What is doxepin?

Doxepin: A Tricyclic Antidepressant with Dual Applications

Doxepin is a tricyclic antidepressant that is FDA-approved for the treatment of depression/anxiety at higher doses (10-150 mg) and for sleep maintenance insomnia at lower doses (3-6 mg), with the low-dose formulation working primarily through histamine H1 receptor antagonism. 1, 2

Pharmacology and Mechanism of Action

Doxepin is a dibenzoxepin derivative tricyclic compound with the following key properties:

• Primary mechanism: At therapeutic doses, it influences adrenergic activity at synapses by preventing norepinephrine reuptake into nerve terminals 2
• Secondary mechanisms: Demonstrates anticholinergic, antiserotonin, and antihistamine effects 2
• At low doses (3-6 mg): Acts primarily as a selective histamine H1 receptor antagonist with high specificity and affinity 3, 4

FDA-Approved Indications

Higher Doses (10-150 mg)

• Psychoneurotic patients with depression and/or anxiety
• Depression and/or anxiety associated with alcoholism
• Depression and/or anxiety associated with organic disease
• Psychotic depressive disorders with associated anxiety 2

Lower Doses (3-6 mg)

• Sleep maintenance insomnia in adults 1

Clinical Efficacy

For Depression/Anxiety (10-150 mg)

• Effectively treats target symptoms including:
  • Anxiety and tension
  • Depression
  • Somatic symptoms
  • Sleep disturbances
  • Guilt and lack of energy
  • Fear, apprehension, and worry 2

For Insomnia (3-6 mg)

• Sleep maintenance: Significantly improves wake time after sleep onset (WASO), total sleep time (TST), and sleep efficiency 1
• Clinical significance: Exceeds clinical significance thresholds for PSG-measured WASO and TST 1
• Rapid onset: Benefits observed after a single administration 4
• Sustained effect: Maintains efficacy for up to 12 weeks without evidence of tolerance 4

Dosing Considerations

For Depression/Anxiety

• Available in 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg capsules
• Dosing typically ranges from 10-150 mg daily 2

For Insomnia

• Recommended at 3 mg and 6 mg doses for sleep maintenance insomnia 1
• Lower doses (1-6 mg) are effective in elderly patients 1

Safety Profile

Advantages

• Generally well-tolerated even in elderly patients 2
• At low doses (3-6 mg), minimal effects on sleep architecture 3
• No evidence of tolerance, rebound insomnia, or discontinuation symptoms at low doses 3, 4
• Relatively safe in patients with cardiovascular conditions at standard doses 5, 6

Common Adverse Effects

• Higher doses: Dry mouth, drowsiness, constipation 5
• Lower doses: Somnolence and headache (often at placebo level) 3

Important Warnings

• Suicidality risk: Carries black box warning regarding increased risk of suicidal thinking and behavior in children, adolescents, and young adults 2
• Contraindications: Glaucoma, urinary retention, hypersensitivity 2
• Not recommended: For children under 12 years of age 2

Comparative Efficacy

For Insomnia

• Recommended over trazodone for sleep maintenance insomnia 1
• Preferred over benzodiazepines in elderly patients due to better safety profile 1

For Depression

• Similar mood-elevating effect to amitriptyline but possibly less marked than imipramine 5
• More effective than benzodiazepines when anxiety is accompanied by significant depression 5

Clinical Practice Guidelines

The American Academy of Sleep Medicine suggests using doxepin (3-6 mg) for sleep maintenance insomnia in adults (weak recommendation) 1. The VA/DoD guidelines also consider low-dose doxepin as an option for patients unable or unwilling to receive cognitive behavioral therapy for insomnia 1.

Special Considerations

• Long-term use: Has demonstrated safety and efficacy in long-term treatment (5-15 years) of chronic depression 6
• Drug interactions: At clinical dosages up to 150 mg/day, does not block antihypertensive effects of guanethidine and related compounds 2
• Dependence potential: Has not been demonstrated to produce physical tolerance or psychological dependence 2

When considering pharmacologic treatment for insomnia, doxepin at low doses (3-6 mg) represents a valuable option with demonstrated efficacy for sleep maintenance problems and a favorable safety profile, particularly in elderly patients.