What are the risks associated with long-term use of bupropion (Zyban, Wellbutrin)?

Long-Term Bupropion Use: Key Risks and Management

The primary risks of long-term bupropion use include dose-dependent seizures (particularly above 450 mg/day), hypertension requiring periodic monitoring, neuropsychiatric adverse events including suicidal ideation (especially in patients under 24 years), and potential activation of mania in undiagnosed bipolar disorder. 1

Seizure Risk: The Most Critical Concern

• The maximum daily dose must not exceed 450 mg to minimize seizure risk, which is the most serious dose-related adverse effect of long-term bupropion therapy 1
• Bupropion is absolutely contraindicated in patients with seizure disorders, current or prior bulimia/anorexia nervosa, or those abruptly discontinuing alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 1
• Over half of reported seizure cases occurred in patients with predisposing factors including head trauma, structural brain lesions, alcohol abuse, eating disorders, or concomitant medications that lower seizure threshold 2
• The seizure rate at doses ≤450 mg/day in divided schedules is comparable to other antidepressants in patients without risk factors 3
• Real-world data suggests approximately one additional seizure per 6,219 first-time bupropion users during the first 28 days of treatment 4

Cardiovascular Monitoring Requirements

• Blood pressure must be monitored before initiating treatment and periodically throughout long-term therapy, as bupropion can cause hypertension 1
• Blood pressure and heart rate should be monitored especially during the first 12 weeks when used in combination formulations (naltrexone-bupropion) 5
• Importantly, bupropion has 10 to 100 times less likelihood of inducing cardiac conduction problems compared to tricyclic antidepressants, and orthostatic hypotension is rare 3
• No evidence suggests bupropion increases risk of sudden death based on large database analysis of 9,329 patients 4

Neuropsychiatric Adverse Events

• Patients under 24 years have increased risk of suicidal thoughts and behaviors, requiring close monitoring for worsening depression and emergence of suicidal ideation 1
• Serious neuropsychiatric events reported include mood changes (depression, mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic 1
• Screen patients for bipolar disorder before initiating therapy, as bupropion can activate mania or hypomania in susceptible individuals 1
• Patients should be instructed to discontinue bupropion and contact their healthcare provider immediately if neuropsychiatric symptoms occur 1

Dose Adjustments for Organ Impairment

• For moderate to severe hepatic impairment, limit total daily dose to 150 mg (or 150 mg every other day per FDA labeling) 6, 1
• For moderate to severe renal impairment (GFR <90 mL/min), reduce total daily dose by half, as bupropion and metabolites are cleared renally and may accumulate 6, 7
• Mild hepatic or renal impairment requires consideration of dose and/or frequency reduction 1

Drug Interactions Requiring Vigilance

• Bupropion inhibits CYP2D6, potentially increasing concentrations of antidepressants (venlafaxine, SSRIs, tricyclics), antipsychotics (haloperidol, risperidone), beta-blockers (metoprolol), and Type 1C antiarrhythmics—consider dose reductions of these medications 1
• Never use with MAOIs or within 14 days of MAOI discontinuation due to increased risk of hypertensive reactions 6, 1
• Avoid concomitant use with opiate medications when using naltrexone-bupropion combination 5
• CYP2B6 inducers (ritonavir, efavirenz, carbamazepine, phenobarbital, phenytoin) may require bupropion dose increases, but not exceeding maximum recommended dose 1

Common Tolerability Issues

• Most common adverse reactions (≥5% incidence, ≥2× placebo) include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash 1
• Insomnia risk can be minimized by administering the second daily dose before 3 PM for sustained-release formulations 6, 7
• Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs, making it advantageous for long-term use in patients concerned about this adverse effect 6, 7

Additional Safety Considerations

• Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants including bupropion 1
• Bupropion can cause false-positive urine test results for amphetamines 1
• The drug was well tolerated in smoking cessation trials, with only 8% stopping treatment prematurely due to headache, insomnia, or dry mouth 5
• Gradual dose titration is essential to minimize seizure risk while achieving therapeutic levels 6, 7