Drugs for neurological disorders I

Depression and anxiety

Dr. Judith C.W. Mak

Department of Pharmacology & Pharmacy

( L11, BBMS3014, Advanced Pharmacology)

 Learning outcomes
At the end of the lecture, students should be able to
• Understand the symptoms, types and pathophysiology of
depression and anxiety
• List the different antidepressants and anti-anxiety
medications available
• Describe their mechanism of action for each class (type)
of drugs
• Recognize their side (adverse) effects including tolerance
and dependence
 Organization of the CNS

Central Nervous System

(CNS)

Peripheral Nervous System

(PNS)
 Depression and anxiety
• Depression and anxiety are two separate
disorders
• There is a high co-morbidity between anxiety
and depression
• They have different symptoms and require
different treatments
• Antidepressants are commonly prescribed to
treat anxiety
• Women are twice as likely to be affected as
men
 What are the types of
depression and anxiety?
Depression Anxiety
• Dysthymia (chronic) • Generalized anxiety
• Minor disorder (GAD)
• Psychotic • Obsessive-compulsive
• Postpartum disorder (OCD)
• Seasonal affective • Panic disorder
disorder (SAD) • Post-traumatic stress
• Bipolar disorder disorder (PTSD)
• Social phobia
 What is depression?
• Are you tired and bad-
tempered all the time?
• Have you lost interest in
your work, family or
hobbies?
• Are you having trouble
sleeping and feeling angry
or aggressive, sad or
worthless?
• Have you been feeing like
this for weeks or months?
Depression symptoms
Depression symptoms
Types of depression

e.g. SAD
PET scans of the brain

Mayo Foundation for Medical Education and Research

What causes depression?
• The exact cause is unknown
• Personal’s genes?
• Personality?
• Brain chemistry?
• Brain hormones?
• Stress?
– Loss of loved one?
– A difficult relationship?
– Physical sexual abuse?

Usually a combination of factors

 Monoamine hypothesis
Neurotransmitters, which are
released from nerve cells in
the brain, only have a short
time to rely their message to
another cell before reuptake
by cells or destroyed by
enzymes

• Depression is caused by low levels or a deficit in function of a

neurotransmitter, such as serotonin, dopamine or norepinephrine
• Evidence – reserpine, which has antihypertensive actions due to its
ability to deplete catecholamines (DA and NE) and 5-HT from
peripheral symapthetic nerve endings, caused depression
 Not a perfect hypothesis
• Many depressed patients do not show alterations in
function or levels of monoamines
• Monoamines increase immediately with
antidepressant use, but maximum beneficial effects
of antidepressants are not seen for many weeks
• It is common for the patient to feel worse for the
first week of treatment
• Removal of serotonin precursor, tryptophan in
humans, did not lead to depressive response
 Neurotrophic (neurogenesis) hypothesis

• An impaired growth of neurones is associated with depression

• Antidepressants promote the growth of neurones and synaptic
connectivity
 Neurotrophic hypothesis
• Depression is associated with 5-10% a loss of
volume in the hippocampus in some studies
• Depressed, stressed or in pain
level of brain-derived neurotrophic factor
(BDNF) drops
• Antidepressants enhances BDNF level in animal
models with chronic treatment
The neurotropic hypothesis
 Not a perfect hypothesis
• BDNF knockout mice do not have an increase
in depressive or anxious behaviors

• Social-stressed animals have increased

levels of BDNF rather than a decrease
 Medications
• Antidepressants work by Generic neurotransmitter system
increasing the amount of
neurotransmitters in the
brain, by preventing them
being broken down or
“reuptake” into the cells

• Usually take several weeks

to work

• Different antidepressants
affect one or more
neurotransmitters to
different extent
 When to give antidepressants
• Antidepressants should only be given when the risk of
untreated depression far outweigh those of
antidepressant medications
 Summary of antidepressants
• Selective serotonin reuptake inhibitors
(SSRIs)
• Norepinephrine reuptake inhibitors
• Serotonin-norepinephrine reuptake inhibitors
(SNRIs)
• Tricyclic antidepressants
• Serotonin antagonist-reuptake inhibitors (SARIs)
• Alpha()2-adrenoceptor antagonists
• Monoamine oxidase inhibitors (MAOIs)
 Selective serotonin reuptake
inhibitors (SSRIs)
• Block reuptake of serotonin by
the presynaptic neuron, thus
maintaining high level of 5-HT in
the synapse
• Inhibition of the serotonin
transporter
– Fluoxetine (Prozac)
– Paroxetine (Paxil)
– Citalopram (Celexa)
– Escitalopram (Lexapro)
– Sertraline (Zoloft)
– Fluvoxamine (Luvox)
Serotonin = 5-hydroxytryptamine (5-HT)
 SSRIs
• One of the most prescribed
medications

• The popularity of SSRIs

stems largely from
– Ease of use
– Safety in overdose
– Relative tolerability
– Cost
 Pharmacokinetics of SSRIs
• Fluoxetine and paroxetine are potential inhibitors
of the CYP2D6 isoenzyme, which contributes to
potential drug interactions
• Tricyclic antidepressants are CYP2D6 substrates,
thus they cannot be used in combination

• Fluvoxamine (SSRI) is a CYP3A4 inhibitor

• Diltiazem (a calcium channel blocker) is a CYP3A4
substrate
• In combination, it can lead to bradycardia or
hypotension
Cytochrome P450 enzyme system

• CYP3A4 isoenzyme is
– the most prevalent in humans (accounts for 60%
of the total CYP450 in the liver and 70% in the
intestine)
– the most important form of enzyme in drug
metabolism
– involved in drug interactions
 Adverse effects of SSRIs
• Nausea, GI upset, diarrhea due to increased serotonergic
activity in the gut

• Diminished sexual function and interest due to increasing

serotonergic tone at the level of the spinal cod and above
– Affects 30-40% SSRI takers
– Effects persist as long as patient remains on drug
• Reduces coagulation/Increased risk of bleeding due to reducing
serotonin-mediated platelet activation

• Favors vasoconstriction due to inhibition of nitric oxide synthase

(NOS)
– Contradicted for pregnant women with hypertension or
preeclampsia (i.e. leading to fetal prematurity)
Norepinephrine reuptake inhibitors
Block reuptakes of noradrenaline selectively

Atomoxetine
Reboxetine
Maprotiline

NA = noradrenaline (norepinephrine, NE)

Adverse effects of norepinephrine
reuptake inhibitors

Noradrenergic effects includes

• Increase blood pressure

• Decrease heart rate

• CNS activation
– Insomnia
– Anxiety
– agitation
 Serotonin and norepinephrine
reuptake inhibitors (SNRIs)
• Binds to both norepinephrine
and serotonin transporters
• Block norepinephrine and
serotonin reuptake
• SNRIs do not have much affinity
for other receptors

Venlafaxine (Effexor)
Duloxetine (Cymbalta)
Desvenlafaxine
Bupropion
Mirtazapine
 Adverse effects of SNRIs
• Have serotonergic adverse effects as SSRIs

• Have noradrenergic adverse effects as

norepinephrine reuptake inhibitors
Tricyclic antidepressants (TCAs)

• Affect the uptake of all

three neurotransmitters
associated with mood
– Serotonin
– Norepinephrine
– Dopamine

• They have more side

effects
 TCAs
• Dominant class of antidepressants before the
introduction of SSRIs in the 1980s

• Nowaday only used in patients who do not respond

to SSRIs

• Loss of popularity because

– Poor tolerability
– Difficulty to use
– Lethality in overdose
– Serious drug interaction
 Chemical structures of TCAs
Tertiary amines
• Imipramine
• Amitriptyline
Secondary amines
• Nortriptyline
• Desipramine

• Tertiary = NE and 5-HT transporter affected (highly anticholinergic), fairly

long acting
• Secondary = predominantly NE (less anticholinergic), a bit shorter acting
• Tertiary amines have more side effects than secondary amines
 Common side (adverse) effects
associated with TCAs
• Anticholinergic effects
– Dry mouth, constipation, urinary retention, blurred vision,
confusion

• Antiadrenergic effects
– Sedation, sexual dysfunction, orthostatic hypotension,
cardiac effects

• Antihistaminic effects
– Weight gain, sedation

• The TCAs are substrate of the CYP2D6 system

• Genetic alterations for CYP2D6 may result in low or
extensive metabolism of TCAs
 Serotonin antagonist-reuptake
inhibitors (SARIs)

• Trazodone’s most potent binding

property is 5-HT2A antagonism

• Its ability to block serotonin

reuptake transporter (SERT) is
100-fold less potent than its ability
to block 5-HT2A receptors
• When serotonin reuptake transporter is
blocked by trazodone, serotonin acts on
the other serotonin subtypes
• There are over 14 known subtypes of
serotonin receptors
• Trazodone is converted into an active
metabolite known as meta-chloro-phenyl
piperazine (mCPP)
• mCPP activates
5HT2C>5HT3>5HT2A>5HT1B>5HT1A
• Agonist actions of serotonin specifically
upon 5-HT1A receptors
antidepressant effects
• Agonist actions of serotonin at other
subtypes side effects of SERT
blockers or mCPP (over time, these
receptors often are desensitized)
SARIs
SARIs
• Trazodone now used as an
unlabeled hypnotic since it is
highly sedating and not
associated with tolerance

• Less popular after the

introduction of SSRIs

• Adverse effects
– Sedation
– GI disturbance
 2-adrenoceptor antagonists

Mianserin
• Blocks 2 presynaptic auto-
receptors and enhances
norepinephrine release
• Adverse effects
– Sedation
– Dry mouth
– Dizziness
– vertigo
Monoamine oxidase inhibitors
• Increase levels of all three neurotransmitters by
inhibiting an enzyme responsible for inactivating them
Two forms of monoamine oxidase
• MAOA metabolizes 5-HT, norepinephrine, epinephrine,
dopamine, tyramine

• MAOB metabolizes dopamine, phenylethylamine,

tyramine

• Non-selective MAOI – phenelzine, tranylcypromine

• Selective MAOAI – moclobemide, selegiline (transdermal

patch)

• Potentially fatal interactions between MAOI and certain

foods (particularly those containing tyramine), as well as
certain drugs – MAOIs are rarely prescribed any more
 MAOIs
• MAOIs were introduced in the 1950s

• Rarely used in clinical practice because of toxicity and

potentially lethal food and drug interactions

• Primary use – treatment of depression unresponsive to

other anti-depressants

• MAOA is present in neurons (brain), gut and placenta

• MAOB primarily in neurons (brain), liver and platelets

 Adverse effects of MAOIs

• Orthostatic hypotension
• Weight gain
• Insomnia
• Restlessness
• Confusion
 Serotonin syndrome
• Combination of an MAOI with a serotonergic agent
(SSRI, SNRI or TCA) may be life-threatening!
Adverse (side) effects of antidepressants
General adverse effects of
antidepressants
• All antidepressants must print
FDA black box warning:
– It increases the risk of suicidality
in patients under the age of 25

• 4% of patients under 25 years

have suicidal ideation and
gestures but not completed
suicides (vs. 2% in placebo)

• For older patients, esp. after

age of 65, no associated risk
with suicidal
 Antidepressant
discontinuation symptoms

Reduce doses gradually over at least a 4-week period

 Black box warning
• Antidepressants
can be safe and
effective for many
people
• But may present
serious risks to
some, especially
children, teens
and young adults
Other applications of antidepressants
 What is Anxiety?
• Anxiety is a natural human experience
that can be crippling when excessive

• Anxiety often complicates various

medical disorders

• Anxiety disorders have a lifetime

prevalence of about 30%
 Physical Symptoms Seen with
Anxiety
• Increase muscle tension
• Shortness of breath
• Rapid heart beat (tachycardia)
• Dizziness
• Restlessness
• Sweating
• Trembling
• Difficulty concentrating
• Insomnia
• Nervousness
Types of anxiety disorders
 Anxiety disorders
• Panic disorder (panic attacks) – rapid-onset attacks of extreme
fear and feeling of heart palpitations, choking and shortness of
breath
 Phobic anxiety – triggered by a particular object, e.g. spiders,
snakes, heights, or open spaces

• Obsessive-compulsive disorder – uncontrollable recurring

anxiety-producing thoughts and uncontrollable impulses, e.g.
compulsive hand-washing or checking that doors are locked.

• Generalized anxiety disorder (GAD) – extreme feeling of

anxiety in the absence of any clear cause
• Post-traumatic stress disorder (PTSD) – recurrent recollections
of a traumatic event of unusual clarity which produce intense
psychological distress
Treatment for anxiety disorders
 Benzodiazepines (BDZs)
• Short-acting (t1/2 < 5 hr) – short-lived or no active
metabolites
– Midazolam
– Triazolam
• Intermediate-acting (t1/2 5-24 hr) – short-lived or no active
metabolites
– Alprazolam
– Lorazepam
– Temazepam
• Long-acting (t1/2 > 24 hr) – long-lived active metabolites
– Chlordiazepoxide
– Clonazepam
– Diazepam (Valium)
– Flurazepam
Actions of Benzodiazepines
• Anxiolytic:
– Alprazolam
– Chlordiazepoxide
– Clonazepam
– Diazepam
– Lorazepam

• Hypnotic:
– Triazolam
– Temazepam
– Flurazepam
Mode of Action - Benzodiazepines

• Selectively activates GABAA receptor

operated chloride channels (bind to specific
benzodiazepine receptors which are part of
the GABAA receptor-chloride ion channel
complex)

• Increase the affinity of GABA for its receptor

GABAA receptor-chloride ion
channel complex

BDZs bind allosterically in a site

between the a and g subnits
subsequently potentiating the
opening of the chloride channel
Mechanism of action for BDZs
 Treatment for Anxiety Disorders

• Panic disorders
 Alprazolam is the drug of choice

• Sleep disorders
 Flurazepam or temazepam

• Alcohol withdrawal
 Diazepam is most commonly used
 Pharmacological Effects of
Benzodiazepines (BDZs)
• Reduction of anxiety and aggression
• Sedation and induction of sleep
• Reduction of muscle tone and
coordination
• Anticonvulsant effect
• BDZs do NOT produce any analgesic or
antipsychotic activity
Side Effects of Benzodiazepines
• Drowsiness and confusion (the most
common)
• Decrease in motor coordination
• Decrease in psychomotor performances
• Anterograde amnesia
• Respiratory depression and death if taken
with ethanol
 Benzodiazepine Antagonist
• Flumazenil
– A competitive antagonist of benzodiazepines at
the GABAA recepotor
– Reversal of benzodiazepine overdose
– Intravenous (iv) use only
– Side effects:
 Dizziness, nausea, vomiting, and agitation
 Withdrawal in dependent patients
 Seizures
Drugs Acting on GABAA Receptors
 Barbiturates
• Low therapeutic index
• Induce tolerance, physical dependence, very
severe withdrawal symptoms
• Induce hepatic microsomal drug-metabolizing
enzymes
• Ability to cause coma in toxic doses
• When used as hypnotics, they suppress REM
sleep more than other stages
 Mode of Action - Barbiturates
• Potentiate GABA action on chloride entry into
the neuron by prolonging the duration of the
chloride channel opening

• Can block excitatory glutamate AMPA

receptors

• Anesthetic concentrations of pentobarbital

also block high-frequency sodium channels
Decreased neuronal activity
Drugs Acting on GABAA Receptors
 Barbiturates
• Ultra-short-acting (10-20 min)
– Thiopental

• Short-acting (2 to 8 hr)
– Pentobarbital
– Amobarbital
– Secobarbital

• Long-acting (1 to 2 days)
– Phenobarbital
Side Effects of Barbiturates
• Drowsiness and decreased motor control
• Induction of the hepatic cytochrome P450
system, which can therefore decrease the
effect of other drugs metabolized by these
enzymes
• High degree of tolerance and dependence
• In high doses, respiratory depression and
coma
Other Anxiolytic Drugs
Buspirone 
(BuSpar ) (1)
• Useful in the treatment of general anxiety
disorder (GAD)
• Mode of action:
– Mediated by serotonin (5-HT1A) receptors
– Displays some affinity for DA2 dopamine receptors
and 5-HT2A serotonin receptors

• Lacks the anticonvulsant, muscle relaxant

and hypnotic properties
• Causes only minimal sedation
Buspirone 
(BuSpar ) (2)
• Causes hypothermia and can increase prolactin and
growth hormone
• Undergoes metabolism by CYP3A4
 Its half-life is shortened if taken with rifampin (an inducer of
the enzyme)
 Its half-life is lengthened if taken with erythromycin (an
inhibitor of the enzyme)

• Adverse effects:
– Headaches
– Dizziness
– Restlessness
– Tachycardia
– Palpitations
– Gastrointestinal distress
 Hydroxyzine
• An antihistamine with antiemetic activity

• Useful for patients with anxiety who have a

history of drug abuse

• Used for sedation prior to dental procedures

or surgery

• Drowsiness is a possible adverse effect

 Antidepressants
• Proven efficacy in managing the long-term
symptoms of chronic anxiety disorders,
especially GAD
 Propranolol (-blocker)
• Very effective in alleviating the somatic
manifestations of anxiety (e.g. social
phobias, performance anxiety) caused by
marked sympathetic arousal, such as
palpitations, tremor, sweating and diarrhoea
• Acts by antagonism at -adrenoceptors so
that excessive catecholamine release does
not produce the sympathetic responses
Other Hypnotic Agents
 Zolpidem and Zaleplon
Zolpidem
• Binds selectively to the BZ1 subtype of
benzodiazepine receptors
• Facilitates GABA-mediated neuronal inhibition
• Antagonized by flumazenil
• No muscle-relaxing and anticonvulsant effects
• The risk of development of tolerance and
dependence with extended use is less than with the
use of benzodiazepines
• Undergoes hepatic oxidation by the cytochrome P-
450 system to inactive products

• Adverse effects:
– Ataxia
– Nightmares
– Agitation
– Headache
– Gastrointestinal upset
– Dizziness
– Daytime drowsiness
– Confusion
Drugs Acting on GABAA Receptors
Zaleplon

• Resembles zolpidem
• Rapid onset and short duration of action
 Summary
• BDZs and zolpidem act at the BDZ site of
the GABAA complex to increase the
frequency of chloride channel openings and
thus increase inhibition
• Barbiturates act at the barbiturate site of the
GABAA complex to increase the duration of
chloride channel openings and thus increase
inhibition as well as blocking the AMPA
receptor thus decreasing glutamate-induced
excitation
 Ramelteon
• A selective agonist at the MT1 and MT2 subtypes of
melatonin receptors
• Stimulation of MT1 and MT2 receptors by melatonin in
the hypothalamus is able to induce and promote
sleep.
• Treatment of insomnia
• Adverse effects:
– Dizziness
– Fatigue
– Drowsiness
– Increased production of prolactin levels
 Chloral Hydrate
• A trichlorinated derivative of acetaldehyde that is
converted to the active metabolite, trichoroethanol in
the body

• An effective sedative and hypnotic that induces sleep

in about 30 minutes and the duration of sleep is
about 6 hr.

• Adverse effects:
– Gastrointestinal distress
– Unpleasant taste
 Antihistamines
• Over-the-counter (nonprescription)
antihistamines with sedating properties:
– Diphenhydramine (Benadryl)
– Doxylamine
– Promethazine

• Side effects:
– Dry mouth
– Blurred vision
– Drowsiness
 Complications
Depression Anxiety
• Alcohol/substance abuse • Depression
• Anxiety • Substance abuse
• Work or school problems • Trouble sleeping (insomnia)
• Family conflicts • Digestive or bowel problems
• Relationship difficulties • Headaches
• Social isolation • Teeth grinding
• Suicide
• Self-mutilation, such as
cutting
• Premature death from other
medical conditions
Animal research in CNS
Recently introduced behavioral tests

A = Multivariate concentric square field; B = Cyclinder test; C = Three-chamber

social approach; D = Dig task; E = OptoMotry; F = Whisker nuisance task
Forced swim test

Swimming Struggling Floating

Translational research in CNS
 References
Basic & Clinical Pharmacology by Katzung, Masters and
Trevor (McGraw-Hill, 12th Edition, 2012)

Goodman & Gilman’s The Pharmacological Basis of

Therapeutics by Brunton, Chabner and Knollman (McGraw-
Hill, 12th Edition, 2011)

Lippincott Illustrated Reviews: Pharmacology by Karen

Whalen (Lippincott William & Wilkins, 6th Edition, 2014)

Rang & Dale’s Pharmacology by Rang, Dale, Ritter, Flower

and Henderson (Churchill Livingstone, 7th Edition, 2012)
 References
• Hurko O & Ryan JL. Translational research in central
nervous system. NeuroRx 2005; 2(4):671-682.

• McGonigle P. Animal models of CNS disorders.

Biochem Pharmacol 2014; 87(1):140-149.

• Hanell A & Marklund N. Structured evaluation of

rodent behavioral tests used in drug discovery
research. Front Behav Neurosci 2014; 8:252.
Thank you!

E-mail: [email protected]