What are the potential complications of Trazodone (triazolopyridine antidepressant)?

Trazodone Complications

Trazodone carries significant risks including priapism, orthostatic hypotension, cardiac arrhythmias, and excessive sedation, with the FDA specifically warning about these complications particularly in elderly patients. 1

Cardiovascular Complications

Cardiac arrhythmias and QT prolongation are serious concerns with trazodone use:

• QT interval prolongation and torsade de pointes have been reported even at doses ≤100 mg/day 1
• Ventricular tachycardia, atrial fibrillation, and cardiac arrest have occurred in post-marketing surveillance 1
• Conduction blocks and myocardial infarction are documented complications 1

Orthostatic hypotension and syncope occur frequently:

• The FDA labels this as a significant warning, particularly problematic in elderly patients or those with pre-existing heart disease 1, 2
• Can lead to falls and subsequent injuries, especially in older adults 3
• The American Academy of Sleep Medicine specifically notes this risk when discussing trazodone's use as a hypnotic 3

Priapism

Priapism is a urologic emergency associated with trazodone:

• Painful erections lasting >6 hours require immediate discontinuation and emergency treatment 1
• If untreated, priapism causes irreversible erectile tissue damage 1
• Men with erections lasting >4 hours (painful or not) must seek immediate medical attention 1
• Approximately 7% of patients discontinued trazodone due to priapism in one veteran study 3
• Higher risk in patients with sickle cell anemia, multiple myeloma, leukemia, or anatomical penile deformities 1

Central Nervous System Effects

Excessive sedation and cognitive impairment are the most common complications:

• Somnolence/sedation occurs at higher rates than other second-generation antidepressants (bupropion, fluoxetine, mirtazapine, paroxetine, venlafaxine) 4, 2
• Impairs mental and physical abilities required for operating machinery or driving 1
• 60% of patients in clinical studies experienced daytime sedation, with 19% discontinuing therapy due to intolerable sedation 3, 4

Extrapyramidal symptoms can occur, particularly in elderly patients:

• Parkinsonism (tremors, rigidity, shuffling gait) has been reported even at low doses 5, 6
• Risk increases with drug interactions (e.g., amiodarone inhibiting trazodone metabolism) 5
• Symptoms typically resolve within one week of discontinuation 5

Bleeding Risk

Increased bleeding events occur with trazodone:

• The FDA warns that serotonin reuptake inhibition increases bleeding risk 1
• Risk amplified when combined with NSAIDs, aspirin, antiplatelet agents, or anticoagulants 1
• Bleeding ranges from ecchymosis and epistaxis to life-threatening hemorrhages 1
• Warfarin patients require careful monitoring of coagulation indices 1

Psychiatric Complications

Activation of mania/hypomania in bipolar patients:

• Treating depression with trazodone may precipitate mixed or manic episodes 1
• Screen all patients for personal or family history of bipolar disorder before initiating therapy 1

Suicidal ideation remains a concern:

• FDA black box warning for increased suicidal thoughts in children, adolescents, and young adults 1
• Risk cannot be excluded even when used as a hypnotic at low doses 3

Metabolic and Hematologic Complications

Hyponatremia can develop:

• Serum sodium levels <110 mmol/L have been reported 1
• May result from syndrome of inappropriate antidiuretic hormone secretion (SIADH) 1
• Elderly patients, those on diuretics, and volume-depleted patients are at highest risk 1
• Symptoms include headache, confusion, weakness, unsteadiness leading to falls, and in severe cases: seizures, coma, respiratory arrest, and death 1

Hematologic effects include hemolytic anemia and leukocytosis 1

Discontinuation Syndrome

Abrupt cessation causes withdrawal symptoms:

• Nausea, sweating, dysphoric mood, irritability, agitation, dizziness, paresthesias (electric shock sensations), tremor, anxiety, confusion, headache, insomnia, and seizures 1
• Gradual dose reduction is mandatory when discontinuing 1

Overdose Complications

Overdose can be fatal, particularly when combined with other CNS depressants:

• Deaths reported with concurrent alcohol, benzodiazepines, or barbiturates 1
• Most severe reactions: priapism, respiratory arrest, seizures, ECG changes including QT prolongation 1
• Most frequent reactions: drowsiness and vomiting 1

Clinical Context: Why Trazodone Is Not Recommended

The 2020 VA/DoD guidelines advise against trazodone for chronic insomnia because low-quality efficacy evidence is outweighed by its adverse effect profile 3. The American Academy of Sleep Medicine notes trazodone is "widely used off-label as a hypnotic, despite virtually no evidence-based data to support its efficacy with older adults" and emphasizes its "significant risks" 3.

Common pitfall: Prescribing trazodone as a "safe" sleep aid in elderly patients without considering fall risk from orthostatic hypotension, cognitive impairment from sedation, and drug-drug interactions that increase toxicity 3, 5.