Trazodone

Indications

• FDA-approved for major depressive disorder in adults at 150-400 mg/day in divided doses, taken shortly after a meal.
• Antidepressant doses are poorly tolerated because of sedation and orthostasis, so trazodone is rarely used as monotherapy for depression.
• Off-label at 25-100 mg at bedtime for insomnia, which accounts for the large majority of trazodone prescriptions written today.
• The American Academy of Sleep Medicine recommends against trazodone for chronic insomnia, citing weak evidence and adverse effects.
• Off-label for insomnia complicating SSRI or stimulant treatment, where it avoids the dependence liability of benzodiazepine receptor agonists.
• Off-label for agitation in dementia and for PTSD-related insomnia, though the supporting evidence in both settings is limited.

Mechanism of action

• Acts as a serotonin antagonist and reuptake inhibitor, with potent 5-HT2A blockade and comparatively weak serotonin transporter inhibition.
• At low doses 5-HT2A, histamine H1, and alpha-1 blockade dominate, which is why 25 to 100 mg produces sedation without antidepressant effect.
• Antidepressant efficacy requires doses high enough to engage the serotonin transporter, generally at or above 150 mg/day.
• Alpha-1 adrenergic blockade causes orthostatic hypotension and dizziness and is the mechanism behind trazodone-associated priapism.
• Its metabolite meta-chlorophenylpiperazine is a serotonin agonist that can provoke anxiety and dysphoria when it accumulates.

Pharmacokinetics

• Absorption is improved and peak concentrations are blunted when taken shortly after a meal, which reduces dizziness and lightheadedness.
• Elimination is biphasic, with an initial phase of about 3 to 6 hours and a terminal phase of roughly 5 to 9 hours.
• The short initial phase suits sleep onset but can leave residual grogginess when higher doses are given late at night.
• Metabolized principally by CYP3A4 to meta-chlorophenylpiperazine, which is then cleared by CYP2D6 and accumulates in poor metabolizers.
• It is 89 to 95 percent protein bound, and clearance falls in older adults, hepatic impairment, and significant renal impairment.

Dosing

• For depression start 150 mg/day in divided doses, increase by 50 mg/day every three to four days, to a maximum of 400 mg/day in outpatients.
• Inpatients with severe depression may be titrated to 600 mg/day in divided doses under close blood pressure monitoring.
• For off-label insomnia start at 25 to 50 mg at bedtime and increase to no more than 100 mg, since higher doses add hangover without added hypnotic effect.
• Available as 50, 100, 150, and 300 mg immediate-release tablets; the extended-release formulation is no longer marketed in the United States.
• Reduce the dose and titrate slowly in older adults and in hepatic impairment, where clearance is meaningfully reduced.
• Taper gradually from antidepressant doses; low bedtime hypnotic doses can usually be stopped without a formal taper.

Adverse effects

• Somnolence and sedation occur in roughly 40 percent of patients at antidepressant doses and are the intended effect at hypnotic doses.
• Orthostatic hypotension and dizziness are common, mediated by alpha-1 blockade, and contribute directly to falls in older adults.
• Priapism occurs in approximately 1 in 6000 treated men and is a urologic emergency, with about one third of reported cases requiring surgery.
• QT prolongation and rare torsades de pointes have been reported, so it should be used cautiously with other QT-prolonging drugs.
• Dry mouth, blurred vision, nausea, headache, and cognitive dulling are frequent, while sexual dysfunction is uncommon.
• Serotonin syndrome, hyponatremia, and treatment-emergent mania apply as with other serotonergic antidepressants.

Monitoring

• Counsel every male patient about priapism before starting and instruct them to seek emergency care for an erection lasting over four hours.
• Check orthostatic blood pressure at baseline and after dose increases, especially in older adults and patients on antihypertensives.
• Assess suicidality, activation, and daytime sedation weekly for the first four weeks and after each dose change.
• Obtain an ECG in patients with cardiac disease, electrolyte disturbance, or concurrent QT-prolonging medications.
• Check serum sodium at baseline and within two to four weeks in older adults or those taking diuretics.

Interactions

• Contraindicated with MAOIs and within 14 days of stopping one, and with linezolid or intravenous methylene blue.
• Strong CYP3A4 inhibitors such as ritonavir, ketoconazole, and clarithromycin raise trazodone levels and require a dose reduction.
• Strong CYP3A4 inducers including carbamazepine and rifampin can lower concentrations substantially and blunt the hypnotic effect.
• Additive sedation and hypotension with alcohol, opioids, benzodiazepines, antihypertensives, and alpha-blockers used for prostatism.
• Additive QT risk with methadone, antipsychotics, ondansetron, and class III antiarrhythmics, and additive serotonergic risk with SSRIs and triptans.

Special populations

• Pregnancy data are limited but do not show a clear teratogenic signal; better-studied agents are preferred when depression is the target.
• Relative infant dose in breast milk is low, under 3 percent, so occasional bedtime use is generally considered acceptable.
• Not approved in pediatrics, and pediatric insomnia use is off-label with essentially no controlled efficacy evidence.
• In older adults start at 25 mg at bedtime and weigh fall risk carefully, since orthostasis and sedation are the dominant hazards.
• Reduce the dose in hepatic impairment and use caution in significant renal impairment, where metabolites can accumulate.

Clinical pearls

• Below 150 mg/day it is a hypnotic, not an antidepressant; the transporter is barely engaged.
• Warn every man about priapism, roughly 1 in 6000, and give clear instructions to seek emergency care.
• AASM recommends against it for chronic insomnia despite its being the most prescribed sleep agent.