What is doxepin?

What is Doxepin?

Doxepin is a tricyclic compound that functions as a highly selective histamine H1 receptor antagonist at low doses (3-6 mg), specifically FDA-approved for treating sleep maintenance insomnia, while at higher doses (≥25 mg) it acts as a traditional antidepressant with additional anticholinergic and monoaminergic effects. 1, 2, 3

Mechanism of Action: Dose-Dependent Pharmacology

Low-Dose Doxepin (3-6 mg) for Insomnia:

• At these doses, doxepin works primarily through subnanomolar affinity for the histamine H1 receptor, blocking histamine's wake-promoting effects without engaging other receptor systems 2, 4, 5
• The H1 selectivity at low doses avoids the dose-limiting anticholinergic, antinoradrenergic, and antiserotonergic effects seen at higher doses 2, 4
• Monoaminergic effects (norepinephrine reuptake inhibition) are not clinically relevant at these low doses, which is why low-dose doxepin treats insomnia without producing antidepressant effects 2

Higher-Dose Doxepin (≥25 mg) for Depression:

• At antidepressant doses, doxepin's mechanism involves preventing deactivation of norepinephrine by blocking reuptake into nerve terminals 3, 6
• Additional effects include anticholinergic, antiserotonin, and antihistamine activity on smooth muscle 3
• The mood-elevating effect is similar to amitriptyline but possibly less marked than imipramine 6

Clinical Applications

FDA-Approved Indications:

For Low-Dose Formulation (3-6 mg):

• Sleep maintenance insomnia—specifically targeting wake after sleep onset and early morning awakening 1, 7
• Demonstrates 22-23 minute reduction in wake after sleep onset with moderate-quality evidence 1
• Improves total sleep time, sleep efficiency, and sleep quality without significant adverse events versus placebo 1

For Higher-Dose Formulation (≥25 mg):

• Psychoneurotic patients with depression and/or anxiety 3
• Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol) 3
• Depression and/or anxiety associated with organic disease 3
• Psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders 3

Position in Treatment Guidelines

The American Academy of Sleep Medicine recommends doxepin 3-6 mg as a treatment option for sleep maintenance insomnia when cognitive behavioral therapy for insomnia (CBT-I) is insufficient or unavailable. 1

• Doxepin is positioned as a second-line pharmacotherapy option after first-line benzodiazepine receptor agonists (BzRAs) or ramelteon 7
• It is particularly appropriate for patients with predominant sleep maintenance problems rather than sleep onset difficulties 1, 4
• CBT-I should always be initiated before or alongside doxepin, as pharmacotherapy should supplement—not replace—behavioral interventions 1

Safety Profile and Tolerability

Low-Dose Doxepin (3-6 mg):

• No statistically significant differences in adverse event rates compared to placebo in randomized controlled trials 1
• Most common adverse effects are sedation/sleepiness and headache, occurring mainly at placebo level or less 5
• No evidence of tolerance, psychomotor impairment, residual sedation, rebound insomnia, or discontinuation symptoms in trials up to 3 months 5
• Minimal effects on sleep architecture 5
• No black box warning for suicide risk at low doses, though the risk for suicidal ideation cannot be excluded 1

Higher-Dose Doxepin (≥25 mg):

• Dry mouth, drowsiness, and constipation are the most common side effects 6
• Generally well tolerated, particularly by elderly patients and those with cardiovascular disease at therapeutic doses 6
• Postural hypotension is uncommon at usual therapeutic doses 6
• Has intrinsic cardiotoxicity on overdosage similar to other tricyclics 6
• Carries FDA black box warning for increased risk of suicidal thinking and behavior in children, adolescents, and young adults 3

Critical Distinctions from Other Medications

• Unlike traditional benzodiazepines, low-dose doxepin has no abuse potential or physical dependence 3
• Unlike antihistamines (diphenhydramine), doxepin at low doses maintains efficacy without tolerance development after 3-4 days 7
• Unlike trazodone (which is explicitly not recommended for insomnia), doxepin has robust evidence for sleep maintenance 1
• The therapeutic use of low-dose doxepin exploits H1 selectivity, avoiding dose-limiting side effects seen at higher antidepressant doses 2

Important Clinical Considerations

• Doxepin is not approved for use in pediatric patients 3
• Contraindicated in individuals who have shown hypersensitivity to the drug, with possibility of cross-sensitivity with other dibenzoxepines 3
• At dosages up to 150 mg per day, doxepin can be given concomitantly with guanethidine without blocking antihypertensive effect; above 150 mg per day, blocking has been reported 3
• The incidence of adverse events appears to increase with longer treatment duration, even at low doses 1