What are the recommended dosing regimens, contraindications, and monitoring recommendations for doxepin when used to treat insomnia, depression, anxiety, or chronic pruritus, particularly in older adults?

Doxepin for Insomnia, Depression, Anxiety, and Chronic Pruritus

Dosing for Insomnia (Primary Indication)

Start doxepin 3 mg at bedtime for sleep-maintenance insomnia; if inadequate after 1–2 weeks, increase to 6 mg. 1

• Low-dose doxepin (3–6 mg) reduces wake after sleep onset by 22–23 minutes and increases total sleep time by 26–32 minutes compared with placebo. 1
• At these hypnotic doses, doxepin exhibits selective H₁-histamine receptor antagonism with minimal anticholinergic, noradrenergic, or serotonergic effects—avoiding the side-effect burden seen at antidepressant doses (≥25 mg). 1, 2
• Efficacy is maintained for up to 12 weeks without tolerance, rebound insomnia, or withdrawal symptoms upon discontinuation. 1, 3
• Adverse-event rates at 3–6 mg are comparable to placebo; the most common side effects are mild somnolence and headache, which are not dose-related. 1, 4
• Doxepin does not meaningfully shorten sleep-onset latency (only 2–5 minutes reduction); it is indicated for sleep-maintenance insomnia, not sleep-onset difficulty. 1

Older Adults (≥65 Years)

Initiate doxepin 3 mg at bedtime in older adults; this is the preferred first-line hypnotic for sleep-maintenance insomnia in this population. 1

• At 3–6 mg, doxepin has minimal anticholinergic activity, no abuse potential, and no increased fall risk—making it especially suitable for elderly patients. 1, 5
• The FDA label advises starting at the low end of the dosing range in elderly patients due to greater frequency of decreased hepatic, renal, or cardiac function. 6
• If 3 mg is well tolerated but insufficient after 1–2 weeks, increase to a maximum of 6 mg. 1

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Dosing for Depression and Anxiety

For major depressive disorder or anxiety disorders, start doxepin 75 mg/day in divided doses or once daily at bedtime; the usual therapeutic range is 75–150 mg/day. 6

• In more severely ill patients, doses may be increased gradually to 300 mg/day if necessary, though additional therapeutic effect is rarely obtained beyond this dose. 6
• In patients with very mild symptomatology or emotional symptoms accompanying organic disease, doses as low as 25–50 mg/day may suffice. 6
• The anti-anxiety effect appears before the antidepressant effect; optimal antidepressant response may not be evident for 2–3 weeks. 6
• The 150 mg capsule strength is intended for maintenance therapy only and is not recommended for initiation of treatment. 6

Important Caveat for Depression with Insomnia

Low-dose doxepin (≤25 mg) does NOT improve sleep onset or maintenance in patients with major depressive disorder and comorbid insomnia. 7

• A retrospective case series of 17 inpatients with MDD and insomnia found no improvement in sleep onset or maintenance during 4 weeks of low-dose doxepin (<25 mg/day). 7
• For depressed patients with insomnia, use therapeutic-dose doxepin (≥75 mg/day) or consider alternative sedating antidepressants such as mirtazapine. 7

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Dosing for Chronic Pruritus

For chronic pruritus, doxepin is typically prescribed at 10–25 mg at bedtime, though specific FDA-approved dosing for this indication is not established. 6

• At these doses, doxepin provides both H₁- and H₂-receptor antagonism, which may reduce pruritus, but anticholinergic side effects become more prominent above 10 mg. 2
• Monitor for dry mouth, constipation, urinary retention, and sedation, which are dose-dependent. 6

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Contraindications

Absolute contraindications include:

• Hypersensitivity to doxepin or other dibenzoxepine compounds. 6
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation (risk of hypertensive crisis, hyperpyrexia, seizures). 6
• Acute recovery phase following myocardial infarction. 6
• Untreated narrow-angle glaucoma (at antidepressant doses; less concern at 3–6 mg). 6
• Severe urinary retention or prostatic hypertrophy (at antidepressant doses; minimal risk at 3–6 mg). 6

Relative contraindications and cautions:

• Severe hepatic or renal impairment—start at the lowest dose and titrate cautiously. 6
• Cardiovascular disease (arrhythmias, conduction defects, recent MI)—tricyclics can prolong QRS duration and cause hypotension or tachycardia. 6
• History of seizures—tricyclics lower the seizure threshold. 6
• Bipolar disorder—tricyclics may precipitate manic episodes; ensure adequate mood stabilization before use. 6

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Monitoring Recommendations

For Insomnia (Low-Dose Doxepin 3–6 mg)

Reassess after 1–2 weeks to evaluate sleep-onset latency, total sleep time, nocturnal awakenings, and daytime functioning. 1

• Monitor for adverse effects: somnolence, headache, morning sedation, or cognitive impairment (though rare at low doses). 1, 4
• Screen for complex sleep behaviors (sleep-driving, sleep-walking, sleep-eating) at every visit; discontinue immediately if these occur. 1
• Continue for up to 12 weeks if effective; studies demonstrate sustained benefit without tolerance or dependence. 1, 3
• Always combine with Cognitive Behavioral Therapy for Insomnia (CBT-I), which provides superior long-term outcomes and facilitates eventual medication tapering. 1

For Depression/Anxiety (Therapeutic Doses ≥75 mg/day)

Obtain baseline ECG in patients with cardiovascular risk factors or age >40 years; monitor QRS duration and QTc interval. 6

• Reassess mood, anxiety, and suicidal ideation after 1–2 weeks and again at 4–6 weeks. 6
• Monitor for anticholinergic effects: dry mouth, constipation, urinary retention, blurred vision, confusion (especially in elderly). 6
• Check orthostatic blood pressure if dizziness or falls occur. 6
• Monitor for withdrawal symptoms if discontinuing after prolonged use; taper gradually by 25% every 1–2 weeks. 6
• Screen for mania or hypomania in patients with bipolar disorder or family history. 6

For Chronic Pruritus (10–25 mg/day)

• Monitor for anticholinergic side effects (dry mouth, constipation, urinary retention) and sedation. 6
• Reassess pruritus severity and quality of life after 2–4 weeks. 6

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Common Pitfalls and Caveats

Do not use low-dose doxepin (3–6 mg) for sleep-onset insomnia—it does not reduce sleep latency; use zaleplon, ramelteon, or zolpidem instead. 1

Do not prescribe low-dose doxepin (<25 mg) for insomnia in patients with major depressive disorder—it is ineffective in this population; use therapeutic-dose doxepin (≥75 mg) or alternative sedating antidepressants. 7

Do not combine doxepin with multiple sedating agents (benzodiazepines, Z-drugs, antipsychotics)—this markedly increases the risk of respiratory depression, falls, cognitive impairment, and complex sleep behaviors. 1

Do not initiate doxepin for insomnia without concurrent CBT-I—behavioral therapy provides more durable benefits than medication alone and is mandated as first-line treatment by the American Academy of Sleep Medicine and the American College of Physicians. 1

Do not abruptly discontinue doxepin after prolonged use at antidepressant doses—taper gradually to avoid withdrawal symptoms (nausea, headache, malaise, irritability). 6

In elderly patients, start at 3 mg for insomnia or 25–50 mg for depression—sedating drugs may cause confusion and oversedation in this population. 6

Monitor for QRS widening >100 ms or QTc prolongation >500 ms—these are clinically significant indicators of tricyclic toxicity and warrant dose reduction or discontinuation. 6

Educate patients taking doxepin for insomnia to take it within 30 minutes of bedtime with at least 7–8 hours remaining before planned awakening—this minimizes next-day residual effects. 1