Antidepressants: classification, mechanism of action (SSRIs, SNRIs, TCAs, MAOIs)

1. Classification

2. SSRIs

• First-line: depression, GAD, panic disorder, OCD, PTSD, social phobia, bulimia, PMDD.
• Fluoxetine: long T½, low discontinuation syndrome risk; active metabolite norfluoxetine.
• Sertraline: safe in cardiac patients, pregnancy; preferred in the elderly.
• Escitalopram: most selective, fewer drug interactions; QT prolongation at doses > 20 mg.
• Paroxetine: most anticholinergic, pronounced discontinuation syndrome; pregnancy category D.
• Fluvoxamine: used for OCD, social phobia; potent CYP1A2 inhibitor.
• Side effects: nausea, diarrhea, sexual dysfunction, insomnia/somnolence, ↑ suicidality in adolescents during the first weeks, bleeding risk (↑ with NSAIDs/anticoagulants), hyponatremia (SIADH) in the elderly.

3. SNRIs

• Venlafaxine: NE effects at doses > 150 mg; better for melancholic depression; hypertension at high doses.
• Duloxetine: approved for diabetic neuropathy, fibromyalgia, chronic musculoskeletal pain.
• Milnacipran: stronger noradrenergic effect, indicated for fibromyalgia.
• Side effects: nausea, hypertension (dose-dependent), profuse sweating, discontinuation syndrome (venlafaxine!).

4. TCAs

• Amitriptyline, imipramine, clomipramine, nortriptyline, doxepin.
• High efficacy in severe/melancholic depression resistant to SSRIs.
• Indications: chronic pain (amitriptyline), neuropathic pain, migraine (prophylaxis), OCD (clomipramine), nocturnal enuresis (imipramine).
• Side effects: anticholinergic (dry mouth, constipation, urinary retention, blurred vision), orthostatic hypotension (α1-blockade), sedation (H1), weight gain, QT prolongation, QRS widening.
• Toxicity in overdose: cardiotoxicity — QRS > 100 ms → risk of arrhythmias; treatment — sodium bicarbonate 1–2 mEq/kg IV.
• Nortriptyline — fewer side effects, preferred in the elderly.

5. MAO inhibitors

• Phenelzine, tranylcypromine, selegiline — irreversible, block MAO-A and MAO-B.
• Moclobemide — reversible, selective for MAO-A, requires fewer dietary restrictions.
• Indications: treatment-resistant depression, atypical depression, social phobia.
• Tyramine-restricted diet (aged cheeses, red wine, cured fish) — risk of «cheese» hypertensive crisis.
• Contraindicated combinations with SSRIs/SNRIs/TCAs (serotonin syndrome), sympathomimetics, meperidine, dextromethorphan.
• 2-week wash-out between MAOIs and SSRIs (5 weeks after fluoxetine).

6. Atypical

Mirtazapine

• α2-antagonist → ↑ release of NA and 5-HT; 5-HT₂/₃ blockade → less nausea and sexual dysfunction.
• Indications: depression with decreased appetite, insomnia (sedating).
• Side effects: weight gain, sedation, agranulocytosis (rare).

Bupropion

• NDRI; activating, no sexual dysfunction, no weight gain.
• Additional: smoking cessation (Zyban), ADHD (off-label), seasonal depression.
• Contraindicated in seizures, bulimia/anorexia (↓ seizure threshold).

Vortioxetine

• Multimodal 5-HT modulator; cognitive enhancement in depression.
• Good safety profile, low sexual dysfunction.

Agomelatine

• MT1/MT2 agonist + 5-HT₂C antagonist — normalization of circadian rhythms.
• No discontinuation syndrome; requires ALT monitoring.

Trazodone

• SARI — weak antidepressant; often used as a hypnotic at doses of 25–100 mg.
• Risk of priapism (rare).

Ketamine/esketamine

• NMDA antagonist; rapid (hours) antidepressant effect.
• Esketamine — nasal spray for treatment-resistant depression and suicidality.
• Requires 2-hour observation after administration.

7. Choice of drug

• First episode of depression — SSRIs (sertraline, escitalopram).
• Insomnia, ↓ appetite — mirtazapine.
• Sexual dysfunction as an issue — bupropion, agomelatine, vortioxetine.
• Chronic pain — duloxetine, amitriptyline.
• OCD — sertraline, fluvoxamine, clomipramine.
• Panic disorder — SSRIs; start with low doses due to ↑ anxiety.
• Pregnancy — sertraline; avoid paroxetine (congenital heart defects).
• Elderly — sertraline, vortioxetine; avoid TCAs, paroxetine.
• Treatment-resistant — augmentation (lithium, T3, atypical antipsychotic aripiprazole/quetiapine, esketamine); combinations; ECT.

8. Effect and duration

• Onset of effect 2–4 weeks; full response 6–8 weeks.
• Assessment at 4 weeks; if no improvement — ↑ dose, at 6–8 weeks — switch drug.
• First episode: continue for 6–12 months after remission.
• Recurrent: ≥ 2 years or lifelong for ≥ 3 episodes.
• Tapering — reduction by 25% every 1–2 weeks to avoid discontinuation syndrome (especially paroxetine, venlafaxine).

9. Serotonin syndrome

• Triad: altered mental status (agitation, confusion), autonomic instability (tachycardia, hyperthermia, diaphoresis, mydriasis), neuromuscular hyperactivity (clonus, hyperreflexia, tremor).
• Hunter criteria: presence of a serotonergic agent + spontaneous clonus, or inducible clonus + agitation/diaphoresis, or ocular clonus + agitation/hyperreflexia.
• Causes: combinations of serotonergic agents (SSRIs + MAOIs/tramadol/linezolid/methylene blue/triptans).
• Treatment: withdrawal, supportive care, benzodiazepines, active cooling; for severe cases — cyproheptadine 12 mg PO + 2 mg every 2 h; intubation and neuromuscular blockade for hyperthermia > 41 °C.

10. Special situations

Pregnancy

• Sertraline — drug of choice.
• Paroxetine — increased risk of congenital heart defects, category D.
• SSRIs in the 3rd trimester — risk of postnatal adaptation syndrome (tremor, hypoglycemia, feeding difficulties) and persistent pulmonary hypertension of the newborn (PPHN).
• Untreated depression also carries risks.

Children and adolescents

• Fluoxetine and escitalopram are approved for depression in adolescents.
• Monitoring for suicidality in the first weeks (FDA black-box warning).

Elderly

• Start at 50% of the usual dose.
• Risk of hyponatremia (SIADH) — monitor Na⁺.
• Avoid anticholinergic TCAs (amitriptyline).

11. FAQ

When to expect the effect of an antidepressant?
Improvement in sleep and appetite — in 1–2 weeks; mood — in 4–6 weeks. If there is no response after 6–8 weeks — switch/augment.

Can you drink alcohol while on SSRIs?
Not recommended: increased sedation, bleeding risk, reduced therapy efficacy. Occasional small doses are permissible for stable patients.

What is discontinuation syndrome?
After abrupt cessation of SSRIs/SNRIs: dizziness, nausea, "brain zaps", anxiety, insomnia. Paroxetine and venlafaxine are the worst. Taper by 25% over 1–2 weeks.

Do antidepressants increase suicide risk?
In the first 2–4 weeks in adolescents and young adults — ↑ activation risk. Suicidality as a feature of depression is more important; frequent contact and monitoring are needed.

Can antidepressants be combined?
Yes, in treatment resistance: SSRIs + mirtazapine, SSRIs + bupropion. Avoid: SSRIs + MAOIs, SSRIs + high-dose TCAs — serotonin syndrome.

See also: Depression · Anxiety disorders · Schizophrenia · Analgesics · Pharmacology catalog