Joseph P. Goldberg & Carrie L. Ernst & Stephen M. Stahl - Managing The Side Effects of Psychotropic Medications-American Psychiatric Publishing (2012) PDF

Managing the Side Effects of
Psychotropic Medications
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Managing the Side Effects of
Psychotropic Medications
Joseph F. Goldberg, M.D., M.S.

Associate Clinical Professor of Psychiatry,
Mount Sinai School of Medicine, New York, New York;
Director, Affective Disorders Research Program,
Silver Hill Hospital, New Canaan, Connecticut
Carrie L. Ernst, M.D.

Assistant Professor of Psychiatry and Assistant Director
of the Psychosomatic Medicine Fellowship Program,
Mount Sinai School of Medicine, New York, New York
Washington, DC
London, England
Note: The authors have worked to ensure that all information in this book is
accurate at the time of publication and consistent with general psychiatric and
medical standards, and that information concerning drug dosages, schedules,
and routes of administration is accurate at the time of publication and consis-
tent with standards set by the U.S. Food and Drug Administration and the gen-
eral medical community. As medical research and practice continue to advance,
however, therapeutic standards may change. Moreover, specific situations may
require a specific therapeutic response not included in this book. For these rea-
sons and because human and mechanical errors sometimes occur, we recom-
mend that readers follow the advice of physicians directly involved in their care
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Library of Congress Cataloging-in-Publication Data
Goldberg, Joseph F., 1963–
Managing the side effects of psychotropic medications / by Joseph F.
Goldberg, Carrie L. Ernst. — 1st ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-58562-402-7 (alk. paper)
I. Ernst, Carrie L., 1975– II. American Psychiatric Publishing. III. Title.
[DNLM: 1. Psychotropic Drugs—adverse effects. QV 77.2]
615.788—dc23
2011039535
British Library Cataloguing in Publication Data

A CIP record is available from the British Library.
To our children, Joshua, Brian, and Hannah,
for their patience, encouragement, and love;
to our parents, Ethel and Daniel Goldberg, and Arline and Robert Zinaman,
for their commitment and omnipresence;
and to each other,

for everything in between.
Contents
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxiii
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . xxvii
List of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxix
PART I
General Considerations
1 The Psychiatrist as Physician . . . . . . . . . . . . . . . . . . . 3
Primary Care Psychiatry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Differentiating Adverse Drug Effects
From Primary Illness Symptoms . . . . . . . . . . . . . . . . . . . . . . 7
The Nocebo Phenomenon and
Proneness to Adverse Effects. . . . . . . . . . . . . . . . . . . . . . . . 16
Negative Therapeutic Reactions . . . . . . . . . . . . . . . . . . . . 20
Attribution and Causality . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Paradoxical Adverse Effects. . . . . . . . . . . . . . . . . . . . . . . . . 23
Extrapolating “Evidence-Based
Research Findings” to “Real-World” Patients . . . . . . . . . 26
Dose Relationships and Adverse Effects . . . . . . . . . . . . . . 28
FDA Warnings and Precautions . . . . . . . . . . . . . . . . . . . . . 32
Risk-Benefit Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
General Approach to Assessing
Adverse Drug Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2 Pharmacokinetics, Pharmacodynamics,
and Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . 47
Pharmacokinetics and Pharmacodynamics. . . . . . . . . . . 47
Toxic Polypharmacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Gender and Racial Differences in Adverse Effects . . . . . 57
Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Brand Versus Generic Formulations . . . . . . . . . . . . . . . . . 60
Enantiomeric Versus Racemic Agents, and
Parent Versus Metabolite Compounds . . . . . . . . . . . . . . . 61
Drug Blood Levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Pharmacogenomic Predictors of Adverse Effects . . . . . . 63
3 Vulnerable Populations . . . . . . . . . . . . . . . . . . . . . . 71
Patients’ Diverse Proneness to Drug Side Effects . . . . . . 71
Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Medically Ill Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Patients Prone to Somatization . . . . . . . . . . . . . . . . . . . . . 76
4 Adverse Psychiatric Effects of

Nonpsychotropic Medications . . . . . . . . . . . . . . . . 83
Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Anticholinergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Antineoplastics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Antiparkinsonian Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Antiretroviral Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Cardiovascular Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Dermatological Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Gastrointestinal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Interferon-α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Oral Contraceptives and Intravaginal Rings . . . . . . . . . . 93
Smoking Cessation Aids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
5 Adverse Psychiatric Effects of

Psychiatric Medications. . . . . . . . . . . . . . . . . . . . . . .97
Activation and Mania/Hypomania
or Mixed States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Anxiety and Panic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Clinical Trial Subjects With Psychiatric Illness . . . . . . . 100
Discontinuation Phenomena . . . . . . . . . . . . . . . . . . . . . . 101
Disinhibition and Impaired Impulse Control . . . . . . . . 101
Emotional Dulling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Suicidal Thinking or Behavior. . . . . . . . . . . . . . . . . . . . . . 103
6 What Nonmedical Therapists

Should Know About Adverse Drug Effects . . . . . 105
PART II
Organ Systems
7 Cardiovascular System . . . . . . . . . . . . . . . . . . . . . 113

Arrhythmias and Palpitations . . . . . . . . . . . . . . . . . . . . . .113
Cerebrovascular Accidents . . . . . . . . . . . . . . . . . . . . . . . . . 122
Dyslipidemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Myocarditis and Cardiomyopathy. . . . . . . . . . . . . . . . . . 139
Orthostatic Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
8 Dermatological System . . . . . . . . . . . . . . . . . . . . . 141

Alopecia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Hyperhidrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Photosensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .143
Pruritus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Skin Rashes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
9 Ear, Nose, and Throat . . . . . . . . . . . . . . . . . . . . . . . 155

Bruxism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Dysarthria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Dysgeusia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Oral Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Sialorrhea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Stomatodynia (Burning Mouth Syndrome) . . . . . . . . . . 161
Xerostomia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
10 Electrolyte Abnormalities . . . . . . . . . . . . . . . . . . . 163

Hyponatremia and SIADH . . . . . . . . . . . . . . . . . . . . . . . . . 163
Metabolic Acidosis and Alkalosis . . . . . . . . . . . . . . . . . . . 166
11 Endocrinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Bone Demineralization and Osteoporosis . . . . . . . . . . . 169
Glycemic Dysregulation and Diabetes Mellitus . . . . . . 170
Hyperprolactinemia, Galactorrhea, and
Gynecomastia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Menstrual Disturbances and
Polycystic Ovary Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 178
Parathyroid Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . 179
Thyroid Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
12 Gastrointestinal System . . . . . . . . . . . . . . . . . . . . 187

Diarrhea, Hypermotility, and Constipation . . . . . . . . . . 187
Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . 188
Hepatic Impairment and Transaminitis . . . . . . . . . . . . . 189
Hyperammonemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Malabsorption Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . 196
Nausea and Gastrointestinal Upset . . . . . . . . . . . . . . . . . 197
Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
13 Genitourinary and Renal Systems. . . . . . . . . . . . 201
Dysuria and Urinary Retention . . . . . . . . . . . . . . . . . . . . . 201
Enuresis and Urinary Incontinence. . . . . . . . . . . . . . . . . 202
Nephrotic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Nephrotoxicity and Nephrogenic
Diabetes Insipidus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Priapism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Renal Calculi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Renal Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Sexual Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
14 Hematological System . . . . . . . . . . . . . . . . . . . . . . 231

Myelosuppression: Agranulocytosis
and Thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . .231
Platelet Aggregation Disorders
and Bleeding Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Red Blood Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
15 Musculoskeletal System . . . . . . . . . . . . . . . . . . . . 239

Joint Pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
Leg Cramps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
Myalgias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .241
16 Neurological System . . . . . . . . . . . . . . . . . . . . . . . 243

Akathisia and Extrapyramidal Adverse Effects . . . . . . . 243
Cognitive Complaints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Delirium and Encephalopathy . . . . . . . . . . . . . . . . . . . . . .247
Dyskinesias and Dystonias . . . . . . . . . . . . . . . . . . . . . . . . . 250
Fatigue and Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .257
Motor Tics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
Muscle Twitching, Fasciculations, and Myoclonus . . .261
Nystagmus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
Oculogyric Crises. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Paresthesias and Neuropathies . . . . . . . . . . . . . . . . . . . . 266
Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Tinnitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
Tremor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
Yawning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
17 Ophthalmological System . . . . . . . . . . . . . . . . . . . 273

Cataracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Diplopia/Blurred Vision. . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Retinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
18 Sleep Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . 277

Hypersomnia and Sleep Attacks . . . . . . . . . . . . . . . . . . . . 277
Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
Nightmares and Vivid Dreams . . . . . . . . . . . . . . . . . . . . . 285
Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
19 Systemic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 289

Allergic Reactions and Angioedema . . . . . . . . . . . . . . . . 289
Antiepileptic Hypersensitivity Reactions . . . . . . . . . . . . 290
Body Temperature Dysregulation . . . . . . . . . . . . . . . . . . 291
Discontinuation Syndromes. . . . . . . . . . . . . . . . . . . . . . . . 291
Drug-Induced Lupus Erythematosus . . . . . . . . . . . . . . . 293
Neuroleptic Malignant Syndrome . . . . . . . . . . . . . . . . . . 294
Serotonin Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Weight Gain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
Weight Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
20 Pregnancy and the Puerperium . . . . . . . . . . . . . . 331

Breast-Feeding and Adverse Events . . . . . . . . . . . . . . . . 332
Growth Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
Teratogenicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
Withdrawal in the Newborn . . . . . . . . . . . . . . . . . . . . . . . 335
21 Emergency Situations . . . . . . . . . . . . . . . . . . . . . . 339

PART III
Summary Recommendations
22 Summary Recommendations . . . . . . . . . . . . . . . . 359

The Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
Appendix 1: Self-Assessment Questions and

Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
Appendix 2: Resources for Practitioners . . . . . . . . 381
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
Foreword
Managing the Side Effects of Psychotropic Medications by Drs. Goldberg and

Ernst provides important information that is otherwise unavailable in
psychopharmacology textbooks. The book is a thoughtful yet practical
compendium of why psychotropic drugs cause side effects and what to do
about them. We practitioners are inundated with clinical trial data that
generally emphasize efficacy over tolerability. If results from randomized
controlled trials generate efficacy information that is sometimes difficult
to figure out how to apply in a clinical practice setting, translating tolera-
bility data from these trials into what to expect in terms of side effects in a
real-world setting can be even more difficult. Often, relevant information
on tolerability is simply lacking because of the way that these data are col-
lected and presented for regulatory purposes. Furthermore, the data on
side effects usually end up in a blizzard of unreadable small-font package
inserts from the U.S. Food and Drug Administration (FDA) or buried in
clinical trial reports on sometimes obscure Web sites. We consult these
sources to learn about side effects, but frequently we find such sources of
information not very useful because these data really are presented as
rules for what pharmaceutical sales personnel can say and not guidelines
for how to practice psychiatry. It takes the approach adopted here by
Drs. Goldberg and Ernst to help us know the straight story on what really
to expect and what to do when we see the unexpected.
How do these authors do it? They combine comprehensive and schol-
arly coverage of just about everything that can happen after taking a psy-
chotropic drug, with pragmatic, old-fashioned “bedside” tips and pearls
about how to manage these problems, explaining the rationale and not
merely giving empirical instructions. Their advice makes sense, and thus
readers are likely to use this information. I found myself learning a number
of things I did not know, remembering numerous facts I had long forgot-
ten, and comprehending a number of points that I knew empirically but
did not really understand. For example, I particularly enjoyed the section
xv
xvi Managing the Side Effects of Psychotropic Medications
helping me to become an amateur dermatologist and the tables on sexual

dysfunction and weight gain. Rashes freak out most psychiatrists, and sex-
ual dysfunction and weight gain are the kiss of death for adherence by most
patients, and I very much appreciated the advice of the authors. There are
many other examples of particularly helpful areas, ranging from what is
the most common to what is the most dangerous. Every reader will have
his or her own response to the various sections, but probably no reader
knows all of the information presented here, and thus every clinician is
likely to benefit from this text in a very unique and personalized manner.
The fingerprints of wise clinician-authors are all over this text, as ex-
emplified by the way they set a context, weigh the strength of the evi-
dence honestly, and discuss broad as well as niche issues. For example,
their discussion in Chapter 1, “The Psychiatrist as Physician,” on the no-
cebo phenomenon (a particularly frustrating bugaboo for me in clinical
practice) gently reminded me that some patients, for their own psycho-
dynamic reasons, try to frustrate our helping efforts rather than align
with them. Where do readers ever see that topic discussed in a textbook
of psychopharmacology or a manufacturer’s package insert?
The authors also deconstruct complex situations into understandable
component parts, ranging from the pharmacokinetic, with useful resur-
rection of often-neglected use of judicious and targeted therapeutic drug
monitoring, to the pharmacodynamic, explicating one drug and one
mechanism at a time in a specialty filled with combination treatments. The
authors grab the bull by the horns to grapple with the question of what
does a clinician do when certain side effects cannot be avoided—resolving
this quandary by providing thoughtful approaches on how to weigh risks
with benefits—and reminding us that sometimes greater benefits come
with justifiable but necessarily greater risks. This is an example of how
these authors handle numerous and quite sophisticated clinical issues.
That is, not only do the authors tell readers a lot, because the authors
clearly know a lot, but they also present information in a way that reminds
us that it is not enough to know it all. In fact, it is only realistic to have all
the information available in a reference source such as this and not com-
plete in our memory. However, the authors leave us with something else:
they impart a bit of wisdom, which is what we learn after we know it all.
Welcome to a valuable and unique work of practical scholarship to
help readers on their voyage throughout the entire field of psychophar-
macology.
Stephen M. Stahl, M.D., Ph.D.

Adjunct Professor of Psychiatry, University of California San Diego;
Honorary Visiting Senior Fellow, University of Cambridge, United Kingdom
Preface
To understand the adverse effects of a medication means to fully appre-

ciate its effects on the body. The pharmacodynamic and pharmacoki-
netic profile of a drug is manifested by the entirety of its actions,
intended and unintended, beneficial or adverse, expected or unex-
pected. We undertook the writing of this book to help mental health
practitioners better understand the consequences of drug therapies
they may prescribe (or avoid), the range of available strategies to effec-
tively manage adverse effects, and the scientific and practical implica-
tions of their treatment decisions.
For our purposes, we interchangeably use the terms adverse effect and
side effect to indicate any undesirable or unintended pharmacodynamic
event that is separate from the intended main effects of a medication. It
is important to recognize that side effects are sometimes capitalized on
for some beneficial action—as in the case of soporific effects caused by
strong histamine H1 receptor antagonists such as quetiapine or mirtaza-
pine, or the appetite suppressant and weight-loss effects associated
with a drug such as topiramate—but not to confuse such a pharmaco-
dynamic by-product with the intended main effects of a drug.
The following are some of the numerous questions that need to be
considered when deciding whether to manage an adverse drug effect or
instead change primary treatments altogether: How medically serious
is an apparent side effect? Is it likely transient or enduring? How exten-
sive and efficacious are the available strategies that might remedy an
adverse effect? How severe is the primary psychiatric illness itself?
How unique is the response of an illness to a particular treatment de-
spite its side-effect burden?
Strategies to best anticipate, identify, and manage drug side effects
vary considerably. Sometimes, fairly extensive databases exist, compar-
ing different types of interventions that have been empirically studied
to counteract a well-known side effect, with varying levels of scientific
xvii
xviii Managing the Side Effects of Psychotropic Medications
rigor and support (e.g., antidotes for antidepressant-induced sexual

dysfunction); at other times, little or no empirical data are available
apart from anecdotal experience. Overreliance on anecdotal impres-
sionism incurs the risk of forming wrong or scientifically implausible
inferences about cause and effect (e.g., the casual impression that bone
marrow toxicity seems especially likely to happen with morning versus
evening dosing of a given drug, or the perception that weight gain oc-
curs less often if a medication is ingested on an empty stomach). At the
opposite extreme, when controlled trials do exist that study interven-
tions to counteract a drug side effect, they may have limited value be-
cause they are seldom conducted with adequate statistical power to
stratify or control for possible confounding factors (e.g., medications
that are intended to counteract psychotropic-induced weight gain may
vary in efficacy depending on which agents cause the weight gain, pa-
tients’ baseline body mass index and other clinical features, concomi-
tant therapies, and other relevant characteristics). Pharmacotherapy
trials undertaken by industry sponsors are usually driven by the pur-
suit of product indications from the U.S. Food and Drug Administration
(FDA), rather than by initiatives to counteract (and draw attention to)
the adverse effects of a proprietary drug—in other words, there is a
dearth of systematic research on the treatment of side effects.
Because the information that exists about options for managing side
effects is often variable in volume and content, we have prefaced dis-
cussions about many clinical problems with general recommendations
that synthesize research-based findings with our own clinical experi-
ence to provide “bottom-line” suggestions for clinical management. A
balance always needs to be struck between scientifically grounded, em-
pirically studied interventions (which often require extrapolation to
heterogeneous patient groups) and homespun remedies that may be too
idiosyncratic or untested to be considered generalizable. For situations
in which little or no data are available in the literature to inform treat-
ment recommendations specific to counteracting adverse drug effects,
we have relied on clinical experience, theoretical rationales, and infer-
ences from other areas to the extent doing so seemed appropriate. Al-
though virtually all of the suggested pharmacological strategies to
counteract adverse drug effects that are described in this volume are
“off label,” we sought to assure that they are scientifically plausible and
informed by the experience of empirical observations.
We deliberated over how annotated a text of this nature should be.
Our purpose was to provide a readable and accessible compendium of
practical information for busy clinicians, rather than a comprehensive,
scholarly review of the supportive literature for any and all possible iat-
Preface xix
rogenic drug effects. We therefore supplemented our own clinical expe-

rience with selective literature reviews when it seemed wise to do so,
citing pertinent randomized trials, open trials, and case reports where
useful. Where data were lacking on issues that clinical experience alone
seemed insufficient to offer recommendations, we contacted pharma-
ceutical manufacturers to determine the availability of information on
areas of clinical concern (e.g., the cross-sensitivity of anticonvulsant
rashes with sulfa antibiotics). The citation of individual case reports al-
ways poses difficulties for purposes of generalizability; they provide a
very limited degree of evidence that may point to an association be-
tween an intervention and an untoward outcome, and their purpose in
the literature is more to prompt thinking or generate hypotheses rather
than test them. On the other hand, for purposes of a book such as this,
case reports afford documentation not on the incidence or generalizabil-
ity of an adverse effect, but rather of the recognition and plausibility for
a suspected link between a treatment and an outcome.
We have strived to provide a reasonably thorough review of com-
mon or clinically important adverse effects while at the same time offer-
ing a context that does not overstate trivial or obscure reported side
effect that have little relevance to everyday practice. Sufficient detail is
crucial for practitioners to feel they are well equipped to manage such
bread-and-butter issues as psychotropic-induced weight gain, metabolic
dysregulation, sexual dysfunction, skin rashes, sleep disturbances, cogni-
tive complaints, and other neurological concerns. Our hope is that read-
ers will gain a greater sense of confidence in their medical decision
making and comfort level in understanding, anticipating, and managing
(rather than simply avoiding) the relative risks of psychotropic agents.
The book has been divided into three main sections. Part I deals with
global issues that bear on the assessment and formulation of possible ad-
verse effects and with pertinent concepts related to basic pharmacology,
physiology, and medical monitoring. The chapters in Part II present in-
formation organized by individual organ systems or specific medical cir-
cumstances rather than by drugs or drug classes. This approach seems to
provide a logical and comprehensible format that allows readers to
search out information as referenced by a particular side effect (and its
varied potential causes) and to locate a discussion of practical manage-
ment strategies. Part III focuses on summary recommendations covering
all the material presented in the book and is followed by helpful appen-
dixes on self-assessment questions and resources for practitioners. The
book is meant to serve as a ready reference that simultaneously provides
scientific and scholarly discussion of available treatment options and
presents their scientific rationales.
xx Managing the Side Effects of Psychotropic Medications
Clinicians who teach medical students and psychiatry residents, who

collaborate with colleagues from other medical disciplines, and who treat
many patients quickly realize that skillful psychopharmacology demands
a reasonable working knowledge of primary care medicine—a knowledge
base that is often minimally addressed during most internships or residen-
cies in psychiatry—and remarkably, is seldom incorporated into formal
continuing medical education activities for psychiatrists. This book is in-
tended as a tool to help bridge that educational gap.
We are deeply grateful to a number of colleagues who have kindly
offered their expertise and provided us with helpful comments on sec-
tions of this book, including Ross J. Baldessarini, M.D., Lesley Berk,
M.A., Elisabeth C. Carpenter, M.S.W., L.C.S.W., David Colbert, M.D.,
Howard Eison, M.D., Marlene Freeman, M.D., Glen O. Gabbard, M.D.,
Steven Glazer, M.D., James W. Jefferson, M.D., Ethan Kisch, M.D.,
Henry Nasrallah, M.D., Janet Rucker, M.D., Sheldon Preskorn, M.D.,
Stephen M. Stahl, M.D., Ph.D., Kimberly Yonkers, M.D., and Rachel Zi-
naman-Fischer, M.P.A., R.D., C.D.N.
As clinicians and educators, we could not have undertaken this task
without the stimulation provided by our patients, students, and col-
leagues. A tremendous sense of gratification comes from being able to
explain in clear and simple terms how and why an intervention causes
an understandable effect—whether desirable or undesirable—and from
navigating through logical strategies to maximize benefits while mini-
mizing risks. At its best, medical decision-making hinges on thoughtful
deliberation and problem solving—reflecting the capacity to integrate
the clinician’s own experience with an awareness of empirically vali-
dated findings and the ability to differentiate between problems caused
by diseases and problems caused by their intended remedies. The sum
of these skills finds its ultimate expression in the ability to balance treat-
ment risks and benefits with logic, forethought, and wisdom.
Joseph F. Goldberg, M.D., M.S.

Carrie L. Ernst, M.D.
Disclosures of Interest xxi
Disclosures of Interest
The authors of this book have indicated a financial interest in or other affiliation with a
commercial supporter, a manufacturer of a commercial product, a provider of a commercial
service, a nongovernmental organization, and/or a government agency, as listed below:
Joseph F. Goldberg, M.D., M.S. Speakers’ bureau: AstraZeneca, Dey

Pharma, L.P., Eli Lilly & Co., Merck, Sunovion Pharmaceuticals; Advisor/consul-
tant: Axon Advisors, Dey Pharma, L.P., Eli Lilly & Co., Grünenthal Group, Med-
scape; Major stockholder: None; Employee: None
Carrie L. Ernst, M.D., is married to Joseph F. Goldberg, M.D., and has no in-
dependent competing interests to disclose.
Introduction
Managing the Side Effects of Psychotropic Medications represents a major

scholarly undertaking to organize and compile information on a large,
growing, and constantly changing topic at the interfaces of psychiatry,
general medicine, and pharmacology. Drs. Goldberg and Ernst present
extensive, detailed, well-documented, and reliable information on the
many adverse effects associated with clinical use of psychotropic drugs.
The volume is organized into three major parts. The first addresses gen-
eral topics, including the essential role of the psychiatrist as physician,
principles of general pharmacology as they apply to adverse effects of
psychotropic drugs, consideration of vulnerable populations including
children and the elderly, psychiatric effects of drugs employed in gen-
eral medicine, and general principles and features of adverse effects of
psychotropic drugs. The second part provides detailed information or-
ganized by organ systems or specific medical circumstances. These in-
clude cardiovascular, dermatological, otolaryngological, electrolyte,
endocrinological, gastrointestinal, urogenital and renal, hematological,
musculoskeletal, neurological, and ophthalmological effects, as well as
sleep, systemic-metabolic, perinatal, and emergency considerations.
The third part contains summary recommendations and is followed by
helpful reference appendixes for the reader.
The breadth and depth of coverage mark this book as an essential
reference work for clinicians dealing with psychiatric patients and with
psychotropic agents. The material is presented in a clear and accessible
manner, with many useful summarizing tabulations of essential infor-
mation. Some aspects of this broad topic can be found in comprehensive
textbooks of psychopharmacology (e.g., Schatzberg and Nemeroff
2009), in sections of comprehensive textbooks of pharmacology (e.g.,
Baldessarini 2005; Baldessarini and Tarazi 2005), or in volumes devoted
to specific topics in psychopharmacology (e.g., Gardner and Teehan
2011). My own monograph on psychopharmacology emphasizes the
xxiii
xxiv Managing the Side Effects of Psychotropic Medications
need to balance risks and benefits of psychotropic drugs by analogy to

chemotherapy for cancer (Baldessarini 2012). Nevertheless, this book by
Drs. Goldberg and Ernst is unique as a comprehensive summary of in-
formation on the broad range of adverse effects associated with psycho-
tropic drugs, organized from a medical perspective rather than by drug
classes, illness types, or clinical indications.
It is difficult to conceive of practicing modern clinical psychiatry
without heavy reliance on psychotropic drugs, whose effects have rev-
olutionized the practice and theory of modern psychiatry. Nevertheless,
their safe and effective application requires a healthy respect for their
risks of particular adverse effects, which range from uncomfortable to
life threatening. Moreover, these risks need to be balanced against the
important, though imperfect and limited, benefits of this significant
class of drugs. It is also important to emphasize that major psychiatric
disorders have the potential of shortening longevity, certainly by sui-
cide but also by common comorbid general medical conditions (Chang
et al. 2010; Ösby et al. 2001). In addition, there is growing concern that
some adverse effects of psychotropic drugs may, themselves, contribute
to mortal risks, especially by exerting a long-term adverse impact on
general health. In this context, the term side effect calls for specific com-
ment. Although in very common daily usage by physicians and by the
general public, the term is somewhat euphemistic. It risks minimizing
the potentially serious impact of adverse effects ascribed to psychotro-
pic or other drugs. Adverse effects that may be considered of relatively
minor clinical importance can produce significant discomfort for pa-
tients and contribute importantly to patient nonadherence to recom-
mended treatments. Omitting or stopping sustained treatment with
most psychotropic drugs also presents major clinical risks of illness re-
currences (Baldessarini et al. 2010). Ironically, however, discontinuing
these medications typically leads to feeling better in the short term and
can encourage further nonadherence.
If I were to define a thesis underlying this book, it may well be the
authors’ call for a return of psychiatry to the mainstream of general
medicine. This is an old and recurring theme in the history of psychia-
try. As the specialties emerged in the nineteenth century, there was a
growing separation of neurology from the work of “alienists” who often
worked in separate mental asylums. By the end of the century, the sep-
aration was so extreme that neurologist Silas Weir Mitchell (1894/1994)
provided a scathing rebuke to psychiatrists in the 1890s:
Introduction xxv
You were the first of the specialists and you have never come back into
line. It is easy to see how this came about. You soon began to live apart,
and you still do so. Your hospitals are not our hospitals; your ways are
not our ways. You live outside the range of critical shot; you are not pre-
ceded and followed in your ward work by clever rivals or watched by
able residents fresh with the learning of the schools. ... (p. 414).
The concerns expressed by Mitchell over a century ago became fur-

ther accentuated, particularly in North American psychiatry, by domi-
nation of the field by psychodynamic theory and practice throughout
the mid-twentieth century. One can argue that the introduction of mod-
ern psychopharmacology with lithium carbonate in 1949 and chlorpro-
mazine in 1952 revolutionized the care of the seriously mentally ill and
the basis of psychiatric theory (Baldessarini 2000). The safe and effective
application of these and other early psychotropic drugs brought an in-
creasing need for basic medical competence to clinical psychiatry. Many
newer psychotropic drugs have been promoted as safer and easier to
use than those introduced in the 1950s and 1960s. However, advances in
the discovery of more effective treatments have been remarkably lim-
ited, and risks of adverse effects have continued, changed, and become
more varied. These circumstances, as well as the very complexity of the
growing numbers of psychotropic agents and their increasingly com-
mon, but largely untested, empirical application in complex combina-
tions, make this book particularly significant and timely.
Regarding the proposed thesis of this book—the need for greater
general medical competence among psychiatrists, particularly in dealing
with adverse effects of psychotropic drugs—Drs. Goldberg and Ernst
take a provocative and somewhat idealistic position for the twenty-first
century. They recommend that psychiatrists practice more like primary
care physicians, including in the medical examination of patients. This
proposal is highly laudable but markedly at variance with current clini-
cal practice as seen in most private offices and in many psychiatric and
general medical institutions in the United States. Moreover, the chal-
lenge of efficient diagnosis and treatment of adverse effects of treatment
is not readily solved by collaborations and shared clinical responsibility
among specialists, given severe limitations imposed on dependable
communications by time constraints and other artifacts of current Amer-
ican medical economics. Perhaps what is required is a reconsideration of
the system of education and training of both primary care physicians and
psychiatrists, aiming to foster a greater common ground for them to
xxvi Managing the Side Effects of Psychotropic Medications
share, and to facilitate more routine, bilateral, consultative interactions.

Such changes should have major salutary effects on the kinds of prob-
lems addressed in this book.
Ross J. Baldessarini, M.D.

Professor of Psychiatry and in Neuroscience,
Harvard Medical School, Boston, Massachusetts;
Director, Psychopharmacology Program and
International Consortium for Bipolar & Psychotic Disorders Research,
McLean Division of Massachusetts General Hospital;
Senior Consulting Psychiatrist, Massachusetts General Hospital;
McLean Hospital, Belmont, Massachusetts
List of Abbreviations
The following abbreviations are used frequently throughout this book

without being spelled out.
ACE angiotensin-converting enzyme

ADHD attention-deficit/hyperactivity disorder
bid twice daily
BMI body mass index
CATIE Clinical Antipsychotic Trials of Intervention Effectiveness
CBC complete blood count
CI confidence interval
Cmax maximal drug plasma concentration
CNS central nervous system
CR controlled release
CYP cytochrome P450
DR delayed release
EPS extrapyramidal symptoms
ER extended release
FDA U.S. Food and Drug Administration
FGA first-generation antipsychotic
GABA γ-aminobutyric acid
GAD generalized anxiety disorder
HDL high-density lipoprotein
IgE immunoglobulin E
INR international normalized ratio
IR immediate release
LA long acting (sustained release)
LDL low-density lipoprotein
MAOI monoamine oxidase inhibitor
NMS neuroleptic malignant syndrome
NNH number needed to harm
NNT number needed to treat
NSAID nonsteroidal anti-inflammatory drug
OCD obsessive-compulsive disorder
po by mouth
xxvii
xxviii Managing the Side Effects of Psychotropic Medications
prn as needed
qd once a day
qid four times daily
SGA second-generation antipsychotic
SNRI serotonin-norepinephrine reuptake inhibitor
SR sustained release
SSRI selective serotonin reuptake inhibitor
TCA tricyclic antidepressant
tid three times daily
XL extended release
XR extended release
List of Drugs
The following drugs mentioned or discussed in this book are listed al-
phabetically by drug class, with brand names in parentheses following
the generic name (only generic names are used in the text). For classifi-
cation of topical steroids for dermatological conditions, see Table 8–3.
Alcohol abuse or dependence treatments

Acamprosate (Campral)
Naltrexone (Revia) [opioid receptor antagonist]
Alzheimer’s disease medications
Acetylcholinesterase inhibitors
Donepezil (Aricept)
Galantamine (Razadyne, Reminyl)
NMDA receptor antagonists
Memantine (Namenda)
Analgesics (nonnarcotic)
Acetaminophen (Tylenol)
Phenazopyridine (Pyridium) [urinary tract local analgesic]
Tramadol (Ultram) [agonist at µ-opioid receptor, serotonin-
releasing agent, norepinephrine reuptake inhibitor]
Antiarrhythmics
Amiodarone (Cordarone) [Class III antiarrhythmic]
Disopyramide (Norpace) [Class Ia antiarrhythmic]
Flecainide (Tambocor) [Class Ic antiarrhythmic]
Procainamide (Pronestyl) [Class Ia antiarrhythmic]
Propafenone (Rythmol) [Class Ic antiarrhythmic]
Sotalol (Betapace) [Class III antiarrhythmic and β-blocker]
Antibiotics
Azithromycin (Zithromax)
Ciprofloxacin (Cipro)
Clarithromycin (Biaxin)
Erythromycin (E-Mycin)
Gemifloxacin (Factive)
xxix
xxx Managing the Side Effects of Psychotropic Medications
Antibiotics (continued)
Levofloxacin (Levaquin)
Lomefloxacin (Maxaquin)
Moxifloxacin (Avelox)
Norfloxacin (Noroxin)
Ofloxacin (Floxin)
Rifampin (Rifadin, Rimactane)
Rufloxacin (Ruflox)
Trimethoprim-sulfamethoxazole (Bactrim)
Anticholinergc agents (all antimuscarinic)
Benztropine (Cogentin) [H1 antihistamine/antiparkinsonian]
Glycopyrrolate (Robinul)
Ipratropium bromide (Atrovent spray) [inhaler]
Orphenadrine (Norflex) [H1 antihistamine/antispasmodic
analgesic, for muscle injuries]
Oxybutynin (Ditropan) [bladder antispasmodic; treatment for
urinary urgency/incontinence
Solifenacin (VESIcare) [bladder antispasmodic; treatment for
urinary urgency]
Tolterodine (Detrol) [treatment for urinary incontinence]
Trihexyphenidyl (Artane) [antiparkinsonian]
Anticoagulants
Warfarin (Coumadin)
Anticonvulsants
Carbamazepine (Tegretol, Equetro)
Divalproex or valproic acid (Depakote, Depakene)
Gabapentin (Neurontin)
Gabapentin enacarbil (Horizant)
Lamotrigine (Lamictal)
Levetiracetam (Keppra)
Oxcarbazepine (Trileptal)
Phenytoin (Dilantin)
Primidone (Mysoline)
Topiramate (Topamax)
Antidepressants
Amitriptyline (Elavil)
Bupropion (Wellbutrin, Zyban)
Citalopram (Celexa)
Desipramine (Norpramin)
Desvenlafaxine (Pristiq)
Doxepin (Silenor, Sinequan)
Duloxetine (Cymbalta)
Escitalopram (Lexapro)
List of Drugs xxxi
Antidepressants (continued)
Fluoxetine (Prozac, Sarafem)
Fluvoxamine (Luvox)
Imipramine (Tofranil)
Isocarboxazid (Marplan)
Maprotiline (Ludiomil)
Mirtazapine (Remeron)
Moclobemide (Aurorix, Manerix)
Nefazodone (Serzone)
Nortriptyline (Pamelor)
Paroxetine (Paxil)
Phenelzine (Nardil)
Sertraline (Zoloft)
Transdermal selegiline (Emsam)
Tranylcypromine (Parnate)
Trazodone (Desyrel)
Venlafaxine (Effexor)
Vilazodone (Viibryd)
Antidiarrheal agents
Loperamide (Imodium) [opioid receptor agonist]
Antiemetic/antinausea agents
Metoclopramide (Reglan) [gastroprokinetic]
Ondansetron (Zofran) [5HT3 receptor antagonist]
Prochlorperazine (Compazine)
Trimethobenzamide (Tigan)
Antiestrogen agents
Letrozole (Femara) [aromatase inhibitor]
Tamoxifen (Nolvadex) [estrogen receptor antagonist]
Antifungal agents
Ketoconazole (Feoris, Nizoral)
Antihistamines
Cetirizine (Zyrtec)
Cyproheptadine (Periactin)
Diphenhydramine (Benadryl)
Hydroxyzine (Atarax, Vistaril)
Loratadine (Claritin)
Promethazine (Phenergan) [phenothiazine derivative]
Antihypertensive agents
ACE inhibitors
Enalapril (Vasotec)
Lisinopril (Zestril)
Ramipril (Altace)
xxxii Managing the Side Effects of Psychotropic Medications
Antihypertensive agents (continued)

α 2-Adrenergic agonists
Clonidine (Catapres)
Guanfacine (Tenex)
α 1-Adrenergic antagonists
Doxazosin (Cardura)
Phentolamine (Regitine)
Prazosin (Minipress)
Terazosin (Hytrin)
β-Blockers
Atenolol (Tenormin)
Betaxolol (Kerlone)
Metoprolol (Toprol)
Propranolol (Inderal)
Calcium channel blockers
Amlodipine (Norvasc)
Amlodipine plus atorvastatin (Caduet)
Isradipine (Dynacirc)
Nifedipine (Adalat, Procardia)
Verapamil (Calan, Verelan)
Antimalarial agents
Chloroquine (Aralen)
Mefloquine (Lariam)
Antimanic treatments (see also certain anticonvulsants)
Lithium carbonate (Lithobid, Eskalith)
Antineoplastic agents
Chlorambucil (Leukeran)
5-fluorouracil (Adrucil, Efudex)
Ifosfamide (Ifex)
Procarbazine (Matulane)
Rituximab (Rituxan)
Antiparkinsonian agents
Amantadine (Symmetrel) [dopamine and norepinephrine agonist]
Biperiden (Akineton) [antimuscarinic]
Anxiolytics (nonbenzodiazepine)
Buspirone (Buspar)
Attention-deficit/hyperactivity disorder treatments (nonstimulant)
Atomoxetine (Strattera)
Guanfacine (Tenex) [α 2 -agonist]
Bronchodilators (beta agonists)
Albuterol (Ventolin)
List of Drugs xxxiii
Calcimimetics
Cinacalcet (Sensipar)
Cholinergic agonists
Bethanechol (Urecholine) [muscarinic]
Diabetes insipidus treatments
Desmopressin intranasal spray (DDAVP)
Diuretics
Amiloride (Midamor)
Hydrochlorothiazide (Microzide, Oretic, Apo-Hydro)
Hydrochlorothiazide plus triamterene (Dyazide)
First-generation antipsychotics
Chlorpromazine (Thorazine)
Haloperidol (Haldol)
Mesoridazine (Serentil)
Molindone (Moban)
Perphenazine (Trilafon)
Pimozide (Orap)
Thioridazine (Mellaril)
Thiothixene (Navane)
Gastrointestinal agents
Antispasmodics
Dicyclomine (Bentyl)
Pirenzepine (Gastrozepin) [muscarinic antagonist, reduces
gastric acid secretion]
Other agents for minor gastrointestinal distress
Bismuth subsalicylate (Pepto-Bismol, Kaopectate)
Histamine H2 inhibitors
Cimetidine (Tagamet)
Nizatidine (Axid)
Omeprazole (Prilosec)
Ranitidine (Zantac)
HIV treatments
Antiretroviral agents
Zidovudine or azidothymidine (AZT) (Retrovir)
Nonnucleoside reverse transcriptase inhibitors
Efavirenz (Sustiva)
Immunosuppressants
Azathioprine (Imuran)
Basiliximab (Simulect)
Cyclosporine (Neoral, Sandimmune)
Muromonab-CD3 (Orthoclone OKT3)
Mycophenolate mofetil (CellCept)
xxxiv Managing the Side Effects of Psychotropic Medications
Immunosuppressants (continued)
Rapamycin or sirolimus (Rapamune)
Tacrolimus (Prograf)
Lipid-lowering agents
Fibrates
Clofibrate (Atromid-S)
Fenofibrate (Tricor)
Gemfibrozil (Lopid)
Inhibitors of intestinal cholesterol absorption
Ezetimibe (Zetia)
Ezetimibe plus Simvastatin (Vytorin)
Statins (HMG-CoA reductase inhibitors)
Atorvastatin (Lipitor)
Fluvastatin (Lescol)
Lovastatin (Mevacor)
Lovastatin plus Niacin-ER (Advicor)
Pravastatin (Pravachol)
Rosuvastatin (Crestor)
Simvastatin (Zocor)
Simvastatin/niacin ER (Simcor)
Other
Niacin/nicotinic acid (Niaspan)
Migraine headache treatments
Sumatriptan (Imitrex)
Zolmitriptan (Zomig)
Muscle relaxant
Carisoprodol (Soma)
Cyclobenzaprine (Flexeril)
Narcolepsy treatments and wakefulness-promoting agents
Armodafinil (Nuvigil)
Modafinil (Provigil)
Sodium oxybate (Xyrem)
Nasal decongestants
Phenylephrine (Dimetapp) [α 1-agonist]
Pseudoephedrine (Sudafed) [indirect nonspecific alpha agonist]
Opiate analgesics
Oxycodone (Oxycontin, Roxicodone)
Oxymorphone (Numorphan, Opana ER, Opana IR)
Opiate partial agonists
Buprenorphine (Subutex)
Buprenorphine plus naloxone (Suboxone)
List of Drugs xxxv
Second-generation antipsychotics
Aripiprazole (Abilify)
Asenapine (Saphris)
Clozapine (Clozaril)
Iloperidone (Fanapt)
Lurasidone (Latuda)
Olanzapine (Zyprexa)
Paliperidone (Invega)
Quetiapine (Seroquel)
Risperidone (Risperdal)
Ziprasidone (Geodon)
Sedative-hypnotics
Benzodiazepines
Alprazolam (Xanax)
Chlordiazepoxide (Librium)
Clorazepate (Tranxene)
Diazepam (Valium)
Flurazepam (Dalmane)
Lorazepam (Ativan)
Oxazepam (Serax)
Temazepam (Restoril)
Triazolam (Halcion)
Nonbenzodiazepines
Eszopiclone (Lunesta)
Ramelteon (Rozerem)
Zaleplon (Sonata)
Zolpidem (Ambien)
Sexual dysfunction treatments
Sildenafil (Viagra) [phosphodiesterase type 5 inhibitor]
Tadalafil (Cialis) [phosphodiesterase type 5 inhibitor]
Vardenafil (Levitra) [phosphodiesterase type 5 inhibitor]
Yohimbine (Yocon)
Smoking cessation aids
Varenicline (Chantix)
Stimulants and stimulant-like drugs
Amphetamine (Dexedrine, Adderall [mixed amphetamine salts])
Methylphenidate (Concerta, Focalin, Methylin, Ritalin)
Phentermine (Adipex-P)
Sympathomimetics (β1-agonists)
Dobutamine (Dobutrex)
Tocolytics
Terbutaline (Brethine, Bricanyl)
PART I
General Considerations
1
The Psychiatrist as
Physician
Primary Care Psychiatry

Although the mandate primum non nocere remains axiomatic throughout
medicine, the practical management of serious illnesses demands that
physicians recognize and appreciate the risks and benefits of available
treatment options relative to alternative treatments—or no treatment. All
therapies, including placebo, involve hazards that could worsen a clinical
condition either directly (usually because of side effects) or indirectly
(due to inappropriate use of an otherwise efficacious therapy or the deci-
sion to forgo a treatment for fear that the cure might be worse than the
disease). Expertise in clinical psychopharmacology depends heavily on
knowledge and experience about how best to balance the risks and bene-
fits of a given treatment relative to its alternatives.
Since the end of the twentieth century, tremendous growth in the
number of psychotropic agents available to treat most if not all manifes-
The symbol ■ is used in this chapter to indicate that the FDA has issued a black
box warning for a prescription medication that may cause serious adverse effects.
3
4 Managing the Side Effects of Psychotropic Medications
tations of psychopathology has contributed profoundly to the pharma-

cologically oriented practice of psychiatry. The use of combination drug
therapy regimens has become increasingly commonplace, informed at
least theoretically by complementary mechanisms of action, potential
pharmacodynamic synergies, and concepts such as “breadth of spec-
trum” to describe psychotropic drugs in analogous fashion to antimi-
crobials or antineoplastics. Yet, despite the fervor with which psychiatrists
often devise complex drug regimens or undertake novel pharmacother-
apies for conditions that respond poorly to traditional agents, many
practitioners are often remarkably uncomfortable confronting and
managing unintended drug effects. Such hesitation may stem in part
from the comparatively lower diversity of adverse effects from pharma-
cologies of generations past, coupled with a historically lower need on
the part of psychiatrists than many other medical subspecialists to
maintain a working knowledge of basic primary care medicine. Increas-
ingly, such a medically hands-off model is no longer practicable given
the diverse end-organ effects of newer psychotropic drugs, coupled
with growing awareness of the medical comorbidities associated with
depression, bipolar disorder, schizophrenia, and other serious forms of
mental illness. Moreover, psychiatrists possess a unique knowledge
base among physicians from which to understand the relative benefits
of a psychotropic medication for a given patient and to determine when
the unique merits of a drug outweigh the risks—and manageability—
of a potential adverse effect.
Routine medical assessment and management of the whole patient
presumes a general appreciation of and comfortable working knowl-
edge of all end organs potentially affected by a pharmacological inter-
vention. One need not be an endocrinologist to identify and manage
lithium-induced hypothyroidism or glycemic dysregulation caused by
SGAs, but competency requires a basic awareness of major organ sys-
tem physiology and the ways in which commonly used medications
exert their pharmacokinetic and pharmacodynamic effects. The “re-
medicalization” of psychiatry has made it more commonplace, if not
routine, for contemporary psychiatrists to conduct focused physical ex-
aminations that include in-office measurement of weight or body mass
index, measurement of abdominal girth, monitoring of blood pressure
and heart rate (including orthostatic measurements when appropriate),
basic neurological examinations (assessing pupillary responses, ex-
traocular movements, cranial nerves, sensation, motor strength, deep
tendon reflexes, gait, and tremor or other movement disorders), detec-
tion of thyromegaly or lymphadenopathy, assessment of skin rashes
(including those affecting the sclerae and other mucocutaneous tissues,
The Psychiatrist as Physician 5
as well as the back, trunk, and extremities), cardiac auscultation, and as-
sessment of fluid volumes (e.g., when evaluating peripheral edema).
Active collaboration with primary care physicians has never been more
fundamental than in the present era, in which patients with significant psy-
chiatric conditions are especially vulnerable to health problems related to
both lifestyle (e.g., overweight and obesity, hypertension, sexually trans-
mitted diseases) and iatrogenic factors (e.g., psychotropic-induced weight
gain or metabolic dysregulation). No medical subspecialty other than psy-
chiatry bears responsibility for possessing the knowledge base necessary to
gauge the relative risks and benefits of treatments that may literally be
lifesaving but nevertheless can carry substantial side-effect burdens
(e.g., implementing clozapine for an overweight, prediabetic, clinically de-
teriorated schizophrenic patient with chronic psychosis and a history of
multiple suicide attempts). Subspecialists from other areas of medicine
may be useful resources to help psychiatrists reason through risks, benefits,
and available alternatives to a given treatment; but these subspecialists, in
turn, may look to psychiatrists for similar guidance.
Medically astute assessments by psychiatrists can be fundamental to
diagnostic formulations and proper pharmacotherapy management.
Consider, for example, the following clinical scenarios.
• A 54-year-old man with chronic major depression, hypertension, hy-

percholesterolemia, obesity, and sleep apnea underwent numerous
iterative pharmacotherapy trials, with eventual marked and endur-
ing improvement on a regimen that included duloxetine 60 mg/day,
mirtazapine 60 mg/day, modafinil 200 mg/day, and lithium carbon-
ate 600 mg/day, in addition to lisinopril 10 mg/day and atorvastatin
10 mg/day. He gained 13.5 kg in 6 months and developed bilateral
pretibial edema. The psychiatrist, assuming that both the edema and
weight gain resulted from any one of his medications, first discontin-
ued lithium and then lowered mirtazapine, without benefit. A 5-day
course of hydrochlorothiazide 50 mg/day produced no diuresis. Ex-
amination by the patient’s internist identified jugular venous disten-
sion and hepatomegaly on abdominal exam. The edema that the
psychiatrist assumed to be peripheral and iatrogenic actually re-
flected right-sided congestive heart failure secondary to the long-
standing sleep apnea, exacerbated by the marked weight gain.
• A 57-year-old man with bipolar II disorder was taking lithium car-
bonate 900 mg/day, lamotrigine 200 mg/day, and escitalopram
10 mg/day. Presently depressed, he described marked anergia and
hypersomnia. Presuming that these symptoms represented reverse
neurovegetative signs of ongoing depression, the psychiatrist added
methylphenidate 5 mg/day and increased the escitalopram to

20 mg/day. The patient collapsed at home the next day and was
taken by ambulance to the emergency department, where he was
found to have new acute renal failure (serum creatinine >4.0 mg/dL)
and was profoundly hypotensive and tachycardic. Though oliguric,
he had an unexpectedly highly dilute urine by specific gravity, point-
ing to a diagnosis of diabetes insipidus that was masked by his poor
nutritional and fluid intake, consequently raising his serum lithium,
and collectively leading to marked hypovolemia that responded to
intravenous hydration and lithium cessation.
• A 47-year-old woman with a history of breast cancer (status postchemo-
therapy and modified radical mastectomy 5 years earlier) presented
with recurrent nonpsychotic major depression involving multiple so-
matic complaints (lethargy, hypersomnia, headaches, nausea) that was
unresponsive to multiple medications, most recently the SNRI duloxe-
tine 120 mg/day. Duloxetine was tapered off over 2 weeks in prepara-
tion for a subsequent MAOI trial planned for 2 weeks later. She
complained of worsening depressed mood, fatigue, headache, nausea,
and progressive dizziness with vertigo, despite the gradual reduction in
duloxetine dosing. Fluoxetine was begun at 20 and then 40 mg/day as a
strategy to counteract a suspected SNRI discontinuation syndrome
but yielded no improvement after 1 week, further unabated by ad-
junctive prochlorperazine 10 mg tid and meclizine 25 mg bid. The
protracted course of symptoms was thought to be unusual for SNRI
withdrawal, and an independent labyrinthitis was suspected. Neuro-
logical examination revealed no nystagmus (as would be expected with
labyrinthitis) but was remarkable for dysmetria on finger-to-nose test-
ing and an unsteady gait. A neurological process was suspected when
the patient developed vomiting, and a computed tomographic (CT) scan
of her head subsequently revealed a likely metastatic cerebellar lesion
that accounted for the symptoms of her posterior fossa syndrome, which
had been misattributed to SNRI discontinuation.
The presence of certain medical comorbidities may pose relative (if

not absolute) contraindications to the use of specific psychotropic
agents. Representative examples are summarized in Table 1–1.
Appropriate medical monitoring of psychotropic agents involves an
awareness of abnormalities detectable by history or physical examination,
as well as pertinent laboratory parameters. Table 1–2 provides a summary
of laboratory measures that warrant monitoring or consideration in the
course of treatment with specific psychotropic compounds. Recommen-
dations for laboratory monitoring that are presented in Table 1–2 are col-
TABLE 1–1. Medical conditions that may contraindicate specific

psychotropic agents
Medical condition Pharmacotherapy implication
Asthma, chronic obstructive β-Blockers are relatively

pulmonary disease contraindicated.
Chronic kidney disease Lithium is relatively
contraindicated depending on
severity and chronicity.
Bradycardia (e.g., sick sinus β-Blockers are relatively
syndrome) contraindicated.
Hepatitis Carbamazepine or divalproex
should be administered with
caution.a
Hypertension (poorly controlled) Strongly adrenergic agents,
including SNRIs, TCAs, or
stimulants, should not be
initiated until hypertension is
treated.
Hypothyroidism Lithium is not contraindicated.
Neutropenia Carbamazepine and clozapine are
contraindicated.
Seizure disorder Bupropion and clozapine are
relatively contraindicated.
Caution should be exercised with
use of antipsychotics and
maprotiline.
Note. SNRI = serotonin-norepinephrine reuptake inhibitor; TCA =tricyclic
antidepressant.
aSee the sections “Hepatic Impairment and Transaminitis” and “Hyperam-
monemia” in Chapter 12, “Gastrointestinal System.”
lectively derived from manufacturers’ package insert information for

specific agents, as well as from published practice guidelines.
Differentiating Adverse Drug Effects

From Primary Illness Symptoms
One of the greatest challenges in treating disturbances of mood, behavior,
thinking, or perception involves the discrimination between symptoms
that are intrinsic to a disorder and potential side effects of somatic thera-
pies. Treatment with antipsychotic drugs may induce akathisia, which can
sometimes be difficult to distinguish from anxiety or hypomania (necessi-
tating the broader assessment of additional symptoms, such as a sleep dis-
turbance or increased goal-directed activity, to help clarify differential
diagnosis). In the case of depression, the presence of reverse neurovegeta-
tive signs (e.g., lethargy, hypersomnia, hyperphagia)—which are typical in
bipolar depression—may confound impressions about the emergence of
these features as being likely attributable to an antidepressant (e.g., seda-
tion), or rather, to symptoms of the illness itself. Similarly, if symptoms
(e.g., agitation, insomnia, suicidal features) worsen after a patient starts a
treatment, it may be difficult to differentiate whether they reflect an ad-
verse drug reaction or simply an exacerbation of illness symptoms (and a
failure of the intervention, at least at that point, to remedy them).
Although no special formula exists by which to differentiate side ef-
fects from illness symptoms, several general principles are useful for
clinical management. First, it is helpful before starting any treatment to
have catalogued in some detail the target symptoms for which a medi-
cation is being used. A psychiatric review of systems (Table 1–3) may be
useful when gathering details of the history of present illness, and select
components from this compilation may be worth inquiring about in re-
lation to past episodes (e.g., suicidal features when depression was his-
torically at its worst).
Second, and perhaps most fundamentally, when a patient reports a
presumed side effect, it is obviously essential to clarify whether the phe-
nomenon was absent before treatment. In the case of illness symptoms
that may intensify during (or despite) pharmacotherapy, this differentia-
tion can be especially difficult. Consider the example of insomnia that
predates the initiation of an SSRI for major depression, which then wors-
ens in the week following treatment initiation. The co-occurrence of ad-
ditional new side effects, particularly those that are not common in
depression (Figure 1–1), may help to corroborate the hypothesis that a
complaint more likely represents an adverse drug effect than a symptom
of depression.
A third consideration involves gathering historical information about
previous medication trials and noteworthy past adverse effects. It is often
helpful before or during an initial evaluation to have patients construct a
summary of past medications they have taken with approximate dates, dos-
ages, benefits (if any), and any recollection of adverse effects. Such a sum-
mary holds obvious value not only for capturing complications of previous
treatments, but also for distinguishing past treatment nonresponses from
intolerances, identifying the adequacy (dose and duration) of past treat-
The Psychiatrist as Physician
TABLE 1–2. Routine laboratory monitoring for commonly used psychotropic agents
Frequency of measurement and

Medication Parameter target ranges Rationale
Carbamazepine Serum carbamazepine No known validity relative to therapeutic May be measured periodically in setting of
level effect in mood disorders; nevertheless, clinical concerns about toxicity or
some clinicians measure serum levels adherence.
despite the absence of research. Expert
Consensus Guidelines (Keck et al. 2004)
identify a favored acute level range
(6.5–11.6 µg/mL) and a maintenance dose
level range (6.1–11.0 µg/mL).
Autoinduction of blood levels.
CBC with platelets Baseline and periodically thereafter (more Carbamazepine induces benign and
often in the presence of signs suggestive of transient myelosuppression in about 10%
bone marrow suppression). of patients but very rarely may cause
sustained aplastic anemia.
Electrolytes Baseline and periodically thereafter. Carbamazepine can cause age-associated
hyponatremia (often modest and benign)
in up to 40%of recipients.
9
10
TABLE 1–2. Routine laboratory monitoring for commonly used psychotropic agents (continued)

Carbamazepine Liver enzymes Baseline and periodically thereafter (more Carbamazepine can cause hepatotoxicity.
Managing the Side Effects of Psychotropic Medications

(continued) often in the presence of hepatic
impairment). (Note: Some experts cast
doubt on the practical utility and cost-
effectiveness of routine laboratory
monitoring and instead favor clinical
monitoring for signs of hepatotoxicity; see
the section “Hepatic Impairment and
Transaminitis” in Chapter 12,
“Gastrointestinal System”).
Clozapine Serum clozapine level Serum clozapine levels >350 ng/mL likely Serum clozapine levels are not routinely
offer no therapeutic advantage measured, but determining a serum level
(VanderZwaag et al. 1996); optimal of the parent compound (clozapine
response in schizophrenia appears to occur without norclozapine) may sometimes
in range of 200–300 ng/mL. help to inform risk-benefit decisions about
further dosage increases when symptoms
persist.

Divalproex Serum valproate level In acute mania, steady-state levels achieved Levels of 50–125 µg/mL are associated with
after five half-lives (about 3–4 days). acute antimanic response (Bowden et al.
2006b); no levels have been established for
maintenance therapy or acute bipolar
depression, although practitioners often
extrapolate from levels in acute mania.
Liver enzymes Some authorities advise monitoring every Divalproex may cause hepatotoxicity.
6 months, whereas others regard
continued monitoring unnecessary in
stable patients (Pellock and Willmore
1991). We advocate semiannual or annual
assessment in stable patients.
Platelet count Periodic CBC. Divalproex may cause thrombocytopenia.
Serum ammonia level Not routinely measured in the absence of Divalproex can deplete carnitine.
clinical signs of hepatic encephalopathy.
Serum lipase and Not routinely measured in the absence of Divalproex recipients who present with an
amylase clinical suspicion of acute pancreatitis. acute abdomen should be evaluated for
possible acute pancreatitis, a clinical
assessment that includes measurement of
serum lipase and amylase.
11
12

Lamotrigine Serum lamotrigine level No established validity in association with Although lamotrigine blood levels can be

therapeutic effect in mood disorders; lower during pregnancy, oral
toxicity correlates with drug levels (more contraceptive use, and cotherapy with
than one-third of epilepsy patients carbamazepine, measurement of
demonstrate neurotoxicity at levels lamotrigine blood levels has no known
> 15 µg/mL (Hirsch et al. 2004). clinical relevance outside of epilepsy.
Lithium Serum lithium level By convention, measure serum levels Acute antimanic efficacy is generally
obtained approximately 8–12 hours after associated with serum levels of 0.6–
the previous dose.a Steady state is 1.2 mEq/L; Expert Consensus Guidelines
achieved five half-lives (5 days) after advise levels of 0.7–1.1 mEq/L (Keck et al.
dosage changes. Frequent monitoring may 2004). Maintenance prophylaxis is
be useful after each dosage change in the associated with levels of 0.8–1.0 mEq/L
acute setting. In stable patients, levels are (Gelenberg et al. 1989); Expert Consensus
usually measured at least twice a year Guidelines advise levels of 0.6–1.0 mEq/L
(Jefferson 2010). (Note: Manufacturers’ (Keck et al. 2004).
product information for all formulations of
lithium advise the monitoring of serum
lithium levels “at least every 2 months,”
although such an onerous schedule has
never been adopted by practice guidelines
as the standard of care.)

Lithium (continued) Renal function (typically Every 2–3 months during the first 6 months Lithium may cause nephrotoxicity.
includes serum of treatment, and every 6–12 months
creatinine to calculate thereafter (or more often in the setting of
estimated GFR and rising creatinine).
urinalysis to measure
specific gravity and
assess for proteinuria)
(Jefferson 2010)
Thyroid function tests Once or twice during the first 6 months of Lithium-induced hypothyroidism (see the
treatment; every 6–12 months thereafter. section “Thyroid Abnormalities” in
Chapter 11, “Endocrinopathies”): In
recipients of thyroid hormone therapy,
optimal reassessment of thyroid function
should occur ~8 weeks after a T4 or T3
dosage adjustment. (Note: If a patient is
also taking supplemental calcium or iron,
a constant temporal relationship should be
maintained when measuring thyroid
hormone due to binding of these
minerals.)
13
14

Lithium (continued) 12-lead ECG Before treatment initiation in adults over Lithium, particularly at high dosages, may

age 40. cause ECG abnormalities (see Table 7–1 in
Chapter 7, “Cardiovascular System”). In
the absence of heart disease, serial ECG
monitoring during lithium therapy is
unnecessary.
CBC Occasionally recommended by some Baseline assessment can help to interpret
authorities before lithium initiation; not whether any subsequent leukocytosis is
routinely monitored in serial fashion. likely iatrogenic.
SGAs Fasting blood sugar At baseline, 12 weeks, and annually SGAs may cause glycemic dysregulation.
thereafter.
Hemoglobin A1c Levels ≥ 6.5 are definitional of diabetes; Hemoglobin A1c is an acceptable indicator
levels of 5.7–6.4 identify patients at of diabetes risk.
increased risk for future diabetes.
Fasting lipid profile At baseline, 12 weeks, and every 5 years SGAs may cause elevation of serum
thereafter. triglycerides and LDL cholesterol.

SGAs (continued) 12-lead ECG No formal recommendation. In older Some antipsychotics may cause arrhythmias
patients, or those for whom concerns may or conduction delays (see Tables 7–1
exist about conduction delays (e.g., risk and 7–2).
factors for QTc prolongation; see Table 7–3),
a baseline ECG may be advisable.
CBC All SGAs can rarely cause leukopenia, but In patients who present with leukopenia or
routine monitoring of blood counts is neutropenia, clinicians should be aware
unnecessary in the absence of clinical that SGAs as a class may contribute to
signs. etiology.
TCAs Serum drug levels Serum nortriptyline levels within an estab- In the setting of an inadequate clinical
lished therapeutic window are associated response, dosages may be increased until
with antidepressant efficacy (see Table 2–5 achievement of a therapeutic level. Dosing
in Chapter 2, “Pharmacokinetics, Pharma- beyond a therapeutic window likely yields
codynamics, and Pharmacogenomics”). no greater efficacy but more adverse effects.
Note. CBC= complete blood count; ECG= electrocardiogram; GFR =glomerular filtration rate; LDL= low-density lipoprotein; SGA=second-
generation antipsychotic; T3 =triiodothyronine; T4 = thyroxine; TCA=tricyclic antidepressant.
aThe rationale for timing of the measurement of serum lithium levels is based on the assumption of twice-daily dosing, with a “trough” level
being measured immediately before the next dose. In practice, however, some experts advocate once-daily dosing of all preparations of lithium
carbonate based on 1) the 24-hour half-life of lithium carbonate and 2) the lesser risk for causing glomerulosclerosis when lithium is dosed once
daily rather than multiple times per day (see the section “Nephrotoxicity and Nephrogenic Diabetes Insipidus” in Chapter 13, “Genitourinary
and Renal Systems”). Serum lithium levels that are obtained 8–12 hours after a once-daily dose are not trough levels, but are considered mean-
15
ingful for assessing serum concentrations relative to lithium’s therapeutic window.
TABLE 1–3. A psychiatric review of systems
Domain Phenomena
General Self-care, grooming, eye contact and gaze, level of

appearance relatedness
Chronobiological Sleep (increase or decrease), nocturnal activity
Cognitive Attention, associative fluency, memory, logical
reasoning, intrusive thoughts, obsessions
Affective Depression, elation, irritability, anger, anxiety,
diurnal variation, subjective dulling,
differentiating negative symptoms (apathy,
avolition), suicidal thoughts or behaviors
Appetitive Eating (increase or decrease; restricting; binging;
purging)
Impulsivity and/ Violent thoughts, self-injurious behavior,
or aggression disinhibition, risk-taking behavior (e.g., sex,
driving, gambling, drugs, spending)
Psychomotor Agitation or pacing, energy, retardation, tremor,
gait, balance, motor stiffness or rigidity, restless
legs
Speech Fluency, prosody, dysarthria, slurring
ments, discovering reasons for discontinuation, gauging an individual pa-

tient’s capacity to tolerate medically benign side effects, and recognizing
potential patterns or sensitivities that may heighten expectations about fu-
ture potential side-effect susceptibilities or concerns. Finally, and perhaps
most obviously, an awareness of particular side-effect sensitivities or con-
cerns can and should inform joint deliberations between prescriber and
patient about possible future treatments. (For example, past sexual dys-
function would probably dissuade most practitioners from advocating an
SSRI or TCA trial when other viable options for depression or anxiety exist,
and past cognitive dulling or sedation would favor the avoidance of benzo-
diazepines or antihistaminergic or anticholinergic agents if practicable.)
The Nocebo Phenomenon and

Proneness to Adverse Effects
Nonspecific side effects that occur during treatment with inert com-
pounds (placebos) have been described as nocebo effects. Predictors of
the nocebo phenomenon have been shown to include patients’ expecta-
Antidepressant Depression
adverse effects Appetite changes
Weight changes
Nausea Fatigue Depressed mood
Headache Insomnia or hypersomnia Anhedonia
Diarrhea Loss of interest in sex Helplessness
Constipation Poor concentration Hopelessness
Dry mouth Psychomotor retardation Indecisiveness
Tremor Agitation Tearfulness
GI upset Anger
Sweating Suicidality
FIGURE 1–1. Overlap between symptoms of depression and common

adverse effects of antidepressants.
GI = gastrointestinal.
tions of adverse effects, past experience of adverse somatic effects of

treatments that may foster conditioned expectations, and clinical phe-
nomena such as depression, anxiety, or a predisposition to somatiza-
tion. Alexithymic traits—that is, an impaired capacity to put emotional
states into words—may also increase the likelihood for certain individ-
uals to express internal distress through somatic complaints.
Patients who identify themselves as being especially sensitive to
side effects are communicating important information about them-
selves and the extent to which they may expectably encounter somatic
problems from treatment of any kind. Nocebo effects elicit from treaters
a unique type of concerned attention to a patient’s physical distress; by
definition, physical complaints from a placebo are not pharmacody-
namic in origin, yet the prospect that they might be linked to treatment
can provide validation and legitimacy to an individual’s subjective
sense of suffering. From a psychodynamic point of view, clinicians
should be especially attuned to the context in which patients may com-
municate excessive nonspecific or ill-defined complaints (e.g., malaise,
“just not feeling right”) in connection with treatment, particularly to the
extent that they may feel poorly cared for or cared about by others. In
such instances, physical complaints may serve to legitimize the occasion
for greater contact with the treater and may fundamentally represent
the expression of unmet emotional needs.
Empirically, in contemporary pharmacotherapy trials for major de-

pression, median response rates for placebo arms are typically about 30%
but may range as high as 50%, and they appear to be on the rise. Few stud-
ies have carefully examined the characteristics of research subjects who
report adverse effects while taking placebos during randomized clinical
trials. Personality characteristics, particularly neuroticism, have been
found to correlate with the number of reported side effects, whereas pho-
bic, obsessive, and hypochondriacal symptoms have been associated
with placebo-induced drowsiness. Factors such as suggestibility and ex-
pectancy regarding outcomes also may contribute to placebo effects (both
good and bad) within psychiatry, as has been demonstrated in studies of
analgesia for chronic pain.
Certain adverse effects tend to be especially likely during treatment
with placebo in clinical trials for particular disorders. For example, across
randomized controlled trials in various phases of bipolar disorder or ma-
jor depression, incidence rates of ≥10% with placebo have been reported
for dizziness, headache, nausea, diarrhea, sedation, insomnia, anorexia,
nervousness, anxiety, and asthenia (i.e., weakness or lack of strength and
energy). Some psychiatric disorders also appear more likely than others
to incur nocebo effects. For example, more varied and higher rates of side
effects with placebo have been reported in drug trials for patients with
anxiety disorders, whereas less extensive or diverse side effects from pla-
cebo are typically observed in trials for patients with schizophrenia. In-
terestingly, a number of reported side effects from placebo (i.e., dry
mouth, nausea, headache, insomnia, somnolence, and sexual dysfunc-
tion) occurred at least twice as often in a randomized comparison to ser-
traline among patients with dysthymic disorder (Thase et al. 1996) than
reported during placebo treatment in similar comparison trials for acute
major depression. These findings further suggest that nocebo effects may
be higher among more chronically ill mood disorder patients.
From a psychodynamic perspective, practitioners might consider
the idea that a medicine can pose a kind of projective stimulus, one that
patients can imbue with malevolent qualities literally capable of de-
stroying them from the inside when ingested. Exposing oneself to a
medication can create a psychologically vulnerable and regressive ex-
perience that taps early developmental processes, such as the defense
mechanism of splitting, in which an individual’s internal experience of
people and things becomes divided into good or bad psychological ob-
jects. Especially in patients with traumatic childhood experiences, bad
objects are projected out onto others and then psychologically internal-
ized (i.e., reintrojected) in an effort to gain mastery over them. A medi-
cation can lend itself as a convenient psychological nidus for the
projection of the bad object (encompassing a range of unconscious or

preconscious fears and anxieties about danger and harm caused by the
supposed caregiver); thus, medication may conceptually represent both
external and internal persecutory forces, creating an array of harmful ef-
fects that may not necessarily have any bearing on the pharmacody-
namic properties of the actual substance being taken.
Patients sometimes perceive and report what they believe to be ad-
verse drug effects using dramatic language that communicates their
feeling harmed (e.g., “It’s as if I was being choked” or “I felt like some-
one was driving a screwdriver into my bones”). True adverse effects
may also be described with a histrionic, exaggerated intensity (e.g., “My
brain went numb” or “I felt electrical shocks all over my body”) that
sometimes may even verge on delusional perception or dissociation
(e.g., “I could feel the blood rushing through my body” or “I could see
my skin moving”). The context of a possible adverse effect may be hard
to understand without an appreciation for a given patient’s psychiatric
disorder or cognitive style of processing information. Therefore, practi-
tioners need to clarify the meaning of self-reported adverse effects that
may be ill defined, histrionic, or psychotic to determine whether they
are meant to communicate true iatrogenic events (e.g., paresthesias, la-
ryngeal dystonias, antihistaminergic cognitive dulling, autonomic acti-
vation) or are simple manifestations of underlying psychopathology.
For everyday practitioners, awareness of the potential for nocebo ef-
fects (and their differentiation from adverse drug effects) is fundamen-
tal to optimal care. The following are some strategies to help minimize
nocebo effects and to differentiate them from true drug effects.
• On initial encounters with patients who are already on complex drug

regimens or who have baseline somatic complaints, avoid making
any pharmacological changes unless an existing drug intolerance or
toxicity state is unambiguous, or unless an existing drug is highly
suspected of worsening the clinical presentation.
• Identify baseline patient characteristics or diagnostic features (nota-
bly, anxiety or somatization) that may predispose to nocebo effects.
• Resist the temptation to overrespond to frequent complaints or
symptoms with excessive dosage changes or medication starts and
stops, which may serve mainly to heighten a sense of anxiety or chaos
for both the patient and the practitioner.
• Recognize the plausibility between reported adverse effects and the
time course for their emergence or relationship to incremental dosing
changes; pay particular attention to patients who report “dramatic”
effects (either beneficial or adverse) within hours or days of taking a
medication if the pharmacodynamic profile of a drug is unlikely to

produce effects on so rapid a timescale.
• Avoid multiple changes (drugs, doses, timing) simultaneously, when-
ever feasible.
A final consideration involves awareness of the psychological dimen-

sions that can moderate a nocebo response. By way of example, Ward
(1991, pp. 75–78) presented the vignette of a chronically depressed woman
manifesting a hostile-dependent stance toward treatment, for whom re-
view of past medications (and providers) yielded only side effects with no
clear benefit. He formulated the case partly based on a sense of anger he
perceived in the patient and surmised an unwitting desire on her part to de-
feat the clinician. Accordingly, he devised the paradoxical injunction of
predicting for the patient a low (but not nil) probability that any medicine
would likely be helpful, although many side effects were likely. Having
thus provided the patient with something to defeat other than the treat-
ment itself (namely, the challenge to defeat the clinician’s prediction of
many side effects and little efficacy), the patient duly obliged by reporting
no side effects and possible early improvement soon after starting a new
antidepressant, to the baffled amazement of the treater. Notably, this en-
counter highlights the pivotal role of the therapeutic alliance and its psy-
chodynamic importance as a central element of treatment outcome.
Negative Therapeutic Reactions

To borrow a concept from classical psychoanalysis, the notion of a nega-
tive therapeutic reaction is meant to describe instances in which patients de-
velop a paradoxical worsening of symptoms in response to accurate
treatment interventions. Freud originally described and regarded this
phenomenon as an unconscious expression of guilt or masochism on the
part of the patient, whose symptoms worsened because the prospect of
improvement was contrary to an unconscious investment in his or her
own suffering. The same mechanism may have similar bearing on psy-
chopharmacology, inasmuch as some symptoms—particularly those
with ambiguous etiologies that could result from either medication or a
primary mood or anxiety disorder—may at times worsen in response to
treatment. Such a process might be considered when patients report ex-
tensive or persistent adverse treatment effects that may not have a clear
pharmacodynamic basis—for example, an intensification of depressed
mood, guilty ruminations, or anhedonia during antidepressant therapy.
A related concept involves the potential for apparent side effects—
or worsening symptoms—in patients who may have a profound sense of
resentment and bitterness toward early caregivers, and who may take ei-
ther conscious or unconscious sadistic pleasure in thwarting the efforts of
their psychiatrist. The operative process can involve a powerful drive to
defeat the helping efforts of a prescribing clinician as an unconscious
means of revenge against internalized representations of early caregivers
as having been ineffective or malicious. Patients who articulate a seem-
ingly endless stream of physical complaints related to treatment, with lit-
tle or no apparent benefit, may engender in the treater a parallel sense of
resentment, frustration, and eventual loss of empathy for the plight of the
patient. Such encounters between patient and treater can become inter-
personally and psychodynamically complex, and they may often go un-
noticed and unaddressed when the framework of treatment is focused
mainly or exclusively around brief, infrequent encounters for “medica-
tion management.” Without the treater’s appreciation for the psycholog-
ical context of symptoms, treatment may become a relentless and
seemingly fruitless effort either to combat side effects or to identify more
benign pharmacotherapies, while yielding minimal if any fundamental
improvement. To break such cycles and gain a broader perspective, the
treater may sometimes benefit from obtaining consultations. Instances
may also arise in which the treater may honestly acknowledge to himself
or herself, and to the patient, that existing pharmacologies may not be ca-
pable of providing discernible benefits that outweigh, or justify, the toll of
side effects. In such situations, alternative treatment strategies, including
psychotherapy, may hold greater promise and warrant deeper consider-
ation as a potential route toward improvement.
Attribution and Causality

A fundamental consideration in managing adverse drug effects in-
volves recognizing causal relationships between drug administration
and effects (whether beneficial or adverse). Often, short of imposing
randomized, blinded, placebo-controlled conditions, clinicians cannot
know with certainty whether a change in clinical presentation can rea-
sonably be attributed to a change in pharmacotherapy. Factors that im-
pinge on the attribution of causality include recognizing the natural
course of illness, the effects of having discontinued a previous drug, the
potential for pharmacokinetic and pharmacodynamic interactions
among two or more psychotropic agents, the potential for poor or er-
ratic treatment adherence, medical comorbidities, and the presence of
alcohol or illicit substances.
One factor relevant to evaluating a possible drug side effect involves
whether a pharmacokinetic or pharmacodynamic rationale can explain an
effect, or rather, whether a drug’s mechanism of action fails to explain (or

even contradicts) a suspected end-organ effect. In the case of highly non-
specific side effects—such as those that may occur as often with placebo as
with an active drug (e.g., headache or insomnia), or those that may in real-
ity simply reflect untreated illness features (e.g., agitation or anxiety)—
pharmacodynamic mechanisms are unnecessary to account for side-effect
plausibility. In other instances, drawing a causal link between a possible
side effect and a drug may be mechanistically implausible (e.g., elevation of
liver enzymes after lithium administration, nausea from prochlorperazine,
a fever increase from acetaminophen). Equally challenging can be idiosyn-
cratic or bizarre adverse effects that do not follow from the known pharma-
codynamic properties of a drug, such as tremors caused by propranolol or
clonazepam (in the absence of withdrawal), sexual dysfunction with psy-
chostimulants, or lethargy caused by modafinil.
Another pertinent factor when judging likely causality involves the
time course for the emergence of a suspected side effect relative to initial
drug exposure. For example, rashes attributable to medications typically
occur within the first few weeks or months after initiation; it is implausi-
ble to construe a rash that arises years after taking a medication as being a
likely side effect. Similarly, hypersensitivity reactions to anticonvulsants
(see the section “Antiepileptic Hypersensitivity Reactions” in Chapter 19,
“Systemic Reactions”) seldom if ever arise more than 8 weeks after a
treatment has begun. Other potential adverse effects are characteristically
encountered only after long-term exposure. Perhaps the best-known ex-
ample is tardive dyskinesia, which, by definition, does not develop until
after at least 3 months of exposure to an antipsychotic, although acute or
withdrawal dyskinesias can occur at any time after exposure.
Naranjo and colleagues (1981) described a rating system for judging
the likelihood that adverse drug reactions were attributable to a sus-
pected medication. In their classification scheme (the Naranjo Scale),
numerical values are assigned for individual criteria so that the clinician
can judge the probability of causal association (definite, probable, pos-
sible, or doubtful) between an adverse drug effect and a given medica-
tion. These criteria are summarized in Table 1–4. The basic principles
incorporated in this rating system are of value for conceptualizing sus-
pected adverse effects outside of research settings.
In practice, clinicians may find the following basic concepts helpful
to minimize some of the confusion that can otherwise occur when at-
tempting to draw causal inferences about drug effects.
• Whenever feasible, make only one change to a medication regimen at

a time.
• Allow for steady-state pharmacokinetics to occur (typically, after five

to six half-lives) before forming conclusions about adverse drug ef-
fects (unless they are time independent and emergent, such as allergic
reactions, dystonias, or serious rashes; see Chapter 21, “Emergency
Situations”).
• Impose a method for systematically tracking target symptoms as
well as potential side effects of concern (e.g., weigh patients at each
visit; devise visual analog scales for patients to track the evolution
and severity of a suspected side effect).
• Inquire about missed medication dosages in an inquisitive, nonjudg-
mental manner; neither take treatment adherence for granted nor
routinely assume its absence.
Paradoxical Adverse Effects

Although it is probably a truism that virtually any side effect can happen
with any drug at any time, clinicians are always struck by the unambig-
uous worsening of a symptom in response to a medication intended to
ameliorate it. Clinicians usually presume, rightly or wrongly, that such
occurrences typically reflect the mere lack of efficacy of a prescribed
treatment to effectively counter the symptom being targeted rather than
a true and paradoxical iatrogenic worsening of the symptom in question
(e.g., when a patient reports feeling more depressed after starting an an-
tidepressant, or when the intensity of hallucinations or delusional think-
ing worsens during treatment with an antipsychotic).
Among the most vivid examples of unexpected or paradoxical adverse
effects is the development of mania or hypomania soon after starting an
SGA, or the emergence of suicidal thoughts or behaviors during treatment
with an antidepressant. Differentiating suspected iatrogenic reactions
from the coincidental introduction of treatment in a still-emerging illness
is often difficult. Nonetheless, hypotheses have been offered to explain
causal links in certain instances (e.g., linking antipsychotic-induced mania
with psychomotor activation caused by noradrenergic and serotonergic
effects; or posing the suspicion that agitation, insomnia, akathisia, or un-
recognized bipolar disorder may contribute to clinical worsening with an-
tidepressants). Some medications have known mechanisms that may
incur paradoxical adverse effects, as in the case of highly GABAergic an-
ticonvulsants such as tiagabine for causing new-onset absence seizures or
status epilepticus, even in hitherto nonepileptic patients.
In the setting of frankly implausible adverse effects, there is little
value in challenging the validity of a dubious self-report, other than to
24
TABLE 1–4. Naranjo scoring system for rating the likelihood of adverse drug reactions
Item Scorea
1. Are there previous conclusive reports on this reaction? 0=No, or do not know, or no information
+1=Yes

2. Did the adverse event appear after the suspected drug was given? 0=Do not know or no information
–1=No
+2=Yes
3. Did the adverse reaction improve when the drug was discontinued 0=No, or do not know, or no information
or a specific antagonist was given? +1=Yes
4. Did the adverse reaction appear when the drug was readministered? –2=No
0=Do not know, or no information
+2=Yes
5. Might alternative causes have caused the reaction? –1=Yes
+2=No
6. Did the reaction reappear when a placebo was given? –1=Yes
+1=No
TABLE 1–4. Naranjo scoring system for rating the likelihood of adverse drug reactions (continued)
Item Scorea
7. Was the drug detected in any body fluid in toxic concentrations? 0=No, or do not know, or no information
+1=Yes
8. Was the reaction more severe when the dose was increased, or less 0=No, or do not know, or no information
severe when the dose was decreased? +1=Yes
9. Did the patient have a similar reaction to the same or similar drugs 0=No, or do not know, or no information
in any previous exposure? +1=Yes
10. Was the adverse event confirmed by any objective evidence? 0=No, or do not know, or no information
+1=Yes
aScoring is basedon a total rating of 0= doubtful adverse drug reaction; 1–4= possible adverse drug reaction; 5–8= probable adverse drug
reaction; and 9–13= definite adverse drug reaction.
Source. Naranjo et al. 1981.
25
assure the patient that the phenomenon poses no medical hazard—

or when the adverse effect is associated with significant distress, to dis-
continue the agent, allow for the resolution of the perceived side effect,
and consider alternative therapies as appropriate.
Extrapolating “Evidence-Based Research

Findings” to “Real-World” Patients
Treatment outcomes for patients seen under ordinary clinical condi-
tions often vary substantially from those reported in controlled trials.
Pivotal randomized controlled trials that are designed to attain approv-
able drug indications from a regulatory agency such as the FDA have
typically involved idealized circumstances; hence, drug effects (both
beneficial and untoward) may generalize poorly to patients treated un-
der more routine circumstances. Numerous factors likely contribute to
the so-called gap between treatment efficacy (i.e., optimal results) and
effectiveness (i.e., customary results), including 1) enrollment of “pris-
tine” cases that rigorously meet nosological criteria (e.g., DSM-IV-TR;
American Psychiatric Association 2000) for a specific disorder (e.g., bi-
polar I but not bipolar II disorder or bipolar disorder not otherwise
specified), 2) absence of comorbid psychiatric or substance use disor-
ders or medical conditions, 3) absence versus allowance of adjunctive
pharmacotherapies, 4) excellent treatment adherence with close super-
vision, 5) high motivation and reliable attendance for close monitoring
of treatment effects, and 6) the tendency for adverse drug effects to be
registered passively and incompletely in randomized controlled trials.
Another relevant consideration when evaluating adverse effects re-
ported from controlled trials involves the illness state under investiga-
tion. FDA registration studies typically focus on patients experiencing
acute episodes of illness, or those who have initially responded to a
short-term treatment for an acute illness, who then enter continuation
or maintenance phases of therapy focused on the prevention of relapses
and recurrences. In routine practice, however, clinicians may very often
initiate a pharmacotherapy for subsyndromal symptoms of a subacute
or even chronic illness state, or may undertake the substitution of one
drug for another in the absence of acute symptoms, in the hopes of al-
leviating the side-effect burden associated with an existing medication.
Unique side-effect concerns may arise in such novel settings (e.g., with-
drawal effects of a first drug, or the reemergence of psychiatric symp-
toms if a new drug is less effective than the one being discontinued), for
which data from controlled trials may offer little or no guidance.
Research trials assess adverse effects either through subjects’ spon-

taneous reporting or, less often, through systematic inventories of pos-
sible side effects. Spontaneously reported adverse effects are typically
coded using a standardized cataloging system, such as the FDA’s Cod-
ing Symbols for a Thesaurus of Adverse Reaction Terms (COSTART),
which has been superceded by the Medical Dictionary for Regulatory
Activities (MedDRA; www.meddramsso.com), developed by the Inter-
national Conference on Harmonisation (ICH) and maintained by the
International Federation of Pharmaceutical Manufacturers and Associ-
ations (IFPMA). Generally, MedDRA and COSTART terms capture the
occurrence of an event during the course of a clinical trial but do not
provide information on the intensity or severity of an event or its tran-
sience versus longevity. These reporting systems also carry a higher risk
of undercounting rather than overcounting of adverse drug effects.
Clinical trials also often report rates of dropout or premature study ter-
mination due to adverse events but do not necessarily stratify prema-
ture dropout by specific reasons, including particular adverse effects.
Moreover, clinical trials seldom if ever permit the use of additional
medications to counteract an adverse effect (with few notable excep-
tions, such as benztropine to treat extrapyramidal side effects from an
antipsychotic drug, or benzodiazepines for insomnia or agitation).
A further challenge for interpreting adverse effects as reported in
clinical trials involves differentiating a possible negative drug effect
from simple lack of efficacy against a target symptom related to the ill-
ness being treated, or the persistence of symptoms from a comorbid
condition—as exemplified by clinical trials that report fairly uninter-
pretable phenomena, such as “personality disorder” or “schizophrenia”
or “nervousness,” as adverse drug effects without commenting on their
likely association to the drug.
In clinical trials, adverse events recorded in Phase II and Phase III
studies do not necessarily attempt to ascribe causality or even plausibil-
ity when subjects report problems (e.g., the emergence of respiratory in-
fections or accidental injuries) that may be entirely unrelated to drug
effects. Making such distinctions is often quite complex, may depend on
small and statistically underpowered subsample sizes (especially for
rare adverse drug effects), and may also pertain selectively to distinct
subpopulations of study subjects. Prominent examples of rare adverse
drug effects include the potential for antidepressants to induce or exac-
erbate suicidal features in youth (<age 24) but not older adults, for SGAs
to increase the risk for all-cause mortality in elderly dementia patients,
and for antidepressants to induce manic or hypomanic symptoms in a
minority of depressed patients.
For clinicians, perhaps a greater practical problem involves reconcil-

ing low reported rates of adverse effects in randomized trials with much
higher rates of an adverse effect under routine conditions. Notable ex-
amples include the often relatively low incidence rates of sexual dys-
function reported in clinical trials with serotonergic antidepressants, the
low expectation for significant weight gain with serotonergic antidepres-
sants, or underappreciation for the risk of akathisia with some SGAs.
Dose Relationships and Adverse Effects

Clinicians often presume that many if not most adverse drug effects can
be diminished by reducing the dosage of a drug. Such assumptions of-
ten derive more from anecdotal experience or expectations than from
empirical data. One obstacle to generalizable information about rela-
tionships between dosage and side effects comes from the rarity of
fixed-dose comparative studies and the risk of drawing wrong infer-
ences from flexible-dose studies; another constraint involves factors
other than dosage that can influence drug tolerability, such as medical
comorbidities (e.g., pretreatment obesity), concomitant drugs, or confu-
sion between drug effects and illness features (e.g., hypersomnolence,
hyperphagia, or loss of libido in depression). Other limitations involve
unknown assumptions about whether dose relationships, if existent,
are predictably linear or nonlinear (as limited by narrow dosing ranges)
and whether such relationships are equally true across all dosing
ranges (e.g., as may arise for linear vs. curvilinear associations).
Some psychotropic agents that have curvilinear dose-response curves
may demonstrate inverse relationships between dosage and adverse ef-
fects, as has been proposed with mirtazapine, in which sedation at lower
dosages (presumably resulting from the drug’s antihistaminergic prop-
erties) has been suggested to attenuate at higher dosages (e.g., >30 mg/
day) due to more prominent noradrenergic effects (Preskorn 2000).
Data exist regarding dose relationships and adverse effects for a select
number of psychotropic agents. For example, in the case of quetiapine,
incidence rates of sedation, somnolence, and orthostatic hypotension
were similar within a narrow dosing range that compared either 300 or
600 mg/day in trials for acute bipolar depression. The magnitude of
weight gain caused by olanzapine has been shown not to correlate with
drug dose in schizophrenia (Kinon et al. 2001), but possible dose relation-
ships with weight gain and other SGAs are less established. Time on drug
may represent a confounding factor with respect to dose (i.e., longer du-
ration of treatment may increase the likelihood and extent of weight gain;
moreover, clinicians may be inclined to raise the dosage of a medication
over time in the setting of incomplete remissions or breakthrough signs of

relapse). By contrast, toxicity related to dosing appears to account for
thrombocytopenia with divalproex or for seizures with bupropion or
clozapine. Table 1–5 provides a summary of known dose relationships
with specific adverse effects identified in manufacturers’ product infor-
mation materials.
A clinical dilemma that arises when considering the relationship be-
tween drug dosing and adverse events involves the mediating effects of
exposure time. When tolerance to an adverse effect is known to occur
over time (as in the case of headaches or nausea during treatment with
SSRIs), it can be difficult to know if and when dosage increases would
worsen adverse effects without taking into account exposure time. Some
psychotropic agents are known to recruit different transmitter systems
at different dosages—for example, greater noradrenergic effects are
thought to occur with mirtazapine when dosed above 30–45 mg/day or
with venlafaxine dosed above 150 mg/day—and as such, dosing may
account for adverse-effect profiles (e.g., resolution of fatigue or sedation
at higher doses), irrespective of time on drug. Because clinicians are of-
ten inclined to raise drug dosages after initial exposure to a lower dos-
age, the clinician could mistakenly presume that the eventual resolution
of an initial side effect was due to prolonged time on drug rather than in-
creased dosing, unless the clinician was aware of dose-related noradren-
ergic receptor profiles.
Most pharmaceutical trials conducted for the purposes of regulatory
agency approval do not track or report the evolution of adverse effects
over time, but rather report only the sheer occurrence of an adverse event
during the course of a drug trial. Study durations are often too short to
provide sufficient exposure time to capture all pertinent adverse effects.
Therefore, it is difficult to project when an adverse effect is likely to atten-
uate with prolonged exposure or how much time should elapse before
anticipating that an adverse effect warrants intervention. An example of
this conundrum involves the antihistaminergic effects of quetiapine rela-
tive to the time course for persistence or resolution of sedation and som-
nolence. Prolonged blockade of histamine H1 receptors should produce
tachyphylaxis or rapid tolerance (i.e., sedation or somnolence would pre-
sumably occur at the outset of treatment and then plateau or diminish
over time following receptor saturation; see also the section “Fatigue and
Sedation” in Chapter 16, “Neurological System”); indeed, this explana-
tion has been invoked by some practitioners, rightly or wrongly, to reas-
sure patients and prescribers that sedation or somnolence generally does
not persist and may not worsen at higher dosages. However, this theoret-
ically plausible concept has not, as yet, been empirically demonstrated.
TABLE 1–5. Common side effects with dose relationships reported by

manufacturers from FDA registration trials
Medications with known dose

Adverse effect relationshipsa
Ataxia Gabapentin, lamotrigine, oxcarbazepine

Blurry vision or diplopia Lamotrigine, oxcarbazepine
Constipation Duloxetine, escitalopram
Dizziness Iloperidone, lamotrigine, oxcarbazepine,
risperidone, topiramate, ziprasidone
Dry mouthb Escitalopram, ziprasidone
Dyslipidemias Desvenlafaxine
Extrapyramidal Most FGAs and SGAs
symptoms, including
akathisia
Fatigue Citalopram, escitalopram, risperidone,
topiramate
Headache Modafinil
Hyperprolactinemia Lurasidone, risperidone
Hypertension Venlafaxine
Hypothyroidism Quetiapine
Insomnia Citalopram, escitalopram
Nausea or Divalproex, escitalopram, iloperidone,
gastrointestinal upsetb lamotrigine, oxcarbazepine, paroxetine,
quetiapine, topiramate
Orthostatic hypotension Paliperidone, ziprasidone
Paresthesias Topiramate
QTc prolongation on ECG FGAs, SGAs
Rashes Lamotrigine (based on rapidity of dosing
titration)
Sedation or somnolence Aripiprazole, citalopram, divalproex,
escitalopram, gabapentin, lurasidone,
oxcarbazepine, paliperidone, paroxetine,
risperidone, topiramate, ziprasidone
Seizures Bupropion, clozapine
Sexual dysfunctionc Citalopram, nefazodone, paroxetine,
sertraline, venlafaxine, risperidone
TABLE 1–5. Common side effects with dose relationships reported by

manufacturers from FDA registration trials (continued)
Medications with known dose

Adverse effect relationshipsa
Sweating Citalopram, escitalopram, paroxetine

Tachycardia Iloperidone
Thrombocytopenia Divalproex
Tremor Divalproex, paroxetine, ziprasidone
Weight gain Iloperidone, quetiapine, risperidone
Yawning Citalopram
Note. ECG= electrocardiogram; FDA= U.S. Food and Drug Administration;
FGA= first-generation antipsychotic; SGA= second-generation antipsychotic.
aWithin usual therapeutic ranges.
bThe duloxetine package insert originally also included nausea, dry mouth,
and hyperhidrosis as dose-related phenomena in major depression; these

three items were removed as dose-related events after safety data were pooled
for major depression and generalized anxiety disorder.
cNo clear dose relationship was found for sexual dysfunction with bupropion,
fluoxetine, or mirtazapine (Clayton et al. 2002).
A further consideration involves the observation that some adverse

effects (e.g., extrapyramidal effects of antipsychotics) may occur at
higher receptor saturations (e.g., dopamine D2 receptor occupancy in
the striatum), whereas beneficial effects (e.g., antipsychotic efficacy rel-
ative to mesolimbic D2 receptor occupancy) may occur at lower receptor
saturations. In some instances, the relationship between adverse effects
and receptor saturation may be relatively linear, whereas the relation-
ship between pharmacodynamic benefits and receptor binding may be
sigmoidal rather than linear.
From the standpoint of clinical care, a final point involves managing
complaints of adverse effects at extremely low drug dosages. Such
events can be vexing not only for patients but especially for prescribers,
in that clinicians may feel an urgency to press forward in raising a drug
dosage to usual therapeutic levels, making the distress of an early ad-
verse effect seem like an impediment to the common goal of doctor and
patient. Such complaints also may sometimes seem ill founded from a
pharmacodynamic standpoint (analogous to self-reported improve-
ment within hours of starting an SSRI for depression) and incur the pre-
scriber’s suspicion about a patient’s suggestibility, histrionic features,
tendencies toward somatization, or even possible psychosis. Bearing in
mind factors such as the potential existence of a slow metabolizer ge-

notype, pharmacokinetic inhibition from a coadministered agent, pos-
sible hepatic or renal insufficiency, excessive self-dosing by a patient, or
simply a heightened sensitivity to drug effects, it usually behooves the
prescriber to follow the lead of the patient; when a patient’s investment
in continuing an appropriate treatment is tenuous, clinical wisdom may
dictate proceeding slowly with dosage increases, despite a belief on the
part of the clinician that true side effects at a low dosage are improbable.
FDA Warnings and Precautions

The FDA tiers its mandated cautionary statements about the severity
and importance of adverse events related to medications. Black box
warnings (synonymous with boxed warnings) carry the highest level of
concern and typically pertain to a proved or suspected risk for medi-
cally serious or potentially life-threatening side effects. Warnings are
statements communicating that serious adverse events or potential
safety hazards have been observed with a particular drug. Precautions
indicate that consideration must be taken in special situations or patient
groups. Contraindications are statements included in manufacturers’
product information that a drug should not be used in certain clinical
situations because its risks significantly outweigh its projected benefits.
Contraindications may be relative or absolute. Table 1–6 provides a
summary of black box warnings associated with commonly prescribed
psychotropic medications. Throughout this book, adverse effects that
reflect FDA black box warnings are also designated symbolically (■).
Notably, class warnings impart no information about possible rela-
tive differences among agents within a given class (e.g., the potential for
glycemic dysregulation may vary considerably among SGAs; suicidal
thinking and behavior can differ across drugs that possess antidepres-
sant properties).
All antipsychotics carry a black box warning (■) regarding a small but
significant increased risk for all-cause mortality in elderly patients with
dementia-related psychosis. This warning derives from an analysis of 17
placebo-controlled trials conducted over an approximate 10-week pe-
riod, which found a 1.6- to 1.7-fold increased risk for all-cause mortality
(4.5% among subjects taking an SGA compared with 2.6% among those
taking placebo), on the basis of safety data analyzed by the FDA.
Risk-Benefit Analyses
The extent to which patients or clinicians prioritize tolerability over effi-
cacy likely varies as a function of illness severity and disease conse-
quences (exemplified perhaps most dramatically in the case of choosing
antineoplastics for a malignancy). Remarkably, in psychiatry, doctors
and patients seldom discuss how to strike a balance between sufficient ef-
ficacy and acceptable adverse effects, despite the high degree of func-
tional disability and excess mortality due not only to suicide, but also to
medical comorbidities in people with significant mood or psychotic dis-
orders (Ösby et al. 2001). Yet, studies of treatment effectiveness point to
the relevance of both dimensions. For example, in the National Institute
of Mental Health–funded CATIE study in schizophrenia, 15% of subjects
discontinued their participation because of drug intolerance, whereas
24% discontinued because of lack of efficacy (Lieberman et al. 2005).
As described below, a number of points merit consideration regard-
ing the balance between risks and benefits of any treatment within the
context of a doctor-patient relationship.
Shared Decision-Making With Patients

The notion of shared risk and shared decision-making between doctor and
patient is in many respects the hallmark of an effective therapeutic alliance.
Because treatment outcomes are often difficult if not impossible to predict,
it can be argued that the most any health care provider can do beyond of-
fering an educated opinion about preferred treatment options is articulate
the likely risks and benefits of a given therapy and provide an informed es-
timate of the probabilities attached to both of these core facets of treatment.
One area that is particularly emblematic of shared risk and decision
making is the approach to planned pregnancy in women taking psycho-
tropic medications. As described more fully in Chapter 20, “Pregnancy
and the Puerperium,” most commonly used psychotropic drugs are
classified by the FDA as lacking known risk for human teratogenicity
(i.e., Category C), but the potential for unknown risk remains a concern;
such uncertainties must be balanced against the more tangible and often
known certainties related to symptomatic or syndromal relapse with
treatment discontinuation during pregnancy in many individuals with
significant Axis I psychiatric disorders.
Known Versus Unknown Drug Risks

A reality of medicine involves the accrual of new information about a
drug after it is made available for marketing by the FDA. Postmarketing
34
TABLE 1–6. FDA black box warnings (■) related to adverse drug effects
Warning or precaution Agents Practical implications
Agranulocytosis Clozapine, carbamazepine Registry-based CBC and ANC monitoring for clozapine is weekly
(alone and especially for the first 6 months, then (if stable) biweekly for the next

combined) 6 months, then (if stable) every 4 weeks thereafter. Specific
information regarding acceptable CBC and ANC levels and
management guidelines are available at www.clozaril.com/
pdfs/MonthlyMonitoring.pdf.
Serious cardiovascular events All formulations of The American Heart Association recommends baseline ECGs in
and sudden death amphetamine or children before initiating a stimulant (Vetter et al. 2008).
methylphenidate
Serious and potentially fatal Carbamazepine, lamotrigine Carbamazepine risk is higher in patients with Asian ancestry who
dermatological reactions, including carry the HLA-B*1502 allelic variant of the HLA-B gene.
toxic epidermal necrolysis and
Stevens-Johnson syndrome
Hepatic failure Nefazodone Nefazodone has been observed to cause life-threatening hepatic
failure in 1 of 250,000 exposed cases. Preexisting liver disease
does not predispose to this occurrence. Nefazodone should not
be administered if serum liver enzymes (AST or ALT) exceed
three times the upper limit of normal.
Hepatotoxicity Divalproex Divalproex carries an increased risk for potentially fatal
hepatotoxicity, particularly in infants given multiple
anticonvulsants, and usually during the first 6 months of
treatment. Liver function tests should be monitored on a regular
basis.
TABLE 1–6. FDA black box warnings (■) related to adverse drug effects (continued)
Increased mortality in elderly All antipsychotics Risks must be weighed against potential benefits; caution is
patients with dementia-related necessary in patients with known cardiovascular or
psychosis cerebrovascular disease.
Myocarditis Clozapine Reported incidence is approximately 1%, typically arising within
the first few weeks of clozapine initiation. CRP levels >100 mg/L
may be an early diagnostic indicator (Ronaldson et al. 2010), as is
occasionally eosinophilia.
Pancreatitis Divalproex Pancreatitis should be considered in the differential diagnosis of
patients who develop signs of an acute abdomen while taking
divalproex.
QTc prolongation (dose related) Mesoridazine, thioridazine Use of mesoridazine or thioridazine is reserved for schizophrenia
that is refractory to other treatments.
Seizures Clozapine Seizures are usually dose related or the result of rapid dosing
titration; some practitioners advocate cotherapy with an
anticonvulsant (e.g., divalproex, carbamazepine, gabapentin)
when clozapine is used at high dosages (Toth and Frankenburg
1994; Usiskin et al. 2000).
35
36
TABLE 1–6. FDA black box warnings (■) related to adverse drug effects (continued)
Increased risk for suicidal thinking Atomoxetine, In patients < age 24, especially close attention is needed to the
and behavior (but no proven all antidepressants, paradoxical worsening or emergence of suicidal thinking during

increased risk for suicide deaths) quetiapine, olanzapine- antidepressant therapy in the first few weeks of treatment, in
fluoxetine combination which case drug cessation may be appropriate.
Teratogenicity Divalproex Divalproex is associated with a 1%–5% incidence of neural tube
defects in the developing fetus; use during pregnancy requires
that the benefits of use outweigh the potential risks to fetal
development.
Note. ALT= alanine aminotransferase; ANC= absolute neutrophil count; AST =aspartate aminotransferase; CBC=complete blood count;
CRP= C-reactive protein; ECG= electrocardiogram; FDA= U.S. Food and Drug Administration.
experience provides the essential opportunity to determine experiences

with a treatment under more ordinary or routine clinical conditions
than is otherwise the case in randomized trials.
Despite the rigors of all phases of safety testing for a drug, pharma-
covigilance data at times emerge in ways that could not be anticipated
initially in the absence of more extensive exposure to larger segments of
the population. Postmarketing surveillance findings sometimes lead to
changes in the labeling or categorization of a drug (e.g., warnings re-
garding the risk for suicidal thoughts or acts with anticonvulsants in ep-
ilepsy patients in nonbipolar, nonepileptic patients [Arana et al. 2010];
hepatic failure with nefazodone or pemoline; the reclassification of par-
oxetine from Category C to Category D after postmarketing drug mon-
itoring cases revealed a small but significantly increased risk for atrial or
ventricular septal defects during first trimester exposure in pregnancy).
Some clinical trials have begun to express the incidence of specific
adverse effects as the number needed to harm (NNH), defined as the num-
ber of patients who need to be exposed to a treatment for an increased
risk of an adverse event in one individual. NNH is computed as follows:
1
event rate among exposed subjects– event rate among subjects not exposed
In clinical trials, this proportion typically reflects 1/(drug rate)–(placebo

rate). The denominator in the equation above might, for example, refer to
the proportion of patients who develop weight gain exceeding 7% of their
pretreatment weight with an SGA less the same proportion among those
who took placebo. NNH, analogous to the number needed to treat (NNT),
expresses the magnitude of effect of an active drug versus a placebo, or of
one treatment relative to another. In practical terms, a high NNH indi-
cates that many patients would need to be exposed to a given therapy be-
fore one would incur an adverse event of interest. (For further discussion
on calculating and using NNT and NNH, see Citrome 2011.)
When considering the risks versus benefits of a particular treatment,
a low NNT (meaning that few patients need to be treated before one re-
sponds) with a high NNH suggests an optimal balance. By way of ex-
ample, in the above instance, an NNH-NNT analysis (i.e., risk-benefit
ratio) comparing olanzapine to lithium or divalproex during mainte-
nance treatment for bipolar I disorder yielded NNHs for olanzapine of
5–8, relative to NNTs of 4–10 for preventing symptomatic relapse into
mania, depression, or a mixed episode (Tohen et al. 2009). Elsewhere,
studies of discontinuation due to adverse events in randomized trials of
olanzapine found an NNH of 24 in bipolar depression and 9 in major

depression; discontinuation attributable to adverse events in trials of
quetiapine XR found NNHs of 9 in bipolar depression and in major de-
pression, 8 in refractory major depression, and 5 in generalized anxiety
disorder (Gao et al. 2011). The NNH:NNT ratio has also been described
as the likelihood of being helped or harmed.
Risk-benefit analyses that consider drug tolerability versus efficacy
often may also be usefully informed by appreciating the magnitude or
clinical meaningfulness of a drug’s beneficial effect. In addition to NNT,
the clinician might consider the concept of effect size—a statistic derived
from the observed difference in mean scores divided by their pooled
standard deviation. Also known as Cohen’s d, effect sizes are generally
ranked as being small (≤0.20), medium (~0.50), or large (~ ≥0.80) (Cohen
1992). Clinicians might wisely be more inclined to encourage patients to
tolerate or manage adverse effects when a drug’s expected benefits cor-
respond to a larger rather than a smaller effect size. Drugs that exert only
a small effect, or merely a “just noticeable difference” from placebo, may
not possess a sufficiently clinically meaningful impact to justify their ad-
verse effects.
Watchful Waiting
It is fundamental for practitioners to know when adverse drug effects
are usually transient and typically resolve with time through the pro-
cess of accommodation to a medication (e.g., nausea after starting an
SSRI) and when a given side effect is likely to endure (e.g., as is common
with medication-induced weight gain). Elements of decision making in
this domain involve an awareness not only of drug exposure time as
contributing to tolerability but also an awareness of association (or lack
of association) between a side effect and progressive dosage increases. In
the latter instance, the clinician might consider the example of sedation
with mirtazapine as being purportedly more common at low rather than
high dosages due to the drug’s greater noradrenergic effects at higher
dosages; and in the former instance, the frequent transience of nonspe-
cific CNS effects, such as headache or dizziness, experienced by a patient
soon after beginning an antidepressant. By contrast, weight gain caused
by psychotropic agents has rarely been shown to diminish with dosage
reductions, and the hope that weight gain will spontaneously halt or re-
verse itself either with time alone or with a lowered dosage is usually un-
realistic. Possession of a fairly strong working knowledge of the time
course, dose relationships, risk factors, and clinical relevance of com-
mon side effects allows the practitioner to make more informed recom-
mendations and forecast outcomes more effectively when anticipating

and managing the potential emergence of adverse effects.
Deciding When to Pursue Antidotes and

When to Switch Medicines
In some respects, practitioners rely more on art than science when deciding
whether to actively manage an adverse effect (either by dosage adjust-
ments or the addition of other medications intended to counteract adverse
effects) or to discontinue a treatment because of its adverse effects. Some
unpredictable or idiosyncratic yet adverse effects obviously defy manage-
ment; these include agranulocytosis, NMS, and serious rashes. Other ad-
verse effects may clearly pose more of an annoyance than a danger to
physical well-being. In such instances, there may be a compelling rationale
to introduce additional medicines to remedy an adverse effect while pre-
serving a benefit (as in the case of β-blockers or benzodiazepines to dimin-
ish akathisia). Still other adverse effects may signal probable drug toxicities
that may be dose related (e.g., tremor caused by lithium, thrombocytope-
nia caused by divalproex). A further conundrum can arise when a particu-
lar side effect has been suggested to correlate with a favorable treatment
response (as in the reported predictive value of weight gain with use of an-
tipsychotics or the antimanic efficacy of some SGAs); such correlations
may be spurious artifacts of drug exposure time or dosage.
“Antidote” drugs that may counteract a psychotropic drug’s ad-
verse effects could themselves have adverse effects that further bear on
risk-benefit analyses. For example, anticholinergic drugs such as benz-
tropine, trihexyphenidyl, or oxybutynin may in themselves cause cog-
nitive impairment, sedation, and visual or gastrointestinal problems.
Clinicians choosing from among several viable antidote drugs should
consider these medications’ relative risks and benefits. (For example,
amantadine may offer a more cognitively benign remedy than anticho-
linergic drugs to counteract antipsychotic-induced extrapyramidal ad-
verse effects.) Prescribers should be familiar with possible adverse
effects of a given nonpsychotropic drug before prescribing it as an in-
tended remedy to counteract adverse psychotropic drug effects.
Practitioners might consider adverse drug effects as falling along a
continuum of severity that can range from “minimal or mild” to “an-
noying but medically inconsequential” to “serious” or even “life threat-
ening.” Table 1–7 lists the levels of difficulty and severity in managing
psychotropic side effects. Practitioners can counsel patients on the like-
lihood that a given side effect is transient or dose related and advise
conservative management strategies (e.g., taking acetaminophen for
headaches when starting an SSRI), assuming that the clinician under-

stands the typical time course for the emergence and resolution of a par-
ticular medication side effect. Sometimes, nuisance side effects can be
averted or at least minimized by changing a medication dosage, formu-
lation (e.g., extended release), cotherapy, or timing of administration
(e.g., giving sedating drugs at night).
Treatment Adherence and Adverse Effects

Randomized studies that report premature dropouts due to adverse ef-
fects can be difficult to extrapolate to real-world treatment settings for
a variety of reasons. Research trial subjects typically have only one di-
agnosis that conforms more closely to DSM-IV-TR criteria than may be
the case in routine practice (where patients with poorly defined condi-
tions may encounter different beneficial or adverse drug effects). Also,
nonresearch patients often take more than one medication at a time,
and their motivations and expectations may differ during a time-
limited clinical trial than is the case for patients in more open-ended
routine treatment. Some researchers point out that in a double-blind
trial, research subjects often will tolerate adverse effects in the context
of clinical response and be less likely to prematurely leave a clinical trial
because of adverse effects than subjects who encounter adverse effects
but minimal or no improvement. One problem when interpreting such
observations involves determining whether the presence of adverse ef-
fects in and of themselves may inadvertently allow patients to discern
whether they are taking an active drug or placebo, which in turn may
influence their decision to remain in a double-blind study if they be-
lieve they are improving while receiving an active therapy.
A frequent, intuitively logical assumption is that medication adher-
ence wanes in the setting of cumulative or substantial adverse drug ef-
fects. However, surprisingly little research has addressed the extent to
which patients across psychiatric disorders are inclined to tolerate ad-
verse effects and remain in treatment if efficacy is robust, or rather, how
much a potential side-effect burden drives adherence and retention
with treatment irrespective of drug efficacy. Some pharmacotherapy
studies suggest that less premature study termination occurs due to ad-
verse effects when efficacy is high relative to placebo, but the balance
between tolerability and efficacy is difficult to express in either a quan-
titative or generalizable format.
Clinicians cannot assume that side-effect burden necessarily drives
medication nonadherence. For example, in the 2000 British National
Psychiatric Morbidity Survey, concerns about psychotropic drug side
TABLE 1–7. Levels of difficulty and severity in managing psychotropic side effects
Relatively simple to manage Often difficult to manage Medically serious
Anticholinergic effects (e.g., dry mouth, Alopecia Neuroleptic malignant syndrome

constipation) Cognitive complaints Serotonin syndrome
Extrapyramidal side effects Insomnia Severe cutaneous reactions
Gastrointestinal upset Nephrogenic diabetes insipidus Sever metabolic dysregulation (e.g.,
Headache Sedation hyperosmotic nonketotic coma)
Tremor Sexual dysfunction Substantial weight gain
Sialorrhea
Tardive dyskinesia
Mild to moderate weight gain
41
effects were identified by only 14% of 634 respondents as a reason for in-
complete adherence with medications (Cooper et al. 2007). Those who
linked side effects with poor adherence were younger, had histories of
psychosis, and had lower intellectual functioning. Elsewhere, Agosti et
al. (2002) found that depressed patients who stopped antidepressant
therapy during randomized placebo-controlled trials with various anti-
depressants were more likely to have high baseline somatization.
In an interesting study of mood stabilizer adherence among individ-
uals with bipolar disorder, Scott and Pope (2002) found that patients’
apprehension or perceptions about possible adverse drug effects, rather
than the actual occurrence of adverse effects, contributed to nonadher-
ence. A corollary to these observations is that patient adherence to phar-
macotherapy may improve if prescribers are better able to anticipate
and desensitize fears about potential drug side effects before they occur.
Clinicians sometimes think that when they disclose possible side effects
to a patient, they are mainly performing an act of due diligence by dis-
charging a medicolegal obligation, with the presumption that provid-
ing more than the minimum necessary amount of information would
heighten fears and inspire nonadherence. In fact, little evidence sup-
ports this notion. Many patients also poorly retain such information af-
ter only a single presentation.
An alternative perspective is that patients may respond more to the
sense of factual openness and confidence with which a practitioner fore-
casts likely outcomes, both good and bad. Physicians who impart their
perspective not only on the likelihood of occurrence of an adverse event
but also on the ability to anticipate and actively manage a side effect if it
arises, are likely to strengthen rather than weaken the therapeutic alli-
ance—which may in turn serve to minimize patients’ fears about un-
known consequences of treatment. Patients, in turn, may also be grateful
for honest appraisals coupled with a sense of empowerment from their
treaters who indicate that no matter what could happen, the patients’ care
will fall under a watchful eye and a proactive guardianship.
Patients and prescribers have been shown to differ in their percep-
tions about drug side effects. Over 60% of survey respondents with self-
identified bipolar disorder in the British Manic Depression Fellowship re-
ported feeling dissatisfied with the level of information their physicians
provided to them regarding the nature and extent of medication side ef-
fects, especially potential sexual adverse effects (Bowskill et al. 2007).
A final consideration relating to medication adherence involves the
potential negative impact of underdosing, potentially as an effort by pre-
scribers to minimize side-effect burden. A study of 312 individuals with
bipolar disorder found that the number of daily medications or pills did
not correlate with medication adherence but that low adherence was sig-
nificantly associated with taking smaller dosages of mood-stabilizing
drugs (Bauer et al. 2010), although that study did not account for the po-
tential moderating effects of illness severity on treatment adherence.
General Approach to Assessing

Adverse Drug Effects
Perhaps a first consideration regarding the assessment of drug side ef-
fects involves differences in their recognition by patients versus psychia-
trists, and the extent to which patients spontaneously report or even
recognize possible side effects. Given pharmacodynamic and pharmaco-
kinetic synergies that occur from combination drug regimens, it is point-
less for a psychiatrist to ask a patient if he or she is aware of any possible
side effects from one drug out of many. It is crucial for practitioners to
assess, rather than merely note, suspected adverse drug effects, because
patients’ physical complaints may, in actuality, be communications of
subjective distress that is unrelated to medications. Implausible adverse
effects or nocebo responses are psychiatric phenomena that require ex-
ploration—for example, sedation or cognitive problems from nonantihis-
taminergic, nonanticholinergic drugs. Astute clinicians also recognize
the presence of pharmacodynamic inconsistencies, as when patients re-
port co-occurring problems that involve opposing mechanisms, such as
dry mouth with diarrhea, or sialorrhea with constipation. Rather than
dispute the validity of a patient’s experience (e.g., “That’s impossible!
This medicine doesn’t even have cholinergic effects!”), the clinician
would be wise to validate the patient’s distress and adopt a more psycho-
therapeutic stance (e.g., “We will figure this out together; let’s go back
and examine more closely what’s been happening since the time you be-
gan this medicine”).
Clinicians sometimes proactively assess adverse drug effects but
must be even more alert to patients’ spontaneous symptom complaints
that require probing to differentiate iatrogenic from illness-based etiol-
ogies (e.g., insomnia, anxiety, agitation). Practitioners vary in how they
track adverse effects using a systematic versus an ad hoc approach. It is
important to note that a minimum standard of care has yet to be estab-
lished in psychiatry for the surveillance monitoring of adverse drug ef-
fects in clinical practice. Perhaps two of the greatest considerations in
monitoring drug safety involve the sheer identification of side effects
(i.e., sensitivity to recognizing when a side effect may be present) and
the ability to attribute proper causality to a possible side effect (i.e., de-
ducing the specificity or likelihood that the cause of a potential side ef-
fect is indeed a particular medication). The former responsibility
involves a strong knowledge of common side effects of all medications
being prescribed (and the resourcefulness to investigate whether or not
an uncommon side effect has been linked with a particular medication),
and their active (rather than passive) recognition. The latter becomes es-
pecially challenging when a patient takes a variety of medications and
attempts are made to discern which one (or which combination) is most
likely producing a given effect.
Practitioners assess potential side effects with great variability.
Some choose not to bring up side effects altogether unless patients do so
themselves for fear of inspiring nonadherence. Others adopt a rather
businesslike stance in disclosing to patients (and documenting) mainly
the potentially serious side effects listed in a manufacturer’s package in-
sert, largely as a matter of medicolegal due diligence. The use of system-
atic rating scales (see “Rating Scales for Measuring Adverse Drug
Effects” in Appendix 2) offers one means for delineating and quantify-
ing the extent of certain adverse drug effects, providing a method for
prospectively tracking potential worsening from baseline. From the
standpoint of providing good medical care, the proverbial middle
ground likely involves assessing an individual patient’s attitudes and
beliefs about medications, both beneficial and harmful, and tailoring an
informed discussion accordingly. Patients with diffuse anxiety and
trepidation about possible hazardous results would be ill served and
cognitively flooded by a recitation of any and all possible side effects;
such individuals likely respond better to the fostering of an emotionally
safe and secure environment in which the prescriber projects a stance of
vigilance on behalf of the patient, guarding against the intrusion of side
effects that lurk beyond the safe confines of the consultation room. By
contrast, obsessional or paranoid patients—who may be inclined to re-
search any and all possible side effects, regardless of their plausibility or
likelihood—may need their safety concerns validated and fare best
when engaged as their own sentries poised to safeguard their own wel-
fare. Individuals with histrionic or dramatic presentation styles may ex-
aggerate their experience of suspected adverse effects, and clinical
wisdom often demands exploring such patients’ subjective complaints
and concerns beyond their face value.
For the majority of patients, perhaps the most honest and reasonable
approach for anticipating side effects is to proactively inform patients of
the most common and medically important side effects to watch for and
to provide some sense of context and proportion about their likelihood,
seriousness, and time course (e.g., “Nausea is the most common side ef-
fect of SSRIs; it typically passes shortly after starting a drug. It is less

likely to occur if the medicine is taken with food than on an empty stom-
ach. If it occurs and is bothersome, an over-the-counter medication such
as famotidine may be helpful until the nausea eventually goes away.”).
Sometimes, such information can also empower patients to know the pa-
rameters under which side effects may happen, especially if clinicians
can impart a sense of predictability and control over an otherwise ran-
dom-risk event. For example, when prescribing lamotrigine, the clini-
cian might inform patients that the greatest risk window for developing
a serious rash during treatment is from weeks 2 through 8, that serious
rashes have a characteristic appearance, and that the risk can be mini-
mized by taking precautions such as avoiding new environmental ex-
posures.
A related point for engaging patients as collaborators in risk-benefit
decision making involves the ability to forecast the probability that a
side effect will occur and to describe a management strategy before it is
needed. For example, in the case of weight gain caused by olanzapine,
patients with bipolar mania who gain 1.8–2.3 kg in the first 2–3 weeks of
treatment have a significantly greater risk for eventual substantial
weight gain (≥9.9 kg) after 30 weeks of continued therapy, as contrasted
with a much smaller risk (~10%) of substantial weight gain later devel-
oping in patients without such increases in the first few weeks (Lipkov-
ich et al. 2006). Speaking from that database, a clinician might suggest to
a patient who is concerned about possible weight gain that within the
first few weeks of treatment, a reasonable estimate can be made on both
the potential for improvement and the likelihood for later weight gain.
In that sense, clinical decision making becomes a nonstatic process, in-
formed by successive (and changing) risk-benefit analyses over time.
2
Pharmacokinetics,
Pharmacodynamics,
and Pharmacogenomics
Pharmacokinetics and
Pharmacodynamics
Pharmacodynamics refers to the effects of a drug on the body, whereas
pharmacokinetics refers to the effect of the body on a drug (absorption,
distribution, metabolism, and elimination).
Drug absorption becomes relevant to pharmacodynamic effects
mainly when external factors exist that hasten or delay absorption,
which in turn may affect the bioavailability of a compound. Malabsorp-
tion syndromes (e.g., dumping syndrome after gastric bypass surgery)
may slow drug absorption or pose implications for the utility of certain
drug formulations (e.g., after gastric bypass, extended-release formula-
tions that are absorbed more distally in the gastrointestinal tract are gen-
erally less well absorbed than are immediate-release formulations).
The absorption of some psychotropic drugs also may vary greatly
when ingested with or without food. Drugs that are administered
parenterally (by injection), transdermally, or sublingually avoid first-
pass hepatic metabolism and may reach maximal blood concentrations
(Cmax) faster than orally ingested formulations, although time until
47
achieving Cmax does not necessarily translate to faster or more substan-

tial therapeutic efficacy (including side-effect burden).
Important concepts related to drug absorption, distribution, metab-
olism, and elimination are summarized in Table 2–1. Manufacturers’
suggested dosing for many pharmaceutical agents is based on the
plasma elimination half-life rather than terminal elimination half-life.
Clinicians sometimes assume (and drug manufacturers sometimes
intimate) that Tmax (time to Cmax) reflects a maximal pharmacody-
namic drug effect (either beneficial or adverse), but such a simple asso-
ciation cannot necessarily be presumed. Drugs exert different effects at
different sites of action (e.g., in the case of TCAs, α1-adrenergic receptor
blockade mediates orthostatic hypotension while central cholinergic re-
ceptors mediate adverse cognitive effects), yet such regional differences
in concentration may not accurately be reflected by the maximal plasma
level. Some adverse effects also occur only after chronic administration
of a drug (e.g., tardive dyskinesia or metabolic syndrome arising from
SGAs; secondary hypothyroidism due to lithium; osteoporosis from an-
ticonvulsants or SSRIs) and are not clearly related to plasma blood lev-
els or maximal concentrations.
Known effects of drug administration on absorption with or without
food are summarized in Table 2–2.
Orodispersible (i.e., orally disintegrating) forms of a medication dis-
solve supralingually and are then swallowed (rather than absorbed to
any appreciable degree through the oral-buccal mucosa). Zydis refers to a
proprietary technology used to manufacture orally disintegrating tablets.
There has been speculation that the Zydis preparation of olanzapine may
have a faster onset by virtue of a shorter Tmax, and preliminary data sug-
gest a slower rate of weight gain than with the tablet formulation of olan-
zapine (Karagianis et al. 2010; see also “Zydis Formulations” in Chapter
19, “Systemic Reactions”); however, evidence to support such hypotheses
has not been documented from controlled trials. Similarly, orally dissolv-
ing risperidone (Risperdal M-tabs) or orally dissolving aripiprazole prep-
arations require the same gastrointestinal (nonbuccal) absorption as
tablet formulations, and do not demonstrate appreciable pharmacody-
namic differences from nonorodispersible forms of these drugs.
Drug metabolism becomes especially pertinent when it may account
for drug side effects. For example, Phase I metabolism refers to the ef-
fects of hepatic microsomal CYP enzymes on drug substrates and in-
cludes chemical reactions such as oxidation (e.g., of carbamazepine to
its epoxide metabolite, as illustrated in Figure 2–1) or reduction (e.g., the
reduction of the keto group at the 10-carbon position of the middle ring
structure of oxcarbazepine to generate its metabolite monohydroxy-
Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics 49
TABLE 2–1. Key concepts related to pharmacokinetic effects
Term Definition
Area under the curve The plasma concentration of a drug plotted

(AUC) against time after administration; relevant for
estimating drug bioavailability and clearance
Bioavailability The extent to which a drug is absorbed and
becomes available to its target tissue;
formally defined as the AUC for a given dose
Cmax The maximum plasma concentration of a drug
(Note: This does not necessarily reflect drug
concentration at the drug’s site of action—
e.g., maximal plasma concentrations of
lithium may not necessarily reflect brain
lithium levels in patients with bipolar
disorder; Sachs et al. 1995)
Plasma elimination The time required until the plasma
half-life (t½) concentration of a drug is reduced by half;
often taken as a proxy for the half-life at end
organs of interest (e.g., brain), following an
exponential decay process (see also Table 2–2)
Steady-state An equilibrium state in which a stable
concentration (Css) concentration of a drug is achieved, typically
after the passage of five half-lives
Therapeutic index The amount of a drug that causes death (i.e., a
lethal dose for 50% of the population, or LD50)
relative to the amount that causes a
therapeutic effect (i.e., the minimum effective
dose for 50% of the population, or ED50);
defined as the ratio of LD50/ED50
Therapeutic window The range between an effective dose (ED50)
and the median toxic dose (TD50, the dose at
which toxicity occurs for 50% of the
population)
Tmax The time to Cmax
oxcarbazepine, as illustrated in Figure 2–2). Similarly, Phase I demeth-

ylation of tertiary amine TCAs (e.g., amitriptyline or imipramine, via
CYP2C19) derives their secondary amine metabolites (nortriptyline and
desmethylimipramine [desipramine], respectively); the latter are often
thought to cause fewer anticholinergic (e.g., cognitive) and sedative ef-

fects—although potentially greater cardiotoxicity—than their tertiary
amine parent compounds.
Phase II drug metabolism involves conjugation of a drug substrate
with a moiety such as glucuronidation, methylation, acetylation, or sul-
fation. An important example of Phase II metabolic effects with respect
to adverse drug effects would be the delayed metabolism of lamotrigine
resulting from divalproex-induced delayed glucuronidation of lamo-
trigine—and the consequent increased risk for serious drug rashes un-
less lamotrigine dosing is halved in the presence of divalproex.
The rate at which a particular individual acetylates a substrate during
Phase II metabolism is mediated by genetic factors, giving rise to so-
called slow acetylators or fast acetylators. The former group may be es-
pecially prone to develop adverse effects at relatively low medication
doses due to slow metabolism, whereas the latter group may have mini-
mal or no adverse effects (or efficacy) at usual dosages and may require
what would otherwise be considered supratherapeutic dosages, either to
achieve a clinical response or develop drug side effects.
Pharmacokinetic interactions represent an extensive subject unto it-
self (for a full review, see Preskorn and Flockhart 2009; Wynn et al.
2009). However, for the current purposes, it is important to recognize
the potential for drug interactions that may cause one agent to inhibit
the CYP enzymes responsible for metabolizing another agent, thereby
increasing serum levels and, in turn, side-effect burden. For example,
fluvoxamine—a potent inhibitor of CYP1A2 metabolism—may increase
blood levels of coadministered psychotropics that are also metabolized
(at least in part) by the same enzyme; these psychotropics include clo-
zapine, olanzapine, and asenapine. Although some practitioners capi-
talize on this phenomenon for the sake of therapeutic efficacy (e.g.,
boosting clozapine levels by deliberately coadministering fluvoxamine
with low-dose clozapine), the clinician must be cognizant of the poten-
tial for more pronounced adverse effects (e.g., sedation) or even frank
toxicity, inasmuch as CYP1A2 inhibition by fluvoxamine can cause a 4-
to 5-fold increase in serum clozapine levels.
Long-acting (e.g., extended-, controlled-, or sustained-release) prepa-
rations of a medication often involve slow-release absorption mecha-
nisms (e.g., osmotic pumps or gel matrix coatings) that do not necessarily
alter plasma half-life or pharmacodynamic properties of a psychotropic
compound. They may produce differences from immediate-release for-
mulations in Tmax or Cmax, but the clinician cannot assume that such al-
tered pharmacokinetics will necessarily lead to pharmacodynamic
differences in efficacy or side-effect profiles.
N N
CONH2 CONH2
FIGURE 2–1. Epoxidation of carbamazepine to its 10,11-epoxide me-

tabolite via CYP3A4.
O OH –
N N
CONH2 CONH2
FIGURE 2–2. Reduction of oxcarbazepine carbonyl group (10-position)

to monohydroxy-derivative oxcarbazepine.
Manufacturers seldom if ever conduct direct, head-to-head compar-

isons of immediate-release versus long-acting preparations of a given
compound for the purposes of prospectively identifying differences in
safety or efficacy in a randomized controlled fashion; therefore, poten-
tial differences in adverse-effect profiles across formulations must be in-
terpreted with caution. Lack of direct head-to-head comparisons also
prevents consideration of drug-placebo differences that may vary
across different studies. Nevertheless, if the clinician were to compare
side by side the incidence rates of common adverse drug effects from
manufacturers’ product information on immediate-release versus long-
acting drug preparations, he or she would find only a limited number of
noteworthy differences. These are summarized in Table 2–3.
52
TABLE 2–2. Mean half-life and differential absorption of psychotropics under fasting conditions versus with
food
Does food alter drug absorption and bioavailability?
Agent Mean t½ No Yes Comment

Atomoxetine 5 hours ✓
Benzodiazepines Alprazolam=11 hours ✓
Clonazepam=18–50 hours ✓
Diazepam=20–100 hours ✓
Lorazepam=10–20 hours ✓
Buspirone 2–3 hours ✓ Administration either with or without food should be
consistent.
Anticonvulsants and lithium
Carbamazepine 25–65 hours ✓
Divalproex 9–16 hours ✓ Food slows rate but not extent of absorption.
Gabapentin 5–7 hours ✓ High-protein meals may increase absorption via intestinal
transport (Gidal et al. 1996).
Lamotrigine 25–33 hours ✓
Lithium 24 hours ✓ Lower absorption on an empty stomach.
Oxcarbazepine 30 hours ✓
Topiramate 21 hours ✓
Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics
food (continued)
Antidepressants
Bupropion 14 hours (IR) ✓
21 hours (SR or XL)
Mirtazapine 20–40 hours ✓
Nefazodone 2–4 hours ✓ Food decreases absorption and bioavailability by ~20%.
SNRIs Desvenlafaxine=11 hours ✓
Duloxetine=12 hours ✓
Venlafaxine=5 hours ✓
SSRIs Citalopram=35 hours ✓ Modest increased bioavailability and higher Cmax with
Escitalopram=27–32 hours ✓ food for sertraline; otherwise, no known associations with
Fluoxetine=4–6 days ✓ other SSRIs.
(norfluoxetine=9 days) ✓
Fluvoxamine=15 hours ✓
Paroxetine=21 hours ✓
Sertraline=26 hours ✓
53
54
food (continued)

TCAs Amitriptyline=10–50 hours ✓
Clomipramine=19–37 hours ✓
Desipramine=7–60 hours ✓
Imipramine=6–18 hours ✓
Nortriptyline=16–90 hours ✓
Vilazodone 25 hours ✓ Should be taken with food; absorption and bioavailability
are reduced by ~50% when taken on an empty stomach.
SGAs
Aripiprazole 75 hours ✓
Asenapine 24 hours ✓ Optimal bioavailability (~35%) via sublingual absorption;
declines to ~28% with food or liquid ingested within
10 minutes of administration; ~2% bioavailability if
swallowed.
Iloperidone 18–33 hours ✓
food (continued)
SGAs (continued)
Lurasidone 18 hours ✓ Cmax reduced 3-fold and bioavailability markedly reduced
if administered without food. Should be administered
within 30 minutes of at least a 350-calorie small meal.
Olanzapine 30 hours ✓
Paliperidone 23 hours ✓ 54%–60% less under fasting conditions.
Quetiapine 7 hours ✓ Food modestly increases absorption and Cmax.
Risperidone 24 hours ✓
Ziprasidone 7 hours ✓ Approximate 2-fold increased absorption when
administered with food.
Note. Cmax = maximal drug plasma concentration; IR=immediate release; SGA= second-generation antipsychotic; SNRI = serotonin-
norepinephrine reuptake inhibitor; SR= sustained release; SSRI = selective serotonin reuptake inhibitor; t½ = plasma elimination half-life;
TCA= tricyclic antidepressant; XL=extended release.
55
56
TABLE 2–3. Noteworthy incidence rates of common adverse effects in short- and long-acting drug preparations
Recipients (%) reporting side effectsa
Medication Indication Side effect(s) Short-acting agent Long-acting agent

Bupropion Major depression, Agitation 32% (IR) 2% (XL)
smoking cessation 3%–9% (SR)
Decreased appetite 18% (IR) 4% (XL)
3%–5% (SR)
Divalproex Acute mania Dyspepsia 9% (DR) 23% (ER)
Quetiapine monotherapy Bipolar mania Somnolence or sedation 18% (IR) 50% (XR)
Bipolar depression Somnolence or sedation 57% (IR) 52% (XR)
Schizophrenia or Agitation 20% (IR) <1% (XR)
bipolar mania
Note. DR= delayed release; ER =extended release; IR =immediate release; SR= sustained release; XL= extended release; XR= sustained
release.
aBased on respective product FDA registration trials, as reported in manufacturers’ product information.
Pharmacodynamic adverse effects of a medication sometimes can be

anticipated based on drug receptor profiles, as summarized in Table 2–4.
Toxic Polypharmacy
Although thoughtful combination pharmacotherapy regimens seek to
capitalize on pharmacodynamic synergies and complementary mecha-
nisms of action, chaos may result from the more haphazard accrual of
multiple (or redundant) agents—or medications with opposing phar-
macodynamic profiles (e.g., stimulants plus sedative-hypnotics, dopa-
mine agonists plus antagonists). Consider, for example, the precarious
combination of multiple SGAs that bind tightly to the dopamine D 2 re-
ceptor—such as risperidone plus ziprasidone or lurasidone—resulting
in an increased potential for adverse extrapyramidal effects or dysto-
nias. Consider also the effects of combining partial agonists with full
antagonists (e.g., the µ-opioid receptor partial agonist buprenorphine
plus the full antagonist methadone; the D2 partial agonist aripiprazole
with any full D2 antagonist neuroleptic or with a D2 agonist such as am-
phetamine or methylphenidate), which at least theoretically may lead
to displacement of receptor binding. For example, buprenorphine
added to methadone might be expected to displace the binding of meth-
adone and trigger opiate withdrawal; coadministration of aripiprazole
with another SGA would virtually dominate the D2 receptor and might
therefore at least theoretically prevent or minimize binding of coadmin-
istered dopaminergic agents, resulting either in lack of efficacy or sim-
ply additive adverse effects—e.g., changes in appetite, sedation, or level
of alertness—without a rationale-based benefit. Noncontrolled studies
of two or more SGAs used in combination have demonstrated greater
anticholinergic and other side-effect burdens, but no greater efficacy,
than single-agent SGAs in the case of bipolar disorder or other serious
mental illness (Megna et al. 2007). Weight gain does not necessarily ap-
pear to be more substantial with the use of one versus two or more
SGAs. Risks must be carefully weighed against observable benefits
when such combination pharmacotherapy approaches are undertaken.
Gender and Racial Differences

in Adverse Effects
Sex differences in pharmacokinetic parameters include slower absorp-
tion due to lower gastrointestinal blood flow in women than men, a rela-
tively smaller volume of distribution and higher percentage of body fat
58
TABLE 2–4. Common adverse effects associated with specific drug receptor targets
Receptor Examples Common adverse events
Adrenergic
α1 Agonism Phenylephrine, modafinil Headache, restlessness, mydriasis, reflex bradycardia, tremor

α1 Antagonism Prazosin Hypotension and orthostatic hypotension (by vasodilating vascular
smooth muscle), lightheadedness, reflex tachycardia, nasal congestion
α2 Agonism Clonidine, guanfacine Hypotension (by vasodilating vascular smooth muscle), sedation (by inhibit-
ing norepinephrine release from noradrenergic autoreceptors in locus coe-
ruleus), initial hypertension with reflex bradycardia, first-degree AV block
α2 Antagonism Yohimbine, idazoxan, Anxiety or panic, tachycardia, hypertension, insomnia, headaches,
phentolamine dizziness, skin flushing
β1 Agonism Dobutamine Tachycardia, hypertension, angina, arrhythmia
β1 Antagonism Atenolol, metoprolol Hypotension, bradycardia, fatigue, dizziness, headache, cold extremities,
diarrhea, sedation
β2 Agonism Albuterol, terbutaline Nausea, headache, tremor, rhinorrhea, nervousness, palpitations
β2 Antagonism Propranolol Nausea, diarrhea, insomnia
Histaminergic
H1 blockade Diphenhydramine, TCAs, Sedation, weight gain, cognitive dulling
most antipsychotics
Cholinergic
M1 blockade Benztropine, trihexyphenidyl Blurry vision, dry mouth, constipation, urinary retention, reduced REM
sleep
TABLE 2–4. Common adverse effects associated with specific drug receptor targets (continued)
Receptor Examples Common adverse events
Dopaminergic
D2 blockade— All antipsychotics Parkinsonian symptoms, akathisia
nigrostriatal
D2 blockade— All antipsychotics Exacerbation of negative symptoms; cognitive dulling
mesocortical
D2 blockade— All antipsychotics with pure D2 Hyperprolactinemia, galactorrhea, amenorrhea, sexual dysfunction
tuberoinfundibular antagonisma
Serotonergic
5-HT2A agonism SSRIs, SNRIs; not mirtazapine Agitation, sexual dysfunction
(which antagonizes 5-HT2A)
5-HT2C agonism m-Chlorophenylpiperazine Appetite increase
(m-CPP)
5-HT3 agonism SSRIs, SNRIs; not mirtazapine Nausea, increased gastrointestinal motility
(which antagonizes 5-HT3)
Note. AV =atrioventricular; REM =rapid eye movement; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin re-
uptake inhibitor; TCA= tricyclic antidepressant.
aD partial agonists, such as aripiprazole, are unlikely to increase prolactin levels.
2
59
in women, sex differences in drug metabolism, and lower glomerular fil-

tration rates in women. With respect to rates of drug metabolism, at least
some reports suggest that women have higher activity of CYP2D6 and
CYP3A4, with relatively lesser activity of CYP2C19 and CYP1A2; no sex
differences have been identified in Phase II metabolism.
Some adverse drug effects are known to be more pronounced among
women than men, most notably hyperprolactinemia from antipsychotic
medications and a greater incidence of sexual dysfunction (particularly
anorgasmia) from serotonergic antidepressants. Another common ad-
verse effect that may stratify by gender includes antipsychotic-associated
weight gain, with a higher risk among women reported for at least some
SGAs (notably, olanzapine, risperidone, and clozapine).
Racial differences in drug effects can occur as a result of variations in
CYP isoforms. For example, in a pooled analysis of trials involving
SGAs, African Americans appeared more likely than other racial groups
to develop hyperglycemia and possible diabetes, whereas East Asians
were more likely than other groups to develop extrapyramidal side ef-
fects (Ormerod et al. 2008). Among children and adolescents, African
Americans appear more likely than other racial groups to develop obe-
sity, sexual side effects, or dyslipidemias during treatment with SGAs,
antimanic agents, or antidepressants (Stauffer et al. 2010).
Alcohol
All psychotropic drugs described in the Physicians’ Desk Reference (2012)
include cautionary language warning that patients should be advised
to avoid alcohol, or that the concomitant use of alcohol with a given
psychiatric medication is not recommended. Such admonitions largely
reflect the absence of controlled data on the safety and efficacy of most
psychotropic drugs with alcohol, as well as the potential for additive
sedative or adverse cognitive effects from alcohol in combination with
a psychotropic medication.
Brand Versus Generic Formulations

The FDA requires that generic formulations of approved compounds
must have between 80% and 125% of the bioavailability of the propri-
etary (branded) compound. Bioavailability is determined by calculat-
ing a 90% confidence interval for Cmax and area under the curve (see
Table 2–1); that confidence interval must thus fall entirely within the
range of 80% and 125%. Determinations of bioequivalence are based
solely on a drug’s pharmacokinetic profile (e.g., the comparable

achievement of plasma drug levels between two different preparations
of the same drug) rather than its clinical properties (e.g., the measure-
ment of intended therapeutic efficacy or drug safety). In the case of
some medications, brand-name compounds have better efficacy or tol-
erability over generic formulations (e.g., Tegretol over carbamazepine
[Borgheini 2003], Synthroid over levothyroxine [Stoffer and Szpunar
1980]). Additionally, variations in generic medications across manufac-
turers lead to further interindividual pharmacodynamic variation
among generic products.
In some patients with epilepsy, seizure frequency has been shown to
increase after substitution of generic for branded anticonvulsant formu-
lations (Borgheini 2003). Less systematic information exists on the substi-
tution of generic for branded psychotropic agents. Notable examples
include reports of patients with anxiety disorder stably maintained with
long-term brand-name Celexa who relapse after generic citalopram sub-
stitution, then recover after having the brand-name drug reintroduced
(Van Ameringen et al. 2007), and case reports of depression relapse when
patients switch from brand-name Paxil to generic paroxetine (Borgheini
2003). Usually, generic psychotropic drugs are reasonable cost-efficient
treatments for many patients, although some may carry the price of “nui-
sance” side effects, such as poorer gastrointestinal tolerability. Because
bioequivalence studies of brand versus generic drugs do not compare
their relative pharmacodynamic efficacies or adverse-effect profiles, cli-
nicians should be mindful of the possibility that a generic drug may
sometimes prove to be less desirable than its brand-name counterpart for
a given patient.
Enantiomeric Versus Racemic Agents, and

Parent Versus Metabolite Compounds
A number of psychotropic agents are racemic (mirror-image) mixtures
of the S (dextrorotatory [+]) and L (levorotatory [–]) enantiomeric forms
of a drug. Resolution of those chiral molecules creates enantiopure
drugs that may have biological activity and may (or may not) differ
from their racemic mixture formulations in efficacy, potency, or ad-
verse effects. “Inactive” enantiomers can diminish the activity of pure
“active” isomers (e.g., as in the case of d-threo-methylphenidate (dex-
methylphenidate), the active isomer of methylphenidate) so that po-
tency may differ by varying degrees. A comparison of reported adverse
drug effects between racemic and enantiopure forms, as reported in
FDA registration trials, yields few meaningful differences. For example,

armodafinil was associated with a lower incidence of headache (17%)
than was modafinil (34%), although doses are not directly comparable
between the racemic and enantiopure compounds. Insomnia was more
prevalent with venlafaxine (15%–24% across dosages) than with des-
venlafaxine (9%–15% across dosages). Also noteworthy is the lesser in-
cidence of specific subtypes of sexual dysfunction with desvenlafaxine
than venlafaxine, particularly at the more commonly used dosages of
50–100 mg/day (e.g., delayed ejaculation in 1%–5% and erectile dys-
function in 3%–6% of subjects taking desvenlafaxine, as contrasted with
abnormal ejaculation occurring in 16% of subjects with major depres-
sion taking venlafaxine XR).
Drug Blood Levels

Clinicians often express interest in the measurement of serum levels of
a drug or its metabolite, although the research base to support the clin-
ical utility of drug-level monitoring is variable, largely inconclusive,
and not adequate to guide clinical treatment. Important caveats that
may limit the clinical relevance of monitoring serum drug levels in-
clude the extent of intraindividual and interindividual variability and
possibly invalid assumptions about pharmacokinetic dose relation-
ships. (For example, the Cmax for nefazodone after a single 100-mg
dose can vary from 29% to 131% [Barbhaiya et al. 1996], precluding gen-
eralizations about relationships between dosing and blood level.)
In general, the measurement of serum drug levels may be useful for
one of several reasons:
• To detect the presence or absence of a prescribed agent (i.e., as an in-

dicator of treatment adherence).
• As a possible marker for drug toxicity, especially in the case of med-
ications that have a narrow therapeutic index.
• As a potential correlate of therapeutic efficacy (as has been estab-
lished for a handful of psychotropic compounds with an established
therapeutic window, described in Table 2–5).
• For some agents, as a means to gauge whether “room” exists to in-
crease a drug dose in the setting of an incomplete response when ad-
verse effects are not in themselves apparent or limiting. The dosing of
divalproex ER in acute mania represents a ready example, inasmuch
as serum valproate levels exceeding 105 µg/mL incur more extensive
gastrointestinal adverse events with no greater efficacy as compared
with levels below this threshold (Bowden et al. 2006b).
Serum levels of a drug also may not extrapolate from one clinical set-
ting to another. For example, although serum levels of valproate have
been correlated with acute antimanic response, no data exist to inform
optimal levels for the use of divalproex in acute bipolar depression,
maintenance phases of therapy for bipolar disorder, or off-label use for
impulsive aggression in disorders other than bipolar illness. Similarly,
in the case of other anticonvulsants, established therapeutic ranges for
epilepsy (as exist for carbamazepine or lamotrigine) usually have no
known relevance to the psychotropic properties of these agents, apart
from affirming possible toxicity states.
Psychotropic agents for which measurement of serum levels hold es-
tablished value (for efficacy and/or safety) are summarized in Table 2–5.
Pharmacogenomic Predictors
of Adverse Effects
As advances have occurred in the recognition of functionally significant
single nucleotide polymorphisms within the human genome, interest
has grown in examining potential associations between genetic markers
and adverse drug effects. Within psychiatry, it has been suggested that
pharmacogenomics (i.e., the study of genome-wide targets that may con-
tribute to explain variation on drug response) and pharmacogenetics (a
subset of pharmacogenomics, focusing on individual candidate genes or
combinations of individual alleles at different sites for a given single nu-
cleotide polymorphism [haplotypes] that are thought to confer risk for
particular drug effects) may hold particular value for predicting adverse
drug effects in predisposed groups of individuals. For example, in Chi-
nese Han patients, especially males, presence of the –759C/T polymor-
phism of the serotonin type 2C (5-HT2C) receptor may be associated
with a substantially reduced risk for developing weight gain during
treatment with clozapine (Reynolds et al. 2003). Similarly, variation in
the leptin G2548 polymorphism may represent a risk allele for suscep-
tibility to clozapine-induced weight gain in men with schizophrenia
(Zhang et al. 2007). Human leukocyte antigen (HLA) genotypes have
been implicated as potentially conferring increased risk for clozapine-
induced agranulocytosis.
Perhaps the best-known example of pharmacogenetic testing with re-
spect to predicting adverse drug effects lies in the identification of indi-
viduals who are so-called poor metabolizers of drugs that are substrates
for CYP enzymes (resulting in elevated drug levels and potentially more
side effects) and those patients considered to be ultrarapid metabolizers
TABLE 2–5. Clinical relevance of serum drug levels
Agent Known relevance

Carbamazepine No established correlation between the serum
levels used in epilepsy and psychotropic
effects (though typical reference ranges are
50–100 ng/mL).
Divalproex Acute antimanic efficacy associated with serum
levels of 50–125 ng/mL; optimal levels not
established for maintenance therapy.
Gabapentin None.
Lamotrigine None.
Lithium Acute antimanic efficacy associated with serum
levels of 0.6–1.2 mEq/L; maintenance efficacy
generally associated with serum levels of 0.8–
1.0 mEq/L.
Topiramate None.
Antidepressants
Bupropion Possibly better antidepressant response
associated with blood levels of 10–29 ng/mL
than with higher levels in adults based on
preliminary open label data (Goodnick 1992),
although there is no well-established
association between blood levels and
therapeutic efficacy.
Duloxetine Serum duloxetine levels above 58 ng/mL have
been proposed, based on ROC curve analysis,
to predict substantial improvement
(Waldschmitt et al. 2009).
MAOIs No established relationship between blood
levels and psychotropic effects (although the
degree of MAO inhibition can be estimated
from platelet MAO-B levels).
Mirtazapine None.
Nefazodone None.
TABLE 2–5. Clinical relevance of serum drug levels (continued)
SSRIs Fluoxetine and norfluoxetine levels, or their
ratios, are not associated with acute
antidepressant response (Amsterdam et al.
1997) or with relapse prevention during
maintenance treatment for depression
(Brunswick et al. 2002); lack of Css from long t½
also impedes assessment of relationships
between dose and levels.
TCAs Amitriptyline: No definitive association between
serum levels and response in major
depression, although some experts consider
the range of 150–300 ng/mL to be therapeutic.
Desipramine: No clear association between
serum levels and response in major
depression.
Imipramine: Established therapeutic window
(sum of imipramine+desipramine) between
175 and 350 ng/mL.
Nortriptyline: Established therapeutic window
between 50 and 150 ng/mL; levels >500 ng/mL
are considered toxic, and dosages >150 mg/
day are not recommended.
Venlafaxine and Magnitude of desmethylvenlafaxine serum
desvenlafaxine levels, and lower ratios of enantiomeric [+]/
[–] venlafaxine ratios, may predict speed of
antidepressant response (Gex-Fabry et al.
2004); a therapeutic range of 125–400 ng/mL
for the sum of venlafaxine and
desmethylvenlafaxine levels has been
proposed (Charlier et al. 2002), although not
widely adopted.
SGAs
Aripiprazole None.
Asenapine None.
TABLE 2–5. Clinical relevance of serum drug levels (continued)
SGAs (continued)
Clozapine Greater efficacy with serum clozapine levels in
the range of 200–300 ng/mL (VanderZwaag et
al. 1996); higher likelihood of drug toxicity
>1,000 ng/mL (Freeman and Oyewumi 1997);
monitoring of serum clozapine levels may be
useful only in specific situations, including
poor response with routine dosages, signs of
toxicity (e.g., seizures), cotherapy with
CYP1A2 inhibitors (e.g., fluvoxamine,
fluoroquinolones) or inducers (e.g., tobacco,
omeprazole), presence of liver disease,
changes in caffeine or nicotine consumption,
or nonadherence.
Iloperidone None.
Lurasidone None.
Olanzapine 12-hour serum olanzapine levels >23.2 ng/mL
have been reported in association with
therapeutic response in acutely ill patients with
schizophrenia (Perry et al. 2001), but
measurement is uncommon in clinical practice.
Quetiapine None.
Risperidone None.
Ziprasidone Large interindividual variation; no established
relationship between blood levels and
psychotropic effects.
Note. Css = steady-state concentration; MAOI= monoamine oxidase inhibi-
tor; ROC = receiver operating characteristic; SGA= second-generation antipsy-
chotic; SSRI = selective serotonin reuptake inhibitor; t½ = plasma elimination
half-life; TCA= tricyclic antidepressant.
(for whom higher medication dosages may be necessary to achieve ther-

apeutic responses). Up to about 20% of the general population, depend-
ing on race and ethnicity, may be genetically predisposed to poorly
metabolize drugs that undergo Phase I oxidation by the CYP system.
Table 2–6 describes known genetic variants that correspond to pheno-
typic status for drug metabolism involving CYP2D6, which contributes in

whole or part to the metabolism of a majority of psychotropic agents
(based on rates reported by Bernard et al. 2006 and Bertilsson 1995),
alongside examples of major psychotropic drugs that are CYP substrates,
inhibitors, or inducers (Preskorn and Flockhart 2009).
Provisional studies have been reported during antidepressant phar-
macotherapy that link side-effect burden with the CYP2D6 poor metab-
olizer phenotype and nonresponse with the ultrarapid metabolizer
phenotype (Rau et al. 2004). Case reports of drug toxicity reactions with
drugs such as risperidone (Strauss et al. 2010) have identified the pres-
ence of the CYP2D6 poor metabolizer phenotype as causing markedly
elevated blood levels at usual doses, leading to excessive adverse ef-
fects. However, some CYP2D6 poor metabolizers show fewer adverse
effects than would be expected from their genotype. Notably, because
the incidences of both the poor and ultrarapid metabolizer phenotypes
are rare in the general population, it is unlikely that this feature will ac-
count for adverse effects (or lack of therapeutic efficacy) in the majority
of patients encountered by a clinician.
From a practical standpoint, patients who are identified (or sus-
pected) as CYP2D6 slow metabolizers may encounter fewer adverse ef-
fects if the clinician chooses medications cleared by other pathways. For
example, in the case of SGAs, ziprasidone altogether avoids CYP2D6 me-
tabolism and is instead metabolized in part via CYP1A2 and CYP3A4/5;
moreover, reduction by cytosolic aldehyde oxidase is the predominant
pathway of metabolism (accounting for two-thirds of the drug’s metabo-
lism). Most other SGAs (aripiprazole, asenapine, risperidone, paliperi-
done, iloperidone, and quetiapine) are metabolized by CYP3A4/5 in
addition to CYP2D6, whereas olanzapine is metabolized by CYP1A2 and
CYP2D6.
In addition to slow metabolizer genotypes, other provisional find-
ings on possible pharmacogenetic predictors of adverse effects of psy-
chotropic drugs include the following:
• A Ser9Gly variant of the dopamine D3 receptor gene DRD3 was as-

sociated with an increased risk for developing tardive dyskinesia in
patients taking antipsychotics (Lerer et al. 2002).
• Discontinuation of paroxetine due to adverse effects in a randomized
clinical trial was significantly predicted by allelic variants in the se-
rotonin type 2A (5-HT2A) locus (Murphy et al. 2003).
68
TABLE 2–6. Cytochrome P450 (CYP) metabolizer subtypes
Ultrarapid Psychotropic Psychotropic

CYP family Poor metabolizers metabolizers Psychotropic substrates inhibitors inducers
CYP2D6 Whites: 6%–10% Whites: 4% Amphetamine Bupropion None

Blacks: 2%–7% Blacks: 5% Atomoxetine Citalopram
(South African blacks: (Ethiopians: 29%) Desvenlafaxine Doxepin
29%) Asians: 1% Duloxetine Duloxetine
Asians: 0%–2% Hispanics: 1%–2% Haloperidol Fluoxetine
Hispanics: 2%–6% Perphenazine Imipramine
SSRIs Paroxetine
TCAs Risperidone
Thioridazine
Venlafaxine
All SGAs other than
asenapine, lurasidone, or
ziprasidone
CYP1A2 Asenapine Fluvoxamine Modafinil
Clozapine
Fluvoxamine
Haloperidol
Imipramine
Olanzapine
TABLE 2–6. Cytochrome P450 (CYP) metabolizer subtypes (continued)
Ultrarapid Psychotropic Psychotropic

CYP family Poor metabolizers metabolizers Psychotropic substrates inhibitors inducers
CYP3A4 Alprazolam Fluvoxamine Carbamazepine

Buspirone Nefazodone Modafinil
Diazepam Oxcarbazepine
Haloperidol
Lurasidone
Paliperidone
Pimozide
Quetiapine
Risperidone
Trazodone
Vilazodone
Ziprasidone
Zolpidem
CYP2C19 Whites: 3%–5% TCAs Fluoxetine Carbamazepine
Asians: 15%–20% Citalopram Fluvoxamine
Moclobemide Moclobemide
Primidone Modafinil
Oxcarbazepine
Topiramate
Note. SGA= second-generation antipsychotic; SSRI= selective serotonin reuptake inhibitor; TCA =tricyclic antidepressant.
69
• Schizophrenia patients with the D2 receptor gene allele DRD2*A1

show a greater risk for developing antipsychotic-induced hyperpro-
lactinemia when compared with patients without this allele (Young
et al. 2004).
• Severe hypercholesterolemia or hypertriglyceridemia arising during
treatment with SGAs appears significantly more likely in patients
with identified variants in the acetyl-coenzyme A carboxylase alpha
gene (Diaz et al. 2009).
• The emergence of sexual dysfunction during citalopram treatment
for depression was associated with variants in glutamatergic genes
(GRIA3 and GRIK2 with decreased libido, GRIA1 with difficulty
achieving orgasm, and GRIA2 and GRIN3A with erectile dysfunc-
tion) (Perlis et al. 2009).
• Increased likelihood of insomnia and agitation during fluoxetine
treatment occurred among major depression patients with the ho-
mozygous “short/short” genotype of the serotonin transporter gene
polymorphism (locus SLC6A4) (Perlis et al. 2003).
• The development of suicidal ideation during antidepressant phar-
macotherapy was associated with markers that reside within specific
genes that encode the sulfated glycoprotein papilin (PAPLN) and the
interleukin 28 receptor (IL28RA) (Laje et al. 2009).
• An increased risk for antidepressant-induced mania occurs among
patients with bipolar disorder who receive an SSRI and carry the
short allelic variant of the serotonin transporter gene polymorphism
SLC6A4 (Mundo et al. 2001).
Most if not all findings within pharmacogenetics at present remain

provisional and await replication, and the literature presently contains
more negative than positive studies (e.g., CYP2D6 variation failed to pre-
dict adverse effects in a controlled study of paroxetine for major depres-
sion [Murphy et al. 2003]). The extent to which pharmacodynamic drug
effects are either heritable or otherwise under genetic control remains un-
certain, as does the extent to which factors other than genetics more prox-
imally contribute to treatment effects (both therapeutic and adverse).
With few exceptions (notably, the Roche AmpliChip microarray test for
variants of CYP2D6 or CYP2C19 [http://molecular.roche.com/assays/
pages/AmpliChipCYP450Test.aspx], approved by the FDA in 2004),
genotyping for candidate markers of possible adverse drug effects is not
yet within the commercial mainstream (or cost subsidized by health in-
surers), but such technology may eventually become a cost-efficient
procedure within the scope of clinical psychopharmacology practice.
3
Vulnerable Populations
Patients’ Diverse Proneness

to Drug Side Effects
Limited data are available from studies that track the course of adverse
effects from psychotropic drugs and that seek to identify risk factors for
their development. Although efforts to identify robust predictors of ad-
verse effects (or for that matter, efficacy) represent a clinically and sci-
entifically laudable research goal, there is frankly little incentive for
pharmaceutical manufacturers to identify such factors—if they indeed
exist—because such information would serve to limit the potential mar-
ket share of a proprietary compound. Nonetheless, one study of 85 de-
pressed outpatients treated with fluoxetine or paroxetine found that
more severely depressed patients were more likely than less severely
depressed patients to report significant adverse effects, although the re-
porting of adverse effects diminished over time in similar fashion for
both high- and low-severity depressed groups (Demyttenaere et al. 2005).
This study also found that eventual habituation to side effects was faster
in men than in women, in study completers than in early terminators, and
in men with recurrent rather than first-episode depression.
71
As described in Chapter 2, “Pharmacokinetics, Pharmacodynamics,

and Pharmacogenomics,” individuals who are poor metabolizers of
CYP isoenzymes may expectably be more prone to the known adverse
effects of drugs that are substrates for a given CYP enzyme if it is the
drug’s primary or sole metabolic pathway. Apart from individuals with
genetic predispositions for poor drug metabolism, other patient sub-
groups may have heightened sensitivities to the adverse drug effects of
psychotropic agents. Information is available on the pharmacological
management of psychiatric disorders in medically ill patients and other
specialized populations. In this chapter, we focus on broad concepts
and issues regarding adverse psychotropic drug reactions that are
unique or especially pertinent to populations with heightened vulnera-
bilities or sensitivities to untoward drug effects.
Children
The potential for SGAs to cause weight gain and metabolic dysregula-
tion appears especially high in children and adolescents, even after a
first-time course of treatment (Correll et al. 2009). In the case of short-
term trials of olanzapine for pediatric mania or schizophrenia, for ex-
ample, weight gain was reported in 30% of subjects, as contrasted with
6% of adult subjects. The magnitude of weight gain in short-term con-
trolled studies of SGAs among pediatric patients varies by agent: mean
weight changes from baseline range as follows: 3.6–16.2 kg with olanza-
pine, 0.9–9.45 kg with clozapine, 1.8–7.2 kg with risperidone, 2.3–5.9 kg
with quetiapine, and 0–4.5 kg with aripiprazole (Fraguas et al. 2011).
Children and adolescents may differ from adults in their susceptibility
to a number of other specific adverse effects, including the following:
• Markedly increased risk for severe skin rashes in children and ado-
lescents during treatment with lamotrigine.
• Weight gain from psychotropics other than SGAs (e.g., venlafaxine
XR and mirtazapine; see Table 19–4 in Chapter 19, “Systemic Reac-
tions”) appears greater in children <age 12 than in adolescents ≥age
12 or in adults.
• Greater sensitivity to somnolence and sedation in children and ado-
lescents (e.g., in 22%–30% of subjects taking risperidone for pediatric
mania and in 49% of risperidone monotherapy–treated children in
FDA registration trials for autism, in contrast to an incidence of <7%
in adults with schizophrenia or of 5% in adults with bipolar mania
taking risperidone).
Vulnerable Populations 73
• A significantly increased risk for the induction or exacerbation of sui-

cidal thinking or behavior (but not deaths) during treatment with an-
tidepressants among individuals <age 24 (■); this risk has not been
demonstrated in patients >age 24, and in fact antidepressants demon-
strate a protective effect against suicidal behavior in adults >age 65.
Medically Ill Patients

Issues of particular concern to people with chronic medical conditions
involve an increased potential for pharmacokinetic interactions with
other medications, greater difficulty in parsing side effects and their at-
tribution to specific agents, and increased sensitivity to side effects of
psychotropic medications.
Liver Disease
For individuals with hepatic impairment, drugs that are metabolized
by Phase I or Phase II liver metabolism often may be administered with
caution, depending on the extent of hepatic dysfunction. The Child-
Pugh classification for liver disease (Pugh et al. 1973; Table 3–1) was de-
vised as a prognostic estimate for survival in patients with chronic liver
impairment, with progressive classification ratings (A, B, and C) reflect-
ing increasingly low 1-year and 5-year survival rates. Scores of 5–6 are
designated as Class A liver failure, scores of 7–9 indicate Class B failure,
and scores of 10–15 are termed Class C. Dosing adjustments in patients
with liver disease are often recommended based on Child-Pugh classi-
fication.
HIV/AIDS
Because HIV/AIDS preferentially affects subcortical CNS structures,
including the basal ganglia, patients are especially susceptible to ad-
verse drug effects related to motor coordination and cognition (such as
akathisia and other extrapyramidal side effects) as well as NMS. This
susceptibility includes dopamine-blocking drugs, which typically
should be administered at dosages lower than they might otherwise.
Relatedly, by virtue of their immunosuppressed status, patients with
HIV/AIDS who are given drugs that can lower white blood cell counts
(e.g., carbamazepine, SGAs) should be monitored with particular vigi-
lance. A further concern regarding heightened susceptibility to psycho-
tropic drug effects stems from pharmacokinetic interactions with
antiretroviral and antimicrobial agents, which can induce or inhibit
TABLE 3–1. Child-Pugh score for assessing the severity of liver

disease
Measure 1 point 2 points 3 points
Total bilirubin <34 34–25 >50

(µmol/L [or mg/dL]) (or <2) (or 2–3) (or >30)
Serum albumin (g/L) >35 28–35 <28
INRa <1.7 1.71–2.20 >2.20
Ascites None Mild Severe
Hepatic None Grade I–IIb Grade III–IVc
encephalopathy
aINR, or international normalized ratio, accounts for prothrombin time rela-
tive to an international sensitivity index.

bOr suppressed with medication.
cOr refractory.
Source. Pugh et al. 1973
CYP enzymes. Protease inhibitors such as ritonavir exert numerous and

extensive pharmacokinetic interactions, serving as an inducer, inhibi-
tor, and substrate of various CYP effects. Similarly, CYP inducers such
as carbamazepine may diminish the efficacy of antiretroviral drugs.
Psychiatrists who treat individuals with HIV or AIDS should be espe-
cially attentive to obtaining a careful history of psychiatric problems that
predate the suspected onset of HIV and its treatments, reviewing all
medications within a global regimen that may contribute to psychiatric
symptoms, and differentiating probable iatrogenic from primary psychi-
atric disturbances. The psychiatrist and the patient’s primary medical
doctor should collaborate in making decisions about “treating through”
the suspected psychiatric side effects of antiretroviral agents (see section
“Antiretroviral Agents” in Chapter 4, “Adverse Psychiatric Effects of
Nonpsychotropic Medications”), considering the severity of a suspected
side effect (e.g., insomnia vs. suicidality), the patient’s capacity to tolerate
an adverse psychiatric effect, the presence or absence of realistic alterna-
tive HIV therapies, and the degree to which a psychiatric side effect can
be successfully and safely managed with psychotropic drugs.
When prescribing psychiatric medications to patients with HIV or
AIDS, clinicians must also be cognizant of potential pharmacokinetic in-
teractions with antiretroviral agents (for review, see Repetto and Petitto
2008), as well as the frequent necessity to use low medication dosages
(e.g., in the case of antipsychotics, given the high penetrance of HIV in
the basal ganglia, which can render patients especially susceptible to

adverse motor and other dopaminergically based side effects). Patients
with HIV nephropathy or coinfection with hepatitis also may require
dosing adjustments based on impaired renal function (see Table 13–2 in
Chapter 13, “Genitourinary and Renal Systems”) or hepatic dysfunction
(see Table 12–1 in Chapter 12, “Gastrointestinal System”).
Older Adults
A general rule of thumb among psychiatrists who treat older adults is
that low dosages (even dosages that sometimes might otherwise seem in-
adequate) are the usual standard. Renal clearance declines with age; for
every decade beyond age 40, glomerular filtration rate declines by about
10 mL/min. Accordingly, many (but not all) psychotropic agents require
downward dosing adjustments in elderly patients, often based on pre-
sumptions about age-related reduced hepatic metabolism or renal clear-
ance. Hepatic dysfunction is typically a more salient contributor than
renal impairment to drug tolerability. Very few controlled studies have
been conducted with most psychotropic agents specifically in geriatric
patients with mood, anxiety, or psychotic disorders, and inferences about
safety and tolerability often are drawn from post hoc analyses of enrolled
subjects usually ≥age 65 (and seldom >age 75). However, some con-
trolled trials specifically in geriatric settings have yielded several impor-
tant observations. For example, a multisite placebo-controlled trial of
divalproex ER for agitation in elderly patients with dementia (mean
age=83) that used a relatively high dose (20 mg/kg, titrated by incre-
ments of 125 mg/day) yielded excessive somnolence, dehydration, and
reduced nutritional intake (manufacturer’s product information, Abbott
Laboratories). Manic older adults may poorly tolerate divalproex doses
exceeding ~15 mg/kg (Tariot et al. 2001).
Studies addressing the management of psychosis or disruptive
behaviors in elderly patients with dementia have found significant ad-
verse effects, as exemplified most dramatically in the 1.6-fold increased
risk for all-cause mortality with antipsychotic drugs. The review of find-
ings by the FDA that led to a black box warning (■) of increased risk for
death dovetailed with a meta-analysis of 15 randomized placebo-
controlled trials involving aripiprazole (3 trials), olanzapine (5 trials),
quetiapine (3 trials), and risperidone (5 trials) for the treatment of demen-
tia-related psychosis, encompassing a collective group of 3,353 subjects
receiving active drug and 1,757 randomly assigned to placebo (Schneider
et al. 2005). That meta-analysis identified an odds ratio of 1.54 (95% CI,
1.06–2.23) for increased risk of death, with no observed differences

among individual drugs. In calculating NNH and NNT, the authors de-
termined that one death would likely occur for every 9–15 elderly demen-
tia patients helped by an SGA, but predictors of that increased risk among
antipsychotic recipients were not identified.
Presumably, cumulative risk factors for cardiovascular or cerebrovas-
cular disease may play a contributing role, as would other preexisting
conditions, such as esophageal dysmotility (with consequent risk for as-
piration pneumonia). All of these concerns must be weighed against the
risks posed by untreated psychosis or agitated behavior, as well as find-
ings from other studies, which suggest that even FGAs (particularly at
high dosages) may carry a risk for excess mortality in older adults that is
at least as high as that seen with SGAs (Schneeweiss et al. 2007). (Hence,
in June 2008, the FDA extended its black box warning (■) for increased
mortality in elderly dementia patients to FGAs as well as SGAs.)
General considerations for the dosing and monitoring of adverse ef-
fects with psychotropic drugs used in older adults are summarized in
Table 3–2.
Generally, the types of adverse effects that become of particular con-
cern for older adults include the following:
• Cognitive effects of anticholinergic drugs

• Greater risk for syndrome of inappropriate antidiuretic hormone se-
cretion (SIADH) during treatment with SSRIs or some anticonvul-
sants (notably, oxcarbazepine)
• Greater risk for orthostatic hypotension from drugs with α1-adrener-
gic blocking properties
• The potential for disinhibition with the use of benzodiazepines
• Excessive somnolence from antihistaminergic agents or other possi-
ble sedative agents
Other well-recognized concerns relevant to adverse drug effect sensitiv-

ities in elderly patients include decreased protein binding (hence the
potential for more circulating unbound drug fractions) and the greater
likelihood of multiple drug interactions.
Patients Prone to Somatization

Special consideration is warranted when anticipating and evaluating
possible adverse drug effects in individuals prone to somatization.
Clinical wisdom would dictate several basic principles when prescrib-
ing psychotropic medications to people with somatic preoccupations.
TABLE 3–2. Dosing considerations for psychotropic drug use in

geriatric populations
Manufacturer’s dosing recommendation

Medication in geriatric patients
Atomoxetine None.
Buspirone No special dosing is recommended,
although known renal insufficiency can
increase plasma half-life (see Table 13–2
in Chapter 13, “Genitourinary and Renal
Systems”).
Anticonvulsants
Carbamazepine No studies exist in geriatric patients to
guide dosing recommendations.
Divalproex The manufacturer advises a reduced
starting dosage and more gradual
dosage increases. Monitor for a greater
potential for somnolence than in
younger patients.
Gabapentin Dosage selection should be cautious,
usually starting at the low end of the
dosing range. Higher incidence of
peripheral edema and ataxia found in
older adults.
Lamotrigine Formal studies do not exist in adults over
age 65. The manufacturer recommends
dosage initiation at the low end of the
dosing range due to the potential for
decreased hepatic, renal, or cardiac
function in older adults.
Oxcarbazepine Observed increases in plasma levels
among older adults (>age 60) are
attributable to decreased CrCl. There are
otherwise no formal recommendations
for dosage reductions in elderly patients.
Topiramate No age-related differences in adverse
effects are known. Dosage reductions are
advised when CrCl is <70 mL/min.

geriatric populations (continued)

Antidepressants
Bupropion None unless renal function is diminished.
Desvenlafaxine None unless renal function is diminished
(see Table 13–2). Higher risk of orthostatic
hypotension in patients ≥age 65.
Duloxetine Dosing adjustment based on age is
unnecessary.
Escitalopram Maximum for elderly patients is 10 mg/
day.
Fluoxetine The manufacturer advises using lower
dosages in elderly patients. No age-
related differences in adverse effects are
known apart from those attributable to
decreased renal clearance. FDA
registration studies in major depression
included 687 drug-treated patients
≥age 65 and 93 drug-treated patients
who were ≥age 75.
Fluvoxamine Mean plasma concentrations in older
adults are 40%–50% higher than in
younger adults. The manufacturer
recommends slower initial dosing
increases in geriatric patients. No age-
related differences in adverse effects are
known apart from those attributable to
decreased renal clearance. FDA
registration studies included 230
patients ≥age 65 who took immediate-
release fluvoxamine and 5 patients
≥age 65 who took the controlled-release
formulation.

geriatric populations (continued)

Mirtazapine Diminished drug clearance in elderly
patients was due to renal insufficiency
and was more prominent in men than in
women.
Nefazodone The manufacturer advises initial dosing at
half the usual dosage, although eventual
therapeutic dosages may be the same as
in younger patients.
Paroxetine No age-related differences in adverse
effects are known apart from greater
side-effect burden in cases of known
renal insufficiency. FDA registration
studies in major depression included
approximately 700 drug-treated patients
≥age 65.
Sertraline No age-related differences in adverse
effects are known. FDA registration
663 drug-treated patients ≥age 65 and
180 drug-treated patients ≥age 75.
Transdermal selegiline Somewhat higher risk for skin rash
reported in patients ≥age 50 (4.4% vs. 0%
with placebo); no other age-related
adverse effects are known.
Recommended dosing in patients
≥age 65 is 6 mg/day. FDA registration
198 drug-treated patients ≥age 65.
Venlafaxine None.
Note. CrCl= creatinine clearance; FDA= U.S. Food and Drug Administration.
To minimize the potential for further (or paradoxical) side effects, the
following principles are recommended:
1. Use the smallest effective dosages possible.

2. Make changes to a medication regimen very gradually.
3. Minimize the cumulative number of medications to the extent that is
feasible.
4. Make an extra effort to avoid medications that involve more exten-
sive or severe possible side effects.
5. Change no more than one medication at a time to minimize pharma-
codynamic and pharmacokinetic confusions.
6. Reduce dosages or eliminate medications rather than add additional
drugs as intended antidotes.
From a diagnostic standpoint, practitioners also may wish to consider

whether somatic preoccupations suggest the presence of a psychotic pro-
cess or body dysmorphic disorder that may warrant treatment with low-
dose antipsychotics having the fewest potential adverse effects.
Nonpharmacological approaches may be especially important in the
comprehensive treatment of individuals with somatic preoccupations
or conversion disorders, conditions that may be suspected when exten-
sive complaints emerge about multiple perceived side effects. Some
awareness of psychodynamic concepts also may help to foster greater
tolerability and engagement in the therapeutic alliance. A practical cor-
ollary to this approach involves deciding how to share information (and
how much to share) with patients in anticipation of the potential for de-
veloping adverse drug effects.
Sparse literature exists on the pharmacotherapy of somatization and
related disorders (e.g., hypochondriasis). Interestingly, a 12-week
placebo-controlled study of fluoxetine for hypochondriasis yielded no
differences between drug and placebo in rates of premature discontin-
uation due to adverse effects, although no significant improvements
were observed with active drug versus placebo on outcome measures
related specifically to illness concerns or somatization (Fallon et al.
2008). In our experience, preoccupations for some patients about real or
imagined side effects (or the sheer prospect of them) can become a dis-
tracting pseudofocal point of treatment, one that may altogether derail
pharmacologically based efforts to alleviate symptoms. For patients
who undergo multiple aborted trials with successive pharmacothera-
pies that are inevitably deemed intolerable, redirecting efforts to ad-
dress the capacity to tolerate physical distress often becomes necessary.
In the setting of persistent nonpsychotic somatic preoccupations, par-
ticularly when they coincide with maladaptive personality traits (con-

scious or otherwise), iterative pharmacotherapy efforts may at some
point become counterproductive and frankly inadvisable. Such circum-
stances may warrant a reappraisal of realistic therapeutic goals and a
shift away from efforts aimed at disease modification and instead to-
ward the improvement of coping skills. The latter sometimes may be
pursued more productively through primarily cognitive-behavioral or
other purely psychotherapeutic approaches.
4
Adverse
Psychiatric Effects of
Nonpsychotropic
Medications
Contrary to what might otherwise be expected, the majority of people

who develop adverse psychiatric effects from nonpsychotropic medica-
tions do not have preexisting psychiatric conditions. For example, in a
review of manias secondary to medications (e.g., isoniazid or the anti-
neoplastic procarbazine), Krauthammer and Klerman (1978) noted that
pretreatment histories of affective illness were not apparent in the ma-
jority of cases.
83
Analgesics
Carisoprodol
Carisoprodol, a combination analgesic and muscle relaxant, is a prodrug
of the Schedule IV anxiolytic agent meprobamate and is classified as a
Schedule IV drug in certain states (viz., Alabama, Arizona, Arkansas,
Florida, Georgia, Hawaii, Indiana, Kentucky, Louisiana, Massachusetts,
Minnesota, Mississippi, New Mexico, Nevada, Oklahoma, Oregon, and
Texas). It can cause physical dependence with prolonged use and, be-
cause it is a CNS depressant, may cause additive sedating effects when
combined with alcohol or other sedating psychotropic drugs.
Opiates
Opiates may show great variability and unpredictability in their psy-
chotropic effects. Anxiety and nervousness are identified as possible
adverse effects, occurring in 1%–5% of patients in premarketing studies
of most opiates taken for extended periods of time, although it is diffi-
cult to know the extent to which preexisting or comorbid psychiatric
symptoms account for such occurrences. Acute psychosis and delirium
have been reported with synthetic opiates.
Although some clinicians express concern about the potential for
long-term opiates to induce anhedonia, there is actually a small, mostly
anecdotal literature to suggest that some long-acting semisynthetic opi-
ates such as oxycodone (10–30 mg/day) or oxymorphone (8 mg/day),
as well as the partial agonist buprenorphine, can safely and effectively
treat depressive syndromes that are unresponsive to more traditional
pharmacotherapies (or electroconvulsive therapy) in people with uni-
polar or bipolar depression.
Tramadol
The centrally acting Schedule IV synthetic opioid analgesic tramadol
warrants separate mention from other opiate analgesics by virtue of its
inherent noradrenergic-serotonergic reuptake mechanism, which has
been known to hinder or prolong efforts to discontinue its use because
of withdrawal-like features similar to those reported with pure SNRIs
(see the section “Discontinuation Syndrome” in Chapter 19, “Systemic
Reactions”). Tramadol has been shown to cause nervousness or anxiety,
hallucinations, agitation, and depression (incidence rates of 1%–5% in
manufacturer’s FDA registration trials).
Adverse Psychiatric Effects of Nonpsychotropic Medications 85
Anticholinergics
Detrimental psychiatric effects of centrally active anticholinergic drugs
can include diffuse cognitive deficits, in addition to somnolence or se-
dation. Anticholinergic drugs may be especially deleterious in patients
with intrinsic cognitive deficits or dementias (in whom cholinomimetic
drugs are used in efforts to counteract primary cognitive deficits).
Anticonvulsants
Case reports have described patients with epilepsy or other primary
neurological disorders (e.g., essential tremor, neuropathic pain) and no
prior psychiatric history who have developed new-onset psychosis
with several anticonvulsant agents, including levetiracetam (particu-
larly in children), topiramate, vigabatrin, and lamotrigine, as well as de-
pression in connection with the use of topiramate (Goldberg 2008) or
zonisamide (occurring in 6% of epilepsy patients during adjunctive
zonisamide FDA registration trials; manufacturer’s package insert,
Elan Pharma International). It is speculative whether psychotomimetic
or other adverse psychiatric effects of anticonvulsants seen in epilepsy
patients generalize to other clinical populations, including patients
with primary psychiatric disorders. Some authors have suggested that
temporal lobe pathology may predispose patients to psychosis from an-
ticonvulsants.
In 2008, the FDA issued a warning (non–black box) indicating that all
anticonvulsant drugs carry an increased risk for suicidal thinking or be-
havior, although this observation appears to vary based on the clinical
population being treated (see the section “Suicidal Thinking or Behavior”
in Chapter 5, “Adverse Psychiatric Effects of Psychiatric Medications”).
Other possible iatrogenic psychiatric phenomena that have been reported
in connection with anticonvulsants include catatonia, agitation, or hostil-
ity with levetiracetam.
Antimicrobials
Antibiotics
Psychiatric adverse effects caused by antibiotics are considered to be ex-
tremely rare (ranging from 1 per 100 to 1 per 10,000 prescriptions), but
case reports have identified dramatic and sudden presentations of de-
pression, psychosis, or suicidal ideation, often in individuals with no
psychiatric history. Current or recent use of the antimicrobial agents

listed in Table 4–1 should be considered as one possible factor in the eti-
ology of new-onset psychiatric symptoms.
Antifungal Agents
Ketoconazole has been described in case reports to cause visual and
command auditory hallucinations of self-harm in patients with no prior
psychiatric history.
Antineoplastics
In addition to the adverse psychiatric effects that may occur with inter-
feron-α (see the section “Interferon-α” later in this chapter) or systemic
corticosteroids (see the section “Steroids” later in this chapter), such as
prednisone or dexamethasone used in cancer chemotherapy, untoward
psychotropic effects have known associations with several other anti-
neoplastic agents, as summarized in Table 4–2. Antineoplastics known
to impair attention, memory, or other cognitive domains without caus-
ing psychopathological symptoms are not considered here. Malignan-
cies that penetrate the CNS can account for or contribute to acute
mental status changes. In the absence of known mechanisms of action
to explain iatrogenic psychiatric effects, the clinician must always con-
sider the possibility that spontaneous cases of psychopathology may
arise coincidentally with the use of a given agent, and suspected iatro-
genic etiologies should not necessarily be assumed with certainty.
The term chemo brain has gained popular use to describe the phe-
nomenology of persistent postchemotherapy cognitive impairment and
so-called “foggy thinking” that has been observed to occur in 10%–40%
of individuals (mainly women) who undergo high-dose antineoplastic
chemotherapy, particularly for breast cancer. Although observations of
persistent cognitive deficits have been reported following chemother-
apy since the 1980s, the validity of chemo brain as a distinct and defin-
able syndrome has been the subject of debate. Measurable cognitive
deficits exist in a substantial minority of antineoplastic chemotherapy
recipients, although some authors have raised questions as to the rela-
tive contribution of depression, anxiety, subjective distress, fatigue, and
other emotional and physical experiences that may contribute to the
phenomenon. The magnitude of cognitive impairment following che-
motherapy has been described as mild in severity. No pharmacological
strategies have been reported to counteract cognitive effects attributable
to antineoplastic drugs.
TABLE 4–1. Adverse psychiatric effects of antimicrobials
Agent Adverse effects
Antimalarials (e.g., Reports of secondary psychosis,

mefloquine, depersonalization, and anxiety or mania in
chloroquine) individuals with no psychiatric history
Fluoroquinolones Psychosis associated with ciprofloxacin;
(e.g., ciprofloxacin, sudden-onset depressive symptoms and
levofloxacin, suicidal ideation associated with
rufloxacin, ofloxacin) levofloxacin plus trimethoprim-
sulfamethoxazole or lomefloxacin
Gentamicin Rare reports of secondary psychosis
Isoniazid Reports of secondary mania (Krauthammer
and Klerman 1978)
Rifampin or Reports of exacerbation of existing panic
sulfonamide disorder
antibiotics (e.g.,
trimethoprim-
sulfamethoxazole)
Antiparkinsonian Agents
Probably the most well-known adverse psychiatric effects of dopamine
agonists used to treat Parkinson’s disease are psychotomimetic effects.
The dopamine agonists pramipexole and ropinirole are both sometimes
used in off-label fashion to treat depression in unipolar or bipolar disor-
der, to ameliorate cognitive complaints, or to counteract hyperprolactin-
emia and sexual dysfunction caused by dopamine antagonists. When
used in patients with Parkinson’s disease or restless legs syndrome, each
has been reported to rarely cause pathological gambling, other impulsive
and compulsive behaviors, or psychosis. Rare case reports of new-onset
pathological gambling during pramipexole treatment for bipolar depres-
sion have been described up to 35 weeks after treatment initiation and
have been ameliorated by drug cessation. Although incidence rates or
predictive factors do not exist for this unusual phenomenon, clinicians
should be alert to the possibility for its occurrence.
Antiretroviral Agents
The majority of adverse psychiatric effects related to pharmacotherapies
used in HIV and AIDS have been reported to involve the antiretroviral
TABLE 4–2. Adverse psychiatric effects associated with

antineoplastic agents
Agent Adverse effects Comments
L-Asparaginase Dose-related confusion, —

depression,
hallucinations,
personality changes
Chlorambucil Agitation, confusion, or —
hallucinations
5-Fluorouracil Mania, psychosis —
Ifosfamide Hypomania, Neurotoxicity
hallucinations involving
encephalopathy and
confusional states is
seen more commonly
than affective or
psychotic symptoms.
Interleukin-2 Depression, suicidality —
Letrozole Mania Aromatase inhibitors
used in breast cancer
may induce mania by
reducing circulating
levels of estrogen.
Procarbazine Mania or psychosis —
Tamoxifen Depression, psychosis; —
may have antimanic
properties
agent efavirenz. The most common adverse CNS effects of efavirenz re-
ported by patients include sleep disturbances (e.g., vivid dreams, night-
mares, insomnia) and dizziness or other vestibular complaints (i.e.,
imbalance, positional vertigo), which usually resolve after the first few
weeks of treatment. Rare complications of efavirenz, as compared with
treatment with protease inhibitors, may include increases in somatic con-
cerns, anxiety, depression, and obsessive-compulsive behavior, although
many of these effects appear to attenuate with time. Other reports have
idenztified rare cases of mania or psychosis in the short term following
treatment initiation. It remains controversial as to whether or not the ap-
parent adverse psychiatric consequences of efavirenz are dose related,

and uncertainty persists about differentiating possible dosing effects
from the relative contributions of CD4+ (T-cell) count or hepatitis coinfec-
tion on psychiatric symptoms. Importantly, neuropsychiatric adverse
effects of efavirenz are rare and often mild, and they generally are out-
weighed by the benefits of efavirenz with respect to HIV treatment.
Early reports exist of mania and psychosis during treatment with nu-
cleoside reverse transcriptase inhibitors such as zidovudine, often among
patients with a family history of mood disorders, although the majority of
that literature involved mostly monotherapy at higher dosages than are
now customarily recommended. Many of the existing reports failed to in-
clude adequate information about immune status, comorbidity, sub-
stance abuse, and other related factors that may contribute to psychiatric
symptoms.
Cardiovascular Drugs
α2-Adrenergic Agonists
In addition to the potential for causing sedation or fatigue, the centrally
acting antihypertensive α2-adrenergic agonist clonidine has been re-
ported to cause depression in 1%–10% of people treated for hyperten-
sion. Other psychiatric adverse effects that have infrequently been
reported with clonidine use include irritability, fear, nervousness, “psy-
chic distress,” and rare cases of hypomania or paranoia.
α1-Adrenergic Antagonists
α 1-Adrenergic antagonists such as prazosin, terazosin, or doxazosin
tend to be viewed as second- or third-line interventions for hyperten-
sion, because of their potential for orthostatic hypotension and risk for
sudden falls in blood pressure (so-called first-dose phenomenon), and
are more often used to treat benign prostatic hyperplasia. They have
rarely been described in case reports to cause hallucinations or other
psychotic features.
Antiarrhythmics
A limited number of antiarrhythmic agents have been reported to cause
adverse psychiatric effects. Among them are amiodarone, which has
been identified in case reports as causing depression secondary to amio-
darone-induced hypothyroidism; the hypothyroidism may be amelio-
rated by supplemental levothyroxine. Digitalis toxicity can be associated
with mania, depression, hallucinations, or other acute cognitive changes

suggestive of delirium. Paranoia and psychosis have also been associated
with toxicities of flecainide, procainamide, or quinidine.
β-Adrenergic Agonists
Psychiatric adverse effects are not mentioned in manufacturers’ product
information materials for inhaled β-adrenergic agonists, such as al-
buterol. However, rare postmarketing reports have described either the
new onset or worsening of preexisting hallucinations, paranoid thinking,
mania, or other psychotic features after excessive use in both children
and adults. Predictors of such phenomena have not been identified, al-
though cessation of the probable offending agent generally resolves the
disturbance without sequelae.
β-Adrenergic Antagonists
Since early anecdotal case observations, controversy has existed about
the potential for centrally acting β-blockers to cause depression based
on their antiadrenergic effects. In the late 1960s and early 1970s, depres-
sion was spontaneously reported as an adverse effect of propranolol
treatment in <6% of hypertensive patients (reviewed by Paykel et al.
1982). A comprehensive review of 15 randomized trials involving over
35,000 subjects with hypertension who received a β-blocker for at least
6 months found no appreciably increased risk for treatment-related de-
pressive symptoms (6 per 1,000 patients) (Ko et al. 2002). Small, clini-
cally nonsignificant increased rates of fatigue or sexual dysfunction also
were identified among β-blocker recipients in this latter study. Never-
theless, mental depression is listed (but without a reported incidence
rate) among adverse events identified by the manufacturer in associa-
tion with propranolol. In addition, propranolol specifically has been
linked with depressive symptoms (but not necessarily syndromes) dur-
ing the first few months of use among elderly patients.
Dermatological Agents
The acne product isotretinoin (Accutane) is reported to confer an in-
creased risk for depression and suicidal thoughts or behaviors and is
among the leading medications reported by the FDA as being associ-
ated with depression and suicide, although this relationship remains
highly controversial. Empirical studies of affective psychosis newly
arising after exposure to isotretinoin suggest a greater propensity

among individuals with a personal history of obsessive-compulsive
disorder or neurological disease, or a family history of major psychiat-
ric illness.
Gastrointestinal Agents
A handful of case reports in the literature suggest that histamine H 2
blockers (e.g., cimetidine or ranitidine) may cause depression, although
case-control studies have failed to affirm those reports and instead
point to other demographic or clinical factors as more likely proximal
contributors to the development of depression in individuals who take
H2 blockers.
Immunosuppressants
Immunosuppressants are often administered for inflammatory or other
medical conditions that may in themselves carry an increased risk for
neuropsychiatric disturbances (e.g., systemic lupus erythematosus).
Moreover, coadministration of immunosuppressants with corticoste-
roids (e.g., prednisone) may further contribute to adverse psychiatric
effects. Known adverse psychiatric effects of immunosuppressants are
largely identified in case reports, further limiting the ability to draw
causal inferences about drug effects versus other possible contributors
to psychiatric morbidity. Patients taking immunosuppressants often re-
ceive other medications (e.g., corticosteroids, antineoplastics), which
can be additional sources for adverse psychiatric effects.
When patients develop new psychiatric symptoms while taking an
immunosuppressant (Table 4–3), clinicians should comprehensively as-
sess possible contributing factors—including the coincidental indepen-
dent presence of a psychiatric disorder or of a psychiatric disturbance
secondary to a general medical condition or a substance other than an
immunosuppressant—before drawing conclusions about an iatrogenic
etiology. When medically feasible, substitution of an alternative immu-
nosuppressant may help to affirm etiology and to resolve symptoms
(e.g., anxiety symptoms linked with azathioprine dissipated after sub-
stitution of methotrexate [van der Hoeven et al. 2005]). Symptomatic
management with antipsychotics—similar to the approach taken with
corticosteroid-induced psychosis (see the section “Steroids” later in this
chapter)—may be necessary for agitation, psychosis, or marked anxiety.
TABLE 4–3. Adverse psychiatric effects of immunosuppressants
Agent Adverse effects
Azathioprine Case reports of obsessive-

compulsive behavior and panic
attacks
Cyclosporine Case reports of psychosis
Monoclonal antibodies (e.g., Case reports of psychosis or
muromonab-CD3, basiliximab, encephalopathy; anxiety (≤5%
rituximab) incidence) with rituximab in U.S.
Food and Drug Administration
registration trials for non-
Hodgkin’s lymphoma
Mycophenolate mofetil None reported
Sirolimus (or rapamycin) None reported
Tacrolimus Neurotoxicity at high doses may be
associated with psychosis or
delirium
Interferon-α
The antiviral drug interferon-α is widely used in the treatment of
chronic hepatitis B or C, certain lymphomas and leukemias, and mela-
noma. It is known to cause major depression in one-third or more of
cases through poorly understood mechanisms that have been hypothe-
sized to include activation of cytokines that in turn may decrease CNS
serotonin production and downregulation of dopaminergic tone.
About one in three recipients of interferon-α develop new-onset de-
pression. More rarely, new-onset mania or hypomania has been re-
ported in connection with the use of interferon-α.
Several small studies have suggested that prophylactic treatment
with SSRIs such as citalopram begun before interferon-α therapy may
reduce the incidence of subsequent depression, although such findings
are difficult to interpret because of small sample sizes, the lack of pla-
cebo control groups, and the failure to consider pretreatment risk fac-
tors for depression. A review of the collective literature suggests that
prophylactic treatment with antidepressants (including paroxetine) is
no better than placebo for the prevention of interferon-α–induced de-
pression (Galvão-de Almeida et al. 2010). On the other hand, in prospec-
tive trials of antidepressants, including citalopram (Kraus et al. 2008),
the drugs appear better than placebo in reducing depressive symptoms

among hepatitis C patients who developed depressive symptoms dur-
ing interferon-α therapy.
The use of psychostimulants such as methylphenidate monotherapy
also has been described as a possible rapid, safe, and effective strategy
for reducing vegetative symptoms in patients who develop protracted
depression in the context of interferon-α therapy.
Oral Contraceptives and

Intravaginal Rings
General Recommendations. Oral contraceptives can have
variable and unpredictable effects on mood. Adverse mood ef-
fects may be more likely with contraceptives containing levo-
norgestrel than desogestrel. The emergence or exacerbation of
mood or anxiety symptoms shortly after beginning an oral con-
traceptive may warrant its discontinuation.
Oral contraceptives combine an estrogen formulation (typically ethinyl

estradiol or mestranol) with a progestin (typically a synthetic proges-
terone-like compound). Progestins have been associated with dysphoria
and anger. Concerns often arise about the extent to which oral contracep-
tives may exert either a beneficial or an adverse effect on mood, either in
the presence or absence of preexisting premenstrual mood disturbances.
Indeed, package insert information for all oral contraceptive pills in-
cludes the following precaution:
Patients becoming significantly depressed while taking oral contracep-

tives should stop the medication and use an alternate method of contra-
ception in an attempt to determine whether the symptom is drug related.
Women with a history of depression should be carefully observed and the
drug discontinued if depression recurs to a serious degree.
Key points regarding oral contraceptive preparations are as follows:
• Concentrations of ethinyl estradiol range from 20–50 µg.

• Synthetic progestins include levonorgestrel, desogestrel, and dro-
spirenone (a spironolactone analogue with antimineralocorticoid
and antiandrogenic properties).
• Monophasic oral contraceptives involve the administration of 21 days
of estrogen followed by 7 days of placebo, whereas triphasic formula-
tions contain three varying hormone doses across the first 21 days of
active treatment.
• Second-generation oral contraceptives combine ethinyl estradiol and
a synthetic progestin, with varying concentrations of both hormones.
• Third-generation oral contraceptives use desogestrel as the progestin
(e.g., Yasmin, Yaz).
Importantly, monophasic desogestrel oral contraceptives have been

associated with less mood dysregulation than monophasic or triphasic
levonorgestrel compounds, making Yaz and Yasmin popular among
many gynecologists for women with sensitivities to premenstrual or per-
imenstrual mood disturbances. The pairing of ethinyl estradiol with dro-
spirenone rather than levonorgestrel has been associated with greater
improvement in affective symptoms of menstrual distress in healthy
women (Kelly et al. 2010). Adverse mood effects associated with oral con-
traceptives appear higher in women under age 20, women with a history
of perinatal depression or dysmenorrhea, women with current postpar-
tum status, and women with a family history of obsessive-compulsive–
related mood symptoms (Oinonen and Mazmanian 2002). Although
some authors believe that mood worsening from oral contraceptives may
vary depending on ratios of ethinyl estradiol to progestin, this theory re-
mains debated.
Notably, a limited number of psychotropic agents are known to in-
duce the metabolism of estrogen-containing oral contraceptives via in-
duction of CYP isoenzymes and may therefore diminish the efficacy for
preventing conception. These agents include topiramate, carbamaz-
epine, oxcarbazepine, and modafinil—thus prompting the need to con-
sider the use of contraceptive preparations that contain higher estrogen
concentrations for patients also taking these medications. (No reduc-
tion in efficacy of oral contraceptives occurs during coadministration
with divalproex, gabapentin, lamotrigine, levetiracetam, tiagabine, or
zonisamide.) When a hepatic enzyme–inducing agent is taken in con-
junction with an oral contraceptive, it may be advisable to use an oral
contraceptive with a higher dose of ethinyl estradiol than might other-
wise be the case.
In addition, estrogen-containing oral contraceptives may reduce the
bioavailability or efficacy of other psychotropic medications. Pharma-
cokinetic studies show that conjugated estrogens such as those found in
oral contraceptives may reduce the bioavailability of lamotrigine,
which may prompt the need for modestly increasing the dose of lamo-
trigine if clinically warranted (i.e., in the setting of breakthrough signs
of illness). Oral contraceptives may also diminish the efficacy of (and
potential for sedation from) certain benzodiazepines (i.e., lorazepam,

oxazepam, and temazepam) but potentiate the effects of others (i.e., al-
prazolam, chlordiazepoxide, diazepam, flurazepam, and triazolam).
Polymeric intravaginal contraceptive rings that contain and release
estrogen and progestin (e.g., NuvaRing, containing etonogestrel [the
metabolite of desogestrel] and ethinyl estradiol), considered to be third-
generation contraceptives, have been available in the United States
since 2002. Depression has been reported as an adverse effect of Nuva-
Ring, although no incidence rate is reported in the manufacturer’s prod-
uct information materials. There is no contraindication to its use in
women with a history of depression or other mood disorders.
Smoking Cessation Aids

Oral varenicline is a nicotinic receptor partial agonist smoking cessa-
tion aid whose labeling package carries a black box warning (■) identi-
fying a risk for “changes in behavior, hostility, agitation, depressed
mood, and suicidal thoughts” that can develop during treatment in in-
dividuals either with or without a history of psychiatric illness. Inci-
dence rates of depression associated with varenicline are not well
identified and remain controversial, but the magnitude of risk appears
small. Notably, a 12-week manufacturer-sponsored randomized com-
parison of varenicline or placebo in 110 smokers without past psychiat-
ric histories found no differences in the emergence of depressive,
anxiety, or aggressive features (Garza et al. 2011). Similarly, a British co-
hort study of 80,660 primary care patients revealed no significant in-
creased risk for suicidal thoughts or depression among varenicline
recipients; this report identified a possible but statistically nonsignifi-
cant 2-fold increased risk for self-harm that could not be ruled out based
on the upper limit of observed confidence intervals (Gunnell et al.
2009). Hence, a history of depression should not contraindicate the use
of varenicline, although all patients who receive varenicline should be
monitored for the possible emergence of depressive or suicidal features.
Steroids
Corticosteroids are well known to cause a variety of adverse psychiatric
effects, including agitation, psychosis, anxiety, mania, depression, and
delirium. Affective symptoms are generally considered to be more
common than psychosis as a consequence of steroids, with mania being
more common than depression. Adverse psychiatric effects are esti-
mated to occur in approximately 2%–20% of corticosteroid recipients,
with increasing likelihood as dosages escalate. (For example, the Boston

Collaborative Drug Surveillance Program [1972] identified new-onset
affective or psychotic symptoms in 1.3% of recipients taking ≤40 mg/
day of prednisone, 4.6% of those taking 41–80 mg/day, and 18.4% of
those taking >80 mg/day.) Symptoms appear unrelated to age, may be
somewhat more common in women than men, and usually arise within
the first several days after steroid initiation. Importantly, neither preex-
isting psychiatric conditions nor a history of previous steroid-induced
psychiatric symptoms are known to increase the risk for developing ste-
roid-induced psychiatric symptoms. Without intervention, symptoms
may persist for several weeks after steroids are tapered off.
Alternatives to steroids may sometimes be feasible in specific clini-
cal settings (e.g., the immunosuppressant mycophenolate mofetil may
be used instead of prednisone for patients with systemic lupus erythe-
matosus). In patients who require high-dose or prolonged steroid treat-
ment, symptomatic management of iatrogenic psychiatric symptoms
may be necessary. Wada and colleagues (2001) reported efficacy and
good tolerability using traditional mood stabilizers (lithium, dival-
proex, or carbamazepine) to treat steroid-induced mania in patients
without bipolar disorder, as permissible based on renal or hepatic func-
tion. Adequately dosed antipsychotics are also considered fairly stan-
dard for managing steroid-induced mania or psychosis, although the
evidence base for their use derives mainly from case reports. Dosing of
antipsychotics needs to be based on symptom severity and response to
initial dosages, as well as duration of a projected steroid course, bal-
anced against medical comorbidity and tolerability.
5
Adverse
Psychiatric Effects of
Psychiatric Medications
Activation and Mania/Hypomania
or Mixed States
The largest existing meta-analysis of antidepressant-associated mania
or hypomania suggests an incidence of only about 10%–15% in patients
with bipolar disorder, and coadministration of an antimanic agent does
not necessarily and reliably prevent the potential for affective polarity
switch (Tondo et al. 2010). However, available studies are limited by
their retrospective study designs, variability in treatment regimens, rec-
ognition of patient-specific factors that increase risk for antidepressant-
induced mania (summarized in Table 5–1), and nonstandardization of
definitions and assessments of polarity switch. Clinicians sometimes
broadly use the term activation as a catchphrase to describe features sug-
gestive of various phenomena, ranging from mania or hypomania to
akathisia to anxiety to psychomotor agitation. Regardless of terminol-
ogy, signs of increased psychomotor activity during treatment with any
psychotropic drug warrant systematic and thoughtful evaluation by the
prescriber. Relevant signs of treatment-emergent mania or hypomania
97
may be subtle and can include new-onset sleep disturbance, anger, and
irritability, as well as other DSM-IV-TR (American Psychiatric Associa-
tion 2000) symptoms of a manic or hypomanic episode. The following
are important points to consider:
• How recently a medication was begun or dosages were changed

• Whether or not an apparent dose relationship corresponds to the
emergence of symptoms
• The presence or absence of bipolar disorder
• A known history of prior antidepressant-associated mania or hypo-
mania
• The possible contributing role of concomitant medications
• The loss of need for sleep without consequent fatigue (as opposed to
simple insomnia or phase advancement of the sleep-wake cycle)
• The absence of alcohol intoxication or withdrawal states, or illicit
substance abuse that could mimic psychomotor activation otherwise
attributable to a prescribed medication
The emergence of mania or hypomania following exposure to an an-

tidepressant or stimulant touches on the distinction between a frank
side effect of a drug and the precipitation of a diathesis (in this instance,
to mania or hypomania) that becomes revealed by exposure to a partic-
ular medication. Current nosological classification identifies psychotro-
pically induced mania or hypomania as a substance-induced mood
disorder rather than true bipolar disorder, although some experts
harken back to DSM-III-R (American Psychiatric Association 1987),
which conceptualized antidepressant-induced mania or hypomania as
defining of bipolar disorder. In the case of antidepressant-associated
mania or hypomania, some experts would contend that beyond 12 weeks
after treatment initiation, it becomes difficult to reasonably attribute
signs of mania or hypomania to an antidepressant rather than to the nat-
ural course of illness.
It is presently unknown whether antidepressant-induced mania or
hypomania may be a dose-related (vs. an all-or-none exposure) phe-
nomenon and whether antimanic drugs effectively “counterbalance” or
reliably prevent antidepressant-induced mania or hypomania. Psycho-
motor activation that is possibly caused by a psychotropic agent should
be evaluated to differentiate agitation, akathisia, anxiety, and mania or
hypomania. Mania or hypomania resulting from psychostimulants re-
mains a theoretical risk that has received remarkably little study in pa-
tients with known bipolar disorder, limiting the ability to make broad
assumptions about either the safety or efficacy of psychostimulants in
Adverse Psychiatric Effects of Psychiatric Medications 99
TABLE 5–1. Risk factors associated with the emergence of mania or

hypomania during treatment with antidepressants
Factor Finding
History of antidepressant- 2- to 5-fold increased risk for

induced mania or hypomania subsequent antidepressant-
induced mania or hypomania,
regardless of antidepressant
Recent mania preceding Higher risk for antidepressant-
current depressive episode associated mania if current
depressive episode was
preceded by manic phase
Bipolar I vs. bipolar II subtype Greater risk for switch in bipolar I
Comorbid alcohol or substance 5- to 7-fold increased risk for
use disorder antidepressant-associated mania
Noradrenergic vs. serotonergic Possible higher risk for mania
antidepressants induction with TCAs or SNRIs
than with bupropion or SSRIs
Concurrent mania symptoms Increased risk for mania in patients
during a depressive episode with mild or subthreshold mania
symptoms during a depressive
episode
Hyperthymic temperamental Increased likelihood of
traits antidepressant-induced mania
Note. SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective se-
rotonin reuptake inhibitor; TCA=tricyclic antidepressant.
Source. Adapted from Goldberg JF: “Antidepressants in Bipolar Disorder:
Seven Myths and Realities.” Current Psychiatry 9:41–49, 2010.
patients with bipolar disorder. Suspected inductions of true mania or

hypomania warrant cessation of the suspected causal agent, and if res-
olution does not occur, initiation of an antipsychotic or similar anti-
manic agent may be advisable.
Open trials and cases have reported that new-onset mania results
from some SGAs, such as risperidone and ziprasidone, and even lith-
ium. Although various theoretical mechanisms have been proposed to
explain the foregoing observations (e.g., mania resulting from the SNRI
properties of ziprasidone), it remains difficult to draw generalizable
pharmacodynamic inferences about such cases relative to the natural
course of illness in bipolar disorder.
Anxiety and Panic

Manufacturers’ product information materials for many psychotropic
compounds identify anxiety or nervousness as self-reported adverse ef-
fects, although it is often difficult to determine whether such phenomena
reflect true iatrogenic effects or symptoms of the primary psychiatric dis-
order being treated. Certain psychotropic drugs, such as bupropion, have
acquired popular perceptions that they may be anxiogenic despite a lack
of evidence from controlled trials to suggest either lesser efficacy in anx-
ious depression or a higher incidence of treatment-emergent anxiety as
compared to SSRIs. For other sympathomimetic psychotropic drugs such
as stimulants, incidence rates of anxiety or agitation are typically re-
ported in the range of ~5%–10% of adult subjects.
The possible iatrogenic emergence of panic attacks merits specific
consideration with some psychotropics. Most antidepressants carry
package insert information indicating that panic attacks have been re-
ported in both children and adults being treated for major depression,
although little empirical information exists on the timing, phenomenol-
ogy, and course of new-onset panic among depressed patients after
starting an antidepressant. High baseline comorbidity rates of panic dis-
order with both major depression and bipolar disorder (about 10%
[Kessler et al. 1998] and 20% [Chen and Dilsaver 1995], respectively,
based on findings from large-scale epidemiologic studies) also compli-
cate efforts to differentiate iatrogenic from primary panic attacks. Sev-
eral isolated case reports appear in the literature linking panic attacks
with the use of topiramate (50–150 mg/day) in patients with bipolar
disorder, drawing on the hypothesis that its carbonic anhydrase activity
could potentially induce panic via carbon dioxide retention.
Clinical Trial Subjects

With Psychiatric Illness
A dilemma arises when subjects who are psychiatrically ill enroll in
clinical trials and then report psychiatric symptoms as adverse effects;
it is often difficult if not impossible to discern whether such complaints
reflect true iatrogenic phenomena, whether they reflect untreated or
undertreated manifestations of the illness state being treated, or
whether they are spurious observations that may have no direct bearing
either on the target symptoms of the condition being treated or on the
effects of treatment itself. Pertinent examples would include purported
side effects such as personality disorder or psychosis that may be re-
ported during treatment for schizophrenia.
Discontinuation Phenomena
Abrupt cessation of short-acting serotonergic antidepressants may lead
to discontinuation syndromes involving mainly gastrointestinal or neu-
rological (e.g., vestibular) phenomena (see “Discontinuation Syn-
dromes” in Chapter 19, “Systemic Reactions”), although an induction
or exacerbation of psychiatric symptoms is rare. Mania has been de-
scribed following the rapid discontinuation of antidepressants in pa-
tients previously identified with unipolar depression (Goldstein et al.
1999); this discontinuation is thought to reflect disruption of a homeo-
static state. For patients with major depression or panic disorder, rapid
antidepressant cessation (≤7 days) also appears to significantly hasten
time to relapse as compared to more gradual discontinuation schedules
(>14 days) (Baldessarini et al. 2010). Case reports also exist of new-onset
mania, psychosis, or delirium resulting from the abrupt withdrawal of
either short- or long-acting benzodiazepines. In patients with bipolar
disorder, discontinuation of lithium over less than a 2-week period can
markedly hasten the time to affective relapse (Faedda et al. 1993).
Disinhibition and Impaired

Impulse Control
Benzodiazepines have been associated with the development of disin-
hibited behavior or paradoxical aggression in vulnerable populations,
particularly in patients who are elderly or patients with preexisting
frontal lobe disease. Individuals with a history of impulse control dis-
orders (including substance use disorders and borderline or antisocial
personality disorders) are also sometimes considered to be at greater
risk for disinhibition with benzodiazepine use.
A chart review of disinhibited behaviors in 323 inpatients found no
differences among those receiving alprazolam, clonazepam, or no ben-
zodiazepine (Rothschild et al. 2000), although underlying diagnoses
were heterogeneous and patients varied in their use of additional med-
ications. The authors surmised that contrary to some popular impres-
sions, behavioral disinhibition may be no more likely with short-acting
than with long-acting benzodiazepines.
Emotional Dulling
SSRIs have been reported, although rarely, to induce a state of emo-
tional indifference or apathy that is sometimes confused with depres-
sion. A literature review of this phenomenon in 2004 identified 12 case
reports and determined apathy to be a rare, reversible, dose-related

side effect (Barnhart et al. 2004). A prevalence rate of about 5% has been
reported in pediatric populations treated with fluvoxamine and other
SSRIs. The ability of SGAs to increase prefrontal dopamine transmis-
sion via serotonin type 2A (5-HT2A) blockage has been identified as a
possible mechanistic strategy that might counteract avolition or apathy.
In an 8-week pilot study of 21 formerly depressed patients who mani-
fested signs of apathy after ≥3 months of treatment with an SSRI (citalo-
pram, fluoxetine, sertraline, or paroxetine), Marangell et al. (2002)
found significant improvement in apathy symptoms after the addition
of olanzapine (2.5–20 mg/day; mean dosage=5.4 mg/day), although
subjects had a mean weight gain of 3 kg. Other SGAs have not, as yet,
been studied for this purpose but may merit consideration. With the
FDA approvals of adjunctive aripiprazole or quetiapine to SSRIs or
other antidepressants after an incomplete response to antidepressant
monotherapy, it may be useful to consider whether a lower incidence of
apathy complaints occurs with such combination regimens.
Psychosis
A limited number of psychotropic medications may have psychotomi-
metic effects—not to be confused with reports of “psychosis” that be-
come identified in the course of clinical trials of antipsychotic drugs,
which usually simply reflect a lack of antipsychotic efficacy against the
primary illness being treated. Psychosis is a known risk of psychostim-
ulants, usually in dose-related fashion, as well as from dopamine ago-
nists such as ropinirole, pramipexole, bromocriptine, and amantadine.
Rare case reports of new hallucinations that have been described in
association with the use of some SSRIs (notably, fluvoxamine) or SNRIs
(venlafaxine) are thought to reflect serotonergic overstimulation, elim-
inated by dosage reductions or by drug cessation. Cases also exist of
new-onset psychosis associated with bupropion, typically within days
to weeks of treatment initiation, and observed even at relatively low
dosages (100–150 mg/day). Hypothesized mechanisms accounting for
rare psychotomimetic effects include the structural similarity of bupro-
pion to amphetamine, and bupropion’s putative inhibition of dopamine
reuptake.
The use of nonbenzodiazepine hypnotics such as zolpidem has been
reported in association with new-onset hallucinations, depersonaliza-
tion, or dissociation rarely in adults (<1%), but more often in pediatric
patients. For example, hallucinations occurred in 7.4% of children or ad-
olescents receiving zolpidem for insomnia associated with attention-

deficit/hyperactivity disorder, as reported by the manufacturer.
Suicidal Thinking or Behavior

On January 31, 2008, the FDA issued an alert that all anticonvulsants
carried the potential to induce or exacerbate suicidal thoughts or behav-
iors, based on its review of 199 placebo-controlled trials involving 11
anticonvulsant agents and 43,900 subjects, over a median duration of
12 weeks, that were linked with an overall 1.8-fold increased risk. No
black box warning was imposed despite the concerns raised by the
FDA’s Scientific Advisory Committee. The FDA ranked agents by risk
for suicidal behavior as levetiracetam > topiramate > zonisamide>
oxcarbazepine >pregabalin >gabapentin > lamotrigine>divalproex >
carbamazepine (Pompili and Baldessarini 2010). Notably, contrary
findings that dispute a relationship between anticonvulsant use and
suicidal behavior have been reported in patients with bipolar disorder
(Gibbons et al. 2009). Similarly, a cohort study of 5.1 million prescrip-
tion recipients in the United Kingdom found no increased risk for sui-
cide-related events in patients with either epilepsy or bipolar disorder
who received anticonvulsant medication; however, anticonvulsant use
was associated with a 1.7-fold increased risk for suicidality in patients
with major depression and a 2.6-fold increased risk among patients
with disorders other than major depression, epilepsy, or bipolar disor-
der (Arana et al. 2010). The relationship between suicidal thoughts or
behaviors and anticonvulsants appears to be complex, with some au-
thors pointing out unexpectedly high risks for suicide among epilepsy
patients, likely attributable to psychiatric comorbidity (Pompili and
Baldessarini 2010).
Antidepressant medications have come under particular scrutiny
since the FDA issued a black box warning (■) in October 2004 that all
antidepressants can increase suicidal thinking or behavior in individu-
als <age 24; this risk does not apply to individuals >age 24, and antide-
pressants appear to confer protection against suicidal behavior in adults
≥age 65. These observations derived from an FDA advisory panel that
reviewed 25 drug trials (16 in patients with depression) involving ap-
proximately 4,000 children or adolescents, in which 109 events were
deemed “possibly suicide-related,” although no suicide completions
occurred. “Events” ranged from attempted hangings or overdoses to
behaviors such as self-mutilation or self-slapping. Those data were cor-
roborated by an observed 1.5-fold increased risk for suicide attempts
and 15.6-fold increased risk for suicide deaths among youth ages 6–18
years in a nationwide Medicaid database case-control study of individ-
uals ages 6–64 who did not have bipolar disorder, schizophrenia, de-
mentia/delirium, or mental retardation and who were not pregnant
(Olfson et al. 2006).
Purported links between suicidal behavior and antidepressant use
have been challenged by naturalistic population studies, such as the
finding that a 1% increase in antidepressant use appears associated
with a decrease of 0.23 suicides per 100,000 adolescents ages 10–19 per
year (Olfson et al. 2003), or National Vital Statistics data from the Cen-
ters for Disease Control indicating that the use of SSRIs and other
newer-generation antidepressants is linked with lower rates of suicide
deaths in the general population (Gibbons et al. 2005). Suicide comple-
tion rates declined 13% from 1985 to 1999, accompanied by a 4-fold in-
crease in rates of SSRI and other newer-generation antidepressant
prescriptions (Grunebaum et al. 2004).
6
What Nonmedical
Therapists Should
Know About
Adverse Drug Effects
Although prescribers often have difficulty discerning the etiology of

physical complaints, differentiating their probable associations with
treatment versus underlying illness, and recognizing the necessity (or
nonnecessity) of interventions, such challenges can be even more
daunting for nonmedical psychotherapists. The potential advantages
and disadvantages of so-called split or collaborative treatments be-
tween two clinicians involve broad issues that fall beyond the scope of
this book (but are well addressed by Riba and Balon 2005; cf. Kelly 1992
on the concept of “parallel” treatments as independent endeavors).
However, because nonmedical therapists have a positive role to play as
a member of a treatment team, we offer the following cautionary con-
siderations that bear on the assessment of adverse drug effects:
• Nonmedical therapists may not recognize which physical complaints

are or are not plausibly iatrogenic and could erroneously reinforce
patients’ misattributions about etiology.
105
• Patients who erratically take sedative-hypnotics or opiates or binge on

alcohol might describe withdrawal phenomena that could be miscon-
strued as psychological or psychiatric rather than physical; similarly, pa-
tients who abuse controlled substances may complain of symptoms that
could be misinterpreted as medication side effects (or primary psychiat-
ric symptoms) that actually reflect intoxication, withdrawal, or neuro-
toxic states.
• Nonmedical therapists may sometimes unwittingly overstep scope-
of-practice boundaries through well-intended but potentially medi-
cally inaccurate suggestions about ways to manage adverse effects
(e.g., advising a patient to alter the dosage of a medicine, proposing a
pharmacological remedy for an adverse effect, or wrongly encourag-
ing patients to “wait out” a serious side effect that they assume will
ultimately resolve with time—rather than advising a patient to redi-
rect medication concerns to the prescriber).
• Nonmedical therapists may be unaware of the medical significance
of a probable adverse drug effect when addressing physical symp-
toms that might also have a psychodynamic or behavioral etiology.
For example, the therapist may examine loss of libido or sexual dys-
function solely in the context of past conflictual or traumatic intimate
relationships, or may perceive complaints of anxiety and restlessness
as manifestations of psychic distress surrounding the material under
scrutiny in psychotherapy (rather than, perhaps, as manifestations of
akathisia or pharmacologically induced psychomotor activation).
• Dynamically oriented psychotherapists also may be unaware of
emotional or cognitive phenomena that could be iatrogenic. For
example, complaints of apathy during SSRI therapy may be miscon-
strued either as depression or as a defensive posture against con-
fronting emotionally upsetting material.
• Nonmedical therapists may fall back on personal experience, biases,
or secondhand information about drug effects, from which they may
make professional or overgeneralized recommendations to patients
who, in turn, may misconstrue the accuracy and authoritative nature
of medical information they receive from a clinician without medical
training. Negative biases on the part of nonprescribing therapists also
can inappropriately intrude into the course of a collaborative treat-
ment in ways that are a disservice to the needs of the patient (e.g., tell-
ing a patient experiencing adverse effects that he is probably better off
if he can get by without a drug, or otherwise implying that pharma-
cotherapy is an elective accessory to psychotherapy that should ide-
ally be halted as soon as feasible).
What Nonmedical Therapists Should Know 107
• The potential arises for splitting to occur between prescriber and

nonprescriber, as well as acting out of relationship dynamics be-
tween medical and nonmedical treaters (e.g., Patient: “My therapist
says my thinking is less sharp from this medicine and says you
should lower the dosage or change it”). Alternatively, nonmedical
psychotherapists can strengthen the integrity of a team approach by
pointing out the appropriate delineation of roles and responsibilities
when patients ask medication questions (e.g., Therapist: “Have you
mentioned that concern to Dr. Smith? What information has she
given you?”).
Nonmedical psychotherapists can provide both patients and prescrib-

ers with invaluable observations on many levels regarding adverse drug
effects. Often, such perspective comes from having more frequent contact
with a patient and a more intimate knowledge about the patient’s per-
sonal habits and coping styles, as well as seemingly routine medical
events. For example, consider a patient who remarks to her nonmedical
therapist that she has begun an oral contraceptive prescribed by her gy-
necologist but may not have discussed with the physician whether there
may be drug interactions with existing psychotropic medications or
whether any subsequent mood changes might be iatrogenic. Patients
who have a closer working alliance with a nonmedical therapist also typ-
ically provide him or her with more personal information and detail, and
consequently may be more comfortable (or selective) in sharing sensitive
information. Common examples include patients’ concerns about sexual
functioning, alcohol or substance misuse, or adverse drug effects that be-
come fodder for interpersonal or family-based conflicts (e.g., Patient: “My
mother says I’m getting too fat; I should stop this medicine”).
Nonmedical psychotherapists may have a particular vantage point
from which to recognize and intercede when patients are inclined to
stop taking medications. Patients, for their part, sometimes may not feel
inclined to tell a prescriber about their wish to discontinue a treat-
ment—perhaps because of the fear of admonition or an otherwise judg-
mental response. By contrast, nonprescribing psychotherapists who are
alert to such issues may be able to provide patients with a more impar-
tial environment in which to discuss thoughts and feelings about med-
ication likes and dislikes. A therapist’s ability to help a patient identify
his or her own concerns about medication (or other health issues) and
articulate them effectively to the physician is modeling behavior for tak-
ing proper care of oneself, while overcoming defeatist expectations
(e.g., Patient: “Dr. Jones will just tell me I have to live with the side ef-
fects. Why bother complaining to him?”) and fostering a sense of re-

sponsibility and empowerment over the patient’s pursuit of treatment
(e.g., Therapist: “You are assuming Dr. Jones won’t be sympathetic to
the problems you’re having, and won’t be able to help you find a solu-
tion for them”).
Finally, although it remains the responsibility of the prescriber to
monitor and address adverse drug effects, nonmedical psychothera-
pists should consider that these actions unfortunately may not always
occur routinely and properly. Rather than taking it upon themselves to
inventory the presence of potential adverse drug effects or other medi-
cation concerns, nonprescribing therapists should periodically ask pa-
tients about the status of their pharmacotherapy and medical follow-up.
Sample gentle prompts and points for discussion might include the fol-
lowing:
• “How often are you and Dr. Smith in contact with one another? How
often has Dr. Smith recommended that you meet with her?”
• “Has Dr. Smith reviewed with you the purpose of the medicines she
is prescribing? Has she discussed dosing and possible side effects
with you?”
• “Did Dr. Smith tell you whether any lab tests are necessary for the
safe use of the medicines you are taking and how often those need to
be done?”
• “Have you asked Dr. Smith if that problem could be related to the
medicine you’re taking?”
• “What did Dr. Smith advise about the effects of alcohol on the med-
icines you’re taking?”
• When poor adherence is suspected, or known: “Many people some-
times have trouble taking their medicines exactly the way their doctors
recommend. Do you?” or “Are you comfortable talking with Dr. Smith
about your reluctance to take medicine? How do you think she would
respond if you brought this up with her?”
• “Have you asked Dr. Smith whether there may be ways to manage
possible side effects, or whether there are alternative medicines worth
considering?”
• “You should let Dr. Smith know that your internist has prescribed a
new medicine to make sure there are no conflicts with the medication
she is prescribing for you.”
• “Don’t forget to tell Dr. Smith that you’re having surgery to find out
if there might be any special issues for postoperative pain manage-
ment—or if there might be any other concerns with the medicines
you’re taking.”
What Nonmedical Therapists Should Know 109
Finally, it makes sense for two (or more) mental health professionals
who share common cases to make clear to their mutual patients the im-
portance of permission for free communication among providers. Such
information exchange helps to minimize misunderstandings, miscom-
munications, and potential hazards about medically or psychiatrically
relevant information that might otherwise go unknown by each clinician.
PART II
Organ Systems
7
Cardiovascular
System
Arrhythmias and Palpitations

General Recommendations. Arrhythmias may occur as a
consequence of treatment with all antipsychotics, TCAs, stimu-
lants, and anticholinergic drugs, or in the setting of toxicity
states. Clinicians should be familiar with cumulative risk factors
for prolonged ventricular repolarization (the QTc interval; see Ta-
ble 7–3), and the necessity of baseline electrocardiographic mon-
itoring (e.g., in adults over age 40 or in patients with known or
suspected cardiac disease, before starting a TCA, lithium, or in
some instances an SGA). Palpitations (the subjective awareness
of heartbeats) are usually benign in the absence of underlying
structural heart disease, but carry a wide differential diagnosis
that involves factors unrelated to psychotropic drugs.
113
Overall Considerations
The arrhythmogenic potential of some psychotropic drugs is long es-
tablished and often poses a significant deterrent to prescribing other-
wise effective medications. Examples of these drugs include TCAs by
virtue of their anticholinergic effects, α-adrenergic blockade, and quini-
dine-like effects from the blockade of fast sodium channels in myocar-
dial cells.
An understanding of basic cardiac physiology is important for mak-
ing medically informed treatment decisions rather than altogether
avoiding medications because of generic cardiac concerns. For example,
prescribers need to recognize why TCAs are contraindicated in the set-
ting of a left bundle branch block (where only one fascicle remains intact
to conduct signals from the His-Purkinje system to the ventricular myo-
cardium) but not a right bundle branch block (where two fascicles—
the left anterior and posterior—are available to innervate the ventricu-
lar myocardium). Examples of other fundamental cardiac or cardiovas-
cular disturbances that bear on psychopharmacology interventions
include the relative contraindication of β-blockers (including pindolol)
in individuals with sick sinus syndrome, and an awareness that in pa-
tients who take warfarin—which is highly protein bound—competition
for binding may lead to increased fractions of unbound warfarin (which
in turn may interfere with INR values) or psychotropics.
Table 7–1 summarizes known relationships between electrocardio-
graphic changes and common psychotropic medications.
Most SGAs carry risks for both tachycardia (presumably due to
anticholinergic effects) and orthostatic hypotension (probably due to
α1-adrenergic blockade). Proper management involves measurement of
heart rate and blood pressure, including orthostatic measurements, and
gradual dosage increases when necessary. If a β-blocker is being used to
treat akathisia or tremor, monitoring heart rate and blood pressure is
especially important to assure no exacerbation of hypotension from
α1-adrenergic blockade.
Palpitations refer to the awareness or subjective experience of irreg-
ular heartbeats. They may or may not reflect actual ectopic beats. Atrial
premature complexes (APCs) or premature ventricular complexes
(PVCs) that are isolated, intermittent, and arise spontaneously are usu-
ally benign and common occurrences in healthy people, unless the con-
tractions are accompanied by other cardiovascular signs (such as chest
pain, dizziness, or syncope) or arise in the setting of structural heart dis-
ease. Psychiatrists who evaluate palpitations should review all of a pa-
Cardiovascular System 115
tient’s medications (both psychiatric and nonpsychiatric) to identify

drugs that may cause tachycardia (e.g., anticholinergics), prolong the
QT interval (see Table 7–2), or pharmacokinetically inhibit the metabo-
lism of anticholinergic or QT-prolonging drugs (see Table 2–6). Pulse
rate and regularity should be measured and the heart auscultated to dis-
cern premature beats, particularly if occurring as couplets or triplets.
Obtaining an electrocardiogram (ECG) is appropriate to assure normal
intervals and identify APCs or PVCs. Runs of bigeminy or trigeminy
warrant more extensive studies (e.g., Holter monitoring) and referral to
a cardiologist. Echocardiography may be indicated for patients with a
murmur who complain of palpitations. Iatrogenically, stimulants may
cause tachyarrhythmias but not APCs or PVCs, although rare reports of
new-onset PVCs have been described with the use of modafinil (Oskoo-
ilar 2005). Clinicians obviously should recognize and consider nonpsy-
chotropic drug causes of a rapid or irregular heart rhythm, including
the effects of thyroid hormone, inhaled beta agonists, antihypertensive
agents, caffeine, and nicotine, as well as the potential contribution of hy-
perthyroidism, electrolyte abnormalities, and anxiety, among other
possible etiologies.
Sudden Cardiac Death

General Recommendations. Clinicians should be aware that
all antipsychotics and psychostimulants carry a small but statisti-
cally significantly increased risk for sudden cardiac death.
Sudden cardiac death due to an arrhythmia is a particular concern in a

number of clinical contexts. All antipsychotics, both FGAs and SGAs,
may carry an increased (approximately 2-fold), dose-related risk for
sudden cardiac death due to presumptive ventricular arrhythmias (Ray
et al. 2009). A review by Glassman and Bigger (2001) identified 10–15
events per 10,000 patient years during treatment with antipsychotics,
also noting an approximate 2-fold increased risk for sudden death dur-
ing antipsychotic therapy as compared to the general population. In ad-
dition, case reports exist of sudden death among children <age 14 after
exposure to TCAs, particularly desipramine, often in the absence of a
preexisting history of cardiac arrhythmia. Although TCAs are currently
seldom used in children, appropriate precautions before their initiation
in pediatric populations should involve a baseline ECG and identifica-
tion of any underlying heart disease.
TABLE 7–1. Electrocardiographic changes associated with

psychotropic medications
Medication Electrocardiographic changes and concerns

Carbamazepine Heart block and ventricular arrhythmias possible in
overdose.
Divalproex Tachycardia or bradycardia.
Gabapentin None known.
Lamotrigine Rare associations reported with lamotrigine
overdose and Brugada patterna on ECG,
presumably via the effect of lamotrigine on sodium
channels, as well as QRS widening; routine ECG
monitoring not indicated.
Lithium Reversible T-wave changes, sinus bradycardia, sick
sinus syndrome, heart block, case reports of
Brugada patterna on ECG.
Oxcarbazepine None known.
Topiramate None known.
Antidepressants
Bupropion Tachycardia, premature beats, nonspecific
ST-T changes, QRS prolongation in overdose.
Mirtazapine Possible association with relatively minor increase
in heart rate (< 5 beats per minute); no other known
electrocardiographic abnormalities.
SNRIs May increase heart rate due to increased
noradrenergic tone.
SSRIs May increase heart rate; rare increase in QTc
intervals with escitalopram, fluoxetine, paroxetine,
and sertraline, and with citalopram dosed >40 mg/
day or in the setting of overdoses; routine ECG
monitoring with SSRIs not considered necessary
but may be appropriate in patients taking high
doses of citalopram or escitalopram.
TABLE 7–1. Electrocardiographic changes associated with

psychotropic medications (continued)
Medication Electrocardiographic changes and concerns
TCAs Tachycardia possible due to vagolytic effects;
quinidine-like effects possible (i.e., blockade of fast
sodium channels causes prolonged depolarization
with decreased myocardial contractility, leading to
PR prolongation, QRS widening, right axis
deviation and bradycardia or heart block in
overdose); potassium channel blockade may
cause QT prolongation (rare torsades de pointes);
contraindicated in presence of left bundle
branch block.
Antipsychotics
FGAs Sinus tachycardia, QTc prolongation (particularly
with pimozide, thioridazine, and intravenous
haloperidol), ventricular arrhythmias.
SGAs Tachycardia (lurasidone, risperidone), first-degree
AV block (lurasidone), QTc prolongation
(ziprasidone and potentially others in dose-related
fashion).
Anxiolytics or sedative-hypnotics
Benzodiazepines Rare reports of QTc prolongation with lorazepam in
patients with underlying arrhythmia.
Buspirone None known.
Zolpidem None known.
Psychostimulants Tachycardia.
Note. AV=atrioventricular; ECG=electrocardiogram; FGA=first-generation
antipsychotic; SGA=second-generation antipsychotic; SNRI=serotonin-norepi-
nephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor;
TCA=tricyclic antidepressant.
aThe Brugada pattern on ECG involves one of three patterns: 1) coved-type ST
elevation with ≥ 2-mm J-point elevation followed by t-wave inversion; 2) a

“saddle-back” pattern with a ≥ 2-mm J-point elevation, ≥ 1-mm ST elevation,
and a positive or biphasic T-wave; 3) persistent ST elevation in leads V1–V3
with right bundle branch block.
Antipsychotics
For many decades, antipsychotics have been known to have the poten-
tial for prolonging the time for ventricular repolarization (i.e., the QT
interval on an ECG, corrected for heart rate [QTc]), with an associated
potential for causing torsades de pointes, but this concern gained par-
ticular attention in 1996 when 12 unexplained deaths and 23 cases of
syncope occurred in 1,446 patients during premarketing drug trials for
the SGA sertindole while it was under consideration for FDA approval.
After the FDA indicated its intention to impose a black box warning re-
garding the risk for sudden death, the manufacturer did not market
sertindole in the United States, but the drug was approved in 1998 in
the United Kingdom for use in patients with schizophrenia. Sertindole
was subsequently withdrawn from the European market in the after-
math of 36 unexplained cases of sudden death (Glassman and Bigger
2001), although this ban was lifted in Europe in 2005.
When Pfizer, the manufacturer of ziprasidone, then sought its indica-
tions from the FDA, a comparative study was conducted to evaluate QTc
prolongation with ziprasidone relative to several other conventional an-
tipsychotics or SGAs, in the presence or absence of CYP inhibitors (see
Glassman and Bigger 2001). Importantly, this is the sole study that pro-
vides direct comparative data across several antipsychotics (ziprasidone,
risperidone, olanzapine, quetiapine, thioridazine, and haloperidol) un-
der controlled conditions. Table 7–2 provides a summary of information
from both that Pfizer-sponsored study and from available FDA registra-
tion trial data of QTc effects with FGAs and SGAs, although absolute dif-
ferences cannot easily be construed about relative QTc effects across
agents due to between-subject differences in baseline risk factors for QTc
duration (Table 7–3).
The aforementioned Pfizer comparative study of antipsychotic effects
on QTc intervals identified marked QTc prolongation with thioridazine,
prompting imposition of a black box warning (■) with thioridazine (see
Table 1–6 in Chapter 1, “The Psychiatrist as Physician”) and a physician
notification letter warning of the risk for QTc prolongation and torsades
de pointes. Mesoridazine received a similar black box warning (■)
shortly thereafter. The FDA traditionally categorizes increasing degrees
of clinically meaningful risk associated with QTc prolongation from base-
line as follows: ≤5 msec as “probably no concern,” 6–10 msec as “increas-
ing concern,” 11–20 msec as “uncertain concern,” and > 20 msec as
“definite concern” (see also U.S. Food and Drug Administration 2005).
Generally, in patients with elevated QTc (i.e., ≥450 msec) and psy-
chotic features, it is advisable to minimize or avoid exposure to all an-
TABLE 7–2. QTc prolongation with FGAs and SGAs (in order of
increasing concern by duration)a
Agent Findings in FDA registration trials
Aripiprazole –4.2-msec decrease from baseline (Marder et al. 2003).

Clozapine No known QTc prolongation.
Asenapine 2- to 5-msec increase from baseline as compared to placebo;
no observations of QTc ≥500 msec (manufacturer’s
product information).
Haloperidolb 4.7-msec increase from baseline
(Glassman and Bigger 2001).
Lurasidone Manufacturer’s product information: at dosages of 120 or
600 mg/day, “no patients experienced QTc increases
> 60 msec from baseline, nor did any patient experience a
QTc >500 msec”; 5.1-msec and 4.5-msec increases from
baseline at 40 mg/day and 120 mg/day doses (Meltzer et
al. 2011).
Olanzapine 6.8-msec increase from baseline
Iloperidone 9-msec increase from baseline (dosed at 12 mg bid)
(manufacturer’s package insert).
Risperidone 11.6-msec increase from baseline
Paliperidone 12.3-msec increase from baseline (8-mg dose); no subjects
had a change exceeding 60 msec or QTc > 500 msec
(manufacturer’s package insert).
Quetiapine 14.5-msec increase from baseline
Ziprasidone 20.3-msec increase from baseline
Thioridazine 35.8-msec increase from baseline
Note. bid= twice daily; FDA =U.S. Food and Drug Administration; FGA =first-
generation antipsychotic; msec=milliseconds; SGA =second-generation antipsy-
chotics.
aThe FDA traditionally categorizes increasing degrees of clinically meaningful risk
associated with QTc prolongation from baseline as follows: ≤5 msec= probably no

concern, 6–10 msec=increasing concern, 11–20 msec= uncertain concern, and
>20 msec=definite concern.
b Anecdotal experience suggests that haloperidol administered intravenously may
carry a greater risk for QTc prolongation than with oral or intramuscular admin-
istration.
TABLE 7–3. Factors associated with QTc prolongation

Advanced age
Alcohol
Certain antihistamines (astemizole and terfenadine onlya)
Certain antiarrhythmics, including amiodarone, disopyramide,
flecainide, procainamide, propafenone, quinidine, sotalol
Certain antibiotics, including azithromycin, ciprofloxacin,
clarithromycin, erythromycin, gemifloxacin, levofloxacin,
mefloquine, moxifloxacin, norfloxacin, ofloxacin, rufloxacin
Certain antiemetics (e.g., ondansetron, prochlorperazine)
Certain antifungal agents (e.g., ketoconazole)
Certain antineoplastics (e.g., anthracyclines, 5-fluorouracil, alkylating
agents)
Certain SSRIs at high doses (e.g., citalopram and escitalopram)
Congenital QT prolongation syndrome (arising in ~1/5,000 live births)
Cyclobenzaprine
Female sex
Hypokalemia
Hypomagnesemia
Hypothyroidism
Methadone
Solifenacin
Thyroid abnormalities
TCAs, maprotiline, trazodone
Vardenafil
Note. SSRI= selective serotonin reuptake inhibitor; TCA= tricyclic antide-
pressant.
aBoth agents have been withdrawn from the U.S. market; noted for historical
purposes.
tipsychotics unless the perceived benefit outweighs the potential risk. In

such patients, cautious observation with serial ECG monitoring may be
warranted, as well as the elimination or correction of other potential
causes of QTc prolongation (see Table 7–3). QTc intervals ≥500 msec
pose a substantial hazard for developing potentially fatal ventricular ar-
rhythmias (notably, torsades de pointes) and generally signal the need
to eliminate antipsychotic drugs.
From a practical standpoint, it is often useful to compare current

ECGs to prior ECGs in order to determine whether suspected abnormal-
ities represent internal changes. New findings may warrant drug cessa-
tion or consultation with a cardiologist, whereas stable features may
pose lesser concern for iatrogenic risks. Clinicians also should be mind-
ful of cumulative risk factors for arrhythmias in a given patient, such as
electrolyte abnormalities, hypothyroidism, advanced age, effects of al-
cohol, and the synergistic arrhythmogenic potential of concomitant
drugs (e.g., fluoroquinolone antibiotics, anticholinergics, and other
drugs noted in Table 7–3).
Some authors recommend that because of the potential for sudden
cardiac death with all antipsychotics, clinicians should determine, be-
fore initiating an antipsychotic, whether a patient has had syncope, has
relatives with known congenital QT prolongation syndrome, or has rel-
atives who experienced sudden death at an early age, and should obtain
a baseline ECG in older adults or those with a history of known cardiac
disease (Glassman and Bigger 2001). The American Heart Association
(AHA) also advises obtaining a baseline ECG (mainly to assure the ab-
sence of QT prolongation) before beginning a TCA or phenothiazine in
children or adolescents (Gutgesell et al. 1999), with repeat assessment
after steady-state dosing is achieved. Adult women generally may have
a greater risk than men for developing torsades de pointes from medi-
cations that prolong QTc.
Antidepressants
TCAs may be arrhythmogenic by virtue of their anticholinergic and quin-
idine-like effects. Orthostatic hypotension may result from α1-adrenergic
blockade with tertiary amine TCAs (e.g., amitriptyline, imipramine).
SSRIs generally lack effects on cardiac conduction with the apparent ex-
ception of high-dose citalopram and its enantiomer escitalopram; in Au-
gust 2011, the FDA issued an alert that dosages of citalopram >40 mg/
day may prolong QT intervals and advised against the use of citalopram
in patients with congenital long QT syndrome. Caution is recommended
when using citalopram or escitalopram at high doses in patients with
other risk factors for QT prolongation (see Table 7–3). Citalopram also
has been associated with significantly greater QT prolongation in over-
doses as compared with changes seen in fluoxetine, fluvoxamine, parox-
etine, or sertraline (Isbister et al. 2004). It is advisable to obtain a baseline
ECG in patients taking ≥40 mg/day of citalopram.
MAOIs lack anticholinergic adverse effects but may cause ortho-
static hypotension, bradycardia, and shortened PR and QTc intervals on
ECG (McGrath et al. 1987).
Stimulants
Controversy remains about the necessity of routine ECG screening before
the initiation of stimulant therapy (e.g., for attention-deficit/hyper-
activity disorder). Stimulants can slightly raise heart rate and blood
pressure, but the risk for sudden cardiac death from stimulants appears
to be no higher than the background rate seen in the general popula-
tion. Nonetheless, an AHA Scientific Statement suggests that in chil-
dren and adolescents, it is “reasonable” to obtain a prestimulant ECG to
identify underlying risk factors for sudden cardiac death, such as hy-
pertrophic cardiomyopathies, long QT syndrome, and preexcitation or
reentrant arrhythmias such as Wolff-Parkinson-White syndrome (Vet-
ter et al. 2008). No similar AHA recommendation exists regarding base-
line ECG screening in adults. More important than whether or not one
obtains an ECG is the process by which a clinician evaluates cardiovas-
cular risk before starting any sympathomimetic agent. An appropriate
history would include assessment of the following:
• A history of fainting or dizziness

• Chest pain or shortness of breath on exertion
• Palpitations
• Hypertension
• History of heart murmur or known arrhythmia
• Current medications
• Family history of unexplained or sudden death before age 35
• Family history of cardiac arrhythmias
Decisions to obtain a baseline ECG or consultation with a cardiologist

before stimulant initiation in adults are usually best determined in case-
by-case fashion depending on an individual’s history and suspected
cardiac risk factors.
Other Cardiac Disturbances

Cardiomyopathies have been reported to occur during treatment with
clozapine and risperidone. Myocarditis may occur with clozapine (■),
and pericarditis is a rare adverse effect of gabapentin.
Cerebrovascular Accidents
General Recommendations. Elderly patients with underly-
ing cerebrovascular or cardiovascular disease may be at greater
risk for cerebrovascular events from use of SGAs, although causal

links remain controversial. Clinicians should recognize the pres-
ence of baseline vascular disease when formulating risk-benefit
treatment decisions.
Four controlled treatment studies of risperidone for dementia-related

psychosis from 1999 to 2003 identified a significantly increased risk for
transient ischemic attacks or cerebrovascular accidents with risperi-
done (4%) compared with placebo (2%), prompting a subsequent FDA
public health advisory linking the use of SGAs with an increased risk
for cerebrovascular accidents. Subsequent case-control studies that
failed to replicate these observations have pointed to possible con-
founding factors, such as vascular dementia, hypertension, and other
noniatrogenic risk factors for transient ischemic attacks or cerebrovas-
cular accidents that may have been overrepresented among antipsy-
chotic recipients. At the same time, because SGAs demonstrate low
efficacy but high dropout rates in dementia-related psychosis, enthusi-
asm for their use is modest. The absence of highly effective remedies for
dementia-related psychosis requires thoughtful risk-benefit analyses
when considering treatments, in addition to close monitoring for ad-
verse neurological or cardiovascular changes.
Dyslipidemias
General Recommendation. Patients who develop dyslipi-
demias while taking SGAs or some antidepressants may warrant co-
therapy with lipid-lowering agents prescribed in conjunction with
the primary care physician or cardiologist. Decisions must be made
on a case-by-case basis about the relative merits of switching from
an existing SGA to an alternative agent with potentially lesser risk
for lipid dysregulation versus treating abnormal lipids with statins
or other lipid-lowering agents, depending on the magnitude of
benefit with an existing psychotropic agent and the likelihood that
a replacement drug would yield at least comparable efficacy.
Abnormal elevations of total serum cholesterol and serum triglycer-

ides have been linked directly with most SGAs and represent a key as-
pect of metabolic syndrome. The mechanisms by which SGAs may
cause dyslipidemias, other than as a secondary consequence of obesity
caused by increased caloric intake, remain elusive. In addition, abdom-
inal obesity and hypercholesterolemia have been associated with some
SSRIs—sertraline, fluoxetine, and fluvoxamine—but not with citalo-
pram, whereas weight gain with paroxetine appears to be independent

of new-onset dyslipidemias (Raeder et al. 2006).
The long-term CATIE study (Lieberman et al. 2005) in chronic schizo-
phrenia found the greatest rises in serum cholesterol with olanzapine and
the greatest reductions from baseline with ziprasidone (Table 7–4).
Some studies have reported a lower incidence of hypertriglyceri-
demia and elevations in serum leptin levels in patients with schizophre-
nia during treatment with quetiapine, and a minimal change during
risperidone therapy, as compared to during therapy with clozapine or
olanzapine (Atmaca et al. 2003).
Hypertriglyceridemia is generally thought to pose a less direct athero-
sclerotic risk than other lipid parameters (e.g., high LDL cholesterol or
low HDL cholesterol), and it carries an increased risk mainly for pancre-
atitis or cholelithiasis. Hypertriglyceridemia also has been identified as a
risk factor for the development of hyperglycemia and eventual non–insu-
lin-dependent diabetes mellitus (NIDDM) (Tirosh et al. 2008), although
hypertriglyceridemia is thought to be a covariate (rather than a cause) of
NIDDM that becomes evident before the emergence of frank diabetes.
The National Cholesterol Education Program (2001) Expert Panel on De-
tection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III [ATP III]) suggests that moderate or greater
hypertriglyceridemia alters lipoprotein metabolism and still represents
an independent risk factor for coronary artery disease, especially in
women (McBride 2007). The ATP III defines normal triglycerides as
<150 mg/dL, borderline-high triglycerides as 150–199 mg/dL, high tri-
glycerides as 200–499 mg/dL, and very high triglycerides as ≥500 mg/dL.
The components of metabolic syndrome, summarized in Table 7–5,
collectively increase the risk for coronary heart disease, regardless of
LDL cholesterol levels. The ATP III defines metabolic syndrome as the
presence of three or more of these risk factors.
Longitudinal studies indicate that risk factors for the development of
diabetes or prediabetes during treatment with an SGA include HDL con-
centrations <28 mg/dL, age >58 if HDL is ≥28 mg/dL, serum glucose lev-
els ≥92 mg/dL, posttreatment rises in triglyceride values ≥145 mg/dL
(for diabetes) or ≥59 mg/dL (for prediabetes), and rapid weight gain
(within 2 weeks) of ≥6.1 kg in conjunction with a triglyceride increase of
≥145 mg/dL (Reaven et al. 2009). On the basis of the nontrivial risks for
coronary heart disease caused by iatrogenic dyslipidemias, many psychi-
atrists often favor replacing an SGA that is suspected of causing dyslipid-
emia or metabolic dysregulation with a different SGA of presumed lower
risk, or possibly even an FGA, regardless of possible differences in psy-
chotropic efficacy. However, the risk-benefit analysis of this proposition

is not always straightforward. A significant dyslipidemia certainly pre-
sents a compelling rationale for considering a switch to alternative
agents. The main uncertainties in doing so involve whether the substi-
tuted new agent indeed possesses more benign metabolic effects for a
given patient, and has at least comparable efficacy to sustain the benefit of
a previous agent. Unless there are no viable alternatives to a known effec-
tive SGA with substantial cardiovascular adverse effects, patients with
significant cardiovascular risk factors generally should receive psycho-
tropic agents with minimal metabolic or cardiovascular adverse effects
(e.g., aripiprazole, ziprasidone, asenapine, iloperidone, lurasidone, or
FGAs with minimal glycemic or lipid-altering effects).
On the other hand, circumstances may arise in which the benefit of a
particular agent is so dramatic and unique (e.g., in the case of patients with
schizophrenia in whom clozapine exerts unequivocally greater efficacy
than other antipsychotics) that active treatment of an iatrogenic dyslipid-
emia may be advisable. In the case of clozapine, metabolic dysregulation
has been linked with serum norclozapine but not serum clozapine levels—
a finding that led to a preliminary randomized study of adjunctive fluvox-
amine (50 mg/day) or placebo added to clozapine (≤250 mg/day with flu-
voxamine or ≤600 mg/day with placebo), yielding greater reductions in
weight, serum glucose, and triglycerides (but not cholesterol) with flu-
voxamine cotherapy (Lu et al. 2004). Such a strategy demands careful
monitoring of other adverse effects (e.g., lowered seizure threshold, anti-
cholinergic effects), signs of toxicity, and clozapine levels, due to the po-
tential for marked increases in serum clozapine levels.
To date, surprisingly little study has been done of efforts to treat hy-
percholesterolemia or hypertriglyceridemia using lipid-lowering drugs
in patients who have developed dyslipidemias secondary to SGA ther-
apy. Landry et al. (2008) retrospectively examined outcomes in 18 cloza-
pine-treated schizophrenia patients with hyperlipidemia who were
followed for a mean of 4.4 years while taking lipid-lowering medications
(either pravastatin, atorvastatin, fenofibrate, gemfibrozil, or lovastatin).
Mean triglyceride and total cholesterol levels declined significantly from
baseline. Similarly, a 28-day open trial of omega-3 fatty acids (~10 g/day
of fish oil, containing 1.8 g/day of eicosapentaenoic acid and 1.2 g/day of
docosahexaenoic acid) among 28 clozapine recipients was associated
with a significant (22%) reduction in LDL and a 22% reduction in trigly-
cerides (Cantiano et al. 2006). These dosages are higher than the more cus-
tomary 2–4 g/day of omega-3 fatty acids sometimes recommended by
primary care physicians for hyperlipidemia. Notably, however, the clin-
126
TABLE 7–4. Changes in lipid parameters during FDA registration trials or randomized studies of second-generation
antipsychotics
Agent Changes in total cholesterol Changes in serum triglycerides
Aripiprazole Randomized trials in schizophrenia; median change In 6-week adjunctive trials for major depression:

in total cholesterol across five acute placebo- 5% increase from baseline. In 26-week randomized
controlled studies (n=860)=+1.0 mg/dL (Marder et trial in schizophrenia: –37.2 mg/dL (Pigott et al.
al. 2003). LDL declined by –5.1 mg/dL over 2003).
26 weeks (Pigott et al. 2003). Acute or long-term
schizophrenia FDA trials: no differences from
placebo.
Asenapine Acute bipolar or schizophrenia trials: mean changes Acute bipolar or schizophrenia trials: mean changes
from +1.1 to +0.4 mg/dL; 1-year open extension from –3.5 to +3.8 mg/dL; 1-year open extension
trial in schizophrenia: –6.0 mg/dL. trial in schizophrenia: –9.8 mg/dL.
Iloperidone Acute schizophrenia trials: net 0 mg/dL change –26.5 mg/dL (Weiden et al. 2008).
(Weiden et al. 2008).
Lurasidone Manufacturer’s short-term trials in schizophrenia: Manufacturer’s collective short-term trials in
across dosages, –8.2 mg/dL. schizophrenia: across dosages, –9.3 mg/dL.
Manufacturer’s longer-term studies: at 24 weeks, Manufacturer’s longer-term studies: at 24 weeks,
–4.2 mg/dL; at 36 weeks, –1.9 mg/dL; at 52 weeks: –13.6 mg/dL; at 36 weeks, –3.5 mg/dL;
–3.6 mg/dL. at 52 weeks, –6.5 mg/dL.
Cardiovascular System
TABLE 7–4. Changes in lipid parameters during FDA registration trials or randomized studies of second-generation
antipsychotics (continued)
Agent Changes in total cholesterol Changes in serum triglycerides
Olanzapine +21.1 mg/dL over 24 weeks (Newcomer et al. 2009). +30.9 mg/dL over 24 weeks (Newcomer et al. 2009).
+9.4±2.4 mg/dL in CATIE (Lieberman et al. 2005). +40.5±8.9 mg/dL in CATIE (Lieberman et al. 2005).
Paliperidone <0.1 mg/dL across three 6-week trials in <0.1 mg/dL across three 6-week trials in
schizophrenia (Meltzer et al. 2008). schizophrenia (Meltzer et al. 2008).
Quetiapine +13.1 mg/dL over 24 weeks (Newcomer et al. 2009). +21.2±9.2 mg/dL in CATIE (Lieberman et al. 2005).
+6.6±2.4 mg/dL in CATIE (Lieberman et al. 2005).
Risperidone –1.3±2.4 mg/dL in CATIE (Lieberman et al. 2005). –2.4 ±9.1 mg/dL in CATIE (Lieberman et al. 2005).
Ziprasidone –8.2±3.2 mg/dL in CATIE (Lieberman et al. 2005); –16.5±12.2 mg/dL in CATIE (Lieberman et al. 2005);
median change of –14.5 mg/dL from baseline in median change of –37.0 mg/dL from baseline in
acute industry trials for psychosis. acute industry trials for psychosis.
Note. CATIE= Clinical Antipsychotic Trials of Intervention Effectiveness; FDA =U.S. Food and Drug Administration; LDL= low-
density lipoprotein.
127
TABLE 7–5. Risk determinants for metabolic syndromea
Risk factor Defining level
Central obesityb Waist circumference

Men ≥90 cm in South Asians, Chinese, or
Japanese; ≥94 cm in Europids
Women ≥ 80 cm
plus any two of the following factors:
Triglycerides ≥150 mg/dL
HDL cholesterol
Men <40 mg/dL
Women <50 mg/dL
Blood pressure ≥130/≥85 mm Hg
Fasting glucose ≥100 mg/dL
Note. HDL=high-density lipoprotein.
aBased on the International Diabetes Foundation Consensus Worldwide Def-
inition of the Metabolic Syndrome. Brussels, Belgium, IDF Communications,

2006, pp. 1–24.
bCan be assumed if BMI > 30 kg/m2
ical end-point data do not robustly demonstrate the efficacy of omega-3

fatty acids to reduce the risk for coronary heart disease, and they are not
considered first-line therapies for diagnosed hyperlipidemia.
Ostensibly, it seems a simple enough proposition for psychiatrists to
prescribe lipid-lowering drugs and monitor relevant safety labs for
their patients who develop iatrogenic dyslipidemias. However, proba-
bly the most compelling reason to pursue lipid-lowering medications in
collaboration with a patient’s primary care physician rests on the need
to further risk-stratify a hyperlipidemic patient for cardiovascular dis-
ease (e.g., on the basis of additional factors such as blood pressure,
smoking status, family history of heart disease, and additional param-
eters such as C-reactive protein [CRP; an indicator of chronic inflamma-
tion that may signal increased risk for a myocardial infarction] or stress
testing). Lipid-lowering drugs are usually prescribed when other signif-
icant risk factors for coronary artery disease are present and when diet
and exercise alone have proved insufficient or unsuccessful in lowering
overall risk for a myocardial infarction.
The first level of intervention for weight gain and dyslipidemias
continues to be lifestyle modification (i.e., aerobic exercise lasting about
4 hours/week, dietary changes that include the minimization of simple

sugars such as fructose, and elimination of smoking). The ATP III panel
advises initiating lipid-lowering drugs based on the number of coro-
nary heart disease risk factors and the patient’s LDL levels, as summa-
rized in Table 7–6.
Statins vary in the extent to which they reduce LDL, and the magni-
tude of desired LDL reduction may depend on the presence and extent of
other cardiac risk factors. Dosages may vary depending on the presence
of additional factors (e.g., comorbid hypothyroidism), and all statins may
require monitoring of liver enzymes and the clinical emergence of myal-
gias (which could reflect rhabdomyolysis).
Psychiatrists need to be aware of the risks and benefits of psychotro-
pic drugs that may cause dyslipidemias, weight gain, or glycemic dys-
regulation, and they should collaborate proactively with primary care
physicians when the observed psychiatric benefits are substantial and
not easily re-created by an alternative medication. To that end, psychi-
atrists should be conversant with the use of available lipid-lowering
agents, their specific indications (e.g., including dosing variations and
the extent to which statins can reduce triglycerides as well as LDL), and
relative safety profiles (Table 7–7).
Edema
General Recommendations. Clinicians should be aware of
psychotropic drugs that may be associated with peripheral edema
and assure the absence of other etiologies (i.e., cardiogenic factors,
hepatic dysfunction, lymphatic obstruction, nephrotic syndrome,
hypothyroidism) by history taking, physical examination, and ap-
propriate laboratory measures (i.e., thyroid-stimulating hormone,
serum protein, liver enzymes, urinalysis). After determining the ab-
sence of other noniatrogenic causes, diuresis may be advisable as
an initial step in management.
Peripheral edema has a wide differential diagnosis that can include nu-
merous drug-induced etiologies. It may result from a number of drug
classes, including vasodilators (e.g., β-blockers and α1-adrenergic receptor
antagonists), calcium channel blockers, NSAIDs, estrogen-containing com-
pounds, and thiazolidinediones. The mechanisms by which some psycho-
tropic agents may cause peripheral edema are not well understood,
although it is thought that extravasation from capillary beds in the lower
extremities may result from vasodilation caused by α 1-blocking drugs,
TABLE 7–6. Common criteria by which lifestyle changes or

pharmacotherapy is undertaken for hyperlipidemia
LDL level
Lifestyle changes Drug therapy

Risk category LDL goal usually initiated usually considered
Presence of CHD or < 100 mg/dL ≥100 mg/dL ≥ 130 mg/dL

multiple risk
equivalents
≥ 2 risk factors < 130 mg/dL ≥130 mg/dL ≥130–160 mg/dL
0–1 risk factors < 160 mg/dL ≥160 mg/dL ≥ 190 mg/dL
Note. CHD =coronary heart disease; LDL =low-density lipoprotein.
such as antipsychotics. Edema caused by some GABAergic anticonvul-

sants, such as divalproex, gabapentin, or tiagabine, has been hypothesized
to result from direct GABAergic effects on peripheral vascular resistance.
Case reports of lithium-associated peripheral edema date to the early
1970s and are thought to reflect redistribution of sodium from the intra-
cellular to the extracellular compartment (water follows sodium) or alter-
ations in renal tubular absorption of sodium. The phenomenon does not
appear related to serum lithium levels or dosing toxicity and may variably
resolve either spontaneously, via dosage reductions, or through coadmin-
istration of a potassium-sparing diuretic such as amiloride 5 mg bid.
Manufacturers’ package insert information identifies peripheral
edema as an uncommon side effect associated with olanzapine (3%) and
divalproex (1%–5%), in the latter often arising during long-term ther-
apy. Edema has also been reported in postmarketing studies during
treatment with quetiapine, ziprasidone, risperidone, gabapentin, esci-
talopram, trazodone, and mirtazapine. Case reports also have described
peripheral edema arising during cotherapy with divalproex plus ris-
peridone or divalproex plus quetiapine.
The evaluation of peripheral edema involves the following consid-
erations, which can greatly facilitate communication exchange and col-
laboration with primary care physicians when appropriate.
• Is the edema unilateral or bilateral? Unilateral edema in a lower extrem-

ity suggests an etiology that is less likely pharmacological than struc-
tural-anatomical (e.g., deep venous thrombosis, pelvic malignancies,
lymphedema) or infectious (e.g., cellulitis).
• Is there a suggestion of cardiopulmonary (rather than medication-induced)

origin? Edema caused by congestive heart failure or pulmonary hy-
pertension will typically present with physical examination findings
involving the lungs (e.g., wheezing or rales), heart (e.g., presence of
an S3 gallop), head and neck (e.g., jugular venous distension), or ab-
domen (e.g., hepatomegaly in right-sided heart failure). The presence
of jugular venous distension suggests either a cardiac or pulmonary
origin or the possibility of acute renal failure.
• Is the onset acute or chronic? Edema caused by medications typically
has a relatively acute onset in close proximity to the initiation of a
suspected causal medication. By contrast, chronic lower-extremity
edema in adults over age 50 is most often caused by venous insuffi-
ciency.
• Are electrolyte abnormalities present? Hyponatremia may lead to pe-
ripheral edema due to fluid overload (e.g., water intoxication from
polydipsia).
• Is an eating disorder present? Rebound fluid retention can occur from
alternating patterns of dehydration, vomiting, and laxative or di-
uretic abuse.
• Are serum protein and albumin normal? Peripheral edema that is likely
related to medications typically involves normal serum protein lev-
els. Other medical etiologies of peripheral edema with normal serum
protein levels include severe hypothyroidism, lymphedema, and an-
gioedema (see the section “Allergic Reactions and Angioedema” in
Chapter 19, “Systemic Reactions”). The presence of low serum pro-
tein and albumin raises the suspicion of hepatic or renal disease or of
severe malnutrition.
• Is proteinuria present? Low serum protein or albumin levels with pro-
teinuria point to nephrotic syndrome.
• Are liver enzymes normal? In the absence of proteinuria, abnormal
liver enzymes suggest primary hepatic disease (e.g., cirrhosis).
Table 7–8 summarizes key points for psychiatrists in the assessment and
management of peripheral edema.
If the absence of other medical etiologies has been established, the cli-
nician can treat drug-induced edema—often a benign phenomenon—
either conservatively (i.e., by leg elevation or compression stockings) or
with the short-term use of a diuretic. Pitting pretibial edema caused by
antipsychotics or anticonvulsants may respond to a brief (e.g., 3- to 5-day)
course of furosemide 10–40 mg/day or spironolactone 50–100 mg/day
[maximum 100 mg qid]). Generally, monitoring serum potassium levels
is unnecessary in a normokalemic individual who begins a short course of
132
TABLE 7–7. Lipid-lowering medications
Indication or usual Common

Agent clinical profile Dosing range adverse effects Laboratory monitoring
Statins (HMG-CoA First-line therapies, usually — Myalgias; rare risk for Serum ALT monitoring is
reductase inhibitors) recommended for LDL rhabdomyolysis or recommended at baseline

≥190 mg/dL or LDL ≥ 160 mg/ diabetes mellitus and periodically
dL and positive family history thereafter.
of premature coronary artery
disease or ≥2 coronary risk
factors present in adolescents
Atorvastatin — 10–80 mg/day — —
Fluvastatin — 20–80 mg/day — —
Lovastatin — 20–80 mg/day — —
Pravastatin — 20–40 mg/day — —
Rosuvastatin The most potent statin; FDA 5–40 mg/day — —

approved for men > age 50 or
women > age 60 with normal
LDL but elevated CRP and one
other risk factor for coronary
artery disease (e.g., smoking,
low HDL, family history)
TABLE 7–7. Lipid-lowering medications (continued)

Statins (HMG-CoA
reductase inhibitors)
(continued)
Simvastatin Lowers LDL by > 30%; 20–80 mg/day — —
appropriate in diabetes or
known heart disease as well as
primary or secondary
prevention indications
Omega-3 fatty acids Reduce triglycerides (FDA ≥1,000 mg/day Fishy aftertaste, GI upset, None
approved for triglycerides eructation, potential risk
>500 mg/dL) and may increase for increased bleeding
HDL; have not been shown to time
reduce LDL or to lower risk for
myocardial infarction or
cardiovascular mortality
Lovazaa Hypertriglyceridemia — — None
133
134

Fibrates Reduce triglycerides and VLDL — Contraindicated in setting May cause elevation in
levels, increase HDL; typically of hepatic or renal disease; serum creatinine; periodic

second-line agents after statins; may cause GI upset, monitoring is
reduce risk of nonfatal diarrhea, abdominal pain, recommended, with
myocardial infarctions but not myalgias discontinuation if
fatal myocardial infarctions creatinine rises exceed
30% (Sica 2009).
Clofibrate — 1,000 mg bid — —
Fenofibrate — 200 mg/day — —
Gemfibrozil — 600 mg bid — —
Niacin (Vitamin B3) Reduces LDL and triglycerides; 500–2,000 mg/ Skin flushing, rashes; rare Periodic monitoring of
increases HDL day hepatic toxicity associated blood glucose, uric acid,
with slow-release and liver enzymes.
formulations, rare blurred
vision, nausea, vomiting,
exacerbation of peptic
ulcers
Extended-release — 1–2 g/day — —
nicotinic acid

Combination regimens
Atorvastatin/ Combination treatment for 2.5/10–10/ Constipation, diarrhea, As per statins.
amlodipine hypercholesterolemia and 80 mg/day nausea, headaches,
hypertension dizziness, flushing,
fatigue, weakness
Ezetimibe/simvastatin Decreases total cholesterol, LDL 10/10–10/ Headache, arthralgias, As per statins.
cholesterol, apolipoprotein B, 80 mg/day GI upset
triglycerides, and non-HDL
cholesterol; increases HDL
Lovastatin/niacin ER Indicated when treatment with 500–2,000 mg/ Flushing, headaches, pain, As per statins and niacin.
both lovastatin and niacin ER is day nausea, myalgias,
appropriate infection
Simvastatin/niacin ER Indicated when simvastatin 500/20–2,000/ Headache, arthralgias, As per statins and niacin.
or niacin alone is considered 40 mg/day gastrointestinal upset,
inadequate flushing
Note. ALT= alanine aminotransferase; bid =twice daily; CRP=C-reactive protein; ER =extended release; FDA= U.S. Food and Drug Administra-
tion; GI=gastrointestinal; HDL=high-density lipoprotein; HMG-CoA= 3-hydroxy-3-methylglutaryl coenzyme A; LDL =low-density lipoprotein;
VLDL =very-low-density lipoprotein.
aA 1-g capsule contains 47% eicosapentaenoic acid and 38% docosahexaenoic acid.
135
TABLE 7–8. Key points in the management of drug-induced

peripheral edema
Determine the timing, onset, location, and extent of edema. Clarify if
patient has a history of trauma, surgery, or predisposing medical
conditions (e.g., past malignancy or liver disease) that may indicate
etiologies other than drug-induced edema.
By physical examination, determine location of edema (lower

extremities [ankle or pretibial], upper extremities, sacral regions when
recumbent), bilaterality, and degree of pitting. The presence of
ulcerations or warmth may suggest cellulitis. Determine normal
bilateral pedal and popliteal pulses. Palpable calf cords or tenderness,
calf warmth, or pain on dorsiflexion may suggest deep venous
thrombosis. Affirm normal cardiac and breath sounds by auscultation,
and the absence of jugular venous distension. Physical examination
may also help to assure the absence of ascites or hepatomegaly.
Assure that serum protein, liver enzymes, and electrolytes are normal;
determine the absence of proteinuria (by urinalysis).
Consider diuresing normokalemic and normonatremic patients with a

brief (e.g., 5-day) course of furosemide or spironolactone.
Track progress of diuresis by measuring baseline and daily weights.
Obtain primary medical consultation if edema persists or if drug

discontinuation and diuresis fail to resolve the problem, or when
indicated when laboratory abnormalities or physical examination
findings suggest a noniatrogenic underlying process.
furosemide, although this may be warranted during longer-term therapy.

Thiazide diuretics, such as hydrochlorothiazide 25 mg/day, also may be
used but tend to produce a less robust diuresis than does furosemide.
In the case of lithium-associated peripheral edema, the potassium-
sparing diuretic amiloride (e.g., 5 mg bid) is preferred to diuretics that act
on the distal convoluted tubule, such as hydrochlorothiazide, because
amilorides are less likely to raise serum lithium levels. Loop-acting diuret-
ics (e.g., furosemide) also have not been shown to increase serum lithium
levels (Jefferson and Kalin 1979). If electing to diurese peripheral edema
with a thiazide diuretic, the clinician might choose to reduce a standing
lithium dosage or to monitor serum lithium levels more closely depending
on the existing lithium dosage and duration of diuretic therapy.
Referral to a primary care doctor should occur when causes other

than drug-induced edema are suspected, laboratory abnormalities or
physical examination findings suggest causes other than drug-induced
bilateral edema, or edema persists despite diuresis.
The clinician should keep in mind that cessation of a likely causal
agent typically leads to resolution of drug-induced edema, and the de-
cision to discontinue a presumed offending agent (rather than manage
the side effect of edema) depends on the persistence of the problem, re-
currence after response to acute treatment of the edema, and availability
of viable alternative primary psychotropic compounds.
Hypertension
General Recommendations. Patients who receive psychotro-
pic drugs that can alter blood pressure should have their blood
pressure monitored on a regular basis by the prescriber. Sympath-
omimetic (e.g., noradrenergic) agents reported to cause hyperten-
sion should not be administered in patients with unstable
hypertension. Present recommendations are not to use sublingual
or oral nifedipine for probable drug-induced hypertensive crises,
but rather to obtain blood pressure measurements for suspected
hypertension-induced signs (e.g., headache) and to seek medical
attention as appropriate.
Catecholaminergic agents, including psychostimulants and noradrener-

gic agents (e.g., SNRIs, TCAs, atomoxetine, and bupropion), carry the
risk of raising blood pressure and increasing heart rate via their sympath-
omimetic effects. In premarketing studies of venlafaxine XR (across dos-
ages from 75 to 375 mg/day), sustained hypertension (defined as a dias-
tolic blood pressure >90 mm Hg and ≥10 mm Hg above baseline, on three
consecutive occasions) occurred in 3% of patients with major depression,
with incidence rates of <1% in patients with anxiety disorders (i.e., panic
disorder, generalized anxiety disorder, or social anxiety disorder). Inci-
dence rates of sustained diastolic hypertension rose proportionally with
increasing dosages, reaching 13% at dosages >300 mg/day. Among pa-
tients treated with venlafaxine XR across diagnoses in FDA registration
trials, 1% of patients had a ≥20 mm Hg rise in systolic blood pressure
(manufacturer’s package insert, Wyeth Pharmaceuticals). The manufac-
turer of venlafaxine advises against initiating therapy in patients with
poorly controlled preexisting hypertension, and either decreasing the
dosage or discontinuing therapy in patients with new-onset hyperten-
sion arising during treatment with venlafaxine.
Rates of sustained diastolic hypertension with desvenlafaxine (0.7%–

1.3%) or venlafaxine XR (0.5%–3%) are lower than the dose-related rates
seen with venlafaxine IR (3%–13%). The SNRI duloxetine was associated
with trivial changes in diastolic blood pressure (<1 mm Hg) across its in-
dications at dosages ≤120 mg/day. The time course for developing hy-
pertension that is likely attributable to an SNRI has not been identified
from clinical trials, but hypertension may be dose dependent and more
likely to arise sooner rather than later after treatment initiation. In normo-
tensive patients who are stably dosed on an SNRI but who later develop
elevated blood pressure, investigation and treatment of other causes of
hypertension may be warranted before it is advisable or necessary to dis-
continue a long-standing SNRI.
As reported in manufacturers’ prescribing information, the inci-
dence of hypertension with bupropion is <1%, which is no different
from placebo. In FDA registration trials, hypertension occurred in only
1% of subjects taking mirtazapine, despite its noradrenergic properties,
and it occurred less frequently than in subjects taking TCAs (Watanabe
et al. 2010).
Hypertensive crises are of well-known concern during pharmaco-
therapy with MAOIs. A contentious literature has emerged on the pros
and cons of instructing MAOI recipients to carry 10-mg nifedipine cap-
sules to swallow, bite and swallow, or place sublingually in the event of
developing a headache that could be a manifestation of a hypertensive
crisis. A 1996 review challenged the safety and efficacy of this practice,
citing an increased risk for adverse cardiovascular or cerebrovascular
consequences—with little evidence of benefit—from the practice of in-
structing patients to take nitroglycerin capsules if headaches occur dur-
ing MAOI therapy (Grossman et al. 1996). Another issue regarding
cardiovascular safety with MAOIs involves the question about the ne-
cessity of discontinuing their use before surgery (or electroconvulsive
therapy) in which general anesthesia is used. The manufacturers of tran-
ylcypromine, phenelzine, isocarboxazid, and transdermal selegiline
caution against the use of MAOIs during surgery that involves general
anesthesia and recommend discontinuing an MAOI at least 10 days be-
fore undergoing elective surgery with general anesthesia. However, con-
temporary studies report no differences in blood pressure and heart rate
attributable to the continued use of MAOIs during surgery involving
general anesthesia, and most experts believe that discontinuing MAOIs
preoperatively is not routinely necessary (El-Ganzouri et al. 1985). Nev-
ertheless, cardiovascular safety may be jeopardized by the use of inject-
able sympathomimetic vasoconstrictors such as epinephrine during
surgical procedures in patients taking MAOIs.
Myocarditis and Cardiomyopathy

General Recommendations. Clinicians should recognize
that myocarditis is a rare adverse effect with clozapine and should
be alert to its presenting signs (e.g., fever, chest pain, shortness of
breath), particularly during the first 1–2 months after treatment
initiation. ECG and measurement of serum troponin or creatine
kinase-MB and CRP should be obtained, along with consultation
from a cardiologist in the setting of laboratory abnormalities.
Clozapine should be discontinued and not reintroduced when
myocarditis occurs.
Clozapine carries a known, rare risk for myocarditis (■), which arises
through poorly understood mechanisms that may include clozapine-
induced release of inflammatory cytokines, hypercatecholaminemia, and
type I IgE–mediated acute hypersensitivity reactions (Merrill et al. 2006).
Eosinophilia appears not to be a useful parameter in diagnosing cloza-
pine-induced myocarditis, although elevated CRP (>100 mg/dL) has
been reported even when troponin levels are normal. The majority of
cases become manifest within the first 4–8 weeks of treatment initiation,
and patients can present with a variety of signs and symptoms, including
fever, chest pain, shortness of breath, tachycardia, and leukocytosis. Im-
portantly, 20% of individuals may develop a benign and transient fever
during clozapine initiation, making it important for clinicians to pay
close attention to other systemic features that could signal the presence of
myocarditis, NMS, or other correlates of fever during clozapine ther-
apy—particularly given the rarity of myocarditis (with a reported inci-
dence of 0.015%–0.188%) (Merrill et al. 2006). In their systematic review
of the phenomenon, Merrill et al. (2006) advised that for clozapine recip-
ients who develop chest pain, fever, dyspnea, or flulike symptoms, clini-
cians should consider obtaining an ECG (observing for ST segment
elevation) and serum troponin or creatine kinase-MB. Consultation with
a cardiologist is advisable in the presence of abnormal parameters.
Management of clozapine-induced myocarditis hinges on discontin-
uation of clozapine without subsequent rechallenge, as well as the possi-
ble use of β-blockers (e.g., metoprolol), ACE inhibitors, and diuretics; the
role of corticosteroids appears more controversial (Merrill et al. 2006).
Case reports also have described myocarditis occurring rarely during
treatment with quetiapine, potentially as a drug hypersensitivity reaction
associated with eosinophilia, leukopenia, and thrombocytopenia. Suc-
cessful rechallenge with clozapine after resolution of myocarditis has
been anecdotally described.
Orthostatic Hypotension
drugs that can cause orthostatic hypotension, typically resulting
from α 1-adrenergic blockade. Orthostatic hypotension may not
necessarily be dose related and may represent a persistent phe-
nomenon during continued administration of a causal agent.
Blood pressure and heart rate should be measured while the pa-
tient is sitting and standing, several minutes apart, to evaluate
the presence and extent of autonomic changes. Increased oral
hydration likely will not counteract pharmacological orthostatic
hypotension, but avoiding dehydration may help to diminish ex-
acerbation of the phenomenon. Patients should be advised to
get up slowly from sitting or supine positions. Significant ortho-
static hypotension, particularly in patients with low resting
blood pressure or cardiac disease, may warrant cessation of the
causal agent.
Orthostatic hypotension may be associated with a wide range of psy-

chotropic agents that cause vasodilation by blocking peripheral vascular
α 1-adrenoreceptors. These agents include TCAs, MAOIs (e.g., tranyl-
cypromine at dosages >30 mg/day), mirtazapine, atomoxetine, duloxe-
tine, venlafaxine, desvenlafaxine, and SGAs, as well as cannabinoids.
Antihypertensive α1-blocking drugs such as prazosin (used sometimes to
counteract nightmares; see the section “Nightmares and Vivid Dreams”
in Chapter 18, “Sleep Disturbances”) and terazosin (used sometimes to
counteract hyperhidrosis; see the section “Hyperhidrosis” in Chapter 8,
“Dermatological System”) may cause orthostatic hypotension and syn-
cope, particularly after a first dose. Patients who report dizziness upon
standing or sitting after rising from a supine position should be examined
for postural hypotension and tachycardia. Clinicians should consider
other nonpharmacological etiologies when relevant, such as dehydra-
tion, prolonged bed rest, dysautonomias, anemia, and Parkinson’s dis-
ease. The use of nonpsychotropic vasodilators or diuretics also may play
contributing roles. The differential diagnosis of orthostatic hypotension
also includes vasovagal syncope, as might occur when sudden-onset
light-headedness includes visual, auditory, and other sensory abnormal-
ities. Conservative management of pharmacologically induced ortho-
static hypotension involves counseling patients to rise slowly from seated
or supine positions, avoid dehydration, and assure the safe use of any
concomitant drugs that may further cause anticholinergic, vasodilatory,
arrhythmogenic, or extrapyramidal adverse effects.
8
Dermatological
System
Alopecia
General Recommendations. Mineral supplements (e.g., zinc
and selenium) or topical minoxidil may be worth attempting for
the treatment of alopecia, but scalp hair loss attributable to psy-
chotropic medications may be difficult if not impossible to coun-
teract except through cessation of the suspected causal agent.
Diffuse scalp hair loss (telogen effluvium) has been reported in conjunc-
tion with several psychotropic medications, perhaps most notably with
divalproex (incidence from 12% to 24%), lithium (incidence up to 10%),
and carbamazepine (incidence up to 6%) (McKinney et al. 1996), and
more rarely with fluoxetine, sertraline, venlafaxine, fluvoxamine, am-
phetamine, and mirtazapine. Reports also exist of hair loss occurring
with one SSRI but not another in the same patient. A World Health Or-
ganization database for international drug monitoring also identified
141
337 cases of suspected lamotrigine-associated alopecia through April 1,

2009, occurring most often in women age <40 and often resolving after
drug cessation (Tengstrand et al. 2010).
Hair loss has been reported as a relatively rare adverse effect of several
medications, which include isotretinoin, allopurinol, androgens (testos-
terone formulations), anticoagulants, β-blockers, calcium channel block-
ers, colchicine, efavirenz, ergot alkaloids (migraine prophylaxis), meth-
ylphenidate, NSAIDs, oral contraceptives, propylthiouracil, ribavirin,
perphenazine, some antidepressants (SSRIs, TCAs), and topiramate. A
number of medical causes of alopecia warrant investigation before assum-
ing that hair loss is an adverse effect of a suspected psychotropic agent.
These include hypothyroidism, autoimmune diseases such as systemic lu-
pus erythematosus or rheumatoid arthritis, vitiligo, and ulcerative colitis.
Chemical damage caused by permanent curls or other caustic cosmetic
products may cause hair loss in some individuals. Patchy areas of hair loss
or hair loss in nonscalp areas might prompt clinicians to consider the pos-
sible presence of trichotillomania. Sudden physical or emotional stresses
can be associated with hair loss over a period of weeks to months.
Alopecia from divalproex has been suggested to arise from interfer-
ence with absorption of dietary zinc and selenium, for which supplemen-
tation (25–50 mg/day of zinc and 10–20 µg/day of selenium) is sometimes
recommended. However, in clinical practice, the efficacy of this strategy
may not be robust. Cessation of divalproex generally halts the problem.
The extended-release formulation of divalproex has been suggested by
some to minimize the potential for alopecia (as reflected in a 7% incidence
of alopecia during trials of Depakote ER for migraine headache, as com-
pared with 13%–24% with Depakote DR for complex partial seizures),
possibly via more distal absorption of the drug with lesser likelihood to in-
terfere with gastrointestinal absorption of dietary minerals. Dosage reduc-
tions generally have not been shown to reverse drug-associated alopecia,
although comparative studies of high- versus low-dose divalproex for
complex partial seizures demonstrated more frequent alopecia among
high-dose (24%) than low-dose (13%) recipients. Other clinicians advocate
the use of topical minoxidil as a potential remedy; this option is likely safe,
although it has not been systematically studied for this purpose.
Hyperhidrosis
General Recommendation. For sweating induced by SSRIs,
SNRIs, or TCAs, clonidine 0.1 mg/day or terazosin 1–2 mg/day may
be more effective than anticholinergic remedies such as benz-
Dermatological System 143
tropine 1 mg/day. Preliminary data also support the use of oxybuty-

nin 5 mg tid.
Excessive sweating (hyperhidrosis) occurs in up to 20% of individuals

who take antidepressants, both as a daytime phenomenon or as night
sweats, and may be dose related. It does not appear to dissipate during
prolonged treatment but does remit when the causal antidepressant is
stopped. Mechanisms thought to account for this phenomenon include
dysregulation of cholinergically innervated sweat glands and dysregula-
tion of the hypothalamic thermoregulatory center, mediated by pro-
dopaminergic tone with reciprocal downregulation of serotonergic tone.
Consequently, the most frequently employed strategies to counteract
antidepressant-induced hyperhidrosis include anticholinergic agents,
such as benztropine dosed at 1 mg/day (although its apparent benefit
may be transient), and antiadrenergic agents, such as the α2-adrenergic
agonist clonidine (0.1 mg/day) or the α1-adrenergic antagonist terazosin
(1–2 mg/day), with visible efficacy within 3–4 weeks. The likelihood of se-
dation from either of the latter two agents would favor their use in a single
nighttime dose. Other anticholinergic drugs that may be of value to coun-
teract iatrogenic hyperhidrosis include glycopyrrolate 1 mg qd or bid or
oxybutynin 5–10 mg qd or bid. Case reports also identify benefit with ad-
junctive mirtazapine (up to 60 mg/day) or the serotonin-blocking drug
cyproheptadine 4 mg qd or bid, without reversing antidepressant efficacy.
Adjunctive aripiprazole 10 mg/day, but not ziprasidone, has been
reported to alleviate daytime hyperhidrosis caused by fluoxetine or du-
loxetine, with a mechanism hypothesized to involve both its serotonin
type 2A (5-HT2A) antagonism and its dopaminergic partial agonism as
modulating the hypothalamic thermoregulatory center (Lu et al. 2008).
Photosensitivity
General Recommendations. Clinicians should counsel pa-
tients about the potential for sun exposure to cause burnlike or
hyperpigmentation reactions to antipsychotics (mainly FGAs)
and less often to TCAs. Adequate prophylactic use of sunscreen is
essential when patients are outdoors during warmer months.
Photosensitivity reactions should be treated by use of conserva-
tive interventions (e.g., aloe lotions) and avoidance of further
sun exposure until the resolution of signs and symptoms.
Phototoxic (i.e., nonimmune-mediated) sunburn-like reactions have long

been recognized after sun exposure in patients taking FGAs (particularly
chlorpromazine, occurring in up to 25% of patients, typically with dos-

ages ≥400 mg/day) (Harth and Rapoport 1996). Case reports of photo-
toxic reactions also exist with some SGAs, including risperidone and
clozapine. Photosensitivity-induced hyperpigmentation has been de-
scribed as a relatively rare phenomenon in patients taking TCAs.
Adequate prevention of phototoxic reactions involves counseling
patients who take antipsychotic medications to minimize sun exposure
and make use of full skin protection from ultraviolet A and B (UVA,
UVB) wavelengths. Typical treatment for photosensitivity reactions
should include avoidance of further sun exposure and application of
cool, wet dressings and emollient (e.g., aloe-based) lotions. Topical cor-
ticosteroids, NSAIDs, and oral antipruritic ( e.g., antihistamine) agents
are also sometimes helpful. Oral corticosteroids are more rarely indi-
cated in the setting of more severe or persistent phototoxic reactions
that do not remit with more conservative management.
Pruritus
General Recommendations. Evaluation of acute pruritus
should include a general medical assessment with awareness of
the most common dermatological and systemic conditions other
than drug rashes that may be causal.
Generalized pruritus in the absence of a visible skin rash can occur with
a variety of psychotropic agents, although the differential diagnosis of
pruritus with respect to underlying medical etiologies is considerable.
The sheer presence or absence of pruritus conveys little information
about the nature of a suspected drug rash, other than that certain dis-
tinct types of rashes are usually pruritic (notably, atopic or allergic con-
tact dermatitis, psoriasis, and seborrheic dermatitis); whether or not a
rash is pruritic does not help to determine if it is likely drug related.
Pruritic drug reactions may be allergic and usually are morbilliform or
urticarial (see definitions in Table 8–1).
The evaluation of patients who complain of itching should include
assessment for the presence of skin lesions, which potentially could be
self-inflicted from scratching or skin picking. Psychiatrists, in particu-
lar, should be alert to phenomena such as delusional parasitosis or so-
matoform pain disorders that involve complaints about unusual skin
sensations. Skin picking that can cause excoriated lesions (dermatillo-
mania) is less likely to be iatrogenic than to be a manifestation of under-
lying conditions such as impulse control disorders, body dysmorphic

disorder, and obsessive-compulsive or other anxiety disorders.
Drugs known to cause pruritus include opiates, aspirin, NSAIDs, and
drugs that may cause hepatotoxicity. Clinicians should consider whether
an allergic, pruritic contact dermatitis is caused by environmental exposure
(e.g., to cosmetics, detergents, rosins, epoxy resins). Psychotropic drugs
(other than opiates or synthetic opiates such as tramadol) rarely cause pru-
ritus apart from idiosyncratic hypersensitivity reactions. In fact, some
SSRIs have been reported to improve pruritus associated with lymphoma,
uremia, cholestasis, and opiate use. Similarly, some antipsychotics with an-
tihistamine effects (notably, promethazine begun at 25 mg/day) are often
referred to as antiallergic neuroleptics for the treatment of pruritus.
Nonsedating antihistamines such as loratadine or cetirizine are gen-
erally safe interventions for nonspecific pruritus. Sedating antihistamines
such as hydroxyzine (25–100 mg at bedtime) or doxepin (10–25 mg at bed-
time) may be especially useful not only to counteract the degranulation of
mast cells in suspected allergic reactions but also for their anxiolytic prop-
erties. Pruritus also may be managed with the use of hypoallergenic, non-
alcohol-based skin lubricants; menthol-camphor-based topical agents
(e.g., Sarna lotion); or Aveeno oatmeal bath treatments.
Skin Rashes
General Recommendations. Any drug can cause a skin rash,
either from an allergic or a hypersensitivity reaction. Rashes should
be evaluated to determine their location, appearance, and probable
association with a suspected causal agent. Drugs suspected of caus-
ing a serious drug rash should be immediately discontinued, and
appropriate dermatological evaluation should be obtained.
General Evaluation
Psychiatrists may feel ill equipped to evaluate potential medication-
related skin rashes and to incorporate into their practice a working
knowledge of the nature and characteristics of common skin rashes
caused by psychotropic drugs. Although seeking formal consultation
from a dermatologist for certain types of rashes is often helpful, psychi-
atrists can and should be familiar with the language used to describe
the appearance of skin rashes, perform an initial assessment, and form
an impression about likely associations with prescribed psychotropic
medications on the basis of time course and appearance.
Upon discovering a skin rash, practitioners should obtain a basic pa-

tient history that identifies where the rash appears to be, when it began,
what current medications are being taken (and whether doses or adher-
ence have deviated from prescribed recommendations), and whether
other novel environmental exposures (including concomitant medica-
tions, botanicals, animals, insect bites, or skin care products) may be
contributing factors.
Allergic drug rashes usually arise within several days to a few weeks
after beginning a medication. True allergic reactions are type I (imme-
diate) hypersensitivity reactions mediated by IgE antibodies. These re-
actions require prior exposure to an allergen that sensitizes mast cells
and basophils, which, upon reexposure, degranulate and cause the re-
lease of histamine, leukotrienes, and prostaglandins that cause an in-
flammatory reaction. Drug rashes are highly unlikely to arise for the
first time after many months (or years) of stable exposure. A further
consideration involves the potential for an allergic reaction to the vehi-
cle coating the active drug (rather than the drug itself). If a rash occurs,
the clinician should consider whether it is a possible idiosyncratic reac-
tion in the aftermath of renewing an existing prescription, changing the
formulation (e.g., from extended to immediate release), or substituting
a generic for a branded product formulation.
A next step involves describing the appearance and location of a
rash. Appropriate terminology for describing the appearance of sus-
pected drug rashes is presented in Table 8–1, and common types of skin
rashes are described in Table 8–2.
The most commonly encountered true drug rashes appear on the
trunk and are exanthematous or morbilliform in appearance. Attention
should be paid to whether the area is flat or raised, bumpy, red, and
weepy or dry. An urticarial wheal-and-flare rash should be identified as
a probable allergic reaction, and the patient should be assessed for other
potentially serious manifestations of impending anaphylaxis, such as
laryngeal constriction or shortness of breath. Rashes that occur in a der-
matomal distribution are suggestive of varicella zoster (shingles), which
classically occurs with painful vesicular lesions but may also be non-
raised or pruritic.
Common topical steroids that are sometimes used to treat rashes
such as contact dermatitis are summarized in Table 8–3, grouped by rel-
ative strength.
TABLE 8–1. Descriptive terminology in assessing skin rashes
Term Description
Blanching Transient white discoloration of a skin lesion

that occurs with pressure
Bullous Fluid-filled blisters greater than 5 mm in
diameter
Confluent Lesions that intermingle, often with ill-defined
borders
Exanthematous Meaning “eruptive”; skin eruptions or rashes
(synonymous with
maculopapular)
Exfoliative Peeling or shedding of skin in flakes or scales
(also desquamative)
Lichenified Skin that has become thickened and leatherlike
Maculopapular Macular: flat and circumscribed (typically
(synonymous with <1 cm in diameter); papular: solid and
exanthematous) elevated above the surrounding skin
Morbilliform Rash that is measles-like in appearance
Pruritic Itchy rash
Pustular Visible collections of pus
Raised Rash that rises above skin level
Red Rash that indicates an inflammatory process
Ulcerative Inflamed areas with loss of surrounding tissue,
often surrounded by red, swollen, and tender
skin
Urticarial A wheal-and-flare reaction, often allergic in
origin (hives), involving red, raised, pruritic,
bumpy skin lesions
Weepy Lesions that exude a liquid, often in very small
droplets
148
TABLE 8–2. Common skin rashes
Rash Description Likely drug associations Common treatments
Acne (as caused or Red papules and pustules Lithium may cause or exacerbate Oral or topical antibiotics; benzoyl
exacerbated by peroxide cream or lotion; tretinoin

medications) (Retin-A)
Acne rosacea Red (inflammatory) diffuse facial None Oral or topical antibiotics to help
rash reduce episodes
Atopic dermatitis Scaly, itchy, red areas commonly None Topical hydrocortisone,
(a type of eczema) affecting the face, neck, elbows, betamethasone, or fluticasone
inner knees, and ankles; may burn creams or ointments commonly
or itch recommended
Bacterial rashes Red, itchy, patchy skin areas that None Topical antibiotics often ineffective;
(e.g., impetigo, become pustular may require oral antibiotics
caused by local
staphylococcal
infection)
Contact dermatitis Skin irritation usually caused within None Medium- to high-strength topical
12–24 hours of reexposure to a specific steroid ointments
allergen, following an initial expo-
sure (sensitization); represents a type
IV (delayed-type hypersensitivity
[non–antibody-mediated]) reaction;
typically manifests as papular, vesic-
ular, scaly lesions
Dermatological System
TABLE 8–2. Common skin rashes (continued)
Fungal rashes Scaly, exfoliative appearance, or may None Antifungal topical creams
(e.g., candida) appear within skin folds (e.g., (e.g., clotrimazole 1% or
under the breast, inner groin) as terbinafine 1%)
red, flat, and tender to touch; may
have small pustular edges
Hives or urticaria Raised, itchy, wheal-and-flare reac- Any drug Antihistamines

tion; may blanch; usually but not
necessarily an allergic reaction; rep-
resents a type I (IgE-mediated)
hypersensitivity reaction
Psoriasis Heritable condition involving red or Lithium often may exacerbate; less Topical corticosteroids, vitamin D
pink, dry, flaky, patchy, or raised commonly (case reports) associated creams (e.g., calcipotriene),
skin areas, usually nonpruritic; com- with carbamazepine, divalproex, topical retinoids, salicylic acid,
monly affecting knees, elbows, and fluoxetine, paroxetine coal tar, ultraviolet light, or
scalp psoralen plus ultraviolet A
Purpura Red or purple nonblanching discolor- Carbamazepine; otherwise unlikely Discontinuation of suspected
ations <1 cm in diameter caused by except with other drugs that cause causal agents and treatment of
bleeding under the skin, commonly immunologically mediated underlying vascular, platelet, or
resulting from infection, vasculitis, thrombocytopenia coagulation disorders
coagulopathies, or platelet disorders
149
150
TABLE 8–2. Common skin rashes (continued)
Seborrhea Red, itchy, exfoliative rash that Divalproex (incidence 1%–5%) Medicated shampoos, topical
affects skin areas containing antifungal agents (e.g.,

sebaceous glands (scalp, face, ketoconazole, clotrimazole),
and trunk) or topical steroids
Stevens-Johnson Systemic condition and May be caused by bupropion, Cessation of causal agent; systemic
syndromea dermatological emergency that carbamazepine, chlorpromazine, steroids sometimes administered
usually involves blistering, divalproex, lamotrigine, early in the course of illness;
burnlike lesions on oral and other venlafaxine monitoring of electrolytes;
mucocutaneous tissues, avoidance of suprainfections or
accompanied by fever, fatigue, sepsis
and pharyngitis
Viral rashes (e.g., Variable appearance and None Treatment of underlying disease
shingles caused by characteristics; shingles follows process
varicella zoster) dermatomal distributions;
postviral exanthematous rashes
may involve diffuse tiny red bumps
that may or may not be pruritic
Xerosis (dry skin) Dry, dull, flaky skin with visible None Nonprescription emollients (e.g.,
fine lines Lubriderm or Eucerin cream or
lotion)
Note. IgE =immunoglobulin E.
aStevens-Johnson syndrome is considered a milder variant of toxic epidermal necrolysis.
Dermatological System
TABLE 8–3. Topical steroids grouped from highest strength (Group I) to lowest strength (Group VII)
Group I Group II Group III Group IV Group V Group VI Group VII
Betamethasone Amcinonide Betamethasone Fluocinolone Desonide Desonide Hydrocortisone 1%

dipropionate 0.05% dipropionate acetonide 0.05% (Tridesilon, 0.05% (DesOwen (nonprescription)
0.25% (Diprolene) (Cyclocort) 0.05% 0.01%–0.2% DesOwen ointment) cream, lotion)
Hydrocortisone
(Diprosone) (Synalar, Synemol,
Clobetasol Desoximetasone Fluocinolone Fluocinolone 2.5%
Fluonid)
propionate 0.05% 0.25% (Topicort) Fluticasone acetonide acetonide 0.01% (nonprescription)
(Temovate) propionate Flurandrenolide 0.025% (Synalar, (Capex
Fluocinonide 0.05%
0.005% 0.05% (Cordran) Synemol cream) shampoo,
Diflorasone (Lidex)
(Cutivate) Derma-
diacetate 0.05% Hydrocortisone Fluticasone
Halcinonide 0.05% Smoothe/FS)
(Psorcon) Mometasone butyrate 0.1% propionate
(Halog)
furoate 0.1% (Locoid) 0.05% (Cutivate Prednicarbate
Halobetasol
(Elocon cream) 0.05%
propionate 0.05% Hydrocortisone
ointment) (Dermatop
(Ultravate) valerate 0.2% Hydrocortisone
cream, ointment)
Triamcinolone (Westcort) valerate 0.2%
acetonide 0.5% (Westcort cream) Triamcinolone
Mometasone furoate
(Kenalog, acetonide 0.025%
0.1% (Elocon Triamcinolone
Aristocort (Aristocort A
cream, lotion) acetonide 0.1%
cream) cream, Kenalog
(Kenalog, Aristocort
Triamcinolone lotion)
cream, lotion)
acetonide 0.1%
(Kenalog,
Aristocort A
ointment)
151
Lithium-associated psoriasis has been reported to improve with the

use of 4–6 g/day of omega-3 fatty acids or inositol 3–6 g/day. Case re-
ports have indicated that atopic dermatitis and nondrug-induced pso-
riasis are responsive to treatment with bupropion.
Clinicians sometimes wonder whether a history of a drug rash with a
particular medication class may help to predict the likelihood of the pa-
tient’s developing a future rash with a drug that has not previously been
taken (e.g., due to cross-sensitivity). For example, a history of rashes
with other anticonvulsants has been shown to confer a 3-fold increased
risk for developing a nonserious rash with lamotrigine (Hirsch et al.
2006), although a history of prior anticonvulsant-associated rashes ap-
pears less predictive for developing a rash with lamotrigine than with
other anticonvulsants (Alvestad et al. 2008). According to the manufac-
turer of lamotrigine, a history of rash with penicillin or sulfa antibiotics
increases the risk for nonserious rashes with lamotrigine.
Serious Rashes
Serious rashes require immediate evaluation and determination of the
presence of an allergic reaction that could progress to anaphylaxis, a
nonallergic systemic hypersensitivity reaction for which a suspected
causal agent should be promptly discontinued, or an altogether unre-
lated phenomenon that may require independent medical management
(e.g., poison ivy, shingles). The time course for developing a rash repre-
sents one element of its evaluation, because rashes that occur many
months or years after drug initiation are unlikely to be iatrogenic. Seri-
ous rashes have been recognized in particular with lamotrigine and
with carbamazepine—agents that both carry black box warnings in
their manufacturers’ product information materials regarding the po-
tential for developing a serious rash. Additionally, a relatively small
number of pediatric patients receiving the wakefulness-promoting
agent modafinil for attention-deficit disorder (ADD) developed serious
rashes, which prevented FDA approval of modafinil for children and
adolescents with ADD.
Carbamazepine
The incidence of either Stevens-Johnson syndrome or toxic epidermal
necrolysis during treatment with carbamazepine (■) has been reported
by the manufacturer as 1 per 500,000 patients. Notably, individuals of
Han Chinese ancestry have been shown to carry an increased risk for
developing carbamazepine-induced Stevens-Johnson syndrome or
toxic epidermal necrolysis in association with the HLA-B*1502 allele,
which may represent a risk allele for which the FDA has recommended
genotyping among Han Chinese Asians. With carbamazepine, as with
lamotrigine, the risk for developing a serious skin rash is highest in the
first few months of treatment.
Lamotrigine
Serious, life-threatening rashes—including Stevens-Johnson syndrome
and toxic epidermal necrolysis—were observed in early studies of la-
motrigine dosed aggressively for pediatric epilepsy. Subsequent studies
identified that the risk for serious rashes with lamotrigine (■) appears
highest when the dose escalation schedule occurs faster than recom-
mended by the manufacturer (the recommendation is 25 mg/day for
2 weeks, followed by 50 mg/day for 2 weeks, then 100 mg/day for
1 week, then 200 mg/day; when combined with divalproex, dose esca-
lation should occur at half this rate [i.e., 12.5 mg/day for 2 weeks, fol-
lowed by 25 mg/day for 2 weeks, then 50 mg/day for 1 week, then
100 mg/day]). Divalproex delays Phase II metabolism (glucuronida-
tion) of lamotrigine, effectively increasing its levels and bioavailability.
Risks of serious rashes also are higher when lamotrigine is coadminis-
tered with divalproex (particularly if the aforementioned dosing ad-
justment is not made) or when lamotrigine is used in children and
adolescents. The risk for significant rashes appears to be highest during
weeks 2–8 of treatment. Serious rashes typically involve blistering or
burnlike lesions on soft, mucocutaneous tissues (as found in the oral
cavity, nares, or conjunctivae) or skin exfoliation on the palms of the
hands and soles of the feet. Systemic involvement often occurs, in which
case patients may experience fever, malaise, lymphadenopathy, muscle
pain, or facial edema. Serious rashes must be contrasted with benign
rashes, which may occur on the extremities or trunk and are more often
exanthematous (maculopapular), nonblanching, and nonpruritic.
The mechanism by which lamotrigine can cause serious rashes is not
well understood. Reports have implicated an immune-mediated hyper-
sensitivity response that involves elevated IgE titers and eosinophilia
(i.e., drug rash with eosinophilia and systemic symptoms, referred to as
the DRESS syndrome). Unlike delayed-type hypersensitivity reactions,
the DRESS syndrome does not require prior exposure to the drug be-
cause the rash does not occur from a reactivation of sensitized mast cells
and basophils.
Some authors have suggested undertaking dermatological precau-
tions to minimize the risk for developing false-positive rashes that
could be misattributed to lamotrigine rather than other more likely
causes. Such precautions include avoiding exposure to other new med-

ications or foods, cosmetics, deodorants, detergents, fabric softeners,
sunburn, and environmental antigens such as poison ivy or poison oak.
The potential for a rash to develop may also be diminished by avoiding
the introduction of lamotrigine for 2 weeks following a prior rash, viral
syndrome, or vaccination. Efforts such as these may lower the incidence
of nonserious rash to about 5%.
Evidence suggests that patients taking lamotrigine who develop a
nonserious rash that resolves after drug cessation may safely be rechal-
lenged with lamotrigine, without recurrence of rash, by using a conser-
vative dosing titration schedule (e.g., 5 mg every other day for 14 days,
then increased every 14 days by 5 mg/day until reaching 25 mg/day,
and thereafter following the manufacturer’s usual recommended dos-
ing schedule) (Aiken and Orr 2010; Lorberg et al. 2009).
Serious rashes thought to result from use of lamotrigine warrant
prompt drug cessation and evaluation by a dermatologist. Steroids are
sometimes indicated for the treatment of Stevens-Johnson syndrome
during early phases of the rash but are sometimes controversial because
they may also delay recovery.
Modafinil
During randomized placebo-controlled trials of modafinil for the treat-
ment of ADD in 933 children and adolescents, 12 cases of severe cuta-
neous reactions (possible erythema multiforme or Stevens-Johnson
syndrome, with one case identified as being definite) were identified
(Cephalon 2006). Subsequently, the FDA issued a “nonapprovable” let-
ter regarding the pursuit by the manufacturer Cephalon of an ADD in-
dication for modafinil in children and adolescents. The manufacturer
ceased further efforts to obtain such an indication and did not conduct
additional safety studies in children and adolescents with ADD. The
risk of a serious dermatological reaction with modafinil in pediatric
populations has been reported to be approximately 0.8%, with a me-
dian time to discontinuation (due to rash) of 13 days in clinical trials
(manufacturer’s product information). Although rare, rash warrants
consideration during off-label treatment in pediatric patients.
9
Ear, Nose, and Throat
Bruxism
General Recommendations. Benzodiazepines such as clo-
nazepam probably offer the most reliable and immediate relief
for bruxism. Acrylic dental guards are considered the optimal
strategy for long-term management. In severe or persistent
cases, injection of botulinum toxin into the masseter muscle may
provide symptomatic relief.
Bruxism is an involuntary grinding and gnashing of the teeth that may

occur during sleep and in some instances may be considered a form of
akathisia. Nocturnal bruxism is considered a type of non–rapid eye
movement parasomnia and may be caused by a number of psychotropic
agents, including SSRIs, buspirone, antipsychotics, and dopaminergic
compounds such as amphetamine or dopamine agonists used to treat
Parkinson’s disease. Several authors have suggested that at least in the
case of SSRIs, iatrogenic bruxism may arise via inhibition of dopamin-
ergic pathways controlling masticatory muscle activity. The persistence
of bruxism over time may lead to erosion of dental enamel and potential
tooth fractures or receding gums.
No standard pharmacological treatment exists for bruxism, although
acrylic dental guards worn at night are considered the usual intervention
for persistent bruxism. Dosage reductions have been anecdotally re-
155
TABLE 9–1. Medication-induced bruxism improved with other

agents
Bruxism induced by Improvement shown with
Antipsychotic-induced akathisia Propranolol, 60–160 mg/day

in three divided doses (Amir et
al. 1997)
SSRI (sertraline) or venlafaxine Buspirone, 10 mg bid or tid; poten-
tially exerting an antibruxing
effect via postsynaptic dopamin-
ergic effect (Bostwick and Jaffee
1999; Jaffee and Bostwick 2000)
Venlafaxine Gabapentin, 300 mg/day (Brown
and Hong 1999)
Note. bid =twice daily; tid =three times daily.
ported as having potential benefit in SSRI-induced bruxism. Data from

preliminary controlled trials suggest that in unmedicated, psychiatri-
cally healthy sleep bruxers, benzodiazepines (notably, clonazepam
1 mg) may reduce bruxism and improve associated measures of sleep
quality (Saletu et al. 2010). Anecdotal observations also support the
possible value of cyclobenzaprine dosed from 2.5 to 10 mg at bedtime.
Botulinum toxin injections into the masseter muscles also have been de-
scribed as a novel periodontal procedure that can significantly reduce
the number of bruxism events and consequent myofacial pain over time
in individuals with persistent bruxism. There have also been anecdotal
observations of preexisting bruxism improving after the initiation of
SSRIs. Case reports identify potential improvement from medication-
induced bruxism with several described agents, all yielding benefit
within 2–7 days (Table 9–1).
Dysarthria
General Recommendations. Slow, slurred speech may be a
consequence of psychotropic drugs, usually reflecting toxicity.
Clinicians should be alert to the possible neurotoxic effects and
the dosages of all medications and illicit substances being taken
by a patient with dysarthric speech, as well as consider and eval-
uate other pertinent noniatrogenic (e.g., neurological) etiolo-
Ear, Nose, and Throat 157
gies. Nondevelopmental stuttering may rarely occur as a

possible dose-related consequence of antipsychotic pharmaco-
therapy. Lack of improvement from dosage reductions may re-
quire discontinuation of a suspected causal agent.
Dysarthria involves impaired pronunciation of speech. When dysar-

thria is thought to result from psychotropic drugs, it usually reflects ex-
cessive dosing or toxicity, particularly during the use of benzodiazepines
or other sedative-hypnotics and opiate analgesics, as well as lithium, di-
valproex, buspirone, antipsychotics, TCAs, and rarely, SSRIs. Dysarthria
accompanied by difficulty clearing oral secretions may suggest possible
laryngeal dystonia during antipsychotic therapy. The evaluation of dys-
arthria should include pertinent history taking; an assessment of the mo-
tor branch of the trigeminal nerve (V), facial nerve (VII), glossopharyngeal
nerve (IX), vagus nerve (X), and hypoglossal nerve (XII) (see Table 9–2);
and assessment of overall motor strength and deep tendon reflexes, in or-
der to rule out upper motor neuron disease (e.g., strokes, basal ganglia
deficits).
Nondevelopmental stuttering is a rare, possibly dose-dependent ad-
verse drug event that has been identified in a handful of case reports
with risperidone, olanzapine, clozapine, and FGAs. An equal number of
cases have been reported that describe treatment of developmental (i.e.,
noniatrogenic) stuttering with SGAs, including risperidone, olanza-
pine, and aripiprazole. The mechanisms by which antipsychotics could
either cause or treat stuttering are not well understood, although pre-
liminary functional imaging studies suggest that developmental stut-
tering may be related to increased hyperdopaminergic tone in the
striatum. However, early suspicions that antipsychotic-induced stutter-
ing could represent an extrapyramidal symptom were unsustained
when adjunctive benztropine failed to demonstrate efficacy in its treat-
ment. From a practical clinical standpoint, if new-onset stuttering does
not improve via reducing the dosage of the suspected causal agent,
drug discontinuation is likely warranted. Further neurological or oto-
laryngological evaluation is advisable if problems persist despite drug
cessation.
Dysgeusia
General Recommendations. Abnormal taste sensation in
the absence of other neurological adverse effects likely represents
a benign phenomenon for which no intervention is medically nec-
TABLE 9–2. Evaluation of cranial nerves that control speech and

phonation
Cranial nerve Evaluation
V Trigeminal nerve, Assess jaw strength by palpating the

motor branch temporal and masseter muscles as the
patient clenches and moves the jaw.
VII Facial nerve Ask the patient to raise the eyebrows, frown,
resist opening the eyes while shut, smile
(showing teeth), and puff out both cheeks.
IX Glossopharyngeal Observe the symmetry of palatal rise and
nerve fall; assess gag reflex (afferent limb).
X Vagus nerve Assess gag reflex (efferent limb).
XII Hypoglossal nerve As the patient protrudes and moves the
tongue in various directions, inspect it for
asymmetries, fasciculations, and deviation
from the midline.
essary. A suspected causal medication may be eliminated if the

problem persists, jeopardizes adherence, or otherwise remains
objectionable to the patient. Drug cessation may be necessary.
Dysgeusia refers to an impaired sense of taste. It may result from a num-

ber of psychotropic agents, including topiramate, carbamazepine, and
lithium. In addition to being a side effect of nonpsychotropic medica-
tions (e.g., anti-inflammatory drugs, antineoplastic agents, allopurinol),
dysgeusia can occur with numerous primary medical conditions, in-
cluding oropharyngeal infections, vitamin deficiencies, malignancies,
Sjögren’s syndrome, and smoking.
Oral Lesions
General Recommendations. New oral lesions that arise
within the first few days or weeks after starting any new medica-
tion should be evaluated for their possible association with a
drug, as well as alternative (noniatrogenic) explanations. Partic-
ular attention should be paid to blistering lesions on oral mucos-
al tissue and any associated systemic features (e.g., fever,
lymphadenopathy) that could be suggestive of serious dermato-
logical reactions; the expected time course for such drug hyper-
sensitivity reactions to occur is usually within the first 2 months

of treatment initiation.
Oral ulcers may occur from a variety of causes. They may be aphthous
ulcers (canker sores), typically 3–10 mm in diameter, arising from a va-
riety of causes, including physical trauma, stress, and immune deficien-
cies, among others. Aphthous lesions seldom persist beyond 1–2 weeks,
typically remit spontaneously, and likely do not represent iatrogenic
phenomena. Ulcerative tongue lesions can sometimes represent a
chronic inflammatory process, the presence of autoimmune disease, or
other immunocompromised states. They may be common phenomena
in individuals with HIV. Persistent lesions sometimes warrant brush bi-
opsies by an otolaryngologist or oral surgeon to evaluate the possibility
of an oropharyngeal malignancy. Visually, malignancies usually do not
appear synchronously as multiple lesions.
Inspection of the oral cavity should include assessment for the pres-
ence of thrush. Among patients taking psychotropic agents, rare cases
of nonspecific oral ulcerations or mucositis have been reported in con-
nection with carbamazepine, lithium, fluoxetine, and meprobamate.
Among patients taking common nonpsychotropic drugs, oral lesions
may rarely occur from the use of NSAIDs, β-blockers, thiazide diuretics,
spironolactone, ACE inhibitors, and certain antibiotics. Of primary con-
cern when evaluating oral lesions in the aftermath of starting a psycho-
tropic drug is the recognition of blistering oropharyngeal lesions that
may occur as part of the clinical presentation of a systemic rash, such as
Stevens-Johnson syndrome or toxic epidermal necrolysis (see the sec-
tion “Serious Rashes” in Chapter 8, “Dermatological System”).
Symptomatic management of benign but painful oral ulcerative le-
sions can often be achieved by rinsing with oral solutions of viscous
lidocaine with diphenhydramine and elixir antacids.
Sialorrhea
General Recommendation. If dosage reductions prove un-
helpful for sialorrhea, the most compelling data support the use
of glycopyrrolate 1 mg bid or biperiden 2 mg qd or bid.
Excessive drooling (sialorrhea) is a medically benign but often distressing

side effect associated with several psychotropic agents, most notably
clozapine (arising in about one-third to one-half of clozapine-treated
patients with schizophrenia), as well as risperidone, olanzapine, and
quetiapine. Hypersalivation from clozapine appears to be a paradoxical

phenomenon, in light of clozapine’s antimuscarinic-anticholinergic and
α2-adrenergic antagonistic effects. Hypersalivation has been described
in the absence of extrapyramidal symptoms and thus is unlikely a man-
ifestation of parkinsonism. Sialorrhea also does not appear to be dose
dependent in the case of clozapine, although a dose relationship may
exist in cases associated with risperidone or quetiapine. Several mecha-
nisms have been proposed to account for antipsychotic-induced hyper-
salivation, including postsynaptic α-adrenergic blockade at salivary
glands; increased saliva production via M4-muscarinic cholinergic re-
ceptor stimulation; and blockade of receptors at pharyngeal muscles
that regulate swallowing.
Antimuscarinic anticholinergic agents likely represent the most ex-
tensively studied pharmacological class in efforts to counteract cloza-
pine- or risperidone-induced sialorrhea. Significant improvement has
been demonstrated from randomized data examining both oral glyco-
pyrrolate (1 mg bid) and biperiden (2 mg qd or bid), with more robust
effects seen with glycopyrrolate in the case of clozapine-induced sialor-
rhea (Liang et al. 2010). Glycopyrrolate, as a peripherally acting agent, is
significantly less likely than biperiden to impair cognitive function.
Case reports also suggest possible value with oxybutinin 5 mg once or
twice daily. Inasmuch as anticholinergic agents as a class carry the risk
of cognitive dulling and sedation, their use becomes a further consider-
ation that must be balanced against the potential for relief from hyper-
salivation.
A variety of other anticholinergic compounds have been used, with
most having shown potential value from small proof-of-concept studies,
often followed by lack of separation from placebo in larger randomized
trials. These agents include the antimuscarinic-anticholinergic spray ipra-
tropium bromide (favorable data from case reports, but negative findings
from placebo-controlled trials) and the selective M4-muscarinic receptor
antagonist pirenzepine (significant reductions in hypersalivation from
baseline in open-trial data reported at a dose of 50 mg/day or 25–100 mg/
day, but negative data from an 8-week placebo-controlled trial begun at
25 mg/day and increased by 25 mg/week to a target dose of 100 mg/day
[Bai et al. 2001]). Open data with trihexyphenidyl (mean dose=10.7 mg/
day) have shown about a 50% reduction in hypersalivation, although no
randomized controlled trials have as yet been reported for this use. The
anticholinergic agent benztropine—popularly used to counteract par-
kinsonian adverse effects of antipsychotics, and known to cause dry
mouth—has received little if any study for the intended purpose of coun-
teracting hypersalivation.
Open case reports have also described benefits from the α2-adrenergic
agonist clonidine (orally dosed from 50 to 100 mg/day) or a clonidine
patch (0.1 mg/week), although randomized controlled trials have not
been reported.
Stomatodynia
(Burning Mouth Syndrome)
General Recommendations. Stomatodynia is rarely associ-
ated with psychotropic medicines. Topical clonazepam has been
reported as being among the more successful interventions, al-
though referral to an otolaryngologist may be necessary to clar-
ify etiology and address therapeutic management.
Burning mouth syndrome involves a painful burning sensation of the

tongue or oral mucous membranes that, in the absence of any visible
physical or laboratory abnormalities, has been associated with the pres-
ence of major depressive disorder or generalized anxiety disorder. It is
especially common in postmenopausal women and is rare in men, and it
may be either constant or intermittent. It has no known pathophysiology
or structural etiology, although conditions such as mucosal diseases, nu-
tritional deficiencies (notably, deficiencies of vitamins B1, B2, B6, or B12; ni-
acin; iron; folate; or zinc), oral thrush, non–insulin-dependent diabetes
mellitus, xerostomia, or cranial nerve injuries should be ruled out when
considering differential diagnosis. Some authors regard stomatodynia as
a type of somatoform pain disorder. It may derive from depression or an
anxiety disorder, rather than being a true pharmacodynamic conse-
quence of treatment.
Psychotropic medications associated with burning mouth syndrome
are quite rare and limited to case reports with some SSRIs (notably, flu-
oxetine or sertraline), venlafaxine, and clonazepam. A small number of
nonpsychotropic medications, particularly ACE inhibitors such as lisino-
pril or enalapril, have been reported to cause burning mouth syndrome.
The otolaryngological literature describes the use of TCAs and gabapen-
tin as potentially beneficial for treating stomatodynia, as well as topical
clonazepam (i.e., patients suck a 1-mg clonazepam tablet bid or tid near
the pain site for several minutes, then spit).
Xerostomia
General Recommendations. Dry mouth is one of the most
common side effects of numerous psychotropic drugs and is not
necessarily dose related. It is usually of no medical consequence
unless its chronic persistence leads to dental complications. Dry
mouth that is of mild severity may attenuate with time or can
sometimes be ameliorated by sugarless gum or glycerin-based
oral lubrication solutions. Severe persistent dry mouth may ne-
cessitate drug discontinuation.
Xerostomia, or dry mouth, may result from a variety of psychotropic med-

ications, most often from anticholinergic drugs and lithium, although dry
mouth is identified as a more common adverse effect than seen with pla-
cebo in controlled trials of most classes of psychotropic compounds,
regardless of an absence of known anticholinergic effects or other anti-
cholinergic manifestations (e.g., constipation). It is often unrelated to
drug dose (see Table 1–5 in Chapter 1, “The Psychiatrist as Physician”),
although empirically, dosage reductions may sometimes lessen severity.
Xerostomia differs from sheer thirst (as often occurs with lithium, which,
as a salt, may stimulate the need for increased fluid intake).
Sugarless gums that contain aspartame, mannitol, sorbitol, or xylitol
may help to stimulate saliva production. A number of nonprescription
glycerin-based aerosolized sprays or gels may serve as oral moisturiz-
ers, including the glycerate polymer Biotene Oral Balance Gel, car-
boxymethyl cellulose or hydroxyethyl cellulose solutions (e.g., Oralube
saliva substitute, Salivart Oral Moisturizer, Xero-Lube Artificial Saliva),
and the water-glycerin solution Plax. Procholinergic drugs are some-
times used to counteract the antimuscarinic effects of medications
thought to cause xerostomia. These include oral pilocarpine 10–30 mg/
day in two or three divided doses (Masters 2005) and cevimeline 30 mg/
day (typically used in Sjögren’s syndrome or xerostomia after head and
neck antineoplastic radiation therapy). Notably, in our experience, a
single 10-mg dose of pilocarpine can cause profuse sweating, rhinor-
rhea, and diarrhea; therefore, the prudent action may be to initiate dos-
ing at 2.5 or 5 mg to assure tolerability. Salivary stimulants versus saliva
substitutes appear similar with respect to patient preference for their ef-
fects on xerostomia.
10
Electrolyte
Abnormalities
Hyponatremia and SIADH

General Recommendations. Hyponatremia, with or without
syndrome of inappropriate antidiuretic hormone secretion
(SIADH), is a relatively rare complication of treatment with virtu-
ally all antidepressants, some anticonvulsants (notably, oxcar-
bazepine and carbamazepine), and many antipsychotics. In the
absence of a known noniatrogenic cause for hyponatremia, psy-
chotropic medications may need to be withheld pending deter-
mination of the etiology. Some authors advocate changing to an
alternative psychotropic agent with a different pharmacological
profile and closely monitoring serum sodium levels. Fluid restric-
tion is usually the first-line treatment for mild psychotropically
induced hyponatremia. Adjunctive demeclocycline or lithium
sometimes may also help to reduce the risk of a recurrence of hy-
ponatremia during continued therapy with a psychotropic drug
suspected of contributing to SIADH or hyponatremia.
Hypotonic hyponatremia (often defined as a serum sodium level

<130 mmol/L) has been reported in association with numerous psycho-
tropic agents, including bupropion, carbamazepine, divalproex, lithium,
lamotrigine, MAOIs, oxcarbazepine, SSRIs, SNRIs (including duloxetine
163
and venlafaxine), mirtazapine, tertiary amine TCAs, other norepineph-

rine reuptake inhibitors such as reboxetine, and most FGAs and SGAs.
Hyponatremia that has been observed to occur during treatment with
an SSRI (citalopram) has been shown to recur after substitution with an
SNRI (duloxetine), although SIADH is a generally rarer phenomenon
with non-SSRI antidepressants. Known risk factors for psychotropic-
induced hyponatremia include increasing age and smoking (because
nicotine increases antidiuretic hormone [ADH] secretion) (Spigset and
Hedenmalm 1995). Case reports also exist of antipsychotic-associated
hyponatremia leading to NMS (Spigset and Hedenmalm 1995).
Mechanisms by which psychotropic drugs may cause SIADH are not
well understood, although one proposal is that SSRIs may cause release
of ADH or renal responsiveness to ADH. SIADH has been reported to oc-
cur anywhere from 2 days to many months after the initiation of a causal
psychotropic agent; typically it occurs during the first few weeks of treat-
ment with an antidepressant but may have a more variable time of onset
during therapy with other psychotropic agents. Many nonpsychotropic
agents also may cause hyponatremia or SIADH; these drugs include,
among others, diuretics (e.g., amiloride and thiazide diuretics), antineo-
plastic drugs (e.g., vinca alkaloids), and the fibrate clofibrate.
The formal diagnosis of SIADH entails the presence of hypotonic hy-
ponatremia plus lower serum osmolality (usually ~240–275 mOsm/kg)
than urine osmolality (usually >100–200 mOsm/kg), as well as increased
urine sodium (>30 mEq/L). Patients are typically euvolemic and have
normal hepatic, renal, cardiac, thyroid, and adrenal function. (Impor-
tantly, hyponatremia with high serum osmolality points to other medical
etiologies than SIADH, such as hyperglycemia or hyperosmolar hyper-
glycemic nonketotic coma.) Hyponatremia may manifest without symp-
toms or may involve nonspecific features such as weakness, lethargy,
headache, and weight gain. Neuropsychiatric signs (e.g., confusion, sei-
zures) may occur when serum sodium levels fall below ~120 mmol/L.
The differential diagnosis of noniatrogenic hyponatremia is vast, as sum-
marized in Table 10–1.
Laboratory assessment of hyponatremia includes measurement of
urine electrolytes and osmolality. A diagnosis of SIADH is supported
by concentrated urine (i.e., elevation of both urine Na+ [>20 mmol/L] and
urine osmolality [>100 mmol/L]), whereas dilute urine (i.e., urine Na+
<20 mmol/L and urine osmolality <100 mmol/L) more likely suggests
psychogenic polydipsia.
In mild euvolemic hyponatremia caused by psychotropic agents,
elimination of the suspected causal agent in addition to fluid restriction to
Electrolyte Abnormalities 165
TABLE 10–1. Medical (noniatrogenic) causes of SIADH

Acute intermittent porphyria Hypothyroidism
Asthma Malignancies
Brain abscess Meningitis
COPD Multiple sclerosis
Cirrhosis Pneumonia
Congestive heart failure Pneumothorax
Cystic fibrosis Psychogenic polydipsia
Delirium tremens Stroke
Empyema Subarachnoid or subdural
Encephalitis hemorrhage
Guillain-Barré syndrome Thiazide diureticsa
Head trauma Tuberculosis
Hydrocephalus
Note. COPD= chronic obstructive pulmonary disease; SIADH= syndrome of
inappropriate antidiuretic hormone secretion.
aHypokalemia and renal insufficiency typically present.
about 1 L/day is usually the preferred first-line intervention and often

leads to resolution of the abnormality. This intervention may require at
least temporarily withholding most classes of major psychotropic drugs
or, if necessary, choosing an alternative pharmacotherapy that involves
a novel mechanism from that of the suspected causal agent. Most au-
thorities caution against rapid correction of low serum sodium levels
(e.g., via aggressive infusion of hypertonic saline) because of the risk for
inducing central pontine myelinolysis. Severe acute hyponatremia
should be gradually corrected in a medical setting via intravenous infu-
sion of sodium chloride solution, usually no faster than an initial rate of
1–2 mmol/L per hour.
The tetracycline antibiotic demeclocycline is sometimes used in the
treatment of hyponatremia because of its ability to inhibit the renal ef-
fects of ADH. For instances in which continued therapy with a suspected
causal psychotropic agent is deemed clinically necessary, adjunctive de-
meclocycline initially dosed at 900–1,200 mg/day may be advisable
(Spigset and Hedenmalm 1995). Polyuria typically occurs within 1–2
weeks, and the dosage may then be gradually reduced, usually to 300–
900 mg/day, in order to maintain normal serum sodium levels. Notably,
lithium also inhibits the renal effects of ADH and is sometimes recom-
mended as an alternative strategy in the management of hyponatremia.
Metabolic Acidosis and Alkalosis

General Recommendations. A very limited number of psy-
chotropic medications are associated, although rarely, with met-
abolic acidosis or alkalosis. Most notably, renal tubular acidosis
can be induced by topiramate and lithium; toxicity is associated
with TCA overdose; and hypokalemic hyperglycemic nonketotic
acidosis can occur during treatment with SGAs. Mild acidosis
may involve no presenting signs, but more severe acid-based de-
rangements can involve an array of physical symptoms. Diagno-
sis is made by laboratory assessment, including arterial blood
gas sampling. Treatment involves discontinuation of a presump-
tive causal agent, followed by supportive medical management.
Disorders of acid-base chemistry may manifest with metabolic acidosis

or alkalosis, and may be either acute or chronic. When resulting from
psychotropic medications, mild acidosis may be asymptomatic; or
when more severe, it may manifest with variable symptoms that can in-
clude nausea, vomiting, malaise, headache, chest or abdominal pain,
muscle or bone pain, and hyperpnea (long, deep breaths).
The anion gap represents the concentration of unmeasured ions in
serum, as determined by calculating the sum of routinely measured cat-
ions (i.e., [Na+]+[K+]) minus routinely measured anions (i.e., [Cl–]+
[HCO3–]). A normal anion gap is usually 8–12 mEq/L. Causes of an in-
creased anion gap are summarized in the mnemonic MUDPILES: Meth-
anol, Uremia, Diabetic ketoacidosis, Propylene glycol, Isoniazid, Lactic
acidosis, Ethylene glycol, Salicylates.
A normal anion gap acidosis may be caused by carbonic anhydrase
inhibitors (e.g., topiramate), spironolactone, hyperparathyroidism, am-
monium chloride, Addison’s disease, diarrhea, hyperchloremia, or-
ganic solvents, diarrhea, or excess saline.
Hyperchloremic metabolic acidosis, without an anion gap, has been
reported with the use of topiramate, due to renal bicarbonate loss result-
ing from carbonic anhydrase inhibition by topiramate. Acidosis may
manifest clinically with dyspnea and confusion or other acute mental
status changes, alongside laboratory values reflecting a rising serum
chloride level with diminishing serum bicarbonate. This rare phenom-
enon has been reported to occur at any point during topiramate treat-
ment and warrants consideration and evaluation of a basic metabolic
laboratory panel in any patient receiving topiramate who develops
acute mental status changes. Existing case reports suggest that the pro-
cess generally ceases upon discontinuation of topiramate.
Electrolyte Abnormalities 167
Other acid-base disturbances that can develop with specific psychotro-

pic drugs include renal tubular acidosis caused by lithium and respiratory
alkalosis resulting from TCA overdoses. Hypokalemic ketoacidosis may
occur in association with sudden dramatic rises in blood glucose levels
(e.g., as seen in hyperosmolar hyperglycemic nonketotic coma), a rare but
potential risk associated with most if not all SGAs.
Lactic acidosis also can be a complication of treatment with the oral
hypoglycemic agent metformin, usually when given at higher dosages.
Patients taking metformin for possible reversal of psychotropic-induced
weight gain (see Chapter 19, “Systemic Reactions,” and Table 19–6)
should be cautioned to pay attention to the development of sore muscles,
which could indicate the presence of lactic acidosis.
11
Endocrinopathies
Bone Demineralization and Osteoporosis

General Recommendations. There is a small increased po-
tential risk for osteoporosis during treatment with carbamazepine
or SSRIs. Older adults or other patients who have an increased risk
for osteoporosis may warrant periodic monitoring of bone mineral
density during treatment with anticonvulsants or SSRIs, and con-
sideration may be given to alternative pharmacotherapies when
feasible.
Certain anticonvulsant drugs, particularly those that induce liver en-

zymes (e.g., carbamazepine), are known to decrease bone mineral den-
sity. In nongeriatric adults with epilepsy, long-term use of divalproex
has been linked with an increased risk for osteoporosis or osteopenia in
some studies but not others. Some investigators have suggested that
drugs that inhibit histone deacetylase (e.g., divalproex) may have value
in promoting osteoblast maturation, thereby mitigating a risk for bone
demineralization. To date, no published reports have linked osteoporo-
sis or osteopenia with gabapentin, lamotrigine, oxcarbazepine, topira-
mate, levetiracetam, or tiagabine.
Separately, SSRIs have been shown to reduce bone mineral density in
hip and lumbar spinal joints by approximately 4%–6% in older adult men
and women, presumably due to inhibition of serotonin sites in osteoblasts
169
and osteoclasts. One prospective population-based study of 7,983 indi-

viduals found a 2.35-fold increased risk for nonvertebral fractures among
SSRI recipients among individuals ≥age 55 (Ziere et al. 2008). Whether
these observations pose a broad, clinically meaningful risk for fractures in
older adults remains the subject of controversy, and at present no formal
recommendation has been made either to perform bone densitometry
studies on patients before and during treatment with SSRIs or to refrain
from using SSRIs in osteoporotic patients for whom no other safety con-
cerns exist regarding their use. Furthermore, depression itself has been
suggested to induce bone loss via hypothalamic-pituitary-adrenocortical
axis hyperactivity (Schweiger et al. 2000).
Of note, the use of hypermetabolic thyroid hormone as a psychotropic
intervention (e.g., as may occur in rapid-cycling bipolar disorder) poses a
potential risk for hastening bone demineralization. Some authorities ad-
vise periodic bone mineral densitometry testing in patients who continue
high-dose thyroid hormone as a long-term therapy.
Glycemic Dysregulation and

Diabetes Mellitus
General Recommendations. Patients taking SGAs should
have fasting blood glucose assessments before or upon the initi-
ation of therapy, after 12 weeks of treatment, and annually
thereafter while continuing an SGA. Measurement of hemoglo-
bin A1C also may be informative regarding patterns of hypergly-
cemia and assessment of diabetes or risk for the development of
diabetes. The introduction of oral hypoglycemic agents such as
metformin may be useful to counter weight gain and possible
insulin resistance caused by psychotropic agents. Progression of
insulin resistance or glycemic dysregulation may warrant dis-
continuation of a presumptive causal agent, particularly in the
setting of other risk factors for coronary artery disease—unless a
particular psychiatric agent appears to exert a unique benefit
that outweighs metabolic risk, in which case active manage-
ment of glycemic dysregulation to permit continued pharmaco-
therapy may be warranted.
Impaired glucose homeostasis is a known risk with SGAs and a number

of other psychotropic compounds. Pharmaceutical manufacturers are
quick to point out that individuals with serious mental illnesses such as
bipolar disorder and schizophrenia have an inherently increased risk
Endocrinopathies 171
for the eventual development of diabetes and cardiovascular disease,

independent of pharmacotherapies. Such observations, however, pro-
vide clinicians with little perspective on the independent contributions
of specific psychotropic agents to a given patient’s cumulative meta-
bolic risk.
Above and beyond the increased vulnerability to diabetes caused by
bipolar disorder or schizophrenia, SGAs can to varying degrees disrupt
glucose metabolism by causing insulin resistance. For example, short-
term (8-day) exposure of olanzapine in healthy men has been shown to
impair insulin-mediated glucose metabolism, as well as to impede insu-
lin-induced declines of free fatty acids and triglycerides (Vidarsdottir et
al. 2010)—a finding at variance with earlier industry-sponsored reports
that claimed to find no adverse effects on glucose disposal rate or insulin
sensitivity among healthy volunteers after 3 weeks of exposure to olan-
zapine or risperidone (Sowell et al. 2003). Preclinical studies also indicate
that the acute infusion of olanzapine in animals leads to rapid increases in
blood sugar and marked reductions of plasma insulin and C-peptide in
response to glucose challenge (Chintoh et al. 2008). In patients with
schizophrenia treated over 24 months with an SGA, significant reduc-
tions from baseline in insulin sensitivity have been shown with olanza-
pine (~19%) or risperidone (~16%) but not with quetiapine (Newcomer et
al. 2009). At least in schizophrenia, antipsychotic polypharmacy does not
appear to increase the risk for metabolic syndrome over and above the
risk incurred by use of a single SGA.
The reporting of changes in fasting blood glucose levels from short-
term randomized trials is far less informative than long-term data, inas-
much as impaired glucose tolerance is a phenomenon that arises over the
course of months to years, rather than weeks to months. In addition,
pharmaceutical manufacturers of SGAs sometimes imply that their own
reported fasting glucose rates may be overstated because some study par-
ticipants may not reliably be tested under fasting conditions. By contrast,
obviously, clinicians and patients are more concerned with manufactur-
ers’ underestimation rather than overestimation of metabolic parameters.
The American Diabetes Association (2010) identifies diabetes mellitus
on a continuum based on degrees of hyperglycemia and impaired glu-
cose tolerance, as summarized in Table 11–1. Current recommendations
from the American Diabetes Association and the American Psychiatric
Association for patients taking an SGA include monitoring of fasting glu-
cose and blood pressure at baseline, 12 weeks, and annually thereafter.
Metabolic monitoring for SGA recipients also includes weight or BMI
measurement at baseline and at 4, 8, and 12 weeks, followed by quarterly
assessments, waist circumference measurement at baseline and annually
TABLE 11–1. Operational definitions of diabetes mellitus
Category Operational definition
Increased risk for Fasting blood glucose of 100–125 mg/dL or

diabetes 2-hour blood glucose of 140–199 mg/dL during
a 75-g oral glucose tolerance test or
Hemoglobin A1C of 5.7%–6.4%
Diabetes mellitus Hemoglobin A1C ≥6.5% or
Fasting (≥8 hours) blood glucose ≥126 mg/dL
or
2-hour blood glucose ≥200 mg/dL during 75-g
oral glucose tolerance test or
Random blood glucose >200 mg/dL
Source. American Diabetes Association 2010.
thereafter, and fasting lipid profiles at baseline, 12 weeks, and every

5 years thereafter (American Diabetes Association et al. 2004).
Insulin resistance refers to the body’s inability to transport and use
glucose from the vascular to the intracellular compartment. One theory
to account for hyperglycemia associated with SGAs involves their ap-
parent capacity to increase insulin resistance. An elevated ratio of se-
rum triglycerides to HDL cholesterol (specifically, >3.8) is predictive of
coronary disease and is sometimes taken as a rough proxy for insulin re-
sistance (although the relationship appears less robust among blacks
than whites). Insulin resistance and pancreatic beta-cell function also
can be quantified using the homeostatic model assessment of insulin re-
sistance (HOMA-IR) defined by the following equation:
fasting glucose (nmol/L)×fasting insulin µU/L)

HOMA-IR=
22.5
HOMA-IR values ≥2.6 are sometimes viewed as a threshold cutoff to de-

fine insulin resistance (Ascaso et al. 2003).
Table 11–2 reports incidence rates for changes in blood glucose levels
identified in randomized clinical trials of SGAs.
Since 2003, manufacturers’ package inserts for all SGAs have carried a
class warning from the FDA regarding their potential to increase blood
sugar. Hyperglycemia may arise after short-term exposure to SGAs and
may occur independently of weight gain (which separately can contrib-
ute to peripheral insulin resistance). Both clozapine and olanzapine in-
hibit glucose-induced insulin release from pancreatic beta cells (Chintoh

et al. 2009), posing an independent cause of iatrogenic hyperglycemia.
In addition to the risk factors for metabolic syndrome previously
identified in Table 7–5 (in Chapter 7, “Cardiovascular System”) a per-
sonal or family history of non–insulin-dependent diabetes (e.g., gesta-
tional diabetes) increases the risk specifically for hyperglycemia or the
eventual development of diabetes. Racial differences also may contribute
to differential effects on metabolic dysregulation. For example, the risk
for metabolic syndrome during treatment with aripiprazole appears
higher in black or Hispanic subjects than in whites, whereas no such ra-
cial differences have been observed in the case of olanzapine (Meyer et al.
2009) even though weight gain may be significantly greater during olan-
zapine treatment among black versus white patients with primary psy-
chotic disorders (Stauffer et al. 2010).
Although no absolute contraindication exists for the use of SGAs
among individuals with known type 2 diabetes, minimal literature is
available on the safety and efficacy of using such agents in this popula-
tion. The CATIE study (Lieberman et al. 2005) included about 10% of sub-
jects with known type 2 diabetes at baseline, but all were treated with oral
hypoglycemics or additional antidiabetic regimens, which would have
confounded post hoc analyses regarding differential effects of antipsy-
chotics on blood glucose levels. No prospective randomized studies of
SGAs have been undertaken specifically among individuals with preex-
isting type 2 diabetes; consequently, decisions about the relative risks ver-
sus benefits of SGAs for diabetic patients must be individualized based
on the magnitude and extent of metabolic dysregulation and cardiovas-
cular risk versus the severity of psychopathology and availability of other
effective, metabolically neutral pharmacotherapies.
Certain antidepressants, including SSRIs, venlafaxine, and TCAs,
have also been implicated with the development of impaired glucose ho-
meostasis and diabetes. In patients with diabetic neuropathic pain, for ex-
ample, duloxetine significantly increased fasting glucose (by 12.5 mg/dL
over 52 weeks) and hemoglobin A1C (by 0.5%) versus placebo. A nested
case-control study of 165,958 patients with major depression in the
United Kingdom found that over a period of at least 2 years’ exposure, re-
cipients of an SSRI or TCA had an approximate 2-fold increased risk for
new-onset diabetes mellitus compared with matched comparison sub-
jects who did not take an antidepressant (Andersohn et al. 2009); among
studied agents, the highest rates were seen with amitriptyline (risk
ratio=9.05) or venlafaxine (risk ratio=3.01), and the lowest rates were
seen with fluvoxamine (risk ratio=1.75). The risk for developing type 2
diabetes with an SSRI was lower in patients whose exposure was shorter
TABLE 11–2. Changes in blood sugar reported in FDA registration

and other representative randomized trials of
second-generation antipsychotics
Agent Observations
Aripiprazole In a 26-week randomized trial in schizophrenia,

+0.13-mg/dL from baseline (Pigott et al. 2003);
mean of 4.1 mg/dL less than seen with
olanzapine across three schizophrenia trials
(N=1,487) (Rummel-Kluge et al. 2010).
Asenapine In 3-week registration trials for bipolar mania
and 6-week registration trials for schizophrenia,
mean change from baseline=–0.6 mg/dL and
+3.2 mg/dL, respectively. In 52-week open
extension data in schizophrenia, mean change
from baseline=+2.4 mg/dL.
Iloperidone Mean serum glucose: +7.2 mg/dL to
+16.2 mg/dL (dose dependent and greater than
seen with placebo) (Weiden et al. 2008).
Lurasidone Fasting glucose levels across dosages from
manufacturer’s pooled short-term trials in
schizophrenia=+1.3 mg/dL. From open-label
extension data: at 24 weeks: +1.6 mg/dL; at
36 weeks: +0.3 mg/dL; at 52 weeks: +1.2 mg/dL.
Olanzapine In CATIE, mean change in fasting glucose=
+15.0 mg/dL (Lieberman et al. 2005).
Paliperidone Mean change from baseline in serum glucose
level= +0.1 mg/dL across three pooled 6-week
randomized trials in schizophrenia (Meltzer
et al. 2008).
Quetiapine Incidence of fasting glucose ≥126 mg/dL=
2%–12% across indications in FDA randomized
trials. In CATIE, mean change in fasting
glucose=+6.8 mg/dL (Lieberman et al. 2005);
mean of 9.3 mg/dL less than olanzapine across
four schizophrenia trials (N=986) (Rummel-
Kluge et al. 2010).
TABLE 11–2. Changes in blood sugar reported in FDA registration

and other representative randomized trials of
second-generation antipsychotics (continued)
Agent Observations
Risperidone In CATIE, mean change in fasting glucose=

+6.7 mg/dL (Lieberman et al. 2005); mean of
5.9 mg/dL less than olanzapine across nine
schizophrenia trials (N=986) (Rummel-Kluge
et al. 2010).
Ziprasidone In CATIE, mean change in fasting glucose=
+2.3 mg/dL (Lieberman et al. 2005); mean of
8.35 mg/dL less than olanzapine across four
schizophrenia trials (N=1,420) (Rummel-Kluge
et al. 2010).
Note. CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness;
FDA= U.S. Food and Drug Administration.
and in whom dosages were lower. In this study, glycemic dysregulation

was thought to arise secondarily to weight gain rather than other mech-
anisms (e.g., time spent depressed).
The oral hypoglycemic agent metformin is perhaps the most exten-
sively studied of adjunctive pharmacotherapies used for patients who
gain significant weight or develop increased metabolic risk due to psy-
chotropic drugs, most notably SGAs. A meta-analysis by Ehret et al.
(2010) showed no significantly decreased risk for the eventual develop-
ment of type 2 diabetes in patients taking SGAs in tandem with met-
formin, although significant reductions nonetheless were observed in
weight, body mass index, and waist circumference.
Hyperprolactinemia, Galactorrhea, and

Gynecomastia
General Recommendations. Symptomatic hyperprolactin-
emia warrants either changing from a prolactin-elevating to a
within-class prolactin-sparing drug or augmentation with a
dopamine agonist such as bromocriptine or amantadine. Ad-
junctive aripiprazole also has preliminarily been shown to coun-
teract hyperprolactinemia caused by other antipsychotics.
Clinically asymptomatic hyperprolactinemia poses a long-term

risk for osteoporosis and infertility and merits either periodic
laboratory monitoring (if current benefits outweigh potential
risks) or intervening by a medication change or augmentation
with a dopamine agonist.
Antipsychotic-induced blockade of dopamine D2 receptors on mammo-

tropic cells of the anterior pituitary can cause release of prolactin. Hyper-
prolactinemia is a well-known consequence of virtually all FGAs and
several SGAs (notably, risperidone and paliperidone). The clinician
must bear in mind that hyperprolactinemia can result from other medi-
cations, including calcium channel blockers, TCAs, the sleep aid ramel-
teon, opiates, and histamine H2 antagonists. Psychotropic agents other
than antipsychotics have also been reported, although more rarely, to
cause hyperprolactinemia and consequent gynecomastia with galactor-
rhea; these include venlafaxine, fluoxetine, paroxetine, and diazepam
(in the case of diazepam, possibly secondary to estrogen elevation). Hy-
perprolactinemia from serotonergic antidepressants may arise through
indirect GABAergic modulation of tuberoinfundibular dopaminergic
projections (Emiliano and Fudge 2004). Among SSRIs, the risk for hyper-
prolactinemia may be especially low with sertraline (Sagud et al. 2002).
Rarely, carbamazepine and divalproex also have been implicated as
causes of hyperprolactinemia. Hyperprolactinemia also can result from
a wide range of primary medical conditions, including pituitary tumors,
macroprolactinomas, polycystic ovary syndrome, pregnancy, sarcoido-
sis, adrenal insufficiency, and hypothyroidism, as well as from de-
creased elimination due to renal or hepatic failure. Serum prolactin
elevations due to antipsychotics or other psychotropic medications typ-
ically rise no higher than 100 mg/dL, whereas serum levels exceeding
200 mg/dL most often reflect pituitary adenomas (Citrome 2008).
Some SGAs, including aripiprazole and asenapine, have been re-
ported in clinical trials to significantly lower serum prolactin levels from
baseline. However, it is often a matter of speculation as to whether reduc-
tions in prolactin occur via an active normalizing effect of a newly intro-
duced agent, or rather, the diminution of hyperprolactinemia after
simply discontinuing a previous prolactin-elevating drug. SGAs appear
less prone to elevate serum prolactin if they minimally interfere with tu-
beroinfundibular dopamine transmission and have “loose” D2 binding
affinities (i.e., high dissociation constants), as seen with quetiapine and
clozapine. On the other hand, lurasidone demonstrates minimal prolactin
elevation despite its low D2 dissociation constant. It has been suggested
that differences in prolactin elevation among SGAs may reflect their dif-
ferential blood-brain disposition, with greater likelihood for hyperpro-

lactinemia among agents with higher pituitary than striatal D2 occupancy
(Kapur et al. 2002).
Risk for hyperprolactinemia with a given agent may also vary on the
basis of patients’ clinical characteristics. For example, in studies that con-
trolled for risperidone dosage, episode number, or illness duration, se-
rum prolactin levels were significantly higher among risperidone-treated
patients with paranoid versus disorganized schizophrenia or schizoaffec-
tive disorder—possibly reflecting differences in basal dopaminergic tone
among subtypes of psychotic disorders. The clinician does not routinely
measure serum prolactin levels in patients taking antipsychotics without
a clinical reason to do so. For example, because hyperprolactinemia is ex-
pectable with FGAs, its documentation may help to affirm treatment ad-
herence. In patients who develop gynecological disturbances (e.g.,
amenorrhea, oligomenorrhea, gynecomastia, galactorrhea), measure-
ment of serum prolactin can help clarify etiology.
No authoritative recommendation indicates whether or when iatro-
genic hyperprolactinemia requires intervention. Persistent hyperpro-
lactinemia can lead to osteoporosis, infertility, and hypogonadism in
men. Some authors advise favoring prolactin-sparing SGAs (e.g., que-
tiapine, olanzapine, aripiprazole) in patients with existing osteoporosis,
or in women with breast cancer or a history of breast cancer, inasmuch as
prolactin may be trophic to some breast tumors (such that aripiprazole
may be the preferred agent) (Citrome 2008).
In symptomatic patients with antipsychotic-induced hyperpro-
lactinemia, most authorities favor changing from a prolactin-elevating
antipsychotic (e.g., risperidone, paliperidone) to a prolactin-sparing an-
tipsychotic (e.g., aripiprazole, asenapine, quetiapine; see Table 11–3) as
the first-line intervention. Alternatively, the cautious use of adjunctive
dopamine agonists (e.g., bromocriptine 2.5–10 mg/day, amantadine
100–300 mg/day, pramipexole ≤1 mg/day, pergolide 0.05–0.1 mg/day,
or ropinirole 0.75–3 mg/day) may effectively suppress antipsychotic-
induced hyperprolactinemia, although the clinician must observe for
rare but possible exacerbations of psychosis or mania. Adjunctive low-
dose aripiprazole (3 mg/day) has also been described in open trials as an
effective strategy to normalize hyperprolactinemia induced by risperi-
done or paliperidone and in a randomized placebo-controlled study
(dosed at 15–30 mg/day) to counteract haloperidol-induced prolactin el-
evation (Shim et al. 2007), with no adverse effect on psychopathology.
Gynecomastia occurs from a hypertrophic effect of prolactin on mam-
mary tissue. Although gynecomastia is not medically significant, it can be
a distressing side effect for men or women. Long-standing high prolactin
exposure to mammary tissue may cause a pharmacologically irreversible

hypertrophy that may be remediable only by surgical procedures (e.g.,
liposuction, breast reduction). Treatment with dopamine agonists has not
shown reductions in hypertrophic mammary tissue caused by elevated
prolactin levels.
Several apparently safe herbal remedies have been reported to coun-
teract antipsychotic-induced hyperprolactinemia, although their mecha-
nisms of action are not well defined. Peony-glycyrrhiza decoction dosed at
45 g/day significantly reduced risperidone-induced hyperprolactinemia
over 4 weeks, with magnitude comparable to that seen with bromocrip-
tine 5 mg/day; other herbal remedies with open or preliminary random-
ized controlled data to reduce antipsychotic-induced hyperprolactinemia
without exacerbating psychiatric symptoms include Shakuyaku-kanzo-to,
Zhuang Yang capsule, and Tongdatang serial recipe (reviewed by Hasani-
Ranjbar et al. 2010).
Reported rates of hyperprolactinemia with SGAs in controlled trials
are summarized in Table 11–3.
Menstrual Disturbances and

Polycystic Ovary Syndrome
General Recommendations. New-onset menstrual distur-
bances should be evaluated for changes related to medications
that may elevate serum prolactin or otherwise interfere with the
menstrual cycle. In women of childbearing potential, menstrual
cycles should be monitored during treatment with divalproex due
to a potential increased risk for polycystic ovary syndrome (PCOS).
A number of psychotropic agents can cause menstrual irregularities

through a variety of mechanisms. Irregular menstruation caused by hy-
perprolactinemia (e.g., secondary to antipsychotic medications) is
readily diagnosed by measurement of serum prolactin levels.
PCOS was defined by the National Institutes of Health as the presence
of hyperandrogenism with oligomenorrhea (Zawadski and Dunaif 1992).
Documented anatomical evidence of subcapsular ovarian cysts (known
as polycystic ovaries) is not considered necessary for the diagnosis of
PCOS, although it is often present.
Concerns that divalproex might contribute to PCOS arose following
a large observational study of 238 women with epilepsy, in whom the
use of divalproex was associated with a higher prevalence of irregular
menses (45%) or anatomical evidence of polycystic ovaries (43%) than
occurred during treatment with carbamazepine or other anticonvul-

sants (Isojärvi et al. 1993). Extensive subsequent debate ensued about
parsing the effects of divalproex on the menstrual cycle relative to the
potential unique contributions of epilepsy, obesity, and other factors. A
later study specifically in women with bipolar disorder found a 7.5-fold
increased relative risk for developing PCOS during divalproex treat-
ment than during therapy with other anticonvulsants (Joffe et al. 2006).
Collectively, these reproductive findings and the drug’s teratogenic
risks have prompted some authorities to advise against the use of dival-
proex among women of childbearing potential. Less extreme perspec-
tives would favor monitoring the menstrual cycle of any woman of
reproductive potential who receives divalproex, and further evaluation
(i.e., measurement of serum androgen levels) would likely be war-
ranted in the presence of clinical signs of a change in menstrual patterns.
The treatment of PCOS involves the discontinuation of agents that may
be causing it or the administration of oral contraceptives.
There is no absolute contraindication to prescribing divalproex in
women with preexisting PCOS. In other words, no evidence indicates
clinical worsening of existing PCOS after superimposition of divalproex,
although most practitioners would likely be reluctant to risk further dis-
ruption of the hypothalamic-pituitary-gonadal steroid axis by prescrib-
ing divalproex.
Table 11–4 provides recommendations for monitoring reproductive
safety in women who take divalproex during reproductive years.
Parathyroid Abnormalities
General Recommendations. Noniatrogenic causes of hyper-
calcemia in conjunction with hyperparathyroidism should be in-
vestigated medically. Iatrogenic hyperparathyroidism may result
from lithium and thiazide diuretics. Suspected causal agents
should be discontinued.
Hypercalcemia in conjunction with hyperparathyroidism has been

reported as a rare but possible adverse effect associated with long-term
lithium therapy. Rifai et al. (2001) noted that only 26 cases of this phenom-
enon had been reported in the literature from 1968 to 2001, although some
authors estimate that up to 20% of patients may develop hypercalcemia
during long-term lithium therapy (Mallette and Eichhorn 1986). Lithium
can directly stimulate parathyroid hormone release, as well as inhibit
renal excretion of calcium, causing hypercalcemia with hypocalciuria
180
TABLE 11–3. Incidence rates of hyperprolactinemia with second-generation antipsychotics
Changes from baseline in serum prolactin levels
Agent Acute trials Long-term trials

Aripiprazole Bipolar disorder: –12.7-mg/dL reduction from baseline Schizophrenia: –34.2 mg/dL over 26 weeks in a
(significantly greater than with placebo: multisite randomized industry-supported trial in
–7.2 mg/dL) (Keck et al. 2003); –12.6-mg/dL schizophrenia (Hanssens et al. 2008)
reduction from baseline (significantly greater than
with placebo: –7.8 mg/dL) (Sachs et al. 2006b).
Schizophrenia: –56.5% reduction from baseline
(Marder et al. 2003).
Asenapine Bipolar disorder: +4.9 mg/dL over 3 weeks. Schizophrenia: –26.9 mg/dL over 52 weeks
Schizophrenia: –6.5 mg/dL over 6 weeks
(manufacturer’s package insert, Merck
Pharmaceuticals).
Clozapine Schizophrenia: No appreciable changes (Hamner Schizophrenia: No appreciable changes (Hamner
2002). 2002)
Endocrinopathies
TABLE 11–3. Incidence rates of hyperprolactinemia with second-generation antipsychotics (continued)
Iloperidone Schizophrenia: FDA registration trials reported a mean Unavailable

serum prolactin change of +2.6 mg/dL over
4 weeks, with elevated prolactin levels seen in 26%
of iloperidone recipients. A pooled analysis of
6-week acute phase trials demonstrated significant
reductions from baseline in serum prolactin levels
(ranging from –23.1 to –38.0 mg/dL) (Weiden et al.
2008).
Lurasidone Schizophrenia: –1.1 mg/dL change from baseline (dose Changes from baseline, from schizophrenia open-
dependent; +0.3 ng/ml with 40 mg/day; +1.1 mg/dL label extension phase studies by manufacturer:
with 80 mg/day; +3.3 mg/dL with 120 mg/day; –1.9 mg/dL at 24 weeks; –5.4 mg/dL at 36 weeks;
manufacturer’s package insert, Sunovion –3.3 mg/dL at 52 weeks
Pharmaceuticals).
181
182

Olanzapine Pooled FDA registration trial data across adult –8.1 mg/dL over 9.2-month median exposure in
indications: +30% increase from baseline over CATIE (Lieberman et al. 2005)
12 weeks (cf. 10.5% of placebo-treated patients).
Adolescents with schizophrenia or bipolar disorder: Serum
prolactin elevations observed in 47% (cf. 7% with
placebo) (manufacturer’s package insert, Eli Lilly
and Company).
Paliperidone Schizophrenia: 6-week placebo-controlled
monotherapy (comparison to quetiapine)a trial
+38.4±42.8 mg/dL (Canuso et al. 2009).
Quetiapine Bipolar disorder: 84-day placebo-controlled Schizophrenia: –10.6 mg/dL over 9.2-month median
monotherapy trial, mean±SD change from baseline exposure in CATIE (Lieberman et al. 2005)
of –15.3±40.9 mg/dL (no different from placebo)
(Adler et al. 2007).
Schizophrenia: In 6-week placebo-controlled
monotherapy (comparison to paliperidone)a trial,
–8.9+20.6 mg/dL (Canuso et al. 2009).
Endocrinopathies
Risperidone Schizophrenia: Up to 66% of women and 45% of men +13.8 mg/dL over 9.2-month median exposure in
demonstrated significant elevations in serum CATIE (Lieberman et al. 2005)
prolactin from baseline (Kinon et al. 2003).
Across diagnoses in children and adolescents: In FDA
registration trials, up to 87% had dose-dependent
serum prolactin elevations (manufacturer’s package
insert, Janssen Pharmaceutica).
Ziprasidone Transient elevation from baseline that normalizes in –5.6 mg/dL over 9.2 month median exposure in
healthy volunteers or across studies in psychotic CATIE (Lieberman et al. 2005)
disorders (Hamner 2002).
Note. CATIE= Clinical Antipsychotic Trials of Intervention Effectiveness; FDA= U.S. Food and Drug Administration; SD= standard de-
viation.
aIndustry trial sponsored by Ortho-McNeil Janssen Scientific Affairs, Johnson & Johnson Pharmaceutical Research and Development, and
Janssen-Cilag.
183
TABLE 11–4. Reproductive safety considerations during divalproex

therapy in premenopausal women
1. Discuss possibility of reproductive and endocrinological side effects
with female patients before beginning divalproex treatment.
2. Measure baseline body weight and body mass index, and follow
both at each visit; evaluate weight gain.
3. Obtain baseline information about menstrual cycle and assess for
menstrual irregularities at each visit.
4. Consider obtaining baseline and subsequent information about
ovarian structure and serum sex hormone concentrations.
5. Obtain baseline and annual serum lipid profiles.
6. Evaluate at baseline signs of androgen excess (e.g., hirsutism,
alopecia, acne) and follow up at each visit.
7. Measure blood levels of dehydroepiandrosterone and bioavailable
testosterone, and refer to a reproductive endocrinologist if two or
more of the following symptoms are found: hirsutism, menstrual
disturbances, obesity, alopecia, or infertility; consider discontinuing
divalproex if a thorough risk-benefit analysis demonstrates
unfavorable risk.
8. Counsel patient on nutrition and weight management strategies.
9. For women <age 20 years:
• Divalproex is not contraindicated, but use with caution and
follow the recommendations listed above.
• Consider pretreatment workup consisting of serum testosterone
level and pelvic ultrasound, and consider repeating annually.
• Consider changing to a different mood stabilizer if clinical
symptoms of hyperandrogenism or polycystic ovary syndrome
appear.
Source. Adapted from Ernst CL, Goldberg JF: “The Reproductive Safety Pro-
file of Mood Stabilizers, Atypical Antipsychotics, and Broad-Spectrum Psy-
chotropics.” Journal of Clinical Psychiatry 63 (suppl 4):42–55, 2002.
measurable by 24-hour urine collection. (By contrast, primary hyper-

parathyroidism typically causes both hypercalcemia and hypercalci-
uria.) Exacerbations of preexisting hyperparathyroidism, as well as
multiglandular disease, have both been implicated in the pathogenesis
of lithium-induced hyperparathyroidism (Szalat et al. 2009). Some au-
thorities recommend that patients who chronically take lithium should
undergo periodic screening for hypercalcemia, with the use of calcimi-

metic agents (e.g., cinacalcet) to reduce parathyroid hormone release
when necessary (Saunders et al. 2009).
Thyroid Abnormalities
General Recommendations. Lithium, carbamazepine, and
quetiapine all may infrequently cause secondary hypothyroidism.
Baseline measurement of thyroid function tests should include
measurement of antithyroid antibodies when serum thyroid-
stimulating hormone (TSH) is elevated. Repletion typically in-
volves supplemental L-thyroxine (T4), usually begun at 0.025 mg/
day, followed by reassessment of thyroid function tests after
6 weeks, with increases by 0.025 mg every 3–6 weeks until TSH lev-
els normalize.
Subclinical hypothyroidism may arise as a consequence of lithium use

in 5%–35% of individuals receiving lithium, usually within the first 6–
18 months of treatment. The condition is thought to result from several ef-
fects of lithium, including antagonism of TSH, reduced deiodination of
peripheral T4 to triiodothyronine (T3), and interference with cyclic aden-
osine monophosphate–mediated production of thyroid hormone within
the thyroid gland. More rarely, lithium may also cause hyperthyroidism
due to thyroiditis or Graves’ disease (Lazarus 2009). Some studies suggest
that lithium-associated hypothyroidism may be more common among
individuals who have circulating thyroid antibodies. Typically, in pa-
tients with an elevated serum TSH level, the clinician measures anti-
peroxidase and antithyroglobulin to determine whether autoimmune
thyroiditis is present. Note that in contrast to goiter, thyroid nodules are
generally not thought to result from treatment with lithium.
No firm consensus exists on when supplemental thyroid hormone
should be added to the regimen of patients with an elevated serum TSH
level who are taking lithium. Some authorities advocate more frequent
monitoring of serum TSH levels (e.g., every 3 months) in the setting of
biochemical hypothyroidism, without adding exogenous thyroid hor-
mone unless serum TSH levels exceed 10 mU/L or clinical manifestations
emerge. Others advise a lower threshold for adding supplemental thy-
roid hormone whenever serum TSH levels rise above normal, particularly
in the setting of affective symptoms. T4 is usually preferred over T3 to pro-
duce steadier hormone levels, even though T3 may exert more potent psy-
chotropic (e.g., antidepressant) effects.
Supplementation of thyroid hormone for lithium-induced hypothy-

roidism usually begins with the addition of 0.025 mg/day of T4, followed
by a reassessment of thyroid function tests after 6 weeks, and iterative
increases of T4 by 0.025 mg/day until TSH levels have normalized. High-
dose exogenous thyroid hormone—as is sometimes used to achieve su-
prametabolic levels of free T4 in rapid-cycling bipolar disorder—requires
clinicians to recognize the potential for developing arrhythmias (notably,
atrial fibrillation) and promoting bone demineralization and osteoporosis
(sometimes prompting a need for obtaining periodic bone mineral densi-
tometry assessments).
Carbamazepine also hastens the metabolism of T4 and T3 and may
produce secondary hypothyroidism. In addition, a handful of case re-
ports have described hypothyroidism induced by quetiapine, usually in
patients with a history of past thyroid abnormalities (Kelly and Conley
2005), and potentially subject to spontaneous resolution (Kontaxakis et al.
2009). Proposed mechanisms include competitive metabolism of thyroid
hormones and quetiapine by uridine diphosphate–glucuronosyltrans-
ferase (Kelly and Conley 2005) or possibly an autoimmune-mediated pro-
cess, although the rarity of this phenomenon does not appear to warrant
routine monitoring of thyroid function during quetiapine treatment.
12
Gastrointestinal
System
Diarrhea, Hypermotility, and

Constipation
General Recommendations. Loose stools may occur during
initiation of treatment with serotonergic antidepressants or as
part of discontinuation syndromes upon abrupt cessation of
these drugs. Loose stools are usually self-limited phenomena
that can be managed conservatively (e.g., via oral replenishment
of fluid losses and over-the-counter remedies such as loperamide
or bismuth subsalicylate).
Serotonergic antidepressants may cause gastrointestinal (GI) hypermotil-

ity, usually near treatment initiation. Symptoms are usually self-limited
and resolve with time on the drug. As identified in manufacturers’ prod-
uct information materials, FDA registration trials of SSRIs across their in-
dications collectively report incidence rates of diarrhea generally within
187
the range of ~6%–20%, with the highest being vilazodone (28%). Some
SNRIs (e.g., duloxetine, desvenlafaxine) identify lower rates (~10%),
while the lowest rates among antidepressants (>1%–2%, but no different
from placebo) are described with bupropion XL, mirtazapine, and ven-
lafaxine XL. Among mood-stabilizing agents, significant or persistent di-
arrhea with lithium or divalproex should be considered as a possible
indicator of drug toxicity. Frank microscopic colitis also has been associ-
ated with paroxetine, sertraline, and carbamazepine, remediable by drug
cessation (Beaugerie and Pardi 2005).
When necessary, conservative interventions to manage diarrhea
symptoms include increasing dietary fiber (e.g., psyllium husk–contain-
ing products, such as Metamucil), use of nonprescription magnesium
hydroxide (e.g., milk of magnesia) or aluminum hydroxide (e.g., Am-
phojel) products, cyproheptadine, or over-the-counter antidiarrheal
medicines such as loperamide or bismuth subsalicylate. Oral probiotics
(e.g., lactobacillus acidophilus) also represent popular nonprescription
antidiarrheal remedies, but their potential efficacy for psychotropically-
induced GI hypermotility has not been formally studied. Severe or per-
sistent diarrhea in the absence of other identified etiologies may warrant
drug cessation.
Constipation is among the more common adverse effects associated
with drugs that possess antimuscarinic anticholinergic properties (e.g.,
many SGAs, TCAs, benztropine, and some SSRIs [notably, paroxetine]).
Similar incidence rates for constipation (ranging from ~3% to 16%) have
been reported in manufacturers’ product information materials from
FDA registration trials involving SSRIs, SNRIs, bupropion, and mirtaza-
pine. Clinicians obviously should, when possible, attempt to minimize
the cumulative anticholinergic burden of an overall drug regimen. Short-
term use of bulk-forming hydrophilic laxatives (e.g., methylcellulose,
psyllium seed) or stimulant laxatives (e.g., senna) offer conservative first-
line interventions, while agents that stimulate peristalsis (e.g., metoclo-
pramide or bethanechol) may offer additional mechanistically specific
strategies to counteract anticholinergic-associated constipation.
Gastrointestinal Bleeding
General Recommendations. SSRIs, particularly in combina-
tion with NSAIDs or aspirin, may increase the risk for upper GI
bleeding. In SSRI recipients with a history of peptic ulcer disease
or upper GI bleeding, gastroprotective cotherapy (e.g., with a
proton pump inhibitor) may be advisable.
Gastrointestinal System 189
SSRIs have been associated with an approximate 2-fold increased risk

for upper GI bleeding, with a crude incidence rate of 1 in 8,000 SSRI pre-
scriptions (Andrade et al. 2010). Mechanisms thought to account for this
phenomenon include decreased platelet aggregation due to inhibition
of serotonin uptake from blood into platelets, as well as a direct effect
causing increased gastric acid secretion. SSRIs (but not TCAs) have also
been shown to increase the risk for peptic ulcer disease by 1.5-fold, with
a 24% reduction in risk observed with concomitant proton pump inhib-
itors (e.g., omeprazole, lansoprazole, or pantoprazole) (Dall et al. 2010).
Identified risk factors for upper GI bleeding during SSRI therapy in-
clude concomitant use of NSAIDS, aspirin, or antiplatelet drugs (con-
ferring an 8- to 28-fold increased likelihood) or the presence of liver
failure or cirrhosis (Andrade et al. 2010), while cotherapy with proton
pump inhibitors among SSRI recipients as a group may reduce bleeding
risk (Dall et al. 2009). No increased risk of lower GI bleeding during
SSRI treatment has been reported.
Some authors advocate the coadministration of a proton pump in-
hibitor or other gastroprotective agent (e.g., H2 histamine blocker) in
SSRI recipients with a history of upper GI bleeding or peptic ulcer dis-
ease, although the low absolute risk for upper GI bleeding likely obvi-
ates the necessity of gastroprotective measures for most SSRI recipients.
Some authors also advise the discontinuation of SSRIs before elective
surgery in patients with a history of upper GI bleeding, although that
recommendation has not become widely or universally embraced.
Hepatic Impairment and Transaminitis

General Recommendations. Most psychotropic drugs re-
quire lower dosing in the setting of hepatic failure, but few abso-
lute contraindications exist for use of these drugs in patients
with hepatic dysfunction. Although many anticonvulsants and
some antidepressants and SGAs can infrequently raise hepatic
enzyme levels, routine laboratory monitoring is generally less
useful or relevant than regular clinical monitoring for signs and
symptoms suggestive of hepatotoxicity.
The evaluation of hepatic function involves assessment of liver en-

zymes (i.e., alanine aminotransferase [ALT] and aspartate aminotrans-
ferase [AST]), as well as other enzymes (e.g., alkaline phosphatase) and
synthetic proteins made by the liver (e.g., serum albumin, total protein,
total bilirubin, prothrombin time). AST:ALT ratios of 2:1 or 3:1 often
suggest alcohol-induced hepatotoxicity. The detection of recent heavy

alcohol use can be aided by the measurement of serum carbohydrate-
deficient transferrin, a highly specific but only moderately sensitive
marker for drinking behavior. γ-Glutamyl transpeptidase (γGTP), an-
other enzyme synthesized exclusively by the liver, is a nonspecific mea-
sure of liver dysfunction that is sometimes used as an indicator of even
modest alcohol consumption or as a means to clarify hepatic- versus
bone-based causes of an elevated serum alkaline phosphatase. An ele-
vated γGTP level also may occur in congestive heart failure or other
conditions that involve liver injury and by itself does not help to distin-
guish a cause for hepatic dysfunction.
Medication-induced hepatotoxicity often involves serum ALT>AST.
In overweight individuals at risk for metabolic syndrome, mild trans-
aminitis (in which ALT and AST levels usually do not exceed 4 times the
upper limit of normal) may reflect nonalcoholic steatohepatitis, a hepatic
inflammatory condition affecting 2%–5% of Americans (particularly mid-
dle-aged, overweight adults) that can lead to hepatocellular damage, fi-
brosis, and eventual cirrhosis. Importantly, 10%–25% of Americans have
simple fatty liver without inflammation (nonalcoholic fatty liver disease),
addressable by treating the underlying metabolic risk factors (particu-
larly obesity and hyperlipidemia).
Many psychotropic drugs, including divalproex, carbamazepine,
TCAs, SNRIs, and SGAs, can be associated with modest elevation of se-
rum liver enzyme levels. For example, incidence rates of transaminitis
with carbamazepine in epilepsy patients range from 5% to 15%, although
fewer than 20 cases of significant liver impairment were reported over a
12-year period studied (Pellock and Willmore 1991). Frank hepatotoxicity
has been reported in connection with the use of carbamazepine, dival-
proex (■), duloxetine, and nefazodone (■). Hepatic enzyme elevation
may be caused by numerous nonpsychotropic medications, including
acetaminophen, NSAIDs, statins, ACE inhibitors, omeprazole, allopur-
inol, certain antibiotics, and oral contraceptives, among others. There are
no formal manufacturers’ recommendations or guidelines on the indica-
tions for monitoring of liver enzymes, with the exceptions of divalproex
and carbamazepine (see Table 1–2 in Chapter 1, “The Psychiatrist as Phy-
sician”), unless indicated based on the emergence of clinical signs (e.g.,
icteric sclerae or jaundice, changes in stool color).
Some authorities point out that regular, routine laboratory monitor-
ing of liver enzymes or other parameters that reflect hepatic function
(e.g., prothrombin time, partial thromboplastin time, protein levels) are
often normal in anticonvulsant recipients who subsequently develop
hepatotoxicity; more relevant to safety monitoring is the ability to rec-
ognize clinical signs of hepatic failure (e.g., nausea, vomiting, anorexia,

lethargy, jaundice) (Pellock and Willmore 1991).
In general, most hepatically cleared drugs can be continued unless
liver enzymes exceed 3 times the upper limit of normal. Preexisting liver
disease (e.g., hepatitis, alcoholic liver disease) does not automatically
contraindicate the use of hepatically metabolized psychotropic drugs.
Degrees of hepatic impairment are rated by the Child-Pugh classifica-
tion scale (see Table 3–1 in Chapter 3, “Vulnerable Populations”), which
takes into account total bilirubin, serum albumin, ascites, INR, and the
presence of hepatic encephalopathy. The extent to which hepatic dys-
function may alter drug clearance, and potentially necessitate hepatic
dosing of psychotropic medications, is summarized in Table 12–1.
Hyperammonemia
General Recommendation. In patients with an acute men-
tal status change who are taking divalproex or carbamazepine,
serum ammonia level should be measured to determine the pos-
sible presence of hyperammonemia. If either of these agents is
the suspected cause of hyperammonemia, discontinue the drug
and consider administration of L-carnitine 1,000 mg twice daily
and/or lactulose to hasten the elimination of serum ammonia.
Asymptomatic hyperammonemia caused by divalproex or car-
bamazepine does not necessarily require intervention.
Laboratories vary in defining reference range upper limits for serum

ammonia levels, although levels exceeding 70 µg/dL in adults are gen-
erally thought to reflect clinically significant elevation. Hyperammon-
emia may be associated with hepatic encephalopathy and warrants
consideration in the differential diagnosis of patients with an acute
mental status change when hepatic disease (e.g., cirrhosis, hepatitis, al-
cohol withdrawal) may be present. Clinicians should be attentive to the
presence of vomiting and asterixis or other focal neurological signs
(e.g., hyperreflexia) when considering the possibility of hepatic enceph-
alopathy.
In the early 1980s, case reports began to emerge describing asymp-
tomatic hyperammonemia as well as hyperammonemic encephalopa-
thy in both child and adult epilepsy patients taking divalproex. A pro-
spective case series by Raja and Azzoni (2002) identified asymptomatic
hyperammonemia (serum ammonia>97 µg/dL) with normal liver en-
zyme levels in 51% of adult psychiatric inpatient recipients of dival-
TABLE 12–1. Dosing adjustments or precautions in the presence of

hepatic failure
Agent Comment

Carbamazepine Caution is advised when used in patients with
hepatic dysfunction.
Divalproex Drug is contraindicated in the setting of significant
Gabapentin Drug is not appreciably metabolized and is excreted
unchanged; dosing adjustment in the setting of
hepatic disease therefore is unnecessary.
Lamotrigine Dosing should be reduced by 25%–50% in the
setting of moderate or severe hepatic impairment,
according to the manufacturer’s package insert.
Metabolized by Phase II glucuronidation.
Lithium All preparations of lithium are renally excreted
with no hepatic metabolism; no dosing
adjustment is necessary in the setting of hepatic
failure.
Oxcarbazepine No dosing adjustment is necessary in patients with
mild to moderate hepatic impairment; caution is
advised when used in patients with severe
Topiramate Dosing should be reduced and intervals between
doses should be increased in the setting of hepatic
dysfunction.
Antidepressants and related agents
Atomoxetine Initial dosing should be reduced by 50% in patients
with moderate hepatic impairment and by 75% in
those with severe hepatic impairment.
Bupropion Caution is advised in the setting of mild to
moderate hepatic impairment; in severe hepatic
impairment, the manufacturer of bupropion XL
advises dosages no higher than 150 mg every
other day.

hepatic failure (continued)
Agent Comment
Antidepressants and related agents (continued)

Buspirone Hepatic insufficiency may increase serum
buspirone levels 13-fold. The manufacturer
advises against using buspirone in individuals
with severe hepatic dysfunction.
Duloxetine Administration is not recommended for patients
with any hepatic insufficiency.
Mirtazapine Oral clearance of mirtazapine is decreased by
approximately 30% with hepatic insufficiency.
Consequently, dosages should be reduced in
patients with moderate or severe hepatic
impairment.
Nefazodone Plasma concentrations increase by ~25% in the
setting of liver disease. Black box warning (■)
indicates that nefazodone should not be
administered in patients with active liver disease
or when liver enzymes exceed 3 times the upper
limit of normal.
SSRIs Citalopram: Half-life approximately doubles in the
setting of hepatic dysfunction; a dosage of 20 mg/
day is recommended.
Escitalopram: A dosage of 10 mg/day is
recommended with hepatic impairment.
Fluoxetine: Lower or less frequent doses are
advised.
Fluvoxamine: Plasma clearance is decreased by
~30%; low initial dosing is advised.
Paroxetine: Plasma concentrations are increased
approximately 2-fold; low initial dosing is
advised.
Sertraline: Plasma concentrations are increased
approximately 3-fold; low initial dosing is
advised.
Transdermal No dosing adjustment is necessary in patients with
selegiline mild or moderate hepatic impairment.

hepatic failure (continued)
Agent Comment
Antidepressants and related agents (continued)

Venlafaxine or In the setting of mild or moderate hepatic
desvenlafaxine impairment, total daily dosages of venlafaxine
or desvenlafaxine should be reduced by 50%
or more based on individual variation.
Desvenlafaxine should not be dosed >100 mg/
day in the setting of hepatic impairment.
Vilazodone No dosing adjustment is necessary in patients with
mild or moderate hepatic impairment.
SGAs
Asenapine Drug is not recommended for use in patients with
hepatic failure. It is metabolized by Phase I
oxidation (CYP1A2) and Phase II glucuronidation
(UGT1A4).
Lurasidone In the setting of moderate or severe hepatic
impairment, maximum dosage recommended by
the manufacturer is 40 mg/day.
Olanzapine Mild hepatic impairment (Child-Pugh classes A
and B) produces little effect on clearance of
olanzapine.
Paliperidone No dosing adjustments are necessary for mild to
moderate hepatic impairment.
Quetiapine The manufacturer advises that patients with
hepatic impairment begin treatment at
25 mg/day, with daily increases of 25–50 mg/day
based on clinical response and tolerability.
Risperidone In the setting of hepatic impairment, dosage
increases should be no higher than 0.5 mg twice
daily, and increases above 1.5 mg twice daily
should occur at least 1 week apart.
Ziprasidone No dosing adjustments are necessary for mild to
moderate hepatic impairment.
Note. CYP=cytochrome P450; SGA=second-generation antipsychotic; SSRI=
selective serotonin reuptake inhibitor; XL=extended release.
proex, ameliorated solely by divalproex dosage reductions. Notably, no

clear correlation has been demonstrated between asymptomatic hyper-
ammonemia and serum valproate levels. The clinical significance of
asymptomatic hyperammonemia due to divalproex, if any, is uncertain.
Hyperammonemia has also been reported as an idiosyncratic phe-
nomenon in association with carbamazepine in the absence of labora-
tory indices of hepatic impairment, remedied by oral lactulose and the
cessation of carbamazepine. Other possible causes of hyperammonemia
include barbiturates, opiates, diuretics, and cigarette smoking, as well
as hemolytic processes (e.g., GI bleeding), reduced ammonia clearance
due to fulminant hepatic failure (e.g., following acetaminophen over-
dose), and inborn errors of metabolism in both children and adults. Ex-
cessive exercise or seizures can also increase direct ammonia produc-
tion from skeletal muscle.
Numerous factors can predispose to the development of hyperam-
monemia among divalproex recipients, including severe alcoholism,
high dietary nitrogen intake in the setting of low caloric intake, urea cycle
disorders among pediatric patients, and combinations of anticonvulsant
drugs among epilepsy patients. Importantly, divalproex may directly el-
evate serum ammonia levels by depleting body stores of carnitine, a qua-
ternary ammonium compound synthesized from the essential amino
acids methionine and lysine in the liver that is a necessary cofactor for
β-oxidation of fatty acids. Measurement of serum carnitine levels is
thought to be uninformative in estimating its bioavailability in the liver
because it is stored mainly in muscle. The use of oral lactulose is gener-
ally reserved for hyperammonemic patients who manifest clinical signs
of encephalopathy.
Case reports have suggested that supplemental dietary L-carnitine
(1 g po bid) can reverse signs of lethargy and mental slowing in the set-
ting of otherwise asymptomatic hyperammonemia during divalproex
therapy. There is presently no consensus recommendation within the
field as to the necessity for routinely monitoring serum ammonia levels in
the absence of lethargy or other CNS features suggestive of encephalop-
athy, or in routine supplementation of oral L-carnitine in asymptomatic
divalproex recipients. In our experience, given the relative rarity of symp-
tomatic hyperammonemia and the dubious clinical significance of its
asymptomatic presence, we concur with the manufacturer in not advo-
cating routine measurement of serum ammonia levels during divalproex
treatment, although it likely warrants evaluation in patients taking dival-
proex who develop acute mental status changes, for which treatment
with supplemental L-carnitine (1 g bid) may be ameliorative.
Malabsorption Disorders
General Recommendations. Some anticonvulsants may in-
terfere with absorption or metabolism of vitamin B12 and folic
acid. Folic acid supplementation is commonly recommended
during anticonvulsant therapy in pregnancy to minimize risk for
neural tube defects. However, routine screening or repletion of
these vitamins during anticonvulsant therapy in nonepileptic
patients generally is not done in the absence of clinical signs of
deficiency.
Low serum levels of vitamin B12 (cobalamin) and folic acid found in epi-
leptic adults have been associated with a number of anticonvulsants, in-
cluding carbamazepine, divalproex, gabapentin, oxcarbazepine, and
topiramate (but not lamotrigine or zonisamide) (Kishi et al. 1997; Sander
and Patsalos 1992). Impaired GI absorption has been proposed as one
possible mechanism, although other plausible explanations for this phe-
nomenon include impaired plasma binding, disrupted renal secretion,
and (at least in the case of carbamazepine, oxcarbazepine, or topiramate)
hastened metabolism via induction of CYP microenzymes (Belcastro et
al. 2010; Linnebank et al. 2010). Because folic acid and vitamin B12 are
necessary to convert homocysteine to methionine, deficient levels can
elevate plasma homocysteine, in turn predisposing to vascular endo-
thelial damage and cardiovascular or cerebrovascular disease. Clini-
cally, low levels of vitamin B12 or folic acid may also cause megaloblastic
anemia, neuropathy, cognitive deficits, and osteoporosis, among other
metabolic or homeostatic disturbances. Low serum folic acid levels due
to anticonvulsant exposure during pregnancy are well-recognized con-
tributors to neural tube defects (see the section “Teratogenicity” in Chap-
ter 20, “Pregnancy and the Puerperium”). Although some authors
advocate periodic laboratory monitoring of serum folic acid and vitamin
B12 levels during therapy with most anticonvulsants in women (irrespec-
tive of pregnancy status) as well as men, with repletion (e.g., 1 mg/day of
oral folic acid [Morrell 2002] or 1,000–2,000 µg/day of oral vitamin B12
[Kuzminski et al. 1998]), there is no formal recommendation by the
American Epilepsy Society or the American Academy of Neurology ei-
ther for routine serum monitoring or replacement therapy in asymp-
tomatic anticonvulsant recipients.
Nausea and Gastrointestinal Upset

General Recommendations. Nausea often occurs as a tran-
sient side effect from serotonergic antidepressants that indis-
criminately stimulate postsynaptic serotonin type 3 (5-HT3)
receptors, and may be minimized by coadministration with food
or over-the-counter antiemetics such as bismuth subsalicylate or
antihistamines. Prescription-strength antihistamine antiemet-
ics, such as trimethobenzamide or promethazine, may be useful
if significant nausea persists.
Serotonergic agents commonly cause nausea due to their undesirable

affinity for 5-HT3 receptors, resulting in the most frequent adverse effect
associated with SSRIs. Accordingly, psychotropic agents that block post-
synaptic 5-HT3 receptors (notably, mirtazapine or olanzapine) have a
lower likelihood for causing nausea than do drugs that nonselectively ag-
onize this receptor and may in fact possess potent antiemetic properties.
Nausea and GI upset are usually transient phenomena with most
psychotropic medications that cause them. Antipsychotic drugs gener-
ally do not cause nausea, and some in fact are commercially marketed as
antiemetics (e.g., phenothiazines such as prochlorperazine, or the do-
pamine D2 antagonist metoclopramide)—albeit with high risk for extra-
pyramidal side effects by virtue of their D2 antagonistic effects, includ-
ing in the chemoreceptor trigger zone. Patients’ complaints of nausea
should be evaluated not only from the standpoint of their acclimation to
a new drug but also as possibly indicating erratic treatment adherence
with frequent missed doses and withdrawal states. Anecdotally, com-
pared with branded formulations, generic formulations of serotonergic
antidepressants may be more likely to cause nausea and GI upset. Spe-
cifically, in the case of lithium, long-acting preparations that are ab-
sorbed more distally in the GI tract (e.g., Eskalith CR) or lithium citrate
solution may be associated with less upper GI upset but potentially more
lower GI symptoms (e.g., loose stools or diarrhea).
Adjunctive pharmacotherapies may sometimes be appropriate and
useful to counteract transient nausea, although a more overriding con-
cern is determining whether nausea represents a more serious adverse
drug effect (e.g., pancreatitis from divalproex) or drug toxicity state (e.g.,
elevated lithium levels). In patients taking lithium, associated neurologi-
cal signs (e.g., ataxia, tremor) or other GI symptoms (e.g., abdominal
cramping) should alert the clinician to recognize nausea as a potential

indicator of drug toxicity rather than merely a benign adverse effect re-
mediable by symptomatic treatment. Antihistamines with antiemetic
properties, such as trimethobenzamide (300 mg tid prn) or promethazine
(12.5–25 mg bid prn), are perhaps the most reliable and safe pharmaco-
logical interventions for transient nausea. Antiemetic phenothiazines
such as prochlorperazine or the D2 antagonist/5-HT3 antagonist metoclo-
pramide also may be of value, although their potential for causing move-
ment disorders due to their nigrostriatal antidopamine effects limits
enthusiasm for their long-term use. (The FDA has approved use of meto-
clopramide for no longer than 4–12 weeks.)
Pancreatitis
General Recommendations. Patients who develop an acute
abdomen require prompt evaluation. Patients taking divalproex,
or less commonly, some SGAs (e.g., quetiapine, olanzapine, clo-
zapine), should be assessed for iatrogenic pancreatitis through
physical examination, measurement of serum lipase and amy-
lase, and possible radiographic evaluation. In the setting of acute
pancreatitis, the aforementioned drugs should be discontinued
and not reintroduced.
Divalproex (both delayed- and extended-release formulations) may

rarely be associated with the development of acute pancreatitis (■). The
mechanism by which this may occur is not well understood. From 1979
to 2005, 90 cases were reported worldwide, although the true incidence
may be underrecognized and underreported (Gerstner et al. 2007).
Cases have been reported to occur during both recent and long-term
treatment, up to 19 years after drug initiation (Taira et al. 2001). Routine
screening of serum lipase or amylase levels in divalproex recipients is
neither recommended nor clinically indicated in the absence of clinical
signs that are suggestive of acute pancreatitis (i.e., development of an
acute abdomen).
Some SGAs (e.g., quetiapine, olanzapine, clozapine) have been asso-
ciated with acute pancreatitis independent of hypertriglyceridemia or
hyperglycemia, arising via poorly understood mechanisms.
Many nonpsychotropic drugs can also cause acute pancreatitis; these
include estrogen, calcium, anticholinesterases, thiazide diuretics, pen-
tamidine, ACE inhibitors, furosemide, tetracycline, metronidazole, iso-
niazid, rifampin, sulfonamides, cyclosporine, asparaginase, vinca

alkaloids, and other antineoplastic drugs. Careful attention should be
paid to other factors that may predispose patients to acute pancreatitis—
notably, alcohol abuse or dependence (which often may be comorbid
with conditions for which divalproex or an SGA may be used, such as bi-
polar disorder or impulsive aggression)—or hyperlipidemic states. Di-
valproex or the aforementioned SGAs should be discontinued and not
reintroduced following the identification and proper medical manage-
ment of acute pancreatitis.
13
Genitourinary and
Renal Systems
Dysuria and Urinary Retention

General Recommendations. Anticholinergic drugs or α2-adren-
ergic blocking agents, as well as SNRIs, may in rare cases cause uri-
nary hesitancy or retention. Risk factors apart from preexisting
benign prostatic hypertrophy have not been identified. Drugs
suspected of causing urinary hesitancy or retention generally
should be discontinued. Dysuria is an uncommon consequence
of psychotropic agents that if not secondary to urinary hesitancy
or retention, likely warrants independent urological evaluation.
Symptomatic relief from urinary hesitancy or retention may occur
from the temporary use of bethanechol (10–50 mg tid to qid), and
dysuria may respond to the urinary tract analgesic phenazo-
pyridine (200 mg tid with meals).
Anticholinergic agents can be associated with dysuria or urinary hesi-

tancy, as well as urinary retention. Acute urinary retention also has been
reported with SSRIs, SNRIs, and their combination (e.g., fluoxetine plus
venlafaxine). Randomized controlled trials of duloxetine for major de-
pression have collectively identified an incidence of 1% (20 of 2,097 sub-
jects) encountering obstructive voiding symptoms, although no subjects
201
developed urinary retention requiring catheterization (Viktrup et al.

2004). SNRI-associated urinary retention presumably arises due to
α2-adrenergic receptor antagonism, leading to contraction of the striated
urethral sphincter. The risk for urinary hesitancy or urinary retention
would presumably be higher in individuals with existing risk factors,
such as benign prostatic hypertrophy, or in patients taking additional
medications that may constrict bladder outflow. Urinary retention also
has been reported as a rare adverse effect (~1% incidence) with the novel
stimulant modafinil (manufacturer’s product information, Cephalon).
The parasympathomimetic agent bethanechol is sometimes used to
counteract urinary hesitancy. Typical adult dosing is 10–50 mg tid to
qid. Pyridium is a urinary tract analgesic that is frequently used for the
symptomatic relief of pain caused by irritation of the urinary tract mu-
cosa. Adult dosing is typically 200 mg tid with meals.
Enuresis and Urinary Incontinence

General Recommendations. Urinary incontinence may be a
rare adverse effect with a number of antipsychotic, antidepres-
sant, or anticonvulsant drugs. Enuresis is not clearly dose related,
although it may be influenced in part if heavy sedation occurs.
Reasonable pharmacological remedies for enuresis and urinary
incontinence include adjunctive anticholinergic drugs (e.g., benz-
tropine), ephedrine, intranasal desmopressin acetate (DDAVP;
10 µg in each nostril at bedtime), oxybutynin (5 mg bid to tid), or
substitution of alternative pharmacotherapies for the presump-
tive offending agent.
Enuresis is a relatively infrequent adverse effect associated with cloza-

pine and may respond to the anticholinergic drugs trihexyphenidyl
(5 mg nightly) or benztropine (0.5–2 mg nightly). Urinary incontinence
has been reported with risperidone (especially during cotherapy with
SSRIs such as fluoxetine, which may increase serum risperidone levels),
olanzapine, clozapine, gabapentin, SSRIs (including paroxetine and ser-
traline), and some SNRIs (e.g., venlafaxine). Diagnostic evaluation of en-
uresis with SGAs may require determining the absence of diabetes
mellitus and nocturnal seizures or the presence of neurogenic bladder
dysfunction. Ephedrine, up to 150 mg/day, has been reported as a poten-
tially useful strategy to counteract olanzapine- or clozapine-induced uri-
nary incontinence.
Drugs that may cause urinary retention (e.g., modafinil, anticholin-
ergic drugs, and SNRIs such as duloxetine) may potentially counterbal-
Genitourinary and Renal Systems 203
ance urinary incontinence if cotherapy is otherwise appropriate within

an overall pharmacotherapy regimen. With respect to more traditional
strategies for managing urinary incontinence, lack of efficacy was re-
ported with the bladder-specific antimuscarinic agent tolterodine 2 mg
bid in an adolescent female whose clozapine-induced enuresis was ul-
timately ameliorated by intranasal desmopressin (English et al. 2001).
When used to counteract clozapine-induced enuresis, desmopressin na-
sal spray (typically dosed as 10 µg in each nostril at bedtime) may be as-
sociated with significant hyponatremia (Sarma et al. 2005). Oxybutynin,
dosed at 5 mg bid or tid, also may be of value in the general manage-
ment of iatrogenic enuresis. Persistent enuresis that is unresponsive to
the pharmacological interventions recommended in this section and
that does not eventually remit spontaneously may ultimately require
replacement of the suspected causal agent with an alternative psycho-
tropic medication.
Nephrotic Syndrome
General Recommendations. In rare cases, lithium may
cause nephrotic syndrome, which is remediable by cessation of
the drug.
Nephrotic syndrome arises from damage to the glomerular basement

membrane (causing leakage of protein from filtered blood to urine),
therefore manifesting with proteinuria without hematuria (cf. nephritic
syndrome), as well as hypoalbuminemia, edema, and hyperlipidemia.
A handful of published cases have linked its occurrence with lithium
therapy, although no risk factors for its development have been identi-
fied. Drug cessation, sometimes followed by corticosteroids, generally
leads to resolution of symptoms. Clinicians should bear in mind that
nephrotic syndrome may also arise as part of the syndrome of drug-
induced lupus erythematosus (see the section “Drug-Induced Lupus
Erythematosus” in Chapter 19, “Systemic Reactions”) and may warrant
pertinent laboratory evaluation.
Nephrotoxicity and Nephrogenic

Diabetes Insipidus
General Recommendations. Lithium-associated polyuria or
nephrogenic diabetes insipidus (NDI) can usually be effectively
managed by the addition of amiloride 5 mg qd or bid; periodic

monitoring of serum potassium levels would be appropriate in
cases of ongoing or long-term amiloride use. Once-daily lithium
dosing may diminish the potential for developing long-term lith-
ium-induced glomerulosclerosis.
During the course of lithium therapy, urinary frequency or quantity

(i.e., polyuria) is common (evident in up to 70% of otherwise healthy in-
dividuals). NDI is the most common adverse renal effect of lithium, oc-
curring with an incidence of up to 40% (Grünfeld and Rossier 2009), and
is a clinical diagnosis defined by the presence of polyuria, polydipsia,
and a dilute urine with low urine electrolytes and osmolality, caused by
impaired urinary concentrating ability. In contrast to diabetes mellitus,
NDI involves an absence of glycosuria or hyperglycemia. A first step in
identification involves obtaining a urinalysis to determine whether
urine specific gravity is low, as well as measurements of urine electro-
lytes and osmolality. Serum sodium levels may be elevated due to hy-
povolemia caused by polyuria. Although some authorities believe that
the development of NDI warrants cessation of lithium, others advise
treating it with the potassium-sparing diuretic amiloride (typically
dosed at 5 mg bid) (Finch et al. 2003), which has been shown to restore
renal medullary osmolytes (i.e., concentrating ability). NSAIDs such as
indomethacin also can reduce urinary free water loss and are some-
times used to help manage NDI.
Lithium-associated nephrotoxicity has long been recognized as a
possible consequence of acute overdose, but whether it occurs at thera-
peutic dosages during long-term maintenance treatment has been more
controversial. Before 2000, an extensive literature challenged the neph-
rotoxicity of lithium, or the assertion that long-term lithium use caused
changes in glomerular filtration rate (GFR) (Gitlin 1999; Schou 1988,
1997). Histopathological evidence from autopsy studies demonstrated
unequivocal evidence of lithium-induced chronic tubulointerstitial
nephrotoxicity (primarily affecting distal and collecting tubules) and
segmental or global glomerulosclerosis (Markowitz et al. 2000), which
challenged prior assumptions about the rarity (or even nonexistence) of
structural kidney changes caused by lithium. Reports in the literature
have estimated the incidence of renal insufficiency as ranging from 4%
(Gitlin 1993) to 20% (Lepkifiker et al. 2004), with variability based on the
duration of exposure and the definition of renal insufficiency (e.g.,
loosely defined in some retrospective studies based on serum creatinine
levels ≥1.5 mg/dL). Although existing proprietary formulations of lith-
ium carbonate advise administration in divided doses two or three
times daily, it can be dosed all at once, given its 24-hour elimination
half-life; moreover, once-daily lithium dosing has been suggested to
pose a lesser risk than multiple daily doses for developing glomerulo-
sclerosis (Plenge et al. 1982). On the other hand, some authorities express
concern about the potential for once-daily lithium dosing to increase neu-
rotoxicity due to a resultant high maximum plasma concentration.
The customary practice is to monitor serum creatinine levels every
6 months for patients receiving long-term lithium therapy. Generally, if
serum creatinine levels rise >25% from a patient’s own previous level,
or exceed 1.6 ng/mL, further investigation is warranted (Gitlin 1993).
Creatinine clearance (CrCl), which is an approximation of the GFR, is a
more specific measurement of renal function than serum creatinine. It
reflects the flow rate of fluid undergoing filtration through the renal tu-
bular system. Moreover, serum creatinine alone may be insensitive to
milder degrees of renal insufficiency and can be normal even in the set-
ting of substantially reduced GFR (Jefferson 2010). As noted in the sec-
tion “Older Adults” in Chapter 3 (“Vulnerable Populations”), GFR
typically diminishes by 10 mL/min for every decade after age 40 and is
also dependent on weight. A normal GFR is approximately 97–137 mL/
min for men and 88–128 mL/min for women.
CrCl can be estimated by the Cockcroft-Gault equation:
(140–age)×weight (in kg)×(0.85 if female)

CrCl =
72×serum creatinine
Use of estimating equations such this one are considered the best overall
indicator of kidney function (National Kidney Foundation 2002) but can
be imprecise in early stages of chronic kidney disease and may sometimes
underestimate true GFR (Jefferson 2010). In patients who complain of ex-
cessive fluid intake and urinary frequency or polyuria, direct measure-
ment of CrCl by 24-hour urine collection is usually advisable (Jefferson
2010). Although this procedure can be easily done on an outpatient basis,
it requires careful attention to accurate specimen collection and transport.
A usual reference range for healthy adults is 85–125 mL/min. Lower lev-
els may warrant further investigation. Degrees of chronic kidney disease
are classified by the National Kidney Foundation’s Kidney Disease Out-
comes Quality Initiative (2002), as summarized in Table 13–1.
Patients who exercise heavily or lift weights may have elevated levels
of muscle creatinine kinase, prompting some authorities to recommend
measurement of serum cystatin C, a low-molecular-weight renally fil-
tered protein that can serve as a separate marker of renal function and is
inversely related to GFR. Clinicians also should consider other possible
TABLE 13–1. Classification of chronic kidney disease
Stage Description Glomerular filtration rate (GFR)
1 Kidney damage with no ≥90 mL/min/1.73 m2

GFR increase
2 Kidney damage with mild 60–89 mL/min/1.73 m2
GFR decrease
3 Moderately decreased GFR 30–59 mL/min/1.73 m2
4 Severely decreased GFR 15–29 mL/min/1.73 m2
5 Kidney failure <15 mL/min/1.73 m2 (or dialysis)
Source. National Kidney Foundation 2002.
causes of age-related inappropriately diminished CrCl, such as medica-

tions (e.g., cimetidine, ACE inhibitors, and certain nephrotoxic antibiot-
ics such as trimethoprim and cephalosporins).
Priapism
General Recommendations. Iatrogenic priapism is a rare
phenomenon that may occur during treatment with trazodone,
as well as several SGAs, SSRIs, or bupropion. Priapism constitutes
a medical and possible surgical emergency and requires urgent
evaluation in an appropriate medical setting such as an emer-
gency department.
Priapism is defined by the American Urological Association as an erec-

tion that occurs without sexual stimulation and lasts longer than 4 hours.
As a type of compartment syndrome, it poses a medical (if not surgical)
urological emergency and involves a specific management strategy as
outlined in clinical guidelines published by the American Urological As-
sociation (Montague et al. 2003). Urologists differentiate between pri-
apism that is ischemic (low-flow, painful) and nonischemic (high-flow,
less common, and generally nonemergent, usually resulting from arterial
steal or shunting of blood). Psychotropically induced priapism involves
ischemic priapism. Nonischemic priapism may result from several pri-
mary medical conditions, including sickle cell anemia, hematological ma-
lignancies, thalassemia, and genital trauma.
By definition, ischemic priapism is not ameliorated by sexual inter-
course or masturbation. Its proper evaluation and treatment should occur
in an emergency department or similar medical setting. The American

Urological Association advises urgent intracavernous injection of an
α-adrenergic sympathomimetic agent, such as phenylephrine, with or
without evacuation of blood in the corpus cavernosum, performed with
local or regional anesthesia. If this treatment fails to alleviate priapism, a
surgical shunting procedure may be necessary. Oral medications such as
β2-adrenergic agonists (e.g., terbutaline) or the oral α-adrenergic agonist
pseudoephedrine, although sometimes used in nonischemic priapism,
are not recommended for the treatment of ischemic priapism.
Priapism is an exceedingly rare but often-mentioned adverse effect
associated with trazodone (incidence of approximately 1 in 6,000; re-
ports include its occurrence after only a single dose). Less well recog-
nized are rare cases of priapism associated with both FGAs and SGAs,
possibly mediated by α1-adrenergic blockade (Andersohn et al. 2010),
including reports involving quetiapine, risperidone, ziprasidone, clo-
zapine, and olanzapine. Rare cases of priapism also have been reported
with fluoxetine, fluvoxamine, citalopram, and bupropion. In addition,
cases of clitoral priapism that manifest with vulvar pain lasting from 24
to 60 hours have been described in connection with the use of trazodone,
olanzapine, nefazodone, citalopram, and bupropion; this effect is man-
aged with drug cessation and the administration of α-adrenergic agonists
in analogous fashion to that of male priapism. Clinicians should consider
a broad differential diagnosis for priapism, particularly in women with
respect to vascular obstruction due to pelvic floor and bladder malig-
nancies.
Renal Calculi
General Recommendations. A history of renal calculi is a
relative contraindication to treatment with topiramate. Ade-
quate hydration is imperative in all patients taking topiramate
to minimize the risk of stone formation.
Calcium phosphate renal calculi are a known risk (approximately 1%

incidence) in individuals taking topiramate, attributable to topira-
mate’s inhibition of carbonic anhydrase in the kidney, which in turn can
cause hypocitraturia, hypercalciuria, and acidified urine. Accordingly,
a history of nephrolithiasis is a relative contraindication to the use of
topiramate. Some practitioners advise increased oral water intake in pa-
tients taking topiramate, although it is not clear whether this precaution
meaningfully counters the risk for developing renal calculi. Notably, in-
dividuals who follow a ketogenic diet (i.e., high-protein diet with

avoidance of carbohydrates) may be independently predisposed to the
development of renal calculi due to hypercalciuria, decreased urinary
citrate excretion, and acidified urine; hence, the use of topiramate in
conjunction with a ketogenic diet may warrant particular caution with
respect to monitoring for nephrolithiasis (Paul et al. 2010).
Renal calculi (composed of calcium or urate salts) appear to be a rare
phenomenon with zonisamide (15 cases reported from 1,296 clinical
trial subjects [1.2% incidence] over an 8.7-year period; Wroe 2007).
However, the manufacturer’s product information identifies a 4% inci-
dence rate during drug development for adult epilepsy, arising most of-
ten from 6 to 12 months after drug initiation but with new cases still
occurring > 1 year after beginning therapy. The manufacturer advises
that patients drink 6–8 glasses of water daily to help prevent kidney
stone formation.
Renal Insufficiency
General Recommendations. Random creatinine measure-
ments are advisable semiannually with lithium; serum creati-
nine rises of >25% from a prior baseline may warrant collection
of 24-hour urine for direct measurement of CrCl. No absolute
value has been established for GFRs below which lithium or other
renally cleared drugs should be discontinued, but progressive
declines in renal function or the emergence of moderate to se-
vere renal impairment signals the need for closer, more frequent
renal monitoring, as well as renal dosing of many medications
and their probable eventual discontinuation.
Most psychotropic drugs either are directly excreted renally or have ac-
tive metabolites that are renally excreted. Hence, the presence of im-
paired renal clearance often requires reduced dosing depending on the
magnitude of renal insufficiency, as described in Table 13–1. Table 13–2
summarizes manufacturers’ recommendations for dosing adjustments of
psychotropic medications in the setting of renal insufficiency.
Sexual Dysfunction
Impaired Arousal, Erectile Dysfunction,
and Anorgasmia
General Recommendations. Among SSRIs, fluvoxamine ap-
pears to be the least likely to cause sexual dysfunction. SNRIs may
be somewhat less likely than SSRIs to cause this phenomenon, al-
though such differences have not been affirmed in comparative
trials. Bupropion has a low incidence of sexual dysfunction, but its
addition to SSRIs does not clearly overcome existing iatrogenic
sexual dysfunction. Adjunctive sildenafil 50–100 mg/day, up to
200 mg/day, appears to be the most effective pharmacological in-
tervention to remedy sexual arousal that is diminished by sero-
tonergic antidepressants in men or women.
Patient concerns about impaired sexual functioning resulting from

psychotropic medications rank among the highest reasons for poor ad-
herence to continued treatment with antidepressants and other (usually
serotonergic or antidopaminergic) agents (Kennedy and Rizvi 2009;
Serretti and Chiesa 2011). However, because patients often may not
spontaneously discuss sexual functioning, either as a possible drug side
effect or illness symptom, clinicians need to proactively assess sexual
function with an awareness of the relative adverse sexual effects of dif-
ferent psychotropic agents, as well as the distinct areas of human sexual
responsivity affected by common medications. Indeed, although pre-
marketing studies of many antidepressants identify relatively low rates
of spontaneously reported sexual dysfunction, adverse sexual effects
are often not proactively assessed in pivotal trials, and hence are under-
reported. Findings from studies in which patients were specifically
asked about sexual dysfunction with SSRIs or other antidepressants
suggest that incidence rates may be as high as 80% (Hu et al. 2004). For-
mal assessment ratings, such as the Arizona Sexual Experiences Scale
(ASEX; McGahuey et al. 2000), the Changes in Sexual Functioning Ques-
tionnaire (CSFQ; Clayton et al. 1997), or the Psychotropic-Related Sexual
Dysfunction Questionnaire (PRSexDQ; Montejo and Rico-Villademoros
2008) (see “Rating Scales for Measuring Adverse Drug Effects” in Appen-
dix 2) may aid clinicians in detecting and monitoring sexual dysfunction
during longitudinal treatment.
The human sexual response cycle is divided into three components,
including interest (libido), excitation and arousal (i.e., erections in men
and vaginal lubrication in women), and orgasm. Diminished interest in
TABLE 13–2. Renal considerations for psychotropic

agents
Agent Recommendations
Atomoxetine No dosing adjustment is necessary in the setting of

renal insufficiency.
Buspirone Patients with CrCl of 10–70 mL/min demonstrate
an approximate 4-fold increase in serum drug
levels. Dosages should be reduced accordingly.
Carbamazepine No dosing adjustment is necessary in the setting of
Divalproex Renal failure is associated with an increased
unbound fraction (and slightly reduced
clearance) of free valproic acid. No dosage
adjustment is necessary in the setting of renal
failure.
Gabapentin For CrCl of 30–60 mL/min, maximum dosage=
300 mg bid; for CrCl of 15–30 mL/min, maximum
dosage=300 mg/day; for CrCl <15 mL/min,
maximum dosage=300 mg every other day.
Lamotrigine Manufacturer’s product information states that
“reduced maintenance doses may be effective for
patients with significant renal impairment” and
that “Lamictal should be used with caution in
these patients” because “there is inadequate
experience in this population.”
Lithium In chronic kidney disease patients for whom
alternatives to lithium may not be feasible, some
authors advise the following: for GFR >50 mL/
min, no dosing modification is necessary; for
GFR=10–50 mL/min, administer 50%–75% of
usual dose; for GFR <10 mL/min, administer
20%–50% of usual dose (Aronoff et al. 1999). In
end-stage renal disease patients undergoing
hemodialysis, administer a single dose of 200–
600 mg after each hemodialysis session, guided
by levels checked immediately before
hemodialysis (Cohen et al. 2004).

agents (continued)
Anticonvulsants and lithium (continued)

Oxcarbazepine Dosing is halved when CrCl is <30 mL/min (in
which case, dosing should be started at 150 mg
bid).
Pregabalin Dosing must be reduced in the presence of renal
failure (for CrCl of 30–60 mL/min, maximum
dosage=75–300 mg/day in 2–3 divided doses; for
CrCl of 15–30 mL/min, maximum dosage=
25–150 mg/day given once or in 2 divided doses
daily; for CrCl of <15 mL/min, maximum
dosage=25–75 mg/day).
Topiramate For CrCl of <70 mL/min, the usual dosage is
halved and upward titration is done slowly.
Antidepressants
Citalopram No dosing adjustment is necessary for individuals
with mild to moderate renal impairment. Caution
is advised for use in severe renal disease.
Desvenlafaxine Recommended dosage in the setting of moderate
renal impairment is 50 mg/day; 50 mg every
other day is advised in severe renal impairment.
Duloxetine Administration is not recommended for patients
with end-stage renal disease or severe renal
impairment (i.e., CrCl of <30 mL/min).
Escitalopram No dosing adjustment is necessary for individuals
with mild to moderate renal impairment. Caution is
advised for use in severe renal disease.
Fluoxetine No dosing adjustment is necessary in the setting of
Fluvoxamine Low initial dosing is advised in the setting of mild
to moderate renal impairment.
Mirtazapine Clearance of mirtazapine is reduced by ~30% in
moderate renal insufficiency (CrCl of 11–39 mL/
min) and by ~50% for CrCl ≤10 mL/min). The
manufacturer advises caution when administer-
ing to patients with renal impairment.

agents (continued)
Nefazodone No dosing adjustment is necessary in the setting of
Paroxetine Mean plasma concentrations increase
approximately 4-fold in the setting of severe renal
impairment (i.e., CrCl of <30 mL/min), and about
2-fold when CrCl is 30–60 mL/min. Dosage
reductions and slowed titration schedules are
therefore advised.
Sertraline No dosing adjustment is necessary in the setting of
Transdermal No dosing adjustment is necessary in the setting of
selegiline renal insufficiency.
Venlafaxine For CrCl of 10–70 mL/min, total daily dosing
should be decreased by 25%–50%.
Vilazodone No dosing adjustment is necessary in the setting of
Benzodiazepines Short-acting agents, and those with fewer active
metabolites, such as oxazepam or lorazepam, are
preferred over longer-acting agents (e.g.,
clonazepam or chlordiazepoxide) and those with
many active metabolites (e.g., diazepam).
SGAs
Asenapine No dosing adjustment is necessary in the setting of
renal impairment.
Lurasidone For CrCl of 10–50 mL/min (i.e., moderate to severe
renal impairment), the manufacturer
recommends that daily dosage should not exceed
40 mg/day.
Olanzapine No dosing adjustment is necessary in the setting of
renal impairment.

agents (continued)
SGAs (continued)
Paliperidone In mild impairment (CrCl of 50–80 mL/min),
recommended dosage is 3–6 mg/day. In
moderate to severe impairment (CrCl of
10–50 mL/min), recommended initial dosage is
1.5 mg/day and maximum dosage is 3 mg/day.
Quetiapine Plasma concentrations of quetiapine appear no
different in the setting of renal insufficiency.
Dosing adjustment is therefore not necessary in
the setting of renal impairment.
Risperidone The manufacturer advises an initial dosage not
exceeding 0.5 mg bid in patients with renal
impairment, with subsequent increases of no
more than 0.5 mg bid; dosage increases above
1.5 mg bid should occur at least 1 week apart.
Ziprasidone Dosing adjustment is not necessary in the setting of
renal impairment.
Note. bid= twice daily; CrCl=creatinine clearance; GFR= glomerular filtra-
tion rate; SGA= second-generation antipsychotic.
sex is a common adverse effect of serotonergic antidepressants, although

even nonserotonergic antidepressants have been associated with an in-
creased risk for delayed ejaculation in some studies. Men taking antide-
pressants appear significantly more likely than women to encounter
impaired sexual desire and orgasm, whereas women may be more prone
to impaired arousal (Clayton et al. 2006b). SSRI treatment may be more
likely to lead to remission of impaired sexual desire and arousal in de-
pressed women, but not orgasmic dysfunction in depressed men.
Serotonergic antidepressants may adversely affect all components
of sexual functioning, as well as sexual satisfaction. Although it is often
difficult to distinguish whether depression itself or antidepressants are
the proximal cause of decreased libido and sexual dysfunction, antide-
pressants are often thought to be more prone to impair excitation and
arousal (i.e., erectile dysfunction and delayed ejaculation in men, or im-
paired lubrication in women) and orgasm, whereas depression may
more often impair libido than other phases of the sexual response cycle.
Agonism of serotonin type 2A (5-HT2A) postsynaptic receptors is be-

lieved to contribute to impaired sexual functioning and, consequently,
may be an unintended effect of serotonergic agents that fail to block or an-
tagonize 5-HT2A receptors. Correspondingly, serotonergic agents that
block postsynaptic 5-HT2A receptors may incur minimal sexual dysfunc-
tion, as has been demonstrated in preliminary open-label fashion with
mirtazapine (Saiz-Ruizet al. 2005) or adjunctive trazodone for SSRI-
induced sexual dysfunction (Stryjer et al. 2009). No studies have yet ex-
amined whether adjunctive mirtazapine may counteract SSRI- or SNRI-
associated sexual dysfunction.
A prospective multicenter study comparing various SSRIs found that
paroxetine caused significantly more orgasmic delay, ejaculation, or impo-
tence than did fluoxetine, sertraline, or fluvoxamine (Montejo-González et
al. 1997). These authors also found SSRI-induced sexual dysfunction to be a
dose-related phenomenon. Similarly, paroxetine 20 mg/day was signifi-
cantly more likely than citalopram 20 mg/day (Waldinger et al. 2001) or
mirtazapine 30 mg/day (Waldinger et al. 2003) to delay orgasm and ejacu-
lation in affectively healthy men with premature ejaculation. Another
study of men with premature ejaculation, comparing paroxetine 20 mg/
day, fluoxetine 20 mg/day, sertraline 50 mg/day, fluvoxamine 100 mg/
day, and placebo, found that paroxetine caused the greatest delay in ejacu-
lation and that fluvoxamine caused the least (Waldinger et al. 1998).
Another prospective trial comparing paroxetine, sertraline, ven-
lafaxine, and moclobemide found that men were more likely than
women to encounter diminished sexual desire but that no gender dif-
ferences emerged in arousal and orgasm (Kennedy et al. 2000). Overall
rates of sexual dysfunction were lower with moclobemide or venlafax-
ine than with SSRIs. Other trials similarly suggest a lower incidence of
sexual dysfunction with SNRIs (e.g., duloxetine, dosed at 40–120 mg/
day) than with pure serotonergic reuptake inhibitors (e.g., paroxetine,
dosed at 20 mg/day) (Delgado et al. 2005).
SGAs might be expected to incur relatively low rates of sexual dys-
function by virtue of their postsynaptic 5-HT2A blockade, although
agents that increase prolactin release can in turn induce sexual adverse
effects. In patients with chronic schizophrenia, findings from the CATIE
study found relatively similar rates of sexual dysfunction (19%–27%)
across the FGAs and SGAs studied, without clear links to differences in
reported changes in serum prolactin (Lieberman et al. 2005). In fact,
even agents that showed reductions from baseline serum prolactin levels
in CATIE (i.e., quetiapine and ziprasidone) had approximate 20% inci-
dence rates of sexual dysfunction. Because of interindividual variability
between changes in serum prolactin and the potential for sexual dys-
function, other endocrinological or physiological factors likely contrib-

ute to (or mediate) iatrogenic sexual dysfunction from SGA.
A meta-analysis of reported incidence rates of sexual dysfunction
with FGAs and SGAs (N=7,975 subjects) identified the following rank or-
dering of global sexual dysfunction (most dysfunction to least dysfunc-
tion): thioridazine >clozapine>haloperidol>risperidone>olanzapine>
aripiprazole>perphenazine>ziprasidone>quetiapine. In addition, ari-
piprazole and ziprasidone caused the least degree of impaired sexual de-
sire, whereas aripiprazole and quetiapine both caused the least degree of
arousal dysfunction and orgasmic dysfunction (Serretti and Chiesa 2011).
Tables 13–3 through 13–6 summarize information regarding iatrogenic
sexual dysfunction from randomized controlled trials with commonly
used psychotropic medications: SGAs (Table 13–3), sedative-hypnotics
(Table 13–4), lithium and anticonvulsants (Table 13–5), and antidepressant
and related noradrenergic or serotonergic agents (Table 13–6).
Case reports exist of divalproex-associated anorgasmia and de-
creased libido in men and women with bipolar disorder, migraine, or
epilepsy; these effects are possibly dose related and are generally in the
context of cotherapy with other medications. Dosage reductions have
not reliably eliminated sexual side effects in reported cases, although
drug cessation has. With respect to lithium, one study of 104 outpatients
with bipolar disorder revealed an incidence of sexual dysfunction
among 14% of those undergoing monotherapy but among 49% of those
taking lithium plus a benzodiazepine (Ghadirian et al. 1992).
Controlled trials conducted outside of industry, for purposes other
than label indications, often reveal higher rates of sexual dysfunction
with antidepressants than identified in FDA registration trials. These in-
clude incidence rates for overall sexual dysfunction of 22% and 25% with
bupropion IR and SR, respectively, over a variable duration from less
than 1 week to more than 3 years (Clayton et al. 2002); 33% with duloxe-
tine over 8 months (Clayton et al. 2007); and 49% with escitalopram over
8 months (Clayton et al. 2007).
Strategies to manage anorgasmia or other sexual side effects of
SSRIs—apart from switching altogether to alternative primary agents—
focus mainly on the use of adjunctive pharmacotherapies, although the
concept of “weekend holidays” from an SSRI (specifically, sertraline or
paroxetine, but not fluoxetine) has been suggested to significantly im-
prove sexual functioning (Rothschild 1995). The potential benefit of such
a break must be weighed against the potential for SSRI-discontinuation
withdrawal symptoms.
A wide range of pharmacotherapy strategies have been proposed on
mechanistic grounds and studied empirically as intended remedies to
TABLE 13–3. Incidence of sexual dysfunction in clinical trials of

second-generation antipsychotics
Rates reported in FDA registration trials or

Agent randomized controlled studies
Aripiprazole Libido either increased or decreased in <1% across

FDA registration trials. Greater improvement
from baseline in overall sexual functioning was
seen with aripiprazole compared with
olanzapine, risperidone, or quetiapine in a
26-week multisite open randomized industry-
supported study (Schizophrenia Trial of
Aripiprazole; Hanssens et al. 2008).
Asenapine In all registration trials for bipolar mania or
schizophrenia, both short- and long-term,
incidence of sexual dysfunction was ≤1%
(per manufacturer).
Iloperidone In schizophrenia FDA registration trials,
decreased libido and anorgasmia were reported
in ≥1%; ejaculation failure occurred in 2% across
dosages.
Lurasidone NR
Olanzapine Across indications, FDA registration trials
reported decreased libido in ≤1%. In CATIE,
sexual dysfunction was reported in 27%
(Lieberman et al. 2005).
Paliperidone NR
Quetiapine Across all indications, FDA registration trials
reported decreased libido in 1%–2% and
abnormal ejaculation in ≤1%. In CATIE, sexual
dysfunction was reported in 20% (Lieberman
et al. 2005).
Risperidone Across indications, FDA registration trials and
postmarketing reports identified impaired
ejaculation in ≤1%, and decreased libido and
anorgasmia in <1%. In CATIE, sexual
dysfunction was reported in 27% (Lieberman
et al. 2005).
TABLE 13–3. Incidence of sexual dysfunction in clinical trials of

second-generation antipsychotics (continued)

Ziprasidone In FDA registration trials for schizophrenia,

impotence, anorgasmia, or abnormal ejaculation
occurred in ≤1%. In CATIE, sexual dysfunction
was reported in 19% (Lieberman et al. 2005).
Incidence rates of sexual dysfunction in trials for
bipolar disorder were not reported.
Note. CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness;
FDA= U.S. Food and Drug Administration; NR= not reported.
counteract antidepressant-induced sexual dysfunction. Some capitalize

on putative mechanisms of action (e.g., introducing blockade of 5-HT2
receptors) or efforts to reverse antidepressant-induced increases in pe-
ripheral/genitourinary serotonergic tone (e.g., cyproheptadine) or to
“override” serotonergic effects by introducing catecholaminergic agents
(e.g., bupropion, stimulants). Others focus on the role of nitric oxide and
phosphodiesterase (PDE) inhibitors, such as sildenafil, vardenafil, or ta-
dalafil. Inhibition of PDE prevents the catabolism of cyclic guanosine
monophosphate, which in turn facilitates the relaxation of smooth muscle
lining the corpus cavernosum. A related strategy involves using L-argi-
nine, a precursor of nitric oxide, for a similar purpose.
PDE inhibitors were initially studied and adapted for the treatment
of sexual dysfunction in men, although more recent studies have also
demonstrated their value in SSRI-associated sexual dysfunction in
women (see Table 13–7). Notably, however, adjunctive sildenafil in
women appears better than placebo in helping to improve anorgasmia
but not desire, arousal-sensation, arousal-lubrication, or orgasmic satis-
faction (Nurnberg et al. 2008). By contrast, in men, all measured compo-
nents of sexual functioning, including sexual desire, arousal, erectile
function, ability to orgasm, and orgasmic satisfaction, have shown sig-
nificant improvement with adjunctive sildenafil (Nurnberg et al. 2003).
PDE inhibitors represent the best studied and most robust strategy to
counteract sexual dysfunction caused by serotonergic antidepressants.
Prescribers must be aware of the potential of PDE inhibitors to cause
modest decreases in blood pressure (e.g., sildenafil has been shown to
lower blood pressure in healthy volunteers by about 9/6 mmHg). The
TABLE 13–4. Incidence of sexual dysfunction in sedative-hypnotic

clinical trials

Benzodiazepines In general, ≤1%–3% incidence of sexual

dysfunction across agents
Eszopiclone Decreased libido in <3% of patients taking
3 mg/day; no reports of erectile dysfunction
or anorgasmia
Zaleplon Decreased libido or impotence in <1%
Zolpidem Decreased libido or impotence in <0.1%
Note. FDA= U.S. Food and Drug Administration.
vasodilatory effects of sildenafil pose at least a theoretical risk for exac-

erbating underlying cardiovascular disease, although adverse hemo-
dynamic effects in men with coronary artery disease have not been
demonstrated and are not necessarily contraindicated.
There have been rare reports of vision loss from sildenafil or var-
denafil due to nonarteritic anterior ischemic optic neuropathy. The
manufacturers of these drugs point out that most people who take them
have underlying predispositions to visual problems (e.g., diabetic retin-
opathy), although risk factors for developing loss of vision with PDE in-
hibitors have not been described. Patients who begin a PDE inhibitor
should be counseled to inform the prescriber if they notice any visual
changes, and treatment should be discontinued unless alternative ex-
planations are identified.
A number of other pharmacological approaches have been de-
scribed and studied with more variable results, as summarized in Table
13–7. Also, with few exceptions, there has been little study of combina-
tion therapy approaches that use complementary and possible synergis-
tic mechanisms to overcome impaired sexual functioning caused by
psychotropic agents.
Noteworthy from the findings presented in Table 13–7 is the failure
in two studies (DeBattista et al. 2005; Masand et al. 2001) of adjunctive
bupropion to reverse SSRI-induced sexual dysfunction with dosages of
150 mg/day, but the apparent benefit in other studies with dosages of
75–150 mg/day (Ashton and Rosen 1998) or 150 mg twice daily (Safa-
rinejad 2010). A further corollary to these observations is that replace-
ment (rather than augmentation) of purely serotonergic agents with
TABLE 13–5. Incidence of sexual dysfunction in FDA registration

trials of lithium and anticonvulsants
Decreased Delayed
Agent Impotence libido ejaculation Anorgasmia
Carbamazepine <5% NR NR NR
Divalproex NR NR NR NR
Gabapentin NR ≥1% <1% <1%
Lamotrigine <1% <1% <1% NR
Lithium NR NR NR NR
Oxcarbazepine NR NR NR NR
Topiramate NR 1%–3% NR NR
Note. FDA= U.S. Food and Drug Administration; NR= not reported.
catecholaminergic, nonindoleaminergic antidepressants (such as bu-

propion) or with antidepressants that selectively block 5-HT2A postsyn-
aptic receptors (e.g., mirtazapine) may produce substantially less sexual
dysfunction than seen with an SSRI. The incidence of sexual dysfunc-
tion with SNRIs (i.e., duloxetine, venlafaxine, desvenlafaxine) appears
less than that seen with purely serotonergic agents.
In unmedicated men with erectile dysfunction (Lebret et al. 2002) or
women with sexual arousal disorder (Meston and Worcel 2002), the
combination of yohimbine (6 mg/day) with the nitric oxide precursor
L-arginine glutamate (6 g/day) has shown benefits over placebo that
may reflect synergistic effects (presynaptic α 2 blockade may both en-
hance genital nitric oxide release and reduce risk of hypotension from
nitric oxide–related vasodilation, while nitric oxide donation may in-
crease genital effects of yohimbine). However, this combination has not
been studied specifically as a strategy to counteract sexual dysfunction
induced by antidepressants or other psychotropics. Other possible via-
ble strategies for noniatrogenic hypoactive sexual arousal in postmeno-
pausal women include dehydroepiandrosterone (DHEA) 300 mg/day.
In addition to the findings from randomized trials summarized in Ta-
ble 13–7, a handful of case reports and proof-of-concept open trials de-
scribe novel strategies to counteract antidepressant-induced sexual
dysfunction. One such example, focusing on patients who developed sex-
ual dysfunction after successful treatment for generalized anxiety disor-
der with an SSRI or SNRI, involved substituting the novel GABAergic
anticonvulsant tiagabine for the original agent; the change yielded signif-
220
TABLE 13–6. Incidence of sexual dysfunction in FDA registration trials of antidepressant and related noradrenergic or
serotonergic agentsa
Decreased Erectile Delayed

Agent Impotence libido dysfunction ejaculation Anorgasmia

Atomoxetine NR 4% 9% 3% ≥2%
Bupropion <1% <1% NR <1% NR
Buspirone <0.1% <1% NR <0.1% NR
Citalopram 3% 3.8% (men), NR 6.1% 1.1% (women)
1.3% (women)
Desvenlafaxineb NR 4%–5% 3%–6% 1%–5% 0–3%
Duloxetinec NR NR NR NR NR
Escitalopram 2% 6% (men), NR 12% 3% (women)
3% (women)
Fluoxetine NR 4% NR NR NR
Fluvoxamine 2% 4%–8% 3% 11% 4%–5%
MAOIs other than transdermal NR NR NR NR NR
selegiline: isocarboxazid,
phenelzine, tranylcypromine
Mirtazapine <1% ≥1% NR ≥1% NR
Paroxetine 10% 7%–9% NR 26%–27% NR
Genitourinary and Renal Systems
TABLE 13–6. Incidence of sexual dysfunction in FDA registration trials of antidepressant and related noradrenergic or
serotonergic agentsa (continued)
Decreased Erectile Delayed

Agent Impotence libido dysfunction ejaculation Anorgasmia
Sertraline NR 6% NR 14% NR
TCAs NR NR NR NR NR
Transdermal selegiline ≤1% ≤1% NR ≤1% ≤1%
Venlafaxine NR 3%–8% NR 8%–19% NR
Vilazodone NR 3%–5% 2% 2% 2%–4%
Note. FDA=U.S. Food and Drug Administration; MAOI=monoamine oxidase inhibitor; NR=not reported; TCA=tricyclic antidepressant.
aReported incidence rates are based on spontaneous reports rather than on systematic assessments, unless otherwise noted.
bAdverse effects as reported with desvenlafaxine dosages of 50–100 mg/day for major depression.
cAdverse sexual effects with duloxetine were assessed in FDA trials using the Arizona Sexual Experiences Scale (McGahuey et al. 2000),
which revealed significantly poorer scores versus placebo for global sexual function among men but not women and significantly greater
difficulty reaching orgasm with duloxetine than placebo in men but not women. No significant drug-placebo differences were observed
in sex drive; arousal; ability to achieve erections (men) or lubrication (women); orgasmic satisfaction; or ease of reaching orgasm (women).
221
222
TABLE 13–7. Pharmacological strategies used to counteract drug-induced sexual dysfunction
Agent Rationale Positive data Equivocal or negative data
Phosphodiesterase Nitric oxide–mediated Case reports describe improvement or None.

type 5 inhibitors vasodilator resolution of SSRI-associated ejaculatory

(e.g., sildenafil, delay with sildenafil 50–100 mg/day prn or
vardenafil, tadalafil) higher (up to 200 mg/day; Seidman et al.
2003), including improvement of
anorgasmia in women (Nurnberg et al.
2008). Significant improvement also
identified from placebo-controlled data
(Fava et al. 2006; Nurnberg et al. 2003), and
in placebo-controlled trials of sildenafil (25–
50 mg/day) to counteract antipsychotic-
associated sexual dysfunction
(Gopalakrishnan et al. 2006). Vardenafil
(10 mg 30 minutes before sexual activity;
Berigan 2004) and tadalafil (20 mg/day;
Segraves et al. 2007) have been described
in case reports and open trials as a strategy
to counteract sexual dysfunction secondary
to antidepressants.
TABLE 13–7. Pharmacological strategies used to counteract drug-induced sexual dysfunction (continued)
Amantadine Dopamine agonism Case reports indicate favorable results In women with sexual
when used to treat anorgasmia related dysfunction secondary
to fluoxetine (Balogh et al. 1992; Balon 1996) to fluoxetine, adjunctive
or paroxetine (Shrivastava et al. 1995). amantadine (50–
100 mg/day) was no
different from placebo
(Michelson et al. 2000).
Aripiprazole Relatively prolactin Over 12–26 weeks, open-label add-on or None.
sparing substitution from another SGA significantly
improved libido and overall sexual
satisfaction in men and women (N=27),
ejaculatory or erectile dysfunction in men,
and menstrual dysfunction in women (Mir
et al. 2008).
Bethanechol Procholinergic, may help Case reports used 10–50 mg/day None.
counteract sexual (Gross 1982).
dysfunction caused by
anticholinergic drugs
(e.g., TCAs or MAOIs)
223
224
Bupropion Prodopaminergic and Outpatients (N=47) taking SSRIs received In 6-week randomized
noradrenergic agent open-label bupropion 75–150 mg 1–2 hours comparison of

without known before sexual activity, yielding improve- bupropion SR 150 mg/
serotonergic effects ment in 38%; a standing adjunctive dose of day or placebo (N=41)
bupropion 75 mg tid for 2 weeks reversed added to SSRIs in
sexual dysfunction in 66% of patients
remitted depressed
(Ashton and Rosen 1998).
patients with SSRI-
In a 12-week randomized comparison of
induced sexual
bupropion SR 150 mg bid or placebo added
to SSRIs in 234 remitted male depressed dysfunction, no
patients with SSRI-induced sexual dysfunc- differences were found
tion, significantly greater improvement between drug and
occurred in overall sexual functioning (by placebo on any measures
ASEX) with bupropion than placebo of sexual functioning
(Safarinejad 2010). (DeBattista et al. 2005);
In 12-week randomized comparison of identical findings in a
bupropion SR 150 mg bid or placebo added similarly designed
to SSRIs in 218 remitted female depressed 3-week study with the
patients with SSRI-induced sexual dysfunc-
same dosing (N=30)
tion, significantly greater improvement in
were reported by
desire and lubrication occurred with bupro-
Masand et al. (2001).
pion than placebo (Safarinejad 2011).
Buspirone 5-HT1A partial agonist In 4-week comparison of placebo vs. flexibly Among women with
dosed buspirone (20–60 mg/day; mean sexual dysfunction
dose=49 mg/day) added to citalopram or secondary to fluoxetine,
paroxetine, greater improvement in sexual adjunctive buspirone
function occurred with buspirone (58%) (20–30 mg/day) was no
than placebo (20%); results more different from placebo
pronounced in women than men (Landén (Michelson et al. 2000).
et al. 1999).
Cyproheptadine Serotonin antagonist Case series data show improvement of None.
delayed male ejaculation from fluoxetine,
fluvoxamine, or clomipramine using
adjunctive cyproheptadine (4–12 mg) 1–2
hours before sexual activity (Aizenberg et al.
1995).
225
226
Ginkgo biloba Hypothesized effects on Favorable open-label data were reported in In 2-month comparison
vasodilation and men and women (N=63) with dosages of of Gingko biloba (N=19)

stimulation of 60–120 mg/day (Cohen and Bartlik 1998). or placebo (N=18), no
prostaglandin synthesis significant differences
were found (Kang et al.
2002).
In 12-week trial of Ginkgo
biloba 240 mg/day or
placebo in 24
antidepressant-treated
subjects, no significant
differences were found
(Wheatley 2004).
Maca root Unknown In 12-week double-blind, randomized
(Lepidium meyenii; comparison of 1.5 vs. 3.0 mg/day of maca in
a Peruvian plant) 20 SSRI-treated outpatients with remitted
major depression, improved libido and
sexual functioning from baseline were seen
with 3.0-mg/day dosage (Dording et al.
2008).
Methylphenidate Dopamine agonism Case reports (Roeloffs et al. 1996). No significant differ-
may increase sexual ences were found
function between methylpheni-
date extended release
(OROS) and placebo
with respect to change
in ASEX scores for
sexual functioning
over 4 weeks in patients
with treatment-resistant
major depression (Pae
et al. 2009).
Mirtazapine Postsynaptic 5-HT2A In depressed outpatients in remission with Improvement from base-
blockade may counteract SSRIs receiving open-label adjunctive line found with mirtaza-
5-HT2A serotonergic mirtazapine 15–30 mg/day (N=49), pine (N=36) but similar
stimulation significant improvement was seen usually to placebo (N=39) over
after 4 weeks (Ozmenler et al. 2008). 1 month in premeno-
pausal women receiving
fluoxetine (Michelson et
al. 2002).
227
228
Trazodone 5-HT2A postsynaptic Open-trial data using trazodone

antagonism 50–100 mg/day added to SSRIs for 4 weeks

led to improvement in desire, arousal,
orgasm, and overall satisfaction in men
and women (N=20) (Stryjer et al. 2009).
Yohimbine Presynaptic α2-adrenergic In 2-week crossover study of yohimbine Improvement from
(+/– L-arginine antagonism increases 6 mg/day+ L-arginine glutamate 6 g/day baseline found with
glutamate) noradrenergic tone vs. yohimbine 6 mg/day or placebo (N=45), yohimbine (N=35)
combination therapy was found superior but similar to placebo
to placebo (Lebret et al. 2002). (N=39) after 1 month
Five favorable outcomes were found in among women with
6 open cases receiving yohimbine as needed SSRI-induced sexual
for SSRI-induced sexual dysfunction dysfunction (Michelson
(Hollander and McCarley 1992). et al. 2002).
Improved sexual function was found in 8 of May cause anxiety,
9 fluoxetine-treated outpatients given open- tachycardia, and
label yohimbine 5.4 mg tid (Jacobsen 1992). hypertension.
Note. 5-HT1A = serotonin type 1A ; 5-HT2A = serotonin type 2A ; ASEX=Arizona Sexual Experiences Scale; bid= twice daily;
MAOI = monoamine oxidase inhibitor; OROS =osmotic-release oral system; prn= as needed; SGA= second-generation antipsychotic;
SR= sustained release; SSRI = selective serotonin reuptake inhibitor; TCA= tricyclic antidepressant; tid=three times daily.
icant overall improvement in sexual function with sustained improve-

ment in anxiety symptoms (Schwartz et al. 2007).
Drug-induced sexual dysfunction typically remits after cessation of
the suspected causal agent. However, some case reports describe sexual
dysfunction that may persist indefinitely after the discontinuation of
citalopram, fluoxetine, or sertraline and that remains unimproved with
a variety of dopamine agonists.
Sexual dysfunction due to antipsychotic medications has been attrib-
uted to likely effects of hyperprolactinemia, although the postsynaptic
5-HT2A blockade exerted by SGAs should, at least in theory, minimize
sexual adverse effects. As noted in Table 13–7, adjunctive sildenafil has
demonstrated value in improving erectile dysfunction and orgasmic sat-
isfaction in men taking antipsychotics (Gopalakrishnan et al. 2006). Also,
according to a Cochrane Database analysis, sildenafil constitutes the sole
known effective adjunctive therapy to counteract antipsychotic-associ-
ated sexual dysfunction (Berner et al. 2007) apart from the use of adjunc-
tive dopamine agonists.
Remarkably, only a small literature exists describing the use of
dopamine agonists such as bromocriptine (dosed at 5–7.5 mg/day) to
overcome sexual dysfunction caused by antipsychotics. Perhaps this
dearth of studies results from concerns that dopamine agonism could
potentially reverse the antipsychotic effects of dopamine D2 antagonism
or otherwise cause a direct psychotomimetic effect. Preliminary open-
trial data suggest value for ropinirole (begun at 0.25 mg/day and in-
creased to 2–4 mg/day, with a mean dose of about 2 mg/day to alleviate
antidepressant-induced sexual dysfunction). Dopamine agonists such
as bromocriptine, amantadine, pramipexole, or ropinirole could at least
in theory diminish antipsychotic-associated sexual dysfunction via
reduction of antipsychotic-induced hyperprolactinemia.
Retrograde Ejaculation
General Recommendations. Retrograde ejaculation may be
caused by a select number of FGAs or SGAs. Dosage reductions, or if
necessary, drug cessation typically ameliorates the complication.
The phenomenon of retrograde ejaculation has been reported with a

limited number of antipsychotic agents, most notably thioridazine, ris-
peridone, and clozapine. Some authors have suggested that retrograde
ejaculation more likely occurs due to α 1-adrenergic antagonism than to
other mechanisms (e.g., hyperprolactinemia) because of the lack of in-
terference with arousal or the ability to attain or sustain erections. Short

of altogether discontinuing the causal agent, the prescriber can try dos-
age reductions to resolve the side effect.
14
Hematological
System
Myelosuppression: Agranulocytosis
and Thrombocytopenia
General Recommendations. Clinicians should recognize the
risk for agranulocytosis in patients taking carbamazepine or
clozapine, and more infrequently in those taking other SGAs or
mirtazapine. Drug discontinuation is necessary in the setting of
neutropenia.
Myelosuppression refers broadly to the failure of bone marrow to produce

blood cells (red cells [anemia], white cells [agranulocytosis], and platelets
[thrombocytopenia]). Aplastic anemia refers to a more serious form of my-
elosuppression. Neutropenia refers to an abnormally low number of neu-
trophils, and the absolute neutrophil count (ANC) is calculated from the
percentage of neutrophils plus the percentage of bands (immature neu-
231
trophils). The ANC is typically defined on the basis of severity gradations

that indicate the risk for infection as being mild (1,000–1,500/mm3), mod-
erate (500–1,000/mm3), or severe (<500/mm3). Myelosuppression can
occur as rare adverse effects associated with a select number of psycho-
tropic agents, as described in the following subsections.
Carbamazepine
Benign, transient leukopenia is a common phenomenon during initial
treatment with carbamazepine. In the original Veterans Administration
Multicenter Antiepileptic Drug Trial, leukocyte counts <5,000/mm3
were observed in approximately 30% of carbamazepine recipients dur-
ing the first 6 months of treatment (Mattson et al. 1985). Frank aplastic
anemia is an exceedingly rare event with carbamazepine (■), with an
estimated occurrence of 1 in 200,000 exposures. Thrombocytopenia
from carbamazepine, potentially related to immunologically mediated
platelet destruction, typically occurs in conjunction with other systemic
signs (e.g., rash, liver enzyme elevation). Some authorities advise ob-
taining a complete blood count (CBC) at baseline, then weekly for
2 months, and then once every 3 months. The myelosuppressive effects
of carbamazepine are thought to result from toxicity caused by its ep-
oxide metabolite (see Figure 2–1 in Chapter 2, “Pharmacokinetics, Phar-
macodynamics, and Pharmacogenomics”).
Divalproex
Mild, asymptomatic leukopenia occurs in rare instances with divalproex
and typically reverses upon dosage reductions or drug cessation. Throm-
bocytopenia has typically been defined on the basis of serum platelet
counts <140,000×109 per liter. Initial case reports and case series in the
late 1970s and early 1980s suggested that thrombocytopenia could be an
immune-mediated reaction to divalproex caused by structural similari-
ties between the drug and the cell membrane constituents. Later studies
have suggested that the phenomenon reflects a dose-related toxicity
rather than peripheral destruction or a dose-independent immunologi-
cally based event. Risk may be mediated by duration of exposure and
may be higher in elderly patients and in women. Thrombocytopenia
caused by divalproex typically remits after dosage reductions, without
the need for drug discontinuation. No formal recommendation exists for
surveillance monitoring of platelet counts during acute or ongoing ther-
apy with divalproex, but periodic assessment (e.g., every 6–12 months) is
advisable, particularly in older adults or patients taking >1,000 mg/day.
Hematological System 233
Second-Generation Antipsychotics
Clozapine is the most widely recognized SGA that carries a risk for de-
veloping agranulocytosis (~1%) (■). The mechanism by which clozapine
can suppress leukocyte counts is not well understood but is thought to in-
volve an immunologically mediated cytotoxic effect of clozapine or its
metabolites; however, research efforts have not demonstrated immuno-
logically associated features such as eosinophilia. Clozapine-associated
myelosuppression is most likely to occur within the first 6 months of
treatment, although exceedingly rare single case reports have been pub-
lished involving the development of clozapine-induced agranulocytosis
after 17 months, 2.5 years, or even 11 years, lengthy time frames that rep-
resent the exception rather than the rule. Research efforts have not iden-
tified predictors of eventual agranulocytosis, although risk may increase
somewhat with age and female sex. An earlier literature also suggested
that rises in total white blood cell (WBC) counts by ~15% may sometimes
precede agranulocytosis from clozapine. Guidelines for WBC monitoring
during clozapine therapy are presented in Table 14–1.
In July 2009, the FDA imposed a class effect on SGAs, warning of an as-
sociation with leukopenia/neutropenia and possible agranulocytosis. The
clinical significance of the warning does not involve a need for widespread
or routine monitoring of CBCs among patients taking SGAs, but rather an
awareness that this drug class should be considered in the differential di-
agnosis of individuals who may present with low WBC counts. Antipsy-
chotics should be discontinued in the setting of an ANC <1,000/mm3),
with subsequent close monitoring of WBC counts until recovery.
It should be noted that reports exist of agranulocytosis as well as
thrombocytopenia during treatment with FGAs, although no class warn-
ing has been imposed by the FDA, and guidelines for routine periodic
monitoring of CBCs during long-term treatment with these agents have
not been set forth. The risk for agranulocytosis may increase whenever a
new antipsychotic agent is introduced and may be mediated in part by a
longer duration of high-dose therapy.
Clinicians sometimes think of using lithium as a strategy to promote
leukocytosis and boost WBC counts. At one time, it was thought that
leucocytosis during lithium therapy merely reflected increased demar-
gination of WBCs from blood vessel endothelial linings, rather than
truly increasing the new production and differentiation of granulocytes
from bone marrow. However, more recent efforts suggest that lithium
may indeed foster a true myeloproliferative response (rather than demar-
gination) by increasing granulocyte colony–stimulating factor and aug-
menting its effects (Focosi et al. 2009). Granulocyte colony–stimulating
TABLE 14–1. Monitoring of white blood cell counts during clozapine

treatment
Complete blood count (CBC)

Event monitoring
0–6 months Monitor weekly.

6–12 months Monitor biweekly.
>12 months Monitor monthly.
Substantial drop within Repeat CBC. If WBC=3,000–
3 weeks (WBC≥3,000/mm3 or 3,500/mm3 and ANC<2,000/mm3,
ANC≥1,500/mm ) 3 monitor twice weekly.
WBC=3,000–3,500/mm3 or Monitor twice weekly until
ANC=1,500–2,000/mm3 WBC>3,500/mm3 and
ANC>2,000/mm3.
WBC=2,000–3,000/mm3 or Monitor CBC daily until
ANC=1,000–1,500/mm3 WBC>3,000/mm3 and
ANC>1,000/mm3; then twice
weekly until WBC>3,500/mm3 and
ANC>2,000/mm3; then weekly.
May then rechallenge and monitor
weekly for 1 year.
WBC<2,000/mm3 and Discontinue clozapine. Monitor
ANC<1,000/mm3 CBC daily until WBC>3,000/mm3
and ANC>1,500/mm3; then twice
weekly until WBC>3,500/mm3 and
ANC>2,000/mm3; then weekly.
ANC≤500/mm3 Discontinue clozapine. Monitor
(agranulocytosis) CBC daily until WBC>3,000/mm3
and ANC>1,500/mm3; then twice
weekly until WBC>3,500/mm3
and ANC>2,000/mm3; then
weekly.
Note. ANC= absolute neutrophil count; WBC= white blood cell (count).
factor itself is often used to treat neutropenia from myelodysplastic syn-

dromes or myelosuppression caused by antineoplastic agents, although
its use to counteract drug-induced agranulocytosis is less well estab-
lished except in cases of severe bone marrow hypoplasia. Generally,
psychotropic-induced agranulocytosis resolves after cessation of a
causal agent, and new granulocytes arise within 21 days, obviating the
need for further intervention other than supportive measures (as in the
setting of fever or infection).
Other Agents
Agranulocytosis has been described as a rare, potentially immune-
mediated occurrence during long-term treatment with chlordiazep-
oxide, diazepam, midazolam, and modafinil. Rare reports exist of pan-
cytopenia, including aplastic anemia and pure red blood cell aplasia,
occurring during treatment with lamotrigine. In premarketing studies
of mirtazapine, agranulocytosis was observed in 2 of 2,796 patients,
with one-third developing severe neutropenia, yielding a crude inci-
dence of 1.1 per 1,000 exposed patients. All observed cases resolved af-
ter drug cessation. Mirtazapine should be stopped in patients who
develop signs of an infection with an accompanying low WBC count.
Platelet Aggregation Disorders

and Bleeding Risk
General Recommendations. Individuals with a history of
gastrointestinal bleeding or other risk factors for bleeding (e.g.,
use of anticoagulants or NSAIDs, liver disease) may have a low
but statistically significantly increased risk for bleeding during
therapy with serotonergic antidepressants. The presence of
clear, identifiable increased risk factors for bleeding may favor
the use of nonserotonergic over serotonergic antidepressants
when feasible, possible cotherapy with a proton pump inhibitor
in individuals at particular risk for gastrointestinal bleeding,
and the temporary discontinuation of serotonergic antidepres-
sants before elective surgery on a case-by-case basis.
There is unresolved controversy surrounding the potential for bleeding

disorders due to platelet serotonin dysfunction during therapy with se-
rotonergic antidepressants. Some reports suggest a roughly 2-fold in-
creased risk for upper gastrointestinal bleeding with SSRIs, particularly
when combined with NSAIDs, anticoagulants including aspirin, or anti-
platelet drugs (e.g., Andrade et al. 2010), whereas other studies have
failed to replicate such concerns and dispute their validity. SSRI-induced
thrombocytopenia also represents a separate mechanism by which some
serotonergic antidepressants, such as citalopram, have reportedly been
associated with bleeding disorders (Andersohn et al. 2009).
Clinicians should keep in mind that the differential diagnosis of iatro-

genic abnormal bleeding extends beyond pharmacologically induced
disruption of platelet aggregation and may include hepatic failure (e.g.,
diminished production of clotting factors, elevated prothrombin time),
disseminated intravascular coagulopathy (which may rarely occur in the
setting of serotonin syndrome), and inherited bleeding disorders (e.g.,
von Willebrand disease), among other factors.
Red Blood Cells

General Recommendations. Decreased red blood cell pro-
duction is rarely iatrogenic and should prompt a comprehensive
review of risk factors for anemia or suppression of other cell lines.
Although a number of psychotropic agents may cause fulminant aplas-

tic anemia, relatively few have been associated solely with the suppres-
sion of red blood cell production (reticulocytopenia). Macrocytic anemia
has been described in case reports following treatment with divalproex,
oral contraceptives, sulfa antibiotics, and reverse transcriptase inhibi-
tors, among other drugs. Drug-induced hemolytic anemias seldom are
associated with psychotropic drugs (e.g., levodopa) and more often may
result from antibiotics (e.g., cephalosporins or penicillins) or from
NSAIDs. The evaluation and differential diagnosis of reticulocytopenia
is extensive, and in addition to iron deficiency, may include liver or renal
failure, myelodysplastic syndromes, nutritional deficiencies, toxicities
(e.g., lead, arsenic), and endocrinopathies (e.g., hypothyroidism, hyper-
parathyroidism), among other causes. Table 14–2 identifies key consid-
erations in the initial assessment of anemia.
TABLE 14–2. Considerations in the assessment of anemia
Parameter Relevance
Is patient’s anemia macrocytic The most common causes of

or microcytic? macrocytic anemias are alcoholism,
malnutrition, or malabsorption
disorders leading to vitamin B12
or folic acid deficiency. The most
common cause of microcytic
anemia is iron deficiency.
Drug-induced hemolytic anemias
are usually normocytic.
Is the reticulocyte count A compensatory increase in
elevated? reticulocytes would be expected
due to blood loss, hypoxia, or
hemolytic anemia.
Are there indications of Jaundice may indicate a hemolytic
jaundice (e.g., icteric sclerae)? process.
Are chronic inflammatory These conditions may indicate
(e.g., rheumatoid arthritis) or anemia of chronic disease.
neoplastic conditions present?
15
Musculoskeletal
System
Joint Pain
General Recommendations. Joint pains are rarely iatro-
genic. Clinicians should determine whether such complaints
may reflect other medical causes. Persistent idiosyncratic joint
pains may warrant discontinuation of suspected causal agents
to help clarify etiologies.
Joint pain or stiffness has been identified as a rare, idiosyncratic adverse

effect that can occur in connection with virtually every existing psycho-
tropic drug at any time in the course of treatment. However, it is difficult
to articulate a pharmacodynamic mechanism by which any antidepres-
sant, antipsychotic, anxiolytic, or anticonvulsant would plausibly cause
musculoskeletal pain. Clinicians should assure that the emergence of
joint pain is not the mere result of trauma or an intensification of existing
arthritis; determine by physical examination the presence of an effusion,
inflammation, or tenderness on movement; and obtain a history of rheu-
matoid or connective tissue diseases, including autoimmune diseases
(e.g., systemic lupus erythematosus), gout, thyroid disease and other en-
docrinopathies, Lyme disease and other infectious processes, fibromy-
algia, malignancies, and inflammatory conditions such as sarcoidosis.
239
No evidence has been reported in the literature attaching medical

significance or consequences to idiosyncratic iatrogenic joint pain.
However, if symptoms do not resolve spontaneously or with conserva-
tive interventions, such as acetaminophen or NSAIDs, cessation of the
suspected offending agent may be warranted to assuage patient con-
cerns. Persistent joint discomfort after drug cessation would further
indicate the role for independent medical evaluation and diagnostic as-
sessment.
Leg Cramps
General Recommendations. Leg cramps rarely result from
psychotropic medications and more often result from endocrine
or electrolyte abnormalities or from nutritional or mineral defi-
ciencies. Possible underlying medical etiologies should be in-
vestigated (e.g., dehydration, hypothyroidism, hypocalcemia,
hypomagnesemia) and corrected as appropriate.
Lower-extremity muscle cramps may result from a wide range of causes,

including dehydration, hypomagnesemia, hypocalcemia, hypokalemia,
hypothyroidism, or abrupt discontinuation of an SSRI or SNRI. Primarily
nonpsychotropic medications often used in psychiatry that are known to
cause muscle cramps include albuterol, amlodipine, clonidine, cloraze-
pate, donepezil, galantamine, ibuprofen and other NSAIDs, nimodipine,
nifedipine, and selegiline.
Quinine was long considered a viable treatment for leg cramps until
the FDA banned all prescription formulations of it in 2007—other than
the antimalarial agent Qualaquin—because of the drug’s dubious ef-
ficacy and serious risks for causing extensive hematological, cardiac,
neurological, and renal toxicities. Tonic water, which contains minute
quantities of quinine (e.g., ~20 mg in 6 fluid ounces of tonic water, in
contrast to 324 mg of active ingredient in quinine sulfate capsules), has
been described as a popular remedy for leg cramps but has received lit-
tle formal study of its safety and efficacy for that purpose.
Alternative evidence-based treatments for noniatrogenic leg cramps
(i.e., those resulting from vascular, neurological, or arthritic underlying
causes) include verapamil (≤120 mg qid), gabapentin (≤400 mg tid), car-
isoprodol, and orphenadrine (Guay 2008), in addition to carbamazepine
(200 mg tid), vitamin E 400–800 IU/day, vitamin B complex capsules (fur-
sultiamine 50 mg/day, hydroxocobalamin 250 µg/day, pyridoxal phos-
phate 30 mg/day, and riboflavin 5 mg/day), and calcium 0.5–1.0 g qid.
Musculoskeletal System 241
Although some clinicians advocate supplemental magnesium for leg

cramps, randomized trials in the absence of known deficiencies have
found no differences from placebo.
Myalgias
General Recommendations. Myalgias may be common,
nonspecific, and often benign phenomena associated with nu-
merous psychotropic drugs. Clinicians should determine
whether myalgias entail muscle rigidity (suggestive of NMS),
signs of metabolic acidosis (e.g., lactic acidosis secondary to oral
hypoglycemics), cramping (suggestive of dehydration or electro-
lyte [e.g., calcium and magnesium] deficiencies), or myopathy
attributable to other medicines (e.g., statins, steroids).
Muscle spasms or myalgias are often listed by drug manufacturers as

rare side effects (typically with an incidence of <5%) of numerous psy-
chotropic agents (e.g., acamprosate, atomoxetine, certain antidepressants
[e.g., bupropion, citalopram, duloxetine, escitalopram, paroxetine, ser-
traline, venlafaxine], many anticonvulsants [e.g., carbamazepine, dival-
proex, lamotrigine, tiagabine, topiramate], some benzodiazepines [e.g.,
alprazolam, clonazepam], some antipsychotics [e.g., aripiprazole, cloza-
pine, olanzapine, paliperidone, pimozide, risperidone, ziprasidone],
clonidine, modafinil, nimodipine, some dopamine agonists [e.g., prami-
pexole, ropinirole], triptans [e.g., sumatriptan, zolmitriptan], phospho-
diesterase inhibitors [e.g., sildenafil, tadalafil, vardenafil], and some
benzodiazepine agonists [e.g., zaleplon, zolpidem]). In patients taking
paliperidone for schizoaffective disorder, those taking 9–12 mg/day ex-
perienced more myalgias than did those taking 3–6 mg/day (manufac-
turer’s product information).
Several important points require consideration in the evaluation of
patient complaints about muscle aches or discomfort. Because antide-
pressant discontinuation syndromes may involve myalgias and other
flulike symptoms, consideration should be given to erratic treatment
adherence among patients being prescribed short-acting SSRIs or
SNRIs. Among patients taking antipsychotic drugs, probably the most
critical concern is the potential for NMS to manifest as muscle pain or
stiffness (see “Neuroleptic Malignant Syndrome” in Chapter 19, “Sys-
temic Reactions”). A diagnosis of fibromyalgia may warrant consider-
ation in patients whose examinations reveal multiple “trigger” points of
musculoskeletal tenderness. Myalgias or even rhabdomyolysis can be
caused by a number of nonpsychotropic medications, including statins,

metformin (due to lactic acidosis, usually at high doses), and corticoste-
roids such as prednisone. Rhabdomyolysis also can occur from excessive
alcohol use, as well as use of methamphetamine, cocaine, 3,4-methylene-
dioxymethamphetamine (i.e., MDMA or Ecstasy), and cannabis.
Evaluation of myalgias should address possible noniatrogenic causes
and other associated symptoms, as well as the time course of their onset
relative to changes in a psychotropic drug regimen. Treatment, if any,
should target identifiable underlying medical etiologies.
16
Neurological System
Akathisia and Extrapyramidal

Adverse Effects
General Recommendations. Centrally acting β-blockers (e.g.,
propranolol) or benzodiazepines remain the most evidence-based
adjunctive treatment strategies to counteract antipsychotic-
induced akathisia. Preliminary studies also support the adjunctive
use of gabapentin or trazodone, as well as amantadine, although
benefits with amantadine may be transient. The use of anticholin-
ergic drugs such as benztropine is less well established.
Akathisia—either the objective manifestation or subjective experience of

physical restlessness—is a common problem related to treatment with
many if not most dopamine antagonists. A handful of case reports also
suggest that true akathisia may also be inducible by lithium, chronic use
of mirtazapine, and some SSRIs, possibly in dose-related fashion (pre-
sumably via striatal dopamine antagonism resulting from the inhibitory
243
effects of serotonin). Sertraline is thought to be the most potent dopa-

mine reuptake inhibitor among the SSRIs, and as such, its potential for
causing adventitious movements may be minimal. Some authors have
also linked the emergence or exacerbation of suicidal features during
SSRI treatment with the presence of SSRI-induced akathisia (Rothschild
and Locke 1991).
The incidence of akathisia with antipsychotics has been reportedly
lower with agents that dissociate rapidly and are thus considered “loose”
binders of the dopamine D2 receptor (Kapur and Seeman 2001), such as
quetiapine or clozapine, and higher among agents with “tight” D 2 re-
ceptor binding affinities, such as risperidone and aripiprazole (Table
16–1). Akathisia also may be more likely to occur during combination
therapy with mood-stabilizing drugs or antidepressants in bipolar dis-
order or major depression, respectively, than might otherwise occur as
monotherapy in bipolar disorder or schizophrenia.
TABLE 16–1. Reported rates of akathisia among second-generation

antipsychotics in FDA registration trialsa
Agent Incidence
Aripiprazole 10%–13% in acute monotherapy trials across

indications; 19%–25% when added to lithium
or divalproex (bipolar disorder) or
antidepressants (major depression)
Asenapine 4%–11% across indications
Clozapine 3%
Iloperidone 1.7%–2.3%; parkinsonism in 0.2%–0.3%
Lurasidone 6%–22% in acute trials for schizophrenia
Olanzapine 3% in acute trials across indications
Paliperidone 6%–9% in acute schizophrenia trials
Quetiapine 1%–4% across indications
Risperidone 5%–9% (across indications); parkinsonism in
12%–20% across indications
Ziprasidone 8%–10% (across indications); other
extrapyramidal symptoms in 14%–31%
across indications
aBased on manufacturers’ product information.
Neurological System 245
The traditional cornerstones of treatment to counteract akathisia in-

clude centrally acting β-blockers, benzodiazepines, or anticholinergic
agents. Among β-blockers, propranolol is perhaps the best studied for
akathisia caused by antipsychotics or lithium, and is usually dosed from
30 to 90 mg/day in two or three divided doses. Another centrally acting
β-blocker, betaxolol (10–20 mg/day), has shown comparable efficacy to
propranolol (20–40 mg/day) for this purpose (Dumon et al. 1992; Du-
puis et al. 1987), although other non–centrally acting β-blockers such as
sotalol seem less effective to ameliorate antipsychotic-associated akathi-
sia (Dumon et al. 1992; Dupuis et al. 1987). Amantadine, dosed from 100
to 200 mg bid, has been shown to rapidly improve signs of akathisia, but
its effects may dissipate within several weeks of initiation.
Case reports also have suggested potential value with adjunctive
gabapentin for antipsychotic-induced akathisia. The serotonin type 2A
(5-HT2A)-blocking agent trazodone, dosed at 100 mg/day, also has re-
ceived preliminary support for the treatment of neuroleptic-induced
akathisia in a small (N=13) double-blind placebo-controlled crossover
study (Stryjer et al. 2009), as has the 5-HT2A antagonist mirtazapine.
Benzodiazepines are perhaps the best studied and most effective
short-term strategy to manage akathisia. A 2002 Cochrane Database anal-
ysis based on two small randomized trials (N=27) found clonazepam su-
perior to placebo for reducing symptoms of akathisia within 7–14 days of
initiation (Resende Lima et al. 1999).
Finally, anticholinergic drugs such as benztropine are sometimes
used in the treatment of akathisia, although their value for this intended
purpose appears less well established than for the amelioration of an-
tipsychotic-induced extrapyramidal side effects. Indeed, a 2006 Coch-
rane Database review found no relevant randomized controlled trials
from which to draw broad recommendations or that support or refute
the efficacy of anticholinergic drugs to treat akathisia (Rathbone and
Soares-Weiser 2006).
Cognitive Complaints
General Recommendations. Clinicians should carefully eval-
uate patients to determine whether subjective cognitive com-
plaints reflect true cognitive deficits, psychiatric symptoms, or
other deficits (e.g., learning disabilities). Clinicians should recog-
nize common cognitive adverse effects of specific psychotropic
agents and reduce dosages or eliminate likely offending agents
when possible. Clinicians also should address other exogenous
factors that may contribute to cognitive problems (e.g., alcohol or

substance abuse, sleep disorders). Psychostimulants (amphet-
amine, methylphenidate, and modafinil or armodafinil) may aid
attentional processing and verbal fluency in patients who are suit-
able candidates. Dopamine agonists (e.g., pramipexole) also may
be helpful for attention deficits in some patient groups.
Numerous factors in addition to psychotropic medications can contrib-

ute to subjective cognitive complaints and include affective or psy-
chotic symptoms, anxiety disorders or symptoms, substance abuse,
attention-deficit disorder, and a variety of comorbid medical condi-
tions. Furthermore, at least in some conditions (e.g., bipolar disorder),
subjective cognitive complaints often correlate poorly with objective
deficits in cognitive performance, making it essential for clinicians to
discern the nature of cognitive complaints beyond patients’ superficial
reports of their presence.
Any psychoactive drug may impair judgment, thinking, or motor
skills, although demonstrated adverse cognitive effects related to psychi-
atric medications are relatively circumscribed. Cognitive dulling that is
plausibly attributable to sedating psychotropics (e.g., anticholinergic
drugs, benzodiazepines, FGAs, SGAs, and certain anticonvulsants [in
particular, topiramate]) poses difficult obstacles that are not easily over-
come short of dosage reductions, or when necessary, elimination of a
causal agent. In the case of topiramate, adverse cognitive effects may be
dose-related and typically include psychomotor slowing, word-finding
problems, impaired working memory, poor attention and concentration,
and decreased verbal and nonverbal fluency (reviewed in Goldberg
2008). In some instances, agents with a high potential for cognitive dull-
ing or disorganization can be replaced with other, more cognitively neu-
tral medications (e.g., replacing the anticholinergic drug benztropine
with the dopamine agonist amantadine as an alternative method to coun-
teract extrapyramidal side effects of antipsychotic drugs).
Few if any rigorous data implicate antidepressants as having ad-
verse cognitive effects, with the exception of adverse cognitive effects
attributable to anticholinergicity. In fact, given their potential neuropro-
tective effects as demonstrated from preclinical studies (e.g., increasing
brain-derived neurotrophic factor), nonanticholinergic antidepressants
conceivably may have some potential benefit for enhancing neuronal
viability and function. Open trials suggest the potential for SSRIs and
SNRIs to improve attention, working memory, and other executive do-
mains. A summary of known adverse cognitive effects associated with
psychotropic medications is provided in Table 16–2.
Few strategies have been formally studied or even articulated from

impressionistic observations in the literature regarding strategies di-
rected to counteract adverse cognitive effects caused by psychotropic
agents. Interest and curiosity surround the potential for cognitive en-
hancement associated with procholinergic agents (e.g., donepezil or ga-
lantamine) or glutamate antagonists (e.g., memantine), although the
efficacy of these agents has not been examined for purposes of counter-
acting cognitive deficits caused by psychotropic agents. In our clinical
experience, it is unlikely for procholinergic drugs or glutamate agonists
to ameliorate the cognitive dulling caused by benzodiazepines, anticho-
linergic drugs, or sedating antipsychotics.
Although all SGAs carry an FDA warning label identifying the po-
tential for cognitive and motor impairment, the absence of head-to-head
comparison studies focusing on changes in cognitive function makes it
difficult to judge whether some SGAs may be more cognitively sparing
than others.
The novel stimulant modafinil, as well as its enantiomer armodafi-
nil, has been the subject of considerable interest as a strategy to counter-
act sedation and possible adverse cognitive effects, although few formal
studies have addressed that specific purpose. The dopamine D2/D 3
agonist pramipexole has been suggested to improve attentional pro-
cessing in euthymic bipolar disorder patients and could potentially be
of value for iatrogenic cognitive dysfunction (Burdick et al. 2011).
Delirium and Encephalopathy

General Recommendations. Acute mental status changes
that involve disorientation, a waxing-and-waning level of arousal,
and other focal neurological signs rarely result from psychotropic
drugs apart from specific toxicity states (e.g., anticholinergic delir-
ium, serotonin syndrome). Underlying etiologies (including sys-
temic infections or neurological processes and toxic-metabolic
states) should be thoroughly evaluated in the assessment of delir-
ium or related acute changes in mental status.
Relatively rare reports exist of individual psychotropic agents or com-

binations of agents that may cause delirium or encephalopathy. Per-
haps the best known of these is the oft-mentioned possible adverse
interaction between lithium and FGAs, based on a handful of anecdotal
case observations beginning in the mid-1970s. Some authors of retro-
spective case reviews subsequently suggested that dose-dependent
neurotoxicity (notably, delirium with extrapyramidal signs, and more
rarely, cerebellar signs) could result from lithium, antipsychotics, or
TABLE 16–2. Adverse cognitive effects of common psychotropic

agents
Agent Cognitive effects
Atomoxetine None known.

Buspirone None known.
Carbamazepine In epilepsy studies, reports of subtle adverse
effects on learning, delayed visuospatial
processing, and impaired visual memory
(reviewed in Goldberg 2008).
Divalproex Subtle dose-related attentional and memory
deficits, impaired verbal memory, and delayed
decision time (reviewed in Goldberg 2008).
Gabapentin Minimal adverse cognitive effects.
Lamotrigine “Concentration disturbance” noted as an adverse
event in 2% of epilepsy patients during
premarketing studies; clinical trials in bipolar
disorder suggest improvement (rather than
worsening) of working and verbal memory,
verbal fluency, and immediate recall (reviewed
in Goldberg 2008); lamotrigine toxicity may
manifest with diffuse cognitive impairment
(Bouman et al. 1997).
Lithium Diminished creativity, associative fluency, and
verbal memory; no significant effects on visual
memory, attention, executive function,
processing speed, and psychomotor
performance (Wingo et al. 2009).
Oxcarbazepine No adverse effects on memory seen acutely in
healthy volunteers (taking 300–600 mg/day);
possible enhanced attention and motor speed,
which may decline with dosages ≥1,200 mg/day
(reviewed in Goldberg 2008).
TABLE 16–2. Adverse cognitive effects of common psychotropic

agents (continued)
Agent Cognitive effects

Topiramate Possible marked impairment (not clearly dose
related) of global cognitive functioning,
including attention, concentration, verbal and
nonverbal fluency, processing speed, language
skills, working memory, and perception; in
epilepsy patients, cognitive deficits were shown
to attenuate with time in some studies but not
others (reviewed in Goldberg 2008).
Antidepressants
Bupropion None known.
MAOIs None known.
Mirtazapine None known.
Nefazodone Dose-dependent increased reaction time (van Laar
et al. 1995).
SNRIs None known.
SSRIs None known.
Trazodone None known.
Vilazodone None known.
Benzodiazepines Possible impaired attention, arousal, and verbal or
nonverbal memory, as well as motor speed and
reaction time; anterograde amnesia may be
common (reviewed by Buffett-Jerrott and
Stewart 2002).
SGAs Possible impaired attention, spatial working
memory and visuospatial function, processing
speed, verbal memory, verbal fluency, set
shifting, and other executive functions—all
independent of sedative effects or severity of
psychopathology in bipolar or schizophrenia
patients (reviewed by Goldberg 2008).
Note. MAOI=monoamine oxidase inhibitor; SGA=second generation antipsy-
chotic; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective se-
rotonin reuptake inhibitor.
their combination. Modern interpretations of this anecdotal literature

have been tempered by vast experience for several decades with the
safe and effective use of combination therapy involving lithium with
FGAs and SGAs. The possibility of idiosyncratic neurotoxic interactions
between these drugs is considered remote.
Clinicians should be aware, however, of more common causes of
delirium or acute encephalopathic states; these include drug toxicities,
acute cerebral events, hypoxia, infection, and neoplasm. Anticholinergic
delirium typically manifests with associated signs of antimuscarinic (M1)
anticholinergic toxicity (commonly described as follows):
• “Mad as a hatter” (i.e., altered mental states),

• “Dry as a bone” (i.e., dry skin and mucous membranes),
• “Red as a beet” (i.e., flushing),
• “Blind as a bat” (i.e., mydriasis with loss of accommodation),
• “Full as a flask” (i.e., urinary retention), and
• “Hot as a hare” (i.e., fever).
Anticholinergic delirium must be recognized in patients receiving drugs

such as diphenhydramine, TCAs, antispasmodics (e.g., dicyclomine),
low-potency FGAs, histamine H2 blockers, and some calcium channel
blockers (e.g., nifedipine). Certain systemic neurological drug reactions—
notably, serotonin syndrome—also may manifest with delirium.
Dyskinesias and Dystonias

Restless Legs Syndrome
General Recommendations. Adjunctive benzodiazepines or
dopamine agonists (e.g., pramipexole, pergolide) may help to
curtail restless legs caused by psychotropic agents. Restless legs
caused by FGAs or SGAs may be a manifestation of dose-related
akathisia, which may improve with dosage reductions, or if nec-
essary, changing to alternative within-class agents that may be
associated with a lower incidence of akathisia.
Restless legs syndrome (RLS) is sometimes regarded as a form of dys-

kinesia that reportedly may be provoked by a number of medications
in addition to dopamine antagonists, including mirtazapine (particu-
larly when coadministered with tramadol or dopamine antagonists;
S.W. Kim et al. 2008), escitalopram, and citalopram. Some authors have
suggested that RLS induced by SSRIs may reflect the consequences of
SSRI-induced downregulation of dopamine tone in the basal ganglia,

for which replacement with bupropion (as a dopaminergic alternative
antidepressant) may be useful. Some SGAs have been reported to cause
RLS or periodic limb movements during sleep that occur indepen-
dently of other motor abnormalities and potentially in dose-related
fashion. RLS has been linked with olanzapine and risperidone. Treat-
ment with benzodiazepines or dopamine agonists (e.g., ropinirole) may
not be efficacious to counteract RLS induced by SGAs, although chang-
ing to an alternative SGA with loose D2 receptor binding affinity, such
as quetiapine, may be ameliorative. Anticholinergic drugs are not
known to ameliorate RLS despite the likely pathogenic role of the basal
ganglia and related extrapyramidal structures.
Tardive Dyskinesia
General Recommendations. Tardive dyskinesia (TD) is a
potentially severe and sometimes irreversible movement disor-
der caused by antipsychotic drugs. The emergence of early signs
of TD (e.g., involuntary oral-buccal movements) suggests the lim-
ited use—if not complete cessation—of antipsychotics if clini-
cally feasible, balanced against the risk for worsening underlying
psychosis or other psychopathology. A lower incidence of TD may
occur with clozapine, quetiapine, or olanzapine than with other
antipsychotics. Supplemental vitamin E may diminish progres-
sion of TD symptoms but seems less clearly able to reverse exist-
ing symptoms. Reports of paradoxical increased cardiovascular
mortality among high-dose vitamin E recipients remain a sub-
ject of debate. Data from preliminary randomized controlled tri-
als suggest safety and potential benefit with vitamin B6, Ginkgo
biloba, levetiracetam, melatonin, and amantadine.
The incidence of TD has been estimated at 3%–5% per year during treat-
ment with FGAs; the risk during treatment with SGAs is lower but still
observable (with a weighted annual mean incidence of 0% in children,
0.8% in adults, 6.8% in adults plus older adults combined, and 5.4% in
adults over age 54; Correll et al. 2004). Risk factors for TD include dura-
tion of antipsychotic exposure, advanced age, high dosages, and Afri-
can or African American race. Although the likelihood of occurrence of
TD is probably less with SGAs, cases have been reported with virtually
all SGAs, particularly those with tight binding affinity to the D 2 recep-
tor (e.g., risperidone and aripiprazole). Clinicians must also keep in
mind that lifetime risk is cumulative and may be higher in patients tak-
ing SGAs as a result of past exposure to FGAs.
Proposed mechanisms to account for TD include dopamine supersen-

sitivity as well as neurotoxic effects related to oxidative stress. Generally
speaking, there are no known established remedies to counteract TD,
although preliminary studies have identified a number of compounds
that may offer at least potential value either to diminish symptoms or to
slow its progression during continued antipsychotic pharmacotherapy.
Anecdotal experience has shown that increasing dosages of an antipsy-
chotic may temporarily mask TD rather than improve it.
Antioxidants are among the most extensively studied agents for the
treatment of TD. Historically, adjunctive vitamin E has been regarded as
one of the few strategies thought to reduce the potential progression (if
not reverse the existing symptoms) of TD, although empirical studies
have yielded conflicting results. For example, one short-term (i.e.,
2-month) randomized double-blind trial found greater reductions in
abnormal involuntary movements in patients with schizophrenia who
took 800 international units (IU) of vitamin E twice daily as compared
with patients taking placebo, with an overall reduction of 24% from base-
line in Abnormal Involuntary Movement Scale (AIMS) scores during
active drug therapy (Lohr and Calagiuri 1996). Findings were most
robust among subjects with TD of less than 5 years’ duration. In a 12-week
randomized double-blind Chinese study, vitamin E dosed at 1,200 IU
yielded significantly greater reductions in AIMS scores than did placebo,
with clinical responses correlated with blood levels of the enzyme super-
oxide dismutase (Zhang et al. 2004). On the other hand, a large (N=107)
multisite 2-year prospective Veterans Affairs study found no differences
between placebo and 1,600 IU/day of vitamin E (Adler et al. 1999). Simi-
larly, Egan et al. (1992) found no difference in AIMS scores over 6 weeks
in 21 patients with schizophrenia given 1,600 IU/day of vitamin E or pla-
cebo in a randomized crossover study. A 2001 Cochrane Database review
of 10 randomized studies found no evidence for reduction of TD symp-
toms with vitamin E but did indicate greater progression of TD symp-
toms in subjects randomized to placebo (Soares-Weiser et al. 2011). (Of
note, only 3 of the 10 studies included in that review involved treatment
durations of 5 months or longer.)
Controversy regarding the use of supplemental vitamin E arose fol-
lowing a meta-analysis of 19 randomized trials of high-dose vitamin E
(defined as ≥400 IU/day, with a dosing range from 16.5 to 2,000 IU/
day), involving 135,967 subjects undergoing treatment of chronic
inflammatory diseases (mostly coronary heart disease), in which the
authors reported an increased risk for all-cause mortality (Miller et al.
2005). High-dose vitamin E has been suggested to exert pro-oxidant
rather than antioxidant effects, as well as anticoagulant effects that may
increase the risk for hemorrhagic stroke. Notably, however, a reanalysis

of these data in conjunction with additional sources disputed the
reported link between increased mortality and high-dose vitamin E,
suggesting instead a confounding association between male sex and
mortality independent of vitamin E use (Gerss and Köpcke 2005).
Potential hazards related to high-dose vitamin E use have not been
demonstrated in patients being treated (or at risk) for TD, although the
magnitude of vitamin E’s potential efficacy to curtail the risk of devel-
oping or worsening TD does not appear to be robust.
Among other antioxidants, vitamin B6 (dosed at 1,200 mg/day) was
found to be superior to placebo in reducing parkinsonian and dyskinetic
movements as well as extrapyramidal symptoms during a 26-week ran-
domized double-blind study conducted in 50 patients with schizophrenia
or schizoaffective disorder and TD (Lerner et al. 2007). Similarly, the
antioxidant piracetam (orally dosed at 4,800 mg/day) was superior to
placebo during a 9-week randomized crossover study in 40 patients with
schizophrenia or schizoaffective disorder and TD (Libov et al. 2007).
Relatedly, a randomized controlled study using the ethylated congener of
piracetam, levetiracetam (dosed from 500 to 3,000 mg/day; mean final
dose=2,156 mg/day), was found to be superior to placebo over 12 weeks
in reducing moderately severe TD symptoms among 50 patients with
schizophrenia, with a mean reduction in AIMS scores of 43.5% (as com-
pared with 18.7% for patients given placebo) (Woods et al. 2008); con-
sistent with these observations, an open case series of adjunctive
levetiracetam (mean dose=2,290 mg/day) found significant improve-
ment from baseline of abnormal involuntary movements in 16 patients
with TD after 1–3 months (Meco et al. 2006). It has been hypothesized that
levetiracetam may improve motor function via free radical oxidative
scavenging, enhancing of GABA function, enhancing of nitric oxide pro-
duction, or reduction of neuronal hypersynchrony in the basal ganglia.
Lastly, the hormone melatonin also possesses antioxidant properties and
was associated with greater reductions in abnormal involuntary motor
movements and high tolerability during one 6-week double-blind cross-
over study, dosed nightly (8 P.M.) as a single 10-mg tablet, in 22 schizo-
phrenia patients with TD (Shamir et al. 2001).
Other agents have been studied on the basis of the rationale of pre-
sumptive damage to striatal cholinergic neurons associated with TD.
Favorable preliminary open-label data have been reported with the
procholinergic agent donepezil (5–10 mg/day for 6 weeks) (Caroff et al.
2001), although findings were negative from a larger, controlled trial of
the cholinesterase inhibitor galantamine (dosed at 8–24 mg/day for
12 weeks) (Caroff et al. 2007). By contrast, the M1 selective anticholin-
ergic drug biperiden (2 mg bid) improved both parkinsonian symptoms

and abnormal involuntary motor movements better than did placebo
during a double-blind crossover study of 32 schizophrenia inpatients
with TD (Silver et al. 1995).
Certain dopamine agonists have demonstrated value in treating TD
symptoms in patients with schizophrenia. The most notable is amanta-
dine (100 mg bid), which in a study of 32 schizophrenia inpatients with
TD yielded better efficacy than placebo and comparable reductions in
AIMS scores as compared to biperiden during successive 2-week single-
blind randomized crossover trials (Silver et al. 1995). During a 12-week
double-blind placebo-controlled trial, extract of Ginkgo biloba—another
antioxidant and free radical scavenger—was found to significantly
reduce AIMS scores without impeding cognitive function when dosed
at 240 mg/day (Zhang et al. 2011).
GABAergic drugs such as baclofen, divalproex, progabide, and tet-
rahydroisoxazolopyridine also have been studied preliminarily in
patients with TD. In a Cochrane Database meta-analysis of eight short-
term studies, Alabed et al. (2011) described the evidence for each of
these agents as “inconsistent and unconvincing,” adding that any po-
tential benefits were typically outweighed by substantial adverse effects
involving sedation or the exacerbation of psychotic symptoms.
Eicosapentaenoic acid dosed at 2 g/day was no different from pla-
cebo in a study of 84 subjects with schizophrenia or schizoaffective dis-
order and TD over 12 weeks (Emsley et al. 2006).
Optimistic results were reported from a pilot study of open-label high-
dose buspirone (180 mg/day for 12 weeks) in a small group (N=8) of
schizophrenia patients with TD (Moss et al. 1993), although these findings
have not been replicated, and supratherapeutic doses of buspirone have
been associated with seizures, gastrointestinal problems, sedation, pares-
thesias, and blurred vision. Coadministration of buspirone with other
serotonergic agents also may increase the risk for serotonin syndrome.
Branched-chain amino acids received interest as a potential strategy
for treating TD on the basis of observations that the large neutral amino
acid phenylalanine appears associated with TD, whereas ingestion of
branched-chain amino acids (i.e., valine, leucine, isoleucine) may corre-
spondingly diminish brain phenylalanine availability—which in turn
may reduce TD symptoms (Richardson et al. 1999; 2003). A proprietary
powdered drink mix containing large branched-chain amino acids (Tar-
vil) became commercially available in 2002 but in 2007 was discontin-
ued by its manufacturer, Nutricia North America.
A number of studies have examined the potential for some atypical
antipsychotics to diminish the symptoms of TD (in contrast to the mask-
ing of TD, which can be observed using increased doses of FGAs).

Among these drugs, low-dose clozapine has perhaps the most robust
evidence, with global improvement rates in TD symptoms reportedly in
the range of 70%–80% over periods of up to 18 weeks (Spivak et al.
1997). Some case reports suggest that the D2 partial agonist aripiprazole
may improve (Karabulut et al. 2008) or cause (Abbasian and Power
2009) TD, and other reports suggest improvement in TD symptoms
after substituting quetiapine for other antipsychotics (Abbasian and
Power 2009). The substitution of olanzapine for other atypical antipsy-
chotics or FGAs in schizophrenia patients with TD has been associated
with reductions in TD symptoms, with improvements sustained over
an 8-month period, and no rebound worsening of TD symptoms during
imposed dosage reduction periods (Kinon et al. 2004).
In our experience, none of the available pharmacological options to
reduce TD symptoms or curtail their progression yields a dramatic or
substantial benefit. TD remains a difficult and often intransigent prob-
lem for which there is no reliable or well-proven remedy. Realistic
expectations should be established with patients before embarking on
experimental strategies such as those described in this section. In some
cases, despite the presence of TD, the severity of psychotic symptoms
may be sufficiently great to outweigh the risks of potential worsening of
TD and warrant continued dopamine antagonist therapy. In such in-
stances, the use of antipsychotic agents with relatively loose D2 receptor
affinities, such as clozapine or quetiapine, may at least theoretically help
to minimize the known and sometimes accepted risk for TD worsening.
Withdrawal Dyskinesias
General Recommendations. To minimize the potential for
withdrawal dyskinesias, the preferable action is to gradually
taper off or cross-taper an existing antipsychotic rather than to
abruptly discontinue it.
Abrupt cessation of antipsychotics may provoke motor adverse effects

suggestive of a withdrawal dyskinesia. The clinician should consider this
possibility as being especially likely with antipsychotics that have short
half-lives (cf. aripiprazole, with a half-life of 75 hours) or agents with
especially tight D2 binding affinities in the basal ganglia (e.g., risperidone,
haloperidol). Withdrawal dyskinesias are generally self-limited and often
require no intervention. If appropriate, their management can include
1) reintroducing a discontinued antipsychotic, followed by a slower taper;
2) substituting an alternative antipsychotic with lesser known risk for dis-
turbing extrapyramidal movements; 3) introducing a benzodiazepine; or

4) short-term use of adjunctive clonidine. Withdrawal dyskinesias pose no
known increased risk for future development of TD.
Fatigue and Sedation

General Recommendations. Sedation from psychotropic
drugs, particularly those that are antihistaminergic, may or may
not tolerize with time or dosage reductions. Effective manage-
ment involves identifying and eliminating or managing addition-
al potential causes of sedation (e.g., sleep apnea, alcohol abuse,
concomitant pharmacotherapies, comorbid medical conditions).
Adjunctive stimulants, including modafinil, armodafinil, amphet-
amine, or methylphenidate, may help to alleviate persistent or
significant sedation in patients for whom stimulants may be safe
and appropriate short-term adjunctive treatments.
Fatigue encompasses a wide range of phenomena that may include the

soporific effects of a drug (e.g., drowsiness, somnolence, sedation), loss
of energy, and physical weakness independent of level of arousal. In
premarketing FDA registration trials, MedDRA terms such as sedation
or somnolence are differentiated by a matter of relative degree. Most ran-
domized trials do not report information on the longitudinal trajectory
of sedation (i.e., whether it is an early or late phenomenon, whether it
plateaus over time), variations in severity, or timing during the day
(e.g., sedation arising shortly after administration vs. excessive daytime
sleepiness following nighttime administration).
A summary of reported incidence rates of sedation or somnolence
across major psychotropic drug classes in FDA registration trials is pre-
sented in Table 16–3. For comparative purposes, Table 16–3 also includes
information regarding drug-associated insomnia, a topic further dis-
cussed in the section “Insomnia” in Chapter 18, “Sleep Disturbances.”
Histamine H1 antagonism is considered to be one of the most common
causes of sedation or somnolence caused by psychotropic agents. Some
authors have proposed that tolerance may develop to the sedating ef-
fects of H1 blockade over time during continued treatment with psycho-
tropic drugs that have antihistaminergic properties. Indeed, one small
(N = 15) randomized trial demonstrated this effect with diphenhydra-
mine 50 mg/day over 4 days in a group of healthy men (Richardson et
al. 2002). However, this finding has not been replicated, and to our
knowledge no data are available from any randomized trials that docu-
ment the serial course of somnolence or sedation as a function of time on
drug with any currently available psychotropic medication; extrapolation

of this observation to individuals with psychiatric disorders taking anti-
manic, antipsychotic, antidepressant, anxiolytic, or related compounds re-
mains speculative, and in our experience is not routinely evident.
Adjunctive psychostimulants likely represent the most obvious phar-
macological strategy to counteract sedation from other psychiatric med-
icines. Many clinicians consider the wakefulness-promoting agent
modafinil (or possibly armodafinil) to be among the safest, best tolerated,
and least abusable specific agents for adjunctive use in patients with se-
rious psychiatric disorders; however, randomized trials have generally
failed to demonstrate an advantage for adjunctive modafinil over placebo
in diminishing either fatigue or cognitive functioning in patients with
schizophrenia. In studies of patients with major depression, open-label
trials have suggested some value for adjunctive modafinil in reducing as-
sociated symptoms of fatigue and sleepiness, although subsequent ran-
domized placebo-controlled trials have failed to replicate earlier open-
label findings. Some studies also suggest an advantage for adjunctive
modafinil over placebo during the first few weeks of antidepressant treat-
ment, but these effects may attenuate over time.
In our experience, initial sedation that persists from antihistaminergic
compounds such as quetiapine can be effectively managed with adjunc-
tive modafinil dosed at 100–300 mg/day (in one or two divided doses) or
armodafinil dosed at 150–250 mg/day (in one or two divided doses). Tra-
ditional psychostimulants such as methylphenidate or amphetamine are
also sometimes considered as viable adjunctive treatments to counteract
iatrogenic sedation from other medications, although concerns about
abuse potential as well as dose-related sympathomimetic or psychoto-
mimetic effects from traditional stimulants sometimes limit enthusiasm
for their use for such purposes.
Headache
General Recommendations. Headaches are common, non-
specific side effects that often occur initially and transiently with
many psychotropic agents and are best treated, if necessary,
with over-the-counter analgesics as needed. Persistent head-
aches merit careful evaluation for other (i.e., noniatrogenic) eti-
ologies. Psychotropic agents that are suspected of causing
persistent headaches (notably, lamotrigine or some SSRIs) may
warrant discontinuation for the purposes of diagnostic clarifica-
tion as well as relief of the presumed side effect.
TABLE 16–3. Reported incidence rates of somnolence, sedation, and

insomnia across FDA registration trials
Agent Somnolence or sedation Insomnia
Anticonvulsants
Carbamazepine 32% (Equetro in bipolar ≤ 5% (Equetro in bipolar
mania; 12% in open-label mania)
extension)
Divalproex 17% (migraine), ≤5% (all indications)
19% (bipolar mania),
27% (epilepsy)
Gabapentin 21% (postherpetic > 1% (but ≤ placebo)
neuralgia)
Lamotrigine 9% (bipolar maintenance), 6% (epilepsy), 10%
14% (epilepsy) (bipolar maintenance)
Oxcarbazepine 20%–36% (epilepsy; 2%–4% (epilepsy; no
apparent dose apparent dose
relationship) relationship)
Topiramate 15% (epilepsy; no 4% (epilepsy; no apparent
apparent dose dose relationship)
relationship)
Antidepressants
Bupropion 2%–3% (major depression, 11%–16% (major
300–400 mg/day) depression, 300–400 mg/
day); 20% (seasonal
affective disorder,
150–300 mg/day)
Citalopram 18% 15%
Desvenlafaxine 4%–12% 9%–15% (major
(major depression, depression, 50–400 mg/
50–400 mg/day) day)
Escitalopram 6% (major depression), 9% (major depression),
13% (GAD) 12% (GAD)
Fluoxetine 13%–17% across disorders 16%–33% across disorders
Fluvoxamine 32%–35% across disorders 26%–27% across disorders

Mirtazapine 54% 0%
Paroxetine 19%–24% across disorders 18%–24% across disorders
Sertraline 13%–15% across disorders 12%–28% across disorders
Venlafaxine 12%–20% 15%–24% across disorders
Vilazodone 3% 6%
TABLE 16–3. Reported incidence rates of somnolence, sedation, and

insomnia across FDA registration trials (continued)
Agent Somnolence or sedation Insomnia
SGAs
Aripiprazole 11% (across acute adult 18% (across acute adult

indications) indications)
Asenapine 13% (schizophrenia), 6% (bipolar mania),
24% (bipolar disorder) in 16% (schizophrenia)
acute trials
Clozapine 39% 2%
Iloperidone 9%–15% (schizophrenia, Incidence rates not
across doses) reported
Lurasidone 22% (combined data for 8% (combined data for
20–120 mg/day over 20–120 mg/day over
6 weeks) 6 weeks)
Olanzapine 29% (across acute trial 12% (across acute trial
indications) indications)
Paliperidone 6%–11% (acute Incidence rates not
schizophrenia, reported
across doses);
12% (schizoaffective
disorder, across doses)
Quetiapine Quetiapine XR: 25% Quetiapine XR: ≥ 1% (acute

(acute schizophrenia), mania or schizophrenia),
50% (bipolar mania), 9% (long-term
52% (bipolar depression) placebo-controlled
schizophrenia trials)
Risperidone 2%–7% (acute 25%–32% (acute
schizophrenia, across schizophrenia. across
doses); 5% (1–6 mg/day, doses); 4% (adjuvant
as monotherapy for therapy in acute
bipolar mania) bipolar mania)
Ziprasidone 14% (schizophrenia acute Incidence rates not
trials), 31% (bipolar acute reported
mania trials)
Note. FDA= U.S. Food and Drug Administration; GAD= generalized anxiety
disorder; SGA= second-generation antipsychotic; XR= extended release.
Headache is among the most commonly reported adverse effects in

both active drug and placebo arms in randomized trials of psychotropic
compounds. The often nonspecific nature of headache can pose some
difficulties in determining its iatrogenic from noniatrogenic etiologies,
particularly in the absence of other neurological or systemic symptoms.
Incidence rates of headache from controlled trials of common psycho-
tropic drugs are reported in Table 16–4. Importantly, because headache
is among the most frequently occurring of all adverse effects from pla-
cebo (see the section “The Nocebo Phenomenon and Proneness to
Adverse Effects” in Chapter 1, “The Psychiatrist as Physician”), the in-
cidence rates with active drug reported from controlled trials in Table
16–4 likely highly overestimate true drug effects. For example, in the
case of escitalopram for GAD, the active drug incidence rate of 24% is
counterbalanced by a nocebo incidence rate for headache of 17%.
In patients taking lithium, chronic headaches have been associated,
rarely, with pseudotumor cerebri, a syndrome that also involves bilat-
eral papilledema and increased intracranial pressure on lumbar punc-
ture but no localized neurological signs or structural abnormalities
visible on neuroimaging.
Motor Tics
General Recommendation. No clear pharmacological reme-
dies are available to counteract tics. Identification and elimination
of the causal agent are advisable if the symptom produces distress.
Tics rarely may be caused by psychotropic medications. Obviously, the

clinician’s first task is to affirm whether the development of a new, sud-
den repetitive movement or vocalization likely represents a tic (as op-
posed to a compulsive behavior or motor neuron disease) and whether
other more primary etiologies (e.g., Tourette syndrome, usually in indi-
viduals under age 18; head trauma; stroke; infection) are plausible expla-
nations. Tics commonly include coughing, throat clearing, grunting,
sniffing, blinking, and head jerking, and they may include more complex
behaviors such as shouting or touching objects or people. Rare neurolog-
ical conditions such as gelastic seizures (sudden paroxysms of laughter)
or chorea may also pose unusual symptoms that require differentiation
from tics and determination of a primary neurological etiology versus a
secondary iatrogenic phenomenon.
Psychotropic drugs that have been reported to cause (or exacerbate)
tics include stimulants (i.e., amphetamine and methylphenidate),
bupropion, sertraline, fluoxetine, imipramine, and certain anticonvul-

sants (notably, carbamazepine and lamotrigine). Although the manu-
facturer’s product information for atomoxetine states that the drug does
not worsen tics in patients with ADHD and comorbid Tourette syn-
drome, cases have been reported linking tic exacerbations with use of
atomoxetine. In the great majority of case reports involving the emer-
gence or exacerbation of tics with each of the aforementioned agents,
subjects were usually those with preexisting tic disorders. Increased
dopaminergic tone is thought to contribute to pharmacologically
induced or exacerbated tics; mechanisms by which some anticonvul-
sants may cause tics are less well understood but are thought to involve
antiglutamatergic effects that may affect motor control. In general, the
recommendation is to discontinue a medication if it is believed to cause
or exacerbate a tic.
Pharmacotherapies intended to counteract or treat iatrogenic motor
tics are generally not undertaken, although medications used to sup-
press tics include α 2-adrenergic agonists such as clonidine or guan-
facine, benzodiazepines such as diazepam, antipsychotic agents
(haloperidol and pimozide being among the best studied), and possibly
donepezil (2.5–10 mg/day). In children with ADHD and chronic tics,
desipramine suppresses tics while reducing ADHD symptoms better
than placebo (Spencer et al. 2002), suggesting a broader role for TCAs in
managing tics. Of note, discontinuation of any of these agents (or poor
adherence) could lead to the reemergence of tics that are no longer being
suppressed.
Muscle Twitching, Fasciculations,

and Myoclonus
General Recommendations. Medication-induced fascicula-
tions or muscle twitches are generally benign phenomena that re-
quire no intervention. Clinicians should assure the absence of
noniatrogenic and remediable causes of fasciculations (e.g.,
dehydration, hypomagnesemia, hypocalcemia) that may occur as
phenomena that arise coincidentally during pharmacotherapy.
Fasciculations refer to small, involuntary contractions of a skeletal mus-

cle fascicle visible under the skin, whose movement may or may not be
rhythmic. Fasciculations that occur in periorbital muscle groups are a
focal dystonia described as blepharospasms. Although most instances of
muscle twitching or fasciculations are benign in nature, they can also
TABLE 16–4. Associations between psychotropic agents and

treatment-emergent headaches
Agent Comments
Atomoxetine Incidence of 19% in acute (≤18-week) child and

adolescent ADHD studies (cf. 15% with
placebo).
Buspirone Incidence of 6% in FDA registration trials.
Anticonvulsants
Carbamazepine Incidence of 22% in manufacturer’s 6-month
open-label trial of Equetro in bipolar disorder.
Divalproex Incidence of 31% in FDA registration trials as
adjunctive therapy for complex partial
seizures (cf. 21% incidence with placebo);
reported incidence >5% but no different from
placebo in trials for acute mania.
Gabapentin Incidence of 3.3% in postherpetic neuralgia
(monotherapy); >1% (but no different from
placebo) as add-on therapy in epilepsy.
Lamotrigine Incidence of ~30% of migraine-like headaches in
clinical trials for bipolar disorder; however,
case reports also support efficacy of
lamotrigine to prevent migraine with aura.
Oxcarbazepine Incidence of 26%–32% (no clear dose
relationship) in add-on therapy studies for
epilepsy.
Topiramate Not reported.
Antidepressants
Bupropion Incidence of 25% (bupropion SR 400 mg/day)–
26% (bupropion SR 300 mg/day) (cf. 23%
incidence with placebo) and 34% (bupropion
XL across doses; cf. 26% with placebo).
Citalopram Incidence of >2% but less than seen with placebo
in FDA registration trials for major depression.
Desvenlafaxine Incidence of 20%–22% (doses of 50–100 mg/
day) in FDA registration trials for major
depression (no different from placebo).
TABLE 16–4. Associations between psychotropic agents and

treatment-emergent headaches (continued)
Agent Comments
Duloxetine Incidence of 14% across indications in FDA
registration trials (no different from placebo).
Escitalopram Incidence of 24% in FDA registration trials for
GAD; in FDA registration trials for major
depressive disorder, incidence of ≥2% but
comparable or higher with placebo than
escitalopram; specific incidence rate in major
depressive disorder trials not reported.
Fluoxetine Approximate incidence of 20% in FDA
registration trials for all indications.
Fluvoxamine Incidence of 22% in FDA registration trials for
combined adult OCD and major depression.
Mirtazapine Incidence of ≥1% in FDA registration trials.
Paroxetine Approximate incidence of 18% in FDA
registration trials for GAD or major depression.
Sertraline Approximate incidence of 25% in FDA
registration trials for all indications.
Venlafaxine Incidence of 38% in social anxiety disorder (but
no different from placebo across other
indications).
Vilazodone Migraine reported in ≥1% in FDA registration
trials for major depression.
Note. ADHD=attention-deficit/hyperactivity disorder; FDA=U.S. Food and
Drug Administration; GAD=generalized anxiety disorder; OCD=obsessive-
compulsive disorder; SR=sustained release; XL=extended release.
result from mineral deficiencies or other medical or neurological causes

that may warrant consideration depending on clinical circumstances.
Etiologies of particular relevance to psychiatry include dehydration,
hypomagnesemia, hypocalcemia, hypoparathyroidism, excessive caf-
feine intake, benzodiazepine withdrawal, serotonin syndrome, Lyme
disease, myasthenia gravis, amyotrophic lateral sclerosis, and lower
motor neuron disease (e.g., denervation). Stress or anxiety may exacer-
bate existing fasciculations. In the case of blepharospasm, fatigue (or
poor sleep), dry eyes, and local irritants should be considered during
clinical evaluation. Psychotropic medications known to be associated
with benign fasciculations include anticholinergic agents, diphenhy-
dramine, amphetamine, dopamine agonists (e.g., ropinirole and similar
antiparkinsonian drugs), trazodone, selegiline, phenelzine, tranyl-
cypromine, theophylline, and depolarizing muscle blockers such as
succinylcholine (as used during electroconvulsive therapy).
Myoclonic movements are sudden jerklike contractions or twitches of
whole muscle groups (e.g., shoulder twitch, elbow flexion, wrist exten-
sion) that are usually benign. They may occur during sleep onset (known
as hypnic jerks) or while awake, although sometimes they may reflect
underlying CNS disease (e.g., myoclonic epilepsy, strokes, multiple scle-
rosis, chronic neuroimmune disease, Parkinson’s disease), infection, or
other systemic disorders (e.g., metabolic disorders, systemic lupus ery-
thematosus). They rarely result from psychotropic drugs, apart from
their presence as part of serotonin syndrome, or sometimes as an early
sign of lithium toxicity. Medications that have been associated with
myoclonus include SSRIs, TCAs, morphine, midazolam, and tramadol.
Myoclonic jerks that become intrusive or persistent can be treated with
clonazepam, baclofen, fluoxetine, and propranolol.
Nystagmus
General Recommendations. Nystagmus may indicate neu-
rotoxicity from a medication. A careful review should be made of
all medications, their dosages, and patient adherence, as well as
illicit substances. Additionally, the clinician should assess the
patient for other neurological or systemic signs of toxicity. Labo-
ratory assessments (e.g., serum drug levels) to determine supra-
therapeutic doses may sometimes provide corroborative
information. When nystagmus is thought to represent neuro-
toxicity, dosage reductions or the elimination of a suspected
causal agent may be necessary.
Nystagmus is a focal neurological sign with a wide differential diagnosis

that may include neurotoxicity from a number of psychotropic drugs. It
may occur as part of alcohol or benzodiazepine withdrawal or intoxica-
tion states, as well as intoxication from phencyclidine, phenobarbital,
and organic solvents. Nystagmus can variably be described as down-
beat, upbeat, rotary, horizontal, pendular, and gaze evoked. Distinct
types of nystagmus may reflect localized CNS lesions: upward nystag-
mus often reflects cerebellar or medullary disease, whereas horizontal
nystagmus is the most common type of drug-induced nystagmus,

involving low-amplitude beating with slow-velocity movements.
Drug-related nystagmus may occur without other clinical signs of tox-
icity. Lithium, for example, has been reported to cause downbeat nystag-
mus even at dosages producing nontoxic blood levels, and dosage
reductions do not necessarily ameliorate or diminish the phenomenon.
Other medications known to cause nystagmus include carbamazepine,
divalproex, lamotrigine, MAOIs, and propranolol. Gabapentin has been
used successfully to treat congenital nystagmus and is not known to cause
drug-related nystagmus. Nystagmus may occur as part of serotonin syn-
drome (but not NMS), although it has not otherwise been described in
association with the use of serotonergic antidepressants. It may be a rare
adverse effect of SNRIs. Nystagmus has not been reported in conjunction
with the use of antipsychotics, apart from one report of coarse horizontal
nystagmus after an ultimately fatal overdose of olanzapine.
The presence of nystagmus signals the need for a review of all existing
medications and dosages, with an awareness of pertinent pharmacoki-
netic interactions (e.g., lamotrigine toxicity from unadjusted dosing when
coadministered with divalproex). A basic neurological examination
should target cranial nerve abnormalities and neurotoxic signs (e.g.,
slurred speech, tremor, ataxia), and laboratory measures should include a
toxicology screen and assessment of pertinent drug levels (see Table 1–2
in Chapter 1, “The Psychiatrist as Physician”). Suspected causal drugs
should be discontinued if dosage reductions alone do not resolve symp-
toms or if other systemic manifestations of toxicity are evident.
Oculogyric Crises
General Recommendations. Antidopaminergic agents are
among the most common causes of oculogyric crises. These cri-
ses can be treated with diphenhydramine or benzodiazepines,
should the benefit of continuing the antipsychotic drug be
thought to outweigh the risk of the side effect.
An oculogyric crisis is a type of dystonic reaction that involves a sustained

involuntary upward deviation of the eyes. It may be caused by antipsy-
chotic medications (including both FGAs and SGAs, as has been reported
with olanzapine, ziprasidone, and clozapine) or the cessation of antipsy-
chotic agents, as well as from the use of other psychotropic agents,
including lithium, carbamazepine, oxcarbazepine, amantadine, SSRIs,
and benzodiazepines, among other compounds. Antipsychotic-induced
oculogyric crises have been reported to occur often in association with

autonomic features (e.g., flushing, sweating) and transient exacerbations
of psychotic symptoms (e.g., hallucinations, delusions, catatonia).
Episodes are typically self-limited, but their resolution may be has-
tened by anticholinergic medications such as benztropine or diphenhy-
dramine. Case reports also suggest that oculogyric crises caused by
FGAs or some SGAs may not necessarily resolve solely by discontinua-
tion of the antipsychotic but may improve after the initiation of quetia-
pine. It may also be worth considering the substitution of lower-potency
antipsychotics or those with relatively “loose” binding at D2 receptors
(although case reports of oculogyric crises exist with clozapine or olan-
zapine—both relatively “loose” D2 antagonists) as a strategy to counter-
act dystonia manifesting as an oculogyric crisis. It is unknown whether
recurrent or chronic antipsychotic-induced oculogyric crises increase the
probability of developing long-term movement disorders such as TD.
Relatively long-acting benzodiazepines, such as clonazepam, may
also provide benefit for alleviating antipsychotic-induced oculogyric
crises, with clonazepam being among the best studied in case reports
(Horiguchi and Inami 1989; Viana Bde et al. 2009).
Paresthesias and Neuropathies

General Recommendations. Paresthesias attributable to
psychotropic medications are usually benign phenomena that
may result from drug properties such as carbonic anhydrase in-
hibition or other direct effects on sensory nerve endings. They
generally pose no medical concern and require no intervention,
other than the ruling out of other possible etiologies unrelated
to a suspected pharmacotherapy. Neuropathies rarely result
from psychotropic drugs, benignly arising most often from lith-
ium or phenelzine.
Paresthesias commonly occur during treatment with carbonic anhy-

drase inhibitors (e.g., topiramate was associated with paresthesias in
35%–49%of migraine patients at doses of 50 mg/day and 200 mg/day,
respectively) and are identified in package insert labels as a rare event
reported with a wide range of psychotropic drugs, including divalproex,
most SGAs and SSRIs, venlafaxine, desvenlafaxine, duloxetine, mirtaza-
pine, stimulants, and some nonbenzodiazepine sedative-hypnotics.
Other nonpsychotropic medications that are known to cause paresthesias
include certain antibiotics (e.g., doxycycline), acetazolamide, antineo-
plastic agents, and a number of antiretroviral agents, among other com-

pounds. In addition, potential medical causes of paresthesias include
hyperventilation (e.g., secondary to panic attacks), local trauma or nerve
entrapment (e.g., carpal tunnel syndrome, disk herniation), diabetic neu-
ropathy, migraine, peripheral vascular disease, vitamin B12 deficiency,
toxic exposures, malignancy, infections, or connective tissue diseases.
Withdrawal from SSRIs or SNRIs may be associated with paresthesias, re-
mediable by undertaking more protracted drug tapers or by allowing for
the passage of time alone, inasmuch as paresthesias in this context are
medically benign. Iatrogenic paresthesias that occur in the absence of
other focal neurological signs require no intervention.
Psychotropic drugs are rarely associated with peripheral neuropa-
thies. Anticonvulsants other than phenytoin are not known to cause
neuropathy (and in fact are often used in the treatment of diabetic neu-
ropathy or neuropathic pain). Neuropathy has been reported in connec-
tion with lithium toxicity. Antipsychotics are not associated with
neuropathy, although some case reports identify its development in the
course of NMS. Antidepressants are not associated with the devel-
opment of peripheral neuropathy, with the exception of the MAOI
phenelzine—a compound that falls within a chemical class known as
hydrazines, which have been shown in preclinical and human studies to
reduce levels of vitamin B6 (pyridoxine)—which, in turn, can lead to pe-
ripheral neuropathy that may be remediable within several weeks’ time
by the administration of supplemental pyridoxine dosed 150–300 mg/
day (Stewart et al. 1984). Measurement of serum pyridoxine levels is not
necessary to justify an empirical trial of supplemental therapy in this
dosing range, which is a relatively benign intervention.
Seizures
General Recommendations. The seizure threshold may be
lowered by antidopaminergic drugs and bupropion, often in
dose-related fashion. Coadministration of anticonvulsants may
be advisable in patients for whom high doses of antipsychotics
(particularly clozapine) or bupropion are deemed necessary.
Continued use of anticonvulsant drugs raises the seizure threshold,

which can, at least in theory, pose an increased risk for seizures follow-
ing abrupt drug discontinuation.
Clozapine-induced seizures (■) are more likely to occur at high clo-
zapine dosages (incidence rate of 5% above 600 mg/day per the manu-
facturer), during rapid dose increases, during concomitant use of other

medications that lower the seizure threshold, or in patients with a neu-
rological deficit (Toth and Frankenburg 1994). Clinicians sometimes
coadminister an anticonvulsant with clozapine when the latter is dosed
>500–600 mg/day to help minimize the potential for seizures. All anti-
psychotics have the potential to lower an individual’s seizure threshold,
although risks appear highest with clozapine, loxapine, and chlorpro-
mazine, and appear lowest with haloperidol, pimozide, molindone,
thiothixene, and most SGAs other than clozapine (<1%–2% incidence).
Risk factors include a past history of seizures, concomitant medications
that also lower the seizure threshold, and rapid dose escalations.
Tinnitus
General Recommendation. Tinnitus is a rare, medically be-
nign adverse effect without a clear antidote other than drug ces-
sation if the symptom produces significant distress.
A small number of psychotropic drugs, including bupropion, bus-

pirone, and venlafaxine, have been suggested in case reports or premar-
keting studies to cause tinnitus. In addition, tinnitus can occur as part
of withdrawal phenomena from SNRIs such as venlafaxine or short-
half-life SSRIs such as sertraline. Divalproex has been reported both to
cause tinnitus (Hori et al. 2003; Reeves et al. 2000) and to treat it (Men-
kes and Larson 1998). Tinnitus has not been observed to be dose related
and often occurs in the first few weeks or months after drug initiation.
Risk factors remain unidentified.
Primary (i.e., noniatrogenic) tinnitus has been shown to be respon-
sive to carbamazepine, fluoxetine, or duloxetine, whereas randomized
trials with paroxetine and with trazodone produced negative findings
in treating tinnitus in nondepressed subjects. There are no published re-
ports of any pharmacotherapies that specifically ameliorate tinnitus
caused by psychotropic agents. Cessation of the likely causal agent typ-
ically eliminates the problem if tinnitus causes substantial distress.
Tremor
General Recommendations. Clinicians should properly eval-
uate the characteristics and likely primary versus secondary etiol-
ogy of a newly observed tremor, reduce dosages when feasible,
and assure the absence of other signs of neurotoxicity. Propra-

nolol begun at 10 mg tid or primidone dosed 100–300 mg/day
(maximum of 750 mg/day) in two or three divided doses may
help to reduce or ameliorate a drug-induced tremor.
Numerous psychotropic agents may cause tremor, and its presence

should signal the need for careful evaluation before changing treat-
ments or initiating adjunctive pharmacotherapies. Tremor sometimes
represents a sign of neurotoxicity that should be evaluated in the con-
text of other features that could suggest supratherapeutic dosing of a
given agent (e.g., lithium tremor in the setting of gastrointestinal upset
and ataxia would be consistent with probable lithium toxicity). A care-
ful history should include the assessment of caffeine intake, use of sym-
pathomimetic agents, risk for alcohol or benzodiazepine withdrawal,
history of familial or essential tremor, and other pertinent factors that
may contribute to the emergence of tremor. The evaluation of a tremor
should include 1) localization of affected regions (i.e., upper and/or
lower extremities; head and neck or trunk; unilateral or bilateral pres-
ence), 2) characteristics (e.g., occurring at rest or with action; qualitative
dimensions such as a pill-rolling or parkinsonian tremor vs. resting
tremor), 3) pupillary examination and assessment of nystagmus, 4) as-
sessment of deep tendon reflexes, and 5) identification of the presence
of cerebellar signs (e.g., ataxia, dysdiadochokinesia, Romberg sign).
In the absence of other signs of frank neurotoxicity, tremor can be a
benign but disruptive adverse drug effect that may be remediable either
by dosage reductions or by the use of adjunctive medications. β-Block-
ers such as propranolol likely represent the most commonly undertaken
medication strategy to counteract drug-induced tremors. For tremors
caused by lithium, divalproex, or most other psychotropics, dosing is
typically begun at 10 mg tid and may increase to 20 mg tid prn. Clini-
cians should monitor for bradycardia and hypotension, although the
latter is less common at relatively low doses of propranolol. Long-acting
or once-daily preparations of β-blockers such as propranolol (Inderal
LA) may sometimes be substituted for the immediate-release formula-
tion, provided that the higher doses in which Inderal LA are formulated
pose no risk for hypotension in a given patient. β-Blockers are relatively
contraindicated in the presence of hypotension, significant bradycardia,
sick sinus syndrome, second- or third-degree atrioventricular block,
and forms of chronic obstructive pulmonary disease such as asthma.
Alternatively, the pyrimidinedione anticonvulsant primidone is
commonly used in off-label fashion for the treatment of essential
tremor, with comparable efficacy to propranolol (Zesiewicz et al. 2005).
Dosing is typically begun at 100 mg at bedtime for the first few days,
then increased to 100 mg bid for an additional 2–3 days, and then ti-
trated further upward if necessary (based on response) to 100 mg tid or
as high as 250 mg tid. In studies of primidone in essential tremor, high-
dose primidone (i.e., 750 mg/day) has not demonstrated superior effi-
cacy to a daily dose of 250 mg (Serrano-Dueñas 2003). It should be noted
that the use of primidone as an anecdotal remedy to counteract psycho-
tropic-induced tremor is an extrapolation from data involving its use in
essential tremor; formal studies of primidone for this specific purpose
have not been reported.
Other anticonvulsants that have shown at least preliminary value in
the treatment of essential tremor include topiramate, gabapentin, leve-
tiracetam, and oxcarbazepine.
Lithium-associated tremor has been reported in open trials to im-
prove with vitamin B6 (900–1,200 mg/day) over 4 weeks, with no ad-
verse effects (Miodownik et al. 2002).
Orthostatic tremor refers to tremulousness of the lower extremities
on standing, which is typically alleviated by positional changes (includ-
ing walking or lying down) but not by traditional pharmacotherapies
for essential tremor such as propranolol or primidone. It is considered a
type of essential tremor and is seldom believed to occur secondary to
medications.
Yawning
General Recommendations. Yawning is a generally medi-
cally benign, uncommon side effect of some antidepressants. It
requires no intervention. It is not clearly dose related. If yawning
is sufficiently distressing to the patient, the presumed causal
agent might be discontinued and substituted with another med-
ication with a presumptive different mechanism of action (e.g.,
switching from an SSRI or SNRI to bupropion or a TCA).
Excessive daytime yawning has been described in postmarketing re-

ports with the SSRIs fluoxetine, sertraline, and citalopram, among oth-
ers, as well as the SNRIs duloxetine and venlafaxine. Yawning has been
hypothesized to occur as a reflex that is modulated by catecholaminer-
gic, serotonergic, and other transmitter systems (including cholinergic,
glucocorticoids, nitric oxide) in the paraventricular nucleus of the hy-
pothalamus (De Las Cuevas and Sanz 2007) and that may become al-
tered during antidepressant therapy. Usually, yawning is a benign
phenomenon, although reports exist that its frequency may occasion-

ally pose a disabling effect (e.g., yawning-associated orgasms during
clomipramine therapy [McLean et al. 1983]). Iatrogenic yawning some-
times may be diminished by adjunctive cyproheptadine.
17
Ophthalmological
System
Cataracts
General Recommendations. Product labeling for quetiapine
includes mention of the potential for development of cataracts,
as well as a recommendation for periodic slit-lamp examina-
tions, although no human studies have affirmed a clear distinc-
tion between cataracts that develop due to quetiapine and senile
cataracts that develop as part of normal aging.
Cataracts normally occur in 0.2% of the general population. They are

generally categorized as congenital, age related (i.e., senile cataracts),
traumatic, or secondary (e.g., to pharmacotherapies, radiation exposure,
or diseases such as diabetes), and are further classified by their degree of
opacity and location within the lens. The occurrence of cataracts in ani-
mal studies of high-dose quetiapine (specifically, in beagles) led its man-
ufacturer to advise baseline and semiannual slit-lamp ophthalmological
examinations. A review of the National Registry of Drug-Induced Ocu-
lar Side Effects in 2004 identified 34 spontaneous case reports of cataracts
associated with quetiapine use in nonelderly adults, occurring at a mean
of 29 weeks after treatment initiation, and leading the author to conclude
that quetiapine-induced cataracts were a rare event for which semian-
nual ophthalmological examinations are probably unnecessary (Fraun-
273
felder 2004). Another survey of 620,000 adult quetiapine recipients

identified an incident risk for cataracts of 0.005%, markedly lower than
the base rate in the general population (Shahzad et al. 2002). Complicat-
ing the discovery of a relationship between adult human cataracts and
quetiapine use is the virtually impossible ability to differentiate between
senile cataracts and secondary cataracts. Some FGAs, including phe-
nothiazines and haloperidol, also have been implicated as possible
causes of cataracts, although the validity of such associations remains
controversial (Shahzad et al. 2002).
TCAs as well as some SSRIs or SNRIs have also been suggested to pose
a small but observable increased risk for cataracts. For example, a nested
case-control study of 18,784 cases and matched control subjects found 1.2-
to 1.4-fold increased risk ratios for cataracts during treatment with flu-
voxamine, venlafaxine, or paroxetine, with a mean appearance at about
2 years after treatment initiation (Etminan et al. 2010). Corticosteroids rep-
resent another known pharmacological cause of secondary cataracts.
Diplopia/Blurred Vision
General Recommendations. Blurry vision is a common, of-
ten dose-related phenomenon caused most often by anticholin-
ergic drugs. When iatrogenic, it is typically nonpermanent, but if
time or dosage reductions fail to improve symptoms, patients
may prefer to discontinue a causal agent depending on the level
of severity and distress.
Blurry vision commonly results from the anticholinergic action of psy-

chotropic medications on the ciliary muscle of the eye. Indeed, patients
who wear corrective lenses or who are planning to have their eyes re-
fracted should be advised that the introduction of some psychotropic
medicines may cause blurry vision, which could interfere with the abil-
ity to accurately determine visual acuity until the possible effects of a
new medication or medication change are fully known.
Glaucoma
General Recommendations. Secondary narrow-angle glau-
coma is a rare adverse effect of topiramate, usually occurring in
the first few weeks after treatment initiation. Patients who start
topiramate should be counseled to be alert to visual changes or
eye pain and to seek immediate evaluation should these occur.
Ophthalmological System 275
Increased intraocular pressure leading to secondary narrow-angle

glaucoma has been reported as a rare event in association with topira-
mate, leading to a manufacturer’s “warning letter” sent to physicians in
2001, followed by an FDA package warning label. A 2004 literature re-
view identified 86 reported cases, although an absolute risk estimate is
unavailable (Fraunfelder et al. 2004). Narrow-angle glaucoma typically
manifests with myopia and blurred vision in the first few weeks after
initiation of treatment. Intraocular pressure may not necessarily be ele-
vated. Preexisting demographic or other risk factors have not been
identified. The phenomenon has been reported to be reversible via drug
cessation when recognized early, or with administration of topical atro-
pine 1% solution and topical steroids (e.g., prednisone acetate 1% solu-
tion). Screening for a history of glaucoma appears not to be either useful
or necessary for anticipating possible visual changes during topiramate
therapy. Topiramate should likely be discontinued if a patient develops
blurry vision, other visual changes, or eye pain, particularly in the first
month of treatment.
Retinopathies
the rare and possibly permanent known risk for retinal changes
caused by thioridazine and chlorpromazine.
Macular degeneration and retinal pigmentation are both rare complica-

tions associated with thioridazine. Although pigmentary changes can
continue during ongoing thioridazine exposure, debate exists about
whether functional visual changes can be progressive. Cases have been
reported of the continued loss of retinal pigment epithelium (presumably
because thioridazine remains bound to melanin), as well as diminished
visual acuity with normal funduscopic appearance years after drug ces-
sation; however, establishing causality can be difficult in such instances.
Risk appears linked to the use of high dosages (i.e., ≥800 mg/day).
Pigmentary retinopathy has been reported with very high dosages
of chlorpromazine (e.g., ≥2,400 mg/day) and may be irreversible.
18
Sleep Disturbances
Hypersomnia and Sleep Attacks

General Recommendations. Sleep attacks may occur, al-
though rarely, with several psychotropic agents, most notably cer-
tain dopamine agonists (e.g., pramipexole, ropinirole) and MAOIs.
Antihistaminergic psychotropic drugs often cause insomnia at
treatment initiation, which may or may not diminish with contin-
ued use. Consideration should be given to the role of sleep studies
to assess excessive daytime sleepiness, particularly if noniatro-
genic etiologies (e.g., sleep apnea, narcolepsy) are suspected. Ad-
junctive stimulants, particularly modafinil or armodafinil, may be
of value to counteract excessive daytime somnolence or suspected
sleep attacks. Persistent symptoms that disrupt or imperil normal
daytime functioning may require drug cessation.
Sleep attacks may involve sleep-onset rapid eye movement (REM) peri-
ods and may be a manifestation of narcolepsy when accompanied by
sleep paralysis upon falling asleep or waking, cataplexy, and hypnagogic
hallucinations. A limited number of psychotropic drugs have been re-
ported to cause sleep attacks, which may include falling asleep while
driving. The most well known among these drugs are dopamine agonists
(e.g., pramipexole and ropinirole) when used in patients with Parkin-
son’s disease, producing an approximate 5-fold increased risk for somno-
lence as compared to placebo across several randomized trials. It is
277
unknown whether this risk similarly pertains to other patient groups

(e.g., those with restless legs syndrome or bipolar depression) who may
take these medicines. (Notably, patients with restless legs syndrome typ-
ically have intrinsic sleep architecture disturbances that neither prami-
pexole nor ropinirole directly alters, either beneficially or adversely,
apart from improving nighttime sleep quantity and adequacy.)
Anecdotal reports exist of daytime sleep attacks with MAOIs (nota-
bly, phenelzine). Although MAOI-induced sleep attacks are not feasibly
addressed by the adjunctive use of traditional stimulants such as meth-
ylphenidate or amphetamine, the novel stimulant modafinil (or armo-
dafinil) is not contraindicated during treatment with an MAOI and may
provide benefit. If amphetamines or methylphenidate is prescribed, clini-
cians should bear in mind that cessation can sometimes trigger rebound
increases in non-REM sleep, which in turn may increase daytime fatigue
and somnolence.
Insomnia
General Recommendations. Insomnia, whether iatrogenic
or primary, can be difficult to treat. The clinician must rule out
other contributing medical causes (e.g., obstructive sleep apnea,
restless legs syndrome, pain, substance withdrawal) or psychiat-
ric etiologies (e.g., mania, depression). Initial conservative ap-
proaches for managing simple insomnia caused by psychotropic
drugs involve modifying drug dosing schedules and assuring
sleep hygiene. Iatrogenic insomnia is often transient but may
warrant treatment with sedative-hypnotics or other soporific
agents; its persistence, particularly after resolution of other psy-
chiatric symptoms being treated, may signal the presence of an
independent sleep disorder that merits independent evaluation.
Insomnia is among the most common phenomena whose etiologies

can be difficult to discriminate among iatrogenic or illness-related
causes. In the case of depression, for example, initial, middle, or termi-
nal insomnia may be a target symptom of a depressive episode, a treat-
ment-emergent adverse effect, or both. In the treatment of patients with
bipolar mania, experts emphasize the importance of differentiating a
loss of the need to sleep from difficulty falling or staying asleep with
consequent fatigue the following day. A complaint of insomnia must be
assessed as the possible manifestation of a more fundamental psychiat-
ric or medical problem, for which proper remediation requires more ef-
fective treatment of the underlying cause.
Sleep Disturbances 279
Although many catecholaminergic and sympathomimetic agents are

thought to cause insomnia via an alerting or stimulating effect, the degree
to which some agents may cause either insomnia or hypersomnia is often
unpredictable. For example, package insert descriptions from FDA regis-
tration trials of paroxetine for major depression report insomnia as occur-
ring in 13% of patients but somnolence in 23% of patients. Insomnia rates
may also vary substantially with the same agent across different disor-
ders; for example, higher rates of insomnia were seen in FDA trials of flu-
oxetine for bulimia (33%) or obsessive-compulsive disorder (28%) than
for major depression (16%). In the case of sertraline, insomnia rates were
highest in obsessive-compulsive disorder (28%) and lowest in major de-
pression (16%).
Depression increases sleep latency, increases waking after sleep on-
set, decreases REM latency but increases REM density and duration, in-
creases early morning awakenings, decreases stages 3 and 4 (slow-wave)
sleep, and shifts REM sleep to earlier in the night. The effects of antide-
pressants and other psychotropics on sleep architecture vary, as summa-
rized in Tables 18–1 through 18–3. The clinician should be aware of the
ways in which the drugs may disrupt sleep latency or continuity, while
bearing in mind the effects of depression itself on these sleep parameters.
Antihistaminergic drugs generally increase sleep continuity and may
have variable effects on other elements of sleep architecture. Anticholin-
ergic drugs as well as many serotonergic, noradrenergic, and dopamin-
ergic binding agents generally suppress REM sleep and increase REM
latency. Postsynaptic serotonin type 2A (5-HT2A) antagonists (e.g., SGAs)
typically increase sleep continuity and increase slow-wave sleep.
Decreases in slow-wave sleep can interfere with patients’ feeling
rested after waking from sleep. Conflicting data exist on the extent to
which disruption of REM sleep may interfere with memory consolida-
tion, as had once been more widely assumed. Most antidepressants (with
the notable exceptions of bupropion, mirtazapine, and nefazodone)
markedly suppress REM and yet do not adversely affect learning and
memory; paradoxically, SSRI- or SNRI-induced REM suppression may
even improve verbal memory (Rasch et al. 2008). Antidepressant cessa-
tion initially leads to decreased REM latency and increases the percentage
of time spent in REM sleep.
Minimal research has specifically examined strategies to counteract
iatrogenic sleep disturbances caused by psychotropic medications, as op-
posed to adjunctive medications to selectively target poor sleep quality as
part of the syndrome of depression. Most pharmacotherapy antidotes to
iatrogenic insomnia have been extrapolated from use in primary sleep dis-
orders. Perhaps the most obvious interventions when a medication ap-
280
TABLE 18–1. Known effects of antidepressants and anxiolytics on sleep architecture
Agent REM REM latency Slow-wave sleep Sleep continuity
Benzodiazepines Suppress Decrease Decrease Increase

Bupropion Increases Decreases No effect No effect or may impair

Buspirone No effect No effect No effect No effect
MAOIs Suppress (virtually Increase No effect No effect or may impair
abolish)
Mirtazapine No suppression or No effect No effect or may increase Improves
increase
Nefazodone Increases Decreases No effect Improves
SNRIs Decrease Increase No effect or may decrease Impair
SSRIs Suppress Increase No effect or may decrease No effect or may impair
TCAs Suppress Increase No effect or may increase No effect or may improve
Trazodone No effect or may Increases No effect or may increase Improves
suppress
Vilazodone Suppresses Increases Increases Not reported
Note. MAOI = monoamine oxidase inhibitor; REM = rapid eye movement; SNRI = serotonin-norepinephrine reuptake inhibitor;
SSRI= selective serotonin reuptake inhibitor; TCA= tricyclic antidepressant.
Sleep Disturbances
TABLE 18–2. Known effects of antipsychotics on sleep architecture
Aripiprazole Not reported Not reported Not reported Not reported

Asenapine Not reported Not reported Not reported Not reported
Clozapine Suppresses Increases Increases Improves
Olanzapine Suppresses Increases Increases Improves
Quetiapine Suppresses No effect Increases Improves
Risperidone Suppresses Increases Increases Improves
Ziprasidone Suppresses Increases Increases Improves
Note. REM= rapid eye movement.
281
pears to cause insomnia include altering its dosing schedule (e.g., morning
instead of evening administration), determining whether any concomitant
medications might better account for iatrogenic insomnia, eliminating
other factors that may disrupt sleep (e.g., alcohol or caffeine intake), and
assuring normal sleep hygiene. To the extent that some SSRIs such as flu-
oxetine have been shown to cause significant periodic limb movement dis-
orders during sleep, adjunctive sedative-hypnotics that also diminish
restless legs (e.g., clonazepam) may be particularly effective as sleep aids.
Moreover, depressed patients who begin fluoxetine treatment with ad-
junctive clonazepam develop less treatment-emergent insomnia and anx-
iety than do those taking fluoxetine alone (Londborg et al. 2000).
Table 18–4 summarizes information on the use and sleep architectural
effects of agents that are commonly used to counteract simple insomnia.
Often, clinicians find themselves choosing between benzodiazepines and
nonbenzodiazepine soporific drugs to counteract insomnia. Nonbenzo-
diazepine sleep aids increase total sleep time while disrupting sleep
architecture less extensively than benzodiazepines. They also generally
carry less abuse potential, less often cause rebound insomnia or with-
drawal upon cessation, and are often less likely to cause the types of cog-
nitive problems (e.g., retrograde memory impairment) associated with
benzodiazepines.
The treatment of apparent iatrogenic insomnia first requires a differ-
ential diagnostic assessment. For example, individuals with bipolar dis-
order who have trouble sleeping require a thorough assessment for other
possible signs of mania or hypomania, and the use of sedating antide-
pressants as sleep aids (e.g., trazodone, mirtazapine, TCAs) would be less
desirable than nonantidepressant sedative-hypnotics (e.g., benzodiaz-
epines or benzodiazepine agonists) while optimizing patients’ funda-
mental antimanic regimen. Individuals with sleep problems caused by
restless legs syndrome may benefit more from a dopamine agonist (e.g.,
pramipexole, ropinirole) than a dopamine antagonist (e.g., quetiapine).
Individuals with sleep apnea likely would be better served by a continu-
ous positive airway pressure (CPAP) device and possible use of modafi-
nil, armodafinil, or sodium oxybate.
Insomnia that results from nonsedating antidepressants (e.g., SSRIs,
SNRIs, bupropion) is often an initial, transient phenomenon. Morning
rather than evening dosing may help to minimize the potential for in-
terference with normal sleep. Some reports suggest that independent
treatment of antidepressant-induced insomnia with a hypnotic agent
(e.g., adjunctive benzodiazepine at night) yields better overall outcomes
than when antidepressant-associated insomnia receives no indepen-
dent treatment.
Sleep Disturbances
TABLE 18–3. Known effects of anticonvulsants and lithium on sleep architecture
Carbamazepine Suppresses Increases Increases Increases

Divalproex Suppresses Not reported Increases Increases
Gabapentin Increases Not reported Increases Increases
Lamotrigine Increases No known effect Decreases No known effect
Lithium Suppresses Increases Increases Increases
Note. REM= rapid eye movement.
283
TABLE 18–4. Pharmacological strategies for psychotropic-induced

insomnia
Agent Comments
Benzodiazepines Promotes more time in light sleep (stage 2),

reduction in slow-wave sleep and REM;
potential for tolerance, abuse, and
rebound insomnia after cessation
Chloral hydrate Decreases sleep latency
Eszopiclone Does not alter slow-wave sleep or REM
Gabapentin Increases slow-wave sleep
Melatonin Causes minimal disruption of sleep
architecture
Mirtazapine Decreases sleep latency; increases total
sleep time and sleep efficiency; increases
time spent in stage 2 sleep, REM sleep,
and slow-wave sleep (Schittecatte et al.
2002; Winokur et al. 2000)
Ramelteon Increases REM and slow-wave sleep;
~10-fold higher binding affinity to M1
and M2 melatonin receptors than
melatonin itself
Trazodone Decreases sleep stages 1 and 2, increases
slow-wave sleep, has little effect on REM
sleep; few efficacy studies focusing on
insomnia, although some suggestion of
a lesser reduction in sleep latency than
zolpidem for primary insomnia; no
known studies on use in counteracting
psychotropic-induced insomnia
Zaleplon Plasma half-life ~1 hour; better for sleep
initiation than maintenance
Zolpidem Preserves slow-wave sleep
Note. REM = rapid eye movement.
A fundamental issue in choosing from among sedative-hypnotics in-

volves the relative advantages or disadvantages of using a benzodiaz-
epine versus a nonbenzodiazepine. With benzodiazepines, the patient
incurs greater potential disruption to sleep architecture, a potential for
rebound insomnia and withdrawal, the possibility for developing de-

pendence and tolerance over time, the potential for abuse, a risk for res-
piratory suppression (particularly among individuals with underlying
pulmonary disease), and the risk for daytime cognitive impairment and
retrograde memory impairment; nonbenzodiazepine sedatives, such as
zolpidem, zaleplon, ramelteon, and eszopiclone, carry relatively lesser
risks in these domains (Wagner and Wagner 2000).
Nightmares and Vivid Dreams

General Recommendations. Nightmares and vivid dreams
may occur at any point during treatment with a variety of antide-
pressants and other psychotropic drugs. It is unknown whether the
phenomenon may be dose related, and presumptive mechanisms
are not well understood. Abnormal dreams are medically benign,
but if they create substantial distress, then a causal agent may
need to be stopped if dosage reductions alone prove ineffective.
Vivid dreams have been reported as a relatively uncommon, medi-

cally benign adverse effect associated with dopaminergic agents (includ-
ing bupropion and antiparkinsonian drugs) and with many serotonergic
or serotonergic-noradrenergic antidepressants. Other psychotropic
drugs with which vivid or abnormal dreams have been identified as pos-
sible adverse effects include lamotrigine, gabapentin, quetiapine (2% in-
cidence in FDA registration trials), and lurasidone (<1% incidence in FDA
registration trials).
Serotonergic agents have been shown to suppress REM sleep in a
dose-related fashion and, correspondingly, would be expected to dimin-
ish (or disrupt) dream activity. Over time, tolerance to antidepressant-
associated REM suppression may account for the development of vivid
dreams as treatment progresses. Some authors have suggested that 5-HT2
receptor agonism may also lead to vivid dreams or nightmares and noted
the potential value of 5-HT2 antagonists (e.g., trazodone, mirtazapine,
SGAs, or cyproheptadine) to counteract nightmares. On the basis of ex-
trapolations from the literature on nightmares associated with posttrau-
matic stress disorder (PTSD), α2-adrenergic agonists such as guanfacine
(0.5–1 mg at bedtime) or clonidine (0.1–0.3 mg at bedtime), or the
α1-blocking agent prazosin (dosed from 1–4 mg at night, or potentially as
high as 10 mg/day as studied in PTSD-related nightmares among combat
veterans [Raskind et al. 2003]), may help to diminish nightmares by pro-
viding a soporific effect at bedtime as well as by reducing noradrenergic
hyperactivity. Blood pressure monitoring by the prescriber is advisable to

assure the absence of clinically meaningful hypotension.
Of note, when prescribing prazosin, the clinician must be aware of the
potential for orthostatic syncope to occur after an initial first dose. Hence,
the recommendation is to begin no higher than 1 mg/night for the first
few days, with a subsequent increase to 2 mg/day for several days if
necessary; dosing may then be increased to 4 mg/day for 1 week if im-
provement does not occur, followed by an increase to 6 mg/day after
1 week if necessary. Additional dosage increases (by 2 mg/week) have
been described such that 2–4 mg are administered in the afternoon fol-
lowed by up to 6 mg at bedtime (Raskind et al. 2003). Furthermore, the
clinician must be cautious not to abruptly discontinue prazosin or other
α1-blockers (typically, they are tapered off over days to weeks), in order to
minimize the potential for rebound hypertension; patients should be
counseled about this potential risk if doses are missed.
Other medications that have been described by the Standards of Prac-
tice Committee of the American Academy of Sleep Medicine as gen-
erally having potential value for the treatment of nightmares include
topiramate, low-dose cortisol, fluvoxamine, triazolam and nitrazepam,
phenelzine, gabapentin, and TCAs; notably, venlafaxine is considered in-
advisable for the treatment of PTSD-associated nightmares (Aurora et al.
2010). Each of these agents would involve extrapolation to use for the
treatment of iatrogenic nightmares.
Parasomnias
General Recommendations. Some antidepressants and
nonbenzodiazepine hypnotics (e.g., zolpidem, zopiclone, eszopi-
clone) carry an increased risk for abnormal REM and non-REM
sleep behavior disorders (notably, sleepwalking, sleep-driving,
and sleep-related eating disorders). Suspected causal agents
should be stopped in patients who report such events.
Parasomnias comprise a series of sleep disorders that occur during tran-

sitions from wakefulness and REM or non-REM sleep. REM parasomnias
(often also referred to as REM sleep behavior disorders) involve loss of
muscle atonia (i.e., loss of paralysis normally associated with REM sleep)
that can manifest as the acting out of dreams through uncoordinated
movements (e.g., kicking or punching). Non-REM parasomnias occur dur-
ing slow-wave sleep and involve intact muscle tone, leading to bruxism,
restless legs syndrome, and more complex behaviors such as sleepwalk-
ing, sleep-related eating disorders, sleep-driving, sexual activity, or con-

versations. After waking, patients usually are amnestic for parasomnic
events. Although parasomnias are not in themselves thought to represent
psychopathology, epidemiological studies suggest that they may be
more common among people with major depression (but not primary
psychotic disorders or bipolar illness) (Lam et al. 2008). Iatrogenic para-
somnias most often result from antidepressants or nonbenzodiazepine
hypnotics. Antidepressants (notably, fluoxetine, venlafaxine, and TCAs)
have been known to induce or worsen preexisting REM sleep behavior
disorders (Schenck and Mahowald 2002). Although incidence rates with
specific nonbenzodiazepines are not available, manufacturers’ product
information for zolpidem and eszopiclone warn of the potential for com-
plex hazardous behaviors such as sleep-driving and advise drug discon-
tinuation if patients report such experiences.
A review of parasomnias among 1,235 psychiatric outpatients found
that parasomnias among SSRI recipients typically were associated with
sleep-related eating disorders and REM sleep behavior disorders,
whereas sedating antidepressants (e.g., TCAs, trazodone) more often in-
volved sleepwalking and sleep-related eating disorders (Lam et al. 2008).
Among nonbenzodiazepine hypnotics, zolpidem was linked with both
sleepwalking and sleep-related eating disorders, whereas zopiclone led
only to sleepwalking. Parasomnia risk was higher among regular versus
intermittent nonbenzodiazepine hypnotic users. Dose relationships have
not been reported, although coadministration with alcohol or other CNS
depressants may increase the risk for REM sleep behavior disorders. In-
terestingly, antipsychotics may be negatively associated with some para-
somnias. Benzodiazepines and mood stabilizers have not been reported
to cause parasomnias.
19
Systemic Reactions
Allergic Reactions and Angioedema

General Recommendations. Allergic angioedema is a medi-
cal emergency that necessitates airway protection and treat-
ment with antihistamines or possibly steroids. Psychotropic
drugs that cause angioedema should be immediately discontin-
ued, and rechallenges generally should not be undertaken.
Adverse cutaneous reactions have been reported to occur in up to 5% of

individuals who receive antipsychotic medications. True allergic reac-
tions are IgE–mediated phenomena. Angioedema refers to the relatively
rapid development of facial edema with swelling of oropharyngeal mu-
cosal membranes and possible airway constriction. Allergic angioedema
is similar to anaphylactic shock and may involve urticarial eruptions. In
the presence of stridor or other signs of respiratory distress, allergic an-
gioedema constitutes a medical emergency that may require intubation to
maintain an intact airway.
289
Case reports have described the occurrence of urticaria and angio-

edema with asenapine, bupropion, lurasidone, oxcarbazepine (oxcarba-
zepine-related angioedema has been determined to arise in 9.8 per 1 mil-
lion pediatric cases; Knudsen et al. 2007), paroxetine, risperidone (with
uneventful rechallenge), and ziprasidone.
Antiepileptic Hypersensitivity Reactions

General Recommendations. Hypersensitivity reactions should
be suspected in anticonvulsant recipients who develop systemic,
multiorgan system disturbances, regardless of the presence or ab-
sence of a skin rash. Hypersensitivity reactions are potentially life
threatening, and the suspected causal agent should be immedi-
ately discontinued. Prompt medical attention involves supportive
measures and a possible role for steroids. The suspected causal
agent should not subsequently be reintroduced.
Certain anticonvulsants have been associated with rare idiosyncratic

hypersensitivity reactions (often referred to in the literature as drug
rash (or reaction) with eosinophilia and systemic symptoms [DRESS]
syndrome), which have been described most extensively with carba-
mazepine, lamotrigine, phenytoin, and phenobarbital. Through mech-
anisms that are not well understood, such reactions are thought to
involve an immunological response to toxic effects of the parent com-
pound or a metabolite. When hypersensitivity reactions occur, they
usually do so within the first 8 weeks of treatment. Characteristic fea-
tures involve fever, multiorgan system involvement, and possible skin
eruptions. Associated phenomena may include rhabdomyolysis (iden-
tifiable by myoglobinuria on urinalysis), which in itself should prompt
a review of all medications that are known to cause this phenomenon,
including statins and antiparkinsonian agents.
In August 2010, the FDA issued a warning that aseptic meningitis
may arise as a type of rare hypersensitivity reaction to lamotrigine, par-
ticularly during the first few months after treatment initiation. This warn-
ing was based on 40 reported postmarketing cases from December 1994
through November 2009. Symptoms typically arose within days 1–42
after drug initiation (mean=16 days). Accordingly, the onset of menin-
geal signs (headache, fever, nausea, vomiting, nuchal rigidity, photopho-
bia, and myalgias) during this time frame likely warrants cessation of
therapy. Symptoms typically resolve after drug discontinuation.
Systemic Reactions 291
Body Temperature Dysregulation

General Recommendations. Patients who take FGAs or SGAs
should be counseled about the potential disruption to maintain-
ing their core body temperature when they are exposed to ambi-
ent extremes.
Both hypo- and hyperthermia can result from the use of FGAs and
SGAs, most often arising near the time of treatment initiation or dosage
increases. Antipsychotics disrupt the medullary chemoreceptor trigger
zone, which among other functions, maintains homeostatic core body
temperature. Pharmacological mechanisms thought to impair ther-
moregulation and thereby cause poikolothermia include the blockade
of D1 and D2 dopamine receptors, as well as possible disruption of com-
pensatory peripheral vasoconstriction due to α 1-adrenergic blockade
by most antipsychotics. Antipsychotic-induced temperature dysregula-
tion may lead to medical hospitalization (nearly 70% of cases) or mor-
tality (~4% of cases) (van Marum et al. 2007).
Patients who take FGAs or SGAs should be warned that their body
temperature could rise significantly under conditions such as strenuous
exercise or exposure to hot climates and should be instructed to monitor
their body temperature periodically in such circumstances, as well as in
the setting of infection. Management of hyperthermia typically involves
hydration, acetaminophen, and cooling blankets or ice packs if necessary,
along with removing the patient from exposure to high ambient temper-
ature. Antipsychotic-induced hypothermia is rare and routine screening
is considered unnecessary, although the possible presence of hypother-
mia should be considered in antipsychotic recipients who develop sub-
jective coldness along with acute mental status changes, bradycardia,
fatigue, and focal neurological signs, such as ataxia.
Discontinuation Syndromes
General Recommendations. Withdrawal symptoms from
abrupt cessation of most short-acting SSRIs and all SNRIs warrant
gradual tapers that may require many days to weeks. Antidepres-
sant withdrawal symptoms are medically benign but uncomfort-
able and can be managed either by extending the duration of
tapering off the medication or by providing supportive pharma-
cotherapies as indicated (e.g., trimethobenzamide or prometha-
zine for nausea; acetaminophen or ibuprofen for headaches or
myalgias). Augmentation or switching an SNRI or short-acting

SSRI to fluoxetine, followed by discontinuation of fluoxetine, may
also help diminish the potential for symptoms of discontinuation
syndrome.
In the middle to late 1990s, withdrawal syndromes were first described

in the setting of abrupt cessation of short-acting SSRIs (see Table 2–2,
Chapter 2, “Pharmacokinetics, Pharmacodynamics, and Pharmacoge-
nomics”), with features including dizziness, insomnia, nervousness,
nausea, or agitation; fluoxetine, by virtue of the long elimination half-life
of its metabolite norfluoxetine, appears significantly less likely to cause
this phenomenon than are other SSRIs (Rosenbaum et al. 1998). No
demographic or clinical characteristics appear to predict the likelihood
of developing withdrawal symptoms after SSRI discontinuation, and
withdrawal phenomena have been reported to persist for up to 3 weeks
or longer following drug cessation, although symptoms usually resolve
within 24 hours of SSRI resumption. Withdrawal features from the
abrupt cessation (or sometimes even a few missed doses) of SNRIs can
be even more substantial and protracted than occurs with SSRIs.
Two main strategies are usually advocated for managing SSRI or
SNRI withdrawal discontinuation syndromes. The first involves resum-
ing either a discontinued agent or a dose that had been reduced and
then undertaking a protracted taper of the existing antidepressant (per
manufacturers’ recommendations)—in some instances, over the course
of several weeks or longer, with supportive management of emergent
withdrawal symptoms using antinausea drugs (e.g., trimethobenza-
mide, promethazine, prochlorperazine) and analgesics (e.g., acetamin-
ophen, ibuprofen) as needed for headaches and myalgias. The second
approach is to augment the initial antidepressant with fluoxetine for
several days, then discontinue the original antidepressant entirely and
capitalize on the long half-life of fluoxetine plus its metabolite, norflu-
oxetine, and then discontinue fluoxetine after several days with a lesser
likelihood of withdrawal phenomena.
Abrupt cessation of MAOIs has been associated with discontinua-
tion phenomena that may include hallucinations, anxiety, agitation,
paranoia, and delirium. It is therefore recommended that MAOIs be
tapered over at least several days or more rather than being abruptly
stopped, except in the setting of palpitations or frequent headaches that
may be thought to reflect a hypertensive crisis.
Drug-Induced Lupus Erythematosus

General Recommendations. Drug-induced lupus erythe-
matosus (DILE) is rarely caused by psychotropic drugs. In sus-
pected cases, symptoms mirror those seen with systemic lupus
erythematosus (SLE) and involve flulike symptoms, myalgias, ar-
thralgias and fever. The causal agent should be discontinued and
not subsequently reintroduced. Symptoms typically resolve
within 1–2 weeks either spontaneously or with the use of NSAIDs
or (more infrequently) oral steroids.
DILE is an autoimmune phenomenon with clinical features and labora-

tory findings similar to those of SLE. Symptoms may include flulike
symptoms, myalgias, arthralgias, and fever. Rashes or other skin lesions
(e.g., oral ulcers) are less common with DILE than with SLE. More severe
cases of DILE can involve cardiac or pulmonary inflammation. By defini-
tion, DILE is triggered by the use of certain medications, including sev-
eral psychotropic agents—each considered by the Lupus Foundation of
America (www.lupus.org) to have a low or very low risk. From among
the nearly 40 known drugs associated with DILE, cases most commonly
result from the use of procainamide, hydralazine, and quinidine. Psycho-
tropic agents that have rarely been associated with DILE include carba-
mazepine, oxcarbazepine, lithium, clonidine, pindolol, chlorpromazine,
perphenazine, and phenelzine. Limited risk factors have been identified
for developing DILE, including chronicity of drug therapy, male sex, age
>50, and the presence of the so-called “slow acetylator” phenotype (see
the section “Pharmacokinetics and Pharmacodynamics” in Chapter 2,
“Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics”).
Diagnosis of DILE depends on clinical presentation as well as corrob-
oration from laboratory indices (notably, antinuclear antibody and anti-
histone antibodies). Treatment involves discontinuing the causal agent
alongside supplemental NSAIDs or oral steroids, corticosteroid creams to
treat skin rashes, and hydroxychloroquine to treat arthralgias. More
rarely, immunosuppressants such as azathioprine or cyclophosphamide
are also necessary. Reintroduction of a causal agent is generally not ad-
vised. DILE is an iatrogenic phenomenon that is fundamentally different
from SLE. Long-term consequences or recurrences of DILE would not be
expected unless the suspected causal agent was reintroduced.
Neuroleptic Malignant Syndrome

General Recommendations. NMS can occur with any FGAs
or SGAs and should be considered in any patient receiving an an-
tipsychotic who develops a fever. Treatment involves immediate
cessation of dopamine antagonists followed by supportive mea-
sures (e.g., hydration and autonomic monitoring).
NMS is a relatively rare adverse systemic reaction to any antipsychotic

drugs (including antiemetic phenothiazines such as prochlorperazine
and related compounds such as metoclopramide) as well as other non-
neuroleptic drugs with antidopaminergic effects, such as phenelzine,
some TCAs (e.g., desipramine, trimipramine), and lithium. NMS rarely
arises beyond 1 month after initiation of an antidopaminergic drug.
(DSM-IV-TR [American Psychiatric Association 2000] indicates that two-
thirds of cases occur within the first 7 days of starting an antidopaminer-
gic drug.) Although clear risk factors have not been empirically deter-
mined, some authors have observed that NMS may be more likely to
occur in patients with psychomotor agitation or dehydration, in those
who receive high doses of antipsychotics, and in recipients of frequent in-
tramuscular injections of FGAs. Key symptoms include fever, muscle ri-
gidity, acute mental status changes (e.g., delirium), autonomic instability,
elevation of serum creatine phosphokinase, tremor, and leukocytosis.
However, NMS is a clinical diagnosis that can manifest in various ways,
and no one symptom is pathognomonic. The clinician must also recog-
nize nonpsychotropic drugs that may cause myalgias with possible rhab-
domyolysis (e.g., statins), which could be mistaken for the muscle
rigidity of NMS. Indeed, it is critical for practitioners to differentiate NMS
from other systemic drug reactions (e.g., serotonin syndrome [see the sec-
tion “Serotonin Syndrome” below] or anticholinergic delirium) as well as
other forms of delirium or encephalopathy, infectious etiologies, or heat
stroke, and also to avoid mistaking it for manifestations of primary psy-
chopathology (including catatonia).
NMS is a medical emergency. Treatment hinges on the prompt discon-
tinuation of antipsychotics and other potential antidopaminergic drugs,
supportive treatment of hyperthermia (e.g., cooling blankets, ice packs),
and hydration (usually intravenous, both for circulatory support and to
minimize the potential for kidney damage due to myoglobinuria). Intrave-
nous use of the muscle relaxant dantrolene (1–2.5 mg/kg initially, followed
by 1 mg/kg every 6 hours) is typically reserved for extreme hyperthermia
and the persistent abnormalities of marked vital signs despite supportive
care. In patients not responding to the above treatments, electroconvulsive

therapy (ECT) is sometimes advised based on the rationale of its known ef-
ficacy for malignant catatonia (reviewed by Davis et al. 1991). A history of
prior NMS may increase the likelihood of future episodes of NMS. There is
no contraindication to resuming antipsychotic drugs after the resolution of
NMS, although recurrence happens in up to 30% of individuals; SGAs are
preferred over FGAs, and clinicians should use the lowest possible dosages
and monitor carefully for early signs of reemergent NMS.
Serotonin Syndrome
General Recommendations. Serotonin syndrome is a medi-
cally emergent toxicity state resulting from excessive serotoner-
gic activity, usually caused by an interaction among drugs that
increase serotonin through different mechanisms. Management
involves cessation of serotonergic drugs and supportive mea-
sures that fundamentally include hydration and airway moni-
toring and protection.
A constellation of signs and symptoms related to serotonergic hyper-

stimulation has come to be known as serotonin syndrome, which may
be one of a family of CNS toxicity states that also includes NMS. The cri-
teria classically described by Sternbach (1991) for defining serotonin
syndrome include the following:
• At least three of the following: agitation, ataxia, diaphoresis, diar-

rhea, hyperreflexia (particularly in lower extremities), mental status
changes (may include hypervigilance, psychosis, confusion, or agita-
tion), myoclonus, shivering, tremor, or hyperthermia
• Emergence of signs and symptoms temporally following either the
addition of a serotonergic drug or a dosage increase of an existing
serotonergic agent
• No recent addition of an antipsychotic, or dosage increase of an
existing antipsychotic
• Features that are not better accounted for by other causes such as
infection, intoxication, metabolic derangement, substance abuse, or
substance withdrawal
Low specificity of the Sternbach criteria, coupled with observations

that clonus appears to be more specific to serotonin syndrome than other
drug toxicity states (e.g., NMS, anticholinergic delirium), prompted
refinements that led to the Hunter Serotonin Toxicity Criteria (Dunkley

et al. 2003), which emphasize the importance of clonus (inducible, spon-
taneous, or ocular), agitation, diaphoresis, tremor, and hyperreflexia for
establishing diagnostic specificity.
Serotonin syndrome typically is associated with drug interactions that
increase central serotonergic tone. Drugs that affect serotonin through
varied mechanisms of action are thought to incur a greater risk for sero-
tonin syndrome than are drugs with a single mechanism (as in the case of
overdosing on a single SSRI; even the combination of an SSRI plus SNRI
involves mechanistic redundancy rather than serotonergic novelty, and
hence is unlikely to produce serotonin syndrome). Examples of poten-
tially toxic interactions include the following:
• MAOIs+serotonergic antidepressants
• MAOIs+meperidine
• Dextromethorphan (which blocks neuronal serotonin uptake)+
MAOIs
• Buspirone+SSRIs or lithium
• Triptans+SSRIs or SNRIs (note that in 2006 the FDA issued an alert re-
garding this combination, although this relative contraindication
remains controversial and unnecessarily overconservative in the opin-
ions of some authorities, such as the American Headache Society
[Evans et al. 2010])
• Amphetamines (which release serotonin)
• 3,4-Methylenedioxymethamphetamine (i.e., Ecstasy)
• Tramadol+SSRIs or SNRIs
Treatment of serotonin syndrome depends on supportive treatment

plus cessation of all serotonergic agents. Fundamentally, the condition
is self-limited and eventually resolves spontaneously after discontinu-
ation of the offending agent(s). Supportive measures may include intra-
venous hydration, clonazepam for myoclonus, cooling blankets or ice
packs for centrally mediated hyperthermia, and airway protection
(with the possible need for mechanical ventilation).
Weight Gain
General Recommendations. Interventions focused on diet
and exercise appear to have the greatest overall efficacy in helping
to counteract psychotropic-induced weight gain, particularly in
patients with poor nutritional habits and sedentary lifestyles.
Pharmacological strategies that have demonstrated clinically

meaningful weight loss include metformin, topiramate, zonisa-
mide, sibutramine, amantadine, lamotrigine, and either switches
to or augmentation with aripiprazole or ziprasidone. Adjunctive
orlistat has shown modest benefit in men with psychotropic-
induced weight gain.
Iatrogenic obesity and overweight are among the most common and
difficult-to-treat problems that confront prescribers of almost all classes
of psychotropic medications and represent a leading cause of medication
cessation. Differences may exist across types of medicines regarding
probable mechanisms of weight gain, time course to weight gain, and risk
factors—although particular risk factors for weight gain with a specific
psychotropic agent have not been well described in the literature. Many
agents that cause significant weight gain (e.g., lithium, divalproex) do so
only after extended periods of treatment, limiting the extent to which
short-term randomized controlled trials of FDA registration studies are
able to detect long-term risk. Risks also may differ with a given com-
pound across varying disease states (e.g., schizophrenia vs. bipolar disor-
der; major depression vs. anxiety disorders), within a given disease state
(e.g., atypical depression vs. agitated or melancholic depression), in the
presence or absence of common comorbidities (e.g., alcohol abuse), or
when used as a monotherapy versus in conjunction with other agents.
As a rule of thumb, ideal body weight for men is 47.7 kg for the first
5 feet and an additional 2.7 kg for each inch above 5 feet; in women, ideal
body weight is 45 kg at 5 feet with 2.3 kg added per inch above 5 feet.
Medically, clinicians should assure the absence of other causes of weight
gain before assuming it is the result of psychotropic medications. Careful
assessment includes the following considerations:
• Differentiating weight gain caused by adipose tissue versus fluid re-

tention; rapid and substantial weight gain should prompt examina-
tion for edema
• Assuring the absence of hypothyroidism
• Assessment of dietary habits, including alcohol
• Differentiating hyperphagia due to depression or anxiety from appe-
tite stimulation caused by medications
• Identification of all medications, both psychiatric and nonpsychiat-
ric, that may predispose to weight gain (Table 19–1)
• Identification of any nonprescribed nutritional supplements, such as
high-dose vitamins, minerals, and antioxidants, that potentially
could interfere with treatment
TABLE 19–1. Weight changes associated with common medications
Minimal or no Moderate or variable Substantial

weight gain weight gain weight gain
ACE inhibitors Aripiprazole Clozapine

Asenapine Divalproex Mirtazapine
Atomoxetine Duloxetine Olanzapine
β-Blockers Gabapentin Quetiapine
Bupropion Lithium Risperidone
Buspirone Monoamine oxidase
Carbamazepine inhibitors
Desvenlafaxine Pregabalin
Fluoxetine SSRIs other than fluoxetine
H2 blockers or vilazodone
Iloperidone Tricyclic antidepressants
Lamotrigine Venlafaxine
Lurasidone
Naltrexone
Psychostimulants
Topiramate
Transdermal
selegiline
Vilazodone
Ziprasidone
Note. ACE= angiotensin-converting enzyme; SSRI= selective serotonin re-
uptake inhibitors.
Industry-sponsored clinical trials typically define substantial weight

gain by convention as increases of ≥7% from baseline weight, but this
metric can be clinically uninformative if it is not normalized by baseline
weight or BMI (i.e., less weight gain is needed to fulfill this criterion in
subjects with low initial weight). In adults, but not children, absolute
weight gain offers a more robust and clinically useful statistic. In addi-
tion, although weight gain has been reported in some industry clinical
trials as being more likely among subjects with low rather than high
pretreatment BMI, this distinction has not been borne out in naturalistic
studies.
Second-Generation Antipsychotics
Representative rates of weight gain with SGAs as reported in clinical
trials, stratified by psychiatric disorders, are summarized in Table 19–2.
Appetite Stimulation
In the case of SGAs, it is thought that weight gain, to varying degrees,
may occur from appetite stimulation caused by blockade of histamine H1
receptors and antagonism of serotonin type 2C (5-HT2C) receptors, which
together disrupt hypothalamic satiety control. Pharmacogenetic studies
also have suggested that SGAs may induce lipogenic genes (Kristiana et
al. 2010) and activate protein kinase C-beta, which in turn may foster the
differentiation and proliferation of preadipocytes (Pavan et al. 2010).
Other proposed mechanisms of weight gain include decreased thermo-
genesis and decreased energy expenditure. Weight gain associated with
some SGAs also has been associated with changes in levels of the appe-
tite-stimulating peptide hormone ghrelin and the appetite-suppressing
hormones leptin and adiponectin. However, the relationships between
changes in these hormones and appetite increases induced by SGAs are
not straightforward. Several studies have identified increases in serum
leptin after administration of some SGAs (notably, clozapine [Atmaca et
al. 2003] and olanzapine [Atmaca et al. 2003; Hosojima et al. 2006], with a
lesser effect from risperidone [Atmaca et al. 2003]). Serum ghrelin levels
have been shown to decrease during treatment with olanzapine in some
studies (Hosojima et al. 2006; B.J. Kim et al. 2008), whereas adiponectin
levels appear unaffected during the first few weeks after starting an SGA
(Hosojima et al. 2006). Still other investigators have found elevated ghre-
lin levels with relatively unchanged leptin levels in connection with
weight gain related to clozapine, olanzapine, or risperidone (Esen-Danaci
et al. 2008). In all likelihood, leptin levels rise as a result (rather than
cause) of the increased fat stores induced by some SGAs, and persistent
hunger fails to override the leptin signal that would otherwise promote
satiety.
Predictors of Weight Gain

The literature is surprisingly sparse in identifying robust predictors of
weight gain caused by SGAs, with few exceptions. Substantial weight
gain appears more likely to occur during treatment with olanzapine in
patients who are younger, are nonwhite, have a low BMI, have a non–
rapid-cycling course of illness, and have psychotic features (Lipkovich
et al. 2006). Weight gain seems to correlate with clinical response
(which may be an artifact of the amount and duration of exposure to
therapy), as well as rises in blood pressure, total serum cholesterol, and
nonfasting blood glucose levels (Hennen et al. 2004). In short-term
(~6-week) trials of olanzapine or risperidone in patients with schizo-
phrenia, predictors of weight gain included younger age, male gender,
300
TABLE 19–2. Representative rates of weight gain with second-generation antipsychotics as reported in FDA registration
trials and other randomized studiesa
Short-term Long-term
Incidence of clinically Incidence of clinically

Drug Disorder Mean weight changes significant weight ↑b Mean weight changes significant weight ↑b
Aripiprazole Schizophrenia +0.7 kg across 4- to 8% +0.3 kg over 28 weeks 16%

6-week trials (Kane et al. 2009)
Bipolar disorder +0.1 kg across 3-week 2% +0.4 kg across three 20%
trials randomized trials (McIntyre 2010)
Major depression +1.7 kg across two 5.2% — —
randomized 6-week
trials (Fava et al. 2009)
Asenapine Schizophrenia +1.1 kg 4.9% +0.7 kg over 26 weeks’ 8.0%
randomized (Kane et al. 2011)
monotherapy (Kane et
al. 2010)
Bipolar disorder +1.3 kg 5.8% — —
Clozapine Schizophrenia +4.5 kg (meta-analysis — +7.7 kg; 75% gained —
of acute trials; Allison ≥4.5 kg over 6 months
et al. 1999) (Lamberti et al. 1992);
+11.7 kg over 8 years
(Bai et al. 2006)
Systemic Reactions
trials and other randomized studiesa (continued)

Iloperidone Schizophrenia +1.5 kg to +2.1 kg 12%–18% — —

(Weiden et al. 2008)
Lurasidone Schizophrenia +0.5 kg to +0.9 kg 5.6% –0.4 kg to –0.7 kg (24- to —

(Meltzer et al. 2011) 52-week open-label
extension data)
Olanzapine All indications Across 13 acute placebo- 22% +4.3 to +13.2 kg over 30%
controlled FDA 6 months to 2.5 years (Lieberman et al.
registration trials, (Kinon et al. 2001; 2005) to 75%
mean change of Lieberman et al. 2005; (Perez-Iglesias et al.
+2.6 kg; +4.2 kg in Newcomer et al. 2009; 2005)
meta-analysis of acute Vanina et al. 2002); +5.6 kg
trials (Allison et al. over 48 weeks in FDA
1999) registration trials
Paliperidone Schizophrenia +0.6 to +1.1 kg across 6%–9% +1.4 kg across 24 weeks; 32% (52-week open-
three 6-week acute +2.6 kg at 52 weeks in label extension data)
trials open-label extension
301
trials
302

Quetiapine Schizophrenia +2.0 kg 23% +0.5 kg to +3.7 kg (up to 16%

18 months) (Lieberman (Lieberman et al.
et al. 2005; Newcomer 2005)
et al. 2009)
Bipolar disorder +1.7 kg (mania) 21% In maintenance trials, 11.5% as adjunct to

+1.0 kg to +1.6 kg 8.5%–9% +3.1 kg as monotherapy lithium or divalproex
(depression; Calabrese in first 36 weeks, then over 104 weeks
et al. 2005) +0.5 kg as adjunct to (Suppes et al. 2009)
lithium or divalproex in
weeks 37–104 (Suppes
et al. 2009)
Risperidone All indications +2.1 kg (meta-analysis 18% (acute +0.4 kg to +9.5 kg (up to 14% (Lieberman et al.
of acute trials; Allison schizophrenia trials); 18 months) (Lieberman 2005) to 71% (Perez-
et al. 1999) 2.5% (bipolar mania et al. 2005; Newcomer Iglesias et al. 2008)
trials) et al. 2009; Perez-
Iglesias et al. 2008;
Vanina et al. 2002)
Systemic Reactions

Ziprasidone All indications Stratifies by BMI: 10% –0.7± 0.5 kg (CATIE; 7%

baseline BMI < 23: Lieberman et al. 2005) (Lieberman et al.
1.4-kg gain; 2005)
BMI >27: 1.3-kg loss
Note. — =no data; BMI= body mass index; CATIE =Clinical Antipsychotic Trials of Intervention Effectiveness; FDA =U.S. Food and Drug Ad-
ministration.
aData based on FDA registration trail data as reported in manufacturers’ package insert information, unless otherwise noted.
b”Clinically significant weight gain” defined as ≥ 7% increase of initial weight.
303
nonwhite race, and favorable clinical response (Basson et al. 2001).

Longer-term randomized trials (≥39 weeks) of olanzapine in schizo-
phrenia identified low baseline BMI as a robust predictor of weight gain
(Kinon et al. 2001). Other reported predictors of weight gain with olan-
zapine, risperidone, or clozapine include female gender, parents’ BMI,
younger age, and nonsmoking status (Gebhardt et al. 2009).
Time Course and Magnitude of Weight Gain

The time course and magnitude of weight gain with SGAs can vary. In
the case of olanzapine in the treatment of schizophrenia, weight gain
appears to persist for up to 39 weeks before eventually plateauing (Ki-
non et al. 2001). As noted in the section “General Approach to Assessing
Adverse Drug Effects” in Chapter 1, “The Psychiatrist as Physician,” an
initial weight gain of 1.8–2.3 kg during the first 2–3 weeks of treatment
with olanzapine also may confer a significantly increased risk for more
substantial weight gain during longer-term (up to 30 weeks) treatment
(Lipkovich et al. 2006). While most SGAs carry some liability for weight
gain, they may vary considerably in magnitude and extent. In the CATIE
chronic schizophrenia trial (Lieberman et al. 2005) for example, prema-
ture study termination due to weight gain or metabolic effects was sig-
nificantly more likely among subjects taking olanzapine (9%) than all
other agents (1–4%).
Zydis Formulations
Anecdotal observations and reports from small case series have sug-
gested that the Zydis orally dissolving formulation of olanzapine may
cause less weight gain than the conventional formulation (reviewed by
Karagianis et al. 2008). At least one rather speculative mechanism has
been proposed to account theoretically for this possibility, involving the
faster absorption of orally dissolving olanzapine when administered sub-
lingually (Markowitz et al. 2006), which in turn may lead to decreased
ghrelin signaling, possibly because of the lesser quantity of olanzapine
coming into proximity with ghrelin-containing cells in the fundus of the
stomach (Chawla and Luxton-Andrew 2008).
A preliminary 6-week randomized comparison of orally dissolving
olanzapine versus standard olanzapine in 38 first-onset psychosis pa-
tients found significantly less weight gain occurring in those taking the
orally dissolving formulation (Arranz et al. 2007), although a larger and
more definitive industry-sponsored 16-week multisite trial randomized
trial, involving 149 bipolar or primary psychotic disorder patients who
had gained at least 5 kg with standard olanzapine tablets, found no sig-
nificant differences between conventional olanzapine and the Zydis for-

mulation (administered sublingually) in any parameters related to
weight gain (Karagianis et al. 2009).
Lithium, Anticonvulsants, and Antidepressants

Tables 19–3 and 19–4 summarize information from controlled trials,
including FDA registration trials, regarding the incidence and corre-
lates of weight gain during treatment with lithium or anticonvulsants
and with antidepressants, respectively.
Mechanisms for iatrogenic weight gain with lithium or anticonvul-
sants are less well-understood than appears to be the case with SGAs or
antidepressants. Notably, however, divalproex may increase body mass
via raising serum leptin levels (Verrotti et al. 1999) as well as by reducing
thermogenesis and increasing long-chain fatty acids through competi-
tive binding to serum albumin (Vanina et al. 2002). Lithium-induced
weight gain (unrelated to peripheral edema or hypothyroidism) has
been suggested to result from thirst-related increased consumption of
high-sugar beverages and increased body stores of carbohydrates and
lipids (Vanina et al. 2002). Compared with olanzapine, weight gain with
lithium or divalproex may follow a more gradual trajectory and result in
less total weight gain than seen with certain SGAs.
Studies that report weight gain with anticonvulsants other than di-
valproex (e.g., gabapentin; DeToledo et al. 1997) typically have focused
on high doses in epilepsy populations rather than in psychiatric pa-
tients. Extended-release carbamazepine and lamotrigine each appear
weight-neutral during long-term treatment for bipolar disorder (Ketter
et al. 2004; Sachs et al. 2006a). In fact, lamotrigine has been associated
with weight loss in obese nonpsychiatric patients as well as obese pa-
tients with bipolar disorder (see Table 19–6).
Data from FDA registration studies have important limitations re-
garding inferences for patients treated in routine clinical practice: 1) trials
are generally brief, providing no information on weight gain with long-
term use; 2) most trials involve monotherapy, whereas many patients
with mood or anxiety disorders take combinations of drugs with additive
or synergistic risks for weight gain; and 3) subjects enrolled in FDA reg-
istration trials often are already overweight and lack risk factors for
weight gain that pertain to the general population. These include the ab-
sence of unstable medical problems (e.g., diabetes, nonalcoholic steato-
hepatitis or nonalcoholic fatty liver disease [see the section “Hepatic Im-
pairment and Transaminitis” in Chapter 12, “Gastrointestinal System”]);
an absence of concurrent psychiatric disorders (e.g., eating disorders) or
306
TABLE 19–3. Representative rates of weight change with lithium or anticonvulsants reported in FDA registration trials
and other randomized studies
Agent Weight change and time course Notable risk factors
Lithium Up to 66% of patients gained an average of 10 kg over 2– Obesity at baseline; mechanism of weight

10 years (Vanina et al. 2002); 13% of bipolar I patients had gain may be related to lithium-induced
weight gain with monotherapy over 1 year (Bowden et al. decreases in serum leptin levels (Atmaca et
2000). In a 1-year comparison of lithium with lamotrigine al. 2002) or direct serotonergic effects; no
or placebo for bipolar relapse prevention, mean weight clear dose relationship.
changes with lithium monotherapy were +6.1 kg among
initially obese subjects and +1.1 kg in initially nonobese
subjects (Bowden et al. 2006a).
Carbamazepine Weight gain is not identified as an adverse effect in FDA None known.
registration trials, although isolated case reports of weight
gain have been described in the epilepsy literature.
Divalproex 21% of bipolar I patients had weight gain during divalproex Serum valproate levels >125 ng/mL
maintenance treatment over 1 year (Bowden et al. 2000). (Bowden et al. 2000).
Gabapentin 2% of patients had weight gain in trials for postherpetic None known.
neuralgia; 3% of patients had weight gain in add-on
therapy trials for epilepsy.
Systemic Reactions
TABLE 19–3. Representative rates of weight change with lithium or anticonvulsants reported in FDA registration trials
and other randomized studies (continued)
Agent Weight change and time course Notable risk factors
Lamotrigine In trials for bipolar disorder, weight gain was reported in None known.
1%–5%. Mean weight change at 52 weeks was –4.2 kg
among initially obese patients and –0.5 kg among
nonobese patients (Bowden et al. 2006a).
Oxcarbazepine 1%–2% incidence of any weight gain during trials of None known.
adjunctive therapy for epilepsy. Postmarketing case
reports also identify weight loss.
307
308
TABLE 19–4. Representative rates of weight changes across antidepressants reported in clinical trials
Agent Weight changes in FDA registration trials Additional studies and observations
Bupropion Major depression: Bupropion IR: 9% gained weight over 3– Mean weight loss identified in meta-analysis was
6 weeks; 28% had weight loss of > 2.3 kg. Bupropion SR: 2.8 kg (95% CI, 1.1–4.5 kg) over 6–12 months (Li et
2%–3% gained >2.3 kg in 4–6 weeks (300 or 400 mg/day); al. 2005).

14% (300 mg/day) to 19% (400 mg/day) had weight loss
> 2.3 kg.
Seasonal affective disorder: Bupropion XL: 11% gained > 2.3 kg;
23% lost >2.3 kg.
Citalopram Major depression: Mean weight change was –0.5 kg over 4– Meta-analysis suggests greater weight loss than gain
6 weeks. (Li et al. 2005).
Desvenlafaxine Major depression: 1%–2% of subjects reported weight loss None.
across dosages (50–400 mg/day). Mean weight change
ranged from –0.4 to –1.1 kg in acute trials at dosages up to
400 mg/day. Mean weights did not differ significantly from
placebo by the end of a 6-month placebo-controlled
extension phase for acute responders.
Duloxetine Major depression: Weight loss in 2% (cf. < 1% with placebo). Major depression: A 7-week open trial (N= 128)
Major depression and GAD: Mean weight change over 10 weeks yielded a mean weight loss of –1.2 kg, which then
of –0.5 kg (cf. +0.2 kg with placebo). normalized by 20 weeks and subsequently
All other indications: Mean weight change over 26 weeks increased to a gain of +2.4 kg at 1 year and 3.1 kg
was –0.6 kg (cf. +0.2 kg with placebo). after 2 years (Wohlreich et al. 2007).
Major depression: Mean +2.4-kg weight gain over
1 year (N= 1,279) (Raskin et al. 2003).
Systemic Reactions
TABLE 19–4. Representative rates of weight changes across antidepressants reported in clinical trials (continued)
Escitalopram Major depression: No difference from placebo in weight change. In three 8-month placebo-controlled trials for GAD,
mean weight gain was +1.4 kg (Davidson et al.
2005).
Fluoxetine Major depression: Decreased appetite in 11% and weight loss Major depression: –0.4 kg weight loss in first 4 weeks;
in 1.4%. no significant weight differences from placebo over
OCD: Decreased appetite in 17%, weight loss in 2%. 50 weeks of continuation/maintenance therapy for
Bulimia nervosa: Decreased appetite in 8% with mean weight depression (Michelson et al. 1999); meta-analysis of
loss of –0.45 kg, with dosages of 60 mg/day over 15 weeks. studies using fluoxetine to treat obesity shows
weight changes from –14.5 to +0.4 kg after 12 or
more months (Li et al. 2005). (Note: Studies of
fluoxetine targeting weight loss have typically
involved higher dosages [~60 mg/day] than
generally used for major depression [Li et al.
2005].)
Fluvoxamine OCD: Decreased appetite in > 5%; specific weight changes not None.
reported in manufacturer’s package insert, other than no
differences from placebo were observed.
309
310
MAOIs other than Incidence rates for weight changes not reported in Weight gain during treatment for depression
transdermal manufacturers’ product information materials. reportedly more common with phenelzine than
selegiline: tranylcypromine (Cantú and Korek 1988).

isocarboxazid,
phenelzine,
tranylcypromine
Mirtazapine Major depression: Increased appetite in 17% of subjects in acute None.
trials (cf. 2% with placebo); 7.5% of mirtazapine recipients
gained ≥ 7% of their baseline weight (cf. 0% with placebo), as
did 49% of subjects in pediatric trials (cf. 5.7% with placebo).
Nefazodone Major depression: Weight gain in > 1% of subjects. No significant None.
differences from placebo in incidence of substantial weight
gain (i.e., ≥ 7% of initial body weight). Weight loss occurred
in <1% of subjects.
Paroxetine Across indications: Increased appetite in 2%–4%; decreased None.
appetite in 6%–9%. Average weight change in short-term
trials was approximately –2.2 kg. Weight gain occurred in
>1% across indications.
Sertraline Incidence rates for weight changes not reported in OCD: Mean +1.6-kg weight gain (+2.5% of baseline
manufacturer’s product information materials (although weight) over 2.5 years (Maina et al. 2004).
weight increase reported as occurring in > 1% of subjects
across all FDA registration trials).
Systemic Reactions
TCAs Acute trials of tertiary amine TCAs (e.g., imipramine or None.

amitriptyline) have been associated with mean weight gains
of 2.0–7.0 kg; secondary amine TCAs (e.g., desipramine or
nortriptyline) have shown minimal weight gain in trials,
presumably because of lower H1 histamine or anticholinergic
effects (Vanina et al. 2002).
Transdermal Major depression: Over 6–8 weeks, 2.1% of subjects gained ≥ 5% None.
selegiline of their initial body weight, and 5.0% lost ≥5% of their
baseline weight. Mean weight change was –0.5 kg (cf. +0.1 kg
with placebo).
Venlafaxine Major depression: 7% of patients lost ≥5% of their initial body None.
weight.
GAD, social anxiety disorder, or panic disorder: 3%–4% of subjects
lost ≥ 7% of their initial body weight.
Across indications: Weight gain occurred in ≥1% of subjects.
Vilazodone Major depression: In 8-week placebo-controlled trials, no None.
observed differences from placebo (+0.2 kg with either drug
or placebo; gains of ≥7% from baseline weight occurred in
0.9% of vilazodone recipients and 1.2% of placebo recipients).
Note. CI= confidence interval; FDA =U.S. Food and Drug Administration; GAD=generalized anxiety disorder; IR= immediate release;
MAOI=monoamine oxidase inhibitor; OCD=obsessive-compulsive disorder; SR=sustained release; TCA=tricyclic antidepressant; XL=extended
311
release.
substance use disorders (notably, alcoholism) that may influence body

weight and nutritional intake; and minimal if any contribution from co-
therapies that may pose additive weight gain, such as anticholinergic
drugs or sedative-hypnotics. A further consideration regarding iatro-
genic weight gain in both research trials and routine treatment for mood
disorders involves the distinction between the restoration of lost appetite
attributable to the treatment of depression versus the stimulation of ap-
petite and weight gain above and beyond changes caused by treating de-
pression.
The prevalence and magnitude of weight gain associated with anti-
depressants is less extensive than with SGAs, even though almost all
classes of antidepressants—with the notable exception of bupropion—
have been associated with some weight gain. FDA registration trials for
most antidepressants involve relatively short durations of treatment
(typically 4–8 weeks) for acute major depressive episodes, but changes
in weight may be more likely to occur during long-term rather than
short-term therapy. Among SSRIs, fluoxetine may have a lower inci-
dence of weight gain than other agents, based mainly on early studies
involving its use for the treatment of obesity. A few randomized trials
comparing SSRIs over approximately 6–9 months found more weight
gain with paroxetine than sertraline, and often the least amount with
fluoxetine. Significant weight gain also was more extensive during
short- and long-term treatment with SSRIs or TCAs than with nefaz-
odone (Sussman et al. 2001).
Lifestyle Modification
Lifestyle modification remains the first-line, and arguably safest and
best studied, level of intervention to counteract psychotropic-induced
weight gain, although in real life it is often very hard to achieve. The ev-
idence base in support of this statement includes the following:
• A 12-week randomized study of overweight or obese outpatients

with psychotic disorders receiving a variety of SGAs, comparing
usual care versus individual twice-weekly exercise training plus
nutritional counseling, found significant weight loss and decreased
cholesterol:HDL ratio (Blouin et al. 2009).
• A 24-week intensive program of diet, exercise, and nutritional coun-
seling in 22 obese or overweight patients with chronic psychotic dis-
orders yielded an average 6-kg weight loss (5.7% of baseline weight)
and 11% reduction in blood pressure; 77% of subjects completed the
program (Centorrino et al. 2006).
• A 12-week program of exercise (20 minutes three times per week)

plus nutritional and behavioral counseling (e.g., learning to read
food labels, meal planning, portion control, healthy snacking) in 31
overweight or obese schizophrenia or schizoaffective disorder pa-
tients taking SGAs led to a 2.7-kg weight loss; 87% of participants
completed the program (Vreeland et al. 2003). Notably, a 40-week
extension of this program (completed by 65% of subjects) further
demonstrated significant reductions from baseline in hemoglobin
A1C, blood pressure, and hip and waist circumference, but not lipid
parameters, and most of the observed weight loss occurred in the first
3 months with a subsequent plateau despite continued SGA therapy
(Menza et al. 2004).
• A 12-week study in 48 obese or overweight schizophrenia or schizoaf-
fective subjects who had been taking olanzapine for at least 12 weeks
and gained >7% of their pretreatment weight compared usual care
versus a program of diet management (i.e., keeping a food diary, diet
planning with a nutritionist, learning about food exchange tables,
reading food labels, healthy snacking, and low-calorie food prepara-
tion) combined with exercise management (i.e., keeping an exercise
diary and pursuing a tailored exercise plan with an exercise man-
ager). Subjects randomly assigned to the weight management pro-
gram lost a mean of 4 kg, with significant differences visible at week 8.
No significant reductions in lipid parameters were observed. The pro-
tocol was completed by 75% of enrollees (Kwon et al. 2006).
• An 18-month open, prospective comparison of usual treatment versus
a supervised, facility-based exercise program with dietary counseling
in 110 schizophrenia, schizoaffective disorder, or bipolar disorder
patients with antipsychotic-induced weight gain revealed a 3.5% re-
duction in body weight; subjects in the weight management arm had
significantly greater reductions in total cholesterol, LDL, triglycer-
ides, and fasting glucose, as well as significantly greater increases in
HDL when compared with subjects receiving usual care (Poulin et al.
2007).
• In a 10-week open weight control program involving 33 Taiwanese
schizophrenia patients with obesity resulting from SGAs, observed
weight loss was 2.1 kg after 10 weeks, 3.7 kg at 6 months, and 2.7 kg at
12-month follow-up, with significant declines in triglycerides but not
other lipid or glycemic parameters (Chen et al. 2009).
Among the comprehensive issues relevant to weight management

and metabolic risk, nutritional factors should be considered alongside
pharmacological and lifestyle factors. Foods with a higher content of pro-
tein, fiber, and water have been associated with greater satiety. Efforts
toward improving nutritional intake can often be aided by consultation
with a registered dietitian, who can make specific recommendations tai-
lored to an individual patient. Monitoring caloric intake and increasing
physical activity can help to maintain a stable weight. Diet recommenda-
tions often include eating small, frequent meals throughout the day to
minimize rebound hunger from prolonged daytime periods of not eating,
as well as incorporating lean sources of protein with every meal and
snack for satiety and more stable blood glucose levels following intake
(spikes in blood sugar after high-carbohydrate meals lead to quick drops,
and the patient will feel hungry soon after). Nutritionists often focus on
the value of vegetables, which are low in calories and provide vitamins,
minerals, and antioxidants. Fruits provide many beneficial nutrients but
should be limited to two to four servings per day—and are best con-
sumed with a protein, such as a handful of almonds or 1/2 cup of low-fat
cottage cheese. Carbohydrate choices should be complex rather than sim-
ple, which means whole grains (brown rice instead of white, whole wheat
pasta and bread, whole oats, buckwheat, quinoa, barley) and legumes
(lentils, beans); these reflect food choices that are higher in fiber, which
helps stabilize blood sugar and increases satiety. Patients should avoid
greasy and fried foods, as well as high-fat salad dressings, cream sauces,
or gravies. Patients are often advised to choose low-fat dairy products
(e.g., skim or 1% milk, low or nonfat yogurt and cottage cheese) and to
keep hard cheeses to a minimum (1 oz is one serving). Dietitians often
advise healthy snacks that can foster satiety, such as whole wheat pita
with hummus, apple with 1 tablespoon of peanut butter, fresh deli turkey
wrapped in lettuce leaves, six to eight crackers with part-skim mozzarella
cheese, clementines, or a bunch of grapes with 1/4 cup almonds. Certain
food items, such as cinnamon, may help to reduce gastric emptying and
postprandial glucose, consequently promoting satiety, as suggested by a
limited but sometimes inconsistent database.
In addition to monitoring food intake, increasing physical activity
should be strongly emphasized. Strategies include finding activities that
patients enjoy (e.g., walking, dancing, tennis, gardening) so as to mini-
mize the likelihood that exercise could feel like a chore. Before patients
begin a new exercise regimen, the clinician must assure the absence of any
physical health constraints, such as unstable cardiopulmonary diseases.
For weight loss, at least 60 minutes/day is recommended, whereas 45–
60 minutes most days of the week is usually recommended to maintain a
stable weight.
With both diet and exercise, goal setting is an important factor to
help patients remain focused. Goals should be positive and quantita-
tive. Patients can begin with small goals and broaden them gradually
over time. For example, rather than declare an intention to no longer eat
fried foods in restaurants, the patient might reframe the goal: “When
I eat out, I will order a side salad instead of french fries.” Instead of pro-
nouncing a moratorium on dessert, the patient might say, “I will wait
20 minutes after a meal, and if still hungry, I will have some fresh fruit
and a cup of tea.” Instead of declaring an intention to join a gym, the
patient might first set the goal of walking 20 minutes 3 days a week, and
once that is met, to then increase the walk by 10 minutes or by adding a
fourth day a week for walking. Staying with an exercise program often
poses as much if not a greater challenge than initiating one; therefore,
undertaking a gradual, realistic pace is important.
Pharmacological Management of
Psychotropic-Induced Weight Gain
The management of weight gain caused by serotonergic antidepressants
has received comparatively less attention than the weight gain caused
by SGAs, for which more pervasive metabolic disturbances appear to be
more extensive. Adjunctive topiramate represents one of the best stud-
ied remedies for weight gain associated with SSRI treatment, as well as
with a range of other psychotropic agents. These studies, summarized in
Table 19–5, are all limited by their small sample sizes, use of concomitant
therapies, lack of treatment randomization, and heterogeneity of diag-
nostic groups and clinical states. Potential benefits also may be coun-
tered by other adverse effects caused by topiramate, such as cognitive
impairment (see Table 16–2 in Chapter 16, “Neurological System”) or
paresthesias (see the section “Paresthesias and Neuropathies” in Chap-
ter 16). Nevertheless, the studies provide convergent data supporting
weight loss with adjunctive topiramate for psychotropically induced
weight gain.
Psychostimulants, which are sometimes used to promote weight
loss, have not been extensively studied specifically for counteracting
psychotropic-induced weight gain. In patients with primary psychotic
disorders, stimulants pose obvious concerns for the potential psychoto-
mimetic effects. In children and adolescents receiving SGAs for aggres-
sion and disruptive behavioral disorders, no differences were found
over 12 weeks in body weight or metabolic parameters among those who
did (N=71) or did not (N=82) also receive stimulants under naturalistic
conditions (Penzer et al. 2009). Notably, unlike amphetamine or meth-
ylphenidate, the novel stimulants modafinil or armodafinil do not ap-
pear to be associated with clinically meaningful weight loss.
316
TABLE 19–5. Open-label studies of adjunctive topiramate and weight loss in patients with mood and anxiety
disorders
Study population N Duration Dosing Mean weight loss
Weight gain induced by SSRIs for 15 10 weeks, open label Mean dose=135± 44 mg/day 4.2±6.0 kg.

anxiety disorders (Van
Ameringen et al. 2002)
Bipolar or unipolar depressed 12 6–12 months Begun at 25 mg/day and At 3 months, 5.0± 3.3 kg; at 6 months,
patients (Kirov and Tredget increased by 25–50 mg every 7.8±6.9 kg; patients completing
2005) 1–2 weeks to a maximum of 12 months lost a mean of 9.6± 6.7 kg.
600 mg/day; mean dose=
296 mg/day
Bipolar I or schizoaffective manic 20 5 weeks Begun at 25 mg/day, increased –4.3 kg (range: –1.4 to –10.5 kg by
patients (Chengappa et al. 1999) by 25–50 mg every 3–5 days; 5 weeks).
mean dose at week 5= 211 mg/
day
Bipolar I, II, not otherwise 31 ≤6 months Mean dose=202± 65 mg/day –2.3± 1.3 kg.
specified, or schizoaffective
bipolar disorder patients (Vieta
et al. 2002)
Bipolar I, II, or schizoaffective 26 12 months Topiramate (25- to 50-mg/day –0.5± 1.1 kg.
bipolar disorder patients (Vieta weekly increases) plus
et al. 2004) olanzapine concurrently
begun; mean modal topiramate
dose= 271.1±117.6 mg/day
Systemic Reactions
TABLE 19–5. Open-label studies of adjunctive topiramate and weight loss in patients with mood and anxiety
disorders (continued)
Study population N Duration Dosing Mean weight loss
Refractory bipolar disorder 14 1–64 weeks Mean dose=100± 72 mg/day 4 subjects with a baseline BMI >28 had
patients (Guille and Sachs 2002) (mean= 22.4 weeks) a mean weight loss of –13.5± 7.4 kg.
Diversity of mood, anxiety, 41 1–39 months Begun at 50 mg/day; median Any weight loss occurred in 59%
psychotic, and personality (mean= 16.2 months) maximum dose of 100 mg/day (mean weight loss= 2.2 kg); modest
disorders (Cates et al. 2008) reductions from baseline weight or
BMI (<2%); more substantial weight
loss occurred among those who had
any weight loss (7.2 kg); any weight
loss was more likely among heavier
subjects (i.e., baseline weight >91 kg
at topiramate initiation); 76%
completed at least 6 months, 59%
completed at least 1 year; 27%
completed 2 years.
Adverse effects, reported in 17% of
subjects, included cognitive dulling,
appetite increase, behavioral
activation, and 61 disturbances.
Note. BMI= body mass index; SSRI=selective serotonin reuptake inhibitor.
317
A number of pharmacotherapies have been described to help counter

obesity in otherwise healthy adults for whom weight gain was not the
result of psychotropic medications. Such medications, which by extrap-
olation may warrant consideration as possible strategies for psychotro-
pic weight gain, include the following:
• Bupropion SR: A 24-week randomized comparison of placebo versus

bupropion SR (300–400 mg/day) in obese, otherwise healthy adults
found significantly greater reductions from baseline weight among
those receiving bupropion SR 300 mg/day (7.2% loss from baseline) or
400 mg/day (10.1% loss from baseline) than among those receiving pla-
cebo (Anderson et al. 2002). In addition, a 26-week randomized pla-
cebo-controlled trial in 193 subsyndromally depressed subjects yielded
a significantly greater mean weight loss in those taking bupropion SR
(4.4 kg, or 4.6% of baseline weight) than placebo (1.7 kg, or 1.8% of base-
line weight), with a significant correlation observed between improve-
ment in depressive symptoms and weight loss (Jain et al. 2002).
• Bupropion SR plus naltrexone: This combination was examined on
the basis of the ability of bupropion to activate hypothalamic pro-
opiomelanocortin neurons and the theoretical ability of naltrexone to
block opioid-mediated pro-opiomelanocortin autoinhibition. The
combination of bupropion SR (360 mg/day) plus naltrexone (16 or
32 mg/day) was associated with substantial reductions from base-
line weight over 56 weeks (half of subjects lost 5% of their baseline
weight with the 16-mg/day naltrexone dose; a mean 6% loss from
baseline weight occurred with the 32-mg/day naltrexone dose) in a
34-site study of 1,742 overweight or obese adults in the United States
(Greenway et al. 2010). Of note, because of concerns about cardiovas-
cular safety and abuse potential, the FDA opted in February 2011 not
to approve a proprietary formulation of this combination being de-
veloped by Orexigen, despite recommendations by the FDA’s own
advisory committee that favored its approval.
• Zonisamide plus bupropion: A 12-week open-label randomized study
was conducted in 18 psychiatrically healthy obese women comparing
the anticonvulsant zonisamide (begun at 100 mg/day and increased to
400 mg/day over 4 weeks) alone or with bupropion (the latter begun at
100 mg/day and increased to 200 mg/day after 2 weeks). Combination
therapy yielded significantly more weight loss (mean=7.2 kg) than
zonisamide alone (mean=2.9 kg) (Gadde et al. 2007).
• Phentermine: This amphetamine-like stimulant is an appetite sup-
pressant used for the short-term management of obesity. In a pooled
analysis of 9 randomized trials occurring from 2 to 24 weeks, with
dosages of 15–30 mg/day, subjects lost a mean of 3.6 kg (95% CI, 0.6–
6.0 kg) (Li et al. 2005). Side effects of phentermine appear modest and
bear mainly on its sympathomimetic effects (e.g., tachycardia, hyper-
tension).
• Phentermine plus topiramate: In a 56-week trial with 2,487 obese or
overweight adults, the combination of phentermine (7.5 or 15 mg/
day) plus topiramate (46 or 92 mg/day) produced significantly greater
mean weight loss (–8.1 kg [95% CI, –8.5 to –7.1 kg] and –10.2 kg [95%
CI, –10.4 to –9.3 kg] at each respective dose pairing) as compared with
placebo (mean weight loss=–1.4 kg [95% CI, –1.8 to –0.7 kg]), with 62%
and 70% losing at least 5% of their initial weight with each respective
dose pairing of active drug arms; adverse effects that were more com-
mon with active drug than placebo included dry mouth, paresthesias,
constipation, insomnia, dizziness, and dysgeusia (Gadde et al. 2011).
Clozapine-induced weight gain may at least partly derive from the

more potent 5-HT2C antagonism caused by its metabolite norclozapine.
Lu et al. (2004) capitalized on the pharmacokinetic effect of coadminis-
tering fluvoxamine (50 mg/day) with clozapine (250 mg/day), which
raises clozapine levels by ~2.3-fold while decreasing norclozapine lev-
els, to demonstrate significantly less weight gain over 12 weeks than
with clozapine alone. Careful monitoring of serum clozapine levels dur-
ing deliberate coadministration of fluvoxamine is important to mini-
mize the risk of toxicity and seizures.
Finally, it is important to keep in mind that some psychiatric disor-
ders, such as bipolar disorder, may involve an intrinsic risk for devel-
oping obesity or substantial weight gain, posing a confounding factor
when attempting to apportion the etiology of weight gain to a treatment
versus a disease state itself.
Among studies of pharmacotherapies used to counteract psychotro-
pic-induced weight gain, a meta-analysis of 32 studies involving 1,482
subjects and 15 medications or medication combinations to remedy
antipsychotic-associated weight gain, used over diverse time periods,
found the most extensive mean weight loss as compared to placebo with
metformin (2.9 kg), followed by D-fenfluramine (2.6 kg), sibutramine
(2.6 kg), topiramate (2.5 kg), and the noradrenergic reuptake inhibitor re-
boxetine (1.9 kg) (Maayan et al. 2010). (D-Fenfluramine was withdrawn
from the U.S. market by the FDA in 1997 due to reports of cardiac valve
disease and pulmonary hypertension; however, the agent is included
here because of its historical role and known efficacy for weight loss.)
Table 19–6 summarizes major findings with randomized pharmaco-
logical intervention studies to counteract psychotropic-induced weight
320
TABLE 19–6. Pharmacological strategies with at least one randomized trial to manage psychotropic-induced weight
gain
Agent Rationale Study designs and findings
Amantadine Possible dopaminergic and Randomized comparison of adjunctive amantadine (up to 300 mg/day) (N= 60)

noradrenergic anorexic effect; or or placebo (N=65) over 16 weeks in schizophrenia, schizoaffective, schizo-
via effects of adrenal and gonadal phreniform, or bipolar disorder patients who gained ≥ 5% of their initial body
steroids through reduction of weight with olanzapine. Significantly greater weight loss with amantadine
prolactin. (mean= –0.2± 4.6 kg) than placebo (+1.3± 4.3 kg) (Deberdt et al. 2005).
Randomized comparison of adjunctive amantadine (N = 12) or placebo (N= 9)
for 12 weeks in schizophrenia, schizoaffective, or bipolar disorder patients
who had gained ≥2.3 kg from olanzapine; amantadine recipients lost a mean
of 0.4± 3.5 kg, whereas placebo recipients gained a mean of 4.0± 5.9 kg
(Graham et al. 2005).
Aripiprazole Considered among the more weight- 10-week placebo-controlled double-blind crossover study of adjunctive ari-
neutral SGAs, potentially via its piprazole (15 mg/day) in overweight schizophrenia patients (N=15) stable on
modest H1 antihistamine blockade olanzapine for at least 1 month; aripiprazole was associated with significantly
and serotonin type 2C (5-HT2C) more weight loss (mean= –1.3± 2.1 kg) than placebo (mean gain= +1.0± 1.5 kg),
agonism; may promote weight loss as well as greater reduction in triglycerides (–52 mg/dL vs. –48 mg/dL,
despite concomitant treatment with respectively) and very-low-density lipoprotein reductions (Henderson et al.
other weight-promoting agents. 2009).
Systemic Reactions
gain (continued)
Lamotrigine Apparent weight neutrality or 18-month maintenance comparison of lamotrigine (N= 217), lithium (N=166),
weight loss observed in clinical or placebo (N= 190); mean weight changes were –1.2 kg (lamotrigine), +2.2 kg
trials for bipolar disorder. (lithium), and +0.2 kg (placebo) (Sachs et al. 2006a). Among obese subjects in
this group (N = 155), mean weight changes at 52 weeks were –4.2 kg
(lamotrigine), +6.1 kg (lithium), and –0.6 kg (placebo) (Bowden et al. 2006a).
Weight loss observed in obese 26-week study in 40 obese psychiatrically healthy adults; significantly greater
nonpsychiatric patients. weight loss with lamotrigine (200 mg/day) than placebo (–2.9±4.7 kg vs.
–0.5± 3.2 kg, respectively) and mean changes in BMI from baseline to
endpoint (–1.5± 2.8 and –0.1± 1.1 for lamotrigine and placebo, respectively)
(Merideth 2006).
321
322
gain (continued)
Metformina Oral hypoglycemic agent; decreases 12-week comparison of placebo, metformin (250 mg tid with meals), metformin

insulin sensitivity and prolongs the plus lifestyle intervention, or lifestyle intervention alone in 128 adults with
duration of postprandial falls in schizophrenia in China whose weight increased > 10% from antipsychotics.
plasma levels of ghrelin, the Mean reductions in BMI were greatest among subjects randomly assigned to
gastrointestinal hormone that metformin plus lifestyle intervention (1.8), followed by metformin alone (1.2),
promotes satiety (English et al. and lifestyle alone (0.5) (Wu et al. 2008).
2007); inhibits expression of 16-week comparison of placebo or metformin (initially 500 mg with dinner for
neuropeptide Y and may increase 1 week, then 500 mg with breakfast and dinner for 1 week, then 850 mg with
expression of hypothalamic leptin breakfast and dinner) in 39 children and adolescents who had > 10% weight
receptors (Aubert et al. 2011). increase from olanzapine, risperidone, or quetiapine. Placebo recipients
gained an additional mean of +4.0± 6.2 kg, whereas metformin recipients lost
a mean of –0.1± 2.9 kg (Klein et al. 2006).
14-week double-blind placebo-controlled trial in 40 schizophrenia patients
taking olanzapine; glucose levels declined significantly with metformin but
no significant changes observed in weight gain or insulin resistance (Baptista
et al. 2006).
Systemic Reactions
gain (continued)
Nizatidine H2 receptor antagonism may exert a Single-case report of 5% body weight loss after 4 weeks with nizatidine 150–
direct appetite-suppressant effect 300 mg bid in a 90-kg 23-year-old olanzapine-treated schizophrenia patient
or an indirect weight loss effect by (Sacchetti et al. 2000).
reducing gastric acid secretion. 16-week comparison of nizatidine 150 mg or 300 mg bid vs. placebo in 175
schizophrenia patients beginning treatment with olanzapine; significantly
less weight gain with high-dose nizatidine than placebo at weeks 3 and 4 but
not at week 16 (Cavazzoni et al. 2003).
8-week randomized comparison of adjunctive nizatidine or placebo in 35
schizophrenia patients who gained >2.3 kg from SGAs; significant weight loss
and reduction in serum leptin levels (Atmaca et al. 2004).
2.5-month open-label adjunctive nizatidine (N =47) 150 mg bid followed by
8-week randomized adjunctive nizatidine or placebo (N=28) for quetiapine-
associated weight gain in schizophrenia patients; no significant reductions in
weight or serum leptin levels (Atmaca et al. 2004).
323
324
gain (continued)
Orlistat Interferes with absorption of 16-week randomized placebo-controlled study of orlistat dosed at 360 mg/day

intestinal fat. in 63 obese or overweight schizophrenia patients taking clozapine or
olanzapine. Men (but not women) had significantly greater weight change
with orlistat (loss of –2.36 kg) than with placebo (gain of +0.62 kg) (Joffe et al.
2008).
A 16-week open-label extension phase trial in 44 of these subjects yielded
significant further weight loss (–1.29± 3.04 kg), with men but not women
showing the most robust declines (Tchoukhine et al. 2011).
Sibutramineb Centrally acting serotonin and Randomized, placebo-controlled study in 37 overweight schizophrenia or
norepinephrine reuptake inhibitor, schizoaffective disorder patients taking olanzapine; over 12 weeks,
thought to modulate satiety via its adjunctive sibutramine (up to 15 mg/day) produced a mean –3.8± 1.1 kg
serotonergic effects in the weight loss vs. a –0.8± 0.7 kg weight loss with placebo (Henderson et al. 2005).
hypothalamus and amygdala. Randomized placebo-controlled 12-week study in 10 schizophrenic or
schizoaffective bipolar clozapine recipients; no significant changes in any
metabolic or weight-related parameters (Henderson et al. 2007).
Randomized 24-week comparison with topiramate led to mean weight loss of
–4.1± 5.7 kg (McElroy et al. 2007).
Systemic Reactions
gain (continued)
Topiramate Direct appetite suppressant effect by 24-week randomized comparison of flexibly dosed topiramate (mean
unknown mechanism; may reduce dose= 209±145 mg/day) or sibutramine (mean dose=12± 7 mg/day) in 46
fat deposition by stimulating overweight bipolar disorder outpatients; statistically similar magnitude of
energy expenditure. weight loss with topiramate (–2.8 ±3.5 kg) or sibutramine (–4.1± 5.7 kg) but
high dropout rates in both groups (McElroy et al. 2007).
12-week double-blind comparison of olanzapine plus topiramate (100 mg/day)
or placebo in first-episode schizophrenia: mean weight loss of –1.3±2.3 kg
with topiramate (significantly greater than placebo) alongside significantly
greater reductions in serum leptin and other metabolic parameters (Narula et
al. 2010).
Zonisamide Possible dopaminergic and In randomized study, 60 obese, psychiatrically healthy adults had significantly
serotonergic effects may affect more weight loss (mean=–5.9 kg at 16 weeks and –9.2 kg at 32 weeks) with
satiety. zonisamide (initially 100 mg/day increased to a maximum of 600 mg/day)
than placebo (Gadde et al. 2003).
Open trial of adjunctive zonisamide (final mean dose of 375±206 mg/day;
range: 75–800 mg/day) in 25 obese recovered bipolar I or II patients over a
mean of 14 weeks; mean weight loss of 1.2±1.9 BMI points; notably, 44% of
subjects prematurely discontinued participation due to worsening mood
symptoms (Wang et al. 2008).
Note. bid =twice daily; BMI=body mass index; SGA =second-generation antipsychotic; tid= three times daily.
aIn the United States, only 500-mg nonscored tablets of metformin are manufactured, and cannot easily be split.
325
bSibutramine was voluntarily withdrawn by Abbott Laboratories in October 2010 from the U.S. market following U.S. Food and Drug Adminis-
tration concerns regarding increased risk for heart attack and stroke.
gain in patients with primary mood or psychotic disorders. Alterna-

tively, psychiatrically stable patients who have gained weight from an
SGA with high risk for weight gain (e.g., olanzapine) have been shown
to lose significantly more weight and lower their total cholesterol levels
by switching within class to another agent that may be less prone to
cause weight gain (e.g., aripiprazole or ziprasidone); however, stable
psychiatric symptoms have been shown to worsen after switching from
olanzapine to aripiprazole (Newcomer et al. 2008), and clinicians cannot
assume comparable efficacy among SGAs for patients with primary
psychotic disorders. Significant weight loss also has been demonstrated
after switching stable schizophrenic outpatients from olanzapine to
ziprasidone (median ziprasidone dose=90 mg/day; mean weight loss =
1.8 kg) or from risperidone to ziprasidone (median ziprasidone dose=
92 mg/day; mean weight loss=0.9 kg) (Weiden et al. 2003a). Stable but
symptomatic schizophrenia patients who are switched from either olan-
zapine or risperidone to ziprasidone demonstrated weight loss but nei-
ther improvement nor decline in global symptoms (Weiden et al. 2003b).
Weight Loss Supplements

There are a number of over-the-counter supplements that people some-
times use in attempts to hasten weight loss. Although evidence to sup-
port the efficacy of such approaches is often inconsistent, clinicians
should be aware of safety considerations relevant to commonly used
supplements, as summarized in Table 19–7.
Weight Loss
General Recommendations. Stimulants and some antide-
pressants (certain SSRIs or SNRIs, bupropion, nefazodone) may be
associated with weight loss. If significant or undesirable weight
loss occurs, drug discontinuation and substitution may be advis-
able (e.g., switching methylphenidate or amphetamine to atom-
oxetine, guanfacine, or modafinil/armodafinil).
Psychotropic-induced weight loss is a generally less common phenom-

enon than weight gain but nevertheless may pose an obstacle to treat-
ment with a number of causal agents. The most well known among
medications that can exert a proanorectic effect are psychostimulants
(i.e., methylphenidate and amphetamine). No clear differences exist
among specific preparations of these compounds (e.g., methylpheni-
date preparations Ritalin LA vs. Concerta vs. Focalin) or between meth-
Systemic Reactions
TABLE 19–7. Nutritional supplements commonly used to promote weight loss
Supplement Rationale Evidence Possible adverse effects
Caffeine Modest appetite suppression and Most trials involve combinations Hypertension; reduces glucose
stimulation of thermogenesis. of caffeine with thermogenic tolerance
drugs such as ephedra or
ephedrine.
L-Carnitine Carnitine deficiency impairs fatty No differences from placebo in None known
acid β-oxidation. controlled trials.
Chromium picolinate Trace element that can decrease 12-week randomized trial in Reports of acute renal failure,
insulin sensitivity and reduce overweight healthy adults concerns about potential for
carbohydrate craving in found no differences in BMI or causing chromosomal damage
patients with atypical central adiposity (measured by (clastogenicity)
depression. computed tomography)
between chromium picolinate
(1,000 µg/day) and placebo
(Yazaki et al. 2010).
Cissus quadrangularis (CQ) or CQ Unknown. 10 weeks of CQ (150 mg bid) or Headache, insomnia, GI upset
plus Irvingia gabonensis (CQ-IG) CQ-IG (250 mg bid) in 72 obese
or overweight adults led to an
8.8% reduction from baseline
weight with CQ and an 11.9%
reduction with CQ-IG (both
superior to placebo) (Oben et al.
2008).
327
328
TABLE 19–7. Nutritional supplements commonly used to promote weight loss (continued)
Citrus aurantium and synephrine Direct appetite suppression. Case reports but only one Headache, tachycardia, and
alkaloids (negative) placebo-controlled hypertension (although touted

trial (Bent et al. 2004). as a safer alternative to
ephedra); cerebrovascular and
cardiovascular events reported;
tyramine content poses hazard
when taken with MAOIs
Ephedra (ma huang) Increased metabolic rate. Modest short-term weight loss Hypertension, excessive
(about 0.9 kg/month) for up to cardiovascular stress leading to
6 months, based on meta- strokes or arrhythmias;
analysis of 284 reports (Shekelle consumer alert issued by the
et al. 2003). FDA in 2008
Garcinia atroviridis Thought to block lipogenesis and Favorable animal studies None known
promote lipid oxidation. (reviewed by Hasani-Ranjbar et
al. 2009).
Garcinia cambogia–derived Competitive inhibitor of ATP Meta-analysis of 12 placebo- GI upset
(-)-hydroxycitric acid (HCA) citrate lyase, which in turn controlled trials revealed a
facilitates fatty acid synthesis. small, significantly greater
short-term weight loss with
HCA than placebo (mean
difference =0.88 kg) (Onakpoya
et al. 2011).
Systemic Reactions
TABLE 19–7. Nutritional supplements commonly used to promote weight loss (continued)
Green tea catechins with caffeine 270–1,200 mg/day empirically Meta-analysis of 15 studies Tachycardia, insomnia,
observed to reduce appetite; indicates statistically but not dizziness, nausea
may promote thermogenesis clinically significant reductions
and fat oxidation. in BMI (~0.55) or weight
(~1.4 kg) (Phung et al. 2010).
Hydroxycut Nutraceutical mixture containing No peer-reviewed published Liver failure, rhabdomyolysis,
Garcinia cambogia, Gymnema efficacy data. death; recalled by the
sylvestre, chromium manufacturer after the FDA
polynicotinate, caffeine, and issued a warning in May 2009;
green tea. reformulated and placed back
on market
Sambucus nigra (elderberry) Antioxidant; possible weight loss Favorable animal studies None known
mechanism unknown. (reviewed by Hasani-Ranjbar
et al. 2009).
Note. ATP=adenosine triphosphate; bid =twice daily; BMI=body mass index; FDA =U.S. Food and Drug Administration; GI= gastrointestinal;
MAOI= monoamine oxidase inhibitor.
329
ylphenidate versus amphetamine. In the treatment of attention-deficit

disorder, nonstimulant treatment options such as atomoxetine or guan-
facine may be viable alternatives with relatively lesser risk of weight
loss. Among antidepressants, some SSRIs (notably, fluoxetine or bupro-
pion) are thought to promote weight loss in some patients, and con-
trolled trials with SNRIs such as duloxetine, venlafaxine, or desven-
lafaxine also tend to show somewhat less weight gain than occurs with
other antidepressant classes (see Table 19–4).
The evaluation of weight loss or appetite reduction should include
careful assessment of possible noniatrogenic causes, both medical and
psychiatric, including the presence of 1) depression, 2) anorexia nervosa
or other eating disorders, 3) hypothyroidism, or 4) malignancy.
20
Pregnancy and
the Puerperium
Psychotropic adverse effects during pregnancy generally do not differ

qualitatively from those that may occur at other times, although preg-
nancy may be a time of increased susceptibility to certain conditions
relevant to adverse drug effects (e.g., gestational diabetes and subse-
quent metabolic dysregulation with SGAs). Pregnancy also may alter
drug metabolism in ways that affect both efficacy and tolerability—
for example, the third trimester involves both the greatest increase in
volume of distribution as well as estrogen-mediated induction of CYP
enzymes. Consequently, dosages of SSRIs and other drugs metabolized
by CYP isoenzymes may require upward dosing to maintain consistent
efficacy, although rapid fluid shifts at the time of delivery may necessi-
tate subsequent dosage reductions to minimize the risk of toxicity.
Teasing apart potential teratogenic effects from base rates of minor
or major malformations in the general population is often difficult if not
impossible. Complicating the situation further is the need to consider
factors such as the adequacy of prenatal care and the possible deleteri-
ous effects of undertreated psychopathology on the developing fetus
(e.g., the impact of hypercortisolemia in depression on the developing
hippocampus).
331
Breast-Feeding and Adverse Events

General Recommendations. No absolute contraindications
exist to breast-feeding during treatment with any psychotropic
drug. Potential benefits of psychotropic drug therapy during
breast-feeding must be balanced on a case-by-case basis against
the potential for unknown risks.
Virtually all psychotropic drugs are detectable in breast milk, al-

though the clinical significance of this, if any, is often unknown. Among
mood stabilizers, carbamazepine and divalproex are often considered
relatively safe during breast-feeding, although case reports exist of in-
fants developing through breast-feeding hepatic dysfunction from expo-
sure to carbamazepine and thrombocytopenia or anemia from exposure
to divalproex (Chaudron and Jefferson 2000). Most practitioners advise
against breast-feeding during lithium therapy, although it is no longer an
absolute contraindication. Serum lithium levels, as well as renal and thy-
roid function, require monitoring in the newborn during breast-feeding.
Growth Effects
Conflicting and nonsystematic data exist on the potential relationship be-
tween antidepressant exposure during pregnancy and low birth weight
or intrauterine growth retardation. Although some studies suggest that
antidepressant exposure may lead to lower birth weight and size (e.g.,
length and head circumference), the potential confounding effects of
parental size and metabolic parameters, as well as maternal depression
influencing fetal growth and development, often are underappreciated.
Teratogenicity
Since 1979, the FDA has identified the safety of medications for the
developing fetus during pregnancy using a five-category classification
scheme ranging from Category A (safest) to D and X (least safe) (Table
20–1). Although most psychotropic drugs are identified as Category C,
a select number are Category B, although such a designation often
reflects historical ratings by the FDA rather than demonstrated safety
(as in the case of the “B” categorization of clozapine). Occasionally,
drugs that carry a Category B rating may undergo reevaluation and be
moved to Category C if the manufacturer applied to the FDA for a new
indication of the same drug (as occurred for bupropion in 2006 when its
Pregnancy and the Puerperium 333
TABLE 20–1. U.S. Food and Drug Administration categorization of

teratogenic risk of drugs
Category Description
A Adequate and well-controlled studies have failed to

demonstrate a risk to the fetus in the first trimester of
pregnancy (and there is no evidence of risk in later
trimesters).
B Animal reproduction studies have failed to demonstrate
a risk to the fetus, and there are no adequate and
well-controlled studies in pregnant women.
C Animal reproduction studies have shown an adverse
effect on the fetus, and there are no adequate and well-
controlled studies in humans, but potential benefits may
warrant use in pregnant women despite potential risks.
D There is positive evidence of human fetal risk based on
adverse reaction data from investigational or marketing
experience or studies in humans, but potential benefits
may warrant use of the drug in pregnant women despite
potential risks.
X Studies in animals or humans have demonstrated fetal
abnormalities and/or there is positive evidence of
human fetal risk based on adverse reaction data from
investigational or marketing experience, and the risks
involved in use of the drug in pregnant women clearly
outweigh potential benefits.
Source. Food and Drug Administration: Federal Register 44:37434–37467,
1980.
manufacturer sought a new indication for seasonal affective disorder).

Although Category B ratings may cast the impression of greater safety
with respect to human teratogenicity, such a designation can be obtained
only when drugs reveal no teratogenic effects in two separate animal spe-
cies, alongside no known risk for teratogenicity in humans. In fact, there
is no requirement for human data at the time of category assignment,
making the utility of the ranking questionable if not severely limited. This
places a potential incentive before the pharmaceutical industry to pro-
cure animal data that satisfy FDA criteria for a Category B designation,
even though those data may impart no greater safety data specific to
human pregnancy.
In 2008, the FDA issued a proposed amendment to its existing reg-

ulations for prescription drug labeling regarding safety in pregnancy
and lactation, which would eliminate the A, B, C, D, and X categoriza-
tions and instead provide a summary of risks and a discussion of their
supportive data, along with relevant clinical information to aid health
care workers in counseling women about the safety of drug therapies
during pregnancy and lactation (Food and Drug Administration 2008).
Some reasonable guidelines in selecting medications for pregnant
women and those planning for pregnancy include the following:
1. Select medications that are likely to benefit the woman following a

risk-benefit calculation that includes the risk of mental illness to the
woman, because untreated psychiatric disorders are known to in-
crease obstetrical complications and poor neonatal outcomes.
2. Because the literature regarding pregnancy and psychotropics is
evolving and can be difficult to interpret, rely on current literature
rather than the FDA categories.
3. Consider consultation with perinatal psychiatrists, who specialize in
helping women and their providers make educated evidence-based
decisions that take into account maternal mental health and repro-
ductive safety of medications.
4. In general, it is best to treat women of reproductive potential with
medications that would be reasonable in pregnancy, because many
women will require long-term maintenance of psychotropics and
will plan pregnancies or become pregnant during their treatment.
A number of psychotropic agents have relatively well-established

associations with specific potential adverse effects during pregnancy
(either anatomical or behavioral teratogenicity, or gestational complica-
tions) that are often small but significant, and that typically represent a
topic for risk-benefit discussions to be had between doctor and patient
rather than absolute contraindications (Table 20–2).
As a general rule, the clinician should strive during patients’ preg-
nancy to minimize the number of exposures to different drugs, each with
their own (often unknown) risks; this principle often favors the retention
of an existing psychotropic drug once a pregnancy is confirmed rather
than switching to a new drug that introduces additional teratogenic un-
certainties. One point of consideration regarding most teratogenic risks
is that their relevance often pertains mainly (but not exclusively) to the
first trimester, inasmuch as organogenesis is largely completed by the
end of the twelfth week of life (cf. the risk for preterm delivery or bleeding
diatheses in the newborn due to vitamin K deficiency with third-trimester
Pregnancy and the Puerperium 335
divalproex exposure). An example of possible teratogenic risk beyond the

third trimester is persistent pulmonary hypertension of the newborn
(PPHN), a condition typically arising in 1 in 700 live births but found in
one study to have an approximate 6-fold increased risk when mothers
had been exposed to an SSRI specifically after the twentieth week of ges-
tation (Chambers et al. 2006). Several subsequent studies, however, have
failed to support this risk, with most demonstrating no association what-
soever. Therefore, the relationship between PPHN and antidepressants is
questionable at this time, but patients must be made aware of this litera-
ture and its inconsistent findings. Individual risk-benefit analyses for a
given patient must consider the severity of symptoms and the magnitude
of response to an SSRI, as well as additional factors that may indepen-
dently contribute to PPHN (e.g., presence of obesity or diabetes in the
mother). Of all the psychotropic medications that have received system-
atic study in pregnancy, divalproex is the medication most associated
with teratogenicity, with a reported rate of 1%–6% of neural tube defects,
and long-term neurocognitive deficits demonstrated in exposed 3-year-
olds (Meador et al. 2009). In comparison, the risk of cardiovascular anom-
aly with first-time lithium use is small, less than 1%, and the association
between lamotrigine and oral clefting has been only inconsistently ob-
served in registries.
Withdrawal in the Newborn

General Recommendations. In general, little rationale ex-
ists for stopping or lowering a mother’s dosages of antidepres-
sants before delivery during pregnancy. The likelihood of
antidepressant discontinuation symptoms in the neonate is low,
and if they are suspected, are typically transient and can be man-
aged conservatively with supportive measures. By contrast, the
risks for third-trimester or postpartum affective relapse may be
considerable and on the whole outweigh the minimal risk for
withdrawal phenomena occurring in the newborn.
SSRIs in neonates have been described in case reports to cause possible

withdrawal phenomena, comprised of features such as constant crying,
shivering, increased muscle tone, and feeding problems. Such phenom-
ena, if they even occur, are typically self-limited and readily managed
by supportive care. Furthermore, naturalistic case registry data have
shown no significant differences in neonatal health outcomes in preg-
nant women for whom SSRIs were discontinued versus continued
throughout the third trimester (Warburton et al. 2010).
336
TABLE 20–2. Known adverse effects of psychotropic agents during pregnancy
Agent FDA categorya Adverse effect Practical implications
Carbamazepine D Neural tube defects, spina bifida, head Drug is relatively contraindicated in
and facial deformities, cardiac pregnancy unless benefits are thought to

malformations; neonates may have outweigh risks (more often the case in
seizures, vomiting, diarrhea, pulmonary epilepsy than other conditions).
problems.
Divalproex D Neural tube defects (■), potential Some clinicians advise supplemental
vitamin K deficiency in newborn. folic acid for divalproex recipients of
childbearing potential, although it is
not known whether this practice meaning-
fully counteracts the potential disruption
of CNS formation due to first-trimester
divalproex exposure.
Lamotrigine C Approximate 10-fold increased risk of Patients should be apprised of current
cleft lips or palates in infants with first- information as part of the informed
trimester in utero exposure to consent process. Most experts and the
lamotrigine compared with FDA attach little importance or
nonlamotrigine-exposed deliveries generalizability to this never-replicated
(Holmes et al. 2008). observation from a single-case registry.
Pregnancy and the Puerperium
TABLE 20–2. Known adverse effects of psychotropic agents during pregnancy (continued)
Agent FDA categorya Adverse effect Practical implications
Lithium D Approximate 1/1,000 to 1/2,000 risk for Contemporary perspectives often favor
Ebstein’s anomaly during cardiac benefits over risk, depending on severity
development; increased risk for of response to lithium.
polyhydramnios.
Paroxetine D Increased risk for cardiac malformations. Although paroxetine has become relatively
contraindicated in pregnancy, some
authorities believe that existing data
regarding its possible teratogenicity are
too preliminary to draw firm conclusions.
Other SSRIs C As a broad class, may increase risk for SSRIs, particularly fluoxetine and
preterm labor (specifically, may decrease sertraline, are considered among the
gestational period by ~7–10 days). safest psychotropic drugs in pregnancy.
Topiramate D Increased incidence of cleft lip or palate Given the minimal psychotropic effects of
(1.4%) relative to other antiepileptic topiramate, benefits would seldom
drugs (0.38–0.55%). outweigh risks.
Note. ■ =FDA black box warning; CNS= central nervous system; FDA= U.S. Food and Drug Administration; SSRI = selective serotonin
reuptake inhibitor.
aSee categories in Table 20–1.
337
In December 2010, the FDA Center for Drug Evaluation and Re-
search modified the warnings and precautions for all antipsychotics to
include a statement identifying the risk for extrapyramidal side effects
and withdrawal in neonates. Such occurrences appear to be self-limited
and of little medical consequence.
21
Emergency Situations
A number of emergency situations may arise from iatrogenic effects of

psychotropic medications. Such situations demand rapid identification.
Discontinuation of a suspected causal agent often leads to resolution of
many suspected iatrogenic emergencies, although a number of situa-
tions require specific forms of medical management. Table 21–1 pro-
vides a summary of common adverse psychotropic drug effects that
may constitute medical emergencies.
Overdoses of psychotropic medications constitute their own form of
medical emergency. Apart from the underlying psychiatric implications
of an overdose (e.g., suicide attempts), some agents with relatively wide
therapeutic indices may cause little more than an exaggeration of the ad-
verse effects sometimes seen at lower dosages (e.g., sedation, nausea,
emesis, headache, tremor). Others may cause more grave end-organ
damage that requires vigilant monitoring of cardiovascular status, sei-
zure risk, or renal or CNS sequelae. Although it is beyond the scope of
this summary to provide a comprehensive discussion of emergency
medical management and detailed consequences of medication over-
doses, Table 21–2 describes common signs and symptoms associated
with overdoses of specific psychotropic drugs, as well as basic elements
of their management.
339
340
TABLE 21–1. Emergency management of serious adverse drug effects
Emergent adverse effect Clinical description Associated agents Management
Cardiovascular
Hypertensive crisis Blood pressure exceeding MAOIs, SNRIs Discontinue causal agent.

180/110; may include
headache, dyspnea,
mental status changes.
Cutaneous
Purpura Nonblanching hemorrhagic Carbamazepine Indicative of thrombocytopenia;
eruptions beneath the skin. discontinue likely causal agent
and refer for medical
management.
Stevens-Johnson Blistering, burnlike lesions on Bupropion, carbamazepine, Discontinue likely causal agent.
syndrome or toxic mucocutaneous tissues; facial lamotrigine Steroids may be indicated
epidermal necrolysis edema, lymphadenopathy. early in the course of disease
but are contraindicated later in
course. Do not rechallenge
after a serious rash.
TABLE 21–1. Emergency management of serious adverse drug effects (continued)
Gastrointestinal
Acute pancreatitis Acute abdominal presentation; Divalproex Discontinue divalproex and do
diagnose by clinical examina- not reintroduce. Medical
tion and elevated serum lipase management mainly involves
and amylase. A history of taking no food by mouth
pancreatitis unrelated to accompanied by intravenous
divalproex is not a known con- hydration and rest.
traindication or predisposing
risk factor for developing
pancreatitis from divalproex.
Hematological
Aplastic anemia — Carbamazepine, clozapine Discontinue offending agent.
Monitor for the development
of and treat infections
(e.g., pharyngitis) that arise
in the setting of an immuno-
compromised state. Bone
marrow typically replenishes
within 21 days without the
341
need for further intervention.
342
Neurological
Acute dystonia Markedly increased muscle All FGAs, particularly higher- Administer oral or

tone and rigidity in potency agents that lack intramuscular anticholinergic
extremities; difficulty anticholinergic effects (e.g., agents (e.g., diphenhydramine
swallowing or clearing haloperidol, fluphenazine) or benztropine).
salivary secretions may
indicate laryngospasm.
Seizure — All FGAs, SGAs, bupropion Maintain airway and safety;
avoid aspiration or head injury.
Systemic
Aseptic meningitis Systemic illness involving Lamotrigine Discontinue lamotrigine.
high fever, nuchal rigidity,
nausea, vomiting,
photophobia, confusion,
depressed sensorium.
Systemic (continued)
Neuroleptic malignant Fever, abdominal cramping, All antipsychotics Discontinue the antipsychotic;
syndrome muscle rigidity; elevated hydrate; administer
CPK. dantrolene for marked
autonomic instability that
does not respond adequately
to supportive treatment.
Serotonin syndrome Clonus SSRIs, SNRIs, tramadol Discontinue serotonergic drugs;
hydrate, maintain airway,
consider cooling blankets.
Note. CPK=creatine phosphokinase; FGA=first-generation antipsychotic; MAOI=monoamine oxidase inhibitor; SGA=second-generation
antipsychotic; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor.
343
344
TABLE 21–2. Clinical features associated with medication overdoses, and managementa
Maximum reported
Agent dose in overdose Medical consequences Management
Atomoxetine 1,400 mg Gastrointestinal symptoms, somnolence, Gastric lavage with administration of activated

dizziness, tremor, abnormal behavior; charcoal if recent ingestion. Monitor cardiac
reports of seizures, hyperactivity, and vital signs.
agitation; rare QTc prolongation,
disorientation, hallucinations.
Buspirone 375 mg Nausea, vomiting, dizziness, miosis, Gastric lavage if recent ingestion. Monitor vital
gastric distress. signs. No specific management strategies
apart from general supportive measures.

Carbamazepine >6,000 mg Neuromuscular disturbances, irregular Maintain adequate airway; gastric lavage with
breathing, respiratory depression, activated charcoal may be considered;
tachycardia, hyper- or hypotension, monitor cardiac rhythm and vital signs.
shock, arrhythmias, impaired level of
consciousness, nausea, vomiting.
Divalproex Maximum dose not Somnolence, heart block, coma; fatalities Supportive measures, gastric lavage with
reported; maximum reported. emesis. Naloxone may reverse the CNS
reported serum depressant effects of divalproex.
valproate level=
2,120 µg/mL
TABLE 21–2. Clinical features associated with medication overdoses, and managementa (continued)
Maximum reported

Gabapentin 49,000 mg Ataxia, labored breathing, ptosis, Supportive care, cardiovascular monitoring,
sedation, hypoactivity, excitation, gastric lavage. Gabapentin is dialyzable.
double vision, slurred speech,
drowsiness, lethargy, diarrhea; no
fatalities reported.
Lamotrigine 15,000 mg Dizziness, diplopia or blurry vision, Supportive care, cardiovascular monitoring,
rotatory or downbeat nystagmus, induction of emesis, gastric lavage.
truncal ataxia, cognitive
disorganization; fatalities reported.
345
346
Maximum reported

Lithium Not reported Neurotoxicity (ataxia, nystagmus, tremor, Consequences of lithium toxicity may persist
slow shuffling gait, myoclonic jerks, for weeks or even months after serum lithium
confusion and disorientation), GI levels become undetectable, due to lithium
symptoms (nausea, vomiting, absorption by bone and fat stores (including
abdominal cramps, diarrhea), and brain). Following acute overdose,
cardiac toxicity (including sinus measurement of plasma lithium–erythrocyte
bradycardia and sinoatrial- or lithium ratios may reveal higher lithium in
atrioventricular block that can produce plasma than erythrocytes. Management
complete heart block [Serinken et al. involves hydration, gastric lavage, and
2009]); reports of pulmonary edema. cardiac monitoring; hemodialysis is rarely
necessary for serum lithium levels <2.5 mEq/L
but is usually required for levels >6 mEq/L, or
for lower levels in medically debilitated
patients or patients with coma, convulsions,
cardiovascular symptoms, or respiratory
failure.
Oxcarbazepine 24,000 mg No specific symptoms associated with Supportive care, gastric lavage with activated
overdose reported by manufacturer; charcoal is recommended.
no fatalities reported.
Maximum reported

Topiramate 110,000 mg Stupor or coma, severe metabolic Gastric lavage or induction of emesis if recent
acidosis, convulsions, drowsiness, ingestion. Activated charcoal is not thought to
speech disturbances, blurred vision, absorb topiramate.
diplopia, cognitive impairment,
lethargy, abnormal coordination,
hypotension, abdominal pain, agitation,
dizziness, depression.
Antidepressants
Bupropion 17,500 mg Seizure (~1/3 of cases), hallucinations, Maintain adequate airway; cardiac monitoring;
loss of consciousness, tachycardia. gastric lavage if soon after ingestion (but not
induction of emesis), with administration of
activated charcoal. EEG monitoring is advised
for first 48 hours.
Citalopram 6,000 mg Dizziness, sweating, nausea, vomiting, Maintain adequate airway; gastric lavage with
tremor, somnolence, tachycardia; QTc activated charcoal may be considered;
prolongation, nodal rhythms, monitor cardiac rhythm and vital signs.
ventricular arrhythmias, and torsades
de pointes reported.
347
348
Maximum reported
>600 mg

Desvenlafaxine Tachycardia, somnolence, mydriasis, Maintain adequate airway; monitor cardiac
seizures, vomiting, hypotension, rhythm and vital signs; gastric lavage if soon
liver necrosis, rhabdomyolysis, after ingestion.
serotonin syndrome; QTc or QRS
prolongation and bundle branch block
on ECG.
Escitalopram >1,000 mg Seizures, coma, dizziness, hypotension, Maintain adequate airway; cardiac monitoring;
insomnia, acute renal failure, tachycar- gastric lavage if soon after ingestion.
dia; QTc prolongation and rare torsades
de pointes on ECG.
Maximum reported
Fluoxetine 8,000 mg Variable outcomes (e.g., full recovery) Maintain adequate airway; cardiac rhythm and
after 8,000-mg ingestion, although vital sign monitoring; gastric lavage if soon
34 fatalities reported by manufacturer after ingestion. Do not induce emesis. Beware
following 633 monotherapy overdoses; of coingestion of TCAs and the
signs of overdose include seizures, pharmacokinetic potential for their increased
nausea, vomiting, tachycardia, accumulation.
somnolence; more severe overdoses may
lead to visual and gait disturbances,
confusion, unresponsiveness,
nervousness, respiratory distress,
tremor, hypertension, impotence,
movement disorders, hypomania.
Fluvoxamine 12,000 mg Variable outcomes (e.g., full recovery Maintain adequate airway; cardiac rhythm and
after 12,000-mg ingestion but lethality vital sign monitoring; gastric lavage if soon
after 1,400-mg ingestion); signs of after ingestion. Beware of coingestion of TCAs
overdose include GI upset, coma, and the pharmacokinetic potential for their
hypokalemia, hypotension, respiratory increased accumulation.
difficulties, somnolence, tachycardia,
bradycardia, QTc prolongation, first-
degree AV block and other arrhythmias,
349
seizures, tremor, hyperreflexia.
350
Maximum reported

Mirtazapine Not reported Disorientation, drowsiness, impaired Maintain adequate airway; monitor cardiac
memory, tachycardia; no known rhythm and vital signs. Gastric lavage with
potential for seizures or ECG activated charcoal if soon after ingestion.
abnormalities. Induction of emesis is not recommended.
Nefazodone 11,200 mg Nausea, vomiting, somnolence; fatalities Maintain adequate airway; monitor cardiac
reported when overdoses occurred in rhythm and vital signs. Gastric lavage if soon
combination with other substances. after ingestion. Induction of emesis is not recom-
mended.
Paroxetine 2,000 mg Somnolence, coma, nausea, tremor, Maintain adequate airway; gastric lavage if
tachycardia, confusion, vomiting, soon after ingestion (but not induction of
dizziness. emesis), with administration of activated
charcoal.
Maximum reported
TCAs Not reported Drowsiness, lethargy, confusion, Cardiac monitoring; intravenous hydration
tachycardia, hyper- or hypotension, (observe for hypotension due to sodium
urinary retention with desipramine channel blockade); gastric lavage with
(highest risk for fatality due to potent activated charcoal if within first few hours after
sodium channel blockade), ingestion; intravenous administration of
nortriptyline, imipramine, sodium bicarbonate (alkalinize urine) if QRS
amitriptyline, clomipramine, >100 msec, ventricular arrhythmias; observe
protriptyline, doxepin. for seizure risk (highest in first several hours
after ingestion; may require anticonvulsant
benzodiazepines, phenobarbital, or other
antiseizure therapy). Avoid β-blockers,
calcium channel blockers, ipecac syrup.
Vilazodone 280 mg Serotonin syndrome, lethargy, Maintain adequate airway; monitor cardiac
restlessness, hallucinations, rhythm and vital signs. Gastric lavage with
disorientation. activated charcoal if soon after ingestion.
Induction of emesis is not recommended.
351
352
Maximum reported
Anxiolytics

Benzodiazepines Not reported Somnolence, confusion, coma, Supportive care including cardiovascular
hyporeflexia, hypotension. monitoring, gastric lavage, and intravenous
hydration. Flumazenil may be administered
to reverse sedative effects of benzodiazepines.
Buspirone 375 mg Nausea, vomiting, dizziness, Supportive care, cardiovascular monitoring.
drowsiness, miosis, gastric distress;
no fatalities reported.
Psychostimulants
Modafinil 12,000 mg Excitation, agitation, restlessness, Supportive care, cardiovascular monitoring,
insomnia, disorientation, confusion, induction of emesis or gastric lavage if not
hallucinations, nausea, diarrhea, contraindicated.
tremor, tachycardia, bradycardia,
hypertension, chest pain; no fatalities
reported.
SGAs
Asenapine 400 mg Agitation, confusion. Maintain adequate airway; cardiac monitoring.
Monitor for possible hypotension and
circulatory collapse. Anticholinergic
medication should be used if severe EPS
occur.
Maximum reported
SGAs (continued)
Iloperidone 576 mg Drowsiness, sedation, tachycardia, Maintain adequate airway; cardiac monitoring;
hypotension, EPS, QTc prolongation; gastric lavage if soon after ingestion with
no fatalities reported. activated charcoal plus a laxative should be
considered. Cardiac monitoring should
include continuous electrocardiography due
to the risk for arrhythmias. Monitor for
seizure risk and dystonic reactions.
Lurasidone 560 mg Recovery without medical sequelae. Avoid α-adrenergic blocking agents or
sympathomimetic drugs with β-agonist
activity (e.g., epinephrine, dobutamine) to
minimize risk for hypotension; avoid
disopyramide, procainamide, or quinidine if
arrhythmias occur, to minimize additive risk
for QTc prolongation. No sequelae following
single overdose case of 560 mg/day.
353
354
Maximum reported
SGAs (continued)

Olanzapine 1,500 mg Agitation, dysarthria, tachycardia, EPS, Maintain adequate airway; cardiac monitoring;
reduced level of consciousness or coma; gastric lavage if soon after ingestion with acti-
fatality from overdoses of olanzapine vated charcoal plus a laxative should be con-
alone reported from doses as low as sidered. Cardiac monitoring should include
450 mg. continuous electrocardiography due to the risk
for arrhythmias.
Paliperidone 405 mg Gait unsteadiness, drowsiness, EPS, Maintain adequate airway; cardiac monitoring;
seizures, QTc prolongation, gastric lavage if soon after ingestion.
tachycardia, hypotension. Anticholinergic agents should be used for
severe EPS. Intravenous hydration may be
necessary to counteract hypotension. Avoid
parenteral epinephrine or dopamine because
beta stimulation may exacerbate hypotension
from paliperidone-induced alpha blockade.
Quetiapine 9,600 mg Drowsiness, sedation, tachycardia, Maintain adequate airway; cardiac monitoring;
hypotension, hypokalemia, first-degree gastric lavage with activated charcoal and a
heart block; prolonged delirium laxative if soon after ingestion; continuous
described in adolescents. ECG monitoring.
Maximum reported
SGAs (continued)
Risperidone 360 mg Drowsiness, sedation, tachycardia, Maintain adequate airway; cardiac monitoring;
hypotension, EPS, electrolyte gastric lavage with activated charcoal and a
abnormalities, seizures, QTc laxative if soon after ingestion; continuous
prolongation with QRS widening ECG monitoring.
on ECG.
Ziprasidone 3,240 mg Sedation, slurred speech, transient Maintain adequate airway; cardiac monitoring;
hypertension, EPS, somnolence, gastric lavage if soon after ingestion.
tremor, anxiety.
Note. AV=atrioventricular; CNS=central nervous system; ECG=electrocardiogram; EEG=electroencephalogram; EPS=extrapyramidal symp-
toms; GI=gastrointestinal; SGA=second-generation antipsychotic; TCA=tricyclic antidepressant.
aInformation based on manufacturers’ package insert materials.
355
PART III
Summary
Recommendations
22
Summary
Recommendations
Decisions about when to pursue antidotes for adverse psychotropic drug

effects versus when to choose alternative pharmacotherapies must be tai-
lored to the needs and circumstances of an individual patient. Risk-benefit
analyses usually favor drug retention with active management of adverse
effects when efficacy is dramatic and few if any comparable alternatives
exist, unless insurmountable hazards exceed potential benefits, or unless
the true inability to manage benign but bothersome adverse events would
likely cause treatment nonadherence. A goal of this book has been to af-
ford readers a greater awareness of viable options and resources for man-
aging adverse effects than they might have previously realized, and of the
circumstances under which the active management of side effects can pro-
duce better treatment outcomes. One of the greatest challenges in practic-
ing contemporary psychopharmacology involves recognizing the factors
and contexts that comprise risk-benefit analyses while considering the
gravity of psychiatric symptoms alongside the manageability and medical
dangerousness of adverse psychotropic drug effects.
In some respects, psychiatry has only fairly recently joined the ranks
of other medical specialties in which treatment risk-benefit analyses have
long been routine. As Baldessarini noted in the introduction to this book,
excess morbidity and mortality attributable to untreated or undertreated
359
psychopathology pose disease risks that have become recognized and

quantified in just the past two decades. By contrast, patients and clini-
cians alike have for centuries been aware of the excess morbidity and
mortality associated with primary medical problems such as arrhyth-
mias, infectious diseases, and cancer, yet seldom if ever avoid effective
treatments due to safety concerns or the need for careful end-organ mon-
itoring. Drugs such as warfarin, digitalis, amphotericin B, interferon,
prednisone, and most antineoplastics all entail substantial (and some-
times life-threatening) adverse effects, yet the potential life-saving benefit
of such drugs is seldom accorded secondary importance to tolerability.
It is particularly striking that mental health professionals may eschew
drugs that require end-organ monitoring and have narrow therapeutic
indices (e.g., lithium), may be lethal in overdose (e.g., lithium, MAOIs, or
TCAs), or carry the potential for metabolic dysregulation (most notably,
clozapine) when many of these very agents have been shown to dramat-
ically reduce mortality from suicide (in the case of lithium) or suicide at-
tempts (in the case of clozapine). It is equally disconcerting when
clinicians undertake complex combination drug regimens without
clearly knowing whether efficacy even exists, or whether benefits do in
fact outweigh risks. This is especially worrisome for treatments involving
understudied patient groups, such as psychopharmacology for mood
and behavior disorders in children younger than age 10 years, or man-
agement of agitation and psychosis related to dementia in older adults.
When clinical problems outpace the existing evidence-based literature, it
becomes all the more vital for practitioners to articulate the thought pro-
cess behind their decision making and the rationales that lead them to fa-
vor one course of action over another.
When psychiatric symptoms are mild, nondisabling, and nonseri-
ous, high drug tolerability (i.e., a high NNH) often rightly assumes
greater importance than the magnitude of efficacy (i.e., large effect size).
Milder forms of psychopathology also may be more responsive to ad-
junctive psychotherapies, allowing for less exclusive focus on drug ef-
ficacy. Successful clinicians who opt for low-efficacy, high-tolerability
drugs may underappreciate nonpharmacodynamic aspects of treat-
ment that may be contributing to favorable outcomes, such as “inad-
vertent” psychotherapy or the importance of the therapeutic alliance in
itself. By contrast, with more moderate to severe forms of psychopathol-
ogy, drugs with more robust effects (large effect sizes, low NNTs) are of-
ten necessary to cause meaningful improvement. In such instances, it is
often hard to justify the use of high-tolerability (high-NNH) drugs with
small effect sizes (or negative efficacy data) when the hazards of under-
Summary Recommendations 361
treated psychopathology are substantial. High tolerability in such set-

tings becomes practically meaningless.
One of the greatest psychotherapeutic challenges during pharmaco-
therapy involves helping patients to cope with adverse effects that are
bothersome, medically inconsequential, and without viable antidotes.
There are unfortunately no panaceas or special strategies to navigate
such obstacles, but the sheer avoidance of low-NNH drugs has little
merit if efficacy is inconsequential. Sometimes, a useful approach is to
coach patients in skills that may help them to better distress. Such ef-
forts obviously require educating patients about adverse effects that are
benign but bothersome (e.g., dry mouth, sexual dysfunction, modest
weight gain, chronic insomnia, tinnitus), and differentiating those ef-
fects from others that may be more easily treated (e.g., nausea, akathisia,
tremor) or frankly dangerous (e.g., fever, dystonia, serious rashes). Dis-
cussing benign or bothersome versus medically hazardous iatrogenic
events can be a formidable task for which a strong therapeutic alliance
and sense of partnership are likely necessary prerequisites. As much as
most clinicians would probably prefer to avoid discussing or having to
deal with adverse effects altogether—and may fear that even mention-
ing potential side effects serves to invite nonadherence—engaging pa-
tients in a dialogue around their reality is fundamental to providing
proper care. Such a dialogue involves a number of core principles:
• Encourage an environment that invites open discussion about possi-

ble adverse events; normalize the inclination to want to stop a medi-
cine if it causes problems; and empathize with potential hesitation on
the part of the patient to raise treatment objections (“I’m committed to
helping you the best that I can if a problem comes up; if you’re think-
ing about stopping a medicine because of a side effect, or for any other
reason, I hope you’ll consider first talking with me about the problem,
since we might find the best solution if we work on it together”).
• Educate patients about differentiating benign or bothersome versus
hazardous adverse drug effects.
• Clarify misconceptions and presumptions about specific types of ad-
verse drug effects.
• Review the risks and benefits of any treatment; explain the rationale
for deciding what is the “best” treatment for a given malady and dis-
cuss whether or not alternative options are likely to be comparable.
• Recognize the patient’s past experiences with adverse events and
sensitivities about particular types of adverse drug effects.
• Estimate the likelihood and transience or persistence of a particular
adverse effect.
• Project the time course for clinical improvement versus the emer-
gence of adverse events (and their magnitude), and establish bench-
marks for periodic reassessments of risk-benefit analyses.
• Provide reassurance that the clinician will monitor adverse effects as
well as efficacy, and intervene when necessary to assure medical
safety; patients are more apt to trust the treatment if they believe the
clinician cares as much about their concerns as they themselves do.
The Future
Research-based strategies to manage the most common and vexing ad-
verse effects of psychotropic drugs lag far behind the pace of efforts to
develop novel treatments for psychiatric disorders. We might imagine
that as current proprietary formulations of psychotropic drugs lose
patent protection with the passage of time, clinician interest will con-
tinue to wane in the prescribing of drugs with high side-effect burdens.
The development of new psychotropic compounds that provide high-
efficacy drugs with few adverse effects has long been an elusive pur-
suit—a conundrum that has unfortunately prompted a number of
prominent pharmaceutical companies to divest their efforts altogether
from new CNS drug development. Perhaps a next generation of psy-
chopharmacology progress will involve greater incentives for drug
manufacturers to devote greater resources toward developing more ef-
fective strategies to counteract common adverse iatrogenic effects.
Until the time arrives when high-efficacy psychotropic drugs that
lack adverse effects come into existence, it remains the challenge for
mental health practitioners to understand drug efficacy, tolerability,
and suitability for a given patient on a case-by-case basis, and—as
occurs in all areas of medicine—to engage the patient as a partner in an
ongoing process of shared decision making that provides the founda-
tion for a meaningful therapeutic alliance.
APPENDIX 1
Self-Assessment
Questions and Answers
Select the single best response for each question.
Questions
1. The rationale for using metformin to counteract psychotropic-
ally induced weight gain involves which of the following?
A. Decreasing insulin sensitivity.

B. Direct appetite suppression via the hypothalamic satiety center.
C. Blockade of postsynaptic 5-HT2C receptors.
D. Agonism of H1 receptors.
2. All of the following have been shown in preliminary studies to

improve tardive dyskinesia or slow its progression except
A. Levetiracetam 500–3,000 mg/day.

B. Vitamin B6 1,200 mg/day.
C. Vitamin C 1,000 mg/day.
D. Amantadine 100 mg bid.
3. All of the following have been shown to potentially diminish or

help manage SSRI-induced bruxism except
A. Risperidone 0.25–0.5 mg at night.

B. An acrylic dental bite guard.
363
C. Buspirone 10 mg bid or tid.

D. Clonazepam 1 mg at night.
4. Signs of lamotrigine toxicity include all of the following except
A. Ataxia.
B. Tremor.
C. Downbeat nystagmus.
D. Ventricular arrhythmia.
5. A medically healthy woman successfully treated for major de-

pression with sertraline 150 mg/day complains of anorgasmia.
Which of the following would be the most evidence-based inter-
vention to help remedy her SSRI-associated sexual dysfunction?
A. Adjunctive sildenafil 50–100 mg/day.

B. Adjunctive buspirone 10 mg tid.
C. Adjunctive mirtazapine 7.5–15 mg at night.
D. Adjunctive methylphenidate 5–10 mg before sex.
6. Priapism has been associated with all of the following medica-

tions except
A. Citalopram.
B. Quetiapine.
C. Divalproex.
D. Trazodone.
7. A 28-year-old Asian man with bipolar disorder and unintelligi-

ble speech presents to the medical emergency department with
fever and blisters in his oropharynx and skin exfoliation on his
palms and soles. All of the following would be consistent with
his history except
A. Presence of the HLA-B*1502 allele.

B. Han Chinese ancestry.
C. Presently taking carbamazepine.
D. Early age at onset of bipolar disorder.
Appendix 1: Self-Assessment Questions and Answers 365
8. Which of the following adverse drug effects commonly occurs

early during treatment with escitalopram but is unlikely to
spontaneously remit during continued therapy?
A. Orgasmic dysfunction.
B. Headache.
C. Nausea.
D. Dizziness.
9. A 32-year-old man with bipolar disorder has been taking topi-

ramate 150 mg/day for 2 months in an effort to counteract a
13.5-kg weight gain caused by psychotropic drugs. He also has
been following the Atkins diet, has begun a program of regular
exercise, and has lost 5 kg in 3 weeks. He calls to report sharp
lower back pain and blood-tinged urine. What is the likely for-
mulation?
A. Lumbosacral strain and probable myoglobinuria from excessive

exercise; he should take an NSAID and, if no better in several
days, contact his internist.
B. Probable nephrolithiasis that may be caused by topiramate,
compounded by hypocitraturia and hypercalciuria from his ke-
togenic diet; he should stop the topiramate and his Atkins diet,
hydrate, and be evaluated for renal calculi.
C. Unclear etiology; discontinue the topiramate and observe for
several days.
D. Likely nephrotic syndrome from possible drug-induced lupus.
10. You newly begin treating a 61-year-old man with bipolar disor-
der who is on a stable regimen of lithium carbonate 900 mg/day
and divalproex 1,500 mg/day. His medical history is notable for
asthma and diabetes. You notice a bilateral upper-extremity
tremor that appears worse with movement and ask if it is new
and whether it has previously been addressed. He remarks that
he has noticed it for several years but his prior doctor never sug-
gested any type of treatment. What would be the most appro-
priate next steps in management?
A. Ignore the tremor if it does not bother the patient.

B. Measure serum creatinine, lithium, and divalproex levels to as-
sure that the tremor does not reflect toxicity.
C. Begin propranolol 10 mg tid.
D. Begin primidone 100 mg bid or tid.
11. Alopecia has been reported to occur with each of the following
medications except
A. Lithium carbonate.
B. Carbamazepine.
C. Fluoxetine.
D. Modafinil.
12. Which of the following would be the most appropriate interven-

tion for lower-extremity edema in an otherwise healthy 31-year-
old woman with bipolar disorder who is psychiatrically stable
on lithium monotherapy 900 mg/day with a 12-hour serum lith-
ium level of 0.9 mEq/L?
A. Amiloride 5 mg bid with monitoring of serum potassium.

B. Hydrochlorothiazide 100 mg/day.
C. Reduce lithium by 300 mg/day.
D. Reduce salt intake and increase free water intake.
13. Paresthesias are commonly associated with which of the follow-

ing anticonvulsants?
A. Gabapentin.
B. Topiramate.
C. Oxcarbazepine.
D. Lamotrigine.
14. Predictors of more severe adverse effects caused by placebo in-

clude all of the following except
A. Hypochondriacal features.
B. Phobic and obsessive traits.
C. Severity of depression at baseline.
D. High suggestibility and expectancy about treatment outcomes.
15. Patients who identify side-effect burden as a reason for poor ad-
herence to psychotropic medications have been shown from re-
search studies to have all of the following characteristics except
A. Female sex.
B. High baseline somatization.
C. Psychosis.
D. Younger age.
16. Interventions that may help to manage dry mouth caused by an-
ticholinergic drugs include all of the following except
A. Glycopyrrolate 1 mg bid.
B. Pilocarpine 20 mg/day.
C. Carboxymethyl cellulose solution.
D. Cevimeline 30 mg/day.
17. A 23-year-old psychotropically naive South African black

woman presents for treatment of social anxiety and generalized
anxiety disorder. She identifies herself as being “especially sen-
sitive” to side effects in general and asks that you prescribe “the
lowest possible dose” of any medication you think appropriate.
One week after beginning paroxetine at 10 mg/day, she calls to
complain of severe nausea, headaches, and dizziness, and asks
for your guidance. What is your impression and recommenda-
tion?
A. Her anxiety is likely exacerbating her sensitivity to side effects;

encourage her to stay with the medication at this dose to over-
come the very problem for which she is seeking treatment.
B. Suspect that her adherence is spotty and she is having with-
drawal symptoms; emphasize to her the importance of regular
daily dosing and full adherence.
C. Recognize that she has a 1 in 5 likelihood of being a poor CYP2D6
metabolizer and is probably supratherapeutic on a paroxetine
dose of 10 mg/day; advise her to lower the dose to 5 mg/day and
reassess after several days.
D. Declare her a “negative therapeutic reactor” and refer her for
more intensive psychotherapy.
18. Insomnia rates reported from FDA registration trials with fluox-
etine or with sertraline are lowest in which of the following dis-
orders?
A. Major depression.
B. Panic disorder.
C. Obsessive-compulsive disorder.
D. Bulimia nervosa.
19. In studies of aripiprazole for adults with schizophrenia, which

of the following adverse effects demonstrated a dose relation-
ship?
A. Sedation or somnolence.
B. Extrapyramidal adverse effects.
C. Akathisia.
D. Nausea.
20. All of the following statements regarding skin rashes associated

with lamotrigine are true except
A. Rapid dose escalation is a known risk factor for the emergence

of serious rashes.
B. Systemic steroids are sometimes used to treat serious rashes
soon after their emergence.
C. Lamotrigine should always be immediately discontinued when-
ever any skin rash emerges.
D. Cotherapy with divalproex may increase the risk of rash be-
cause divalproex inhibits the Phase II hepatic metabolism of la-
motrigine.
21. Identified risk factors for the development of type 2 diabetes

during treatment with SSRIs include which of the following?
A. High baseline body mass index.

B. Lengthy exposure and high dosing.
C. Severity of depression symptoms.
D. Atypical depressive symptoms.
22. Sexual dysfunction has been shown to be a dose-related phe-

nomenon with all of the following medications except
A. Fluoxetine.
B. Citalopram.
C. Venlafaxine.
D. Risperidone.
23. All of the following are more common in women than men except
A. Higher rates of anorgasmia from SSRIs.

B. Greater risk for SSRI-associated osteoporosis.
C. More extensive hyperprolactinemia from antipsychotic medica-

tions.
D. Higher risk of weight gain from olanzapine or risperidone.
24. Which of the following adverse drug effects is usually a tran-

sient phenomenon?
A. Cognitive impairment associated with topiramate.

B. Tremor associated with divalproex.
C. Sexual dysfunction during SSRI therapy.
D. Nausea associated with SSRI initiation.
25. Which of the following physical signs would be useful in differ-

entiating serotonin syndrome from NMS?
A. Tremor.
B. Clonus.
C. Muscle rigidity.
D. Fever.
Answer Guide
1. The rationale for using metformin to counteract psychotropic-
ally induced weight gain involves which of the following?
A. Decreasing insulin sensitivity.

B. Direct appetite suppression via the hypothalamic satiety center.
C. Blockade of postsynaptic 5-HT2C receptors.
D. Agonism of H1 receptors.
The correct response is option A.
Metformin is thought to promote weight loss by decreasing in-

sulin sensitivity. None of the other answers is a correct or plau-
sible explanation for its presumed mechanism of action.
2. All of the following have been shown in preliminary studies to

improve tardive dyskinesia or slow its progression except
A. Levetiracetam 500–3,000 mg/day.

B. Vitamin B6 1,200 mg/day.
C. Vitamin C 1,000 mg/day.

D. Amantadine 100 mg bid.
The correct response is option C.
There are no data to support the utility of vitamin C in the treat-

ment or prevention of tardive dyskinesia. At least one positive
randomized placebo-controlled trial exists to provide prelimi-
nary evidence for levetiracetam, vitamin B6, or amantadine in
the treatment of tardive dyskinesia. Other positive randomized
controlled trial data additionally support the use of vitamin E.
3. All of the following have been shown to potentially diminish or

help manage SSRI-induced bruxism except
A. Risperidone 0.25–0.5 mg at night.

B. An acrylic dental bite guard.
C. Buspirone 10 mg bid or tid.
D. Clonazepam 1 mg at night.
Risperidone, by virtue of its relatively “tight” binding affinity at

the D2 receptor, carries a substantial risk for movement disor-
ders. Bruxism has been conceptualized within the literature as
both a non–rapid-eye-movement sleep disorder as well as a
movement disorder and, as such, would likely not be aided by
the introduction of a dopamine antagonist. By contrast, each of
the remaining choices is an evidence-based strategy used to
counteract bruxism.
4. Signs of lamotrigine toxicity include all of the following except
A. Ataxia.
B. Tremor.
C. Downbeat nystagmus.
D. Ventricular arrhythmia.
The correct response is option D.
Lamotrigine toxicity has not been shown to include cardiac ar-

rhythmia, but may include ataxia, tremor, and downbeat nys-
tagmus.
5. A medically healthy woman successfully treated for major de-

pression with sertraline 150 mg/day complains of anorgasmia.
Which of the following would be the most evidence-based inter-
vention to help remedy her SSRI-associated sexual dysfunction?
A. Adjunctive sildenafil 50–100 mg/day.

B. Adjunctive buspirone 10 mg tid.
C. Adjunctive mirtazapine 7.5–15 mg at night.
D. Adjunctive methylphenidate 5–10 mg before sex.
The safety and efficacy of sildenafil for SSRI-induced sexual

dysfunction in both men and women is supported by a large-
scale randomized placebo-controlled trial, demonstrating sig-
nificantly improved ability to achieve orgasm and greater qual-
ity of orgasm, but no significant improvements in desire,
arousal-sensation, or arousal-lubrication (Nurnberg et al. 2008).
None of the other agents listed has robust data from placebo-
controlled trials involving women.
6. Priapism has been associated with all of the following medica-

tions except
A. Citalopram.
B. Quetiapine.
C. Divalproex.
D. Trazodone.
Priapism has rarely been reported in connection with the use of

citalopram, quetiapine, and trazodone, but not with divalproex.
7. A 28-year-old Asian man with bipolar disorder and unintelligi-

ble speech presents to the medical emergency department with
fever and blisters in his oropharynx and skin exfoliation on his
palms and soles. All of the following would be consistent with
his history except
A. Presence of the HLA-B*1502 allele.

B. Han Chinese ancestry.
C. Presently taking carbamazepine.
D. Early age at onset of bipolar disorder.
The clinical presentation of a severe cutaneous reaction is most

consistent with Stevens-Johnson syndrome due to carba-
mazepine, with heightened risk in an individual of Han Chinese
ancestry who carries the HLA-B*1502 allele. Indeed, the FDA
black box warning for carbamazepine specifically advises geno-
typing for the HLA-B*1502 allelic variant of the HLA-B gene
among high-risk Asian individuals prior to beginning treatment
with carbamazepine, because this risk allele confers increased
susceptibility to serious dermatological reactions with carba-
mazepine. Historical age at onset of bipolar disorder in an adult
is extraneous to developing a drug-induced dermatological re-
action.
8. Which of the following adverse drug effects commonly occurs

early during treatment with escitalopram but is unlikely to
spontaneously remit during continued therapy?
A. Orgasmic dysfunction.
B. Headache.
C. Nausea.
D. Dizziness.
Sexual dysfunction associated with SSRIs has rarely been

shown to attenuate with time. By contrast, headache, nausea,
and dizziness are common initial adverse effects of SSRIs that
usually diminish with time.
9. A 32-year-old man with bipolar disorder has been taking topira-

mate 150 mg/day for 2 months in an effort to counteract a 13.5-kg
weight gain caused by psychotropic drugs. He also has been fol-
lowing the Atkins diet, has begun a program of regular exercise,
and has lost 5 kg in 3 weeks. He calls to report sharp lower back
pain and blood-tinged urine. What is the likely formulation?
A. Lumbosacral strain and probable myoglobinuria from excessive

exercise; he should take an NSAID and, if no better in several
days, contact his internist.
B. Probable nephrolithiasis that may be caused by topiramate,
compounded by hypocitraturia and hypercalciuria from his ke-
togenic diet; he should stop the topiramate and his Atkins diet,
hydrate, and be evaluated for renal calculi.
C. Unclear etiology; discontinue the topiramate and observe for

several days.
D. Likely nephrotic syndrome from possible drug-induced lupus.
The correct response is option B.
Topiramate has an approximate 1% incidence of causing kidney

stones. A high-protein, ketogenic diet can increase renal calcium
excretion, further increasing his risk for the formation of calcium
oxalate renal calculi.
10. You newly begin treating a 61-year-old man with bipolar disor-
der who is on a stable regimen of lithium carbonate 900 mg/day
and divalproex 1,500 mg/day. His medical history is notable for
asthma and diabetes. You notice a bilateral upper-extremity
tremor that appears worse with movement and ask if it is new
and whether it has previously been addressed. He remarks that
he has noticed it for several years but his prior doctor never sug-
gested any type of treatment. What would be the most appro-
priate next steps in management?
A. Ignore the tremor if it does not bother the patient.

B. Measure serum creatinine, lithium, and divalproex levels to as-
sure that the tremor does not reflect toxicity.
C. Begin propranolol 10 mg tid.
D. Begin primidone 100 mg bid or tid.
Tremors associated with either lithium carbonate or divalproex

may be dose-related phenomena; an older adult with diabetes
may have decreased renal clearance of both drugs, and the
tremor should first be assessed as an indicator of possible toxic-
ity. In the absence of an underlying toxicity, treatment of the
tremor with propranolol would be ill advised in the setting of
asthma due to the potential for beta blockade to aggravate pul-
monary function. Primidone may represent a more viable phar-
macological remedy for the tremor, but only after an assessment
for neurotoxicity has occurred.
11. Alopecia has been reported to occur with each of the following
medications except
A. Lithium carbonate.
B. Carbamazepine.
C. Fluoxetine.
D. Modafinil.
Modafinil has not been associated with alopecia, unlike each of

the other choices.
12. Which of the following would be the most appropriate interven-

tion for lower-extremity edema in an otherwise healthy 31-year-
old woman with bipolar disorder who is psychiatrically stable
on lithium monotherapy 900 mg/day with a 12-hour serum lith-
ium level of 0.9 mEq/L?
A. Amiloride 5 mg bid with monitoring of serum potassium.

B. Hydrochlorothiazide 100 mg/day.
C. Reduce lithium by 300 mg/day.
D. Reduce salt intake and increase free water intake.
The potassium-sparing diuretic amiloride is often used to treat

edema caused by lithium. Hydrochlorothiazide incurs a greater
risk for causing elevation of serum lithium levels. Reduction of
oral lithium dose is unlikely to alter the presence of peripheral
edema. Reduction of salt intake would be expected to cause in-
creased reabsorption of lithium by the kidney, resulting in ele-
vated serum lithium levels without remediation of fluid
overload and extravasation of fluid in lower extremities.
13. Paresthesias are commonly associated with which of the follow-

ing anticonvulsants?
A. Gabapentin.
B. Topiramate.
C. Oxcarbazepine.
D. Lamotrigine.
Paresthesias occur with topiramate in about one-third to one-

half of patients at dosages of 50–200 mg/day. They are not asso-
ciated with the other drug choices listed.
14. Predictors of more severe adverse effects caused by placebo in-

clude all of the following except
A. Hypochondriacal features.
B. Phobic and obsessive traits.
C. Severity of depression at baseline.
D. High suggestibility and expectancy about treatment outcomes.
Greater severity of depression at baseline is typically associated

with a lower rate of either benefits or adverse effects with pla-
cebo, whereas each of the other choices has been linked with a
higher incidence of nocebo effects.
15. Patients who identify side-effect burden as a reason for poor ad-
herence to psychotropic medications have been shown from re-
search studies to have all of the following characteristics except
A. Female sex.
B. High baseline somatization.
C. Psychosis.
D. Younger age.
Gender has not been implicated as a contributor to the link be-

tween medication adherence and drug side-effect burden. In the
2000 British National Psychiatric Morbidity Survey, individuals
who linked treatment adherence with medication side-effect
burden were of younger age, had a history of psychosis, and
had lower intellectual functioning. Other reports have found
that depressed patients who have prematurely dropped out of
antidepressant clinical trials due to perceived adverse effects
were more likely to have baseline somatic preoccupations.
16. Interventions that may help to manage dry mouth caused by an-
ticholinergic drugs include all of the following except
A. Glycopyrrolate 1 mg bid.
B. Pilocarpine 20 mg/day.
C. Carboxymethyl cellulose solution.
D. Cevimeline 30 mg/day.
Glycopyrrolate 1 mg bid has been shown to improve sialorrhea

(not xerostomia) caused by several SGAs. Each of the other in-
terventions has been reported as a potential remedy for dry
mouth caused by anticholinergic drugs.
17. A 23-year-old psychotropically naive South African black

woman presents for treatment of social anxiety and generalized
anxiety disorder. She identifies herself as being “especially sen-
sitive” to side effects in general and asks that you prescribe “the
lowest possible dose” of any medication you think appropriate.
One week after beginning paroxetine at 10 mg/day, she calls to
complain of severe nausea, headaches, and dizziness, and asks
for your guidance. What is your impression and recommenda-
tion?
A. Her anxiety is likely exacerbating her sensitivity to side effects;

encourage her to stay with the medication at this dose to over-
come the very problem for which she is seeking treatment.
B. Suspect that her adherence is spotty and she is having with-
drawal symptoms; emphasize to her the importance of regular
daily dosing and full adherence.
C. Recognize that she has a 1 in 5 likelihood of being a poor CYP2D6
metabolizer and is probably supratherapeutic on a paroxetine
dose of 10 mg/day; advise her to lower the dose to 5 mg/day and
reassess after several days.
D. Declare her a “negative therapeutic reactor” and refer her for
more intensive psychotherapy.
South African blacks have a high incidence of the CYP2D6 poor

metabolizer genotype (~29%) and therefore may be especially
sensitive to adverse effects of drugs that are substrates for this
enzyme (which include many psychotropic medications, includ-
ing paroxetine).
18. Insomnia rates reported from FDA registration trials with fluox-
etine or with sertraline are lowest in which of the following dis-
orders?
A. Major depression.
B. Panic disorder.
C. Obsessive-compulsive disorder.
D. Bulimia nervosa.
Both sertraline and fluoxetine have a 16% incidence of insomnia

in FDA registration trials for major depression. Highest rates of
insomnia were seen with fluoxetine in patients with bulimia
nervosa (33%) and with sertraline in patients with obsessive-
compulsive disorder (28%). Sertraline but not fluoxetine is FDA
approved for bulimia nervosa.
19. In studies of aripiprazole for adults with schizophrenia, which

of the following adverse effects demonstrated a dose relation-
ship?
A. Sedation or somnolence.
B. Extrapyramidal adverse effects.
C. Akathisia.
D. Nausea.
In both adult and pediatric trials of aripiprazole for schizophre-

nia (as well as adult trials in acute bipolar mania), sedation or
somnolence was more prominent at higher than lower doses.
No other adverse effects showed a dose relationship in adult
schizophrenia studies. Extrapyramidal side effects and akathi-
sia appeared to be dose related in registration trials of aripipra-
zole in patients with acute bipolar mania and in adolescents
with schizophrenia.
20. All of the following statements regarding skin rashes associated

with lamotrigine are true except
A. Rapid dose escalation is a known risk factor for the emergence

of serious rashes.
B. Systemic steroids are sometimes used to treat serious rashes
soon after their emergence.
C. Lamotrigine should always be immediately discontinued when-
ever any skin rash emerges.
D. Cotherapy with divalproex may increase the risk of rash be-
cause divalproex inhibits the Phase II hepatic metabolism of la-
motrigine.
Rashes that arise during treatment with lamotrigine, as well as

other anticonvulsants, should be carefully evaluated. Serious
rashes are most likely to occur between weeks 2–8 of treatment
and are associated with rapid dose escalations, coadministra-
tion with divalproex, and use in children and adolescents (al-
though the latter two parameters are not contraindications to
lamotrigine therapy). Rashes that cannot likely be explained by
other causes (e.g., acne rosacea, contact dermatitis) or those that
involve soft mucocutaneous tissues generally should prompt
immediate discontinuation of the drug. Prescribers should exer-
cise clinical judgment, which may include dermatological con-
sultation, when deciding about the clinical significance of a
rash, its likely association with lamotrigine or other etiologies,
and the necessity of drug cessation.
21. Identified risk factors for the development of type 2 diabetes

during treatment with SSRIs include which of the following?
A. High baseline body mass index.

B. Lengthy exposure and high dosing.
C. Severity of depression symptoms.
D. Atypical depressive symptoms.
Studies of relative risk for developing type 2 diabetes in associ-

ation with SSRI use have found a lower risk in patients with
shorter drug exposure and the use of lower doses. None of the
other characteristics listed has been linked with SSRI-associated
type 2 diabetes.
22. Sexual dysfunction has been shown to be a dose-related phe-

nomenon with all of the following medications except
A. Fluoxetine.
B. Citalopram.
C. Venlafaxine.
D. Risperidone.
No clear dose relationship has been found between sexual drug

side effects and fluoxetine, in contrast to demonstrated dose-
related sexual dysfunction with citalopram, venlafaxine, and

risperidone.
23. All of the following are more common in women than men except
A. Higher rates of anorgasmia from SSRIs.

B. Greater risk for SSRI-associated osteoporosis.
C. More extensive hyperprolactinemia from antipsychotic medica-
tions.
D. Higher risk of weight gain from olanzapine or risperidone.
The potential for bone demineralization and osteoporosis attrib-

utable to SSRIs appears to be similar in men and women. Each
of the other statements regarding gender differences is true.
24. Which of the following adverse drug effects is usually a tran-

sient phenomenon?
A. Cognitive impairment associated with topiramate.

B. Tremor associated with divalproex.
C. Sexual dysfunction during SSRI therapy.
D. Nausea associated with SSRI initiation.
Nausea is a common, typically transient occurrence after begin-

ning treatment with an SSRI. Adverse cognitive effects associ-
ated with topiramate are diverse and may include attentional
deficits, memory impairment, word-finding difficulties, im-
paired verbal and nonverbal fluency, psychomotor slowing,
and delayed processing speed, sometimes thought to be dose
dependent, and usually persistent until treatment is discontin-
ued. Tremor is often a dose-related phenomenon associated
with the use of divalproex.
25. Which of the following physical signs would be useful in differ-

entiating serotonin syndrome from NMS?
A. Tremor.
B. Clonus.
C. Muscle rigidity.
D. Fever.
Clonus is associated with serotonin syndrome but not NMS.

Muscle rigidity, fever, and tremor may occur in either syn-
drome.
APPENDIX 2
Resources for
Practitioners
Summary of Commonly Reported Adverse Effects

of Psychotropic Agents
Common Psychotropic Drug Interactions
Useful Web Sites
Rating Scales for Measuring Adverse Drug Effects
381
Agent
Buspirone
Bupropion
Duloxetine
Citalopram
Atomoxetine
Desvenlafaxine
Antidepressants
✓
Agitation
Anxiety
Appetite ↑
✓
✓
✓
Appetite ↓
Asthenia
Ataxia
✓
Blurry vision
✓
✓
✓
Constipation
✓
Diarrhea
✓
✓
✓
Dizziness
✓
✓
✓
Dry mouth
EPS and akathisia

Summary of commonly reported adverse effects of psychotropic agentsa
Gastrointestinal upset
✓
✓
Headache
✓
✓
✓
✓
Insomnia
✓
✓
✓
✓
✓
Nausea
✓
✓
✓
✓
✓
✓
Sedation, somnolence, or fatigue
Sexual dysfunction
✓
✓
Sweating
✓
Tachycardia
✓
Tremor
✓
Weight gain
✓
Weight loss
Managing the Side Effects of Psychotropic Medications 382

Agent
Sertraline
Fluoxetine
Paroxetine
Mirtazapine
Nefazodone
Fluvoxamine
Escitalopram
Agitation
✓
Anxiety
✓
Appetite ↑
✓
Appetite ↓
✓
✓
Asthenia
Ataxia
Blurry vision
✓
✓
✓
Constipation
✓
✓
✓ Diarrhea
✓
✓
✓
Dizziness
✓
✓
✓
✓
Dry mouth
EPS and akathisia

✓
✓
✓
✓
✓
✓
Headache
Summary of commonly reported adverse effects of psychotropic agentsa (continued)
✓
✓
✓
✓
✓
Insomnia
✓
✓
✓
✓
✓
Nausea
✓
✓
✓
✓
✓
✓

✓
✓
✓
✓
Sexual dysfunction
✓
Sweating
Tachycardia
✓
Tremor
✓
Weight gain
Weight loss
383 Appendix 2: Resources for Practitioners

Agent
selegiline
Vilazodone
Divalproexb
Transdermal
Venlafaxine XR
Carbamazepine
Anticonvulsants
Agitation
✓
Anxiety
Appetite ↑
Appetite ↓
✓
✓
Asthenia
Ataxia
Blurry vision
Constipation
✓
✓
Diarrhea
✓
✓
✓
Dizziness
✓
Dry mouth
EPS and akathisia
✓
✓
Headache
✓
✓
Insomnia
✓
✓
✓
✓
Nausea
✓
✓
✓

✓
Sexual dysfunction
✓
Sweating
Tachycardia
Tremor
Weight gain
Weight loss

SGAs
Agent
Asenapine
Topiramate
Gabapentin
Lamotrigine
Aripiprazole
Oxcarbazepine
Agitation
✓
✓
Anxiety
Appetite ↑
✓
Appetite ↓
Asthenia
✓
✓
Ataxia
✓
Blurry vision
✓
Constipation
Diarrhea
✓
✓
✓
✓
Dizziness
Dry mouth
✓
EPS and akathisia
✓
✓
Headache
✓
✓
✓
Insomnia
✓
✓
✓
✓
Nausea
✓
✓
✓
✓
✓
Sexual dysfunction
Sweating
Tachycardia
Tremor
Weight gain
Weight loss

Agent
Clozapine
Quetiapine
Lurasidone
Olanzapine
Iloperidone
Paliperidone
SGAs (continued)
Agitation
Anxiety
✓c
Appetite ↑
Appetite ↓
✓
Asthenia
Ataxia
Blurry vision
✓
✓
✓
Constipation
Diarrhea
✓
✓
✓
✓
Dizziness
✓
✓
✓
Dry mouth
✓
✓
✓
EPS and akathisia

✓
✓
Headache
Insomnia
✓
✓
Nausea
✓
✓
✓
✓
✓
✓
Sexual dysfunction
Sweating
✓
✓
✓
Tachycardia
Tremor
Weight gain
Weight loss

Agent
Ziprasidone
Risperidone
Armodafinil
Lisdexamfetamine
Psychostimulants
Methylphenidated
Agitation
Anxiety
Appetite ↑
✓
Appetite ↓
Asthenia
Ataxia
Blurry vision
Constipation
Diarrhea
✓
Dizziness
Dry mouth
✓
✓
EPS and akathisia

✓
✓
Headache
Insomnia
✓
Nausea
✓
✓
Sexual dysfunction
Sweating
Tachycardia
Tremor
Weight gain
Weight loss

388


Sexual dysfunction
EPS and akathisia
Constipation
Blurry vision
Weight gain
Tachycardia
Weight loss
Dry mouth
Appetite ↑
Appetite ↓
Headache
Agitation
Insomnia
Sweating
Dizziness
Asthenia
Diarrhea
Anxiety
Nausea
Tremor
Ataxia
Agent
Psychostimulants (continued)
Mixed ✓ ✓ ✓ ✓
amphetamine
salts
Modafinil ✓ ✓
Note. EPS =extrapyramidal symptoms FDA= U.S. Food and Drug Administration; SGA= second-generation antipsychotic;
XR= extended release.
aAs reported in ≥ 10% of subjects in adult FDA registration trials. Data based on manufacturers’ product information, collectively for all
FDA-approved indications.
bBased on adverse effects reported for divalproex in acute mania.
cIncreased appetite ≥ 10% observed only with quetiapine in 8-week trials for acute bipolar depression.
dIncidence rates are not reported by the manufacturer for adverse events with methylphenidate in FDA registration trials, although nervous-
ness and insomnia are identified as the most common adverse reactions. In pediatric studies of Focalin XR or Concerta, most common adverse
effects were anxiety, insomnia, dry mouth, headache, and loss of appetite, as well as nonspecific gastrointestinal complaints.
Appendix 2: Resources for Practitioners 389
Common psychotropic drug interactions
Drug Clinical effect
Buprenorphine
+ benzodiazepines Postmarketing reports of coma and death.
Carbamazepine
+ cimetidine, erythromycin, Increased carbamazepine levels.
clarithromycin, or
fluconazole
Fluvoxamine
+ alprazolam or diazepam Approximate doubling of alprazolam or
diazepam levels.
+ clozapine Fluvoxamine may cause up to a 500% rise in
serum clozapine levels, increasing risk for
toxicity and seizures.
+ pimozide Increased risk of QTc prolongation.
+ ramelteon Marked increase in Cmax and serum levels of
ramelteon; ramelteon and fluvoxamine
should not be coprescribed.
Lamotrigine
+ carbamazepine Carbamazepine induces Phase II hepatic
glucuronidation, effectively halving the
bioavailability of lamotrigine; lamotrigine
dosing must therefore be doubled during
carbamazepine cotherapy.
+ divalproex Divalproex inhibits Phase II hepatic
glucuronidation, effectively doubling the
bioavailability of lamotrigine and
consequently increasing the risk for serious
drug rashes; lamotrigine dosing must
therefore be halved during divalproex
cotherapy.
+ oral contraceptives Estrogen-containing oral contraceptives can
reduce serum lamotrigine levels by ~50%;
lamotrigine dosages may need to be
increased by as much as 2-fold during oral
contraceptive coadministration; downward
dosing adjustments are generally not
recommended during the “placebo” week of
an oral birth control regimen.
Common psychotropic drug interactions (continued)
Lithium
+ ACE inhibitors (e.g., ramipril, May decrease lithium elimination (causing
lisinopril, enalapril) increased lithium levels) due to decreased
glomerular perfusion pressure.
+ β-blockers May decrease lithium elimination (causing
increased lithium levels) due to decreased
+ excessive caffeine May increase renal lithium elimination
(causing decreased lithium levels) due to
increased glomerular perfusion.
+ first-generation Reports of encephalopathy.
antipsychotics
+ nifedipine or isradipine Coadministration may increase renal lithium
elimination (causing decreased lithium
levels) by altering glomerular perfusion or
reducing proximal tubular reabsorption of
lithium.
+ NSAIDs Can increase serum lithium levels by ~20%
due to increased distal tubule reabsorption;
frequent or long-term use may warrant
reducing lithium dosages accordingly.
+ theophylline May increase renal lithium elimination
(causing decreased lithium levels) due to
increased glomerular perfusion.
+ thiazide diuretics May increase serum lithium levels.
+ topiramate Topiramate may increase serum lithium
levels; may pertain mainly to topiramate
dosages > 200 mg/day.
+ verapamil May decrease lithium elimination (causing
increased lithium levels) due to decreased
Appendix 2: Resources for Practitioners 391
MAOIs
+ buspirone Risk for serotonin syndrome.
+ carbamazepine or Because the tricyclic ring structure of
oxcarbazepine carbamazepine or oxcarbazepine resembles
a TCA, there is a theoretical (but
undemonstrated) potential to induce a
serotonergic or pressor effect; most
practitioners view this as clinically unlikely
and not relevant. An older literature
identified isoniazid-induced elevation of
carbamazepine levels, but this has not been
demonstrated with other MAOIs.
+ general anesthesia Case reports of excitatory reactions (e.g.,
hypertension, hyperreflexia) or increased
CNS depression; however, most
anesthesiologists consider it unnecessary to
discontinue MAOIs before elective surgery.
+ noradrenergic agents Increased risk for hypertensive crisis.
+ opiates Additive potential for sedation;
contraindicated in manufacturer’s product
information materials.
+ SSRIs Risk for serotonin syndrome.
Mirtazapine
+ clonidine Possible opposing actions (clonidine agonizes
presynaptic α2 autoreceptors, while
mirtazapine antagonizes this receptor);
reports of hypertensive urgency when
mirtazapine is added to clonidine.
Olanzapine
Intramuscular olanzapine Reports of excessive sedation,
+ intramuscular cardiopulmonary depression, and death.
benzodiazepine
Quetiapine
+ other drugs that can prolong Additive risk for QTc prolongation and
QTc (e.g., Class IA torsades de pointes.
antiarrhythmics [e.g.,
quinidine], Class III
antiarrhythmics [e.g.,
amiodarone],
fluoroquinolone antibiotics,
methadone, certain other
antipsychotics [e.g.,
ziprasidone, thioridazine])
SSRIs
+ NSAIDs, aspirin, antiplatelet May increase risk for upper GI bleeding by
drugs 8- to 28-fold (Dall et al. 2009).
+ TCAs SSRIs may increase tricyclic blood levels.
+ tramadol Increased risk for seizures, serotonin
syndrome.
+ triptans Increased risk for serotonin syndrome.
Note. ACE=angiotensin-converting enzyme; Cmax=maximal drug plasma
concentration; CNS=central nervous system; GI=gastrointestinal; MAOI=
monoamine oxidase inhibitor; NSAID=nonsteroidal anti-inflammatory drug;
SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant.
Appendix 2: Resources for Practitioners
Useful Web sites
Topic Source Site
Bioequivalence of brand versus generic The U.S. Food and Drug Administration’s “Orange www.accessdata.fda.gov/scripts/
drug formulations Book: Approved Drug Products With Therapeutic cder/ob/default.cfm
Equivalence Evaluations”
Drug interactions Indiana University School of Medicine, Division of www.medicine.iupui.edu/
Clinical Pharmacology, “Drug Interactions” (table clinpharm/DDIs
of CYP drug interactions)
General drug information, dosing, Thomson Reuters Micromedex www.micromedex.com
interactions
Pharmacy tools (renal dosing protocols, GlobalRPh www.globalrph.com
laboratory reference ranges, medical
calculators)
Pregnancy (environmental hazards) REPROTOX information system (developed by the www.reprotox.org
Reproductive Toxicology Center)
Developmental and Reproductive Toxicology http://toxnet.nlm.nih.gov/cgi-bin/
Database (DART) sis/htmlgen?DARTETIC
Pregnancy (lactation) United States National Library of Medicine, http://toxnet.nlm.nih.gov/cgi-bin/
TOXNET Toxicology Data Network, Drugs and sis/htmlgen?LACT
Lactation Database (LactMed)
Pregnancy (teratology information) Organization of Teratology Information Specialists www.otispregnancy.org
(OTIS)
393
394
Rating scales for measuring adverse drug effects
Phenomenon Scale Description
Akathisia Barnes Akathisia Scale (Barnes 1989) 4-item clinician-rated scale assessing objective and
subjective awareness of restlessness, related

distress, and global assessment
Simpson-Angus Extrapyramidal Side Effects Scale 10-item clinician-rated assessment of gait; arm drop;
(Simpson and Angus 1970) stiffness of shoulder, elbow, and wrist; leg swing;
www.outcometracker.org/library/SAS.pdf head drop; glabellar tap; tremor; and
hypersalivation
Antidepressant side effects Toronto Side Effects Scale (Vanderkooy et al. 2002) 29-item self-reported symptom inventory rating
frequency and severity on individual 5-point
subscales
Involuntary movements Abnormal Involuntary Movement Scale 12-item clinician-rated scale assessing orofacial
(including, but not (AIMS; Munetz and Benjamin 1988) movements, extremity and truncal dyskinesias,
exclusively, tardive global severity, incapacitation, patient awareness of
dyskinesia) movements and distress associated with them, and
problems with teeth or dentures
Sexual dysfunction Arizona Sexual Experiences Scale 5-point self-administered scale with each item
(ASEX; McGahuey et al. 2000) ranging from 1 (high) to 6 (none) assessing strength
www.mirecc.va.gov/visn22/Arizona_Sexual_ of sex drive, sexual arousal, penile erections or
Experiences_Scale.pdf vaginal lubrication, ease of orgasm, and orgasmic
satisfaction
Appendix 2: Resources for Practitioners
Rating scales for measuring adverse drug effects (continued)
Phenomenon Scale Description
Sexual dysfunction Changes in Sexual Functioning Questionnaire 36- or 35-item (male or female, respectively)
(continued) (CSFQ; Clayton et al. 1997) semistructured interview or self-report rating
assessing sexual desire/frequency, sexual desire/
interest, sexual pleasure, arousal/excitement, and
orgasm/completion rated via 5-point Likert scale
items
Psychotropic-Related Sexual Dysfunction 7-item self-report measure assessing loss of libido,
Questionnaire (PRSexDQ; Montejo and Rico- delayed orgasm or ejaculation, lack of orgasm or
Villademoros 2008) ejaculation, erectile dysfunction or vaginal
lubrication dysfunction, and tolerance of sexual
dysfunction, with individual items scored from 0
(lowest) to 3 (highest) and total scores ranging from
0 to 15
395
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Index
Page numbers printed in boldface type refer to tables or figures;

those followed by n refer to footnotes.
Abbreviations, xxvii–xxviii Acid-base disturbances, 166–167

Abdominal pain, fibrate-induced, Acne, 148
134 Acne rosacea, 148
Abilify. See Aripiprazole Activated charcoal, for drug
Abnormal Involuntary Movement overdose, 344, 346–347, 350–351,
Scale (AIMS), 252, 253, 254, 394 353–355
Absolute neutrophil count (ANC), Adalat. See Nifedipine
231–232, 233, 234 Adderall. See Mixed amphetamine
Absorption of drug, 47–48, 50 salts
administration route and, 47 Addison’s disease/adrenal
food effects on, 47, 52–55 insufficiency, 166, 176
after gastric bypass surgery, 47 ADH (antidiuretic hormone), 164
gender differences in, 57 syndrome of inappropriate
for long-acting preparations, 50 secretion of, 76, 163–165, 165
Acamprosate, xxix, 241 ADHD (attention-deficit/
Accutane. See Isotretinoin hyperactivity disorder),
ACE inhibitors. See Angiotensin- treatments for, xxxii, 261, 330
converting enzyme inhibitors Adherence to treatment
Acetaminophen, xxix, 22 adverse effects and, xvi, xxiv, 23,
for headache or myalgias, 39–40, 40, 42–43, 361
291–292 nonmedical therapists’ attention
hepatic effects of, 190 to, 107, 108
hyperammonemia induced by Adipex-P. See Phentermine
overdose of, 195 Adiponectin, 299
for hyperthermia, 291 Administration routes for drugs, 47
for joint pain, 240 α1-Adrenergic agonists, xxxii, 58, 89
Acetazolamide, 266 α2-Adrenergic agonists, xxxii, 58, 89,
Acetylation, 50 261, 285. See also Clonidine;
Acetyl-coenzyme A carboxylase Guanfacine
alpha gene variants, 70 β-Adrenergic agonists, xxxv, 58, 90
425
α1-Adrenergic antagonists, 58, 89 Agranulocytosis, drug-induced, 39,

for nightmares, 285–286 231–235
orthostatic hypotension induced resolution after drug cessation,
by, 140, 286 234–235
peripheral edema induced by, 129 specific drugs
α2-Adrenergic antagonists, 58 antipsychotics, 233
urinary retention induced by, 201 carbamazepine, 34, 231, 232
β-Adrenergic antagonists, xxxii, 90 chlordiazepoxide, 235
for akathisia, 39, 114, 243, 245 clozapine, 34, 63, 231, 233, 234
alopecia induced by, 142 diazepam, 235
for clozapine-induced midazolam, 235
myocarditis, 139 mirtazapine, 235
heart rate and blood pressure modafinil, 235
monitoring during treatment treatment of, 234
with, 114 AHA (American Heart Association),
interaction with lithium, 390 34, 121, 122
medical conditions as AIDS. See HIV/AIDS
contraindication to, 7, 114, AIMS (Abnormal Involuntary
269 Movement Scale), 252, 253, 254,
oral lesions induced by, 159 394
peripheral edema induced by, 129 Akathisia, drug-induced, 8, 28, 39,
receptor occupancy and effects of, 58, 106, 243–245, 244, 361, 382–
58 388
for tremor, 114, 269 differential diagnosis of, 8
weight changes induced by, 298 dose relationships and, 30
Adrucil. See 5-Fluorouracil in HIV/AIDS, 73
Advicor. See Lovastatin plus niacin- restless legs syndrome and, 250
ER treatment of, 39, 114, 243, 245
Agitation, 8 Akineton. See Biperiden
benzodiazepines for, 27 Alanine aminotransferase (ALT),
drug-induced, 382–388 189–190
anticonvulsants, 85 Albuterol, xxxii, 58, 90, 240
bupropion, 56 Alcohol use or abuse, 106
chlorambucil, 88 drug interactions with, 60
corticosteroids, 95 carisoprodol, 84
immunosuppressants, 91 insomnia and, 282
quetiapine, 56 intoxication or withdrawal from,
SNRIs, 59 106, 269
SSRIs, 59, 70 nystagmus induced by, 264
stimulants, 100 pancreatitis and, 199
tramadol, 84 rhabdomyolysis and, 242
varenicline, 95 treatments for, xxix
due to MAOI discontinuation, 292 Alexithymia, 17
in serotonin syndrome, 295l, 296 Alkaline phosphatase, 190
Index 427
Allergic drug reactions, 23, 289–290 American Heart Association (AHA),

skin rashes, 145, 146 34, 121, 122
Allopurinol American Urological Association,
alopecia induced by, 142 206, 207
dysgeusia induced by, 158 Amiloride, xxxiii
hepatic effects of, 190 hyponatremia or SIADH induced
Alopecia, drug-induced, 41, 141–142 by, 164
Alprazolam, xxxv for nephrogenic diabetes
cytochrome P450 metabolism insipidus, 204
and, 69 for peripheral edema, 136
disinhibition induced by, 101 Amiodarone, xxix, 89, 120, 392
drug interactions with Amitriptyline, xxx
fluvoxamine, 389 cardiovascular effects of, 121
oral contraceptives, 95 demethylation of, 49
mean half-life and food effects on glycemic dysregulation and
absorption of, 52 diabetes induced by, 173
myalgias induced by, 241 mean half-life and food effects on
ALT (alanine aminotransferase), absorption of, 54
189–190 serum level of, 65
Altace. See Ramipril Amlodipine, xxxii, 240
Aluminum hydroxide, 188 Amlodipine plus atorvastatin, xxxii,
Alzheimer’s disease medications, 135
xxix Ammonia serum level, 191, 195
Amantadine, xxxii Ammonium chloride, 166
for akathisia, 243, 245 Amphetamine, xxxv
for drug-induced sexual alopecia induced by, 141
dysfunction, 223, 229 bruxism induced by, 155
for drug-induced weight gain, cardiovascular effects of, 34
296, 320 cytochrome P450 metabolism
for extrapyramidal symptoms, 39 and, 68
for hyperprolactinemia, 175, 177 for drug-induced cognitive
oculogyric crisis induced by, 265 complaints, 246
psychosis induced by, 102 for drug-induced sedation, 256,
replacing benztropine with, 246 257
for tardive dyskinesia, 251, 254 for drug-induced weight gain,
Ambien. See Zolpidem 315
Amcinonide 0.05%, 151 fasciculations induced by, 264
Amenorrhea, 59, 177 serotonin syndrome and, 296
American Academy of Neurology, for sleep attacks, 278
196 summary of adverse effects of,
American Academy of Sleep 387–388
Medicine, 286 tics induced or exacerbated by,
American Diabetes Association, 171 260
American Epilepsy Society, 196 weight loss induced by, 326, 330
American Headache Society, 296 Amphojel. See Aluminum hydroxide
Amphotericin B, 360 blurry vision induced by, 274

Analgesics, xxix, 84 cognitive effects of, 39, 76, 85, 160,
Anaphylaxis, 152 246
ANC (absolute neutrophil count), delirium induced by, 247, 250
231–232, 233, 234 for dystonia, 342
Anemia, 231 dysuria or urinary retention
assessment and differential induced by, 58, 201
diagnosis of, 236, 237 effect on sleep architecture, 279
drug-induced, 236 for enuresis and urinary
Anergia, 5, 256 incontinence, 202
Anesthesia, interaction with MAOIs, fasciculations induced by, 264
138, 391 for hyperhidrosis, 142–143
Anger. See Hostility/anger lack of efficacy for restless legs
Angina, dobutamine-induced, 58 syndrome, 251
Angioedema, allergic, 289–290 for oculogyric crisis, 266
Angiotensin-converting enzyme receptor occupancy and effects of,
(ACE) inhibitors, xxxi 58
for clozapine-induced for sialorrhea, 160
myocarditis, 139 for urinary incontinence, 202
hepatic effects of, 190 xerostomia induced by, 162
interaction with lithium, 390 Anticholinergic effects of drugs, 41,
oral lesions induced by, 159 58
pancreatitis induced by, 198 Anticoagulants, 142, 235
stomatodynia and, 161 Anticonvulsants, xxx, 85. See also
weight changes induced by, 298 specific drugs
Anhedonia, opiate-induced, 84 cardiovascular effects of, 116
Anion gap, 166 cognitive effects of, 246, 248–249
Anorgasmia, 214, 215, 217, 219, 229. dosing and precautions in
See also Sexual dysfunction hepatic failure, 192
Antiarrhythmic agents, xxix, 89–90 renal disease, 210–211
interaction with quetiapine, 392 effect on sleep architecture, 283
QTc prolongation induced by, 120 generic vs. brand-name
Antibiotics, xxix–xxx, 85–86, 87 formulations of, 61
anemia induced by, 236 headache induced by, 262
drug interactions with hepatic effects of, 10, 11, 34, 189,
carbamazepine, 389 190
quetiapine, 392 hypersensitivity reactions to, 22,
hepatic effects of, 190 290
oral lesions induced by, 159 hyponatremia induced by, 163
paresthesias induced by, 266 insomnia induced by, 258
QTc prolongation induced by, 120 interaction with oral
for skin rashes, 148 contraceptives, 94
Anticholinergic agents, xxx, 39, 85. mean half-life and food effects on
See also specific drugs absorption of, 52
for akathisia, 243, 245 myalgias induced by, 241
Index 429
nystagmus induced by, 265 glycemic dysregulation and

for older adults, 76, 77 diabetes induced by, 173, 175
osteoporosis induced by, 48 headache induced by, 262–263
overdose of, 344–347 hepatic effects of, 189, 190
peripheral edema induced by, hyperhidrosis induced by, 142–
130, 131 143
in pregnancy, 12, 36, 179, 196, 335, hyponatremia or SIADH induced
336–337 by, 163–164
carbamazepine, 336 insomnia induced by, 258, 282
divalproex, 36, 179, 335, 336 mania/hypomania induced by, 27
lamotrigine, 12, 336 SLC6A4 gene polymorphism
topiramate, 337 and, 70
psychiatric side effects of, 85 mean half-life and food effects on
serum level of, 9, 11, 12, 62–63, 64 absorption of, 53–54
SIADH induced by, 76 myalgias induced by, 241
somnolence or sedation induced for older adults, 78–79
by, 258 overdose of, 347–351, 360
suicidality and, 37, 85, 103 overlap between depression
summary of adverse effects of, symptoms and side effects of,
384–385 8, 17
tics induced or exacerbated by, panic attacks induced by, 100
261 parasomnias induced by, 286, 287
for tremor, 269–270 paresthesias induced by, 266, 267
vitamin B12 and folic acid in pregnancy
deficiencies induced by, 196 dosing of, 331
weight changes induced by, 298, fetal growth effects of, 332
305, 306–307 prophylaxis for interferon-α–
Antidepressants, xxx–xxxi. See also induced depression, 92–93
specific drugs and classes rating scale for side effects of, 394
alopecia induced by, 141, 142 receptor occupancy and effects of,
cardiovascular effects of, 116–117 58, 59
cataracts induced by, 274 serum level of, 64–65
cognitive function and, 246, 249 sexual dysfunction induced by,
diarrhea induced by, 187–188 209, 213–214, 215, 220–221
discontinuation syndromes with, pharmacological management
6, 240, 291–292 of, 215, 217–219, 222–228
in newborn, 335 somatization and nonadherence
dosing and precautions in to, 42
hepatic failure, 192–194 somnolence or sedation induced
renal disease, 211–212 by, 258
effect on sleep architecture, 279, suicidality and, 23, 27, 36, 73, 103–
280 104
gastrointestinal bleeding induced gene variants associated with,
by, 188–189, 235, 392 70
Antidepressants (continued) for nightmares, 286

summary of adverse effects of, overdose of, 351, 360
382–384 parasomnias induced by, 287
vivid dreams induced by, 285 receptor occupancy and effects of,
weight changes induced by, 298, 48, 58
308–311, 312, 326 serum levels of, 15, 65
yawning induced by, 270 sexual dysfunction induced by,
Antidepressants, tricyclic (TCAs) 221
acid-base disturbances induced for stomatodynia, 161
by, 166 use in hypertension, 7
alopecia induced by, 142 weight changes induced by, 298,
anticholinergic delirium induced 310, 312
by, 250 Antidiarrheal agents, xxxi
cardiovascular effects of, 48, 113, Antidiuretic hormone (ADH), 164
114, 117, 121 syndrome of inappropriate
orthostatic hypotension, 48, secretion of, 76, 163–165, 165
140 Antidotes for side effects, 39–40, 41
QTc interval prolongation, Antiemetics, xxxi, 120, 197, 198, 291,
117, 120, 121 292
sudden death in children, 115 Antiestrogen agents, xxxi
cataracts induced by, 274 Antifungal agents, xxxi, 86, 120
for children, 115 Antihistamines, xvii, xxxi, 58
constipation induced by, 188 for allergic angioedema, 289
cytochrome P450 metabolism effect on sleep architecture, 279
and, 68, 69 for hives or urticaria, 149
demethylation of tertiary amines, for nausea, 197, 198
49–50 for photosensitivity reactions, 144
dysarthria induced by, 157 for pruritus, 145
effect on sleep architecture, 280 QTc prolongation induced by, 120
electrocardiogram before sedation induced by, 256, 257
initiation of, 113, 115, 121 side effects in older adults, 76
glycemic dysregulation and Antihypertensive agents, xxxi–xxxii,
diabetes induced by, 173 115
hepatic effects of, 190 Antimalarial agents, xxxii, 87
hyperprolactinemia induced by, Antimanic agents, xxxii
176 Antineoplastic agents, xxxii, 91, 360
hypertension induced by, 137 dysgeusia induced by, 158
hyponatremia induced by, 164 hyponatremia or SIADH induced
for insomnia, 282 by, 164
interaction with SSRIs, 392 myelosuppression induced by,
mean half-life and food effects on 234
absorption of, 54 pancreatitis induced by, 199
myoclonus induced by, 264 paresthesias induced by, 266–267
neuroleptic malignant syndrome psychiatric effects of, 86, 88
induced by, 294 QTc prolongation induced by, 120
Index 431
Antioxidants, for tardive dyskinesia, hyperprolactinemia induced by,

251, 252–253 59, 60, 70, 175–178, 180–183
Antiparkinsonian agents, xxxii, 87, hyponatremia induced by, 163,
102. See also Anticholinergic 164
agents interaction with lithium, 247, 250,
bruxism induced by, 155 390
rhabdomyolysis induced by, 290 mortality risk in elderly dementia
vivid dreams induced by, 285 patients, 27, 32, 35, 75–76
Antiplatelet drugs, 189, 235 myalgias induced by, 241
interaction with SSRIs, 392 myelosuppression induced by,
Antipsychotics. See also 233
Antipsychotics, first-generation; neonatal withdrawal from, 338
Antipsychotics, second- neuroleptic malignant syndrome
generation; specific drugs induced by, 267, 294–295, 343
akathisia induced by, 8, 28, 59, oculogyric crisis induced by, 265–
243–245, 244, 250, 251 266
antiemetic properties of, 197 peripheral edema induced by,
body temperature dysregulation 130, 131
induced by, 291 phototoxicity of, 143–144
bruxism induced by, 155, 156 priapism induced by, 206, 207
cardiovascular effects of, 114, 117 for pruritus, 145
dyslipidemias, 14, 60, 70, 123– restless legs syndrome induced
125, 126–127 by, 250, 251
QTc interval prolongation, seizures induced by, 267–268,
118–121, 119 342
sudden cardiac death, 115 sexual dysfunction induced by,
cataracts induced by, 273–274 59, 214–215, 216–217
Clinical Antipsychotic Trials of retrograde ejaculation, 229–230
Intervention Effectiveness treatment of, 229
(CATIE), 33, 124, 127, 173, for steroid-induced mania or
174–175, 214, 216–217, 304 psychosis, 96
cognitive effects of, 58, 59, 246, stuttering and, 157
247, 249 tardive dyskinesia induced by,
delirium and encephalopathy, 251–255
with lithium and, 247, 250 use in HIV/AIDS, 73, 74–75
dopamine D2 receptor occupancy use in seizure disorder, 7
and effects of, 31, 59 Antipsychotics, first-generation
dose relationships and side effects (FGAs), xxxiii. See also
of, 30 Antipsychotics; specific drugs
dysarthria induced by, 157 dystonia induced by, 342
electrocardiogram monitoring of, nondevelopmental stuttering
15, 113, 121 induced by, 157
gender differences in side effects retinopathies induced by, 275
of, 60 for tic disorders, 261
Antipsychotics, second-generation orthostatic hypotension induced

(SGAs), xxxv. See also by, 114, 140
Antipsychotics; specific drugs overdose of, 352–355
adverse effects related to pancreatitis induced by, 198,
combination of, 57 199
allergic angioedema induced by, paresthesias induced by, 266
290 QTc interval prolongation
for apathy/avolition, 102 induced by, 118–121, 119,
cerebrovascular accidents 353–355
associated with, 123 racial differences in side effects
constipation induced by, 188 of, 60
cytochrome P450 metabolism serum level of, 65–66
and, 68, 69 sialorrhea induced by, 159–160
for developmental stuttering, 157 side effects in children, 72
dosing and precautions in somnolence or sedation induced
hepatic failure, 194 by, 259
renal disease, 212–213 sudden cardiac death due to,
dyslipidemias induced by, 14, 115
123–125, 126–127 summary of adverse effects of,
acetyl-coenzyme A 385–387
carboxylase alpha gene for tardive dyskinesia, 254–255
variants and, 70 urinary incontinence induced by,
effect of weight loss on, 313 202
racial differences in, 60 weight gain induced by, 28, 37,
effect on sleep architecture, 279, 298, 298–305, 300–303
281 in children, 72
glycemic dysregulation and correlation with treatment
diabetes mellitus induced by, response, 39, 299
4, 14, 170–173, 174–175 due to appetite stimulation,
hepatic effects of, 189, 190 299
hyperosmolar hyperglycemic management of, 296–297,
nonketotic coma induced by, 312–326
167 lifestyle modification,
hypokalemic hyperglycemic 312–315
nonketotic acidosis induced pharmacological, 315–326,
by, 166 316–317, 320–325
insomnia induced by, 259 weight loss supplements,
laboratory monitoring of, 14–15, 326, 327–329
233 predictors of, 45, 299, 304
mania/hypomania induced by, time course and magnitude of,
23, 99 304
mean half-life and food effects on with Zydis formulations,
absorption of, 54–55 304–305
metabolism of, 67 withdrawal dyskinesias
for nightmares, 285 associated with, 22, 255–256
Index 433
Antiretroviral agents, xxxiii, 73–74, Aphthous ulcers, 158

87–89 Aplastic anemia, drug-induced, 236
drug interactions with, 73–74 carbamazepine, 9, 232
macrocytic anemia induced by, 236 emergency management of, 341
paresthesias induced by, 267 Apo-Hydro. See
Antispasmodics, xxxiii Hydrochlorothiazide
Antithyroid antibodies, 185 Appetite changes. See also Weight
Anxiety. See also Panic gain; Weight loss
cardiac effects of, 115 drug-induced, 382–388, xvii
differentiating akathisia from, 8 bupropion, 56
drug-induced, 100, 382–388 m-chlorophenylpiperazine, 59
antimalarial agents, 87 evaluation of, 330
azathioprine, 91 SGAs, 299
bupropion, 100 placebo-induced, 18
corticosteroids, 95 Aralen. See Chloroquine
efavirenz, 88 Area under the curve (AUC), 49
idazoxan, 58 L -Arginine glutamate, 217, 219
immunosuppressants, 91, 92 Aricept. See Donepezil
opiates, 84 Aripiprazole, xxxv
oral contraceptives, 93 akathisia induced by, 244, 244
phentolamine, 58 cardiovascular effects of, 119
stimulants, 100 for developmental stuttering, 157
tramadol, 84 dose relationships and side effects
yohimbine, 58 of, 30
due to MAOI discontinuation, 292 drug interactions with, 57
nocebo phenomenon and, 18 for drug-induced sexual
nonmedical therapists’ dysfunction, 223
perception of, 106 for drug-induced weight gain,
placebo-induced, 18 296, 320, 326
stomatodynia and, 161 dyslipidemias induced by, 126
Anxiolytics, xxxii. See also specific effect on prolactin level, 175, 176,
drugs 177, 180
cardiovascular effects of, 117 effect on sleep architecture, 281
dosing and precautions in glycemic dysregulation and
hepatic failure, 193 diabetes induced by, 174
renal disease, 210 for hyperhidrosis, 143
effect on sleep architecture, 280 insomnia induced by, 259
electrocardiogram changes with, mean half-life and food effects on
117 absorption of, 54
mean half-life and food effects on metabolic syndrome induced by,
absorption of, 52 173
overdose of, 352 metabolism of, 67
Apathy, SSRI–induced, 101–102 mortality risk in elderly dementia
APCs (atrial premature complexes), patients, 75
114–115 myalgias induced by, 241
Aripiprazole (continued) Artane. See Trihexyphenidyl

orally dissolving formulation of, Asenapine, xxxv
48 akathisia induced by, 244
for SSRI–induced apathy, 102 allergic angioedema induced by,
serum level of, 65 290
sexual dysfunction induced by, cardiovascular effects of, 119
215, 216 cytochrome P450 metabolism
somnolence or sedation induced and, 68
by, 259 dosing and precautions in
summary of adverse effects of, 385 hepatic failure, 194
for tardive dyskinesia, 255 renal disease, 212
tardive dyskinesia induced by, 251 dyslipidemias induced by, 126
weight changes induced by, 298, effect on prolactin level, 176, 180
300 effect on sleep architecture, 281
in children, 72 glycemic dysregulation and
withdrawal dyskinesias diabetes induced by, 174
associated with, 255 insomnia induced by, 259
Aristocort cream. See Triamcinolone interaction with fluvoxamine, 50
acetonide mean half-life and food effects on
Arizona Sexual Experiences Scale absorption of, 54
(ASEX), 209, 224, 227, 394 metabolism of, 67
Armodafinil, xxxiv, 62 overdose of, 352
for drug-induced cognitive serum level of, 65
complaints, 246, 247 sexual dysfunction induced by,
for drug-induced sedation, 256, 216
257 somnolence or sedation induced
lack of efficacy for drug-induced by, 259
weight gain, 315 summary of adverse effects of,
for sleep apnea, 282 385
for sleep attacks, 277, 278 weight changes induced by, 298,
summary of adverse effects of, 300
387 Aseptic meningitis, lamotrigine-
switching from stimulant drug to, induced, 290, 342
326 ASEX (Arizona Sexual Experiences
Aromatase inhibitors, 88 Scale), 209, 224, 227, 394
Arrhythmias, 113–122. See also Asparaginase, 88, 199
Cardiovascular effects; specific Aspartate aminotransferase (AST),
arrhythmias 189–190
considerations for evaluation of, Aspiration pneumonia, 76
114–115 Aspirin
induced by weight loss pruritus induced by, 145
supplements, 328, 329 SSRI–induced gastrointestinal
QTc interval prolongation, 118– bleeding with use of, 189,
122, 119, 120 235, 392
sudden cardiac death due to, 115 Assessment of side effects, 43–45
Index 435
AST (aspartate aminotransferase), Atorvastatin plus amlodipine, xxxii,

189–190 135
Astemizole, 120 ATP III Panel (National Cholesterol
Asthenia Education Program Expert
drug-induced, 382–388 Panel on Detection, Evaluation,
placebo-induced, 18 and Treatment of High Blood
Asthma, β-blockers contraindicated Cholesterol in Adults), 124, 129
in, 7, 269 Atrial premature complexes (APCs),
Atarax. See Hydroxyzine 114–115
Ataxia Atrioventricular block
drug-induced, 382–388 β-blockers contraindicated in, 269
dose relationships and, 30 drug-induced
gabapentin, 77 clonidine, 58
in serotonin syndrome, 295 guanfacine, 58
tremor and, 269 lurasidone, 117
Atenolol, xxxii, 58 Atromid-S. See Clofibrate
Ativan. See Lorazepam Atrovent spray. See Ipratropium
Atomoxetine, xxxii bromide
cognitive function and, 248 Attention-deficit/hyperactivity
cytochrome P450 metabolism disorder (ADHD), 261, 330
and, 68 treatments for, xxxii
dosing and precautions in Attribution and causality of side
hepatic failure, 192 effects, 21–23, 24–25, 43–44
renal disease, 210 AUC (area under the curve), 49
headache induced by, 262 Aurorix. See Moclobemide
hypertension induced by, 137 Autonomic instability, in neuroleptic
mean half-life and food effects on malignant syndrome, 294
absorption of, 52 Avelox. See Moxifloxacin
myalgias induced by, 241 Axid. See Nizatidine
for older adults, 77 Azathioprine, xxxiii, 91, 92, 293
orthostatic hypotension induced Azidothymidine (AZT), xxxiii, 89
by, 140 Azithromycin, xxix, 120
overdose of, 344 AZT (azidothymidine), xxxiii, 89
sexual dysfunction induced by,
220 Baclofen, 254, 264
suicidality and, 36 Bacterial rashes, 148
summary of adverse effects of, Bactrim. See Trimethoprim-
382 sulfamethoxazole
switching from stimulant drug to, Barbiturates, 195
326, 330 Barnes Akathisia Scale, 394
tics induced or exacerbated by, Basiliximab, xxxiii, 92
261 Benadryl. See Diphenhydramine
weight changes induced by, 298 Benign prostatic hyperplasia, 89, 201,
Atopic dermatitis, 148, 152 202
Atorvastatin, xxxiv, 125, 132 Bentyl. See Dicyclomine
Benzodiazepines, xxxv for oculogyric crisis, 266

abrupt discontinuation of, 101 receptor occupancy and effects of,
abuse potential of, 285 58
agranulocytosis induced by, 235 replacing with amantadine, 246
for akathisia, 39, 243, 245 for sialorrhea, 160
for antipsychotic-associated Betamethasone dipropionate, 151
withdrawal dyskinesias, 256 Betapace. See Sotalol
for bruxism, 155, 156 Betaxolol, xxxii, 245
cardiovascular effects of, 117 Bethanechol, xxxiii, 188
cognitive effects of, 246, 249, 282, for drug-induced sexual
285 dysfunction, 223
disinhibition induced by, 101 for urinary retention, 201, 202
in older adults, 76 Bigeminy, 115
dosing and precautions in renal Bioavailability of drug, 47, 49
disease, 212 food effects on, 52–55
drug interactions with for generic vs. brand-name drugs,
buprenorphine, 389 60–61, 393
olanzapine, 391 Biotene Oral Balance Gel, 162
oral contraceptives, 95 Biperiden, xxxii
dysarthria induced by, 157 for sialorrhea, 160
effect on sleep architecture, 280 for tardive dyskinesia, 254
for insomnia, 27, 282, 284, 284–285 Bipolar disorder. See also Mania
mean half-life and food effects on adherence to pharmacotherapy
absorption of, 52 for, 42
myalgias induced by, 241 antidepressant-induced mania/
nystagmus induced by, 264 hypomania in, 97–98, 99
for oculogyric crisis, 265, 266 diabetes mellitus and, 170–171
for older adults, 76 insomnia in, 278, 282
overdose of, 352 nocebo phenomenon in, 18
for restless legs syndrome, 250, relapse after rapid lithium
251 cessation, 101
sexual dysfunction induced by, risk-benefit analysis of
218 maintenance treatments for,
for tic disorders, 261 37
withdrawal from, 269, 285 treatment in medically ill
Benzoyl peroxide, 148 patients, 5
Benztropine, xxx underdosing of mood stabilizers
adverse effects of, 39 for, 42–43
for akathisia, 243 Bismuth subsalicylate, xxxiii, 187,
constipation induced by, 188 188, 197
for dystonia, 342 Black box warnings, 3n, 32, 34–36,
for enuresis and urinary 71n, 75, 76, 83n, 95, 97n, 103,
incontinence, 202 113n, 118, 122, 139, 141n, 152,
for extrapyramidal side effects, 27 153, 187n, 190, 193, 198, 231n,
for hyperhidrosis, 142–143 232, 233, 243n, 267, 289n
Index 437
Bleeding disorders lithium, 116

drug-induced, 235–236 MAOIs, 121
gastrointestinal, 188–189, 195, metoprolol, 58
235, 392 modafinil, 58
inherited, 236 phenylephrine, 58
Blepharospasm, 261, 263–264 propranolol, 269
β-Blockers. See β-Adrenergic TCAs, 117
antagonists Brain metastases, 6
Blood pressure monitoring, 137, 140. Brain-derived neurotrophic factor,
See also Hypertension; 246
Hypotension Branched-chain amino acids, for
Blurry vision. See Vision problems tardive dyskinesia, 254
BMI. See Body mass index Brand-name vs. generic drugs, 60–
Body dysmorphic disorder, 80 61, 393
Body mass index (BMI) Breast cancer, 6, 86, 88
metabolic monitoring, 171 Breast-feeding and psychotropic
metabolic syndrome, 128 drug use, 332, 393
weight changes and, 303 Brethine. See Terbutaline
weight gain and, 298, 299, 304 Bricanyl. See Terbutaline
weight loss and, 317, 321, 322, British Manic Depression
325, 327, 329 Fellowship, 42
Body temperature dysregulation, British National Psychiatric
antipsychotic-induced, 291 Morbidity Survey, 40, 42
Body weight. See also Weight gain; Bromocriptine, 102
Weight loss for drug-induced sexual
drug-associated changes in, 298, dysfunction, 229
382–388 for hyperprolactinemia, 175, 177,
weight gain, 286–326, 300–303, 178
306–311, 361 Bronchodilators, xxxii
weight loss, 326, 330 Brugada pattern on
ideal, 297 electrocardiogram, drug-
Bone demineralization induced, 116
depression and, 170 Bruxism, 155–156, 156, 286
drug-induced, 48, 169–170 Buprenorphine, xxxiv, 84
Boston Collaborative Drug drug interactions with
Surveillance Program, 96 benzodiazepines, 389
Botulinum toxin injections, for methadone, 57
bruxism, 155, 156 Buprenorphine plus naloxone, xxxiv
Bradycardia Bupropion, xxx
β-blockers contraindicated in, 7 adverse effects of short- vs. long-
drug-induced acting preparations of, 56
atenolol, 58 agitation induced by, 56
clonidine, 58 allergic angioedema induced by,
divalproex, 116 290
guanfacine, 58 anxiety induced by, 100
Bupropion (continued) somnolence or sedation induced

appetite suppression induced by, by, 258
56 summary of adverse effects of,
for atopic dermatitis and 382
psoriasis, 152 tics induced or exacerbated by,
cardiovascular effects of, 116 261
cognitive function and, 249 tinnitus induced by, 268
constipation induced by, 188 vivid dreams induced by, 285
cytochrome P450 metabolism weight changes induced by, 298,
and, 68 308, 312, 326, 330
dermatological effects of, 150, Burning mouth syndrome, 161
340 Buspar. See Buspirone
dose relationships and side effects Buspirone, xxxii
of, 30 bruxism and, 155, 156
dosing and precautions in hepatic cognitive function and, 248
failure, 192 cytochrome P450 metabolism
for drug-induced sexual and, 69
dysfunction, 209, 217, 218– dosing and precautions in
219, 224 hepatic failure, 193
for drug-induced weight gain, renal disease, 210
318 for drug-induced sexual
combined with naltrexone, 318 dysfunction, 225
combined with zonisamide, dysarthria induced by, 157
318 effect on sleep architecture, 280
effect on sleep architecture, 280 electrocardiogram changes with,
headache induced by, 262 117
hypertension induced by, 137, 138 headache induced by, 262
hyponatremia induced by, 163 interaction with MAOIs, 391
insomnia induced by, 258, 282 mean half-life and food effects on
mean half-life and food effects on absorption of, 52
absorption of, 53 for older adults, 77
myalgias induced by, 241 overdose of, 344, 352
for older adults, 78 serotonin syndrome and, 296
overdose of, 347 sexual effects of, 220
in pregnancy, 332 summary of adverse effects of,
priapism induced by, 206, 207 382
psychosis induced by, 102 for tardive dyskinesia, 254
seizure disorder as tinnitus induced by, 268
contraindication to, 7 weight changes induced by, 298
seizures induced by, 29, 267
for SSRI–induced restless legs Caduet. See Amlodipine plus
syndrome, 251 atorvastatin
serum level of, 64 Caffeine
sexual dysfunction induced by, arrhythmias and, 115
215, 220 insomnia and, 282
Index 439
interaction with lithium, 390 hepatic effects of, 10, 190

to promote weight loss, 327 hyperammonemia induced by,
with green tea catechins, 329 191, 195
tremor and, 269 hyperprolactinemia induced by,
Calan. See Verapamil 176
Calcimimetics, xxxiii hypersensitivity reaction to, 290
Calcipotriene cream, 149 hyponatremia induced by, 163
Calcium hypothyroidism induced by, 185,
for leg cramps, 240 186
pancreatitis induced by, 198 insomnia induced by, 258
Calcium channel blockers, xxxii, 129, laboratory monitoring of, 9–10,
142, 176, 250 232
Campral. See Acamprosate for leg cramps, 240
Canker sores, 158 lupus erythematosus induced by,
Cannabinoids/cannabis, 140, 242 293
Capex shampoo. See Fluocinolone mean half-life and food effects on
acetonide absorption of, 52
Carbamazepine, xxx medical conditions as
alopecia induced by, 141 contraindication to, 7
during breast-feeding, 332 myalgias induced by, 241
cardiovascular effects of, 116 nystagmus induced by, 265
cognitive effects of, 248 oculogyric crisis induced by,
colitis induced by, 188 265
cytochrome P450 metabolism for older adults, 77
and, 69 oral lesions induced by, 159
dermatological effects of, 34, 149, osteoporosis induced by, 169
150, 152–153, 340 overdose of, 344
dosing and precautions in serum level of, 9, 63, 64
hepatic failure, 192 somnolence or sedation induced
renal disease, 210 by, 258
drug interactions with for steroid-induced mania, 96
antimicrobial agents, 389 suicidality and, 103
antiretroviral agents, 74 summary of adverse effects of,
lamotrigine, 12, 389 384
MAOIs, 391 teratogenicity of, 336
oral contraceptives, 94 tics induced or exacerbated by,
dysgeusia induced by, 158 261
effect on body weight, 298, 305, 306 for tinnitus, 268
effect on sleep architecture, 283 use in HIV/AIDS, 73
epoxide metabolite of, 48, 51, 232 vitamin B12 and folic acid
generic vs. brand-name deficiencies induced by, 196
formulations of, 61 Carbamazepine-10,11-epoxide, 48,
headache induced by, 262 51, 232
hematological effects of, 9, 34, Carbohydrate-deficient transferrin,
231, 232, 340, 341 190
Carbonic anhydrase inhibitors, 166, lorazepam, 117

266 MAOIs, 138, 140
Cardiac malformations, drug- methylphenidate, 34
induced, 336, 337 mirtazapine, 116
Cardiomyopathy, antipsychotic- modafinil, 58, 115
induced, 122, 139 phentolamine, 58
Cardiovascular drugs, 89–90 phenylephrine, 58
Cardiovascular effects phosphodiesterase type 5
of drugs, 113–140 inhibitors, 217–218
arrhythmias and palpitations, SNRIs, 116, 140
113–122 SSRIs, 116
QTc interval prolongation, stimulants, 34, 113, 115, 117,
118–122, 119, 120 122
sudden cardiac death, 115 TCAs, 48, 113, 114, 115, 117,
cardiomyopathy, 122, 139 121, 140
cerebrovascular accidents, vitamin E, 251, 252–253
122–123 yohimbine, 58
due to drug overdose, 339 sudden cardiac death, 115
dyslipidemias, 123–129, of weight loss supplements,
126–128, 130, 132–135 328–329
hypertension, 137–138 Cardura. See Doxazosin
hypertensive crisis Carisoprodol, xxxiv, 84, 240
management, 340 L -Carnitine
myocarditis, 122, 139 for hyperammonemia, 191, 195
orthostatic hypotension, 140 to promote weight loss, 327
pericarditis, 122 Carnitine depletion, divalproex-
peripheral edema, 129–131, induced, 11, 195
136, 136–137 Cataplexy, 277
specific drugs Catapres. See Clonidine
amphetamine, 34 Cataracts, 273–274
anticholinergic agents, 113 Catatonia
antipsychotics, 15, 30, 35, anticonvulsant-induced, 85
113, 115, 117, 118–121, malignant, 295
119, 139 CATIE (Clinical Antipsychotic Trials
α1-blockers, 58, 140 of Intervention Effectiveness),
bupropion, 116 33, 124, 127, 173, 174–175, 214,
carbamazepine, 116 216–217, 304
clonidine, 58 Causality and attribution of side
clozapine, 35, 122, 139 effects, 21–23, 24–25, 43–44
divalproex, 116 Celexa. See Citalopram
dobutamine, 58 CellCept. See Mycophenolate mofetil
guanfacine, 58 Cerebrovascular events, 122–123
idazoxan, 58 induced by weight loss
lamotrigine, 116 supplements, 328
lithium, 116 Cetirizine, xxxi, 145
Index 441
Cevimeline, for xerostomia, 162 Cimetidine, xxxiii, 91

Changes in Sexual Functioning interaction with carbamazepine,
Questionnaire (CSFQ), 209, 395 389
Chantix. See Varenicline Cinacalcet, xxxiii
Chemo brain, 86 Cipro. See Ciprofloxacin
Child-Pugh classification of hepatic Ciprofloxacin, xxix, 87, 120
disease, 73, 74, 191 Cirrhosis, 131, 189, 190. See also
Children and adolescents, 72–73, 360 Hepatic disease
antidepressants and suicidality Cissus quadrangularis (CQ), to
among, 27, 36, 73, 103–104 promote weight loss, 327
Chloral hydrate, for insomnia, 284 combined with Irvingia gabonensis
Chlorambucil, xxxii, 88 (CQ-IG), 327
Chlordiazepoxide, xxxv Citalopram, xxx
agranulocytosis induced by, 235 apathy induced by, 102
dosing and precautions in renal cardiovascular effects of, 116, 120,
disease, 212 121
interaction with oral cytochrome P450 metabolism
contraceptives, 95 and, 68, 69
m-Chlorophenylpiperazine dose relationships and side effects
(m-CPP), 59 of, 30, 31
Chloroquine, xxxii, 87 dosing and precautions in renal
Chlorpromazine, xxv, xxxiii disease, 211
dermatological effects of, 150 electrocardiogram monitoring of,
lupus erythematosus induced by, 116, 121
293 gastrointestinal bleeding induced
phototoxicity of, 144 by, 235
pigmentary retinopathy induced generic vs. brand-name
by, 275 formulations of, 61
seizures induced by, 268 glutamatergic gene variants and
Cholelithiasis, 124 sexual dysfunction induced
Cholinergic agonists, xxxiii by, 70
Cholinergic M1 receptors, 58 headache induced by, 262
Cholinesterase inhibitors. See also hyponatremia induced by, 164
specific drugs insomnia induced by, 258
for drug-induced cognitive mean half-life and food effects on
complaints, 247 absorption of, 53
pancreatitis induced by, 198 myalgias induced by, 241
for tardive dyskinesia, 253 overdose of, 347
Chorea, 260 priapism induced by, 207
Chromium picolinate, to promote prophylaxis for interferon-α–
weight loss, 327 induced depression, 92
Chronic obstructive pulmonary restless legs syndrome induced
disease, β-blockers by, 250
contraindicated in, 7 sexual dysfunction induced by,
Cialis. See Tadalafil 214, 220, 225
Citalopram (continued) mean half-life and food effects on

sexual dysfunction induced by absorption of, 52
(continued) myalgias induced by, 241
persistence after drug for myoclonus, 264
cessation, 229 for oculogyric crisis, 266
somnolence or sedation induced for sleep disturbances, 282
by, 258 stomatodynia and, 161
summary of adverse effects of, Clonidine, xxxii, 58, 89, 240
382 for antipsychotic-associated
weight changes induced by, 308 withdrawal dyskinesias, 256
yawning induced by, 270 for hyperhidrosis, 142, 143
Citrus aurantium, to promote weight interaction with mirtazapine, 391
loss, 328 lupus erythematosus induced by,
Clarithromycin, xxix, 120 293
interaction with carbamazepine, myalgias induced by, 241
389 for nightmares, 285
Claritin. See Loratadine sedation induced by, 58, 89, 143
Clastogenic effects of chromium for sialorrhea, 161
picolinate, 327 for tic disorders, 261
Cleft lip/palate, anticonvulsant- Clorazepate, xxxv, 240
induced, 336, 337 Clotrimazole, 149, 150
Clinical Antipsychotic Trials of Clozapine, xxxv, 5
Intervention Effectiveness akathisia induced by, 244, 244
(CATIE), 33, 124, 127, 173, cardiovascular effects of, 119, 122
174–175, 214, 216–217, 304 myocarditis, 35, 122, 19
Clinical trials combined with fluvoxamine, 125
extrapolating findings to real- cytochrome P450 metabolism
world patients, 26–28, 40 and, 68
subjects with psychiatric illness dose relationships and side effects
in, 100 of, 30
Clitoral priapism, drug-induced, dyslipidemias induced by, 124,
207 125
Clobetasol propionate 0.05%, 151 effect on prolactin level, 176, 180
Clofibrate, xxxiv, 134, 164 effect on sleep architecture, 281
Clomipramine enuresis and urinary incontinence
mean half-life and food effects on induced by, 202, 203
absorption of, 54 genetic variations and side effects
sexual dysfunction induced by, of, 63
225 glycemic dysregulation induced
Clonazepam, 22 by, 172
for akathisia, 245 hematological effects of, 34, 63,
for bruxism, 155, 156 139, 231, 233, 234, 341
disinhibition induced by, 101 insomnia induced by, 259
dosing and precautions in renal interaction with fluvoxamine, 50,
disease, 212 125, 319, 389
Index 443
laboratory monitoring of, 10, 233, anticholinergic agents, 39, 76,

234 85, 160, 246
medical conditions as anticonvulsants, 246, 248–249
contraindication to, 7 antineoplastic agents (chemo
myalgias induced by, 241 brain), 86
oculogyric crisis induced by, 265, antipsychotics, 58, 59, 246, 247,
266 249
pancreatitis induced by, 198 benzodiazepines, 246, 249, 282,
phototoxicity induced by, 144 285
in pregnancy, 332 diphenhydramine, 58
priapism induced by, 207 lithium, 248
to reduce suicide risk, 360 TCAs, 48, 58
seizures induced by, 29, 35, 267– factors contributing to, 246
268 in HIV/AIDS, 73
serum level of, 10, 66, 125 management of, 246–247
sexual dysfunction induced by, in serotonin syndrome, 295
215 Cohen’s d, 38
retrograde ejaculation, 229 Colchicine, 142
sialorrhea induced by, 159–160 Cold extremities, drug-induced,
somnolence or sedation induced 58
by, 259 Collaborative treatment, 105–109
stuttering induced by, 157 Combination drug therapy, 4, 57
summary of adverse effects of, Communication
386 with patients about possible side
tardive dyskinesia and, 251, 255 effects, 42, 44–45, 361–362
weight gain induced by, 60, 63, between psychiatrist and
298, 300 nonmedical therapist,
in children, 72 105–109
due to appetite stimulation, 299 for shared decision-making with
pharmacological management patients, 33
of, 319 Compazine. See Prochlorperazine
predictors of, 304 Computed tomography (CT), 6
Clozaril. See Clozapine Concerta. See Methylphenidate
Cmax (maximal blood concentration Confusion
of drug), 47–48, 49, 50 drug-induced
Coal tar, for psoriasis, 149 L-asparaginase, 88
Cocaine, 242 chlorambucil, 88
Cockcroft-Gault equation, 205 in serotonin syndrome, 295
Coding Symbols for a Thesaurus of in SIADH, 164
Adverse Reaction Terms Conjugation reactions, 50
(COSTART), 27 Constipation, drug-induced, 41, 188,
Cogentin. See Benztropine 382–388
Cognitive complaints, xix, 245–247 anticholinergic agents, 58
drug-induced, 41, 43, 245–247, dose relationships and, 30
248–249 management of, 188
Contact dermatitis, 146, 148 Creatinine serum level, 205, 208

pruritic, 145 Crestor. See Rosuvastatin
Continuous positive airway pressure CRP (C-reactive protein), 35, 128,
(CPAP), 282 132, 139
Controlled-release drug CSFQ (Changes in Sexual
preparations, 50 Functioning Questionnaire),
Conversion disorder, 80 209, 395
Cordarone. See Amiodarone Css (steady-state concentration of
Cordran. See Flurandrenolide 0.05% drug), 49
Corticosteroids, 86, 91, 95–96 CT (computed tomography), 6
for allergic angioedema, 289 Cutaneous drug reactions. See
cataracts induced by, 274 Dermatological effects of drugs
for clozapine-induced Cutivate. See Fluticasone propionate
myocarditis, 139 Cyclobenzaprine, xxxiv, 120, 156
for drug-induced lupus Cyclocort. See Amcinonide 0.05%
erythematosus, 293 Cyclophosphamide, for drug-
myalgias or rhabdomyolysis induced lupus erythematosus,
induced by, 242 293
for photosensitivity reactions, Cyclosporine, xxxiii, 92, 199
144 Cymbalta. See Duloxetine
for skin rashes, 146, 148–150 CYP. See Cytochrome P450
topical, 144, 146, 151 enzymes
Cortisol, for nightmares, 286 Cyproheptadine, xxxi
COSTART (Coding Symbols for a for diarrhea, 188
Thesaurus of Adverse Reaction for drug-induced sexual
Terms), 27 dysfunction, 217, 225
CPAP (continuous positive airway for hyperhidrosis, 143
pressure), 282 for iatrogenic yawning, 271
m-CPP (m-chlorophenylpiperazine), for nightmares, 285
59 Cystatin C, 205
CQ (Cissus quadrangularis), to Cytochrome P450 (CYP) enzymes,
promote weight loss, 327 48, 49
CQ-IG (Cissus quadrangularis plus drug interactions related to, 50,
Irvingia gabonensis), to promote 74
weight loss, 327 drug metabolizer phenotypes
Cranial nerves controlling speech and, 66–70, 68–69, 72
and phonation, 157, 158 gender differences in activity of,
CrCl (creatine clearance), 77, 60
205–206, 208, 210–213 in pregnancy, 331
C-reactive protein (CRP), 35, 128, racial differences in, 60
132, 139 Roche AmpliChip microarray test
Creatine clearance (CrCl), 77, for variants of, 70
205–206, 208, 210–213 substrates, inhibitors, and
Creatine phosphokinase, 294 inducers of, 68–69
Creatinine kinase, 205 Cytosolic aldehyde oxidase, 67
Index 445
Dalmane. See Flurazepam Depression

Dantrolene, for neuroleptic bipolar, 8
malignant syndrome, 294 bone loss and, 170
DART (Developmental and differentiating drug adverse
Reproductive Toxicology effects from symptoms of, 8,
Database), 393 17, 28
DDAVP (desmopressin intranasal drug-induced
spray), xxxiii, 202, 203 amiodarone, 89
Decision-making antibiotics, 85, 87
about when to pursue antidotes L-asparaginase, 88
and when to switch β-blockers, 90
medicines, xvii, 39–40, 41 clonidine, 89
sharing with patients, 33 corticosteroids, 95
Dehydroepiandrosterone (DHEA), digitalis, 90
219 efavirenz, 88
Delirium histamine H2 blockers, 91
after abrupt benzodiazepine interferon-α, 92–93
withdrawal, 101 interleukin-2, 88
drug-induced, 247, 250 isotretinoin, 90
anticholinergic agents, 247, 250 Nuva-Ring, 95
corticosteroids, 95 oral contraceptives, 93–94
digitalis, 90 tamoxifen, 88
opiates, 84 topiramate, 85
tacrolimus, 92 tramadol, 84
due to MAOI discontinuation, varenicline, 95
292 zonisamide, 85
in neuroleptic malignant insomnia in, 278, 279
syndrome, 294 nocebo phenomenon in, 18
Delusional parasitosis, 144 parasomnias in, 287
Delusions, 23 relapse after rapid antidepressant
Demeclocycline, for hyponatremia, cessation, 101
163, 165 stomatodynia and, 161
Dementia treatment in medically ill
antipsychotic-related risks in patients, 5
cerebrovascular accidents, 123 treatment-resistant, opiates for, 84
mortality in elderly patients, Derma-Smoothe/FS. See
27, 32, 35, 75–76 Fluocinolone acetonide
use of anticholinergic agents in, Dermatillomania, 144
85 Dermatological agents, 90–91
Demethylation, 49 Dermatological effects of drugs, xvi,
Dental guards, for bruxism, 155 xix, 4–5, 22, 23, 39, 41, 141–154
Depakene; Depakote. See Divalproex allergic reactions, 145, 146, 289–
Depersonalization, drug-induced 290
antimalarial agents, 87 alopecia, 41, 141–142
zolpidem, 102 dose relationships and, 30
Dermatological effects of drugs diarrhea induced by, 188

(continued) dose relationships and side effects
hyperhidrosis, 142–143 of, 30
oral mucosal lesions, 158–159 dosing and precautions in
photosensitivity, 143–144 hepatic failure, 194
pruritus, 144–145 renal disease, 211
skin rashes, 145, 147–150, 152–154 headache induced by, 262
emergency management of, 340 hypertension induced by, 138
specific drugs insomnia induced by, 62, 258
bupropion, 150, 340 mean half-life and food effects on
carbamazepine, 34, 149, 150, absorption of, 53
152–153, 340 for older adults, 78
chlorpromazine, 150 orthostatic hypotension induced
divalproex, 150 by, 140
lamotrigine, 34, 45, 50, 150, overdose of, 348
152, 153–154, 340 paresthesias induced by, 266
in children, 72 serum level of, 65
lithium, 148, 149 sexual dysfunction induced by,
modafinil, in children, 152, 154 62, 219, 220
niacin, 134 somnolence or sedation induced
venlafaxine, 150 by, 258
Dermatop. See Prednicarbate 0.05% summary of adverse effects of, 382
Desipramine, xxx, 49 weight changes induced by, 298,
for children with attention- 308, 330
deficit/hyperactivity Desyrel. See Trazodone
disorder and tics, 261 Detrol. See Tolterodine
mean half-life and food effects on Developmental and Reproductive
absorption of, 54 Toxicology Database (DART),
neuroleptic malignant syndrome 393
induced by, 294 Dexamethasone, 86
serum level of, 65 Dexedrine. See Amphetamine
sudden death in children Dexmethylphenidate, 61
associated with, 115 Dextromethorphan, interaction with
Desmethylimipramine, 49. See also MAOIs, 296
Desipramine DHEA (dehydroepiandrosterone), 219
Desmopressin intranasal spray Diabetes insipidus, 6
(DDAVP), xxxiii, 202, 203 nephrogenic, 41, 203–204
Desogestrel oral contraceptives, treatments for, xxxiii
93–95 Diabetes mellitus
Desonide 0.05%, 151 drug-induced
DesOwen. See Desonide 0.05% antidepressants, 173, 175
Desoximetasone 0.25%, 151 SGAs, 170–173
Desvenlafaxine, xxx laboratory monitoring for,
cytochrome P450 metabolism 14, 170, 171–172
and, 68 metformin for, 170, 175
Index 447
personal or family history DILE (drug-induced lupus

and risk for, 173 erythematosus), 203, 293
racial differences in, 60, 172, Dimetapp. See Phenylephrine
173 Diphenhydramine, xxxi
risk factors for, 124 anticholinergic delirium induced
gestational, 331 by, 250
hypertriglyceridemia and, 124 for dystonia, 342
operational definitions of, 172 fasciculations induced by, 264
risk in bipolar disorder or for oculogyric crisis, 265, 266
schizophrenia, 170–171 receptor occupancy and effects of,
use of SGAs in patients with, 173 58
Diabetic ketoacidosis, 166 sedation induced by, 256
Diaphoresis. See Sweating viscous lidocaine with, 159
Diarrhea Diplopia, drug-induced, 274
drug-induced, 187–188, 382–388 dose relationships and, 30, 274
atenolol, 58 Diprolene; Diprosone. See
fibrates, 134 Betamethasone dipropionate
metoprolol, 58 Disclosure and discussion of
management of, 187, 188 possible side effects with
metabolic acidosis induced by, 166 patient, 42, 44–45, 361–362
placebo-induced, 18 Discontinuation syndromes, 101,
Diazepam, xxxv 291–292
agranulocytosis induced by, 235 with MAOIs, 292
cytochrome P450 metabolism with SNRIs, 6, 240, 291–292
and, 69 with SSRIs, 240, 291–292
dosing and precautions in renal Disinhibition, benzodiazepine-
disease, 212 induced, 101
drug interactions with in older adults, 76
fluvoxamine, 389 Disopyramide, xxix, 120
oral contraceptives, 95 Disorientation, 247
hyperprolactinemia induced by, Disseminated intravascular
176 coagulopathy, 236
mean half-life and food effects on Dissociation, zolpidem-induced, 102
absorption of, 52 Ditropan. See Oxybutynin
for tic disorders, 261 Diuretics, xxxiii
Dicyclomine, xxxiii, 250 for clozapine-induced
Diet/nutrition myocarditis, 139
for drug-induced weight gain, hyperammonemia induced by, 195
296, 312–315 hyponatremia or SIADH induced
for dyslipidemia, 129 by, 164
increasing fiber in, 188 interaction with lithium, 390
ketogenic, 208 oral lesions induced by, 159
Diflorasone diacetate 0.05%, 151 pancreatitis induced by, 198
Digitalis, 89–90, 360 for peripheral edema, 131, 136,
Dilantin. See Phenytoin 136
Divalproex, xxx polycystic ovary syndrome

adverse effects of short- vs. long- induced by, 178–179
acting preparations of, 56 reproductive safety in
alopecia induced by, 141, 142 premenopausal women, 179,
anemia induced by, 236, 332 184
during breast-feeding, 332 serum level of, 11, 62–63, 64
cardiovascular effects of, 116 sexual dysfunction induced by,
cognitive effects of, 248 215
dermatological effects of, 149, 150 somnolence or sedation induced
diarrhea induced by, 188 by, 258
dose relationships and side effects for steroid-induced mania, 96
of, 30, 31 suicidality and, 103
dosing and precautions in summary of adverse effects of,
hepatic failure, 192 384
renal disease, 210 teratogenicity of, 36, 179, 335, 336
dysarthria induced by, 157 thrombocytopenia induced by,
dyspepsia induced by, 56 11, 29, 31, 39, 232
effect on sleep architecture, 283 tinnitus induced by, 268
headache induced by, 262 tremor induced by, 269
hepatic effects of, 11, 34, 190 vitamin B12 and folic acid
hyperammonemia induced by, deficiencies induced by, 196
191, 195 weight gain induced by, 297, 298,
hyperprolactinemia induced by, 305, 306
176 Dizziness, 114, 140
hyponatremia induced by, 163 drug-induced, 382–388
insomnia induced by, 258 atenolol, 58
interaction with lamotrigine, 50, dose relationships and, 30
153, 265, 389 efavirenz, 88
laboratory monitoring of, 11, 232 idazoxan, 58
lack of efficacy for tardive metoprolol, 58
dyskinesia, 254 phentolamine, 58
leukocytopenia induced by, 232 transient, 38
mean half-life and food effects on yohimbine, 58
absorption of, 52 induced by weight loss
medical conditions as supplements, 329
contraindication to, 7 placebo-induced, 18
myalgias induced by, 241 Dobutamine, xxxv, 58
nystagmus induced by, 265 Dobutrex. See Dobutamine
for older adults, 75, 77 Docosahexaenoic acid, 125, 133
overdose of, 344 Donepezil, xxix, 240
pancreatitis induced by, 11, 35, for drug-induced cognitive
197, 198, 199, 341 complaints, 247
paresthesias induced by, 266 for tardive dyskinesia, 253
peripheral edema induced by, 130 for tic disorders, 261
Index 449
Dopamine agonists, 87 Drug interactions. See also specific

for antipsychotic-induced sexual drugs
dysfunction, 229 with alcohol, 60
for attention deficits, 246 with antiretroviral agents, 73–74
bruxism induced by, 155 with buprenorphine, 389
fasciculations induced by, 264 with buspirone, 296
myalgias induced by, 241 with carisoprodol, 84
psychosis induced by, 102 with fluvoxamine, 389
for restless legs syndrome, 250, with lamotrigine, 389
251, 282 with lithium, 390
sleep attacks induced by, 277– with MAOIs, 296, 391
278 in medically ill patients, 73
for tardive dyskinesia, 254 with mirtazapine, 391
vivid dreams induced by, 285 with olanzapine, 391
Dopamine receptors in older adults, 76
D2, 31, 57, 59, 176–177 with oral contraceptives, 94–95
D3, 67 pharmacokinetic, 50
Dose relationships and side effects, with quetiapine, 392
28–32, 30–31, 38 with SSRIs, 296, 392
Dosing adjustments serotonin syndrome due to,
in HIV/AIDS, 75 295–296, 343, 391, 392
in liver disease, 73, 192–194 with warfarin, 114
for older adults, 75, 77–79 Web sites for information about,
in renal disease, 210–213 393
for somatizing patients, 80 Drug metabolizer phenotypes, 32,
Doxazosin, xxxii, 89 50, 63, 66–70, 68–69, 72
Doxepin, xxx Drug rash with eosinophilia and
cytochrome P450 metabolism systemic symptoms (DRESS
and, 68 syndrome), 153, 290
for pruritus, 145 Drug-induced lupus erythematosus
Doxycycline, 266 (DILE), 203, 293
Dreams, vivid, drug-induced, Drugs and Lactation Database
285 (LactMed), 393
efavirenz, 88 Dry mouth
DRESS syndrome (drug rash with drug-induced, 41, 162, 361,
eosinophilia and systemic 382–388
symptoms), 153, 290 anticholinergic agents, 58
Drooling, drug-induced, 41, 159– dose relationships and, 30
161 management of, 162
Drospirenone, 93, 94 placebo-induced, 18
Drowsiness. See also Sedation; Dry skin, 150
Somnolence Duloxetine, xxx
drug-induced, 256 cytochrome P450 metabolism
placebo-induced, 18 and, 68
Drug development, 362 diarrhea induced by, 188
Duloxetine (continued) acetyl-coenzyme A

dose relationships and side effects carboxylase alpha gene
of, 30 variants and, 70
dosing and precautions in effect of weight loss on, 313
hepatic failure, 193 racial differences in, 60
renal disease, 211 dose relationships and, 30
glycemic dysregulation and insulin resistance and, 172
diabetes induced by, 173 management of, 124–125
headache induced by, 263 lifestyle changes, 128–129, 130
hepatic effects of, 190 lipid-lowering agents, 123, 125,
hyperhidrosis induced by, 143 128–129, 132–135
hypertension induced by, 138 pancreatitis and, 199
hyponatremia induced by, 163– Dyspepsia. See Nausea/
164 gastrointestinal upset
mean half-life and food effects on Dysphoria, progestin-induced, 93
absorption of, 53 Dysthymic disorder, nocebo
myalgias induced by, 241 phenomenon in, 18
for older adults, 78 Dystonia, 23, 361
orthostatic hypotension induced emergency management of, 342
by, 140 laryngeal, 157
paresthesias induced by, 266 oculogyric crisis, 264–265
serum level of, 64 polypharmacy and, 57
sexual dysfunction induced by, restless legs syndrome, 250–251
214, 215, 219, 220 Dysuria, drug-induced, 201–202
summary of adverse effects of, 382
for tinnitus, 268 Ear, nose, and throat effects of drugs,
for urinary incontinence, 202 155–162
urinary retention induced by, bruxism, 155–156, 156
201–202 dysarthria, 156–157, 158
use in medically ill patients, 5, 6 dysgeusia, 157–158
weight changes induced by, 298, oral lesions, 158–159
308, 330 sialorrhea, 159–161
yawning induced by, 270 stomatodynia, 161
Dumping syndrome after gastric xerostomia, 162
bypass surgery, 47 Eating disorders, sleep-related, 286,
Dyazide. See Hydrochlorothiazide 287
plus triamterene Ebstein’s anomaly, lithium and, 337
Dynacirc. See Isradipine ECG. See Electrocardiogram
Dysarthria, 156–157 Echocardiography, 115
Dysdiadochokinesia, 269 Ecstasy (3,4-methylenedioxymetham-
Dysgeusia, 157–158 phetamine, MDMA), 242, 296
Dyslipidemias, drug-induced, 123– ECT (electroconvulsive therapy)
129 for neuroleptic malignant
antipsychotics, 14, 123–125, 126– syndrome, 295
127 succinylcholine for, 264
Index 451
Eczema, 148 metabolic acidosis or alkalosis,

ED50 (minimum effective dose for 166–167
50% of population), 49 Elocon. See Mometasone furoate
Efavirenz, xxxiii, 88–89, 142 0.1%
Effect size, 38, 360 Emergency situations, 339
Effexor. See Venlafaxine neuroleptic malignant syndrome,
Efficacy vs. effectiveness of 294–295, 343
treatment, 26 priapism, 206–207
Efudex. See 5-Fluorouracil psychotropic drug overdose, 339,
Eicosapentaenoic acid, 125, 133, 254 344–355
Ejaculation. See also Sexual serotonin syndrome, 295–296, 343
dysfunction Emotional dulling, SSRI–induced,
delayed, 213, 214, 219–221 101–102
premature, 214 Emsam. See Selegiline, transdermal
retrograde, 229–230 E-Mycin. See Erythromycin
Elavil. See Amitriptyline Enalapril, xxxi, 161, 390
Elderberry, to promote weight loss, Enantiomeric vs. racemic drugs, 61
329 Encephalopathy
Electrocardiogram (ECG) drug-induced, 247, 250
before/during drug use, 113, 121 immunosuppressants, 92
antipsychotics, 15, 113, 121 hepatic, 191
lithium, 14, 113 hyperammonemic, 191
stimulants, 34, 122 Endocrinopathies, 169–186
TCAs, 113, 115, 121 bone demineralization and
in evaluation for clozapine- osteoporosis, 169–170
induced myocarditis, 139 glycemic dysregulation and
in evaluation of palpitations, 115 diabetes mellitus, 170–175,
psychotropic drug effects on, 172, 174–175
116–117 (See also hyperparathyroidism, 179, 184–
Cardiovascular effects) 185
antipsychotics, 15, 35, 117, hyperprolactinemia, galactorrhea,
118–121, 119 and gynecomastia, 175–178,
MAOIs, 121 180–183
QTc interval prolongation, menstrual disturbances and
118–122, 119, 120 polycystic ovary syndrome,
TCAs, 117, 120, 121 178, 184
Electroconvulsive therapy (ECT) thyroid disorders, 185–186
for neuroleptic malignant Enuresis, drug-induced, 202–203
syndrome, 295 Eosinophilia, 139
succinylcholine for, 264 Ephedra, to promote weight loss, 328
Electrolyte abnormalities, 163–167 Ephedrine, for enuresis and urinary
hyponatremia and SIADH, 163– incontinence, 202
165, 165 Epinephrine, MAOIs and, 138
leg cramps due to, 240–241 Equetro. See Carbamazepine
Erectile dysfunction, 220–221. See Ethylene glycol, 166

also Sexual dysfunction Etonogestrel, 95
Ergot alkaloids, 142 Evidence-based research,
Erythema multiforme, modafinil extrapolating findings to real-
and, 154 world patients, 26–28, 40
Erythromycin, xxix, 120 Excessive daytime sleepiness, 256,
interaction with carbamazepine, 277
389 Exercise
Escitalopram, xxx, 5–6 for drug-induced weight gain,
cardiovascular effects of, 116, 120, 296, 312–315
121 for dyslipidemia, 128–129
dose relationships and side effects Extended-release drug preparations,
of, 30, 31 50
dosing and precautions in renal absorption after gastric bypass
disease, 211 surgery, 47
electrocardiogram monitoring for side effects of, 51, 56
use of, 116 Extrapyramidal side effects, 41, 382–
headache induced by, 260, 263 388
insomnia induced by, 258 akathisia, 243–245, 244
mean half-life and food effects on amantadine for, 39
absorption of, 53 benztropine for, 27
myalgias induced by, 241 dopamine D2 receptor saturation
for older adults, 78 and, 31
overdose of, 348 dose relationships and, 30
peripheral edema induced by, 130 in HIV/AIDS, 73
restless legs syndrome induced polypharmacy and, 57
by, 250 racial differences in, 60
sexual dysfunction induced by, rating scales for
215, 220 Abnormal Involuntary
somnolence or sedation induced Movement Scale, 252, 253,
by, 258 254, 394
summary of adverse effects of, Barnes Akathisia Scale, 394
383 Simpson-Angus
weight changes induced by, 309 Extrapyramidal Side
Eskalith; Eskalith CR. See Lithium Effects Scale, 394
Estrogens risk-benefit analysis of antidotes
in contraceptives, 93–95 for, 39
pancreatitis induced by, 198 Ezetimibe, xxxiv
peripheral edema induced by, 129 Ezetimibe plus simvastatin, xxxiv,
Eszopiclone, xxxv 135
for insomnia, 284, 285
parasomnias induced by, 286, 287 Facial nerve, 157, 158
sexual dysfunction induced by, Factive. See Gemifloxacin
218 Famotidine, for nausea, 45
Ethinyl estradiol, 93–95 Fanapt. See Iloperidone
Index 453
Fasciculations, 261, 263–264 Fluonid. See Fluocinolone acetonide

Fast acetylators, 50 5-Fluorouracil, xxxii, 88, 120
Fasting blood glucose, 14, 170, 171 Fluoxetine, xxxi, 6
Fatigue, drug-induced, 256–257, 382– alopecia induced by, 141
388. See also Sedation; apathy induced by, 102
Somnolence cardiovascular effects of, 116
β-blockers, 58, 90 hypercholesterolemia, 123
dose relationships and, 30 cytochrome P450 metabolism
Fatty liver disease, 190 and, 68, 69
FDA. See U.S. Food and Drug depression severity and side
Administration effects of, 71
Fear. See also Anxiety; Panic dermatological effects of, 149
clonidine-induced, 89 discontinuation of, 292
Femara. See Letrozole dosing and precautions in renal
D-Fenfluramine, for drug-induced disease, 211
weight gain, 319 gene variants related to insomnia
Fenofibrate, xxxiv, 125, 134 and agitation induced by, 70
Feoris. See Ketoconazole headache induced by, 263
Fetal drug exposure. See Pregnancy hyperhidrosis induced by, 143
and puerperium; Teratogenicity hyperprolactinemia induced by,
of drugs 176
Fever, 361 for hypochondriasis, 80
antipsychotic-induced, 291 insomnia induced by, 258, 279
in drug-induced lupus interaction with risperidone, 202
erythematosus, 293 mean half-life and food effects on
in neuroleptic malignant absorption of, 53
syndrome, 294 for myoclonus, 264
in serotonin syndrome, 295 for older adults, 78
FGAs. See Antipsychotics, first- oral lesions induced by, 159
generation overdose of, 349
Fibrates, xxxiv, 125, 134 parasomnias induced by, 287
Fibromyalgia, 239, 241 periodic limb movements during
First-pass metabolism, 47 sleep induced by, 282
Fish oil, 125, 133 in pregnancy, 337
Flecainide, xxix, 90, 120 priapism induced by, 207
Flexeril. See Cyclobenzaprine serum level of, 65
Floxin. See Ofloxacin sexual dysfunction induced by,
Fluconazole, interaction with 214, 220, 223, 225
carbamazepine, 389 persistence after drug
Fluid restriction, for hyponatremia, cessation, 229
163, 164–165 somnolence or sedation induced
Flumazenil, for benzodiazepine by, 258
reversal, 352 stomatodynia and, 161
Fluocinolone acetonide, 151 summary of adverse effects of,
Fluocinonide 0.05%, 151 383
Fluoxetine (continued) somnolence or sedation induced

tics induced or exacerbated by, 261 by, 258
for tinnitus, 268 summary of adverse effects of, 383
urinary retention induced by, 201 weight changes induced by, 309
weight changes induced by, 298, Focalin. See Methylphenidate
309, 312, 330 Folic acid deficiency, drug-induced,
yawning induced by, 270 196
Fluphenazine, dystonia induced by, Food effects on drug absorption, 47,
342 52–55
Flurandrenolide 0.05%, 151 Fractures, SSRIs and, 170
Flurazepam, xxxv, 95 Freud, Sigmund, 20
Flushing, drug-induced Fungal rashes, 149
idazoxan, 58 Furosemide
niacin, 134 pancreatitis induced by, 198
phentolamine, 58 for peripheral edema, 131, 136,
yohimbine, 58 136
Fluticasone propionate, 151 Fursultiamine, 240
Fluvastatin, xxxiv, 132 Future drug development, 362
Fluvoxamine, xxxi
alopecia induced by, 141 Gabapentin, xxx
cataracts induced by, 274 for akathisia, 243, 245
combined with clozapine, 125 for bruxism, 156
cytochrome P450 metabolism cardiovascular effects of, 116, 122
and, 68, 69 cognitive effects of, 248
dosing and precautions in renal dose relationships and side effects
disease, 211 of, 30
drug interactions with, 389 dosing and precautions in
asenapine, 50 hepatic failure, 192
clozapine, 50, 125, 319, 389 renal disease, 210
olanzapine, 50 effect on sleep architecture, 283
glycemic dysregulation and headache induced by, 262
diabetes induced by, 173 insomnia and, 258, 284
headache induced by, 263 for leg cramps, 240
hypercholesterolemia induced by, mean half-life and food effects on
insomnia induced by, 258 for nightmares, 286
mean half-life and food effects on for nystagmus, 265
absorption of, 53 for older adults, 77
for nightmares, 286 overdose of, 345
for older adults, 78 peripheral edema induced by, 77,
overdose of, 349 130
priapism induced by, 207 serum level of, 64
psychosis induced by, 102 somnolence or sedation induced
sexual dysfunction induced by, by, 258
214, 220, 225 for stomatodynia, 161
Index 455
suicidality and, 103 anticholinergic agents, 39, 58

summary of adverse effects of, antipsychotics, 188
385 atenolol, 58
for tremor, 270 benztropine, 188
urinary incontinence induced by, bupropion, 188
202 carbamazepine, 188
vitamin B12 and folic acid divalproex, 56, 62–63
deficiencies induced by, 196 fibrates, 134
vivid dreams induced by, 285 metoprolol, 58
weight changes induced by, 298, mirtazapine, 188
305, 306 niacin, 134
Gabapentin enacarbil, xxx SNRIs, 59, 188
Galactorrhea, 59, 176, 177 SSRIs, 29, 38, 44–45, 59,
Galantamine, xxix, 240 187–189
for drug-induced cognitive TCAs, 188
complaints, 247 vilazodone, 188
lack of efficacy for tardive of weight loss supplements,
dyskinesia, 253 327–329
Garcinia atroviridis, to promote Gastrozepin. See Pirenzepine
weight loss, 328 Gemfibrozil, xxxiv, 125, 134
Garcinia cambogia–derived Gemifloxacin, xxix, 120
(-)-hydroxycitric acid, to Gender differences
promote weight loss, 328 in cytochrome P450 enzyme
Gastric bypass surgery, 47 activity, 60
Gastric lavage, for drug overdose, in glomerular filtration rate, 60,
344–355 205
Gastrointestinal agents, xxxiii, 91 in side effects, 57, 60, 71
Gastrointestinal bleeding, drug- sexual dysfunction, 60, 213, 214
induced, 188–189, 195, 235, 392 torsades de pointes, 121
Gastrointestinal effects Generic vs. brand-name drugs, 60–
of drugs, 187–199, 382–388 61, 393
diarrhea, hypermotility, and Genetic markers and adverse drug
constipation, 187–188 effects, 63, 66–70, 68–69
dose relationships and, 30 carbamazepine-induced skin
gastrointestinal bleeding, 188– rashes, 152–153
189, 195, 235, 392 Genotyping for cytochrome P450
hepatic impairment and enzyme variants, 70
transaminitis, 189–191, Gentamicin, 87
192–194 Geodon. See Ziprasidone
hyperammonemia, 191, 195 GFR. See Glomerular filtration rate
malabsorption disorders, 196 Ghrelin, 299
nausea and gastrointestinal Ginkgo biloba
upset, 197–198 for drug-induced sexual
pancreatitis, 198–199, 341 dysfunction, 226
specific drugs, 41 for tardive dyskinesia, 251, 254
Glaucoma, topiramate-induced, 274– switching from stimulant drug to,

275 326, 330
GlobalRPh, 393 for tic disorders, 261
Glomerular filtration rate (GFR), 206 Gynecomastia, 176, 177–178
gender differences in, 60, 205
lithium effects on, 204, 205 Hair loss, drug-induced, 41, 141–142
in older adults, 75, 205 Halcinonide 0.05%, 151
Glomerulosclerosis, lithium- Halcion. See Triazolam
induced, 204–205 Haldol. See Haloperidol
Glossopharyngeal nerve, 157, 158 Hallucinations, 23
Glucuronidation reactions, 50 drug-induced
Glutamatergic gene variants, α1-adrenergic antagonists, 89
citalopram-induced sexual antineoplastic agents, 88
dysfunction and, 70 digitalis, 90
γ-Glutamyl transpeptidase (γGTP), ketoconazole, 86
190 tramadol, 84
Glycemic dysregulation, drug- zolpidem, 102–103
induced, 170–175. See also due to MAOI discontinuation, 292
Diabetes mellitus hypnagogic, 277
antidepressants, 173, 175 Halobetasol propionate 0.05%, 151
caffeine, 327 Halog. See Halcinonide 0.05%
metformin for, 170, 175 Haloperidol, xxxiii
SGAs, 4, 14, 170–173, 174–175 cardiovascular effects of, 117, 119
laboratory monitoring for, 170, cataracts induced by, 274
171–172 cytochrome P450 metabolism
metformin for, 170, 175 and, 68, 69
personal or family history and dystonia induced by, 342
risk for, 173 hyperprolactinemia induced by,
racial differences in, 60, 172, 173 176
risk factors for, 124 seizures induced by, 268
Glycerin-based oral lubrication sexual dysfunction induced by,
solutions, 162 215
Glycopyrrolate, xxx for tic disorders, 261
for hyperhidrosis, 143 withdrawal dyskinesias
for sialorrhea, 159, 160 associated with, 255
Granulocyte colony–stimulating Headache
factor, 233–234 drug-induced, 41, 257, 260, 262–
Graves’ disease, 185 263, 382–388
Green tea catechins with caffeine, to armodafinil, 62
promote weight loss, 329 atenolol, 58
γGTP (γ-glutamyl transpeptidase), 190 dose relationships and, 30
Guanfacine, xxxii due to drug overdose, 339
for nightmares, 285 escitalopram, 260
receptor occupancy and effects of, idazoxan, 58
58 lamotrigine, 257
Index 457
lithium, 260 drug-induced gastrointestinal

management of, 257 bleeding in, 189, 235, 236
metoprolol, 58 HIV-related, 75
modafinil, 58, 62 hyperammonemia and, 191
phentolamine, 58 nonalcoholic steatohepatitis, 190
phenylephrine, 58 peripheral edema and, 131
SSRIs, 29, 38, 39–40, 257 use of psychotropic drugs in, 7,
transient, 38 189, 190
yohimbine, 58 dosing and precautions in
due to antidepressant hepatic failure, 192–194
discontinuation, 291–292 Hepatic effects
induced by weight loss of drugs, 189–191
supplements, 327, 328 carbamazepine, 10, 190
placebo-induced, 18, 260 in breast-fed infants, 332
in SIADH, 164 divalproex, 11, 34, 190
Heart block, drug-induced duloxetine, 190
carbamazepine, 116 monitoring for, 189, 190–191
lithium, 116 nefazodone, 34, 37, 190
TCAs, 117 niacin, 134
Hematological effects of drugs, 231– nonpsychotropic drugs, 190
236 pemoline, 37
myelosuppression, 231–235 of Hydroxycut, 329
platelet aggregation disorders Hepatic encephalopathy, 191
and bleeding risk, 235–236 Hepatic function, evaluation of, 189–
reticulocytopenia, 236, 237 190
specific drugs Herbal remedies
antineoplastic agents, 234 for drug-induced sexual
antipsychotics, 233 dysfunction, 226
carbamazepine, 9, 34, 231, 232, for hyperprolactinemia, 178
340, 341 to promote weight loss, 327–329
chlordiazepoxide, 235 for tardive dyskinesia, 251, 254
clozapine, 34, 63, 139, 231, 233, Histamine H1 inhibitors. See
234, 341 Antihistamines
diazepam, 235 Histamine H2 inhibitors, xxxiii, 91,
divalproex, 232 176, 250, 298
lamotrigine, 235 History taking, 8, 16
lithium, 14, 233 HIV/AIDS
midazolam, 235 adverse drug effects in patients
mirtazapine, 235 with, 73–74
modafinil, 235 dosing adjustments in, 75
Hemoglobin A1C, 14, 170, 173 oral lesions and, 159
Hemolytic anemia, 236, 237 treatments for, xxxiii
Hepatic disease, 73 drug interactions with, 73–74
Child-Pugh classification of, 73, psychiatric side effects of, 87–
74, 191 89
Hives, 149. See also Urticaria Hypercalciuria, 207, 208

HLA (human leukocyte antigen) Hyperchloremic metabolic acidosis,
genotypes, 63 166
HLA-B*1052 allele and Hypercholesterolemia, 5, 128. See
carbamazepine-induced skin also Dyslipidemias
rashes, 152–153 antipsychotic-induced, 14, 123–
Holter monitoring, 115 125, 126–127
HOMA-IR (homeostatic model acetyl-coenzyme A
assessment of insulin carboxylase alpha gene
resistance), 172 variants and, 70
Homocysteine, 196 effect of weight loss on, 313
Homeostatic model assessment of lipid-lowering agents for, xxxiv,
insulin resistance (HOMA-IR), 123, 125, 128–129, 132–135
172 SSRI–induced, 123–124
Horizant. See Gabapentin enacarbil Hyperglycemia. See also Diabetes
Hostility/anger, drug-induced mellitus; Glycemic
levetiracetam, 85 dysregulation
progestins, 93 hypertriglyceridemia and, 124
varenicline, 95 SGA–induced, 172–173
Human leukocyte antigen (HLA) Hyperhidrosis, drug-induced, 142–
genotypes, 63 143
HLA-B*1052 allele and dose relationships and, 31
carbamazepine-induced skin Hyperosmolar hyperglycemic
rashes, 152–153 nonketotic coma, 167
Hunter Serotonin Toxicity Criteria, Hyperosmotic nonketotic coma, 41
296 Hyperparathyroidism
Hydralazine, 293 lithium-induced, 179, 184–185
Hydrochlorothiazide, xxxiii, 5, 136 metabolic acidosis induced by, 166
Hydrochlorothiazide plus Hyperphagia, 8, 28, 297
triamterene, xxxiii Hyperpigmentation,
Hydrocortisone, topical, 148, 151 photosensitivity-induced, 143–
Hydrocortisone butyrate 0.1%, 151 144
Hydrocortisone valerate, 151 Hyperprolactinemia, drug-induced,
Hydroxychloroquine, for drug- 175–178
induced lupus erythematosus, antipsychotics, 59, 175–178, 180–
293 183
Hydroxycobalamin, 240 dose relationships and, 30
Hydroxycut, 329 DRD2*A1 allele and, 70
Hydroxyzine, xxxi, 145 gender differences in, 60
Hyperammonemia, drug-induced, herbal remedies for, 178
191, 195 management of, 175–176, 177
Hyperandrogenism with menstrual irregularities due
oligomenorrhea, 178 to, 178
Hypercalcemia, lithium-induced, gynecomastia and, 177–178
179, 184–185 nonantipsychotic drugs, 176
Index 459
sexual dysfunction and, 214–215, Hypertriglyceridemia, 124, 128. See

229 also Dyslipidemias
Hyperreflexia, in serotonin antipsychotic-induced, 14, 124,
syndrome, 295, 296 126–127
Hypersalivation, drug-induced, 41, acetyl-coenzyme A
159–161 carboxylase alpha gene
Hypersensitivity reactions variants and, 70
anaphylactic, 152 effect of weight loss on, 313
to anticonvulsants, 22, 290 lipid-lowering agents for, xxxiv,
skin rashes, 145, 146, 148 123, 125, 128–129, 132–135
oral lesions of, 158–159 Hypnic jerks, 264
Hypersomnia, drug-induced, 8, 277– Hypochondriasis, 80
278 Hypoglossal nerve, 157, 158
Hypertension, 5 Hypokalemic hyperglycemic
drug-induced, 137–138 nonketotic acidosis, 166
atomoxetine, 137 Hypokalemic ketoacidosis, 167
bupropion, 137, 138 Hypomania
clonidine, 58 differentiating akathisia from, 8
dobutamine, 58 drug-induced, 97–99
dose relationships and, 30 antidepressants, 27, 97–98, 99
guanfacine, 58 antipsychotics, 23, 99
idazoxan, 58 clonidine, 89
phentolamine, 58 ifosfamide, 88
SNRIs, 137–138 interferon-α, 92
stimulants, 137 stimulants, 98–99
TCAs, 137 insomnia and, 282
yohimbine, 58 Hyponatremia
induced by weight loss drug-induced, 9, 163–165
supplements, 327, 328 intranasal desmopressin, 203
psychotropic agents risk factors for, 164
contraindicated in, 7 hypotonic, 163–164
rebound, after discontinuation of laboratory assessment of, 164
α1-blockers, 286 management of, 163, 164–165
Hypertensive crisis, 137 peripheral edema and, 131
management of, 340 SIADH and, 164
MAOI–induced, 138, 292 Hypotension, drug-induced, 140
Hyperthermia, 361 α1-adrenergic antagonists, 58, 89,
antipsychotic-induced, 291 140
in drug-induced lupus atomoxetine, 140
erythematosus, 293 β-blockers, 58, 114
in neuroleptic malignant cannabinoids, 140
syndrome, 294 clonidine, 58
in serotonin syndrome, 295 conservative management of, 140
Hyperthyroidism, 115 dose relationships and, 30
lithium-induced, 185 guanfacine, 58
Hypotension, drug-induced glycemic dysregulation and

(continued) diabetes induced by, 174
MAOIs, 121, 140 hyperprolactinemia induced by,
mirtazapine, 140 181
in older adults, 76 insomnia induced by, 259
prazosin, 58, 286 mean half-life and food effects on
propranolol, 269 absorption of, 54
quetiapine, 28 metabolism of, 67
SGAs, 114, 140 overdose of, 353
SNRIs, 78, 140 serum level of, 66
TCAs, 48, 121, 140 sexual dysfunction induced by, 216
Hypothermia, antipsychotic- somnolence or sedation induced
induced, 291 by, 259
Hypothyroidism summary of adverse effects of, 386
alopecia due to, 142 weight changes induced by, 298,
drug-induced, 185–186 301
amiodarone, 89 Imipramine, xxxi
carbamazepine, 185, 186 cardiovascular effects of, 121
dose relationships and, 30 cytochrome P450 metabolism
lithium, 4, 13, 48, 185–186 and, 68
quetiapine, 185, 186 demethylation of, 49
hyperprolactinemia due to, mean half-life and food effects on
levothyroxine for, 185–186 serum level of, 65
subclinical, 185 tics induced or exacerbated by, 261
use of lithium in, 7 Imitrex. See Sumatriptan
weight gain and, 297 Immunosuppressants, xxxiii–xxxiv,
Hytrin. See Terazosin 91, 92, 293
Imodium. See Loperamide
Ibuprofen, 240, 291–292 Impetigo, 148
ICH (International Conference on Implausible drug effects, 22, 23, 43
Harmonisation), 27 Impotence, 214, 219–221. See also
Idazoxan, 58 Sexual dysfunction
Idiosyncratic drug reactions, 22, 39 Imuran. See Azathioprine
Ifex. See Ifosfamide Inderal; Inderal LA. See Propranolol
Ifosfamide, xxxii, 88 Indiana University School of
IFPMA (International Federation of Medicine, Division of Clinical
Pharmaceutical Manufacturers Pharmacology, 393
and Associations), 27 Indomethacin, for nephrogenic
Iloperidone, xxxv diabetes insipidus, 204
akathisia induced by, 244 Inositol, for lithium-induced
cardiovascular effects of, 119 psoriasis, 152
dose relationships and side effects Insomnia, 8, 278–285. See also Sleep
of, 30, 31 disturbances
dyslipidemias induced by, 126 in depression, 278, 279
Index 461
drug-induced, 41, 256, 258–259, Isoniazid, 83, 87, 166

361, 382–388 pancreatitis induced by, 198–199
desvenlafaxine, 62 Isotretinoin, 90–91, 142
dose relationships and, 30 Isradipine, xxxii
efavirenz, 88 interaction with lithium, 390
fluoxetine, 70
idazoxan, 58 Jaundice, 237
phentolamine, 58 Joint pain, 239–240, 293
venlafaxine, 62
yohimbine, 58 Kaopectate. See Bismuth
induced by weight loss subsalicylate
supplements, 327, 329 Kenalog. See Triamcinolone
in mania, 278 acetonide
placebo-induced, 18 Keppra. See Levetiracetam
treatment of, 27, 278, 279, 282, Kerlone. See Betaxolol
284–285 Ketoconazole, xxxi, 86, 120, 150
Insulin resistance. See also Glycemic Kidney stones, 207–208
dysregulation
dyslipidemias and, 172 Laboratory monitoring of
homeostatic model assessment of, psychotropic agents, 6–7, 9–15.
172 See also specific drugs
SGA–induced, 170–172 Lactation and psychotropic drug
Interferon-α, 86, 92–93, 360 use, 332, 393
Interleukin-2, 88 Lactic acidosis, 166, 167, 241, 242
Interleukin 28 receptor (IL28RA) LactMed (Drugs and Lactation
gene variants, 70 Database), 393
International Conference on Lactobacillus acidophilus, 188
Harmonisation (ICH), 27 Lactulose, for hyperammonemia,
International Federation of 195
Pharmaceutical Manufacturers Lamictal. See Lamotrigine
and Associations (IFPMA), 27 Lamotrigine, xxx, 5
Intravaginal contraceptive rings, 95 alopecia induced by, 142
Invega. See Paliperidone aseptic meningitis induced by,
Ipratropium bromide, xxx 290, 342
for sialorrhea, 160 cardiovascular effects of, 116
Iron deficiency anemia, 236 cognitive effects of, 248
Irritability, clonidine-induced, 89 dose relationships and side effects
Irvingia gabonensis plus Cissus of, 30
quadrangularis (CQ-IG), to dosing and precautions in
promote weight loss, 327 hepatic failure, 192
Isocarboxazid, xxxi renal disease, 210
discontinuation before general drug interactions with
anesthesia, 138 carbamazepine, 12, 389
sexual dysfunction induced by, 220 divalproex, 50, 153, 265, 389
weight changes induced by, 310 oral contraceptives, 12, 94, 389
Lamotrigine (continued) Leukeran. See Chlorambucil

for drug-induced weight gain, Leukocytosis
296, 305, 320, 321 drug-induced
effect on body weight, 298, 305, clozapine, 139
307 lithium, 14, 233
effect on sleep architecture, 283 in neuroleptic malignant
headache induced by, 257, 262 syndrome, 294
hypersensitivity reaction to, 290 Leukopenia, drug-induced
hyponatremia induced by, 163 antipsychotics, 233
insomnia induced by, 258 carbamazepine, 232
mean half-life and food effects on divalproex, 232
absorption of, 52 Levaquin. See Levofloxacin
myalgias induced by, 241 Levetiracetam, xxx
nystagmus induced by, 265 hostility induced by, 85
for older adults, 77 psychosis induced by, 85
overdose of, 345 side effects in children, 85
psychosis induced by, 85 suicidality and, 103
rash induced by, 34, 45, 50, 150, for tardive dyskinesia, 251, 253
152, 153–154, 340 for tremor, 270
in children, 72 Levitra. See Vardenafil
serum level of, 12, 63, 64 Levodopa, 236
somnolence or sedation induced Levofloxacin, xxx, 87, 120
by, 258 Levonorgestrel oral contraceptives,
suicidality and, 103 93, 94
summary of adverse effects of, 385 Levothyroxine
teratogenicity of, 336 generic vs. brand-name
tics induced or exacerbated by, 261 formulations of, 61
vivid dreams induced by, 285 for hypothyroidism, 89, 185–186
Lansoprazole, 189 Lexapro. See Escitalopram
Lariam. See Mefloquine Librium. See Chlordiazepoxide
Laryngeal dystonia, 157 Lidex. See Fluocinonide 0.05%
Latuda. See Lurasidone Lidocaine, viscous, with
Laxatives, 188 diphenhydramine, 159
LD50 (lethal dose for 50% of Lifestyle modifications for drug-
population), 49 induced weight gain, 312–315
Left bundle branch block, 114, 117 Lightheadedness, prazosin-induced,
Leg cramps, 240–241 58
Lepidium meyenii, for drug-induced Lipid-lowering agents, xxxiv, 123,
sexual dysfunction, 226 125, 128–129, 132–135
Leptin, 299 Lipitor. See Atorvastatin
Lescol. See Fluvastatin Lisdexamfetamine, 387
Lethal dose for 50% of population Lisinopril, xxxi, 161, 390
(LD50), 49 Lithium, xxv, xxxii, 5–6, 22
Lethargy, 8, 22, 164 akathisia induced by, 243
Letrozole, xxxi, 88 alopecia induced by, 141
Index 463
during breast-feeding, 332 oral lesions induced by, 159

cardiovascular effects of, 116 overdose of, 346, 360
cognitive effects of, 248 peripheral edema induced by,
dermatological effects of, 148, 149, 130, 136
152 renal effects of, 13, 166, 167, 203–
diarrhea induced by, 188 205, 208
dosing and precautions in serum level of, 12, 64, 346
hepatic failure, 192 sexual dysfunction induced by,
renal disease, 210 215
drug interactions with, 390 for steroid-induced mania, 96
antipsychotics, 247, 250 teratogenicity of, 335, 337
buspirone, 296 toxicity of, 197–198, 264, 269, 346
dysarthria induced by, 157 tremor induced by, 39, 269
dysgeusia induced by, 158 use in chronic kidney disease, 7
effect on sleep architecture, 283 weight gain induced by, 297, 298,
electrocardiogram before 305, 306
initiation of, 14, 113 xerostomia induced by, 162
headache/pseudotumor cerebri Lithium citrate, 197
induced by, 260 Lithobid. See Lithium
hypercalcemia induced by, 179, Liver function tests, 10, 11, 189–190
184–185 Locoid. See Hydrocortisone butyrate
hyperthyroidism induced by, 185 0.1%
for hyponatremia, 163, 165 Lomefloxacin, xxx, 87
hyponatremia induced by, 163 Long-acting drug preparations, 50–
hypothyroidism induced by, 4, 51
185 absorption after gastric bypass
laboratory monitoring of, 12–14 surgery, 47
lupus erythematosus induced by, side effects of, 51, 56
293 Loperamide, xxxi, 187, 188
mania/hypomania induced by, Lopid. See Gemfibrozil
99 Loratadine, xxxi, 145
maximal plasma concentration of, Lorazepam, xxxv
49 cardiovascular effects of, 117
mean half-life and food effects on dosing and precautions in renal
absorption of, 52 disease, 212
myoclonus induced by, 264 interaction with oral
nausea induced by, 197–198 contraceptives, 95
nephrotic syndrome induced by, mean half-life and food effects on
neuroleptic malignant syndrome Lovastatin, xxxiv, 125, 132
induced by, 294 Lovastatin plus niacin-ER, xxxiv,
neuropathy induced by, 266 135
nystagmus induced by, 265 Lovaza, 133
oculogyric crisis induced by, 265 Loxapine, seizures induced by, 268
once-daily dosing of, 205 Ludiomil. See Maprotiline
Lunesta. See Eszopiclone Macular degeneration, 275

Lupus erythematosus Magnesium, for leg cramps, 241
drug-induced, 203, 293 Magnesium hydroxide, 188
systemic, 91, 96, 142, 239, 264 Malabsorption disorders, 47, 196
Lupus Foundation of America, 293 Malignant catatonia, 295
Lurasidone, xxxv Manerix. See Moclobemide
akathisia induced by, 244 Mania. See also Bipolar disorder
allergic angioedema induced by, after abrupt drug withdrawal, 101
290 drug-induced, 97–99
cardiovascular effects of, 117, 119 antidepressants, 27, 97–98, 99
combined with other SGAs, 57 SLC6A4 gene
cytochrome P450 metabolism polymorphism and, 70
and, 69 antimalarial agents, 87
dose relationships and side effects antineoplastic agents, 83, 88
of, 30 antipsychotics, 23, 99
dosing and precautions in antiretroviral agents, 88, 89
hepatic failure, 194 corticosteroids, 95–96
renal disease, 212 digitalis, 90
dyslipidemias induced by, 126 interferon-α, 92
effect on prolactin level, 176, 181 isoniazid, 83, 87
glycemic dysregulation and lithium, 99
diabetes induced by, 174 stimulants, 98–99
insomnia induced by, 259 insomnia and, 278, 282
mean half-life and food effects on MAOIs. See Monoamine oxidase
absorption of, 55 inhibitors
overdose of, 353 Maprotiline, xxxi, 7, 120
serum level of, 66 Marplan. See Isocarboxazid
sexual dysfunction induced by, Matulane. See Procarbazine
216 Maxaquin. See Lomefloxacin
somnolence or sedation induced Maximal blood concentration of
by, 259 drug (Cmax), 47–48, 49, 50
summary of adverse effects of, MDMA (3,4-methylenedioxymeth-
386 amphetamine, Ecstasy), 242, 296
vivid dreams induced by, 285 Meclizine, 6
weight changes induced by, 298, Medical conditions, 4, 5–6
301 adverse drug effects in patients
Luvox. See Fluvoxamine with, 73–75
Lyme disease, 239, 264 HIV/AIDS, 73–75
Lymphadenopathy, 4 liver disease, 73, 74
alopecia due to, 142
Ma huang, to promote weight loss, as contraindication to
328 psychotropic therapy, 6, 7
Maca root, for drug-induced sexual differentiating adverse drug
dysfunction, 226 effects from symptoms of, 7–
Macrocytic anemia, 236, 237 8, 16, 28, 43
Index 465
dosing and precautions in gender differences in, 60

hepatic failure, 192–194 in liver disease, 73
renal disease, 210–213 in older adults, 75
dysgeusia due to, 158 Phase I, 48–50, 51
hyperprolactinemia due to, 176 Phase II, 50
nonischemic priapism and, 206 in pregnancy, 331
paresthesias due to, 267 Metamucil, 188
SIADH due to, 164, 165 Metformin
Medical Dictionary for Regulatory for drug-induced diabetes, 170,
Activities (MedDRA), 27 175
Medication history, 8, 16 for drug-induced weight gain,
Mefloquine, xxxii, 87, 120 170, 175, 296, 319, 322
Melatonin myalgias or rhabdomyolysis
for insomnia, 284 induced by, 242
for tardive dyskinesia, 251, 253 Methadone, 120
Mellaril. See Thioridazine drug interactions with
Memantine, xxix, 247 buprenorphine, 57
Memory impairment, quetiapine, 392
benzodiazepine-induced, 282, Methamphetamine, 242
285 Methanol, 166
Menstrual irregularities, drug- Methotrexate, 91
induced, 178 Methylation, 50
Meperidine, interaction with Methylcellulose, 188
MAOIs, 296 3,4-Methylenedioxymethamphet-
Meprobamate, 84, 159 amine (MDMA, Ecstasy), 242,
Mesoridazine, xxxiii, 35, 118 296
Mestranol, 93 Methylin. See Methylphenidate
Metabolic acidosis or alkalosis, 166– Methylphenidate, xxxv, 6
167 alopecia induced by, 142
Metabolic dysregulation, cardiovascular effects of, 34
antipsychotic-induced, xix, 4, 5, for drug-induced cognitive
41, 48, 360 complaints, 246
in children, 72 for drug-induced sedation, 256,
dyslipidemias, 123–129 257
glycemic dysregulation and for drug-induced sexual
diabetes mellitus, 170–175, dysfunction, 227
172, 174–175 for drug-induced weight gain, 315
laboratory monitoring for, 170, 171 for interferon-α–induced
in pregnancy, 331 depression, 93
racial differences in, 173 for sleep attacks, 278
risk determinants for, 128 summary of adverse effects of,
Metabolism of drugs, 48–50 387
drug metabolizer phenotypes, 32, tics induced or exacerbated by,
50, 63, 66–70, 68–69, 72 260
first-pass, 47 weight loss induced by, 326, 330
Metoclopramide, xxxi, 188 orthostatic hypotension induced

for nausea, 197, 198 by, 140
neuroleptic malignant syndrome overdose of, 350
and, 294 paresthesias induced by, 266
Metoprolol, xxxii, 58 peripheral edema induced by, 130
for clozapine-induced restless legs syndrome induced
myocarditis, 139 by, 250
Metronidazole, pancreatitis induced serum level of, 64
by, 198 sexual dysfunction induced by,
Mevacor. See Lovastatin 219, 220
Microcytic anemia, 237 somnolence or sedation induced
Microzide. See Hydrochlorothiazide by, xvii, 28, 38, 258
Midamor. See Amiloride summary of adverse effects of, 383
Midazolam, 235, 264 weight gain induced by, 298, 310
Migraine headache treatments, in children, 72
xxxiv. See also Triptans Mitchell, Silas Weir, xxiv–xxv
Milk of magnesia, 188 Mixed amphetamine salts, xxxv, 388
Minimum effective dose for 50% of Moban. See Molindone
population (ED50), 49 Moclobemide, xxxi, 69, 214
Minipress. See Prazosin Modafinil, xxxiv, 5, 22
Minoxidil, for alopecia, 141, 142 agranulocytosis induced by, 235
Mirtazapine, xxxi, 5 cardiovascular effects of, 58, 115
agranulocytosis induced by, 235 cytochrome P450 metabolism
akathisia and, 243, 245 and, 68, 69
alopecia induced by, 141 dose relationships and side effects
cardiovascular effects of, 116 of, 30
cognitive function and, 249 for drug-induced cognitive
constipation induced by, 188 complaints, 246, 247
dose relationships and side effects for drug-induced sedation, 256, 257
of, 28, 29, 38 headache induced by, 62
dosing and precautions in interaction with oral
hepatic failure, 193 contraceptives, 94
renal disease, 211 lack of efficacy for drug-induced
drug interactions with, 391 weight gain, 315
for drug-induced sexual myalgias induced by, 241
dysfunction, 214, 227 overdose of, 352
effect on sleep architecture, 280 rash induced in children by, 152,
headache induced by, 263 154
for hyperhidrosis, 143 receptor occupancy and effects of,
hyponatremia induced by, 164 58
for insomnia, 282, 284 for sleep apnea, 282
mean half-life and food effects on for sleep attacks, 277, 278
absorption of, 53 summary of adverse effects of, 387
for nightmares, 285 switching from stimulant drug to,
for older adults, 79 326
Index 467
for urinary incontinence, 202 Mortality

urinary retention induced by, 202 antipsychotic-related, in elderly
Molindone, xxxiii, 268 dementia patients, 27, 32, 35,
Mometasone furoate 0.1%, 151 75–76
Monoamine oxidase inhibitors sudden cardiac death
(MAOIs) antipsychotics and, 115, 118, 121
cardiovascular effects of, 121 TCAs and, 115
hypertensive crisis, 138, 292, Motor tics, drug-induced, 260–261
138, 292, 340 Moxifloxacin, xxx, 120
orthostatic hypotension, 121, Mucositis, 159
140 MUDPILES mnemonic, 166
cognitive function and, 249 Muromonab-CD3, xxxiii, 92
discontinuation syndrome with, Muscarinic M1 receptors, 58
292 Muscle relaxants, xxxiv
drug interactions with, 296, 328, Muscle rigidity, 241, 294
391 Muscle twitches/fasciculations, 261,
general anesthesia, 138, 391 263–264
effect on sleep architecture, 280 Musculoskeletal effects of drugs
hyponatremia induced by, 163 joint pain or stiffness, 239–240
nystagmus induced by, 265 leg cramps, 240–241
overdose of, 360 myalgias, 241–242
serum level of, 64 Myalgias
sexual dysfunction induced by, drug-induced, 241–242
220 fibrates, 134
sleep attacks induced by, 277, 278 statins, 132
switching from other in drug-induced lupus
antidepressants to, 6 erythematosus, 293
weight changes induced by, 298, due to antidepressant
310 discontinuation, 292
Mood stabilizers. See also Mycophenolate mofetil, xxxiii, 92, 96
Anticonvulsants; Lithium Mydriasis, drug-induced, 58
adherence to, 42 Myeloproliferative response
during breast-feeding, 332 to clozapine, 139
cardiovascular effects of, 116 to lithium, 14, 233
cognitive effects of, 248–249 Myelosuppression, drug-induced,
diarrhea induced by, 188 xviii, 231–235
dosing and precautions in resolution after drug cessation,
hepatic failure, 192 234–235
renal disease, 210–211 specific drugs
mean half-life and food effects on antineoplastic agents, 234
absorption of, 52 antipsychotics, 233
overdose of, 344–347 carbamazepine, 9, 231, 232
for steroid-induced mania, 96 clozapine, 34, 63, 231, 233,
underdosing of, 42–43 234
Morphine, 264 treatment of, 233–234
Myocarditis, drug-induced induced by weight loss

clozapine, 35, 122, 139 supplements, 328, 329
quetiapine, 139 management of, 197–198, 291, 292
Myoclonus, 264 placebo-induced, 18
in serotonin syndrome, 295 Navane. See Thiothixene
Myoglobinuria, 290, 294 NDI (nephrogenic diabetes
Mysoline. See Primidone insipidus), 41, 203–204
Nefazodone, xxxi
Naloxone, for divalproex overdose, clitoral priapism induced by, 207
344 cognitive effects of, 249
Naltrexone, xxix cytochrome P450 metabolism
combined with bupropion for and, 69
drug-induced weight gain, dose relationships and side effects
318 of, 30
effect on body weight, 298 dosing and precautions in
Namenda. See Memantine hepatic failure, 193
Naranjo Scale, 22, 24–25 renal disease, 212
Narcolepsy, 277 effect on sleep architecture, 280
treatments for, xxxiv hepatic effects of, 34, 37, 190
Nardil. See Phenelzine mean half-life and food effects on
Nasal congestion, prazosin-induced, absorption of, 53
58 for older adults, 79
Nasal decongestants, xxxiv overdose of, 350
National Cholesterol Education serum level of, 62, 64
Program Expert Panel on summary of adverse effects of,
Detection, Evaluation, and 383
Treatment of High Blood weight changes induced by, 310,
Cholesterol in Adults (ATP III 312, 326
Panel), 124, 129 Negative therapeutic reactions, 20–
National Kidney Foundation, 205, 21
206 Neonatal drug withdrawal, 335, 338
National Library of Medicine, 393 Neoral. See Cyclosporine
National Registry of Drug-Induced Nephrogenic diabetes insipidus
Ocular Side Effects, 273 (NDI), 41, 203–204
Nausea/gastrointestinal upset Nephrolithiasis, 207
drug-induced, 197–198, 361, 382– Nephrotic syndrome, 131
388 lithium-induced, 203
dose relationships and, 30 Nervousness
due to drug overdose, 339 drug-induced, 100
lithium, 197–198 clonidine, 89
niacin, 134 opiates, 84
SNRIs, 59 tramadol, 84
SSRIs, 29, 38, 44–45, 59, 197 placebo-induced, 18
due to antidepressant Neural tube defects, anticonvulsants
discontinuation, 291, 292 and, 196, 335, 336
Index 469
Neuroleptic malignant syndrome Neutropenia, drug-induced, 231

(NMS), 39, 41, 267, 294–295 antipsychotics, 233
differential diagnosis of, 241, 294 mirtazapine, 235
drugs associated with, 294 psychotropic agents
emergency management of, 294– contraindicated in, 7
295, 343 treatment of, 233–234
in HIV/AIDS, 73 Niacin, xxxiv, 134
hyponatremia leading to, 164 Niaspan. See Niacin
symptoms of, 294 Nicotine, 115
Neurological effects of drugs, xix, Nicotinic acid, xxxiv, 134
243–271 Nifedipine, xxxii, 240
akathisia and extrapyramidal side anticholinergic delirium induced
effects, 243–245, 244 by, 250
cognitive complaints, 245–247, for hypertensive crisis, 137, 138
248–249 interaction with lithium, 390
delirium and encephalopathy, Nightmares
247, 250 drug-induced, 285–286
due to drug overdose, 339 efavirenz, 88
dyskinesias and dystonias, 250–256 in posttraumatic stress disorder,
restless legs syndrome, 250– 285
251 Nimodipine, 240, 241
tardive dyskinesia, 251–255 Nitrazepam, for nightmares, 286
withdrawal dyskinesias, 22, Nitric oxide, 217, 219, 222, 253
255–256 Nizatidine, xxxiii, 323
emergency management of, 342 Nizoral. See Ketoconazole
fatigue and sedation, 256–257, NMS. See Neuroleptic malignant
258–259 syndrome
headache, 257, 260, 262–263 NNH (number needed to harm) and
motor tics, 260–261 NNT (number needed to treat),
muscle twitching, fasciculations, 37, 360–361
and myoclonus, 261, 263–264 Nocebo phenomenon, xvi, 16–20, 43
nystagmus, 264–265 minimizing and differentiating
oculogyric crisis, 265–266 from true drug effects, 19–20
paresthesias and neuropathies, personality and, 18
266–267 predictors of, 16–17
seizures, 267–268 psychodynamic theory of, 18–19
tinnitus, 268 in specific psychiatric disorders,
tremor, 268–270 18
yawning, 270–271 therapeutic alliance and, 20
Neurological examination, 4 Nolvadex. See Tamoxifen
Neurontin. See Gabapentin Nonarteritic anterior ischemic optic
Neuropathies, drug-induced, 266– neuropathy, phosphodiesterase
267 type 5 inhibitor–induced, 218
Neuroticism, 18 Nonmedical psychotherapists, 105–
Neurovegetative signs, 5, 8 109
Nonsteroidal anti-inflammatory Obsessive-compulsive behavior,

drugs (NSAIDs) drug-induced
alopecia induced by, 142 azathioprine, 92
for drug-induced lupus efavirenz, 88
erythematosus, 293 Oculogyric crisis, 265–266
gastrointestinal bleeding induced Ofloxacin, xxx, 87, 120
by, 235 Olanzapine, xxxv
SSRIs and, 188, 189, 392 akathisia induced by, 244
hemolytic anemia induced by, 236 cardiovascular effects of, 119
hepatic effects of, 190 cytochrome P450 metabolism
interaction with lithium, 390 and, 68
for joint pain, 240 for developmental stuttering, 157
leg cramps induced by, 240 dosing and precautions in
for nephrogenic diabetes hepatic failure, 194
insipidus, 204 renal disease, 212
oral lesions induced by, 159 drug interactions with
peripheral edema induced by, 129 benzodiazepines, 391
for photosensitivity reactions, 144 fluvoxamine, 50
pruritus induced by, 145 dyslipidemias induced by, 124, 126
Norclozapine, 125, 319 effect on sleep architecture, 281
Norflex. See Orphenadrine glycemic dysregulation and
Norfloxacin, xxx, 120 diabetes induced by, 171, 174
Norfluoxetine, 53, 65 hyperprolactinemia induced by,
Noroxin. See Norfloxacin 182
Norpace. See Disopyramide insomnia induced by, 259
Nortriptyline, xxxi, 49 for maintenance treatment of
mean half-life and food effects on bipolar disorder, 37
absorption of, 54 mean half-life and food effects on
serum level of, 15, 65 absorption of, 55
Norvasc. See Amlodipine metabolism of, 67
NSAIDs. See Nonsteroidal anti- mortality risk in elderly dementia
inflammatory drugs patients, 75
Number needed to harm (NNH) and myalgias induced by, 241
number needed to treat (NNT), nondevelopmental stuttering
37, 360–361 induced by, 157
Numorphan. See Oxymorphone number needed to harm analyses
Nuva-Ring, 95 of, 37–38
Nuvigil. See Armodafinil nystagmus induced by, 265
Nystagmus, 264–265, 269 oculogyric crisis induced by, 265,
266
Obesity/overweight, 5, 28 overdose of, 354
due to drug-induced weight gain, pancreatitis induced by, 198
296–326, 298 peripheral edema induced by,
dyslipidemia and, 123 130
hepatic disease and, 190 priapism induced by, 207
Index 471
restless legs syndrome induced Opiate partial agonists, xxxiv

by, 251 Opiates, xxxiv
for SSRI–induced apathy, 102 dysarthria induced by, 157
serum level of, 66 hyperammonemia induced by, 195
sexual dysfunction induced by, hyperprolactinemia induced by,
215, 216 176
sialorrhea induced by, 159 interaction with MAOIs, 391
somnolence or sedation induced intoxication or withdrawal from,
by, 259 106
summary of adverse effects of, 386 for pain, 84
tardive dyskinesia and, 251, 255 pruritus induced by, 145
urinary incontinence induced by, Oral contraceptives, 93–95, 107
202 alopecia induced by, 142
weight gain induced by, 28, 45, drug interactions with, 12, 94–95
48, 60, 298, 301 lamotrigine, 389
in children, 72 hepatic effects of, 190
due to appetite stimulation, macrocytic anemia induced by, 236
299 for polycystic ovary syndrome, 179
predictors of, 299, 304 Oral hypoglycemic agents, 170, 173,
switching medication due to, 175, 241
326 Oral lesions, drug-induced, 158–159
time course and magnitude of, Oralube saliva substitute, 162
304 Orap. See Pimozide
with Zydis formulation, 304– Oretic. See Hydrochlorothiazide
305 Organization of Teratology
Zydis preparation of, 48, 304–305 Information Specialists (OTIS),
Olanzapine-fluoxetine combination, 393
36 Orgasmic disorders, 214, 215, 217,
Older adults, 75–76, 77–79. See also 219, 229. See also Sexual
specific drugs dysfunction
Oligomenorrhea, 177, 178 Orlistat, for drug-induced weight
Oliguria, 6 gain, 296, 324
Omega-3 fatty acids Orodispersible drugs, 48
for dyslipidemias, 125, 128, 133 Orphenadrine, xxx, 240
for lithium-induced psoriasis, 152 Orthoclone OKT3. See Muromonab-
Omeprazole, xxxiii, 189, 190 CD3
Ondansetron, xxxi, 120 Orthostatic hypotension, drug-
Opana ER; Opana IR. See induced, 140
Oxymorphone α1-adrenergic antagonists, 58, 89,
Ophthalmological effects of drugs, 140
273–275 atomoxetine, 140
cataracts, 273–274 cannabinoids, 140
diplopia/blurred vision, 274 conservative management of, 140
glaucoma, 274–275 dose relationships and, 30
retinopathies, 275 MAOIs, 121, 140
Orthostatic hypotension, drug- mean half-life and food effects on

induced (continued) absorption of, 52
mirtazapine, 140 monohydroxy-derivative, 48–49,
in older adults, 76 51
prazosin, 286 oculogyric crisis induced by, 265
quetiapine, 28 for older adults, 76, 77
SGAs, 114, 140 overdose of, 346
SNRIs, 78, 140 reduction of, 48–49, 51
TCAs, 48, 121, 140 SIADH induced by, 76
Orthostatic tremor, 270 somnolence or sedation induced
Osteoporosis/osteopenia by, 258
drug-induced, 48, 169–170 suicidality and, 103
hyperprolactinemia as risk factor summary of adverse effects of,
for, 176 385
vitamin B12 or folic acid for tremor, 270
deficiency and, 196 vitamin B12 and folic acid
OTIS (Organization of Teratology deficiencies induced by, 196
Information Specialists), 393 Oxidation reactions, 48
Overdose of drug, 339, 344–355, 360. Oxybutynin, xxx, 39
See also specific drugs for enuresis and urinary
Oxazepam, xxxv incontinence, 202, 203
dosing and precautions in renal for hyperhidrosis, 143
disease, 212 for sialorrhea, 160
interaction with oral Oxycodone, xxxiv, 84
contraceptives, 95 Oxycontin. See Oxycodone
Oxcarbazepine, xxx Oxymorphone, xxxiv, 84
allergic angioedema induced by,
290 Pain
cardiovascular effects of, 116 analgesics for, xxxiv, 84
cognitive effects of, 248 joint, 239–240, 293
cytochrome P450 metabolism neuropathic, 267
and, 69 postoperative management of, 108
dose relationships and side effects somatoform pain disorders, 144
of, 30 stomatodynia, 161
dosing and precautions in Paliperidone, xxxv
hepatic failure, 192 akathisia induced by, 244
renal disease, 211 cardiovascular effects of, 119
drug interactions with cytochrome P450 metabolism
MAOIs, 391 and, 69
oral contraceptives, 94 dose relationships and side effects
headache induced by, 262 of, 30
hyponatremia induced by, 163 dosing and precautions in
insomnia induced by, 258 hepatic failure, 194
lupus erythematosus induced by, renal disease, 213
293 dyslipidemias induced by, 126
Index 473
glycemic dysregulation and Parenteral drug administration, 47

diabetes induced by, 174 Paresthesias, drug-induced, 266–267
hyperprolactinemia induced by, dose relationships and, 30
176, 177, 182 Parkinsonism, antipsychotic-
insomnia induced by, 259 induced, 59, 244. See also
mean half-life and food effects on Extrapyramidal side effects
absorption of, 55 Parkinson’s disease, 87, 140, 264,
metabolism of, 67 277
myalgias induced by, 241 Parnate. See Tranylcypromine
overdose of, 354 Paroxetine, xxxi
sexual dysfunction induced by, 216 allergic angioedema induced by,
by, 259 apathy induced by, 102
summary of adverse effects of, 386 cardiovascular effects of, 116
weight changes induced by, 301 cataracts induced by, 274
Palpitations, 113, 114–115 colitis induced by, 188
Pamelor. See Nortriptyline constipation induced by, 188
Pancreatitis cytochrome P450 metabolism
drug-induced, 198–199 and, 68
antipsychotics, 197 depression severity and side
divalproex, 11, 35, 197, 198, 341 effects of, 71
management of, 199, 341 dermatological effects of, 149
hypertriglyceridemia and, 124 dose relationships and side effects
Pancytopenia, lamotrigine-induced, of, 30, 31
235 dosing and precautions in renal
Panic, drug-induced, 100. See also disease, 212
Anxiety generic vs. brand-name
antidepressants, 100 formulations of, 61
antimicrobial agents, 87 headache induced by, 263
azathioprine, 92 hyperprolactinemia induced by,
idazoxan, 58 176
phentolamine, 58 insomnia induced by, 258, 279
topiramate, 100 lack of efficacy for tinnitus, 268
yohimbine, 58 mean half-life and food effects on
Panic disorder relapse, after rapid absorption of, 53
antidepressant cessation, 101 myalgias induced by, 241
Pantoprazole, 189 for older adults, 79
Papilin (PAPLN) gene variants, 70 overdose of, 350
Paradoxical adverse effects, 23, 26 prophylaxis for interferon-α–
Paranoia induced depression, 92
drug-induced serotonin type 2A receptor
antiarrhythmic agents, 90 variant and adverse effects
clonidine, 89 of, 67
due to MAOI discontinuation, 292 sexual dysfunction induced by,
Parasomnias, 286–287 214, 220, 223, 225
Paroxetine (continued) Persistent pulmonary hypertension

somnolence or sedation induced of the newborn (PPHN), SSRI
by, 258, 279 exposure and, 335
summary of adverse effects of, 383 Personality
teratogenicity of, 37, 337 L -asparaginase–induced changes
urinary incontinence induced by, in, 88
202 placebo effects and, 18
weight changes induced by, 124, Pharmacodynamics, 4, 21–22, 31
310, 312 adverse effects related to drug
Partial thromboplastin time, 190 receptor targets, 57, 58–59
Pathological gambling, dopamine definition of, 47
agonists and, 87 toxic polypharmacy, 57
Paxil. See Paroxetine Pharmacogenetics, 63
PCOS (polycystic ovary syndrome), Pharmacogenomic predictors of
176, 178–179 adverse drug effects, 63, 66–70,
PDE inhibitors. See Phosphodiesterase 68–69, 72
type 5 inhibitors Pharmacokinetic drug interactions,
Pemoline, 37 50
Pentamidine, 198 with antiretroviral agents, 73–74
Peony-glycyrrhiza decoction, for in medically ill patients, 73
hyperprolactinemia, 178 Pharmacokinetics, 4, 21–22, 32
Peptic ulcer disease, 134, 188, 189 definition of, 47
Pepto-Bismol. See Bismuth factors affecting drug absorption,
subsalicylate 47–48
Pergolide, for restless legs gender differences in side effects,
syndrome, 250 57, 60, 71
Periactin. See Cyproheptadine key concepts related to, 49
Pericarditis, gabapentin-induced, in pregnancy, 331
122 racial differences in side effects, 60
Periodic limb movements during steady-state, 23, 49
sleep, 251, 282 Phase I drug metabolism, 48–50, 51
Peripheral edema, drug-induced, 5, Phase II drug metabolism, 50
77, 129–131, 136, 136–137 Phenazopyridine, xxix, 201, 202
evaluation of, 130–131 Phenelzine, xxxi
management of, 131, 136, 136–137 discontinuation before general
Peripheral neuropathies, drug- anesthesia, 138
induced, 266–267 fasciculations induced by, 264
Perphenazine, xxxiii lupus erythematosus induced by,
alopecia induced by, 142 293
cytochrome P450 metabolism neuroleptic malignant syndrome
and, 68 induced by, 294
lupus erythematosus induced by, neuropathy induced by, 266, 267
293 for nightmares, 286
sexual dysfunction induced by, sexual dysfunction induced by,
215 220
Index 475
sleep attacks induced by, 278 Pirenzepine, xxxiii, 160

weight changes induced by, 310 Placebo, 3
Phenergan. See Promethazine nocebo effects from, 16–20 (See
Phenobarbital, hypersensitivity also Nocebo phenomenon)
reaction to, 290 response rates to, 18
Phentermine, xxxv Plasma elimination half-life of drug
for drug-induced weight gain, (t1/2), 48, 49, 52–55
318–319 Platelet aggregation disorders, drug-
combined with topiramate, 319 induced, 235–236
Phentolamine, xxxii, 58 Plax solution, 162
Phenylalanine, tardive dyskinesia Poison ivy, 152
and, 254 Polycystic ovary syndrome (PCOS),
Phenylephrine, xxxiv, 58 176, 178–179
intracavernous injection for Polydipsia, 204
priapism, 207 Polypharmacy, toxic, 57, 360
Phenytoin, xxx Polyuria, 203, 204, 205
hypersensitivity reaction to, 290 Poor metabolizers, 32, 50, 63, 66–67,
neuropathy induced by, 267 68–69, 72
Phosphodiesterase (PDE) type 5 Postmarketing drug surveillance, 33,
inhibitors, xxxv 37
myalgias induced by, 241 Posttraumatic stress disorder
for sexual dysfunction, 217–218, (PTSD), 285
222 PPHN (persistent pulmonary
use in women, 217, 222 hypertension of the newborn),
Photosensitivity, drug-induced, 143– SSRI exposure and, 335
144 Pramipexole, 87, 102
Physical examination, 4 for antipsychotic-induced sexual
Physicians’ Desk Reference, 60 dysfunction, 229
Pigmentary retinopathy, for drug-induced cognitive
antipsychotic-induced, 275 complaints, 247
Pilocarpine, for xerostomia, 162 myalgias induced by, 241
Pimozide, xxxiii for restless legs syndrome, 250,
cardiovascular effects of, 117 282
cytochrome P450 metabolism sleep attacks induced by, 277
and, 69 Pravachol. See Pravastatin
interaction with fluvoxamine, 389 Pravastatin, xxxiv, 125, 132
myalgias induced by, 241 Prazosin, xxxii, 58, 89, 140
seizures induced by, 268 for nightmares, 285–286
for tic disorders, 261 Prednicarbate 0.05%, 151
Pindolol Prednisone, 86, 91, 96, 242, 360
lupus erythematosus induced by, Pregabalin
293 dosing and precautions in renal
sick sinus syndrome as disease, 211
contraindication to, 114 suicidality and, 103
Piracetam, for tardive dyskinesia, 253 weight changes induced by, 298
Pregnancy and puerperium, 331– Prograf. See Tacrolimus

338. See also Teratogenicity of Prolactin serum level
drugs drug-induced elevation of, 175–
breast-feeding and adverse drug 178, 180–183 (See also
events, 332, 393 Hyperprolactinemia)
psychotropic drug use in, 33 drug-induced sexual dysfunction
anticonvulsants, 196 and, 214–215, 229
carbamazepine, 336 Promethazine, xxxi
divalproex, 36, 179, 335, 336 for nausea, 197, 198, 291, 292
lamotrigine, 12, 336 for pruritus, 145
topiramate, 337 Pronestyl. See Procainamide
antidepressants Propafenone, xxix, 120
fetal growth effects of, 332 Propranolol, xxxii, 22, 58, 90
SSRIs, 37, 331, 335, 337 for akathisia, 243, 245
guidelines for, 334–335 for bruxism, 156
lithium, 335, 337 long-acting preparations of, 269
neonatal withdrawal and, 335, for myoclonus, 264
338 nystagmus induced by, 265
teratogenicity of, 33, 331, 332– for older adults, 90
336, 333, 336–337 for tremor, 269
Web sites for information on, Propylene glycol, 166
393 Propylthiouracil, 142
Premature ejaculation, 214. See also Protease inhibitors, 74, 88
Sexual dysfunction Protein binding of drugs, in older
Premature ventricular complexes adults, 76
(PVCs), 114–115 Proteinuria, 131, 203
Priapism, drug-induced, 206–207 Prothrombin time, 190
Prilosec. See Omeprazole Proton pump inhibitors, 188, 189
Primary care physicians, Provigil. See Modafinil
collaboration with, 5 Prozac. See Fluoxetine
Primary care psychiatry, 3–7 PRSexDQ (Psychotropic-Related
Primidone, xxx, 69 Sexual Dysfunction
for tremor, 269–270 Questionnaire), 209, 395
Primum non nocere, 3 Pruritus, drug-induced, 144–145
Pristiq. See Desvenlafaxine Pseudoephedrine, xxxiv, 207
Probiotics, 188 Pseudotumor cerebri, lithium-
Procainamide, xxix, 90, 120, 293 associated, 260
Procarbazine, xxxii, 83, 88 Psorcon. See Diflorasone diacetate
Procardia. See Nifedipine 0.05%
Prochlorperazine, xxxi, 6, 22, 120 Psoriasis, 149, 152
for nausea, 197, 198, 292 Psychiatric effects of
neuroleptic malignant syndrome nonpsychotropic drugs, 83–96
induced by, 294 analgesics, 84
Progabide, 254 anticholinergics, 85
Progestins, 93–95 anticonvulsants, 85
Index 477
antimicrobial agents, 85–86, 87 FDA warnings and precautions,

antineoplastic agents, 86, 88 3n, 32, 34–36, 71n, 75, 76, 83n,
antiparkinsonian agents, 87 95, 97n, 103, 113n, 118, 122,
antiretroviral agents, 87–89 139, 141n, 152, 153, 187n, 190,
cardiovascular drugs, 89–90 193, 198, 231n, 232, 233, 243n,
corticosteroids, 95–96 267, 275, 289n, 290
dermatological agents, 90–91 known vs. unknown drug risks,
gastrointestinal agents, 91 33, 37–38
immunosuppressants, 91, 92 laboratory monitoring of
interferon-α, 92–93 psychotropic agents, 6–7, 9–15
oral contraceptives and medical comorbidities and
intravaginal rings, 93–95 psychotropic therapy, 4, 5–6,
smoking cessation aids, 95 7
Psychiatric effects of psychotropic negative therapeutic reactions,
agents, 97–104 20–21
activation and mania/hypomania nocebo phenomenon and
or mixed states, 97–99, 99 proneness to adverse effects,
anxiety and panic, 100 16–20
in clinical trial subjects with paradoxical adverse effects, 23, 26
psychiatric illness, 100 primary care psychiatry, 3–7
discontinuation syndromes, 101 risk-benefit analyses, 33, 359–361
disinhibition and impaired self-assessment questions and
impulse control, 101 answers, 363–380
emotional dulling, 101–102 shared decision-making with
psychosis, 102–103 patients, 33
suicidal thinking or behavior, treatment adherence and adverse
103–104 effects, xvi, xxiv, 23, 40, 42–
Psychiatric review of symptoms, 8, 16 43, 361
Psychiatrist as physician, xxiv–xxv, watchful waiting, 38–39
3–45 Psychic distress, clonidine-induced,
approach to assessing adverse 89
drug effects, 43–45 Psychomotor activation, drug-
attribution and causality of side induced, 97, 98, 106
effects, 21–23, 24–25, 43–44 Psychosis
deciding when to pursue after abrupt benzodiazepine
antidotes and when to switch withdrawal, 101
medicines, xvii, 39–40, 41 drug-induced, 102–103
differentiating adverse drug α1-adrenergic antagonists, 89
effects from primary illness antiarrhythmic agents, 90
symptoms, 7–8, 16, 43 anticonvulsants, 85
dose relationships and adverse antimicrobial agents, 85, 87
effects, 28–32, 30–31 antineoplastic agents, 88
extrapolating evidence-based antiretroviral agents, 88, 89
research findings to real- bupropion, 102
world patients, 26–28, 40 corticosteroids, 91, 95–96
Psychosis (continued) Quetiapine, xvii, xxxv

drug-induced (continued) adverse effects of short- vs. long-
dopamine agonists, 87, 102 acting preparations of, 56
fluvoxamine, 102 agitation induced by, 56
immunosuppressants, 91, 92 akathisia induced by, 244, 244
isotretinoin, 90–91 cardiovascular effects of, 119
opiates, 84 myocarditis, 139
stimulants, 102 cataracts induced by, 273–274
venlafaxine, 102 cytochrome P450 metabolism
zolpidem, in children, 102–103 and, 69
in serotonin syndrome, 295 dose relationships and side effects
Psychotherapists, nonmedical, 105– of, 28, 30, 31
109 dosing and precautions in
Psychotherapy, 21, 81, 106 hepatic failure, 194
Psychotropic-Related Sexual renal disease, 213
Dysfunction Questionnaire drug interactions with, 392
(PRSexDQ), 209, 395 dyslipidemias induced by, 124,
Psyllium, 188 126
PTSD (posttraumatic stress effect on prolactin level, 176, 182
disorder), 285 effect on sleep architecture, 281
Purpura, 149, 340 exposure time and side effects of,
PVCs (premature ventricular 29
complexes), 114–115 glycemic dysregulation and
Pyridium. See Phenazopyridine diabetes induced by, 174
Pyridoxine hypothyroidism induced by, 185,
phenelzine-induced deficiency of, 186
267 insomnia induced by, 259
for tardive dyskinesia, 251, 253 mean half-life and food effects on
absorption of, 55
QTc interval prolongation, 115 metabolism of, 67
classification of risk associated mortality risk in elderly dementia
with, 118 patients, 75
congenital, 120, 121 number needed to harm analyses
drug-induced, 120 of, 38
antipsychotics, 15, 35, 117, for oculogyric crisis, 266
118–121, 119, 353–355, 392 overdose of, 354
atomoxetine, 344 pancreatitis induced by, 198
desvenlafaxine, 348 peripheral edema induced by,
dose relationships and, 30 130
lorazepam, 117 priapism induced by, 207
maprotiline, 120 for SSRI–induced apathy, 102
SSRIs, 116, 121, 348, 349 serum level of, 66
trazodone, 120 sexual dysfunction induced by,
TCAs, 117, 120, 121 214, 215, 216
factors associated with, 120 sialorrhea induced by, 160
Index 479
somnolence or sedation induced Reboxetine

by, 28, 29, 56, 259 for drug-induced weight gain,
suicidality and, 36 319
summary of adverse effects of, hyponatremia induced by, 164
386 Red blood cells, decreased
for tardive dyskinesia, 255 production of, 236, 237
tardive dyskinesia induced by, Reduction reactions, 48
251 Regitine. See Phentolamine
vivid dreams induced by, 285 Reglan. See Metoclopramide
weight changes induced by, 298, REM (rapid eye movement) sleep
302 parasomnias during, 286–287
in children, 72 psychotropic drug effects on, 279,
Quinidine, 90, 120, 293 280, 281, 283, 285
interaction with quetiapine, 392 “Remedicalization” of psychiatry, 4
Quinine, for leg cramps, 240 Remeron. See Mirtazapine
Reminyl. See Galantamine
Racemic vs. enantiomeric drugs, 61 Renal disease
Racial differences acute renal failure, 6
in cytochrome P450 isoforms, 60 chronic, classification of, 205, 206
in drug metabolizer phenotypes, dosing and precautions for
68, 69 psychotropic drug use in,
in drug side effects, 60 210–213
antipsychotic-induced HIV nephropathy, 75
glycemic dysregulation, lithium contraindicated in, 7
60, 172, 173 Renal effects of drugs, 201–208
carbamazepine-induced skin due to drug overdose, 339
rashes, 152–153 dysuria and urinary retention,
extrapyramidal side effects, 60 201–202
Ramelteon, xxxv enuresis and urinary
hyperprolactinemia induced by, incontinence, 202–203
176 nephrotic syndrome, 203
for insomnia, 284, 285 nephrotoxicity and nephrogenic
interaction with fluvoxamine, 389 diabetes insipidus, 203–206,
Ramipril, xxxi, 390 206
Ranitidine, xxxiii, 91 renal calculi, 207–208
Rapamune. See Rapamycin renal insufficiency, 208
Rapamycin, xxxiv, 92 renal tubular acidosis, 166, 167
Rapid eye movement (REM) sleep specific drugs
parasomnias during, 286–287 anticholinergic agents, 201
psychotropic drug effects on, 279, chromium picolinate, 327
280, 281, 283, 285 fibrates, 134
Rash. See Skin rashes lithium, 13, 166, 167, 203–205,
Rating scales for side effects, 44, 394– 208
395 SGAs, 202, 203
Razadyne. See Galantamine SNRIs, 201–202
Renal function number needed to harm and

monitoring during lithium number needed to treat, 37–
therapy, 13 38, 360–361
in older adults, 77–79 periodic reassessments of, 362
Renal tubular acidosis, 166, 167 Risperdal. See Risperidone
REPROTOX information system, 393 Risperdal M-Tabs. See Risperidone,
Research trials orally dissolving
drug adverse effects in subjects Risperidone, xxxv
with psychiatric illness in, 100 akathisia induced by, 244, 244
extrapolating findings to real- allergic angioedema induced by,
world patients, 26–28, 40 290
Respiratory alkalosis, 167 cardiovascular effects of, 117, 119,
Restless legs syndrome (RLS), 87, 122
250–251, 278, 282, 286 cerebrovascular accidents
Restlessness, drug-induced. See also associated with, 123
Akathisia combined with other SGAs, 57
modafinil, 58 cytochrome P450 metabolism
nonmedical therapists’ and, 68, 69
perception of, 106 for developmental stuttering, 157
phenylephrine, 58 dose relationships and side effects
Restoril. See Temazepam of, 30, 31
Reticulocytopenia, 236, 237 dosing and precautions in
Retin-A. See Tretinoin hepatic failure, 194
Retinoids, topical, 148, 149 renal disease, 213
Retinopathy, antipsychotic-induced, drug metabolizer phenotype and
275 response to, 67
Retrovir. See Zidovudine dyslipidemias induced by, 124, 126
Revia. See Naltrexone effect on sleep architecture, 281
Review of systems, psychiatric, 8, 16 glycemic dysregulation and
Rhabdomyolysis, 241–242, 290, 329 diabetes induced by, 171, 175
vs. neuroleptic malignant hyperprolactinemia induced by,
syndrome, 241, 294 176, 177, 183
Rheumatoid arthritis, 142 insomnia induced by, 259
Ribavirin, 142 interaction with fluoxetine, 202
Riboflavin, 240 mania/hypomania induced by,
Rifadin. See Rifampin 99
Rifampin, xxx, 87, 199 mean half-life and food effects on
Right bundle branch block, 114 absorption of, 55
Rimactane. See Rifampin mortality risk in elderly dementia
Risk–benefit analyses, xvi, xxiv, 3, 4, patients, 75
5, 33, 359–361 myalgias induced by, 241
of antidotes for adverse effects, 39 nondevelopmental stuttering
effect size and, 38, 360 induced by, 157
forecasting probability of side orally dissolving, 48
effects, 45 overdose of, 355
Index 481
peripheral edema induced by, 130 Rozerem. See Ramelteon

phototoxicity of, 144 Ruflox. See Rufloxacin
priapism induced by, 207 Rufloxacin, xxx, 87, 120
restless legs syndrome induced Rythmol. See Propafenone
by, 251
serum level of, 66 Salicylic acid, for psoriasis, 149
sexual dysfunction induced by, Saliva substitutes, 162
215, 216 Salivart Oral Moisturizer, 162
retrograde ejaculation, 229 Salivary stimulants, 162
sialorrhea induced by, 159–160 Sambucus nigra, to promote weight
side effects in children, 72 loss, 329
somnolence or sedation induced Sandimmune. See Cyclosporine
by, 259 Saphris. See Asenapine
summary of adverse effects of, 387 Sarafem. See Fluoxetine
tardive dyskinesia induced by, 251 Schizophrenia
urinary incontinence induced by, diabetes mellitus and, 170–171
202 nocebo phenomenon in, 18
weight gain induced by, 60, 298, Seborrhea, 150
302 Sedation, 43
due to appetite stimulation, drug-induced, 41, 256–257, 258–
299 259, 382–388
predictors of, 299, 304 administration schedule and,
switching medication due to, 40
326 anticholinergic agents, 39, 85,
withdrawal dyskinesias 160
associated with, 255 anticonvulsants, 258
Ritalin, Ritalin LA. See antidepressants, 258
Methylphenidate antihistamines, 256, 257
Ritonavir, 74 antipsychotics, 58, 259
Rituxan. See Rituximab atenolol, 58
Rituximab, xxxii, 92 carisoprodol, 84
RLS (restless legs syndrome), 87, clonidine, 58, 89, 143
250–251, 278, 282, 286 diphenhydramine, 58
Robinul. See Glycopyrrolate dose relationships and, 28, 29,
Romberg sign, 269 30
Ropinirole, 87, 102 due to drug overdose, 339
for antipsychotic-induced sexual guanfacine, 58
dysfunction, 229 management of, 256, 257
fasciculations induced by, 264 metoprolol, 58
myalgias induced by, 241 mirtazapine, xvii, 28, 38
for restless legs syndrome, 251, quetiapine, xvii, 28, 29, 56
282 risperidone, in children, 72
sleep attacks induced by, 277 terazosin, 143
Rosuvastatin, xxxiv, 132 TCAs, 58
Roxicodone. See Oxycodone placebo-induced, 18
Sedative-hypnotics, xxxv. See also diarrhea induced by, 187–188

Benzodiazepines; specific drugs discontinuation syndrome with,
cardiovascular effects of, 117 240, 291–292
dysarthria induced by, 157 in newborn, 335
for insomnia, 278, 282, 284, 284– dosing and precautions in
285 hepatic failure, 193
intoxication or withdrawal from, renal disease, 211, 212
106 drug interactions with, 392
parasomnias induced by, 286, 287 MAOIs, 391
paresthesias induced by, 266 dysarthria induced by, 157
sexual dysfunction induced by, effect on sleep architecture, 279,
218 280
Seizures emotional dulling induced by,
drug-induced, 267–268 101–102
bupropion, 29, 267 gastrointestinal bleeding induced
clozapine, 29, 35, 267–268 by, 188–189, 235, 392
dose relationships and, 30 glycemic dysregulation and
due to drug overdose, 339 diabetes induced by, 173, 175
emergency management of, 342 headache induced by, 29, 38, 39–
other antipsychotics, 268 40, 257, 262–263
tiagabine, 23 hyperhidrosis induced by, 142, 143
gelastic, 260 hyperprolactinemia induced by,
hyperammonemia induced by, 176
195 hyponatremia or SIADH induced
psychotropic agents by, 76, 163, 164
contraindicated for patients insomnia induced by, 279, 282
with, 7 mean half-life and food effects on
in SIADH, 164 absorption of, 53
Selective serotonin reuptake myalgias induced by, 241
inhibitors (SSRIs). See also myoclonus induced by, 264
specific drugs nausea induced by, 29, 38, 44–45,
akathisia induced by, 243–244 59, 197
alopecia induced by, 141, 142 oculogyric crisis induced by, 265
bruxism induced by, 155–156, 156 for older adults, 78, 79
cardiovascular effects of, 116, 120, osteoporosis induced by, 48, 169–
121 170
hypercholesterolemia, 123–124 overdose of, 347–351
orthostatic hypotension, 78, 140 parasomnias induced by, 287
QTc interval prolongation, paresthesias induced by, 266, 267
116, 121, 348, 349 periodic limb movements during
cataracts induced by, 274 sleep induced by, 282
cognitive function and, 246, 249 in pregnancy, 37, 331, 335, 337
constipation induced by, 188 priapism induced by, 206, 207
cytochrome P450 metabolism prophylaxis for interferon-α–
and, 68, 69 induced depression, 92
Index 483
for pruritus, 145 Selenium, for alopecia, 141, 142

psychosis induced by, 102 Self-assessment questions and
restless legs syndrome induced answers, 363–380
by, 250–251 Self-harm. See also Suicidality
serotonergic receptor occupancy varenicline-induced, 95
and effects of, 59 Senna, 188
serotonin syndrome and, 296, 343 Sensipar. See Cinacalcet
serum level of, 65 Serax. See Oxazepam
sexual dysfunction induced by, Serentil. See Mesoridazine
59, 70, 209, 214, 220–221 Seroquel. See Quetiapine
persistence after drug Serotonergic (5-HT) receptors, 59
cessation, 229 nausea related to drug affinity
pharmacological management for, 197
of, 215, 217–219, 222–228 sexual dysfunction related to
somnolence or sedation induced drug affinity for, 214
by, 258 vivid dreams related to drug
stomatodynia and, 161 affinity for, 285
suicidality and, 104, 244 Serotonin-norepinephrine reuptake
summary of adverse effects of, inhibitors (SNRIs). See also
382–384 specific drugs
teratogenicity of, 335, 337 cardiovascular effects of, 116
tinnitus induced by, 268 hypertension, 137–138, 340
tolerance to side effects of, 29 orthostatic hypotension, 78, 140
urinary incontinence induced by, cataracts induced by, 274
202 cognitive function and, 246, 249
urinary retention induced by, 201 constipation induced by, 188
weekend holidays from, 215 diarrhea induced by, 188
weight changes induced by, 298, discontinuation syndrome with,
308–310, 312, 316, 326, 330 6, 240, 291–292
yawning induced by, 270 dosing and precautions in
Selegiline, 240 hepatic failure, 193, 194
fasciculations induced by, 264 renal disease, 211, 212
transdermal, xxxi effect on sleep architecture, 280
discontinuation before general headache induced by, 262–263
anesthesia, 138 hepatic effects of, 190
dosing and precautions in hyperhidrosis induced by, 142,
hepatic failure, 193 143
renal disease, 212 hyponatremia induced by, 163–
for older adults, 79 164
sexual dysfunction induced insomnia induced by, 282
by, 221 mean half-life and food effects on
summary of adverse effects of, absorption of, 53
384 myalgias induced by, 241
weight changes induced by, nystagmus induced by, 265
298, 310 for older adults, 78, 79
Serotonin-norepinephrine reuptake dose relationships and side effects

inhibitors (SNRIs) (continued) of, 30
overdose of, 348 dosing and precautions in renal
paresthesias induced by, 266, 267 disease, 212
psychosis induced by, 102 headache induced by, 263
serotonergic receptor occupancy insomnia induced by, 258, 279
and effects of, 59 mean half-life and food effects on
serotonin syndrome and, 296, 343 absorption of, 53
sexual dysfunction induced by, myalgias induced by, 241
59, 209, 214, 219, 220–221 for older adults, 79
somnolence or sedation induced in pregnancy, 337
by, 258 sexual dysfunction induced by,
summary of adverse effects of, 214, 221
382, 384 persistence after drug
tinnitus induced by, 268 cessation, 229
for urinary incontinence, 202 somnolence or sedation induced
urinary retention induced by, by, 258
201–202 stomatodynia and, 161
use in hypertension, 7 summary of adverse effects of, 383
vivid dreams induced by, 285 tics induced or exacerbated by,
weight changes induced by, 298, 261
308, 311, 326, 330 tinnitus induced by, 268
yawning induced by, 270 urinary incontinence induced by,
Serotonin syndrome, 41, 236, 247, 202
254, 263, 264, 265, 295–296 weight changes induced by, 310,
drugs associated with, 296, 343, 312
391, 392 yawning induced by, 270
emergency management of, 295, Serum drug levels, 62–63
296, 343 anticonvulsants, 62–63, 64
Hunter Serotonin Toxicity carbamazepine, 9, 63
Criteria for, 296 divalproex, 11, 62
vs. neuroleptic malignant lamotrigine, 12, 63
syndrome, 294 antidepressants, 64–65
Sternbach criteria for, 295 nefazodone, 62
Serotonin transporter gene variants, TCAs, 15
70 lithium, 12, 64
Sertindole, 118 monitoring of, 62
Sertraline, xxxi SGAs, 65–66
akathisia induced by, 244 clozapine, 10, 125
alopecia induced by, 141 Serzone. See Nefazodone
apathy induced by, 102 Sexual dysfunction
bruxism induced by, 156 in depression, 28, 213
cardiovascular effects of, 116 drug-induced, xix, xvi, 28, 41,
hypercholesterolemia, 123 209–230, 361, 382–388
colitis induced by, 188 dose relationships and, 30, 214
Index 485
gender differences in, 60, 213, Sibutramine, for drug-induced

214 weight gain, 296, 319, 324
impaired arousal, erectile Sick sinus syndrome
dysfunction, and β-blockers contraindicated in, 7,
anorgasmia, 209, 213–229 114, 269
incidence rates of, 209 lithium-induced, 116
past history of, 16 Side effects of drugs
persistence after drug approach to assessment of, 43–45
cessation, 229 attribution and causality of, 21–
pharmacological management 23, 24–25, 43–44
of, 215, 217–219, 222–228 beneficial, xvii
racial differences in, 60 benign vs. easily treatable or
rating scales for, 209, 394–395 dangerous, 361
retrograde ejaculation, 229–230 in children, 72–73
specific drugs conservative management of, 39–
anticonvulsants, 219 40
antidepressants, 209, 213– continuum of severity and
214, 215, 220–221 management of, 39, 41
antipsychotics, 59, 214–215, deciding when to pursue
216–217, 229–230 antidotes and when to switch
β-blockers, 90 medicines due to, xvii, 39–40,
desvenlafaxine, 62 41
divalproex, 215 differentiating from primary
lithium, 215, 219 illness symptoms, 7–8, 16, 28,
sedative-hypnotics, 218 43
SNRIs, 59, 209, 214, 219 disclosure and discussion with
SSRIs, 59, 70, 209, 214 patient about, 42, 44–45, 361–
venlafaxine, 62 362
nonmedical therapists’ dose relationships and, 28–32, 30–
perception of, 106 31, 38
placebo-induced, 18 due to drug overdose, 339, 344–
treatments for, xxxv 355
Sexual response cycle, 209–210 effect size and, 38, 360
SGAs. See Antipsychotics, second- emergency management of, 339,
generation 340–355
Shakuyaku-kanzo-to, for for enantiomeric vs. racemic
hyperprolactinemia, 178 drugs, 61–62
Shingles, 146, 150, 152 evolution over time, 29
Shivering, in serotonin syndrome, exposure time and, 28–29, 38
295 FDA warnings and precautions
SIADH (syndrome of inappropriate for, 3n, 32, 34–36, 71n, 75, 76,
antidiuretic hormone secretion), 83n, 85, 95, 97n, 103, 113n,
76, 163–165, 165 118, 122, 139, 141n, 152, 153,
Sialorrhea, drug-induced, 41, 159– 187n, 190, 193, 198, 231n, 232,
161 233, 243n, 267, 275, 289n, 290
Side effects of drugs (continued) summary recommendations for,

future drug development and, 359–362
362 time course for emergence of, 22
gender differences in, 57, 60, 71 tolerance to, 29
idiosyncratic, 22, 39 transient vs. enduring, 38
for immediate-release vs. long- treatment adherence and, xvi,
acting preparations, 51, 56 xxiv, 23, 40, 42–43, 361
implausible, 22, 23, 43 underdosing and, 42–43
known vs. unknown risks for, 33, watchful waiting for, 38–39
37–38 what nonmedical therapists
in medically ill patients, 73–75 should know about, 105–109
HIV/AIDS, 73–75 Sildenafil, xxxv
liver disease, 73, 74 myalgias induced by, 241
Naranjo Scale for rating for sexual dysfunction, 209, 217–
likelihood of, 22, 24–25 218, 222, 229
nocebo phenomenon and use in women, 217, 222
proneness to, xvi, 16–20 Silenor. See Doxepin
in older adults, 75–76, 77–79 Simcor. See Simvastatin/niacin ER
paradoxical, 23, 26 Simpson-Angus Extrapyramidal
patient history of, 8, 16, 361 Side Effects Scale, 394
patients’ diverse proneness to, Simulect. See Basiliximab
71–72 Simvastatin, xxxiv, 133
pharmacogenomic predictors of, Simvastatin/niacin ER, xxxiv, 135
63, 66–70, 68–69 Sinequan. See Doxepin
polypharmacy and, 57, 360 Single nucleotide polymorphisms, 63
postmarketing surveillance for, Sirolimus, xxxiv, 92
33, 37 Sjögren’s syndrome, 158, 162
psychiatric effects of Skin flushing, drug-induced
nonpsychotropic idazoxan, 58
medications, 83–96 niacin, 134
for psychiatric medications, 97– phentolamine, 58
104 yohimbine, 58
racial differences in, 60 Skin picking, 144
rating scales for, 44, 394–395 Skin rashes. See also Dermatological
related to drug receptor targets, effects of drugs
57, 58–59 drug-induced, xvi, xix, 4–5, 22, 23,
in research trials vs. real-world 39, 145, 152–154
patients, 26–28, 40 allergic reactions, 145, 146,
self-assessment questions and 289–290
answers about, 363–380 descriptive terminology for, 147
self-reports of, 19 dose relationships and, 30
in slow vs. fast acetylators, 50 in DRESS syndrome, 153, 290
in somatizing patients, 76, 80–81 emergency management of, 340
sources for data about, xv, 393 evaluation of, 145–146
summary of, 382–388 oral lesions of, 159
Index 487
serious rashes, 152–154, 361 specific drugs, 382–388

specific drugs anticholinergic agents, 58
bupropion, 340 dopamine agonists, 277–278
carbamazepine, 34, 149, efavirenz, 88
150, 152–153, 340 insomnia, 258–259
divalproex, 149, 150 MAOIs, 277, 278
fluoxetine, 149 Sleep hygiene, 278
lamotrigine, 34, 45, 50, 72, Sleep paralysis, 277
150, 152, 153–154, 340 Sleep-driving, 286, 287
lithium, 148, 149 Sleep-related eating disorders, 286, 287
modafinil, in children, 152, Sleepwalking, 286–287
154 Slow acetylators, 32, 50, 293
niacin, 134 Slow-wave sleep, 279, 280, 281, 283
paroxetine, 149 Smoking
topical steroids for, 146, 151 aids for cessation of, xxxv, 95
types of, 146, 148–150 hyperammonemia and, 195
in drug-induced lupus SNRIs. See Serotonin-norepinephrine
erythematosus, 293 reuptake inhibitors
pruritic, 144–145 Sodium oxybate, xxxiv, 282
SLC6A4 gene polymorphism, 70 Solifenacin, xxx, 120
SLE (systemic lupus erythematosus), Soma. See Carisoprodol
91, 96, 142, 239, 264 Somatization, 42, 76, 80–81
Sleep apnea, 5, 277, 278, 282 Somatoform pain disorders, 144
Sleep attacks, 277–278 Somnolence, 28. See also Sedation
Sleep disturbances, drug-induced, drug-induced, 256–257, 258–259,
xix, 277–287 382–388
hypersomnia and sleep attacks, anticholinergic agents, 85
277–278 dopamine agonists, 277
insomnia, 41, 256, 258–259, 278– dose relationships and, 28, 29,
285, 382–388 (See also 30
Insomnia) in older adults, 76
treatment of, 278, 279, 282, paroxetine, 279
284–285, 284 quetiapine, 28, 29, 56
nightmares and vivid dreams, risperidone, in children, 72
285–286 placebo-induced, 18
nocturnal bruxism, 155–156 Sonata. See Zaleplon
nocturnal myoclonus, 264 Soporific effects of drugs. See
parasomnias, 286–287 Sedation; Somnolence
periodic limb movements during Sotalol, xxix, 120, 245
sleep, 251, 282 Speech
psychotropic drug effects on dysarthric, 156–157
sleep architecture, 279, 280, evaluation of cranial nerves
281, 283 controlling phonation and,
restless legs syndrome, 87, 250– 157, 158
251, 278, 282 stuttering, 157
Spironolactone for sleep attacks, 277

metabolic acidosis induced by, 166 summary of adverse effects of,
oral lesions induced by, 159 387–388
for peripheral edema, 131, 136 tics induced or exacerbated by,
Split treatment, 105–109 260
Splitting, 18, 107 use in hypertension, 7
SSRIs. See Selective serotonin weight changes induced by, 298,
reuptake inhibitors 315, 326, 330
Statins, xxxiv, 123, 129, 132–133 Stomatodynia, 161
hepatic effects of, 190 Strattera. See Atomoxetine
myalgias or rhabdomyolysis Stuttering, 157
induced by, 242, 290, 294 Sublingual drug administration, 47
Status epilepticus, tiagabine- Suboxone. See Buprenorphine plus
induced, 23 naloxone
Steady-state concentration of drug Subutex. See Buprenorphine
(Css), 49 Succinylcholine, 264
Steatohepatitis, nonalcoholic, 190 Sudafed. See Pseudoephedrine
Sternbach criteria for serotonin Sudden cardiac death
syndrome, 295 antipsychotics and, 115, 118, 121
Stevens-Johnson syndrome, 34, 150 TCAs and, 115
drugs associated with, 340 Sugarless gums, 162
carbamazepine, 152–153 Suicidality, 8
lamotrigine, 153–154 clozapine to reduce risk of, 360
modafinil, 154 drug overdose and, 339
emergency management of, 340 drug use and, 36, 103–104
oral lesions of, 159 antibiotics, 85, 87
Stimulants, xxxv anticonvulsants, 37, 85, 103
abuse potential with, 257 antidepressants, 23, 27, 36, 73,
anxiety or agitation induced by, 103–104
100 gene variants associated
cardiovascular effects of, 34, 113, with, 70
115, 117, 122 SSRIs, 104, 244
for drug-induced cognitive interleukin-2, 88
complaints, 246 isotretinoin, 90
for drug-induced sedation, 256, 257 varenicline, 95
for drug-induced weight gain, 315 Sulfa antibiotics, xix, 199, 236
electrocardiogram before Sulfation reactions, 50
initiation of, 34, 122 Sumatriptan, xxxiv, 241
hypertension induced by, 137 Sustained-release drug preparations,
for interferon-α–induced 50, 51, 56
depression, 93 Sustiva. See Efavirenz
mania/hypomania induced by, Sweating
98–99 drug-induced, 142–143, 382–388
paresthesias induced by, 266 dose relationships and, 31
psychosis induced by, 102 in serotonin syndrome, 295, 296
Index 489
Symmetrel. See Amantadine divalproex, 116

Sympathomimetics, xxxv dobutamine, 58
Synalar. See Fluocinolone acetonide dose relationships and, 31
Syncope, 114 idazoxan, 58
drug-induced α1-adrenergic lurasidone, 117
antagonists, 140 phentolamine, 58
sertindole, 118 prazosin, 58
vasovagal, 140 risperidone, 117
Syndrome of inappropriate SGAs, 114
antidiuretic hormone secretion stimulants, 115, 117
(SIADH), 76, 163–165, 165 TCAs, 117
Synemol. See Fluocinolone acetonide yohimbine, 58
Synephrine alkaloids, to promote induced by weight loss
weight loss, 328 supplements, 328–329
Synthroid. See Levothyroxine Tacrolimus, xxxiv, 92
Systemic drug reactions, 289–330 Tadalafil, xxxv, 217, 222, 241
allergic reactions and Tagamet. See Cimetidine
angioedema, 289–290 Tambocor. See Flecainide
antiepileptic hypersensitivity Tamoxifen, xxxi, 88
reactions, 290 Tardive dyskinesia (TD),
body temperature dysregulation, antipsychotic-induced, 22, 41,
291 48, 251–255
discontinuation syndromes, 291– Abnormal Involuntary
292 Movement Scale for, 252, 253,
drug-induced lupus 254, 394
erythematosus, 293 DRD3 receptor variant and, 67
emergency management of, 342– incidence of, 251
343 mechanisms of, 252
neuroleptic malignant syndrome, oculogyric crisis and, 266
294–295 risk factors for, 251
serotonin syndrome, 295–296 treatment of, 251, 252–255
weight gain, 296–326, 298 withdrawal dyskinesias and, 256
weight loss, 326, 330 Taste alterations, drug-induced, 157–
Systemic lupus erythematosus (SLE), 158
91, 96, 142, 239, 264 TCAs. See Antidepressants, tricyclic
TD. See Tardive dyskinesia
t1/2 (plasma elimination half-life of TD50 (toxic dose for 50% of
drug), 48, 49, 52–55 population), 49
T3 (triiodothyronine), 185 Tegretol. See Carbamazepine
T4 (thyroxine), 61, 89, 185–186 Temazepam, xxxv, 95
Temovate. See Clobetasol propionate
Tachycardia, 140
0.05%
drug-induced, 115, 382–388
Tenex. See Guanfacine
bupropion, 116
Tenormin. See Atenolol
clozapine, 139
Teratogenicity of drugs, 33, 331, 332– Thomson Reuters Micromedex, 393

336, 336–337. See also Pregnancy Thorazine. See Chlorpromazine
anticonvulsants, 196, 335, 336 Thrombocytopenia, drug-induced,
divalproex, 36, 179, 335 231
FDA categorization of risk for, carbamazepine, 232, 340
332–334, 333 divalproex, 11, 28, 31, 39, 232
guidelines for drug use in in breast-fed infants, 332
pregnancy, 334–335 SSRIs, 235
lithium, 335 Thrush, 159, 161
SSRIs, 335, 337 Thyroid function tests, 13, 185
paroxetine, 37, 337 Thyroid hormone
Web sites for information on, 393 bone demineralization induced
Terazosin, xxxii, 89, 140 by, 170
for hyperhidrosis, 142, 143 cardiovascular effects of, 115
Terbinafine 1% cream, 149 Thyroiditis, 185
Terbutaline, xxxv, 58, 207 Thyroid-stimulating hormone (TSH),
Terfenadine, 120 185
Testosterone preparations, 142 Thyromegaly, 4
Tetracycline, 198 L -Thyroxine (T4)
Tetrahydroisoxazolopyridine, 254 generic vs. brand-name
Theophylline, 264 formulations of, 61
interaction with lithium, 390 for hypothyroidism, 89, 185–186
Therapeutic alliance Tiagabine, 23
disclosure and discussion of myalgias induced by, 241
possible side effects, 42, 44– peripheral edema induced by, 130
45, 361–362 for serotonergic antidepressant–
nocebo phenomenon and, 20 induced sexual dysfunction,
with nonmedical therapist, 107 219
shared decision-making with Tics, drug-induced, 260–261
patients, 33 Tigan. See Trimethobenzamide
with somatizing patients, 80 Time to maximal blood
Therapeutic index, 49, 62 concentration of drug (Tmax),
Therapeutic window, 49 48, 49, 50
Thiazolidinediones, 129 Tinnitus, drug-induced, 268, 361
Thioridazine, xxxiii Tmax (time to maximal blood
cardiovascular effects of, 35, 117, concentration of drug), 48, 49, 50
118, 119 Tocolytics, xxxv
cytochrome P450 metabolism Tofranil. See Imipramine
and, 68 Tolterodine, xxx, 203
interaction with quetiapine, 392 Tongdatang, for hyperprolactinemia,
retinopathies induced by, 275 178
sexual dysfunction induced by, Tongue lesions, ulcerative, 158
215 Tonic water, for leg cramps, 240
retrograde ejaculation, 229 Tooth grinding, 155–156, 156
Thiothixene, xxxiii, 268 Topamax. See Topiramate
Index 491
Topicort. See Desoximetasone 0.25% Toronto Side Effects Scale, 394

Topiramate, xvii, xxx Torsades de pointes, drug-induced
alopecia induced by, 142 antipsychotics, 118, 120
cardiovascular effects of, 116 gender differences in risk for, 121
cognitive effects of, 246, 249 TCAs, 117
cytochrome P450 metabolism Tourette syndrome, 260, 261
and, 69 Toxic dose for 50% of population
dose relationships and side effects (TD50), 49
of, 30 Toxic epidermal necrolysis, 34
dosing and precautions in drugs associated with, 340
hepatic failure, 192 carbamazepine, 152–153
renal disease, 211 lamotrigine, 153–154
drug interactions with emergency management of, 340
lithium, 390 oral lesions of, 159
oral contraceptives, 94 Toxic polypharmacy, 57, 360
for drug-induced weight gain, TOXNET Toxicology Data Network,
296, 315, 316–317, 319, 325 393
combined with phentermine, Tramadol, xxix, 84
319 interaction with SSRIs, 296, 392
dysgeusia induced by, 158 myoclonus induced by, 264
glaucoma induced by, 274–275 serotonin syndrome and, 343
headache and, 262 Transaminitis, 189–190
insomnia induced by, 258 Transdermal drug administration,
mean half-life and food effects on 47. See also Selegiline,
absorption of, 52 transdermal
metabolic acidosis induced by, Transient ischemic attacks,
166 antipsychotic-related, 123
myalgias induced by, 241 Tranxene. See Clorazepate
for older adults, 76 Tranylcypromine, xxxi
overdose of, 347 discontinuation before general
panic attacks induced by, 100 anesthesia, 138
paresthesias induced by, 266 fasciculations induced by, 264
psychosis induced by, 85 orthostatic hypotension induced
renal calculi induced by, 207–208 by, 140
serum level of, 64 sexual dysfunction induced by,
by, 258 weight changes induced by, 310
suicidality and, 103 Trazodone, xxxi
summary of adverse effects of, 385 for akathisia, 243, 245
teratogenicity of, 337 cardiovascular effects of, 120
for tremor, 270 cognitive function and, 249
vitamin B12 and folic acid cytochrome P450 metabolism
deficiencies induced by, 196 and, 69
weight changes induced by, 298 for drug-induced sexual
Toprol. See Metoprolol dysfunction, 214, 228
Trazodone (continued) Trimethoprim-sulfamethoxazole,

effect on sleep architecture, 280 xxx, 87
fasciculations induced by, 264 Trimipramine, 294
for insomnia, 282, 284 Triptans, xxxiv
lack of efficacy for tinnitus, 268 interaction with SSRIs, 296, 392
for nightmares, 285 myalgias induced by, 241
parasomnias induced by, 287 TSH (thyroid-stimulating hormone),
peripheral edema induced by, 185
130 Tylenol. See Acetaminophen
priapism induced by, 206, 207
Tremor Ulcerative colitis, 142
drug-induced, 22, 41, 268–270, Ulcers
361, 382–388 oral, 158–159
divalproex, 269 peptic, 134, 188, 189
dose relationships and, 31 Ultram. See Tramadol
due to drug overdose, 339 Ultrarapid metabolizers, 63, 68–69
lithium, 39, 269 Ultravate. See Halobetasol
modafinil, 58 propionate 0.05%
phenylephrine, 58 Ultraviolet light
evaluation of, 269 photosensitivity reactions to, 143–
in neuroleptic malignant 144
syndrome, 294 for psoriasis, 149
orthostatic, 270 Urecholine. See Bethanechol
in serotonin syndrome, 295, 296 Uremia, 166
treatment of, 114, 269 Urinary incontinence, drug-induced,
Tretinoin, 148 202–203
Triamcinolone acetonide, 151 Urinary retention, drug-induced, 58,
Triazolam, xxxv, 95 201–202
for nightmares, 286 Urine electrolytes and osmolality,
Trichotillomania, 142 164, 204
Tricor. See Fenofibrate Urticaria, 146, 149
Tricyclic antidepressants (TCAs). See allergic angioedema and, 289–290
Antidepressants, tricyclic U.S. Food and Drug Administration
Trigeminal nerve, 157, 158 (FDA), xv, xviii, 26
Trigeminy, 115 adverse effect warnings and
Trihexyphenidyl, xxx, 39 precautions issued by, 3n, 32,
for enuresis, 202 34–36, 71n, 75, 76, 83n, 85, 95,
receptor occupancy and effects of, 97n, 103, 113n, 118, 122, 139,
58 141n, 152, 153, 187n, 190, 193,
for sialorrhea, 160 198, 231n, 232, 233, 243n, 267,
Triiodothyronine (T3), 185 275, 289n, 290
Trilafon. See Perphenazine about neonatal antipsychotic
Trileptal. See Oxcarbazepine withdrawal, 338
Trimethobenzamide, xxxi, 197, 198, about weight loss supplements,
291, 292 319, 328, 329
Index 493
categorization of teratogenic risks mean half-life and food effects on

of drugs, 33, 332–334, 333 absorption of, 53
classification of risk associated myalgias induced by, 241
with QTc interval for older adults, 79
prolongation, 118 orthostatic hypotension induced
Coding Symbols for a Thesaurus by, 140
of Adverse Reaction Terms, parasomnias induced by, 287
27 paresthesias induced by, 266
requirements for bioequivalence psychosis induced by, 102
of generic drugs, 60, 393 serum level of, 65
U.S. National Library of Medicine, sexual dysfunction induced by,
393 62, 214, 219, 221
somnolence or sedation induced
Vaginal contraceptive rings, 95 by, 258
Vagus nerve, 157, 158 stomatodynia and, 161
Valium. See Diazepam summary of adverse effects of,
Valproic acid. See Divalproex 384
Vardenafil, xxxv, 120, 217–218, 222, tinnitus induced by, 268
241 urinary incontinence induced by,
Varenicline, xxxv, 95 202
Varicella zoster, 146, 150, 152 urinary retention induced by,
Vasotec. See Enalapril 201
Venlafaxine, xxxi weight changes induced by, 298,
alopecia induced by, 141 310, 330
bruxism induced by, 156 in children, 72
cataracts induced by, 274 yawning induced by, 270
contraindicated for nightmares in Ventolin. See Albuterol
posttraumatic stress Verapamil, xxxii, 240
disorder, 286 interaction with lithium, 390
cytochrome P450 metabolism Verelan. See Verapamil
and, 68 VESIcare. See Solifenacin
dermatological effects of, 150 Vestibular problems
dose relationships and side effects after abrupt antidepressant
of, 29, 30 discontinuation, 101
dosing and precautions in efavirenz-induced, 88
hepatic failure, 194 Veterans Administration Multicenter
renal disease, 212 Antiepileptic Drug Trial, 232
glycemic dysregulation and Viagra. See Sildenafil
diabetes induced by, 173 Vigabatrin, 85
headache induced by, 263 Viibryd. See Vilazodone
hyperprolactinemia induced by, Vilazodone, xxxi
176 cognitive function and, 249
hypertension induced by, 137 cytochrome P450 metabolism
hyponatremia induced by, 164 and, 69
insomnia induced by, 62, 258 diarrhea induced by, 188
Vilazodone (continued) von Willebrand disease, 236

dosing and precautions in Vytorin. See Ezetimibe plus
hepatic failure, 194 simvastatin
renal disease, 212
effect on sleep architecture, 280 Wakefulness-promoting agents,
headache induced by, 263 xxxiv. See also Stimulants
insomnia induced by, 258 Warfarin, xxx, 114, 360
mean half-life and food effects on Watchful waiting, 38–39
absorption of, 54 Weakness
overdose of, 351 drug-induced, 256
sexual dysfunction induced by, in SIADH, 164
221 Web sites for drug information, 393
somnolence or sedation induced Weight gain
by, 258 drug-induced, xvi, xviii, xix, 5, 28,
summary of adverse effects of, 384 41, 296–326, 298, 361, 382–
weight changes induced by, 298, 388
310 anticonvulsants, 297, 298, 305,
Viral rashes, 150 306–307
Vision problems, drug-induced, 274, antidepressants, 308–311, 312
382–388 mirtazapine, 72
anticholinergic agents, 39, 58 paroxetine, 124
dose relationships and, 30 TCAs, 58
niacin, 134 venlafaxine, 72
phosphodiesterase type 5 assessment of, 297–298
inhibitors, 218 diphenhydramine, 58
Vistaril. See Hydroxyzine dose relationships and, 31
Vitamin B complex, for leg cramps, drugs associated with, 298
240 endurance of, 38
Vitamin B3, 134 forecasting probability of, 45
Vitamin B6 lithium, 297, 305, 306
phenelzine-induced deficiency of, risk factors for, 297
267 SGAs, 28, 37, 58, 298, 298–305,
for tardive dyskinesia, 251, 253 300–303
Vitamin B12 deficiency, 196, 267 in children, 72
Vitamin D creams, 149 correlation with treatment
Vitamin E response, 39, 299
cardiovascular mortality risk due to appetite stimulation,
with, 251, 252–253 299
for leg cramps, 240 metformin for, 170, 175,
for tardive dyskinesia, 251, 252 296, 319
Vitamin K deficiency in newborn, polypharmacy and, 57
divalproex-induced, 334–335, predictors of, 45, 299, 304
336 racial and gender
Vivid dreams, drug-induced, 285 differences in, 60
efavirenz, 88
Index 495
time course and magnitude Yohimbine, xxxv, 58

of, 304 for drug-induced sexual
with Zydis formulations, dysfunction, 219, 228
304–305
ideal body weight, 297 Zaleplon, xxxv
management of, 296–297, 312–326 for insomnia, 284, 285
lifestyle modification, 312–315 myalgias induced by, 241
pharmacological, 315–326, sexual dysfunction induced by,
316–317, 320–325 218
weight loss supplements, 326, Zantac. See Ranitidine
327–329 Zestril. See Lisinopril
psychiatric disorders associated Zetia. See Ezetimibe
with, 297, 319 Zhuang Yang, for
in SIADH, 164 hyperprolactinemia, 178
Weight loss, drug-induced, xvii, 326, Zidovudine, xxxiii, 89
330, 382–388 Zinc, for alopecia, 141, 142
Weight loss supplements, 326, 327– Ziprasidone, xxxv
329 akathisia induced by, 244
Wellbutrin. See Bupropion allergic angioedema induced by,
Westcort. See Hydrocortisone 290
valerate cardiovascular effects of, 117, 118,
White blood cell count monitoring, 119
during clozapine treatment, 233, combined with other SGAs, 57
234 cytochrome P450 metabolism
Withdrawal dyskinesias, 22, 255–256 and, 69
Wolff-Parkinson-White syndrome, dose relationships and side effects
122 of, 30, 31
dosing and precautions in
Xanax. See Alprazolam hepatic failure, 194
Xero-Lube Artificial Saliva, 162 renal disease, 213
Xerosis, 150 for drug-induced weight gain,
Xerostomia 296, 326
drug-induced, 41, 162, 361, 382– dyslipidemias induced by, 124,
388 126
anticholinergic agents, 58 effect on prolactin level, 183
dose relationships and, 30 effect on sleep architecture, 281
management of, 162 glycemic dysregulation and
placebo-induced, 18 diabetes induced by, 175
Xyrem. See Sodium oxybate insomnia induced by, 259
interaction with quetiapine, 392
Yasmin; Yaz. See Desogestrel oral mania/hypomania induced by,
contraceptives 99
Yawning, drug-induced, 270–271 mean half-life and food effects on
dose relationships and, 31 absorption of, 55
Yocon. See Yohimbine metabolism of, 67
Ziprasidone (continued) for insomnia, 284, 285

myalgias induced by, 241 myalgias induced by, 241
oculogyric crisis induced by, 265 parasomnias induced by, 286,
overdose of, 355 287
peripheral edema induced by, 130 psychosis induced in children
priapism induced by, 207 by, 102–103
serum level of, 66 sexual dysfunction induced by,
sexual dysfunction induced by, 218
214, 215, 217 Zomig. See Zolmitriptan
somnolence or sedation induced Zonisamide
by, 259 for drug-induced weight gain,
summary of adverse effects of, 387 296, 325
weight changes induced by, 298, combined with bupropion,
303 318
Zithromax. See Azithromycin renal calculi induced by, 208
Zocor. See Simvastatin suicidality and, 103
Zofran. See Ondansetron Zopiclone, parasomnias induced
Zolmitriptan, xxxiv, 241 by, 286, 287
Zoloft. See Sertraline Zyban. See Bupropion
Zolpidem, xxxv Zydis formulations, 48
cardiovascular effects of, 117 olanzapine, 48, 304–305
cytochrome P450 metabolism Zyprexa. See Olanzapine
and, 69 Zyrtec. See Cetirizine

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Managing the Side Effects of

Joseph F. Goldberg, M.D., M.S.

Carrie L. Ernst, M.D.

British Library Cataloguing in Publication Data

and to each other,

List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . xxvii

List of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxix

4 Adverse Psychiatric Effects of

5 Adverse Psychiatric Effects of

6 What Nonmedical Therapists

7 Cardiovascular System . . . . . . . . . . . . . . . . . . . . . 113

8 Dermatological System . . . . . . . . . . . . . . . . . . . . . 141

9 Ear, Nose, and Throat . . . . . . . . . . . . . . . . . . . . . . . 155

10 Electrolyte Abnormalities . . . . . . . . . . . . . . . . . . . 163

12 Gastrointestinal System . . . . . . . . . . . . . . . . . . . . 187

14 Hematological System . . . . . . . . . . . . . . . . . . . . . . 231

15 Musculoskeletal System . . . . . . . . . . . . . . . . . . . . 239

16 Neurological System . . . . . . . . . . . . . . . . . . . . . . . 243

17 Ophthalmological System . . . . . . . . . . . . . . . . . . . 273

18 Sleep Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . 277

19 Systemic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 289

20 Pregnancy and the Puerperium . . . . . . . . . . . . . . 331

21 Emergency Situations . . . . . . . . . . . . . . . . . . . . . . 339

22 Summary Recommendations . . . . . . . . . . . . . . . . 359

Appendix 1: Self-Assessment Questions and

Appendix 2: Resources for Practitioners . . . . . . . . 381

Managing the Side Effects of Psychotropic Medications by Drs. Goldberg and

helping me to become an amateur dermatologist and the tables on sexual

Stephen M. Stahl, M.D., Ph.D.

To understand the adverse effects of a medication means to fully appre-

rigor and support (e.g., antidotes for antidepressant-induced sexual

rogenic drug effects. We therefore supplemented our own clinical expe-

Clinicians who teach medical students and psychiatry residents, who

Joseph F. Goldberg, M.D., M.S.

Joseph F. Goldberg, M.D., M.S. Speakers’ bureau: AstraZeneca, Dey

Managing the Side Effects of Psychotropic Medications represents a major

need to balance risks and benefits of psychotropic drugs by analogy to

The concerns expressed by Mitchell over a century ago became fur-

share, and to facilitate more routine, bilateral, consultative interactions.

Ross J. Baldessarini, M.D.

The following abbreviations are used frequently throughout this book

ACE angiotensin-converting enzyme

Alcohol abuse or dependence treatments

Antihypertensive agents (continued)

Primary Care Psychiatry

tations of psychopathology has contributed profoundly to the pharma-

• A 54-year-old man with chronic major depression, hypertension, hy-

methylphenidate 5 mg/day and increased the escitalopram to

The presence of certain medical comorbidities may pose relative (if

TABLE 1–1. Medical conditions that may contraindicate specific

Medical condition Pharmacotherapy implication

Asthma, chronic obstructive β-Blockers are relatively

monemia” in Chapter 12, “Gastrointestinal System.”

lectively derived from manufacturers’ package insert information for

Differentiating Adverse Drug Effects

Frequency of measurement and

Frequency of measurement and

Managing the Side Effects of Psychotropic Medications

Frequency of measurement and