1. Pharmacology of
Antidepressants
Dr.Ameya Puranik
(Junior Resident)
JNMC,Sawangi(M)

2. Contents
• History
• Classification
• Tricyclic antidepressants
• SSRIs
• SNRIs
• Atypical antidepressants
• Recent advances

3. History
1950 : Discover of chlopramazine.
1958 : Imipramine was found to benefit selectively depressed but not
agitated psychotics.
1961: Discovery of Amitriptyline.
1987: SSRI Fluoxetin was introduced.

4. Classification
1) Tricyclic Antiderpressants (NE+5HT):
• Amytriptyline, Imipramine, Clomipramine, Doxepin.
2) Selective Serotonin,Norepinehrine Reuptake Inhibitors (SNRIs):
• Duloxetine, Venlafaxine, Milnacipran.
3) Predominantly NA reuptake inhibitors:
• Desipramine, Nortriptyline, Amoxapine, Reboxetine.
4) Selective serotonin reuptake inhibitors(SSRIs):
• Fluoxetine,Paroxetine, Dapoxetine, Sertaline, Citalopram, Escitalopram

5. 5) Atypical antiderpressants:
• Trazodone, Mianserin, Mirtazapine, Bupropion, Taineptine,
Amineptine, Atomoxetine.
6) Reversible inhibitors of MAO(A): (Obsolete)
• Moclobemide, Clorgyline.

6. Tricyclic antidepressants

7. Mechanism of action
• TCAs acts by inhibiting NET and SERT monoamine transporters which
mediate reuptake NA and 5HT into there respective neurons leading
to antidepressant action.
• Most TCAs do not inhibit DA uptake, thus indirectly facilitating
dopaminergic transmission, leading to mood elevating action.
• They also potentiate actions histamine, anticholinergics and alpha
adrenergic receptors.

8. Pharmacokinetics
• Absorbed orally
• Highly plasma protein bound, hence large volume of
distribution(20L/Kg).
• Extensively metabolized by liver by CYP family isoenzymes.
• Renal excretion takes place after 1 to 2 weeks.
• Because of longer half life once daily dosing is advised for
maintenance phase.
• Therapeutic window for imipramine, amitritypline and nortrptyline is
seen between plasma concentrations of 50 to 200 ng/ml.

9. Phamacological actions
1) CNS:
Normal individuals:
• Clumsiness
• Tiredness
• light headedness, sleepiness,
• Difficulty in concentration, unsteady gait.
• No mood elevation or euphoria
• Effects are rather unpleasant and may become more so on repeated
administration.

10. Contd.
In depressed patients:
• Antidepressant action takes 2 to 3 weeks to develop.
• Mood is gradually elevated.
• Patient becomes more communicative and start taking interest in self
and surroundings.
• Preponderance of REM sleep in depressed patients is suppressed and
awakenings during night are reduced.

11. ANS:
• Most TCAs are potent anticholinergics.
causes:
• Dry moth, blurring of vision, constipation, urinary hesitancy
• Some TCAs have alpha adrenergic blocking and antihistaminic actions
as well.
CVS:
• Tachycardia, due to anticholinergic and NA potentiating actions.
• Postural hypotension due to alpha adrenergic blockade.
• ECG changes: T wave suppression/inversion, arrhythmias.
• SSRIs and SNRIs are preferable drugs in susceptible patients.

12. Adverse effects
• Anticholinergic: dry mouth, bad taste, constipation, epigastric
distress, urinary retention, blurred vision, palpitations.
• Sedation, mental confusion and weakness especially with
amtriptypline and congeners.
• Increased appetite and weight gain.
• Seizure threshold is lowered, especially with bupropion,
clomipramine and amoxapine.
• Cardiac arrhythmias, especially in IHD patients is seen with
Amitriptypline and dosulpin.
• Postural hypotension, sexual dysfunction, rashes and jaundice are
other adverse effects.

13. Acute poisoining
• Poisoining is very common especially in depressed patients.
Symptoms:
• Excitement, delirium and other features of atropine poisoining.
• Followed by muscle spasms, convulsions, respiratory derpression and
coma.
• Fall in BP, tachycardia and ventricular arrhythmias are common.
Treatment:
• Primarily supportive with gastric lavage, respiratory support,
maintenance of BP, correction of acidosis.
• Diazepam i.v. injected to control convusions and delirium.
• For Arrhythmias propranolol and lidocaine are preferred drugs.

14. SSRIs

15. SSRIs
 First line drugs in depression and also used in anxiety, phobia, OCD and
related disorders.
 Relatively safe and well tolerated than TCAs.
 Fewer side effects.
 No sedation and anticholinergic actions.
 No seizure precipitating propensity.

16. History
• The first drug in the SSRI class was Prozac (Fluoxetine), which hit
the United States market in 1987. Prozac was FDA approved in
December 29, 1987. It is manufactured by Eli Lilly and Company.
• Subsequently other SSRIs were introduced.
• Fluoxetine 1987
• Sertraline 1992
• Paroxetine 1993
• Fluvoxamine 1994
• Citalopram 1998
• Escitalopram 2002

17. Mechanism of action

18. Pharmacokinetics
 Absorption – Well absorbed orally and have peak effects in the range
of 3-8hrs. Absorption of Sertraline may be slightly increased by food.
 Distribution – Differences in plasma protein binding percentages;
with Sertraline, Fluoxetine & Paroxetine most highly bound; &
Escitalopram is least bound.
 Metabolism – All SSRIs are metabolized in the liver by CYP 450
enzymes. Wide Therapeutic Index-So their concentration not affected
by other drugs.

21. Other indications
• Bipolar depression
• Psychosomatic conditions
• Irritable bowel syndrome (IBS)
• Menopausal symptoms
• Premature ejaculation
• Migraine headache prophylaxis
• Chronic headache
• Musculo-skeletal pain
• Fibromyalgia

23. • Selectivity
– Citalopram and Escitalopram is the most selective
• Serotonergic reuptake blockade
– paroxetine is the most potent
• Dopamine reuptake blockade
– Sertraline is the most potent

24. Fluoxetine
Pros
Longer Half life, hence:
• Good for paitents with medication noncompliance issues.
• Decreased incidence of discontinuation syndromes.
• Can be used to does tapering.
• Once daily dosing (or even day after day).
Cons
• Long ½ life + active metabolite ↑ build-up of metabolites( liver dysfunction)

25. Sertaline
Pros
• Relatively fewer side-effects .
• Lower potential for drug-drug interactions (very weak P450
interactions).
• Intermediate ½ life + less active metabolite hence lower build-up of
metabolites.
Less sedating when compared to paroxetine.
Cons
• Increased number of GI adverse drug reactions (associated with
higher incidence of diarrhoea than other SSRI).

26. Paroxetine
Pros
• Short ½ life + No active metabolite ,No build-up of metabolites.
• Sedating properties offers good initial relief from anxiety and insomnia.
• Available in sustained release form.
Cons
• Likely to cause a discontinuation syndrome (short ½ life ).
• Worst side effect profile (sedation, weight gain, sexual dysfunction and
anticholinergic side effects).
• Potential for drug-drug interactions (Significant CYP2D6 inhibition).

27. Citalopram
Pros
• Lower potential for drug-drug interactions (Low inhibition of P450 enzymes).
• Fewer side effects at low doses.
• Intermediate ½ life ( once daily dosing).
Cons
• Dose-dependent QT interval prolongation with doses of 10-40mg/day
• Can be sedating (has mild antagonism at H1 histamine receptor).
• GI side effects (less than Sertraline).

28. Escitalopram
• Pros
• Low overall inhibition of P450s enzymes so fewer drug-drug interactions.
• Intermediate ½ life ( once daily dosing).
• More effective than Citalopram in acute response and remission.
Cons
Dose-dependent QT interval prolongation with doses of 10-30mg daily

29. Adverse effects
• GIT – nausea, vomiting, diarrhea
• Neuropsychiatry – Headache, Irritability, Restless(Akathisia)-EPS more
common in SSRI than TCA, Agitation, Tremor, Insomnia and daytime
somnolence, Seizures and Mania.
• Sexual dysfunctions – Ejaculatory delay, anorgasmia
• Suicidal Behavior
• Serotonin syndrome upon intoxication or drug interactions

30. Serotonin syndrome
 SSRIs are contraindicated with concomitant use of MAOIs (monoamine oxidase
inhibitors).
 This can lead to increased serotonin levels which could cause a serotonin
syndrome.
 Clinical Features :-
• – NEURO: Myoclonus, Nystagmus, Headache,
• Tremors, Rigidity, Seizures
• – MENTAL STATE: Irritability, Confusions, Agitations,
• Hypomania, Coma
• – OTHERS: Hyperpyrexia, sweating, diarrhoea,cardiac arrythmia, death.

31. Management of serotonin syndrome
• Discontinuation of all serotonergic agents
• Supportive care aimed at normalization of vital signs (oxygen and intravenous
fluids, continuous cardiac monitoring, and correction of vital signs).
• Sedation with benzodiazepines
• Administration of serotonin antagonists eg. (Cyproheptadine)

32. SNRIs

33. Venalafaxine
 Selectively inhibit reuptake of noradrenaline and 5HT.
 No interaction with cholinergic and histaminergic receptors.
 Faster onset of action
 Similar potency as TCAs and also effective in resistant cases.
 Useful in mood changes and hot flushes of menopause.
Adverse effects:
 Nausea, vomiting, dizziness, impotence, anxiety

34. Duloxetine
 Similar pharmacokinetics as Venalafaxine.
 No sedation.
 Antidepressant potency similar to TCAs.
 Other indications: Panic attacks, neuropathic pain, fibromyalgia, stress
incontinenece.
Adverse effects:
Agitation, insomnia, rise in BP.

35. Atypical antidepressants

36. Bupropion
• Bupropion: (smoking cessation)
• Acts at unidentified site. It has minimal effects on NE or 5-HT systems,
but blocks DA reuptake
• Its short half-life may require more than once-a-day dosing or the
administration of an extended release formulation, it decreases the
craving of nicotine in tobacco abusers.
• Side effects include: dry mouth ,sweating ,tremor and seizures at high
doses.

37. Mirtazapine
• Blocks 5-HT2 and α2 receptors.
• It is a sedative because of its potent antihistaminic activity, which
may be used to advantage in depressed patients having difficulty
sleeping,
• No antimuscarinic side effects of TCAs.
• Does not interfere with sexual functioning, as do the SSRIs.
• Increased appetite and weight gain frequently occur.

38. Nefazodone and Trazodone
• Nefazodone blocks both NE and 5-HT reuptake, and 5-HT2 antagonist.
• Trazodone weak inhibitor of serotonin reuptake by blocking 5-HT1
presynaptic autoreceptors and thereby, increase serotonin release,
and is a 5-HT2 antagonist.
• Both are sedating because of potent H1 blocking activity.
• Trazodone has been associated with causing priapism.

39. Recent advances
1) Vortiovetine:
• It functions as a SMS (serotonin modulator and stimulator) with a
majority of activity geared towards serotonin and 5-HT receptors.
• It is also thought to affect adrenergic receptors to less of a degree as
well as concentrations of acetylcholine and histamine.
• Vortioxetine was approved by the U.S.FDA for the treatment of major
depressive disorder in adults in September 2013 and it was approved
in Europe later that year.

40. Recent advances
2) SNDRIs
• Acts as a combined reuptake inhibitor of the monoamine
neurotransmitters serotonin, norepinephrine, and dopamine.
• Inhibits the serotonin transporter (SERT), norepinephrine transporter
(NET), and dopamine transporter (DAT), respectively.
• Inhibition of the reuptake of these neurotransmitters increases their
extracellular concentrations and, therefore, results in an increase in
serotonergic, adrenergic, and dopaminergic neurotransmission.
• Approved drugs: Mazindol and Nefazodone

41. Recent advances
3) Vilazodone:
• Acts as serotonin reuptake inhibitors.
• Approved by USFDA in 2011.
• Indication: Major Depressive Disorders.
4) ALKS 5461
• Buprenorphine/samidorphan combination.
• In August 2017, based on the third trial, Alkermes announced the
initiation of a rolling submission of a New Drug Application for ALKS-
5461 to the USFDA.