What are the serious side effects of Doxepin (tricyclic antidepressant)?

Serious Side Effects of Doxepin

Doxepin can cause serious cardiovascular, neurological, and other systemic adverse effects, with cardiac toxicity being particularly concerning in patients with preexisting heart conditions or the elderly. 1

Cardiovascular Side Effects

• Doxepin can cause significant cardiovascular effects including hypotension, hypertension, and tachycardia 1
• QTc interval prolongation has been documented after 6 weeks of treatment (from 417 ± 36 to 439 ± 28 msec), which can increase the risk of dangerous arrhythmias 2
• Cardiac conduction abnormalities may occur, with QRS duration correlating with serum doxepin concentrations (r = 0.78, p < 0.0001) 2
• Orthostatic hypotension is a significant risk, particularly in elderly patients or those with cardiovascular disease 3
• Despite previous beliefs, doxepin has cardiovascular effects comparable to other tricyclic antidepressants and does not offer greater cardiac safety 4, 3

Neurological Side Effects

• Seizures may occur, especially in patients with preexisting seizure disorders 1
• Extrapyramidal symptoms, tardive dyskinesia, and tremor have been reported 1
• Confusion, disorientation, hallucinations, numbness, paresthesias, and ataxia can occur 1

Anticholinergic Effects

• Severe dry mouth, urinary retention, and blurred vision can occur, especially when combined with other medications like cimetidine 1
• Constipation, which can be severe in some cases 1
• Angle closure glaucoma is a risk, particularly in susceptible patients 1

Hematologic Effects

• Bone marrow depression manifesting as agranulocytosis, leukopenia, thrombocytopenia, and purpura have been reported 1
• Eosinophilia has been reported in some patients 1

Psychiatric Effects

• Increased risk of suicidal thinking and behavior, particularly in children, adolescents, and young adults (through age 24) 1
• Potential for triggering mania or hypomania in bipolar patients 1
• Paradoxical worsening of psychotic symptoms may occur 1

Overdose Risks

• Overdose can be fatal and is characterized by cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma 1
• Multiple drug ingestion (including alcohol) is common in deliberate overdose and increases toxicity 1
• QRS axis or width changes on ECG are clinically significant indicators of toxicity 1

Endocrine and Metabolic Effects

• Syndrome of inappropriate antidiuretic hormone secretion (SIADH) 1
• Raised or lowered blood sugar levels, with severe hypoglycemia reported when combined with tolazamide 1
• Sexual dysfunction, testicular swelling, gynecomastia in males, breast enlargement and galactorrhea in females 1

Special Populations Concerns

• Elderly patients are at higher risk for confusion and oversedation and should be started on lower doses 1
• Patients with renal or hepatic impairment require careful dosing adjustments 1
• Doxepin is contraindicated in patients taking MAO inhibitors due to risk of serotonin syndrome 1

Drug Interactions

• Potentially dangerous interactions with MAO inhibitors, requiring at least two weeks between stopping MAOIs and starting doxepin 1
• Cimetidine can significantly increase doxepin levels, leading to toxicity 1
• Alcohol potentiates the effects of doxepin and increases overdose risk 1
• Interactions with CYP2D6 inhibitors (including SSRIs) can increase doxepin plasma concentrations 1

Withdrawal Effects

• Abrupt discontinuation after prolonged use can cause withdrawal symptoms; gradual tapering is recommended 1

When prescribing doxepin, careful patient selection, appropriate dosing, and regular monitoring are essential to minimize these serious risks while achieving therapeutic benefits.