Antidepressant Drugs

Classification

1. Selective Serotonin Reuptake Inhibitors (SSRIs)

• Fluoxetine (Prozac) - long half-life (~1-4 days), good for adherence issues
• Sertraline (Zoloft) - broad use, relatively few drug interactions
• Paroxetine (Paxil) - also for anxiety/OCD; most anticholinergic of SSRIs
• Citalopram / Escitalopram - QTc prolongation risk at higher doses
• Fluvoxamine - mainly used for OCD

• GI: nausea, diarrhea (common early)
• Sexual dysfunction (common - in a proportion of patients)
• Insomnia or hypersomnia
• Weight changes
• Serotonin syndrome in overdose or combination with other serotonergic agents: delirium, hypertension, tachycardia, diaphoresis, muscle rigidity, myoclonus, hyperthermia, clonus, dilated pupils
• May precipitate mania in unrecognized bipolar disorder
• Pulmonary hypertension risk in neonates of mothers exposed during pregnancy

2. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Venlafaxine (Effexor) - monitor diastolic BP; requires extended-release form for less GI upset; relatively linear dose-response
• Duloxetine (Cymbalta) - approved for diabetic neuropathy, fibromyalgia, GAD, chronic musculoskeletal pain
• Desvenlafaxine - active metabolite of venlafaxine
• Levomilnacipran - most noradrenergic SNRI; potentially better for fatigue/anergia

3. Tricyclic Antidepressants (TCAs)

• Tertiary amines (imipramine, amitriptyline, doxepin, trimipramine): inhibit both NE and 5-HT reuptake; more sedating
• Secondary amines (desipramine, nortriptyline, protriptyline, amoxapine): preferential NE reuptake inhibition; better tolerated

• Neuropathic pain (diabetic neuropathy, postherpetic neuralgia) at lower doses than required for depression - effect appears independent of antidepressant action
• Migraine prophylaxis (amitriptyline)
• IBS (motility modulation + visceral sensory effects)
• Fibromyalgia, chronic low back pain, tension headache

• Anticholinergic: dry mouth, constipation, urinary retention, blurred vision
• Sedation (antihistaminic)
• Orthostatic hypotension
• Cardiac: conduction delay, heart block, arrhythmias - contraindicated in cardiovascular disease
• Memory impairment (especially in elderly)
• Overdose is lethal - cardiac tachyarrhythmias and AV block. Desipramine carries the greatest overdose risk. Prescribe only 10-day supply when suicide risk is present.

4. Monoamine Oxidase Inhibitors (MAOIs)

• Irreversible, non-selective: Phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid - oldest agents
• Selective MAO-B inhibitor: Selegiline (transdermal patch = Emsam) - transdermal delivery minimizes GI/hepatic MAO-A inhibition, reducing tyramine risk
• Reversible MAO-A inhibitor (RIMA): Moclobemide - available in 50+ countries; safer tyramine profile

• MAO-A in intestinal mucosa normally metabolizes dietary tyramine
• When inhibited, tyramine enters the circulation, triggers norepinephrine/epinephrine release - causes hypertensive crisis
• Foods to avoid: aged cheese, cured meats, fermented foods, wine/beer, broad beans

• SSRIs + MAOIs = serotonin syndrome (must observe 1-2 week washout when switching)
• TCAs + MAOIs = hyperadrenergic crisis
• Sympathomimetics = hypertensive crisis

5. Atypical Antidepressants

Bupropion (Wellbutrin)

• Mechanism: enhances noradrenergic (and possibly dopaminergic) function
• No anticholinergic, sedating, or orthostatic effects; minimal sexual side effects (unlike SSRIs)
• Also approved for smoking cessation
• Lowers seizure threshold - avoid in eating disorders and seizure history
• Stimulant-like side effects possible
• An extended-release formulation combining bupropion + dextromethorphan (NMDA antagonist) may accelerate response

Mirtazapine (Remeron)

• Tetracyclic; blocks presynaptic α2-adrenergic receptors (increasing NE/5-HT release) and postsynaptic 5-HT2 and 5-HT3 receptors
• Strongly antihistaminic - produces sedation (useful in depressed patients with insomnia)
• Notable weight gain
• Relatively few sexual side effects

Trazodone / Nefazodone

• Block serotonin reuptake and 5-HT2 receptors
• Sedating; trazodone widely used for insomnia at low doses

Vortioxetine

• SERT blocker + 5-HT1A agonist, 5-HT1B partial agonist, 5-HT1D/5-HT3/5-HT2 antagonist
• May improve cognitive symptoms of depression
• Relatively linear dose-response curve

Vilazodone

• SERT blocker + partial 5-HT1A agonist

Gepirone

• Partial 5-HT1A agonist and 5-HT2 antagonist; recently approved

General Principles of Use

• Onset of action: Therapeutic effect typically takes 2-4 weeks - patients must be counseled about this
• First-line: SSRIs or SNRIs in most cases, due to tolerability and safety in overdose
• Switching: If an SSRI fails at full doses after 4-6 weeks, switching to bupropion, sertraline, venlafaxine, or an MAOI is reasonable (25% success rate in one major NIH-funded trial)
• Maintenance: Continued for 6-12 months after remission; longer for recurrent depression
• Treatment-resistant depression: ECT, rTMS, VNS; intravenous/intranasal ketamine (esketamine FDA-approved); investigationally, psilocybin and deep brain stimulation

Side Effect Comparison (by class)

• Adams and Victor's Principles of Neurology, 12th Ed., Tricyclic Antidepressants & Serotonin Reuptake Inhibitors sections
• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Depressive Disorders chapter
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Antidepressant section with side-effect table
• Harrison's Principles of Internal Medicine, 22nd Ed., Antidepressant Medications for Pain Management