1. ANTIDEPRESSANTS
Dr. Bushra Hasan Khan
JR-1
Department of Pharmacology
JNMC, AMU, Aligarh.
1

2. OUTLINE
• DEPRESSION CRITERIA
• EPIDEMIOLOGY
• PHARMACOLOGY OF ANTIDEPRESSANT DRUGS
• OTHER TREATMENT MODALITIES
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3. MAJOR DEPRESSION
3
AT LEAST 5 OF THESE 9 SYMPTOMS , PRESENT NEARLY EVERY DAY:
1. DEPRESSED MOOD OR IRRITABLE MOST OF THE DAY
2. DECREASED INTEREST OR PLEASURE IN ACTIVITIES
3. SIGNIFICANT WEIGHT CHANGE (5%) OR CHANGE IN APPETITE
4. CHANGE IN SLEEP : INSOMNIA OR HYPERSOMNIA
5. CHANGE IN ACTIVITY : PSYCHOMOTOR AGITATION OR RETARDATION
6. FATIGUE OR LOSS OF ENERGY
7. GUILT/WORTHLESSNESS
8. CONCENTRATION - DIMINISHED , INDECISIVENESS
9. SUICIDALITY: THOUGHTS OF DEATH OR SUICIDE, OR HAS SUICIDE
PLAN

4. • PREVALENCE OF MAJOR DEPRESSION IS 5%
• MALE: FEMALE = 1:2
• INCIDENCE INCREASES WITH AGE IN BOTH SEXES
• 15% POPULATION - MAJOR DEPRESSIVE EPISODE AT
SOME POINT IN LIFE
• 10–15% OF DEPRESSION CASES : SECONDARY TO
GENERAL MEDICAL ILLNESS OR SUBSTANCE ABUSE
• APPROXIMATELY 4–5% OF ALL DEPRESSED PATIENTS
COMMIT SUICIDE
4
EPIDEMIOLOGY

5. DEPRESSION : SECONDARY TO
GENERAL MEDICAL ILLNESSES
• Endocrine disturbances
(hyper- or hypocortisolemia, Hyper- or
hypothyroidism),
• Autoimmune diseases,
• Parkinson's disease,
• Traumatic brain injury,
• Certain cancers,
• Asthma,
• Diabetes, and
• Stroke.
Depression and obesity/metabolic syndrome are
important risk factors for each other. 5

6. CLASSIFICATION OF ANTIDEPRESSANT
DRUGS
1) SSRIs: Citalopram, Escitalopram, Fluoxetine, Fluvoxamine,
Paroxetine, Sertraline.
2) SNRIs: Duloxetine, Venlafaxine, Desvenlafaxine, Milnacipram.
3) SEROTONIN RECEPTOR ANTAGONIST: Mirtazapine,
Nefazodone, Trazodone, Atomoxetine, Bupropion, Mianserin.
4) MAOIs: Phenelzine, Selegiline, Tranylcypromine, Moclobemide.
5) TCAs: Amitriptyline, Clomipramine, Doxepin,
Imipramine,Trimipramine, Reboxetine ,Amoxapine, Desipramine,
Maprotiline, Nortriptyline, Protriptyline. 6

7. SITES OF ACTION OF
ANTIDEPRESSANTS
NORADRENERGIC NERVE
TERMINAL
SEROTONERGIC NERVE
TERMINAL
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8. SELECTIVE SEROTONIN REUPTAKE INHIBITORS
 CITALOPRAM
 ESCITALOPRAM
 FLUOXETINE
 PAROXETINE
 FLUVAXAMINE
 SERTRALINE
 VORTIOXETINE
 VILAZODONE
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9. • SSRI initially blocks SERT and results in enhanced serotonergic
neurotransmission by blocking the reuptake of serotonin by
SERT.
• Increased synaptic availability of serotonin stimulates a large
number of postsynaptic 5-HT receptor subtypes, as well as
presynaptic terminal receptors that regulate serotoninergic
neuron activity and serotonin release.
• 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, and this
reduces serotonin synthesis and release toward pre-drug
levels.
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SSRIs MECHANISM OF ACTION

10. SSRIs MECHANISM OF ACTION
(contd.)
• With repeated treatment with SSRIs, there is a gradual down-
regulation and desensitization of these autoreceptors.
• In addition, down-regulation of postsynaptic 5-HT2A receptors
may contribute to antidepressant efficacy directly or by
influencing the function of noradrenergic and other neurons
via serotonergic heteroreceptors.
• 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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11. SSRIs PHARMACOKINETICS
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• All of the SSRIs are orally active
• Once-daily dosing .
• Hepatic metabolism: CYP2D6
• In post-menopausal women taking Tamoxifen ; the parent
molecule is converted to a more active metabolite by CYP2D6,
and SSRIs may inhibit this activation and diminish the
therapeutic activity of tamoxifen.
• Care should be used in combining SSRIs with drugs that are
metabolized by CYPs 1A2, 2D6, 2C9, and 3A4 (e.g., Warfarin,
tricyclic antidepressants, paclitaxel).

12. SSRIs uses
• Depression (CITALOPRAM 20mg/day)
• Anxiety : generalized anxiety, panic, social
anxiety, and obsessive-compulsive disorders.
• Posttraumatic stress disorder (Sertraline and
Paroxetine )
• Premenstrual dysphoric syndrome
• Vasovagal symptoms in post-menopausal
• Obsessive-compulsive disorder
12

13. SSRIs ADVERSE EFFECTS
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• Excessive stimulation of brain 5-HT2 receptors : insomnia,
increased anxiety, irritability, and decreased libido.
• Excess activity at spinal 5-HT2 receptors : sexual side
effects including erectile dysfunction, anorgasmia, and
ejaculatory delay
• Stimulation of 5-HT3 receptors in the CNS and periphery -
GI effects : nausea , diarrhea and emesis.

14. SSRIs ADVERSE EFFECTS (contd.)
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• Withdrawal syndrome : dizziness, headache,
nervousness, nausea, and insomnia.
• Paroxetine - risk of congenital cardiac malformations.
• Venlafaxine - risk of perinatal complications.
• Citalopram – QT Prolongation (>40 mg / day)

15. SSRIs DRUG INTERACTIONS
• Paroxetine and fluoxetine are potent inhibitors of
CYP2D6 : increase in plasma concentrations of drugs
metabolized by CYP2D6 when doses of these drugs are
increased.
• Fluvoxamine directly inhibits CYP1A2 and CYP2C19
• Fluoxetine and Fluvoxamine also inhibit CYP3A4.
• Increase in TCA exposure may be observed during co-
administration of TCAs and SSRIs. 15

16. • MAOIs enhance the effects of SSRIs due to inhibition of
serotonin metabolism.
• Serotonin syndrome :
Hyperthermia, muscle rigidity, myoclonus, tremors,
autonomic instability, confusion, irritability, and
agitation; this can progress toward coma and death.
16

17. • Since MAOIs bind irreversibly to MAO and block the
enzymatic metabolism of monoaminergic neurotransmitters,
SSRIs should not be started until at least 14 days following
discontinuation of treatment with MAOI; this allows for
synthesis of new MAO.
• For all SSRIs but Fluoxetine, at least 14 days should pass prior
to beginning treatment with MAOI following the end of
treatment with an ssri.
• Since the active metabolite norfluoxetine has a t1/2 of 1-2
weeks, at least 5 weeks should pass between stopping
fluoxetine and beginning MAOI.
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18. SEROTONIN-NOREPINEPHRINE REUPTAKE
INHIBITORS
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• VENLAFAXINE
• DESVENLAFAXINE
• DULOXETINE
• MILNACIPRAN

19. SNRIs MECHANISM OF ACTION
• SNRIs inhibit both SERT and NET.
• SNRIs cause enhanced serotonergic and/or
noradrenergic neurotransmission.
• The initial inhibition of SERT induces activation of 5-
HT1A 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.
19

20. VENLAFAXINE
• The reuptake effects of venlafaxine are dose-
dependent.
• At low doses (<150 mg/day), it acts only on
serotonergic transmission.
• At moderate doses (>150 mg/day), it acts on
serotonergic and noradrenergic systems
• Whereas at high doses (>300 mg/day), it also affects
dopaminergic neurotransmission.
20

21. SNRIs PHARMACOKINETICS
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• The elimination half-life : Venlafaxine - 5 hours
Desmethylvenlafaxine -11 hours
• Desmethylvenlafaxine is eliminated by hepatic
metabolism and by renal excretion.
• Duloxetine has a t1/2 of 12 hours.

22. USES OF SNRIs
• Major Depressive Disorder (MDD)
• Generalised Anxiety Disorder (GAD)
• Social Anxiety Disorder (SAD)
• Panic Disorder
• Neuropathic Pain (Duloxetine )
• Fibromyalgia (Milnacipram , Duloxetine)
• Chronic Musculoskeletal Pain
• Stress Urinary Incontinence (Duloxetine)
• PTSD (Venlafaxine)
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23. SNRIs ADVERSE EFFECTS
• Nausea, constipation, insomnia, headaches,
and sexual dysfunction.
• Venlafaxine : cardiotoxicity
• Duloxetine : hepatic failure
23

24. SNRIs DRUG INTERACTIONS
• While 14 days are suggested to elapse from ending
MAOI therapy and starting Venlafaxine treatment, an
interval of only 7 days after stopping Venlafaxine is
considered safe before beginning MAOI.
• Duloxetine has a similar interval to initiation following
MAOI therapy, but requires only a 5-day waiting period
to begin MAOI treatment after ending Duloxetine.
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25. SEROTONIN RECEPTOR
ANTAGONISTS
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• MIRTAZAPINE
• BUPROPION
• TRAZODONE
• NEFAZODONE
• MIANSERIN

26. SEROTONIN RECEPTOR ANTAGONISTS
MECHANISM OF ACTION
• TRAZODONE : Blocks 5-HT2A
receptor, inhibits reuptake of 5-HT
and desensitises 5-HT autoreceptor, enhances 5-HT release.
TRAZODONE also blocks Alpha1 adrenergic receptors.
• NEFAZODONE : blockade of the 5-HT2 receptors.
• MIRTAZAPINE: Tetracyclic structure : stimulates norepinephrine
and serotonin release through its central presynaptic Alpha2-
adrenergic antagonist effects ; potent antagonist of 5-HT2c and
histamine receptors
• MIANSERIN: blocks presynaptic Alpha2 receptors
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27. SEROTONIN RECEPTOR ANTAGONISTS
PHARMACOKINETICS
• Mirtazapine : Elimination t1/2 : 20 to 40 hours
• Trazodone : Elimination t1/2 : 7-10 hours
• Nefazodone : Elimination t1/2 : 2-4 hours
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28. SEROTONIN RECEPTOR ANTAGONISTS :
USES
• Depression : Trazodone typically is started at 150 mg/day in
divided doses with 50 mg increments every 3-4 days. The
maximally recommended dose is 400 mg/day for outpatients
and 600 mg/day for inpatients.
• Insomnia : Low doses of Trazodone (50-100 mg)
• Depressed patients with Insomnia : Mianserin and
Mirtazapine
• Mirtazapine : 15 mg po hs ; may increase dose no more
frequently than 1-2weeks; not to exceed 45 mg hs 28

29. SEROTONIN RECEPTOR ANTAGONISTS
ADVERSE EFFECTS
• Mirtazapine : somnolence, increased appetite,
weight gain, Xerostomia, constipation.
• Trazodone : Blurred vision, Dizziness, Headache ,
Drowsiness, Dry mouth, Fatigue, Nausea,
vomiting, Postural Hypotension , Priapism.
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30. SEROTONIN RECEPTOR ANTAGONISTS
DRUG INTERACTIONS
• Trazodone dosing may need to be lowered
when given together with drugs that inhibit
CYP3A4.
• Trazodone and nefazodone are weak inhibitors
of serotonin uptake and should not be
administered with MAOIs due to concerns
about the serotonin syndrome.
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31. BUPROPION
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• Norepinephrine dopamine reuptake inhibitor
• May act through dopaminergic or
noradrenergic pathways

32. BUPROPION PHARMACOKINETICS
• Peak serum time: 2 hr (immediate-release)
3 hr (extended-release)
• Metabolism : Hepatic via CYP2B6
• Elimination t1/2 : 8-24 hours
• Elimination : hepatic and renal
32

33. BUPROPION USES
• Depression : Bupropion is widely used in
combination with SSRIs
• Prevention of seasonal depressive disorder
• Smoking cessation treatment
• ADHD: 150 mg per day
• Neuropathic pain : 150 mg BD for 6 weeks
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34. BUPROPION ADVERSE EFFECTS
• Headache
• Dizziness
• Insomnia
• Agitation
• Dry mouth
• Nausea
• Risk of seizures
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35. BUPROPION DRUG INTERACTIONS
• The major route of metabolism for Bupropion is
CYP2B6
• Consideration for a decreased dose should be
made in cases of -
oPatients with severe hepatic cirrhosis
oRenal impairment.
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36. MONOAMINE OXIDASE INHIBITORS
• MOCLOBEMIDE
• SELEGILINE
• TRANYLCYPROMINE
• PHENELZINE
• ISOCARBOXAZID
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37. MECHANISM OF ACTION OF
MONOAMINE OXIDASE INHIBITORS
• The MAOIs nonselectively and irreversibly inhibit both MAO-A
and MAO-B, which are located in the mitochondria and
metabolize (inactivate) monoamines, including 5-HT and NE
• Selegiline inhibits MAO-B at lower doses, with effects on
MAO-A at higher doses.
• Selegiline also is a reversible inhibitor of monoamine oxidase,
which may reduce the potential for serious adverse drug and
food interactions. 37

38. MONOAMINE OXIDASE INHIBITORS
PHARMACOKINETICS
• MAOIs are metabolized by acetylation.
• A significant portion of the population are "slow acetylators"
and will exhibit elevated plasma levels.
• The nonselective MAOIs used in the treatment of depression
are irreversible inhibitors ; thus, 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.
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39. MONOAMINE OXIDASE INHIBITORS
ADVERSE EFFECTS
39
• HYPERTENSIVE CRISIS :
MAO-A within the intestinal wall and MAO-A and MAO-B in the liver
normally degrade dietary tyramine.
However, when MAO-A is inhibited, the ingestion of certain aged
cheeses, red wines, sauerkraut, fava beans, and a variety of other
tyramine-containing foods leads to accumulation of tyramine in
adrenergic nerve endings and neurotransmitter vesicles and induces
norepinephrine and epinephrine release.
• HEPATOTOXICITY

40. MONOAMINE OXIDASE INHIBITORS
DRUG INTERACTIONS
• CNS depressants including Meperidine and other narcotics,
alcohol, and anesthetic agents should not be used with
MAOIs. Meperidine and other opioid agonists in combination
with MAOIs also induce the serotonin syndrome.
• SSRIs and SNRIs are contraindicated in patients on MAOIs, and
vice versa, to avoid the serotonin syndrome.
• In general, other antidepressants such as TCAs and bupropion
also should be avoided in patients taking an MAOI.
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41. TRICYCLIC ANTIDEPRESSANTS
• IMIPRAMINE
• CLOMIPRAMINE
• AMITRIPTYLINE
• DOXEPIN
• DESIPRAMINE
• NORTRIPTYLINE
• PROTRIPTYLINE
• AMOXAPINE
• REBOXETINE
• MAPROTILINE
41

42. TRICYCLIC ANTIDEPRESSANTS
MECHANISM OF ACTION
• SERT and NET blocker (Imipramine, Amitriptyline)
• NET blocker (Desipramine, Nortriptyline, Protriptyline,
Amoxapine)
• (H1, 5-HT2, Alpha1, and Muscarinic).
• Amoxapine - also a dopaminergic receptor antagonist :
extrapyramidal side effects such as tardive dyskinesia. 42

43. TRICYCLIC ANTIDEPRESSANTS
PHARMACOKINETICS
• The TCAs, or their active metabolites, have plasma
exposure half-lives of 8-80 hours; once-daily dosing.
• Steady-state concentrations occur within several days
to several weeks of beginning treatment.
• TCAs are largely eliminated by hepatic CYPs.
• Determination of plasma levels may be useful in
identifying patients who appear to have toxic effects
and may have excessively high levels of the drug.
43

44. • Narrow therapeutic window.
About 7% of patients metabolize TCAs slowly due
to a variant CYP2D6 isoenzyme, causing a 30-fold
difference in plasma concentrations among
different patients given the same TCA dose.
To avoid toxicity in "slow metabolizers," plasma
levels should be monitored and doses adjusted
downward.
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45. TRICYCLIC ANTIDEPRESSANTS
ADVERSE EFFECTS
45
• H1 receptor antagonism : sedative effects of TCAs
• Antagonism of muscarinic receptors : cognitive dulling , blurred
vision, dry mouth, tachycardia, constipation, difficulty urinating.
• Antagonism of 1 adrenergic receptors : orthostatic hypotension
and sedation.
• Weight gain.
• Quinidine-like effects on cardiac conduction : limit the use of
TCAs in patients with coronary heart disease.
• TCAs also lower the seizure threshold.

46. TRICYCLIC ANTIDEPRESSANTS
DRUG INTERACTIONS
46
• Drugs that inhibit CYP2D6, such as SSRIs, may increase
plasma exposures of TCAs.
• TCAs can potentiate the actions of sympathomimetic
amines and should not be used concurrently with MAOIs or
within 14 days of stopping MAOIs.

47. PSYCHIATRIC USES
ENDOGENOUS
DEPRESSION
PANIC
DISORDERS
OCDADHD
SCHOOL PHOBIA,
PTSD,
IMPULSE
CONTROL
DISORDERS
47

48. ENURESIS
AND
BEDWETTING IN CHILDREN
CHRONIC NEUROPATHIC
PAIN
MIGRAINE ETHANOL ABUSE
NON
PSYCHIATRIC
USES
48

49. MISCELLANEOUS USES
• ATOPIC DERMATITIS
• LICHEN SIMPLEX
5% TOPICAL
DOXEPIN
• BULLIMIA NERVOSA
FLUVOXAMINE
FLUOXETINE
• SMOKING CESSATIONBUPROPION
49

50. Electroconvulsive therapy
• Onset of action may be more rapid than that of drug
treatments, with benefit often seen within 1 week of
commencing treatment.
• A course of ECT (usually up to 12 sessions) is the treatment
of choice for patients who do not respond to drug therapy.
Indications for the use of ECT :
• Need for a rapid antidepressant response
• Failure of drug therapies
• History of good response to ECT
• Patient preference
• High risk of suicide
• High risk of medical morbidity and mortality
50

51. BRIGHT-LIGHT THERAPY
• Bright-light therapy for seasonal affective
disorder is used at an intensity of 10,000 lux
for 30-90 minutes daily, usually within 1 hour
of arising in the morning.
51

52. • Psychotherapy :
o Cognitive behavioral therapy
o Family therapy
o Interpersonal therapy
• Other non-pharmacological interventions :
o Transmagnetic stimulation of the brain
o Deep brain stimulation
o Vagus nerve stimulation
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53. THANK YOU
53

54. Sites of action of Antidepressants
• SSRIs, SNRIs, and TCAs increase noradrenergic or serotonergic
neurotransmission by blocking the norepinephrine or serotonergic
transporter at presynaptic terminals (NET, SERT).
• MAOIs inhibit the catabolism of norepinephrine and serotonin.
• Chronic treatment with a number of antidepressants desensitizes
presynaptic autoreceptors and heteroreceptors, producing long-lasting
changes in monoaminergic neurotransmission.
• Post-receptor effects of antidepressant treatment, including modulation
of GPCR signaling and activation of protein kinases and ion channels, are
involved in the mediation of the long-term effects of antidepressant
drugs. Note that NE and 5-HT also affect each other's neurons.
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