What are the potential side effects of Trazodone (triazolopyridine antidepressant) in older adults or patients with a history of falls, gastrointestinal issues, or bleeding disorders?

Trazodone Side Effects

Trazodone carries significant risks in older adults, particularly orthostatic hypotension leading to falls, excessive sedation, cardiac arrhythmias including QT prolongation, priapism, and increased bleeding risk when combined with anticoagulants or antiplatelet agents. 1, 2

Cardiovascular Complications

Orthostatic Hypotension and Falls

• Orthostatic hypotension and syncope are among the most clinically significant side effects, particularly problematic in elderly patients or those with pre-existing heart disease, resulting in falls and subsequent injuries 1, 2
• The American Academy of Sleep Medicine specifically highlights that these cardiovascular effects can lead to serious fall-related injuries in older adults 1
• Concomitant use with antihypertensive medications may require dose reduction of the antihypertensive agent 2

Cardiac Arrhythmias

• Trazodone prolongs the QT/QTc interval and can cause cardiac arrhythmias including torsade de pointes, even at doses of 100 mg or less 2
• The drug is arrhythmogenic in patients with preexisting cardiac disease, with identified arrhythmias including isolated PVCs, ventricular couplets, and tachycardia with syncope 2
• Avoid trazodone in patients with known QT prolongation, history of cardiac arrhythmias, symptomatic bradycardia, hypokalemia, hypomagnesemia, or during the initial recovery phase of myocardial infarction 2
• Do not combine with CYP3A4 inhibitors (itraconazole, clarithromycin, voriconazole) or other QT-prolonging drugs (Class 1A/3 antiarrhythmics, certain antipsychotics, certain antibiotics) 2

Central Nervous System Effects

Sedation and Cognitive Impairment

• Approximately 60% of patients experience daytime sedation, with 19% discontinuing therapy due to intolerable sedation 1
• Trazodone causes somnolence and impairs mental and physical abilities required for operating hazardous machinery 2
• Patients should avoid driving or operating heavy machinery until they know how the drug affects them 2
• Do not combine with alcohol or other CNS depressants without medical supervision 2

Parkinsonism (Rare but Serious)

• Case reports document trazodone-induced parkinsonism presenting with coarse tremors, cogwheel rigidity, shuffling gait, and falls 3
• Symptoms resolved within one week of discontinuation 3
• Risk may be amplified by drug interactions (e.g., amiodarone hindering trazodone metabolism) and polypharmacy in older adults 3

Bleeding Risk

Gastrointestinal and Other Hemorrhage

• Trazodone increases bleeding risk, ranging from ecchymosis and epistaxis to life-threatening hemorrhages 2
• The European Society of Cardiology recommends avoiding combination of drugs that interfere with serotonin reuptake (including trazodone) with anticoagulants, NSAIDs, SSRIs, or SNRIs due to significantly increased hemorrhagic complications 4
• For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing trazodone 2
• Concomitant use with aspirin, NSAIDs, other antiplatelet drugs, or anticoagulants substantially increases bleeding risk 2

Urologic Emergency

Priapism

• Cases of priapism (painful erections >6 hours) have been reported and can result in irreversible erectile tissue damage if not treated promptly 2
• Approximately 7% of patients discontinued trazodone due to priapism in one veteran study 1
• Men with erections lasting >4 hours (painful or not) should immediately discontinue trazodone and seek emergency medical attention 2
• Use with extreme caution in men with conditions predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia) or anatomical penile deformation 2

Metabolic and Electrolyte Disturbances

Hyponatremia and SIADH

• Hyponatremia may occur, with cases reported of serum sodium <110 mmol/L 2
• Often results from syndrome of inappropriate antidiuretic hormone secretion (SIADH) 2
• Symptoms include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness leading to falls 2
• Severe cases can present with hallucinations, syncope, seizures, coma, respiratory arrest, and death 2
• Elderly patients, those taking diuretics, and volume-depleted patients are at greatest risk 2
• Discontinue trazodone in patients with symptomatic hyponatremia 2

Psychiatric Complications

Suicidal Ideation and Behavior

• FDA black box warning for increased suicidal thoughts in children, adolescents, and young adults 1
• This risk cannot be excluded even when trazodone is used as a hypnotic at low doses 1
• Monitor all patients for worsening depression, suicidal thoughts, or unusual behavior changes, especially during initial treatment or dose changes 2

Activation of Mania/Hypomania

• In patients with bipolar disorder, trazodone may precipitate a mixed/manic episode 2
• Screen patients for personal or family history of bipolar disorder, mania, or hypomania before initiating treatment 2

Serotonin Syndrome

• Potentially life-threatening condition when trazodone is combined with other serotonergic drugs (triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort) or MAOIs 2
• Symptoms include agitation, hallucinations, delirium, coma, tachycardia, labile blood pressure, hyperthermia, tremor, rigidity, myoclonus, hyperreflexia, incoordination, seizures, nausea, vomiting, and diarrhea 2
• Concomitant use with MAOIs is absolutely contraindicated 2
• Discontinue trazodone immediately if serotonin syndrome symptoms occur 2

Other Notable Side Effects

Common Adverse Effects

• Most common side effects include swelling, blurred vision, dizziness, sleepiness, tiredness, diarrhea, stuffy nose, and weight loss 2
• Drowsiness, headache, dizziness, and dry mouth are frequently reported 5

Angle-Closure Glaucoma

• Pupillary dilation may trigger angle-closure attack in patients with anatomically narrow angles without patent iridectomy 2
• Avoid in patients with untreated anatomically narrow angles 2

Withdrawal Syndrome

• Abrupt discontinuation can cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, paresthesias, tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures 2
• Gradual dose reduction is recommended rather than abrupt cessation 2

High-Risk Populations

Older Adults (≥75 years)

• Population-based cohort studies show trazodone is associated with highest rates of all-cause mortality (11.43% over 1 year), attempted suicide/self-harm, stroke/TIA, fractures, and epilepsy/seizures compared to other antidepressant classes 6
• The 2020 VA/DoD guidelines advise against trazodone for chronic insomnia in older adults due to its adverse effect profile 1
• Maximum tolerated doses in elderly are 300-400 mg/day (compared to 600 mg/day in younger patients) 7

Patients with Cardiovascular Disease

• Use with extreme caution and close monitoring in patients with cardiac disease 2
• Not recommended during initial recovery phase of myocardial infarction 2

Patients with History of Falls

• The American Geriatrics Society identifies trazodone as contributing to fall risk through orthostatic hypotension and sedation 4
• Particularly problematic when combined with other fall-risk medications 4

Patients on Anticoagulation or with Bleeding Disorders

• Absolute avoidance of combination with anticoagulants, antiplatelets, NSAIDs, SSRIs, or SNRIs is recommended 4, 8
• If combination is unavoidable, monitor closely for signs of bleeding 2