What is the recommended use and dosage of Doxepin (tricyclic antidepressant) for treating major depressive disorder, anxiety disorders, and insomnia?

Doxepin for Major Depressive Disorder, Anxiety Disorders, and Insomnia

For major depressive disorder, doxepin should be initiated at 75 mg/day and titrated to an optimal dose range of 75-150 mg/day, while for insomnia, low-dose doxepin (3-6 mg) is recommended due to its selective H1 receptor antagonism and favorable safety profile.

Dosing for Major Depressive Disorder

Doxepin is FDA-approved for the treatment of major depressive disorder, with specific dosing recommendations:

• Initial dosing: 75 mg/day for most patients with mild to moderate depression 1
• Optimal dose range: 75-150 mg/day 1
• Maximum dose: Can be increased gradually to 300 mg/day in severely ill patients, though additional therapeutic benefit is rarely obtained above 300 mg/day 1
• Administration: Can be given as a divided dose or once-daily schedule; if once-daily, maximum recommended dose is 150 mg/day, typically administered at bedtime 1
• Lower doses: For patients with very mild symptoms or emotional symptoms accompanying organic disease, lower doses of 25-50 mg/day may be sufficient 1

Special Considerations for Depression

• Anti-anxiety effects typically appear before antidepressant effects
• Optimal antidepressant effect may not be evident for 2-3 weeks 1
• The 150 mg capsule strength is intended for maintenance therapy only and not recommended for treatment initiation 1

Dosing for Anxiety Disorders

Doxepin is effective for anxiety, particularly when co-occurring with depression:

• Dosing: Similar to depression dosing (75-150 mg/day) 1
• Comparative efficacy: More effective than benzodiazepines (chlordiazepoxide or diazepam) when anxiety is accompanied by significant depression 2
• Target symptoms: Particularly effective for anxiety, tension, somatic symptoms, sleep disturbances, fear, apprehension, and worry 1

Dosing for Insomnia

For insomnia, low-dose doxepin has emerged as an effective option:

• Recommended dose: 3-6 mg for adults with insomnia 3, 4, 5
• Mechanism: At low doses (1-6 mg), doxepin acts as a selective H1 receptor antagonist 4, 5
• Efficacy: Significantly improves sleep latency, duration, and disturbances compared to placebo 6, 7
• Advantages over higher doses: Fewer side effects while maintaining sleep benefits 4, 5
• Comparative efficacy: Low-dose doxepin (12.5 mg/day) showed superior improvement in sleep latency compared to citalopram after 8-12 weeks of treatment 6

Safety Considerations

Side Effects

• Common side effects: Dry mouth, drowsiness, constipation 1, 2
• Cardiovascular effects: Generally well-tolerated at therapeutic doses, particularly in elderly and those with cardiovascular disease, but has intrinsic cardiotoxicity on overdosage similar to other tricyclics 2
• CNS effects: Drowsiness is most common and tends to diminish with continued therapy 1
• Anticholinergic effects: Dry mouth, blurred vision, constipation, urinary retention 1

Warnings and Precautions

• Suicide risk: Black box warning for increased risk of suicidal thinking and behavior in children, adolescents, and young adults; not approved for pediatric use 1
• Monitoring: All patients started on doxepin should be monitored for clinical worsening, suicidality, or unusual changes in behavior 1
• Contraindications: Glaucoma, urinary retention, hypersensitivity to dibenzoxepines 1
• Elderly patients: Should be started on lower doses due to decreased renal function and increased sensitivity to sedating effects 1

Treatment Algorithm

1. For Major Depressive Disorder:

   • Start with 75 mg/day
   • After 2-3 weeks, assess response
   • If inadequate response, increase gradually to 150 mg/day
   • For severe illness, may increase up to 300 mg/day if needed

2. For Anxiety Disorders:

   • Use similar dosing as for depression (75-150 mg/day)
   • Consider doxepin particularly when anxiety co-occurs with depression

3. For Insomnia:

   • Use low-dose doxepin (3-6 mg) taken 30 minutes before bedtime
   • Particularly useful when insomnia is accompanied by depression or anxiety
   • Monitor for improvement in sleep latency, duration, and quality

4. For Comorbid Conditions:

   • When insomnia and anxiety co-occur, low-dose doxepin (12.5 mg) may be particularly effective 6
   • For depression with sleep disturbances, standard antidepressant doses (75-150 mg) are appropriate, with administration at bedtime to leverage sedative effects

Clinical Pearls

• Doxepin has a unique dual benefit at different dose ranges: selective H1 antagonism at low doses (1-6 mg) for insomnia and broader antidepressant/anxiolytic effects at higher doses (75-300 mg)
• The sedative properties of doxepin make it particularly useful for depressed patients with sleep disturbances 2
• Unlike benzodiazepines, doxepin does not appear to develop tolerance, cause rebound insomnia, or lead to withdrawal symptoms when used for insomnia 5
• Therapeutic effects for depression may take 2-3 weeks to become fully evident 1
• Consider lower starting doses in elderly patients, those with mild symptoms, or patients with comorbid medical conditions 1