What is the recommended use and dosage of doxepin for treating depression, anxiety, and insomnia?

Doxepin: Recommended Use and Dosing

Doxepin is recommended at low doses (3-6 mg) specifically for sleep maintenance insomnia in adults, NOT for depression or anxiety, where higher doses (75-300 mg) are required but other agents are generally preferred. 1, 2

For Insomnia (Sleep Maintenance)

Low-dose doxepin (3-6 mg) is a first-line pharmacologic option for sleep maintenance insomnia according to the American Academy of Sleep Medicine. 1

Efficacy Data

• Reduces wake after sleep onset by 22-23 minutes compared to placebo 1
• Increases total sleep time by 26-32 minutes compared to placebo 1
• Improves sleep efficiency with small-to-moderate improvements in sleep quality 1
• Superior to zolpidem 5-10 mg in head-to-head trials for sleep maintenance parameters 1

Dosing for Insomnia

• Start: 3 mg at bedtime 1
• Maximum: 6 mg at bedtime 1
• The 3-6 mg range provides selective H1-receptor antagonism without broader tricyclic antidepressant effects 1
• Do NOT use 20 mg or higher doses for insomnia - this shifts to non-selective tricyclic effects with significantly increased adverse effects 1

Safety Profile at Low Doses

• Comparable to placebo in clinical trials 1
• Most common adverse effects: somnolence (particularly at 6 mg) and headache 1
• Minimal psychomotor impairment or residual sedation 3
• No tolerance, rebound insomnia, or discontinuation symptoms in trials up to 3 months 3

Treatment Algorithm Position

• Cognitive Behavioral Therapy for Insomnia (CBT-I) remains first-line treatment 1
• Low-dose doxepin is a second-line pharmacologic option when CBT-I is insufficient, unavailable, or patient is unable/unwilling to receive it 1
• Alternative second-line options include eszopiclone 2-3 mg, temazepam 15 mg, suvorexant 10-20 mg, or zolpidem 10 mg 1

For Depression

For depression, doxepin requires substantially higher doses (75-300 mg daily) and is NOT a preferred first-line agent. 2

Dosing for Depression

• Start: 75 mg daily (can be divided or given once daily at bedtime if ≤150 mg) 2
• Usual therapeutic range: 75-150 mg daily 2
• Severe illness: May increase gradually to 300 mg daily if necessary 2
• Mild symptoms: 25-50 mg daily may suffice 2
• Maximum single daily dose: 150 mg at bedtime 2

Important Caveats for Depression Use

• Anti-anxiety effect appears before antidepressant effect 2
• Optimal antidepressant effect may not be evident for 2-3 weeks 2
• Additional therapeutic effect rarely obtained by exceeding 300 mg daily 2
• Doxepin has sedative properties similar to amitriptyline, making it useful for depressed patients with sleep disturbances 4
• Mood elevation may be less marked than imipramine and slower to take effect 4

Comparative Considerations

• At equivalent doses, doxepin causes fewer or less troublesome side effects than imipramine or amitriptyline 4
• More useful than imipramine in depression with sleep disturbances and anxiety 4
• Generally well tolerated, particularly in elderly and those with cardiovascular disease 4

For Anxiety

Doxepin at antidepressant doses (75-300 mg) can be used for anxiety, but benzodiazepines remain preferred for pure anxiety states. 4

When to Consider Doxepin for Anxiety

• Depression accompanied by significant anxiety - doxepin is more effective than chlordiazepoxide or diazepam in this scenario 4
• Anxiety associated with alcoholism (not to be taken concomitantly with alcohol) 2
• Anxiety associated with organic disease 2
• Psychoneurotic patients with combined depression and anxiety 2

Target Symptoms

• Anxiety, tension, somatic symptoms and concerns 2
• Sleep disturbances, guilt, lack of energy 2
• Fear, apprehension, and worry 2

Special Populations

Elderly Patients

• Start at low end of dosing range due to greater frequency of decreased hepatic, renal, or cardiac function 2
• Sedating drugs may cause confusion and oversedation in elderly 2
• Observe closely and use cautious dose selection 2
• For insomnia in elderly: low-dose doxepin (3-6 mg) is well-studied and effective 1, 3

Pediatric Use

• NOT recommended for children under 12 years of age due to lack of clinical experience 2
• No FDA approval or clinical practice guidelines support pediatric use 1
• Limited safety and efficacy data in this population 1

Pregnancy and Nursing

• Avoid in pregnancy and nursing 5

Critical Safety Warnings

Black Box Warning

• Increased risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18-24) with major depressive disorder 2
• All patients started on antidepressant therapy should be monitored closely for clinical worsening, suicidality, or unusual changes in behavior 2
• Risk reduction with antidepressants compared to placebo in adults aged 65 and older 2

Contraindications

• Hypersensitivity to doxepin or other dibenzoxepines 2
• Glaucoma 2
• Urinary retention tendency 2

Common Adverse Effects (at antidepressant doses)

• Dry mouth, drowsiness, and constipation are most common 2, 4
• Blurred vision, urinary retention (anticholinergic effects) 2
• Cardiovascular effects including hypotension, hypertension, tachycardia (occasional) 2
• Postural hypotension is uncommon compared to other tricyclics 4

Serious Adverse Effects

• Confusion, disorientation, hallucinations 2
• Seizures, extrapyramidal symptoms, tardive dyskinesia 2
• Bone marrow depression (agranulocytosis, leukopenia, thrombocytopenia) - rare 2
• Cardiotoxicity on overdosage similar to other tricyclics 4

Drug Interactions

• At doses up to 150 mg daily, can be given with guanethidine without blocking antihypertensive effect 2
• At doses above 150 mg daily, may block antihypertensive effect of guanethidine and related compounds 2
• Caution with other sedating medications due to additive effects 5

Important Clinical Pitfalls

Common Dosing Errors

• Do NOT use antidepressant doses (75-300 mg) for insomnia - this causes unnecessary side effects without additional benefit for sleep 1
• Do NOT use low doses (3-6 mg) for depression - these are inadequate for treating major depression 5
• When insomnia coexists with depression requiring treatment, use full-dose antidepressant plus low-dose doxepin for sleep, or choose a different sedating antidepressant 5

Withdrawal Considerations

• Gradual withdrawal recommended after prolonged administration to avoid withdrawal symptoms 2
• Discontinue over 10-14 days to limit withdrawal symptoms 6

Monitoring Requirements

• Obtain ECG and cardiac monitoring in overdose situations 2
• Monitor for clinical worsening and suicidality, especially early in treatment 2
• After 9 months of antidepressant treatment, consider dosage reduction to reassess need 6