What are the side effects, risks, and monitoring recommendations for Wellbutrin (bupropion)?

Wellbutrin (Bupropion) Side Effects, Risks, and Monitoring

Most Common Side Effects

The most frequently reported adverse effects of bupropion include dry mouth, insomnia, headache, nausea, anxiety, agitation, tremor, dizziness, sweating, and palpitations. 1 These occur at rates ≥5% and at least twice the placebo rate. 1

• Dry mouth and insomnia are the only side effects that occur significantly more frequently with bupropion than placebo in controlled trials. 2
• Agitation is the most common reason for discontinuation, occurring in approximately 9% of patients. 3
• Most common side effects are generally transient and often resolve within the first 2 weeks without intervention. 2, 4
• Discontinuation rates due to adverse events are low (6-12% in clinical trials), indicating good overall tolerability. 2

Serious Adverse Effects and Safety Warnings

Seizure Risk (Critical Safety Concern)

Bupropion lowers the seizure threshold, with a dose-dependent risk of approximately 0.1% (1 in 1,000) at doses ≤300 mg/day; risk increases markedly above 450 mg/day. 5, 3, 1, 2

• The maximum daily dose must not exceed 450 mg/day to maintain seizure risk at 0.1%. 5, 1
• Nearly half of reported seizures occurred in patients who had pre-existing risk factors that should have contraindicated use. 4
• Seizure manifestations may include brief lapses in awareness, automatisms, and post-event confusion. 3
• Discontinue bupropion immediately if seizure occurs. 3, 1

Suicidality (Black Box Warning)

Bupropion carries an FDA black box warning for increased risk of suicidal thoughts and behaviors in patients younger than 24 years, with the greatest risk during the first 1-2 months of treatment. 5, 1

• Monitor intensively during weeks 1-2 for suicidal ideation, agitation, irritability, or unusual behavioral changes. 5, 1
• The risk of suicide attempts is highest in the initial 1-2 months of antidepressant therapy. 5
• In the French pharmacovigilance database, 66% of patients who attempted suicide while on bupropion had pre-existing risk factors (history of depression, prior suicide attempts). 4

Neuropsychiatric Adverse Events

Postmarketing reports document serious neuropsychiatric events including mood changes (depression, mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, and panic attacks. 1

• These events have been reported both in patients using bupropion for smoking cessation and for depression. 1
• Instruct patients to discontinue bupropion and contact a healthcare provider immediately if such symptoms occur. 1

Cardiovascular Effects

Bupropion can elevate blood pressure and heart rate, making it contraindicated in patients with uncontrolled hypertension. 5, 1

• Monitor blood pressure before initiating treatment and periodically during therapy, especially in the first 12 weeks. 5, 1
• In controlled trials, no significant changes in mean heart rate or blood pressure occurred with bupropion SR alone. 2
• Cardiovascular serious adverse reactions (ischemic heart disease, sudden death) were often associated with pre-existing coronary artery disease in smokers. 4

Severe Hypersensitivity Reactions

Severe allergic reactions including angioedema and serum sickness-like reactions occur in approximately 0.1% of patients. 2, 4

• Cutaneous and allergic reactions accounted for 31.2% of serious adverse reactions in the French pharmacovigilance database. 4
• Younger patients appear at higher risk for angioedema, with a dose-dependent effect observed. 4
• These reactions typically occur within a median of 12-14 days after drug initiation. 4
• Bupropion is contraindicated in patients with known hypersensitivity to bupropion or tablet ingredients. 1

Activation of Mania/Hypomania

Screen patients for bipolar disorder before initiating bupropion and monitor for manic or hypomanic symptoms during treatment. 1

• Bupropion may be less likely to provoke mania than antidepressants with prominent serotonergic effects. 6
• Avoid bupropion monotherapy in patients with identified bipolar disorder; use mood stabilizers or atypical antipsychotics as first-line treatment instead. 5

Angle-Closure Glaucoma

Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants including bupropion. 1

Absolute Contraindications

Bupropion is absolutely contraindicated in the following situations: 1

• Seizure disorder or any condition predisposing to seizures (head trauma, brain tumor, stroke). 5, 1
• Current or prior diagnosis of bulimia or anorexia nervosa (increased seizure risk). 5, 1
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs (precipitates withdrawal seizures). 5, 1
• Concurrent MAOI use or within 14 days of MAOI discontinuation (risk of hypertensive crisis). 5, 1
• Uncontrolled hypertension (bupropion can further elevate blood pressure). 5, 1
• Known hypersensitivity to bupropion. 1

Monitoring Recommendations

Baseline Assessment

• Screen for seizure risk factors, including history of head trauma, eating disorders, alcohol/substance abuse, and concurrent medications that lower seizure threshold. 5, 1
• Measure baseline blood pressure and heart rate. 5, 1
• Assess for bipolar disorder to avoid precipitating mania. 1
• Evaluate suicidal ideation, particularly in patients under 24 years. 5

Ongoing Monitoring

• Monitor patient status, therapeutic response, and adverse effects within 1-2 weeks of initiation. 5
• Blood pressure and heart rate should be checked periodically, especially during the first 12 weeks. 5, 1
• Assess for neuropsychiatric symptoms including agitation, anxiety, mood changes, and suicidal ideation throughout treatment. 5, 1
• Allow 6-8 weeks at therapeutic dose before determining treatment response. 5

Special Population Considerations

Hepatic Impairment

• Moderate to severe hepatic impairment: maximum dose 150 mg every other day. 5, 1
• Mild hepatic impairment: consider reducing dose and/or frequency. 5, 1

Renal Impairment

• Moderate to severe renal impairment (GFR <90 mL/min): reduce total daily dose by 50%. 5, 1
• End-stage renal disease: avoid bupropion entirely (metabolites accumulate and dialysis does not clear them effectively). 5

Older Adults

• Start with lower doses (37.5 mg every morning) and titrate gradually by 37.5 mg every 3 days to minimize adverse reactions. 5
• Maximum dose for older adults: 150 mg twice daily (300 mg total). 5

Pregnancy and Breastfeeding

• Limited data suggest no major congenital malformations, though small increases in specific cardiovascular defects have been reported. 5
• Bupropion is present in breast milk at low levels; two case reports of seizures in breastfed infants warrant caution. 5

Advantages Over Other Antidepressants

Bupropion offers distinct tolerability advantages compared to SSRIs: 5, 6

• Significantly lower rates of sexual dysfunction compared to SSRIs like escitalopram and paroxetine. 5, 6
• Minimal weight gain or even weight loss, unlike many other antidepressants. 5, 6
• 10 to 100 times less likely to cause cardiac conduction problems than tricyclic antidepressants. 7
• Orthostatic hypotension is rare. 7
• Minimal anticholinergic effects. 8, 7

Drug Interactions

• CYP2D6 inhibition: Bupropion inhibits CYP2D6 and can increase concentrations of antidepressants (venlafaxine, SSRIs, tricyclics), antipsychotics (haloperidol, risperidone), beta-blockers (metoprolol), and Type 1C antiarrhythmics. 1, 6
• Drugs that lower seizure threshold should be used with extreme caution. 1
• Dopaminergic drugs (levodopa, amantadine): CNS toxicity can occur with concurrent use. 1
• False-positive urine drug screens: Bupropion can cause false-positive results for amphetamines. 1

Overdose Safety

Bupropion is relatively safe in overdose, with seizures being the predominant concern. 6, 7 This makes it a safer option for patients with suicidal ideation compared to tricyclic antidepressants. 8