What is the recommended dosage and usage of doxepin for treating depression, anxiety, and sleep disorders?

Doxepin Dosing and Usage

Doxepin is FDA-approved for depression and anxiety at doses of 75-300 mg/day (typically divided or given once daily at bedtime up to 150 mg), while low-dose doxepin (3-6 mg) is specifically indicated for insomnia, though off-label use of 12.5-50 mg has shown efficacy for sleep disorders. 1

Depression and Anxiety Dosing

Standard Dosing Protocol

• Starting dose: 75 mg/day for mild to moderate illness 1
• Optimal therapeutic range: 75-150 mg/day for most patients 1
• Severe illness: May require gradual titration up to 300 mg/day, though additional benefit beyond this dose is rare 1
• Mild symptoms or organic disease: 25-50 mg/day may suffice 1

Administration Schedule

• Once-daily dosing: Maximum 150 mg at bedtime (the 150 mg capsule is for maintenance only, not treatment initiation) 1
• Divided dosing: Can be used for total daily doses, particularly when exceeding 150 mg 1
• Time to effect: Anti-anxiety effects appear before antidepressant effects; optimal antidepressant response may take 2-3 weeks 1

Therapeutic Drug Monitoring

The widely cited "therapeutic range" of 150-250 ng/mL (parent plus metabolite) lacks solid evidence—88% of patients fall below this range on standard doses, with mean concentrations around 89 ng/mL at therapeutic doses of 143 mg/day 2. A more realistic working range of 50-250 ng/mL is appropriate based on actual clinical data 2.

Sleep Disorder Dosing

Low-Dose for Insomnia

• Effective dose: 12.5 mg/day has demonstrated significant improvement in sleep latency, duration, and disturbances over 12 weeks 3
• Mechanism: Low-dose doxepin acts as a preferential H1 histamine antagonist, particularly effective for sleep maintenance insomnia 4
• Comparative efficacy: Low-dose doxepin (12.5 mg) significantly improved sleep latency compared to citalopram 20 mg at 8 and 12 weeks 3

PTSD-Associated Nightmares

• Dosing range: 50-100 mg daily, though evidence is limited and mixed 5
• Important caveat: In one case series, patients on doxepin (alone at 100 mg or in combination) showed no improvement in nightmares, suggesting it may not be the optimal choice for this indication 5

Special Population Considerations

Elderly Patients

• Critical approach: Start at the low end of the dosing range due to increased risk of confusion, oversedation, and decreased hepatic/renal/cardiac function 1
• Monitoring: Close observation is essential; sedating drugs cause confusion and oversedation more readily in this population 1
• Cardiovascular safety: Doxepin is generally well-tolerated in elderly patients and those with cardiovascular disease, with less postural hypotension than other tricyclics 6

Cardiac Precautions

• ECG screening: Obtain baseline ECG in patients over 40 years old 5
• Dose limitation: Keep doses below 100 mg/day when possible in patients with ischemic cardiac disease or ventricular conduction abnormalities 5
• Overdose risk: Despite better tolerability at therapeutic doses, doxepin has similar cardiotoxicity to other tricyclics in overdose 6

Safety Profile and Side Effects

Common Adverse Effects

• Most frequent: Dry mouth, drowsiness, and constipation 1, 6
• Anticholinergic effects: Blurred vision, urinary retention (may require dose reduction if severe) 1
• CNS effects: Drowsiness typically diminishes with continued therapy; confusion, disorientation, and hallucinations occur infrequently 1
• Cardiovascular: Hypotension, hypertension, and tachycardia reported occasionally, but postural hypotension is uncommon compared to other tricyclics 1, 6

Serious but Rare Complications

• Hematologic: Bone marrow depression (agranulocytosis, leukopenia, thrombocytopenia) has been reported 1
• Neurologic: Seizures, extrapyramidal symptoms, tardive dyskinesia possible 1
• Withdrawal: Gradual tapering is necessary to avoid withdrawal symptoms after prolonged use 1

Critical Clinical Pitfalls

Suicide Risk Monitoring

• Black box warning: All patients, especially those under 24 years old, require close monitoring for clinical worsening, suicidality, or unusual behavioral changes when starting antidepressant therapy 1
• Not approved: Doxepin is not approved for pediatric use (under 12 years) 1

Drug Interactions

• Contraindicated with alcohol: Do not use concomitantly in patients with alcoholism, though doxepin can treat depression/anxiety associated with alcoholism when alcohol is avoided 1
• Guanethidine interaction: At doses up to 150 mg/day, doxepin does not block antihypertensive effects; above 150 mg/day, blocking has been reported 1

Absolute Contraindications

• Glaucoma: Must be ruled out before initiating therapy 1
• Urinary retention tendency: Screen for this, particularly in older patients 1
• Hypersensitivity: Cross-sensitivity with other dibenzoxepines is possible 1

Comparative Efficacy

Doxepin demonstrates similar antidepressant efficacy to amitriptyline but with a more sedative profile, making it particularly useful for depressed patients with sleep disturbances and anxiety 6. It causes fewer or less troublesome side effects than imipramine or amitriptyline at equivalent response rates 6. When anxiety accompanies significant depression, doxepin is more effective than benzodiazepines like chlordiazepoxide or diazepam 6.