Doxepin

Indications

• FDA-approved as capsules and oral solution for depression and anxiety, including anxiety or depression associated with alcoholism or organic disease.
• FDA-approved as Silenor 3 mg and 6 mg tablets for insomnia characterized by difficulty with sleep maintenance in adults.
• Approved as topical 5 percent cream for short-term relief of pruritus in atopic dermatitis and lichen simplex chronicus in adults.
• Off-label at low oral doses for chronic urticaria and pruritus, exploiting its extremely potent histamine H1 antagonism.
• Off-label at conventional antidepressant doses for comorbid depression with prominent insomnia, though tolerability limits its use.
• Silenor is the only hypnotic approved for sleep maintenance that is not a scheduled controlled substance in the United States.

Mechanism of action

• One of the most potent histamine H1 antagonists in clinical medicine, which is why single-digit milligram doses produce hypnotic effect.
• At 3 to 6 mg the H1 blockade is essentially selective, avoiding the muscarinic and adrenergic actions that appear at antidepressant doses.
• At 75 mg and above it inhibits both serotonin and norepinephrine reuptake, with the desmethyl metabolite favoring norepinephrine.
• Antidepressant doses add substantial muscarinic and alpha-1 blockade, generating anticholinergic effects, orthostasis, and weight gain.
• Selective H1 antagonism consolidates sleep in the second half of the night without the reinforcing properties of benzodiazepine receptor agonists.

Pharmacokinetics

• Rapidly absorbed with peak concentrations at about 3.5 hours for Silenor; a high-fat meal delays the peak and raises exposure substantially.
• Parent half-life is roughly 15 hours and the active metabolite N-desmethyldoxepin averages about 31 hours, so morning grogginess can occur.
• Metabolized principally by CYP2C19 and CYP2D6, with minor contributions from CYP1A2 and CYP2C9 to the overall clearance.
• CYP2D6 poor metabolizers and CYP2C19 poor metabolizers accumulate drug; the Silenor label caps such patients at 3 mg at bedtime.
• Highly protein bound with extensive tissue distribution, so hemodialysis is not useful and overdose management is entirely supportive.

Dosing

• For depression start 25-75 mg PO at bedtime and titrate to a usual range of 75-150 mg/day, with 300 mg/day the maximum.
• For insomnia give Silenor 6 mg once daily within 30 minutes of bedtime, or 3 mg in adults 65 and older.
• Do not take Silenor within 3 hours of a meal, because food markedly delays absorption and blunts the hypnotic effect.
• Capsules come in 10, 25, 50, 75, 100, and 150 mg strengths; oral concentrate is 10 mg per mL and must be diluted before use.
• Limit Silenor to 3 mg in patients on strong CYP2D6 inhibitors or with known poor metabolizer status, and in hepatic impairment.
• Taper antidepressant doses gradually when stopping; hypnotic doses of 3 to 6 mg can generally be stopped without a formal taper.

Adverse effects

• At antidepressant doses sedation, dry mouth, constipation, blurred vision, and weight gain are common and frequently dose limiting.
• At 3 to 6 mg the profile resembles placebo, with somnolence, nausea, and upper respiratory infection the only frequent complaints.
• Orthostatic hypotension at higher doses is a significant fall risk in older adults with cardiovascular disease or polypharmacy.
• Complex sleep behaviors including sleepwalking and sleep driving are described with hypnotics and warrant discontinuation if they occur.
• Antidepressant doses slow cardiac conduction and are dangerous in overdose, producing wide-complex arrhythmia, seizures, and coma.
• Rare reports include agranulocytosis, cholestatic jaundice, and syndrome of inappropriate antidiuretic hormone secretion.

Monitoring

• Obtain a baseline ECG before antidepressant dosing in patients over 50 years or with any known cardiac conduction disease.
• Reassess insomnia after 7 to 10 days on Silenor; failure to improve should prompt evaluation for an underlying medical or psychiatric cause.
• Screen for untreated narrow-angle glaucoma and severe urinary retention before starting either formulation, since both are contraindications.
• Track weight, blood pressure with orthostatics, and anticholinergic symptoms at each visit when using antidepressant doses.
• Monitor for emergent suicidality and mood switch in the first weeks of antidepressant treatment and after each dose increase.

Interactions

• Contraindicated with monoamine oxidase inhibitors and within 14 days of stopping one because of hypertensive crisis and serotonin syndrome.
• Strong CYP2D6 and CYP2C19 inhibitors such as fluoxetine, paroxetine, cimetidine, and fluvoxamine raise concentrations and require dose reduction.
• Additive sedation with alcohol, opioids, benzodiazepines, and Z-drugs; the Silenor label warns against alcohol use entirely.
• Anticholinergic load compounds with antihistamines, oxybutynin, and low-potency antipsychotics, raising delirium risk in older adults.
• At antidepressant doses it adds to QT prolongation from methadone, ondansetron, and class IA or III antiarrhythmic agents.

Special populations

• Pregnancy data are limited; a case report describes neonatal sedation and respiratory depression from breast milk exposure to doxepin.
• Breastfeeding is generally discouraged with doxepin because the long-lived desmethyl metabolite accumulates in nursing infants.
• Silenor is not approved under age 18, and antidepressant doxepin is not established as safe or effective in pediatric patients.
• Use 3 mg of Silenor in adults 65 and older; Beers Criteria flag doxepin above 6 mg daily as potentially inappropriate in this group.
• Reduce doses in hepatic impairment; no formal renal adjustment exists but metabolites accumulate in advanced kidney disease.

Clinical pearls

• Silenor 3-6 mg is a selective H1 hypnotic with none of the anticholinergic load of full doses.
• Do not give Silenor within 3 hours of a meal or the hypnotic effect is delayed and blunted.
• The only non-scheduled hypnotic approved specifically for sleep maintenance insomnia.