trazodone

General Information

Trazodone is a serotonin antagonist and reuptake inhibitor (SARI) approved for major depressive disorder and commonly used off label at low doses for insomnia in patients with depression or serious mental illness.

Low doses primarily function as a sedating hypnotic via H1 and α1 antagonism, whereas antidepressant-range doses require daytime dosing and bring more orthostasis and GI adverse effects.

Evidence for chronic insomnia benefit is limited and guidelines caution against routine trazodone use for chronic insomnia; treat it as a time-limited adjunct while addressing underlying drivers (mood episodes, PTSD, substance use, pain, sleep hygiene).

The trazodone compare view, trazodone evidence feed, and trazodone print page can support aligning sleep goals with mood treatment and safety planning.

Chronic insomnia evidence is limited and guidelines caution against routine trazodone use; treat it as a time-limited adjunct while addressing comorbid depression, substance use, pain, and sleep hygiene. Low-dose-only regimens often function primarily as hypnotics—make the target explicit, reassess frequently, and avoid dose escalation without a clear goal.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Antagonizes serotonin 5-HT2A/5-HT2C receptors and weakly inhibits the serotonin transporter (SERT), producing antidepressant and anxiolytic effects at higher doses.

Potent H1 and α1 antagonism drives sedation and orthostatic hypotension—effects that are often leveraged for insomnia at low doses.

• 5-HT2A/2C antagonism with weak SERT inhibition (SARI profile).
• H1 antagonism (sedation) and α1 antagonism (orthostasis).

Metabolism and Pharmacokinetics

• Metabolized primarily by CYP3A4; active metabolite mCPP.
• <1% of an oral dose is excreted unchanged in urine (extensive metabolism).
• Reported terminal half-life ~5–13 hours (varies with dose and patient factors).

Dosing and Administration

• Insomnia (off label): start 25–50 mg at bedtime; typical 50–150 mg nightly based on tolerability; reassess frequently and avoid open-ended dose escalation.
• Depression (label): initiate around 150 mg/day in divided doses; titrate gradually based on response and adverse effects; higher-dose regimens require daytime dosing and closer orthostasis monitoring.
• Take shortly after food to reduce nausea and improve tolerability; taper gradually after long-term use to reduce rebound insomnia and irritability.
• If next-day grogginess or orthostasis occurs, reduce the dose, shift timing, or switch agents rather than layering additional sedatives to “treat” side effects.

Monitoring & Labs

• Monitor orthostatic symptoms and falls risk during initiation and after dose increases, especially in older adults or those on antihypertensives.
• Reassess mood and suicidality during antidepressant initiation and titration; ensure the dose matches the target (sleep vs depression).
• Review QT-risk co-medications and consider ECG/electrolytes when risk factors stack.
• If used primarily for insomnia, document a stop plan and reassess regularly rather than continuing indefinitely.

Sources: FDA/DailyMed label; AASM insomnia guideline; evidence reviews.

Adverse Effects

Interactions

• Contraindicated with MAOIs; allow ≥14-day washout.
• CYP3A4 inhibitors increase exposure (sedation/hypotension); inducers may reduce efficacy.
• Additive CNS depression with alcohol, opioids, benzodiazepines, and sedating antipsychotics.
• Serotonergic combinations increase serotonin syndrome risk; educate and monitor.
• When strong CYP3A4 inhibitors (e.g., azoles, macrolides, ritonavir) are added or stopped, reassess sedation and orthostasis; consider dose reduction or alternatives.

Other Useful Information

• Align trazodone use with a clear target (sleep latency, sleep maintenance, depression) and document an exit plan.
• For insomnia, prioritize CBT-I and sleep hygiene; reassess need at every follow-up.
• Consider baseline ECG in patients with cardiac disease, electrolyte disturbances, or multiple QT-risk medications.
• Counsel on priapism warning signs and urgent care thresholds, and review fall-risk mitigation (nighttime bathroom trips, orthostasis precautions) when trazodone is used for sleep.

References

1. Trazodone hydrochloride prescribing information — DailyMed (2025)
2. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline — Journal of Clinical Sleep Medicine (2017)
3. The efficacy and safety of trazodone for sleep problems in depressive patients — Psychopharmacology (2025)
4. Comparative efficacy and acceptability of 21 antidepressant drugs for major depressive disorder — The Lancet (2018)Meta-analysisdepressionefficacy