Introduction
Doxepin is a tricyclic antidepressant (TCA) that has been used clinically since the 1960s. It possesses both antidepressant and anxiolytic properties and is FDA-approved for the treatment of depression and anxiety. More recently, lower-dose formulations have been approved for the treatment of insomnia characterized by difficulties with sleep maintenance. Doxepin is unique among TCAs due to its potent histamine H1 receptor antagonism, which contributes to its sedative properties.
Mechanism of Action
Doxepin primarily exerts its therapeutic effects through inhibition of the reuptake of serotonin and norepinephrine in the central nervous system. Its antidepressant activity is attributed to these monoamine reuptake inhibition properties. For insomnia treatment at lower doses (3-6 mg), doxepin acts predominantly as a potent histamine H1 receptor antagonist, promoting sleep maintenance without significantly affecting other neurotransmitter systems. The drug also has moderate anticholinergic and anti-α1-adrenergic activity, which contributes to both its therapeutic effects and side effect profile.
Indications
FDA-approved indications:
- Major depressive disorder
- Anxiety associated with depressive disorders
- Insomnia characterized by difficulties with sleep maintenance (low-dose formulation)
Off-label uses may include:
- Chronic pain management (neuropathic pain)
- Pruritus (itching) due to its antihistamine properties
- Migraine prophylaxis
Dosage and Administration
Depression/Anxiety:- Initial dose: 25-50 mg orally once daily or in divided doses
- May increase gradually to 300 mg/day maximum
- Maintenance dose: 75-150 mg/day
- 3 mg orally 30 minutes before bedtime
- May increase to 6 mg if clinically indicated
- Maximum dose: 6 mg daily
- Geriatric patients: Lower initial doses recommended (10-25 mg/day for depression)
- Hepatic impairment: Dose reduction required
- Renal impairment: Use with caution; consider dose reduction
Pharmacokinetics
- Absorption: Well absorbed from GI tract; extensive first-pass metabolism
- Distribution: Highly lipophilic; widely distributed throughout tissues and CNS
- Protein binding: 68-86% bound to plasma proteins
- Metabolism: Extensive hepatic metabolism via CYP2C19 and CYP2D6 to active metabolite (desmethyldoxepin)
- Elimination: Half-life: 8-24 hours; excreted primarily in urine as metabolites
- Time to peak concentration: 2-4 hours
Contraindications
- Hypersensitivity to doxepin or other TCAs
- Glaucoma (narrow-angle)
- Urinary retention
- Use with or within 14 days of MAO inhibitors
- Acute recovery phase following myocardial infarction
Warnings and Precautions
- Suicidal ideation: Monitor for worsening depression or emergent suicidality
- Sedation: May impair mental/physical abilities required for hazardous tasks
- QT prolongation: May increase risk of cardiac arrhythmias
- Seizures: May lower seizure threshold
- Elderly patients: Increased risk of falls, cognitive impairment, and anticholinergic effects
- Discontinuation syndrome: Taper gradually to avoid withdrawal symptoms
- Bone marrow suppression: Rare reports of agranulocytosis
Drug Interactions
- MAO inhibitors: Risk of serotonin syndrome (contraindicated)
- CNS depressants: Additive sedation with alcohol, benzodiazepines, opioids
- Anticholinergics: Increased anticholinergic effects
- QT-prolonging agents: Increased arrhythmia risk with other QT-prolonging drugs
- CYP2D6 inhibitors: May increase doxepin levels (e.g., fluoxetine, paroxetine)
- Sympathomimetics: Enhanced pressor effects
- Warfarin: May increase anticoagulant effect
Adverse Effects
Common (≥1%):- Sedation/drowsiness
- Dry mouth
- Constipation
- Blurred vision
- Weight gain
- Orthostatic hypotension
- QT prolongation
- Suicidal ideation
- Seizures
- Hyponatremia/SIADH
- Hepatotoxicity
- Blood dyscrasias
- Neuroleptic malignant syndrome-like reactions
Monitoring Parameters
- Mental status and mood assessment at regular intervals
- Blood pressure (sitting and standing) during dose titration
- ECG monitoring in patients with cardiac risk factors
- Liver function tests at baseline and periodically
- Complete blood count with long-term use
- Serum sodium in elderly patients
- Therapeutic drug monitoring (if available): Therapeutic range 50-150 ng/mL
Patient Education
- Take medication exactly as prescribed; do not abruptly discontinue
- Avoid alcohol and other CNS depressants
- Rise slowly from sitting/lying position to prevent dizziness
- May cause drowsiness; use caution when driving or operating machinery
- Report any thoughts of self-harm or worsening depression immediately
- Inform all healthcare providers about doxepin use before any procedures
- Use sugar-free products if dry mouth occurs
- Avoid excessive heat exposure due to reduced sweating ability
References
1. FDA Prescribing Information: Silenor (doxepin) and Sinequan (doxepin) 2. Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. Cambridge University Press; 2013. 3. Richelson E. Pharmacology of antidepressants. Mayo Clinic Proceedings. 2001;76(5):511-527. 4. Krystal AD, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30(11):1555-1561. 5. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010. 6. Lexicomp Online, Lexi-Drugs. Hudson, OH: Wolters Kluwer Health, Inc.; 2023.