Generic Name

Trazodone

Mechanism

• Serotonin Modulation – Inhibits serotonin reuptake via the 5‑HT₂A receptor, increasing synaptic serotonin.
• 5‑HT₂A Receptor Antagonism – Blocks presynaptic inhibitory autoreceptors, amplifying serotonin release.
• α₂C‑Adrenergic Receptor Blockade – Enhances noradrenergic and dopaminergic neurotransmission.
• Low‑Affinity 5‑HT2C Antagonism – Modulates mood and anxiety with fewer sexual side effects.
• NMDA Receptor Modulation (low‑dose) – Contributes to sleep‑promoting action due to its hypnotic properties.

Overall, the drug produces sedation at low doses for insomnia, and antidepressant effects at higher doses.

Pharmacokinetics

• Absorption – Rapid, peak plasma 1–2 h; ~80 % oral bioavailability.
• Food Effect – High‑fat meals delay peak by ~0.5 h, but overall exposure unchanged.
• Metabolism – Primarily hepatic via CYP3A4 → active metabolites (hydroxy‑, dihydro‑trazodone).
• Elimination – 90 % renal excretion; terminal half‑life 6–12 h (extended to 12–25 h in elderly).
• Drug Interactions – Strong CYP3A4 inhibitors (ketoconazole, ritonavir) raise plasma levels; grapefruit juice may also inhibit CYP3A4.

Indications

• Major Depressive Disorder (MDD) – Primary antidepressant therapy.
• Insomnia – Especially when sleep architecture is disrupted (preferred low‑dose regimen).
• Generalized Anxiety Disorder – Off‑label, anxiolytic effect via 5‑HT₂A antagonism.
• Alcohol Withdrawal – Off‑label adjunct for sleep disturbances and anxiety.
• Post‑traumatic Stress Disorder (PTSD) – Sedative benefit for nightmares.

Contraindications

• Contraindications
• Hypersensitivity to trazodone or sulfa‑related drugs.
• Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI withdrawal (“MAOI interaction”).
• Known QT‑interval prolongation or ventricular arrhythmias.
• Warnings
• Severe orthostatic hypotension or syncope (especially in the first 2 weeks).
• Priapism: rare but emergent; requires immediate evaluation.
• Severe hepatic impairment → dose reduction or avoidance.
• Pregnancy Category C: potential fetal risk; use only if benefits > risks.

Dosing

• Administration – Oral tablets; can be crushed for patients with dysphagia.
• Timing – Bedtime for hypnotic effect; morning dosing may reduce sedation.
• Long‑Term Use – Generally considered stable; however, depression remission requires longer course (≥12 weeks).

Adverse Effects

Common (≥10 %)
• Dizziness, orthostatic hypotension, light‑headedness
• Somnolence, dry mouth, blurred vision
• Nausea, constipation

Serious (≤1 %)
• Priapism (erectile dysfunction, prolonged erection)
• QT‑interval prolongation → torsades de pointes
• Severe orthostatic hypotension → syncope
• Hallucinations or mania in susceptible patients

Rare
• Photosensitivity, Stevens‑Johnson syndrome (rare skin reaction)

*Monitoring*: Treat hypotension with fluid loading, salt tablets, or antihypertensives. For priapism, immediate urology consultation; for QT prolongation, baseline & serial ECG if indicated.

Monitoring

• Baseline – Complete metabolic panel, CBC, liver enzymes, ECG if history of repolarization abnormalities.
• Follow‑up – Re‑check liver enzymes every 3 months in chronic users; monitor serum creatinine with dose adjustments in renal impairment.
• Safety Checks – Schedule regular orthostatic vitals (supine, standing) during initiation and if dose increases.
• Screening – Patient education on priapism warning signs; consider urologic evaluation for long‑term therapy.

Clinical Pearls

• “Dose‑Dependent Dual Action” – Low‑dose trazodone (≤50 mg) is predominantly hypnotic; high‑dose (>150 mg) achieves antidepressant efficacy.
• “Sedation as a Benefit” – Use bedtime tapering for insomnia; abrupt discontinuation may precipitate rebound insomnia or withdrawal anxiety.
• “CYP3A4 Dependency” – Be vigilant when adding potent CYP3A4 inhibitors or inducers; adjust dose or consider alternative therapy.
• “Prior Hypertension” – Initiate at minimal dose (12.5 mg) and titrate slowly while monitoring systolic BP; hold if >20 mmHg drop OR syncopal event.
• “Priapism Vigilance” – Although uncommon, educate patients in the first 2 weeks of therapy and instruct immediate medical contact if erection >4 h.

_Key Takeaway_: Trazodone offers a unique profile: it provides both antidepressant and hypnotic effects with a lower incidence of sexual side effects compared to SSRIs. Proper titration, monitoring for hypotension, and patient education are essential for safe and effective use.