Can Wellbutrin (bupropion) be used as first‑line therapy for an adult with major depressive disorder, and what are the appropriate dosing, contraindications, and monitoring?

Bupropion for Major Depressive Disorder

Bupropion is an appropriate and effective first-line antidepressant for major depressive disorder in adults, with particular advantages in patients concerned about sexual dysfunction, weight gain, or who have comorbid smoking cessation needs. 1

First-Line Status and Efficacy

The American College of Physicians strongly recommends that clinicians select between cognitive behavioral therapy or second-generation antidepressants (including bupropion) to treat major depressive disorder after discussing treatment effects, adverse effects, cost, and patient preferences. 1 All second-generation antidepressants demonstrate similar efficacy for treatment-naive patients, with remission rates of 42–49%, so medication selection should be driven by side-effect profiles and patient-specific factors. 2

Bupropion has established efficacy through multiple placebo-controlled trials, with FDA approval based on studies showing superiority to placebo on Hamilton Depression Rating Scale scores, Clinical Global Impressions scales, and Montgomery-Asberg Depression Rating Scale. 3 The drug demonstrates equivalent efficacy to SSRIs (sertraline, escitalopram) and SNRIs (venlafaxine) in head-to-head comparisons. 4, 5, 6

Dosing and Administration

Standard Dosing for Depression

• Start bupropion SR at 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) if tolerated. 7
• For bupropion XL, start at 150 mg once daily, with a maintenance dose of 150–300 mg once daily. 7
• Maximum dose is 400 mg/day for SR formulation or 450 mg/day for XL formulation. 7

Timing Considerations

• Administer the first dose in the morning to leverage bupropion's activating properties. 7
• Give the second SR dose before 3 PM to minimize insomnia risk. 7
• For XL formulation, take 300 mg once daily in the morning. 7

Special Population Adjustments

• For older adults (≥65 years), 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). 7 Bupropion is a preferred antidepressant for elderly patients due to minimal anticholinergic effects. 2
• For moderate to severe hepatic impairment, do not exceed 150 mg daily (one tablet). 7
• For moderate to severe renal impairment (GFR <90 mL/min), reduce the total daily dose by 50%. 7
• Avoid bupropion entirely in end-stage renal disease. 7

Absolute Contraindications

Do not prescribe bupropion in patients with:

• Seizure disorders or any condition predisposing to seizures (prior head trauma, brain tumor, stroke, brain metastases). 7
• Current or recent MAOI use (within 14 days of discontinuation). 7
• Eating disorders (bulimia nervosa or anorexia nervosa) due to increased seizure risk. 7
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. 7
• Uncontrolled hypertension (especially for naltrexone-bupropion combinations). 7

Monitoring Requirements

Initial Phase (Weeks 1–2)

• Assess for suicidal ideation, agitation, irritability, and unusual behavioral changes within 1–2 weeks of initiation, as suicide risk is highest during the first 1–2 months. 7 This monitoring is critical for patients younger than 24 years, who carry an FDA black-box warning for increased suicidal thoughts with all antidepressants. 7
• Monitor blood pressure and heart rate, especially in the first 12 weeks, as bupropion can cause elevations. 7

Response Assessment

• Allow 6–8 weeks at therapeutic doses before determining treatment response. 7, 2 Energy levels may improve within the first few weeks, but full antidepressant effects require the full 6–8 week trial. 7
• If no adequate response occurs by 6–8 weeks, modify treatment by increasing the dose, switching agents, or adding augmentation therapy. 7

Clinical Advantages Over Other Antidepressants

Bupropion offers distinct benefits that make it preferable in specific clinical scenarios:

• Significantly lower rates of sexual dysfunction compared to SSRIs (fluoxetine, sertraline, paroxetine, escitalopram). 1, 2 This is the most clinically relevant advantage for many patients.
• Minimal weight gain or even weight loss, unlike most SSRIs and SNRIs. 7
• Lower rates of sedation compared to SSRIs. 7
• Activating properties beneficial for patients with low energy, apathy, or hypersomnia. 7
• Dual benefit for patients with comorbid depression and nicotine dependence, addressing both conditions simultaneously. 7

Seizure Risk and Safety

The seizure rate with bupropion at 300 mg/day is approximately 0.1% (1 in 1,000 patients). 7, 8 This rate is within the range observed with other marketed antidepressants. 8 The risk increases with doses exceeding 450 mg/day, rapid dose escalation, or predisposing medical conditions. 7

To maintain seizure risk at 0.1%, never exceed 300 mg/day for smoking cessation or 450 mg/day for depression. 7

Treatment Duration

• For a first depressive episode, continue bupropion for at least 4–9 months after achieving remission. 2
• For recurrent depression (≥2 episodes), maintain therapy for ≥1 year or longer, as relapse risk is 70% after two episodes and 90% after three episodes. 7

Augmentation Strategies for Partial Response

If bupropion monotherapy fails after 6–8 weeks, augment with an SSRI or SNRI rather than switching. 7 Adding an SSRI to bupropion demonstrates superior efficacy compared to other augmentation strategies, with remission rates of approximately 30% and significantly lower discontinuation rates (12.5%) compared to buspirone augmentation (20.6%, P < 0.001). 7

Alternatively, augmentation with cognitive behavioral therapy is superior to medication alone for treatment-resistant depression. 7

Common Pitfalls to Avoid

• Do not discontinue treatment before 6–8 weeks unless significant adverse effects occur, as premature switching leads to missed opportunities for response. 7
• Do not skip intensive monitoring during weeks 1–2, as this period carries the highest risk for emergent suicidal ideation. 7
• Do not combine bupropion with MAOIs or initiate within 14 days of MAOI discontinuation. 7
• Do not exceed maximum daily doses (400 mg SR or 450 mg XL), as seizure risk increases markedly. 7