What is doxepin used for and how is it typically prescribed?

Doxepin: Clinical Overview

Primary Indication and Mechanism

Doxepin is a tricyclic antidepressant available in two distinct formulations: high-dose (10-100 mg) for depression and anxiety disorders, and low-dose (3-6 mg) specifically FDA-approved for insomnia characterized by sleep maintenance difficulties. 1

Low-Dose Formulation (3-6 mg)

• Mechanism: Selective histamine H1 receptor antagonism at subnanomolar affinity, which is the primary mechanism for its hypnotic effects at low doses 2, 3
• FDA approval: Since 2005 for treatment of insomnia, particularly sleep maintenance insomnia 4
• Does NOT work through: GABA pathways, monoamine oxidase inhibition, or significant anticholinergic effects at these doses 1, 2

High-Dose Formulation (10-100 mg)

• Mechanism: Prevents deactivation of norepinephrine by blocking reuptake into nerve terminals, along with anticholinergic, antiserotonin, and antihistamine effects 1
• FDA-approved indications 1:
  • Psychoneurotic patients with depression and/or anxiety
  • Depression/anxiety associated with alcoholism (not to be taken with alcohol)
  • Depression/anxiety associated with organic disease
  • Psychotic depressive disorders with associated anxiety, including involutional depression and manic-depressive disorders

Prescribing for Insomnia

Dosing Recommendations

• Standard dose: 3-6 mg at bedtime for insomnia 5, 6
• No significant difference in efficacy between 3 mg and 6 mg doses 7
• Elderly patients: Start with 3 mg; both doses are well-tolerated 7
• Hepatic impairment: Dose adjustment may be needed for high-dose formulations 4

Efficacy Profile

• Sleep maintenance: Small to medium effect size; significantly reduces waking after sleep onset and increases total sleep time 7, 8
• Sleep duration: Effective into the last third of the night (early morning awakening) 7
• Sleep onset: Does NOT significantly affect latency to sleep onset 7, 8
• Sleep architecture: Minimal effects on sleep stages 2

Clinical Positioning

According to the American Academy of Sleep Medicine guidelines 4, 5:

• Third-line option for insomnia after benzodiazepine receptor agonists and ramelteon
• Consider earlier when comorbid depression exists or other treatments have failed 4
• Preferred over other tricyclics due to minimal anticholinergic effects at low doses 6

Safety Profile

Tolerability

• Most common adverse events: Sedation/somnolence and headache, occurring at rates comparable to placebo 2, 7, 8
• No next-day residual effects: Studies show no significant psychomotor impairment or residual sedation 2, 7, 8
• No tolerance: No signal for tolerance development in trials up to 3 months 2
• No dependence: Does not produce physical tolerance or psychological dependence characteristic of addictive compounds 1

Withdrawal and Rebound

• Rebound insomnia: Some patients (minority) may experience severe rebound insomnia upon discontinuation, particularly with higher doses (25-50 mg) 9
• Low-dose formulation: Minimal discontinuation symptoms reported 2, 8

Contraindications and Warnings

• Absolute contraindications 1:

  • Hypersensitivity to doxepin or other dibenzoxepines
  • Glaucoma
  • Urinary retention tendency (particularly in older patients)

• Black Box Warning (applies to antidepressant doses) 1:

  • Increased risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18-24) with major depressive disorder
  • Close monitoring required for clinical worsening, suicidality, or unusual behavior changes
  • NOT approved for pediatric use

Drug Interactions

• Guanethidine: At doses ≤150 mg/day, does not block antihypertensive effect; at >150 mg/day, blocking has been reported 1
• Alcohol: Contraindicated when treating depression/anxiety associated with alcoholism 1

Clinical Pearls and Pitfalls

When to Choose Low-Dose Doxepin

• Best for: Sleep maintenance insomnia and early morning awakening 5, 7
• Avoid for: Sleep onset insomnia as primary complaint (consider ramelteon instead) 5
• Special advantage: Minimal risk of triggering mania in patients with potential bipolar disorder 5
• Elderly patients: Well-suited due to safety profile, though American Geriatrics Society recommends caution with doses >7.5 mg 10

Common Pitfalls

• Wrong dose selection: Using antidepressant doses (25-300 mg) for insomnia increases side effects without additional sleep benefit 4, 9
• Unrealistic expectations: Patients expecting immediate sleep onset improvement will be disappointed; emphasize sleep maintenance benefits 7, 8
• Inadequate screening: Must rule out glaucoma and urinary retention, especially in older patients 1
• Combining with other sedatives: Risk of additive sedative effects when combined with other CNS depressants 4, 10

Monitoring

• High-dose formulations: Monitor for anticholinergic effects, cardiac effects, and in rare cases, hematologic abnormalities (leukopenia, thrombopenia) and liver enzyme elevation 9
• All patients: Monitor for mood changes, particularly when using antidepressant doses 1

Comparison to Other Insomnia Treatments

Advantages Over Benzodiazepines/BzRAs

• No dependence or tolerance risk 2
• No short-term usage restrictions 4
• Effective for sleep maintenance throughout the night 7

Limitations Compared to First-Line Agents

• Does not improve sleep onset 7, 8
• Limited evidence base compared to BzRAs (predominantly industry-sponsored studies) 8
• Third-line positioning per guidelines 4, 5