Antidepressants

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Pharmacology

Mechanism

Major classes of antidepressants

Selective serotonin reuptake inhibitors (SSRIs)

• Examples
• Fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram, citalopram.

• Mechanism
• Inhibit 5‑HT reuptake. It normally takes 4-8 weeks for antidepressants to show appreciable effect.

• Clinical use
• Depression, generalized anxiety disorder, panic disorder, OCD, bulimia, binge‑eating disorder, social anxiety disorder, PTSD, premature ejaculation, premenstrual dysphoric disorder.

• Adverse effects
• Fewer than TCAs; serotonin syndrome, GI upset, SIADH, sexual dysfunction (anorgasmia, erectile dysfunction, reduced libido), mania precipitation if underlying bipolar disorder.

Serotonin–norepinephrine reuptake inhibitors (SNRIs)

• Examples
• Venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran.

• Mechanism
• Inhibit reuptake of 5‑HT and NE.

• Clinical use
• Depression, generalized anxiety disorder, diabetic neuropathy; venlafaxine also for social anxiety disorder, panic disorder, PTSD, OCD; duloxetine and milnacipran also for fibromyalgia.

• Adverse effects
• Increased blood pressure, stimulant effects, sedation, sexual dysfunction, nausea.

Tricyclic antidepressants (TCAs)

• Examples
• Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin, amoxapine.

• Mechanism
• Inhibit 5‑HT and NE reuptake.

• Clinical use
• Major depressive disorder, peripheral neuropathy, chronic neuropathic pain, migraine prophylaxis, OCD (clomipramine), nocturnal enuresis (imipramine).

• Adverse effects
• Sedation; α₁‑blockade with postural hypotension; and atropine-like (anticholinergic) adverse effects (tachycardia, urinary retention, dry mouth). 3° TCAs (amitriptyline) have more anticholinergic effects than 2° TCAs (nortriptyline). Risk of QT prolongation.
• Tri-CyCliC’s: Convulsions, Coma, Cardiotoxicity (arrhythmia due to Na⁺ channel inhibition); also respiratory depression, hyperpyrexia. Confusion/hallucinations are more common in elderly due to anticholinergic adverse effects (2° amines [eg, nortriptyline] better tolerated). Treatment: sodium bicarbonate, NaHCO₃ to prevent arrhythmia.

Monoamine oxidase inhibitors (MAOIs)

• Examples
• Tranylcypromine, phenelzine, isocarboxazid, selegiline (selective MAO‑B inhibitor).

• Mechanism
• Non‑selective MAO inhibition → increased levels of amine neurotransmitters (norepinephrine, 5‑HT and dopamine).

• Clinical use
• Atypical depression, anxiety disorders, Parkinson disease (selegiline).

• Adverse effects
• CNS stimulation; hypertensive crisis especially with ingestion of tyramine. Contraindicated with SSRIs, TCAs, St. John’s wort, meperidine, dextromethorphan, pseudoephedrine, linezolid (to avoid precipitating serotonin syndrome).
• Wait 2 weeks after stopping MAOIs before starting serotonergic drugs or stopping dietary restrictions.