What are the guidelines for prescribing Doxepin (tricyclic antidepressant) for adults with depression, anxiety, or insomnia, considering their medical history and potential side effects?

Doxepin for Depression, Anxiety, and Insomnia

Primary Indication: Sleep Maintenance Insomnia

Low-dose doxepin (3-6 mg) is specifically recommended for sleep maintenance insomnia in adults, NOT for depression or anxiety at these doses. 1, 2

Evidence-Based Dosing

• Use only 3-6 mg doses for insomnia - these doses provide selective H1-receptor antagonism for sleep without the broader tricyclic antidepressant effects and adverse effects seen at higher doses 2
• Do NOT use 20 mg or higher doses for insomnia - higher doses shift from selective histamine blockade to full tricyclic effects with significantly increased anticholinergic burden, cardiovascular risks, and adverse effects 2, 3
• Total sleep time improves by 26-32 minutes compared to placebo (95% CI: 18-40 minutes) 1, 2
• Wake after sleep onset reduces by 22-23 minutes compared to placebo (95% CI: 14-30 minutes) 1, 2
• Sleep quality shows small-to-moderate improvement 1, 2

Critical Prescribing Algorithm

Step 1: Verify the indication

• Low-dose doxepin (3-6 mg) is ONLY for sleep maintenance insomnia (difficulty staying asleep, not falling asleep) 1, 2
• For depression or anxiety, standard antidepressant doses (75-300 mg) would be required, which is a completely different clinical scenario 3

Step 2: Implement Cognitive Behavioral Therapy for Insomnia (CBT-I) first

• CBT-I must be offered as initial treatment before or alongside any pharmacotherapy 1, 2
• Pharmacotherapy should supplement, not replace, behavioral interventions 1, 4

Step 3: Screen for contraindications

• Absolute contraindications: hypersensitivity to doxepin, glaucoma, urinary retention 3
• Relative contraindications: anatomically narrow angles without patent iridectomy (risk of angle-closure glaucoma), compromised respiratory function, hepatic or heart failure 3
• Screen for bipolar disorder risk before initiating - antidepressants may precipitate manic episodes 3

Step 4: Assess medical history for dose adjustments

• Elderly patients: start with 3 mg dose due to increased sensitivity, higher fall risk, and likely decreased renal function 3
• Hepatic impairment: requires dose reduction 5
• Renal impairment: use with caution, though extent of renal excretion is not fully determined 3

Step 5: Evaluate for drug interactions

• Avoid combining with: other CNS depressants (increases respiratory depression, cognitive impairment, fall risk), MAO inhibitors, anticholinergic agents 5, 3
• Caution with: guanethidine (doses >150 mg may block antihypertensive effect, though low doses for insomnia unlikely to cause this) 3

Safety Profile and Adverse Effects

Common adverse effects (generally mild at low doses):

• Somnolence (particularly at 6 mg dose) - most common side effect 1, 3
• Headache 1, 3
• Adverse event rates comparable to placebo at 3-6 mg doses 2, 6

Serious adverse effects to monitor (rare at low doses but possible):

• Anticholinergic effects: dry mouth, blurred vision, constipation, urinary retention 3
• CNS effects: confusion, disorientation, hallucinations (more common at higher doses) 3
• Cardiovascular: hypotension, hypertension, tachycardia 3
• Hematologic: agranulocytosis, leukopenia, thrombocytopenia (rare) 3
• Withdrawal symptoms upon abrupt cessation after prolonged use 3

Special Population Considerations

Pediatric patients:

• NOT recommended for children under 12 years - no FDA approval, limited safety data, and no clinical practice guidelines supporting pediatric use 2, 3

Elderly patients (≥65 years):

• Start with 3 mg dose maximum 2, 3
• Higher risk of confusion, oversedation, falls, and cognitive impairment 3
• Monitor closely for next-day residual effects 2

Pregnancy and lactation:

• Safety not established in pregnancy despite animal studies showing no harm 3
• Apnea and drowsiness reported in nursing infant whose mother was taking doxepin - use with extreme caution 3

Patients with sleep apnea:

• Low-dose doxepin (3-6 mg) can be considered with appropriate OSA treatment (CPAP/mandibular advancement device) in place 2
• Substantially safer than benzodiazepines (which are contraindicated) or quetiapine (which has caused acute respiratory failure in OSA) 2
• Monitor for worsening daytime sleepiness or morning headaches indicating nocturnal hypoxemia 2

Suicide Risk and Psychiatric Monitoring

Black Box Warning - Suicidality in Young Adults:

• Increased risk of suicidal thinking/behavior in children, adolescents, and young adults (ages 18-24) with major depressive disorder 3
• Risk decreases in adults >24 years and is reduced in adults ≥65 years 3
• Monitor closely for: clinical worsening, suicidality, unusual behavior changes, agitation, panic attacks, insomnia worsening, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania 3
• Families/caregivers must be educated to observe daily and report symptoms immediately 3

Treatment Duration and Discontinuation

• Prescribe smallest quantity consistent with good management to reduce overdose risk 3
• Regular follow-up required to assess effectiveness, side effects, and ongoing need 1, 2
• Use lowest effective maintenance dose 4
• Taper gradually when discontinuing to avoid withdrawal symptoms (not indicative of addiction but can occur) 3
• Anti-anxiety effects appear before antidepressant effects; optimal antidepressant effect may take 2-3 weeks (though this applies to higher antidepressant doses, not low-dose insomnia treatment) 3

Alternative First-Line Options for Insomnia

For sleep maintenance insomnia specifically:

• Eszopiclone 2-3 mg: TST improvement 28-57 minutes, moderate-to-large sleep quality improvement 1, 2
• Temazepam 15 mg: TST improvement 99 minutes (though limited WASO data) 1, 2
• Suvorexant 10-20 mg: WASO reduction 16-28 minutes 1, 2
• Zolpidem 10 mg (5 mg in elderly): TST improvement 29 minutes, WASO reduction 25 minutes 1, 2

NOT recommended alternatives:

• Trazodone: explicitly recommended AGAINST by American Academy of Sleep Medicine - harms outweigh benefits 5, 4
• Over-the-counter antihistamines: lack efficacy data, cause daytime sedation and delirium risk in elderly 4
• Herbal supplements/melatonin: insufficient evidence 4

Common Prescribing Pitfalls to Avoid

• Using antidepressant doses (75-300 mg) for insomnia - this introduces unnecessary anticholinergic, cardiovascular, and CNS risks without additional sleep benefit 2, 3
• Prescribing for sleep onset insomnia - doxepin is specifically for sleep maintenance, not initiation 1, 2
• Failing to implement CBT-I alongside medication - behavioral interventions provide superior long-term outcomes 1, 4
• Using in pediatric populations - no evidence base and not recommended 2, 3
• Combining with multiple CNS depressants - significantly increases fall risk, respiratory depression, and cognitive impairment 5, 4
• Continuing long-term without reassessment - periodic evaluation essential 1, 4

Overdose Management

Critical manifestations: cardiac dysrhythmias, severe hypotension, convulsions, CNS depression/coma, QRS widening on ECG 3

Immediate management:

• Obtain ECG and initiate cardiac monitoring immediately 3
• Protect airway, establish IV line, initiate gastric decontamination 3
• Large volume gastric lavage followed by activated charcoal (emesis contraindicated) 3
• Minimum 6 hours observation with cardiac monitoring; extend if any toxicity signs 3
• Intravenous sodium bicarbonate to maintain serum pH 7.45-7.55 for QRS ≥0.10 seconds 3
• Deaths have been reported with doxepin overdose 3