What is the appropriate use and dosage of Doxepin for an adult or geriatric patient with depression, anxiety, or sleep disorders?

Doxepin: Clinical Use and Dosing

Primary Indications and Dosing

Doxepin has two distinct clinical applications with markedly different dosing regimens: low-dose (3-6 mg) for sleep maintenance insomnia, and standard doses (75-300 mg) for depression and anxiety disorders. 1

For Depression and Anxiety (Standard Dosing)

• Starting dose: 75 mg daily for patients with mild to moderate illness 1
• Dose range: 75-150 mg daily represents the usual optimum therapeutic range 1
• Maximum dose: 300 mg daily for severely ill patients, though additional therapeutic effect beyond this is rarely obtained 1
• Low-severity cases: 25-50 mg daily may suffice for very mild symptomatology or emotional symptoms accompanying organic disease 1
• Once-daily dosing option: Maximum 150 mg at bedtime when using once-daily schedule; the 150 mg capsule is for maintenance only, not treatment initiation 1

For Insomnia (Low-Dose Formulation)

• Recommended dose: 3-6 mg for sleep maintenance insomnia 2
• Mechanism: Selective histamine H1 receptor antagonism at subnanomolar concentrations, distinct from antidepressant effects 3, 4
• Important caveat: The American Academy of Sleep Medicine recommends doxepin 3-6 mg specifically for sleep maintenance insomnia, not sleep onset 2

Critical Geriatric Considerations

Elderly patients require dose reduction and careful monitoring due to increased risk of adverse effects. 1

• Start with low doses in geriatric patients 1
• Sedating drugs cause confusion and oversedation more readily in the elderly 1
• Increased risk of falls, particularly when combined with other sedating medications 5
• Elderly patients are more likely to have decreased renal function, requiring careful dose selection 1
• Once-daily dosing in geriatric patients should be adjusted carefully based on individual condition 1

Contraindications and Major Warnings

Absolute Contraindications

• Hypersensitivity to doxepin or cross-sensitivity with other dibenzoxepines 1
• Glaucoma (angle-closure risk with pupillary dilation) 1
• Urinary retention tendency, particularly in older patients 1

Black Box Warning: Suicidality Risk

• Increased risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18-24) with major depressive disorder 1
• Risk differences by age group: 14 additional cases per 1,000 patients under age 18; 5 additional cases per 1,000 patients ages 18-24 1
• Close monitoring required during initial treatment months and dose changes 1
• Prescribe smallest quantity consistent with good management to reduce overdose risk 1

Special Populations Requiring Caution

• Pregnancy: Safety not established; apnea and drowsiness reported in nursing infant 1
• Hepatic impairment: Dose reduction required 2
• Renal impairment: Use with caution 1
• Cardiovascular disease: Monitor for hypotension, hypertension, tachycardia 1
• Respiratory compromise: Exercise caution 2

Therapeutic Timeline and Monitoring

• Anti-anxiety effect: Appears before antidepressant effect 1
• Optimal antidepressant effect: May not be evident for 2-3 weeks 1
• Minimum treatment trial: 4-8 weeks required for full therapeutic assessment 5
• Reassessment: After 9 months, consider dose reduction to reassess need for continued medication 5
• Discontinuation: Taper over 10-14 days to limit withdrawal symptoms 5

Common Adverse Effects

Most Frequent (by system)

• CNS: Drowsiness (most common), confusion, disorientation, dizziness 1
• Anticholinergic: Dry mouth, blurred vision, constipation, urinary retention 1
• Cardiovascular: Hypotension, hypertension, tachycardia (occasional) 1
• Other: Weight gain, sweating, headache 1

Serious but Rare

• Bone marrow depression (agranulocytosis, leukopenia, thrombocytopenia) 1
• Seizures, tardive dyskinesia, extrapyramidal symptoms 1
• Syndrome of inappropriate antidiuretic hormone secretion 1
• Angle-closure glaucoma in susceptible individuals 1

Critical Drug Interactions

High-Risk Combinations

Opioids (e.g., hydrocodone) with doxepin carry FDA black box warning for respiratory depression and death. 2

• Both cause additive CNS depression 2
• Use lowest effective doses with close monitoring for respiratory depression 2
• Educate patients on warning signs: slow breathing, extreme drowsiness, difficulty waking 2
• Consider prescribing naloxone for high-risk patients 2

Benzodiazepines combined with doxepin increase oversedation and respiratory depression risk. 2

• Particularly dangerous when combined with olanzapine (fatalities reported) 5
• Monitor for additive sedation 2

Other Significant Interactions

• Cytochrome P450 2D6 poor metabolizers: 8-fold increase in plasma concentrations possible 1
• Guanethidine: Doses above 150 mg daily may block antihypertensive effect 1
• Alcohol: Contraindicated for concomitant use 1

Comparative Position in Treatment Algorithms

For Insomnia

Doxepin 3-6 mg is a second-line agent specifically for sleep maintenance insomnia, not first-line. 2

First-line treatment:

• Cognitive behavioral therapy for insomnia (CBT-I) 2

Second-line pharmacologic options (preferred over doxepin for most cases):

• Eszopiclone 2-3 mg, zolpidem 10 mg, or temazepam 15 mg for sleep onset and maintenance 2
• Suvorexant for sleep maintenance 2
• Zaleplon 10 mg, ramelteon 8 mg for sleep onset only 2

Third-line (doxepin's position):

• Consider after benzodiazepine receptor agonists and ramelteon have failed 2
• More appropriate when comorbid depression or anxiety present 2

Important Limitation for Depression with Insomnia

Low doses used for insomnia (3-6 mg or even 12.5 mg) are inadequate for treating major depression. 2

• Antidepressant doses start at 75 mg daily 1
• If treating both depression and insomnia, use full antidepressant dose (75-150 mg) rather than adding low-dose doxepin 2

Evidence Against Trazodone (Common Alternative)

The American Academy of Sleep Medicine recommends against trazodone for insomnia. 2

• Trazodone 50 mg showed modest improvements but no subjective sleep quality improvement 2
• Benefits do not outweigh potential harms 2
• Doxepin 3-6 mg is preferred over trazodone for sleep maintenance insomnia 2

Overdose Management

Deaths have been reported from doxepin overdose; hospital monitoring required immediately. 1

Critical Manifestations

• Cardiac dysrhythmias, severe hypotension, convulsions, CNS depression including coma 1
• QRS duration ≥0.10 seconds on ECG is best indicator of overdose severity 1

Management Protocol

• Obtain ECG and initiate cardiac monitoring immediately 1
• Protect airway, establish IV line, initiate gastric decontamination 1
• Minimum 6 hours observation with cardiac monitoring 1
• Large volume gastric lavage followed by activated charcoal (emesis contraindicated) 1
• Sodium bicarbonate IV to maintain serum pH 7.45-7.55 for cardiac toxicity 1
• Extended monitoring if any signs of toxicity occur 1

Key Clinical Pitfalls to Avoid

• Never use low-dose doxepin (3-6 mg) to treat depression—it is subtherapeutic 2, 1
• Never combine with opioids without compelling indication and intensive monitoring 2
• Never use as first-line for primary insomnia—CBT-I and FDA-approved hypnotics come first 2
• Never assume tolerance to one sedating medication confers safety when adding doxepin 2
• Never prescribe without screening for bipolar disorder in depressed patients 1
• Never use in children under 12 years—safety not established 1