Is doxepin (tricyclic antidepressant) effective for treating insomnia?

Effectiveness of Doxepin for Insomnia

Low-dose doxepin (3 mg or 6 mg) is effective for treating sleep maintenance insomnia, showing clinically significant improvements in wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE), with minimal adverse effects. 1

Efficacy Profile

• Low-dose doxepin (3 mg and 6 mg) demonstrates clinically significant improvements in sleep maintenance parameters but minimal improvement in sleep onset 1
• Meta-analyses show that doxepin significantly improves:
  • Wake after sleep onset (WASO) at both 3 mg and 6 mg doses 1
  • Total sleep time (TST) at 3 mg (both objectively and subjectively) and 6 mg (objectively) 1
  • Sleep efficiency (SE) at both 3 mg and 6 mg doses 1
• Sleep latency improvements are modest and generally below clinical significance thresholds 1, 2
• Sleep quality shows moderate improvement at 3 mg and mild improvement at 6 mg 1

Evidence from Clinical Trials

• Multiple randomized controlled trials show that doxepin's effects on sleep maintenance are evident after a single administration and maintained for up to 12 weeks 3, 4
• A pooled analysis of two phase 3 trials found that doxepin 3 mg produced a statistically significant 22% improvement in latency to persistent sleep compared to placebo, though this did not reach clinical significance thresholds 2
• In a recent comparative study (2024), doxepin 6 mg was more effective than zolpidem in improving:
  • Wake after sleep onset (WASO): 80.3 ± 21.4 min vs 132.9 ± 26.5 min 5
  • Total sleep time (TST): 378.9 ± 21.9 min vs 333.2 ± 24.2 min 5
  • Sleep efficiency (SE): 77.8 ± 4.2% vs 68.6 ± 5.0% 5
  • Executive function as measured by the Wisconsin sorting card test 5

Safety Profile

• Low-dose doxepin (3 mg and 6 mg) has a safety profile comparable to placebo in clinical trials 4
• Meta-analyses of side effects show only a mild increase in somnolence at the 6 mg dose 1
• No significant anticholinergic effects, memory impairment, or hangover/next-day residual effects were reported 4
• Unlike benzodiazepines and non-benzodiazepine hypnotics, low-dose doxepin has not shown evidence of physical dependence or rebound insomnia after withdrawal 3
• However, some studies report higher adverse event rates with longer treatment duration 1

Clinical Guidelines Recommendations

• The American Academy of Sleep Medicine (AASM) suggests using doxepin as a treatment for sleep maintenance insomnia (weak recommendation) 1
• The VA/DoD guidelines recognize that while non-pharmacologic behavioral interventions (CBT-I) are more effective than pharmacologic therapies, low-dose doxepin may be considered for patients unable or unwilling to receive CBT-I 1
• Both guidelines emphasize that doxepin should be administered at the lowest effective dose (3 or 6 mg) and for the shortest possible duration 1

Treatment Algorithm

1. First-line: Cognitive Behavioral Therapy for Insomnia (CBT-I) 1, 6
2. Second-line (for patients unable/unwilling to use CBT-I):
   • For sleep maintenance problems: Low-dose doxepin (3 mg or 6 mg) 1
   • For sleep onset problems: Consider other agents as doxepin has minimal effect on sleep latency 1, 2
3. Dosing considerations:
   • Start with 3 mg for most patients 1
   • Consider 6 mg if response is inadequate and no adverse effects 1
   • Use for the shortest duration possible 1

Important Caveats

• Low-dose doxepin is primarily effective for sleep maintenance insomnia rather than sleep onset difficulties 1, 2
• While standard antidepressant doses of doxepin (25-50 mg) may also improve sleep, they carry a higher risk of side effects 7
• Low-dose doxepin has no black box warning for suicide risk, but the risk for suicidal ideation cannot be completely excluded 1
• Regular reassessment of efficacy and adverse effects is recommended 6