What are the recommended adult dosing regimens, contraindications, adverse effects, and monitoring requirements for doxepin when used to treat depression, anxiety, insomnia, or chronic pruritus?

Doxepin: Clinical Use, Dosing, and Safety Profile

Approved Indications and Dosing

Depression and Anxiety (Standard-Dose Doxepin)

For mild-to-moderate depression, start doxepin at 75 mg daily, then titrate to an optimal range of 75–150 mg daily based on response. 1 In more severe illness, doses may be increased gradually to a maximum of 300 mg daily, though additional benefit beyond this threshold is rare. 1

• Very mild symptoms or emotional distress accompanying medical illness may respond to 25–50 mg daily. 1
• The total daily dose can be given once at bedtime (maximum 150 mg for single-dose administration) or divided throughout the day. 1
• Antianxiety effects appear before antidepressant effects; optimal mood elevation may require 2–3 weeks. 1
• Doxepin combines antidepressant activity with sedation, making it particularly useful in depressed patients with sleep disturbances or comorbid anxiety. 2

Insomnia (Low-Dose Doxepin)

Low-dose doxepin 3–6 mg at bedtime is recommended specifically for sleep-maintenance insomnia, reducing wake after sleep onset by 22–23 minutes with minimal anticholinergic effects and no abuse potential. 3, 4

• Start with 3 mg at bedtime; if insufficient after 1–2 weeks, increase to 6 mg. 3, 4
• At hypnotic doses (3–6 mg), doxepin acts as a selective H₁-histamine antagonist, promoting sleep initiation and maintenance without the anticholinergic burden seen at antidepressant doses. 5, 6, 7
• Efficacy is evident after a single dose, with sustained benefit for up to 12 weeks and no evidence of physical dependence or rebound insomnia upon withdrawal. 7
• Low-dose doxepin improves polysomnographic sleep efficiency, total sleep time, and patient-reported sleep quality significantly more than placebo. 3, 7

Chronic Pruritus (Topical Doxepin)

Topical doxepin may be prescribed for generalized pruritus of unknown origin, but treatment must be limited to 8 days, applied to ≤10% body surface area, and not exceed 12 g daily due to risk of allergic contact dermatitis and systemic toxicity. 3

Contraindications and Precautions

Absolute Contraindications

• Concurrent use with MAO inhibitors or within 14 days of discontinuing MAO inhibitors (risk of hypertensive crisis). 1
• Acute recovery phase following myocardial infarction. 1
• Known hypersensitivity to doxepin or other tricyclic compounds. 1

Use with Caution

• Elderly patients: Start at the low end of the dosing range (e.g., 25 mg for depression, 3 mg for insomnia) due to increased risk of confusion, oversedation, falls, and decreased hepatic/renal function. 1
• Cardiovascular disease: Although doxepin causes fewer cardiovascular side effects at therapeutic doses than other tricyclics, it retains intrinsic cardiotoxicity in overdose. 2
• Urinary retention, angle-closure glaucoma, or significant anticholinergic sensitivity: Anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention) may necessitate dose reduction. 1

Adverse Effects

Common (Dose-Related)

• Drowsiness is the most frequent side effect, typically diminishing with continued therapy. 1
• Dry mouth, blurred vision, constipation, and urinary retention occur due to anticholinergic activity; if severe or persistent, reduce the dose. 1
• Weight gain, dizziness, and sweating are occasionally reported. 1

Cardiovascular

• Hypotension, hypertension, and tachycardia have been reported occasionally. 1
• Postural hypotension is uncommon with doxepin compared to other tricyclics. 2

Central Nervous System

• Confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia, and tremor are infrequently reported. 1

Hematologic

• Eosinophilia, agranulocytosis, leukopenia, thrombocytopenia, and purpura have been reported rarely; monitor for signs of bone marrow depression. 1

Endocrine and Metabolic

• Altered libido, testicular swelling, gynecomastia, breast enlargement, galactorrhea, blood sugar fluctuations, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported. 1

Allergic

• Skin rash, edema, photosensitization, and pruritus occur occasionally. 1

Withdrawal

• Abrupt cessation after prolonged use may cause withdrawal symptoms (not indicative of addiction); taper gradually over 10–14 days to minimize rebound insomnia, anxiety, and irritability. 8, 1

Overdose Management

Deaths have been reported from doxepin overdose, often involving multiple drug ingestion including alcohol. 1

Critical Manifestations

• Cardiac dysrhythmias, severe hypotension, convulsions, CNS depression (including coma), and QRS widening on ECG are clinically significant indicators of toxicity. 1
• Other signs include confusion, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, muscle rigidity, vomiting, hypothermia, or hyperpyrexia. 1

Immediate Management

• Obtain an ECG and initiate continuous cardiac monitoring immediately. 1
• Protect the airway, establish IV access, and perform large-volume gastric lavage followed by activated charcoal; emesis is contraindicated. 1
• Observe for a minimum of 6 hours with cardiac monitoring; if toxicity signs appear, extend monitoring because fatal dysrhythmias can occur late after overdose. 1
• Plasma drug levels should not guide management. 1

Monitoring Requirements

During Initiation and Dose Adjustment

• Reassess after 1–2 weeks for efficacy (sleep parameters, mood, anxiety) and adverse effects (sedation, anticholinergic symptoms, cardiovascular changes). 3, 4
• Monitor for confusion and oversedation, especially in elderly patients. 1

Long-Term Therapy

• Conduct periodic reassessment every 4–6 weeks to evaluate ongoing need, side effects, and potential for tapering. 4
• Monitor for hematologic abnormalities (CBC) if signs of infection, bruising, or bleeding develop. 1
• Assess for cardiovascular changes (blood pressure, heart rate, ECG if indicated) in patients with preexisting cardiac disease. 1

Special Populations

Elderly

• Start at 25 mg daily for depression or 3 mg for insomnia; titrate cautiously due to increased sensitivity, fall risk, and decreased organ function. 1
• Doxepin is generally well tolerated in the elderly, particularly at low doses for insomnia. 2, 7

Hepatic or Renal Impairment

• Use caution and start at the low end of the dosing range; renal excretion extent is undetermined, but decreased renal function warrants careful dose selection. 1

Common Pitfalls to Avoid

• Using standard antidepressant doses (≥25 mg) for insomnia instead of low-dose formulations (3–6 mg), which increases anticholinergic burden and side effects without additional sleep benefit. 5, 6
• Abruptly discontinuing doxepin after prolonged use, leading to withdrawal symptoms; always taper over 10–14 days. 8, 1
• Failing to monitor elderly patients closely for confusion, oversedation, and falls, which are more common in this population. 1
• Combining doxepin with other CNS depressants (benzodiazepines, alcohol, opioids) without recognizing additive sedation and respiratory depression risk. 1
• Ignoring cardiovascular monitoring in patients with preexisting heart disease, despite doxepin's relatively favorable cardiac profile at therapeutic doses. 2
• Expecting immediate antidepressant effects; optimal mood elevation requires 2–3 weeks, though antianxiety and sedative effects appear earlier. 1