What are the adult dosing guidelines for Wellbutrin (bupropion) for major depressive disorder and smoking cessation, and what are its contraindications, precautions, and common adverse effects?

Bupropion (Wellbutrin) Dosing, Contraindications, and Safety Profile

Adult Dosing for Major Depressive Disorder

For major depressive disorder, initiate bupropion SR at 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) if tolerated. 1

• The standard therapeutic dose is 300 mg/day, with a maximum of 400 mg/day for sustained-release (SR) or 450 mg/day for extended-release (XL) formulations. 1
• Bupropion XL is typically administered as 300 mg once daily in the morning. 1
• For older adults, start with 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). 1
• The second dose of SR formulation must be administered before 3 PM to minimize insomnia risk. 1

Allow 6–8 weeks at an adequate dose before determining treatment response; full antidepressant efficacy typically emerges within this timeframe, though energy improvements may occur earlier. 1, 2

Adult Dosing for Smoking Cessation

Begin bupropion 1–2 weeks before the target quit date at 150 mg once daily for days 1–3, then increase to 150 mg twice daily (300 mg total) from day 4 onward. 3, 4

• The maximum dose for smoking cessation is 300 mg per day—do not exceed this to maintain seizure risk at approximately 0.1%. 3, 4
• Continue treatment for 7–12 weeks after the quit date, with formal efficacy assessment after this period. 3, 4
• The 1–2 week lead time is essential to establish therapeutic drug levels before cessation attempts. 4
• Bupropion increases 12-month abstinence rates by approximately 9–10 percentage points compared to placebo (≈19% vs 11%). 4, 2

Absolute Contraindications

Bupropion is absolutely contraindicated in patients with any seizure disorder, history of seizures, or conditions predisposing to seizures (stroke, brain metastases, head trauma, brain tumor). 3, 4

• Current or recent (within 14 days) monoamine oxidase inhibitor (MAOI) use is an absolute contraindication due to hypertensive crisis risk. 3, 4
• Concurrent tamoxifen therapy is contraindicated due to CYP2D6 inhibition. 3
• Closed-angle glaucoma is a contraindication due to intraocular pressure elevation risk. 3
• Eating disorders (bulimia, anorexia nervosa) are contraindicated due to increased seizure risk. 1
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is an absolute contraindication due to increased seizure risk. 1
• Uncontrolled hypertension should preclude bupropion use, as the medication can elevate blood pressure and heart rate. 1, 2

Critical Precautions and Monitoring

All patients younger than 24 years must be monitored intensively during the first 1–2 weeks for suicidal ideation, agitation, irritability, or unusual behavioral changes, as bupropion carries an FDA black-box warning for increased suicide risk in this age group. 1, 2

• The risk for suicide attempts is greatest during the first 1–2 months of treatment. 1
• Monitor blood pressure and heart rate periodically, especially during the first 12 weeks, as bupropion can cause elevations in both parameters. 1, 2
• Assess for neuropsychiatric adverse effects including hostility, agitation, and depressive mood throughout treatment. 3, 4

Dose Adjustments for Special Populations

For moderate to severe hepatic impairment, the maximum dose is 150 mg daily (one tablet). 4, 1

• For moderate to severe renal impairment (eGFR <90 mL/min), reduce the total daily dose by 50%. 4, 1
• Bupropion should be avoided entirely in end-stage renal disease, as hemodialysis does not effectively clear the active metabolite hydroxybupropion. 1

Common Adverse Effects

Insomnia is the most common adverse effect, occurring in approximately 24% of patients versus 15% with placebo; mitigate by scheduling the second daily dose before 3 PM. 4

• Dry mouth occurs in approximately 13% versus 5% with placebo. 4
• Headache and nausea are more common than placebo. 4
• Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs, making it advantageous for patients concerned about this side effect. 1, 2
• Bupropion is associated with minimal weight gain or even modest weight loss, unlike many other antidepressants. 1, 2

Serious Adverse Effects

The seizure risk at 300 mg/day is approximately 0.1% (1 in 1,000); this risk increases markedly above 450 mg/day. 3, 4, 5

• Severe hypersensitivity reactions (urticaria, angioedema) occur in approximately 1 per 1,000 to 1 per 10,000 patients. 4
• The large EAGLES trial (n=8,144) found no significant increase in neuropsychiatric adverse events with bupropion compared to nicotine patch or placebo, even among participants with pre-existing psychiatric disorders. 3, 4

Clinical Advantages and Combination Therapy

Bupropion may be particularly beneficial for patients with comorbid depression and smoking cessation goals, addressing both conditions simultaneously. 3, 4, 2

• Combining bupropion with nicotine replacement therapy (NRT) yields 12-month abstinence rates of 35.5% versus 30.3% with bupropion alone, though the difference is not statistically significant. 4
• Bupropion achieves remission rates of 42–49% in major depressive disorder, equivalent to SSRIs. 1
• When augmenting SSRIs with bupropion for treatment-resistant depression, discontinuation rates due to adverse events are significantly lower (12.5%) compared to buspirone augmentation (20.6%, P<0.001). 1