What is doxepin used for?

What is Doxepin?

Doxepin is a tricyclic antidepressant that, at low doses (3-6 mg), functions as a highly selective histamine H1 receptor antagonist and is FDA-approved specifically for treating sleep maintenance insomnia in adults. 1, 2

Pharmacological Profile

• Doxepin is a dibenzoxepin tricyclic compound with subnanomolar affinity for the histamine H1 receptor, making it one of the most potent H1 antagonists available. 3, 4
• At low doses (1-6 mg), doxepin selectively blocks H1 receptors without significant anticholinergic, antinoradrenergic, or antiserotonin effects that occur at higher antidepressant doses (typically 75-300 mg). 3, 5
• At antidepressant doses (≥25 mg), doxepin's mechanism shifts to inhibiting norepinephrine reuptake at synapses, with additional anticholinergic and antihistamine effects on smooth muscle. 1

Primary Clinical Use: 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 or unwilling to receive it. 2, 6

Specific Sleep Benefits

• Wake After Sleep Onset (WASO): Reduces WASO by 22-23 minutes compared to placebo (95% CI: 14-30 minutes). 2, 6
• Total Sleep Time (TST): Increases TST by 26-32 minutes compared to placebo (95% CI: 18-40 minutes). 2, 6
• Sleep Efficiency: Produces clinically significant improvements in sleep efficiency at both 3 mg and 6 mg doses. 2, 6
• Sleep Quality: Demonstrates small-to-moderate improvement in subjective sleep quality. 2

Dosing Specifics

• Recommended doses are 3 mg or 6 mg at bedtime—NOT higher doses like 20-25 mg—because the higher doses shift from selective H1 antagonism to broader tricyclic effects with increased adverse events. 2
• The 3-6 mg range maintains selective histamine antagonism without significant anticholinergic burden. 2, 3

Secondary Use: Depression and Anxiety Disorders

• At doses of 75-300 mg daily, doxepin is indicated for treating psychoneurotic patients with depression and/or anxiety, depression associated with alcoholism or organic disease, and psychotic depressive disorders including involutional depression and manic-depressive disorders. 1
• Target symptoms that respond well include anxiety, tension, depression, somatic symptoms, sleep disturbances, guilt, lack of energy, fear, apprehension, and worry. 1

Safety Profile

• At low doses (3-6 mg), doxepin has a safety profile comparable to placebo in clinical trials, with only mild increases in somnolence at the 6 mg dose. 2, 6
• Common adverse effects at low doses include somnolence (particularly at 6 mg) and headache, both occurring at rates similar to placebo. 2, 6
• At higher antidepressant doses, significant anticholinergic side effects occur, including potential for urinary retention, glaucoma exacerbation, and cardiovascular effects. 1

Critical Safety Warnings

• Doxepin carries an FDA black box warning for increased risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18-24) with major depressive disorder when used at antidepressant doses. 1
• Doxepin is contraindicated in patients with glaucoma or urinary retention tendency. 1
• Doxepin is not approved for pediatric use due to lack of FDA approval and limited safety data in children. 2, 1

Important Clinical Considerations

Rebound Insomnia Risk

• While overall rebound insomnia is not typically observed, patients with severe rebound insomnia were significantly more frequent in the doxepin group during withdrawal (nights 29-31, p < 0.05). 7
• Both the American Academy of Sleep Medicine and VA/DoD guidelines emphasize administering doxepin at the lowest effective dose for the shortest possible duration. 6

Tolerance and Dependence

• Doxepin is virtually devoid of euphoria as a side effect and has not been demonstrated to produce physical tolerance or psychological dependence associated with addictive compounds. 1
• No signal for tolerance was observed in trials up to 3 months duration. 3

Drug Interactions

• At clinical dosages up to 150 mg per day, doxepin can be given concomitantly with guanethidine without blocking its antihypertensive effect; at doses above 150 mg, blocking has been reported. 1
• Doxepin should not be taken concomitantly with alcohol when treating depression associated with alcoholism. 1

Population-Specific Guidance

• Not recommended for children under 12 years of age due to lack of clinical experience in the pediatric population. 1, 2
• Safe and well tolerated in elderly patients at low doses for insomnia. 1, 3
• Dose adjustment may be needed in patients with hepatic impairment when using higher antidepressant doses. 8

Comparative Effectiveness

• A head-to-head trial found doxepin 6 mg superior to zolpidem 5-10 mg for sleep maintenance parameters, including wake after sleep onset, total sleep time, and sleep efficiency. 2
• Alternative first-line options for sleep maintenance insomnia include eszopiclone 2-3 mg, temazepam 15 mg, suvorexant 10-20 mg, and zolpidem 10 mg. 2

Limitations in Specific Populations

• In patients with major depressive disorder and comorbid insomnia, low-dose doxepin (< 25 mg) does not appear to improve sleep onset or maintenance, contrasting with its efficacy in primary insomnia. 9
• Low-dose doxepin does not constitute adequate treatment of major depression in individuals with comorbid insomnia; full antidepressant doses are required. 8