doxepin
Last reviewed 2025-12-29
Reviewed by PsychMed Editorial Team.
Brands: Sinequan, Silenor
Sources updated 2025 • 4 references
General Information
Doxepin is a tertiary amine tricyclic antidepressant (TCA) with pronounced antihistaminic and anticholinergic properties used for depression, anxiety, and low-dose insomnia adjuncts.
Potent H1 antagonism drives sedation and weight gain, while anticholinergic effects limit use in older adults and those with glaucoma or urinary retention.
The compare view and doxepin evidence feed can support weighing sedation, anticholinergic load, and cardiac monitoring; mania-prevention planning can be coordinated via the bipolar disorder hub.
U.S. approvals
- Depression/anxiety (1969)
- Insomnia (low-dose tablets) (2010)
Formulations & strengths
- Capsules: 10–150 mg; oral solution 10 mg/mL; low-dose tablets (3 mg, 6 mg) for insomnia.
Generic availability
- Capsules and solution available generically; low-dose tablets also generic.
Lower doses (≤6 mg) primarily treat insomnia (Silenor®); higher doses are reserved for resistant depression/anxiety and warrant therapeutic drug monitoring (target combined doxepin + nordoxepin 150–250 ng/mL) to balance efficacy and toxicity. Coordination with the bipolar disorder hub can support mania-prevention planning in bipolar-spectrum illness.
View labelExactMechanism of Action
Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.
Inhibits serotonin (SERT) and norepinephrine (NET) reuptake while strongly antagonizing histamine H1, muscarinic M1, and α1-adrenergic receptors.
- SNRI activity plus potent H1 antagonism and significant muscarinic/α1 blockade; weak sodium-channel blockade contributes to cardiotoxicity in overdose.
Metabolism and Pharmacokinetics
Dosing and Administration
- Depression/anxiety: typical start is 25–50 mg at bedtime; titrate by 25–50 mg every 3–4 days to 75–150 mg/day (single HS dose or divided BID). Max 300 mg/day inpatient with ECG monitoring.
- Insomnia: 3–6 mg taken once nightly on an empty stomach 30 minutes before bed; label maximum is 6 mg/day, and taking it within 3 hours of a meal can delay absorption.
- Lower initial doses (10–25 mg) in elderly, hepatic impairment, or concomitant CYP2D6 inhibitors. Gradual tapering (often ≥4 weeks) is common when discontinuing to reduce cholinergic rebound.
Monitoring & Labs
- Sedation, next-day impairment, and falls risk (especially in older adults); driving and occupational safety are often reassessed after dose changes.
- Orthostatic vitals during titration and when combined with other hypotensive medications; hydration and slow position changes are commonly emphasized.
- Anticholinergic burden (constipation, urinary retention, confusion); bowel regimen planning and avoiding additive anticholinergic polypharmacy are common considerations when feasible.
- ECG monitoring for patients with cardiac disease, electrolyte abnormalities, or higher antidepressant doses; repeat ECGs are often considered when adding other QT-active agents.
- Therapeutic drug monitoring can be helpful in higher-dose depression regimens, drug interactions (CYP2D6/2C19 inhibitors), unexpected nonresponse, or suspected toxicity.
- Mood activation (mania/hypomania) in bipolar-spectrum illness and suicidal thinking during initiation; coordination via the bipolar disorder hub can support planning.
Low-dose insomnia therapy is mainly safety-focused (sedation timing + fall risk). Antidepressant-dose therapy adds cardiotoxicity and interaction monitoring, especially in patients with complex polypharmacy.
Adverse Effects
FDA boxed warnings
- Boxed warning: Antidepressants increase suicidality in young adults; closer monitoring is common.
Common side effects (≥10%)
- Sedation: Profound due to H1 antagonism—daytime impairment and fall risk are common considerations.
- Anticholinergic effects: Dry mouth, constipation, urinary retention, blurred vision; consider bowel regimen and hydration.
- Orthostatic hypotension: Fall precautions are often used, especially in older adults.
- Weight gain/increased appetite: Weight, BMI, and metabolic labs are commonly monitored.
Other notable effects
- QT prolongation and conduction slowing—baseline ECG is often obtained if cardiac history or doses >100 mg/day.
- Cognitive impairment/delirium, especially in older adults or dementia; dose reduction or alternative agents may be necessary.
- Angle-closure glaucoma precipitation and urinary retention; screen screening is common in higher-risk patients.
Interactions
- Contraindicated with MAOIs; a ≥14-day washout is typically used to reduce serotonin syndrome risk.
- Strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine, terbinafine) raise serum levels—consider dose reductions and monitor for toxicity.
- Enzyme-inducing anticonvulsants (carbamazepine, phenytoin) reduce concentrations—monitor efficacy or choose alternatives.
- Additive sedation with alcohol, benzodiazepines, opioids, antihistamines, or other CNS depressants; counseling often covers impaired alertness.
- Combined anticholinergic burden with low-potency antipsychotics or bladder antimuscarinics increases urinary retention and delirium risk.
Other Useful Information
- Glaucoma, urinary retention, and constipation risk are commonly screened for; Beers Criteria guidance often informs use in older adults.
- Baseline ECG and metabolic labs are often obtained when using higher doses; repeated periodically during long-term therapy.
- Counseling often covers recognizing signs of anticholinergic toxicity and when to seek urgent care for palpitations, syncope, or vision changes.
- For insomnia dosing, sleep-hygiene counseling is common; taking the dose on an empty stomach can preserve efficacy.
References
- Doxepin prescribing information — DailyMed (2025)
- Silenor (doxepin) insomnia label — DailyMed (2023)
- Roth2011 Doxepin Insomnia
- Roth2012 Doxepin Elderly
- Maudsley2021 Psych Guidelines
- CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)