What is the appropriate dosage and precautions for using doxepin in adults with depression, anxiety, or insomnia, considering factors such as age, medical history, and potential side effects?

Doxepin: Dosing and Clinical Use

Primary Indication and Dosing

For insomnia characterized by sleep maintenance difficulties, use low-dose doxepin at 3-6 mg at bedtime, which provides selective H1 receptor antagonism without the anticholinergic and cardiovascular side effects seen at antidepressant doses. 1

Insomnia Treatment

• Low-dose doxepin (3 mg and 6 mg) is recommended specifically for sleep maintenance insomnia in adults, with the American Academy of Sleep Medicine suggesting its use based on trials demonstrating benefits outweigh harms 1
• The 2017 American Academy of Sleep Medicine guideline provides a weak recommendation for doxepin at these low doses, noting very low quality evidence but favorable benefit-to-harm ratio 1
• Controlled-release melatonin and doxepin are recommended as first-line agents in older adults with insomnia, with z-drugs reserved for second-line use 2
• For the general population with difficulty staying asleep, low-dose doxepin should be considered as a first-line option 2

Depression and Anxiety Treatment

For depression and anxiety disorders, the standard antidepressant dosing of doxepin is 75-150 mg/day for mild to moderate illness, with a starting dose of 75 mg daily. 3

• Dosage may be increased or decreased at appropriate intervals according to individual response, with the usual optimum range being 75-150 mg/day 3
• In more severely ill patients, higher doses may be required with gradual increase to 300 mg/day if necessary, though additional therapeutic effect is rarely obtained by exceeding 300 mg/day 3
• In patients with very mild symptomatology or emotional symptoms accompanying organic disease, doses as low as 25-50 mg/day may suffice 3
• The total daily dosage may be given on a divided or once-daily schedule; if once-daily dosing is employed, the maximum recommended dose is 150 mg/day given at bedtime 3
• Anti-anxiety effect is apparent before the antidepressant effect, with optimal antidepressant effect not evident for 2-3 weeks 3

Age-Specific Considerations

Elderly Patients

Elderly patients should be started on low doses of doxepin and observed closely due to increased risk of confusion and oversedation. 3

• Dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function 3
• The extent of renal excretion of doxepin has not been determined, but because elderly patients are more likely to have decreased renal function, care should be taken in dose selection 3
• Sedating drugs may cause confusion and oversedation in the elderly 3

Pediatric Patients

• Doxepin is not approved for use in pediatric patients 3

Critical Safety Considerations

Cardiovascular Effects

• Doxepin at doses up to 50 mg does not increase QTc intervals, as demonstrated in a thorough QT study, suggesting therapy for insomnia is unlikely to cause cardiac repolarization abnormalities 4
• Cardiovascular effects including hypotension, hypertension, and tachycardia have been reported occasionally at antidepressant doses 3

Anticholinergic Effects

• At antidepressant doses (≥75 mg), anticholinergic effects are common: dry mouth, blurred vision, constipation, and urinary retention 3
• If anticholinergic effects do not subside with continued therapy or become severe, dosage reduction may be necessary 3
• Low-dose doxepin (3-6 mg) for insomnia minimizes anticholinergic effects due to selective H1 antagonism at these doses 5, 6

Central Nervous System Effects

• Drowsiness is the most commonly noticed side effect, which tends to disappear as therapy is continued 3
• Other infrequently reported CNS side effects include confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia, and tremor 3
• Low-dose doxepin (1-6 mg) showed minimal psychomotor impairment, residual sedation, or rebound insomnia in trials up to 3 months duration 5

Suicidality Risk

Antidepressants, including doxepin, increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies. 3

• Anyone considering the use of doxepin in a child, adolescent, or young adult must balance this risk with clinical need 3
• Short-term studies did not show an increase in suicidality risk with antidepressants compared to placebo in adults beyond age 24 3
• There was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older 3
• Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior 3

Withdrawal Symptoms

• The possibility of withdrawal symptoms upon abrupt cessation after prolonged doxepin administration should be considered 3
• These symptoms are not indicative of addiction, and gradual withdrawal of medication should not cause these symptoms 3

Overdose Risk

• Deaths may occur from overdosage with tricyclic antidepressants like doxepin 3
• Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma 3
• Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity 3
• Hospital monitoring is required as soon as possible after suspected overdose, with minimum six hours of observation with cardiac monitoring 3

Clinical Context and Limitations

Insomnia in Depression

Low-dose doxepin does not appear effective for insomnia in patients with major depressive disorder (MDD), contrasting with its efficacy in primary insomnia. 7

• A retrospective case series of 17 inpatients with MDD and comorbid insomnia showed no improvement in sleep onset or maintenance during 4 weeks of low-dose doxepin (<25 mg/day) treatment 7
• This suggests that low-dose doxepin should be reserved for primary insomnia rather than insomnia comorbid with depression 7
• For depression with insomnia, standard antidepressant doses (75-150 mg/day) are more appropriate 3

Alternative Positioning in Guidelines

• The 2008 American Academy of Sleep Medicine guideline positioned sedating low-dose antidepressants (including doxepin) as third-line options after benzodiazepine receptor agonists and benzodiazepines, noting relatively weak evidence for efficacy 1
• However, the 2017 guideline elevated low-dose doxepin (3-6 mg) to a recommended option specifically for sleep maintenance insomnia, reflecting newer evidence at these selective H1-antagonist doses 1

Common Pitfalls to Avoid

• Do not use antidepressant doses (≥75 mg) for primary insomnia, as this exposes patients to unnecessary anticholinergic and cardiovascular side effects without additional sleep benefit 3, 5
• Do not assume low-dose doxepin will be effective for insomnia in patients with active major depression—these patients require standard antidepressant dosing or alternative approaches 7
• Do not abruptly discontinue doxepin after prolonged use—taper gradually to avoid withdrawal symptoms 3
• Do not overlook the need for close monitoring in elderly patients, who are at higher risk for confusion and oversedation even at low doses 3
• Do not prescribe doxepin to pediatric patients, as it is not approved for this population 3