What is doxepin?

What is Doxepin?

Doxepin is a tricyclic compound with dual clinical applications: at high doses (≥25 mg) it functions as an antidepressant with anticholinergic and antinoradrenergic properties, while at low doses (1-6 mg) it acts as a highly selective histamine H1 receptor antagonist specifically approved for treating sleep maintenance insomnia. 1, 2

Chemical Structure and Pharmacology

• Doxepin hydrochloride is a dibenzoxepin tricyclic compound with the molecular formula C19H21NO•HCl and molecular weight of 315.84 1
• It exists as an isomeric mixture and is a white crystalline powder freely soluble in water and alcohol 1
• The drug has subnanomolar affinity for the histamine H1 receptor, which underlies its sleep-promoting effects at low doses 3

Clinical Applications by Dose

High-Dose Use (≥25 mg): Antidepressant

• FDA-approved for treating psychoneurotic patients with depression and/or anxiety, depression associated with alcoholism, depression with organic disease, and psychotic depressive disorders 1
• The antidepressant mechanism involves preventing norepinephrine reuptake at nerve terminals, though the exact mechanism is not definitively established 1
• At antidepressant doses, doxepin combines mood-elevating effects with sedative properties similar to amitriptyline 4
• Common side effects at higher doses include significant anticholinergic effects (dry mouth, constipation), drowsiness, and potential cardiovascular effects 4, 5

Low-Dose Use (1-6 mg): Sleep Maintenance Insomnia

• The American Academy of Sleep Medicine recommends low-dose doxepin (3-6 mg) as a second-line pharmacotherapy option for adults with chronic insomnia when Cognitive Behavioral Therapy for Insomnia (CBT-I) is insufficient, unavailable, or the patient is unable/unwilling to receive it 6, 7
• At these low doses, doxepin functions as a preferential H1 antagonist without significant anticholinergic or antinoradrenergic effects 2, 3
• Low-dose doxepin demonstrates clinically significant improvements in wake after sleep onset (22-23 minutes reduction), total sleep time (26-32 minutes improvement), and sleep efficiency compared to placebo 6, 7
• The safety profile at 3-6 mg is comparable to placebo, with only mild somnolence at the 6 mg dose 6

Treatment Algorithm Position

• Cognitive Behavioral Therapy for Insomnia (CBT-I) remains first-line treatment for chronic insomnia 8, 6
• Low-dose doxepin (3-6 mg) is positioned as second-line therapy specifically for sleep maintenance problems when CBT-I is not feasible 6, 7
• The American Academy of Sleep Medicine and VA/DoD guidelines emphasize using the lowest effective dose (3 or 6 mg) for the shortest possible duration 6

Important Safety Considerations

Black Box Warning for Antidepressant Use

• Doxepin carries an FDA black box warning for increased risk of suicidal thinking and behavior in children, adolescents, and young adults when used as an antidepressant 1
• This warning applies to antidepressant doses; the risk for suicidal ideation with low-dose doxepin as a hypnotic is unknown but cannot be excluded 8
• Doxepin is not approved for use in pediatric patients 1

Contraindications and Precautions

• Contraindicated in individuals with hypersensitivity to the drug, with possible cross-sensitivity to other dibenzoxepines 1
• At doses above 150 mg daily, doxepin may block the antihypertensive effect of guanethidine and related compounds 1
• The drug has intrinsic cardiotoxicity on overdosage similar to other tricyclics, though it causes fewer cardiovascular side effects at usual therapeutic doses 4

Key Clinical Distinctions

• The critical distinction is dose-dependent: low-dose doxepin (1-6 mg) is NOT an antidepressant and does not provide adequate treatment for major depression 8
• At 3-6 mg, doxepin selectively antagonizes H1 receptors without the broader tricyclic effects seen at higher doses 7, 2
• There is no evidence of tolerance, psychomotor impairment, residual sedation, rebound insomnia, or discontinuation symptoms in trials up to 3 months duration at low doses 3
• Unlike benzodiazepines, doxepin does not produce physical tolerance or psychological dependence associated with addictive compounds 1