What are the recommended doses, contraindications, and adverse effects of bupropion for treating major depressive disorder and for smoking cessation?

Bupropion for Major Depressive Disorder and Smoking Cessation

Bupropion is an effective second-generation antidepressant and smoking cessation agent with a favorable side-effect profile, particularly regarding sexual dysfunction and weight gain, making it a preferred choice for patients concerned about these adverse effects. 1

Recommended Dosing

Major Depressive Disorder

For bupropion SR (sustained-release), start with 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total daily dose) if tolerated. 2 For older adults, begin more conservatively 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. 2

• Bupropion XL (extended-release) is dosed at 150 mg once daily initially, with a maintenance dose of 150–300 mg once daily. 2
• The maximum dose for SR formulation is 400 mg per day; for XL formulation, it is 450 mg per day. 2
• Administer the second dose of SR before 3 PM to minimize insomnia risk. 2

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, starting 1–2 weeks before the target quit date. 1, 2 This lead time allows therapeutic drug levels to establish before cessation attempts. 2

• Continue treatment for 7–12 weeks after the quit date, with formal efficacy assessment after this period. 1, 2, 3
• The maximum dose for smoking cessation is 300 mg per day to maintain seizure risk at approximately 0.1%. 1, 2
• Combining bupropion with nicotine replacement therapy (NRT) yields the highest abstinence rates—35.5% at 12 months versus 30.3% with bupropion alone. 2

Absolute Contraindications

Bupropion is absolutely contraindicated in patients with:

• Seizure disorders or any condition predisposing to seizures (history of head trauma, brain tumor, stroke, brain metastases) because bupropion lowers the seizure threshold. 1, 2, 3
• Current or recent MAOI use (within 14 days of discontinuation) due to increased risk of hypertensive reactions. 1, 2
• Eating disorders (bulimia nervosa, anorexia nervosa) due to increased seizure risk. 2
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs due to increased seizure risk. 2
• Uncontrolled hypertension, particularly when considering naltrexone-bupropion combinations. 2
• Concurrent tamoxifen therapy due to CYP2D6 inhibition. 1
• Closed-angle glaucoma. 1

Dose Adjustments for Special Populations

Hepatic Impairment

For moderate to severe hepatic impairment, the total daily dose should not exceed 150 mg daily (one tablet). 2 For mild hepatic impairment, reduce the dose and/or frequency. 2

Renal Impairment

For moderate to severe renal impairment (GFR <90 mL/min), reduce the total daily dose by 50%. 2 Bupropion and its metabolites are cleared renally and accumulate when kidney function is reduced. 2

Avoid bupropion entirely in end-stage renal disease or patients on dialysis, as hemodialysis does not effectively clear the primary active metabolite hydroxybupropion. 2

Common Adverse Effects

The most common adverse effects include:

• Insomnia, headache, dry mouth, dizziness, nausea, and constipation. 1, 4, 5
• Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs (fluoxetine, sertraline, escitalopram, paroxetine). 1, 2, 3
• Bupropion is associated with minimal weight gain or even modest weight loss, unlike many other antidepressants. 2
• Lower rates of sedation compared to SSRIs. 2

Serious Adverse Effects

Seizure Risk

The seizure risk at 300 mg/day is approximately 0.1% (1 in 1,000 patients). 1, 2 This risk increases markedly above 450 mg/day or with rapid dose escalation. 2

Neuropsychiatric Effects

All antidepressants, including bupropion, carry an FDA black-box warning for increased risk of suicidal thoughts and behaviors in individuals younger than 24 years, with the greatest risk during the first 1–2 months of therapy. 2, 3

• Monitor patients closely during weeks 1–2 for suicidal ideation, agitation, irritability, or unusual behavioral changes. 2, 3
• The high-quality EAGLES trial (n=8,144) demonstrated no statistically significant increase in neuropsychiatric adverse events with bupropion compared to nicotine patch or placebo, even among participants with pre-existing psychiatric disorders. 2

Cardiovascular Effects

Bupropion can elevate blood pressure and heart rate. 2 Monitor blood pressure and heart rate periodically, especially during the first 12 weeks of treatment. 2

Monitoring and Efficacy Assessment

Assess patient status, therapeutic response, and adverse effects within 1–2 weeks of initiation. 2, 3 This early monitoring is critical for detecting worsening depression, suicidal ideation, or behavioral changes. 2

Allow 6–8 weeks at therapeutic doses before determining treatment response. 2, 3 If no adequate response occurs by 6–8 weeks, modify the treatment approach by increasing the dose, switching agents, or adding augmentation therapy. 2

Clinical Advantages

Bupropion may be particularly beneficial for:

• Patients with depression characterized by low energy, apathy, or hypersomnia due to its activating properties. 2
• Patients concerned about sexual dysfunction or weight gain, as bupropion has the lowest incidence of these effects among second-generation antidepressants. 1, 2
• Patients with comorbid depression and nicotine dependence, addressing both conditions simultaneously. 1, 2, 3

Critical Safety Pitfalls to Avoid

Do not exceed 450 mg/day total dose to minimize seizure risk. 2

Do not skip intensive monitoring during weeks 1–2, as this period carries the highest risk for emergent suicidal ideation, particularly in patients younger than 24 years. 2

Do not combine with MAOIs or initiate within 14 days of MAOI discontinuation. 1, 2

Do not prescribe to patients with uncontrolled hypertension without first achieving blood pressure control. 2

Ensure patients with eating disorders, seizure history, or conditions predisposing to seizures are not prescribed bupropion. 1, 2, 3