Is doxepin the same as trazodone for treating depression and insomnia in adults or older adults?

No, Doxepin and Trazodone Are Different Medications

Doxepin and trazodone are two distinct antidepressant medications with different chemical structures, mechanisms of action, and clinical applications, though both are used off-label for insomnia. 1, 2

Chemical and Pharmacological Differences

Chemical Structure:

• Doxepin is a dibenzoxepin tricyclic compound, part of the tricyclic antidepressant (TCA) class 1
• Trazodone is a triazolopyridine derivative, chemically unrelated to tricyclic antidepressants 3

Mechanism of Action:

• Doxepin prevents deactivation of norepinephrine by blocking reuptake into nerve terminals, with anticholinergic, antiserotonin, and antihistamine effects 1
• Trazodone works as both a selective serotonin reuptake inhibitor (SSRI) and a 5-HT2A/5-HT2C receptor antagonist, with additional alpha-1 adrenergic receptor antagonism 2

Clinical Use Distinctions

FDA-Approved Indications:

• Both medications are FDA-approved for treating major depressive disorder in adults 1, 2
• Neither is FDA-approved specifically for insomnia, though both are used off-label for this purpose 4, 5

Dosing Differences for Insomnia:

• Doxepin for insomnia: 3-6 mg at bedtime (very low dose) 5, 6
• Trazodone for insomnia: 25-50 mg at bedtime (though evidence at 50 mg shows limited benefit) 5, 6

Antidepressant Dosing:

• Doxepin: 10-100 mg capsules for depression 1
• Trazodone: Maximum 400 mg/day outpatient, up to 600 mg/day inpatient for depression 7

Guideline Recommendations for Insomnia

The American Academy of Sleep Medicine provides contrasting recommendations for these two medications:

Doxepin (3-6 mg):

• Recommended for sleep maintenance insomnia 5, 6
• Has minimal anticholinergic effects compared to other tricyclics at this low dose 8
• Positioned as a second-line pharmacologic option after cognitive behavioral therapy for insomnia (CBT-I) 5

Trazodone (50 mg):

• Recommended AGAINST for both sleep onset and sleep maintenance insomnia 5, 6
• Clinical trials showed only modest improvements with no significant improvement in subjective sleep quality 5
• The American Academy of Sleep Medicine states that benefits do not outweigh potential harms 5

Treatment Algorithm Position

According to the American Academy of Sleep Medicine guidelines, these medications occupy different positions in the treatment hierarchy: 4

1. First-line: Cognitive behavioral therapy for insomnia (CBT-I)
2. Second-line: Short-intermediate acting benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon, temazepam) or ramelteon; doxepin 3-6 mg for sleep maintenance
3. Third-line: Sedating antidepressants including trazodone, but only after first and second-line treatments fail, especially when comorbid depression/anxiety is present

Important Clinical Caveats

When Trazodone Might Be Considered Despite Weak Evidence:

• When comorbid depression is present requiring full antidepressant dosing (though low doses used for insomnia are inadequate for treating major depression) 4, 5
• As an adjunct to another full-dose antidepressant for patients with depression and insomnia 5
• Trazodone has less anticholinergic activity than doxepin at antidepressant doses 4

Safety Considerations:

• Trazodone: Risk of priapism, daytime drowsiness, dizziness, postural hypotension 5, 2
• Doxepin: At low doses (3-6 mg), minimal anticholinergic effects; at higher antidepressant doses, typical TCA side effects apply 8, 1

Common Prescribing Error to Avoid:

• Do not confuse low-dose doxepin (3-6 mg for insomnia) with standard antidepressant doses (10-100 mg) 5, 1
• Do not use trazodone as first-line therapy for primary insomnia when better-studied alternatives exist 5, 6

Bottom Line for Clinical Practice

If treating primary insomnia and pharmacotherapy is indicated after CBT-I, choose doxepin 3-6 mg over trazodone based on current guideline recommendations. 5, 6 Trazodone should be reserved for situations where comorbid depression exists or when other treatments have failed. 4, 5