What is doxepin (tricyclic antidepressant) used for and how is it prescribed, particularly in patients with a history of cardiovascular disease, glaucoma, or urinary retention?

Doxepin: Clinical Overview

Doxepin is a tricyclic antidepressant with dual clinical applications: higher doses (75-300 mg/day) for depression and anxiety disorders, and low doses (1-6 mg) for insomnia through selective H1-receptor antagonism. 1

Primary Indications

Depression and Anxiety (Higher Doses)

• Approved for psychoneurotic patients with depression and/or anxiety, depression associated with alcoholism (not taken concomitantly with alcohol), depression with organic disease, and psychotic depressive disorders including involutional depression and manic-depressive disorders 1
• Target symptoms that respond particularly well include anxiety, tension, depression, somatic symptoms, sleep disturbances, guilt, lack of energy, fear, apprehension, and worry 1
• The anti-anxiety effect appears before the antidepressant effect, with optimal antidepressant response taking 2-3 weeks 1

Insomnia (Low Doses)

• Low-dose doxepin (1-6 mg) acts as a selective H1 antagonist for chronic primary insomnia, with preferential effects on sleep maintenance rather than sleep initiation 2, 3
• Phase II and III studies demonstrate efficacy on sleep onset, maintenance, and early awakening outcomes with minimal effects on sleep architecture 3
• No evidence of tolerance, psychomotor impairment, residual sedation, rebound insomnia, or discontinuation symptoms in trials up to 3 months 3

Dosing Guidelines

For Depression/Anxiety

• Starting dose: 75 mg/day for mild to moderate illness 1
• Usual optimum range: 75-150 mg/day 1
• Severely ill patients may require up to 300 mg/day; additional therapeutic effect is rarely obtained beyond this dose 1
• Very mild symptomatology: 25-50 mg/day may suffice 1
• Maximum once-daily dose: 150 mg at bedtime (the 150 mg capsule is for maintenance only, not treatment initiation) 1

For Insomnia

• Low doses of 1-6 mg are used, though this represents off-label use at these doses 2, 3

Critical Contraindications

Doxepin is absolutely contraindicated in patients with glaucoma or urinary retention, which must be ruled out particularly in older patients 1

Additional contraindications include:

• Hypersensitivity to doxepin (consider cross-sensitivity with other dibenzoxepines) 1
• Concomitant use with MAO inhibitors or within 14 days of discontinuing MAO inhibitors 1
• Angle-closure glaucoma risk: pupillary dilation may trigger an attack in patients with anatomically narrow angles without patent iridectomy 1

Cardiovascular Considerations

The Doxepin "Safety Myth"

Despite widespread clinical belief that doxepin is the safest tricyclic for cardiovascular patients, rigorous prospective evaluation demonstrates comparable cardiovascular effects to imipramine and nortriptyline, with no greater margin of safety 4

In a study of 32 depressed patients with preexisting left ventricular impairment, ventricular arrhythmias, and/or conduction disease, doxepin:

• Did not robustly affect heart rate 4
• Did not adversely affect left ventricular function 4
• Had significant antiarrhythmic effects 4
• Slowed cardiac conduction 4
• Caused significant orthostatic hypotension 4
• Led to 16% dropout due to cardiovascular side effects, with 41% overall dropout rate 4

Safer Alternatives for Cardiovascular Patients

The American Heart Association recommends sertraline as the preferred agent in cardiovascular disease patients due to minimal cardiovascular toxicity and lower QTc prolongation risk 5, 6

Mirtazapine is considered a safer alternative to tricyclics with demonstrated cardiovascular safety and additional benefits like appetite stimulation 5, 6

High-Risk Populations

Elderly Patients

• Start on low doses and observe closely, as sedating drugs cause confusion and oversedation in the elderly 1
• Dose selection should be cautious, starting at the low end of the dosing range due to greater frequency of decreased hepatic, renal, or cardiac function 1
• Once-daily dosing in geriatric patients must be adjusted carefully based on the patient's condition 1
• Despite concerns, doxepin has been shown to be safe and well tolerated in elderly patients in clinical experience 1, 7

Patients with Cardiovascular Disease

Avoid doxepin in patients with known QT prolongation, recent MI, or those taking other QT-prolonging medications 5

• Tricyclic antidepressants have significant cardiovascular toxicity including QTc prolongation, orthostatic hypotension, and arrhythmogenic potential, particularly dangerous in elderly patients with structural heart disease 8
• At clinical dosages up to 150 mg/day, doxepin can be given concomitantly with guanethidine without blocking antihypertensive effect; above 150 mg/day, blocking has been reported 1

Patients with Glaucoma or Urinary Retention

These are absolute contraindications and must be ruled out before initiating therapy 1

Critical Drug Interactions

MAO Inhibitors

• Absolute contraindication: serious side effects and death have occurred when similar tricyclics were used concomitantly 1
• The exact washout period varies depending on the specific MAO inhibitor, duration of administration, and dosage 1

Cimetidine

• Produces clinically significant fluctuations in steady-state serum concentrations of tricyclics 1
• Serious anticholinergic symptoms (severe dry mouth, urinary retention, blurred vision) occur with elevated serum levels when cimetidine is initiated 1
• Discontinuation of cimetidine in well-controlled patients decreases tricyclic levels and compromises therapeutic effects 1

Alcohol

• Alcohol ingestion increases the danger of intentional or unintentional doxepin overdose, especially important in patients who use alcohol excessively 1
• Patients should be cautioned that their response to alcohol may be potentiated 1

Antihypertensives and Diuretics

Do not combine doxepin with antihypertensives or diuretics without careful monitoring, as this increases fall risk and hypotension severity 5, 6

Tolazamide

• A case of severe hypoglycemia occurred in a type II diabetic patient on tolazamide 11 days after adding doxepin 75 mg/day 1

Adverse Effects Profile

Most Common

• Drowsiness is the most commonly noticed side effect, which tends to disappear with continued therapy 1
• Dry mouth, blurred vision, constipation, and urinary retention (anticholinergic effects) 1
• If anticholinergic effects do not subside with continued therapy or become severe, dosage reduction may be necessary 1

Cardiovascular

• Hypotension, hypertension, and tachycardia reported occasionally 1
• Orthostatic hypotension is a significant concern, particularly in elderly patients and those with cardiovascular disease 7, 4

Central Nervous System

• Confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia, and tremor reported infrequently 1

Other Notable Effects

• Allergic reactions: skin rash, edema, photosensitization, pruritus 1
• Hematologic: eosinophilia, occasional bone marrow depression (agranulocytosis, leukopenia, thrombocytopenia, purpura) 1
• Gastrointestinal: nausea, vomiting, indigestion, taste disturbances, diarrhea, anorexia 1
• Endocrine: altered libido, testicular swelling, gynecomastia, breast enlargement, galactorrhea, blood sugar changes, SIADH 1

Suicide Risk and Monitoring

All patients on antidepressants must be monitored closely for clinical worsening, suicidality, and unusual behavioral changes, especially during initial months of therapy or dose changes 1

Age-Specific Suicide Risk

• Ages <18: 14 additional cases per 1,000 patients treated compared to placebo 1
• Ages 18-24: 5 additional cases per 1,000 patients 1
• Ages 25-64: 1 fewer case per 1,000 patients 1
• Ages ≥65: 6 fewer cases per 1,000 patients 1

Warning Signs to Monitor

• Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania 1
• Families and caregivers must be instructed to monitor daily and report symptoms immediately 1
• Prescriptions should be written for the smallest feasible amount to reduce overdose risk 1

Bipolar Disorder Screening

Prior to initiating doxepin, patients with depressive symptoms must be adequately screened for bipolar disorder risk through detailed psychiatric history, including family history of suicide, bipolar disorder, and depression 1

• Treating a major depressive episode with an antidepressant alone may precipitate a mixed/manic episode in at-risk patients 1
• Doxepin is not approved for bipolar depression 1

Pregnancy and Lactation

• Reproduction studies in rats, rabbits, monkeys, and dogs showed no evidence of harm to animal fetus, but relevance to humans is unknown 1
• Safety in pregnancy has not been established due to lack of experience in pregnant women 1
• A report exists of apnea and drowsiness in a nursing infant whose mother was taking doxepin 1

Pediatric Use

Doxepin is not recommended for children under 12 years of age due to lack of established safe conditions for use 1

• Safety and effectiveness in the pediatric population have not been established 1
• Anyone considering use in a child or adolescent must balance potential risks (including increased suicidality risk) with clinical need 1

Withdrawal and Discontinuation

Abrupt cessation after prolonged administration may cause withdrawal symptoms, which are not indicative of addiction 1

• Gradual withdrawal of medication prevents these symptoms 1

Overdose Considerations

Deaths may occur from overdose with tricyclic antidepressants 1

• Doxepin has intrinsic cardiotoxicity on overdosage similar to other tricyclics, despite causing fewer cardiovascular side effects at therapeutic doses 7

Long-Term Use

• A 15-year prospective study demonstrated that long-term doxepin use (5-15 years) is feasible, efficacious, and safe for chronic depression 9
• Advantages include lack of adverse interactions with prescription and non-prescription drugs and high degree of safety in patients with concomitant cardiovascular and other physical disorders 9
• For patients who have had 2 or more episodes of depression, longer duration of therapy may be beneficial 10

Clinical Pearls

• Doxepin combines antidepressant activity with sedative effects, resembling amitriptyline in clinical profile 7
• The mood-elevating effect is similar to amitriptyline but probably less marked than imipramine, and may be slower to take effect 7
• At dosages achieving similar overall response rates, doxepin causes fewer or less troublesome side-effects than imipramine, amitriptyline, or amitriptyline-perphenazine 7
• More marked sedative properties make it more useful than imipramine in depressed patients with sleep disturbances and depression associated with anxiety 7
• When anxiety is accompanied by significant depression, doxepin is more effective than chlordiazepoxide or diazepam 7