What is the recommended use and dosage of doxepin for treating depression, anxiety, and insomnia?

Doxepin: Clinical Use and Dosing

Primary Indication: Sleep Maintenance Insomnia

For insomnia, use low-dose doxepin (3-6 mg) specifically for sleep maintenance problems, NOT the higher antidepressant doses (75-300 mg). 1

Evidence-Based Dosing for Insomnia

• Low-dose doxepin (3-6 mg) is recommended by the American Academy of Sleep Medicine as a second-line pharmacotherapy option for chronic insomnia when Cognitive Behavioral Therapy for Insomnia (CBT-I) is insufficient, unavailable, or the patient is unable/unwilling to receive it 1

• At these low doses (3-6 mg), doxepin functions as a selective H1-receptor antagonist rather than a tricyclic antidepressant, which minimizes adverse effects 1

• Clinical benefits include:

  • Wake after sleep onset (WASO) reduction of 22-23 minutes compared to placebo 1
  • Total sleep time (TST) improvement of 26-32 minutes compared to placebo 1
  • Small-to-moderate improvement in sleep quality 1
  • Safety profile comparable to placebo in clinical trials 1

Treatment Algorithm for Insomnia

First-line treatment: Cognitive Behavioral Therapy for Insomnia (CBT-I) 2, 3

Second-line pharmacotherapy options (when CBT-I fails or is unavailable):

For sleep maintenance insomnia specifically:

• Doxepin 3-6 mg at bedtime 1
• Eszopiclone 2-3 mg 1
• Temazepam 15 mg 1
• Suvorexant 10-20 mg 1
• Zolpidem 10 mg 1

Important distinction: The American Academy of Sleep Medicine recommends doxepin at 3-6 mg doses for sleep maintenance insomnia, NOT 20 mg, as the higher dose represents a shift from selective H1-receptor antagonism to broader tricyclic antidepressant effects with increased adverse effects 1

Depression and Anxiety Treatment

Standard Antidepressant Dosing

For depression and anxiety disorders, doxepin requires much higher doses (75-300 mg daily) than those used for insomnia 4

• Starting dose: 75 mg daily for mild to moderate illness 4
• Optimal dose range: 75-150 mg daily 4
• Severe illness: May require gradual increase to 300 mg daily 4
• Very mild symptoms: 25-50 mg daily may suffice 4

Dosing Schedule

• Total daily dose can be given as divided doses or once daily 4
• If using once-daily dosing, maximum recommended dose is 150 mg at bedtime 4
• The 150 mg capsule strength is for maintenance therapy only, not treatment initiation 4

Time to Effect

• Anti-anxiety effect appears before antidepressant effect 4
• Optimal antidepressant effect may not be evident for 2-3 weeks 4

Position in Treatment Algorithm

For Depression/Anxiety

Doxepin is NOT a first-line antidepressant. When treating depression in older adults, medication selection should be guided by side effect profiles and potential drug interactions rather than efficacy differences 3

Preferred first-line options for depression include:

• Sertraline (minimal anticholinergic effects, fewer drug interactions) 3
• Citalopram or escitalopram (favorable side effect profiles) 3
• Venlafaxine (higher nausea/vomiting incidence) 3
• Duloxetine (beneficial if pain symptoms accompany depression) 3
• Bupropion (lower sexual adverse events) 3
• Mirtazapine (useful if insomnia and weight loss are prominent) 3

Doxepin's position: Listed as a sedating antidepressant option, especially when used in conjunction with treating comorbid depression/anxiety, but only after first-line benzodiazepine receptor agonists or ramelteon have been tried for insomnia 2

For Insomnia in Depression

Critical caveat: Low-dose doxepin (< 25 mg/day) does NOT appear to improve sleep onset or maintenance in patients with major depressive disorder, contrasting with its efficacy in healthy subjects 5

When antidepressants are used for insomnia at lower than therapeutic antidepressant dosages (including doxepin), they are NOT FDA approved for insomnia and their efficacy for this indication is not well established 2

Special Populations

Elderly Patients

• Start at the low end of the dosing range 4
• Elderly patients should be started on low doses and observed closely due to risk of confusion and oversedation 4
• Caution and downward dosage adjustment advised 2
• Doxepin is generally safe and well tolerated even in elderly patients when used appropriately 4

Pediatric Patients

Doxepin is NOT approved for use in pediatric patients 4

• The American Academy of Sleep Medicine does not support the use of doxepin in pediatric populations due to lack of FDA approval and limited safety data 1
• Not recommended for use in children under 12 years of age due to lack of clinical experience 4

Pregnancy and Nursing

• Not recommended during pregnancy or nursing 2

Contraindications and Cautions

Absolute Contraindications

• Hypersensitivity to doxepin 4
• Glaucoma 4
• Urinary retention 4

Use with Caution

• Signs/symptoms of depression (monitor for suicidality, especially in young adults) 2, 4
• Compromised respiratory function (asthma, COPD, sleep apnea) 2
• Hepatic or heart failure 2
• Premature ventricular contractions (when using for mood stabilization) 2
• Elderly patients (increased risk of confusion, oversedation) 4

Common Adverse Effects

At Antidepressant Doses (75-300 mg)

Most common:

• Dry mouth 4
• Drowsiness (most commonly noticed, tends to disappear with continued therapy) 4
• Constipation 4

Other anticholinergic effects:

• Blurred vision 4
• Urinary retention 4

Cardiovascular:

• Hypotension, hypertension, tachycardia (reported occasionally) 4

CNS effects:

• Confusion, disorientation, hallucinations 4
• Numbness, paresthesias, ataxia 4
• Extrapyramidal symptoms, seizures, tardive dyskinesia, tremor 4

At Low Doses for Insomnia (3-6 mg)

• Somnolence (particularly at 6 mg doses) 1
• Headache 1
• Minimal effects overall, with safety profile comparable to placebo 1

Drug Interactions

Guanethidine Interaction

• At clinical dosages up to 150 mg per day, doxepin can be given concomitantly with guanethidine without blocking the antihypertensive effect 4
• At dosages above 150 mg per day, blocking of the antihypertensive effect has been reported 4

CNS Depressants

• Additive effect on psychomotor performance with concomitant CNS depressants and/or alcohol use 2
• Caution advised with benzodiazepine receptor agonist hypnotics combined with alcohol, other sedatives, and sleep restriction 2

Monitoring and Follow-Up

For Antidepressant Use

• Patients should be followed every few weeks in the initial period of treatment to assess for effectiveness, possible side effects, and need for ongoing medication 2
• Monitor for clinical worsening, suicidality, or unusual changes in behavior, especially in young adults 4
• After 9 months, dosage reduction should be used to reassess the need to medicate 2

Discontinuation

• Discontinue over 10-14 days to limit withdrawal symptoms 2
• Rapid dose decrease or abrupt discontinuance can produce withdrawal symptoms, including rebound insomnia 2
• Medication tapering and discontinuation are facilitated by CBT-I 2

Key Clinical Pitfalls

Do not confuse insomnia dosing with antidepressant dosing: The 3-6 mg dose for insomnia is vastly different from the 75-300 mg range for depression/anxiety 1, 4

Do not use low-dose doxepin for insomnia in patients with active major depressive disorder: Evidence suggests it is ineffective in this population 5

Do not use as first-line for insomnia: CBT-I should be attempted first, and doxepin is a second-line option 2, 1, 3

Do not use higher doses (20 mg or more) for insomnia: This shifts the mechanism from selective H1 antagonism to broader tricyclic effects with increased adverse events 1

Avoid in elderly without dose adjustment: Start low and titrate carefully to avoid confusion and oversedation 4