumulates as you get tired, it
DAYTIME SLEEPINESS essentially is taking account of your homeostatic drive
and some say that adenosine acts as the “accountant” or
Why treat sleepiness? If the most common cause of
“bean counter” of fatigue, documenting and quantitating
sleepiness is sleep deprivation can’t we treat sleepiness
the homeostatic drive for sleep. Interestingly, one way
with sleep and not with drugs? The short answer is
to make a deposit into this homeostatic account to
unfortunately not. Here we will discuss the treatment
reduce this drive and diminish fatigue is with a coffee
of excessive daytime sleepiness with various wake-
bean! That is, caffeine, from coffee or other sources, is
promoting agents such as caffeine, stimulants, modafinil/
wake-promoting, reduces fatigue, and diminishes the
armodafinil, and others, as well as some newer agents,
homeostatic sleep drive. How does it do this? Caffeine is
including an NDRI (norepinephrine–dopamine reuptake
an antagonist of adenosine and thus can block some of
inhibitor) and an H3 antagonist. Non-pharmacological
the effects of adenosine buildup, both molecularly and
treatments are also presented.
behaviorally (Figure 10-59).
If disorders characterized by excessive daytime
Native dopamine 2 (D2) receptors bind dopamine
sleepiness can be conceptualized as deficient daytime
with high affinity (Figure 10-59A) but in the presence of
arousal (Figure 10-44), then wake-promoting treatments
adenosine, D2 receptors can couple (i.e., heterodimerize)
can be seen as agents that increase brain activation and
with adenosine receptors, reducing the affinity of the D2
arousal (Figure 10-58). There are a number of ways to do
receptor for dopamine (Figure 10-59B). However, caffeine
this, but most involve enhancing the release of wake-
blocks adenosine binding to the adenosine receptor and
promoting neurotransmitters, especially dopamine and
restores the affinity of the D2 receptor for dopamine even
histamine.
Promoting Wakefulness Figure 10-58 Promoting

wakefulness. To treat excessive
daytime sleepiness, one can administer
medications that promote arousal by
enhancing neurotransmission involved
To Promote Wakefulness
in wakefulness; most notably, by
awake
Inhibit enhancing dopamine and histamine
alert GABA neurotransmission.
creative
problem solving Enhance
hypocretin/orexin
acetylcholine
dopamine
norepinephrine
serotonin
histamine
excessive daytime
sleepiness
440
Figure 10-59 Caffeine. Caffeine is

Mechanism of Action of Caffeine: Adenosine and Endogenous an antagonist at purine receptors,
DA Actions at D2 Receptors Purines Reduce DA Binding and in particular adenosine receptors.
(A) These receptors are functionally
coupled with certain postsynaptic
dopamine (DA) receptors, such
as dopamine D2 receptors, at
which dopamine binds and has a
stimulatory effect. (B) When adenosine
binds to its receptors, this causes
reduced sensitivity of D2 receptors. (C)
Antagonism of adenosine receptors
by caffeine prevents adenosine from
binding there, and thus can enhance
dopaminergic actions.
adenosine
D2 purine
receptor receptor
+
A B
Caffeine Antagonizes Adenosine Binding

and Enhances DA Actions
caffeine
C
+
+ 10
in the presence of adenosine (Figure 10-59C). When norepinephrine–dopamine reuptake inhibitors and, in
caffeine does this, dopamine action is enhanced and this the case of the amphetamines, as dopamine releasers and
is wake-promoting and reduces fatigue (Figure 10-59C). competitive VMAT2 inhibitors as well. VMAT2 inhibition
was discussed in Chapter 5 and illustrated in Figures
Amphetamine and Methylphenidate 5-10A and 5-10B. Norepinephrine–dopamine reuptake
Wake promotion from enhancing the wake-promoting inhibition as an antidepressant mechanism was discussed
neurotransmitters dopamine and norepinephrine is in Chapter 7 and illustrated in Figures 7-34 through 7-36.
classically done with amphetamines and methylphenidate D-amphetamine, DL-amphetamine, and methylphenidate
(Figure 10-60). Because this is activating, wake- are all approved for use specifically as wake-promoting
promoting, and fatigue-reducing, the effects of agents in the treatment of narcolepsy, but not in
amphetamines and methylphenidate are stimulating, obstructive sleep apnea or shift work disorder, although
and these drugs have classically been called stimulants. often used “off-label” for these indications. Many
Here we will refer to these agents by their properties as formulations of both amphetamine and methylphenidate
441
Amphetamine and Methylphenidate
amphetamine
methylphenidate
Figure 10-60 Amphetamine and methylphenidate. Amphetamine and methylphenidate are both norepinephrine (left) and dopamine
(right) reuptake inhibitors; amphetamine has the additional property of inhibition of the vesicular monoamine transporter 2 (VMAT2),
which can lead to dopamine release. Enhancing these neurotransmitters in sleep/wake circuitry (far right) can be wake-promoting and
fatigue-reducing; thus, they are both approved for excessive daytime sleepiness in narcolepsy and used off-label in other conditions
associated with hypersomnia.
are now available for the treatment of ADHD and are approved for the treatment of narcolepsy, but also as
reviewed in detail in Chapter 11 (see Figures 11-9, 11-10, adjunctive treatments for obstructive sleep apnea and
11-33, 11-35, and 11-36) and in Chapter 13 on substance for shift work disorder. These agents are thought to act
abuse (see Figure 13-8). predominantly as inhibitors of the dopamine transporter
Amphetamine and methylphenidate can be dosed to (DAT) or dopamine (DA) reuptake pump (Figure
treat sleepiness in narcolepsy in order to enhance the 10-62). Although modafinil is a weak DAT inhibitor,
synaptic availability of the wake-promoting and arousal the concentrations of the drug achieved after oral
neurotransmitters dopamine and norepinephrine and dosing are quite high, and sufficient to have substantial
thereby improve wakefulness in narcolepsy without actions on DATs. In fact, the pharmacokinetics of
causing significant reinforcement (Figure 10-60). modafinil suggest that this drug acts via a slow rise in
Nevertheless, amphetamine and methylphenidate plasma levels, sustained plasma levels for 6–8 hours,
are controlled substances because of high abuse and and incomplete occupancy of DAT, all properties that
diversion potential, as well as the possibility of inducing could be ideal for enhancing tonic dopamine activity
psychosis, mania, high blood pressure, and other side to promote wakefulness (Figure 10-63) rather than
effects, especially at doses higher than those used to treat phasic dopamine activity to promote reinforcement
sleepiness or ADHD (discussed in Chapters 11 and 13). and abuse (see Chapter 11 on ADHD and Figures 11-9,
However, they are highly effective agents to promote 11-10, 11-33, 11-35, and 11-36 as well as Chapter 13 on
wakefulness in narcolepsy. substance abuse and Figure 13-8). Once dopamine release
is activated by modafinil, and the cortex is aroused, this
Modafinil/Armodafinil
can apparently lead to downstream release of histamine
Mechanism of Action from the tuberomammillary nucleus (TMN) and then
Racemic modafinil and its R enantiomer armodafinil further activation of the lateral hypothalamus with
(Figure 10-61) are wake-promoting agents not only orexin release to stabilize wakefulness (Figure 10-63).
442
Figure 10-61 Modafinil and

armodafinil. Modafinil consists of two
enantiomers, R and S; the R enantiomer
has been developed and marketed
as armodafinil. Both modafinil
and armodafinil are thought to act
predominantly as inhibitors of the
dopamine transporter (DAT).
T TA
DA D
R modafinil S modafinil
However, the activation of the lateral hypothalamus for which amphetamine and methylphenidate are
and release of orexin do not appear to be necessary for not approved, namely, for shift work disorder and as
the action of modafinil, since modafinil still promotes adjunctive treatment for obstructive sleep apnea (OSA).
wakefulness in patients who have loss of hypothalamic
Obstructive Sleep Apnea
orexin neurons in narcolepsy. The activation of TMN
and lateral hypothalamic neurons may be secondary and First-line treatment for OSA (Figure 10-49) is continuous
downstream actions resulting from modafinil’s effects on positive airway pressure (CPAP) (Figure 10-64). Although
dopamine neurons. CPAP treatment is quite effective and has been shown
A related wake-promoting agent is the R enantiomer to reduce hospitalization rates and healthcare costs,
of modafinil, called armodafinil (Figure 10-61). adherence rates are poor (54%). For patients who find
Armodafinil has a later time to peak levels, a longer CPAP intolerable, there are other treatment options that
half-life, and higher plasma drug levels 6–14 hours may be considered, including bilevel positive airway
after oral administration than racemic modafinil. pressure (BPAP), auto-titrating positive airway pressure
The pharmacokinetic properties of armodafinil could (APAP), oral appliances designed to stabilize the jaw
theoretically improve the clinical profile of modafinil, and/or tongue during sleep, and various surgeries aimed 10
with greater activation of phasic dopamine firing, at correcting physical attributes that may contribute to
possibly eliminating the need for a second daily dose, as OSA. Additionally, several behavioral interventions may
is often required with racemic modafinil. be useful for ameliorating OSA; these include weight
loss (to a BMI <25), exercise, the avoidance of alcohol
Narcolepsy and sedatives at bedtime, and positional therapy (i.e.,
Modafinil/armodafinil are effective treatments of the use of a backpack or other object that prevents the
sleepiness in narcolepsy, although possibly not as patient from sleeping on their back). Modafinil and
powerful as amphetamine and methylphenidate. armodafinil are approved specifically as adjuncts to
However, head-to-head trials have not been conducted. standard treatment of underlying airway obstruction,
Furthermore, the abuse potential of modafinil/ which is frequently inadequate to treat the hypersomnia
armodafinil is much reduced compared to amphetamine associated with OSA. Given the low adherence rates to
and methylphenidate, and the side effects are not as CPAP, modafinil/armodafinil are sometimes used “off-
severe. In addition, both modafinil and armodafinil label” for OSA as monotherapies for patients who do not
are approved for treatment of two additional disorders tolerate CPAP.
443
Mechanism of Action of when needing to function during the daytime when

sleepy. Exposure to light alters circadian rhythms and
Modafinil/Armodafinil suppresses melatonin release. Treatment with 10,000
lux, bright, blue light for 30 minutes a day may be used
to reset circadian rhythms (Figure 10-56). Importantly,
the administration of bright light therapy must be
appropriately timed in accordance with the patient’s
circadian phase of melatonin secretion, with light
administration occurring approximately 8 hours after
evening melatonin secretion (possibly amplified by
DA reuptake oral dosing with a melatonin agent, Figure 10-57) or
pump
in accordance with a predetermined bright light phase
response curve. One form of bright light therapy, dawn
simulation therapy, applies a slow, incremental light
DA signal at the end of the sleep cycle. Data show that
modafinil performance, alertness, and mood during the night shift
can be improved in shift workers using bright light re-
entrainment of circadian rhythms.
Solriamfetol, a Wake-Promoting NDRI
+ Solriamfetol is a recently approved agent for daytime
+ sleepiness, both in patients with narcolepsy and as an
adjunct to mechanical treatments for airway obstruction
+ in patients with OSA. It works by norepinephrine and
+ dopamine reuptake inhibition (see Chapter 7 and Figures
7-34 through 7-36), and seems to be more potent than
bupropion in this aspect, and less potent but more tolerable
increase in tonic firing, and less abusable than amphetamines or methylphenidate.
downstream increase in HA Its short half-life is consistent with morning dosing wearing
and activation of wake-related
circuits off in time for sleep.
Figure 10-62 Mechanism of action of modafinil/ Pitolisant, H3 Presynaptic Antagonist

armodafinil. Modafinil and armodafinil bind with weak affinity
for the dopamine transporter (DAT); however, their plasma
Pitolisant (Figure 10-65) is a drug with a novel
levels are high and this compensates for the low binding. mechanism for improving wakefulness in narcolepsy
Increased synaptic dopamine (DA) following blockade of DAT
leads to increased tonic firing and downstream effects on
by blocking the normal action of presynaptic H3
neurotransmitters involved in wakefulness, including histamine autoreceptors (Figure 10-66A,B) to inhibit histamine
(HA) and orexin/hypocretin. release. Inhibiting the presynaptic H3 receptor causes
the disinhibition (that is, the release) of presynaptic
Shift Work Disorder histamine (Figure 10-66C), and this is wake-promoting.
Shift work disorder (Figure 10-51) can be tricky to Pitolisant, a presynaptic H3 autoreceptor antagonist
treat, especially if the patient has an ever-evolving and (Figures 10-65 and 10-66C), is approved for the treatment
unstable shift work schedule. Suffice it to say, shift of narcolepsy, and there are anecdotal observations that
workers are frequently sleepy, but still must work, it may be effective in cataplexy as well. Pitolisant is not a
drive, and function. Modafinil/armodafinil can make controlled substance and has no known abuse potential
a big difference in an individual’s ability to function and is in testing for improving excessive daytime
with alertness when suffering from shift work disorder. sleepiness in OSA. Pitolisant can be overly activating,
Supplementing modafinil/armodafinil with circadian causing anxiety or insomnia. Studies suggest it may
rhythm adjunctive therapy is often helpful (Figure be about as effective as modafinil but perhaps not as
10-55). This includes trying to reset the biological effective as amphetamine/methylphenidate for improving
clock with morning light (Figure 10-56), especially excessive daytime sleepiness.
444
Figure 10-63 Modafinil/armodafinil
Modafinil/Armodafinil in wake circuits. Blockade of the
dopamine transporter (DAT) by
modafinil/armodafinil leads to
increased tonic dopaminergic
firing and downstream effects on
wake-promoting neurotransmitters.
Specifically, cortical release of
wake-promoting neurotransmitters is
increased, which leads to downstream
release of histamine from the
tuberomammillary nucleus (TMN)
and further activation of the lateral
hypothalamus (LH), with corresponding
orexin release that stabilizes
wakefulness.
thalamus
basal
forebrain
VLPO PPT/
LH VTA LDT
TMN
LC
RN
GABA
modafinil/armodafinil hypocretin/orexin
acetylcholine
dopamine
norepinephrine
histamine
Figure 10-64 Treating obstructive

Treating Obstructive Sleep Apnea sleep apnea. First-line treatment
for obstructive sleep apnea (OSA) is
continuous positive airway pressure
Oral Appliances (CPAP). Other treatment options
are also available, including oral
appliances and surgical interventions.
CPAP Medications can be used as adjuncts
to treat excessive daytime sleepiness
associated with OSA.
airflow
nosemask
expiratory
resistance 10
Surgical Intervention
mouth is
unobstructed
445
Sodium Oxybate and Narcolepsy/Cataplexy levels are low. GHB is actually a natural product
Sodium oxybate (Figure 10-67) is also known as present in the brain with its own GHB receptors
γ-hydroxybutyrate (GHB), and acts as a full agonist upon which it acts (Figure 10-68). GHB is formed
at GHB receptors and a partial agonist at GABAB from the neurotransmitter GABA. It is hypothesized
receptors (Figure 10-68). As a GABAB partial agonist, that sodium oxybate increases slow-wave sleep
sodium oxybate acts as an antagonist when GABA and improves cataplexy via these actions at GABAB
levels are elevated and as an agonist when GABA receptors.
Figure 10-65 Pitolisant. Figure 10-67 Sodium

Pitolisant is an antagonist H oxybate. Sodium
at presynaptic histamine B oxybate, also known as
H 3 (H3) autoreceptors. γ-hydroxybutyrate (GHB),
3 It is approved for the acts as a full agonist at
treatment of excessive GHB receptors and as a
daytime sleepiness in partial agonist at GABAB
patients with narcolepsy. receptors. It is approved
for use both in cataplexy
pitolisant gamma and for excessive
hydroxybutyrate sleepiness, and appears
to enhance slow-wave
sleep.
H3
autoreceptor
HA

pitolisant. Histamine 3 (H3) receptors
are presynaptic autoreceptors and
H3
function as gatekeepers for histamine
autoreceptor (HA). (A) When H3 receptors are not
bound by histamine, the molecular gate
is open and allows histamine release.
(B) When histamine binds to the H3
pitolisant receptor, the molecular gate closes
disinhibits HA and prevents histamine from being
release released. (C) When pitolisant blocks the
H3 receptor, this disinhibits, or turns on,
B C
the release of histamine.
446
Mechanism of Action of
Figure 10-68 Mechanism of
action of sodium oxybate. Sodium
oxybate binds as a full agonist to
γ-hydroxybutyrate (GHB) receptors and
Sodium Oxybate (Xyrem, GHB) as a partial agonist at GABAB receptors.
Its actions at GABAB receptors are
presumed to be responsible for its
clinical effects of improving slow-wave
sleep and reducing cataplexy. As a
partial agonist, sodium oxybate causes
less stimulation of GABAB receptors
than GABA itself, but more than in the
absence of GABA. Thus, it can reduce
GABAB stimulation when GABA levels
are high, and increase it when GABA
levels are low.
GHB
(sodium
GABA oxybate)
GABA B GHB
GABA A receptor receptor
receptor
complex
10
cataplexy
slow-wave sleep
excessive daytime sleepiness
Sodium oxybate is approved for use in both cataplexy Because of its abuse potential and colorful history, it
and excessive sleepiness, and it appears to enhance slow- is scheduled as a controlled substance and its supplies
wave sleep and reduce hypnagogic hallucinations and sleep are tightly regulated through a central pharmacy in the
paralysis. Thus, rather than improving wake-promoting US. It has been labeled a “date rape” drug by the press as
neurotransmitters as every other treatment for excessive it can be used with alcohol for this purpose, “knocking
daytime sleepiness does, sodium oxybate supposedly someone out” and causing amnesia for the time while
makes you sleep so well at night with slow-wave sleep involuntarily intoxicated. Because it profoundly
restoration that you are not sleepy in the daytime. increases slow-wave sleep and the growth hormone
447
surge that accompanies slow-wave sleep, it was also hypothalamic sleep/wake switch, with wake-promoter
used (abused) by athletes as a performance-enhancing neurons in the tuberomamillary nucleus that utilize
drug, especially in the 1980s when it was sold over the histamine as neurotransmitter, and sleep-promoter
counter in health food stores. GHB is used in some neurons in the ventolateral preoptic nucleus that utilize
European countries as a treatment for alcoholism. GABA as neurotransmitter. The synthesis, metabolism,
Due to the observed enhancement of slow-wave sleep, receptors, and pathways for the neurotransmitter
GHB has been successfully tested in fibromyalgia (see histamine and orexin are reviewed in this chapter.
Chapter 9 for discussion of pain syndromes such as Insomnia and its treatments are reviewed, as are the
fibromyalgia) and is occasionally used “off-label” to mechanisms of action of several classic hypnotic agents
treat refractory cases. including the benzodiazepines and the popular “Z drugs,”
which act as positive allosteric modulators (PAMs) for
GABAA receptors. Other hypnotics reviewed include
SUMMARY
trazodone, melatonergic hypnotics, and antihistamines,
The neurobiology of wakefulness is linked to an arousal as well as the novel dual orexin receptor antagonists
system that utilizes the five neurotransmitters histamine, (DORAs). Excessive daytime sleepiness is also described
dopamine, norepinephrine, acetylcholine, and serotonin as are the mechanisms of action of the wake-promoting
and the wake-stabilizing neurotransmitters orexins drugs modafinil, caffeine, and stimulants. The actions of
as components of the ascending reticular activating γ-hydroxybutyrate (GHB) plus a number of novel sleep-
system. Sleep and wakefulness are also regulated by a and wake-promoting drugs are also reviewed.
448
11 Attention Deficit Hyperactivity
Disorder and Its Treatment
Symptoms and Circuits: ADHD as a Disorder of the Treatments for ADHD 466
Prefrontal Cortex 449 Which Symptoms Should Be Treated First? 466
ADHD as a Disorder of Inefficient “Tuning” Stimulant Treatment of ADHD 467
of the Prefrontal Cortex by Dopamine and Noradrenergic Treatment of ADHD 480
Norepinephrine 454
Future Treatments for ADHD 484
Neurodevelopment and ADHD 463
Summary 485
Attention deficit hyperactivity disorder (ADHD) is from inefficient information processing in various
not just a disorder of “attention,” nor does it have to circuits involving the prefrontal cortex (Figures 11-2
include “hyperactivity.” Paradigm shifts are altering the through 11-8). Specifically, the prominent symptom
landscape for treatment options across the full range of of “inattention” in ADHD can also be described more
ADHD symptoms, from inattention to impulsivity to precisely as “executive dysfunction” and the inability
hyperactivity, as well as across all the waking hours and to sustain attention long enough to solve problems.
across the whole lifespan, from young children through Executive dysfunction is hypothetically linked to
adulthood. This chapter will provide an overview of the inefficient information processing in the dorsolateral
psychopharmacology of ADHD, including only short prefrontal cortex (DLPFC) (Figures 11-2, 11-3, and
discussions of the symptoms of ADHD. The mechanism 11-7). The DLPFC is activated by a cognitive task known
of action of treatments classically called stimulants as the n-back test which can be monitored in living
and nonstimulants for ADHD will be emphasized. patients doing it while in a functional brain scanner
Information on the full clinical descriptions and formal (shown in Figure 11-3). Having difficulty in efficiently
criteria for how to diagnose and rate ADHD and its activating this part of the brain cuts across many
symptoms should be obtained by consulting standard psychiatric disorders that share the symptom of executive
reference sources. The discussion here will emphasize dysfunction, not just ADHD but also schizophrenia
the links between various brain circuits and their (discussed in Chapter 4), major depression (discussed
neurotransmitters with the various symptoms and in Chapter 6), mania (discussed in Chapter 6), anxiety
comorbidities of ADHD and how these are linked to (discussed in Chapter 8), pain (Chapter 9), and disorders
effective psychopharmacological treatments. The goal of of sleep and wakefulness (discussed in Chapter 10).
this chapter is to acquaint the reader with ideas about the One can see how inefficient information processing
clinical and biological aspects of attention, impulsivity, in this particular DLPFC circuit, especially when put
and hyperactivity. For details of doses, side effects, drug under a cognitive “load,” can be associated with the
interactions, and other issues relevant to the prescribing same symptom of executive dysfunction and difficulty
of drugs for ADHD in clinical practice, the reader in sustaining attention and solving problems in many
should consult standard drug handbooks (such as Stahl’s different psychiatric disorders. This is why diagnosis in
Essential Psychopharmacology: the Prescriber’s Guide). psychiatry is now progressively moving from describing
categorical syndromes that mix together many symptoms
SYMPTOMS AND CIRCUITS: to make a diagnosis (as in the DSM and ICD), towards
ADHD AS A DISORDER OF THE characterizing single symptom dimensions or domains
such as executive dysfunction that cut across many
PREFRONTAL CORTEX
psychiatric disorders. The emphasis on symptoms rather
ADHD is noted for a trio of symptoms: inattention, than diagnosis is the trend in much of neurobiological
hyperactivity, and impulsivity (Figure 11-1). It is research, with the goal of finding better correlates with
currently hypothesized that all these symptoms arise neuroimaging, biomarkers, and genetics.
449
Figure 11-1 Symptoms of

ADHD: Deconstruct the Syndrome into Diagnostic Symptoms ADHD. There are three major
categories of symptoms
associated with attention deficit
hyperactivity disorder (ADHD):
ADHD inattention, hyperactivity, and
impulsivity. Inattention itself can
be divided into difficulty with
selective attention and difficulty
with sustained attention and
problem solving.
inattentive symptoms
selective sustained attention
attention problem solving
hyperactive symptoms impulsive symptoms
Figure 11-2 Matching ADHD

ADHD: Core Symptoms Hypothetically Linked to symptoms to circuits. Problems with
Malfunctioning Prefrontal Cortex selective attention are believed to
be linked to inefficient information
processing in the dorsal anterior
dACC DLPFC cingulate cortex (dACC), while problems
with sustained attention are linked to
inefficient information processing in the
dorsolateral prefrontal cortex (DLPFC).
Hyperactivity may be modulated by the
selective prefrontal motor cortex and impulsivity
sustained attention by the orbital frontal cortex.
attention problem solving
hyperactive symptoms impulsive symptoms
prefrontal motor orbitofrontal

cortex cortex
Another dimension of executive dysfunction in ADHD 11-2, 11-4, and 11-7). The dACC can be activated
is selective inattention, or not being able to focus, and by tests of selective attention, such as the Stroop test
thus differs from problems with sustaining attention (explained in Figure 11-4). ADHD patients may either
described above. The symptom of problems focusing/ fail to activate the dACC when they should be focusing
selective inattention is hypothetically linked to inefficient their attention, or they may activate this part of the brain
information processing in a different brain area, namely very inefficiently and only with great effort and easy
the dorsal anterior cingulate cortex (dACC) (Figures fatiguability.
450
Chapter 11: Attention Deficit Hyperactivity Disorder and Its Treatment
Assessing Sustained Attention and Problem Solving Figure 11-3 Sustained attention
and problem solving: the n-
with the N-Back Test back test. Sustained attention is
hypothetically modulated by a
N-back test cortico-striato-thalamo-cortical loop
1 that involves the dorsolateral prefrontal
cortex (DLPFC) projecting to the
2 3 1
1
2 3
4 2 3 1
4
4
2 3 striatal complex. Inefficient activation
4
of the DLPFC can lead to difficulty
following through or finishing tasks,
inattentive disorganization, and trouble sustaining
mental effort. Tasks such as the n-back
test are used to measure sustained
attention and problem-solving abilities.
In the 0-back variant of the n-back test,
a participant looks at a number on the
screen, and presses a button to indicate
which number it is. In the 1-back
variant, a participant only looks at the
first number; when the second number
appears the participant is supposed
to press a button corresponding to
the first number. Higher “n” values are
correlated with increased difficulty in
the test.
overactivation
normal
baseline
hypoactivation
Assessing Selective Attention with the Stroop Task Figure 11-4 Selective attention: the
Stroop task. Selective attention is
hypothetically modulated by a cortico-
The striato-thalamo-cortical loop arising
Stroop Task from the dorsal anterior cingulate cortex
(dACC) and projecting to the striatal
Blue complex, then the thalamus, and back
to the dACC. Inefficient activation of
dACC can result in symptoms such as
Red paying little attention to detail, making
Orange inattentive
careless mistakes, not listening, losing
Red things, being distracted, and forgetting
things. An example of a test that
Green involves selective attention, and thus
Green should activate the dACC, is the Stroop
task. The Stroop task requires the
participants to name the color in which
a word is written, instead of saying the
word itself. For example, if the word
“blue” is written in orange, then the 11
correct answer is “orange,” while “blue”
is the incorrect choice.
overactivation
normal
baseline
hypoactivation
451
Figure 11-5 Impulsivity. Impulsivity
Impulsivity Is Modulated by the Orbitofrontal Cortex is associated with a cortico-striato-
thalamo-cortical loop that involves the
I know it! orbital frontal cortex (OFC), the striatal
complex, and the thalamus. Examples of
impulsive symptoms in ADHD include
talking excessively, blurting things out,
not waiting one’s turn, and interrupting.
impulsivity
overactivation
normal
baseline
hypoactivation
Figure 11-6 Hyperactivity. Motor
Motor Hyperactivity Is Modulated by the Prefrontal Cortex activity, such as hyperactivity and
psychomotor agitation or retardation,
can be modulated by a cortico-
striato-thalamo-cortical loop from the
prefrontal motor cortex to the putamen
(lateral striatum) to the thalamus and
back to the prefrontal motor cortex.
Common symptoms of hyperactivity in
hyperactivity children with ADHD include fidgeting,
leaving one’s seat, running/climbing,
being constantly on the go, and having
trouble playing quietly.
overactivation
normal
baseline
hypoactivation
452
ADHD Core Symptoms: Figure 11-7 ADHD core symptoms:

regional problems of PFC tuning. The
Regional Problems of PFC “Tuning” symptoms of ADHD may occur because
patients do not activate prefrontal
cortical areas appropriately in response
to cognitive tasks. Alterations within
the orbital frontal cortex (OFC) are
hypothesized to lead to problems with
impulsivity or hyperactivity. Inadequate
tuning of the dorsolateral prefrontal
OFC DLPFC dACC cortex (DLPFC) or the dorsal anterior
cingulate cortex (dACC) can respectively
lead to sustained or selective attention
symptoms.
limbic motor cognitive
interrupt fidget does not finish does not listen

blurt out leave seat disorganized distracted
not waiting turn climb avoids sustained effort forgetful
careless
impulsivity hyperactivity problems of problems of
sustained attention selective attention
& problem solving
Figure 11-8 ADHD and comorbid

ADHD Comorbid Symptoms: symptoms. Inadequate tuning of the
Additional Problems in the PFC ventromedial prefrontal cortex (VMPFC)
may be associated with comorbid
symptoms often seen in patients with
ADHD, such as symptoms of conduct
disorder or oppositional defiant
disorder, as well as mood instability and
anxiety.
VMPFC
limbic
11
steal a car mood instability temper tantrums

cruelty mania argumentative
pick a fight anxiety disobedient
aggressive
conduct disorder bipolar/anxiety oppositional

spectrum defiant disorder
453
Other areas of prefrontal cortex that are hypothetically psychiatric disorders including substance abuse, eating
functioning inefficiently in ADHD are the orbital frontal disorders, obsessive–compulsive disorder (OCD), and
cortex (OFC), linked to symptoms of impulsivity (Figures others.
11-2, 11-5, and 11–7), and the supplementary motor
area, linked to symptoms of motor hyperactivity (Figures ADHD AS A DISORDER OF
11-2, 11-6, and 11–7). The OFC is hypothetically linked INEFFICIENT “TUNING”
to a wide variety of symptoms that cut across several OF THE PREFRONTAL
psychiatric conditions, including impulsivity in ADHD CORTEX BY DOPAMINE AND
(Figures 11-2, 11-5, and 11-7), impulsivity and violence NOREPINEPHRINE
in schizophrenia (discussed in Chapter 4), suicidality in
depression (discussed in Chapter 6), impulsivity in Hypothetically, ADHD patients do not activate prefrontal
mania (discussed in Chapter 6), and impulsivity/ cortex areas appropriately in response to cognitive
compulsivity in substance abuse and related disorders tasks of attention and problem solving (executive
(discussed in Chapter 13). Impulsive symptoms in functioning) (Figures 11-7 through 11-21). This could
other psychiatric conditions commonly comorbid with be due to the observed neurodevelopmental delays
ADHD are also hypothetically related to the OFC such in prefrontal cortical synaptic connections in ADHD
as conduct disorder, oppositional defiant disorder, and (see Figures 11-22 and 11-23), causing inefficient
bipolar disorder (Figure 11-8). See Chapter 13 for further “tuning” of information processing in prefrontal circuits
discussion of impulsivity and compulsivity in a variety of regulated by norepinephrine (NE) and dopamine (DA)
Figure 11-9 Baseline norepinephrine

Baseline NE and DA Neuronal Firing Is Tonic and dopamine tonic firing. Modulation
of prefrontal cortical function, and
PFC therefore regulation of attention and
behavior, rely on the optimum release
NE DA of norepinephrine (NE) and dopamine
neuron neuron (DA). Under normal conditions,
NE and DA in the prefrontal cortex
(PFC) stimulate a few receptors on
postsynaptic neurons, allowing for
optimal signal transmission and
VMAT2 VMAT2 neuronal firing. At modest levels,
NE can improve prefrontal cortical
functioning by stimulating postsynaptic
α2A receptors. Similarly, modest levels
of DA will stimulate dopamine 1 and 3
(D1 and D3) receptors and be beneficial
to prefrontal cortical functioning. In the
case of both the NE and DA systems,
NE NET moderation is certainly key.
DA
α2B α 2C α2A α1 D1 D1 D1 D1
+ + D3 + + D3
D3 D3
+ + + +
+ + + +
NE/DA
firing
tonic firing
454
Salience Provokes Phasic DA Neuronal too low. Low NE tone hypothetically contributes
to the cognitive dysfunction in ADHD (Figure 11-
Firing in Reward Centers
11) and preferentially stimulates the most sensitive
Nucleus Accumbens noradrenergic receptors on postsynaptic neurons
(Figure 11-12). Increasing NE levels modestly would
DA
neuron
hypothetically improve prefrontal cortical function by
stimulating the more sensitive postsynaptic α2A receptors
(Figure 11-12) but increasing NE too high – as may
occur in stressful situations or in various comorbid
VMAT2
conditions such as anxiety, substance abuse, and mania
– could lead to impaired working memory when the
less sensitive α1 and β1 receptors are also recruited
(Figures 11-13 to 11-15). Thus, NE neurotransmission
must occur within a “sweet spot” of neither too high nor
too low (Figure 11-15) in order to optimize cognitive
functioning.
Similarly, if the firing of DA neurons innervating the
prefrontal cortex is also too low in ADHD, there would
D1 D2 D2
D2 D1 hypothetically be inadequate “tonic” DA stimulation,
setting the baseline “tone” of the DA synapse too low
D3 + + + + D3
at rest (Figures 11-11 and 11-12). Low release of DA
D3
+ + + + D3
preferentially stimulates the most sensitive DA receptors
on postsynaptic neurons (i.e., D3 receptors; Figure 11-9;
+ + ++
see also Chapter 4 and Figure 4-9) but inadequately
stimulates the less sensitive D1 receptors (Figures
11-11, 11-12, 11-15, and 11-16), and this would cause
NE/DA inadequate downstream neuronal signaling and cognitive
firing dysfunction. Increasing DA levels modestly would
tonic firing with burst of phasic firing hypothetically improve prefrontal cortical function in
Figure 11-10 Salience-provoked phasic dopamine part by first boosting tonic signaling at D3 receptors, then
firing. While tonic firing, as seen in the prefrontal cortex, is at moderately sensitive D2 receptors, and finally at the
often preferred in neuronal systems, a little bit of phasic firing
of dopamine (DA) neurons in the nucleus accumbens can be least sensitive D1 receptors (Figures 11-9, 11-11 through
a good thing. Phasic firing will lead to bursts of DA release 11-13, 11-15, and 11–16; see also Chapter 4 and Figure
and when this happens in a controlled manner it can reinforce
learning and reward conditioning, which can provide the
4-9).
motivation to pursue naturally rewarding experiences (e.g., Dopamine neurons also exhibit bursts of firing called
education, career development, etc.). When this system is out
of bounds, however, it can induce uncontrolled DA firing that
phasic DA stimulation (Figure 11-10), with a flurry of
reinforces the reward of taking drugs of abuse, for example, in dopamine release that recruits all three DA receptor
which case the reward circuitry can be hijacked, and impulses subtypes. Phasic DA release is thought to reinforce
are followed by the development of uncontrolled compulsions
to seek drugs. learning and reward conditioning, providing the
motivation to pursue naturally rewarding experiences. 11
The DA system is adaptively programmed to fire
neurotransmission (Figure 11-9 and Figure 11-10). in a phasic manner when there are pertinent and
This is the same arousal network that was discussed in notable sensory inputs such as those associated with
Chapter 10 on sleep and illustrated in Figures 10-1 and education, recognition, career development, enriching
10-44. social and family connections, etc. Enhancing phasic
If the firing of NE neurons innervating the prefrontal DA signaling modestly so that cognitive tasks can be
cortex is too low in ADHD (Figures 11-11 and 11-12), performed efficiently is hypothetically the therapeutic
there would be inadequate “tonic” NE stimulation setting goal in treatment of ADHD. However, when the phasic
the baseline “tone” of noradrenergic neurotransmission DA system is overly activated by stress or comorbid
455
Cognitive Function in ADHD:

Is It Deficient?
I know it!
impulsive inattentive
$
hyperactive
awake
alert
problem solving insomnia


sleepiness/
drowsiness/
sedation HA
DA
ACh
5HT
NE psychosis
overactivation
normal
baseline
hypoactivation
NE/DA
firing
low tonic firing

Figure 11-11 Cognitive function in ADHD: is it deficient? Arousal exists as if on a dimmer switch, with many phases along the
spectrum. Where on the spectrum one lies is influenced by several key wake-promoting neurotransmitters, including histamine (HA),
dopamine (DA), norepinephrine (NE), serotonin (5HT), and acetylcholine (ACh). When neurotransmission is balanced, one is awake,
alert, and able to function well. Alterations in the functioning of these key neurotransmitters, whether too much or too little, can cause
cognitive dysfunction. Cognitive dysfunction in ADHD may be a result of low tonic noradrenergic and dopaminergic firing.
conditions such as anxiety, substance abuse, or mania, receptor stimulation is what is thought to be beneficial to
it worsens cognitive functioning with too much arousal set the optimal tone and to optimize prefrontal cortical
(Figures 11-13 through 11-16). The phasic DA system functioning (Figures 11-15 and 11-16). Postsynaptic D1
can even be hijacked by drugs, and induce uncontrolled receptors predominate in the prefrontal cortex and the
DA firing, reinforcing the reward of drugs, leading to best functional outcome is when they are “tuned” and
compulsive drug abuse (discussed extensively in Chapter neither understimulated nor overstimulated (Figures
13). Therefore, moderate, but not high or low, levels of D1 11-15 and 11-16).
456
Figure 11-12 ADHD and deficient

ADHD and Deficient Arousal: arousal. Besides being a key player in
Weak NE and DA Signals the arousal pathways, the prefrontal
cortex (PFC) is also the main brain area
where imbalances in norepinephrine
PFC (NE) and dopamine (DA) systems
NE DA hypothetically occur in ADHD. Deficient
neuron signaling in prefrontal cortical NE and
neuron
DA pathways is reflected by reduced
stimulation of postsynaptic receptors.
Specifically, D1 receptors, which are
relevant to cognitive functioning, are
not very sensitive to dopamine; thus,
VMAT2 VMAT2 they are not stimulated when DA
levels are low. Increasing levels of NE
and DA would hypothetically improve
prefrontal cortical functioning through
increased stimulation of postsynaptic
α2A receptors and increased stimulation
of D1 receptors.
NE NET
DA
+
+
In the prefrontal cortex, α2A and D1 receptors are and down the neuron, thereby strengthening network
often located on the spines of cortical pyramidal connectivity with similar neurons (Figure 11-18). So,
neurons, and can thus gate incoming signals (Figures in general, in the prefrontal cortex, stimulation of α2A
11-17 through 11-21). Alpha-2A receptors are linked to receptors strengthens an incoming signal.
the molecule cyclic adenosine monophosphate (cAMP) By contrast, stimulation of D1 receptors leads to
via the inhibitory G protein (Gi) (Figure 11-17). D1 weakening of the signal (Figure 11-19). That is, when
receptors, on the other hand, are linked to the cAMP DA, or a DA agonist, binds to a D1 receptor, the activated
signaling system via the stimulatory G protein (Gs) Gs-linked system will lead to increased stimulation – or
(Figure 11-17). In either case, the cAMP molecule links opening – of HCN channels. The opening of the HCN
the receptors to the hyperpolarization-activated cyclic channels, especially if excessive, will lead to leakage of
nucleotide-gated (HCN) cation channels. An open the signal, thereby shunting any input out of the spine.
channel will lead to a low membrane resistance, thus So, excessive stimulation of D1 receptors will, in contrast
shunting inputs out of the spine. In the presence of to stimulation of α2A receptors, result in the dissipation 11
an open channel, the signal leaks out and is therefore and/or weakening of a signal. The mechanism of action
lost. However, when these channels are closed, the of α2A (Figure 11-18) and D1 receptors (Figure 11-19)
incoming signal survives and can be directed down explains in general why moderate stimulation of both
the neuron to strengthen the network connectivity of types of receptors (Figure 11-17) is preferred in order to
similar neurons and lead to the appropriate signal and strengthen the signal-to-noise ratio in prefrontal cortical
response. neurons (see Figure 11-20).
When NE, or a noradrenergic agonist, binds to an α2A What happens following concurrent stimulation of
receptor, the activated Gi-linked system inhibits cAMP, α2A and D1 receptors by NE and DA, respectively (Figure
thereby closing the HCN channel (Figure 11-18). Closure 11-20)? While the exact localization and density of α2A
of the channel allows the signal to go through the spine and D1 receptors within various cortical areas are still
457
Cognitive Function in ADHD:

Is It Excessive?
substance
$ abuse
bipolar
$
awake
alert
problem solving insomnia anxiety


sleepiness/
drowsiness/ HA
sedation
DA
ACh
5HT
NE psychosis
overactivation
normal
baseline
hypoactivation
Figure 11-13 Cognitive function in ADHD: is it excessive? Arousal exists as if on a dimmer switch, with many phases along the
spectrum. Where on the spectrum one lies is influenced by several key wake-promoting neurotransmitters, including histamine (HA),
dopamine (DA), norepinephrine (NE), serotonin (5HT), and acetylcholine (ACh). When neurotransmission is balanced, one is awake,
alert, and able to function well. Alterations in the functioning of these key neurotransmitters, whether too much or too little, can cause
cognitive dysfunction. Increasing norepinephrine or dopamine too high could lead to excessive stimulation of postsynaptic receptors
and cause cognitive dysfunction.
under intense investigation, it is possible to imagine the in adequate guided attention (Figures 11-15, 11-16),
same pyramidal neuron receiving NE input from the focus on a specific task, and adequate control of emotions
locus coeruleus (LC) on one spine and DA input from and impulses.
the ventral tegmental area (VTA) on another spine. If What happens, however, when there is low release
the systems are properly “tuned,” D1 receptor stimulation of both DA and NE and thus low stimulation of both
can reduce the noise and α2A receptor stimulation can D1 and α2A receptors on the spines of these pyramidal
increase the signal to result in proper prefrontal cortex neurons (Figure 11-21)? Deficient DA and NE input
functioning (Figure 11-20). Theoretically, this will result will theoretically lead to increased noise and decreased
458
ADHD and Excessive Arousal: Figure 11-14 ADHD and excessive arousal. When
Impact of Stress and Comorbidities norepinephrine (NE) and dopamine (DA) neurotransmission
in the prefrontal cortex (PFC) are optimally tuned, modest
stimulation of postsynaptic α2A receptors and D1 receptors
PFC allows for efficient cognitive functioning. If NE or DA
NE DA neurotransmission is excessive, as in situations of stress or
neuron neuron comorbid conditions such as anxiety or substance abuse,
this can lead to overstimulation of postsynaptic receptors
and consequently to cognitive dysfunction as well as
stress
other symptoms. Specifically, excessive noradrenergic
neurotransmission can lead to impaired working memory
due to stimulation of α1 (and β1) receptors. Excessive
dopaminergic neurotransmission can lead to overstimulation
of D1 receptors in the prefrontal cortex.
+ + ++ + + + ++ ++
++ ++ ++
+ + + + +
++ ++ ++
++ ++ ++
+ + + + +
++ ++ ++
+ ++ + + + ++ ++
+
inattention/
alcohol abuse/ anxiety from
problems
impulsivity excessive arousal
concentrating
from excessive arousal
Figure 11-15 ADHD and maladaptive

Tuning Cortical Pyramidal Neurons in ADHD signal-to-noise ratios. In order for the
prefrontal cortex to work properly,
moderate stimulation of α2A receptors
by norepinephrine (NE) and of D1
receptors by dopamine (DA) is
required. In theory, the role of NE is
to increase the incoming signal by
allowing for increased connectivity
of the prefrontal networks, while the
role of DA is to decrease the noise by
preventing inappropriate connections
from taking place. At the top of the
pyramidal cell function
inverted U-shaped curve depicted

here, stimulation of both α2A and D1
receptors is moderate and pyramidal
11
optimal D1, α2A activity cell function is optimal. If stimulation
at α2A and D1 receptors is too low (left
side), all incoming signals are the same,
making it difficult for a person to focus
on one single task (unguided attention).
If stimulation is too high (right side),
incoming signals get jumbled as
additional receptors are recruited,
resulting in the misdirection of attention.
D1, α 2A too low D1, α2A too high;
α1 stimulation recruited
459
Functional Output of Cortical Dopamine
Cognitive Performance
activity
optimal
D1, α 2A D1, α 2A
dopamine dopamine
receptor receptor cognitive symptoms
activity too activity too
low high
Neurotransmitter Levels (PFC)

Figure 11-16 Functional output of cortical dopamine. In order for the prefrontal cortex (PFC) to work properly and for cognitive
performance to be optimized, moderate stimulation of α2A receptors by norepinephrine (NE) and D1 receptors by dopamine (DA) is
required. If stimulation at α2A and D1 receptors is either too low or too high, cognitive dysfunction can occur.
Figure 11-17 Signal distribution in

Signal Distribution in a Dendritic Spine a dendritic spine. The location of α2A
and D1 receptors on dendritic spines
of cortical pyramidal neurons in the
prefrontal cortex allows them to gate
incoming signals. Both α2A and D1
receptors are linked to the molecule
cyclic adenosine monophosphate
(cAMP). The effects on cAMP from
signal lost/
norepinephrine (NE) and dopamine
leaks out (DA) binding at their respective
NE receptors are opposite (inhibitory
in the case of NE and excitatory in
the case of DA). In either case, the
cAMP molecule links the receptors
to the hyperpolarization-activated
cAMP cyclic nucleotide-gated (HCN) cation
α 2A channels. When HCN channels are
open, incoming signals leak out before
incoming they can be passed along. However,
information when these channels are closed, the
incoming signal survives and can be
D1 directed down the neuron.
cAMP
signal lost/
DA
leaks out
surviving
signal
strength
460
Figure 11-18 Norepinephrine
NE Actions at Alpha -2A Receptors Strengthen Signal actions at α2A receptors strengthen
the incoming signal. Alpha-2A
receptors are linked to cyclic adenosine
monophosphate (cAMP) via an inhibitor
G protein (Gi). When NE occupies
these α2A receptors, the activated
Gi-linked system inhibits cAMP and
the hyperpolarization-activated cyclic
nucleotide-gated (HCN) channel is
closed, preventing loss of the incoming
NE signal.
cAMP
α 2A
incoming
information
cAMP
strengthened
signal
Figure 11-19 Dopamine actions at

DA Actions at D1 Receptors Weaken Signal D1 receptors weaken the incoming
signal. D1 receptors are linked to cyclic
adenosine monophosphate (cAMP)
via a stimulatory G protein (Gs). When
dopamine (DA) occupies these D1
receptors, the activated Gs-linked
system activates cAMP leading to
opening of hyperpolarization-activated
cyclic nucleotide-gated (HCN) channels.
The opening of HCN channels,
especially if excessive, will lead to loss
of the incoming signal before it can be
cAMP
passed along.
incoming
information
D1 11
cAMP
DA
weakened or
lost signal
461
Figure 11-20 Dopamine and

How DA and NE Hypothetically “Tune” the PFC: norepinephrine “tune” the prefrontal
Signal Increased and Noise Reduced cortex (PFC). The same pyramidal
neuron may receive norepinephrine
(NE) input from the locus coeruleus
(LC) on one spine and dopamine (DA)
input from the ventral tegmental area
(VTA) on another spine. When properly
“tuned,” D1 receptor stimulation will
reduce the noise while α2A receptor
stimulation will increase the signal,
resulting in appropriate prefrontal
cortical functioning, guided attention,
focus on a specific task, and control of
noise normal NE emotions and impulses.
release LC
normal DA
release
signal
VTA
noise reduced signal increased
Figure 11-21 Dopamine and

How DA and NE Hypothetically “Tune” the PFC: norepinephrine improperly “tune” the
Low NE and Low DA: ADHD with Signals prefrontal cortex (PFC) in ADHD. The
Reduced and Noise Increased same pyramidal neuron may receive
norepinephrine (NE) input from the
locus coeruleus (LC) on one spine and
dopamine (DA) input from the ventral
tegmental area (VTA) on another spine.
Deficient DA input will theoretically
lead to increased noise, while deficient
NE input will cause a decrease in the
incoming signal. Hypothetically, this
improper tuning of the PFC by DA
and NE can lead to hyperactivity, or
inattention, or both.
noise low NE
release LC
low DA
release
signal
VTA
noise increased signal reduced
462
signal, respectively, thus preventing a coherent signal are able to compensate for these prefrontal cortical
from being sent (Figure 11-21). Hypothetically, this abnormalities by new synapse formation after age 12 and
could cause hyperactivity, inattention, impulsivity, or into early adulthood may be the ones who “grow out of
some combination of symptoms, depending upon the their ADHD” and why the prevalence of ADHD in adults
localization of the mis-tuned pyramidal neuron in is only half that in children and adolescents.
the prefrontal cortex (see Figures 11-3 through 11-8). What causes these problems in the circuits of the
Furthermore, if one neurotransmitter is low while the prefrontal cortex in ADHD? Currently, leading hypotheses
other is high, then a person could be exhibiting a whole propose that neurodevelopmental abnormalities
different set of symptoms. By knowing both the levels of occur in the circuits of the prefrontal cortex in ADHD
DA and NE neurotransmission and the specific area of (Figures 11-2 through 11-8). Many of the ideas about
the possible disturbances, it may one day be possible to the neurodevelopmental basis of schizophrenia, such
predict the degree and type of symptoms from which a as abnormal synapse formation and abnormal synaptic
patient is ailing. With this in mind, Figures 11-7 and 11-8 neurotransmission, serve as a conceptual framework
show how pyramidal neurons in different brain areas may and neurobiological model for ADHD as well, and are
be responsible for the different symptom presentations in discussed in Chapter 4. The impact of neurodevelopment
ADHD. on the specific symptom patterns of ADHD is shown
in Figure 11-24. Inattentive symptoms can exist but
NEURODEVELOPMENT AND are not easily identified in preschool children with
ADHD, perhaps because they do not have a sufficiently
ADHD
mature prefrontal cortex to manifest this symptom
ADHD is traditionally considered a childhood disorder, in a manner that is abnormal compared to normal
but the concept of ADHD has evolved to be considered development. Preschool ADHD and its treatment are a
childhood in onset but often persisting into adulthood. In current controversial concept in the field because most
fact, most psychiatric disorders have onset in childhood and studies of stimulants involve children over the age of
young adult years and then persist into adulthood (Figures 6. Once inattention becomes a prominent symptom of
11-22 and 11-23). The reason for this may be that childhood ADHD, it remains so over the life cycle (Figure 11-24).
and young-adult development is when the brain is However, impulsivity and hyperactivity decline notably
undergoing critical maturation (Figure 11-22A and 11-23). by adolescence and early adulthood, while recognized
Brain development is directed by both genetic and comorbidities skyrocket in frequency as ADHD patients
environmental influences (discussed for psychotic enter adulthood (Figure 11-24).
disorders in Chapter 4 and illustrated in Figures 4-61 The diagnostic criteria most recently changed from
and 4-62). ADHD has one of the strongest genetic requiring onset prior to age 7 in the past diagnostic
components in psychiatry at about 75%. Multiple genes schemes of DSM-IV, now to onset prior to age 12 in DSM-
are implicated in ADHD and the genetic causation 5. There is even debate as to whether or not there is such
is complex and multifactorial, as it is in any mental a thing as adult-onset ADHD (or at least recognized first
disorder. A unifying formulation of ADHD is that it as an adult with unclear onset). The prevalence of ADHD
is caused by delayed maturation of prefrontal cortex in adults may be only about half of that in children, but
circuitry that manifests in ADHD symptoms at least it is not recognized nearly as often as it is in children,
by age 12. Synapses rapidly increase in the prefrontal possibly because it is much harder to diagnose and its
cortex by age 6, and then up to half of them are rapidly symptoms are very often not treated. Whereas half of 11
eliminated by adolescence (Figure 11-22A; see also all children or adolescents with ADHD are thought to
Chapter 4 and Figures 4-63 and 4-64). The timing of be diagnosed and treated, less than one in five adults
onset of ADHD suggests that the formation of synapses with ADHD is thought to be diagnosed and treated. The
and, perhaps more importantly, the selection of synapses reasons for this are multiple, starting with the diagnostic
for removal in the prefrontal cortex during childhood requirement that ADHD symptoms must begin by age 12.
may contribute to the onset and lifelong pathophysiology Adults often have difficulty making accurate retrospective
of this condition (Figures 11-22 and 11-23). Those who diagnoses, especially if the condition was not identified
463
Synaptogenesis in Prefrontal Cortex and the Development
of Executive Functions
age at which
inattentive
symptoms of
Age 6 ADHD become
noticeable
Age 14-60
planning skills emerge;
ability to sustain
attention on one
number of synapses in PFC
task but not

perseverate;
Birth recognition memory;
formation of
abstract concepts
executive
functioning
working emerges rapid expansion
memory of executive
emerges functions
attending to one task
preschool: little ability while ignoring
to sustain attention irrelevant stimuli;
on task; easily cognitive flexibility and
distracted by inhibition; verbal
irrelevant stimuli memory performance
newborn 1 5 10 15 20 40 60 80 100
years
A
Most Psychiatric Disorders Have Onset in

Child and Young-Adult Years During Cortical Development
14
12
10
8
percent
0-3 7-9 13-15 25-27

B
age at onset (years)
Figure 11-22 Cortical development and ADHD. Synaptogenesis in the prefrontal cortex (PFC) might be responsible for altered
connections that could prime the brain for ADHD. Specifically, executive function develops throughout adolescence. (A) At 1 year of
age, working memory emerges. Around 3–4 years of age, children do not yet have the capability to sustain attention for long periods
of time, and can be easily distracted. By age 6–7, this changes; attention can be sustained and planning can take place. This age is also
characterized by “synaptic pruning,” a process during which overproduced or “weak” synapses are “weeded out,” thus allowing for the
child’s cognitive intelligence to mature. Errors in this process could hypothetically affect the further development of executive function
and be one of the causes of ADHD. This timeline also represents when symptoms of ADHD often become noticeable, which is around
the age of 6. (B) Most psychiatric disorders have onset in childhood and young-adult years and then persist into adulthood, coinciding
with critical cortical development.
464
Developmental Course of Brain Maturation
Sensorimotor Cortex
Amygdala
Striatum
Hippocampus
Prefrontal Cortex
0 5 10 15 20 25
age (years)
Median Age at Onset of Psychiatric Disorders

Across Development
relative incidence
Anxiety
Disorders
Schizophrenia
Mood
Disorders
ADHD/
Conduct Substance
Abuse
0 5 10 15 20 25
age (years)
Figure 11-23 Developmental course of brain maturation and onset of psychiatric disorders. The developmental course of brain 11
development is such that the sensorimotor cortex and limbic brain regions develop first, and the prefrontal cortex develops later. In
ADHD, this same pattern is observed; however, cortical development is delayed. This may account for the childhood onset of ADHD and
why, although ADHD may continue into adulthood, its onset does not occur in adulthood. In contrast, other disorders can also begin in
childhood but are typically diagnosed later than ADHD, with onset continuing into adulthood.
and treated as a child. Furthermore, many experts now patients have ADHD? Or is their executive dysfunction
question whether it is appropriate to exclude from the a symptom of a comorbid disorder such as depression,
diagnosis of ADHD those adults whose ADHD symptoms anxiety, or sleep disorder? The point is to screen for
started after age 12, so-called late-onset ADHD. Some cognitive symptoms and to treat them, whether part of an
cases may even have onset up to the age of 45. Do these ADHD disorder or a comorbidity.
465
Impact of Development on ADHD Figure 11-24 Impact of development

on ADHD. Consistent with our
understanding of neurodevelopment,
inattention the evolution of symptoms in ADHD
shows that inattention is generally not
identified in preschool but becomes
prevalent as the patient ages and
continues into adulthood. Hyperactivity
and impulsivity are key symptoms in
childhood but are less likely to manifest
overtly in adulthood, although they may
simply be expressed differently. The
impulsivity
rates of comorbidities increase over
time; this could be due to the fact that
the comorbidities were overlooked in
children with ADHD or that they truly
subthreshold hyperactivity develop later, consistent with data
comorbidity recognized showing later onset of other psychiatric
disorders compared to ADHD.
preschool school age adolescence college age adulthood

- behavioral - behavioral - academic - academic - occupational
disturbances disturbances problems failure failure
- academic - difficulty with - occupational - self-esteem
problems social interactions difficulties issues
- difficulty with - self-esteem issues - self-esteem - relationship
social interactions - legal issues, issues problems
- self-esteem issues smoking and injury - substance abuse - injury/accidents
- injury/accidents - substance abuse
TREATMENTS FOR ADHD difficult to treat substance abuse, mood disorders, and
anxiety disorders that the focus of therapeutic attention
Which Symptoms Should Be Treated First? never gets to ADHD, and certainly not to nicotine
It can be helpful in managing ADHD to prioritize which dependence. That is, ADHD can be considered a mere
symptoms to target first with psychopharmacological afterthought in adults to be addressed if cognitive
treatments, even at the expense of delaying treatment symptoms do not remit once the primary focus of
for a while for some conditions, or even making some therapeutic intervention, namely the mood or anxiety
of these comorbid conditions transiently worse if other disorder, is treated. It is interesting that ADHD is not
symptoms are targeted for improvement first (Figure often the focus of treatment in adults unless it presents
11-25). Although there are no definitive studies on this with no comorbid conditions. Since lack of comorbidity
approach, clinical experience from many experts suggests in adults with ADHD is rare, this may explain why the
that, in complex cases, it can be very difficult to make majority of adults with ADHD are not treated.
any therapeutic progress if the patient continues to abuse The modern, sophisticated psychopharmacologist
alcohol or stimulants; thus, substance abuse problems keeps a high index of suspicion for the presence of
must often be managed top line (Figure 11-25). Treating ADHD in mood, anxiety, and substance abuse disorders
ADHD may also have to await improvement from mood especially in adults, always aiming for complete
and anxiety disorder treatments, with ADHD cognitive symptomatic remission in patients under treatment.
symptoms seen as more of a fine-tune adjustment to a In practice, this means exploring the use of ADHD
patient’s overall symptom portfolio (Figure 11-25). treatments as augmenting agents to first-line treatments
There are problems, however, with this approach of of mood, anxiety, and substance abuse disorders, rather
setting priorities of which symptoms and disorders to than the other way around. It also means that long-
treat first. For example, many children are treated for term management of ADHD is eventually to address
their ADHD first, and without adequately evaluating the treatment of nicotine dependence in ADHD once
possible comorbidities until patients fail to respond cognitive symptoms are under control (Figure 11-25).
robustly to stimulant treatment. In adults, it can be so Adults and adolescents with ADHD smoke as frequently
466
Figure 11-25 ADHD and

comorbidities: what should be treated
first? In a patient with ADHD and
comorbid disorders, it is imperative
to treat all disorders appropriately,
alcohol/stimulant/ and in terms of highest degree of
substance abuse impairment. This might mean that
in one patient it is necessary to first
stabilize the alcohol abuse, while
in another patient the symptoms
of ADHD might be more impairing
mood than the underlying anxiety disorder.
disorders Additionally, some medications
used to treat these disorders could
exacerbate the comorbid ailment.
Thus, care needs to be taken when
or anxiety choosing the appropriate treatment. An
de
ro individualized treatment plan should
ft disorders
re be established for each patient based
atm on his/her symptomatic portfolio.
en
t
ADHD
nicotine
dependence
treatment in treatment in
adults often children/adolescents
ends here often begins here
as adults and adolescents with schizophrenia, about twice be done both by norepinephrine and dopamine reuptake
the rate of the normal population in the US. This may be blocking stimulants and by some noradrenergic agents as
due to the fact that nicotine subjectively improves ADHD discussed below. Strengthening prefrontal cortical output
symptoms, especially in patients who are not treated is hypothesized to be beneficial in restoring a patient’s
for their ADHD. Nicotine enhances dopamine release ability to tease out important signals from unimportant
and enhances arousal, so it is not surprising that it may ones, and to manage to sit still and focus.
be subjectively effective for ADHD symptoms. Nicotine What if NE and DA signals are excessive? Excessive as
dependence and psychopharmacological treatments for well as deficient activation of NE and DA in the prefrontal
smoking cessation are discussed in more detail in Chapter cortex can lead to ADHD, as discussed above, namely
13 on impulsivity, compulsivity, and addiction. by increasing the noise and decreasing the signal (see
Figures 11-13 through 11-16). The theory is that at first,
Stimulant Treatment of ADHD
and in some patients, the added stress of suffering from
General Principles ADHD plus other stressors from the environment can
As discussed above and as illustrated in Figures 11-11 and even further dial up the noise and reduce the signal, 11
11-12, when both DA and NE are too low, the strength resulting at first in high NE and DA release, causing
of signal output in the prefrontal cortex is also too low, reduced signals and inefficient information processing
thus leading to reduced signal and increased noise (Figure 11-27A). As stress becomes chronic, however, NE
(Figure 11-26A; see also Figures 11-15, 11-16, and 11-21). and DA levels eventually plummet due to depletion over
Behaviorally, this could translate into a person not being time, but with no relief in terms of poor signal output
able to sit in his/her seat and focus, and to fidget and shift (Figure 11-27B). Ultimately the appropriate treatment
attention, respectively (Figure 11-26A). In order to treat is to increase NE and DA concentrations to allow for
these symptoms, it is necessary to increase signal strength normalization of behavior (Figure 11-27C, noise is
output by dialing up the release of both DA and NE until reduced and signal is increased).
they reach the optimal levels (Figure 11-26B). This can
467
Figure 11-26 The importance of

Importance of NE and DA Levels in PFC in ADHD norepinephrine and dopamine levels
in the prefrontal cortex in ADHD. (A)
ADHD: Hypothetically Low Signals When both norepinephrine (NE) and
and/or High Noise in PFC dopamine (DA) are too low (on the left
side of the inverted U-shaped curve),
the strength of output in the prefrontal
cortex (PFC) is too low, leading to
PFC strength of output

reduced signal and increased noise. The
PFC
inability to sit still and focus, together
with fidgeting and shifting attention,
are often clinical manifestations of this
imbalanced signal-to-noise ratio. (B)
noise signal In order to treat these symptoms, it is
NE concentration DA concentration necessary to increase strength output
by dialing up the concentrations of both
NE low - signal reduced NE and DA until they reach the optimal
fidget / sit in seat /
shift attention
dose (top of the inverted U-shaped
focus DA low - noise increased curve).
A
Treatment: Increase NE, Increase DA

PFC
noise signal
NE concentration DA concentration
fidget / sit in seat / NE optimized - signal increased

shift attention focus
DA optimized - noise reduced
B
Experienced clinicians are well aware that such Thus, conditions associated with hypothetically
patients with too much DA and NE (represented in excessive DA activation suggest treatment with dopamine
Figure 11-27A), too little DA and NE (represented in blocking agents (see Chapter 5), yet comorbid ADHD
Figure 11-27B), or a combination of these in different suggests treatment with a stimulant. Can dopamine
pathways, can be very difficult to treat. For example, in blockers and stimulants be combined? In fact, in heroic
children, the combination of tics generally representing cases, stimulants can be combined with serotonin–
hypothetically excessive DA activation in the motor dopamine antagonists. The rationale for this combination
striatum, and requiring DA blockade for treatment, exploits the fact that serotonin–dopamine blockers
can be very difficult to manage simultaneously in hypothetically release DA in the prefrontal cortex, to
patients with ADHD who have hypothetically deficient stimulate postsynaptic D1 receptors there (see Figure
DA activation in the cortex, requiring DA-enhancing 5-17C), while simultaneously blocking D2 receptors in
stimulants. Stimulants may help the ADHD symptoms limbic areas, to reduce DA activity at D2 receptors there.
but worsen the tics. Children and adolescents who have Such an approach is controversial and best left to experts
conduct disorder, oppositional disorders, intermittent for difficult patients who fail to improve adequately on
explosive disorder, disruptive behavioral disorder, monotherapies. This mechanism of action of dopamine–
psychotic disorders and/or bipolar mania, or mixed serotonin blockers and their actions in different areas of
conditions (theoretically associated with excessive DA the brain are discussed in detail in Chapter 5.
activation in some prefrontal circuits) (Figure 11-8), For patients with ADHD and anxiety, it can be difficult
who are unlucky enough to have comorbid ADHD or even self-defeating to try to improve the ADHD
(theoretically associated with deficient DA activation in with stimulant treatment, only to cause the anxiety to
different prefrontal circuits) (Figure 11-7), are among the worsen. For patients with ADHD and substance abuse, it
most challenging patients for clinicians. makes little sense to give stimulants to drug abusers in
468
Figure 11-27 Chronic stress in

Effects of Chronic Stress in ADHD ADHD. Excessive activation of
norepinephrine (NE) and dopamine
ADHD and Stress: Hypothetically Low (DA) in the prefrontal cortex (PFC) can
Signals and/or High Noise in PFC lead to ADHD by increasing the noise
At first, high NE and DA and decreasing the signal. (A) At first,
the added stress of suffering from the

PFC disorder can further dial up the noise
and reduce the signal (high NE and DA
concentration leading to decreased
noise signal output). (B) As chronic stress sets in,
NE and DA levels plummet (low NE
NE concentration DA concentration and DA concentration also leading to
decreased output), but with no relief in
fidget / sit in seat / NE high - signal reduced terms of signal output. (C) Treatments
shift attention focus
A DA high - noise increased that increase NE and DA concentrations
may reduce symptoms by increasing
strength output (noise is reduced and
Chronic Stress signal is increased).
Eventually, NE and DA depletion

PFC
noise signal
fidget / sit in seat /

NE low - signal reduced
B shift attention focus DA low - noise increased
Treatment: Increase NE, Increase DA

PFC
noise signal
NE optimized - signal increased

C fidget / sit in seat /
shift attention
DA optimized - noise reduced
focus
order to treat their ADHD. In these cases, augmenting the transporters both for NE and DA (NETs and DATs,
antidepressant or anxiolytic therapies with a tonic respectively) (Figures 11-28 and 11-29A–C). Normally,
activator of DA and/or NE systems, such as a long- DA is released (arrow 1 in Figure 11-29A), and then
lasting norepinephrine transport (NET) inhibitor or an taken back up into the dopaminergic neuron by DATs
α2A-adrenergic agonist, rather than a stimulant, can be (arrows 2 in Figure 11-29A), and finally stored in the
an effective long-term approach for comorbid anxiety, synaptic vesicle by VMATs (arrows 3 in Figure 11-29A).
depression, or substance abuse with ADHD. Some Methylphenidate blocks DATs and NETs allosterically, 11
studies of NET inhibitors report improvement in both stopping the reuptake of DA via DATs (Figure 11-29B)
ADHD and anxiety symptoms, and other studies report and NE via NETs (Figure 11-29C), with no actions on
improvement in both ADHD and heavy drinking. VMAT2 (Figures 11-29B and 11-29C). Methylphenidate
blocks NETs and DATs in much the same way as reuptake
Methylphenidate blockers used to treat depression (see discussion in
The mechanism of action of the so-called stimulants Chapter 7 and Figure 7-36), namely by binding to NETs
– perhaps better designated as norepinephrine and and DATs at sites distinct from where monoamines bind
dopamine reuptake blockers – is shown in Figures 11-28 NETs and DATs, i.e., allosterically. Thus, methylphenidate
through Figure 11-37. Oral administration of clinically stops the reuptake pumps so that no methylphenidate is
approved doses of the stimulant methylphenidate blocks
469
transported into the presynaptic neuron (Figure 11-29B Methylphenidate is also available as the single enantiomer
and 11-29C). D-methylphenidate, in both immediate-release and
Methylphenidate has a D- and an L-isomer (Figure controlled-release preparations. A listing of the wide range
11-28), with the D-isomer being much more potent of D,L-methylphenidate preparations is shown in Table 11-
than the L-isomer on both NET and DAT binding. 1, and those for D-methylphenidate shown in Table 11-2.
Table 11-1 D,L-Methylphenidate formulations
Formulation Brand names Duration Dosing Approval

Immediate-release Ritalin Early peak, 3–4-hr Second dose at Ages 6 to 12 and
tablet duration lunch adults
Immediate-release Methylin Early peak, 3–4-hr Second dose at Ages 6 to 12
oral solution duration lunch
Extended-release Ritalin SR Early peak, 3–8-hr Lunch dosing Ages 6 and older
tablet Methylin ER duration may be needed
Metadate ER
Extended-release Concerta Small early peak, 12-hr Once daily in the Ages 6 and older
tablet duration morning
Extended-release QuilliChew ER Peak at 5 hr, 8-hr duration Once daily in the Ages 6 and older
chewable tablet morning
Extended-release Metadate CD Strong early peak, Once daily in the Ages 6 to 17
capsule 8-hr duration morning
Extended-release Ritalin LA Two strong peaks (early Once daily in the Age 6 to 12
capsule and at 4 hrs), 6–8-hr morning
duration
Extended-release Aptensio XR Up to 12-hr duration Once daily in the Ages 6 and older
capsule morning
Extended-release oral Quillivant XR Peak at 5 hr, 12-hr Once daily in the Ages 6 and older
suspension duration morning
Extended-release Daytrana One peak at 7–10 hrs, 12- Once daily in the Ages 6 to 17
transdermal patch hr duration morning
Orally disintegrating Cotempla XR-ODT 12-hr duration Once daily in the Ages 6 to 17
tablet morning
Extended-release Jornay PM Initial absorption delayed Once daily in the Ages 6 and older
capsule by 10 hrs, single peak at evening
14 hrs
Extended-release Adhansia XR Two peaks (at 1.5 and 12 Once daily in the Ages 6 and older
capsule hrs) morning
Table 11-2 D-Methylphenidate formulations
Formulation Brand Names Duration Dosing Approval

Immediate-release Focalin Early peak, 4–6-hr Second dose at lunch Ages 6 to 17
tablet duration
Extended-release Focalin XR Two peaks (after 1.5 and Once daily in the Ages 6 to 17
capsule 6.5 hrs), 8–10-hr duration morning and adults
470
D,L-Methylphenidate Figure 11-28 D,L-methylphenidate. Methylphenidate consists

of two enantiomers, D and L; both racemic D,L-methylphenidate
and D-methylphenidate are available as therapeutic options.
D,L-methylphenidate and D-methylphenidate both block the
norepinephrine transporter (NET) and the dopamine transporter
(DAT). D-methylphenidate has greater potency for both
transporters than does the L enantiomer.
NET TEN
DAT TAD
D-methylphenidate L-methylphenidate
Regulation of the Transport and Figure 11-29A Regulation of

transport and availability of synaptic
Availability of Synaptic DA dopamine. The regulation of synaptic
dopamine (DA) is dependent upon
proper functioning of two transporters,
namely the dopamine transporter
(DAT) and the vesicular monoamine
transporter (VMAT). After DA is released
(1) it can act at postsynaptic receptors
or it can be transported back into the
terminal via DATs (2). Once inside the
terminal, DA is “encapsulated” into
vesicles via VMAT (3). These DA-
filled vesicles can then merge with
the membrane and lead to more DA
3 release. This finely tuned machinery
VMAT ensures that DA levels never reach
toxic levels in the synapse or in the DA
terminal. By “engulfing” DA into vesicles
it is possible for the DA neuron to
3
ensure the viability of DA.
2
3
11
2
1
dopamine (DA) 2
1 = release of DA
2 = DAT transport of DA
A
3 = VMAT transport of DA
471
Mechanism of Action of Methylphenidate Mechanism of Action of Methylphenidate
DA neuron NE neuron
methylphenidate C
methylphenidate
B
Figure 11-29C Mechanism of action of methylphenidate

Figure 11-29B Mechanism of action of methylphenidate at at norepinephrine neurons. Methylphenidate blocks the
dopamine neurons. Methylphenidate blocks the reuptake of reuptake of norepinephrine (NE) into the terminal by binding
dopamine (DA) into the terminal by binding at an allosteric at an allosteric site (i.e., different than the NE binding site).
site (i.e., different than the DA binding site). Methylphenidate Methylphenidate basically stops the transporter, preventing NE
basically stops the transporter, preventing DA reuptake and thus reuptake and thus leading to increased synaptic availability of
leading to increased synaptic availability of DA. NE.
Amphetamine the vesicular transporter (VMAT2) for both DA and NE

Oral administration of clinically approved doses of the (Figure 11-32, top right). Once amphetamine hitch-
stimulant amphetamine, like methylphenidate, also hikes another ride into synaptic vesicles, it displaces
blocks the transporters both for NE and DA (NETs DA there, causing a flood of DA release (Figure 11-32,
and DATs), but in a different manner (Figures 11-30 bottom left). As DA accumulates in the cytoplasm of
through 11-32). Unlike methylphenidate and reuptake the presynaptic neuron, it causes the DATs to reverse
blocking drugs used for depression, amphetamine is directions, spilling intracellular DA into the synapse,
a competitive inhibitor and pseudosubstrate for NETs and also opening presynaptic channels to further
and DATs (Figure 11-32, top left), binding at the same release DA in a flood into the synapse (Figure 11-
site that the monoamines bind to the transporters, thus 32, bottom right). These pharmacological actions of
inhibiting NE and DA reuptake (Figure 11-32, top left). high-dose amphetamine are not linked to therapeutic
At the doses of amphetamine used for the treatment of action in ADHD but to reinforcement, reward, and
ADHD, the clinical differences between the actions of euphoria in amphetamine abuse. Actions of high-
amphetamine versus methylphenidate can be relatively dose amphetamine, methamphetamine, and cocaine
small. However, at the high doses of amphetamine (another inhibitor of DATs), given orally in immediate-
used by stimulant addicts, additional pharmacological release formulations, or intranasally, intravenously, or
actions of amphetamine are triggered. Following smoked, are discussed further in Chapter 13 on drug
competitive inhibition of DATs (Figure 11-32, top left) abuse.
amphetamine is actually transported as a hitch-hiker Amphetamine has a D- and an L-isomer (Figure
into the presynaptic DA terminal, an action not shared 11-30). The D-isomer of amphetamine is more potent
by methylphenidate or reuptake blocking drugs used than the L-isomer for DAT binding, but D- and L-
for depression (Figure 11-32, top left). Once there in amphetamine isomers are more equally potent in
sufficient quantities, such as occurs at doses taken for their actions on NET binding. Thus, D-amphetamine
abuse, amphetamine is also a competitive inhibitor of preparations will have relatively more action on DATs
472
D,L-Amphetamine at lower therapeutic doses utilized for the treatment of

ADHD. D-amphetamine also comes in a formulation
linked to the amino acid lysine (lisdexamfetamine; Figure
11-31) which is not absorbed until slowly cleaved into
active D-amphetamine in the stomach, and slowly, rather
than rapidly, absorbed. A listing of the wide range of D,L
amphetamine preparations is shown in Table 11-3, and
NET TEN
those for D-amphetamine shown in Table 11-4.
The Mysterious DAT
DAT TAD
Targeting the dopamine transporter (DAT) is not like
VMAT TAMV
targeting any other site in psychopharmacology. There
are at least three parts to solving the mystery of why
D-amphetamine L-amphetamine there are so many different outcomes from targeting the
same DAT, simply depending upon how you zero in on
it. Targeting DATs can result in immediate therapeutic
Figure 11-30 D,L-amphetamine. Amphetamine consists of actions (in ADHD and daytime sleepiness), delayed
two enantiomers, D and L; both racemic D,L-amphetamine
and D-amphetamine are available as therapeutic options. therapeutic actions (in depression), immediate abuse
D,L-amphetamine and D-amphetamine are both competitive (euphoria, high), and delayed addiction, all depending
inhibitors at norepinephrine transporters (NETs), dopamine
transporters (DATs), and vesicular monoamine transporters
upon how the DAT is engaged: how fast, how long, and
(VMATs). D-amphetamine has greater potency for DAT binding how much. Understanding the neurobiology of DATs and
than does the L enantiomer, while the D and L enantiomers are
equipotent for NET binding.
dopamine will not only unravel this mystery and solve the
riddle of the curious properties of this site, but empower
the prescriber to best engage this target for best outcomes
Lisdexamfetamine for whatever clinical application is intended.
First, we have discussed how engaging monoamine
neurotransmitter transporters leads to delayed
therapeutic actions in depression hypothetically linked
NET
to downstream molecular events such as neurotrophic
factor production (discussed in Chapter 6 and illustrated
VMAT in Figure 6-27 and in Chapter 7 and Figure 7-62). The
immediate rise in dopamine levels (often accompanied
DAT by increasing norepinephrine levels from simultaneously
lysine blocking the NET) are not linked to antidepressant
effects. Instead, DATs (and NETs) must be engaged
at therapeutic levels more or less continuously, round
the clock, so synaptic levels of neurotransmitter are
D-amphetamine sufficiently robust and sustained to trigger delayed
downstream molecular events, usually taking a few
Figure 11-31 Lisdexamfetamine. Lisdexamfetamine is the
prodrug of D-amphetamine, linked to the amino acid lysine. It is weeks. Likely, these therapeutic actions may be linked to 11
only centrally active as D-amphetamine once it has been cleaved improvement of tonic dopamine neurotransmission that
in the stomach into the active compounds D-amphetamine plus
free L-lysine. is theoretically deficient in depression.
Second, engaging this same DAT can produce
immediate onset of therapeutic effects in ADHD and
than NETs; mixed salts of both D- and L-amphetamine in daytime sleepiness by attaining occupancy levels
will have relatively more action on NETs than D- above a critical threshold, with therapeutic action that is
amphetamine but overall still more action on DATs than immediately terminated as soon as DAT occupancy falls
NETs (Figure 11-33). These pharmacological mechanisms below this threshold (Figure 11-34A). This notion of a
of action of the stimulants come into play particularly threshold for immediate therapeutic action onset and
473
Mechanism of Action of Amphetamine:

The Yin and the Yang
3 VMAT
2
3
2
1 = competitive inhibition
2 = DAT transport of 3 = VMAT transport of
amphetamine amphetamine
1
4
4
6
4
4
4 4 5
5 = high DA opens channel

4 = amphetamine and spills out 5 6
displacement 6 = high DA reverse
of dopamine transports DA out
Figure 11-32 Mechanism of action of amphetamine at dopamine (DA) neurons. Amphetamine is a competitive inhibitor at the
dopamine transporter (DAT), thus blocking DA from binding (1). This is unlike methylphenidate’s actions at DATs and NETs, which are
not competitive. Additionally, since amphetamine is also a competitive inhibitor of VMAT (a property that methylphenidate lacks) it is
actually taken into the DA terminal via DATs (2), where it can then be packaged into vesicles (3). At high levels, amphetamine will lead to
the displacement of DA from the vesicles into the terminal (4). Furthermore, once a critical threshold of DA has been reached, DA will be
expelled from the terminal via two mechanisms: the opening of channels to allow for a massive dumping of DA into the synapse (5) and
the reversal of DATs (6). This fast release of DA will lead to the euphoric effect experienced after amphetamine use. Amphetamine has
these same actions at noradrenergic neurons.
offset is also seen in another area of psychopharmacology, capture the best way to attain, sustain, and drop below
namely, for treatments of insomnia discussed in Chapter the threshold in just the exact manner desired. There are
10 and illustrated in Figure 10-41A. A similar idea is over two dozen versions of the two stimulant molecules
illustrated here, with a minimum threshold for ADHD methylphenidate and amphetamine now available for
therapeutic action, probably around 50–60% DAT clinical use (Tables 11-1 through 11-4) and several
occupancy (Figure 11-34). more in development. Each version tries to capture the
This property of DAT targeting for ADHD above a ideal drug delivery for the ideal DAT occupancy for a
critical threshold is so prominent that it has spawned given patient type (e.g., Figure 11-34B). That usually
an entire industry of technologies in an attempt to takes the form of rapidly getting above threshold levels
474
Table 11-3 D,L-Amphetamine formulations

Immediate-release Adderall 4–6 hrs Second dose at Ages 3 and older
tablet lunch
Immediate-release Evekeo 6 hrs Second dose at Ages 3 and older
tablet lunch
Extended-release Adzenys XR-ODT 8–12 hrs, peak at Once daily in the Ages 6 and older
orally disintegrating 5 hrs morning
tablets
Extended-release Dyanavel XR 10–12 hrs, peak at Once daily in the Ages 6 to 17
oral suspension 4 hrs morning
Extended-release Adderall XR 8–12 hrs, peak at Once daily in the Ages 6 and older
capsule 6–8 hrs morning
Extended-release Mydayis Up to 16 hrs Once daily in the Ages 13 and older
capsule morning
Extended-release Adzenys ER Not published Once daily in the Ages 6 and older
oral suspension morning
Table 11-4 D-Amphetamine formulations

Immediate-release Zenzedi 4–5 hrs Second dose at lunch Ages 3 to 16
tablet
Immediate-release ProCentra (previously 4–6 hrs Second dose at lunch Ages 3 to 16
oral solution Liquadd)
Extended-release Dexedrine 6–8 hrs Once daily in the Ages 6 to 16
capsule morning
Lisdexamfetamine Vyvanse Up to 12 hrs, peak at Once daily in the Ages 6 to 17 and
dimesylate capsule 3.5 hrs morning adults
upon awakening in the morning, staying at this DAT There is no “one size fits all” profile of stimulant
occupancy level for as long as needed for a productive delivery that fits every patient every day and no single
day, yet getting below threshold levels in time for bed. technology that is ideal for all patients. For that reason,
And to do this with once-daily dosing. Doing this too it can be prudent to search among the many options
late means morning symptoms (Figure 11-34B); having available for the best fit for an individual patient (see
it last too short a time means late afternoon and evening Tables 11-1 through 11-4). Do you want the effect to 11
symptoms (Figure 11-34B); having this last too long last 6 hours or 16 hours? Do you want greater or lesser
a time means late afternoon and evening side effects effect in the evening hours before bedtime? Morning
and insomnia (Figure 11-34C). There is also a rebound can be difficult for many with ADHD, so do you want
phenomenon, in which evening serum levels drop too rapid morning onset or even waking up with drug
early and hyperactivity and insomnia ensue. Just as above threshold? All of these are currently attainable
was discussed for hypnotic actions, the goal is not “too from available formulations (Tables 11-1 through 11-4).
hot” (too long, too high, too fast), not “too cold” (too Different patients have different responses, and the
low, too short) but “just right” (Figure 11-34A), the same patient may wish different responses on different
ideal “Goldilocks” solution, more a goal than a perfectly days to fit a flexible lifestyle. And all this because of the
executed reality. mysterious DAT and its threshold for therapeutic efficacy
475
“Slow-Dose” Stimulants Amplify Tonic NE and DA Signals

PFC nucleus accumbens
NE DA DA
neuron neuron neuron
VMAT2 VMAT2 VMAT2
NET
D >> L methylphenidate DAT

DA DA D >> L methylphenidate
NE D = L amphetamine
D > L amphetamine
α2A D1 D1 D2
+ + + +
+ + + +
+ + + +
+ + + +
slow-dose stimulants
OROS - methylphenidate, LA - methylphenidate, XR - D-methylphenidate, transdermal methylphenidate

D-amphetamine spansules, XR - D,L mixed amphetamine salts, prodrug D-amphetamine (lisdexamfetamine)
Figure 11-33 Slow-dose stimulants amplify tonic norepinephrine (NE) and dopamine (DA) signals. Hypothetically, whether a drug
has abuse potential depends on how it affects the DA pathway. In other words, the pharmacodynamic and pharmacokinetic properties
of stimulants affect their therapeutic as well as their potential abuse profiles. Extended-release formulations of oral stimulants, the
transdermal methylphenidate patch, and the prodrug lisdexamfetamine are all considered “slow-dose” stimulants and may amplify tonic
NE and DA signals, presumed to be low in ADHD. These agents block the norepinephrine transporters (NETs) in the prefrontal cortex
and the DA transporters (DATs) in the nucleus accumbens. Hypothetically, the “slow-dose” stimulants occupy NETs in the prefrontal
cortex (PFC) with slow enough onset, and for long enough duration, that they enhance tonic NE and DA signaling via α2A and D1
postsynaptic receptors, respectively, but they do not occupy DATs quickly or extensively enough in the nucleus accumbens to increase
phasic signaling via D2 receptors. The latter hypothetically suggests reduced abuse potential.
in ADHD (and excessive daytime sleepiness). Likely and Figure 13-7). In fact, the more rapidly and completely
these therapeutic actions may be linked to judicious the DATs are blocked, the more reinforcing and abusable
and controlled enhancement of phasic dopamine a drug will be. This applies not only to methylphenidate,
neurotransmission, along with a boost in tonic dopamine modafinil, and amphetamine as DAT blockers, but also
neurotransmission, both of which may be theoretically to methamphetamine and cocaine that are also DAT
somewhat deficient in ADHD and sleepiness. blockers. Oral ingestion can get a DAT inhibitor to the
One last piece of the puzzle. How can the DAT target brain, but not as fast as snorting nasally, and not as fast as
that is therapeutic immediately for ADHD and sleepiness intravenously, and certainly not as fast as smoking. High
and with a delay for depression lead to problematic drug dosing especially by these other routes of administration
abuse rather than therapeutic use? This only makes sense provides complete, catastrophic, and sudden blockade
if you are aware that the DAT functions very differently of DATs. The rapid build-up of synaptic dopamine
depending upon how fast, how completely, and how long (Figure 11-35) is nothing like what is seen with more
you engage it (compare Figures 11-35 pulsatile action gradual, sustained, and lower levels of DAT occupancy
with Figure 11-33 sustained action). That is, rapid and (Figure 11-33). In fact, dopamine levels can build up so
high degrees of DAT occupancy cause euphoria and lead high that the DATs can actually be reversed to transport
to abuse and addiction (Figure 11-35; see also Chapter 13 dopamine out of the presynaptic terminal to add to the
476
rapid Figure 11-34 Dopamine transporter (DAT) occupancy

morning offset in levels and therapeutic effects. The therapeutic
onset time for sleep effects of DAT blockade are dependent upon
attaining occupancy levels above a critical therapeutic
threshold, with therapeutic action terminated as
threshold for
ADHD therapeutic
soon as occupancy falls below this threshold. The
effect critical threshold of receptor occupancy for onset of
concentration
therapeutic actions in ADHD is likely between 50%

and 60%. Both the onset to achieving the threshold,
drug
and the duration of time above the threshold, are

important for efficacy and tolerability. (A) Ideally,
onset of achieving therapeutic DAT occupancy
would be immediately upon waking, with levels
maintained within the critical threshold throughout
the day and dropping below the threshold in time
for sleep. (B) Delayed onset of DAT blockade in the
critical threshold can lead to morning symptoms,
while inadequate duration of DAT blockade can cause
evening symptoms. (C) If DAT blockade remains within
A the critical threshold for too long, this can result in
evening side effects, notably insomnia.
0 24 48 72
hours (taken daily)
delayed
morning too soon offset; late afternoon
onset- and evening symptoms
morning
symptoms
threshold for
ADHD therapeutic
effect
concentration
drug
0 24 48 72
hours (taken daily)
too offset; late,

insomnia
threshold for
ADHD therapeutic
effect
concentration
11
drug
0 24 48 72
hours (taken daily)
477
Pulsatile Stimulants Amplify Tonic

and Phasic NE and DA Signals
PFC nucleus accumbens
NE DA DA
neuron amphetamine neuron neuron amphetamine
NET DAT
methylphenidate DA
NE methylphenidate
α1 α2A α2A α 1 D1 D1 D1 D1 D1 D2 D1 D2 D1 D2
+ + ++ ++ + + ++ ++ ++ ++
+ + ++ + ++ ++ ++ ++
++ ++ ++
+ +
+ + + + + ++ ++ ++ ++
++ ++ ++ ++ ++ ++ ++
++ ++ ++ + +
+ + + + + ++ ++ ++ ++
++ ++ ++ + + ++ ++ ++ ++
++ + + ++ ++
+ + +
pulsatile stimulants
oral immediate-release, intravenous, intranasal, smoked, D-amphetamine,

D,L amphetamine salts, methylphenidate, D-methylphenidate, cocaine,
methamphetamine
Figure 11-35 Pulsatile stimulants amplify tonic and phasic norepinephrine (NE) and dopamine (DA) signals. Hypothetically, whether
a drug has abuse potential depends on how it affects the DA pathway. In other words, the pharmacodynamic and pharmacokinetic
properties of stimulants affect their therapeutic as well as their potential abuse profiles. Immediate-release oral stimulants – similarly to
intravenous, smoked, or snorted stimulants (which are considered pulsatile stimulants) – lead to a rapid increase in NE and DA levels
through blockade of the norepinephrine transporters (NETs) in the prefrontal cortex (PFC) and the DA transporters (DATs) in the nucleus
accumbens. Rapidly amplifying the phasic neuronal firing of DA in the nucleus accumbens is associated with euphoria and abuse. The
abuse potential of immediate-release formulations of methylphenidate and amphetamine may be due to increased phasic as well as
tonic DA signaling.
massive release of dopamine from sudden, complete, long, but also how quickly the DAT is inhibited, all to
and catastrophic DAT blockade (discussed earlier in this maximize therapeutic effects in ADHD and minimize
chapter and illustrated in Figure 11-32, bottom right). abuse and side effects (Figure 11-36 and Tables 11-
So, understanding how a more gentle and prudent 1 through 11-4). The goal is to enhance phasic DA
administration of DAT inhibition can be therapeutic neurotransmission with low to moderate, continuous
whereas the same drug can be disastrous can allow drug delivery (Figure 11-36, top), trying to increase
the best judicious administration of a DAT inhibitor. mostly tonic DA firing and only judiciously to increase
Be careful, and don’t mess incorrectly with your DAT! phasic DA firing, recognizing that this may be playing
Mystery solved. a bit with fire. In order not to get burned, as happens
with pulsatile drug delivery in drug abuse situations
Slow-Release Versus Fast-Release Stimulants
(see Figure 11-36, bottom), to achieve prudent and
Based upon now having solved the mystery of the DAT, therapeutic improvement of tonic and phasic DA
many drug delivery systems are not only designed to neurotransmission without disastrous increases in
control how much DAT inhibition there is, and for how phasic DA neurotransmission, leading to abuse and
478
Pulsatile vs. Slow/Sustained Drug Delivery: Figure 11-36 Pulsatile versus slow and
sustained drug delivery. The difference
Implications for Stimulants between stimulants as treatments and
stimulants as drugs of abuse lies less in
their mechanism of action and more in
drug the route of administration and dose,
concentration and thus the onset and duration of
dopamine transporter (DAT) blockade.
time (A) When using stimulants to treat a
dose patient it may be preferable to obtain a
slow-rising, constant, steady-state level
of the drug. Under those circumstances
DA the firing pattern of DA will be tonic,
firing regular, and not at the mercy of
fluctuating levels of DA. (B) While
A
time some pulsatile firing can be beneficial,
especially when involved in reinforcing
learning and salience, higher doses of
drug DA will mimic the actions of DA in stress
concentration and mimic drug abuse at the highest
doses. Unlike a constant administration
of DA, pulsatile administration of DA
may lead to the highly reinforcing
time
dose dose dose dose pleasurable effects of drugs of abuse
and lead to compulsive use and
addiction.
DA
firing
B
time
addiction, sustained delivery is what is wanted. Thus, ADHD (and sleepiness) targets both NETs and DATs
controlled-release preparations for stimulants result rather than raising the dose to get predominantly DAT
in slowly rising, constant, steady-state levels of the effects, many of which will be unwanted. Optimization
drug (Figures 11-33, 11-34A; 11-35, top). Under those for ADHD means not only targeting DATs, but also
circumstances the firing pattern of DA will theoretically targeting NETs to occupy enough of these NETs in the
be mostly tonic, regular, and not at the mercy of prefrontal cortex at a slow enough onset and a long
fluctuating levels of DA. Some pulsatile firing is fine, enough duration of action to enhance tonic NE signaling
especially when involved in reinforcing learning and there via α2A receptors (see discussion in Chapter 7 and
salience (Figure 11-10). However, as seen in Figures Figure 7-33 for how NET inhibition leads to enhanced
11-15 and 11-16, DA stimulation follows an inverted NE action). NET inhibition can also increase tonic DA
U-shaped curve, such that somewhat excessive DA signaling in the prefrontal cortex via D1 receptors, as
will mimic the actions of DA in stress (Figure 11-14) explained in Chapter 7 and illustrated in Figure 7-33.
and, at much higher doses, mimic drug abuse (Figure This allows good therapeutic effects in ADHD while
11-36B). Thus, pulsatile drug administration that occupying carefully a lower number of mysterious DAT
causes immediate release of DA, unlike controlled- targets, especially in the nucleus accumbens, so as not to
release preparations, could potentially lead to the highly increase phasic signaling there via D2 receptors (Figures
reinforcing pleasurable effects of drug abuse, especially 11-35 and 11-36). 11
at high enough doses and rapid enough administration. In summary, it appears that ADHD patients have
For this reason, using immediate-release stimulants, their therapeutic improvement by stimulants at the
especially in adolescents and adults, is increasingly being mercy of how quickly, how much, and how long
avoided. stimulants occupy NETs and DATs. When this is done
Just as importantly, the “slow-dose” stimulants, in an ideal manner with slow onset, robust but sub-
shown in Figure 11-33, optimize the rate, the amount, saturating levels of transporter blockade, together with
and the length of time that a stimulant occupies not only a long duration of action before declining and wearing
DATs for therapeutic use in ADHD, but also exploits the off, the patient ideally benefits with improved ADHD
slow-dose occupancy of NETs for therapeutic actions symptoms, hours of relief, and no euphoria (Figures
in ADHD. Best pharmacological use of stimulants in 11-34 and 11-36).
479
Noradrenergic Treatment of ADHD both DA and NE in the prefrontal cortex (Figure 11-38)
Atomoxetine and is why NET inhibitors are thought to work in ADHD.
Atomoxetine (Figure 11-37) is a selective norepinephrine However, since there are few NE neurons and NETs in
reuptake inhibitor (NRI). Sometimes called NET nucleus accumbens, inhibiting NET does not lead to an
inhibitors, the selective NRIs have known antidepressant increase in either NE or DA there (Figure 11-38) and is
properties (discussed in Chapter 7). In terms of their why NET inhibitors are thought not to have reinforcing,
mechanism of therapeutic action in ADHD, it is the same abuse, or addiction potential.
as just discussed for stimulants acting at the NETs here Bupropion is a weak NRI and also a weak DAT
in Chapter 11, and as previously discussed for drugs used inhibitor known as a norepinephrine–dopamine reuptake
to treat depression in Chapter 7 and illustrated in Figure inhibitor (NDRI), and was previously discussed as a
7-33. Blocking NETs in the prefrontal cortex increases treatment for depression in Chapter 7 and illustrated
in Figures 7-34 through 7-36; see also Figure 11-37).
Several tricyclic antidepressants (TCAs) have notable
NRI actions, such as desipramine and nortriptyline. All of
these agents with NRI properties have been utilized in the
Comparing the Molecular Actions of
treatment of ADHD, with varying amounts of success, but
Atomoxetine and Bupropion only atomoxetine is well-investigated and approved for
this use in children and adults.
DAT
Atomoxetine’s hypothetical actions in ADHD patients
NDRIs with stress and comorbidity states, presumably linked
NET to excessive and phasic DA and NE release, are shown
conceptually by comparing the untreated states in Figures
11-11 and 11-12 with the changes that theoretically follow
chronic treatment with atomoxetine in Figure 11-39. That
is, ADHD linked to conditions that are associated with
NE DA
neuron neuron chronic stress and comorbidities is theoretically caused
by overly active NE and DA circuits in the prefrontal
cortex, resulting in an excess of phasic NE and DA
activity (Figure 11-13). When slow onset, long duration,
and essentially perpetual NET inhibition occurs in the
prefrontal cortex due to atomoxetine, this theoretically
restores tonic postsynaptic D1 and α2A-adrenergic
signaling, downregulates phasic NE and DA actions, and
desensitizes postsynaptic NE and DA receptors (Figure
11-39). The possible consequence of this is to reduce
stress as ADHD symptoms are improved. If so, decreases
in ADHD symptoms could potentially be accompanied
by decreases in anxiety, depression, and heavy drinking.
Unlike stimulant use, where the therapeutic actions are
at the mercy of plasma drug levels and momentary NET/
NRIs
DAT occupancies, actions from long-term NRI actions
NET
give 24-hour symptom relief, in much the same manner
as do SSRIs (selective serotonin reuptake inhibitors) and
Figure 11-37 Comparing the molecular actions of atomoxetine
and bupropion. Atomoxetine is a selective norepinephrine SNRIs (serotonin–norepinephrine reuptake inhibitors)
reuptake inhibitor (NRI), while bupropion is a norepinephrine– for the treatment of depression and anxiety. Selective
dopamine reuptake inhibitor (NDRI). Both agents block the
norepinephrine transporters (NETs) in the prefrontal cortex, NRIs generally have smaller effect sizes for reducing
which leads to an increase in both norepinephrine (NE) and ADHD symptoms than stimulants in short-term trials,
dopamine (DA) there (because NETs also transport dopamine).
NDRIs also block the dopamine transporters (DATs), which especially in patients without comorbidity. However,
are not present in the prefrontal cortex but are present in the NRIs are not necessarily inferior in ADHD patients who
nucleus accumbens.
480
Atomoxetine in ADHD with Weak Figure 11-38 Atomoxetine in
ADHD with weak prefrontal
Prefrontal NE and DA Signals norepinephrine (NE) and dopamine
(DA) signals. Through its blockade of
prefrontal cortex nucleus accumbens - no action norepinephrine transporters (NETs),
NE DA DA
atomoxetine causes NE and DA levels
neuron neuron neuron to increase in the prefrontal cortex,
where inactivation of both of these
neurotransmitters is largely due to
VMAT2 VMAT2 VMAT2 NETs (on the left). At the same time,
the relative lack of NETs in the nucleus
accumbens prevents atomoxetine from
NET increasing NE or DA levels in that brain
area, thus reducing the risk of abuse (on
atomoxetine
DAT the right). Other NET inhibitors would
DA DA
NE be expected to have the same effects.
α2A D1 D1 D2
+ + + +
+ +
+ +
+ +
NET inhibitors
atomoxetine (NRI), reboxetine (NRI), bupropion (NDRI), venlafaxine (SNRI),

duloxetine (SNRI), desvenlafaxine (SNRI), milnacipran (SNRI),
desipramine (TCA), nortriptyline (TCA)
Chronic Treatment with Atomoxetine in ADHD have not been previously treated with stimulants, nor in
with Excessive Prefrontal NE and DA Signals ADHD patients who have been treated long term (more
than 8–11 weeks). NRIs may actually be preferred to
prefrontal cortex
excessive NE and DA signals
stimulants in patients with complex comorbidities, side
effects, or lack of response to stimulants.
stress stress
ADHD anxiety substance Alpha-2A-Adrenergic Agonists
abuse
Norepinephrine receptors are discussed in Chapter 6
chronic treatment with atomoxetine
and illustrated in Figures 6-14 through 6-16. There are
NE DA numerous subtypes of α-adrenergic receptors, from
neuron neuron
presynaptic autoreceptors, generally of the α2A subtype
(Figure 6-14) to postsynaptic α2A, α2B, α2C, and α1
VMAT2
VMAT2 subtypes α1A, α1B, and α1D (Figures 6-14 through 6-16).
NET
Alpha-2A receptors are widely distributed throughout the
central nervous system, with high levels in the cortex and
atomoxetine
DA
locus coeruleus. These receptors are thought to be the
NE
primary mediators of the effects of NE in the prefrontal
cortex, regulating symptoms of inattention, hyperactivity,
α2A D1 and impulsivity in ADHD. Alpha-2B receptors are in high
+ + concentrations in the thalamus and may be important
11
+ +
in mediating sedating actions of NE, while α2C receptors
+ +
are densest in striatum. Alpha-1 receptors generally have
+ +
opposing actions to α2 receptors, with α2 mechanisms
RESPONSE predominating when NE release is low or moderate
Figure 11-39 Chronic treatment with atomoxetine in ADHD
(i.e., for normal attention), but with α1 mechanisms
with excessive signals. ADHD linked to conditions that are predominating at NE synapses when NE release is
associated with chronic stress and comorbidities is theoretically
caused by overly active NE and DA circuits. Continuous
high (e.g., associated with stress and comorbidity) and
blockade of NETs could restore tonic postsynaptic D1 and α2A- contributing to cognitive impairment. Thus, selective
adrenergic signaling, downregulate phasic NE and DA actions, NRIs at low doses will first increase activity at α2A
and desensitize postsynaptic NE and DA receptors.
481
postsynaptic receptors to enhance cognitive performance, ADHD. Both clonidine and guanfacine, especially in the
but at high doses may swamp the synapse with too controlled-release formulations, are used “off-label” for
much NE and cause sedation, cognitive impairment, the treatment of conduct disorder, oppositional defiant
or both. Patients with these responses to selective NRIs disorder, and Tourette syndrome. Unlike clonidine,
may benefit from lowering the dose. Alpha-2-adrenergic guanfacine is 15–60 times more selective for α2A receptors
receptors are present in high concentrations in the than for α2B and α2C receptors. Additionally, guanfacine
prefrontal cortex, but only in low concentrations in the is 10 times weaker than clonidine at inducing sedation
nucleus accumbens. and lowering blood pressure, yet it is 25 times more
There are two direct-acting agonists for α2 receptors potent in enhancing prefrontal cortical function. The
used to treat ADHD, guanfacine (Figure 11-40) and therapeutic benefits of both clonidine and guanfacine are
clonidine (Figure 11-41). Guanfacine is relatively hypothetically related to direct effects on postsynaptic
more selective for α2A receptors (Figure 11-40). It has receptors in the prefrontal cortex, which lead to the
been formulated into a controlled-release product, strengthening of network inputs, and to behavioral
guanfacine ER, that allows once-daily administration, improvements, as seen in Figures 11-42 and 11-43.
and lower peak-dose side effects than immediate-release Who are the best candidates for monotherapy with
guanfacine. Only the controlled-release version of an α2 agonist? Hypothetically, the symptoms of ADHD
guanfacine is approved for treatment of ADHD. Clonidine could be caused in some patients by NE levels being low
is a relatively nonselective agonist at α2 receptors, with in the prefrontal cortex, without additional impairments
actions on α2A, α2B, and α2C receptors (Figure 11-41). In in DA neurotransmission (Figure 11-43A). This would
addition, clonidine has actions on imidazoline receptors, lead to scrambled signals lost within the background
thought to be responsible for some of clonidine’s sedating noise, which could be seen behaviorally as hyperactivity,
and hypotensive actions (Figure 11-41). Although the impulsivity, and inattention (Figure 11-43A). In this
actions of clonidine at α2A receptors exhibit therapeutic instance, treatment with a selective α2A agonist would
potential for ADHD, its actions at other receptors may lead to an increased signal via direct stimulation of
increase side effects. Clonidine is approved for the
treatment of hypertension, but only the controlled-
release version of clonidine is approved for treatment of Clonidine
Guanfacine
α 2A α 2B
α 2A α 2C
imidazoline
Figure 11-41 Clonidine. Clonidine is an α2 receptor agonist.

Figure 11-40 Guanfacine. Guanfacine is a selective α2A It is nonselective and thus binds to α2A, α2B, and α2C receptors.
receptor agonist. Specifically, guanfacine is 15–60 times more Clonidine also binds to imidazoline receptors, which contributes
selective for α2A receptors than for α2B and α2C receptors. to its sedating and hypotensive effects.
482
The Mechanism of Action of Clonidine and Guanfacine Figure 11-42 Mechanism of action
of clonidine and guanfacine. Alpha-
and How They Affect the Three Alpha-2 Receptors 2-adrenergic receptors are present in
high concentrations in the prefrontal
prefrontal cortex cortex, but only in low concentrations
in the nucleus accumbens. There are
NE DA three types of α2 receptors: α2A, α2B,
neuron neuron and α2C. The most prevalent subtype in
the prefrontal cortex is the α2A receptor.
Alpha-2B receptors are mainly located
in the thalamus and are associated with
sedation sedative effects. Alpha-2C receptors
α 2B hypotension are located in the locus coeruleus, with
NET
sedation few in the prefrontal cortex. Besides
α2C being associated with hypotensive
effects, they also have sedative actions.
DA
In ADHD, clonidine and guanfacine – by
clonidine guanfacine stimulating postsynaptic receptors – can
increase NE signaling to normal levels.
The lack of action at postsynaptic DA
α2A α2A D1 D2 receptors parallels their lack of abuse
sedation + + + potential.
hypotension imidazoline
receptor +
+
+
Effects of an Alpha-2A Agonist in ADHD Figure 11-43 Effects of an α2A

agonist in ADHD. (A) The symptoms
of ADHD could hypothetically be
ADHD: Hypothetically Low Signals due to low norepinephrine (NE)
Due to Low NE levels in the prefrontal cortex (PFC),
without additional impairments in
dopamine (DA) neurotransmission.
The resulting scrambled signals may
manifest as hyperactivity, impulsivity,

and inattention. (B) Treatment with a
selective α2A agonist would lead to
VMPFC
increased signal via direct stimulation
of postsynaptic receptors, resulting in
an increased ability to sit still and focus.
noise signal NE concentration DA concentration
VMPFC: ventromedial prefrontal cortex.
NE low - signal reduced

sit still DA optimized - noise reduced
hyperactivity behave
impulsivity pay attention
inattention
A
Treatment with Alpha-2A Agonist
11
VMPFC
noise signal
sit still NE optimized - signal enhanced

hyperactivity behave
impulsivity pay attention DA optimized - noise reduced
inattention
483
postsynaptic receptors, and this would translate into the Augmenting a stimulant with an α2A agonist (Figure
patient being able to focus, sit still, and behave adequately 11-44C) could hypothetically solve the problem by
(Figure 11-43B). There is currently no way to identify optimizing the levels of NE, thus enhancing the signal,
these patients in advance, other than by an empiric trial in the presence of an already optimized DA output.
of guanfacine ER. Behaviorally, this could hypothetically result in a patient
Patients suffering from ADHD and oppositional cooperating and behaving appropriately. Guanfacine
symptoms can be argumentative, disobedient, aggressive, ER has been approved as an augmenting agent for
and exhibit temper tantrums (Figures 11-8 and 11-44A). patients inadequately responsive to stimulants, and
These behaviors are hypothetically linked to very low may be especially helpful in patients with oppositional
levels of NE and low levels of DA in the ventromedial symptoms.
prefrontal cortex (VMPFC), thus leading to much
Future Treatments for ADHD
reduced signal and increased noise (Figure 11-44A).
While treatment with a stimulant will improve the There are ever-evolving new technologies for drug
situation by reducing the noise, it would not solve delivery of amphetamine and methylphenidate and more
any strong hypothetical NE deficiencies (Figure 11- of these are in development, partly because they allow
44B), therefore only partially improving behavior. customization of the duration of desired therapeutic
Figure 11-44 How to treat ADHD and

How to Treat ADHD and Oppositional Symptoms oppositional symptoms. Argumentative,
disobedient, and aggressive behaviors
ADHD and Oppositional Symptoms: are often seen in patients suffering from
ADHD and oppositional symptoms. (A)
Hypothetically Very Low Signals in VMPFC These behaviors could theoretically be
due to very low levels of norepinephrine
VMPFC (NE) and low levels of dopamine (DA)

in the ventromedial prefrontal cortex
(VMPFC), leading to much reduced
noise signal signal and increased noise. (B) While
treatment with a stimulant may
NE concentration DA concentration reduce the noise, it will not solve the
behave strong NE deficiencies, therefore only
temper tantrums
argumentative cooperate NE very low - signal much reduced partially improving behavior. (C) The
disobedient DA low - noise increased augmentation of a stimulant with an
A aggressive α2A agonist could optimize the levels
of NE, thus enhancing the signal in the
presence of an already optimized DA
Treatment: Stimulant output.
VMPFC
noise signal
temper tantrums behave
argumentative cooperate NE still low - signal still reduced
disobedient DA optimized - noise reduced
aggressive
B
Treatment: Augment
Stimulant with Alpha-2A Agonist
VMPFC
noise signal
temper tantrums behave
argumentative cooperate NE optimized - signal increased
disobedient DA optimized - noise reduced
aggressive
C
484
Viloxazine ER The DAT inhibitor mazindol, once approved for

appetite suppression, is in testing and so is a triple (5HT–
NE–DA) reuptake inhibitor centanafadine.
SUMMARY
ADHD has core symptoms of inattentiveness, impulsivity,
5HT2B
and hyperactivity, linked theoretically to specific
NET malfunctioning neuronal circuits in the prefrontal
5HT2C
cortex. ADHD can also be conceptualized as a disorder
of dysregulation of norepinephrine and dopamine in
the prefrontal cortex, including some patients with
deficient norepinephrine and dopamine and others with
excessive norepinephrine and dopamine. Treatments
theoretically return patients to normal efficiency of
Figure 11-45 Viloxazine ER. Viloxazine is an inhibitor of
the norepinephrine transporter (NET) and also has actions at
information processing in prefrontal circuits. There are
serotonin 2B (5HT2B) and 5HT2C receptors. A controlled-release differences between children and adults with ADHD,
formulation is in late-stage clinical development for ADHD. and special considerations exist for how to treat these
two populations. The mechanisms of action, both in
terms of pharmacodynamics and pharmacokinetics,
action, and partially because they are patentable and for stimulant treatments of ADHD are discussed in
commercializable. One newer aspect of controlled-release detail. The goal is to amplify tonic but not phasic
formulations is the potential to make them in a matrix norepinephrine and dopamine actions in ADHD by
that resists attempts to powderize for inhaling, snorting, controlling the rate of stimulant drug delivery, the degree
smoking, or injecting. of transporter occupancy, and the duration of transporter
A selective NRI called viloxazine (Figure 11-45), occupancy. Theoretical mechanisms of action of selective
once marketed abroad for the treatment of depression norepinephrine reuptake inhibitors such as atomoxetine
but never marketed in the US, has been repurposed in a and their possible advantages in adults with chronic
controlled-release formulation for use in ADHD, and is stress and comorbidities are discussed. Actions of α2A-
now in late-stage clinical development for ADHD. adrenergic agonists are also presented.
11
485
Dementia: Causes,
12
Symptomatic Treatments,
and the Neurotransmitter
Network Acetylcholine
Dementia: Diagnosis and Causes 487 Targeting Glutamate for the Symptomatic Treatment
What Is Dementia? 487 of Memory and Cognition in Alzheimer Disease 515
What Is Mild Cognitive Impairment (MCI)? 487 Memantine 516
Four Major Causes of Dementia 488 Targeting the Behavioral Symptoms of Dementia 521
Pursuit of Disease-Modifying Therapies by Targeting Defining Agitation and Psychosis in Alzheimer
Aβ in Alzheimer Disease 496 Disease 521
The Amyloid Cascade Hypothesis 496 Pharmacological Treatment of Psychosis and Agitation
Current Status of the Amyloid Cascade Hypothesis in Dementia 523
and Treatments Targeting Aβ 499 Targeting Serotonin for the Symptomatic Treatment
Diagnosing Alzheimer Disease Before It Is Too of Dementia-Related Psychosis 524
Late 499 Neuronal Networks of Agitation in Alzheimer
Presymptomatic Stage 1 499 Disease 528
MCI Stage 2 500 Targeting Multimodal Neurotransmitters
(Norepinephrine, Serotonin, and Dopamine) for the
Dementia Stage 3 502
Symptomatic Treatment of Agitation in Alzheimer
Overview of Symptomatic Treatments for
Disease 530
Dementia 503
Targeting Glutamate for the Symptomatic Treatment
Targeting Acetylcholine for the Symptomatic
of Agitation in Alzheimer Disease 533
Treatment of Memory and Cognition in Alzheimer
Treating Depression in Dementia 534
Disease 505
Pseudobulbar Affect (Pathological Laughing and
Acetylcholine: Synthesis, Metabolism, Receptors, and
Crying) 535
Pathways 505
Apathy 536
Symptomatic Treatment of Memory and
Cognition in Alzheimer Disease by Inhibiting Other Treatments for the Behavioral Symptoms of
Acetylcholinesterase 509 Dementia 537
Summary 537
This chapter will provide a brief overview of the various reader with ideas about the clinical and biological aspects
causes of dementia and their pathologies, including the of dementia and its current management with various
most recent diagnostic criteria, and how biomarkers are approved drugs as well as novel agents on the horizon.
beginning to be integrated into clinical practice, especially Although hopes have faded for the early development of
for Alzheimer disease (AD). Full clinical and pathological disease-modifying treatments that could slow, halt, or
descriptions and formal criteria for how to diagnose reverse the pathological processes underlying dementia,
the numerous known dementias should be obtained by several new treatments improve behavioral symptoms
consulting standard reference sources. The discussion of dementia such as psychosis and agitation, which are
here will emphasize how various pathological mechanisms becoming more problematic as the number of patients
in different dementias disrupt brain circuits and their with dementia explodes. Thus, the emphasis here is on
neurotransmitters. We will also show how disruption the biological basis of symptoms of dementia and of their
of these brain circuits is linked to various symptoms of relief by psychopharmacological agents, as well as the
dementia, and how drugs targeting these brain circuits mechanism of action of drugs that treat these symptoms.
and their neurotransmitters lead to symptomatic For details of doses, side effects, drug interactions,
improvement, emphasizing memory, psychosis, and and other issues relevant to the prescribing of these
agitation. The goal of this chapter is to acquaint the drugs in clinical practice, the reader should consult
486
Chapter 12: Dementia: Causes, Symptomatic Treatments, and the Neurotransmitter Network Acetylcholine
standard drug handbooks (such as Stahl’s Essential Instead, MCI represents only mild cognitive decline
Psychopharmacology: the Prescriber’s Guide). that does not (yet) significantly affect the ability to
carry out activities of daily living. Not all patients with
DEMENTIA: DIAGNOSIS AND MCI will go on to develop dementia. In fact, there is
CAUSES great debate about what MCI is versus “normal aging.”
What Is Dementia? Table 12-1 All-cause dementia diagnosis
The term “dementia” describes cognitive and
All-cause dementia
neuropsychiatric symptoms severe enough to interfere
with the ability to perform usual activities, causing • Cognitive/neurospsychiatric symptoms that
definite decline from previous levels of functioning (Table interfere with ability to perform usual activities
• Decline from previous levels of functioning
12-1). These symptoms include cognitive dysfunction,
• Not attributable to delirium or a major psychiatric
memory loss, reasoning impairment, visual spatial disorder
impairment, language and communication issues, and • Cognitive impairment diagnosed through
behavioral symptoms such as psychosis and agitation neuropsychological testing or patient informant
(Table 12-1). • Cognitive impairment involves two of the
following:
What Is Mild Cognitive Impairment (MCI)? oo Impaired ability to acquire/retain new information
Mild cognitive impairment (MCI) is often confused oo Reasoning impairment
with dementia and is often a precursor of dementia but oo Visuospatial impairment
oo Changes in personality or behavior
MCI itself is not dementia (Figure 12-1 and Table 12-2).
Mild Cognitive Impairment Figure 12-1 Mild cognitive impairment

(MCI). Many older adults have
subjective memory complaints. A subset
of those adults has mild cognitive
impairment (MCI), which denotes the
presence of mild cognitive decline
that does not significantly affect the
ability to carry out activities of daily
living and does not meet the threshold
15-20% of for dementia. Although MCI is evident
in the early, prodromal stages of
individuals age 65+
Alzheimer disease (AD), not all patients
have MCI with MCI will go on to develop AD. In
fact, many individuals with cognitive
impairment may actually have a
psychiatric disorder (e.g., depression)
or a sleep disorder. Within 3 years,
approximately 35% of individuals with
MCI develop AD.
JUNE
35% of individuals
3 years
with MCI develop AD
12
487
Hopefully, the study of biomarkers and neuroimaging of MCI should be pursued vigorously, properly diagnosed,
will be able to settle this in the future. From a purely and treated whenever possible.
clinical perspective, over half of elderly residents living
in the community have four common subjective memory Four Major Causes of Dementia
complaints (SMCs). Compared to their functioning of Over 35 million individuals worldwide have some form
5 or 10 years ago, they experience diminished ability of dementia and this number is growing rapidly. There
(1) to remember names, (2) to find the correct word, are numerous causes of dementia with many different
(3) to remember where objects are located, and (4) to pathological origins, but these all have both overlapping
concentrate. When such complaints occur in the absence as well as distinctive clinical characteristics (Table 12-2)
of overt dementia, depression, anxiety disorder, sleep/ and neuroimaging findings (Table 12-3). The four major
wake disorder, pain disorder, or ADHD (attention deficit causes are AD, vascular dementia, Lewy body dementias
hyperactivity disorder), they are called MCI by many (LBD), and frontotemporal dementia (FTD) (Table 12-2
experts. Others reserve the term MCI only for those and Table 12-3).
in the earliest stages of AD (“predementia AD,” “MCI
due to AD,” or “prodromal AD”), but at this time it is Alzheimer Disease (AD)
not possible to determine those with SMCs who are Alzheimer disease (AD) is the most common cause of
destined to progress to AD and those who are not. Thus, dementia and arguably the most devastating age-related
MCI tends to be used as a general term encompassing disorder, with profound consequences to patients, family
all causes of subjective memory complaints. Attempts members, caregivers, and the economy. An estimated
are being made to use biomarkers to distinguish those 5.4 million Americans currently have AD and, in the
with normal aging from those with reversible conditions absence of any disease-modifying treatment, cases
such as depression, from those destined to progress to will more than double to 14 million by 2050. The three
AD or another dementia. On clinical grounds alone and pathological hallmarks of AD seen in the brain at autopsy
without biomarkers, studies show that between 6% and are: (1) amyloid-beta (Aβ), aggregated into plaques; (2)
15% of MCI patients convert to a diagnosis of dementia neurofibrillary tangles composed of hyperphosphorylated
every year; after 5 years about half meet the criteria tau protein; and (3) substantial neuronal cell loss
for dementia; after 10 years or autopsy, up to 80% will (Figure 12-2). The loss of neurons is often so profound
prove to have AD. Thus, MCI is not always a prodrome of that it can be seen with the naked eye upon postmortem
dementia, but it often is. Reversible and treatable causes examination of the brain (Figure 12-3).
Table 12-2 Differential diagnosis: clinical presentation
Mild cognitive Alzheimer disease Vascular dementia Lewy body Frontotemporal

impairment (MCI) (AD) dementias (LBD) degeneration (FTD)
Reduced speed of Short-term Impaired abstraction, Visual hallucinations Progressive
mental processing memory loss mental flexibility, Spontaneous behavioral and
and choice reaction Impaired executive processing speed, parkinsonism personality changes
times function and working memory Cognitive fluctuations that impair social
Benign Difficulty with Verbal memory is Visuospatial, attention, conduct (apathy,
forgetfulness that is activities of daily better preserved and executive function disinhibition, etc.)
mild, inconsistent, living Slower cognitive deficits are worse Language
and not associated Time and spatial decline Memory impairment is impairment
with functional disorientation Dementia occurs not as severe Possibly preserved
impairment Language within several months Earlier presentation episodic memory
impairment, of a stroke of psychosis and
personality personality changes
changes Rapid eye movement
(REM) sleep
disturbances
488
Table 12-3 Differential diagnosis: neural imaging
Alzheimer Vascular dementia Lewy body Frontotemporal

disease (AD) dementias (LBD) degeneration (FTD)
MRI Medial temporal Medial temporal lobe atrophy; Medial temporal lobe Medial temporal
lobe atrophy white matter abnormalities atrophy lobe atrophy
FDG PET Temporo-parietal Fronto-subcortical networks Parieto-occipital and Frontotemporal
cortices temporo-parietal cortices cortices
Figure 12-2 Alzheimer disease

Alzheimer Disease Pathology pathology. Two of the major pathological
hallmarks seen in the Alzheimer disease
brain at autopsy are plaques composed of
Aβ and neurofibrillary tangles composed
of hyperphosphorylated tau protein.
plaque
tangle

Alzheimer Disease Pathology: pathology: neuronal death. The third
Neuronal Death major pathological hallmark seen in
the Alzheimer disease (AD) brain at
Healthy brain AD brain autopsy is neuronal cell loss; it is often
so profound that it can be seen with the
naked eye on postmortem examination.
Loss of neurons occurs in limbic and
cortical regions and profoundly affects
cholinergic neurons, although other
neurotransmitter systems are also
impacted.
12
489
FDG PET
decreasing
glucose
metabolism
normal MCI Alzheimer disease
Figure 12-4 FDG PET. In living brains, neuronal loss in Alzheimer disease can be detected using 18F-2-fluoro-2-deoxy-D-glucose positron
emission tomography (FDG PET), which measures glucose metabolism in the brain. In the normal brain, glucose metabolism is robust. In mild
cognitive impairment (MCI), reductions in glucose metabolism are evident in more posterior brain regions such as the temporo-parietal cortex.
In Alzheimer disease (AD), glucose hypometabolism in posterior regions becomes even more evident. The FDG PET abnormalities seen in
patients with AD are believed to reflect accumulating neurodegeneration. FDG PET results can be informative but are not diagnostic for AD.
Magnetic Resonance Imaging Figure 12-5 Magnetic resonance

imaging. In living brains, neuronal
loss in Alzheimer disease (AD) can be
detected using magnetic resonance
imaging (MRI), particularly in the medial
temporal lobes; changes that have been
seen include hippocampal atrophy (A),
ventricular enlargement (B), and loss of
cortical thickness (C). MRI results can
be informative but are not diagnostic
for AD.
A B
hippocampal atrophy ventricular enlargement
loss of cortical thickness
Neuronal loss in AD can be detected in living in brain glucose metabolism in more posterior brain
patients by measuring brain glucose utilization, using regions such as temporo-parietal cortex (Figure 12-4).
fluorodeoxyglucose positron emission tomography (FDG As the disease progresses to full-blown AD, brain glucose
PET) (Figure 12-4). The brains of normal, healthy controls hypometabolism in posterior areas becomes more and
show robust glucose metabolism throughout the brain, but more evident on FDG PET (Figure 12-4). The worsening of
in mild cognitive impairment (MCI) there can be reduction glucose metabolism with the progression of AD is believed
490
to reflect accumulating neurodegeneration, especially in enlargement (Figure 12-5). By the time a patient begins to
key brain areas such as temporo-parietal cortices. exhibit even mild signs of dementia due to AD, damage to
Magnetic resonance imaging (MRI) can also detect loss the brain may already be extensive and irreversible.
of neurons in living patients with AD, particularly in the
Vascular Dementia
medial temporal lobes (Figure 12-5). Even patients with
mild AD may have 20–30% loss of entorhinal cortex volume, Vascular dementia is the second most common form
15–25% loss of hippocampal volume, as well as ventricular of dementia and accounts for about 20% of dementia
cases (Figure 12-6). Vascular dementia is essentially a
Vascular Dementia
FDG PET
Vascular Alzheimer’s
Alzheimer decreasing
Dementia Disease glucose
metabolism
MRI
12
Inccrreasing
Increasing g severity
severrity of w
white
white-matter
hite m
matter
atter h
hyperintensities
yperinttensitiess in V
Vascular
vascular
ascular D
Dementia
dementia
ementtia
Figure 12-6 Vascular dementia. Vascular dementia is a neurological manifestation of cardiovascular disease, with decreased
cerebral blood flow attributable to myriad pathologies including atherosclerosis, arteriosclerosis, infarcts, white-matter changes,
and microbleeds, as well as deposition of Aβ into cerebral blood vessels. Vascular dementia and Alzheimer disease (AD) frequently
overlap. In “pure” vascular dementia, the pattern of hypoperfusion on FDG PET is different than that for AD, with hypometabolism in
the sensorimotor and subcortical areas and a relative sparing of the association cortex. On MRI, patients with vascular dementia show
increasing severity of white-matter hyperintensities.
491
Alzheimer Disease/Vascular Dementia Comorbidity Figure 12-7 Alzheimer disease/vascular dementia

comorbidity. A large portion of individuals with Alzheimer
disease have comorbid vascular dementia pathology. This
is hypothesized to occur due to a dynamic relationship
between Aβ metabolism and cerebral vasculature integrity.
That is, the deposition of Aβ into cerebral blood vessels
hypothetically increases risk for vascular dementia;
conversely, loss of integrity and increased permeability of
the blood–brain barrier hypothetically increases production
or decreases clearance of Aβ.
Increased production/decreased
clearance of A
Loss of cerebral
blood-vessel integrity
Lewy Bodies and Lewy Neurites
neurological manifestation of cardiovascular disease,

with decreased cerebral blood flow attributable to Lewy bodies Lewy neurites
atherosclerosis, infarcts, white-matter changes, and

microbleeds, as well as deposition of Aβ into cerebral blood
vessels (Figure 12-6). In fact, approximately 30% of elderly
individuals who have a stroke will experience post-stroke
cognitive impairment and/or dementia. Many of the risk
factors associated with peripheral cardiovascular disease
(e.g., hypertension, smoking, heart disease, high cholesterol,
diabetes) are also linked with vascular dementia.
Vascular dementia and AD frequently overlap.
Relatively “pure” vascular dementia cases show a different
pattern of hypoperfusion (diminished blood flow) on
FDG PET than AD (Figure 12-6). In vascular dementia,
FDG PET indicates hypometabolism in sensorimotor and
subcortical areas, with relative sparing of the association Figure 12-8 Lewy bodies and Lewy neurites. The pathology of
cortex whereas – as mentioned above – in AD, FDG-PET both dementia with Lewy bodies (DLB) and Parkinson’s disease
dementia (PDD) includes the abnormal accumulation of a
scans show reduction in brain glucose metabolism in protein called α-synuclein. These aggregates form Lewy bodies
more posterior brain regions such as the temporo-parietal and Lewy neurites, which are observable upon histopathological
staining. In addition to α-synuclein, Lewy bodies and Lewy
cortex (Figures 12-4 and 12-6). neurites may also contain various other proteins, such as
A large portion of individuals with AD, however, also neurofilaments, parkin, and ubiquitin.
have comorbid vascular dementia pathology, and this
overlap may occur in part due to a dynamic relationship Lewy Body Dementias (LBD)
between Aβ metabolism and cerebral vasculature Dementia with Lewy bodies (DLB) and the related
integrity (Figure 12-7). That is, deposition of Aβ into Parkinson’s disease dementia (PDD) are collectively
cerebral blood vessels hypothetically increases the risk known as Lewy body dementias (LBD), and account
for vascular dementia and, conversely, loss of integrity for about 10–15% of all cases of dementia. However,
and increased permeability of the blood–brain barrier only an estimated 20% of LBD patients have “pure” LBD
hypothetically increases production or reduces clearance since approximately 80% of LBD patients will also have
of Aβ from the brain (Figure 12-7). pathological features of other dementias, especially AD
492
Table 12-4 Dementia with Lewy bodies (DLB): diagnosis pathology. DLB and PDD share pathological links to the
Presence of Dementia abnormal accumulation of a protein called α-synuclein,
and thus both are also called “synucleinopathies.” In LBD,
core features
for unknown reasons, α-synuclein proteins aggregate to
• Fluctuating attention and concentration
• Recurrent well-formed visual hallucinations form oligomers, eventually turning into “Lewy bodies”
• Spontaneous parkinsonism and Lewy neurites, as neurons degenerate (Figure 12-8).
The diagnostic criteria for the diagnosis of probable
suggestive clinical features
• Rapid eye movement (REM) sleep behavior disorder DLB and for possible DLB are given in Table 12-4.
• Severe neuroleptic sensitivity In terms of PDD, the majority (~80%) of patients
• Low dopamine transporters uptake in basal with Parkinson’s disease (PD) will develop cognitive
ganglia on SPECT or PET dysfunction from one cause or another as the disease
supportive clinical features progresses, with the average time from diagnosis of PD
• Repeated falls to onset of dementia being 10 years. PDD is associated
• Transient loss of consciousness with increased morbidity and death ultimately occurring,
• Hallucinations in other sensory modalities on average, 4 years after PDD onset. As with AD, the
• Severe autonomic dysfunction harbinger of dementia in PD is often MCI. Symptoms
• Depression of PDD include impairments in memory (including
• Delusions
recognition), executive dysfunction, deficits in attention,
• Syncope
and altered visual perception. The pathological basis for
factors that make dlb diagnosis less likely PDD is hypothesized to be neuronal degeneration and
• Presence of cerebrovascular disease
atrophy occurring in the thalamus, caudate nucleus,
• Presence of any other physical illness or brain
disorder that may account in part or in total for the
and hippocampus, as Lewy bodies and Lewy neurites
clinical picture accumulate there (Figure 12-9). Lewy body pathology
• Parkinsonism appears for the first time at a stage is also often found in neocortical areas; however, the
of severe dementia
Figure 12-9 Parkinson’s disease dementia. The

Parkinson’s Disease Dementia pathological basis for Parkinson’s disease
dementia (PDD) is hypothesized to be neuronal
degeneration and atrophy occurring in the
thalamus, caudate nucleus, and hippocampus.
Lewy body pathology is also often found in
neocortical areas; however, the severity of
dementia in Parkinson’s disease correlates with
neocortex the severity of α-synuclein (as well as amyloid and
caudate nucleus tau) pathology in limbic regions.
12
thalamus
hippocampus
493
severity of α-synuclein (as well as amyloid and tau) pathology. DLB shares many neuropsychiatric features
pathology in limbic regions correlates with the severity with AD as well as many motor features (albeit often less
of dementia in PDD. There is much debate over whether severe) with PD. Due to this overlap in pathology and
DLB and PDD are actually the same disease with clinical presentation, some now propose that AD and PD
slightly different clinical expression and progression, may lie on opposite ends of a spectrum, with DLB falling
or two distinct diseases (Figure 12-10). Certainly, PDD somewhere between AD and PD (Figure 12-11). It has
and DLB share many pathophysiological and clinical been proposed that an individual’s neuropsychiatric and
characteristics, and the differential diagnosis between physical clinical presentation may be a result of the unique
DLB and PDD relies mainly on when there is onset of combination of pathological proteins present in the brain
motor symptoms versus when there is onset of dementia. as well as the particular brain regions most affected (i.e.,
That is, if motor symptoms precede dementia by 1 year or more or less AD pathology plus more or less PD pathology
more, the diagnosis is PDD; however, if dementia occurs combined with a cortical versus subcortical abundance of
at the same time or precedes the onset of parkinsonism, pathology determines where they land on the spectrum.)
the diagnosis is DLB. Many argue that this “1-year rule” is
Frontotemporal Dementia
arbitrary and offers little in terms of treatment guidance.
Although AD and PD have historically been viewed as Frontotemporal dementia (FTD) is about as common as
two distinct entities, the overlap between the disorders LBD, with a worldwide prevalence of 3–26% in individuals
has increasingly been recognized. As many as 70% of aged 65 years and older and an average age of onset of 50–
patients with AD eventually show extrapyramidal and 65 years. FTD (Figure 12-12) is divided into four subtypes:
parkinsonian symptoms, and Lewy bodies are seen in a behavioral variant (bvFTD) (Table 12-5), and three
~30% of patients with AD. Likewise, ~50% of patients primary progressive aphasia variants (Figure 12-12). The
with PD develop dementia and often have Alzheimer-type behavioral variant, bvFTD, the most common of the FTD
subtypes, usually presents with gradual and progressive
personality changes (such as disinhibition, apathy, and
Differential Diagnosis: Dementia with Lewy loss of sympathy and empathy), hyperorality, perseverative
Bodies vs. Parkinson’s Disease Dementia
or compulsive behaviors, and, eventually, cognitive deficits
with a general sparing of visuospatial abilities. Patients
with bvFTD are often unaware of their inappropriate
Motor symptoms precede dementia
by at least 1 year behaviors, and contrary to patients with AD, do not
typically have rapid memory loss and may do fairly well
in memory tasks if provided cues. Pathologically, bvFTD
PDD is characterized by frontal and anterior temporal cortex
atrophy, particularly the prefrontal cortex, insula, anterior
cingulate, striatum, and thalamus, with the non-dominant
hemisphere typically more affected. The diagnosis of
FTD can be somewhat complex as clinical presentation
and pathology often overlap with those of several other
Dementia occurs at the same
time or precedes motor symptoms dementias, and many patients exhibit parkinsonian-like
by up to 1 year features. FTD can often be differentiated from AD by the
absence of AD biomarkers.
DLB Frontotemporal lobar degeneration (FTLD) is an
umbrella term describing a group of different disorders
with varying clinical presentations, genetics, and
pathophysiology. We have already mentioned that
Figure 12-10 Dementia with Lewy bodies versus Parkinson’s
aggregation of phosphorylated tau into neurofibrillary
disease dementia. Dementia with Lewy bodies (DLB) and tangles is a hallmark feature of AD (Figure 12-2).
Parkinson’s disease dementia (PDD) share many pathophysiological Mutations in the gene coding for the tau protein
and clinical characteristics. The differential diagnosis relies mainly on
the onset of motor symptoms versus the onset of dementia. If motor (microtubule-associated protein tau; MAPT) is actually
symptoms precede dementia by 1 year or more, the diagnosis is not associated with AD but with several forms of FTLD
PDD. If dementia occurs at the same time or precedes the onset of
parkinsonism, the diagnosis is DLB. Many argue that this “1-year that may have aggregation and progression of tau
rule” is arbitrary and offers little in terms of treatment guidance. pathology (Figure 12-13).
494
Figure 12-11 Parkinson’s disease–

Parkinson's Disease-Alzheimer Disease Alzheimer disease spectrum
hypothesis. There are clinical and
Spectrum Hypothesis pathological overlaps between
Parkinson’s disease (PD) and Alzheimer
disease (AD). As many as 70% of
AD DLB PD patients with AD eventually show
extrapyramidal and parkinsonian
symptoms, and Lewy bodies are seen
in approximately 30% of patients with
AD. Likewise, approximately half of
patients with PD develop dementia and
often have Alzheimer-type pathology.
Dementia with Lewy bodies (DLB)
shares many neuropsychiatric features
with AD as well as many motor features
(albeit often less severe) with PD. Due
to this overlap in pathology and clinical
Lewy Body Pathology and Motor Dysfunction presentation, some now propose
that AD and PD may lie on opposite
ends of a spectrum, with DLB falling
somewhere between AD and PD. It
has been proposed that an individual’s
A /Tau Pathology and Memory Deficits clinical presentation may be a result of
the unique combination of pathological
proteins present in the brain as well
as the particular brain regions most
affected.
A NFT Lewy body
neurofibrillary tangle
Frontotemporal Dementia
Table 12-5 Behavioral variant frontotemporal dementia (bvFTD)
FTD Clinical presentation

Progressive personality changes:
• disinhibition
• apathy
bvFTD Primary Progressive Aphasias
• loss of sympathy/empathy
Hyperorality
Perseverative/compulsive behaviors
Cognitive deficits
svPPA nfvPPA IvPPA
Cued memory and visuospatial abilities spared
Pathological presentation
Figure 12-12 Frontotemporal dementia. Frontotemporal Atrophy in:
dementia (FTD) is divided into four subtypes: behavioral variant
FTD (bvFTD) and three primary progressive aphasias (semantic • prefrontal cortex
variant primary progressive aphasia [svPPA], non-fluent variant • insula
primary progressive aphasia [nfvPPA]), and logopenic variant • anterior cingulate
primary progressive aphasia [lvPPA]); bvFTD is the most
common subtype. The diagnosis of FTD can be somewhat • striatum
complex as clinical presentation and pathology often overlap • thalamus 12
with that of other dementias. FTD can often be differentiated Non-dominant hemisphere more affected
from Alzheimer disease (AD) by the absence of AD biomarkers.
Mixed Dementia clinical practice (Figure 12-14). Postmortem analyses

As can be seen from our discussion so far, many indeed reveal that most dementia patients exhibit mixed
individuals present with the clinical, neuroimaging, and pathology, comprising various combinations of abnormal
pathological characteristics of more than one dementia protein aggregates plus vascular changes (Figure 12-14).
(i.e., “mixed dementia”), making distinctions amongst If each dementia were not complicated enough,
the various causes of dementia often very difficult in combinations of dementia in a single individual
495
compound the complexity of diagnosis and eventually underlying pathologies (AD in combination with either
will compound the complexity of treatment. For LBD, cerebrovascular injuries, or both). After adjusting
example, in one study of community-dwelling adults, for age, individuals with multiple diagnoses were deemed
56% of dementia patients were diagnosed with multiple to be nearly three times more likely to develop dementia
as those with a single underlying pathology. In another
study, 59–68% of patients with AD neuropathology also
Microtubule-Associated Protein Tau (MAPT)
displayed Lewy body pathology or vascular brain injury.
Differential diagnosis of the various dementias during life
Mutations in MAPT gene will become more important when specific treatments for
specific forms of dementia become available. However,
most patients will have more than one cause of dementia
Altered ratio of tau 3R and 4R isoforms
and ultimately may require more than one type of
treatment.
3R tau (three micr otubule-
binding domains) PURSUIT OF DISEASE-
MODIFYING THERAPIES BY
TARGETING Aß IN ALZHEIMER
DISEASE
4R tau (four The Amyloid Cascade Hypothesis
microtubule-
binding domains) According to this hypothesis, Alzheimer disease (AD) is
microtubule caused by the accumulation of toxic Aβ, which form into
plaques, hyperphosphorylation of tau, neurofibrillary
tangle formation, synaptic dysfunction, and ultimately
Figure 12-13 Microtubule-associated protein tau. Mutations
in the gene coding for the tau protein (microtubule-associated neuron loss with memory loss and dementia (Figure 12-
protein tau; MAPT) are associated with several forms of 15). This notion is somewhat analogous to how abnormal
frontotemporal lobar degeneration. Typically, these mutations
change the ratio of tau 3R and 4R isoforms, leading to an
deposition of cholesterol in blood vessels is thought to
accumulation of pathological tau. cause atherosclerosis. A corollary to the amyloid cascade
Figure 12-14 Mixed dementia. Dementias

Mixed Dementia with only one type of pathology are likely the
exception rather than the rule. Postmortem
pathological analyses reveal that most patients
No pathology Non-AD pathology only with dementia have mixed pathology, comprising
AD pathology only Vascular pathology only various combinations of abnormal protein
aggregates and vascular changes.
AD + Non-AD pathology Non-AD + Vascular pathology
AD + Vascular pathology AD + Non-AD + Vascular pathology
1%1% 3%
5%
8%
8%
47%
27%
496
hypothesis is that if the cascade could be blocked and Table 12-6 Potential disease-modifying treatments for
Alzheimer disease
Aβ prevented from forming, aggregating, and creating
plaques and tangles, AD would be prevented, halted, or Agents targeting Aß pathology
even reversed. Anti-amyloid antibodies
Aβ is formed when a precursor protein (amyloid Active Aβ immunization
precursor protein or APP) is cut by enzymes into ß-secretase inhibitors
smaller peptides (Figures 12-16 and 12-17). There γ-secretase inhibitors
are two enzymatic cleavage pathways by which APP α-secretase promoters
may be processed: the non-amyloidogenic and the Aβ aggregation inhibitors
amyloidogenic pathways. In the non-amyloidogenic Agents targeting tau pathology
pathway, APP is cleaved by the enzyme α-secretase Anti-tau antibodies
directly in the portion of APP where Aβ sits; thus, Active tau immunization
processing of APP by α-secretase thereby precludes Tau aggregation inhibitors
production of Aβ. In the amyloidogenic pathway, APP Microtubule stabilizers
is first cleaved by β-secretase and then by γ-secretase Tau phosphorylation inhibitors
(Figure 12-16). Gamma-secretase cuts APP into several
Aβ peptides, ranging from 38 to 43 amino acids long Mutations in several genes associated with AD lead
(Figure 12-17). The Aβ40 isoform is the most common to increased processing of APP via the amyloidogenic
form; however, the Aβ42 isoform is more prone to pathway, supporting the amyloid cascade hypothesis.
aggregation into oligomers and is considered the more Another genetic factor related to Aβ processing that
toxic form of Aβ peptides. The Aβ43 isoform is relatively is linked to AD is the gene (called APOE) for a protein
rare but is thought to be even more prone to aggregation called apolipoprotein E (ApoE), which transports the
than Aβ42. The Aβ-processing enzymes α-, β-, and cholesterol needed by neurons for synapse development,
γ-secretase have all been the targets of novel potential dendrite formation, long-term potentiation, and axonal
treatments for AD in the hopes that by preventing the guidance. ApoE protein is also hypothesized to have an
processing of APP into amyloidogenic peptides, this intricate relationship with Aβ metabolism, aggregation,
would prevent AD (Table 12-6). Unfortunately, to date, and deposition in the brain. There are several forms of
these therapeutic approaches have been ineffective, the APOE gene (Figure 12-18). Inheritance of even one
unsafe, or both. copy of the APOE4 gene results in a threefold increase in
Figure 12-15 Importance of early

The Importance of Early Detection detection. Alzheimer disease is
hypothesized to be caused by increased
synaptic production and/or reduced degradation
increased of Aβ leading to plaque formation,
dysfunction hyperphosphorylation of tau, and
production/ and neuron neurofibrillary tangle (NFT) formation,
reduced hyperphosphorylation loss synaptic dysfunction, and ultimately
degradation of of tau neuronal cell loss that presents with
amyloid beta P memory loss and cognitive deficits.
P
P
P
Intervention at the stage of obvious
P
memory loss and cognitive decline may
P
P
P
P
be too late, as neurodegeneration has
P
P
P
already occurred. If intervention were
plaque NFT possible much earlier, then perhaps 12
the cascade of toxic events could be
formation formation memory loss/ avoided.
cognitive deficits
Intervene here? Too late for

intervention
497
Figure 12-16 Amyloid precursor

Amyloid Precursor Protein protein. The Aβ peptide is cut from
a larger protein called the amyloid
precursor protein (APP). There are two
NH2 COOH cleavage pathways by which APP may
be processed: the non-amyloidogenic
and the amyloidogenic pathways. In
the non-amyloidogenic pathway, APP is
cleaved by an enzyme termed α-secretase
directly in the portion of APP where Aβ
sits; processing of APP by α-secretase
thereby precludes production of Aβ. In
Non-amyloidogenic pathway the amyloidogenic pathway, APP is first
cleaved by β-secretase at the amino (NH2)
border of Aβ and then by γ-secretase.
NH2 COOH
-secretase
Amyloidogenic pathway
COOH
NH2
-secretase
-secretase
Amyloid-Beta Isoforms Figure 12-17 Aβ isoforms. Gamma-secretase cuts

APP into several Aβ peptides, ranging from 38 to
43 amino acids long. The Aβ40 isoform is the most
common form; however, the Aβ42 isoform is more
prone to aggregation into oligomers. The Aβ43
isoform is relatively rare but is thought to be even
more prone to aggregation than the Aβ42 isoform.
-secretase
Most common isoform

40 Less prone to aggregation
Less common isoform

42 More prone to aggregation
Rare isoform
43 Most prone to aggregation
498
the risk of developing AD; inheritance of two copies of AD (Table 12-6). Given the many failures of treatments
APOE4 leads to a tenfold increased AD risk. Conversely, that target Aβ in AD, not all experts are convinced any
the APOE2 gene appears to offer some protection from AD more that the amyloid cascade hypothesis is correct. An
whereas the APOE3 gene (the most common form of the alternate theory is that Aβ formation is an epiphenomenon
APOE gene) conveys a risk that falls between APOE2 and in AD that occurs simultaneously alongside
APOE4. Approximately 15% of individuals in the general neurodegeneration and thus is only a “tombstone” serving
population carry the APOE4 allele (Figure 12-18). However, as a marker of neuronal death, but is not the cause of
amongst individuals with AD, 44% carry the APOE4 allele. neurodegeneration. Just as eliminating all tombstones
will not halt people from dying, eliminating Aβ will not
Current Status of the Amyloid Cascade Hypothesis
necessarily prevent neurons from degenerating in AD.
and Treatments Targeting Aß
On the other hand, remaining proponents of the
The amyloid cascade hypothesis has dominated thinking amyloid cascade hypothesis claim that previous anti-Aβ
about the pathogenesis of AD for over 30 years, and clinical trials have failed not because the hypothesis is
has led to a several-decades-long pursuit of treatments wrong, but because the subjects enrolled in such trials
targeting Aβ in the hope that this would prevent, halt, or have progressed too far in terms of irreversible damage
even reverse AD. Although numerous drugs have been to the brain (Figure 12-15). The many negative trials of
developed that successfully engage Aβ-related targets, Aβ-targeting therapies have all enrolled patients with
none has (yet) been shown to have therapeutic benefit in clinically diagnosable AD or MCI and supporters of
the amyloid cascade hypothesis theorize that once the
Apolipoprotein E amyloid cascade is set into motion, the detrimental effects
(including oxidative stress, inflammation, the formation
of neurofibrillary tangles, and synaptic dysfunction)
may become a self-perpetuating cycle of destruction
whereby further Aβ accumulation becomes irrelevant
(Figure 12-15). Accordingly, these proponents believe
8% 15% that anti-Aβ therapies must be initiated at the earliest
sign of Aβ accumulation possible – before the amyloid
cascade is irreversibly set into motion and consequently
before clinical signs of AD or even MCI are evident. Thus,
for successful future treatment, there is the need to be
able to diagnose AD in the asymptomatic stage. To that
77%
end, a great deal of research has focused on diagnosing
AD not only long before death but also long before
neurodegeneration sets in. Thus, AD is now conceptualized
as occurring in three stages: presymptomatic, MCI, and
dementia stages (Figure 12-19).
DIAGNOSING ALZHEIMER
Figure 12-18 Apolipoprotein E. Of the genetic factors that
contribute to the risk of developing Alzheimer disease (AD), the DISEASE BEFORE IT IS TOO LATE
gene for apolipoprotein E (ApoE) appears to have the greatest
influence. ApoE is a protein that transports the cholesterol
needed by neurons for synapse development, dendrite Presymptomatic Stage 1
formation, long-term potentiation, and axonal guidance. ApoE
The presymptomatic stage 1 of AD (Figure 12-19) is also 12
is also hypothesized to affect Aβ metabolism, aggregation,
and deposition in the brain. Inheritance of even one copy of called asymptomatic amyloidosis. The neurodegenerative
the APOE4 allele results in a threefold increase in the risk of
developing AD; inheritance of two copies of APOE4 leads process in AD appears to start silently as Aβ accumulates in
to a tenfold increased risk of developing AD. Approximately the brain. Aβ is detectable at the presymptomatic stage of
15% of individuals in the general population carry the APOE4
allele; however, among individuals with AD, 44% carry the
AD using PET scans and radioactive neuroimaging tracers
APOE4 allele. Conversely, the APOE2 allele appears to offer that label Aβ plaques (Figure 12-20). It is rarely detected in
some protection from AD, whereas the APOE3 allele (the most
common form of the APOE gene) conveys a risk that falls
the brains of individuals under the age of 50 and although
between APOE2 and APOE4. most cognitively normal healthy elderly people show no
499
Three Stages of Alzheimer Disease
amyloid PET
CSF Aβ
asymptomatic
amyloidosis FDG PET
100%
1. presymptomatic
CSF tau
MRI
neurodegeneration
cognitive function
2. MCI episodic memory

no dementia
3. dementia
0%
actual disease apparent current diagnosis

onset (amyloidosis) neurodegeneration made and
and actual symptomatic
symptom onset treatments given
Figure 12-19 The three stages of Alzheimer disease. Stage 1 of Alzheimer disease (AD) is called presymptomatic or asymptomatic
amyloidosis. During stage 1, cognition is intact despite elevated levels of Aβ in the brain as evidenced by both positive Aβ positron
emission tomography (PET) and reduced levels of Aβ toxic peptides in cerebrospinal fluid (CSF). In the second stage, clinical signs of
cognitive impairment in the form of episodic memory deficits begin to manifest. The onset of clinical symptoms in stage 2 appears to be
correlated with neurodegeneration, as evidenced by elevated CSF tau, brain glucose hypometabolism on fluorodeoxyglucose positron
emission tomography (FDG PET) scans, and volume loss in key brain regions on magnetic resonance imaging (MRI) scans. During stage
3 of AD (dementia), cognitive deficits can be severe. Currently, treatment of AD symptoms does not typically begin until stage 3, long
after the actual disease onset.
fluid (CSF) levels of Aβ are also low at this stage of the

evidence of Aβ deposition (Figure 12-20A), about a quarter illness because Aβ is being deposited in the brain instead of
of cognitively normal elderly controls are Aβ positive leaving the brain (Figure 12-19).
(Figure 12-20B and Figure 12-21), and are thus considered
to have presymptomatic AD. Seeing Aβ on a PET scan MCI Stage 2
may mean that the fuse is already lit for the development The second stage of AD is called “predementia AD,” or
of AD even if there are no symptoms yet. Cerebrospinal “MCI due to AD,” or even “prodromal AD.” These patients
500
A. Normal controls, no amyloid B. Normal controls, amyloid moderately positive Figure 12-20 Aβ PET imaging. Positron emission
tomography (PET) using Aβ tracers can be used to
detect the presence of Aβ during the progression
of Alzheimer disease (AD). (A) In most cognitively
normal controls, Aβ PET imaging shows the absence
of Aβ. (B) Individuals who are cognitively normal but
have moderate accumulation of Aβ are likely in the
presymptomatic first stage of AD. (C) Although mild
cognitive impairment (MCI) is often present in the
prodromal second stage of AD, not all patients with
increasing MCI have brain Aβ deposition. In such cases, the clinical
amyloid presence of cognitive impairments is likely attributable
to a cause other than AD. (D) Unfortunately, MCI is
often a harbinger of impending AD. In these cases, Aβ
deposition accompanies cognitive impairments. (E) Both
Aβ accumulation and clinical symptoms of MCI worsen
as AD progresses. (F) In the third and final stage of AD,
when full-blown dementia is clinically evident, a large
accumulation of brain Aβ can readily be seen.
C. MCI amyloid negative D. MCI amyloid moderately positive
increasing
amyloid
E. MCI more severe F. Alzheimer Disease
increasing
amyloid
12
501
have progressed from asymptomatic amyloidosis and (Figure 12-20C), and presumably have a cause of their
stage 1 AD to stage 2 AD by manifesting both the clinical mild cognitive symptoms other than AD, including
symptoms of MCI and the signs of neurodegeneration. depression or another dementia-causing disorder
Neurodegeneration is demonstrated by the presence of (Table 12-2). The other half of MCI patients do indeed
elevated tau protein levels in CSF, by atrophy on MRI show either moderate (Figure 12-20D) or severe Aβ
or by the presence of neurofilament light (NfL) in CSF deposition (Figure 12-20E) and almost 100% of patients
or possibly plasma. Tau is a microtubule-associated with clinically probable AD (stage 3 AD with dementia)
binding protein and, in its nonpathological form, show heavy Aβ deposition (Figure 12-20F). About half
binds to and stabilizes microtubules within axonal of Aβ-positive MCI patients progress to dementia within
projections (Figure 12-22A). Synaptic vesicles carrying a year, and 80% may progress to dementia within 3
neurotransmitters are normally transported along these years. However, it is really neurodegeneration and not
microtubules to the synapse (Figure 12-22A). When amyloidosis that is thought to drive stage 1 AD to stage
hyperphosphorylated, tau is no longer able to bind 2 with MCI symptoms, as well as to drive stage 2 AD to
microtubules, so microtubules become destabilized stage 3 dementia.
and synaptic dysfunction results (Figure 12-22B).
Dementia Stage 3
Hyperphosphorylated tau also forms paired helical
filaments which aggregate into neurofibrillary tangles The final stage of AD is dementia (Figure 12-19). To
(NFTs), one of the hallmarks of AD (Figure 12-22C). diagnose probable AD by clinical criteria, the patient
As neurodegeneration and neuronal loss progresses, must first meet the diagnostic criteria for all-cause
tau levels rise in CSF. Neuroimaging can also show dementia (see Table 12-1). In addition, the patient must
neurodegeneration on MRI (Figure 12-5) or FDG PET have a dementia which is insidious in onset with clearly
(Figure 12-4). Hypometabolic FDG PET in MCI subjects demonstrated worsening of cognition over time, and
predicts progression to dementia of up to 80–90% within either an amnestic (problems with learning and recall)
1–1.5 years. or a non-amnestic presentation (language, visuospatial,
Stage 2 AD now is symptomatic with MCI, but not all or executive dysfunction). Probable AD with evidence
MCI patients have measurable amyloidosis (Figure 12- of the Alzheimer pathophysiological process includes
20C, D, and E). All MCI patients are presumed therefore clearly positive biomarker evidence either of brain Aβ
not to be on a trajectory towards AD. In fact, about half deposition/amyloidosis (Figure 12-20), or of downstream
of patients with MCI show no evidence of Aβ deposition neuronal degeneration (Figures 12-4 and 12-5).
Does the Presence of Mean Alzheimer Figure 12-21 Aβ and risk of Alzheimer
disease. Not all individuals with Aβ
Disease Is Inevitable? detectable in the brain have Alzheimer
disease. Although the presence of
Aβ has been associated with slightly
poorer cognitive performance,
approximately 25–35% of individuals
Age 50-60 Age 60-70 Age 70-80 Age 80-90 with Aβ accumulation in the brain
perform within normal limits on tests of
cognition. Some hypothesize that such
individuals may be in the preclinical or
prodromal phases of dementia and will
inevitably develop dementia should
they live long enough.
<5% 10% 25% >50%
Percentage of Individuals with in the Brain
502

pathology: tangles. Tau is a microtubule-
associated binding protein. (A) In its non-
pathological form, it binds to and stabilizes
microtubules within axonal projections. It
is along these microtubules that synaptic
vesicles carrying neurotransmitters are
transported to the synapse. (B) When
tau is hyperphosphorylated, it is no
longer able to bind microtubules, which
causes destabilization of microtubules
and leads to synaptic dysfunction. (C)
Hyperphosphorylated tau also forms paired
helical filaments, which then aggregate into
neurofibrillary tangles (NFTs).
NFT
OVERVIEW OF SYMPTOMATIC symptoms in psychiatric disorders are topographically

localized to hypothetically malfunctioning brain circuits,
TREATMENTS FOR DEMENTIA whether in psychosis, depression, mania, anxiety,
The first approved treatments for AD target the sleep, pain, ADHD, or dementia. Furthermore, this
symptoms of cognitive and memory decline, but do not point of view incorporates the possibility that the same
halt the relentless march of neurodegeneration. They symptom can appear in many different disorders if
are symptomatic treatments, but not disease-modifying the same circuit is malfunctioning. Thus, for example,
treatments. As hopes fade for early development of psychotic symptoms can appear in dementia as well as
treatments that can prevent, halt, or reverse AD, new schizophrenia, hypothetically because the same circuit
drug development has pivoted back to treating the malfunctions in both conditions. Specifically, psychotic
symptoms of dementia to improve the suffering of symptoms seem to be related to pathology in the
patients and to reduce the burden of their caregivers neocortex, and like all symptoms in dementia (e.g. visual
as the number of people who have dementia explodes. versus auditory hallucinations, delusions, disturbances in
These treatments target neurotransmitters in different memory and cognition, agitation; Figure 12-23) each is 12
brain circuits that hypothetically regulate the different likely to reflect damage to unique cortical areas.
symptoms in dementia (Figure 12-23). This treatment Treatment strategies for symptoms in dementia
approach is based upon the notion that different likewise arise from this notion that each symptom
symptoms in dementia arise from different anatomical is hypothetically regulated by a unique network or
sites of neurodegeneration no matter what the cause of circuit of neurons. Each network connects specific
that neurodegeneration (Figure 12-23). This is the same glutamate, GABA (γ-aminobutyric acid), serotonin, and
concept developed throughout this book that behavioral dopamine neurons at nodes (synapses) between these
503
Circuits of Treatable Symptoms in Dementia
memory network psychosis network agitation network
dextromethorphan+
bupropion
pimavanserin
AChE
cortex cortex cortex brexpiprazole
memantine
memory output psychosis output agitation output
A B C
Acetylcholinesterase inhibitors 5HT2A antagonist NMDA antagonist DXM

and NMDA antagonist pimavanserin for and multifunctional
memantine for psychosis 1, 2, D2, 5HT1A, 5HT2A
memory brexpiprazole for
agitation
plaque tangle
stroke
Figure 12-23 Circuits of treatable symptoms in dementia. Treatment of dementia is currently symptomatic rather than disease-modifying.
There are three main treatable symptoms in dementia: memory problems, psychosis, and agitation. Treatment strategies for each of these
symptoms arise from the notion that each symptom is hypothetically regulated by a unique network or circuit of neurons. Each network
connects specific glutamate, GABA (γ-aminobutyric acid), serotonin, and dopamine neurons at nodes (synapses) between these different
neurons that can influence not only the neuron being directly innervated but the entire network, via downstream effects set in motion at the
node. (A) Acetylcholine and glutamate can be targeted by acetylcholinesterase (AChE) inhibitors and the NMDA (N-methyl-D-aspartate)
antagonist memantine, respectively, to improve cognition in the memory network. (B) Psychosis can be targeted at the serotonin node
as well as the dopamine node of the psychosis network. In particular, the 5HT2A antagonist pimavanserin is approved to treat psychosis
in Parkinson’s disease. (C) Multimodal neurotransmitters (norepinephrine, serotonin, dopamine, and glutamate) can be targeted in the
agitation network to improve the symptom of agitation in dementia. The NMDA antagonist dextromethorphan (DXM) in combination with
bupropion and the multimodal agent brexpiprazole are both being studied for their use in agitation associated with dementia.
different neurons that can influence not only the neuron

being directly innervated but the entire network, via can be targeted at different nodes to improve cognition
downstream effects set in motion at the node. Nodes are in the memory network (Figure 12-23A). Similarly,
the sites of potential therapeutic action by targeting them we now know that psychosis can be therapeutically
with drugs acting on the neurotransmitters normally targeted at the serotonin node as well as the dopamine
working at that node. Thus, acetylcholine and glutamate node of the psychosis network, since both are mutually
504
connected in the same neuronal network (see discussion 25). As will be discussed below, some cholinesterase
in Chapter 4 and Figure 12-23B). Finally, multimodal inhibitors specifically inhibit AChE, whereas others
neurotransmitters (norepinephrine, serotonin, dopamine, inhibit both enzymes. It is AChE that is thought to be the
and glutamate) can be targeted in the agitation network key enzyme for inactivating ACh at cholinergic synapses
to improve the symptom of agitation in dementia (Figure (Figure 12-25), although BuChE can take on this activity
12-23C). This strategy explains why treatment of the if ACh diffuses to nearby glia. AChE is also present in
behavioral symptoms of dementia, particularly psychosis the gut, skeletal muscle, red blood cells, lymphocytes,
and agitation, have made notable progress recently, with and platelets. BuChE is also present in the gut, plasma,
several new drugs on the horizon. skeletal muscle, placenta, and liver. BuChE may be
present in some specific neurons, and it may also be
TARGETING ACETYLCHOLINE present in Aβ plaques.
FOR THE SYMPTOMATIC ACh released from central nervous system neurons is
TREATMENT OF MEMORY AND destroyed too quickly and too completely by AChE to be
COGNITION IN ALZHEIMER available for transport back into the presynaptic neuron;
DISEASE however, the choline that is formed by the breakdown
of ACh is readily transported back into the presynaptic
Degeneration of cholinergic neurons is thought to cholinergic nerve terminal by a transporter similar to
underlie in part some of the earliest symptoms of the transporters for other neurotransmitters already
memory disturbance as MCI progresses to dementia in discussed earlier in relationship to norepinephrine,
AD. Before discussing how targeting this hypothetical dopamine, and serotonin neurons. Once back in the
deficiency in acetylcholine neurotransmission underlies presynaptic nerve terminal, it can be recycled into new
the symptomatic improvement in memory and cognition
by various approved drugs for AD, it is important to
understand acetylcholine neurotransmission, receptors, Acetylcholine Is Produced
and brain circuits.
Acetylcholine: Synthesis, Metabolism, Receptors, and
Pathways
Acetylcholine is formed in cholinergic neurons from
two precursors: choline and acetyl coenzyme A (AcCoA)
(Figure 12-24). Choline is derived from dietary and
intraneuronal sources, and AcCoA is made from glucose
ChAT
glucose in the mitochondria of the neuron. These two choline
substrates interact with the synthetic enzyme choline AcCoA
acetyltransferase (ChAT) to produce the neurotransmitter
acetylcholine (ACh). ACh’s actions are terminated by one
of two enzymes, either acetylcholinesterase (AChE) or ACh
butyrylcholinesterase (BuChE), sometimes also called
“pseudocholinesterase” or “nonspecific cholinesterase”
(Figure 12-25). Both enzymes convert ACh into choline,
which is then transported back into the presynaptic
cholinergic neuron for resynthesis into ACh (Figure
12-25). Although both AChE and BuChE can metabolize 12
ACh, they are quite different in that they are encoded
by separate genes and have different tissue distributions ACh (acetylcholine)
and substrate patterns. There may be different clinical
Figure 12-24 Acetylcholine is produced. Acetylcholine (ACh)
effects of inhibiting these two enzymes as well. High is formed when two precursors – choline and acetyl coenzyme
levels of AChE are present in brain, especially in neurons A (AcCoA) – interact with the enzyme choline acetyltransferase
(ChAT). Choline is derived from dietary and intraneuronal
that receive ACh input (Figure 12-25). BuChE is also sources and AcCoA is made from glucose in the mitochondria of
present in brain, especially in glial cells (Figure 12- the neuron.
505
Acetylcholine Action Is Terminated Figure 12-25 Acetylcholine’s action is

terminated. Acetylcholine’s action can
be terminated by two different enzymes:
acetylcholinesterase (AChE), which is
present both intra- and extracellularly,
and butyrylcholinesterase (BuChE),
which is particularly present in glial cells.
Both enzymes convert acetylcholine
glial cell into choline, which is then transported
out of the synaptic cleft and back into
the presynaptic neuron via the choline
inactive transporter. Once inside the presynaptic
neuron, choline can be recycled into
acetylcholine and then packaged into
vesicles by the vesicular acetylcholine
transporter (VAChT).
AChE
VAChT
choline
transporter
BuChE
ACh
Muscarinic Acetylcholine Receptors
at Cholinergic Synapses
AChE
choline
ACh synthesis (see Figure 12-25). Once synthesized

in the presynaptic neuron, ACh is stored in synaptic
vesicles after being transported into these vesicles by the
vesicular transporter for ACh (VAChT), analogous to the
vesicular transporters for the monoamines and other
neurotransmitters.
There are numerous receptors for ACh (Figures 12-26
through 12-29). The major subtypes are nicotinic and
muscarinic subtypes of cholinergic receptors. Classically, presynaptic M2 presynaptic M4
receptor receptor
muscarinic receptors are stimulated by the mushroom
alkaloid muscarine and nicotinic receptors by the tobacco
alkaloid nicotine. Nicotinic receptors are all ligand-gated,
rapid-onset, and excitatory ion channels blocked by M3 M5 M4
M1
curare. Muscarinic receptors, by contrast, are G-protein- receptor
linked, can be excitatory or inhibitory, and many are + + +
blocked by atropine, scopolamine, and other well-known

so-called “anticholinergics” discussed throughout this
text. Both nicotinic and muscarinic receptors have been Figure 12-26 Muscarinic acetylcholine receptors. Muscarinic
further subdivided into numerous receptor subtypes. acetylcholine receptors are G-protein-linked and can be either
excitatory or inhibitory. M1, M3, and M5 receptors are excitatory
Muscarinic receptors have five subtypes, M1, M2, M3, postsynaptic receptors and stimulate downstream second
M4, and M5 (Figure 12-26). M1, M3, and M5 receptors messenging. M2 and M4 receptors are inhibitory presynaptic
autoreceptors, preventing further release of acetylcholine. M4
are stimulatory to downstream second messengering, receptors are also thought to exist as inhibitory postsynaptic
and are also postsynaptic at cholinergic synapses receptors.
506
(Figure 12-26). M2 and M4 receptors are inhibitory to theoretically reduce psychotic and cognitive symptoms
downstream second messengering and are presynaptic, in AD. Muscarinic M2 and M4 receptors can also be
serving as autoreceptors, inhibiting the further release present on non-cholinergic neurons that release other
of acetylcholine once it builds up in the synapse (Figure neurotransmitters such as GABA and glutamate (Figure
12-26). M4 receptors are thought to be also postsynaptic 12-27). When ACh diffuses away from its synapse to
in some brain areas (Figure 12-26). occupy these presynaptic heteroreceptors, it can block
The M1 receptor is thought to be key to memory the release of the neurotransmitter there (e.g., GABA or
function in the hippocampus and neocortex, where it glutamate) (see Figure 12-27).
may facilitate dopamine release, whereas the M4 receptor A number of nicotinic receptor subtypes also exist in
is thought to be involved in regulating the ventral the brain, with different subtypes outside of the brain in
tegmental dopamine neurons to inhibit dopamine release skeletal muscle and ganglia. Two of the most important
in the mesolimbic pathway and reduce psychosis. In central nervouse system nicotinic cholinergic receptors
Chapter 5, we briefly mentioned that preclinical and are the subtype with all α7 subunits, and the subtype with
postmortem studies in patients with schizophrenia α4 and β2 subunits (Figure 12-28). The α4β2 subtype is
suggest that central cholinergic alterations may be key to postsynaptic and plays an important role in regulating
the pathophysiology of both cognition and the positive dopamine release in the nucleus accumbens. It is thought
symptoms of schizophrenia with M4 receptor agonism to be a primary target of nicotine in cigarettes, and to
reducing psychosis and with M1 receptor agonism contribute to the reinforcing and addicting properties
improving cognition. Xanomeline (see Chapter 5 and of tobacco. The α4β2 subtypes of nicotinic cholinergic
Figure 5-67), as an M4/M1 agonist, decreases dopamine receptors are discussed in further detail in Chapter 13 on
cell firing in the ventral tegmental area in preclinical drug abuse.
studies and improves positive symptoms of psychosis Alpha-7 nicotinic cholinergic receptors can be either
in early clinical studies of schizophrenia. This same presynaptic or postsynaptic (Figures 12-28 and 12-29).
drug or others working by similar mechanisms could When they are postsynaptic, they may be important
Presynaptic Muscarinic Heteroreceptors Inhibit

GABA and Glutamate Release
GABA ACh Glu

M4 12
M2 M2
ACh
Figure 12-27 Presynaptic muscarinic heteroreceptors. M2 and M4 receptors can also be present presynaptically on non-cholinergic
neurons such as GABA (γ-aminobutyric acid) and glutamate (Glu) neurons. When acetylcholine (ACh) diffuses away from the synapse
and occupies these receptors, it can block the release of the neurotransmitter there.
507
Figure 12-28 Nicotinic acetylcholine receptors. Acetylcholine
Nicotinic Acetylcholine Receptors neurotransmission can be regulated by ligand-gated excitatory
at Cholinergic Synapses ion channels known as nicotinic acetylcholine receptors, shown
here. There are multiple subtypes of these receptors, defined by
the subunits they contain. Two of the most important are those that
contain all α7 subunits and those that contain α4 and β2 subunits.
Alpha-7 receptors can exist presynaptically, where they facilitate
acetylcholine release, or postsynaptically, where they are important
for regulating cognitive function in the prefrontal cortex. The α4β2
receptors are postsynaptic and regulate release of dopamine in the
nucleus accumbens.
ACh
7 4ß2
Presynaptic Nicotinic Heteroreceptors Facilitate

Dopamine and Glutamate Release
DA ACh Glu
7 7
DA
ACh Glu
Figure 12-29 Presynaptic nicotinic heteroreceptors. Acetylcholine (ACh) that diffuses away from the synapse can bind to presynaptic
α7 nicotinic receptors on dopamine (DA) and glutamate (Glu) neurons, where it stimulates release of these neurotransmitters.
mediators of cognitive functioning in the prefrontal Allosteric Modulation of Nicotinic Receptors

cortex. When they are presynaptic and on cholinergic
neurons, they appear to mediate a “feed-forward” Ca++
release process where ACh can facilitate its own release

by occupying presynaptic α7 nicotinic receptors (Figure
12-28). Furthermore, α7 nicotinic receptors are present
on neurons that release other neurotransmitters, such as
dopamine and glutamate neurons (Figure 12-29). When
ACh diffuses away from its synapse to occupy these
presynaptic heteroreceptors, it facilitates the release of the
neurotransmitter there (e.g., dopamine or glutamate) (see
Figure 12-29). ACh
Just as described in earlier chapters for other ligand-
gated ion channels such as the GABAA receptor (in
Chapter 6 on mood disorders; see Figures 6-20 and 6-21;
see also Chapter 7 drugs for depression; Figure 7-56) and
the NMDA (N-methyl-D-aspartate) receptor (see Chapter
4 on psychosis and Figure 4-30; and Chapter 10 on sleep
and Figure 10-4), it appears that ligand-gated nicotinic
cholinergic receptors are also regulated by allosteric
modulators (Figure 12-30). Muscarinic receptors may
also be modulated by positive allosteric modulators (not
shown). Positive allosteric modulators (PAMs) have been
well characterized for nicotinic receptors in brain; indeed,
the cholinesterase inhibitor galantamine used in AD has
a second therapeutic mechanism as a PAM for nicotinic allosteric
receptors as described for this agent below. modulator
The principle cholinergic pathways are illustrated in

Figures 12-31 and 12-32. Cell bodies of some cholinergic
pathways arise from the brainstem and project to many
brain regions, including the prefrontal cortex, basal
forebrain, thalamus, hypothalamus, amygdala, and
Figure 12-30 Allosteric modulation of nicotinic
hippocampus (Figure 12-31). Other cholinergic pathways receptors. Nicotinic receptors can be regulated by allosteric
have their cell bodies in the basal forebrain, project to the modulators. These ligand-gated ion channels control the flow
of calcium into the neuron (top panel). When acetylcholine is
prefrontal cortex, amygdala, and hippocampus, and are bound to these receptors, it allows calcium to pass into the
thought to be particularly important for memory (Figure neuron (middle panel). A positive allosteric modulator bound
12-32). Additional cholinergic fibers in the basal ganglia in the presence of acetylcholine increases the frequency of
opening of the channel and thus can allow for more calcium to
are not illustrated. pass into the neuron (bottom panel).
Symptomatic Treatment of Memory and Cognition in cholinergic receptors by increasing ACh levels with
Alzheimer Disease by Inhibiting Acetylcholinesterase acetylcholinesterase inhibition can hypothetically restore
It is well established that cholinergic dysfunction some of the lost function of degenerated cholinergic
12
accompanies age-related cognitive decline, hypothetically neurons (Figure 12-33C; effective cholinergic treatment
due to the early loss of cholinergic neurons from of cognition in early AD). This model is analogous to
the nucleus basalis (compare Figure 12-33A normal Parkinson’s disease treatment with levodopa restoring
cognition and 12-33B mild cognitive impairment). some of the lost function of degenerated dopamine
At this early stage of memory decline, cholinergic neurons. However, as AD progresses from MCI and early
innervation is lost, but cholinergic postsynaptic targets dementia to later stages of dementia, there is progressive
remain (Figure 12-33B), so that stimulating postsynaptic loss of neocortical and hippocampal neurons. In the
509
Cholinergic Projections from Brainstem functioning by stopping the destruction of ACh. This
can be readily accomplished by inhibiting the enzyme
acetylcholinesterase (Figure 12-23A and Figure 12-25).
Inhibition of acetylcholinesterase causes the build-up of
ACh because ACh’s action can no longer be as efficiently
terminated. Enhanced availability of ACh is proven to
impact cognitive and memory symptoms in AD patients,
sometimes enhancing memory, but more often helping
PFC S T
to retain current levels of memory function and thus
NA slowing the decline in memory.
BF
Hy
Donepezil
C
Donepezil is a reversible, long-acting, selective inhibitor
NT
A of AChE without inhibition of BuChE (Figure 12-34).
H
Donepezil inhibits AChE in pre- and postsynaptic
SC
cholinergic neurons, and in other areas of the central
nervous system outside of cholinergic neurons where
Figure 12-31 Cholinergic projections from the brainstem. The
cell bodies of some cholinergic neurons are found in the this enzyme is widespread (Figure 12-34A). Its central
brainstem and project to many different brain regions, including nervous system actions boost the availability of ACh at
the basal forebrain (BF), prefrontal cortex (PFC), thalamus (T),
hypothalamus (Hy), amygdala (A), and hippocampus (H). the remaining sites normally innervated by cholinergic
neurons, but which are now suffering from a deficiency of
Cholinergic Projections from Basal Forebrain ACh as presynaptic cholinergic neurons die off (Figures
12-33B and 12-33C). Donepezil also inhibits AChE in
the periphery, where its actions in the gastrointestinal
(GI) tract can produce GI side effects (Figure 12-34B).
Donepezil is easy to dose, has mostly GI side effects, and
these are mostly transient.
Rivastigmine
PFC S T Rivastigmine is “pseudoirreversible” (which means it
NA
BF reverses itself over hours), intermediate-acting, not only
Hy selective for AChE over BuChE, but perhaps for AChE in
C the cortex and hippocampus over AChE in other areas
A NT of brain (Figure 12-35A). Rivastigmine also inhibits
H BuChE within glia, which may contribute somewhat
SC to the enhancement of ACh levels within the central
nervous system (Figure 12-35A). Inhibition of BuChE
Figure 12-32 Cholinergic projections from the basal
forebrain. The cell bodies of some cholinergic neurons are
within glia may be even more important in patients
found in the basal forebrain (BF) and project to the prefrontal with AD as they develop gliosis when cortical neurons
cortex (PFC), amygdala (A), and hippocampus (H). These
projections may be particularly important for memory.
die, because these glia contain BuChE, and inhibition
of this increased enzyme activity may have a favorable
action on increasing the availability of ACh to remaining
process, receptor targets of cholinergic therapies are cholinergic receptors via this second mechanism (Figure
also lost and symptomatic pro-cholinergic treatment 12-35B). Rivastigmine appears to have comparable safety
with acetylcholinesterase inhibitors begins to lose its and efficacy to donepezil, although it may have more
effectiveness (Figure 12-33D; progression of AD and loss GI side effects when given orally, perhaps due to its
of cholinergic treatment effectiveness). pharmacokinetic profile, and perhaps due to inhibition of
Nevertheless, the most successful approach to both AChE and BuChE in the periphery (Figure 12-35C).
the intermediate-term treatment of cognitive and However, there is now a transdermal formulation of
memory symptoms in AD is to boost cholinergic rivastigmine available that greatly reduces the peripheral
510
12
Figure 12-33A, B Degeneration of cholinergic projections from the basal forebrain: impact on memory. (A) Cholinergic projections
from the basal forebrain to the neocortex and to the hippocampus are thought to be particularly important for memory. (B) Accumulation
of plaques and tangles in the brain can lead to neurodegeneration that may particularly affect these cholinergic projections and thus
lead to memory loss. In early stages, although cholinergic innervation is lost, cholinergic postsynaptic targets remain.
511
Figure 12-33C, D Degeneration of cholinergic projections from the basal forebrain: impact of cholinergic treatment. (C) In early
stages of Alzheimer disease, although cholinergic innervation from the basal forebrain is lost, cholinergic postsynaptic targets remain.
It is therefore possible to potentially improve memory by increasing acetylcholine levels in the hippocampus and neocortex. This can
be achieved with agents that block the metabolism of acetylcholine, such as acetylcholinesterase (AChE) inhibitors. (D) As Alzheimer
disease progresses, loss of neurons in the neocortex and hippocampus means that the receptor targets for acetylcholine are also lost,
and thus AChE inhibitors lose their effectiveness.
512
Figure 12-34 Donepezil actions. Donepezil is a

Donepezil Actions: CNS reversible inhibitor of the enzyme acetylcholinesterase
(AChE), which is present both in the central nervous
system (CNS) and peripherally. (A) Central cholinergic
neurons are important for regulation of memory; thus,
central in the CNS, the boost of acetylcholine (ACh) caused
acetylcholine by AChE blockade contributes to improved cognitive
neuron functioning. (B) Peripheral cholinergic neurons in the gut
are involved in gastrointestinal effects; thus the boost in
glial cell
peripheral acetylcholine caused by AChE blockade may
contribute to gastrointestinal side effects.
donepezil
D
AChE
BuChE
ACh
donepezil
D
AChE
!
A
Donepezil Actions: Peripheral
peripheral
acetylcholine
neuron
donepezil
D
AChE
donepezil
12
ACh
D
BuChE AChE
gut
B
D
513
side effects of oral rivastigmine, probably by optimizing inhibition of AChE (Figure 12-36A) could be enhanced
drug delivery, and reducing peak drug concentrations. when joined by the second action of galantamine at
nicotinic receptors (Figure 12-36B). Thus, raising ACh
Galantamine
levels at nicotinic cholinergic receptors by AChE inhibition
Galantamine is a very interesting cholinesterase could be boosted by the positive allosteric modulating
inhibitor found in snowdrops and daffodils! It has a dual actions of galantamine (Figure 12-36B). However, it has
mechanism of action, matching AChE inhibition (Figure not been proven that this theoretically advantageous
12-36A) with positive allosteric modulation of nicotinic second action as a nicotinic positive allosteric modulator
cholinergic receptors (Figure 12-36B). Theoretically, the (PAM) translates into clinical advantages.
Rivastigmine Actions: CNS

Figure 12-35A Rivastigmine
actions, part one. Rivastigmine is a
pseudoirreversible inhibitor (it reverses
itself over hours) of the enzymes
acetylcholinesterase (AChE) and
butyrylcholinesterase (BuChE), which
are present both in the central nervous
central system (CNS) and peripherally. Central
cholinergic neurons are important for
acetylcholine regulation of memory; thus, in the CNS,
the boost of acetylcholine caused by
neuron AChE blockade contributes to improved
cognitive functioning. In particular,
glial cell rivastigmine appears to be somewhat
R selective for AChE in the cortex and
hippocampus – two regions important
for memory – over other areas of the
brain. Rivastigmine’s blockade of BuChE
R in glia may also contribute to enhanced
acetylcholine levels.
R
rivastigmine
AChE
R
BuChE
R
ACh
R
AChE rivastigmine
514
Figure 12-35B Rivastigmine actions,

Rivastigmine Actions: Gliosis part two. Rivastigmine inhibits the
enzymes acetylcholinesterase (AChE)
and butyrylcholinesterase (BuChE),
which are present both in the central
nervous system (CNS) and peripherally.
central Inhibition of BuChE may be more
acetylcholine important in later stages of disease,
neuron because as more cholinergic neurons
die and gliosis occurs, BuChE activity
glial cell glial cell increases.
R
R R
R
rivastigmine
AChE
R R
BuChE BuChE
gliosis R
AChE rivastigmine
R R
R R
BuChE BuChE
glial cell glial cell
TARGETING GLUTAMATE FOR

THE SYMPTOMATIC TREATMENT and neurofibrillary tangles that release glutamate from
normal inhibition by GABA as GABA interneurons
OF MEMORY AND COGNITION
degenerate (see Chapter 4 and Figure 4-52D and also
IN ALZHEIMER DISEASE compare Figures 12-37A, 12-37B, and12-37C). That
Cholinergic dysfunction of course is not the is, in the resting state, glutamate is normally quiet, 12
only problem in AD, and there is progressive and the NMDA receptor is physiologically blocked
neurodegeneration of both cholinergic and by magnesium ions (Figure 12-37A). When normal
glutamatergic circuits as patients transition from MCI excitatory neurotransmission comes along, a flurry of
to AD. Glutamate has been hypothesized to be released glutamate is released (Figure 12-37B). The postsynaptic
in excess once AD develops (see Figure 4-52D and NMDA receptor is a “coincidence detector” and allows
discussion in Chapter 4; see also Figure 12-23A, left), inflow of ions if three things happen at the same
perhaps in part triggered by neurotoxic Aβ plaques time: neuronal depolarization, often from activation
515
Rivastigmine Actions: Peripheral activation of glutamate neurotransmission and thus

interfere with the pathophysiology of AD, improve
cognitive function, and slow the rate of decline over
peripheral
time (Figure 12-23A and Figure 12-37D). Blocking
acetylcholine
neuron NMDA receptors chronically would hypothetically
R interfere with memory formation and neuroplasticity.
So what do you do to decrease the excessive and
sustained but low level of excitotoxic activation of
NMDA receptors, yet not interfere with learning,
memory, and neuroplasticity, and without inducing a
R schizophrenia-like state?
AChE rivastigmine
The answer seems to be that you interfere with
NMDA-mediated glutamatergic neurotransmission with
R a weak (low-affinity) NMDA antagonist that works at the
R same site, plugging the ion channel where the magnesium
ion normally blocks this channel at rest (Figure 12-37D).
That is, memantine is an uncompetitive open-channel
ACh
R NMDA receptor antagonist with low to moderate affinity,
R voltage dependence, and fast blocking and unblocking
BuChE
AChE
kinetics. That is a fancy way of saying that it only blocks
the ion channel of the NMDA receptor when it is open.
R R
This is why it is called an open-channel antagonist and

gut
R R
why it is dependent upon voltage: namely, to open the
channel. It is also a fancy way of saying that memantine
Figure 12-35C Rivastigmine actions, part three. Rivastigmine blocks the open channel quickly, but is readily and
inhibits the enzymes acetylcholinesterase (AChE) and
butyrylcholinesterase (BuChE), which are present both in the quickly reversible if a barrage of glutamate comes along
central nervous system (CNS) and peripherally. Peripheral from normal neurotransmission (Figure 12-37E).
cholinergic neurons in the gut are involved in gastrointestinal
effects; thus the boost in peripheral acetylcholine caused by This concept is illustrated in Figures 12-37C, 12-37D,
AChE and BuChE blockade may contribute to gastrointestinal and 12-37E. First, the hypothetical state of the glutamate
side effects.
neuron during Alzheimer excitotoxicity is illustrated
of nearby AMPA (α-amino-3-hydroxy-5-methylin Figure 12-37C. Here, steady, tonic, and excessive
4-isoxazole-propionic acid) receptors; glutamate amounts of glutamate are continuously released in a
occupying its binding site on the NMDA receptor; manner that interferes with the normal resting state of
and the cotransmitter glycine occupying its site on the the glutamate neuron (Figure 12-37C), and in a manner
NMDA receptor (Figure 12-37B). If plaques and tangles that interferes with established memory functions,
cause a steady “leak” of glutamate (see Chapter 4 and new learning, and normal neuronal plasticity in AD.
Figure 4-52D), this would theoretically interfere with Eventually, this leads to the activation of intracellular
the fine-tuning of glutamate neurotransmission, and enzymes that produce toxic free radicals that damage
possibly interfere with memory and learning, but not the membranes of the postsynaptic dendrite and
necessarily be damaging to neurons (Figure 12-37C). eventually destroy the entire neuron (Figure 12-37C).
Hypothetically, as AD progresses, glutamate release When memantine is given, it blocks this tonic glutamate
could be increased to a level that is tonically bombarding release from having downstream effects, hypothetically
the postsynaptic receptor, eventually killing off dendrites returning the glutamate neuron to a new resting state,
and then killing off full neurons due to excitotoxic cell despite the continuous release of glutamate (Figure 12-
death (Figure 12-23A and Figure 12-37C). 37D). Theoretically, this stops the excessive glutamate
from interfering with the resting glutamate neuron’s
Memantine physiological activity, therefore improving memory; it
The rationale for the use of memantine (Figure 12-38), also theoretically stops the excessive glutamate from
a type of NMDA antagonist, is to reduce abnormal causing neurotoxicity, therefore slowing the rate of
516
Figure 12-36A Galantamine actions,

Galantamine Actions part one. Galantamine is an inhibitor
of the enzyme acetylcholinesterase
(AChE). Central cholinergic neurons are
important for regulation of memory,
and thus, in the central nervous system,
central the boost of acetylcholine caused by
AChE blockade contributes to improved
acetylcholine cognitive functioning.
neuron
glial cell
G
galantamine
AChE
BuChE
Ca++
ACh
G
galantamine
AChE
!
12
neuronal death and also the associated cognitive decline 12-37E). That is, when a phasic burst of glutamate
that causes the progression in AD (Figure 12-37D). is transiently released during normal glutamatergic
However, at the same time, memantine is not so neurotransmission, this causes a depolarization that
powerful a blocker of NMDA receptors that it stops is capable of reversing the memantine block, until the
all neurotransmission at glutamate synapses (Figure depolarization goes away (Figure 12-37E). For this
517
Figure 12-36B Galantamine actions,

Galantamine Actions: part two. Galantamine is unique among
Nicotinic Allosteric Modulation cholinesterase inhibitors in that it is
also a positive allosteric modulator
(PAM) at nicotinic cholinergic receptors,
which means it can boost the effects
central of acetylcholine at these receptors.
acetylcholine Galantamine’s second action as a PAM
neuron at nicotinic receptors could theoretically
enhance its primary action as a
glial cell cholinesterase inhibitor.
G
galantamine
AChE
G
BuChE
Ca++
ACh
positive allosteric G
modulation galantamine
AChE
G
reason, memantine does not have the psychotomimetic glutamate system is not entirely shut down. Sort of like
actions of other more powerful NMDA antagonists having your cake and eating it, too.
such as phencyclidine (PCP) and ketamine, and does Memantine also has σ binding properties and weak
not shut down new learning or the ability of normal 5HT3 antagonist properties (Figure 12-38), but it is not
neurotransmission to occur when necessary (Figure clear what these contribute to the actions of this agent in
12-37E). The blockade of NMDA receptors by memantine AD. Since its mechanism of action in AD is so different
can be seen as a kind of “artificial magnesium,” more from cholinesterase inhibition, memantine is usually
effective than physiological blockade by magnesium, given concomitantly with a cholinesterase inhibitor to
which is overwhelmed by excitotoxic glutamate release, exploit the potential of both of these approaches and to
but less effective than PCP or ketamine so that the get additive results in patients.
518
Figure 12-37A Glutamatergic
Glutamatergic Neurotransmission in AD: neurotransmission in Alzheimer disease,
Part 1 - Resting State part 1. In the resting state (absence
of glutamate binding), the NMDA (N-
methyl-D-aspartate) receptor is blocked
by magnesium.
glutamate
neuron
Glu
Ca++
Mg++
NMDA
receptor
Figure 12-37B Glutamatergic
Part 2 - Normal Neurotransmission part 2. With normal neurotransmission,
glutamate is released and binds to the
NMDA (N-methyl-D-aspartate) receptor.
If the neuron is depolarized and glycine
glutamate
is simultaneously bound to the NMDA
neuron
receptor, the channel opens and allows ion
influx. This results in long-term potentiation.
Ca++
Glu
depolarization glycine
12
long-term potentiation
learning neuroplasticity
memory
519
Glutamatergic Neurotransmission in AD: Figure 12-37C Glutamatergic
neurotransmission in Alzheimer disease,
Part 3 - Alzheimer Excitotoxicity part 3. Neurodegeneration caused
by plaques and tangles could cause a
steady leak of glutamate and result in
excessive calcium influx in postsynaptic
gluta- neurons, which in the short term may
mate cause memory problems and in the long
neuron term may cause accumulation of free
radicals and thus destruction of neurons.
memory problems
free radical
Figure 12-37D Glutamatergic
Part 4 - Memantine and New Resting State in part 4. Memantine is a noncompetitive,
low-affinity NMDA (N-methyl-D-
Alzheimer Disease aspartate) receptor antagonist that
binds to the magnesium site when the
channel is open. Memantine thus blocks
glutamate the downstream effects of excessive
neuron tonic glutamate release by “plugging”
the NMDA ion channel, which may
improve memory and prevent neuronal
death due to glutamate excitotoxicity.
memantine
memory problems
free radical
520
Glutamatergic Neurotransmission in AD:

Figure 12-37E Glutamatergic
neurotransmission in Alzheimer disease,
part 5. Because memantine has low
Part 5 - Normal Neurotransmission affinity, when there is a phasic burst of
glutamate and depolarization occurs,
this is enough to remove memantine
from the ion channel and thus allow
normal neurotransmission. This
means that memantine does not have
psychotomimetic effects or interfere with
glutamate normal new learning.
neuron
long-term potentiation
learning neuroplasticity
memory
TARGETING THE BEHAVIORAL

SYMPTOMS OF DEMENTIA
Dementia is often seen as fundamentally a disorder of Defining Agitation and Psychosis in Alzheimer Disease
memory and cognition, but there are many important Perhaps no symptom of dementia raises alarm as much as
behavioral symptoms associated with dementia as well agitation, especially when it turns into physical aggression
(Figure 12-39), each potentially regulated by separate with behaviors such as slamming doors, throwing 12
neuronal networks (Figure 12-23). The prevalence of objects, kicking, screaming, pushing, scratching, biting,
specific behavioral symptoms of dementia pooled from wandering, intruding upon others, fidgeting, restlessness,
a large number of studies in AD is shown in Table 12-7. pacing, refusing medications, refusing help with activities
Treatment of dementia-related psychosis, agitation, of daily living, and sexually inappropriate behavior
depression, and apathy are all discussed here. (Table 12-8).
521
Table 12-7 Prevalence of specific behavioral and

memantine psychological symptoms of dementia (BPSD)
Symptom Percentage
Apathy 49
Depression 42
Aggression 40
Sleep disorder 39
Anxiety 39
Irritability 36
Appetite disorder 34
Aberrant motor behavior 32
Mg++
Delusions 31
T3
Disinhibition 17
5H Hallucinations 16
Figure 12-38 Memantine. Memantine is a noncompetitive, low- Euphoria 7
affinity NMDA (N-methyl-D-aspartate) receptor antagonist that Estimates of prevalence are pooled from 48 studies of BPSD in Alzheimer
binds to the magnesium site when the channel is open. It also disease, using the Neuropsychiatric Inventory.
has σ binding properties and weak 5HT3 antagonist properties. Data are from Zhao et al. 2016.
(SIGH) #*@! • manifesting excessive motor activity, verbal

aggression, or physical aggression
• evidencing behaviors that cause excess disability and
are not solely attributable to another disorder
apathy
disinhibition
In contrast, dementia-related psychosis as discussed
above is defined by
• delusions or hallucinations occurring after the onset
anxiety of cognitive decline
• persisting for at least one month
• not better explained by delirium or some other mental
sleep
illness
Whereas psychosis and agitation can be rather readily
distinguished from memory decline in AD, agitation
depression and psychosis can easily be confused with each other.
However, these two symptom domains of agitation and
psychosis psychosis hypothetically arise from entirely separate
agitation/ malfunctioning neuronal networks in dementia (compare
aggression
Figure 12-23B, C) and are giving rise to entirely separate
Figure 12-39 Behavioral symptoms in dementia. Patients with
dementia can exhibit many symptoms in addition to cognitive
treatments. Given that the new treatments on the horizon
and memory impairment, each of which is potentially regulated for psychosis and for agitation have distinct mechanisms
by separate neuronal networks.
that target these neuronal networks individually and
differently, it is more important than ever to be able
Agitation is defined for clinical and research to distinguish agitation from psychosis in dementia.
purposes by the Agitation Definition Work Group of the Furthermore, psychotic symptoms such as intrusive
International Psychogeriatric Association as: hallucinations and/or paranoid delusions can precipitate
• occurring in patients with a cognitive impairment or agitation or lead to aggressive behavior. Thus, some
dementia syndrome dementia patients will have both agitation and psychosis
• exhibiting behavior consistent with emotional distress and require treatment for both.
522
Table 12-8 Assessing agitation
Cohen–Mansfield agitation inventory (CMAI)

Physical/aggressive Physical/non-aggressive
Hitting Pacing, aimless wandering
Kicking Inappropriate dress/disrobing
Grabbing Trying to get to a different place
Pushing Intentional falling
Throwing things Eating/drinking inappropriate substances
Biting Handling things inappropriately
Scratching Hiding things
Spitting Hoarding things
Hurting self or others Performing repetitive mannerisms
Destroying property General restlessness
Making physical sexual advances
Verbal/aggressive Verbal/non-aggressive
Screaming Repetitive sentences or questions
Making verbal sexual advances Strange noises
Cursing or verbal aggression Complaining
Negativism
Constant unwarranted request for attention
Before using medications at all to treat agitation or dopamine receptor blocking agents normally used to
psychosis in dementia, reversible precipitants particularly treat schizophrenia. No topic in the care of the behavioral
of agitation should be managed non-pharmacologically symptoms of dementia has been more contentious than
(Table 12-9):
• pain Table 12-9 Non-pharmacological options for behavioral
symptoms in dementia
• nicotine withdrawal
• medication side effects • Address unmet needs (hunger, pain, thirst, boredom)
• undiagnosed medical and neurological illnesses • Identify/modify environmental stressors
• provocative environments that are either too • Identify/modify daily routine stressors
stimulating or not stimulating enough • Caregiver support/training
• Behavior modification
• Group/individual therapy
PHARMACOLOGICAL • Problem solving
TREATMENT OF PSYCHOSIS • Distraction
AND AGITATION IN DEMENTIA • Provide outlets for pent-up energy (exercise,
activities)
There is no pharmacological treatment for either • Avoid behavior triggers 12
psychosis or agitation in dementia yet approved although • Increase social engagement
several agents are in late-stage trials. Up until now, • Relaxation techniques
psychosis versus agitation in dementia have not been • Reminiscence therapy
• Music therapy
differentiated particularly well clinically because they
• Aromatherapy
either remained untreated or were both nonspecifically
• Pet therapy
and quite controversially treated with unapproved
523
the current management of agitation and psychosis Targeting Serotonin for the Symptomatic Treatment of
in dementia, especially when it comes to the use of Dementia-Related Psychosis
dopamine D2 receptor blocking drugs. Prevalence estimates for psychosis range from 10%
Why are dopamine D2 receptor blocking drugs for FTD to 75% for dementia with Lewy bodies (Table
controversial? This is due to many factors, including 12-10). In the US, it is estimated that over 2 million
the potential for these drugs to act as “chemical people suffer from dementia-related psychosis. Visual
straightjackets” and over-tranquilize patients. There hallucinations are a prominent feature of psychosis in
are also major safety concerns and a “black box” all forms of dementia, especially in dementia with Lewy
warning, specifically about cardiovascular events such bodies and Parkinson’s disease dementia (Table 12-10 and
as stroke and death from using these drugs. Mortality Figures 12-40 and 12-41). Delusions are also observed in
risks may be due to stroke, thromboembolism, falls, all forms of dementia, especially in AD (Figure 12-40),
cardiac complications of QT interval prolongations, and with the most common delusions being paranoid (e.g.,
pneumonia, especially when sedated from drugs that theft or spousal infidelity) and misidentifications, though
increase the risk of aspiration (e.g., anticholinergics, the latter is sometimes considered a type of memory
sedative hypnotics, benzodiazepines, opioids, and deficit rather than psychosis. Psychosis in Parkinson’s
alcohol). disease often heralds the emergence of dementia and
On the other hand, efficacy of some dopamine vice versa. Up to 50–70% of patients with Parkinson’s
receptor blockers coming from small trials or anecdotal disease dementia report hallucinations compared to
observations from clinical practice often find greater only 10% of patients with Parkinson’s disease but no
efficacy than that reported in controlled trials that have dementia (Figure 12-41 and Table 12-10). Approximately
high placebo response rates. Another consideration in 85% of patients with Parkinson’s disease psychosis
the real world is that there are also risks of non-treatment
of agitation, aggression, and psychosis in dementia,
including the risks of early institutionalization and the Psychosis in AD vs. LBD
dangers of such behaviors to the patient and others
around them. Therefore, after careful consideration of
the risks and the benefits to an individual dementia
patient, some are treated cautiously “off-label” with
dopamine blocking drugs, especially risperidone,
olanzapine, and aripiprazole, as well as haloperidol, but
not quetiapine or others (see Chapter 5 for extensive
discussion of drugs for psychosis as well as each of these
individual drugs).
The dilemma caused by necessity to treat yet the
Delusions more common
presence of a “black box” safety warning against the (especially persecutory
Alzheimer Disease
use of dopamine blockers has triggered the search for and misidentification)
drugs proven effective for the treatment of psychosis and
agitation, which have an adequate safety profile. Clinical
trials are proceeding with several new therapeutic agents
on the horizon that separately and more specifically
target either the psychosis network (e.g., with the 5HT2A
antagonist pimavanserin) or the agitation network (with
multimodal glutamate and monoamine agents such as Hallucinations more common
brexpiprazole and dextromethorphan–bupropion). Thus, (especially visual)
it is more important than ever to distinguish agitation Lewy Body Dementias
from psychosis because treatments are directed to Figure 12-40 Psychosis in Alzheimer disease versus Lewy
body dementias. In Alzheimer disease (AD), delusions are
entirely different brain networks, with novel treatments more common than hallucinations, and particularly delusions
for psychosis not proven effective for agitation and vice of persecution or misinformation. In Lewy body dementias
(LBD), hallucinations are more common, particularly visual
versa. hallucinations.
524
Table 12-10 Prevalence ranges (%) for psychosis, delusions, and hallucinations in Alzheimer disease, vascular dementia, dementia
with Lewy bodies, Parkinson’s disease dementia, and frontotemporal dementia
Alzheimer Vascular Dementia with Parkinson’s Frontotemporal

disease dementia Lewy bodies disease dementia dementia
Overall psychosis 30 15 75 50 10
prevalence
Delusions prevalence 10–39 14–27 40–57 28–50 2.3–6
Hallucinations prevalence 11–17 5–14 55–78 32–63 1.2–13
Type of Hallucinations Observed in

Patients with PD Psychosis
Visual 62.5%
Auditory 45%
PD with no Tactile 22.5%

psychosis
hallucinations
Olfactory 2.5%
Minor* 45%
Visual + Auditory + Tactile + Olfactory 2.5%
delusions
hallucinations * Minor hallucinations include passage

+ delusions hallucinations and sense of presence
Figure 12-41 Psychosis in Parkinson’s disease. Psychosis is commonly associated with Parkinson’s disease (PD), and the presence of
psychosis often heralds the emergence of dementia (and vice versa). The hallucinations reported by patients with PD are most often
visual; however, other types of hallucinations may also be experienced.
experience hallucinations only, with 7.5% experiencing 42C). Dementia-related psychosis has consistently been
hallucinations and delusions and 7.5% experiencing associated with greater caregiver burden and more rapid
delusions only (Figure 12-41). The severity of psychosis progression to severe dementia, institutionalization,
and the specific symptoms manifested also vary across and death. Some questions that arise in understanding
the spectrum of dementias (Figures 12-40 and 12-41). dementia-related psychosis include: How could so many
The frequency of psychosis also varies across the time different forms of dementia all have psychosis (Table 12-
course and natural history of dementia, with psychosis 10) when their causes are so different? Also, why doesn’t 12
being more frequently observed in patients with more every patient with dementia have psychosis?
advanced dementia. Psychotic symptoms in any form The answers to these questions may be found by
of dementia seem to be related to pathology in the grasping an understanding of the hypothetical brain
neocortex, and like all symptoms in dementia, specific circuits that mediate psychosis in dementia (Figures
symptoms such as auditory versus visual hallucinations, 12-23B and 12-42B; see also discussion on psychosis in
versus delusions, are likely to reflect damage to specific Chapter 4 and illustrated in Figures 4-34, 4-52D, and
cortical areas (Figures 12-23B and 12-42A through 12- 4-55). Psychosis is theoretically a symptom derived
525
from inefficient information processing in a different Why do some dementia patients experience psychosis
brain circuit from that which theoretically processes and not others? One hypothesis is that in patients with
memory (compare Figures 12-23A and 12-42A). When dementia-related psychosis, neurodegeneration has
the destructive process of any given dementia invades progressed in such a way as to knock out regulatory
the psychosis network that regulates rational thinking neurons, not only in the memory pathway (Figure
and processing of sensory input (Figure 12-42A), the 12-33B) but also in the psychosis pathway (Figure 12-
outcome is hypothetically psychosis (Figure 12-42B; see 42B). In other dementia patients without psychosis, the
also Chapter 4 and Figures 4-34, 4-52D, and 4-55). From neurodegeneration has not (yet) knocked out the neurons
what we know about the psychosis network, delusions regulating the psychosis network.
and hallucinations seem to be regulated by a neuronal Although any node in the psychosis network is a
network that connects glutamate, GABA, serotonin, theoretical site for therapeutic action, at the present
and dopamine neurons (compare Figures 12-42A and time, there is no effective way to attack the psychosis
12-42B). The sites of connections/synapses between these network with GABA or glutamate agents. Although
different neurons are considered to be “nodes” in this blocking dopamine receptors often has antipsychotic
network, where their neurotransmitters act to regulate effects in patients with dementia-related psychosis,
the entire interconnected brain circuit of psychosis these agents increase stroke and death, so they are
(Figure 12-42A). In dementia, the accumulation of not approved for the treatment of dementia-related
Aβ plaques, tau tangles, Lewy bodies, and/or strokes psychosis.
in the cortical node connecting GABA and glutamate, Then, how can we quell the hyperactivity in the
hypothetically can knock out critical regulatory neurons, psychosis network in dementia? The answer is to block
especially inhibitory GABA interneurons, causing the normal excitatory input of serotonin in this network
glutamate hyperactivity and consequential downstream at 5HT2A receptors with the selective agent pimavanserin
dopamine hyperactivity and psychosis (Figure 12-42B). (Figure 12-42C; see Chapter 5 for further discussion of
Figure 12-42A The psychosis network

The Psychosis Network: Serotonin, at baseline. The symptoms of psychosis
Glutamate, and Dopamine Nodes seem to be mediated by communication
at synapses (nodes) between glutamate,
γ-aminobutyric acid (GABA), serotonin,
and dopamine neurons. Glutamate
serotonin neurons in the prefrontal cortex project
node to the ventral tegmental area (VTA)
where they connect with dopamine
neurons (glutamate node). Those
dopamine neurons then project to the
5HT2A receptor glutamate striatum. Serotonin neurons in the raphe
node nucleus project to the prefrontal cortex,
where they connect with glutamate
neurons (serotonin node). Glutamate
neurons project from the prefrontal
cortex to the visual cortex where they
prefrontal cortex visual cortex connect with other glutamate neurons
(glutamate node).
dopamine
node
striatum
glutamate
node
raphe VTA
526
Figure 12-42B The psychosis network

in dementia. (1) Accumulation of
Aβ plaques, tau tangles, and/or
Lewy bodies, as well as the damage
caused by strokes, may destroy some
glutamatergic pyramidal neurons
and GABAergic interneurons while
leaving others intact. The loss of GABA
inhibition upsets the balance of control
over glutamatergic pyramidal neurons,
at least temporarily. When the effects
of stimulation of excitatory 5HT2A
receptors are not countered by GABA
inhibition, there is a net increase in
glutamatergic neurotransmission. (2)
Excessive glutamate release in the visual
cortex can cause visual hallucinations.
(3) Excessive glutamate release into
the ventral tegmental area (VTA)
causes hyperactivity of the mesolimbic
dopamine pathway, resulting in
delusions and auditory hallucinations.
Treatment of Dementia-Related Psychosis Figure 12-42C The psychosis network

in dementia with treatment. (1)
Accumulation of Aβ plaques, tau
tangles, and/or Lewy bodies, as well
1 as the damage caused by strokes, may
pimavanserin destroy some glutamatergic pyramidal
neurons and GABAergic interneurons
while leaving others intact. The loss of
2
GABA inhibition upsets the balance of
3 control over glutamatergic pyramidal
neurons, at least temporarily. (2) When
the 5HT2A antagonist pimavanserin
binds to 5HT2A receptors on glutamate
prefrontal cortex visual cortex neurons in the prefrontal cortex, this
compensates for the loss of GABA
inhibition due to neurodegeneration
of glutamate and GABA neurons.
pimavanserin (3) Normalization of glutamate
5 neurotransmission downstream in
the visual cortex leads to reduction in
visual hallucinations. (4) Normalization
of glutamate neurotransmission
striatum
downstream in the ventral tegmental
area (VTA) leads to (5) normalization
of dopamine neurotransmission and
reduction in delusions and auditory
hallucinations.
raphe VTA 4
12
pimavanserin in psychosis and Figures 5-16, 5-17, and hypothetically rebalances the output of the surviving
5-59). In dementia-related psychosis, pimavanserin glutamate neurons so that 5HT2A antagonism and its
hypothetically reduces overactivity in the psychosis reduction of neuronal stimulation compensates for
network caused by plaques, tangles, Lewy bodies, or the loss of GABA inhibition. The 5HT2A antagonist
strokes, presumably by lowering the normal 5HT2A pimavanserin is approved for the treatment of Parkinson’s
stimulation to surviving glutamate neurons that have disease psychosis and there are positive trials of this agent
lost their GABA inhibition by neurodegeneration. This in dementia-related psychosis of all causes.
527
Neuronal Networks of Agitation in Alzheimer Disease response (Figure 12-45A). Similarly, intact top-down
A simple model for the circuitry of agitation in AD cortical inhibition also filters out emotional input so that it
is that there is an imbalance in “top-down” cortical does not generate an emotional response (Figure 12-46A).
inhibition with “bottom-up” limbic and emotional drives In AD patients, sensory, emotional, and motor areas
(Figures 12-43 and 12-44). Indeed, this simple model of the cortex tend to survive while top-down inhibitor
has been implicated in a wide range of related symptoms neocortical neurons degenerate, keeping the ability to
across multiple disorders, such as the psychomotor express motor and emotional output intact but not the
agitation of psychosis (discussed in Chapter 4), mania ability to inhibit it (Figures 12-45B and 12-46B). Thus,
and mixed features (discussed in Chapter 6), disorders when top-down inhibitory drive is destroyed, sensory
of impulsivity such as ADHD (discussed in Chapter input is able to break out of the thalamus and into
10), and many impulsive–compulsive syndromes such the cortex and to provoke thoughtless reflexive motor
as obsessive–compulsive disorder (OCD), gambling, agitation (Figure 12-45B). Without top-down inhibitory
substance abuse, and even violence (discussed in drive, emotional input also triggers lots of bottom-up
Chapter 13). In AD, neurodegeneration destroys the trouble from the limbic instigator, the amygdala (Figure
neurons responsible for top-down inhibition and this is 12-46B). That is, when emotional input is unfiltered
what is thought to allow bottom-up drives to proceed by the thalamus, it can set off the amygdala to deliver
unabated and thus allow the overt manifestations of bottom-up limbic fervor (Figure 12-46B). Specifically,
agitation. amygdala output to the ventral tegmental area activates
A more sophisticated model of agitation in AD dopamine release in the mesolimbic pathway, worsening
hypothesizes a deficiency in thalamic filtering of sensory the thalamic filter and sparking emotions (Figure 12-
input due to loss of top-down cortical inhibition that 46B). Amygdala output to the locus coeruleus elicits
results in the motor and emotional outputs of agitation norepinephrine release in the cortex mobilizing arousal
(Figures 12-45A, 12-45B, 12-46A, and 12-46B). Normal and emotions (Figure 12-46B). Finally, amygdala
top-down cortical inhibition filters out sensory input so output directly to cortex sets off emotional and affective
it does not generate a reflexive and thoughtless motor agitation (Figure 12-46B).
Figure 12-43 Agitation in Alzheimer

top-down disease. (A) “Top-down” cortical
brake from inhibition and “bottom-up” limbic drive
cortical areas
is in balance. (B) Normal activation of
top-down circuitry inhibits the more
impulsive bottom-up drive from limbic
STOP regions, preventing inappropriate
top-down behavior symptoms. (C) In Alzheimer
brake from disease, neurodegeneration may lead
cortical areas
to insufficient top-down inhibition of
GO bottom-up limbic drive, with resulting
STOP behavioral symptoms.
bottom-up
drive from
limbic areas
B
GO top-down
brake from
cortical areas
bottom-up
drive from
limbic areas STOP
GO
bottom-up
drive from
A
limbic areas
C
528
Figure 12-44 Agitation/impulsivity
The Agitation/Impulsivity Network: Top-Down Brakes network. Bottom-up sensory and
Balance Bottom-Up Sensory and Emotional Drives emotional input from the amygdala,
thalamus, and striatum is relayed to
the cortex. Top-down cortical inhibition
balances the bottom-up input, resulting
cortex in appropriate motor and emotional
output.
motor and
emotional
output
GO STOP STOP GO
STOP
motor and
GO emotional
output
amygdala striatum
thalamus
Figure 12-45A Top-down inhibition

Top-Down Inhibition Prevents Overstimulation of the prevents overstimulation of agitation
Agitation Network: Motor Output network: motor output. (1) Top-
down cortical inhibition occurs when
glutamate neurons in the cortex
release glutamate in the striatum. (2)
This stimulates GABA release in the
thalamus, which filters out sensory input.
top-down inhibition
(3) Thus, thalamic output directly to the
cortex and (4) via the amygdala does
not generate a reflexive motor response.
agitation
cortex
4 3
1
12
+ + +
amygdala 2 striatum
thalamus sensory input
529
Figure 12-45B Neurodegeneration
Neurodegeneration in Dementia Compromises in dementia compromises top-
Top-Down Inhibition: Motor Output down inhibition: motor output. (1)
Accumulation of Aβ plaques and tau
tangles destroys glutamate neurons
projecting to the striatum and thus
reduces top-down cortical inhibition.
(2) GABA input into the thalamus is
top-down inhibition insufficient and sensory input is not
adequately filtered. (3) Excessive
thalamic output directly to the cortex
and (4) via the amygdala generates a
reflexive motor response.
agitation
cortex
4 3
1
amygdala striatum
thalamus sensory input
Up until now, treatments of agitation in AD have not Targeting Multimodal Neurotransmitters

been particularly effective, including dopamine receptor (Norepinephrine, Serotonin, and Dopamine) for the
blockers already mentioned. In the absence of any Symptomatic Treatment of Agitation in Alzheimer
approved agents, first-line pharmacological treatment Disease
of agitation and aggression in dementia is actually Brexpiprazole is a serotonin–dopamine–norepinephrine
considered by many experts to be therapy with selective antagonist/partial agonist discussed in Chapter 5 as
serotonin reuptake inhibitors (SSRIs) and serotonin– one of the drugs approved to treat psychosis (Figure
norepinephrine reuptake inhibitors (SNRIs), which can 5-57) and in Chapter 7 as one of the drugs to augment
help some patients. Second-line treatments that may help SSRIs/SNRI to treat unipolar major depression. This
avoid use of dopamine receptor blocking drugs include agent combines several simultaneous mechanisms to
β blockers, carbamazepine, and perhaps gabapentin and quell the excessive activity of the agitation network in
pregabalin, but not valproate, topiramate, oxcarbazepine, AD: namely by its well-known dopamine D2 partial
or benzodiazepines. Unfortunately, in addition to agonist actions combined with 5HT1A partial agonist
not causing robust efficacy, many of these agents are and 5HT2A antagonist actions, as well as by its relatively
associated with significant side effects including sedation, unique additional actions blocking both α1- and α2-
unsteady gait, diarrhea, and weakness. Carbamazepine has adrenergic receptors (Figure 5-57 and Figure 12-47).
perhaps shown the greatest efficacy amongst unapproved Despite brexpiprazole having a warning for increased
drugs so far in treating neuropsychiatric symptoms of mortality in dementia-related psychosis, using this
dementia but has significant side-effect risks and may agent for agitation in AD and in doses lower than those
interact with other medications commonly prescribed to generally used to treat psychosis in schizophrenia may
elderly patients. Cholinesterase inhibitors have little if any provide a greater safety margin, especially since it is
benefit for most of the behavioral symptoms of dementia the hypothetical synergy of its five actions that leads to
except in patients with Lewy body dementias. therapeutic efficacy in agitation of AD (Figure 12-47).
530
Top-Down Inhibition Prevents Overstimulation of Agitation Figure 12-46A Top-down inhibition

prevents overstimulation of agitation
Network: Emotional Output
network: emotional output. (1)
Top-down cortical inhibition occurs
when glutamate neurons in the cortex
release glutamate in the striatum. (2)
+ top-down inhibition This stimulates GABA release in the
thalamus, which filters out emotional
+
input. (3) Thus, thalamic output to
the amygdala leads to (4) controlled
output to the locus coeruleus (LC)
and cortex and does not generate a
reflexive emotional response. Controlled
agitation output to the ventral tegmental area
(VTA) likewise leads to (5) controlled
cortex dopamine output from the VTA to the
striatum.
1
4
4 4 + 5 + + +
+
LC VTA
amygdala striatum
2
+
3
+
thalamus emotional
input
Neurodegeneration in Dementia Compromises Figure 12-46B Neurodegeneration

in dementia compromises top-down
Top-Down Inhibition: Emotional Output
inhibition: emotional output. (1)
Accumulation of Aβ plaques and tau
tangles destroys glutamate neurons
projecting to the striatum and thus reduces
+ top-down inhibition top-down cortical inhibition. (2) GABA
+ input into the thalamus is insufficient
and emotional input is not adequately
filtered. (3) Excessive thalamic output
to the amygdala leads to (4) excessive
output to the locus coeruleus (LC), cortex,
and ventral tegmental area (VTA). (5)
agitation Dopamine is released from VTA into the
striatum, further reducing the thalamic filter
cortex and contributing to a reflexive emotional
response. (6) Norepinephrine is released
from the LC to the cortex, contributing to a
6 1
reflexive emotional response.
4
4 4 5
+
+ 12
LC VTA
amygdala 2 striatum
+
3
+
thalamus emotional
input
531
Specifically, by reducing dopamine output from the Also, the multimodal actions of brexpiprazole have
ventral tegmental area (VTA) triggered by amygdala several points of interaction to quell excessive cortical
activation, this would lead to improving the thalamic output from surviving pyramidal neurons that drive
filtering of emotional input (shown in Figure 12-46B). motor and emotional agitation (Figure 12-47). Blocking
Multimodal Monoamine Treatment

Reduces Agitation in Alzheimer Disease
5HT1A
NE pathway
5HT2A
from LC NMDA
2
1B
brexpiprazole 2C
Glu pathway 2
from amygdala NMDA
Glu pathway 1
from thalamus D2
NE pathway
from LC
NE pathway
5HT2A from LC
5HT pathway
from raphe
= 2 antagonism
agitation
= 1 antagonism
5HT1A
+ = 5HT2A antagonism
5HT pathway + = 5HT1A partial agonism

from raphe
agitation
Figure 12-47 Multimodal monoamine treatment for agitation. Brexpiprazole has multiple pharmacological mechanisms that may
hypothetically work synergistically to reduce agitation. Blocking activation by norepinephrine (NE) from locus coeruleus (LC) output at
α2c and α1 postsynaptic receptors on dendrites of pyramidal neurons should reduce arousal and emotional responses. Blocking normal
serotonin excitation by antagonist actions at 5HT2A receptors and enhancing normal serotonin inhibition by partial agonist actions at
5HT1A receptors should also combine to reduce limbic drives to motor and emotional outputs of agitation.
532
activation by norepinephrine from locus coeruleus More robust blockade of NMDA receptors is
output at α2c and α1 postsynaptic receptors on dendrites attained by dextromethorphan, discussed in Chapter
of pyramidal neurons should reduce arousal and 7 on drugs for depression and illustrated in Figure
emotional responses (Figure 12-47); blocking normal 7-84. As mentioned in Chapter 7 there are multiple
serotonin excitation by antagonist actions at 5HT2A forms of dextromethorphan in testing, including
receptors and enhancing normal serotonin inhibition a deuterated derivative as well as combinations of
by partial agonist actions at 5HT1A receptors should also dextromethorphan with one or another of two different
combine to reduce limbic drives to motor and emotional CYP450 2D6 inhibitors, either bupropion or quinidine.
outputs of agitation (Figure 12-47). Brexpiprazole is The formulation of dextromethorphan with the CYP450
approved for use in schizophrenia and depression, and is 2D6 inhibitor and norepinephrine–dopamine reuptake
in late-stage clinical testing for agitation in AD. inhibitor (NDRI) bupropion (also known as AXS-05;
Figure 7-84) has promising results in major depressive
Targeting Glutamate for the Symptomatic Treatment
disorder and treatment-resistant depression (discussed
of Agitation in Alzheimer Disease
in Chapter 7 on treatment of mood disorders) and in
Excessive glutamate output in memory circuits has agitation of AD (mentioned here and illustrated in
already been discussed (Figures 12-37A, 12-37B, and 12- Figure 12-48). Although there are several potential
37C; see also Figure 4-52D and discussion in Chapter 4). therapeutic mechanisms of dextromethorphan
Although the NMDA glutamate antagonist memantine combinations, it is likely that NMDA antagonist
has proven effective in symptomatic treatment of action is how this drug works to quell agitation in AD.
cognition/memory in AD, it has not been systematically Hypothetically dextromethorphan–bupropion blocks
tested in agitation of AD. Furthermore, the widespread the excessive excitatory glutamate output from the
use of memantine does not suggest any anecdotal agitation network that leads to motor (Figure 12-45B)
evidence for efficacy in agitation, perhaps because it is and emotional agitation (Figure 12-46B) by blocking
a relatively weak blocker of NMDA receptors, with low NMDA receptors in cortex, thalamus, amygdala, ventral
potency. tegmental area, and locus coeruleus (Figure 12-48).
NMDA Antagonism Reduces Agitation in Alzheimer Disease Figure 12-48 NMDA antagonist
treatment for agitation. The NMDA
antagonist dextromethorphan (DXM), in
combination with the norepinephrine–
dopamine reuptake inhibitor
(NDRI) bupropion, is in testing as a
top-down inhibition treatment for agitation. Hypothetically,
dextromethorphan–bupropion blocks
the excessive excitatory glutamate
output from the agitation network
that leads to motor and emotional
agitation by blocking NMDA receptors
in the cortex, thalamus, amygdala,
ventral tegmental area (VTA), and locus
agitation coeruleus (LC).
cortex
12
LC VTA
amygdala striatum
DXM
= NMDA antagonism
thalamus sensory and
NDRI emotional 533
input
Dextromethorphan combined with quinidine is Given that symptoms of depression can significantly
approved for the treatment of pseudobulbar affect, impact quality of life for patients with dementia and
and dextromethorphan and derivates combined with may actually exacerbate cognitive decline, addressing
either bupropion or quinidine are in late-stage testing depressive symptoms using non-pharmacological (Table
for major depressive disorder, for treatment-resistant 12-9) and/or pharmacological means (Figure 12-50)
depression, and for agitation in AD. should be a priority. Psychosocial interventions are always
worth trying as treatments for depression in dementia,
Treating Depression in Dementia
but the usual drugs for depression discussed in Chapter
A well-established association exists between depression 7 are often not effective in depression associated with
and dementia; however, the exact nature of this dementia, perhaps because the neural circuits these drugs
intricate relationship is not fully understood (Figure act upon may have degenerated. Further complicating
12-49). Individuals with major depressive disorder the treatment of depression in dementia are the potential
often complain of memory problems (so-called depression-exacerbating effects of medications for somatic
pseudodementia when it occurs in the elderly), which can ailments common in the elderly population, as well as the
sometimes be reversed with antidepressant treatment, potential interactions of such medications with standard
but depression may also be an untreatable prodromal antidepressants. In terms of pharmacological management
symptom of, or risk factor for, inevitable dementia of major depressive disorder in patients with dementia,
(Figure 12-49). In fact, a history of major depressive SSRIs including sertraline, citalopram, escitalopram,
disorder is associated with a twofold increase in the risk and fluoxetine have shown some limited efficacy (see
for developing dementia, particularly vascular dementia, Chapter 7 for discussion of these and other drugs for
whereas major depressive disorder with an onset in later depression). In general, long-term antidepressant
life may signify a prodromal sign of AD. Additionally, treatment has been associated with a lower risk of
symptoms of depression are seen in at least 50% of dementia, improved cognition, and a slower rate of decline
individuals diagnosed with dementia, and should be in elderly patients with dementia. Data are somewhat
addressed whenever feasible.
Figure 12-49 Hypothetical associations
between depression and dementia. It
Depression as a risk is well established that an association
Depression Dementia exists between depression and
factor for dementia? dementia; however, the exact nature
of this intricate relationship is not fully
understood.
Depression
Cognitive impairment as
a feature of depression?
Dementia
Depression as a prodromal Depression Dementia

symptom of dementia?
Depression as a reaction Dementia Depression

to cognitive decline?
Depression
Depression and dementia Risk
sharing common risk factors/ factors
neurobiological bases? Dementia
534
inconclusive in terms of their efficacy in treating major (6–8 hours), if dosed only once daily at night, particularly
depressive disorder in dementia; however, SSRIs (e.g., at low doses, it can improve sleep without having daytime
citalopram but has QT prolongation; escitalopram may effects. The utility of trazodone in treating secondary
have similar efficacy without QT prolongation) may behavioral symptoms in patients with dementia may lie
have some additional applicability towards ameliorating more in its ability to improve sleep rather than depression.
agitation and inappropriate behaviors in patients with Trazodone may also improve other behavioral symptoms
dementia. Although considered relatively tolerable, SSRIs of dementia especially in FTD but not particularly in AD.
may be associated with increased falls and osteoporosis, Vortioxetine (Chapter 7 and Figure 7-49) in particular
and they may have interactions with other medications. may improve cognitive function in depression, especially
Additionally, SSRIs may worsen some symptoms of processing speed (Figure 7-50) as can some SNRIs like
Parkinson’s disease such as restless leg syndrome, periodic duloxetine (Figure 7-29) in the elderly with depression.
limb movements, and REM sleep behavior disorders. However, these pro-cognitive effects have not been
Therefore, if a trial of an SSRI (or any other antidepressant demonstrated specifically in dementia patients who have
medication) is deemed necessary, the lowest effective dose depression.
should be used and continuous monitoring should be
exercised. Pseudobulbar Affect (Pathological Laughing and
Another agent for treating depression in dementia Crying)
is trazodone, which blocks the serotonin transporter at Pseudobulbar affect (PBA) is an emotional expression
antidepressant doses (see Chapter 7 and Figures 7-44 disorder, characterized by uncontrolled crying or
and 7-45). Trazodone also has serotonin 2A and 2C, laughing that may be disproportionate or inappropriate
H1 histamine and α1-adrenergic antagonist properties to the social context. It is often mistaken for a mood
(Figures 7-44 and 7-45), which can make it very sedating. disorder but is actually a disorder of the expression of
At low doses, trazodone does not adequately block affect, which is inconsistent or disproportionate to mood.
serotonin reuptake but retains its other properties (Figure PBA can accompany a variety of neurodegenerative
7-46). Because trazodone has a relatively short half-life diseases such as AD and various other dementias,
Figure 12-50 Treating depression in

Treating Depression patients with dementia. The treatment
of depression in elderly patients with
dementia may be complicated by the
fact that the neural circuits acted on
by pharmacological interventions for
depression may have degenerated.
May be ineffective because... Although psychosocial interventions
are an appropriate option, they may be
difficult to implement for cognitively
impaired individuals.
Pharmacological acting on neural circuits which

Interventions may be degenerated
12
striving to change cognitive
Psychosocial functioning in cognitively
Interventions impaired individual
535
multiple sclerosis, amyotrophic lateral sclerosis, as well as mood symptoms, there have been challenges in defining
traumatic brain injury, and others hypothetically due to apathy, since it is not only a symptom of dementia, but
disruption of emotional expression networks (top-down also a symptom of schizophrenia (see Chapter 4 on
inhibition; see Figures 12-44 and 12-46B). PBA can be schizophrenia for discussion of negative symptoms), and
treated with the combination of dextromethorphan and of major depressive episodes, both unipolar and bipolar
quinidine (see Figure 7-84), presumably due to actions (see Chapter 6 on depression for discussion of lack of
on NMDA glutamate and σ receptors. Dextromethorphan motivation and lack of interest).
combined with either quinidine or bupropion is discussed The ABC (Affective/emotional, Behavioral, Cognitive)
as a possible treatment for resistant depression in Chapter model of apathy categorizes three types of apathy, which
7 (Figures 7-84 and 7-85), and above, in this chapter, as can hypothetically be linked to deficits in different brain
a possible treatment for agitation in AD (Figure 12-48). regions, as well as their connections to reward centers in
Serotonergic agents such as SSRIs can also be used “off- the basal ganglia (Figure 12-51). Another subtyping is:
label” for PBA symptoms in some patients. • lack of initiative
• lack of interest
Apathy • emotional blunting
Apathy, characterized as diminished motivation and But no matter how characterized, there is a consensus
reduced goal-directed behavior, accompanied by that lack of motivation is at the core of apathy. Lack of
decreased emotional responsiveness, affects approximately motivation is associated with
90% of patients with dementia across the disease course. • lack of goal-directed behavior (either spontaneous or
Apathy is indeed one of the most persistent and frequent in reaction to the environment)
secondary behavioral symptoms of dementia and has • lack of goal-directed cognitive activity, frequently
been shown to predict disease-worsening and add manifested as loss of interest
tremendously to caregiver burden. Given the current • lack of spontaneous or reactive emotional expression,
conceptual status of apathy as a mix of cognitive and often characterized as emotional blunting
Figure 12-51 Hypothesized
Hypothesized Neurocircuitry and neurocircuitry and treatment of
Treatment of Apathy apathy. The ABC (Affective/emotional,
Behavioral, Cognitive) model of apathy
categorizes three types of apathy, which
can hypothetically be linked to deficits
Cognitive apathy Behavioral apathy in different brain regions, as well as
• Dysfunction in DLPFC • Dysfunction in motor areas and DMPFC their connections to reward centers in
• Loss of motivation to participate in • Deficits in initiating and maintaining the basal ganglia. DLPFC, dorsolateral
goal-directed behavior motor movement prefrontal cortex; DMPFC, dorsomedial
• Loss of interest in events prefrontal cortex; VMPFC, ventromedial
• Difficulty planning and executing behaviors prefrontal cortex; OFC, orbital frontal
cortex.
Basal ganglia
(SIGH)
Affective apathy
• Dysfunction in VMPFC and OFC
• Inability to use emotional context to guide behavior
• Emotional blunting
• Altered social interactions
536
These various descriptions all integrate the notion the underlying cause for many secondary behavioral
of lack of spontaneous behaviors and emotions with symptoms in patients with dementia. Just as with
diminished reactivity to the environment, often the household pets or small children, a patient with dementia
opposite to what is observed in agitation (see Table 12-8). may not be able to express or describe the physical pain
The clinical presentation of apathy often differs they are experiencing; thus it is up to astute clinicians and
among various types of dementias; for instance, affective caregivers to identify and treat causes of pain that may be
apathy is more common in the behavioral variant of FTD leading to neuropsychiatric symptoms, such as agitation
compared to AD. Both dopaminergic and cholinergic and depression, in patients with dementia. If pain is
neurotransmitter systems seem to be involved in the contributing to behavioral symptoms, psychotropic
various types of apathy; potential treatments, therefore, medications may have little effect whereas alleviating the
include dopamine agonists such as bupropion, levodopa, source of the pain may be quite effective. For instance,
and stimulants, as well as cholinesterase inhibitors, but treatment with simple acetaminophen (paracetamol)
none is approved for this use and none is particularly can sometimes ameliorate agitation. Similarly, other
robust in efficacy. modifiable sources of behavioral symptoms (e.g.,
A primary reason why drugs used for depression boredom, excess stimulation, etc.) should be recognized
do not work well in apathy of dementia is that apathy and addressed.
is not depression. That is, guilt, worthlessness, and
hopelessness, the symptom hallmarks of depression SUMMARY
(see Chapter 6 and Figure 6-1), are typically not The most common dementia is Alzheimer disease (AD),
present in patients with apathy in dementia. When and the leading theory for its etiology is the amyloid
use of medications for apathy in dementia is needed, cascade hypothesis. Other dementias including vascular
cholinesterase inhibitors may be effective in some dementia, dementia with Lewy bodies, Parkinson’s
patients and are a first-line consideration in AD, but disease dementia, and frontotemporal dementia are
might work better for prevention of these symptoms than also discussed as well, as are their differing pathologies,
for their treatment once they have emerged. Also, FTD clinical presentations, and neuroimaging findings.
patients may be more likely to benefit from SSRIs (e.g., New diagnostic criteria define three stages of AD:
citalopram or escitalopram) or SNRIs. asymptomatic, mild cognitive impairment, and
dementia. Major research efforts have recently pivoted
Other Treatments for the Behavioral Symptoms of away from attempting to find disease-modifying
Dementia
treatments that could halt or even reverse the course
As mentioned earlier and shown in Table 12-9, of this illness by interfering with Aβ accumulation in
there are several non-pharmacological options for the brain because many such treatments have failed
treating neuropsychiatric symptoms in patients with over the past 30 years. Leading treatments for AD
dementia, and given the risks associated with many today include symptomatic treatment of memory and
pharmacological treatments, the lack of approval of cognition with the cholinesterase inhibitors, based upon
many agents, and their relative lack of efficacy, non- the cholinergic hypothesis of amnesia, and memantine,
pharmacological interventions should always be an NMDA antagonist, based upon the glutamate
considered first-line. This will also be the case even hypothesis of cognitive decline. Novel treatments
if pimavanserin is approved for psychosis in all-cause on the threshold of approval include the 5HT2A
dementia and if brexpiprazole and dextromethorphan– antagonist pimavanserin for symptomatic treatment
bupropion are approved for agitation in AD. of dementia-related psychosis, and both brexpiprazole
It is particularly important to keep in mind that and dextromethorphan–bupropion for symptomatic 12
physical pain, infection, or local irritation can be treatment of agitation in AD.
537
1
13 Impulsivity, Compulsivity,
and Addiction
What Are Impulsivity and Compulsivity? 538 Cannabis 563
Neurocircuitry and the Impulsive–Compulsive Hallucinogens 567
Disorders 539 Empathogens 569
The Dopamine Theory of Addiction: The Dissociatives 569
Mesolimbic Dopamine Circuit as the Final Common Abuse Your Way to Abstinence? 571
Pathway of Reward 542
“Therapeutic” Dissociation, Hallucinations, and
Substance Addictions 544 Empathy? 574
Stimulants 544 Behavioral Addictions 575
Nicotine 547 Binge Eating Disorder 575
Alcohol 553 Other Behavioral Addictions 575
Sedative Hypnotics 556 Obsessive–Compulsive and Related Disorders 576
Gamma-Hydroxybutyrate (GHB) 559 Impulse Control Disorders 577
Opiates or Opioids? 559 Summary 578
Impulsivity and compulsivity are symptoms that cut behavior is performed in a habitual or stereotypical fashion,
across many psychiatric disorders. Some conditions either according to rigid rules or as a means of avoiding
with impulsivity as a prominent feature have already perceived negative consequences. These two symptom
been discussed, including mania (Chapter 4); attention constructs can perhaps be best differentiated by how they
deficit hyperactivity disorder (ADHD; Chapter 11), both fail to control responses: impulsivity as the inability
and agitation in dementia (Chapter 12). Several other to stop initiating actions, and compulsivity as the inability
disorders in which impulsivity and/or compulsivity are to terminate ongoing actions. These constructs have
core features are discussed in this chapter. Full clinical thus been viewed historically as diametrically opposed,
descriptions and formal criteria for how to diagnose with impulsivity being associated with risk seeking and
the numerous known diagnostic entities discussed compulsivity with harm avoidance. Currently the emphasis
here should be obtained by consulting standard is on the fact that both share different forms of cognitive
diagnostic and reference sources. Here we emphasize inflexibility leading to a profound feeling of lack of control.
what is known or hypothesized about the brain circuits More precisely, impulsivity is action without
and neurotransmitters mediating impulsivity and forethought; the lack of reflection on the consequences
compulsivity, and how engaging neurotransmitters at of one’s behavior; the inability to postpone reward with
various nodes in impulsivity/compulsivity networks can preference for immediate reward over more beneficial
result in successful psychopharmacological treatments. but delayed reward; a failure of motor inhibition, often
choosing risky behavior; or (less scientifically) lacking the
will power not to give in to temptations and provocative
WHAT ARE IMPULSIVITY AND
stimuli from the environment. On the other hand,
COMPULSIVITY? compulsivity is action inappropriate to the situation but
Impulsivity can be defined as a predisposition towards which nevertheless persists, and which often results
rapid, unplanned reactions to internal or external stimuli, in undesirable consequences. In fact, compulsions are
with diminished regard for the negative consequences of characterized by the curious inability to adapt behavior
these reactions. In contrast, compulsivity is defined as the after negative feedback.
performance of repetitive and dysfunctionally impairing Habits are a type of compulsion, and can be seen as
behavior that has no adaptive function. Compulsive responses triggered by environmental stimuli, regardless
538
Chapter 13: Impulsivity, Compulsivity, and Addiction
of the current desirability of the consequences of that is thought to be due principally to neurodegeneration
response. Whereas goal-directed behavior is mediated by of top-down controls (see Chapter 12 and Figures
knowledge of and desire for its consequences, habits are 12-45B and 12-46B). In ADHD, impulsivity,
controlled by external stimuli through stimulus–response especially motor impulsivity, is thought to be due to
associations that are stamped into brain circuits through neurodevelopmentally delayed or absent top-down
behavioral repetition and formed after considerable
training, can be automatically triggered by stimuli, and Table 13-1 Impulsive–compulsive disorders
are defined by their insensitivity to their outcomes.
Given that goal-directed actions are relatively cognitively Substance addictions
demanding, for daily routines, it can be adaptive to rely Cannabis
on habits that can be performed with minimal conscious Nicotine
Alcohol
awareness. However, habits can also represent severely
Opioids
maladaptive perseveration of behaviors as components of Stimulants
various impulsive–compulsive disorders (see Table 13-1). Hallucinogens
Another way to look at addiction is as a habit much Empathogens
like the behavior of a Pavlovian dog! That is, drug seeking Dissociatives
and drug taking behaviors can be viewed as conditioned Behavioral addictions
responses to the conditioned stimuli of being around Binge eating disorder
people or places or items associated with drugs, or having Gambling disorder
craving and withdrawal. When addicted, drug seeking Internet gaming disorder
and taking are automatic, thoughtless, conditioned Obsessive–compulsive related disorders
responses that occur in an almost reflexive fashion to Obsessive–compulsive disorder
conditioned stimuli, just as Pavlov’s dogs developed Body dysmorphic disorder
mouth-watering in response to a bell associated with Trichotillomania
food. When such stimulus–response conditioning runs Skin picking
amok in addiction, it does not perform an adaptive Hoarding
Shopping
purpose of sparing cognitive efforts from doing routine
Hypochondriasis
tasks. Instead, the “habit” of drug addiction has become Somatization
a perverse form of learning, almost as though one has
Impulse control disorders
learned how to have a psychiatric disorder!
Agitation in Alzheimer disease
Motor and behavioral impulsivity in ADHD
NEUROCIRCUITRY AND THE Mood disorders
IMPULSIVE–COMPULSIVE Provocative behaviors in mania
DISORDERS Disruptive mood dysregulation disorder
Pyromania
Impulsivity and compulsivity are thought to be mediated Kleptomania
by neuroanatomically and neurochemically distinct, but Paraphilias
in many ways parallel, components of cortico-subcortical Hypersexual disorder
circuitry (Figures 13-1 and 13-2). When these networks Autism spectrum disorders
are dysfunctional, they hypothetically result in “lack Tourette syndrome and tic disorders
of control” of thoughts and behaviors. Simply put, Stereotyped movement disorders
Borderline personality disorder
impulsivity and compulsivity are both symptoms that
Self harm and parasuicidal behaviors
result from the brain having a hard time saying “no.” Conduct disorder
Why can’t impulses and compulsions be stopped Antisocial personality disorder
in various psychiatric disorders? An over-simplified Oppositional defiant disorder
explanation was discussed in Chapter 12 and illustrated Intermittent explosive disorder
in Figures 12-43 and 12-44, showing either too much Aggression and violence:
“bottom-up” limbic emotional drive or too little “top- impulsive
13
down” cortical inhibition of these drives. In Alzheimer psychotic
psychopathic
disease, for example, impulsivity resulting in agitation
539
Impulsivity and Reward Compulsivity and Motor Response Inhibition
dorsal
ventral
Figure 13-1 Circuitry of impulsivity and reward. The “bottom- Figure 13-2 Circuitry of compulsivity and motor response
up” circuit that drives impulsivity is a loop with projections inhibition. The “bottom-up” circuit that drives compulsivity
from the ventral striatum to the thalamus, from the thalamus to is a loop with projections from the dorsal striatum to the
the ventromedial prefrontal cortex (VMPFC) and the anterior thalamus, from the thalamus to the orbitofrontal cortex (OFC),
cingulate cortex (ACC), and from the VMPFC/ACC back to the and from the OFC back to the dorsal striatum. This habit circuit
ventral striatum. This circuit is usually modulated “top-down” can be modulated “top-down” from the OFC. If this top-down
from the prefrontal cortex. If this top-down response inhibition response inhibition system is inadequate or is overcome by
system is inadequate or is overcome by activity from the ventral activity from the dorsal striatum, compulsive behaviors may
striatum, impulsive behaviors may result. result.
cortical controls (see Chapter 11 and Figures 11-17 is hypothesized to be controlled by a habit system
through 11-21). In a wide variety of other disorders that is dorsal (Figure 13-2). That is, many behaviors
discussed below, the problem may lie anywhere within start out as impulses mediated by the ventral loop,
two parallel cortico-striatal circuits, namely at two which reacts to reward and motivation (Figure 13-
striatal nodes (one impulsive and the other compulsive), 1). Over time, however, the locus of control for these
which drive these behaviors, or at two corresponding behaviors migrates dorsally (Figure 13-2) due to a
prefrontal cortical nodes, which restrain them (Figures cascade of neuroadaptations and neuroplasticity that
13-1 and 13-2). Overlap between these two parallel engage a dorsal “habit system” by means of which an
networks exists such that a problem in the impulsive impulsive act eventually becomes compulsive (Figures
circuit can end up as a problem in the compulsive circuit 13-2 and 13-3). This naturally occurring process can
and vice versa, leading to the concept of “impulsive– have adaptive value in everyday life, freeing the brain
compulsive disorders,” all of which have this symptom to spend its efforts on novel, cognitively demanding
domain as one of their core features. Such psychiatric activities. However, when it runs hypothetically amok in
conditions incorporate a wide range of disorders, from a myriad of psychiatric disorders (Table 13-1), the goal
obsessive–compulsive disorder (OCD) to addictions, and is to stop or reverse this spiral of information from the
far beyond (Table 13-1). Although there are many other impulsive neuronal loop to the compulsive “habit” loop.
important symptom domains in these various conditions Unfortunately, there are relatively few highly effective
that distinguish one from another, all can be associated treatments for impulsive–compulsive disorders today.
with disordered impulsivity and/or compulsivity, and We have discussed effective treatments for ADHD in
this is the shared domain of their psychopathology that Chapter 11 and for agitation in Alzheimer disease in
is discussed here. Chapter 12. Here we review the hypothetically shared
Neuroanatomically, impulsivity is thus seen as neurobiology of many other impulsive–compulsive
regulated by an action–outcome ventrally dependent disorders and discuss what treatments are available for
learning system (Figure 13-1) whereas compulsivity some of these conditions.
540
mania ADHD
impulsive
intermittent violence
explosive
disorder
ACC ventral borderline

VMPFC striatum personality
kleptomania disorder
antisocial
pyromania thalamus behavior
IMPULSIVITY
drug addiction
gambling
obesity/
autism
binge eating
spectrum COMPULSIVITY
Tourette hypersexual
syndrome
dorsal
body OFC striatum
dysmorphic paraphilias
disorder
skin internet
picking
thalamus
gambling
trichotillomania
OCD compulsive
somatization shopping
hypochondriasis
Figure 13-3 Impulsive–compulsive disorder construct. Impulsivity and compulsivity are seen in a wide variety of psychiatric disorders.
Impulsivity can be thought of as the inability to stop the initiation of actions and involves a brain circuit centered on the ventral striatum
and linked to the thalamus, to the ventromedial prefrontal cortex (VMPFC), and to the anterior cingulate cortex (ACC). Compulsivity can
be thought of as the inability to terminate ongoing actions and hypothetically involves a brain circuit centered on the dorsal striatum
and linked to the thalamus and orbitofrontal cortex (OFC). Impulsive acts such as drug use, gambling, and over-eating can eventually
become compulsive due to neuroplastic changes that engage the dorsal habit system and theoretically cause impulses in the ventral
loop to migrate to the dorsal loop. 13
541
The Dopamine Theory of Addiction: The Mesolimbic circuit discussed in Chapter 4 on psychosis and
Dopamine Circuit as the Final Common Pathway of hypothesized to be overly active in psychosis, mediating
Reward the positive symptoms of schizophrenia and also
A leading theory of addiction for over 40 years has motivation and reward (see Figures 4-14 through 4-16).
been the dopamine theory, proposing that the final Some even consider the mesolimbic dopamine pathway
common pathway of reinforcement and reward in to be the “pathway of hedonic pleasure” of the brain
the brain for anything pleasurable is the mesolimbic and dopamine to be the “neurotransmitter of hedonic
dopamine pathway (Figure 13-4). This theory is a bit pleasure.” According to this notion, there are many
of an oversimplification and perhaps most applicable natural ways to trigger your mesolimbic dopamine
to drugs that cause the greatest effects upon dopamine neurons to release dopamine, ranging from intellectual
release, especially stimulants and nicotine, but less so accomplishments, to athletic victories, to enjoying a
for marijuana and opioids. The mesolimbic dopamine good symphony, to experiencing an orgasm. These are
pathway is familiar to readers as it is the same brain sometimes called “natural highs” (Figure 13-4).
Reward: DA mesolimbic pathway
nucleus
accumbens
VTA
YES!
YES!
Natural Highs Substance-Induced Highs
Behaviorally Induced Highs
Figure 13-4 Dopamine is central to reward. Dopamine (DA), and specifically the mesolimbic pathway from the ventral tegmental area
(VTA) to the nucleus accumbens, has long been recognized as a major player in the regulation of reinforcement and reward. Naturally
rewarding activities, such as achieving major accomplishments, can cause fast and robust increases in DA in the mesolimbic pathway.
Drugs of abuse also cause DA release in the mesolimbic pathway, and can often increase DA in a manner that is more explosive and
pleasurable than that which occurs naturally.
542
The inputs to the mesolimbic pathway that mediate amphetamine (dopamine itself) (Figure 13-5). Thus, the
these natural highs include a most incredible “pharmacy” idea formed that all drugs of abuse – as well as many
of naturally occurring substances, ranging from the maladaptive behaviors such as gambling, binge eating,
brain’s own morphine/heroin (endorphins), to the using the internet – have a final common pathway of
brain’s own marijuana (anandamide), to the brain’s own causing pleasure. This happens by provoking dopamine
nicotine (acetylcholine), to the brain’s own cocaine and release in the mesolimbic pathway in a manner often
Neurotransmitter Regulation of Mesolimbic Reward

nucleus
accumbens
endocannabinoid
G
lu
GABA
PFC DA in
T rph
amygdala 5H do
hippocampus en
raphe
PPT/LDT
arcuate
nucleus
VTA
endocannabinoid
Glu
5HT
ACh GABA
ACh
end
orp
GABA
hin
endocannabinoid
endocannabinoid
Figure 13-5 Neurotransmitter regulation of mesolimbic reward. The mesolimbic dopamine pathway is modulated by many naturally
occurring substances in the brain in order to deliver normal reinforcement to adaptive behaviors (such as eating, drinking, sex) and thus
to produce “natural highs,” such as feelings of joy or accomplishment. These neurotransmitter inputs to the reward system include the
brain’s own morphine/heroin (endorphins), the brain’s own cannabis/marijuana (endocannabinoids such as anandamide), the brain’s
own nicotine (acetylcholine [ACh]), and the brain’s own cocaine/amphetamine (dopamine [DA] itself), among others. The numerous
psychotropic drugs of abuse that occur in nature bypass the brain’s own neurotransmitters and directly stimulate the brain’s receptors
13
in the reward system, causing dopamine release and a consequent “artificial high.” Thus, alcohol, opioids, stimulants, marijuana,
benzodiazepines, sedative hypnotics, hallucinogens, and nicotine all affect this mesolimbic dopaminergic system.
543
more explosive and pleasurable than that which occurs maladaptive perseveration of behavior – a habit and a
naturally. In this formulation, drugs bypass the brain’s Pavlovian conditioned response, and not any longer being
own neurotransmitters and directly stimulate the simply naughty or giving in to temptation.
brain’s own receptors for these same drugs, causing
dopamine to be released. Since the brain already uses Stimulants
neurotransmitters that resemble drugs of abuse, it is not Stimulants as therapeutic agents have been discussed
necessary to earn your reward naturally since you can in Chapter 11 covering the treatment of ADHD. For
get a much more intense reward in the short run and optimized treatment of ADHD, stimulant dosing is
upon demand from a drug of abuse than you can from carefully controlled to deliver constant drug levels
a natural high with the brain’s natural system. However, within a defined therapeutic range (see Chapter 11 and
unlike a natural high, a drug-induced reward can start Figure 11-34). Theoretically, this amplifies tonic release
the diabolical cascade of neuroadaptation into habit of dopamine (Figure 11-33) to optimize pro-cognitive
formation. ADHD therapeutic effects. On the other hand, these
very same stimulants can also be used as drugs of abuse
SUBSTANCE ADDICTIONS by changing the dose and the route of administration
Addiction is a horrible disease. What starts out as fun to amplify phasic dopamine stimulation and thus their
and increased dopamine release in the ventral striatum reinforcing effects (Figure 11-35). Although therapeutic
with enhanced anterior cingulate cortex (ACC) activity actions of stimulants are thought to be directed at the
and reward ends up with the locus of control in the habit prefrontal cortex to enhance both norepinephrine and
circuit as a mindless, automatic, and powerful compulsive dopamine neurotransmission there, at moderate levels
drive to obtain drugs that is basically irresistible. Since of dopamine transporter (DAT) and norepinephrine
it is not presently known what treatment mechanisms transporter (NET) occupancy (Figure 11-26), the
might suppress the wicked habit circuit that has reinforcing effects and abuse of stimulants occur when
commandeered behavioral control in the addict, DATs in the mesolimbic reward circuit are suddenly
treatments for addiction are few and far between and blasted and massively blocked (Figure 13-6).
often not very effective. What is needed are treatments The speed with which a stimulant enters the brain
capable of wresting control back from the habit circuit dictates the degree of the subjective “high” (Figure 13-
and returning it to voluntary control, perhaps by 7). This was also discussed in Chapter 11 as one of the
neuroplasticity reverse-migrating control from dorsal properties of the “mysterious DAT.” This sensitivity of
back to ventral, where things began before addiction was the DAT to the way in which it is engaged likely explains
present. why stimulants when abused are often not ingested orally
Once addicted, the brain is no longer rewarded but instead are smoked, inhaled, snorted, or injected so
principally by the drug itself, but as well by anticipation they can enter the brain in a sudden explosive manner,
of the drug and its reward. This generates compulsive to maximize their reinforcing nature. Oral absorption
drug-seeking behaviors which are themselves rewarding. reduces reinforcing properties of stimulants because
That is, some studies suggest that dopamine neurons speed of entry to the brain is considerably slowed by the
terminating in the ventral striatum (Figure 13-1) actually process of gastrointestinal absorption. Cocaine is not even
stop responding to the primary reinforcer (i.e., taking the active orally so users have learned over the years to take it
drug, eating the food, doing the gambling) and instead intranasally so that drug rapidly enters the brain directly,
dopamine neurons terminating in the dorsal striatum bypassing the liver, and thus can have a more rapid
(Figure 13-2) begin to respond to the conditioned stimuli onset than even with intravenous administration. The
(i.e., handling the heroin syringe, feeling the crack pipe most rapid and robust way to deliver drugs to the brain
in your hand, entering the casino) before the drug is even is to smoke those that are compatible with this route
taken! Since drug seeking and drug taking become the of administration, as this avoids first-pass metabolism
main motivational drives when addicted, this explains through the liver and is somewhat akin to giving the
why the addicted subject is aroused and motivated when drug by intra-arterial/intra-carotid bolus via immediate
seeking to procure drugs, but is withdrawn and apathetic absorption across the massive surface area of the lung.
when exposed to non-drug-related activities. When drug The faster the drug’s entry into brain, the stronger are its
abuse reaches this stage of compulsivity, it is clearly a reinforcing effects (Figure 13-7), probably because this
544
Stimulant Actions on the Mesolimbic Dopamine Circuit

nucleus
accumbens
endocannabinoid
G
lu
YES!
GABA
n
PFC DA
T hi
rp
amygdala 5H o
hippocampus e nd
substance-induced
stimulants
high
raphe
PPT/LDT
arcuate
nucleus
VTA
endocannabinoid
Glu
5HT
ACh GABA
ACh
end
orp
GABA
hin
endocannabinoid
endocannabinoid
Figure 13-6 Stimulant actions on the mesolimbic dopamine circuit. The reinforcing effects and abuse potential of stimulants occurs
when dopamine transporters (DATs) in the mesolimbic reward circuit are blocked, causing a phasic increase in dopamine (DA) in the
nucleus accumbens.
form of drug delivery triggers phasic dopamine firing, stereotyped behavior. At even higher repetitive doses,
the type associated with reward (see Chapter 11 for stimulants can induce paranoia and hallucinations
discussion and Figure 11-35). resembling schizophrenia (see Chapter 4 and Figures
Amphetamine, methamphetamine, and cocaine are all 4-14 through 4-16) as well as hypertension, tachycardia,
inhibitors of the DAT and the NET. Cocaine also inhibits ventricular irritability, hyperthermia, and respiratory
the serotonin transporter (SERT) and is also a local depression. In overdose, stimulants can cause acute
anesthetic, which Freud himself exploited to help dull heart failure, stroke, and seizures. Over time, stimulant
the pain of his tongue cancer. He may have also exploited abuse can be progressive (Figure 13-8). Initial doses
the second property of the drug, which is to produce of stimulants that cause pleasurable phasic dopamine
euphoria, reduce fatigue, and create a sense of mental firing (Figure 13-8A) give leave to reward conditioning
acuity due to inhibition of dopamine reuptake at the DAT, and addiction with chronic use, causing craving between
at least for a while, until drug-induced reward is replaced stimulant doses and residual tonic dopamine firing with
by drug-induced compulsivity. a lack of pleasurable phasic dopamine firing (Figure 13- 13
High doses of stimulants can cause tremor, emotional 8B). Now addicted, higher and higher doses of stimulants
lability, restlessness, irritability, panic, and repetitive, are needed in order to achieve the pleasurable highs of
545
Dopamine, Pharmacokinetics, and Reinforcing Effects

Cocaine (IV)
120
DAT blockade
100 Self-reported high
80
60
% of Peak
40
20
0
0 10 20 30 40 50 60
Time (minutes)
Figure 13-7 Dopamine, pharmacokinetics, and reinforcing effects. Acute drug use causes dopamine release in the striatum. However,
the reinforcing effects of the drug are largely determined not only by the presence of dopamine, but also by the rate at which dopamine
increases in the brain, which in turn is dictated by the speed at which the drug enters and leaves the brain. This is likely because abrupt
and large increases in dopamine (such as those caused by drugs of abuse) mimic the phasic dopamine firing associated with conveying
information about reward and saliency. As shown here, the self-reported high associated with intravenous (IV) cocaine use correlates
with both the rate and extent of dopamine transporter (DAT) blockade. The rate of drug uptake is subject to the route of administration,
with intravenous administration and inhalation producing the fastest drug uptake, followed by snorting. In addition, different drugs of
abuse have different “reward values” (i.e., different rates at which they increase dopamine) based on their individual mechanisms of
action.
phasic dopamine firing (Figure 13-8C). Unfortunately, Atypical Stimulants

the higher the high, the lower the low, and between “Bath salts” are a form of stimulant. Their name derives
stimulant doses, the individual experiences not only the from efforts to disguise these abusable stimulants
absence of a high, but also withdrawal symptoms such as as common Epsom salts used in baths, with similar
sleepiness and anhedonia (Figure 13-8D). The effort to packaging as white or colorful powders, granules, or
combat withdrawal coupled with habit formation leads crystal forms but quite different chemically! Bath salts
to compulsive use and ultimately dangerous behavior are often labelled “not for human consumption” in a
in order to secure drug supplies (Figure 13-8E). Finally, further attempt to be mistaken for Epsom salts and thus
there may be enduring if not irreversible changes in circumventing drug prohibition laws.
dopamine neurons, including long-lasting depletions of Bath salts, however, are not for bathing, but are
dopamine levels and axonal degeneration, a state that synthetic stimulants that commonly include the active
clinically and pathologically is appropriately called “burn- ingredient methylenedioxypyrovalerone (MDPV) and
out” (Figure 13-8F). may also contain mephedrone or methylone. They are
546
Progression of Stimulant Abuse
amphetamine
cocaine amphetamine cocaine amphetamine
cocaine
postsynaptic
A B C D E F
fun craving reverse anhedonia compulsive enduring

tolerance/ sleepiness use cognitive loss
“where’s my addicted withdrawal marathon sex “burn-out”
dopamine?” “brainwashed” paranoia
HIV
violence
DA
firing
time
Figure 13-8 Progression of stimulant abuse. (A) Initial doses of stimulants such as methamphetamine and cocaine cause pleasurable
phasic dopamine firing. (B) With chronic use, reward conditioning causes craving between stimulant doses and residual tonic dopamine
firing with a lack of pleasurable phasic dopamine firing. (C) In this addicted state, higher and higher doses of stimulants are needed
in order to achieve the pleasurable highs of phasic dopamine firing. (D) Unfortunately, the higher the high, the lower the low, and
between stimulant doses, the individual experiences not only the absence of a high, but also withdrawal symptoms such as sleepiness
and anhedonia. (E) The effort to combat withdrawal can lead to compulsive use and impulsive, dangerous behavior in order to secure
the stimulant. (F) Finally, there may be enduring if not irreversible changes in dopamine neurons, including long-lasting depletions of
dopamine levels and axonal degeneration, a state that clinically and pathologically is appropriately called “burn-out.”
also called “plant food” and like other stimulants can Treatment of Stimulant Addiction
have reinforcing effects but also cause agitation, paranoia, Unfortunately, there are currently no approved drug
hallucinations, suicidality, and chest pain. treatments for stimulant addicts, as many dopamine-
Some would consider inhalants as atypical types of linked and serotonin-linked therapeutics have failed. In
stimulants since they are thought to be direct releasers the future, there may be a cocaine vaccine that removes
of dopamine in the nucleus accumbens. Inhaling fumes the drug before it reaches the brain so there are no more
– called “huffing” – of substances such as toluene found reinforcing effects that accompany drug ingestion.
in paint thinner, felt-tip markers, glue, various aerosol
sprays, and even freon found in air conditioners, can Nicotine
cause a feeling similar to alcohol intoxication, with How common is smoking in clinical psychopharmacology
dizziness, lightheadedness, and disinhibition; it can also practices? Some estimates are that more than half of all
cause impaired judgment and possibly hallucinations. cigarettes are consumed by patients with a concurrent
Long-term huffing can cause depression, weight loss, psychiatric disorder, and that smoking is the most
and brain damage. Huffing can also be dangerous in the common comorbidity among seriously mentally ill
short term, as it can cause sudden death due to cardiac patients. Other estimates are that about 16–20% of the
arrest, aspiration, or suffocation. Freon in particular can general population (in the US) smoke, about 25% of
cause these effects and can also freeze the lungs, making people who regularly see general physicians smoke,
it extremely dangerous. Substances that are huffed do not but that 40–50% of patients in a psychopharmacology 13
show up on drug tests. practice smoke, including 60–85% of patients
547
with ADHD, schizophrenia, and bipolar disorder. that they are. Shorter does not maximize the pleasure.
Unfortunately, histories of current smoking are often not Longer is a waste since by then the receptors are all
carefully taken or recorded as one of the diagnoses for desensitized anyway (Figure 13-10A).
smokers in mental health practices and only about 10% The problem for the smoker is that when the
of smokers report being offered treatment pro-actively by receptors resensitize to their resting state, this initiates
psychopharmacologists and other clinicians even though craving and withdrawal due to the lack of release of
somewhat effective treatments are available. further dopamine (Figure 13-10A). Another interesting
Nicotine acts directly upon nicotinic cholinergic question is: how long does it take to resensitize nicotinic
receptors in mesolimbic reward circuits to release receptors? The answer seems to be: about the length
dopamine (Figure 13-9). Cholinergic neurons and the of time that smokers take between cigarettes. For the
neurotransmitter acetylcholine (ACh) are discussed average one-pack-per-day smoker, awake for 16 hours,
in Chapter 12 and illustrated in Figures 12-24 through that would be about 45 minutes, possibly explaining
12-32. Nicotinic receptors are specifically illustrated in why there are 20 cigarettes in a pack (i.e., enough for an
Figure 12-28. There are several subtypes of nicotinic average smoker to keep his or her nicotinic receptors
receptors present in brain. The α7 nicotinic receptor on completely desensitized all day long).
postsynaptic prefrontal cortex neurons may be linked Putting nicotinic receptors out of business by
to the pro-cognitive and mentally alerting actions of desensitizing them causes neurons to attempt to
nicotine, but not to addictive actions. It is the α4β2 overcome this lack of functioning receptors by
subtype discussed here and illustrated in Figure 13-9 upregulating the number of receptors (Figure 13-10B).
that is thought to be most relevant to smoking and That, however, is futile, since nicotine just desensitizes
nicotine addiction. That is, nicotine’s actions at α4β2 all of them the next time a cigarette is smoked (Figure
nicotinic postsynaptic receptors directly on dopamine 13-10C). Furthermore, this upregulation is self-defeating
neurons in the ventral tegmental area (VTA) are those because it serves to amplify the craving that occurs when
that are theoretically linked to addiction (Figure 13-9). the extra receptors are resensitizing to their resting state
Nicotine also indirectly activates dopamine release from (Figure 13-10C).
the VTA by activating nicotinic presynaptic receptors From a receptor point of view, at first the goal of
on glutamate neurons, causing glutamate release, which smoking is to desensitize all nicotinic α4β2 receptors and
in turn causes dopamine release (Figure 13-9). Nicotine get the maximum dopamine release. Eventually, however,
also appears to desensitize α4β2 postsynaptic receptors the goal is mostly to prevent craving. Positron emission
on inhibitory GABAergic interneurons in the VTA, tomography (PET) scans of α4β2 nicotinic receptors in
indirectly leading to dopamine release in the nucleus human smokers confirm that nicotinic receptors are
accumbens by disinhibiting dopaminergic mesolimbic exposed to just about enough nicotine for just about long
neurons (Figure 13-9). enough from each cigarette to accomplish this. Craving
The α4β2 nicotinic receptors adapt to the chronic seems to be initiated at the first sign of nicotinic receptor
intermittent pulsatile delivery of nicotine in a way resensitization. Thus, the bad thing about receptor
that leads to addiction (Figure 13-10). Initially these resensitization is craving. The good thing from an addicted
receptors in the resting state are opened by delivery of smoker’s point of view is that as the receptors resensitize,
nicotine, which in turns leads to dopamine release and they are available to release more dopamine and cause
reinforcement, pleasure, and reward (Figure 13-10A). By pleasure or suppress craving and withdrawal again.
the time the cigarette is finished, these receptors become
Treatment of Nicotine Addiction
desensitized, so that they cannot function temporarily,
and thus cannot react either to acetylcholine or nicotine Treating nicotine dependence is not easy. There is
(Figure 13-10A). In terms of obtaining any further evidence that nicotine addiction begins with the first
reward, you might as well stop smoking at this point. An cigarette, with the first dose showing signs of lasting
interesting question to ask is: how long does it take for a month in experimental animals (e.g., activation of
the nicotinic receptors to desensitize? The answer seems the anterior cingulate cortex for this long after a single
to be: about as long as it takes to inhale all the puffs of dose). Craving begins within a month of repeated
a standard cigarette and burn it down to a butt. Thus, it administration. Perhaps even more troublesome is the
is probably not an accident that cigarettes are the length finding that the “diabolical learning” of dorsal to ventral
548
Detail of Nicotine Actions
PFC PPT/LDT
Glu neuron ACh neuron
VTA
nicotine
indirectly
activates DA
release
nicotine
nicotine directly desensitizes
activates DA
release
VTA
DA neuron GABA
interneuron
α 4ß2 α7
Glu DA
GABA
ACh
nicotine
Figure 13-9 Actions of nicotine. Nicotine directly causes dopamine (DA) release in the nucleus accumbens by binding to α4β2 nicotinic
postsynaptic receptors on dopamine neurons in the ventral tegmental area (VTA). In addition, nicotine binds to α7 nicotinic presynaptic
receptors on glutamate (Glu) neurons in the VTA, stimulating glutamate release that in turn leads to dopamine release in the nucleus
accumbens. Nicotine also seems to desensitize α4β2 postsynaptic receptors on GABA interneurons in the VTA; the reduction of GABA
neurotransmission disinhibits mesolimbic dopamine neurons and thus is a third mechanism for enhancing dopamine release in the 13
nucleus accumbens.
549
Reinforcement and α4ß2 Nicotinic Receptors
cigarette
cigarette finished
resting open desensitized

- DA releases
initiation of craving
A
Adaptation of α 4ß2 Nicotinic Receptors
upregulated
chronically
desensitized
Addiction and α 4ß2

cigarette cigarette
finished
upregulated, open, desensitized

resting DA release
C
enhanced craving
drug-seeking behavior
impulsive choices
reward sensitivity
Figure 13-10 Reinforcement and α4β2 nicotinic receptors. (A) In the resting state α4β2 nicotinic receptors are closed (left). Nicotine
administration, as by smoking a cigarette, causes the receptor to open, which in turn leads to dopamine release (middle). Long-
term stimulation of these receptors leads to their desensitization, such that they temporarily can no longer react to nicotine (or
to acetylcholine); this occurs in approximately the same length of time it takes to finish a single cigarette (right). As the receptors
resensitize (return to resting state), they initiate craving and withdrawal due to the lack of release of further dopamine. (B) With
chronic desensitization, α4β2 receptors upregulate to compensate. (C) If one continues smoking, however, the repeated administration
of nicotine continues to lead to desensitization of all of these α4β2 receptors and thus the upregulation does no good. In fact, the
upregulation can lead to amplified craving as the extra receptors resensitize to their resting state.
550
migration of control from impulsive to compulsive an intermediate state that is not desensitized and where
circuits may be very, very long-lasting once exposure to the channel opens less frequently than with a full agonist,
nicotine is stopped. Some evidence even suggests that but more frequently than with an antagonist (Figure 13-
these changes last a lifetime, with a form of “molecular 11, middle).
memory” to nicotine, even in long-term abstinent former How addicting is tobacco and how well do NPAs
smokers. One of the first successful agents proven to be work to achieve cessation of smoking? About two-thirds
effective for treating nicotine addiction is nicotine itself, of smokers want to quit, one-third try, but only 2–3%
but in a route of administration other than smoking: succeed long term. Of all the substances of abuse, some
gums, lozenges, nasal sprays, inhalers, and transdermal surveys show that tobacco has the highest probability of
patches. Delivering nicotine by these other routes does making you dependent when you have tried a substance
not attain the high levels nor the pulsatile blasts that are at least once. It could be argued, therefore, that nicotine
delivered to the brain by smoking, so they are not very might be the most addicting substance known. The good
reinforcing, just as discussed for delivery of stimulants news is that the NPA varenicline triples or quadruples
above and illustrated in Figure 13-7. However, these the 1-month, 6-month, and 1-year quit rates compared to
alternative forms of nicotine delivery can help to reduce placebo; the bad news is that this means only about 10%
craving due to a steady amount of nicotine that is of smokers who have taken varenicline are still abstinent
delivered and presumably desensitizing an important a year later. Many of these patients are prescribed
number of resensitizing and craving nicotinic receptors. varenicline for only 12 weeks, which might be far too
Another treatment for nicotine dependence is short a period of time for maximal effectiveness.
varenicline, a selective α4β2 nicotinic acetylcholine Another approach to the treatment of smoking
receptor partial agonist (Figures 13-11 and 13-12). cessation is to try to reduce the craving that occurs
Figure 13-11 contrasts the effects of nicotinic partial during abstinence by boosting dopamine with the
agonists (NPAs) with nicotinic full agonists and with norepinephrine–dopamine reuptake inhibitor (NDRI)
nicotinic antagonists on the cation channel associated bupropion (see Chapter 7 and Figures 7-34 through
with nicotinic cholinergic receptors. Nicotinic full 7-36). The idea is to give back some of the dopamine
agonists include acetylcholine, which is very short-acting, downstream to the craving postsynaptic D2 receptors
and nicotine, which is very long-acting. They open the in the nucleus accumbens while they are readjusting to
channel fully and frequently (Figure 13-11, left). By the lack of getting their dopamine “fix” from the recent
contrast, nicotinic antagonists stabilize the channel in withdrawal of nicotine (Figure 13-13). Thus, while
the closed state, but do not desensitize these receptors smoking, dopamine is happily released in the nucleus
(Figure 13-11, right). NPAs stabilize nicotinic receptors in accumbens because of the actions of nicotine on α4β2
Figure 13-11 Molecular actions of

Molecular Actions of a Nicotinic Partial Agonist (NPA) a nicotinic partial agonist (NPA). Full
agonists at α4β2 receptors, such as
nicotinic acetylcholine and nicotine, cause the
acetylcholine nicotinic antagonist
partial agonist channels to open frequently (left). In
contrast, antagonists at these receptors
stabilize them in a closed state, such
that they do not become desensitized
(right). Nicotinic partial agonists
(NPAs) stabilize the channels in an
intermediate state, causing them to
open less frequently than a full agonist
but more frequently than an antagonist
(middle).
nicotinic full agonist: nicotinic partial agonist (NPA): nicotinic antagonist:

channel frequently open stabilizes channel in less stabilizes channel in closed
frequently open state, state, not desensitized 13
not desensitized
551
Varenicline Actions on Reward Circuits
PFC PPT/LDT
Glu neuron ACh neuron
VTA
varenicline varenicline
VTA
DA neuron GABA
interneuron
α 4ß2 α7
Glu DA
GABA
ACh
varenicline
Figure 13-12 Varenicline actions on reward circuits. Varenicline is a nicotinic partial agonist (NPA) selective for the α4β2 receptor
subtype. When varenicline binds to α4β2 nicotinic receptors – located on dopamine (DA) neurons, glutamate (Glu) neurons, and GABA
interneurons in the ventral tegmental area (VTA) – it stabilizes the channels in an intermediate state, with less frequent opening than
would occur if nicotine were bound, but more frequent than if a nicotinic antagonist were bound. Thus, it can reduce the dopaminergic
reward that would occur if a patient did smoke (by competing with nicotine) but also reduce withdrawal symptoms by stimulating at
least some neurotransmission.
552
receptors on the VTA dopamine neuron (shown in Alcohol

Figure 13-13A). During smoking cessation, resensitized The famous artist Vincent van Gogh reportedly drank
nicotinic receptors no longer receiving nicotine are ruinously, some speculating that he self-medicated his
craving due to an absence of dopamine release in the bipolar disorder this way, a notion reinforced by his
nucleus accumbens (where is my dopamine?) (Figure explanation, “If the storm within gets too loud, I take
13-13B). When the NDRI bupropion is administered, a glass too much to stun myself.” Alcohol may stun
theoretically a bit of dopamine is now released in the but it does not treat psychiatric disorders adaptively
nucleus accumbens, making the craving less but usually long term. Unfortunately, many alcoholics who have
not eliminating it (Figure 13-13C). How effective is comorbid psychiatric disorders continue to self-
bupropion in smoking cessation? Quit rates for bupropion medicate with alcohol rather than seeking treatment
are about half that of the NPA varenicline. Quit rates for with a more appropriate psychopharmacological agent.
nicotine in alternative routes of administration such as In addition to frequent comorbidity with psychiatric
transdermal patches are similar to those of bupropion. disorders, it is estimated that 85% of alcoholics also
Novel approaches to treating nicotine addiction include smoke. Many alcoholics abuse additional drugs as well,
the investigation of nicotine vaccines and other direct- including benzodiazepines, marijuana, opioids, and
acting nicotinic cholinergic agents. others.
Mechanism of Action of Bupropion in Smoking Cessation Figure 13-13 Mechanism of action of

bupropion in smoking cessation. (A)
A regular smoker delivers reliable
ACh
nicotine (circle), releasing dopamine
neuron (DA) in the limbic area at frequent
intervals, which is rewarding to the
limbic dopamine D2 receptors on the
ACh right. (B) However, during attempts
DA DA at smoking cessation, dopamine will
neuron be cut off when nicotine no longer
nicotine releases it from the mesolimbic
neurons. This upsets the postsynaptic
D2 limbic receptors and leads to
craving and what some call a “nicotine
A fit.” (C) A therapeutic approach to
diminishing craving during the early
stages of smoking cessation is to
deliver a bit of dopamine itself by
blocking dopamine reuptake directly
ACh
neuron at the nerve terminal with bupropion.
Although not as powerful as nicotine,
it does take the edge off and can make
abstinence more tolerable.
DA where's my
neuron dopamine??
ACh
neuron
DA
neuron
NDRI
13
C
553
Although we are still struggling to understand how 13-15). Non-benzodiazepine-sensitive GABAA receptors
alcohol actually exerts its psychotropic actions, an overly containing δ subunits are discussed in Chapter 7 and
simplified view of alcohol’s mechanism of action is that illustrated in Figure 7-56. Alcohol also hypothetically
it enhances inhibition at GABA (γ-aminobutyric acid) acts at presynaptic metabotropic glutamate receptors
synapses and reduces excitation at glutamate synapses. (mGluRs) and presynaptic voltage-sensitive calcium
Alcohol actions at GABA synapses hypothetically channels (VSCCs) to inhibit glutamate release (Figure
enhance GABA release via blocking presynaptic GABAB 13-15). mGluRs are introduced in Chapter 4 and
receptors and also by positively allosterically modulating illustrated in Figures 4-23 and 4-24. VSCCs and their
postsynaptic GABAA receptors, especially those role in glutamate release are introduced in Chapter 3 and
containing δ subunits that are responsive to neuroactive illustrated in Figures 3-22 through 3-24. Alcohol may also
steroids but not to benzodiazepines (Figures 13-14 and reduce the actions of glutamate at postsynaptic NMDA
Figure 13-14 Binding sites for

Possible Binding Sites for Sedative Hypnotic Drugs sedative hypnotic drugs. (A)
Benzodiazepines and barbiturates
chloride both act as positive allosteric
GABA channel modulators at GABAA receptors, but
binding site at different binding sites from each
other. Benzodiazepines do not act
at all GABAA receptors; rather, they
are selective for the α1, α2, α3, and α5
benzodiazepine
binding site subtypes of receptors that also contain
α ß γ but not δ subunits. (B) General
anesthetics, alcohol, and neuroactive
γ
ß α steroids may bind to other types of
GABAA receptors, particularly those
barbiturate containing δ subunits.
binding site
A benzodiazepine receptors: α1, α2, α3, α5 subtypes
chloride
GABA channel
binding site
neuroactive steroid binding site

? alcohol binding site
general anesthetics
α4,6 ß
ß α4,6
benzodiazepine receptors: subtypes (α4, α6)

B
554
Detail of Alcohol Actions in the VTA
PFC arcuate
Glu neuron nucleus
opioid
neuron
VTA
alcohol
alcohol
alcohol
VTA
DA neuron GABA
interneuron
ß endorphin GABA A receptor μ-opioid receptor
Glu GABA B receptor

VSCC
GABA NMDA receptor
alcohol
DA mGluR receptor
Figure 13-15 Actions of alcohol in the ventral tegmental area (VTA). Alcohol hypothetically enhances inhibition at GABA synapses by
binding at both GABAA and GABAB receptors, and hypothetically reduces excitation at glutamate synapses by acting at postsynaptic
metabotropic glutamate (mGluR) receptors and presynaptic voltage-sensitive calcium channels (VSCCs). Alcohol may also reduce the
actions of glutamate at postsynaptic NMDA receptors and postsynaptic mGluR receptors. In addition, alcohol’s reinforcing effects may 13
be mediated by actions at opioid synapses within the VTA. Stimulation of μ-opioid receptors there causes dopamine release in the
nucleus accumbens. Alcohol may either directly act upon μ receptors or cause release of endogenous opioids such as enkephalin.
555
(N-methyl-D-aspartate) receptors and at postsynaptic (specifically mGlu5 and perhaps mGlu2). One way or
mGluR receptors (Figure 13-15). another, acamprosate apparently reduces the glutamate
Alcohol’s reinforcing effects are theoretically mediated release associated with alcohol withdrawal (Figure 13-
not only by its effects at GABA and glutamate synapses, 17). Actions, if any, at NMDA receptors may be indirect,
causing downstream dopamine release in the mesolimbic as are actions at GABA systems, both of which may be
pathway, but also by actions at opioid synapses within secondary downstream effects from acamprosate’s actions
mesolimbic reward circuitry (Figure 13-15). Opioid on mGluR receptors (Figure 13-17). Although approved,
neurons arise in the arcuate nucleus and project to the acamprosate is not prescribed very often.
VTA, synapsing on both glutamate and GABA neurons. Disulfiram is the classic drug for treating alcoholism.
The net result of alcohol actions on opioid synapses is It is an irreversible inhibitor of the liver enzyme aldehyde
thought to be the release of dopamine in the nucleus dehydrogenase that normally metabolizes alcohol.
acccumbens (Figure 13-15). Alcohol may do this by either When alcohol is ingested in the presence of disulfiram,
directly acting upon μ-opioid receptors or by releasing alcohol’s metabolism is inhibited and the result is the
endogenous opioids such as β-endorphin. build-up of toxic levels of acetaldehyde. This creates an
aversive experience with flushing, nausea, vomiting,
Treatment of Alcoholism
and hypotension, hopefully conditioning the patient to
The actions of alcohol on opioid synapses create the a negative rather than positive response to drinking.
rationale for blocking μ-opioid receptors with antagonists Obviously, compliance is a problem with this agent, and
such as naltrexone or nalmefene (Figure 13-16). its aversive reactions are occasionally dangerous. Use of
Naltrexone and nalmefene (approved outside the US) disulfiram was greater in the past and is not prescribed
are μ-opioid antagonists that hypothetically block the very often today.
euphoria and “high” of heavy drinking. This theory is Unapproved agents that may be effective in treating
supported by clinical trials that show that naltrexone alcoholism include the anticonvulsant topiramate and
given either orally or by a 30-day-long acting injection the 5HT3 antagonist ondansetron. Several other agents
reduces days of heavy drinking (defined as five or more are used “off-label,” especially in Europe. The subject of
drinks per day for a man and four or more for a woman) how to treat alcohol abuse and dependence is obviously
and also increases the chances of attaining complete complex, and any psychopharmacological treatment
abstinence from alcohol. If you drink when you take an for alcoholism is more effective when integrated with
opioid antagonist, the opioids released by alcohol do not appropriate psychopharmacological treatment of
lead to pleasure, so why bother drinking? Some patients comorbid psychiatric disorders, as well as with structured
may also say, why bother taking the opioid antagonist, therapies such as 12-step programs, a topic which is
of course, and relapse back into drinking alcohol. beyond the scope of this text.
Thus, a long-acting injection may be preferable but,
unfortunately, hardly any of this is prescribed. Sedative Hypnotics
Acamprosate is a derivative of the amino acid Sedative hypnotics include barbiturates and related agents
taurine and interacts with both the glutamate system such as ethchlorvynol and ethinamate, chloral hydrate
to inhibit it, and with the GABA system to enhance it, and derivatives, and piperidinedione derivatives such as
a bit like a form of “artificial alcohol” (compare Figure glutethimide and methyprylon. Experts often include
13-15 with Figure 13-17). Thus, when alcohol is taken alcohol, benzodiazepines, (discussed in Chapter 8), and
chronically and then withdrawn, the adaptive changes Z-drug hypnotics (discussed in Chapter 10) in this class
that it hypothetically causes in both the glutamate as well. The mechanism of action of sedative hypnotics
system and the GABA system create a state of glutamate is basically thought to be the same as those described in
overexcitement and even excitotoxicity as well as GABA Chapter 7 (on drugs for depression), Chapter 8 (on drugs
deficiency. To the extent that acamprosate can substitute for anxiety), and Chapter 10 (on drugs for insomnia) and
for alcohol in patients during withdrawal, the actions of illustrated in Figure 13-14, namely as positive allosteric
acamprosate mitigate the glutamate hyperactivity and modulators (PAMs) of either benzodiazepine-sensitive
the GABA deficiency (Figure 13-17). This occurs because (Figure 13-14A) or benzodiazepine-insensitive (Figure
acamprosate appears to have direct blocking actions on 13-14B) GABAA receptors, or both. Barbiturates are
certain glutamate receptors, particularly mGluR receptors much less safe in overdose than benzodiazepines, cause
556
Actions of μ-Opioid Antagonists Reducing

the Reward of Drinking
PFC arcuate
Glu neuron nucleus
opioid
neuron
VTA
nalmefene/
naltrexone
nalmefene/
naltrexone
VTA
DA neuron GABA
interneuron
ß endorphin GABA A receptor μ -opioid receptor
Glu GABA B receptor

VSCC
GABA NMDA receptor
μ -opioid antagonist
DA mGluR receptor
Figure 13-16 Actions of μ-opioid antagonists in the ventral tegmental area (VTA). Opioid neurons form synapses in the VTA with
GABAergic interneurons and with presynaptic nerve terminals of glutamate (Glu) neurons. Alcohol either acts directly upon μ-opioid 13
receptors or causes release of endogenous opioids such as enkephalin; in either case, the result is increased dopamine (DA) release
to the nucleus accumbens. Mu-opioid receptor antagonists such as naltrexone or nalmefene block the pleasurable effects of alcohol
mediated by μ-opioid receptors.
557
Actions of Acamprosate: Reducing Excessive Glutamate Release

to Relieve Alcohol Withdrawal
PFC arcuate
Glu neuron nucleus
opioid
neuron
VTA
acamprosate
VTA
DA neuron GABA
interneuron
ß endorphin GABA A receptor μ -opioid receptor
Glu GABA B receptor

VSCC
GABA NMDA receptor
acamprosate
DA mGluR receptor
Figure 13-17 Actions of acamprosate in the ventral tegmental area (VTA). When alcohol is taken chronically and then withdrawn, the
adaptive changes that it causes in both the glutamate system and the GABA system create a state of glutamate overexcitation as well
as GABA deficiency. Acamprosate seems to reduce the glutamate release associated with alcohol withdrawal, presumably by blocking
metabotropic glutamate receptors (mGluRs).
558
dependence more frequently, are abused more frequently, morphine” – synapse with postsynaptic sites containing
and produce much more dangerous withdrawal reactions. μ-opioid receptors; neurons that release enkephalin
Because of this they are rarely prescribed today as synapse with postsynaptic δ-opioid receptors; neurons
sedative hypnotics or anxiolytics. that release dynorphin synapse with postsynaptic
κ-opioid receptors (Figure 13-18). All three opioid
Gamma-Hydroxybutyrate (GHB) peptides are derived from precursor proteins called
This agent is discussed in Chapter 10 as a treatment pro-opiomelanocortin (POMC), proenkephalin, and
for narcolepsy/cataplexy. It is sometimes also abused prodynorphin, respectively (Figure 13-18). Parts of these
by individuals wanting to get high or by predators to precursor proteins are cleaved off to form endorphins
intoxicate their dates (GHB is one of the “date rape” or enkephalins or dynorphins, then stored in opioid
drugs; see further discussion in Chapter 10). The neurons, to be released during neurotransmission to
mechanism of action of GHB is as an agonist at its own mediate endogenous opioid actions.
GHB receptors and at GABAB receptors (illustrated in
Figure 10-68). Opioid Addiction
Although illicit opioids derived from poppies have been
Opiates or Opioids? known for their addictive properties for centuries, it has
While subtle, the distinction between opioids and opiates taken a recent sobering epidemic of opioid abuse with
is significant. An opiate is a drug naturally derived from devastating effects on contemporary lives and society
the flowering opium poppy plant. Examples of opiates for us to recognize the powerful destructive potential
include heroin and its derivatives morphine and codeine. of oral opioids prescribed legally for pain relief. Recent
On the other hand, the term opioid is a broader term that surveys suggest that the US consumes 85% of the world’s
includes opiates and refers to any substance, natural or legal and illegal supply of opioids. In the US every year,
synthetic, that binds to the brain’s opioid receptors – the over 60 million people fill at least one prescription for
parts of the brain responsible for controlling pain, reward, an opioid, 20% of them use their opioids in a manner
and addictive behaviors. Some examples of synthetic that was not prescribed, another 20% report sharing
opioids include the prescription painkillers hydrocodone pills, and over 2 million become iatrogenically addicted.
(Vicodin) and oxycodone (OxyContin), as well as fentanyl As the need for higher and higher dosing exceeds the
and methadone. pills that can be obtained from prescribers or from the
street, many patients resort to the more affordable street
Endogenous Opioid Neurotransmitter System heroin inhaled or injected to “chase the dragon” of opioid
There are three parallel opioid systems, each with its addiction. Street supplies of heroin are increasingly
own neurotransmitter and receptor. Neurons that release laced with fentanyl which is 100 times more potent
β-endorphin – sometimes referred to as the “brain’s own than morphine. Fentanyl derivatives like the elephant
Endogenous Opioid Neurotransmitters Figure 13-18 Endogenous opioid

neurotransmitters. Endogenous
opioids are peptides derived from
precursor proteins called POMC (pro-
opiomelanocortin), proenkephalin, and
prodynorphin. Parts of these precursor
proteins are cleaved off to form
E E E endorphins, enkephalins, or dynorphin,
POMC which are then stored in opioid neurons
proenkephalin dynorphin
prodynorphin and released during neurotransmission
enkephalin
ß -endorphin to mediate reinforcement and pleasure.
Neurons that release endorphin
synapse with sites containing
μ-opioid receptors, those that release
enkephalin synapse with sites
containing δ-opioid receptors, and
μ к those that release dynorphin synapse
δ
with sites containing κ-opioid receptors.
13
559
tranquilizer carfentanil are 10,000 times more potent be little room between the dose that causes euphoria
than morphine. In fact, fentanyl and derivatives are so and that which produces toxic effects of an overdose.
powerful that they are unable to be reversed by opioid Another sign that dependence has occurred and that
antagonists such as naloxone, and thus an estimated opioid receptors have adapted is the development of a
one-third of 60,000 annual US overdose deaths from withdrawal syndrome once the chronically administered
opioids are caused by fentanyl and derivatives. A very opioid wears off. The opioid withdrawal syndrome is
sad outcome from what may have started as legitimate characterized by the patient feeling dysphoria, craving
treatment of acute pain. another dose of opioid, being irritable, and having signs
This recent epidemic of opioid addiction has of autonomic hyperactivity such as tachycardia, tremor,
also dashed the fallacy that oral controlled-release and sweating. Pilo-erection (“goose-bumps”) is often
formulations reduce addiction liability. The ongoing associated with opioid withdrawal, especially when the
and sweeping contagion triggered by oral pain- drug is stopped suddenly (“cold turkey”). This is so
relieving opioids of all types has taught us, somewhat subjectively horrible that the opioid abuser will often stop
surprisingly, that opioids may not be highly effective at nothing in order to get another dose of opioid to relieve
analgesics in the long run, but only in the short run, symptoms of withdrawal. Thus, what may have begun as
losing their analgesic effectiveness within days to weeks a quest for pain relief or euphoria may end up as a quest
as tolerance, dependence, and addiction take hold. to avoid withdrawal.
Thus, prescription opioids are being increasingly limited
in amount and in time, both to reduce dependence in Treatment of Opioid Addiction
patients with pain and to prevent diversion of their Treatment of opioid addiction begins with managing
opioids to others. withdrawal. Running out of money and drug supply
At and above pain-relieving doses, opioids induce as well as being incarcerated can be forms of forced
euphoria, a powerful reinforcing property. There is less withdrawal, but a gentler version is to reduce or even
dopamine release with opioids than with stimulants in the avoid withdrawal symptoms. One way to do this is
mesolimbic pleasure center, but certainly not less pleasure, to substitute a prescribed opioid at known dose and
so it is not entirely clear how the “high” of opioids is fully avoid intravenous administration. There are two
mediated. Likely, the impulsive ventral circuit begins options: methadone or buprenorphine. Methadone is
its pleasurable reinforcing work early in the use of an a full agonist at μ-opioid receptors and can suppress
opioid. Opioids induce a very intense but brief euphoria, withdrawal symptoms completely given orally and
sometimes called a “rush,” followed by a profound sense usually administered daily at a clinic. Buprenorphine
of tranquility, which may last several hours, followed in is a μ-opioid partial agonist that has less powerful
turn by drowsiness (“nodding”), mood swings, mental agonist effects, yet can suppress withdrawal symptoms
clouding, apathy, and slowed motor movements. In especially when mild withdrawal has already begun after
overdose, these same opioids act as depressants of stopping abused opioids. Buprenorphine is administered
respiration, and can also induce coma. The acute actions sublingually as it is not well absorbed if swallowed. It
of opioids other than fentanyl and derivatives can be can also be prescribed in a several-day supply and taken
reversed by synthetic opioid antagonists, such as naloxone, as an outpatient instead of returning daily to a clinic.
which compete as antagonists at μ-opioid receptors if Buprenorphine is usually combined with naloxone.
given soon enough and in sufficient dosage. The opioid Naloxone is not absorbed orally or sublingually, yet
antagonists can also precipitate a withdrawal syndrome in prevents intravenous abuse, since naloxone is active
opioid-dependent persons. by injection. The injection of the combination of
When taken chronically, opioids readily cause buprenorphine and naloxone results in no high and
both tolerance and dependence because adaptation of may even precipitate withdrawal, so prevents diversion
opioid receptors occurs quite readily. This adaptation for intravenous abuse of the sublingual preparation.
hypothetically correlates with the migration of behavioral Buprenorphine can also be administered as an
control from ventral circuits to dorsal habit circuits. implantable 6-month formulation or as a 1-month depot
The first sign of this is the need of the patient to take a injection.
higher and higher dose of opioid in order to relieve pain Although tapering off methadone or buprenorphine
or to induce the desired euphoria. Eventually, there may directly to a state of opioid abstinence is theoretically
560
possible, it is rarely successful long term. Of those intensity but not the duration of withdrawal of both
opioid addicts who enter residential rehabilitation and methadone (Figure 13-20) and buprenorphine (Figure
treatment for 30–90 days off all drugs, some analyses 13-21) can be reduced by the addition of an α2A agonist.
suggest relapse back into opioid abuse as high as Both clonidine and lofexidine are α2-adrenergic agonists
60–80% within a month and 90–95% by 3 months. that reduce signs of autonomic hyperactivity during
The drive to reinstitute street opioids coming from the withdrawal and aid in the detoxification process. And
addict’s habit circuit – especially if re-exposed to the finally, in an attempt to enhance successful long-term
environmental cues linked to previous opioid abuse abstinence, opioid addicts may be transitioned not
such as the people, places, and paraphernalia associated to abstinence but to maintenance on a long-acting
with prior opioid abuse – is akin to putting oneself in injectable opioid antagonist like naltrexone. In the short
the situation where bells for Pavlov’s dogs are ringing run, naltrexone shortens the withdrawal time of an α2
loud and clear. Involuntary, mindless, and powerful agonist administered either with methadone (Figure
habit drives then take over reflexively, bypassing 13-20) or with buprenorphine (Figure 13-21). The
voluntary will power, no longer able to suppress advantages of giving naltrexone long term are having
drug seeking and drug taking. This outcome results the drug present at therapeutic levels all day long, in
whether the opioid addict is trying to stop methadone, contrast to administering naltrexone orally (Figure 13-
buprenorphine, or street opioids. 22). Furthermore, with naltrexone monthly injections
How can this dismal outcome be avoided? First of the opioid-abstinent person now only has to make a
all, it is important to recognize that the intensity and decision to take medication once every 30 days instead
duration of withdrawal from most drugs including of 30 times in 30 days. Even better, an impulsive patient
opioids are linked to drug half-life, with short-half-life cannot readily stop his/her injectable naltrexone in order
full agonists such as morphine or heroin producing to relapse.
much more intense and short-lasting withdrawal Agonist substitution treatments like methadone
symptoms than either long-acting methadone, which or buprenorphine – often called medication-assisted
has a less intense but much longer duration withdrawal, therapy (MAT) – are most successful in the setting
or buprenorphine, the withdrawal of which is both less of a structured maintenance treatment program that
intense and shorter (Figure 13-19). Second of all, the includes random urine drug screening and intensive
Figure 13-19 Comparative severity

Comparative Severity and Duration and duration of opioid withdrawal.
of Opioid Withdrawal Following abrupt discontinuation,
the time to onset of peak withdrawal
symptoms and the duration of
symptoms are dependent on the
half-life of the drug involved. With
morphine (and heroin) withdrawal,
morphine symptoms peak within 36–72 hours
and last for 7–10 days. With methadone
withdrawal, symptoms are less
severe and peak at 72–96 hours, but
Severity of Withdrawal
can last for 14 days or more. With

buprenorphine withdrawal, symptoms
peak after a few days and are less
severe than with morphine/heroin;
the duration of symptoms is similar to
morphine/heroin.
methadone
buprenorphine
0 5 10 15 13
Days since opioid
561
Figure 13-20 Severity and duration

Severity and Duration of Withdrawal of withdrawal after methadone
After Methadone Discontinuation discontinuation. With abrupt
discontinuation of methadone,
withdrawal symptoms peak at 72–96
hours but can last for 14 days or more.
The intensity, but not the duration,
of withdrawal symptoms can be
reduced by adding an α2-adrenergic
agonist such as lofexidine or clonidine.
Specifically, these agents can relieve
autonomic symptoms. Adding both an
α2-adrenergic agonist and a μ-opioid
receptor antagonist such as naltrexone

can reduce the severity as well as the
duration of withdrawal symptoms.
abrupt
discontinuation
of methadone
lofexidine alone
lofexidine+
naltrexone
0 5 10 15
Days since last methadone dose

Figure 13-21 Severity and duration
Severity and Duration of Withdrawal of withdrawal after buprenorphine
After Buprenorphine Discontinuation discontinuation. With abrupt
discontinuation of buprenorphine,
withdrawal symptoms peak at around
72 hours and last for about a week.
The intensity, but not the duration,
of withdrawal symptoms can be
reduced by adding an α2-adrenergic
agonist such as lofexidine or clonidine.
Specifically, these agents can relieve
autonomic symptoms. Adding both an

α2-adrenergic agonist and a μ-opioid
receptor antagonist such as naltrexone
can reduce the severity as well as the
abrupt discontinuation duration of withdrawal symptoms.
of buprenorphine
lofexidine alone
lofexidine+
naltrexone
0 3 5 7
Days since last buprenorphine dose
psychological, medical, and vocational services. The receive injectable naltrexone. Whether this is because of
same is true for those on long-acting naltrexone philosophical differences of various treatment facilities,
injections. Unfortunately, only a minority of opioid economic incentives, or therapeutic nihilism is unknown
addicts enter treatment, only a minority of those in but it seems that the currently available best treatments
treatment receive MAT, and almost none of them are insufficiently prescribed.
562
Figure 13-22 Naltrexone formulations.

Naltrexone: Oral vs. Long-Acting Injectable The μ-opioid receptor antagonist
naltrexone is available in both an oral
30 formulation and as a once-monthly
Naltrexone Mean Plasma Levels (ng/mL)
naltrexone 380 mg intramuscular (IM) injection. With

IM injection oral naltrexone, one experiences
25 fluctuating, dose-dependent plasma
oral naltrexone 50 mg concentrations. In addition, one must
20 decide daily whether or not to continue
treatment. With the monthly injection,
one experiences increased and
15 consistent plasma concentrations and
only has to make the decision to take
medication once every 30 days.
10
0
0 5 10 15 20 25 30
Time (Days)
Cannabis and CB2 receptors (Figure 13-25). CBD does not have
You can indeed get stoned without inhaling (see psychoactive properties and its mechanism of action
endocannabinoids released in Figure 13-5)! The brain is really unknown (Figure 13-25). Cannabis comes
makes its own cannabis-like neurotransmitters – in various mixtures of THC and CBD (Figure 13-26).
anandamide and 2-arachidonoylglycerol (2-AG) Higher CBD content has a lower risk of hallucinations,
(Figures 13-23 and 13-24). So does the body. These delusions, and memory impairment (Figure 13-26).
neurotransmitters and their receptors cannabinoid 1 Pure CBD might even be antipsychotic and anxiolytic
and 2 (CB1 and CB2) make up the “endocannabinoid” (Figure 13-26). Over time, cannabis has become more
system – the endogenous cannabinoid system (Figure potent in terms of more THC and less CBD, with
13-23). In the brain, release of classic neurotransmitters resultant higher risk of hallucinations, delusions,
can stimulate the synthesis of endocannabinoids from anxiety, and memory impairment (Figure 13-26). It
precursors stored in postsynaptic lipid membranes is not currently possible to identify in advance those
(Figure 13-24A). Upon release of these endocannabinoids vulnerable to psychosis or to the precipitation of
into the synapse, they travel retrograde to presynaptic schizophrenia by cannabis. Nevertheless, an influential
CB1 receptors and “talk back” to the presynaptic recent study concluded that if nobody smoked high-
neuron where they can inhibit the release of the potency cannabis, 12% of all cases of first-episode
classic neurotransmitter (Figure 13-24B). Retrograde psychosis across Europe would be prevented, rising to
neurotransmission was introduced in Chapter 1 and 32% in London and 50% in Amsterdam. Cannabis can
illustrated in Figure 1-5. Both CB1 receptors and CB2 also exacerbate psychosis in patients who already have a
receptors are localized in brain, with CB1 receptors psychotic illness.
present in greater density. Both receptors bind both In usual intoxicating doses for most persons
endocannabinoids, 2-AG with high efficacy and without risk for psychosis, cannabis produces a sense
anandamide with low efficacy (Figure 13-23). CB2 of well-being, relaxation, a sense of friendliness, a
receptors are also in the periphery, mostly on immune loss of temporal awareness, including confusing the
cells, and also bind the same two endocannabinoids past with the present, slowing of thought processes,
(Figure 13-23). impairment of short-term memory, and a feeling of
Cannabis is a mixture of hundreds of chemicals and achieving special insights. At high doses, cannabis
over 100 alkaloid cannabinoids. The most important of can induce panic, toxic delirium as well as psychosis,
these are tetrahydrocannabinol (THC) and cannabidiol especially in the vulnerable. One complication of long-
(CBD) (Figure 13-25). THC interacts with CB1 and term cannabis use is the “amotivational syndrome” in
13
CB2 receptors and has psychoactive properties. CBD frequent users. This syndrome is seen predominantly
is an isomer of THC and relatively inactive at CB1 in heavy daily cannabis users and is characterized
563
The Endocannabinoid System: Receptors and Ligands

central and peripheral
neuron terminals immune cells
CB1 CB1 CB2 CB2
2-AG: anandamide: 2-AG: anandamide:

high-efficacy low-efficacy high-efficacy very low-efficacy
agonist agonist agonist agonist
CB = cannabinoid
2-AG = 2-arachidonoylglycerol
anandamide
Figure 13-23 The endocannabinoid system: receptors and ligands. There are two main types of cannabinoid (CB) receptors.
CB1 receptors are the most abundant and are present at neuron terminals throughout the central and peripheral nervous systems.
CB2 receptors are not expressed as widely in the brain, although they are present in glial cells and in the brainstem. Instead, CB2
receptors are primarily found in immune cells, where they modulate cell migration and cytokine release. Of the multiple endogenous
cannabinoids, the best understood are anandamide and 2-arachidonoylglycerol (2-AG). Anandamide is a low-efficacy agonist at CB1
receptors and a very low-efficacy agonist at CB2 receptors. 2-AG is a high-efficacy agonist at both CB1 and CB2 receptors.
by the emergence of decreased drive and ambition, agent whereas medical marijuana is an unprocessed
thus “amotivational.” It is also associated with other plant containing 500 chemicals with 100+ cannabinoids.
socially and occupationally impairing symptoms, Prescription drugs require a consistent, well-defined
including a shortened attention span, poor judgment, pharmacokinetic profile, and safety and efficacy data
easy distractibility, impaired communication from double-blind, placebo-controlled, randomized
skills, introversion, and diminished effectiveness clinical trials, as well as warnings for all potential side
in interpersonal situations. Personal habits may effects. However, medical marijuana contains compounds
deteriorate, and there may be a loss of insight, and even that vary from plant to plant, with residual impurities
feelings of depersonalization. such as pesticides and fungal contaminants, and dosing
Recent years have led to a search for potential which is not well regulated. Even so, there have been a
therapeutic uses of cannabis in general and for THC myriad of studies of medical marijuana, and these have
and CBD in particular. The problem with “medical been recently reviewed by a panel of experts who report
marijuana” is that it is not a prescription option that can various benefits and risks for which there is a range
be developed according to the standards of prescription of evidence, from substantial evidence, to moderate
medication. Those standards require consistent, pure, evidence, to limited evidence (Table 13-2), to insufficient
well-defined chemical formulation of the therapeutic evidence (Table 13-3).
564
The Endocannabinoid System: Retrograde Neurotransmission
CB1 CB1
endocannabinoid retrograde
released neurotransmission
classic
neurotransmission
A B
Figure 13-24 The endocannabinoid system: retrograde neurotransmission. (A) Precursors to the endocannabinoids are stored
in the lipid membrane of the postsynaptic neuron. When that neuron is activated, either via depolarization or the presence of a
neurotransmitter binding to a G-protein-coupled receptor, this triggers an enzymatic reaction to form and release the endocannabinoid.
(B) The endocannabinoid then binds to a presynaptic cannabinoid receptor, causing the inhibition of neurotransmitter release. This form
of neurotransmission is known as retrograde neurotransmission.
Figure 13-25
Tetrahydrocannabinol (THC) vs. Cannabidiol (CBD) Tetrahydrocannabinol
(THC) vs. cannabidiol
THC CBD (CBD). There are two
well-known and relatively
well-studied exogenous
cannabinoids: (1)
tetrahydrocannabinol
(THC), which is considered
O
H OH isomer of THC psychoactive and binds
H as a partial agonist at
H CB1 and CB2 receptors,
causing inhibition of
H neurotransmitter release;
and (2) cannabidiol (CBD),
O which is not considered
O
H psychoactive and for
which the binding at CB
receptors is not entirely
psychoactive NOT psychoactive clear, although it does
anxiogenic anxiolytic seem to interact with
other neurotransmitter
anticonvulsant
systems, such as the
serotonin system.
Potential Therapeutic Properties? Potential Therapeutic Properties?
• Anti-inflammatory • Neuropathic pain relief 13
• Euphoria • Anti-inflammatory
• “Opiate type pain relief” • Patient-specific
565
Table 13-2 Areas where there is a range of benefits and risks of cannabis
Associated with benefits to: Associated with risk of:

Substantial Chronic pain Respiratory symptoms
evidence Chemotherapy-induced nausea Motor vehicle crashes
Spasticity in multiple sclerosis Lower birth weight
(patient-reported) Psychosis
Moderate evidence Sleep in obstructive sleep Overdose injuries in pediatric population
apnea, fibromyalgia, chronic Impaired learning, memory, and attention
pain, and multiple sclerosis Increased (hypo)mania in bipolar disorder
Airway dynamics Depressive disorders
Forced vital capacity Suicidality and suicide completion
Cognition in psychosis Social anxiety disorder
Development of substance use disorder for other substances
Limited evidence Increasing appetite/decreasing Testicular cancer
weight loss in HIV/AIDS Acute myocardial infarction
Spasticity in multiple sclerosis Ischemic stroke of subarachnoid hemorrhage
(clinician-reported) Prediabetes
Tourette syndrome Chronic obstructive pulmonary disease
Anxiety Pregnancy complications
PTSD Infant admission to neonatal intensive care
Impaired academic achievement
Increased unemployment
Impaired social functioning
Increased positive symptoms in schizophrenia
Bipolar disorder
Anxiety disorders (other than social anxiety disorder)
Increased severity of PTSD symptoms
THC vs. CBD: Psychiatric Effects
Cannabis with Cannabis with CBD Alone

Low CBD Content High CBD Content
Psychosis symptoms Higher risk of hallucinations Lower risk of hallucinations Possible antipsychotic
and delusions and delusions effects
Psychotic disorder Earlier age of onset Later age of onset
Cognition Higher risk of acute Lower risk of acute

memory impairment memory impairment
Anxiety Anxiogenic Anxiolytic

Increased amygdalar activity Reduced amygdalar activity
Figure 13-26 THC vs. CBD: psychiatric effects. Each strain of cannabis may contain a different combination of the 60–100 known
cannabinoids. Cannabis with THC and low CBD content may carry higher risk of psychotic symptoms, memory impairment, and anxiety.
Cannabis with THC and high CBD content may have lower risk of psychotic symptoms, memory impairment, and anxiety. Pure CBD has
been studied for its potential use as an antipsychotic agent or anxiolytic.
566
Table 13-3 Areas where there is insufficient evidence for benefits or risks of cannabis
Associated with benefits to: Associated with risk of:

Insufficient evidence Dementia Lung, head, and neck cancers
Intraocular pressure associated Esophageal cancer
with glaucoma Prostate and cervical cancer
Depression in chronic pain or Certain leukemias
multiple sclerosis Asthma
Cancer Liver fibrosis or hepatic disease in individuals with
Anorexia nervosa Hepatitis C
Irritable bowel syndrome Adverse immune cell response
Epilepsy Adverse effects on immune status in HIV
Spasticity in spinal cord injury Oral human papilloma virus
Amyotrophic lateral sclerosis All-cause mortality
Huntington's disease Occupational accidents/injuries
Parkinson’s disease Death from overdose
Dystonia Later outcomes to offspring (e.g., sudden infant
Addiction death syndrome, academic achievement, later
Psychosis substance abuse)
Worsening of negative symptoms in schizophrenia
Table 13-4 Approved uses for THC and CBD
Active ingredient Formulation Approval(s) Schedule

Dronabinol Synthetic THC Oral capsule or Chemo-induced nausea and vomiting III
solution (US)
Appetite boost in AIDS wasting
syndrome (US)
Nabilone Synthetic THC Oral capsule Chemo-induced nausea and vomiting II (due to its
analogue (US) potency)
Nabiximols Purified ~1:1 THC Spray Spasticity caused by multiple sclerosis N/A
and CBD (UK, Canada, Europe, Australia, New
Zealand, Israel)
Pain in multiple sclerosis and in cancer
(Canada, Israel)
Epidiolex CBD purified from Oral solution Seizures associated with two rare and Not a controlled
marijuana severe forms of epilepsy, Lennox– substance
Gastaut syndrome and Dravet
syndrome, in patients 2 years of age
and older (US)
However, both pure THC and pure CBD have been Hallucinogens
FDA approved according to traditional drug standards It can be a challenge to categorize the various
for various indications (Table 13-4). Whether some of substances that cause not only occasional
those areas where some degree of benefit and safety hallucinations, but more commonly, non-ordinary
has been described for cannabis (see Table 13-2) psychological states and altered states of consciousness.
will eventually lead to formal FDA approval of pure The terminology for these substances is ever evolving
compounds for any of those indications is currently and more descriptive than scientific. Here we will use 13
under investigation. the category hallucinogen to imply three classes of
567
agents that act, at least in part, as agonists at 5HT2A

receptors (Figure 13-27). These are:
Mechanism of Hallucinogens
• tryptamines (such as psilocybin) at 5HT2A Receptors
• ergolines (such as lysergic acid diethylamide [LSD])
• phenethylamines (such as mescaline) 5HT neuron
Hallucinogens are not selective for 5HT2A receptors
alone, and their actions at other serotonin receptor
subtypes may contribute to their mind-altering
states (see Chapter 7 and Figure 7-88). Psilocybin
(4-diphosphoryloxy-N,N-dimethyltryptamine) is
a prototypical hallucinogen that is derived from
hallucinogenic mushrooms. It is both an active drug
and a prodrug for another hallucinogen called psilocin
(N,N-dimethyltryptamine or DMT). Together, psilocybin,
psilocin, and the other tryptamines, ergolines, and
phenethylamines in this category act not only at 5HT2A
receptors, but also at 5HT2B, 5HT7, 5HT1D, 5HT1E, 5HT2C,
5HT6, and even more serotonin receptor subtypes
(see Figure 7-88). Some evidence suggests that 5HT2A
antagonists, but not D2 dopamine antagonists, can reverse
the action of hallucinogens in humans, supporting the psilocybin
predominant mechanism of action of hallucinogens as
being agonists at 5HT2A receptors (Figure 13-27). LSD
mescaline
Hallucinogens can produce incredible tolerance,
sometimes after a single dose. Desensitization of
5HT2A receptors is hypothesized to underlie this rapid 5HT2A 5HT2A 5HT2A
clinical and pharmacological tolerance. Another unique
dimension of hallucinogen use is the production of
“flashbacks,” namely the spontaneous recurrence of
some of the symptoms of intoxication that lasts from
a few seconds to several hours but in the absence of Figure 13-27 Mechanism of hallucinogens at 5HT2A
recent administration of the hallucinogen, mostly receptors. The primary action of hallucinogenic drugs such as
psilocybin, lysergic acid diethylamide (LSD), and mescaline is
reported with LSD. This occurs days to months after agonism at 5HT2A receptors. These hallucinogens may have
the last drug experience, and can apparently be additional actions at other serotonin receptors.
precipitated by a number of environmental stimuli. The
psychopharmacological mechanism underlying flashbacks (PTSD) and is why hallucinogenic and empathogenic
is unknown but its phenomenology suggests the drugs are now being cautiously used for therapeutic
possibility of a neurochemical adaptation of the serotonin purposes in PTSD (see below).
system and its receptors, related to reverse tolerance The state of hallucinogenic intoxication, sometimes
that is incredibly long-lasting. Alternatively, flashbacks called a “trip,” is associated with changes in sensory
could be a form of emotional conditioning embedded in experiences, including visual illusions and sometimes
the amygdala and then triggered when a later emotional hallucinations. Actually, hallucinogens often don’t cause
experience that one has when one is not taking a hallucinations (the apparent perception of something
hallucinogen nevertheless reminds one of experiences that is not actually present), but are much more likely
that occurred when intoxicated with a hallucinogen. This to cause illusions (distortions of sensory experiences
could precipitate a whole cascade of feelings that occurred that are present). These experiences are produced with
while intoxicated with a hallucinogen. This is analogous to a clear level of consciousness and a lack of confusion
the types of re-experiencing flashbacks that occur without and may be both psychedelic and psychotomimetic.
drugs in patients with posttraumatic stress disorder Psychedelic is the term for the subjective experience that,
568
due to heightened sensory awareness, one’s mind is being inhibiting serotonin reuptake (Figure 13-28, upper left).
expanded or that one is in union with mankind or the At psychoactive doses, following competitive inhibition
universe and having some sort of a religious experience. of the SERT (Figure 13-28, upper left), MDMA is actually
Psychotomimetic means that the experience mimics a transported as a hitch-hiker into the presynaptic serotonin
state of psychosis, but the resemblance between a trip and terminal. Once there in sufficient quantities, MDMA is
psychosis is superficial at best. The stimulants cocaine also a competitive inhibitor of the vesicular monoamine
and amphetamine (see discussion in Chapter 4 and also transporter (VMAT) for serotonin (Figure 12-28, upper
the discussion above for stimulants in this chapter) and right). Once MDMA hitch-hikes another ride into
the club drug phencyclidine (PCP; discussed in Chapter synaptic vesicles, it displaces the serotonin there, causing
4 and also below) much more genuinely mimic psychosis serotonin release from synaptic vesicles into the cytoplasm
than do hallucinogens. Instead, hallucinogen intoxication presynaptically (Figure 12-28, lower left) and then from the
includes visual illusions; visual “trails,” where the image presynaptic cytoplasm into the synapse to act at serotonin
smears into streaks of its image as it moves across a receptors (Figure 12-28, lower right). Once in the synapse,
visual trail; macropsia and micropsia; emotional and the serotonin can play upon any serotonin receptors that
mood lability; subjective slowing of time; the sense that are there, but the evidence suggests that this is mostly upon
colors are heard and sounds are seen; intensification of 5HT2A receptors, just like the hallucinogens. However,
sound perception; depersonalization and derealization; given that the clinical state after MDMA differs somewhat
yet retaining a state of full wakefulness and alertness. from the clinical state after hallucinogens, the pattern
Other changes may include impaired judgment, fear of of action at serotonin receptors likely differs somewhat.
losing one’s mind, anxiety, nausea, tachycardia, increased Both human and animal studies show that MDMA actions
blood pressure, and increased body temperature. Not can be blocked by selective serotonin reuptake inhibitors
surprisingly, hallucinogen intoxication can cause what (SSRIs), supporting the notion that MDMA gets into the
is perceived as a panic attack, often called a “bad trip.” presynaptic neuron to release serotonin aboard the SERT.
As intoxication escalates, one can experience an acute Although there is certainly overlap between the
confusional state called delirium, where the abuser experiences of the so-called hallucinogen psilocybin
is disoriented and agitated. This can evolve further and the so-called empathogen MDMA, some of the
uncommonly into frank psychosis with delusions and differences are more culturally bound than scientific.
paranoia. The subjective effects of MDMA emphasized by users
include a sense of well-being, elevated mood, euphoria,
Empathogens
a feeling of closeness with others, and increased
Another category of psychoactive drug is called sociability. MDMA can produce a complex subjective
an empathogen or an entactogen. Empathogens state, sometimes referred to as “Ecstasy,” which is
produce an altered state of consciousness described also what users call MDMA itself. It is also called
as experiences of emotional communion, oneness, “Molly,” presumably slang for “molecular.” MDMA
relatedness, emotional openness – that is, empathy was initially popular in the nightclub scene and at
or sympathy. The prototype empathogen is MDMA all-night dance parties (“raves”) where dehydration
(3,4-methylenedioxymethamphetamine). MDMA is and overheating from too much dancing in enclosed
a synthetic amphetamine derivative that acts more spaces led to some deaths from hyperthermia. Some
selectively on serotonin transporters (SERTs) than upon MDMA users report experiencing visual hallucinations,
dopamine transporters (DATs) and norepinephrine pseudo-hallucinations/illusions, synesthesia, facilitated
transporters (NETs), whereas amphetamine itself acts recollections or imagination, and altered perception
more selectively on DATs and NETs than on SERTs. of time and space. Others who take MDMA can have
Amphetamine’s primary actions on both dopamine and unpleasant mania-like experiences, anxious derealization,
norepinephrine synapses are explained in Chapter 11 and thought disorders, or fears of loss of thought and body
illustrated in Figure 11-32. control.
For its more important serotonin actions, MDMA
targets the SERT as a competitive inhibitor and Dissociatives
pseudosubstrate (Figure 13-28, upper left), binding at the Dissociatives are the NMDA (N-methyl-D-aspartate) 13
same site where serotonin binds to this transporter, thus receptor antagonists phencyclidine (PCP) and ketamine.
569
Mechanism of MDMA at Serotonin Synapses
serotonin
MDMA
3 VMAT
2
3
2
1 = competitive inhibition
2 = SERT transport of 3 = VMAT transport of
MDMA MDMA
1
4
4
6
4
4
4 4 5
5 = high 5HT opens channel

4 = MDMA and spills out 5 6
displacement 6 = high 5HT reverse
of serotonin transports 5HT out
Figure 13-28 Mechanism of MDMA at serotonin synapses. MDMA is a synthetic amphetamine derivative that acts more selectively
on the serotonin transporter (SERT) than on the dopamine transporter (DAT). MDMA is a competitive inhibitor and pseudosubstrate at
SERTs, thus both blocking serotonin from binding (1) and itself being taken up into the serotonin terminal via SERTs (2). MDMA is also
a competitive inhibitor of vesicular monoamine transporters (VMATs) and can be packaged into vesicles (3). At high levels, MDMA will
lead to the displacement of serotonin from the vesicles into the terminal (4). Furthermore, once a critical threshold of serotonin has been
reached, serotonin will be expelled from the terminal via two mechanisms: the opening of channels to allow for a massive dumping of
serotonin into the synapse (5) and the reversal of SERTs (6).
Both act at the same site on NMDA receptors (discussed or painful procedures, this is considered a form of
in Chapter 4 and illustrated in Figures 4-1, 4-29B, anesthesia called dissociative anesthesia in which the
4-30 through 4-33, and Table 4-1). These agents were patient does not necessarily lose consciousness. The
both originally developed as anesthetics because they patient, however, does experience a sense of conscious
cause a dissociative state characterized by catalepsy, dissociation in which they are disconnected from the
amnesia, and analgesia. In this state patients experience environment and from their body and they experience
distorted perceptions of sight and sound, and feelings a lack of continuity between thoughts, memories,
of detachment – dissociation – from their environment. surroundings, actions, and identity. This dissociative state
Signals from the brain to the conscious mind and to the can be associated with hallucinations, feelings of sensory
body seem to be blocked. If deep enough for surgery deprivation, and a dream-like state or trance.
570
At higher doses, PCP and ketamine have general Figures 7-59 to 7-63. These agents are also in trials for
depressant effects and produce sedation, respiratory rapidly eliminating suicidal thoughts and some studies
depression, analgesia, anesthesia, and ataxia, as well pairing ketamine/esketamine with psychotherapy
as cognitive and memory impairment and amnesia. sessions for various conditions have also begun to appear.
PCP proved to be totally unacceptable for use as an The feelings of dissociation can hypothetically be used to
anesthetic because it induces a powerful and unique shape psychotherapeutic outcomes as discussed below.
psychotomimetic/hallucinatory experience very similar
Abuse Your Way to Abstinence?
to schizophrenia, often when emerging from a state of
anesthesia (see Chapter 4 and Figures 4-1, 4-30 through Essentially all of our current treatments for substance
4-33, and Table 4-1). addiction target the “liking” and “wanting” of drugs, i.e.,
The NMDA receptor hypoactivity that is caused the first phase of addiction driven by impulsively seeking
by PCP has thus become a model for the same reward (Figure 13-29A). They all do this by blocking
neurotransmitter abnormalities postulated to underlie acute receptor actions (i.e., of nicotine, alcohol, or
schizophrenia. PCP also causes intense analgesia, opioids; there are no approved treatments for stimulants).
amnesia, delirium, stimulant as well as depressant However, none of the currently approved treatments for
actions, staggering gait, slurred speech, and a unique substance abuse are able to block the migration of control
form of nystagmus (i.e., vertical nystagmus). Higher from ventral to dorsal (Figures 13-1 and 13-2) and from
degrees of intoxication of PCP can cause catatonia impulsivity to compulsivity (Figure 13-29A). This is
(excitement alternating with stupor and catalepsy), because we do not know the mechanism of this neuronal
hallucinations, delusions, paranoia, disorientation, and adaptation, so we cannot (yet) block it.
lack of judgment. Overdose can include coma, extremely Even more importantly, addicted patients are not
high temperature, seizures, and muscle breakdown often treated during the impulsivity phase when they
(rhabdomyolysis). are still developing addiction and when receptor
PCP’s structurally related and mechanism-related blocking actions of drugs might be most useful to
analogue ketamine is still used as a dissociative prevent stimulus-response conditioning. Instead, those
anesthetic, especially in children, and causes far less with substance addiction almost always seek treatment
of the psychotomimetic/hallucinatory experience than during the compulsivity phase of their illness, once
that seen after PCP administration. It is also used in stimulus-response conditioning has already occurred
veterinary medicine as an animal tranquilizer. Some and the habit circuit is firmly in control. Unfortunately,
people abuse ketamine, one of the “club drugs” that is we are currently unable to reverse this phenomenon
sometimes called “special K.” At subanesthetic doses, pharmacologically, but only by long-term abstinence,
dissociatives alter many of the same cognitive and hoping for reversal of stimulus-response conditioning
perceptual processes affected by other hallucinogenic over time. Staying abstinent long enough for this to occur
drugs such as mescaline, LSD, and psilocybin; hence they while in the grips of addiction is the problem for any
are also considered hallucinogenic and psychedelic. effective treatment, of course.
However, hallucinations are far less common with On the other hand, there are anecdotal reports that
ketamine at the subanesthetic doses used to treat combining psychopharmacological treatments that can
depression, and at these doses the most significant block the drug of abuse with extinction of the reward by
subjective differences between dissociatives and the further abusing that drug can facilitate reversal of the
hallucinogens (such as LSD, psilocybin, and mescaline) drug habit. What?? How can further abuse of a drug lead
are the dissociative effects of ketamine, to non-abuse of the drug? This novel concept comes from
including: depersonalization, the feeling of being unreal, observations that when addicted patients are becoming
disconnected from one’s self, or unable to control one’s abstinent, they often have “slips” and “cheat” along the
actions; and derealization, the feeling that the outside way. They “fall off the wagon” – or any number of other
world is unreal or that one is dreaming. expressions for re-using again – because the nature of
Given as a subanesthetic infusion or as a nasal spray, recovery is to relapse. If you are a horseback rider you are
ketamine and its enantiomer esketamine are discussed as likely familiar with the expression “you are not a rider
breakthrough rapid-onset novel therapies for treatment- until you have fallen off a horse seven times.” That is 13
resistant depression in Chapter 7 and illustrated in because the nature of riding – unfortunately – is to fall,
571
Maladaptations of the Reward Pathway Can Shift

Behavior from Normal to Impulsive to Compulsive
Normal Impulsivity Compulsivity
Salient Stimulus Salient Stimulus Stimulus
Favorable
Outcome Outcome
Pleasurable Reward Pleasurable Reward Pleasurable Reward
Learning Knowing &

Anticipating Binge
Habits
“Liking” “Wanting” Absence
Opioids Dopamine
Anticipation
Figure 13-29A Maladaptations of the reward pathway. Left: Under normal conditions, if a salient stimulus causes a favorable outcome
this behavior will be encoded as a pleasurable reward. The learning of this pleasurable reward is called “liking” and is an opioid-
dependent process. The knowledge and anticipation of this pleasurable reward is called “wanting” and is a dopamine-dependent
process. Center: An increase in “wanting” is thought to underlie impulsivity, such that the drive for the pleasurable reward outweighs the
outcome and the behavior is repeated without forethought. Repetition of the impulsive behavior doesn’t happen all the time, and the
absence of the behavior can lead to a stronger desire, or anticipation, for the reward. It is this cycle of binge–abstinence–anticipation that
can lead to compulsivity. Right: When a behavior becomes compulsive, the reward no longer matters and the behavior is strictly driven
by the stimulus. It is through this mechanism that habits develop.
Reversing Habit Learning and the Potential of

Long-Acting Injectable Naltrexone
Normal Impulsivity Compulsivity
Salient Stimulus Salient Stimulus Stimulus
Favorable
Outcome Outcome Administration of the long-acting
injectable naltrexone may in fact
enhance this process of habit extinction
Pleasurable Reward Pleasurable Reward
Learning Knowing &

Anticipating Binge
Habits
“Liking” “Wanting” Absence
Opioids Dopamine
Anticipation
Figure 13-29B Reversing habit learning. Since drug abuse is a form of learned behavior, it is theoretically possible to induce
pharmacological extinction. In the case of alcohol or opioid dependence, this can theoretically be achieved by administering a μ-opioid
antagonist at the same time that alcohol or opioid use occurs (rather than during abstinence). This prevents any enjoyment or euphoria
associated with taking the substance. If this approach is successful short term and repeated over and again, it begins the process of
extinction or habit reversal. Eventually, the conditioned response of consuming alcohol or taking an opioid in response to conditioned
stimuli (withdrawal and environmental cues) becomes extinguished. Theoretically, the brain is “relearning” to disassociate alcohol or
opioid use from past triggers and control returns to circuits of voluntary actions and away from involuntary habit circuits.
572
especially when you are learning. Similarly, the nature of clinical studies with good reported success. Interesting
recovery is to relapse, and indeed maybe seven times or here is the observation that opioid antagonists are
more before becoming truly abstinent. The novel concept particularly effective when paired with drinking, but
explained here takes advantage of this inevitability of relatively ineffective when given during abstinence.
multiple relapses to reverse the habit circuit by learning This fits with the notion that to reverse the “habit” of
that relapse is no longer rewarding. drinking, extinction learning must take place where the
reward of abusing alcohol is unpaired with taking alcohol
Drink Your Way to Sobriety
(Figure 13-29B). This can also be done when attempting
This idea uses the brain’s own mechanisms of (and failing) to “drink over” a long-acting injection of
neuroplasticity, learning, and migration of control naltrexone. Unfortunately, very little opioid antagonist
in the impulsive–compulsive circuitry to induce therapy is prescribed for alcohol use disorder. One reason
pharmacological extinction. Since drug abuse is a form for this might be that opioid antagonist treatment is most
of learned behavior, patients with alcoholism experience effective in reducing heavy drinking, and not necessarily
enhanced reinforcement (via the opioid system) when as effective in promoting complete abstinence.
they drink (discussed above and illustrated in Figures 13-
15 and 13-16 ). Contrary to earlier beliefs, detoxification Inject Your Way to Heroin Abstinence
and alcohol deprivation do not stop alcohol craving, but Scandinavian and other investigators have also noted
instead increase subsequent alcohol drinking. Recovered that individuals with opioid use disorder act similarly
alcoholics will often mention that many years following to those with alcohol use disorder in response to opioid
their last drink they still get a burst of craving just driving antagonist treatment. That is, individuals dependent
past their favorite bar, a vestige of their incompletely on opioids who attempt to “inject over” long-acting
extinguished alcohol habit. naltrexone with an illicit street opioid find that the opioid
So, the idea is to give alcohol to an active alcoholic is no longer reinforcing. The more times one tries but
and have the patient experience the lack of enjoyment, fails to get high, the faster they develop extinction of their
the lack of euphoria, and the loss of craving that drinking habit, learning that injections are associated with reward
normally produces and that heavy drinking in particular (Figure 13-29B). The learned behavior of reinforcement
produces. The program involves taking an oral opioid from opioids is now slowly reversed as the act of injecting
antagonist (e.g., naltrexone or nalmefene) approximately an opioid is not rewarding. Eventually, the conditioned
1 hour prior to consuming alcohol. When the alcohol response of taking an opioid in response to conditioned
no longer produces the desired effects because of the stimuli (withdrawal and environmental cues) becomes
opioid antagonist, the alcohol is no longer reinforcing. extinguished (Figure 13-29B). Theoretically, the brain is
If this approach is successful short term, and repeated “relearning” to disassociate opioid use from past triggers
over and again, it begins the process of extinction. The and control returns to circuits of voluntary actions and
patient slowly learns that they cannot “drink over” their away from involuntary habit circuits. Unfortunately, very
opioid antagonist and drinking is no longer rewarding. little opioid antagonist treatment is prescribed for opioid
Or at least the reward is greatly blunted and the habit of addicts.
alcohol consumption eventually becomes at least partially
Smoke Your Way to Quitting
extinguished, making eventual abstinence easier to attain,
at least in theory. Blocking the reinforcing properties This same phenomenon of “cheating” assisting the
of alcohol weakens the mindless automatic responses development of abstinence due to behavioral and
to cues in the environment to drink. The theory goes pharmacological extinction has been seen in smoking
that if drinking is not reinforcing, drinking will abate. cessation treatment as well. Many smokers who take
Rather like the conditioned Pavlovian dog whose mouth treatments to stop smoking nevertheless simultaneously
waters at the sound of the bell, but when food is no longer smoke. Thus, such patients “smoke over” their nicotine
associated with the bell, sooner or later the involuntary patch or bupropion and are able to quell craving and
mouth-watering is extinguished and the bell now causes allow their habit to perpetuate in the face of treatment.
no mouth-watering. However, with the nicotinic partial agonist varenicline,
Sometimes called the Sinclair method and they cannot “smoke over” this treatment since it has 13
championed at first in Scandinavia, this therapeutic higher affinity for nicotinic receptors than nicotine itself
intervention for alcoholism has been tested in many and the result is a lack of reinforcement from the cheating
573
while taking varenicline. If smoking on varenicline is no alcohol, with some success. One of the ideas behind the
longer reinforcing and this is repeated again and again, as use of ketamine is to promote prefrontal neural plasticity
for alcohol and opioids, smoking becomes extinguished (see Figures 7-61 and 7-62) to reverse drug-related
as a conditioned response as the brain “unlearns” the ventral to dorsal migration of neuronal control discussed
habit of smoking (Figure 13-29B). extensively in this chapter (see Figure 13-29A), and to
facilitate this with guidance from a psychotherapist.
“Therapeutic” Dissociation, Hallucinations, and
Empathy? Psilocybin-Assisted Psychotherapy
The ability of dissociative agents, hallucinogens, and Originally utilized for the treatment of anxiety related
empathogens to produce mystical-like experiences has to late-stage cancer, psilocybin use has been expanded
been utilized within ancient cultures and indigenous to the treatment of other resistant anxiety disorders
populations for religious and healing purposes for and notably to treatment-resistant depression, with
centuries. In the modern era, these same agents are some promising preliminary results. Psilocybin is also
starting to be used in a process called “dissociation- under investigation in OCD, pain, various addictions,
assisted psychotherapy” to produce these same sexual dysfunction, cluster headaches, mild traumatic
experiences in a controlled setting with a psychotherapist. brain injury, and many more conditions. It is not known
The idea is that mystical states with feelings of oceanic whether the psychological state induced by psilocybin
boundlessness, internal unity, external unity, sacredness, or the pharmacology of psilocybin is responsible for any
“noetic” insights, transcendence of time and space, deeply therapeutic effects, or whether the differences between
felt positive mood, and ineffability can be guided with these variables and those induced by either ketamine
psychotherapy to potentially “heal” some of the most or MDMA play a role in which patients, with which
treatment-resistant disorders in psychiatry. disorders, might respond. Any role of 5HT2A receptors
These are early days for this approach, and the in triggering potentially favorable neuroplastic changes
parameters that might lead to successful outcome are still analogous to those seen with ketamine remains to be
being defined. Some of the variables are “set,” “setting,” determined.
and “cast.” That is, what is the “mind-set” of the patient;
what is the “setting” or environment, including sounds MDMA-Assisted Psychotherapy
of the room where this experience occurs; and who are The idea here is that an empathic state induced by
the “cast,” including therapist and any others that are MDMA may be even better than a mystical state induced
present. Preparation variables to be clarified include by psilocybin or a dissociative state induced by ketamine,
having established a trusting relationship between in that it renders the patient more amenable to exploring
the patient and therapist in advance, explaining to the painful memories. MDMA has been mostly studied in
patient what to expect, and selection of drug, dose, and PTSD, attempting to reduce traumatic memories and the
accompanying psychotherapy. Few of these variables are symptoms they trigger. First-line treatment of PTSD is
well established yet. Most of these approaches to date exposure therapy (fear extinction), but there are many
have used ketamine, psilocybin, or MDMA to induce patients for whom repeated exposure to the traumatic
the dissociative or mystical-like psychological state in memory is either unsuccessful or too painful. Extinction
a therapist’s office, while conducting psychotherapy for of fearful memories was discussed in Chapter 8 on
up to several hours. Psychotherapies studied include anxiety disorders and illustrated in Figures 8-21 and 8-22.
nondirectedness/self-directedness, mindfulness-based MDMA can potentially provide a safe psychological state
behavioral modification, motivational enhancement where there can be self-directed exploration of painful
therapy, and others. traumatic memories in the presence of a therapist, in
order to contextualize them and thus reduce them. In
Ketamine-Assisted Psychotherapy
Chapter 8, the process of reconsolidation of traumatic
Use of ketamine and esketamine without psychotherapy memories was also discussed and illustrated in Figure
for treatment-resistant depression has been discussed 8-21 and 8-22. In this formulation, emotional memories
in Chapter 7 and illustrated in Figures 7-59 to 7-62. are thought to be amenable to weakening or even
Investigators are now evaluating subanesthetic infusions erasure at the time they are re-experienced. The notion
of ketamine for treating the craving and abuse of a wide is that re-experiencing the traumatic memory in a safe
range of substances including cocaine, nicotine, and psychological state induced by MDMA, and accompanied
574
by a trusted and experienced therapist, can facilitate precursor lisdexamfetamine discussed in Chapter 11 on
the blocking or weakening of reconsolidation of painful ADHD and illustrated in Figure 11-31 is the only currently
emotional memories. approved treatment for BED.
Several agents with limited efficacy and side effects
BEHAVIORAL ADDICTIONS used off-label include topiramate, several drugs used
to treat depression, and naltrexone. BED is another
Binge Eating Disorder
condition that belongs in the addictive disorders group
Can you become addicted to food? Can your brain and amongst the impulsive–compulsive disorders as
circuits make you eat it? Although “food addiction” is not it, too, is hypothesized to be linked to abnormalities in
yet accepted as a formal diagnosis, binge eating disorder cortical striatal circuitry where impulsivity (Figure 13-1)
(BED) is now a formal DSM diagnosis. When external leads to compulsivity (Figure 13-2). The mechanism
stimuli are triggers for maladaptive eating habits that are of D-amphetamine reversing binge eating symptoms
performed despite apparent satiety and adverse health may not be due to suppressing appetite since appetite
consequences, this defines a compulsion and a habit, with no longer really drives binge eating disorder when it
the formation of aberrant eating behaviors in a manner becomes compulsive. Instead, it is known that stimulants
that parallels drug addiction. Compulsive eating in BED induce neuroplasticity particularly in the striatum.
and bulimia can be mirrored by compulsive rejection of Hypothetically, promotion of striatal neuroplasticity
food as in anorexia nervosa. BED is characterized by loss could help reverse food-related behaviors that have
of control for eating, much as substance abuse has loss of had their control migrate from ventral to dorsal control
control over seeking and taking a substance. For formal when impulsive eating became compulsive. As for most
diagnostic criteria and clinical descriptions of BED as impulsive–compulsive disorders, most studies adding
well as differentiation from the related disorder bulimia various psychotherapies to drug treatment of BED report
nervosa, the reader is referred to standard reference enhancement of efficacy.
books. Here, we address the construct of BED as falling
within the category of an impulsive–compulsive disorder. Other Behavioral Addictions
Briefly, BED is defined as having recurrent episodes Although behaviors such as gambling and too much
of binge eating, with binges being eaten in a discrete internet gaming have many parallels to BED and to
period of time, an amount of food larger than most people substance abuse disorders, these are not yet generally
would eat in a similar amount of time under similar recognized formally as behavioral “addictions.” Internet
circumstances. What was once perhaps pleasurable eating addiction can involve an inability to stop the behavior,
to satisfy hunger and appetite has now become mindless, tolerance, withdrawal, and relief when reinitiating
compulsive eating, out of control, and associated with the behavior. Many experts believe gambling disorder
marked distress. Not everyone with BED is obese and not should be classified along with drug addiction and
everyone with obesity has BED even though about half BED as a nonsubstance abuse/behavioral addiction
of people with BED are obese. BED is the most common disorder. Gambling disorder is characterized by repeated
eating disorder but is commonly undiagnosed. Many unsuccessful efforts to stop despite adverse consequences,
clinicians do not inquire about this even if the patient tolerance (gambling higher and higher dollar amounts),
is obese, perhaps because of fear that asking will be psychological withdrawal when not gambling, and relief
taken as offensive by the patient. It is a reality that most when reinitiating gambling. Gambling has been observed
BED patients coming to a healthcare professional have a after treatment with dopamine agonists and partial
comorbid psychiatric condition, and are usually seeking agonists, suggesting that stimulating the mesolimbic
treatment for that rather than for binge eating. In fact, dopamine reward system can induce gambling in some
80% of patients with BED meet the criteria for a mood patients. The neurobiology and treatment of other
disorder, anxiety disorder, other substance abuse disorder, behavioral disorders listed in Table 13-1 are all under
or ADHD. One thing for a clinician to remember is to ask investigation as possible impulsive to compulsive and
about binge eating in patients with any of these conditions thus ventral to dorsal shifts of control of the abnormal
because treatment is available and the long-term or undesired behavior. The hope is that therapies useful
complications of obesity are serious (discussed in Chapter for one of the impulsive–compulsive disorders might be 13
5 on drugs for psychosis). In fact, the D-amphetamine helpful across the spectrum of other disorders in this group.
575
OBSESSIVE–COMPULSIVE AND why some diagnostic systems no longer categorize OCD

RELATED DISORDERS as an anxiety disorder.
The compulsive habits provoked by environmental
Obsessive–compulsive disorder (OCD) was once stimuli in OCD are hypothetically the same
classified as an anxiety disorder (Figure 13-30) but is now phenomenon within the same neurocircuits as
placed in its own category by some diagnostic systems described throughout this chapter for addiction. So, are
such as the DSM-5. In OCD, many patients experience OCD patients addicted to their obsessions and to their
an intense urge to perform stereotypic, ritualistic acts compulsions? Certainly, that is one way to look at OCD
despite having full insight into how senseless and symptoms. OCD patients have demonstrated lack of
excessive these behaviors are, and having no real desire efficient information processing in their orbitofrontal
for the outcome of these actions. The most common types cortex (Figure 13-2) and lack of cognitive flexibility, and
of compulsions are checking and cleaning. For OCD, thus cannot inhibit their compulsive responses/habits.
a general propensity towards habit may be expressed Just like drug addicts. Such hypothesized habit learning
solely as avoidance, deriving from the comorbid anxiety in OCD – called addiction when applied to drugs,
reported. In the context of high anxiety, superstitious gambling, and binge eating – can be reduced or reversed
avoidance responses may offer relief, which reinforces the in OCD with exposure and response prevention,
behavior. Stress and anxiety may enhance the formation involving graded exposure to anxiety-provoking stimuli/
of habits, whether positively or negatively motivated. situations, and prevention of the associated avoidance
However, as the habit becomes progressively compulsive, compulsions. This type of cognitive behavioral therapy
the experience of relief may no longer be the driving force is thought to have its therapeutic effect by breaking
and instead the behavior comes under external control the pattern of compulsive avoidance that confers
as a conditioned response. Excessive inflexible behaviors dominant control to the external environment (such
are often thought to be carried out in order to neutralize that the sight of a door elicits checking) and also
anxiety or distress evoked by particular obsessions. maintains inappropriate anxiety. Instead of considering
Paradoxically, although OCD patients feel compelled to compulsions as behavioral reactions to abnormal
perform these behaviors, they are often aware that they obsessions, the reverse may be true: obsessions in OCD
are more disruptive than helpful. So why do they do may in fact be post hoc rationalizations of otherwise
them? Rather than conceptualizing compulsive behaviors inexplicable compulsive urges. Unfortunately, this
as goal-directed to reduce anxiety (Figure 13-30), these same type of cognitive behavioral therapy has often
rituals might be better understood as habits provoked proven less effective in drug and behavioral addictions.
mindlessly from a stimulus in the environment. This is If successful, cognitive behavioral therapy reverses
Figure 13-30 Obsessive–compulsive
disorder (OCD). The symptoms
OCD typically associated with OCD are
shown here and include obsessions
that are intrusive and unwanted and
that cause marked anxiety or distress,
as well as compulsions that are
aimed at preventing or suppressing
the distress related to the obsessive
thoughts. Compulsions can be
repetitive behaviors (e.g., hand-
washing, checking) or mental acts (e.g.,
anxiety/ praying, counting).
fear about
obsessions/
compulsions worry/
obsession
compulsions
576
habits in OCD as it therapeutically helps to migrate the IMPULSE CONTROL DISORDERS

neurocircuit of control of OCD behaviors from dorsal
back to ventral, where it belongs. Some other form of A large variety of disorders that have lack of control
doing this same thing may be the key to developing of impulsivity are listed in Table 13-1. How many
robust treatments for addictions, most of which of these disorders can be conceptualized within the
have little or no highly effective therapeutic drugs or impulsive–compulsive spectrum, with abnormalities of
interventions. cortico-striatal circuitry, remains to be shown, but the
First-line drug treatment of OCD today is one of descriptive parallels between the impulsive symptoms of
the SSRIs, although their efficacy is modest and half of these various and sundry conditions gives face validity
patients treated with these agents show poor responses. to this notion. Since the impulsivity of none of these
Behavioral treatments such as exposure therapy with conditions has an approved treatment, we are left with
response prevention often have greater efficacy than the hope that interventions that work in one of the
serotonergic treatments. It seems as if serotonergic impulsive–compulsive disorders may be effective across
therapies suppress abnormal neurocircuitry, whereas the spectrum of disorders that share this same dimension
exposure therapy may actually reverse abnormal of psychopathology. However, this remains to be proven
neurocircuitry because symptoms continue to be and has the risk of oversimplifying some very complex
improved after stopping exposure therapy but not after and very different disorders (Table 13-1). One general
stopping SSRIs. Although second-line treatments with principle being tested and that may apply across the
one of the tricyclic antidepressants with serotonergic waterfront of these many and varied disorders is that
properties, clomipramine, with serotonin–norepinephrine interventions that can stop the frequent repetition of
reuptake inhibitors (SNRIs) or with monoamine oxidase short-term rewarding impulsive behaviors may hopefully
inhibitors (MAOIs) are all worthy of consideration, act to prevent converting them into long-term habits that
the best pharmacological option for a patient who lead to poor functional outcomes.
has failed several SSRIs is often to consider very high Aggression and violence have long been controversial
doses with an SSRI or augmentation of an SSRI with a issues in psychiatry. Experts categorize violence as
serotonin–dopamine blocker. The mechanisms of action psychotic, impulsive, or psychopathic, with the most
of all of these agents are covered in detail in Chapter 5 common being impulsive (Figure 13-31). Perhaps
and 7. Augmentation of an SSRI with a benzodiazepine, somewhat surprisingly, the least frequent type of
lithium, or buspirone can also be considered. Repetitive violent act is one due to cold, calculated psychopathy.
transcranial magnetic stimulation (rTMS) is an approved Psychopathic violence seems to be the most lethal and
treatment for OCD. Experimental treatments for OCD the least responsive to treatment. Approximately 20%
include deep brain stimulation, or even stereotactic of violent acts are of the psychotic variety and require
ablation of the impulsive–compulsive pathways shown in standard if not aggressive treatment for the underlying
Figures 13-1 and 13-2, for the most resistant of cases. psychotic illness. The most frequent type of violent
Conditions related to OCD may respond somewhat act is impulsive, especially in institutional settings and
to SSRIs, including hoarding, compulsive shopping, especially in patients with underlying psychotic illnesses
skin picking, and body dysmorphic disorder, but not (Figure 13-31).
especially trichotillomania (compulsive hair pulling). Each type of aggression may be attributable to
No agent is officially approved for any of these dysfunction in distinct neural circuits, with impulsive
conditions (Table 13-1). Body dysmorphic disorder violence being linked to the same problems of balancing
for example is preoccupation with perceived defects or top-down inhibition with bottom-up emotional drives,
flaws in appearance that cause repetitive behavior like as discussed in Chapter 12 on agitation in dementia
looking in the mirror, grooming, reassurance seeking. and illustrated in Figures 12-43 and 12-44. Impulsive
Preoccupation with health, body function, and pain exist violence can occur in psychotic disorders of many types,
in hypochondriasis and somatization disorders and some including drug-induced psychosis, schizophrenia, and
experts consider these types of obsessions. It is clear that bipolar mania, as well as in borderline personality
more robust treatments with a different mechanism of disorder and other impulsive–compulsive disorders
action are needed for the group of obsessive–compulsive (Table 13-1). Treatment of the underlying condition, 13
related disorders. often with drugs for psychosis (discussed in Chapter 5),
577
The Heterogeneity of Violence disorders are characterized at first by impulsivity –

defined as behaviors that are difficult to prevent because
Psychotic - 20% short-term reward is chosen over long-term gain. Such
impulsivity is hypothetically mapped onto a prefrontal
Psychopathic - 17% ventral striatal reward circuit. Impulsivity can transition
to compulsivity – defined as an originally rewarding
behavior becoming a habit that is difficult to stop because
it reduces tension and withdrawal effects. Compulsivity
is hypothetically mapped onto a prefrontal dorsal
motor response inhibition circuit. Failure of the balance
between top-down inhibition and bottom-up drives is
Impulsive - 63% the common underlying neurobiological mechanism of
impulsivity and its transition to compulsivity.
Figure 13-31 Heterogeneity of violence. Violence is
categorized as psychotic, impulsive, or psychopathic. The Both drugs and behaviors can be associated with
most common form is impulsive and the least common is impulsivity/compulsivity and are dimensions of
psychopathic. Approximately 20% of violent acts are of the
psychotic variety.
psychopathology for a wide range of drug addictions
and psychiatric disorders. The chapter discusses the
psychopharmacology of reward and the brain circuitry
can be helpful. Aggression and violence in such disorders that regulates reward. We have attempted to explain
can be considered examples of the imbalance between the psychopharmacological mechanisms of actions of
top-down “stop” signals, and bottom-up drives and “go” various drugs of abuse, from nicotine to alcohol, and
signals, as already discussed in dementia (Figures 12-43 also opioids, stimulants, sedative hypnotics, cannabis,
and 12-44) and in several other impulsive–compulsive hallucinogens, empathogens, and dissociative drugs.
disorders (Table 13-1). Impulsive aggression can be In the case of nicotine and alcohol, various novel
considered a type of addictive behavior when it becomes psychopharmacological treatments are discussed,
increasingly compulsive, rather than manipulative including the α4β2 selective nicotine partial agonist (NPA)
and planned, and a habit that must be extinguished varenicline for smoking cessation, opioid replacement
with behavioral interventions rather than with purely therapies for opioid addiction, and opioid antagonists for
psychopharmacological approaches both alcohol and opioid addiction. Use of habit extinction
in treatment of addiction is explored as is the evolving
SUMMARY use of dissociative/hallucinogen-assisted psychotherapy
We have discussed the current conceptualization for treatment-resistant conditions. Binge eating disorder
of impulsivity and compulsivity as dimensions of is discussed as the prototypical behavioral addiction,
psychopathology that cut across many psychiatric and its treatment with stimulants. Impulsive violence is
disorders. Rewarding behaviors and addiction to drugs mentioned as a possible form of impulsive–compulsive
hypothetically share the same underlying circuitry. These disorder as well.
578
Suggested Reading and Selected References
General References: Specialty Stahl SM, Mignon L (2009) Stahl’s Illustrated: Attention Deficit
Hyperactivity Disorder. Cambridge: Cambridge University
Textbooks Press.
Brunton LL (ed.) (2018) Goodman and Gilman’s The Stahl SM, Mignon L (2010) Stahl’s Illustrated: Antipsychotics,
Pharmacological Basis of Therapeutics, 13th edition. New 2nd edition. Cambridge: Cambridge University Press.
York, NY: McGraw Medical. Stahl SM, Grady MM (2010) Stahl’s Illustrated: Anxiety and
Schatzberg AF, Nemeroff CB (eds.) (2017) Textbook of PTSD. Cambridge: Cambridge University Press.
Psychopharmacology, 5th edition. Washington, DC: Stahl SM (2011) Essential Psychopharmacology Case Studies.
American Psychiatric Publishing. Cambridge: Cambridge University Press.
Stahl SM (2018) Stahl’s Essential Psychopharmacology: the
General References:Textbooks Prescribers Guide Children and Adolescents. Cambridge:
Cambridge University Press.
in the Stahl’s Essential Stahl SM (2019) Stahl’s Self-Assessment Examination in
Psychopharmacology Series Psychiatry: Multiple Choice Questions for Clinicians, 3rd
Cummings M, Stahl SM (2021) Management of Complex, edition. Cambridge: Cambridge University Press.
Treatment-Resistant Psychiatric Disorders. Cambridge: Stahl SM (2021) Stahl’s Essential Psychopharmacology: the
Cambridge University Press. Prescribers Guide, 7th edition. Cambridge: Cambridge
Goldberg J, Stahl SM (2021) Practical Psychopharmacology. University Press.
Cambridge: Cambridge University Press. Stahl SM, Davis RL (2011) Best Practices for Medical Educators,
Kalali A, Kwentus J, Preskorn S, Stahl SM (eds.) (2012) 2nd edition. Cambridge: Cambridge University Press.
Essential CNS Drug Development. Cambridge: Cambridge Stahl SM, Grady MM (2012) Stahl’s Illustrated: Substance Use
University Press. and Impulsive Disorders. Cambridge: Cambridge University
Marazzitti D, Stahl SM (2019) Evil, Terrorism and Psychiatry. Press.
Cambridge: Cambridge University Press. Stahl SM, Moore BA (eds.) (2013) Anxiety Disorders: a
Moutier C, Pisani A, Stahl SM (2021) Stahl’s Handbooks: Concise Guide and Casebook for Psychopharmacology and
Suicide Prevention Handbook. Cambridge: Cambridge Psychotherapy Integration. New York, NY: Routledge Press.
University Press. Stahl SM, Morrissette DA (2014) Stahl’s Illustrated: Violence:
Pappagallo M, Smith H, Stahl SM (2012) Essential Pain Neural Circuits, Genetics and Treatment. Cambridge:
Pharmacology: the Prescribers Guide. Cambridge: Cambridge University Press.
Cambridge University Press. Stahl SM, Morrissette DA (2016) Stahl’s Illustrated: Sleep and
Reis de Oliveira I, Schwartz T, Stahl SM. (2014) Integrating Wake Disorders, Cambridge: Cambridge University Press.
Psychotherapy and Psychopharmacology. New York, NY: Stahl SM, Morrissette DA (2018) Stahl’s Illustrated: Dementia.
Routledge Press. Cambridge: Cambridge University Press..
Silberstein SD, Marmura MJ, Hsiangkuo Y, Stahl SM Stahl SM, Schwartz T (2016) Case Studies: Stahl’s Essential
(2016) Essential Neuropharmacology: the Prescribers Psychopharmacology, Volume 2. Cambridge: Cambridge
Guide, 2nd edition. Cambridge: Cambridge University University Press.
Press. Stein DJ, Lerer B, Stahl SM (eds.) (2012) Essential Evidence
Stahl SM (2009) Stahl’s Illustrated: Antidepressants. Based Psychopharmacolgy, 2nd edition. Cambridge:
Cambridge: Cambridge University Press. Cambridge University Press.
Stahl SM (2009) Stahl’s Ilustrated: Mood Stabilizers. Warburton KD, Stahl SM (2016) Violence in Psychiatry.
Cambridge: Cambridge University Press. Cambridge: Cambridge University Press.
Stahl SM (2009) Stahl’s Illustrated: Chronic Pain and Warburton KD, Stahl SM (2021) Decriminalizing Mental
Fibromyalgia. Cambridge: Cambridge University Press. Illness. Cambridge: Cambridge University Press.
579
Chapters 1–3 (Basic Neuroscience): Beaulier JM, Gainetdinov RR (2011) The physiology, signaling
and pharmacology of dopamine receptors. Pharmacol Rev
Textbooks 63: 182–217.
Byrne JH, Roberts JL (eds.) (2004) From Molecules to Belmer A, Quentin E, Diaz SL, et al. (2018) Positive regulation
Networds: An Introduction to Cellular and Molecular of raphe serotonin neurons by serotonin 2B receptors.
Neuroscience. New York, NY: Elsevier. Neuropsychopharmacology 42: 1623–32.
Charney DS, Buxbaum JD, Sklar P, Nestler EJ (2018) Charney Calabresi P, Picconi B, Tozzi A, Ghiglieri V, Di Fillippo M
and Nestler’s Neurbiology of Mental Illness, 5th edition. New (2014) Direct and indirect pathways of basal ganglia: a
York, NY: Oxford University Press. critical reappraisal. Nature Neurosci 17: 1022–30.
Iversen LL, Iversen SD, Bloom FE, Roth RH (2009) Cathala A, Devroye C, Drutel G, et al. (2019) Serotonin 2B
Introduction to Neuropsychopharmacology. New York, NY: receptors in the rat dorsal raphe nucleus exert a GABA-
Oxford University Press. mediated tonic inhibitor control on serotonin neurons. Exp
Neurol 311: 57–66.
Meyer JS, Quenzer LF (2019) Psychopharmacology: Drugs, the
Brain, and Behavior, 3rd edition. New York, NY: Sinauer De Bartolomeis A, Fiore G, Iasevoli F (2005) Dopamine
Associates, Oxford University Press. glutamate interaction and antipsychotics mechanism of
action: implication for new pharmacologic strategies in
Nestler EJ, Kenny PJ, Russo SJ, Schaefer A (2020) Molecular
psychosis. Curr Pharmaceut Design 11: 3561–94.
Neuropharmacology: A Foundation for Clinical
Neuroscience, 4th edition. New York, NY: McGraw Medical. DeLong MR, Wichmann T (2007) Circuits and Ciruit
disorders of the basal ganglia. Arch Neurol 64: 20–4.
Purves D, Augustine GJ, Fitzpatrick D, et al. (2018)
Neuroscience, 6th edition. New York, NY: Sinauer Fink KB, Gothert M (2007) 5HT receptor regulation of
Associates, Oxford University Press. neurotransmitter release. Pharmacol Rev 59: 360–417.
Squire LR, Berg D, Bloom FE, et al. (eds.) (2012) Fundamental Hansen KB, Yi F, Perszyk RE, et al (2018) Structure, function
Neuroscience, 4th edition. San Diego, CA: Academic Press. and allosteric modulation of NMDA receptors. J Gen
Physiol 150: 1081–105.
Chapters 4 (Psychosis, Homayoun H, Moghaddam B (2007) NMDA receptor

hypofunction produces opposite effects on prefrontal
Schizophrenia, and the cortex interneurons and pyramidal neurons. J Neurosci 27:
11496–500.
Neurotransmitter Networks Nicoll RA (2017) A brief history of long-term potentiation.
Dopamine, Serotonin, and Neuron 93: 281–99.
Glutamate) and 5 (Targeting Paoletti P, Neyton J (2007) NMDA receptor subunits: function
and pharmacology. Curr Opin Pharmacol 7: 39–47.
Dopamine and Serotonin Receptors Scheefhals N, MacGillavry HD (2018) Functional organization
for Psychosis, Mood, and Beyond: of postsynaptic glutamate receptors. Mol Cell Neurosci 91:
82–94.
So-called “Antipsychotics”) Sokoloff P, Le Foil B (2017) The dopamine D3 receptor: a
Neuronal Networks – Serotonin, Dopamine, quarter century later. Eur J Neurosci 45: 2–19.
Stahl SM (2017) Dazzled by the dominions of dopamine:
and Glutamate: Selected References clinical roles of D3, D2, and D1 receptors. CNS Spectrums
Alex KD, Pehak EA (2007) Pharmacological mechanisms of 22: 305–11.
serotoninergic regulation of dopamine neurotransmission.
Pharmacol Ther 113: 296–320.
Dopamine, Serotonin, and Glutamate
Amargos-Bosch M, Bortolozzi A, Buig MV, et al. (2004)
Co-expression and in vivo interaction of serotonin 1A and Theories of Psychosis, Including
serotonin 2A receptors in pyramidal neurons of prefrontal Schizophrenia, Parkinson’s Disease
cortex. Cerbral Cortex 14: 281–99.
Psychosis, and Dementia-Related Psychosis
Baez MV, Cercata MC, Jerusalinsky DA (2018) NMDA receptor
subunits change after synaptic plasticity induction and Aghajanian GK, Marek GJ (2000) Serotonin model of
learning and memory acquisition. Neural Plast, doi. schizophrenia: emerging role of glutamate mechanisms.
org/10,1155/2018/5093048. Brain Res Rev 31: 302–12.
580
Bloomfield MAP, Morgan CJA, Egerton A, et al. (2014) Paz RD, Tardito S, Atzori M (2008) Glutamatergic dysfunction
Dopaminergic function in cannabis users and its in schizophrenia: from basic neuroscience to clinical
relationship to cannabis-induced psychotic symptoms. Biol psychopharmacology. Eur Neuropsychopharmacol 18:
Psychiatry 75: 470–8. 773–86.
Brugger SP, Anelescu I, Abi-Dargham A, et al. (2020) Stahl SM (2016) Parkinson’s disease psychosis as a serotonin–
Heterogeneity and striatal dopamine function in dopamine imbalance syndrome. CNS Spectrums 21: 355–9.
schizophrenia: meta analysis of variance. Biol Psychiatry Stahl SM (2018) Beyond the dopamine hypothesis of
67: 215–24. schizophrenia to three neural networks of psychosis:
Bubenikova-Valesova V, Horacek J, Vrajova M, et al. (2008) dopamine, serotonin, and glutamate. CNS Spectrums 23:
Models of schizophrenia in humans and animals based on 187–91.
inhibition of NMDA receptors. Neurosci Biobehav Rev 32: Weinstein JJ, Chohan MO, Slifstein M, et al. (2017) Pathway-
1014–23. specific dopamine abnormalities in schizophrenia. Biol
Demjaha A, Murray RM, McGuire PK (2012) Dopamine Psychiatry 81: 31–42.
synthesis capacity in patients with treatment resistant
schizophrenia. Am J Psychiatry 169: 1203–10.
General Schizophrenia: Selected and
Driesen N, McCarthy G, Bhagwagar Z, et al (2013) The
impact of NMDA receptor blockade on human working Recent References
memory-related prefrontal function and connectivity. Alphs LD, Summerfelt A, Lann H, Muller RJ (1989) The
Neuropsychopharmacol 38: 2613–22. Negative Symptom Assessment: A new instrument
Egerton A, Chaddock CA, Winton-Brown TT, et al. (2013) to assess negative symptoms of schizophrenia.
Presynaptic striatal dopamine dysfunction in people at Psychopharmacol Bull 25: 159–63.
ultra high risk for psychosis: findings in a second cohort. Arango C, Rapado-Castro M, Reig S, et al. (2012) Progressive
Biol Psychiatry 74: 106–12. brain changes in children and adolescents with first-
Gellings Lowe N, Rapagnani MP, Mattei C, Stahl SM episode psychosis. Arch Gen Psychiatry 69: 16–26.
(2012)The psychopharmacology of hallucinations: ironic Cruz DA, Weawver CL, Lovallo EM, Melchitzky DS, Lewis
insights into mechanisms of action. In The Neuroscience of DA. (2009) Selective alterations in postsynaptic markers
Hallucinations, Jardri R, Thomas P, Cachia A and Pins D. of chandelier cell inputs to cortical pyramidal neurons in
(eds.), Berlin: Springer, 471–92. subjects with schizophrenia. Neuropsychopharmacology 34:
Howes OD, Bose SK, Turkheimer F, et al. (2011) Dopamine 2112–24.
synthsis capacity before onset of psychosis: a prospective Dragt S, Nieman DH, Schultze-Lutter F, et al. (2012)
18F-DOPA PET imaging study. Am J Psychiatry 169: Cannabis use and age at onset of symptoms in subjects at
1311–17. clinical high risk for psychosis. Acta Psychiatr Scand 125:
Howes OD, Montgomery AJ, Asselin MC, et al. (2009) 45–53.
Elevated striatal dopamine function linked to Eisenberg DP, Berman KF (2010) Executive function, neural
prodromal signs of schizophrenia. Arch Gen Psychiatry 66: circuitry, and genetic mechanisms in schizophrenia.
13–20. Neuropsychopharmacology 35: 258–77.
Juahar S, Nour MM, Veronese M, et al. (2017) A test of Foti DJ, Kotov R, Guey LT, Bromet EJ (2010) Cannabis use and
the transdiagnostic dopamine hypothesis of psychosis the course of schizophrenia: 10-year follow-up after first
using positron emission tomographic imaging in bipolar hospitalization. Am J Psychiatry 167: 987–93.
affective disorder and schizophrenia. JAMA Psychiatry 74: Fusar-Poli P, Bonoldi I, Yung AR, et al. (2012) Predicting
1206–13. psychosis: meta-analysis of transition outcomes in individuals
Lodge DJ, Grace AA (2011) Hippocampal dysregulation of at high clinical risk. Arch Gen Psychiatry 69: 220–9.
dopamine system function and the pathophysiology of Goff DC, Zeng B, Ardelani BA, et al. (2018) Association of
schizophrenia. Trends Pharmacol Sci 32: 507–13. hippocampal atrophy with duration of untreated psychosis
McCutcheon RA, Abi-Dargham A, Howes OD (2019) and molecular biomarkers during initial antipsychotic
Schizophrenia, dopamine and the striatum: from biology treatment of first episode psychosis. JAMA Psychiatry 75:
to symptoms. Trends Neurosci 42: 205–20. 370–8.
Mizrahi R, Kenk M, Suridjan I, et al (2014) Stress induced Henry LP, Amminger GP, Harris MG, et al. (2010) The
dopamine response in subjects at clinical high risk for EPPIC follow up study of first episode psychosis: longer
schizophrenia with and without concurrent cannabis use. term clinical and functional outcome 7 years after index
Neuropsychopharmacology 39: 1479–89. admission. J Clin Psychiatry 71: 716–28.
581
Kane JM, Robinson DG, Schooler NR, et al. (2016) be helped or harmed? Int J Clin Practice, doi.org 10.1111/
Comprehensive versus usual community care for first- ijcp.12964.
episode psychosis: 2-year outcomes from the NIMH RAISE Citrome L (2017) Deutetrabenazine for tardive dyskinesia: a
early treatment program. Am J Psychiatry 173: 362–72. systematic review of the efficacy and safety profile for this
Kendler KS, Ohlsson H, Sundquist J, et al. (2019) Prediction newly approved novel medication – what is the number
of onset of substance induced psychotic disorder and needed to treat, number needed to harm and likelihood to
its progression to schizophrenia in a Swedish National be helped or harmed? Int J Clin Practice, doi.org 10.1111/
Sample. Am J Psychiatry 176: 711–19. ijcp.13030.
Large M, Sharma S, Compton MT, Slade T, Nielssen O (2011) Jacobsen FM (2015) Second generation antipsychotics and
Cannabis use and earlier onset of psychosis. Arch Gen tardive syndromes in affective illness: a public health
Psychiatry 68: 555–61. problem with neuropsychiatric consequences. Am J Public
Lieberman JA, Small SA, Girgis RR (2019) Early detection and Health 105: e10–16.
preventive intervention in schizophrenia: from fantasy to Niemann N, Jankovic J (2018) Treatment of tardive dyskinesia:
reality. Am J Psychiatry 176: 794–810. a general overview with focus on the vesicular monoamine
Mechelli A, Riecher-Rossler A, Meisenzahl EM, et al. (2011) transporter 2 inhibitors. Drugs 78: 525–41.
Neuroanatomical abnormalities that predate the onset of Stahl SM (2017) Neuronal traffic signals in tardive dyskinesia:
psychosis. Arch Gen Psychiatry 68: 489–95. not enough “stop” in the motor striatum. CNS Spectrums
Morrissette DA, Stahl SM (2014) Treating the violent patient 22: 427–34.
with psychosis or impulsivity utilizing antipsychotic Stahl SM (2018) Mechanism of action of vesicular monoamine
polypharmacy and high-dose monotherapy. CNS Spectrums transporter 2 (VMAT2) inhibitors in tardive dyskinesia:
19: 439–48. reducing dopamine leads to less “go” and more “stop” from
Stahl SM (2014) Deconstructing violence as a medical the motor striatum for robust therapeutic effects. CNS
syndrome: mapping psychotic, impulsive, and predatory Spectrums 23: 1–6.
subtypes to malfunctioning brain circuits. CNS Spectrums Stahl SM (2018) Comparing pharmacological mechanism
19: 357–65. of action for the vesicular monoamine transporter 2
Stahl SM (2015) Is impulsive violence an addiction? The habit (VMAT2) inhibitors valbenazine and deutetrabenazine in
hypothesis. CNS Spectrums 20: 165–9. treating tardive dyskinesia: does one have advantages over
the other? CNS Spectrums 23: 239–47.
Stahl SM, Morrissette DA, Cummings M (2014) California
State Hospital Violence Assessment and Treatment (Cal- Woods SW, Morgenstern H, Saksa JR, et al. (2010) Incidence
VAT) guidelines. CNS Spectrums 19: 449–65. of tardive dyskinesia with atypical versus conventional
antipsychotic medications: a prospective cohort study. J
Wykes T, Huddy V, Cellard C, McGurk SR, Czobar P (2011) A Clin Psychiatry 71: 463–74.
meta-analysis of cognitive remediation for schizophrenia:
methodology and effect sizes. Am J Psychiatry 168: 472–85.
Long-Acting Injectables
Tardive Dyskinesia and Treatments Brissos S, Veguilla MR, Taylor D, et al. (2014) The role of long-
acting injectable antipsychotics in schizophrenia: a critical
Artukoglu BB, Li F, Szejko N, et al. (2020) Pharmacologic appraisal. Ther Adv Psychopharmacol 4: 198–219.
treatment of tardive dyskinesia: a meta analysis and
systematic review. J Clin Psychiatry 81: e1–11. Kishimoto T, Nitto M, Borenstein M, et al. (2013) Long acting
injectable versus oral antipsychotics in schizophrenia:
Bhidayasin R, Jitkretsandakul O, Friedman JH (2018) a systematic review and meta analysis of mirror image
Updating the recommendations for treatment of tardive studies. J Clin Psychiatry 74: 957–65.
syndromes: a systematic review of new evidence and
practical treatment algorithm. J Neurol Sci 389: 67–75. MacEwan JP, Kamat SA, Duffy RA, et al. (2016) Hospital
readmission rates among patients with schizophrenia
Carbon M, Kane JM, Leucht S, et al. (2018) Tardive dyskinesia treated with long acting injectables or oral antipsychotics.
risk with first- and second-generation antipsychotics in Psychiatr Serv 67: 1183–8.
comparative randomized controlled trials: a meta analysis.
World Psychiatry 173: 330–40. Meyer JM (2013) Understanding depot antipsychotics: an
illustrated guide to kinetics. CNS Spectrums 18: 58–68.
Citrome L (2017) Valbenazine for tardive dyskinesia: a
systematic review of the efficacy and safety profile for this Meyer JM (2017) Converting oral to long acting injectable
newly approved novel medication – what is the number antipsychotics: a guide for the perplexed. CNS Spectrums
needed to treat, number needed to harm and likelihood to 22: 17–27.
582
Stahl SM (2014) Long-acting injectable antipsychotics: shall randomized double-blind, placebo-controlled study. Am J
the last be first? CNS Spectrums 19: 3–5. Psychiatry 171: 160–8.
Tiihonen J, Haukka J, Taylor M, et al. (2011) A nationwide Loebel A, Cucchiaro J, Silva R, et al. (2014) Lurasidone as
cohort study of oral and depot antipsychotics after first adjunctive therapy with lithium or valproate for the
hospitalization for schizophrenia. Am J Psychiatry 168: treatment of bipolar I depression: a randomized, double
603–9. blind, placebo-controlled study. Am J Psychiatry 171:
169–77.
Serotonin Dopamine Drugs for Psychosis Marder SR, Davis JM, Couinard G (1997) The effects of
risperidone on the five dimensions of schizophrenia
and Mood: Updates and Newer Drugs derived by factor analysis: combined results of the north
Berry MD, Gainetdinov RR, Hoener MC, et al. (2017) American trials. J Clin Psychiatry 58: 538–46.
Pharmacology of human trace amine-associated receptors: McIntyre RS, Suppes T, Early W, Patel M, Stahl SM (2020)
therapeutic opportunities and challenges. Pharmacol Ther Cariprazine efficacy in bipolar I depression with and
180: 161–80. without concurrent manic symptoms: post hoc analysis
Brannan S (2020) KarXT (a new mechanism antipsychotic of three randomized, placebo-controlled studies. CNS
based on xanomeline) is superior to placebo in patients Spectrums 25: 502–10.
with schizophrenia: phase 2 clinical trial results. Abstract, Meyer JM, Cummings MA, Proctor G, Stahl SM (2016)
American Society of Clinical Psychopharmacology Annual Psychopharmacology of persistent violence and aggression.
Meeting. Psychiatr Clin N Am 39: 541–56.
Citrome L (2015) Brexpiprazole for schizophrenia and as Meyer JM, Stahl SM (2020) Stahl’s Handbooks: the
adjunct for major depressive disorder: a systematic review Clozapine Handbook. Cambridge: Cambridge University
of the efficacy and safety profile for the newly approved Press.
antipsychotic – what is the number needed to treat,
number needed to harm and likelihood to be helped or Nemeth G, Laszlovszky I, Czoboar P, et al. (2017) Cariprazine
harmed? Int J Clin Pract 69: 978–97. versus risperidone monotherapy for treatment of
predominant negative symptoms in patients with
Correll CU, Davis RE, Weingart M, et al. (2020) schizophrenia: a randomized double-blind controlled trial.
Efficacy and safety of lumateperone for treatment Lancet 389: 1103–13.
of schizophrenia: a randomized clinical trial. JAMA
Psychaitry 77: 349–58. Pei Y, Asif-Malik A, Canales JJ (2016) Trace amines and
the trace amine-associated receptor 1: pharmacology,
Dedic N, Jones PG, Hopkins SC, et al. (2019) SEP363856: a neurochemistry and clinical implications. Front Neurosci
novel psychotropic agent with unique non D2 receptor 10: 148.
mechanism of actions. J Pharmacol Exp Ther 371: 1–14.
Perkins DO, Gu H, Boteva K, Lieberman JA (2005)
Earley W, Burgess MV, Rekeda L, et al. (2019) Cariprazine Relationship between duration of untreated psychosis
treatment of bipolar depression: a randomized double- and outcome in first episode schizophrenia: a critical
blind placebo-controlled phase 3 study, Am J Psychiatry review and meta-analysis. Am J Psychiatry 162:
176: 439–48. 1785–804.
Gainetdinov RR, Hoener MC, Berry MD (2018) Trace amines Roth BL. Ki determinations, receptor binding profiles,
and their receptors. Pharmacol Rev 70: 549–620. agonist and/or antagonist functional data, HERG data,
Koblan KS, Kent J, Hopkins SC, Krystal JH, et al. (2020) MDR1 data, etc. as appropriate was generously provided
A non-D2-receptor-binding drug for the treatment of by the National Institute of Mental Health’s Psychoactive
schizophrenia. New Engl J Med 382: 1407–506. Drug Screening Program, Contract # HHSN-271–2008-
00025-C (NIMH PDSP). The NIMH PDSP is directed
by Bryan L. Roth MD, PhD at the University of North
TD and Its Treatment Carolina at Chapel Hill and Project Officer Jamie Driscol
Lieberman JA, Davis RE, Correll CU, et al. (2016) ITI- at NIMH, Bethesda MD, USA. For experimental details
007 for the treatment of schizophrenia: a 4-week please refer to the PDSP website http://pdsp.med.unc.edu/
randomized, double-blind, controlled trial. Biol
Schwartz MD, Canales JJ, Zucci R, et al. (2018) Trace amine
Psychiatry 79: 952–6.
associated receptor 1: a multimodal therapeutic target for
Loebel A, Cucchiaro J, Silva R, et al. (2014) Lurasidone neuropsychiatric diseases. Expert Opin Ther Targets 22:
monotherapy in the treatment of bipolar I depression: a 513–26.
583
Shekar A, Potter WZ, Lightfoot J, et al. (2008) Seletive

muscarinic receptor agonist xanomeline as a novel
Chapters 6 (Mood Disorders) and
treatment approach for schizophrenia. Am J Psychiatry 165: 7 (Treatment of Mood Disorders),
1033–9.
Snyder GL, Vanover KE, Zhu H, et al. (2014) Functional profile
including Norepinephrine and GABA
of a novel modulator of serotonin, dopamine and glutamate
neurotransmission. Psychopharmacology 232: 605–21.
Neuronal Networks – Norepinephrine,
Stahl SM (2013) Classifying psychotropic drugs by mode
GABA, and Neuroactive Steroids: Selected
of action and not by target disorder. CNS Spectrums 18: References
113–17. Alvarez LD, Pecci A, Estrin DA (2019) In searach of GABA
Stahl SM (2013) Role of α1 adrenergic antagonism in A receptor’s neurosteroid binding sites. J Med Chem 62:
the mechanism of action of iloperidone: reducing 5250–60.
extrapyramidal symptoms. CNS Spectrums 18: 285–8. Belelli D, Hogenkamp D, Gee KW, et al. (2020) Realising the
Stahl SM (2014) Clozapine: is now the time for more clinicians therapeutic potential of neuroactive steroid modulators of
to adopt this orphan? CNS Spectrums 19: 279–81. the GABA A receptor. Neurobiol Stress 12: 100207.
Stahl SM (2016) Mechanism of action of brexpiprazole: Botella GM, Salitur FG, Harrison BL, et al. (2017) Neuroactive
comparison with aripiprazole. CNS Spectrums 21: 1–6. steroids. 2. 3α-hydroxy-3β-methyl-21-(4-cyano-1H-
pyrazol-1ʹ-yl)-19-nor-5β-pregnan-20-one (SAGE 217):
Stahl SM (2016) Mechanism of action of cariprazine. CNS
a clinical next generation neuroactive steroid positive
Spectrums 21: 123–7.
allosteric modulator of the GABA A receptor. J Med Chem
Stahl SM (2016) Mechanism of action of pimavanserin in 60: 7810–19.
Parkinson’s disease psychosis: targeting serotonin 5HT2A
Chen ZW, Bracomonies JR, Budelier MM, et al. (2019)
and 5HT2C receptors. CNS Spectums 21: 271–5.
Multiple functional neurosteroid binding sites on GABA A
Stahl SM (2017) Drugs for psychosis and mood: unique receptors. PLOS Biol 17: e3000157; doi.org/10.137/journal.
actions at D3, D2, and D1 dopamine receptor subtypes. CNS pbio.3000157.
Spectrums 22: 375–84.
Gordon JL, Girdler SS, Meltzer-Brody SE, et al. (2015)
Stahl SM, Cucchiaro J, Sinonelli D, et al. (2013) Effectiveness Ovarian hormone fluctuation, neurosteroids and HPA
of lurasidone for patients with schizophrenia following 6 axis dysregulation in perimenopausal depression: a novel
weeks of acute treatment with lurasidone, olanazapine, or heuristic model. Am J Psychiatry 172: 227–36.
placebo: a 6-month, open-label study. J Clin Psychiatry 74:
Gunduz-Bruce H, Silber C, Kaul I, et al. (2019) Trial of SAGE
507–15.
217 in patients with major depressive disorder. New Engl J
Stahl SM, Laredo SA, Morrissette DA (2020) Cariprazine as a Med 381: 903–11.
treatment across the bipolar I spectrum from depression
Luscher B, Mohler H (2019) Brexanolone, a neurosteroid
to mania: mechanism of action and review of clinical data.
antidepressant, vindicates the GABAergic deficit
Ther Adv Psychopharmacol 10: 1–11.
hypothesis of depression and may foster reliance.
Stahl SM, Morrissette DA, Citrome L, et al. (2013) “Meta- F1000Research 8: 751.
guidelines” for the management of patients with
Marek GJ, Aghajanian GK (1996) Alpha 1B-adrenoceptor-
schizophrenia. CNS Spectrums 18: 150–62.
mediated excitation of piriform cortical interneurons. Eur J
Suppes T, Silva R, Cuccharino J, et al. (2016) Lurasidone for Pharmacol 305: 95–100.
the treatment of major depressive disorder with mixed
Marek GJ, Aghajanian GK (1999) 5HT2A receptor or alpha
features: a randomized, double blind placebo controlled
1-adrenoceptor activation induces excitatory postsynaptic
study. Am J Psychiatry 173: 400–7.
currents in layer V pyramidal cells of the medial prefrontal
Tarazi F, Stahl SM (2012) Iloperidone, asenapine and cortex. Eur J Pharmacol 367: 197–206.
lurasidone: a primer on their current status. Expert Opin
Meltzer-Brody S, Kanes SJ (2020) Allopregnanolone in
Pharmacother 13: 1911–22.
postpartum depression: role in pathophysiology and
Thase ME, Youakim JM, Skuban A, et al. (2015) Efficacy and treatment. Neurobiol Stress 12: 100212.
safety of adjunctive brexpiprazole 2 mg in major depressive
Pieribone VA, Nicholas AP, Dagerlind A, et al. (1994)
disorder. J Clin Psychiatry 76: 1224–31.
Distribution of alpha 1 adrenoceptors in rat brain revealed
Zhang L, Hendrick JP (2018) The presynaptic D2 partial by in situ hybridization experiments utilizing subtype
agonist lumateperone acts as a postsynaptic D2 antagonist. specific probes. J Neurosci 14: 4252–68.
Matters: doi: 10.19185/matters.201712000006.
584
Price DT, Lefkowitz RJ, Caron MG, et al. (1994) Localization Roy A, Gorodetsky E, Yuan Q, Goldman D, Enoch MA
of mRNA for three distinct alpha1 adrenergic receptor (2010) Interaction of FKBP5, a stress-related gene, with
sybtypes in human tissues: implications for human alpha childhood trauma increases the risk for attempting suicide.
adrenergic physiology. Mol Pharmacol 45: 171–5. Neuropsychopharmacology 35: 1674–83.
Ramos BP, Arnsten AFT (2007) Adrenergic pharmacology and Semkovska M, Quinlivan L, Ogrady T, et al. (2019) Cognitive
cognition: focus on the prefrontal cortex. Pharmacol Ther function following a major depressive episode: a systematic
113: 523–36. review and meta-analysis. Lancet Psychiatry 6: 851–61.
Santana N, Mengod G, Artigas F (2013) Expression of Stahl SM (2017) Psychiatric pharmacogenomics: how to
alpha1 adrenergic receptors in rat prefrontal cortex: integrate into clinical practice. CNS Spectrums 22: 1–4.
cellular colocalization with 5HT2A receptors. Int J Stahl SM (2017) Mixed-up about how to diagnose and
Neuropsychopharmacol 16: 1139–51. treat mixed features in major depressive episodes. CNS
Zorumski CF, Paul SM, Covey DF, et al. (2019) Neurosteroids Spectrums 22: 111–15.
as novel antidepressants and anxiolytics: GABA A receptors Stahl SM, Morrissette DA (2017) Does a “whiff ” of mania
and beyond. Neurobiol Stress 11: 100196. in a major depressive episode shift treatment from a
classical antidepressant to an atypical/second-generation
Mood Disorders – Depression, Bipolar antipsychotic? Bipolar Disord 19: 595–6.
Disorder: Selected and Recent References Stahl SM, Morrissette DA (2019) Mixed mood states: baffled,
bewildered, befuddled and bemused.Bipolar Disord 21: 560–1.
Bergink V, Bouvy PF, Vervoort JSP, et al. (2012) Prevention of
postpartum psychosis and mania in women at high risk. Stahl SM, Morrissette DA, Faedda G, et al. (2017) Guidelines
Am J Psychiatry 169: 609–16. for the recognition and management of mixed depression.
CNS Spectrums 22: 203–19.
Bogdan R, Williamson DE, Hariri AR. (2012)
Mineralocorticoid receptor Iso/Val (rs5522) genotype Yatham LN, Liddle PF, Sossi V, et al. (2012) Positron emission
moderates the association between previous childhood tomography study of the effects of tryptophan depletion
emotional neglect and amygdala reactivity. Am J Psychiatry on brain serotonin2 receptors in subjects recently remitted
169: 515–22. from major depression. Arch Gen Psychiatry 69: 601–9.
Brites D, Fernandes A (2015) Neuroinflammation and
depression: microglia activion, extracellular microvesicles Serotonin Dopamine Drugs for
and micro RNA dysregulation. Front Cell Neurosci 9: 476.
Fiedorowicz JG, Endicott J, Leon AC, et al. (2011)
Mood
Subthreshold hypomanic symptoms in progression from
unipolar major depression to bipolar disorder. Am J
See above references for Chapters 4 and 5
Psychiatry 168: 40–8. Ketamine/Esketamine and NMDA Antagonists
Goldberg JF, Perlis RH, Bowden CL, et al. (2009) Manic (Dextromethorphan, Dextromethadone)
symptoms during depressive episodes in 1,380 patients
with bipolar disorder: findings from the STEP-BD. Am J Aan het Rot M, Collins KA, Murrough JW, et al. (2010) Safety
Psychiatry 166: 173–81. and efficacy of repeated dose intravenous ketamine for
treatment resistant depression. Biol Psychiatry 67: 139–45.
McIntyre RS, Anderson N, Baune BT, et al. (2019) Expert
consensus on screening assessment of cognition in Abdallah CG, DeFeyter HM, Averill LA, et al. (2018)
psychiatry. CNS Spectrums 24: 154–62. The effects of ketamine on prefrontal glutamate
neurotransmission in healthy and depressed subjects.
Price JL, Drevets WC (2010) Neurocircuitry of mood Neuropsychopharmacology 43: 2154–60.
disorders. Neuropsychopharmacology 35: 192–216.
Anderson A, Iosifescu DV, Macobsen M, et al. (2019) Efficacy
Rao U, Chen LA, Bidesi AS, et al. (2010) Hippocampal changes and safety of AXS-05, an oral NMDA receptor antagonist
associated with early-life adversity and vulnerability to with multimodal activity, in major depressive disorder:
depression. Biol Psychiatry 67: 357–64. results of a phase 2, double blind active controlled trial.
Roiser JP, Elliott R, Sahakian BJ (2012) Cognitive mechanisms Abstract, American Society of Clincal Psychopharmacology
of treatment in depression. Neuropsychopharmacology 37: Annual Meeting.
117–36. Deyama S, Bang E, Wohleb ES, et al. (2019) Role of neuronal VEGF
Roiser JP, Sahakian BJ (2013) Hot and cold cognition in signaling in the prefrontal cortex in the rapid antidepressant
depression. CNS Spectrums 18: 139–49. effects of ketamine. Am J Psychiatry 176: 388-400.
585
DiazGranados N, Ibrahim LA, Brutsche NE, et al. (2010) with multimodal activity in major depressive disorder:
Rapid resolution of suicidal ideation after a single infusion results from the GEMINI phase 3, double blind placebo-
of an N-methyl-D-aspartate antagonist in patients with controlled trial. Abstract, American Society of Clinical
treatment-resistant depressive disorder. J Clin Psychiatry Psychopharmacology Annual Meeting.
71: 1605–11. Phillips JL, Norris S, Talbot J, et al. (2019) Single, repeated and
Duman RS, Voleti B (2012) Signaling pathways underlying maintenance ketamine infusions for treatment resistant
the pathophysiology and treatment of depression: novel depression: a randomized controlled trial. Am J Psychiatry
mechanisms for rapid-acting agents. Trends Neurosci 35: 176: 401–9.
47–56. Price RB, Nock MK, Charney DS, Mathew SJ (2009) Effects
Dwyer JM, Duman RS (2013) Activation of mammalian target of intravenous ketamine on explicit and implicit measures
of rapamycin and synaptogenesis: role in the actions of of suicidality in treatment-resistant depression. Biol
rapid acting antidepressants. Biol Psychiatry 73: 1189–98. Psychiatry 66: 522–6.
Fu DJ, Ionescu DF, Li X, et al. (2020) Esketamine nasal spray Salvadore G, Cornwell BR, Sambataro F, et al.
for rapid reduction of major depressive disorder symptoms (2010) Anterior cingulate desynchronization and
in patients who have active suicidal ideation with intent: functional connectivity with the amygdala during a
double blind randomized study (ASPIRE K). J Clin working memory task predict rapid antidepressant
Psychiatry 61: doi.org/10.4088/JCP.19m13191. response to ketamine. Neuropsychopharmacology 35:
Hanania T, Manfredi P, Inturrisi C, et al. (2020) The NMDA 1415–22.
antagonist dextromethadone acutely improves depressive Stahl SM (2013) Mechanism of action of ketamine. CNS
like behavior in the forced swim test performance of rats. Spectrums 18: 171–4.
AA Rev Public Health 34: 119–38. Stahl SM (2013) Mechanism of action of dextromethorphan/
Hasler G (2020) Toward specific ways to combine ketamine quinidine: comparison with ketamine. CNS Spectrums 18:
and psychotherapy in treating depression. CNS Spectrums 225–7.
25: 445–7. Stahl SM (2016) Dextromethorphan–quinidine-responsive
Ibrahim L, Diaz Granados N, Franco-Chaves J (2012) Course pseudobulbar affect (PBA): psychopharmacological model
of improvement in depressive symptoms to a single for wide-ranging disorders of emotional expression? CNS
intravenous infusion of ketamine vs. add-on riluzole: Spectrums 21: 419–23.
results from a 4-week, double-blind, placebo-controlled Stahl SM (2019) Mechanism of action of dextromethorphan/
study. Neuropsychopharmacology 37: 1526–33. bupropion: a novel NMDA antagonist with multimodal
Li N, Lee, Lin RJ, et al. (2010) mTor-dependent synapse activity. CNS Spectrums 24: 461–6.
formation underlies the rapid antidepressant effects of Wajs E, Aluisio L, Holder R, et al. (2020) Esketamine nasal
NMDA antgonists. Science 329: 959–64. spray plus oral antidepressant in patients with treatment
Monteggia LM, Gideons E, Kavalali EG (2013) The role resistant depression: assessment of long term safety in a
of eukaryotic elongation factor 2 kinase in rapid phase 3 open label study (SUSTAIN2). J Clin Psychiatry 81:
antidepressant action of ketamine. Biol Psychiatry 73: 19m12891.
1199–203. Williams NR, Heifets B, Blasey C, et al. (2018) Attenuation
Mosa-Sava RN, Murdock MH, Parekh PK, et al. (2019) of antidepressant effects of ketamine by opioid receptor
Sustained rescue of prefrontal circuit dysfunction by antagonism. Am J Psychiatry 175: 1205–15
antidepressant induced spine formation. Science 364: doi: Zarate Jr. CA, Brutsche NE, Ibrahim L (2012) Replication of
10.1126/Science.aat80732019. ketamine’s antidepressant efficacy in bipolar depression:
Murrough JW, Perez AM, Pillemer S, et al. (2013) Rapid and a randomized controlled add-on trial. Biol Psychiatry 71:
longer-term antidepressant effects of repeated ketamine 939–46.
infusions in treatment resistant major depression. Biol
Mood Disorder Treatments: Updates and
O’Gorman C, Iosifescu DV, Jones A, et al. (2018) Clinical
development of AXS-05 for treatment resistant depression Other Newer Drugs
and agitation associated with Alzheimer’s disease. Abstract, Alvarez E, Perez V, Dragheim M, Loft H, Artigas F (2012)
American Society of Clinical Psychopharmacology Annual A double-blind, randomized, placebo-controlled, active
Meeting. reference study of Lu AA21004 in patients with major
O’Gorman C, Jones A, Iosifescu DV, et al. (2020) Efficacy depressive disorder. Int J Neuropsychopharmacol 15:
and safety of AXS-05, an oral NMDA receptor antagonist 589–600.
586
BALANCE investigators and collaborators, et al. (2010) Perlis RH, Ostacher MJ, Goldberg JF, et al. (2010) Transition
Lithium plus valproate combination therapy versus to mania during treatment of bipolar depression.
monotherapy for relapse prevention in bipolar I disorder Neuropsychopharmacology 35: 2545–52.
(BALANCE): a randomized open-label trial. Lancet 375: Pompili M, Vazquez GH, Forte A, Morrissette DA, Stahl
385–95. SM (2020) Pharmacological treatment of mixed
Baldessarini RJ, Tondo L, Vazquez GH (2019) Pharmacological states. Psychiatr Clin N Am 43: 157–86. doi:10.1016/j.
treatment of adult bipolar disorder. Mol Psychiatry 24: psc.2019.10.015
198–217. Schwartz TL, Siddiqui US, Stahl SM (2011) Vilazodone: a
Bang-Andersen B, Ruhland T, Jorgensen M, et al. (2011) brief pharmacologic and clinical review of the novel SPARI
Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl] (serotonin partial agonist and reuptake inhibitor). Ther
piperazine (LuAA21004): a novel multimodal compound Adv Psychopharmacol 1: 81–7.
for the treatment of major depressive disorder. J Med Chem Settimo L, Taylor D (2018) Evaluating the dose-dependent
54: 3206–21. mechanism of action of trazodone by estimation of
Carhart-Harris RL, Bolstridge M, Day CMG, et al. occupancies for different brain neurotransmitter targets. J
(2018) Psilocybin with psychological support for Psychopharmacol 32: 960104.
treatment-resistant depression: six month follow up. Stahl SM (2009) Mechanism of action of trazodone: a
Psychopharmacology 235: 399–408. multifunctional drug. CNS Spectrums 14: 536–46.
Carhart-Harris RL, Bolstridge M, Rucker J, et al. (2016) Stahl SM (2012) Psychotherapy as an epigenetic “drug”:
Psilocybin with psychological support for treatment psychiatric therapeutics target symptoms linked to
resistant depression: an open label feasibility study. Lancet malfunctioning brain circuits with psychotherapy as well
Psychiatry 3: 619–27. as with drugs. J Clin Pharm Ther 37: 249–53.
Carhart-Harris RL, Goodwin GM (2017) The therapeutic Stahl SM (2014) Mechanism of action of the SPARI
potential of psychedelic drugs: past, present and future, vilazodone: (serotonin partial agonist reuptake inhibitor).
Neuropsychopharmacology 42: 2105–13. CNS Spectrums 19: 105–9.
Carhart-Harris RL, Leech R, Williams TM, et al. (2012) Stahl SM (2014) Mechanism of action of agomelatine:
Implications for psychedelic assisted psychotherapy: a novel antidepressant exploiting synergy between
a functional magnetic resonance imaging study monoaminergic and melatonergic properties. CNS
with psilocybin. Br J Psychiatry: doi:10.1192/bjp. Spectrums 19: 207–12.
bp.111.103309.
Stahl SM (2015) Modes and nodes explain the mechanism
Chiu CT, Chuan DM (2010) Molecular actions and therapeutic of action of vortioxetine, a multimodal agent (MMA):
potential of lithium in preclinical and clinical studies of enhancing serotonin release by combining serotonin
CNS disorders. Pharmacol Ther 128: 281–304. (5HT) transporter inhibition with actions at 5HT receptors
Cipriani A, Pretty H, Hawton K, Geddes JR (2005) Lithium in (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors). CNS Spectrums
the prevention of suicidal behavior and all-cause mortality 20: 93–7.
in patients with mood disorders: a systematic review of Stahl SM (2015) Modes and nodes explain the mechanism of
randomized trials. Am J Psychiatry 162: 1805–19. action of vortioxetine, multimodal agent (MMA): actions
Frye MA, Grunze H, Suppes T, et al. (2007) A placebo- at serotonin receptors may enhance downstream release of
controlled evaluation of adjunctive modafinil in the four pro-cognitive neurotransmitters. CNS Spectrums 20:
treatment of bipolar depression. Am J Psychiatry 164: 515–19.
1242–9. Stahl SM, Fava M, Trivedi M (2010) Agomelatine in the
Grady M, Stahl SM (2012) Practical guide for prescribing treatment of major depressive disorder: an 8 week,
MAOI: Debunking myths and removing barriers. CNS multicenter, randomized, placebo-controlled trial. J Clin
Spectrums 17: 2–10. Psychiatry 71: 616–26.
Mork A, Pehrson A, Brennum LT, et al. (2012) Undurraga J, Baldessarini RJ, Valenti M, et al. (2012) Bipolar
Pharmacological effects of Lu AA21004: a novel depression: clinical correlates of receiving antidepressants.
multimodal compound for the treatment of major J Affect Disord 139: 89–93.
depressive disorder. J Pharmacol Exp Ther 340: 666–75. Zajecka J, Schatzberg A, Stahl SM, et al. (2010) Efficacy and
Pasquali L, Busceti CL, Fulceri F, Paparelli A, Fornai F (2010) safety of agomelatine in the treatment of major depressive
Intracellular pathways underlying the effects of lithium. disorder: a multicenter, randomized, double-blind, placebo-
Behav Pharmacol 21: 473–92. controlled trial. J Clin Psychopharmacol 30: 135–44.
587
Chapter 8 (Anxiety and Trauma) McEwen BS, Nasca C, Gray JD (2016) Stress effects on
neuronal structure: hippocampus, amygdala and prefrontal
cortex. Neuropsychopharm Rev 41: 3–23.
Anxiety Disorders: Psychopharmacology
McLaughlin KA, Sheridan MA, Gold AL, et al. (2016)
and Psychotherapy Maltreatment exposure, brain structure and
Batelaan NM, Van Balkom AJLM, Stein DJ (2010) Evidence- fear conditioning in children and adolescents.
based pharmacotherapy of panic disorder: an update. Int J Neuropsychopharmacology 41: 1956–65.
Neuropsychopharmacol 15: 403–15. Teicher MH, Anderson CM, Ohashi K, et al. (2014) Childhood
De Oliveira IR, Schwartz T, Stahl SM (eds.) (2014) Integrating maltreatment: altered network centrality of cingulate
Psychotherapy and Psychopharmacology. New York, NY: precuneus, temporal pole and insula. Biol Psychiatry 76:
Routledge Press. 297–305.
Etkin A, Prater KE, Hoeft F, et al. (2010) Failure of anterior Tyrka AR, Burgers DE, Philip NS (2013) The neurobiological
cingulate activation and connectivity with the amygdala correlates of childhood adversity and implications for
during implicit regulation of emotional processing in treatment. Acta Psychiatr Scand 138: 434–47.
generalized anxiety disorder. Am J Psychiatry 167: 545–54. Zhang JY, Liu TH, He Y, et al. (2019) Chronic stress remodels
Monk S, Nelson EE, McClure EB, et al. (2006) Ventrolateral synapses in an amygdala circuit-specific manner. Biol
prefrontal cortex activation and attentional bias in Psychiatry 85: 189–201.
response to angry faces in adolescents with generalized
anxiety disorder. Am J Psychiatry 163: 1091–7.
Fear Conditioning/Fear Extinction/
Otto MW, Basden SL, Leyro TM, McHugh K, Hofmann
SG (2007) Clinical perspectives on the combination of Reconsolidation/Circuitry
D-cycloserine and cognitive behavioral therapy for the Anderson KC, Insel TR (2006) The promise of extinction
treatment of anxiety disorders. CNS Spectrums 12: 59–61. research for the prevention and treatment of anxiety
Otto MW, Tolin DF, Simon NM, et al. (2010) Efficacy of D- disorders. Biol Psychiatry 60: 319–21.
cycloserine for enhancing response to cognitive-behavior Barad M, Gean PW, Lutz B. (2006) The role of the amygdala
therapy for panic disorder. Biol Psychiatry 67: 365–70. in the extinction of conditioned fear. Biol Psychiatry 60:
Stahl SM (2010) Stahl’s Illustrated: Anxiety and PTSD. 322–8.
Cambridge: Cambridge University Press. Bonin RP, De Koninck Y (2015) Reconsolidation and the
Stahl SM (2012) Psychotherapy as an epigenetic “drug”: regulation of plasticity: moving beyond memory. Trends
psychiatric therapeutics target symptoms linked to Neurosci 38: 336–44.
malfunctioning brain circuits with psychotherapy as well Dejean C, Courtin J, Rozeaske RR, et al. (2015) Neuronal
as with drugs. J Clin Pharm Ther 37: 249–53. circuits for fear expression and recovery: recent advances
Stahl SM, Moore BA (eds.) (2013) Anxiey Disorders: A Guide and potential therapeutic strategies. Biol Psychiatry 78:
for Integrating Psychopharmacology and Psychotherapy. 298–306.
New York, NY: Routledge Press. Feduccia AA, Mithoefer MC (2018) MDMA-assisted
psychotherapy for PTSD: are memory reconsolidation
and fear extinction underlying mechanisms. Prog
Stress/Early Life Adversity Neuropsychopharmacol Biol Psychiatry 84: 221–8.
Chen Y, Baram TZ (2016) Toward understanding how early life
Fox AS, Oler JA, Tromp DPM, et al. (2015) Extending the
stress reprograms cognitive and emotional brain networks.
amygdala in theories of threat processing. Trends Neurosci
Neuropsychopharm Rev 41: 187–296.
38: 319–29.
Hanson JL, Nacewicz BM, Suggerer MJ, et al. (2015)
Giustino RF, Seemann JR, Acca GM, et al. (2017) Beta
Behavioral problems after early life stress: contributions
adrenoceptor blockade in the basolateral amygdala, but
of the hippocampus and amygdala. Biol Psychiatry 77:
not the medial prefrontal cortex, rescues the immediate
314–23.
extinction deficit. Neuropsychopharmacol 42: 2537–44.
Kundakavic M, Champagne FA (2015) Early life
Graham BM, Milad MR (2011) The study of fear extinction:
experience, epigenetics and the developing brain.
implications for anxiety disorder. Am J Psychiatry 168:
Neuropsychopharmacol Rev 40: 141–53.
1255–65.
Marusak HA, Martin K, Etkin A, et al. (2015) Childhood trauma
Hartley CA, Phelps EA (2010) Changing fear:
exposure disrupts the automatic regulation of emotional
the neurocircuitry of emotion regulation.
processing. Neuropsychopharmacology 40: 1250–8.
Neuropsychopharmacol Rev 35: 136–46.
588
Haubrich J, Crestani AP, Cassini LF, et al. (2015) Ressler KJ (2020) Translating across circuits and genetics
Reconsolidation allows fear memory to be updated to a toward progress in fear- and anxiety-related disorders. Am
less aversive level through the incorporation of appetitive J Psychiatry 177: 214–22.
information. Neuropsychopharmacology 40: 315–26. Sandkuher J, Lee J (2013) How to erase memory traces of pain
Hermans D, Craske MG, Mineka S, Lovibond PF (2006) and fear. Trends Neurosci 36: 343–52.
Extinction in human fear conditioning. Biol Psychiatry 60: Schwabe L, Nader K, Pruessner JC (2011) Reconsolidation of
361–8. human memory: brain mechanisms and clinical relevance.
Holbrook TL, Galarneau ME, Dye JL, et al. (2010) Morphine Biol Psychiatry 76: 274–80.
use after combat injury in Iraq and post traumatic stress Schwabe L, Nader K, Wold OT (2012) Neural signature of
disorder. New Engl J Med 362: 110–17. reconsolidation impairments by propranolol in humans.
Keding TJ, Herringa RJ (2015) Abnormal structure of fear Biol Psychiatry 71: 380–6.
circuitry in pediatric post traumatic stress disorder. Shin LM, Liberzon I (2010) The neurocircuitry of fear, stress
Neuropsychopharmacology 40: 537–45. and anxiety disorders. Neuropsychopharmacol Rev 35:
Krabbe S, Grundemann J, Luthi A (2018) Amygdala inhibitory 169–91.
circuits regulate associative fear conditioning. Biol Soeter M, Kindt M (2012) Stimulation of the noradrenergic
Psychiatry 83: 800–9. system during memory formation impairs extinction
Kroes MCW, Tona KD, den Ouden HEM, et al. (2016) learning but not the disruption of reconsolidation.
How administration of the beta blocker propranolol Neuropsychopharmacology 37: 1204–15.
before extinction can prevent the return of fear. Stern CAJ, Gazarini L, Takahashi RN, et al. (2012)
Neuropsychopharmacology 41: 1569–78. On disruption of fear memory by reconsolidation
Kwapis JL, Wood MA (2014) Epigenetic mechanisms in fear blockade: evidence from cannabidiol treatment.
conditioning: implications for treating post traumatic Neuropsychopharmacology 37: 2132–42.
stress disorder. Trends Neurosci 37: 706–19. Tamminga CA (2006) The anatomy of fear extinction. Am J
Lin HC, Mao SC, Su CL, et al. (2010) Alterations of excitatory Psychiatry 163: 961.
transmission in the lateral amygdala during expression and Tronson NC, Corcoran KA, Jovasevic V, et al. (2011) Fear
extinction of fear memory. Int J Neuropsychopharmacol 13: conditioning and extinction: emotional states encoded
335–45. by distinct signaling pathways. Trends Neurosci 35:
Linnman C, Zeidan MA, Furtak SC, et al. (2012) Resting 145–55.
amygdala and medial prefrontal metabolism predicts
functional activation of the fear extinction circuit. Am J
Psychiatry 169: 415–23. PTSD
Mahan AL, Ressler KJ (2012) Fear conditioning, synaptic Aupperle RL, Allard CB, Grimes EM, et al. (2012) Dorsolateral
plasticity and the amygdala: implications for post prefrontal cortex activation during emotional anticipation
traumatic stress disorder. Trends Neurosci 35: 24–35. and neuropsychological performance in posttraumatic
stress disorder. Arch Gen Psychiatry 69: 360–71.
Mithoefer MC, Wagner MT, Mithoefer AT, et
al. (2011) The safety and efficacy of {+/−} Bonne O, Vythilingam M, Inagaki M, et al. (2008) Reduced
3,4-methylenedioxymethamphetamine-assisted posterior hippocampal volume in posttraumatic stress
psychotherapy in subjects with chronic, treatment-resistant disorder. J Clin Psychiatry 69: 1087–91.
posttraumatic stress disorder: the first randomized De Kleine RA, Hendriks GJ, Kusters WJC, Broekman TG,
controlled pilot study. J Psychopharmacol 25: 439–52. van Minnen A (2012) A randomized placebo-controlled
Myers KM, Carlezon WA Jr. (2012) D-Cycloserine effects on trial of D-cycloserine to enhance exposure therapy
extinction of conditioned responses to drug-related cues. for posttraumatic stress disorder. Biol Psychiatry 71:
Biol Psychiatry 71: 947–55. 962–8.
Onur OA, Schlaepfer TE, Kukolja J, et al. (2010) The N-methyl- Feduccia AA, Mithoefer MC (2018) MDMA-assisted
D-aspartate receptor co-agonist D-cycloserine facilitates psychotherapy for PTSD: are memory reconsolidation
declarative learning and hippocampal activity in humans. and fear extinction underlying mechanisms. Prog
Biol Psychiatry 67: 1205–11. Neuropsychopharmacol Biol Psychiatry 84: 221–8.
Otis JM, Werner CR, Muelier D (2015) Noradrenergic Ipser JC, Stein DJ (2012) Evidence-based pharmacotherapy
regulation of fear and drug-associated memory of post-traumatic stress disorder (PTSD). Int J
reconsolidation. Neuropsychopharmacology 40: 793–803. Neuropsychopharmacol 15: 825–40.
589
Jovanovic T, Ressler KJ (2010) How the neurocircuitry and van Zuiden M, Geuze E, Willemen HLD, et al. (2011) Pre-
genetics of fear inhibition may inform our understanding existing high glucocorticoid receptor number predicting
of PTSD. Am J Psychiatry 167: 648–62. development of posttraumatic stress symptoms after
Mercer KB, Orcutt HK, Quinn JF, et al. (2012) Acute and military deployment. Am J Psychiatry 168: 89–96.
posttraumatic stress symptoms in a prospective gene X
environment study of a university campus shooting. Arch
Gen Psychiatry 69: 89–97.
Chapter 9 (Pain)
Apkarian AV, Sosa Y, Sonty S, et al. (2004) Chronic back pain
Mithoefer MC, Wagner MT, Mithoefer AT, et is associated with decreased prefrontal and thalamic gray
al. (2011) The safety and efficacy of {+/−} matter density. J Neurosci 24: 10410–15.
3,4-methylenedioxymethamphetamine-assisted
psychotherapy in subjects with chronic, treatment-resistant Bar KJ, Wagner G, Koschke M, et al. (2007) Increased
posttraumatic stress disorder: the first randomized prefrontal activation during pain perception in major
controlled pilot study. J Psychopharmacol 25: 439–52. depression. Biol Psychiatry 62: 1281–7.
Orr SP, Milad MR, Metzger LJ (2006) Effects of beta blockade, Benarroch EE (2007) Sodium channels and pain. Neurology
PTSD diagnosis, and explicit threat on the extinction 68: 233–6.
and retention of an aversively conditioned response. Biol Brandt MR, Beyer CE, Stahl SM (2012) TRPV1 antagonists
Psychol 732: 262–71. and chronic pain: beyond thermal perception.
Perusini JN, Meyer EM, Long VA, et al. (2016) Induction and Pharmaceuticals 5: 114–32.
expression of fear sensitization caused by acute traumatic Davies A, Hendrich J, Van Minh AT, et al. (2007) Functional
stress. Neuropsychopharm Rev 41: 45–57. biology of the alpha 2 beta subunits of voltage gated
Raskind MA, Peskind ER, Hoff DJ (2007) A parallel calcium channels. Trends Pharmacol Sci 28: 220–8.
group placebo controlled study of prazosin for trauma Descalzi G, Ikegami D, Ushijima T, et al. (2015) Epigenetic
nightmares and sleep disturbance in combat veterans with mechanisms of chronic pain Trends Neurosci 38: 237–46.
post-traumatic stress disorder. Biol Psychiatry 61: 928–34. Dooley DJ, Taylor CP, Donevan S, Feltner D (2007) Ca2+
Rauch SL, Shin LM, Phelps EA. (2006) Neurocircuitry models Channel alpha 2 beta ligands: novel modulators of
of posttraumatic stress disorder and extinction: human neurotransmission. Trends Pharmacol Sci 28: 75–82.
neuroimaging research – past, present and future. Biol Farrar JT (2006) Ion channels as therapeutic targets in
Psychiatry 60: 376–82. neuropathic pain. J Pain 7 (Suppl 1): S38–47.
Reist C, Streja E, Tang CC, et al. (2020) Prazocin for treatment Gellings-Lowe N, Stahl SM (2012) Antidepressants in pain, anxiety
of post traumatic stress disorder: a systematic review and depression. In Pain Comorbidities, Giamberardino MA and
and met analysis. CNS Spectrums: doi.org/10.1017/ Jensen TS (eds.), Washington, DC: IASP Press, 409–23.
S1092852920001121.
Gracely RH, Petzke F, Wolf JM, Clauw DJ (2002) Functional
Sandweiss DA, Slymen DJ, Leardmann CA, et al. (2011) magnetic resonance imaging evidence of augmented
Preinjury psychiatric status, injury severity, and pain processing in fibromyalgia. Arthritis Rheum 46:
postdeployment posttraumatic stress disorder. Arch Gen 1222–343.
Khoutorsky A, Price TJ (2018) Translational control
Sauve W, Stahl SM (2019) Psychopharmacological and mechanism in persistent pain. Trends Neuosci 41: 100–14.
neuromodulation treatment of PTSD. In Treating PTSD in
Military Personnel, 2nd edition, Moore BA and Penk WE Luo C, Kuner T, Kuner R (2014) Synaptic plasticity in
(eds.), Guilford Press: 155–72. pathological pain. Trends Neurosci 37: 343–55.
Shin LM, Bush G, Milad MR, et al. (2011) exaggerated McLean SA, Williams DA, Stein PK, et al. (2006) Cerebrospinal
activation of dorsal anterior cingulate cortex during fluid corticotropin-releasing factor concentration is
cognitive interference: a monozygotic twin study of associated with pain but not fatigue symptoms in patients
posttraumatic stress disorder. Am J Psychiatry 168: 979–85. with fibromyalgia. Neuropsychopharmacology 31: 2776–82.
Stein MB, McAllister TW (2009) Exploring the convergence Nickel FT, Seifert F, Lanz S, Maihofner C (2012) Mechanisms
of posttraumatic stress disorder and mild traumatic brain of neuropathic pain. Eur Neuropsychopharmacol 22: 81–91.
injury. Am J Psychiatry 166: 768–76. Norman E, Potvin S, Gaumond I, et al. (2011) Pain inhibition
Vaiva G, Ducrocq F, Jezequel K, et al. (2003) Immediate is deficient in chronic widespread pain but normal in
treatment with propranolol decreases postraumatic stress major depressive disorder. J Clin Psychiatry 72: 219–24.
disorder two months after trauma. Biol Psychiatry 54: Ogawa K, Tateno A, Arakawa R, et al. (2014) Occupancy
947–9. of serotonin transporter by tramadol: a positron
590
emission tomography study with 11C-DSDB. Int J Beuckmann CT, Suzuki M, Ueno T, et al. (2017) In vitro and
Neuropsychopharmacol 17: 845–50. in silico characterization of lemborexant (E2006), a novel
Stahl SM (2009) Fibromyalgia: pathways and neurotransmitters. dual orexin receptor antagonist. J Pharmacol Exp Ther 362:
Hum Psychopharmacol 24: S11–17. 287–95.
Stahl SM, Eisenach JC, Taylor CP, et al. (2013) The diverse Beuckmann CT, Ueno T, Nakagawa M, et al. (2019) Preclinical
therapeutic actions of pregabalin: is a single mechanism in vivo characterization of lemborexant (E2006) a novel
responsible for several pharmacologic activities. Trends dual orexin receptor antagonist for sleep/wake regulation.
Pharmacol Sci 34: 332–9. Sleep: doi 10.1093/sleep/zsz076.
Wall PD, Melzack R (eds.) (1999) Textbook of Pain, 4th edition. Bonnavion P, de Lecea L (2010) Hypocretins in the control
London: Harcourt Publishers Limited. of sleep and wakefulness. Curr Neurol Neurosci Rep 10:
174–9.
Williams DA, Gracely RH (2006) Functional magnetic
resonance imaging findings in fibromyalgia. Arthritis Res Bourgin P, Zeitzer JM, Mignot E (2008) CSF hypocretin-1
Ther 8: 224–32. assessment in sleep and neurological disorders. Lancet
Neurol 7: 649–62.
Brisbare-Roch C, Dingemanse J, Koberstein R, et al. (2007)
Chapter 10 (Sleep/Wake Disorders Promotion of sleep by targeting the orexin system in rats,
and Their Treatment Including dogs and humans. Nat Med 13: 150–5.
Cao M, Guilleminault C (2011) Hypocretin and its emerging
Histamine and Orexin) role as a target for treatment of sleep disorders. Curr Neurol
Neurosci Rep 11: 227–34.
Histamine
Citrome L (2014) Suvorexant for insomnia: a systematic
Broderick M, Masri T (2011) Histamine H3 receptor (H3R) review of the efficacy and safety profile for this newly
antagonists and inverse agonists in the treatment of sleep approved hypnotic – what is the number needed to treat,
disorders. Curr Pharm Design 17: 1426–9. number needed to harm and likelihood to be helped or
Kotanska M, Kuker KJ, Szcaepanska K, et al. (2018) The harmed? Int J Clin Pract 68: 1429–41.
histamine H3 receptor inverse agonist pitolisant reduces Coleman PJ, Schreier JD, Cox CD, et al. (2012) Discovery
body weight in obese mice. Arch Pharmacol 391: 875–81. of [(2R, 5R)-5-{[(5‐fluoropyridin‐2‐yl)oxy]methyl}‐2‐
Nomura H, Mizuta H, Norimoto H, et al. (2019) Central methylpiperidin‐1‐yl] [5-methyl-2-(pyrimidin-2-yl)phenyl]
histamine boosts perirhinal cortex activity and restores methanone (MK-6096): a dual orexin receptor antagonist
forgotten object memories. Biol Psychiatry 86: 230–9. with potent sleep-promoting properties. Chem Med 7,
Romig A, Vitran G, Giudice TL, et al. (2018) Profile of 415–24.
pitolisant in the management of narcolepsy: design, Dauvilliers Y, Abril B, Mas E, et al. (2009) Normalization
development and place in therapy. Drug Des Devel Ther 12: of hypocretin-1 in narcolepsy after intravenous
2665–75. immunoglobulin treatment. Neurology 73: 1333–4.
Schwartz JC (2011) The histamine H3 receptor: from discovery de Lecea L, Huerta R (2015) Hypocretin (orexin) regulation of
to clinical trials with pitolisant. Br J Pharmacol 163: sleep-to-wake transitions. Front Pharmacol 5: 1–7.
713–21. DiFabio R, Pellacani A, Faedo S (2011) Discovery process
Szakacs Z, Dauvilliers Y, Mikhaulov V, et al. (2017) Safety and pharmacological characterization of a novel dual
and efficacy of pitolisant on cataplexy in patients with orexin 1 and orexin 2 receptor antagonist useful for
narcolepsy: a randomized, double-blind placebo controlled treatment of sleep disorders. Bioorg Med Chem Lett 21:
trial. Lancet Neurol 16: 200–7. 5562–7.
Dubey AK, Handu SS, Mediratta PK (2015) Suvorexant:
Orexin the first orexin receptor antagonist to treat insomnia. J
Bennett T, Bray D, Neville MW (2014) Suvorexant, a dual Pharmacol Pharmacother 6: 118–21.
orexin receptor antagonist for the management of Equihua AC, De la Herran-Arita AK, Drucker-Colin R (2013)
insomnia. PT 39: 264–6. Orexin receptor antagonists as therapeutic agents for
Bettica P, Squassante L, Groeger JA, et al. (2012) Differential insomnia. Front Pharmacol 4: 1–10.
effects of a dual orexin receptor antagonist (SB-649868) and Gentile TA, Simmons SJ, Watson MN, et al. (2018) Effects
zolpidem on sleep initiation and consolidation, SWS, REM of suvorexant, a dual orexin hypocretin receptor
sleep, and EEG power spectra in a model of situational antagonist on impulsive behavior associated with cocaine.
insomnia. Neuropsychopharmacology 37: 1224–33. Neuropsychopharmacology 43: 1001–9.
591
Gotter AL, Winrow CJ, Brunner J, et al. (2013) The duration Stahl SM (2016) Mechanism of action of suvorexant. CNS
of sleep promoting efficacy by dual orexin receptor Spectrums 21: 215–18.
antagonists is dependent upon receptor occupancy Steiner MA, Lecourt H, Strasser DS, Brisbare-Roch C, Jenck
threshold. BMC Neurosci 14: 90. F (2011) Differential effects of the dual orexin receptor
Griebel G, Decobert M, Jacquet A, et al. (2012) Awakening antagonist almorexant and the GABAA-α1 receptor
properties of newly discovered highly selective H3 modulator zolpidem, alone or combined with ethanol, on
receptor antagonists in rats. Behav Brain Res 232: motor performance in the rat. Neuropsychopharmacology
416–20. 36: 848–56.
Herring WJ, Connor KM, Ivgy-May N, et al. (2016) Suvorexant Vermeeren A, Jongen S, Murphy P, et al. (2019) On the
in patients with insomnia: results from two 3-month road driving performance the morning after bedtime
randomized controlled clinical trials. Biol Psychiatry 79: administration of lemborexant in healthy adult and elderly
136–48. volunteers. Sleep: doi: 10.1093.sleep/zsy260.
Hoever P, Dorffner G, Benes H, et al. (2012) Orexin receptor Willie JT, Chemelli RM, Sinton CM, et al. (2003) Distinct
antagonism, a new sleep-enabling paradigm: a proof-of- narcolepsy syndromes in orexin recepter-2 and orexin null
concept clinical trial. Clin Pharmacol Ther 91: 975–85. mice: molecular genetic dissection of non-REM and REM
Hoyer D, Jacobson LH (2013) Orexin in sleep, addiction, and sleep regulatory processes. Neuron 38: 715–30.
more: is the perfect insomnia drug at hand? Neuropeptides Winrow CJ, Gotter AL, Cox CD, et al. (2012) Pharmacological
47: 477–88. characterization of MK-6096: a dual orexin receptor
Jones BE, Hassani OK (2013) The role of Hcrt/Orx and antagonist for insomnia. Neuropharmacology 62: 978–87.
MCH neurons in sleep–wake state regulation. Sleep 36: Yeoh JW, Campbell EJ, James MH, et al. (2014) Orexin
1769–72. antagonists for neuropsychiatric disease: progress and
Krystal AD, Benca RM, Kilduff TS (2013) Understanding the potential pitfalls. Front Neurosci 8: 1–12.
sleep–wake cycle: sleep, insomnia, and the orexin system. J
Clin Psychiatry 74 (Suppl 1): 3–20.
Sleep/General/Disorders/Insomia/Restless
Mahler SV, Moorman DE, Smith RJ, et al. (2014) Motivational
activation: a unifying hypothesis of orexin/hypocretin Legs
function. Nat Neurosci 17: 1298–303. Abadie P, Rioux P, Scatton B, et al. (1996) Central
Michelson D, Snyder E, Paradis E, et al. (2014) Safety and benzodiazepine receptor occupancy by zolpidem in the
efficacy of suvorexant during 1-year treatment of insomnia human brain as assessed by positron emission tomography.
with subsequent abrupt treatment discontinuation: a phase Science 295: 35–44.
3 randomised, double-blind, placebo-controlled trial. Allen RP, Burchell BJ, MacDonald B, et al. (2009) Validation
Lancet Neurol 13: 461–71. of the self-completed Cambridge–Hopkins questionnaire
Nixon JP, Mavanji V, Butterick TA, et al. (2015) Sleep (CH-RLSq) for ascertainment of restless legs syndrome
disorders, obesity, and aging: the role of orexin. Aging Res (RLS) in a population survey. Sleep Med 10: 1079–100.
Rev 20: 63–73. Bastien CH, Vallieres A, Morin CM (2001) Validation of
Rosenberg R, Murphy P, Zammit G, et al. (2019) Comparison the Insomnia Severity Index as an outcome measure for
of lemborexant with placebo and zolpidem tartrate insomnia research. Sleep Med 2: 297–307.
extended release for the treatment of older adults with Bonnet MH, Burton GG, Arand DL (2014) Physiological and
insomnia disorder: a phase 3 randomized clinical trial. medical findings in insomnia: implications for diagnosis
JAMA Network Open 2: e1918254 and care. Sleep Med Rev 18: 95–8.
Ruoff C, Cao M, Guilleminault C (2011) Hypocretin Burke RA, Faulkner MA (2011) Gabapentin enacarbil for the
antagonists in insomnia treatment and beyond. Curr treatment of restless legs syndrome (RLS). Expert Opin
Pharm Design 17: 1476–82. Pharmacother 12: 2905–14.
Sakurai T, Mieda M (2011) Connectomics of orexin- Buysse DJ, Reynolds CF III, Monk TH, et al. (1989) The
producing neurons: interface of systems of emotion, Pittsburgh Sleep Quality Index: a new instrument for
energy homeostasis and arousal. Trends Pharmacol Sci 32: psychiatric practice and research. Psychiatry Res 28:
451–62. 193–213.
Scammel TE, Winrow CJ (2011) Orexin receptors: Cappuccio FP, D’Elia L, Strazzullo P, et al. (2010) Sleep
pharmacology and therapeutic opportunities. Annu Rev duration and all-cause mortality: a systematic review and
Pharmacol Toxicol 51: 243–66. meta-analysis of prospective studies. Sleep 33: 585–92.
592
Chahine LM, Chemali ZN (2006) Restless legs syndrome: a Nofzinger EA, Buysse DJ, Germain A, et al. (2004) Functional
review. CNS Spectrums 11: 511–20. neuroimaging evidence for hyperarousal in insomnia. Am J
Dawson GR, Collinson N, Atack JR (2005) Development of Psychiatry 161: 2126–9.
subtype selective GABAA modulators. CNS Spectrums 10: Nutt D, Stahl SM (2010) Searching for perfect sleep: the
21–7. continuing evolution of GABAA receptor modulators as
hypnotics. J Psychopharmacol 24: 1601–2.
De Lecea L, Winkelman JW (2020) Sleep and neuropsychiatric
illness. Neuropsychopharmacol Rev 45: 1–216. Orzel-Gryglewska J (2010) Consequences of sleep deprivation.
Int J Occup Med Environ Health 23: 95–114.
Drover DR (2004) Comparative pharmacokinetics and
pharmacodynamics of short-acting hypnosedatives – Palma JA, Urrestarazu E, Iriarte J (2013) Sleep loss as a risk
zaleplon, zolpidem and zopiclone. Clin Pharmacokinet 43: factor for neurologic disorders: a review. Sleep Med 14:
227–38. 229–36.
Durmer JS, Dinges DF (2005) Neurocognitive consequences of Parthasarathy S, Vasquez MM, Halonen M, et al. (2015)
sleep deprivation. Semin Neurol 25: 117–29. Persistent insomnia is associated with mortality risk. Am J
Med 128: 268–75.
Espana RA, Scammell TE (2011) Sleep neurobiology from a
clinical perspective. Sleep 34: 845–58. Pinto Jr LR, Alves RC, Caixeta E, et al. (2010) New
guidelines for diagnosis and treatment of insomnia. Arq
Fava M, McCall WV, Krystal A, et al. (2006) Eszopiclone Neuropsiquiatr 68: 666–75.
co-administered with fluoxetine in patients with insomnia
coexisting with major depressive disorder. Biol Psychiatry Plante DT (2017) Sleep propensity in psychiatric
59: 1052–60. hypersomnolence: a systematic review and meta-analysis
of multiple sleep latency findings. Sleep Med Rev 31: 48–57.
Freedom T (2011) Sleep-related movement disorders. Dis Mon
57: 438-47. Reeve K, Bailes B. (2010) Insomnia in adults: etiology and
management. JNP 6: 53–60.
Frenette E (2011) Restless legs syndrome in children: a review
and update on pharmacological options. Curr Pharm Richey SM, Krystal AD (2011) Pharmacological advances in
Design 17: 1436–42. the treatment of insomnia. Curr Pharm Design 17: 1471–5.
Roth T, Roehrs T (2000) Sleep organization and regulation.
Garcia-Borreguero D, Allen R, Kohnen R, et al. (2010) Loss
Neurology 54 (Suppl 1): S2–7.
of response during long-term treatment of restless legs
syndrome: guidelines approved by the International Sahar S, Sassone-Corsi P (2009) Metabolism and cancer: the
Restless Legs Syndrome Study Group for use in clinical circadian clock connection. Nature 9: 886–96.
trials. Sleep Med 11: 956–9. Schutte-Rodin S, Broch L, Buysse D, et al. (2008) Clinical
Green CB, Takahashi JS, Bass J (2008) The meter of guideline for the evaluation and management of chronic
metabolism. Cell 134: 728–42. insomnia in adults. J Clin Sleep Med 4: 487–504.
Harris J, Lack L, Kemo K, et al. (2012) A randomized Sehgal A, Mignot E (2011) Genetics of sleep and sleep
controlled trial of intensive sleep retraining (ISR): a brief disorders. Cell 146: 194–207.
conditioning treatment for chronic insomnia. Sleep 35: Tafti M (2009) Genetic aspects of normal and disturbed sleep.
49–60. Sleep Med 10: S17–21.
Hening W, Walters AS, Allen RP, et al. (2004) Impact, Thorpe AJ, Clair A, Hochman S, et al. (2011) Possible sites
diagnosis and treatment of restless legs syndrome (RLS) in of therapeutic action in restless legs syndrome: focus on
a primary care population: the REST (RLS Epidemiology, dopamine and α2δ ligands. Eur Neurol 66: 18–29.
Symptoms, and Treatment) Primary Care Study. Sleep Med Vgontzas AN, Fernadez-Mendoza J, Bixler EO, et al. (2012)
5: 237–46. Persistent insomnia: the role of objective short sleep
Koffel EA, Koffel JB, Gehrman PR (2015) A meta-analysis of duration. Sleep 35: 61–8.
group cognitive behavioral therapy for insomnia. Sleep Med Wu JC, Gillin JC, Buchsbaum MS, et al. (2006) Frontal lobe
Rev 19: 6–16. metabolic decreases with sleep deprivation not totally
Krystal AD, Walsh JK, Laska E, et al. (2003) Sustained efficacy reversed by recovery sleep. Neuropsychopharmacology 31:
of eszopiclone over 6 months of nightly treatment: results 2783–92.
of a randomized, double-blind, placebo-controlled study in Zeitzer JM, Morales-Villagran A, Maidment NT (2006)
adults with chronic insomnia. Sleep 26: 793–9. Extracellular adenosine in the human brain during sleep
Morin CM, Benca R (2012) Chronic insomnia. Lancet 379: and sleep deprivation: an in vivo microdialysis study. Sleep
1129–41. 29: 455–61.
593
Wake Disorders/Sleepiness/OSA/ Carocci A, Catalano A, Sinicropi MS (2014) Melatonergic

drugs in development. Clin Pharmacol Adv Applications 6:
Narcolepsy/Circadian/Shift Work 127–37.
Abad VC, Guilleminault C (2011) Pharmacological treatment Cauter EV, Plat L, Scharf MB, et al. (1997) Simultaneous
of obstructive sleep apnea. Curr Pharm Design 17: 1418–25. stimulation of slow-wave sleep and growth hormone
Adenuga O, Attarian H (2014) Treatment of disorders of secretion by gamma-hydroxybutyrate in normal young
hypersomnolence. Curr Treat Options Neurol 16: 302. men. J Clin Invest 100: 745–53.
Ahmed I, Thorpy M (2010) Clinical features, diagnosis and Cermakian N, Lange T, Golombek D, et al. (2013) Crosstalk
treatment of narcolepsy. Clin Chest Med 31: 371–81. between the circadian clock circuitry and the immune
system. Chronobiol Int 30: 870–88.
Aloia MS, Arnedt JT, Davis JD, Riggs RL, Byrd D (2004)
Neuropsychological sequelae of obstructive sleep apnea– Cirelli C (2009) The genetic and molecular regulation of sleep:
hypopnea syndrome: a critical review. J Int Neuropsychol from fruit flies to humans. Nat Rev Neurosci 10: 549–60.
Soc 10: 772–85. Colwell CS (2011) Linking neural activity and molecular
Arallanes-Licea E, Caldelas I, De Ita-Perez D, et al. (2014) oscillators in the SCN. Nat Rev Neurosci 12: 553–69.
The circadian timing system: a recent addition in the Cook H et al. (2003) A 12-month, open-label, multicenter
physiological mechanisms underlying pathological and extension trial of orally administered sodium oxybate for
aging processes. Aging Dis 5: 406–18. the treatment of narcolepsy. Sleep 26: 31–5.
Artioli P, Lorenzi C, Priovano A, et al. (2007) How do Crowley SJ, Lee C, Tseng CY, et al. (2004) Complete or partial
genes exert their role? Period 3 gene variants and circadian re-entrainment improves performance, alertness,
possible influences on mood disorder phenotypes. Eur and mood during night-shift work. Sleep 27: 1077–87.
Neuropsychopharmacol 17: 587–94.
Czeisler CA, Walsh JK, Roth T, et al. (2005) Modafinil for
Aurora RN, Chowdhuri S, Ramar K, et al. (2012) The excessive sleepiness associated with shift-work sleep
treatment of central sleep apnea syndromes in adults: disorder. New Engl J Med 353: 476–86.
practice parameters with an evidence-based literature
Dallaspezia S, Benedetti F (2011) Chronobiological therapy for
review and meta-analyses. Sleep 35: 17–40.
mood disorders. Expert Rev Neurother 11: 961–70.
Banerjee S, Wang Y, Solt LA, et al. (2014) Pharmacological
Darwish M, Bond M, Ezzet F (2012) Armodafinil in patients
targeting of the mammalian clock regulates sleep
with excessive sleepiness associated with shift work
architecture and emotional behaviour. Nat Commun 5: 5759.
disorder: a pharmacokinetic/pharmacodynamic model
Barger LK, Ogeil RP, Drake CL, et al. (2012) Validation of a for predicting and comparing their concentration-effect
questionnaire to screen for shift work disorder. Sleep 35: relationships. J Clin Pharmacol 52: 1328–42.
1693–703.
Darwish M, Kirby M, D’Andrea DM, et al. (2010)
Benedetti F, Serretti A, Colombo C, et al. (2003) Influence Pharmacokinetics of armodafinil and modafinil after
of CLOCK gene polymorphisms on circadian mood single and multiple doses in patients with excessive
fluctuation and illness recurrence in bipolar depression. sleepiness associated with treated obstructive sleep apnea:
Am J Med Genet B, Neuropsychiatr Genet 123 : 23–6. a randomized, open-label, crossover study. Clin Ther 32:
Black JE, Hull SG, Tiller J, et al. (2010) The long-term 2074–87.
tolerability and efficacy of armodafinil in patients with Dauvilliers Y, Tafti M (2006) Molecular genetics and treatment
excessive sleepiness associated with treated obstructive of narcolepsy. Ann Med 38: 252–62.
sleep apnea, shift work disorder, or narcolepsy: an open-
De la Herran-Arita AK, Garcia-Garcia F (2014) Narcolepsy as
label extension study. J Clin Sleep Med 6: 458–66.
an immune-mediated disease. Sleep Disord 2014: 792687.
Bogan RK (2010) Armodafinil in the treatment of excessive
Dinges DF, Weaver TE (2003) Effects of modafinil on
sleepiness. Expert Opin Pharmacother 11: 993–1002.
sustained attention performance and quality of life in OSA
Bonacci JM, Venci JV, Ghandi MA (2015) Tasimelteon patients with residual sleepiness while being treated with
(HetliozTM): a new melatonin receptor agonist for the CPAP. Sleep Med 4: 393–402.
treatment of non-24 sleep-wake disorder. J Pharm Pract
Dresler M, Spoormaker VI, Beitinger P, et al. (2014)
28: 473–8.
Neuroscience-driven discovery and development of sleep
Brancaccio M, Enoki R, Mazuki CN, et al. (2014) Network- therapeutics. Pharmacol Ther 141: 300–34.
mediated encoding of circadian time: the suprachiasmatic
Eckel-Mahan KL, Patel VR, de Mateo S, et al. (2013)
nucleus (SCN) from genes to neurons to circuits, and back.
Reprogramming of the circadian clock by nutritional
J Neurosci 34: 15192–9.
challenge. Cell 155: 1464–78.
594
Ellis CM, Monk C, Simmons A, et al. (1999) Functional Krakow B, Ulibarri VA (2013) Prevalence of sleep breathing
magnetic resonance imaging neuroactivation studies complaints reported by treatment-seeking chronic insomnia
in normal subjects and subjects with the narcoleptic disorder patients on presentation to a sleep medical center: a
syndrome. Actions of modafinil. J Sleep Res 8: 85–93. preliminary report. Sleep Breath 17: 317–22.
Epstein LJ, Kristo D, Strollo PJ, et al. (2009) Clinical guideline Kripke DE, Nievergelt CM, Joo E, et al. (2009) Circadian
for the evaluation, management and long-term care of polymorphisms associated with affective disorders. J
obstructive sleep apnea in adults. J Clin Sleep Med 5: 263–76. Circadian Rhythms 27: 2.
Erman MK, Seiden DJ, Yang R, et al. (2011) Efficacy and Krystal AD, Harsh JR, Yang R et al. (2010) A double-blind,
tolerability of armodafinil: effect on clinical condition placebo-controlled study of armodafinil for excessive
late in the shift and overall functioning of patients with sleepiness in patients with treated obstructive sleep apnea
excessive sleepiness associated with shift work disorder. and comorbid depression. J Clin Psychiatry 71: 32–40.
J Occup Environ Med 53: 1460–5. Lallukka T, Kaikkonen R, Harkanen T, et al. (2014) Sleep and
Froy O (2010) Metabolism and circadian rhythms: sickness absence: a nationally representative register-based
implications for obesity. Endocr Rev 31: 1–24. follow-up study. Sleep 37: 1413–25.
Golombek DA, Casiraghi LP, Agostino PV, et al. (2013) The times Landrigan CP, Rothschild JM, Cronin JW, et al. (2004) Effect of
they are a-changing: effects of circadian desynchronization reducing interns work hours on serious medical errors in
on physiology and disease. J Physiol Paris 107: 310–22. intensive care units. New Engl J Med 351: 1838–48.
Guo X, Zheng L, Wang J, et al. (2013) Epidemiological Larson-Prior LJ, Ju Y, Galvin JE (2014) Cortical–subcortical
evidence for the link between sleep duration and high interactions in hypersomnia disorders: mechanisms
blood pressure: a systematic review and meta-analysis. underlying cognitive and behavioral aspects of the sleep–
Sleep Med 14: 324–32. wake cycle. Front Neurol 5: 1–13.
Hampp G, Ripperger JA, Houben T, et al. (2008) Regulation Laudon M, Frydman-Marom A (2014) Therapeutic effects
of monoamine oxidase A by circadian-clock components of melatonin receptor agonists on sleep and comorbid
implies influence on mood. Curr Biol 18: 678–83. disorders. Int J Mol Sci 15: 15924–50.
Harrison EM, Gorman MR (2012) Changing the waveform Liira J, Verbeek JH, Costa G, et al. (2014) Pharmacological
of circadian rhythms: considerations for shift-work. Front interventions for sleepiness and sleep disturbances caused
Neurol 3: 1–7. by shift work. Cochrane Database Syst Rev 8: CD009776.
Hart CL, Haney M, Vosburg SK, et al. (2006) Modafinil attentuates Lim DC, Veasey SC (2010) Neural injury in sleep apnea. Curr
disruptions in cognitive performance during simulated night- Neurol Neurosci Rep 10: 47–52.
shift work. Neuropsychopharmacology 31: 1526–36. Liu Y, Wheaton AG, Chapman DP, et al. (2013) Sleep duration
He B, Peng H, Zhao Y, et al. (2011) Modafinil treatment and chronic disease among US adults age 45 years and
prevents REM sleep deprivation-induced brain function older: evidence from the 2010 behavioral risk factor
impairment by increasing MMP-9 expression. Brain Res surveillance system. Sleep 36: 1421–7.
1426: 38–42. Madras BK, Xie Z, Lin Z, et al. (2006) Modafinil occupies
Hirai N, Nishino S (2011) Recent advances in the treatment of dopamine and norepinephrine transporters in vivo and
narcolepsy. Curr Treat Options Neurol 13: 437–57. modulates the transporters and trace amine activity in
Horne JA, Ostberg O (1976) A self-assessment questionnaire vitro. J Pharmacol Exp Ther 319: 561–9.
to determine morningness–eveningness in human Makris AP, Rush CR, Frederich RC, Kelly TH (2004) Wake-
circadian rhythms. Int J Chronobiol 4: 97–100. promoting agents with different mechanisms of action:
Johansson C, Willeit M, Smedh C, et al. (2003) Circadian comparison of effects of modafinil and amphetamine
clock-related polymorphisms in seasonal affective on food intake and cardiovascular activity. Appetite 42:
disorder and their relevance to diurnal preference. 185–95.
Neuropsychopharmacology 28: 734–9. Mansour HA, Wood J, Logue T, et al. (2006) Association
Khalsa SB, Jewett ME, Cajochen C, et al. (2003) A phase of eight circadian genes with bipolar I disorder,
response curve to single bright light pulses in human schizoaffective disorder and schizophrenia. Genes Brain
subjects. J Physiol 549(pt 3): 945–52. Behav 5: 150–7.
Knudsen S, Biering-Sorensen B, Kornum BR, et al. (2012) Martin JL, Hakim AD (2011) Wrist actigraphy. Chest 139:
Early IVIg treatment has no effect on post-H1N1 1514–27.
narcolepsy phenotype or hypocretin deficiency. Neurology Masri S, Kinouchi K, Sassone-Corsi P (2015) Circadian clocks,
79: 102–3. epigenetics, and cancer. Curr Opin Oncol 27: 50–6.
595
Mignot EJM (2012) A practical guide to the therapy of Sangal RB, Thomas L, Mitler MM (1992) Maintenance
narcolepsy and hypersomnia syndromes. Neurotherapeutics of wakefulness test and multiple sleep latency test.
9: 739–52. Measurement of different abilities in patients with sleep
Miletic V, Relja M (2011) Restless legs syndrome. Coll Antropol disorders. Chest 101: 898–902.
35: 1339–47. Saper CB, Lu J, Chou TC, Gooley J (2005) The hypothalamic
Morgenthaler TI, Kapur VK, Brown T, et al. (2007) Practice integrator for circadian rhythms. Trends Neurosci 3: 152–7.
parameters for the treatment of narcolepsy and other Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation
hypersomnias of central origin. Sleep 30: 1705–11. of sleep and circadian rhythms. Nature 437: 1257–63.
Morgenthaler TI, Lee-Chiong T, Alessi C, et al. (2007) Practice Schwartz JRL, Nelson MT, Schwartz ER, Hughes RJ (2004)
parameters for the clinical evaluation and treatment of Effects of modafinil on wakefulness and executive
circadian rhythm sleep disorders. Sleep 30: 1445–59. function in patients with narcolepsy experiencing late-day
Morrissette DA (2013) Twisting the night away: a review of the sleepiness. Clin Neuropharmacol 27: 74–9.
neurobiology, genetics, diagnosis, and treatment of shift Severino G, Manchia M, Contu P, et al. (2009) Association study
work disorder. CNS Spectrums 18 (Suppl 1): 45–53. in a Sardinian sample between bipolar disorder and the
Niervergelt CM, Kripke DF, Barrett TB, et al. (2006) Suggestive nuclear receptor REV-ERBalpha gene, a critical component
evidence for association of circadian genes PERIOD3 of the circadian clock system. Bipolar Disord 11: 215–20.
and ARNTL with bipolar disorder. Am J Med Genet B, Soria V, Martinez-Amoros E, Escaramis G, et al. (2010)
Neuropsychiatr Genet 141: 234–41. Differential association of circadian genes with mood
Norman D, Haberman PB, Valladares EM (2012) Medical disorders: CRY1 and NPAS2 are associated with unipolar
consequences and associations with untreated sleep-related major depression and CLOCK and VIP with bipolar
breathing disorders and outcomes of treatments. J Calif disorder. Neuropsychopharmacology 35: 1279–89.
Dent Assoc 40: 141–9. Stahl SM (2014) Mechanism of action of tasimelteon in non-
O’Donoghue FJ, Wellard RM, Rochford PD, et al. (2012) 24 sleep–wake syndrome: treatment for a circadian rhythm
Magnetic resonance spectroscopy and neurocognitive disorder in blind patients. CNS Spectrums 19: 475–87.
dysfunction in obstructive sleep apnea before and after Stippig A, Hubers U, Emerich M (2015) Apps in sleep
CPAP treatment. Sleep 35: 41–8. medicine. Sleep Breath 19: 411–17.
Ohayon MM (2012) Determining the level of sleepiness in the Tafti M, Dauvilliers Y, Overeem S (2007) Narcolepsy and
American population and its correlates. J Psychiatr Res 46: familial advanced sleep-phase syndrome: molecular
422–7. genetics of sleep disorders. Curr Opin Genet Dev 17:
Oosterman JE, Kalsbeek A, la Fleur SE, et al. (2015) Impact 222–7.
of nutrition on circadian rhythmicity. Am J Physiol Regul Tahara Y, Shibata S (2014) Chrono-biology, chrono-
Integr Comp Physiol 308: R337–50. pharmacology, and chrononutrition. J Pharmacol Sci 124:
Pail G, Huf W, Pjrek E, et al. (2011) Bright-light therapy in 320–35.
the treatment of mood disorders. Neuropsychobiology 64: Takahashi S, Hong HK, McDearmon EL (2008) The genetic of
152–62. mammalian circadian order and disorder: implications for
Palagini L, Biber K, Riemann D (2014) The genetics of physiology and disease. Nat Rev Genet 9: 764–75.
insomnia: evidence for epigenetic mechanisms? Sleep Med Takao T, Tachikawa H, Kawanishi Y, et al. (2007) CLOCK
Rev 18: 225–35. gene T3111C polymorphism is associated with
Partonen T, Treutlein J, Alpman A, et al. (2007) Three Japanese schizophrenics: a preliminary study. Eur
circadian clock genes Per2, Arntl, and Npas2 contribute to Neuropsychopharmacol 17: 273–6.
winter depression. Ann Med 39: 229–38. Tarasiuk A, Reuveni H (2013) The economic impact of
Pigeon WR, Pinquart M, Conner K (2012) Meta-analysis of obstructive sleep apnea. Curr Opin Pulm Med 19:
sleep disturbance and suicidal thoughts and behaviors. J 639–44.
Clin Psychiatry 73: e1160–7. Thaiss CA, Zeevi D, Levy M, et al. (2014) Transkingdom
Qureshi IA, Mehler MF (2014) Epigenetics of sleep and control of microbiota diurnal oscillations promotes
chronobiology. Curr Neurol Neurosci Rep 14: 432. metabolic homeostasis. Cell 159: 514–29.
Rogers RR (2012) Past, present, and future use of oral Thomas RJ, Kwong K (2006) Modafinil activates cortical
appliance therapies in sleep-related breathing disorders. J and subcortical sites in the sleep-deprived state. Sleep 29:
Calif Dent Assoc 40: 151–7. 1471–81.
596
Thomas RJ, Rosen BR, Stern CE, Weiss JW, Kwong KK (2005) Berridge CW, Shumsky JS, Andrzejewski ME, et al. (2012)
Functional imaging of working memory in obstructive Differential sensitivity to psychostimulants across
sleep-disordered breathing. J Appl Physiol 98: 2226–34. prefrontal cognitive tasks: differential involvement of
Thorpy MJ, Dauvilliers Y (2015) Clinical and practical noradrenergic α1- and α2-receptors. Biol Psychiatry 71:
consideration in the pharmacologic management of 467–73.
narcolepsy. Sleep Med 16: 9–18. Biederman J (2004) Impact of comorbidity in adults with
Trotti LM, Saini P, Bliwise DL, et al. (2015) Clarithromycin in attention deficit/hyperactivity disorder. J Clin Psychiatry 65
gamma-aminobutyric acid-related hypersomnolence: a (Suppl 3): 3–7.
randomized, crossover trial. Ann Neurol 78: 454–65. Biederman J, Petty CR, Fried R, et al. (2007) Stability of
Trotti LM, Saini P, Freeman AA, et al. (2013) Improvement executive function deficits into young adult years: a
in daytime sleepiness with clarithromycin in patients prospective longitudinal follow-up study of grown up
with GABA-related hypersomnia: clinical experience. J males with ADHD. Acta Psychiatr Scand 116: 129–36.
Psychopharmacol 28: 697–702. Clerkin SM, Schulz KP, Halperin JM (2009) Guanfacine
Van Someren EJ, Riemersma-Van Der Lek RF (2007) Live potentiates the activation of prefrontal cortex evoked by
to the rhythm, slave to the rhythm. Sleep Med Rev 11: warning signals. Biol Psychiatry 66: 307–12.
465–84. Cortese S, Adamo N, Del Giovane C, et al. (2018) Comparative
Wulff K, Gatti S, Wettstein JG, Foster RG (2010) Sleep efficacy and tolerability of medications for attention deficit
and circadian rhythm disruption in psychiatric and hyperactivity disorder in children, adolescents, and adults:
neurodegenerative disease. Nat Rev Neurosci 11: 589–99. a systematic review and network meta-analysis. Lancet
Zaharna M, Dimitriu A, Guilleminault C (2010) Expert
opinion on pharmacotherapy of narcolepsy. Expert Opin Easton N, Shah YB, Marshall FH, Fone KC, Marsden CA
Pharmacother 11: 1633–45. (2006) Guanfacine produces differential effects in frontal
cortex compared with striatum: assessed by phMRI BOLD
Zawilska JB, Skene DJ, Arendt J. (2009) Physiology and contrast. Psychopharmacology 189: 369–85.
pharmacology of melatonin in relation to biological
rhythms. Pharmacol Rep 61: 383–410. Faraone SV, Biederman J, Spencer T (2006) Diagnosing adult
attention deficit hyperactivity disorder: are late onset
and subthreshold diagnoses valid? Am J Psychiatry 163:
Chapter 11 (Attention Deficit 1720–9.
Hyperactivity Disorder) Franke B, Nucgekubu G, Asherson P, et al. (2018) Live fast,
die young? A review on the developmental trajectories of
Arnsten AFT (2006) Fundamentals of attention deficit/ ADHD across the lifespan. Eur Neuropsychopharmacol 28:
hyperactivity disorder: circuits and pathways. J Clin 1059–88.
Psychiatry 67 (Suppl 8): 7–12.
Fusar-Poli P, Rubia K, Rossi G, Sartori G, Balottin U (2012)
Arnsten AFT (2006) Stimulants: therapeutic actions in ADHD. Striatal dopamine transporter alterations in ADHD:
Neuropsychopharmacology 31: 2376–83. pathophysiology or adaptation to psychostimulants? a
Arnsten AFT (2009) Stress signaling pathways that impair meta-analysis. Am J Psychiatry 169: 264–72.
prefrontal cortex structure and function. Nat Rev Neurosci Grady M, Stahl SM (2012) A horse of a different color: how
10: 410–22. formulation influences medication effects. CNS Spectrums
Arnsten AFT, Li BM (2005) Neurobiology of executive 17: 63–9.
functions: catecholamine influences on prefrontal cortical Hannestad J, Gallezot JD, Planeta-Wilson B, et al. (2010)
functions. Biol Psychiatry 57: 1377–84. Clinically relevant doses of methylphenidate significantly
Avery RA, Franowicz JS, Phil M, et al. (2000) The alpha 2a occupy norepinephrine transporters in humans in vivo.
adrenoceptor agonist, guanfacine, increases regional Biol Psychiatry 68: 854–60.
cerebral blood flow in dorsolateral prefrontal cortex of Jakala P, Riekkinen M, Sirvio J, et al. (1999) Guanfacine, but
monkeys performing a spatial working memory task. not clonidine, improves planning and working memory
Neuropsychopharmacology 23: 240–9. performance in humans. Neuropsychopharmacology 20:
Berridge CW, Devilbiss DM, Andrzejewski ME, et al. (2006) 460–70.
Methylphenidate preferentially increases catecholamine Johnson K, Liranso T, Saylor K, et al. (2020) A phase II double
neurotransmission within the prefrontal cortex at low blind placebo controlled efficacy and safety study of SPN-
doses that enhance cognitive function. Biol Psychiatry 60: 812 (extended release vilaxazine) in children with ADHD. J
1111–20. Atten Disord 24: 348–58.
597
Kessler RC, Adler L, Barkley R (2006) The prevalence and Stahl SM (2009) Norepinephrine and dopamine regulate
correlates of adult ADHD in the United States: results signals and noise in the prefrontal cortex. J Clin Psychiatry
from the National Comorbidity Survey Replication. Am J 70: 617–18.
Psychiatry 163: 716–23. Stahl SM (2010) Mechanism of action of stimulants in
Kessler RC, Green JG, Adler LA, et al. (2010) Structure and attention deficit/hyperactivity disorder. J Clin Psychiatry
diagnosis of adult attention-deficit/hyperactivity disorder. 71: 12–13.
Arch Gen Psychiatry 67: 1168–78. Stahl SM (2010) Mechanism of action of α2A-adrenergic
Kollins SH, McClernon JM, Fuemmeler BF (2005) Association agonists in attention-deficit/hyperactivity disorder with
between smoking and attention deficit/hyperactivity or without oppositional symptoms. J Clin Psychiatry 71:
disorder symptoms in a population based sample of young 223–24.
adults. Arch Gen Psychiatry 62: 1142–7. Steere JC, Arnsten AFT (1997) The alpha 2A noradrenergic
Madras BK, Miller GM, Fischman AJ (2005) The dopamine receptor agonist guanfacine improves visual object
transporter and attention deficit/hyperactivity disorder. discrimination reversal performance in aged rhesus
Biol Psychiatry 57: 1397–409. monkeys. Behav Neurosci 111: 883–91.
Matthijssen AFM, Dietrich A, Bierens M, et al. (2019) Surman CBH, Biederman J, Spencer T (2011) Deficient
Continued benefits of methylphenidate in ADHD after 2 emotional self regulation and adult attention deficit
years in clinical practice: a randomized placebo-controlled hyperactivity disorder: a family risk analysis. Am J
discontinuation study. Am J Psychiatry 176: 754–62. Psychiatry 168: 617–23.
Mattingly G, Anderson RH (2016) Optimizing outcomes of Swanson J, Baler RD, Volkow ND (2011) Understanding
ADHD treatment: from clinical targets to novel delivery the effects of stimulant medications on cognition in
systems. CNS Spectrums 21: 48–58. individuals with attention-deficit hyperactivity disorder: a
Pinder RM, Brogden RN, Speight TM, et al. (1977) Voloxazine: decade of progress. Neuropsychopharmacology 36: 207–26.
a review of its pharmacological properties and therapeutic Turgay A, Goodman DW, Asherson P, et al. (2012) Lifespan
efficacy in depressive illness. Drugs 13: 401–21. persistance of ADHD: the lift transition model and its
Pingault JB, Tremblay RE, Vitaro F, et al. (2011) Childhood application. J Clin Psychiatry 73: 192–201.
trajectories of inattention and hyperactivity and prediction Turner DC, Clark L, Dowson J, Robbins TW, Sahakian BJ
of educational attainment in early adulthood: a 16-year (2004) Modafinil improves cognition and response
longitudinal population-based study. Am J Psychiatry 168: inhibition in adult attention deficit/hyperactivity disorder.
1164–70. Biol Psychiatry 55: 1031–40.
Seidman LJ, Valera EM, Makris N, et al. (2006) Dorsolateral Turner DC, Robbins TW, Clark L, et al. (2003) Cognitive
prefrontal and anterior cingulate cortex volumetric enhancing effects of modafinil in healthy volunteers.
abnormalities in adults with attention-deficit/hyperactivity Psychopharmacology 165: 260–9.
disorder identified by magnetic resonance imaging. Biol Vaughan BS, March JS, Kratochvil CJ (2012) The evidence-
Psychiatry 60: 1071–80. based pharmacological treatment of pediatric ADHD. Int J
Shaw P, Stringaris A, Nigg J, et al. (2014) Emotion Neuropsychopharmacol 15: 27–39.
dysregulation in attention deficit hyperactivity disorder. Volkow ND, Wong GJ, Kollins SH, et al. (2009) Evaluating
Am J Psychiatry 171: 276–93. dopamine reward pathway in ADHD: Clinical implications.
Spencer TJ, Biederman J, Madras BK, et al. (2005) In vivo JAMA 302: 1084–91.
neuroreceptor imaging in attention deficit/hyperactivity Wang M, Ramos BP, Paspalas CD, et al. (2007) α2A-
disorder: a focus on the dopamine transporter. Biol Adrenoceptors strengthen working memory networks
Psychiatry 57: 1293–300. by inhibiting cAMP-HCN channel signaling in prefrontal
Spencer TJ, Bonab AA, Dougherty DD, et al. (2012) cortex. Cell 129: 397–410.
Understanding the central pharmacokinetics of spheroidal Wigal T, Brams M, Gasior M, et al. (2010) Randomized,
oral drug absorption system (SODAS) dexmethylphenidate: double-blind, placebo-controlled, crossover study of the
a positron emission tomography study of dopamine efficacy and safety of lisdexamfetamine dimesylate in
transporter receptor occupancy measured with C-11 adults with attention-deficit/hyperactivity disorder: novel
altropane. J Clin Psychiatry 73: 346–52. findings using a simulated adult workplace environment
Stahl SM (2009) The prefrontal cortex is out of tune in design. Behav Brain Funct 6: 34–48.
attention-deficit/hyperactivity disorder. J Clin Psychiatry Wilens TE (2007) Lisdexamfetamine for ADHD. Curr
70: 950–1. Psychiatry 6: 96–105.
598
Yang L, Cao Q, Shuai L (2012) Comparative study of Aridi YS, Walker JL, Wright ORL (2017) The association
OROS-MPH and atomoxetine on executive function between the Mediterranean dietary pattern and cognitive
improvement in ADHD: a randomized controlled trial. Int J health: a systematic review. Nutrients 9: E674.
Neuropsychopharmacol 15: 15–16. Ballard C, Khan Z, Clack H, et al. (2011) Nonpharmacological
Zang YF, Jin Z, Weng XC, et al. (2005) Functional MRI in treatment of Alzheimer disease. Can J Psychiatry 56:
attention deficit hyperactivity disorder: evidence for 589–95.
hypofrontality. Brain Dev 27: 544–50. Buchman AS, Boyle PA, Yu L, et al. (2012) Total daily physical
Zuvekas SH, Vitiello B (2012) Stimulant medication use in activity and the risk of AD and cognitive decline in older
children: a 12-year perspective. Am J Psychiatry 169: 160–6. adults. Neurology 78: 1323–9.
Burmester B, Leathem J, Merrick P (2016) Subjective cognitive
Chapter 12 (Dementia) and complaints and objective cognitive function in aging:
a systematic review and meta-analysis of recent cross-
Acetylcholine sectional findings. Neuropsychol Rev 26: 376–93.
Cederholm T (2017) Fish consumption and omega-3 fatty acid
Neuronal Networks: Acetylcholine supplementation for prevention or treatment of cognitive
decline, dementia or Alzheimer’s disease in older adults:
Bacher I, Rabin R, Woznica A, Sacvco KA, George TP (2010)
any news? Curr Opin Clin Nutr Metab Care 20: 104–9.
Nicotinic receptor mechanisms in neuropsychiatric disorders:
therapeutic implications. Prim Psychiatry 17: 35–41. Cepoiu-Martin M, Tam-Tham H, Patten S, et al. (2016)
Predictors of long-term care placement in persons with
Fryer AD, Christopoulos A, Nathanson NM (eds.) (2012)
dementia: a systematic review and metaanalysis. Int J
Muscarinic Receptors. Berlin: Springer-Verlag.
Geriatr Psychiatry 31: 1151–71.
Geldmacher DS, Provenano G, McRae T, et al. (2003)
Ercoli L, Siddarth P, Huang SC, et al. (2006) Perceived loss of
Donepezil is associated with delayed nursing home
memory ability and cerebral metabolic decline in persons
placement in patients with Alzheimer’s disease. J Am
with the apolipoprotein E-IV genetic risk for Alzheimer
Geriatr Soc 51: 937–44.
disease. Arch Gen Psychiatry 63: 442–8.
Grothe M, Heinsen H, Teipel SF (2012) Atrophy of the
Gu Y, Brickman AM, Stern Y, et al. (2015) Mediterranean
cholinergic basal forebrain over the adult age range and in
diet and brain structure in a multiethnic elderly cohort.
early states of Alzheimer’s disease. Biol Psychiatry 71: 805–13.
Neurology 85: 1744–51.
Hasselmo ME, Sarter M (2011) Nodes and models of
Hardman RJ, Kennedy G, Macpherson H, et al. (2016) Adherence
forebrain cholinergic neuromodulation of cognition.
to a Mediterranean-style diet and effects on cognition in
Neuropsychopharmacology 36: 52–73.
adults: a qualitative evaluation and systematic review of
Lane RM, Potkin SG, Enz A (2006) Targeting longitudinal and prospective trials. Front Nutr 3: 1–13.
acetylcholinesterase and butyrylcholinesterase in
Hinz FI, Geschwind DH (2017) Molecular genetics of
dementia. Int J Neuropsychopharmacol 9: 101–24.
neurodegenerative dementias. Cold Spring Harb Perspect
Ohta Y, Darwish M, Hishikawa N, et al. (2017) Therapeutic Biol 9: a023705.
effects of drug switching between acetylcholinesterase
Knight A, Bryan J, Murphy K (2016) Is the Mediterranean
inhibitors in patients with Alzheimer’s disease. Geriatr
diet a feasible approach to preserving cognitive function
Gerontol Int 17: 1843–8.
and reducing risk of dementia for older adults in Western
Pepeu G, Giovannini M (2017) The fate of the brain countries? New insights and future directions. Ageing Res
cholinergic neurons in neurodegenerative diseases. Brain Rev 25: 85–101.
Res 1670: 173–84.
Kullmann S, Heni M, Hallschmid M, et al. (2016) Brain insulin
Tariot PN, Farlow MR, Grossberg GT, et al. (2004) Memantine resistance at the crossroads of metabolic and cognitive
treatment in patients with moderate to severe Alzheimer’s disorders in humans. Physiol Rev 96: 1169–209.
disease already receiving donepezil. JAMA 291: 317–24.
Larson EB, Wang L, Bowen JD, et al. (2006) Exercise is
associated with reduced risk for incident dementia among
Diet/Exercise/Genetics/Aging persons 65 years of age and older. Ann Intern Med 144:
Anastasiou CA, Yannakoulia M, Kosmidis MH, et al. (2017) 73–81.
Mediterranean diet and cognitive health: initial results Lee HS, Park SW, Park YJ (2016) Effects of physical activity
from the Hellenic Longitudinal Investigation of ageing and programs on the improvement of dementia symptom: a
diet. PLOS ONE 12: e0182048. meta-analysis. Biomed Res Int 2016: 2920146.
599
Lee SH, Zabolotny JM, Huang H, et al. (2016) Insulin in the

nervous system and the mind: functions in metabolism,
Alzheimer Disease/Vascular Dementia/
memory, and mood. Mol Metab 5: 589–601. Dementia with Lewy Bodies/Parkinson’s
Li Y, Sekine T, Funayama M, et al. (2014) Clinicogenetic study Disease Dementia/Frontotemporal
of GBA mutations in patients with familial Parkinson’s Dementia/Other Dementias/General
disease. Neurobiol Aging 35: 935.e3–8.
Lim SY, Kim EJ, Kim A, et al. (2016) Nutritional factors
Dementia
affecting mental health. Clin Nutr Res 5: 143–52. Annus A, Csati A, Vecsei L (2016) Prion diseases: new
considerations. Clin Neurol Neurosurg 150: 125–32.
Marcason W (2015) What are the components of the MIND
diet? J Acad Nutr Diet 115: 1744. Arai T (2014) Significance and limitation of the pathological
classification of TDP-43 proteinopathy. Neuropathology 34:
Matsuzaki T, Sasaki K, Tanizaki Y, et al. (2010) Insulin 578–88.
resistance is associated with the pathology of Alzheimer
disease. Neurology 75: 764–70. Arendt T, Steiler JT, Holzer M (2016) Tau and tauopathies.
Brain Res Bull 126: 238–92.
Ngandu T, Lehtisalo J, Solomon A, et al. (2015) A 2 year
multidomain intervention of diet, exercise, cognitive Asken BM, Sullan MJ, Snyder AR, et al. (2016) Factors
training, and vascular risk monitoring versus control to influencing clinical correlates of chronic traumatic
prevent cognitive decline in at-risk elderly people (FINGER): encephalopathy (CTE): a review. Neuropsychol Rev 26:
a randomized controlled trial. Lancet 385: 2255–63. 340–63.
O’Donnell CA, Browne S, Pierce M, et al. (2015) Reducing Atri A (2016) Imaging of neurodegenerative cognitive and
dementia risk by targeting modifiable risk factors in mid- behavioral disorders: practical considerations for dementia
life: study protocol for the Innovative Midlife Intervention clinical practice. Handb Clin Neurol 136: 971–84.
for Dementia Deterrence (In-MINDD) randomized Azizi SA, Azizi SA (2018) Synucleinopathies in
controlled feasibility trial. Pilot Feasibility Stud 1: 40. neurodegenerative diseases: accomplices, an inside job and
Olszewska DA, Lonergan R, Fallon EM, et al. (2016) Genetics of selective vulnerability. Neurosci Lett 672: 150–2.
frontotemporal dementia. Curr Neurol Neurosci Rep 16: 107. Ballard C, Mobley W, Hardy J, Williams G, Corbett A (2016)
Petersson SD, Philippou E (2016) Mediterranean diet, Dementia in Down’s syndrome. Lancet Neurol 15: 622–36.
cognitive function, and dementia: a systematic review of Ballard C, Ziabreva I, Perry R, et al. (2006) Differences in
the evidence. Adv Nutr 7: 889–904. neuropathologic characteristics across the Lewy body
Qosa H, Mohamed LA, Batarseh YS, et al. (2015) Extra-virgin dementia spectrum. Neurology 67: 1931–4.
olive oil attenuates amyloid-β and tau pathologies in the Benskey MJ, Perez RG, Manfredsson FP (2016) The
brains of TgSwD1 mice. J Nutr Biochem 26: 1479–90. contribution of alpha synuclein to neuronal survival
Rigacci S (2015) Olive oil phenols as promising multi- and function: implications for Parkinson’s disease. J
targeting agents against Alzheimer’s disease. Adv Exp Med Neurochemistry 137: 331–59.
Biol 863: 1–20. Bonifacio G, Zamboni G (2016) Brain imaging in dementia.
Rosenberg RN, Lambracht-Washington D, Yu G, et al. (2016) Postgrad Med J 92: 333–40.
Genomics of Alzheimer disease: a review. JAMA Neurol 73: Boxer AL, Yu JT, Golbe LI, et al. (2017) Advances in
867–74. progressive supranuclear palsy: new diagnostic criteria,
Schellenberg GD, Montine TJ (2012) The genetics and biomarkers, and therapeutic approaches. Lancet Neurol
neuropathology of Alzheimer’s disease. Acta Neuropathol 166: 552–63.
124: 305–23. Braak H, Del Tredici K, Rub U, et al. (2003) Staging of brain
Valenzuela MJ, Matthews FE, Brayne C, et al. for the Medical pathology related to sporadic Parkinson’s disease. Neurobiol
Research Council Cognitive Function and Ageing Study Aging 24: 197–211.
(2012) Multiple biological pathways link cognitive Burchell JT, Panegyres PK (2016) Prion diseases:
lifestyle to protection from dementia. Biol Psychiatry 71: immunotargets and therapy. ImmunoTargets Ther 5: 57–68.
783–91.
Cheung CY, Ikram MK, Chen C, et al. (2017) Imaging retina to
Yang T, Sun Y, Lu Z, et al. (2017) The impact of study dementia and stroke. Prog Brain Retinal Eye Res 57:
cerebrovascular aging on vascular cognitive impairment 89–107.
and dementia. Ageing Res Rev 34: 15–29.
Chutinet A, Rost NS (2014) White matter disease as a
Zillox LA, Chadrasekaran K, Kwan JY, et al. (2016) Diabetes biomarker for long-term cerebrovascular disease and
and cognitive impairment. Curr Diab Rep 16: 1–11. dementia. Curr Treat Options Cardiovasc Med 16: 292.
600
Dugger BN, Dickson DW (2017) Pathology of Ince PG, Perry EK, Morris CM (1998) Dementia with Lewy
neurodegenerative diseases. Cold Springs Harb Perspect bodies: a distinct non-Alzheimer dementia syndrome?
Biol 9: a028035. Brain Pathol 8: 299–324.
Eddy CM, Parkinson EG, Rickards HE (2016) Changes in Jellinger KA (2018) Dementia with Lewy bodies and
mental state and behavior in Huntington’s disease. Lancet Parkinson’s disease-dementia: current concepts and
Psychiatry 3: 1079–86. controversies. J Neural Transm 125: 615–50.
Emre M (2007) Treatment of dementia associated with Jena A, Renjen PN, Taneja S, et al. (2015) Integrated (18)
Parkinson’s disease. Parkinsonism Relat Disord 13 (Suppl F-fluorodeoxyglucose positron emission tomography
3): S457–61. magnetic resonance imaging ([18]F-FDG PET/MRI), a
Eusebio A, Koric L, Felician O, et al. (2016) Progressive multimodality approach for comprehensive evaluation
supranuclear palsy and corticobasal degeneration: of dementia patients: a pictorial essay. Indian J Radiol
diagnostic challenges and clinicopathological Imaging 25: 342–52.
considerations. Rev Neurol (Paris) 172: 488–502. Jennings LA, Palimaru A, Corona MG, et al. (2017) Patient
Foo H, Mak E, Yong TT (2017) Progression of subcortical and caregiver goals for dementia care. Qual Life Res 26:
atrophy in mild Parkinson’s disease and its impact on 685–93.
cognition. Eur J Neurol 24: 341–8. Johnson BP, Westlake KP (2018) Link between Parkinson
Ford AH (2016) Preventing delirium in dementia: managing disease and rapid eye movement sleep behavior disorder
risk factors. Maturitas 92: 35–40. with dream enactment: possible implications for early
rehabilitation. Arch Phys Med Rehab 99: 410–15.
Galvin JE (2015) Improving the clinical detection of Lewy
body dementia with the Lewy Body Composite Risk Score. Kapasi A, DeCarli C, Schneider JA (2017) Impact of multiple
Alzheimers Dement (Amst) 1: 316–24. pathologies on the threshold for clinically overt dementia.
Acta Neuropathol 134: 171–86.
Giri M, Zhang M, Lu Y (2016) Genes associated with
Alzheimer’s disease: an overview and current status. Clin Karantzoulis S, Galvin JE (2011) Distinguishing Alzheimer’s
Interv Aging 11: 665–81. disease from other major forms of dementia. Expert Rev
Neurother 11: 1579–91.
Goetz CG, Emre M, Dubois B (2008) Parkinson’s disease
dementia: definitions, guidelines, and research Kertesz A, Munoz DG (2002) Frontotemporal dementia. Med
perspectives in diagnosis. Ann Neurol 64 (Suppl 2): Clin North Am 86: 501–18.
S81–92. Knopman DS, Kramer JH, Boeve BF, et al. (2008) Development
Goodman RA, Lochner KA, Thambisetty M, et al. (2017) of methodology for conducting clinical trials in
Prevalence of dementia subtypes in United States Medicare frontotemporal lobar degeneration. Brain 131 (Pt 11):
fee-for-service beneficiaries, 2011-2013. Alzheimers 2957–68.
Dement 13: 28–37. Kobylecki C, Jones M, Thompson JC, et al. (2015) Cognitive-
Gordon E, Rohrer JD, Fox NC (2016) Advances in behavioural features of progressive supranuclear palsy
neuroimaging in frontotemporal dementia. J Neurochem syndrome overlap with frontotemporal dementia. J Neurol
138 (Suppl 1): 193–210. 262: 916–22.
Gray SL, Hanlon JT (2016) Anticholinergic medication use Kolb HC, Andres JI (2017) Tau positron emission tomography
and dementia: latest evidence and clinical implications. imaging. Cold Spring Harb Perspect Biol 9: a023721.
Ther Adv Drug Saf 7: 217–24. Koronyo Y, Biggs D, Barron E, et al. (2017) Retinal amyloid
Harper L, Barkhof F, Scheltens P, et al. (2014) An algorithmic pathology and proof-of-concept imaging trial in
approach to structural imaging in dementia. J Neurol Alzheimer’s disease. JCI Insight 2: 93621.
Neurosurg Psychiatry 85: 692–8. Landin-Romero R, Tan R, Hodges HR, et al. (2016) An update
Hasegawa M, Nonaka T, Masuda-Suzukake M (2017) Prion- on semantic dementia: genetics, imaging, and pathology.
like mechanisms and potential therapeutic targets in Alz Res Ther 8: 52.
neurodegenerative disorders. Pharmacol Ther 172: 22–33. Levy RH, Collins C (2007) Risk and predictability of
Hithersay R, Hamburg S, Knight B, et al. (2017) Cognitive drug interactions in the elderly. Int Rev Neurobiol 81:
decline and dementia in Down syndrome. Curr Opin 235–51.
Psychiatry 30: 102–7. Ling H (2016) Clinical approach to progressive supranuclear
Huey ED, Putnam KT, Grafman J (2006) A systematic palsy. J Mov Disord 9: 3–13.
review of neurotransmitter deficits and treatments in Lippmann S, Perugula ML (2016) Delirium or dementia?
frontotemporal dementia. Neurology 66: 17–22. Innov Clin Neurosci 13: 56–7.
601
Liscic RM, Srulijes K, Groger A, et al. (2013) Differentiation Parkinson’s disease with dementia. Movement Disorders
of progressive supranuclear palsy: clinical, imaging and 19: 60–7.
laboratory tools. Acta Neurol Scand 127: 361–70. Pandya SY, Clem MA, Silva LM, et al. (2016) Does mild
Llorens F, Karch A, Golanska E, et al. (2017) Cerebrospinal cognitive impairment always lead to dementia? A review. J
fluid biomarker-based diagnosis of sporadic Creutzfeldt– Neurol Sci 369: 58–62.
Jakob disease: a validation study for previously established Paoli RA, Botturi A, Ciammola A, et al. (2017) Neuropsychiatric
cutoffs. Dement Geriatr Cogn Disord 43: 71–80. burden in Huntington’s disease. Brain Sci 7: 67.
Mackenzie IR, Neumann M (2016) Molecular neuropathology Park HK, Park KH, Yoon B, et al. (2017) Clinical characteristics
of frontotemporal dementia: insights into disease of parkinsonism in frontotemporal dementia according to
mechanisms from postmortem studies. J Neurochem 138 subtypes. J Neurol Sci 372: 51–6.
(Suppl 1): 54–70.
Purandare N, Burns A, Morris J, et al. (2012) Association of
Mackenzie IR, Munoz DG, Kusaka H, et al. (2011) Distinct cerebral emboli with accelerated cognitive deterioration
subtypes of FTLD-FUS. Acta Neuropathol 121: 207–18. in Alzheimer’s disease and vascular dementia. Am J
Maloney B, Lahiri DK (2016) Epigenetics of dementia: Psychiatry 169: 300–8.
understanding the disease as a transformation rather than Ransohoff RM (2016) How neuroinflammation contributes to
a state. Lancet Neurol 15: 760–74. neurodegeneration. Science 353: 777–83.
McCarter S, St Louis EK, Boeve BF (2016) Sleep disturbances in Raz L, Knoefel J, Bhaskar K (2016) The neuropathology and
frontotemporal dementia. Curr Neurol Neurosci Rep 16: 85. cerebrovascular mechanisms of dementia. J Cereb Blood
McCleery J, Cohen DA, Sharpley AL (2016) Flow Metab 36: 179–86.
Pharmacotherapies for sleep disturbances in dementia Roalf D, Moberg MJ, Turetsky BI, et al. (2017) A quantitative meta-
(review). Cochrane Database Syst Rev 11: CD009178. analysis of olfactory dysfunction in mild cognitive impairment.
McGirt MJ, Woodworth G, Coon AL, et al. (2005) Diagnosis, J Neurol Neurosurg Psychiatry 88: 226–32.
treatment, and analysis of long-term outcomes in Sachdeva A, Chandra M, Choudhary M, et al. (2016) Alcohol-
idiopathic normal-pressure hydrocephalus. Neurosurgery related dementia and neurocognitive impairment: a review
57: 699–705. study. Int J High Risk Behav Addict 5: e27976.
McKeith IG, Dickson DW, Lowe J, et al. (2005) Diagnosis and Sarro L, Tosakulwong N, Schwarz CG, et al. (2017) An
management of dementia with Lewy bodies: third report of investigation of cerebrovascular lesions in dementia with
the DLB consortium. Neurology 65: 1863–72. Lewy bodies compared to Alzheimer’s disease. Alzheimers
Meyer PT, Frings L, Rucker G, et al. (2017) 18F-FDG PET in Dement 13: 257–66.
Parkinsonism: differential diagnosis and evaluation of Schott JM, Warren JD, Barhof F, et al. (2011) Suspected early
cognitive impairment. J Nucl Med 58: 1888–98. dementia. BMJ 343: d5568.
Michel J-P (2016) Is it possible to delay or prevent age-related Schroek JL, Ford J, Conway EL, et al. (2016) Review of safety
cognitive decline? Korean J Fam Med 37: 263–6. and efficacy of sleep medicines in older adults. Clin Ther
Mioshi E, Flanagan E, Knopman D (2017) Detecting change 38: 2340–72.
with the CDR-FTLD: differences between FTLD and AD Schwartz M, Deczkowska A (2016) Neurological disease as
dementia. Int J Geriatr Psychiatry 32: 977–82. a failure of brain-immune crosstalk: the multiple faces of
Mioshi E, Hsieh S, Savage S, et al. (2010) Clinical staging and neuroinflammation. Trends Immunol 37: 668–79.
disease progression in frontotemporal dementia. Neurology Stahl SM (2017) Does treating hearing loss prevent or slow
74: 1591–7. the progress of dementia? Hearing is not all in the ears, but
Montenigro PH, Baugh CM, Daneshvar DH, et al. (2014) who’s listening? CNS Spectrums 22: 247–50.
Clinical subtypes of chronic traumatic encephalopathy: Takada LT, Kim MO, Cleveland RW, et al. (2017) Genetic
literature review and proposed research diagnostic criteria prion disease: experience of a rapidly progressive
for traumatic encephalopathy syndrome. Alz Res Ther 6: 68. dementia center in the United States and a review of the
Nalbandian A, Donkervoort S, Dec E, et al. (2011) The literature. Am J Med Genet B Neuropsychiatr Genet 174:
multiple faces of valosin-containing protein-associated 36–69.
diseases: inclusion body myopathy with Paget’s disease of Tartaglia MC, Rosen JH, Miller BL (2011) Neuroimaging in
bone, frontotemporal dementia, and amyotrophic lateral dementia. Neurotherapeutics 8: 82–92.
sclerosis. J Mol Neurosci 45: 522–31.
Thomas AJ, Attems J, Colloby SJ, et al. (2017) Autopsy
Noe E, Marder K, Bell KL, et al. (2004) Comparison of validation of 123I-FP-CIT dopaminergic neuroimaging for
dementia with Lewy bodies to Alzheimer’s disease and the diagnosis of DLB. Neurology 88: 1–8.
602
Thomas AJ, Taylor JP, McKeith I, et al. (2017) Development of Bronzuoli MR, Iacomino A, Steardo L, et al. (2016) Targeting
assessment toolkits for improving the diagnosis of Lewy neuroinflammation in Alzheimer’s disease. J Inflamm Res
body dementias: feasibility study within the DIAMOND 9: 199–208.
Lewy study. Int J Geriatr Psychiatry 32: 1280–304. Cardenas-Aguayo M. del C, Silva-Lucero, M. del C, Cortes-
Todd TW, Petrucelli L (2016) Insights into the pathogenic Ortiz M, et al. (2014) Physiological role of amyloid beta in
mechanisms of chromosome 9 open reading frame 72 neural cells: the cellular trophic activity. In Neurochemistry,
(C9orf72) repeat expansions. J Neurochem 138 (Suppl 1): Heinbockel T (ed.) InTech Open Access Publisher,
145–62. doi:10.5772/57398.
Togo T, Isojima D, Akatsu H, et al. (2005) Clinical features of Chakraborty A, de Wit NM, van der Flier WM, et al. (2017)
argyrophilic grain disease: a retrospective survey of cases The blood brain barrier in Alzheimer’s disease. Vasc
with neuropsychiatric symptoms. Am J Geriatr Psychiatry Pharmacol 89: 12–18.
13: 1083–91. Chetelat G, Villemagne VL, Villain N, et al. (2012) Accelerated
Tsai RM, Boxer AL (2016) Therapy and clinical trials in cortical atrophy in cognitively normal elderly with high
frontotemporal dementia: past, present, and future. J β-amyloid deposition. Neurology 78: 477–84.
Neurochem 138 (Suppl 1): 211–21. Citron M (2004) β-Secretase inhibition for the treatment
Tyebi S, Hannan AJ (2017) Synaptopathic mechanisms of Alzheimer’s disease: promise and challenge. Trends
of neurodegeneration and dementia: insights from Pharmacol Services 25: 92–7.
Huntington’s disease. Prog Neurobiol 153: 18–45. Clark CM, Schneider JA, Bedell BJ, et al. (2011) Use of
Weishaupt JH, Hyman T, Dikic I (2016) Common florbetapir-PET for imaging β-amyloid pathology. JAMA
molecular pathways in amyotrophic lateral sclerosis and 305: 275–83.
frontotemporal dementia. Trends Mol Med 22: 769–83. Cummings JL (2011) Biomarkers in Alzheimer’s disease drug
Wenning GK, Tison F, Seppi K, et al. (2004) Development and development. Alzheimers Dement 7: e13–44.
validation of the Unified Multiple System Atrophy Rating Cummings J (2011) Alzheimer’s disease: clinical trials and
Scale (UMSARS). Mov Disord 19: 1391–402. the amyloid hypothesis. Ann Acad Med Singapore 40:
Williams DR, Holton JL, Strand C, et al. (2007) Pathological 304–6.
tau burden and distribution distinguishes progressive Deutsch SI, Rosse RB, Deutsch LH (2006) Faulty regulation
supranuclear palsy-parkinsonism from Richardson’s of tau phosphorylation by the reelin signal transduction
syndrome. Brain 130 (Pt 6): 1566–76. pathway is a potential mechanism of pathogenesis
Wimo A, Guerchet M, Ali GC, et al. (2017) The worldwide and therapeutic target in Alzheimer’s disease. Eur
costs of dementia 2015 and comparisons with 2010. Neuropsychopharmacol 16: 547–51.
Alzheimers Dement 13: 1–7. Dickerson BC, Stoub TR, Shah RC, et al. (2011) Alzheimer-
Xu Y, Yang J, Shang H (2016) Meta-analysis of risk factors for signature MRI biomarker predicts AD dementia in
Parkinson’s disease dementia. Transl Neurodegen 5: 1–8. cognitively normal adults. Neurology 76: 1395–402.
Yang L, Yan J, Jin X, et al. (2016) Screening for dementia Ewers M, Sperling RA, Klunk WE, Weiner MW, Hampel H
in older adults: comparison of Mini-Mental State (2011) Neuroimaging markers for the prediction and early
Examination, Min-Cog, Clock Drawing Test and AD8. diagnosis of Alzheimer’s disease dementia. Trends Neurosci
PLOS ONE 11: e0168949. 34: 430–42.
Yang W, Yu S (2017) Synucleinopathies: common features and Fajardo VA, Fajardo VA, LeBlanc PJ, et al. (2018)
hippocampal manifestations. Cell Mol Life Sci 74: 8466–80. Examining the relationship between trace lithium in
drinking water and the rising rates of age-adjusted
Alzheimer’s disease mortality in Texas. J Alzheimers Dis
Dementia/Memory/Cognition/Amyloid/ 61: 425–34.
Alzheimer Fleisher AS, Chen K, Liu X, et al. (2011) Using positron
Albert MS, DeKosky ST, Dickson D, et al. (2011) The diagnosis emission tomography and florbetapir F 18 to image
of mild cognitive impairment due to Alzheimer’s disease: amyloid in patients with mild cognitive impairment
recommendations from the National Institute on Aging or dementia due to Alzheimer disease. Arch Neurol 68:
and Alzheimer’s Association Workgroup. Alzheimers 1404–11.
Dement 7: 270–9. Forster S, Grimmer T, Miederer I, et al. (2012) Regional
Arbor SC, LaFontaine M, Cumbay M (2016) Amyloid-beta expansion of hypometabolism in Alzheimer’s disease
Alzheimer targets: protein processing, lipid rafts, and follows amyloid deposition with temporal delay. Biol
amyloid-beta pores. Yale J Biol Med 89: 5–21. Psychiatry 71: 792–7.
603
Gehres SW, Rocha A, Leuzy A, et al. (2016) Cognitive Lieberman A, Deep A, Shi J, et al. (2018) Downward finger
intervention as an early nonpharmacological strategy in displacement distinguishes Parkinson disease dementia
Alzheimer’s disease: a translational perspective. Front from Alzheimer disease. Int J Neurosci 128: 151–4.
Aging Neurosci 8: 1–4. Lim JK, Li QX, He Z, et al. (2016) The eye as a biomarker for
Gitlin LN, Hodgson NA (2016) Who should assess the needs Alzheimer’s disease. Front Neurosci 10: 1–14.
of and care for a dementia patient’s caregiver? AMA J Ethics MacLeod R, Hillert EK, Cameron RT, et al. (2015) The role
18: 1171–81. and therapeutic targeting of α-, β-, and γ-secretase in
Godyn J, Jonczyk J, Panek D, et al. (2016) Therapeutic Alzheimer’s disease. Future Sci OA 1: FS011.
strategies for Alzheimer’s disease in clinical trials. Mallik A, Drzezga A, Minoshima S (2017) Clinical amyloid
Pharmacol Rep 68: 127–38. imaging. Semin Nucl Med 47: 31–43.
Gomar JJ, Bobes-Bascaran MT, Conejero-Goldberg C, et al. Marciani DJ (2015) Alzheimer’s disease vaccine development:
(2011) Utility of combinations of biomarkers, cognitive a new strategy focusing on immune modulation. J
markers, and risk factors to predict conversion from mild Neuroimmunol 287: 54–63.
cognitive impairment to Alzheimer disease in patients in
the Alzheimer’s Disease Neuroimaging Initiative. Arch Gen McKhann GM, Knopman DS, Chertkow H (2011) The
Psychiatry 68: 961–9. diagnosis of dementia due to Alzheimer’s disease:
recommendations from the National Institute on Aging
Grimmer T, Tholen S, Yousefi BH, et al (2010) Progression of and the Alzheimer’s Association Workgroup. Alzheimers
cerebral amyloid load is associated with the apolipoprotein E Dement 7: 263–9.
ε4 genotype in Alzheimer’s disease. Biol Psychiatry 68: 879–84.
Mendiola-Precoma J, Berumen LC, Padilla K, et al. (2016)
Gurnani AS, Gavett BE (2017) The differential effects of Therapies for prevention and treatment of Alzheimer’s
Alzheimer’s disease and Lewy body pathology on cognitive disease. BioMed Res Int 2016: 2589276.
performance: a meta-analysis. Neuropsychol Rev 27: 1–17.
Panza F, Solfrizzi V, Seripa D, et al. (2016) Tau-centric
Harrison JR, Owen MJ (2016) Alzheimer’s disease: the amyloid targets and drugs in clinical development for the
hypothesis on trial. Br J Psychiatry 208: 1–3. treatment of Alzheimer’s disease. BioMed Res Int 2016:
Herukka SK, Simonsen AH, Andreasen N, et al. (2017) 3245935.
Recommendations for CSF AD biomarkers in the diagnostic Pascoal TA, Mathotaarachchi S, Shin M, et al. (2017)
evaluation of MCI. Alzheimers Dement 13: 285–95. Synergistic interaction between amyloid and tau predicts
Jack CR Jr., Albsert MS, Knopman DS, et al. (2011) the progression to dementia. Alzheimers Dement 13:
Introduction to the recommendations from the National 644–53.
Institute on Aging and the Alzheimer’s Association Rabinovici GD, Rosen HJ, Alkalay A, et al. (2011) Amyloid vs.
Workgroup on diagnostic guidelines for Alzheimer’s FDG-PET in the differential diagnosis of AD and FTLD.
disease. Alzheimers Dement 7: 257–62. Neurology 77: 2034–42.
Jack CR Jr., Lowe VJ, Weigand SD, et al. (2009) Serial PIB and Rapp MA, Schnaider-Beeri M, Grossman HT, et al. (2006)
MRI in normal, mild cognitive impairment and Alzheimer’s Increased hippocampal plaques and tangles in patients
disease: implications for sequence of pathological events in with Alzheimer disease with a lifetime history of major
Alzheimer’s disease. Brain 132: 1355–65. depression. Arch Gen Psychiatry 63: 161–7.
Jonsson T, Atwal JK, Steinberg S, et al. (2012) A mutation in Reisberg B, Doody R, Stöffle A, et al. (2003) Memantine in
APP protects against Alzheimer’s disease and age-related moderate-to-severe Alzheimer’s disease. New Engl J Med
cognitive decline. Nature 488: 96–9. 348: 1333–41.
Kokjohn TA, Maarouf CL, Roher AE (2012) Is Alzheimer’s Ritter AR, Leger GC, Miller JB, et al. (2017)
disease amyloidosis a result of a repair mechanism gone Neuropsychological testing in pathologically verified
astray? Alzheimers Dement 8: 574–83. Alzheimer’s disease and frontotemporal dementia.
Kovari E, Herrmann FR, Hof PR, et al. (2013) The relationship Alzheimer Dis Assoc Disord 31: 187–91.
between cerebral amyloid angiopathy and cortical Rodrigue KM, Kennedy KM, Devous MD Sr., et al. (2012)
microinfarcts in brain ageing and Alzheimer’s disease. Β-Amyloid burden in healthy aging. Regional distribution
Neuropathol Appl Neurobiol 39: 498–509. and cognitive consequences. Neurology 78: 387–95.
Li Y, Li Y, Li X, et al. (2017) Head injury as a risk factor for Ruthirakuhan M, Herrmann N, Seuridjan I, et al. (2016)
dementia and Alzheimer’s disease: a systematic review and Beyond immunotherapy: new approaches for disease
meta-analysis of 32 observational studies. PLOS ONE 12: modifying treatments for early Alzheimer’s disease. Expert
e0169650. Opin Pharmacother 17: 2417–29.
604
Sabbagh MN, Schauble B, Anand K, et al. (2017) Histopathology Wishart HA, Saykin AJ, McAllister TW, et al. (2006) Regional
and florbetaben PET in patients incorrectly diagnosed with brain atrophy in cognitively intact adults with a single
Alzheimer’s disease. J Alzheimers Dis 56: 441–6. APOE ε4 allele. Neurology 67: 1221–4.
Scheinin NM, Aalto S, Kaprio J, et al. (2011) Early detection of Wolk DA, Grachev ID, Buckley C, et al. (2011) Association
Alzheimer disease. Neurology 77: 453–60. between in vivo fluorine 18-labeled flutemetamol
Sharma N, Singh AN (2016) Exploring biomarkers for amyloid positron emission tomography imaging and in
Alzheimer’s disease. J Clin Diag Res 10: KE01–06. vivo cerebral cortical histopathology. Arch Neurol 68:
1398–403.
Simonsen AH, Herukka SK, Andreasen N, et al. (2017)
Recommendations for CSF AD biomarkers in the Yaffe K, Tocco M, Petersen RC, et al. (2012) The epidemiology
diagnostic evaluation of dementia. Alzheimers Dement 13: of Alzheimer’s disease: laying the foundation for drug
285–95. design, conduct, and analysis of clinical trials. Alzheimers
Dement 8: 237–42.
Sperling RA, Aisen PS, Beckett LA, et al. (2011) Toward
defining the preclinical stages of Alzheimer’s disease: Yan R (2016) Stepping closer to treating Alzheimer’s disease
recommendations from the National Institute on Aging patients with BACE1 inhibitor drugs. Transl Neurodegen
and the Alzheimer’s Association Workgroup. Alzheimers 5: 13.
Dement 7: 280–92. Yeh HL, Tsai SJ (2008) Lithium may be useful in the
Spies PE, Claasen JA, Peer PG, et al. (2013) A prediction prevention of Alzheimer’s disease in individuals at risk of
model to calculate probability of Alzheimer’s disease using presenile familial Alzheimer’s disease. Med Hypotheses 71:
cerebrospinal fluid biomarkers. Alzheimers Dement 9: 948–51.
262–8.
Spies PE, Verbeek MM, van Groen T, et al. (2012) Reviewing Behavioral Symptoms of Dementia
reasons for the decreased CSF Abeta42 concentration in Alexopoulos GS (2003) Role of executive function in late life
Alzheimer disease. Front Biosci (Landmark Ed) 17: 2024–34. depression. J Clin Psychiatry 64 (Suppl 14): 18–23.
Spira AP, Gottesman RF (2017) Sleep disturbance: an Ballard C, Oyebode F (1995) Psychotic symptoms in patients
emerging opportunity for Alzheimer’s disease prevention? with dementia. Int J Geriatr Psychiatry 10: 743–52.
Int Psychogeriatr 29: 529–31.
Ballard C, Neill D, O’Brien J, et al. (2000) Anxiety, depression
Tarawneh R, Holtzman DM (2012) The clinical problem and psychosis in vascular dementia: prevalence and
of symptomatic Alzheimer disease and mild cognitive associations. J Affect Disord 59: 97–106.
impairment. Cold Spring Harbor Perspect Med 2: a006148.
Bao AM, Meynen G, Swaab DF (2008) The stress system in
Tariot PN, Aisen PS (2009) Can lithium or valproate untie depression and neurodegeneration: focus on the human
tangles in Alzheimer’s disease? J Clin Psychiatry 70: 919–21. hypothalamus. Brain Res Rev 57: 531–53.
Uzun S, Kozumplik O, Folnegovic-Smalc V (2011) Alzheimer’s Barnes DE, Yaffe K, Byers AL, et al. (2012) Midlife vs. late-life
dementia: current data review. Coll Antropol 35: 1333–7. depressive symptoms and risk of dementia. Arch Gen
Venkataraman A, Kalk N, Sewell G, et al. (2017) Alcohol and Psychiatry 6: 493–8.
Alzheimer’s disease: does alcohol dependence contribute Bassetti CL, Bargiotas P (2018) REM sleep behavior disorder.
to beta-amyloid deposition, neuroinflammation and Front Neurol Neurosci 41: 104–16.
neurodegeneration in Alzheimer’s disease? Alcohol
Bennett S, Thomas AJ (2014) Depression and dementia: cause,
Alcoholism 52: 151–8.
consequence or coincidence? Maturita 79:184–90.
Villemagne VL, Doré V, Bourgeat P, et al. (2017) Aβ-amyloid
Buoli M, Serati M, Caldiroli A, et al. (2017) Pharmacological
and tau imaging in dementia. Semin Nucl Med 47: 75–88.
management of psychiatric symptoms in frontotemporal
Wagner M, Wolf S, Reischies FM, et al. (2012) Biomarker dementia: a systematic review. J Geriatr Psychiatry 30:
validation of a cued recall memory deficit in prodromal 162–9.
Alzheimer disease. Neurology 78: 379–86.
Burns A, Jacoby R, Levy R (1990) Psychiatric phenomena
Weintraub S, Wicklund AH, Salmon DP (2012) The in Alzheimer’s disease. II: disorders of perception. Br J
neuropsychological profile of Alzheimer disease. Cold Psychiatry 157: 76–81, 92–4.
Spring Harb Perspect Med 2 :a006171.
Canevelli M, Valleta M, Trebbastoni A, et al. (2016)
Williams MM, Xiong C, Morris JC, Galvin JE (2006) Survival Sundowning in dementia: clinical relevance,
and mortality differences between dementia with Lewy pathophysiological determinants, and therapeutic
bodies vs. Alzheimer’s disease. Neurology 67: 1935–41. approaches. Front Med (Lausanne) 3: 73.
605
Caraci F, Copani A, Nicoletti F, et al. (2010) Depression and Garay RP, Grossberg GT (2017) AVP-786 for the treatment of
Alzheimer’s disease: neurobiological links and common agitation in dementia of the Alzheimer’s type. Expert Opin
pharmacological targets. Eur J Pharmacol 626: 64–71. Invest Drugs 26: 121–32.
Cohen-Mansfield J, Billig N (1986) Agitated behaviors in the Geerlings MI, den Hijer T, Koudstaal PJ, et al. (2008) History
elderly. I. A conceptual review. J Am Geriatr Soc 34: 711–21. of depression, depressive symptoms, and medial temporal
Corcoran C, Wong ML, O’Keane V (2004) Bupropion in the lobe atrophy and the risk of Alzheimer’s disease. Neurology
management of apathy. J Psychopharm 18: 133–5. 70: 1258–64.
Cummings J, Kohegyi E, Mergel V, et al. (2018) Efficacy and Gessing LV, Sondergard L, Forman JL, et al. (2009)
safety of flexibly dosed brexpiprazole for the treatment Antidepressants and dementia. J Affect Disord 117: 24–9.
of agitation in Alzheimer type dementia: a randomized, Goldman JG, Holden S (2014) Treatment of psychosis and
double blind fixed dose 12 week placebo controlled global dementia in Parkinson’s disease. Curr Treat Options Neurol
clinical trial. Abstract for the American Association of 16: 281.
Geriatric Psychiatry, Honolulu, Hawaii. Goodarzi Z, Mele B, Guo S, et al. (2016) Guidelines for
Cummings JL, Lyketsos CG, Peskind ER, et al. (2015) Effect of dementia or Parkinson’s disease with depression or anxiety:
dextromethorphan–quinidine on agitation in patients with a systematic review. BMC Neurol 16(1): 244.
Alzheimer’s disease dementia: a randomized clinical trial. Grossberg G, Kohegyi E, Amatniek J, et al. (2018) Efficacy
JAMA 314: 1242–54. and safety of fixed dose brexpiprazole for the treatment
Dennis M, Shine L, John A, et al. (2017) Risk of adverse of agitation in Alzheimer type dementia: a randomized,
outcomes for older people with dementia prescribed double blind fixed dose 12-week placebo controlled global
antipsychotic medication: a population based e-cohort clinical trial. Abstract for the American Association of
study. Neurol Ther 6: 57–77. Geriatric Psychiatry, Honolulu, Hawaii.
Ducharme S, Price BH, Dickerson BC (2018) Apathy: a Hacksell U, Burstein ES, McFarland K, et al. (2014) On the
neurocircuitry model based on frontotemporal dementia. J discovery and development of pimavanserin: a novel drug
Neural Neurosurg Psychiatry 89: 389–96. candidate for Parkinson’s disease. Neurochem Res 39:
Evan C, Weintraub D (2010) Case for and against specificity of 2008–17.
depression in Alzheimer’s disease. Psychiatry Clin Neurosci Hongiston K, Hallikainen I, Seldander T, et al. (2018) Quality
64: 358–66. of life in relation to neuropsychiatric symptoms in
Farina N, Morrell L, Banerjee S (2017) What is the therapeutic Alzheimer’s disease: 5-year prospective ALSOVA cohort
value of antidepressants in dementia? A narrative review. study. Int J Geriatr Psychiatry 33: 47–57.
Geriatr Psychiatry 32: 32–49. Jack Jr. CR, Wiste HJ, Weigland SD, et al. (2017) Defining
Fernandez-Matarrubia M, Matias-Guiu JA, Cabrera-Martin imaging biomarker cut point for brain aging and
MN, et al. (2018) Different apathy clinical profile and neural Alzheimer’s disease. Alzheimers Dement 13: 205–16.
correlates in behavioral variant frontotemporal dementia Johnson DK, Watts AS, Chapin BA, et al. (2011)
and Alzheimer’s disease. Int J Geriatr Psychiatry 33: 141–50. Neuropsychiatric profiles in dementia. Alzheimer Dis Assoc
Fernandez-Matarrubia M, Matias-Guiu JA, Moreno-Ramos T, Disord 25: 326–32.
et al. (2016) Validation of the Lille’s Apathy Rating Scale in Kales, HC, Kim HM, Zivin K, et al. (2012) Risk of mortality
very mild to moderate dementia. Am J Geriatr Psychiatry among individual antipsychotics in patients with dementia.
24: 517–27. Am J Psychiatry 169: 71–9.
Ford AH, Almeida OP (2017) Management of depression in Kales HC, Lyketsos CG, Miller EM, et al. (2019) Management
patients with dementia: is pharmacological treatment of behavioral and psychological symptoms in people with
justified? Drugs Aging 34: 89–95. Alzheimer’s disease: an international Delphi consensus. Int
Fraker J, Kales HC, Blazek M (2014) The role of the Psychogeriatr 31: 83–90.
occupational therapist in the management of Kok RM, Reynolds CF (2017) Management of depression in
neuropsychiatric symptoms of dementia in clinical older adults: a review. JAMA 317: 2114–22.
settings. Occup Ther Health Care 28: 4–20. Kong EH (2005) Agitation in dementia: concept clarification. J
Frakey LL, Salloway S, Buelow M, Malloy P (2012) A Adv Nurs 52: 526–36.
randomized, double-blind, placebo-controlled trial of Kumfor F, Zhen A, Hodges JR, et al. (2018) Apathy in
modafinil for the treatment of apathy in individuals with Alzheimer’s disease and frontotemporal dementia:
mild-to-moderate Alzheimer’s disease. J Clin Psychiatry 73: distinct clinical profiles and neural correlates. Cortex 103:
796–801. 350–9.
606
Lanctot KL, Amatniek J, Ancoli-Israel S, et al. (2017) O’Gorman C (2020) Advance 1 phase 2/3 trial of AXS-05 in
Neuropsychiatric signs and symptoms of Alzheimer’s Alzheimer’s disease agitation, personal communication.
disease: new treatment paradigms. Alzheimers Dement Porsteinsson AP, Antonsdottir IM (2017) An update on the
(NY) 3: 440–9. advancements in the treatment of agitation in Alzheimer’s
Lee GJ, Lu PH, Hua X, et al. (2012) Depressive symptoms disease. Expert Opin Pharmacother 18: 611–20.
in mild cognitive impairment predict greater atrophy in Preuss UW, Wong JW, Koller G (2016) Treatment of behavioral
Alzheimer’s disease-related regions. Biol Psychiatry 71: and psychological symptoms of dementia: a systematic
814–21. review. Psychiatr Pol 50: 679–715.
Leroi I, Voulgari A, Breitner JC, et al. (2003) The epidemiology Rosenberg PB, Nowrangi MA, Lyketsos CG (2015)
of psychosis in dementia. Am J Geriatr Psychiatry 11: Neuropsychiatric symptoms in Alzheimer’s disease: what
83–91. might be associated brain circuits? Mol Aspects Med 43–44:
Lochhead JD, Nelson MA, Maguire GA (2016) The treatment 25–37.
of behavioral disturbances and psychosis associated with Sadowsky CH, Galvin JE (2012) Guidelines for the
dementia. Psychiatr Pol 50: 311–22. management of cognitive and behavioral problems in
Lopez OL, Becker JT, Sweet RA, et al. (2003) Psychiatric dementia. J Am Board Fam Med 25: 350–66.
symptoms vary with the severity of dementia in probable Schneider LS, Dagerman KS, Insel P (2005) Risk of death with
Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 15: atypical antipsychotic drug treatment for dementia. JAMA
346–53. 294: 1935–43.
Lyketsos CG, Carillo MC, Ryan JM, et al. (2011) Siever LJ (2008) Neurobiology of aggression and violence. Am
Neuropsychiatric symptoms in Alzheimer’s disease. J Psychiatry 165: 429–42.
Alzheimers Dement 7: 532–9.
Sink KM, Holden KF, Yaffe K (2005) Pharmacological
Lyketsos CG, Lopez O, Jones B, et al. (2002) Prevalence treatment of neuropsychiatric symptoms of dementia.
of neuropsychiatric symptoms in dementia and mild JAMA 293: 596–608.
cognitive impairment: results from the cardiovascular
health study. JAMA 288: 1475–83. Stahl SM (2016) Parkinson’s disease psychosis as a serotonin-
dopamine imbalance syndrome. CNS Spectrums 21: 271–5.
Lyketsos CG, Steinberg M, Tschanz JT, et al. (2000) Mental and
behavioral disturbances in dementia: findings from the Stahl SM (2016) Mechanism of action of pimavanserin in
Cache County Study on memory in aging. Am J Psychiatry Parkinson’s disease psychosis: targeting serotonin 5HT2A
157: 704–7. and 5HT2C receptors. CNS Spectrums 21: 271–5.
Macfarlane S, O’Connor D (2016) Managing behavioural Stahl SM (2018) New hope for Alzheimer’s dementia as
and psychological symptoms in dementia. Aust Prescr 39: prospects for disease modification fade: symptomatic
123–5. treatments for agitation and psychosis. CNS Spectrums 23:
291–7.
Marin RS, Fogel BS, Hawkins J, et al. (1995) Apathy: a
treatable symptom. J Neuropsychiatry 7: 23–30. Stahl SM, Morrissette DA, Cummings M, et al. (2014)
California State Hospital violence assessment and treatment
Maust DT, Kim HM, Seyfried LS, et al. (2015) Antipsychotics, (Cal-VAT) guidelines. CNS Spectrums 19: 449–65.
other psychotropics, and the risk of death in patients with
dementia: number needed to harm. JAMA Psychiatry 72: Torrisi M, Cacciola A, Marra A, et al. (2017) Inappropriate
438–45. behaviors and hypersexuality in individuals with dementia:
an overview of a neglected issue. Geriatr Gerontol Int 17:
Moraros J, Nwankwo C, Patten SB, et al. (2017) The 865–74.
association of antidepressant drug usage with cognitive
impairment or dementia, including Alzheimer disease: a Tsuno N, Homma A (2009) What is the association between
systematic review and meta-analysis. Depress Anxiety 34: depression and Alzheimer’s disease? Exp Rev Neurother 9:
217–26. 1667–76.
Mossello E, Boncinelli M, Caleri V, et al. (2008) Is Van der Linde RM, Dening T, Stephan BC, et al. (2016)
antidepressant treatment associated with reduced cognitive Longitudinal course of behavioural and psychological
decline in Alzheimer’s disease? Dement Geriatr Cogn symptoms of dementia: systematic review. Br J Psychiatry
Disord 25: 372–9. 209: 366–77.
Norgaard A, Jensen-Dahm C, Gasse C, et al. (2017) Van der Spek K, Gerritsen DL, Smallbrugge M, et al. (2016)
Psychotropic polypharmacy in patients with dementia: Only 10% of the psychotropic drug use for neuropsychiatric
prevalence and predictors. J Alz Dis 56: 707–16. symptoms in patients with dementia is fully appropriate:
the PROPER I-study. Int Psychogeriatr 28: 1589–95.
607
Vigen CLP, Mack WJ, Keefe RSE, et al. (2011) Cognitive Greeven A, van Balkom AJLM, van Rood YR, van
effects of atypical antipsychotic medications in patients Oppen P, Spinhoven P (2006) The boundary between
with Alzheimer’s disease: outcomes from CATIE-AD. Am J hypochondriasis and obsessive–compulsive disorder:
Psychiatry 168: 831–9. a cross-sectional study from the Netherlands. J Clin
Volicer L, Citrome L, Volavka J (2017) Measurement of Psychiatry 67: 1682–9.
agitation and aggression in adult and aged neuropsychiatric Kisely S, Hall K, Siskind D, et al. (2014) Deep brain stimulation
patients: review of definitions and frequently used for obsessive compulsive disorder: a systematic review and
measurement scales. CNS Spectrums 22: 407–14. meta analysis. Psychol Med 44: 3533–42.
Wisniewski T, Drummond E (2016) Developing therapeutic Menzies L, Chamberlain SR, Laird AR, et al. (2008) Integrating
vaccines against Alzheimer’s disease. Expert Rev Vaccines evidence from neuroimaging and neuropsychological
15: 401–15. studies of obsessive–compulsive disorder: the orbito-
Wuwongse S, Chang RC, Law AC (2010) The putative fronto-striatal model revisited. Neurosci Biobehav Rev 32:
neurodegenerative links between depression and 525–49.
Alzheimer’s disease. Prog Neurobiol 92: 362–75. Milad MR, Rauch SL (2012) Obsessive–compulsive disorder:
Zhang Y, Cai J, An L, et al. (2017) Does music therapy enhance beyond segregated cortico-striatal pathways. Trends Cogn
behavioral and cognitive function in elderly dementia Sci 16: 43–51.
patients? A systematic review and metaanalysis.Ageing Res Rasmussen SA, Noren G, Greenberg BD (2018) Gamma
Rev 35: 1–11. ventral capsulotomy in intractable obsessive–compulsive
disorder. Biol Psychiatry 84: 355–64.
Chapter 13 (Impulsivity, Richter MA, de Jesus DR, Hoppenbrouwers S, et al.

(2012) Evidence for cortical inhibitory and excitatory
Compulsivity, and Addiction) dysfunction in obsessive compulsive disorder.
Neuropsychopharmacology 37: 1144–51.
OCD Wilhelm S, Buhlmann U, Tolin DF (2008) Augmentation
of behavior therapy with D-cycloserine for obsessive
Bloch MH, Wasylink S, Landeros A, et al. (2012) Effects of
compulsive disorder. Am J Psychiatry 165: 335–41.
ketamine in treatment refractory obsessive compulsive
disorder. Biol Psychiatry 72: 964–70. Yin D, Zhang C, Lv Q, et al. (2018) Dissociable frontostriatal
connectivity: mechanism and predictor of the clinical
Chamberlain SR, Menzies L, Hampshire A, et al. (2008)
efficacy of capsulotomy in obsessive compulsive disorder.
Orbitofrontal dysfunction in patients with obsessive-
Biol Psychiatry 84: 926–36.
compulsive disorder and their unaffected relatives. Science
321: 421–2.
Dougherty DD, Brennan BP, Stewart SE, et al. (2018) Substance Abuse: General
Neuroscientifically informed formulation and treatment Bedi G (2018) 3, 4-Methylenedioxymethamphetamine as a
planning for patients with obsessive compulsive disorder: a psychiatric treatment. JAMA Psychiatry 75: 419–20.
review. JAMA Psychiatry 75: 1081–7. Clark L, Robbins TW, Ersche KD, Sahakian BJ (2006)
Fineberg NA, Potenza MN, Chamberlain SR, et al. (2010) Reflection impulsivity in current and former substance
Probing compulsive and impulsive behaviors, from users. Biol Psychiatry 60: 515–22.
animal models to endophenotypes: a narrative review. Dalley JW, Everitt BJ (2009) Dopamine receptors in the
Neuropsychopharmacology 35: 591–604. learning, memory and drug reward circuitry. Semin Cell
Gillan CM, Papmeyer M, Morein-Zamir S, et al. (2011) Dev Biol 20: 403–10.
Disruption in the balance between goal-directed behavior Ersche KD, Turton AJ, Pradhan S, Bullmore ET, Robbins TW
and habit learning in obsessive–compulsive disorder. Am J (2010) Drug addiction endophenotypes: impulsive versus
Psychiatry 168: 719–26. sensation-seeking personality traits. Biol Psychiatry 68:
Greenberg BD, Malone DA, Friehs GM, et al. (2006) Three year 770–3.
outcomes in deep brain stimulation for highly resistant Field M, Marhe R, Franken I (2014) The clinical relevance of
obsessive–compulsive disorder. Neuropsychopharmacology attentional bias in substance use disorders. CNS Spectrums
31: 2384–93. 19: 225–30.
Greenberg BD, Rauch SL, Haber SN (2010) Invasive circuitry- Haber SN, Knutson B (2010) The reward circuit:
based neurotherapeutics: stereotactic ablation and deep brain linking primate anatomy and human imaging.
stimulation for OCD. Neuropsychopharmacology 35: 317–36. Neuropsychopharmacology 35: 4–26.
608
Koob GF, Le Moal M (2008) Addiction and the brain DeWitte P, Littleton J, Parot P, Koob G (2005) Neuroprotective
antireward system. Ann Rev Psychol 59: 29–53. and abstinence-promoting effects of acamprosate.
Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Elucidating the mechanism of action. CNS Drugs 6:
Neuropsychopharmacology 35: 217–38. 517–37.
Mandyam CD, Koob GF (2012) The addicted brain craves Garbutt JC, Kranzler HR, O’Malley SS, et al. (2005) Efficacy
new neurons: putative role for adult-born progenitors in and tolerability of long-acting injectable naltrexone for
promoting recovery. Trends Neurosci 35: 250–60. alcohol dependence. A randomized controlled trial. JAMA
293: 1617–25.
Nestler EJ (2005) Is there a common molecular pathway for
addiction? Nat Neurosci 11: 1445–9. Kiefer F, Wiedemann K (2004) Combined therapy: what does
acamprosate and naltrexone combination tell us? Alcohol
Nutt DJ, Hughes AL, Erritzoe D, et al. (2015) The dopamine Alcohol 39: 542–7.
theory of addiction: 40 years of highs and lows. Nat Rev
Neurosci 16: 305–22. Kiefer F, Jahn H, Tarnaske T, et al. (2003) Comparing and
combining naltrexone and acamprosate in relapse
Schneider S, Peters J, Bromberg U, et al. (2012) Risk taking prevention of alcoholism. Arch Gen Psychiatry 60: 92–9.
and the adolescent reward system: a potential common
link to substance abuse. Am J Psychiatry 169: 39–46. Mann K, Bladstrom A, Torup T, et al. (2013) Extending the
treatment options in alcohol dependence: a randomized
Solway A, Gu X, Montague PR (2017) Forgetting to be controlled study of as-needed nalmefene. Biol Psychiatry
addicted: reconsolidation and the disconnection of things 73: 706–13.
past. Biol Psychiatry 82: 774–5
Martinez D, Gil R, Slifstein M, et al. (2005) Alcohol
Volkow ND, Wang GJ, Fowler JS, Tomasi D, Telang F (2011) dependence is associated with blunted dopamine
Addiction: beyond dopamine reward circuitry. Proc Natl transmission in the ventral striatum. Biol Psychiatry 58:
Acad Sci USA 108: 15037–42. 779–86.
Mason BJ (2003) Acamprosate and naltrexone treatment
Substance Abuse: Alcohol for alcohol dependence: an evidence-based risk-benefits
Anton RF, O’Malley SS, Ciraulo DA, et al. (2006) Combined assessment. Eur Neuropsychopharmacol 13: 469–75.
pharmacotherapies and behavioral interventions for Mason BJ (2005) Acamprosate in the treatment of alcohol
alcohol dependence. The combine study: a randomized dependence. Expert Opin Pharmacother 6: 2103–15.
controlled trial. JAMA 295: 2003–17.
Mason BJ, Goodman AM, Chabac S, Lehert P (2006) Effect of
Anton RF, Pettinati H, Zweben A, et al. (2004) A multi site oral acamprosate on abstinence in patients with alcohol
dose ranging study of nalmefene in the treatment of dependence in a double-blind, placebo-controlled trial: the
alcohol dependence. J Clin Psychopharmacol 24: 421–8. role of patient motivation. J Psychiatr Res 40: 382–92.
Braus DH, Schumann G, Machulla HJ, Bares R, Mann K (2005) Netzeband JG, Gruol DL (1995) Modulatory effects of acute
Correlation of stable elevations in striatal μ-opioid receptor ethanol on metabotropic glutamate responses in cultured
availability in detoxified alcoholic patients with alcohol Purkinje neurons. Brain Res 688: 105–13.
craving. A positron emission tomography study using carbon
O’Brien CO (2015) In treating alcohol use disorders, why
11-labeled carfentanil. Arch Gen Psychiatry 62: 57–64.
not use evidence-based treatment? Am J Psychiatry 172:
Crevecoeur D, Cousins SJ, Denering L, et al. (2018) 305–7.
Effectiveness of extended release naltrexone to reduce
Palpacuer C, Duprez R, Huneau A, et al. (2017)
alcohol cravings and use behaviors during treatment and at
Pharmacologically controlled drinking in the treatment
follow-up. J Subst Abuse Treat 85: 105–8.
of alcohol dependence or alcohol use disorders: a
Dahchour A, DeWitte P (2003) Effects of acamprosate on systematic review with direct and network meta analyses
excitatory amino acids during multiple ethanol withdrawal on nalmefene, naltrexone, acamprosate, baclofen and
periods. Alcohol Clin Exp Res 3: 465–70. topiramate. Addiction 113: 220–37.
Dakwar E, Levin F, Hart CL, et al. (2020) A single ketamine Petrakis IL, Poling J, Levinson C (2005) Naltrexone and
infusion combined with motivational enhancement disulfiram in patients with alcohol dependence and
therapy for alcohol use disorder: a randomized comorbid psychiatric disorders. Biol Psychiatry 57:
midazolam controlled pilot study. Am J Psychiatry 172: 1128–37.
125–33.
Pettinati HM, O’Brien CP, Rabinowitz AR (2006) The status
DeWitte P (2004) Imbalance between neuroexcitatory and of naltrexone in the treatment of alcohol dependence.
neuroinhibitory amino acids causes craving for ethanol. Specific effects on heavy drinking. J Clin Psychopharmacol
Addict Behav 29: 1325–39. 26: 610–25.
609
Roozen HG, de Waart R, van der Windt DAW, et al. (2005) A Nugent SM, Morasco BJ, O’Neil ME, et al. (2017) The effects of
systematic review of the effectiveness of naltrexone in the cannabis among adults with chronic pain and an overview
maintenance treatment of opioid and alcohol dependence. of general harms: a systematic review. Ann Intern Med 167:
Eur Neuropsychopharmacol 16: 311–23. 319–31.
Smith-Bernardin S, Rowe C, Behar E, et al. (2018) Low
threshold extended release naltrexone for high utilizers Substance Abuse: Nicotine
of public services with severe alcohol use disorder: a pilot Akkus F, Ametamey SM, Treyer V, et al. (2013) Market global
study. J Subst Abuse Treat 85: 109–15. reduction in mGlutR5 receptor binding in smokers and
Soyka M (2014) Nalmefene for the treatment of alcohol ex smokers determined by 11C-ABP688 positron emission
dependence: a current update. Int J Neuropsychopharmacol tomography. Proc Natl Acad Sci USA 10: 737–42.
17: 675–84. Akkus F, Treyer V, Johayem A, et al. (2016) Association of
Van Amsterdam J, van den Brink W (2013) Reduced risk long-term nicotine abstinence with normal metabotropic
drinking as a viable treatment goal in problematic alcohol glutamate receptor 5 binding. Biol Psychiatry 79: 474–80.
use and alcohol dependence. J Psychopharmacol 27: Crunelle CL, Miller ML, Booij J, van den Rink W (2010) The
987–97. nicotinic acetylcholine receptor partial agonist varenicline
Wiers CE, Stelzel C, Gladwin TE, et al. (2015) Effects of and the treatment of drug dependence: a review. Eur
cognitive bias modification training on neural alcohol cue Neuropsychopharmacol 20: 69–79.
reactivity in alcohol dependence. Am J Psychiatry 172: Culbertson CS, Bramen J, Cohen MS (2011) Effect of bupropion
334–43. treatment on brain activation induced by cigarette-related
cues in smokers. Arch Gen Psychiatry 68: 505–15.
Substance Abuse: Cannabis Evins AE, Culhane MA, Alpert JE, et al. (2008) A controlled
Black N, Stockings E, Campbell G, et al. (2019) Cannabinoids trial of bupropion added to nicotine patch and behavioral
for the treatment of mental disorders and symptoms of therapy for smoking cessation in adults with unipolar
mental disorders: a systematic review and meta analysis. depressive disorders. J Clin Psychopharmacol 28: 660–6.
Lancet Psychiatry 6: 995–1010. Franklin T, Wang Z, Suh JJ, et al. (2011) Effects of varenicline
Haney M, Hill MN (2018) Cannabis and cannabinoids: on smoking cue-triggered neural and craving responses.
from synapse to society. Neuropsychopharm Rev 43: Arch Gen Psychiatry 68: 516–26.
1–212. King DP, Paciga S, Pickering E, et al. (2012) Smoking
Hindley G, Beck K, Borgan B (2020) Psychiatric symptoms cessation pharmacogenetics: analysis of varenicline
caused by cannabis constituents: a systematic review and and bupropion in placebo-controlled clinical trials.
meta-analysis. Lancet Psychiatry 7: 344–53. Neuropsychopharmacology 37: 641–50.
Hines LA, Freeman TP, Gage SH, et al. (2020) Association of Lotipour S, Mandelkern M, Alvarez-Estrada M, Brody AL
high potency cannabis use with mental and substance use (2012) A single administration of low-dose varenicline
in adolescence. JAMA Psychiatry 77: 1044–51. saturates α4β2* nicotinic acetylcholine receptors in the
human brain. Neuropsychopharmacology 37: 1738–48.
Hurd YL, Spriggs S, Alishayev J, et al. (2019) Cannabidiol for
the reduction of cue-induced craving and anxiety in drug Steinberg MB, Greenhaus S, Schmelzer AC, et al. (2009)
abstinent individuals with heroin use disorder: a double Triple-combination pharmacotherapy for medically ill
blind randomized placebo controlled trial. Am J Psychiatry smokers. A randomized trial. Ann Intern Med 150: 447–54.
176: 911–22.
James S (2020) A Clinician’s Guide to Cannabinoid Science. Substance Abuse: Opioids
Cambridge: Cambridge University Press. Bell J, Strang J (2020) Medication treatment of opioid use
Kovacs FE, Knop T, Urbanski MJ, et al. (2012) Exogenous disorder. Biol Psychiatry 87: 82–8.
and endogenous cannabinoids suppress inhibitory Chutuape MA, Jasinski DR, Finerhood MI, Stitzer ML (2001)
neurotransmission in the human neocortex. One-, three-, and six-month outcomes after brief inpatient
Neuropsychopharmacology 37: 1104–14. opioid detoxification. Am J Drug Alcohol Abuse 27: 19–44.
Mason BJ, Crean R, Goodell V, et al. (2012) A proof-of-concept Davids E, Gastpar M (2004) Buprenorphine in the treatment of
randomized controlled study of gabapentin: effects on opioid dependence. Eur Neuropsychopharmacol 14: 209–16.
cannabis use, withdrawal and executive function deficits Elkader A, Sproule B (2005) Buprenorphine: clinical
in cannabis-dependent adults. Neuropsychopharmacology pharmacokinetics in the treatment of opioid dependence.
37: 1689–98. Clin Pharmacokinet 44: 661–80.
610
Han B, Compton WM, Blanco C, et al. (2017) Prescription Sullivan MA, Bisage A, Bavlicova M, et al. (2019) A
opioid use, misuse and use disorders in US adults: 2015 randomized trial comparing extended release injectable
national survey on drug use and health. Ann Intern Med suspension and oral naltrexone, both combined with
167: 293–301. behavioral therapy, for the treatment of opioid use
Johansson J, Hirvonen J, Lovro Z, et al. (2019) Intranasal disorder. Am J Psychiatry 176: 129–37.
naloxone rapidly occupies brain mu opioid receptors Tanum L, Solli KK, Latif ZE, et al. (2017) Effectiveness
in human subjects. Neuropsychopharmacology 44: of injectable extended-release naltrexone vs. daily
1667–73. buprenorphine–naloxone for opioid dependence: a
Kowalczyk WJ, Phillips KA, Jobes ML, et al. (2015) Clonidine randomized clinical noninferiority trial. JAMA Psychiatry
maintenance prolongs opioid abstinence and decouples 74: 1197–205.
stress from craving in daily life: a randomized controlled Tiihonen J, Krupitsky E, Verbitskaya E, et al. (2012)
trial with ecological momentary assessment. Am J Naltrexone implant for the treatment of polydrug
Psychiatry 172: 760–7. dependence: a randomized controlled trial. Am J
Krupitsky E, Nunes EV, Ling W, et al. (2011) Injectable Psychiatry 169: 531–6.
extended-release naltrexone for opioid dependence: a Volkow ND (2014) America’s addiction to opioids: Heroin and
double-blind, placebo-controlled, multicenter randomized prescription drug abuse. Presented at the Senate Caucus
trial. Lancet 377: 1506–13. on International Narcotics Control. https://archives.
Lee JD, Nunes EV, Novo P, et al. (2018) Comparative drugabuse.gov/testimonies/2014/americas-addiction-to-
effectiveness of extended-release naltrexone versus opioids-heroin-prescription-drug-abuse.
buprenorphine–naloxone for opioid relapse prevention Volkow ND, Frieden TR, Hyde PS, Cha SS (2014) Medication-
(X:BOT): a multicentre, open label, randomized controlled assisted therapies: tackling the opioid-overdose epidemic.
trial. Lancet 391: 309–18. N Engl J Med 370: 2063–6.
Marquet P (2002) Pharmacology of high-dose World Health Organization (2009) Guidelines for the
buprenorphine. In Buprenorphine Therapy of Opiate Psychosocially Assisted Pharmacological Treatment of
Addiction, Kintz P and Marquet P (eds.), Totawa, NJ: Opioid Dependence. Geneva: World Health Organization.
Humana Press, 1–11.
National Institute on Drug Abuse. Drugs, brains, and behavior. Substance Abuse: Stimulants
www.drugabuse.gov/sites/default/files/soa_2014.pdf.
Bauman MH, Ayestas MA Jr., Partilla JS, et al. (2012) The
Accessed January 2018.
designer methcathinone analogs, mephedrone and
Patel B, Koston TR (2019) Keeping up with clinical advances: methylone, are substrates for monoamine transporters in
opioid use disorder. CNS Spectrums 24: 17–23. brain tissue. Neuropsychopharmacology 37, 1192–203.
Saanijoki T, Tuominen L, Tuulari JJ et al. (2018) Opioid Bradberry CW (2002) Dose-dependent effect of ethanol
release after high intensity interval training in on extracellular dopamine in mesolimbic striatum of
healthy human subjects. Neuropsychopharmacology 43: awake rhesus monkeys: comparison with cocaine across
246–54. individuals. Psychopharmacology 165: 67–76.
Smyth BP, Barry J, Keenan E, Ducray K (2010) Lapse and Collins GT, Narasimhan D, Cunningham AR, et al. (2012)
relapse following inpatient treatment of opiate dependence. Long-lasting effects of a PEGylated mutant cocaine esterase
Ir Med J 103: 176–9. (CocE) on the reinforcing and discriminative stimulus
Spagnolo PA, Kimes A, Schwandt ML, et al. (2019) effects of cocaine in rats. Neuropsychopharmacology 37:
Striatal dopamine release in response to morphine: a 1092–103.
11C-raclopride positron emission tomography study in
Dakwar E, Nunes EV, Hart CL, et al. (2019) A single ketamine
healthy men. Biol Psychiatry 86: 356–64. infusion combined with mindfulness based behavioral
Stahl SM (2018) Antagonist treatment is just as effective as modification to treat cocaine dependence: a randomized
replacement therapy for opioid addition but neither is used clinical trial. Am J Psychiatry 176: 923–30.
often enough. CNS Spectrums 23: 113–16. Ersche KD, Bullmore ET, Craig KJ, et al. (2010) Influence of
Substance Abuse and Mental Health Services Administration. compulsivity of drug abuse on dopaminergic modulation
Key substance use and mental health indicators in the of attentional bias in stimulant dependence. Arch Gen
United States: results from the 2016 National Survey Psychiatry 67: 632–44.
on Drug Use and Health. www.samhsa.gov/data/sites/ Ersche KD, Jones PS, Williams GB, et al. (2012) Abnormal
default/files/NSDUH-FFR1-2016/NSDUH-FFR1-2016. brain structure implicated in stimulant drug addiction.
htm#opioid1. Accessed January 2018. Science 335: 601–4.
611
Ferris MJ, Calipari ES, Mateo Y, et al. (2012) Cocaine Selzer J (2006) Buprenorphine: reflections of an addictions
self-administration produces pharmacodynamic psychiatrist. J Clin Psychiatry 67: 1466–7.
tolerance: differential effects on the potency of dopamine Spencer TJ, Biederman J, Ciccone PE, et al. (2006) Stimulant
transporter blockers, releasers, and methylphenidate. medications: how to minimize their reinforcing effects?
Neuropsychopharmacology 37: 1708–16. Am J Psychiatry 163: 359–61.
Hart CL, Marvin CB, Silver R, Smith EE (2012) Is cognitive Wee S, Hicks MJ, De BP, et al. (2012) Novel cocaine vaccine
functioning impaired in methamphetamine users? A linked to a disrupted adenovirus gene transfer vector
critical review. Neuropsychopharmacology 37: 586–608. blocks cocaine psychostimulant and reinforcing effects.
Heinz A, Reimold M, Wrase J, et al. (2005) Stimulant actions Neuropsychopharmacology 37: 1083–91.
in rodents: implications for attention-deficit/hyperactivity
disorder treatment and potential substance abuse. Biol
Substance Abuse: Hallucinogens,
Leyton M, Boileau I, Benkelfat C, et al. (2002) Amphetamine- Entactogens, Dissociatives
induced increases in extracellular dopamine, drug wanting, Brawley P, Dufield JC (1972) The pharmacology of
and novelty seeking: a PET/[11 C]raclopride study in hallucinogens. Pharmacol Rev 34: 31–66.
healthy men. Neuropsychopharmacology 27: 1027–35. Carhart-Harris RL, Goodwin GM (2017) The therapeutic
Lindsey KP, Wilcox KM, Votaw JR, et al. (2004) Effect potential of psychedelic drugs: past, present and future.
of dopamine transporter inhibitors on cocaine self- Neuropsychopharmacology 42: 2105–13.
administration in rhesus monkeys: relationship to Carhart-Harris RL, Bolstridge M, Day CMG, et al.
transporter occupancy determined by positron emission (2018) Psilocybin with psychological support for
tomography neuroimaging. J Pharmacol Exp Ther 309: treatment-resistant depression: six month follow up.
959–69. Psychopharmacology 235: 399–408.
Little KY, Krolewski DM, Zhang L, Cassin BJ (2003) Loss of Carhart-Harris RL, Bolstridge M, Rucker J, et al. (2016)
striatal vesicular monoamine transporter protein (VMAT2) Psilocybin with psychological support for treatment-
in human cocaine users. Am J Psychiatry 160: 47–55. resistant depression: an open label feasibility study. Lancet
Livni E, Parasrampuria DA, Fischman AJ (2006) PET study Psychiatry 3: 619–27.
examining pharmacokinetics, detection and likeability, and Carhart-Harris RL, Erritzoe D, Williams T, et al. (2012)
dopamine transporter receptor occupancy of short- and Neural correlates of the psychedelic state as determined
long-acting oral methylphenidate. Am J Psychiatry 163: by fMRI studies with psilocybin. Proc Natl Acad Sci USA
387–95. 109: 2138–43.
Martinez D, Narendran R, Foltin RW, et al. (2007) Carhart-Harris RL, Leech R, Williams TM, et al. (2012)
Amphetamine-induced dopamine release: markedly Implications for psychedelic assisted psychotherapy:
blunted in cocaine dependence and predictive of the choice a functional magnetic resonance imaging study with
to self-administer cocaine. Am J Psychiatry 164: 622–9. psilocybin. Br J Psychiatry 200: 238–44.
Narendran R, Lopresti BJ, Martinez D, et al. (2012) In vivo DiIorio CR, Watkins TJ, Dietrich MS (2012) Evidence for
evidence for low striatal vesicular monoamine transporter chronically altered serotonin function in the cerebral
2 (VMAT2) availability in cocaine abusers. Am J Psychiatry cortex of female 3,4-methylenedioxymethamphetamine
169: 55–63. polydrug users. Arch Gen Psychiatry 69: 399–409.
Overtoom CCE, Bekker EM, van der Molen MW, et al. (2009) Erritzoe D, Frokjaer VG, Holst KK, et al. (2011) In
Methylphenidate restores link between stop-signal sensory vivo imaging of cerebral serotonin transporter
impact and successful stopping in adults with attention and serotonin 2a receptor binding in
deficit/hyperactivity disorder. Biol Psychiatry 65: 614–19. 3,4-methylenedioxymethamphetamine (MDMA or
Peng, XO, Xi ZX, Li X, et al. (2010) Is slow-onset long-acting “Ecstasy”) and hallucinogen users. Arch Gen Psychiatry
monoamine transport blockade to cocaine as methadone 68: 562–76.
is to heroin? Implication for anti-addiction medications. Fantegrossi WE, Murnane KS, Reissig CJ (2008) The
Neuropsychopharmacology 35: 2564–78. behavioral pharmacology of hallucinogens. Biochem
Santos MD, Salery M, Forget B, et al. (2017) Rapid Pharmacol 25: 17–33.
synaptogenesis in the nucleus accumbens is induced by a Feduccia AA, Mithoefer MC (2018) MDMA-assisted
single cocaine administration and stabilized by mitogen- psychotherapy for PTSD: are memory reconsolidation
activated protein kinase interacting kinase-1 activity. Biol and fear extinction underlying mechanisms. Prog
Psychiatry 82: 806–18. Neuropsychopharmacol Biol Psychiatry 84: 221–8.
612
Liechti ME (2017) Modern clinical research on LSD. Lawrence AJ, Luty J, Bogdan NA, Sahakian BJ, Clark L (2009)
Neuropsychopharmacology 42: 2114–27. Impulsivity and response inhibition in alcohol dependence
Madsen MK, Fisher PM, Burmester D, et al. (2019) and problem gambling. Psychopharmacology 207: 163–72.
Psychedelic effects of psilocybin correlate with serotonin Lobo DSS, Kennedy JL (2006) The genetics of gambling and
2A receptor occupancy and plasma psilocin levels. behavioral addictions. CNS Spectrums 11: 931–9.
Neuropsychopharmacology 44: 1328–34. McElroy SL, Hudson JI, Capece JA, et al. (2007) Topiramate
Mithoefer MC, Wagner MT, Mithoefer AT, et for the treatment of binge eating disorder associated with
al. (2011) The safety and efficacy of {+/−} obesity: a placebo-controlled study. Biol Psychiatry 61:
3,4-methylenedioxymethamphetamine-assisted 1039–48.
psychotherapy in subjects with chronic, treatment- Miedl SF, Peters J, Buchel C (2012) Altered neural reward
resistant posttraumatic stress disorder: the first representations in pathological gamblers revealed by
randomized controlled pilot study. J Psychopharmacol 25: delay and probability discounting. Arch Gen Psychiatry 69:
439–52. 177–86.
Passie T, Halpern JH, Stichtenoth DO, et al. (2008) The Salamone JD, Correa M, Mingote S, Weber SM (2002) Nucleus
pharmacology of lysergic acid diethylamide: a review. CNS accumbens dopamine and the regulation of effort in
Neurosci Ther 14: 295–314. food-seeking behavior: implications for studies of natural
Pitts EG, Minerva AR, Chandler EB, et al. (2017) motivation, psychiatry, and drug abuse. J Pharmacol Exp
3,4-Methylenedioxymethamphetamine increases affiliative Ther 305: 1–8.
behaviors in squirrel moneys in a serotonin 2A receptor Van Holst RJ, Veltman DJ, Buchel C, van den Brink W,
dependent manner. Neuropsychopharmacology 42: Goudriaan AE. (2012) Distorted expectancy coding in
1962–71. problem gambling: is the addictive in the anticipation? Biol
Quednow BB, Komeer M, Geyer MA, et al. (2012) Psilocybin Psychiatry 71: 741–8.
induced deficits in autonomic and controlled inhibition Zack M, Poulos CX (2007) A D1 antagonist enhances the
are attenuated by ketanserin in healthy human volunteers. rewarding and priming effects of a gambling episode in
Neuropsychopharmacology 37: 630–40. pathological gamblers. Neuropsychopharmacology 32:
Schmid Y, Enzler F, Gasser P, et al. (2015) Acute effects 1678–86.
of lysergic acid diethylamine in healthy subjects. Biol
Impulsivity/Compulsivity
Titeler M, Lyon RA, Gleenon RA (1988) Radioligand binding
Berlin HA, Rolls ET, Iversen SD (2005) Borderline personality
evidence implicates the brain 5HT2 receptor as a site of
disorder, impulsivity, and the orbitofrontal cortex. Am J
action for LSD and phenylisopropylamine hallucinogens.
Psychopharmacology 94: 213–16.
Chamberlain SR, del Campo N, Dowson J, et al. (2007)
Urban NBL, Girgis RR, Talbot PS, et al. (2012) Sustained
Atomoxetine improved response inhibition in adults with
recreational use of Ecstasy is associated with altered pre
attention deficit/hyperactivity disorder. Biol Psychiatry 62:
and postsynaptic markers of serotonin transmission in
977–84.
neocortical areas: a PET study with [11C]DASB and [11C]
MDL 100907. Neuropsychopharmacology 37: 1465–73. Chamberlain SR, Muller U, Blackwell AD, et al. (2006)
Neurochemical modulation of response inhibition and
probabilistic learning in humans. Science 311: 861–3.
Binge Eating/Gambling
Chamberlain SR, Robbins TW, Winder-Rhodes S, et al. (2011)
Balodis IM, Kober H, Worhunsky PD, et al. (2012) Diminished Translational approaches to frontostriatal dysfunction
frontostriatal activity during processing of monetary in attention-deficit/hyperactivity disorder using a
rewards and losses in pathological gambling. Biol computerized neuropsychological battery. Biol Psychiatry
Psychiatry 71: 749–57. 69: 1192–203.
Gearhardt AN, Yokum S, Orr PT, et al. (2011) Neural Dalley JW, Everitt BJ, Robbins TW (2011) Impulsivity,
correlates of food addiction. Arch Gen Psychiatry 68: compulsivity, and top-down cognitive control. Neuron 69:
808–16. 680–94.
Grant JE, Kim SW, Hartman BK (2008) A double-blind, Dalley JW, Mar AC, Economidou D, Robbins TW (2008)
placebo-controlled study of the opiate antagonist Neurobehavioral mechanisms of impulsivity: fronto-
naltrexone in the treatment of pathological gambling urges. striatal systems and functional neurochemistry. Pharmacol
J Clin Psychiatry 69: 783–9. Biochem Behav 90: 250–60.
613
Fineberg NA, Chamberlain SR, Goudriaan AR (2014) Shaw P, Gilliam M, Liverpool M, et al. (2011) Cortical
New developments in human neurocognition: clinical, development in typically developing children with
genetic, and brain imaging correlates of impulsivity and symptoms of hyperactivity and impulsivity: support for
compulsivity. CNS Spectrums 19: 69–89. a dimensional view of attention deficit hyperactivity
Lodge DJ, Grace AA (2006) The hippocampus modulates disorder. Am J Psychiatry 168: 143–51.
dopamine neuron responsivity by regulating the intensity Sugam JA, Day JJ, Wightman RM, Carelki RM (2012) Phasic
of phasic neuron activation. Neuropsychopharmacology 31: nucleus accumbens dopamine encodes risk-based
1356–61. decision-making behavior. Biol Psychiatry 71: 199–205.
Robbins TW, Gillan CM, Smith DG, de Wit S, Ersche KD Weathers JD, Stringaris AR, Deveney CM, et al. (2012) A
(2012) Neurocognitive endophenotypes of impulsivity and development study of the neural circuitry mediating
compulsivity: towards dimensional psychiatry. Trends Cogn motor inhibition in bipolar disorder. Am J Psychiatry 16:
Sci 16: 81–91. 633–41.
614
Index
5HT. See serotonin AIMS (Abnormal Involuntary Movement amyotrophic lateral sclerosis, 353
scale), 174 analgesia, 380
ABC model of apathy, 536 akathisia, 166, 169 anatomical basis of neurotransmission,
abstinence, 571–4 alcohol, 377, 553–6 1–5
acamprosate, 556 abstinence, 573 anesthesia, dissociative, 570
acetyl coenzyme A, 505 co-addictions, 553 anhedonia, 142, 162
acetylcholine, 5, 505–10 treatment of alcoholism, 556 antagonists, 41–3, 57, 58, 60, 62
dopamine and, 166 alcohol abuse, 378 alpha-1, 216, 225, 236, 327–8
acetylcholinesterase, 505 allodynia, 380 alpha-2, 309
acetylcholinesterase inhibition, 509–18 allopregnanolone, 320, 322 silent, 41, 42, 45, 192
action potential, 67, 73 allosteric modulation, 64–6, 261, 262 anticholinergics, 166, 168, 215, 294
active site, 45, 46 alogia, 142 anticonvulsants
acute pain, 379, 380 alpha-1 antagonism, 216, 225, 236, 327–8 doubtful efficacy in bipolar disorder,
addiction, 476, 539 alpha-2 adrenergic agonists, 481–4 352–3
behavioral, 575 alpha-2 antagonism, 309 insomnia treatment, 426
dopamine theory of, 542–3 alpha-2 autoreceptors, 254, 256, 258 mood stabilizers, 346
substance addictions, 544–75 alpha-2-delta ligands, 366, 377, 380 proven efficacy in bipolar disorder,
adenosine, 440 pain alleviation, 398 347–51
ADHD (attention deficit hyperactivity SNRI combinations, 399 antidepressant actions, 195–234, 267, 283
disorder), 34, 449, 485, 539 alpha pore, 69, 70 antihistamines, 161, 215, 295, 425–6
comorbidities, 466, 480 alpha-synuclein, 493, 494 antipsychotic actions, 161–2, 242
neurodevelopment, 463–5 alternative splicing, 26 antipsychotics. See drugs targeting
oppositional symptoms, 484 Alzheimer disease, 487–90, See also serotonin receptors, drugs targeting
prefrontal cortex tuning, 454–63 dementia dopamine D2 receptors
symptoms and circuits, 449–53 agitation in, 521–4, 528–33 anxiety, 78, 145, 359
treatments, future, 484 delusions in, 157 OCD and, 576
treatments, NET inhibitors, 480–4 dementia stage 3, 502 anxiety disorders, 196, 378
treatments, stimulants, 467–79 early detection, importance of, 497 ADHD and, 468
treatments, symptoms and, 466–7 impulsivity, 539 comorbidity, 360
advanced sleep phase disorder, 435, 437 MCI stage 2, 500–2 core symptoms, 360
affective blunting, 142 memory and cognition treatment, definition, 360
affective disorders, 244 509–18 major depression and, 360–2
affective symptoms, 95 Parkinson’s disease comorbidity, 494 MAOIs, 336
positive and negative, 278, 280, 306 pathology, 488 noradrenergic hyperactivity in, 370–2
schizophrenia, 145 presymptomatic stage, 499–501 overlapping symptoms of different,
aggression, 145–7, 521, 577–8 psychosis in, 521–4 362–3
agitation, 145, 521–3 targeting amyloid, 496–9 pain disorders and, 387
dementia, 145, 157, 197 vascular dementia comorbidity, 492 psychotherapy, 359
glutamate target, 533 amantadine, 169 serotonin and, 368–70
neuronal networks of, 528–30 amisulpride, 205 treatment of, 377–8, 421
treatment, 523–4 amotivational syndrome, 563 anxiety phenotype, 363
treatment, multimodal monoamine, AMPA receptors, 101, 104, 330, 331 anxiolytic actions, 196, 366
530–2 amphetamine, 337, 356, 441–2, 472–6, apathy, 78, 536–7
agomelatine, 306–8 569 APOE4 gene, 497
agonist spectrum, 37, 43, 45, 56–62, 184, ADHD, 484 aripiprazole, 192, 229, 239, 326
192 formulations, 475 armodafinil, 442–4
agonists, 57, 58 isomers, 472 arousal, 457, 459
full, 37–41, 56, 192 amygdala, fear and, 364–5, 372, 374 arousal spectrum, 402
inverse, 42, 44–5, 61, 62, 240 amyloid cascade hypothesis, 496–9 asenapine, 220, 232
no agonist, 37 amyloid plaques. See beta-amyloid asociality, 142
partial. See partial agonists amyloid precursor protein, 497–8 asymptomatic amyloidosis, 499–501
615
Index
atomoxetine, 480–1 buspirone, 333, 370 closed state, 63

auditory hallucinations, 113 butyrylcholinesterase, 505, 510 clozapine, 217, 222–5
autoreceptors cocaine, 544, 545
alpha-2, 254, 256, 258 caffeine, 440–1 codeine, 559
monoamine, 8 calcium channel blockers (L-type), 352 cognition, Fab Four of, 317
avolition, 142 cannabidiol (CBD), 563, 565, 567 cognitive behavioral therapy, 374, 377, 576
axoaxonic synapses, 1, 3 cannabis, 150, 563–7 cognitive dysfunction
axodendritic synapses, 1, 3 benefits and risks, 564 ADHD, 455, 456, 458
axosomatic synapses, 1, 3 side effects, 563 Alzheimer disease, 509–18
therapeutic uses, 564 chronic pain, 388
barbiturates, 556 carbamazepine, 350, 530 depression, 273
bath salts, 546 cardiometabolic risk, 196, 224 fibromyalgia, 390, 400
BDNF (brain-derived neurotrophic cardiometabolism, 198–201, 415 Parkinson’s disease, 493
factor), 266, 268, 329 cardiovascular disease, 156, 415, 432, sleep disorders, 402
behavioral addictions, 575 492, 524 sleep disturbance and, 414, 417
behavioral variant FTD, 494 carfentanil, 560 vortioxetine treatment, 315–17
benzodiazepine-insensitive GABAA cariprazine, 192, 231, 240, 328, 343–5 cognitive symptoms, schizophrenia, 95,
receptors, 263–4 cataplexy, 434, 435, 446 144, 157
benzodiazepines, 321, 366, 377 catechol-O-methyltransferase, 253 competitive elimination, 151, 154
caution with, 378 central disorders of hypersomnolence, 432 compulsivity, 538–9, 571, 578
insomnia treatment, 421–2 central pain, 379 impulsive–compulsive disorders,
benzodiazepine-sensitive GABAA central sensitization, 395 539–43, 575
receptors, 259–62 chemical neurotransmission, 1, 28 OCD, 295, 360, 576–7
beta-amyloid, 488, 496–8, 502 anatomical versus, 1–5 conceptual disorganization, 78
detection, 499, 501 epigenetics, 23–6 conditioned responses, 539
beta blockers, 375, 376 ion channels and, 73–6 conditioned stimuli, 539, 544
beta subunits, 68 mood disorders, 252–64 consolidation, 375
bifeprunox, 192 principles of, 5–9 constitutive activity, 37, 57
binge-eating disorder, 575 signal transduction cascades, 9–23, continuous positive airway pressure, 443
bipolar depression, 244 28, 53 controlled substance, 447
drug treatment, 236, 240 triggering gene expression, 18 cortico-brainstem glutamate pathways, 102
family history of, 250 ultradian sleep cycle, 414–16 cortico-cortical glutamate pathways, 105
first-line treatment, 342 chemotherapy, side effects, 309 cortico-striatal glutamate pathways, 104
identifying, 250 child abuse, 370 cortico-striato-thalamo-cortical (CSTC)
missed or delayed diagnosis, 250 chlorpromazine, 161, 181, 201, 202 loops, 87, 362, 365–9
schizophrenia and, 249 choline, 505 cortico-thalamic glutamate pathway, 105
suicide rates, 251 cholinergic agonists, 242 CREB system, 15
versus unipolar, 249–51 cholinergic pathways, 509 criminogenic behavior, 146, 147
bipolar disorder chromatin, 23 cytochrome P450 (CYP450), 49–50, 323
anticonvulsants with proven efficacy, chronic back pain, 388
347–51 chronic pain, 379–400 daridorexant, 424
anticonvulsants with uncertain decreased gray matter, 387–90 DAT transporter. See dopamine
efficacy, 352–3 duloxetine treatment, 302–3 transporters (DATs)
bipolar I, 247 milnacipran treatment, 303 date rape drugs, 447, 559
bipolar II, 244, 247 targeting sensitized circuits, 395–9 delayed sleep phase disorder, 435, 437
combination treatments, 353 treatment, 390–400 delirium, 569
drug treatment, 338–58 circadian rhythm disorders, 430, 435–8 delusions, 77, 141, 524
blocking fear conditioning, 375–7 depression, 271–5 Alzheimer disease, 157
blonanserin, 234, 241 circadian rhythms, 307, 308 dementia, 521
brexanolone, 320 setting of, 275 Parkinson’s disease psychosis, 157
brexpiprazole, 192, 197, 230, 239, 327–8, circadian treatments, 438–40 dementia, 486, 537, See also Alzheimer
378, 530–2 circadian wake drive, 409, 412 disease
bright light therapy, 438, 440, 444 citalopram, 295–6 agitation in, 145, 157, 197
buprenorphine, 560, 561, 562 classic neurotransmission, 6 apathy in, 536–7
bupropion, 306–8, 353–4, 480, 533 clock genes, 271 behavioral symptoms of, 521, 537
nicotine addiction, 551 clomipramine, 335 definition, 487
sertraline combination, 294 clonidine, 390, 482–3, 561 depression in, 534–5
616
Index
major causes of, 488–96 DNA methylation, 24 drugs targeting dopamine D2 receptors,
psychosis in, 110, 134, 157, 521–3 donepezil, 510 159, 242
psychosis in, treatment, 523–7 DOPA decarboxylase, 253 agitation in dementia, 197
symptomatic treatments, 503–5 dopamine, 5 antidepressant actions, 195–234
dendrites, 2 acetylcholine and, 166 anxiolytic actions, 196
depression, 145, See also bipolar conversion to norepinephrine, 253 cardiometabolic actions, 198–201
depression, unipolar depression increase in prefrontal cortex, 299–302 first generation, 179–82, 201–3
affective symptoms, 278, 280 inefficient tuning of PFC by, 454–63 individual properties, 204–41
circadian rhythm disorder in, 271–5 projections, 279 mesocortical, 163
clinical effects of treatment, 284–5 release, 5HT2A regulation, 184–8 mesolimbic/mesostriatal, 161–3
dementia and, 534–5 synthesis, 79, 80 nigrostriatal, 165–81
drug side effects, 200 volume neurotransmission, 8 partial agonists, 189–92, 204–41
drug treatment, 229, 239 dopamine β-hydroxylase, 253 serotonin 2A and, 182–8
insomnia and, 418 dopamine blockers, 468 tuberoinfundibular, 164
major depressive disorder. See major adverse effects, 524 drugs targeting dopamine D3 receptors,
depressive disorder bipolar disorder spectrum, 338–45 210, 240, 241
major depressive episode. See major dopamine D1 receptors drugs targeting serotonin receptors, 159,
depressive episode drugs targeting, 204–41 243
mixed features of, 251 dopamine D2 receptors. See also drugs 1A receptors, 192–5, 207
monoamine hypothesis of, 264–5, 290 targeting dopamine D2 receptors 1B and 1D receptors, 214
monoamine receptor hypothesis of, pre- and postsynaptic, 228 2A receptors, 182–8
264–6, 267, 290 dopamine D3 receptors, 343–5 2C receptor, 211
mood stabilizer treatment, 288 drugs targeting, 210, 240, 241 3 receptor, 212
neuroplasticity and neuroprogression dopamine deficiency syndrome, 306 6 and 7 receptors, 213
hypothesis of, 266–76 dopamine hypothesis of psychosis, agitation in dementia, 197
serotonin or dopamine blockers in, 342 79–95, 110–14, 141 antidepressant actions, 195–234
symptom-based algorithm treatment, dopamine neurotransmitter network, anxiolytic actions, 196
280 79–91 cardiometabolic actions, 198–201
time course of effects of drugs, 266 classic pathways and key brain individual properties, 204–41
depression with mixed features, 248, 342 regions, 84 DSST (digital symbol substitution test), 317
depressive psychosis, 78, 157 mesolimbic pathway, 89, 542–3 dual orexin receptor antagonists
descending spinal norepinephrine nigrostriatal pathway, 87–9 (DORAs), 423–4, 430
pathway, 390, 392 thalamic pathway, 85 duloxetine, 299, 302–3, 535
descending spinal serotonergic pathway, tuberoinfundibular pathway, 85 dynorphins, 390
390, 394 dopamine receptors, 81–5 dyslipidemia, 198
desensitization, 63, 64 dopamine theory of addiction, 542–3 dystonia, drug-induced, 166, 169
desvenlafaxine, 299, 302 dopamine transporters (DATs), 31, 80
deuteration, 175, 177, 354 ADHD treatment, 473–9 eating disorders, 293, 575
dextromethadone, 355–8 inhibition, 294, 333 Ecstasy, 358, 569
dextromethorphan, 306, 353–4, 533, 536 dopaminergic neurons, 79 empathogens, 569
diabetes, 198, 199, 415 dorsal anterior cingulate cortex (dACC), endocannabinoids, 6, 563, 564
diabetic ketoacidosis, 199, 200 450, 451 enkephalins, 390
Diagnostic and Statistical Manual of dorsal horn neurons, 382–4 entactogens, 569
Mental Disorders (DSM-5) dorsal horn, descending spinal synapses enzyme inhibitors, 45
ADHD, 463 in, 390–5 irreversible, 46
insomnia, 420 dorsal root ganglia, 380, 381 reversible, 47
major depressive episode, 245 dorsolateral prefrontal cortex, 387, 400, enzymes, 45–50
manic episode, 245 449 activity, 45
mixed features, 248 doxepin, 425, 427 epigenetics, 23–6
dietary tyramine interaction, 338 drug abuse, 447, 539 Epworth Sleepiness Scale, 430
diphenhydramine, 426 DAT occupancy and, 476, 479 escitalopram, 296
direct (go) dopamine pathway, 89, 90 reversal of habit, 571–4 esketamine, 331, 353, 571
disorganized/excited psychosis, 78 stimulants, 544–7 eslicarbazepine, 352
disorientation, 78 drug-induced dystonia, 166, 169 euphoria, 560
dissociation-assisted psychotherapy, 574 drug-induced parkinsonism, 165, 166–9, excessive daytime sleepiness. See
dissociative anesthesia, 570 181 hypersomnia
dissociatives, 569–71 drugs targeting dopamine D1 receptors, excitation–secretion coupling, 6, 8–9,
disulfiram, 556 204–41 73, 75
617
Index
excitatory amino acid transporter, 96, 99 GABAA, benzodiazepine-insensitive, Parkinson’s disease psychosis, 157
excitement, 78 263–4 visual, 113, 524
executive dysfunction, 144, 449–50 GABAA, benzodiazepine-sensitive, hallucinogen-assisted psychotherapy,
exposure therapy, 374, 378, 574, 576, 577 259–62 355–8, 376
extinction GABA transaminase (GABA-T), 258 hallucinogens, 135, 138, 567–9
fear, 373, 374–5, 574 GABA transporter (GAT), 34, 258 haloperidol, 181, 202, 204
pharmacological, 573 GABAergic drugs, 276 heroin, 559, 561, 573
extrapyramidal symptoms, 166 gabapentin, 352, 366, 395, 426 heteroreceptors, 125
galanthamine, 514 hippocampal-accumbens glutamate
F17464, 241 gambling disorder, 575 pathway, 104
FDG PET, 490, 492, 502 gamma-hydroxybutyrate (GHB), 400, hippocampus, 372, 374
fear, 363–6 446–8, 559 histamine, 35, 402–6, 409
neurobiology of, 364–5 gene activation, 18, 19, 24, 25 histamine 1 antagonism, 425–6, 427
noradrenergic hyperactivity, 371 gene expression histamine receptors, 406
fear conditioning, 370–4 epigenetics, 23–6 histones, methylation, 23
blocking, 375–7 molecular mechanism, 18–23 homeostatic sleep drive, 408, 412
fear extinction, 373, 374–5, 574 neurotransmission triggering, 18 hormone-linked systems, 11, 12
fentanyl, 559 phosphoprotein triggering cascades, hostile belligerence, 78
fibro-fog, 390, 400 15–18 HPA (hypothalamic-pituitary-adrenal)
fibromyalgia, 303, 387–9 gene silencing, 24, 25 axis, 266, 270
cognitive dysfunction, 388, 400 generalized anxiety disorder, 361, 377 human genome, 18
targeting ancillary symptoms, genetic testing, 323–5 Huntington’s disease, 28, 175
399–400 genetics hydrocodone (Vicodin), 559
treatment, 448 ADHD, 463 hyperactivity, 452, 454, 463
fight or flight response, 359, 364 schizophrenia, 148–50 hyperalgesia, 380
first messengers, 11, 13 genotyping, 50 hyperarousal, 418
flashbacks, 568 ghrelin, 415 hyperdopaminergia, 90, 92, 93
flumazenil, 263 glucose metabolism, 490 hyperglycemic hyperosmolar syndrome,
fluoxetine, 293–4 glutamate, 5, 96 199, 200
olanzapine combination, 293, 326, agitation in Alzheimer disease, 533 hyperprolactinemia, 165, 187, 192
343 Alzheimer disease target, 515–18 hypersomnia, 402, 430–40
fluphenazine, 202, 203 key pathways in the brain, 102 causes of, 431–5
fluvoxamine, 295 synthesis, 96–7 treatment of, 440–8
forensic hospitals, 146, 147, 156 synthesis of GABA from, 255 hypervigilance, 402
frontotemporal dementias, 494–6 glutamate hypothesis of psychosis, hypnotic actions, 311
frontotemporal lobar degeneration, 494 95–114 insomnia treatment, 421–30
full agonists, 37–41, 56, 192 glutamate neurotransmitter network, hypnotics, sedative, 556
96–106 hypocretins, 406–11
G protein, 14 glutamate receptors, 99–105 hypodopaminergia, 95
G-protein-linked receptors, 36–45, 50 ionotropic, 54 hypomania, 248
agonist spectrum, 37, 43, 45 metabotropic, 100, 103 hypothalamic neurons, 407
agonists, 37–41 NMDA. See NMDA glutamate
antagonists, 41–3 receptors idiopathic hypersomnia, 432, 433
inverse agonists, 42, 44–5 glutamate transporters, 34 illusions, 568
no agonist, 37 glutamic acid decarboxylase, 255 iloperidone, 225, 236
partial agonists, 41, 43–4 glycine transporters, 34 immediate early genes, 19, 20
structure and function, 36 glycine, synthesis, 97–9 impulse control disorders, 577–8
G-protein-linked systems, 11, 12, 13 Goldilocks solution, 43, 60, 191, 227, impulsive–compulsive disorders, 539
GABA (γ-aminobutyric acid), 5, 257–64, 428 binge eating, 575
349 grandiose expansiveness, 78 neurocircuitry of, 539–43
action termination, 258 gray matter, chronic pain, 387–90 impulsive violence, 147, 577
synthesis, 255 GSK-3 (glycogen synthase kinase), 48 impulsivity, 452, 454, 463, 538–9, 571, 578
GABA interneurons guanfacine, 482–3 inactivation state, 61, 63
5HT receptors on, 121, 125, 130 inattention, 449, 450, 451, 463
prefrontal cortex, 105–10 habit circuit, 544, 561, 571, 572 indirect (stop) dopamine pathway, 89, 90
GABA receptors, 258–64 habits, 538, 539, 576 inhalants, 547
GABAA, 321, 366, 421–3 hallucinations, 77, 113, 141, 435, 568 inherited disease, classic theory of, 148
GABAA receptor subtypes, 258–61 dementia, 521 insomnia, 311, 402, 418–20
618
Index
behavioral treatments, 430 mania monoamine oxidase inhibitors (MAOIs),

diagnosis and comorbidities, 418–20 anticonvulsant treatment, 346 336–7, 377
treatment, 421–31 carbamazepine treatment, 350 bipolar depression, 342
insulin resistance, 197, 198, 200 drug treatment, 195 dietary tyramine interaction, 338
internet addiction, 575 lithium treatment, 345 drug–drug interactions, 338
interneurons, 380 mixed features of, 248, 251 subtypes, 337–41
inverse agonists, 42, 44–5, 61, 62, 240 mood stabilizer treatment, 288 monoamine projections, 279
ion-channel-linked systems, 11, 12 serotonin and dopamine blockers in, monoamine receptor hypothesis of
ion channels, 76 338, 342 depression, 264–6, 267, 290
ligand-gated. See ligand-gated ion valproate treatment, 349 monoamine transporters, 30, 31–4, 208
channels manic episodes, 245, 277, 278 unipolar depression, 285–8
neurotransmission and, 73–6 MAOIs. See monoamine oxidase mood disorders, 244, 282, See also mania,
voltage-sensitive. See voltage-sensitive inhibitors depression
ion channels mazindol, 485 description of, 244–52
ionotropic glutamate receptors, 54 MDMA, 356, 376, 378, 569–71 future treatments for, 353–8
iproniazid, 336 assisted psychotherapy, 574 mixed features of, 248, 251–2
irreversible enzyme inhibitors, 46 MDPV, 546 neurobiology of, 252–76
medication-assisted therapy, 561 pain disorders and, 387
kainate receptors, 101, 104 melatonergic agents, 439, 440 symptom-based treatments, 279–82
ketamine, 106, 328–32, 353, 376, 569–71 melatonin, 275, 439, 440 symptoms and circuits in, 277–82
ketamine-assisted psychotherapy, 574 melatonin receptors, 306 mood episodes, 246
kinase, third messenger, 14, 16 memantine, 520, 521–4, 533 mood related psychosis, 157
memory difficulties, 316 mood spectrum, 244–9
lamotrigine, 350–1 Alzheimer disease, 509–18 mood-stabilizers, 288, 345–6
late genes, 20, 22 memory, traumatic, 356, 366, 375, mood-stabilizing action, 283
lemborexant, 423 574 morphine, 559, 561
leptin, 415 mesocortical dopamine pathway, 95 motivation, lack of, 536
leucine zippers, 19, 20, 21 mesocortical hypodopaminergia, 95 motor disturbances, 78
levodopa, 170 mesolimbic dopamine pathway, 89, motor side effects, 165–81
levomilnacipran, 300, 303 542–3 partial agonists, 192
Lewy bodies, 157 mesolimbic hyperdopaminergia, 90 mu-opioid receptors, 390, 556
Lewy body dementias, 492–5 mesostriatal hyperdopaminergia, 93 multimodal monoamines, 530–2
licarbazepine, 352 messenger RNA (mRNA), 26 Multiple Sleep Latency Test, 431
ligand-gated ion channels, 51–66, 76 metabolic highway, 198, 199, 201 muscarinic receptors, 506–7
agonist spectrum, 56–62 metabolic monitoring, 196, 199
allosteric modulation, 64–6 metabolic toolkit, 201 nalmefene, 556, 573
different states of, 61–4 metabotropic glutamate receptors, 100, naloxone, 560
gatekeeper, 52 103 naltrexone, 306, 556, 561, 563, 573, 575
pentameric subtypes, 53 metformin, 201 NAMs (negative allosteric modulators),
structure and function, 53 methadone, 355, 559, 560, 561, 562 64–6
tetrameric subtypes, 54–5 methylation, 23, 24 narcolepsy, 407, 430, 433, 435, 443, 444,
lisdexamfetamine, 473, 575 methylphenidate, 441–2, 469–72, 484 446
lithium, 48, 332, 345–6 formulations, 470 nausea and vomiting, 309
local anesthesia, 380 mianserin, 309 n-back test, 449, 451
lofexidine, 561 microRNA (miRNA), 27 nefazodone, 311
long-term potentiation, 151 migrants, 150 negative affect, 278, 280
LSD, 358, 568 mild cognitive impairment, 487, 490, negative feedback regulatory signal, 255
lumateperone, 227, 237–9 493, 500–2 negative symptoms, 95, 142–4, 156
lurasidone, 226, 236, 343 milnacipran, 300, 303 secondary, 162–3
mirtazapine, 232, 308–13, 333 NET transporters. See norepinephrine
magic mushrooms, 358 mixed dementia, 495 transporters (NETs)
magnesium, 104 mixed features, 248, 251–2 neuroactive steroids, 320–5
magnetic resonance imaging, 491 modafinil, 333, 442–4 neurobiology
major depressive disorder, 246, 252 Molly, 358, 569 mood disorders, 252–76
anxiety disorder and, 360–2 monoamine autoreceptors, 8 sleep and wakefulness, 402–15
core symptoms, 360 monoamine hypothesis of depression, neurodevelopment, 151, 152
major depressive episode, 248, 277 264–5, 290 ADHD, 463–5
symptoms and circuits, 277 monoamine oxidase (MAO), 253 schizophrenia, 151–3
619
Index
neurofibrillary tangles, 488, 502, 503 projections, 279 Alzheimer disease comorbidity, 494
neuroinflammation, 270 synthesis, 252 cognitive dysfunction, 493
neuroleptic-induced deficit syndrome, norepinephrine–dopamine reuptake Parkinson’s disease dementia, 492–5
162 inhibitors (NDRIs), 303–6, 333 Parkinson’s disease psychosis, 78, 133,
neuroleptic malignant syndrome, 169 norepinephrine receptors, 254–6, 258 136, 139, 157, 524
neuroleptics, 162 norepinephrine transporters (NETs), paroxetine, 294, 295
neuronal cell loss, 488, 490, 491 31, 254 partial agonists, 41, 43–4, 57–61, 189–95,
neurons, 1, 2 norepinephrine transporter (NET) 204–41
general structure, 2 inhibition, 294, 298–303, 370 Pavlov’s dogs, 370
neuropathic pain, 380, 382–90, See also ADHD, 480–4 pentameric ligand-gated ion channels, 53
fibromyalgia norquetiapine, 227 perceptual distortions, 78
central mechanisms, 382–6 NRX101, 237 periaqueductal gray, 390
peripheral mechanisms, 382 NSAIDs (nonsteroidal anti-inflammatory peripheral pain, 379
neuropathic pain syndromes, 380 drugs), 382 perospirone, 233, 241
neuropeptides, 35 nucleosomes, 23 PET scans
neuroplasticity and neuroprogression nucleus accumbens, 162 beta-amyloid, 499, 501
hypothesis of depression, 266–76 FDG PET, 490, 492, 502
neurotransmission, 1, See also chemical obesity, 198, 415, 575 pharmacodynamics, 49
neurotransmission obsessive–compulsive disorder (OCD), pharmacokinetics, 49
anatomical basis of, 1–5 295, 360, 576–7 hypnotic actions, 426–30
neurotransmitters, 5–6 obstructive sleep apnea, 430, 431, 434, pharmacological extinction, 573
enzymes as. See enzymes 443 phasic dopamine system, 455
psychosis pathways, 79 olanzapine, 218, 225 phasic inhibition, 259
transporters. See transporters fluoxetine combination, 293, 326, 343 phencyclidine, 106, 569–71
neurotrophic factors, loss of, 266, 268 ondansetron, 556 phosphatase, third messenger, 15, 16
neurotrophin-linked systems, 11, 12 OPC4392, 193 phosphoprotein cascades, 15–18
neutropenia, 224 open state, 63 phosphoprotein messenger, 13–15
NGF (nerve growth factor), 6 opiates, 559 pimavanserin, 231, 240, 526
nicotine, 63, 466, 547–53 opioid use disorder, 355 pitolisant, 444
alternative forms of delivery, 551 opioids, 375, 390, 556, 559 plasma membrane transporters, 30
treatment of addiction, 548–53 abstinence, 573 polygenic risk score, 150
nicotinic receptors, 506, 507–9, 548 addiction, 559–60 polysomnography, 420, 431
nigrostriatal dopamine pathway, 87–9 addiction, treatment of, 560–2 positive affect, 278, 280, 306
nitric oxide, 6 endogenous neurotransmitter system, positive symptoms, 90, 141, 156
nitric oxide synthase, 295 559 psychosis, 92–3
NMDA antagonism, 328, 330, 355 orbital frontal cortex, 454 postsynaptic dopamine receptors, 81
NMDA glutamate hypofunction orexin, 409, 435 posttraumatic stress disorder (PTSD),
hypothesis of psychosis, 105–14 dual orexin receptor antagonists, 360, 362
NMDA glutamate receptors, 97–101, 104 423–4, 430 drug treatment, 196
histamine at, 406 orexin receptors, 407 fear conditioning, 372
hypofunction, 111, 114 orexins, 406–11 treatments for, 377, 568, 574
NMDA receptor activation, 375 oxcarbazepine, 352 prazocin, 370
nociception, 380, 381 oxycodone (OxyContin), 559 predementia AD, 500–2
pain pathways, 396 prefrontal cortex
nociceptive nerve fibers, activation, 381 pain, 379–84, See also chronic pain disorder of the, 449–53, 463
nociceptive pathway, 381 definition, 380 dopamine neurotransmission, 8
from the spinal cord to the brain, in dementia, 537 dorsolateral, 387, 400, 449
382–4 mood and anxiety disorders and, 387 GABA interneurons, 105–10
to the spinal cord, 381–2 paliperidone, 223, 235 increased dopamine in, 299–302
non-24-hour sleep–wake disorder, 437, PAMs (positive allosteric modulators), inefficient tuning of, 454–63
438 64–6, 421–3 ventromedial, 372, 374
non-REM sleep, 413, 414 panic attacks, 361, 377, 569 pregabalin, 352, 366, 395, 426
noradrenaline. See norepinephrine panic disorder, 361, 372, 377 presymptomatic stage of Alzheimer
noradrenergic hyperactivity, 370–2 paralytic ileus, 167, 183 disease, 499–501
norepinephrine, 5, 252–6, 370 paranoid psychosis, 78 presynaptic dopamine receptors, 81, 82
action termination, 253 parkinsonism, drug-induced, 165, 166–9, primary afferent neurons, 380, 381
inefficient tuning of prefrontal cortex 181 primary transcript, 26
by, 454–63 Parkinson’s disease, 338 prisons, 146, 156
620
Index
processing speed, 317 PTSD. See posttraumatic stress disorder nature and nurture of, 149
prodromal negative symptoms, 143 (PTSD) negative symptoms, 95, 142–4, 156
proinflammatory molecules, 270 neurodegeneration and, 154–6
projection neurons, 380 quetiapine, 219, 220, 227–32, 326, 343 neurodevelopment and, 151–3
prolactin levels, 164, 187, 193 quinidine, 353–4, 534, 536 NMDA receptor hypofunction, 111, 114
pseudobulbar affect, 535 positive symptoms, 141, 156
psilocin, 568 radafaxine, 304 positive symptoms of psychosis in, 92–3
psilocybin, 358, 376, 568, 569 ramelteon, 439 second messenger
assisted psychotherapy, rasagiline, 338 forming, 11–14
psychedelic experience, 568 rashes, 352 to phosphoprotein cascades, 15–18
psychiatric vital sign, 381, 399, 401 receptor tyrosine kinases, 48 to phosphoprotein messenger, 13–15
psychic pain, 302 reconsolidation, 374, 375, 376, 574 secondary negative symptoms, 162–3
psychomotor retardation, 78 recurrence in depression, 284 sedation, 197, 202
psychopathic violence, 147, 577 reduced positive affect, 280, 306 sedative hypnotics, 556
psychosis, 77, 158, See also schizophrenia relapse, 571 segmental central sensitization, 384
cannabis and, 563 in depression, 284, 286 selegiline, 337, 338
dementia, prevalence in, 521 REM sleep, 413, 414, 435 SEP-363856, 242
dementia-related, 110, 134, 157, 521–3 remission in depression, 284, 286 serine, synthesis, 97–9
dementia-related, treatment of, 523–7 repetitive transcranial magnetic serious mental illness (SMI), 156
depressive, 78, 157 stimulation (rTMS), 577 serotonergic hypnotics, 424–5
dopamine hypothesis of, 79–95, reserpine, 174 serotonin, 5, 113
110–14, 141 response in depression, 284 anxiety and, 368–70
drug treatment. See drugs targeting resting state, 57, 61, 63 dementia-related psychosis, 524–7
serotonin receptors, drugs targeting retrograde neurotransmission, 6–7 neuronal network, 121
dopamine D2 receptors reuptake pumps, 174, See also projections, 279
glutamate hypothesis of, 95–114 transporters synthesis and termination of action,
mood-related, 157 reversible enzyme inhibitors, 47 114–15
neurotransmitter pathways, 79 reward, 542, 544 serotonin antagonist/reuptake inhibitors
other psychotic disorders, 156–8 reward conditioning, 545 (SARIs), 311–16
paranoid, 78 reward pathway, 572 serotonin blockers
Parkinson’s disease. See Parkinson’s rheostat analogy, 43 bipolar disorder spectrum, 338–45
disease psychosis ribosomal RNA (rRNA), 27 serotonin hyperfunction hypothesis of
positive symptoms of, 90, 92–3 riluzole, 352 psychosis, 131–41
serotonin hyperfunction hypothesis risperidone, 222, 234, 235 serotonin hypothesis of psychosis,
of, 131–41 rivastigmine, 510–16 111–41
serotonin hypothesis of, 111–41 RNA, 26–7 serotonin network, 113–33
symptoms of, 77–8 RNA interference, 26 constructing, 119–21
psychotherapy roluperidone, 235, 241 serotonin partial agonist reuptake
anxiety disorders, 359 inhibitor (SPARI), 296–9
cognitive behavioral therapy, 374, safinamide, 338 serotonin receptors. See also drugs
377, 576 SAGE-217, 322 targeting serotonin receptors
dissociation-assisted, 574 salivation, excessive, 224 5HT1A, 116, 118, 121, 296–9, 317
hallucinogen-assisted, 355–8, 376 samidorphan, 201 5HT1B, 125, 318
ketamine-assisted, 574 schizoaffective disorder, 249 5HT1B/D, 118, 119, 318
MDMA-assisted, 574 schizophrenia, 141, 156, See also 5HT2A, 125
psilocybin-assisted, 574 psychosis 5HT2A, dopamine release regulation,
PTSD, 378 affective symptoms, 95, 145 184–8
psychotic violence, 146, 577 aggressive symptoms, 145–7 5HT2A, hyperactivity/imbalance,
psychotomimetic experience, 569 bipolar disorder and, 249 111–41
psychotropic drugs cognitive symptoms, 95, 144, 157 5HT2B, 117, 119
enzymes as targets of, 45–50 dopamine hypothesis of psychosis in, 5HT2C, 125, 293–4
G-protein-linked receptors as targets, 92–5 5HT3, 125–9, 309–13, 318
36–45, 50 drug treatment. See drugs targeting 5HT6, 130
ion channels as targets of, 51–76 serotonin receptors, drugs targeting 5HT7, 130–3, 318–24
molecular targets, 29 dopamine D2 receptors overview, 114
nomenclature, 29 future drug treatment, 241–2 serotonin transporters (SERTs), 31, 33
transporters as targets, 29–35, 50 genetics and, 148–50 inhibition of, 289, 296, 317, 318–24
life expectancy, 156 sertindole, 232, 240
621
Index
sertraline, 294, 378 clinical uses of, 289 topiramate, 201, 352, 556, 575
setiptiline, 309 common features of six drugs, 289–92 trace amines, 241–38
shift work disorder, 435, 436, 444 depression in dementia, 534 tradozone, 311–15, 424–5
sigma-1 binding, 294, 295 OCD, 577 transduction, 381
signal propagation, 74 triple-action combo, 333 transfer RNA (tRNA), 27
signal transduction cascades, 9–23, 28, unique properties of six drugs, 292–3 transporters, 29–35, 50
53 stabilizers. See partial agonists classification and structure, 29–31
four important types of, 11, 12 steroids, neuroactive, 320–5 histamine and neuropeptides, 35
second messenger, forming, 11–14 Stevens Johnson syndrome, 352 monoamine, 30, 31–4, 208
second messenger, to phosphoprotein stigma, 145 SLC1 gene family, 31
cascades, 15–18 stimulants, 467–79, 544–7 vesicular, 32, 35
second messenger, to phosphoprotein atypical, 546 tranylcypromine, 337
messenger, 13–15 slow release vs. fast release, 478–9 traumatic memories, 356, 366, 375, 574
time course, 11 targeting DATs, 473–8 trazodone, 535
silent antagonists, 41, 42, 45, 192 treatment of addiction, 547 treatment responsiveness, 155
Sinclair method, 573 stimulus-response conditioning, 571 tricyclic antidepressants (TCAs), 333–7
SLC1 gene family, 31, 35 strengthening, synapse, 151, 154 triglyceride levels, 197, 198, 199
SLC17 gene family, 31, 35 stress, ADHD, 467, 469, 480 tryptophan, 114
SLC18 gene family, 31, 35 stroke, 492, 524 tuberoinfundibular dopamine pathway,
SLC32 gene family, 31, 35 Stroop test, 450, 451 85
SLC6 gene family, 30, 31–5 subjective memory complaints, 487, 488 tuberomammillary nucleus, 406, 408
sleep sublingual formulation, 232 type 2 diabetes, 415
neurobiology of, 402–15 substance addictions, 544–75 tyramine, 338
purpose of, 414–15 substrates, 45, 46 tyrosine, 80, 252
REM and non-REM, 413, 414, 435 suicide, 145, 156 tyrosine hydroxylase, 253
sleepiness, 430–4 clozapine treatment, 223
sleep/wake cycle, 412–13 depressed patients, 251 ultradian sleep cycle, 413–16
disturbance of, 414, 416 mixed feature patients, 251 unipolar depression, 34, 244
small interfering RNA (siRNA), 27 prevention, 346 augmenting strategies for, 325–35
small nuclear RNA (snRNA), 27 suicide inhibitors, 46 drugs for, 289–325
smoking, 476, See also nicotine sulpiride, 202, 205 monoamine reuptake blockers, 285–8
cessation, 306, 573 supersensitivity, 170, 171 or bipolar, 249–51
snare proteins, 73 suprachiasmatic nucleus, 275, 307 second-line monotherapies, 333–8
SNRIs (serotonin–norepinephrine suprasegmental central sensitization, treatment resistance in, 323–38
reuptake inhibitors), 298–303 384, 390
α2δ ligand combinations, 399 suvorexant, 423 valbenazine, 177
anxiety disorders, 368 synapses, 1, 3 valproic acid (valproate), 347–50
arousal combo, 333 enlarged, 5 varenicline, 551, 552, 573
mirtazapine combination, 333 synaptic neurotransmission, 4 vascular dementia, 491–2, 534
pain treatment, 380 synaptogenesis, 151, 154 VEGF (vascular endothelial growth
triple action combo, 333 factor), 329
social anxiety disorder, 362, 372, 377 tardive dyskinesia (TD), 166 venlafaxine, 299, 302
sodium oxybate, 446–8 pathophysiology, 170–4 ventromedial prefrontal cortex, 372, 374
sodium potassium ATPase (sodium treatment, 174–81 vesicular transporter for glutamate, 99
pump), 32, 33 tasimelteon, 439 vesicular transporters, 31, 32, 35
sodium valproate, 347–50 tau protein, 488, 494, 502, 503 VIAATs (vesicular inhibitory amino acid
solriamfetol, 444 tetrabenazine, 175–6 transporters), 255
soma, 2 tetrahydrocannabinol (THC), 563, 565, vilazodone, 296–9
somatic pain, 302 567 viloxazine, 485
somatosensory cortex, 380 tetrameric ligand-gated ion channels, violence, 145–7, 575, 577–8
specific neutral amino acid transporters 54–5 visual hallucinations, 113, 524
(SNATs), 96 thalamic dopamine pathway, 85 vital sign, 381, 399, 401
spinobulbar tracts, 380 thalamo-cortical glutamate pathway, 104 VMAT1, 174
spinothalamic tract, 380 third-messenger kinase, 14, 16 VMAT2 inhibition, 174–81
SSRIs (selective serotonin reuptake third-messenger phosphatase, 15, 16 VMAT2 transporter, 31, 81, 254
inhibitors), 289–96 thyroid, 333 VMATs (vesicular monoamine
anxiety disorders, 368 tonic inhibition, 259, 263 transporters), 35
622
Index
voltage-sensitive calcium channels wake-promoting agents, 440–8 xanomeline, 242

(VSCCs), 70–3, 366, 395 wakefulness, neurobiology of, 402–15
voltage-sensitive ion channels, 66–73, 76 weight gain, 198, 224 Z drugs, 425–6
structure and function, 66 widespread pain index (WPI), 387 ziprasidone, 224, 236
voltage-sensitive sodium channels withdrawal syndrome, 546, 560 zolpidem, 423
(VSSCs), 67–70, 347, 350, 351, 381 worry, 362, 363 zopiclone, 423
volume neurotransmission, 6–9 neurobiology of, 365–9 zotepine, 221, 233
vortioxetine, 311, 315–20, 535 noradrenergic hyperactivity, 372
623

Stahl's Essential Psychopharmacology - 5th Edition

Uploaded by

Copyright:

Available Formats

Stahl's Essential Psychopharmacology - 5th Edition

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Stahl's Essential Psychopharmacology - 5th Edition

Uploaded by

Copyright:

Available Formats

25th

Stahl’s Essential Psychopharmacology

Praise for previous editions: “Essential Psychopharmacology offers a wide range

“As an MRC psychiatry student I have benefited enor-

Cambridge University Press is part of the University of Cambridge.

8 Anxiety, Trauma, and Treatment 359

• Essential Evidence-Based Psychopharmacology, 2nd The NEI Website, www.neiglobal.com

Release/expiration dates Questions? call 888-535-5600, or email

Speakers Bureau: Acadia, Lundbeck, Otsuka, Perrigo, Donna M. Wilcock, PhD

Figure 1-1 General structure of a

neurotransmission is a fundamental requirement for Understanding the chemically addressed

Classic Synaptic Neurotransmission

psychiatric disorders and their symptoms are diagnosed acetylcholine

A Figure 1-6 Volume neurotransmission. Neurotransmission

B Thus, a chemical messenger sent by one neuron to another

Volume Neurotransmission Figure 1-7 Volume neurotransmission:

Synaptic neurotransmission at 1 and diffusion to 2 and 3

diverse biological responses

Time Course of Signal Transduction Figure 1-10 Time course of signal

activation of ion channels

binding of first messenger

The first messenger

G protein can now bind to the receptor

E Figure 1-13 First messenger. In this figure, the

and subsequent chemical messengers. Having many

Figure 1-14 G protein. The next stage in producing a second

Activating a Third-Messenger Kinase through Cyclic AMP

inactive activation third messenger -

Third-Messenger Kinases Put Phosphates on Critical Proteins Figure 1-18 Third-messenger

Figure 1-20 Activation of a gene, part 1: gene

enhancer promoter coding

transcription factor is activated;

Figure 1-22 Activation of a gene, part 3:

DNA gene is activated

inactive activated "early"

Figure 1-24 Early genes activate

fifth messenger nucleus

Figure 1-25 Early genes activate late

inactive activation third messenger -

inactive fourth messenger -

late gene product and

Gene Activation and Silencing

activated gene silenced gene

mRNA (splice variant 1) mRNA (splice variant 2)

The Five Molecular Targets of Psychotropic Drugs

Enzyme 4 transmembrane region 6 transmembrane region

Table 2-1 Presynaptic monamine transporters

Transporter Common abbreviation Gene family Endogenous substrate False substrate

Transporter Common Gene Endogenous

SERT GAT VAChT VGluT

serotonin transporter GABA transporter vesicular acetylcholine vesicular glutamate

Table 2-3 Vesicular neurotransmitter transporters

Transporter Common abbreviation Gene family Endogenous substrate

G-PROTEIN-LINKED RECEPTORS function of G-protein-linked receptors and their role

The Agonist Spectrum

No Agonist: Constitutive Activity Figure 2-4 Constitutive activity. The

Full Agonist: Maximum Signal Transduction

Table 2-4 Key G-protein-linked receptors directly targeted by psychotropic drugs

Neurotransmitter G-protein Pharmacological Therapeutic