What are the reasons to start bupropion (Wellbutrin) versus a selective serotonin reuptake inhibitor (SSRI) in patients with major depressive disorder?

Reasons to Start Bupropion (Wellbutrin) versus an SSRI

Choose bupropion over an SSRI when the patient has concerns about sexual dysfunction, weight gain, or somnolence, or when they have comorbid conditions like obesity or tobacco dependence. 1

Primary Efficacy Considerations

Both bupropion and SSRIs demonstrate equivalent efficacy for treating major depressive disorder, with no clinically meaningful differences in response or remission rates. 1 The American College of Physicians explicitly states that existing evidence does not justify choosing one second-generation antidepressant over another based on greater efficacy. 1 Therefore, the decision should be driven entirely by adverse effect profiles, comorbidities, and patient-specific factors rather than efficacy differences. 1

Specific Clinical Scenarios Favoring Bupropion

Sexual Dysfunction Concerns

• Bupropion has significantly lower rates of sexual adverse events compared to fluoxetine and sertraline. 1
• In contrast, paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline. 1
• This makes bupropion the preferred choice for sexually active patients or those who have experienced sexual side effects with prior antidepressants. 2, 3

Weight and Metabolic Concerns

• Bupropion is associated with minimal weight gain or even weight loss, unlike many SSRIs. 2, 4
• For patients with obesity or overweight with weight-related complications, bupropion (particularly naltrexone-bupropion ER) should be prioritized. 1
• Mirtazapine and paroxetine result in higher weight gain than other antidepressants. 1

Somnolence and Fatigue

• Bupropion has comparable or lower rates of somnolence than placebo and significantly less than many SSRIs. 3, 4
• Choose bupropion for patients who need to maintain alertness for work or daily functioning, or those complaining of fatigue as a depressive symptom. 5

Comorbid Tobacco Dependence

• Bupropion is FDA-approved for smoking cessation and demonstrates efficacy in reducing nicotine use. 1
• In patients needing both depression treatment and smoking cessation support, bupropion addresses both conditions simultaneously. 1
• The EAGLES trial showed bupropion achieved superior abstinence rates compared to placebo (OR 2.07,95% CI 1.75-2.45). 1

Patients with History of Depression and Obesity

• Evidence suggests bupropion may be particularly beneficial for patients with depressed mood who also need weight management. 1
• A small study showed sustained improvement in depressive symptoms at 24 weeks with naltrexone-bupropion ER. 1

Critical Safety Considerations When Choosing Bupropion

Absolute Contraindications

• Avoid bupropion in patients with seizure disorders or conditions that lower seizure threshold (including eating disorders, brain metastases, or abrupt alcohol/benzodiazepine withdrawal). 6
• The seizure risk is approximately 0.1% at therapeutic doses. 1
• Do not use in patients requiring opioid therapy (naltrexone-bupropion formulation). 1

Relative Contraindications

• Use caution in patients with uncontrolled hypertension; monitor blood pressure regularly. 6
• Screen for bipolar disorder history before initiating, as bupropion can precipitate manic episodes. 6
• Reduce dose in hepatic impairment (maximum 150mg every other day in moderate-to-severe impairment). 6

When to Prefer SSRIs Over Bupropion

Suicide Risk Considerations

• SSRIs are associated with increased risk for nonfatal suicide attempts compared to placebo (OR 1.57,95% CI 0.99-2.55). 1
• However, all antidepressants require close monitoring for suicidal thoughts, particularly in patients under 24 years old. 1, 6
• This increased suicide attempt risk with SSRIs should be weighed against bupropion's seizure risk on a case-by-case basis. 1

Anxiety as Prominent Feature

• While bupropion can treat anxiety symptoms in depression, some patients may experience initial agitation or insomnia. 6
• SSRIs may be better tolerated in patients where anxiety is the predominant presenting symptom. 5

Practical Implementation Algorithm

Step 1: Assess for absolute contraindications to bupropion (seizure history, eating disorders, opioid use). 6

Step 2: If no contraindications exist, evaluate patient priorities:

• Sexual function concerns → Choose bupropion 1
• Weight/metabolic concerns → Choose bupropion 1, 2
• Fatigue/somnolence concerns → Choose bupropion 3, 4
• Active tobacco use → Choose bupropion 1

Step 3: Discuss adverse effect profiles with patient before final selection, as recommended by ACP guidelines. 1

Step 4: Monitor within 1-2 weeks of initiation for therapeutic response and adverse effects, including suicidal ideation. 1

Step 5: If inadequate response at 6-8 weeks, modify treatment (consider switching or augmentation strategies). 1

Common Pitfalls to Avoid

• Do not assume bupropion is "activating" and therefore inappropriate for all anxious patients—it successfully treats anxiety symptoms in many MDD patients. 5
• Do not overlook the seizure risk—carefully screen for risk factors including eating disorders, which are often underreported. 6
• Do not forget to taper when discontinuing—reduce from 300mg to 150mg daily before stopping. 6
• Do not combine with MAOIs or use within 14 days of MAOI discontinuation. 6