Antidepressants

Antidepressants are the workhorse drugs of psychiatry pharmacology and a perennial NEET PG favourite. The exam loves the mechanism–adverse effect–drug of choice triad: who blocks what, which agent causes serotonin syndrome versus tyramine crisis, and the single best drug for a clinical vignette.

Classification

Antidepressants are grouped by their primary action on monoamine (serotonin, noradrenaline, dopamine) neurotransmission. Onset of clinical benefit is delayed 2–4 weeks for all classes despite immediate receptor effects — the favourite explanation is down-regulation of post-synaptic β-adrenergic and 5-HT₂ receptors with adaptive changes in neuronal plasticity.

Class	Prototype drugs	Primary mechanism
Tricyclic antidepressants (TCAs)	Imipramine, amitriptyline, clomipramine, nortriptyline, desipramine	Block reuptake of NA + 5-HT; also block muscarinic, H₁, α₁
SSRIs	Fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine	Selective serotonin reuptake inhibition
SNRIs	Venlafaxine, desvenlafaxine, duloxetine, milnacipran	Serotonin + noradrenaline reuptake inhibition
MAO inhibitors	Phenelzine, tranylcypromine (non-selective); moclobemide (RIMA, MAO-A); selegiline (MAO-B)	Inhibit monoamine oxidase → ↑ stored amines
Atypical / newer	Mirtazapine, bupropion, trazodone, vortioxetine, vilazodone, agomelatine	Mixed receptor actions

High-yield: All antidepressants take 2–4 weeks to produce mood benefit. If a vignette says "no improvement after 2 weeks," the answer is usually continue and wait, not switch.

Pharmacology by class

Tricyclic antidepressants (TCAs)

TCAs inhibit reuptake of noradrenaline and serotonin. Secondary amines (nortriptyline, desipramine) are relatively more noradrenergic; tertiary amines (imipramine, amitriptyline, clomipramine) are more serotonergic and have more side effects. Clomipramine is the most serotonergic TCA and is the TCA of choice for OCD.

Their downfall is promiscuity — they block:

• Muscarinic receptors → dry mouth, blurred vision, constipation, urinary retention, tachycardia (anticholinergic).
• H₁ receptors → sedation, weight gain.
• α₁ receptors → postural hypotension, dizziness.
• Fast Na⁺ channels (cardiac) → quinidine-like membrane stabilisation → arrhythmia, QRS widening.

High-yield: Amitriptyline is the most sedating and most anticholinergic; nortriptyline/desipramine are the least. Clomipramine = TCA for OCD.

SSRIs

Block the serotonin transporter (SERT). They are first-line for most depressive and anxiety disorders because of their wide therapeutic index and safety in overdose. Distinguishing facts:

• Fluoxetine — longest half-life (active metabolite norfluoxetine ~7–9 days); least withdrawal; most activating; potent CYP2D6/CYP3A4 inhibitor. Approved in children/adolescents.
• Paroxetine — shortest half-life, most anticholinergic, most weight gain, worst discontinuation syndrome, highest sexual dysfunction; avoid in pregnancy (Category D, cardiac septal defects — Ebstein-like risk).
• Sertraline — preferred in cardiac disease and in lactation (low milk levels).
• Citalopram/escitalopram — cleanest CYP profile; citalopram causes dose-dependent QT prolongation (max 40 mg/day, 20 mg in elderly).
• Fluvoxamine — strong CYP1A2 inhibitor; used in OCD.

High-yield: SSRI of choice in post-MI / cardiac patients = sertraline. SSRI to avoid in pregnancy = paroxetine.

SNRIs

• Venlafaxine — serotonergic at low dose, adds noradrenergic action at higher dose; can cause dose-dependent hypertension; short half-life → marked discontinuation syndrome.
• Duloxetine — useful in depression with somatic pain, diabetic peripheral neuropathy, fibromyalgia, stress urinary incontinence.

MAO inhibitors

Irreversible non-selective MAOIs (phenelzine, tranylcypromine) inhibit both MAO-A and MAO-B, raising stored monoamines. They are reserved for atypical depression (hypersomnia, hyperphagia, mood reactivity, leaden paralysis, rejection sensitivity) and treatment-resistant depression. Two named emergencies define them.

Atypical agents

• Mirtazapine — blocks presynaptic α₂ autoreceptors (↑ NA + 5-HT release) plus 5-HT₂/5-HT₃ and H₁ blockade. Causes sedation, weight gain, increased appetite; little sexual dysfunction. DOC in depressed patients with insomnia and anorexia/cachexia.
• Bupropion — NA + dopamine reuptake inhibitor (NDRI). No sexual dysfunction, no weight gain; used for smoking cessation. Lowers seizure threshold — contraindicated in seizure disorder, bulimia/anorexia (electrolyte risk).
• Trazodone — 5-HT₂ antagonist + weak reuptake inhibitor; strongly sedating, used as a hypnotic; classic cause of priapism.
• Agomelatine — melatonin MT₁/MT₂ agonist + 5-HT₂C antagonist; resets circadian rhythm; needs LFT monitoring (hepatotoxicity).
• Vortioxetine/vilazodone — serotonin modulators with partial 5-HT₁A agonism; fewer sexual side effects.

Mechanism flow

Stress / genetic vulnerability → ↓ synaptic monoamines (5-HT, NA, DA) → depressed mood → drug blocks reuptake/MAO → immediate ↑ synaptic monoamine → over 2–4 weeks → down-regulation of post-synaptic 5-HT₂/β-receptors + ↑ BDNF & neurogenesis → clinical antidepressant effect.

Adverse effects and named syndromes

Serotonin syndrome

A potentially fatal excess of serotonergic activity — from overdose, or combining serotonergic drugs (SSRI + MAOI, SSRI + tramadol/triptan/linezolid/St John's wort, SSRI + TCA).

Hunter criteria (serotonergic agent + one of): spontaneous clonus; inducible clonus + agitation/diaphoresis; ocular clonus + agitation/diaphoresis; tremor + hyperreflexia; hypertonia + temperature >38 °C + ocular/inducible clonus.

The classic triad: (1) neuromuscular — clonus, hyperreflexia, myoclonus, tremor (lower-limb predominant); (2) autonomic — hyperthermia, tachycardia, diaphoresis, mydriasis, diarrhoea; (3) altered mental status — agitation, confusion.

Feature	Serotonin syndrome	Neuroleptic malignant syndrome (NMS)
Offending drug	Serotonergic (SSRI, MAOI, tramadol)	Dopamine antagonist (antipsychotic) / withdrawal of L-DOPA
Onset	Rapid (<24 h)	Slow (days)
Neuromuscular	Hyperreflexia, clonus, myoclonus	Lead-pipe rigidity, bradyreflexia
Pupils	Mydriasis	Normal
Bowel	Hyperactive	Normal/decreased
Antidote	Cyproheptadine	Dantrolene / bromocriptine

High-yield: Treatment of serotonin syndrome = stop drug + supportive care + cyproheptadine (5-HT₂ antagonist); benzodiazepines for agitation. The 14-day washout rule: leave 2 weeks between MAOI and SSRI, and 5 weeks when switching FROM fluoxetine TO an MAOI (long half-life).

Tyramine (cheese) reaction — hypertensive crisis

Intestinal/hepatic MAO normally degrades dietary tyramine (a sympathomimetic). With non-selective MAOI, tyramine from aged cheese, red wine, fermented/pickled foods, cured meats, and beer is absorbed, displaces stored noradrenaline → acute hypertensive crisis (severe occipital headache, palpitations, intracerebral haemorrhage risk).

High-yield: Tyramine crisis treatment = phentolamine (α-blocker) IV; alternative nitroprusside. Moclobemide (RIMA) is reversible and selective for MAO-A → much lower tyramine risk because tyramine can displace the reversible inhibitor.

TCA overdose

The classic lethal poisoning ("3 C's: Convulsions, Coma, Cardiotoxicity"). Anticholinergic toxidrome + wide-complex QRS (>100 ms) from Na⁺-channel block, ventricular arrhythmia, hypotension, seizures.

High-yield: TCA overdose treatment = IV sodium bicarbonate (narrows QRS by ↑ extracellular Na⁺ and alkalinising plasma). Target pH 7.45–7.55. QRS >100 ms predicts seizures; >160 ms predicts ventricular arrhythmia.

SSRI/SNRI adverse effects

• Sexual dysfunction (most common reason for non-adherence; delayed orgasm, ↓ libido) — least with bupropion/mirtazapine.
• GI — nausea (commonest early effect), diarrhoea.
• Hyponatraemia / SIADH — especially elderly.
• Increased bleeding risk (impaired platelet 5-HT) — GI bleed with NSAIDs.
• Discontinuation syndrome (FINISH: Flu-like, Insomnia, Nausea, Imbalance, Sensory disturbance/electric-shock, Hyperarousal) — worst with paroxetine/venlafaxine, least with fluoxetine.
• Increased suicidality in <25 years (black-box warning).

Drug of choice — exam table

Clinical scenario	Drug of choice
Depression (general first-line)	SSRI (escitalopram/sertraline)
OCD	SSRI (high dose) or clomipramine
Depression + neuropathic pain / fibromyalgia	Duloxetine
Depression + insomnia + poor appetite	Mirtazapine
Depression + need to avoid sexual dysfunction / smoking cessation	Bupropion
Post-MI / cardiac depression	Sertraline
Atypical / treatment-resistant depression	MAOI (phenelzine)
Nocturnal enuresis in children	Imipramine
Diabetic neuropathy / PHN	TCA (amitriptyline) or duloxetine
Depression in pregnancy	Sertraline / fluoxetine (avoid paroxetine)
Premature ejaculation	Dapoxetine (short-acting SSRI)
Severe depression with suicidality (rapid effect)	ECT / esketamine

Pharmacokinetics & interactions

• CYP inhibition is heavily tested: fluoxetine and paroxetine are potent CYP2D6 inhibitors; fluvoxamine inhibits CYP1A2 (raises theophylline, clozapine); these raise levels of co-administered TCAs, warfarin, antipsychotics.
• TCAs are highly protein-bound, lipophilic, large volume of distribution → dialysis is ineffective in overdose.
• Venlafaxine and paroxetine — short half-life → withdrawal; fluoxetine — long half-life → self-tapering.

High-yield: Esketamine (intranasal NMDA antagonist) and IV ketamine give rapid antidepressant effect within hours in treatment-resistant depression — exploited for acute suicidality, unlike the weeks-long delay of monoamine drugs.

Complications & special situations

• Switch to mania — antidepressant monotherapy in undiagnosed bipolar disorder can precipitate a manic episode; always screen for past mania.
• Hyponatraemia/SIADH — elderly on SSRI; check sodium if confusion/lethargy.
• Serotonin syndrome with serotonergic combinations (linezolid + SSRI is a classic surgical/ICU trap).
• Priapism — trazodone (urological emergency).
• Hepatotoxicity — agomelatine, nefazodone.
• Seizures — bupropion, overdose of any TCA.

Key differentials

• Serotonin syndrome vs NMS vs anticholinergic toxicity vs malignant hyperthermia — distinguish by offending drug, reflexes (hyper vs lead-pipe rigidity), pupils, bowel sounds, and antidote (see table). Anticholinergic toxicity gives dry, flushed skin and absent bowel sounds without clonus.
• Depression vs hypothyroidism / anaemia / dementia (pseudodementia) — always exclude organic causes before labelling depression.
• Discontinuation syndrome vs relapse — discontinuation is early (within days), self-limiting, includes physical "electric-shock" sensations; relapse is later and progressive.

Mnemonics

• TCA overdose "3 C's": Convulsions, Coma, Cardiotoxicity (+ anticholinergic). Treat with biCarbonate.
• SSRI discontinuation = FINISH: Flu-like, Insomnia, Nausea, Imbalance, Sensory, Hyperarousal.
• "Mirtazapine makes you fat and sleepy" — weight gain + sedation, good for cachectic insomniac depressed patients.
• MAOI tyramine foods — "the 3 C's of food": Cheese, Chianti (wine), Cured/Chocolate — avoid.
• Bupropion = no Bedroom problems, no Bulk gain, but Bursts (seizures) — no sexual dysfunction, no weight gain, lowers seizure threshold.

Recently asked / exam angle

• Hunter criteria and cyproheptadine as antidote for serotonin syndrome (image/clinical vignette of clonus + hyperthermia).
• Sodium bicarbonate for TCA-overdose widened QRS — repeatedly asked as "treatment of choice."
• Drug of choice for nocturnal enuresis = imipramine; OCD = clomipramine/SSRI; diabetic neuropathy with depression = duloxetine.
• Which SSRI is safest in cardiac disease / post-MI = sertraline; avoid in pregnancy = paroxetine.
• Mechanism MCQ: mirtazapine blocks presynaptic α₂ receptors; bupropion = NDRI; trazodone causes priapism.
• Washout period: 5 weeks when switching from fluoxetine to an MAOI; 2 weeks otherwise.
• Citalopram → dose-dependent QT prolongation (max 40 mg/day).
• Phentolamine for MAOI-tyramine hypertensive crisis.
• Fluoxetine has the longest half-life (norfluoxetine) and least discontinuation syndrome.

Rapid revision

1. All antidepressants act in 2–4 weeks; delay due to receptor down-regulation/neuroplasticity.
2. SSRIs are first-line — wide safety margin, safe in overdose.
3. Clomipramine = most serotonergic TCA → DOC for OCD; imipramine for childhood enuresis.
4. Amitriptyline = most sedating/anticholinergic TCA; nortriptyline/desipramine least.
5. TCA overdose → wide QRS, seizures, coma → IV sodium bicarbonate.
6. Serotonin syndrome = clonus + hyperreflexia + hyperthermia → cyproheptadine; NMS = lead-pipe rigidity → dantrolene.
7. MAOI + tyramine → hypertensive crisis → phentolamine; moclobemide (RIMA) is safer.
8. Fluoxetine = longest half-life, least withdrawal; paroxetine = avoid in pregnancy, worst discontinuation; sertraline = safest in cardiac disease/lactation.
9. Mirtazapine (α₂ blocker) → weight gain + sedation; bupropion (NDRI) → no sexual dysfunction, smoking cessation, lowers seizure threshold.
10. Trazodone → priapism; duloxetine → depression with neuropathic pain.
11. Citalopram → dose-dependent QT prolongation (max 40 mg/day).
12. Ketamine/esketamine → rapid (hours) effect in treatment-resistant depression and acute suicidality.