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Antidepressent Drugs

Dr.IramImran

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Learning Objectives
Classify Anti-depressants • Describe the mechanism
of Action of TCAs & SNRIs
Describe the Uses of Anti- depressants • Describe
Adverse effects of TCAs • Describe mechanism of
action & adverse effects of SSRIs
Differentiate between SSRIs & TCAs
 Discuss mechanism of action & adverse effects of
MAOIs
Discuss drug interactions of antidepressants •
Differentiate between typical & atypical anti-
depressants

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Antidepressant Drugs / Agents
Depression:
Types:- Two types
1. Unipolar: Major Depression
2. Bipolar : Manic – depressive illness
Lifetime risk of unipolar depression is ~15%.
Females are affected twice as frequently as males

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 Depressive symptoms also can occur secondary to other
illnesses such as
 Hypothyroidism,
Parkinson’s disease
complicates the management of other medical conditions
(e.g., severe trauma, cancer, diabetes, and cardiovascular
disease, especially myocardial infarction)

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Hamilton depression Rating Scale
The HDRS (also known as the Ham-D) is the most
widely used clinician-administered depression
assessment scale.
a score of 0–7 is generally accepted to be within the
normal
a score of 20 or higher is labeled as depression

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Typesof anxiety
Anxiety disorders encompass a constellation of
symptoms, and include
 generalized anxiety disorder,
obsessive-compulsive disorder,
panic disorder,
 posttraumatic stress disorder,
separation anxiety disorder,
social phobia,
specific phobias, and
acute stress

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Pathogenesis of major Depression:
Amine hypothesis by Schildkraut in 1965 ,it proposed that
depression is due to deficiency of monoamines i.e. Nor-
epinephrine & Serotonin at certain key sites in brain.

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Classification of Antidepressants
1. Tricyclic Antidepressants (TCA)
 Amitryptaline ,

 Nortriptyline,

 Protriptyline

 Imipramine ,
 Trimipramine ,

 Clomipramine

 Desipramine ,

 Doxepin 11
2. Selective Serotonin Reuptake Inhibitors:
(SSRIs)
Fluoxetine

Paroxetine

Citalopram

Fluvoxamine

Sertraline
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3. Mono amine oxidase (MAO) Inhibitors
I. Older agents ---Non-selective , inhibit both
MAO-A > MAO-B
A. Hydrazides: Irreversible Inhibitors
Phenelzine , Isocarboxazid , Iproniazid
B. Non-Hydrazides :Tranylcypromine
II. Selective MAO-B inhibitor: Selegiline (high
doses)

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4. Heterocyclic / Atypical Antidepressants

a. Second generations Antidepressants

 Amoxapine, Bupropion, Maproteline,
Mirtazapine

b. Third generation Antidepressants / Serotonin-

nor epinephrine reuptake inhibitors (SNRI)
 Duloxetine.
 Venlafaxine
 Desvenlafaxine(Demethylated metabolite,
 milnacipran
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c. 5 HT2 receptor antagonists

Nefazodone , Trazodone

5. Miscellaneous: Flupenthixol , Alprazolam

6. Natural Antidepressants: L-Tryptophan. St.

John’s wort

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Generation based classification

First generation Anti depressents

TCAs
MAOIs
2nd generation Anti depressents
SSRIs
SNRIs

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Following initiation of antidepressant drug treatment
there is generally a “therapeutic lag” lasting 3-4
weeks before a measurable therapeutic response
becomes
evident.
This is the reason that electroconvulsive therapy may
be the treatment of choice for agitated, depressed
patients with a high risk of suicide.

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Mechanism of Action

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 MOA of Antidepressantss
MOA of TCAs: .
Normally action of released NE & serotonin is
terminated by active reuptake into the nerve terminal
from the synapse via specific transporters.
TCAs block the amine transporters (uptake
pumps) for nor-epinephrine (NET) & serotonin
(SERT) in brain.
So ↑ conc. of NE & serotonin in the synaptic cleft
& at the receptor site.
improves symptoms of depression .

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Blocking of receptors:
inhibiting NET selectively (Maprotiline ,desipramine,
nortriptyline, protriptyline, amoxapine)
Both SERT and NET inhibition(imipramine,
amitriptyline),
One TCA, amoxapine, also is a dopaminergic receptor
antagonist; some risk for the development of
extrapyramidal side effects such as tardive dyskinesia
TCAs also block other receptors (H1, 5-HT2, α1, and
muscarinic).
These actions produce the Adverse effects .
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MOA of SSRIs:
They selectively block serotonin reuptake
transporter (SERT) responsible for reuptake &
termination of serotonin transmission.
↑ conc. of serotonin in the synaptic cleft.
Potentiation of action at receptors--- ↑ post
synaptic neuronal activity
Relief of symptoms of depression.

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MOA of MAOIs:
They inhibit MAO enzyme responsible for
intraneuronal metabolism of NE & serotonin.
So the amines accumulate in presynaptic stores.
↑ amounts are released.
Enhanced action at receptors.
Relief of symptoms of depression

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Receptor & Post receptor effects:
 Presynaptic α2 receptors are blocked / down
regulated
Long term use of tricyclics & MAOIs leads to
down regulation of post synaptic β receptors.
Long term I/C changes---- Phosphorylation of
Regulatory elements

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 MOA of Hetrocyclic Antidepressants
Trazodone & Nefazodone :
Block post synaptic 5-HT2A receptors & on chronic use
desensetize 5HT1A presynaptic receptors
Mirtazapine :
Blocks 5HT2 , & presynaptic α2 receptors(Involved in
negative feed back inhibition).
Bupropion:
Weak dopamine & NE reuptake inhibitor
Maprotiline:
Potent Nor-Epinephrine uptake inhibitor.
Venlafaxine:
Weak Non selective NE / 5HT / Dopamine uptake inhibitor
at higher doses..
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Actions:

Antidepressants elevate mood ,improve mental

alertness , increase physical activity in major
depression.
Onset of action is slow, generally it takes at least
2 weeks to produce significant improvement in
mood .
Maximum benefit may require 12 or more weeks.

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Tricyclic Antidepressants
Structure
 3 ring nucleus
 Resemble phenothiazines.

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 Pharmacokinetics
Most TCAs are incompletely absorbed.
Lipophilic , widely distributed
Significant 1st pass hepatic metabolism.
High tissue protein binding.
High lipid solubility.
Large Vd. (dialysis ineffective in over dosage)
Plasma half life: 8 – 36 hrs (once daily dosing)
Extensively metabolized in liver, formation of active
metabolite (Amitriptyline --- Nortriptyline &
desipramine)
Metabolism may be induced by inducers & inhibited
by Enzyme inhibitors
Conjugates excreted in urine.

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Pharmacologic Effects
Amine uptake blockade(sympathomimetic effects)
Muscarinic receptor blockade
Alpha blocking effects
Histamine blocking effects
Cardiovascular effects
Seizures (with overdose)
Psychosis
Endocrine effects

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 Therapeutic uses
Endogenous Depression.
Panic attack /acute episode of anxiety.
Enuresis in children and geriatric patients.
Unexplained body pains.
Generalized Anxiety Disorder
Obsessive Compulsive Disorder
Attention deficit hyperkinetic Disorder.
 Neuralgias
Migraine

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Adverse Effects

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Extrapyramidal side effects

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Endocrine adverse effects

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8. Drug interactions

Pharmacodynamic interactions
 Additive effect with other sedative drugs
especially alcohol.
 TCA potentiate effects of anti hypertensive drugs.

Pharmacokinetic interactions
 Metabolism of Dessipramine , Nortriptaline is
inhibited by Paroxetine and Fluoxetine.
 Aspirin and phenylbutazone displace TCA from
PPB sites.

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Overdosage. Extremely dangerous.
Symptoms
1. Pronounced peripheral Atropine like effects
2. Excitement , delirium , convulsions.
3. Coma with shock and metabolic acidosis
4. Respiratory depression.
5. NM irritability and seizures
6. Hyperpyrexia.
7. Cardiac arrhythmias --- may be fatal

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Management of overdosage
Treat in ICU.
1. Supportive Treatment
Gastric lavage with activated charchoal.
Dialysis ineffective
Endotracheal intubation & assistant ventilation may be
required.
2. Specific Treatment: Phenytoin, Lidocaine
Sod. Bicarbonate
Diazepam
Do not use physostigmine

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Selective Serotonin Reuptake Inhibitors: (SSRI)
Fluoxetine (Prozac)
Paroxetine
Fluvoxamine
Citalopram
Escitalopram(Exapro)
Sertraline

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Selective Serotonin Reuptake Inhibitors (SSRIs)
Structure: Distinct from TCAs

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Pharmacokinetic aspects
All of the SSRIs are orally
once-daily dosing
SSRIs are potent inhibitors of CYP2D6
 drug interactions for post-menopausal women taking the breast
cancer drug and estrogen antagonist, tamoxifen
Tamoxifen is converted to active metabolite by CYP2D6,
SSRIs may inhibit this activation and diminish the therapeutic
activity of tamoxifen.
Drug interactions are expected when SSRIs used with drugs that
are metabolized by CYPs 1A2, 2D6, 2C9, and 3A4 (e.g., warfarin,
tricyclic antidepressants, paclitaxel).

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MOA of SSRIs:
They selectively block serotonin transporter
(SERT) responsible for reuptake & termination of
serotonin transmission.
Affinity for Serotonin transporter is 300-3000
times more than Nor-epinephrine transporter.
↑ conc. Of serotonin in synaptic cleft.
Potentiation of action at receptors.
Relief of symptoms of depression.

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SSRI treatment causes stimulation of 5-HT1A and 5-HT7
autoreceptors on cell bodies in the raphe nucleus and of
5-HT1D autoreceptors on serotonergic terminals,
 This reduces serotonin synthesis and release initially .
With repeated treatment with SSRIs, there is a gradual
down-regulation and desensitization of these auto
receptor mechanisms.
down-regulation of postsynaptic 5-HT2A receptors may
also contribute to antidepressant efficacy
Other postsynaptic 5-HT receptors likely remain
responsive to increased synaptic concentrations of 5-HT
and contribute to the therapeutic effects of the SSRIs.

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Serotonin Receptor Subtypes
Receptor Distribution Postreceptor
Subtype Mechanism
5 – HTIA Hippocompus ,raphe Multiple, Gi coupling
nuclie dominates
5 – HTIB Substantia Nigra, basal Gi, ↓cAMP
ganglia, Globus pallidus

5 – HTIDa, b Brain Gi, ↓cAMP

5 – HTIE Cortex, putamen Gi, ↓cAMP
5 – HTIF Cortex, hippcampus Gi, ↓cAMP
5 – HTIP Enteric Nervous System Go ; Slow EPSP
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5 – HT2A Platelets, smooth Gq, ↑IP3
muscle, cerebral cortex

5 – HT2B Stomach fundus Gq, ↑IP3

5 – HT2C Choroid, hippocampus, Gq, ↑IP3
substantia nigra

5 – HT3 Area postrema , Receptor is a Na+-K+ ion

Sensory and enteric channel
Nerves
5 – HT4 CNS, myenteric Gs, ↑cAMP
neurons, smooth
muscle
5 – HT5A,B Brain ↓cAMP
5 – HT Brain G , ↑cAMP 55
 Adverse effects of SSRIs:
Less Antimuscarinic effects. Less dangerous in
overdosage.
GIT symptoms: Nausea vomiting & diarrhea.
Postural hypotension , Cardiac arrhythmias.
Changes in appetite / weight loss/ gain.
Sleep disturbances: Drowsiness or somnolence
with Paroxetine & Fluvoxamine.

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Fluoxetine & Sertraline are more activating.
Anxiety & Tremors.
Sexual dysfunction: Loss of libido , delayed
ejaculation.
Thoughts of suicide & aggression specially in
teenagers.
Teratogenecity-- neonatal abstinence
syndrome , persistent pulmonary hypertension &
convulsions may occur.
Discontinuation syndrome
Drug interactions. Both Pharmacokinetic &
pharmacodynamic D/I may occur

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Pharmacokinetic interaction
Enzyme inhibition:
 Paroxetine and Fluoxetine inhibit metabolism
of drugs metabolized by P450 CYP 2D6, i.e.
Desipramine , Nortriptyline , Flecainide, Lithium,
Warfarin, TCAs.
Fluvoxamine ---- Inhibits metabolism of Alprazolam,
theophylline, TCAs, Warfarin.
Sertraline ---- Inhibit metabolism of tricyclics,
warfarin.

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 Pharmacodynamic Interaction
Serotonin syndrome
Drug Interaction when SSRIs are used ē MAOIs or other
drugs with marked Serotinergic effects
Increased stores of Monoamine
Inhibition of reuptake Marked increase of
Serotonin
Manifestations
Hyperthermia
Muscle rigidity
Myoclonus
Rapid changes in mental status & vital signs– Cardiovascular
collapse.
May be fatal

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Management of Overdosage of SSRIs
Generally no cardiac toxicity.
Seizures may occur
Rarely fatal alone
Only supportive treatment
Dialysis is not useful

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Therapeutic Uses of SSRIs
Endogenous Depression.
Generalized Anxiety Disorder
Eating disorders- bulimia nervosa (fluoxetine)
 Social Anxiety Disorder
Post traumatic stress disorder.
Premenstrual dysphoric disorder.
prevention of vasovagal symptoms in post-menopausal
women
Depressive phase of manic depressive illness
Panic attack/ Acute anxiety.
Attention Deficit Hyperkinetic Disorder.
Enuresis in children and geriatric patients.
Unexplained body pains.
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Merits of SSRIs over TCAs
Less frequent anti-cholinergic, cardiovascular
neurological A/E.
Free of sedation (Fluoxetine & Sertraline )
Better patient’s compliance.
Less likely to produce mania when used in bipolar
disorders.
Greater safety margin.
Specially useful in eating disorders & social phobias.
Elevation of mood & work capacity in post MI &
other chronic smooth illness Patients.

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Demerits of SSRIs over TCAs
Frequent nausea at start of treatment.
↓Libido & sexual dysfunction during maintenance
treatment.
Danger of serotonin syndrome --- potentially
lethal.
More chances of pharmacokinetic drug
interactions.
Paroxetine & Fluoxetine (inhibitor of CYP2D6),
Fluvoxamine (inhibitor of CYP3A4).
Not very useful for treatment of severe
depression.
Thoughts of suicide & increased aggression &
occasionally violence with Fluoxetine specially in
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Monoamine Oxidase Inhibitors
MAOIs--- Amongst the first Antidepressants
Mono amine oxidase enzyme --- 2 types
MAO-A--- Metabolizes nor-epinephrine, serotonin
and tyramine.
Inhibition of MAO-A produces Antidepressant effect
MAO-B---- specific for dopamine.
Inhibition of MAO-B produces Anti-parkinsonian
effect

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 Structure
Older agents: Non- selective for type MAO-A / MAO-B

A. Hydrazides: Phenelzine , Isocarboxazid , Iproniazid

Irreversible Inhibitors, contain C – N – N ; moiety highly reactive &

forms covalent bond.

B. Non-Hydrazides . Tranylcypromine. Closely resembles

Dextroamphetamine.

Prolonged but not Irreversible Inhibitor.

II. Selective MAO-B– Selegiline in high doses , also inhibits MAO-A

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Pharmacokinetic aspects
MAOIs are metabolized by acetylation
“slow acetylators” will elevate its plasma levels.
The nonselective MAOIs used in the treatment of depression are
irreversible (sometimes called “suicide”) inhibitors, it takes up to 2
weeks for MAO activity to recover, even though the parent drug is
excreted within 24 hours
Recovery of normal enzyme function is dependent on synthesis
and transport of new MAO to monoaminergic nerve terminals.
Despite this irreversible enzyme inhibition, MAOIs require daily
dosing.

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MOA of MAOIs:
They inhibit MAO enzyme responsible for intraneuronal
metabolism of NE & serotonin.
So the amines accumulate in presynaptic stores.
↑ amounts are released.
Enhanced action at receptors.
Relief of symptoms of depression

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Adverse Effects Of MAOIs
Interactions with Drugs & Food
Headache, drowsiness.
Weight gain
Postural hypotension
Sexual disturbances (Phenalzine).
Agitation & insomnia with Tranylcypromine &
Selegeline
Atropine like effects less common.
Liver damage, rare –1 in 10000, with hydrazides

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Interactions with Food : Cheese reaction : This occurs
when Tyramine rich foods are taken with MAOIs.
Tyramine rich foods are Ripe cheese , Concentrated yeast
products ,Pickled or smoked fish , Red beans , Red Wine ,
Chicken liver.
MAO-A within the intestinal wall and MAO-A and MAO-B
in the liver normally degrade dietary tyramine.
Patients on MAO inhibitor are unable to degrade the
Tyramine obtained from diet.
Tyramine acts as indirect sympathomometic drug----
causes release of large amounts of catecholamines
from the nerve terminals, resulting in:
Occipital Headache , stiff neck , tachycardia , nausea ,
hypertension , cardiac arrhythmias , seisures & possibly
stroke.
Treatment : Prazocin or phentolamine
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Interactions with Drugs
a. MAOIs & SSRIs--- Serotonin syndrome .
b. MAOIs & TCAs--- Hypertensive episodes,
excitement and hyperactivity
c. MAOIs & Bupropion--- Seizures.
At least 2 weeks ( 6 weeks for fluoxetine) should be
given for wash out effect , before the other class
is started
d. MAOIs & Pethidine Hyperpyrexia, hypotension
, coma.
e. MAOIs & Indirect Sympathomimetics: Severe
Hypertension.
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Overdosage of MAOIs
Agitation , Delirium , N.M. excitability
Followed by Seizures , Shock , Hyperthermia
& Unconsciousness
Treatment is supportive, chlorpromazine may be
helpful.

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Therapeutic uses
1. In endogenous depression, specially patients
non responsive / allergic to TCAs or who experience
severe anxiety. Patients with low psychomotor
activity
may benefit from its stimulant properties.
2.Atypical depression.
3. Phobic states.
Considered to be the last –line agents due to
Drug / Food interactions

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Heterocyclic / atypical Antidepressants
a. Second generation Antidepressants
 Amoxapine,, Maproteline, Trazodone ,
Bupropion.
b. Third generation Antidepressants (SNRIs)
 Nefazodone, Venlafaxine, Mirtazapine ,
Duloxetine

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Newer drugs less efficacious than TCA.
Fewer side effects like sedation & anti-muscarinic
effects.
Lower toxicity in over dosage.
Action with less delay specially Mirtazepine.
Efficacy in patients, non-responsive to TCA or
MAOIs.

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MOA
Similar to the action of SSRIs, the initial inhibition of
SERT induces activation of 5-HT 1A and 5-HT1D
autoreceptors.
This action decreases serotonergic neurotransmission
by a negative feedback mechanism until these
serotonergic autoreceptors are desensitized.
Then, the enhanced serotonin concentration in the
synapse can interact with postsynaptic 5-HT
receptors.

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 MOA of Hetrocyclic Antidepressants
Trazodone & Nefazodone : Block post synaptic 5-
HT2A receptors & on chronic use desensetize 5HT1A
presynaptic receptors, block α1 receptors
Mirtazapine : Blocks 5HT2 , & presynaptic α2
receptors (Involved in negative feed back inhibition),
H1 receptor.
Bupropion: Weak dopamine & NE reuptake
Maprotiline: Potent Nor-Epinephrine uptake inhibitor.
Venlafaxine: Weak Non selective NE / 5HT /
Dopamine uptake inhibitor at higher doses..

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Therapeutic uses:
 Depression specially Endogenous Depression.
 Panic attack/acute episode of anxiety & Generalized Anxiety
Disorder Venlafaxine, Duloxetine,
 Fibromyalgia and neuropathic pain associated with peripheral
neuropathy. (Duloxetine)
 Fibromyalgia pain (milnacipran )
 Off-label uses include
 Stress urinary incontinence (duloxetine),
 autism, binge eating disorders, hot flashes, pain syndromes,
premenstrual dysphoric disorders, and post-traumatic stress disorders
(venlafaxine)
 Neuralgias
 To decrease craving & attenuate the withdrawal symptoms for
nicotine in tobacco users trying to quit smoking--- Bupropion

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A/E of Hetrocyclic Antidepressants
Trazodone & Nefazodone : Drowsiness, dizziness, nausea,
agitation.
Trazodone use is associated with priapism
Mirtazapine : Somnolence, increased appetite, weight gain,
Maprotiline: Similar to tricyclic, seizures are dose related.
Venlafaxine: Nausea, Somnolence, sweating, dizziness,
anxiety, sexual disturbances, hypertension.
Duloxetine: Nausea, dry mouth, decreased appetite,
insomnia, dizziness, sweating.

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Overdosage:
Amoxapine: Severe neurotoxicity with seizures
Maprolitine :seizures & cardiotoxicity.

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Clinical effectiveness of antidepressant treatment
2/3 respond to treatment (>50 % improvement)
1/3 fail to respond to treatment Individual
patients respond better to one group as compared
to other group .

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Therapeutic Uses of Antidepressants
Depression specially Endogenous Depression. All
groups have roughly equivalent inefficacy
Depressive phase of manic depressive illness --- SSRIs
Panic attack/acute episode of anxiety & Generalized
Anxiety Disorder --- TCAs (Imipramine) & hetrocyclics
SSRIs, Venlafaxine, Duloxetine,
Benzodiazepines ---- preferred drugs.
Enuresis in children ---- Imipramine

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Chronic unexplained body pains – TCAs, higher doses
of Venlafaxine, Duloxetine
Neuralgias – TCAs (Imipramine ), Hetrocyclics.
Migraine-(Imipramine ).
Obsessive Compulsive Disorder --- TCAs.
Attention deficit hyperkinetic disorder in children
---- TCAs (Imipramine , Desipramine )and Atomoxetine
To decrease craving & attenuate the withdrawal symptoms
for nicotine in tobacco users trying to quit smoking---
Bupropion

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Only SSRIs useful in:
Eating disorders- bulimia (fluoxetine)
Social phobias
Post traumatic stress disorder.
Premenstrual dysphoric disorder.
Alcohol dependence

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