What is doxepin?

Doxepin: A Medication for Insomnia and Depression

Doxepin is a tricyclic compound that functions primarily as a histamine H1 receptor antagonist at low doses (3-6 mg) for treating insomnia, and as an antidepressant at higher doses (10-150 mg) for treating depression, anxiety, and related conditions. 1

Low-Dose Doxepin for Insomnia

Mechanism of Action

• At low doses (1-6 mg), doxepin acts as a highly selective histamine H1 receptor antagonist, which promotes sleep initiation and maintenance 2
• This selective H1 antagonism differentiates low-dose doxepin from its action at higher antidepressant doses

Efficacy for Insomnia

• Particularly effective for sleep maintenance insomnia rather than sleep initiation problems 3
• Clinical trials demonstrate significant improvements in:
  • Wake time after sleep onset (WASO): Mean reduction of 22-23 minutes compared to placebo 4
  • Total sleep time (TST): Mean improvement of 26-32 minutes compared to placebo 4
  • Sleep efficiency: Clinically significant improvements at both 3 mg and 6 mg doses 4
  • Sleep quality: Small-to-moderate improvement compared to placebo 4

Dosing for Insomnia

• Recommended doses: 3 mg or 6 mg taken once daily before bedtime 4
• Clinical guidelines recommend:
  • Starting with 3 mg for most adults
  • 6 mg may be more effective but with slightly increased risk of somnolence 4
  • Effects are evident after a single administration and can be maintained for up to 12 weeks 2

Safety Profile for Low-Dose Use

• Generally well-tolerated with minimal side effects at low doses 2
• Most common side effects include mild somnolence and headache, often at placebo level 5
• No evidence of:
  • Tolerance development
  • Physical dependence
  • Rebound insomnia upon discontinuation
  • Significant next-day residual effects 2, 5

Higher-Dose Doxepin for Depression and Anxiety

Indications

• FDA-approved for:
  1. Psychoneurotic patients with depression and/or anxiety
  2. Depression and/or anxiety associated with alcoholism
  3. Depression and/or anxiety associated with organic disease
  4. Psychotic depressive disorders with associated anxiety 1

Mechanism at Higher Doses

• At antidepressant doses (10-150 mg), doxepin affects multiple neurotransmitter systems:
  • Prevents reuptake of norepinephrine at nerve terminals
  • Has anticholinergic, antiserotonin, and antihistamine effects 1

Dosing for Depression/Anxiety

• Typical therapeutic range: 10-150 mg daily 1
• At doses above 150 mg/day, may block antihypertensive effects of certain medications 1

Safety Considerations for Higher Doses

• Black box warning: Increased risk of suicidal thinking and behavior in children, adolescents, and young adults 1
• Common side effects at higher doses:
  • Dry mouth
  • Drowsiness
  • Constipation
  • Anticholinergic effects 6
• Not recommended for use in children under 12 years 1

Clinical Decision-Making Algorithm

1. For insomnia (particularly sleep maintenance):

   • First-line: Non-pharmacological approaches (CBT-I or BBT-I) 4
   • If non-pharmacological approaches fail or are unavailable:
     • Consider low-dose doxepin (3-6 mg) for short-term use
     • Start with 3 mg; increase to 6 mg if needed and tolerated
     • Monitor for effectiveness and side effects

2. For depression and/or anxiety:

   • Consider standard antidepressant doses (10-150 mg)
   • Start at lower doses and titrate based on response
   • Monitor closely for side effects and suicidality, especially in younger patients

Important Caveats and Precautions

• Contraindicated in individuals with hypersensitivity to the drug 1
• Use with caution in patients with:
  • Cardiovascular disease (though better tolerated than some other tricyclics) 6
  • Glaucoma or urinary retention (due to anticholinergic effects at higher doses)
• Not approved for pediatric use 1
• Patients started on antidepressant doses should be monitored for clinical worsening, suicidality, or unusual changes in behavior 1

Low-dose doxepin represents a different approach to insomnia treatment compared to traditional hypnotics, with its selective histamine antagonism providing benefits for sleep maintenance with minimal side effects when used appropriately.