What is doxepin (tricyclic antidepressant)?

What is Doxepin?

Doxepin is a tricyclic antidepressant (TCA) with potent antihistamine properties that is FDA-approved for treating depression and anxiety disorders at higher doses (typically 75-300 mg/day), and more recently approved at very low doses (3-6 mg) specifically for insomnia due to its selective histamine H1 receptor antagonism. 1

Chemical Structure and Pharmacology

• Doxepin 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 has subnanomolar affinity for the histamine H1 receptor, making it one of the most potent antihistamines available 2
• The mechanism involves preventing norepinephrine reuptake at nerve terminals, though the exact antidepressant mechanism is not definitively established 1
• At clinical doses, it demonstrates anticholinergic, antiserotonin, and antihistamine effects 1

Clinical Indications and Dosing

For Depression and Anxiety (Higher Doses)

• FDA-approved for psychoneurotic patients with depression and/or anxiety, depression associated with alcoholism or organic disease, and psychotic depressive disorders 1
• Typical antidepressant dosing ranges from 75-300 mg/day, with therapeutic plasma concentrations of 30-150 ng/mL recommended for monitoring 3
• Target symptoms that respond particularly well include anxiety, tension, somatic symptoms, sleep disturbances, guilt, lack of energy, and worry 1
• The mood-elevating effect is similar to amitriptyline but may be less marked and slower to take effect than imipramine 4

For Insomnia (Low Doses)

• The American Academy of Sleep Medicine recommends doxepin 3-6 mg specifically for sleep maintenance insomnia, not sleep onset insomnia 5
• At these low doses (1,3, and 6 mg), doxepin acts as a selective H1 antagonist without significant anticholinergic or antinoradrenergic effects 2, 6
• Low-dose doxepin improves sleep variables including total sleep time and wake after sleep onset with low to moderate strength evidence 3
• It has minimal effects on sleep architecture and shows no signal for tolerance, psychomotor impairment, residual sedation, or rebound insomnia in trials up to 3 months 2
• Low plasma levels may be sufficient when doxepin is used specifically to obtain sedation 3

Comparative Efficacy

• Doxepin combines antidepressant activity with sedative effects, similar to amitriptyline 4
• At equivalent response rates, doxepin causes fewer or less troublesome side effects than imipramine, amitriptyline, or amitriptyline-perphenazine 4
• The marked sedative properties make it more useful than imipramine in depressed patients with sleep disturbances and depression associated with anxiety 4
• When anxiety is accompanied by significant depression, doxepin is more effective than benzodiazepines like chlordiazepoxide or diazepam 4

Safety Profile and Side Effects

At Antidepressant Doses

• Most common side effects include dry mouth, drowsiness, and constipation 4
• Postural hypotension is uncommon compared to other TCAs 4
• Well tolerated in elderly patients and those with cardiovascular disease at usual therapeutic doses 1, 4
• Has intrinsic cardiotoxicity on overdosage similar to other tricyclics, though causes fewer cardiovascular side effects at therapeutic doses 4
• Long-term use (5-15 years) has been shown to be feasible, efficacious, and safe with lack of adverse drug interactions 7

At Low Doses for Insomnia

• Sedation/sleepiness and headache are the most common adverse events, but these occur mainly at placebo level or less 2
• Adverse effects and study withdrawals do not significantly differ from placebo at low doses 3

Important Contraindications and Warnings

• Black Box Warning: Increased risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder 1
• Contraindicated in individuals with hypersensitivity to doxepin or other dibenzoxepines 1
• Not approved for use in pediatric patients under 12 years of age 1
• At doses above 150 mg/day, may block the antihypertensive effect of guanethidine and related compounds 1
• Should not be taken concomitantly with alcohol when used for depression associated with alcoholism 1

Clinical Pearls

• The American Academy of Sleep Medicine recommends against combining two sedating antidepressants due to risks of serotonin syndrome, excessive sedation, and QTc prolongation 5
• Doxepin is virtually devoid of euphoria and does not produce physical tolerance or psychological dependence associated with addictive compounds 1
• Therapeutic drug monitoring is recommended for tricyclic antidepressants to avoid potentially lethal intoxications 3
• The American Heart Association suggests avoiding tricyclic antidepressants when cardiac concerns exist due to cardiovascular side effects 8