Is doxepin (a tricyclic antidepressant) effective and safe for treating insomnia in adults with a history of depression or anxiety?

Doxepin for Sleep: Evidence-Based Recommendations

Low-dose doxepin (3-6 mg) is highly effective and safe for treating sleep maintenance insomnia in adults, including those with comorbid depression or anxiety, and should be considered a first-line pharmacotherapy option when Cognitive Behavioral Therapy for Insomnia (CBT-I) is insufficient or unavailable. 1

Critical Dosing Distinction

You must prescribe doxepin at 3-6 mg for insomnia—NOT the 20-100 mg antidepressant doses. 1 At low doses, doxepin works through selective H1-histamine receptor antagonism without the anticholinergic burden, sedation, and side effects seen at higher antidepressant doses. 1, 2 The 3-6 mg doses are specifically FDA-approved for insomnia and represent a completely different therapeutic application than traditional antidepressant use. 3

Efficacy Profile

Low-dose doxepin demonstrates robust efficacy for sleep maintenance:

• Wake after sleep onset (WASO): Reduces by 22-23 minutes compared to placebo (95% CI: 14-30 minutes) 1
• Total sleep time (TST): Increases by 26-32 minutes compared to placebo (95% CI: 18-40 minutes) 1
• Sleep efficiency: Clinically significant improvements, including in the final third of the night 1, 4
• Sleep quality: Small-to-moderate subjective improvements 1

These improvements are evident after a single dose and maintain efficacy for up to 12 weeks without tolerance development. 2, 4

Position in Treatment Algorithm

Start with CBT-I first for all patients with chronic insomnia. 5, 1 CBT-I includes stimulus control, sleep restriction, relaxation techniques, and cognitive restructuring—it demonstrates superior long-term outcomes compared to medications alone. 5, 1

When pharmacotherapy is needed:

1. First-line options: Short-acting benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon) or ramelteon for sleep onset insomnia 5, 6
2. For sleep maintenance insomnia specifically: Low-dose doxepin (3-6 mg) is a preferred first-line option alongside eszopiclone and suvorexant 5, 1, 6
3. For comorbid depression/anxiety: Low-dose doxepin is particularly appropriate as it addresses both conditions simultaneously 6, 3

Safety Profile

Low-dose doxepin has a safety profile comparable to placebo. 1, 4

• Common adverse effects: Somnolence (particularly at 6 mg) and headache, but rates are similar to placebo 1, 4
• No anticholinergic effects at low doses (unlike higher antidepressant doses) 4, 7
• No next-day residual sedation or psychomotor impairment 4, 7
• No tolerance, dependence, or rebound insomnia after discontinuation 2, 7
• Sleep architecture preserved (no disruption of REM or slow-wave sleep) 4, 7

Special Populations

Elderly patients: Low-dose doxepin 3 mg is one of the safest choices due to minimal fall risk and cognitive impairment compared to benzodiazepines. 1, 6 The American Academy of Sleep Medicine specifically recommends it for older adults with sleep maintenance insomnia. 5, 1

Patients with sleep apnea: Low-dose doxepin (3-6 mg) can be used safely in patients with mild-to-moderate sleep apnea who are on appropriate OSA treatment (CPAP or mandibular advancement device), as it has a favorable safety profile compared to benzodiazepines which are contraindicated. 1

Patients with substance use history: While not the first choice (ramelteon is preferred due to zero abuse potential), low-dose doxepin has no demonstrated tolerance or dependence liability. 2, 7

Critical Prescribing Details

Dosing:

• Start with 3 mg taken 30 minutes before bedtime 1
• Can increase to 6 mg if 3 mg is insufficient 1
• Do NOT use antidepressant doses (25-100 mg) for insomnia 1, 3

Duration:

• FDA-approved for short-term use (4-5 weeks), though studies show maintained efficacy up to 12 weeks 5, 2
• Always combine with CBT-I for optimal long-term outcomes 5, 1

Monitoring:

• Reassess after 1-2 weeks for efficacy and adverse effects 1
• Screen for complex sleep behaviors (though rare with low-dose doxepin) 5
• Monitor for suicidality in patients under age 24 (FDA black box warning for all antidepressants, though risk is primarily at antidepressant doses) 3

Common Pitfalls to Avoid

Do NOT prescribe antidepressant doses (25-100 mg) for insomnia. 1 This shifts the mechanism from selective H1-antagonism to broader tricyclic effects with increased anticholinergic burden, sedation, and adverse effects. 1

Do NOT use doxepin as monotherapy without implementing CBT-I. 5, 1 Pharmacotherapy should supplement, not replace, behavioral interventions which provide more sustained effects. 5, 1

Do NOT use in patients with narrow-angle glaucoma or urinary retention. 3 These are absolute contraindications per FDA labeling. 3

Comparison to Alternatives

Versus trazodone: The American Academy of Sleep Medicine explicitly recommends AGAINST trazodone for insomnia due to insufficient efficacy data and adverse effects outweighing minimal benefits. 6 Low-dose doxepin has superior evidence. 5, 1, 8

Versus benzodiazepines: Low-dose doxepin avoids the fall risk, cognitive impairment, dependence, and respiratory depression associated with benzodiazepines. 1, 6

Versus antihistamines (diphenhydramine): Over-the-counter antihistamines are NOT recommended due to lack of efficacy data, anticholinergic effects, and tolerance development after 3-4 days. 5, 6

Contraindications and Cautions

Absolute contraindications:

• Hypersensitivity to doxepin or dibenzoxepines 3
• Narrow-angle glaucoma 3
• Urinary retention 3

Use with caution:

• Patients under age 24 (increased suicidality risk with antidepressants, though primarily at higher doses) 3
• Concurrent use with MAO inhibitors 3
• Hepatic impairment (dose adjustment may be needed) 1