Bupropion (Wellbutrin): Dosing, Contraindications, and Clinical Management
FDA-Approved Indications
Bupropion is FDA-approved for major depressive disorder, seasonal affective disorder, and smoking cessation. 1 The drug operates through dopamine and norepinephrine reuptake inhibition, distinguishing it from serotonergic antidepressants. 2, 3
Dosing Regimens
Major Depressive Disorder
Start bupropion XL at 150 mg once daily in the morning, then increase to 300 mg once daily after 4 days if tolerated. 4, 1 For the sustained-release (SR) formulation, begin with 150 mg once daily for 3 days, then advance to 150 mg twice daily. 4
- Maximum dose: 450 mg/day for XL formulation; 400 mg/day for SR formulation 4, 1
- Therapeutic target: 300 mg/day demonstrates superior antidepressant efficacy compared to 150 mg 4
- Time to effect: Allow 6–8 weeks at therapeutic dose before assessing response 4, 5
For older adults (≥65 years), start at 37.5 mg every morning and increase by 37.5 mg every 3 days as tolerated, with a maximum of 150 mg twice daily (300 mg total). 4 This gradual titration minimizes adverse reactions in this population.
Smoking Cessation
Begin bupropion SR 150 mg once daily for days 1–3, then increase to 150 mg twice daily (300 mg total) from day 4 onward. 6, 4, 7 Critically, start treatment 1–2 weeks before the target quit date to establish therapeutic drug levels. 6, 4
- Maximum dose: 300 mg/day for smoking cessation—do not exceed this to maintain seizure risk at 0.1% 6, 4, 7
- Treatment duration: Continue for 7–12 weeks after the quit date, then assess efficacy 6, 4, 5
- Efficacy: Achieves 12-month abstinence rates of approximately 19–23% versus 12% with placebo 4, 5
Administer the second daily dose before 3 PM to minimize insomnia risk. 4
Absolute Contraindications
Do not prescribe bupropion in patients with:
- Seizure disorder or any condition predisposing to seizures (prior head trauma, brain tumor, stroke, brain metastases) 6, 5, 1
- Current or prior bulimia or anorexia nervosa (increased seizure risk) 4, 1
- Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs (precipitates withdrawal seizures) 4, 1
- Current MAOI use or within 14 days of MAOI discontinuation (risk of hypertensive crisis) 6, 1
- Concurrent tamoxifen therapy (bupropion inhibits CYP2D6, reducing tamoxifen efficacy) 6
- Known hypersensitivity to bupropion (allergic reactions occur in ~3% of patients) 1, 8
Critical Precautions and Monitoring
Seizure Risk Management
The seizure incidence is approximately 0.1% (1 in 1,000) at doses ≤300 mg/day for smoking cessation and ≤450 mg/day for depression. 6, 7, 8 Risk escalates with:
- Doses exceeding maximum limits 6, 1
- Rapid dose escalation without gradual titration 1
- Concurrent medications that lower seizure threshold 4
If a seizure occurs, discontinue bupropion permanently. 1
Cardiovascular Monitoring
Bupropion can elevate blood pressure and heart rate—measure baseline values and monitor periodically, especially during the first 12 weeks. 4, 1 Uncontrolled hypertension is a relative contraindication; optimize blood pressure control before initiating therapy. 4
Neuropsychiatric Safety
All patients, particularly those younger than 24 years, require close monitoring for suicidal ideation, agitation, irritability, or unusual behavioral changes during the first 1–2 weeks of treatment. 4, 1 The FDA black-box warning highlights increased suicide risk in young adults during the initial treatment phase. 4, 1
Recent high-quality evidence (EAGLES trial, n=8,144) demonstrates no significant increase in neuropsychiatric adverse events with bupropion compared to nicotine patch or placebo, even in patients with pre-existing psychiatric disorders. 6, 7
Dose Adjustments for Special Populations
Hepatic Impairment
- Moderate to severe impairment: 150 mg every other day (maximum) 4, 5, 1
- Mild impairment: Reduce dose and/or frequency 1
Renal Impairment
- Moderate to severe (eGFR <90 mL/min): Reduce total daily dose by 50% (e.g., 150 mg/day instead of 300 mg/day) 4, 5
- End-stage renal disease: Avoid bupropion entirely—metabolites accumulate and dialysis does not effectively clear them 4
Common Adverse Effects
Most frequent side effects (≥5% incidence, ≥2× placebo): dry mouth, nausea, insomnia, dizziness, headache, agitation, anxiety, tremor, and sweating. 1, 8
Bupropion offers distinct advantages over SSRIs:
- Significantly lower rates of sexual dysfunction 4, 5
- Minimal weight gain or modest weight loss (versus weight gain with most antidepressants) 4, 5
- Lower sedation rates 4
Alternative and Augmentation Strategies
For Major Depressive Disorder
If bupropion monotherapy fails after 6–8 weeks at therapeutic dose, augment with an SSRI (e.g., escitalopram 10–20 mg/day or sertraline 50–200 mg/day) rather than switching. 4 STAR*D trial data show bupropion augmentation of SSRIs produces significantly lower discontinuation rates (12.5%) compared to buspirone augmentation (20.6%; P<0.001). 4
Alternatively, switch to an SSRI or SNRI if bupropion is contraindicated or poorly tolerated. 4 Venlafaxine XR 75–225 mg/day may offer superior response in anxious depression but has higher discontinuation rates. 4
For Smoking Cessation
Combine bupropion with nicotine replacement therapy (NRT) for highest abstinence rates—35.5% at 12 months versus 30.3% with bupropion alone (though not statistically significant). 4 Start NRT on the actual quit date, not when initiating bupropion. 4
Varenicline is an alternative first-line agent: 0.5 mg once daily for days 1–3,0.5 mg twice daily for days 4–7, then 1 mg twice daily for weeks 2–12. 6 Varenicline achieves superior abstinence versus placebo (OR 2.07 in EAGLES trial). 5
Clinical Pearls and Common Pitfalls
Optimal Patient Selection
Bupropion is particularly beneficial for:
- Patients with depression and low energy, apathy, or hypersomnia (activating properties) 4
- Smokers with comorbid depression (addresses both conditions simultaneously) 6, 4, 5
- Patients concerned about SSRI-induced sexual dysfunction or weight gain 4, 5
Critical Timing Considerations
Do not skip the 1–2 week lead time before the quit date for smoking cessation—therapeutic drug levels must be established before cessation attempts. 4
Administer the second daily dose before 3 PM to prevent insomnia. 4
Drug Interactions
Bupropion inhibits CYP2D6—use caution when co-prescribing with drugs metabolized by this enzyme (e.g., tamoxifen, certain antipsychotics, beta-blockers). 6, 3
Do not combine naltrexone-bupropion products with opioid therapy—naltrexone will precipitate severe withdrawal. 4 However, bupropion monotherapy does not share this contraindication. 4
Pregnancy and Lactation
Limited data suggest no major congenital malformations with bupropion use during pregnancy, though small increases in specific cardiovascular defects have been reported. 4 Bupropion is present in breast milk at low levels; two case reports of seizures in breastfed infants warrant caution. 4
Maintenance and Discontinuation
After achieving remission in a first depressive episode, continue bupropion for a minimum of 4–9 months. 4 For recurrent depression (≥2 episodes), extend maintenance therapy to ≥1 year, as relapse risk reaches 70% after two episodes and 90% after three. 4
Taper bupropion gradually when discontinuing to minimize potential withdrawal symptoms. 4