Bupropion (Wellbutrin) Dosing
For major depressive disorder, start bupropion at 150 mg once daily in the morning for 3 days, then increase to 150 mg twice daily (maximum 300 mg/day for sustained-release formulations); for smoking cessation, use the same titration schedule for 7-12 weeks, starting 1-2 weeks before the quit date. 1, 2
Major Depressive Disorder Dosing
Standard Dosing:
- Initial: 150 mg once daily (morning) for 3 days
- Maintenance: 150 mg twice daily (maximum 300 mg/day for SR formulations)
- Extended-release (XL): Can be dosed once daily up to 450 mg for IR or 400 mg for SR formulations 3, 4
- Onset of action: Expect improvement within 2 weeks, with full efficacy at 4 weeks 5, 3
The evidence supporting bupropion for depression is robust, with high-certainty data showing it performs comparably to SSRIs like escitalopram and fluoxetine, with the distinct advantage of causing less sexual dysfunction and somnolence 5, 3. At 300 mg daily, bupropion demonstrates effectiveness for long-term treatment of recurrent major depression 6.
Smoking Cessation Dosing
Standard Protocol:
- Start 1-2 weeks before quit date
- Days 1-3: 150 mg once daily (morning)
- Day 4 through 7-12 weeks: 150 mg twice daily if tolerated
- Maximum: 300 mg per day
- Duration: 7-12 weeks initially; may extend to 6 months-1 year for continued cessation 1
The NCCN guidelines emphasize that bupropion can be combined with nicotine replacement therapy (NRT) for enhanced efficacy 1. Recent high-quality evidence from the EAGLES trial demonstrated that neuropsychiatric adverse events with bupropion were not significantly increased compared to nicotine patches or placebo, even in patients with psychiatric disorders 1.
Critical Dose Adjustments
Renal Impairment
Moderate to severe renal impairment:
- Reduce total daily dose by one-half (e.g., 150 mg once daily instead of twice daily) 6
- Avoid in end-stage renal disease 6
- For hemodialysis patients: Consider 150 mg every 3 days rather than daily, as metabolites accumulate significantly 7
Hepatic Impairment
Moderate to severe hepatic impairment:
- Maximum dose: 150 mg once daily (do not exceed) 6
- Bupropion undergoes extensive hepatic metabolism with a half-life of approximately 21 hours, and impaired liver function dramatically increases exposure 4
Absolute Contraindications
Do not prescribe bupropion in patients with:
- Seizure disorders (including history of seizures, stroke, brain metastases) - bupropion lowers seizure threshold 1
- Eating disorders (anorexia, bulimia) - increased seizure risk 8
- Concurrent MAO inhibitor use or within 14 days of discontinuation 6
- Closed-angle glaucoma 1
- Concurrent tamoxifen use (bupropion inhibits CYP2D6, reducing tamoxifen efficacy) 1
Critical Safety Monitoring
Neuropsychiatric Effects
Monitor for development or worsening of depression, suicidal ideation/behavior, hostility, and agitation, particularly in patients under 24 years old 6. While the FDA previously had a black box warning, the EAGLES trial provided reassuring data that serious neuropsychiatric events are uncommon 1.
Cardiovascular Monitoring
- Monitor blood pressure regularly - bupropion can cause hypertension 6
- Avoid in uncontrolled hypertension 6
- Long-term cardiovascular safety data remain unclear as outcome trials were terminated prematurely 6
Common Adverse Effects
- Most common: Dry mouth, insomnia, agitation, headache, nausea 3, 9
- Seizure risk: Approximately 1 in 1,000 at recommended doses 8
- Discontinuation due to adverse events: Higher than placebo (RR 1.37) 9
Special Clinical Considerations
Combination Therapy
- Bupropion + NRT: May provide additive benefit for smoking cessation, though evidence is mixed (RR 1.19,95% CI 0.94-1.51) 9
- Bupropion + naltrexone: FDA-approved combination for obesity; requires different dosing schedule 6
Comparative Efficacy
- Versus varenicline for smoking cessation: Bupropion is inferior (RR 0.71) 9
- Versus NRT for smoking cessation: No significant difference (RR 0.99) 9
- Versus SSRIs for depression: Comparable efficacy with less sexual dysfunction 5, 3
Treatment Response Assessment
- For smoking cessation: If patient continues smoking after 12 weeks on maintenance dose, consider switching therapies 1
- For depression: If no response by 4 weeks, reassess treatment strategy 3
Drug Interactions
- CYP2D6 substrates: Bupropion inhibits CYP2D6; use caution with drugs metabolized by this pathway (e.g., metoprolol, desipramine) 4
- CYP2B6 substrates: Potential interactions as bupropion is metabolized by CYP2B6 4
- Avoid alcohol: May lower seizure threshold further 2
Discontinuation
Taper the dose gradually when discontinuing to minimize withdrawal symptoms, though specific tapering schedules are not well-established in guidelines 10.