Antidepressant Drug Classes & Mechanisms

Overview: Neurochemical Basis

1. Selective Serotonin Reuptake Inhibitors (SSRIs)

Mechanism

• Block the serotonin transporter (SERT) on the presynaptic neuron, preventing reuptake of 5-HT back into the cell
• Net effect: increased 5-HT in the synapse
• Selective for SERT - minimal action on NE or DA transporters (though individual agents vary slightly)

Drugs & Doses

Side Effects (Common)

• GI: Nausea, diarrhea (especially at initiation)
• Sexual dysfunction: Delayed orgasm, decreased libido (very common, >30% with many agents)
• CNS: Insomnia, agitation, tremor
• Serious: Serotonin syndrome (especially with co-administration of MAOIs or other serotonergic drugs), increased bleeding risk (especially with NSAIDs), hyponatremia (SIADH), QTc prolongation (notably citalopram at higher doses)
• Black box warning: Increased suicidal ideation in adolescents and young adults

Clinical Notes

• First-line agents for MDD, GAD, panic disorder, OCD, PTSD, social anxiety
• Escitalopram and sertraline rank highest for combined efficacy + tolerability in network meta-analyses
• "Start low, go slow" in anxious patients - SSRIs can transiently worsen anxiety early in treatment
• Slow taper needed when discontinuing (especially paroxetine) to avoid discontinuation syndrome

2. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Mechanism

• Block both SERT and NET (norepinephrine transporter), increasing synaptic 5-HT and NE
• Agents differ in the ratio: venlafaxine, duloxetine, and desvenlafaxine preferentially block SERT; levomilnacipran predominantly blocks NET

Drugs & Doses

Side Effects

• Similar to SSRIs: nausea, diarrhea, sexual dysfunction
• Additional NE effects: hypertension, tachycardia, tremor, sweating
• Venlafaxine associated with dose-dependent blood pressure elevation
• Pronounced discontinuation syndrome (especially venlafaxine, paroxetine) - always taper slowly

Clinical Notes

• Also effective for neuropathic pain, fibromyalgia (duloxetine), and stress urinary incontinence (duloxetine)
• SNRIs are useful when pain comorbidity is present
• Pre-existing hypertension warrants BP monitoring with venlafaxine

3. Tricyclic Antidepressants (TCAs)

Mechanism

• Inhibit presynaptic reuptake of both serotonin and norepinephrine (in varying proportions depending on agent)
• Additional receptor blockade (explains most side effects):
  • H1 (histamine) blockade → sedation, weight gain
  • Muscarinic (M1) blockade → anticholinergic effects
  • Alpha-1 adrenergic blockade → orthostatic hypotension
  • Sodium channel blockade → cardiac toxicity in overdose (QRS widening → arrhythmia)

Drugs

Side Effects

• Anticholinergic: Dry mouth, urinary retention, constipation, blurred vision, confusion
• Antihistamine: Sedation, weight gain
• Cardiovascular: Orthostatic hypotension, conduction delays (QT prolongation), fatal in overdose due to wide QRS and ventricular arrhythmias
• Overdose = medical emergency: Sodium bicarbonate is the treatment for TCA-induced cardiac toxicity

Clinical Notes

• Now second- or third-line due to side effect profile and toxicity in overdose
• Still useful in: treatment-resistant depression, neuropathic pain, migraine prophylaxis, OCD (clomipramine), nocturnal enuresis (imipramine)
• TCA plasma levels can be checked to guide dosing (therapeutic windows exist)

4. Monoamine Oxidase Inhibitors (MAOIs)

Mechanism

• Inhibit monoamine oxidase (MAO), the enzyme that breaks down 5-HT, NE, and DA in the presynaptic neuron and the gut/liver
• Leads to increased storage and release of all three monoamines
• MAO-A preferentially degrades 5-HT and NE
• MAO-B preferentially degrades DA (and phenylethylamine)

Available Agents

Critical Dangers

• Tyramine in food (aged cheeses, red wine, cured meats, broad beans) is normally destroyed by MAO in the gut
• With MAO-A inhibited, tyramine reaches systemic circulation → enters presynaptic vesicles → massive NE/5-HT release → hypertensive crisis
• Symptoms: severe headache, hypertension, flushing, diaphoresis - can be life-threatening
• Can occur up to 3 weeks after stopping an irreversible MAOI

• Combining MAOIs with any serotonergic drug (SSRIs, SNRIs, meperidine, tramadol, dextromethorphan) → potentially fatal
• Triad: altered mental status + neuromuscular abnormalities (clonus, hyperreflexia) + autonomic instability
• Mandatory washout: at least 14 days between MAOI and SSRI/SNRI (5 weeks for fluoxetine due to long half-life)

Clinical Notes

• Third-line agents due to interaction profile
• Historically preferred for atypical depression (preserved mood reactivity, hypersomnia, hyperphagia) - but current evidence shows SSRIs are equally effective
• Selegiline transdermal patch bypasses gut MAO-A, reducing dietary tyramine risk at lower doses
• Moclobemide (RIMA - Reversible Inhibitor of MAO-A) available in many countries - fewer dietary restrictions, lower risk

5. Atypical / Novel Antidepressants

Quick Comparison: Mechanism Summary

Monoamine     SSRI    SNRI    TCA     MAOI    Bupropion   Mirtazapine
─────────────────────────────────────────────────────────────────────
5-HT           +++    +++     ++      +++        -           ++
NE              -     +++     ++      +++       +++          ++
DA              -      -      +       ++        ++           +
Mechanism    SERT   SERT+   SERT+   MAO      NET+DAT      Alpha-2
             block  NET     NET     inhibit  block        antag.
                    block   block

Key Drug Interactions to Know

Washout Periods

• MAOI → SSRI or SSRI → MAOI: 14 days
• Fluoxetine → MAOI: 5 weeks (due to long half-life of fluoxetine and its active metabolite norfluoxetine)

• Goldman-Cecil Medicine, Table 362-5 (Oral Antidepressant Medications)
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry (Antidepressant Treatment Strategies, p. 5147-5150)
• Goodman & Gilman's Pharmacological Basis of Therapeutics (Drug Facts: Depression and Anxiety Disorders)
• Rosen's Emergency Medicine (MAOI Toxicity & Tyramine Syndrome)