What are the considerations for using Wellbutrin (bupropion) as an adjunct in an adult patient with a history of major depressive disorder and incomplete response to selective serotonin reuptake inhibitors (SSRIs)?

Bupropion as Adjunct for SSRI-Resistant Major Depressive Disorder

Augmenting an SSRI with bupropion is a reasonable and evidence-supported strategy for adults with major depressive disorder who have incomplete response to SSRI monotherapy, offering potential benefits in reducing depression severity with favorable tolerability compared to other augmentation options.

Evidence for Augmentation Strategy

When an adult patient with MDD has an inadequate response to SSRI treatment, augmentation with bupropion represents a viable second-line approach supported by guideline-level evidence:

• Augmenting citalopram with bupropion showed no difference in response or remission rates compared to buspirone augmentation, but bupropion demonstrated superior reduction in depression severity scores 1.

• Moderate-quality evidence indicates that discontinuation due to adverse events was significantly lower with bupropion augmentation compared to buspirone augmentation, suggesting better tolerability 1.

• Low-quality evidence showed no difference in serious adverse events or suicidal ideation between bupropion and buspirone augmentation strategies 1.

Comparison with Alternative Strategies

The American College of Physicians guidelines provide context for choosing between augmentation and switching strategies:

• Switching from one SSRI to bupropion showed no difference in response or remission rates compared to switching to other SSRIs (sertraline or venlafaxine), with moderate-quality evidence 1.

• Augmentation with bupropion performed similarly to augmentation with cognitive behavioral therapy in terms of response, remission, and depression severity, with no difference in adverse events 1.

FDA-Approved Efficacy Data

Bupropion has established efficacy as monotherapy for MDD:

• Bupropion demonstrated efficacy in multiple placebo-controlled trials at doses of 300-450 mg/day, with significant improvements in HAMD total scores, HAMD item 1 (depressed mood), and CGI-S scores 2.

• A randomized withdrawal trial showed that patients maintained on bupropion 300 mg/day experienced significantly lower relapse rates over 44 weeks compared to placebo, supporting its role in maintenance treatment 2.

Practical Implementation

Dosing Considerations

• Start bupropion extended-release at 150 mg once daily for one week, then increase to 300 mg once daily 2.

• The therapeutic dose range is 300-450 mg/day, with most patients responding to 300-450 mg/day 2.

• When used as augmentation, typical doses range from 150-400 mg/day 3.

Key Safety Considerations

Critical contraindications and warnings:

• Bupropion lowers the seizure threshold and should be avoided in patients with epilepsy or history of seizures 1.

• Avoid in patients with eating disorders (bulimia, anorexia nervosa) due to increased seizure risk 1.

• Do not use with MAO inhibitors or within 14 days of discontinuing MAOIs 1.

• Monitor for neuropsychiatric adverse effects, including suicidal thoughts and behaviors, especially in patients under 24 years 1.

Advantages Over Other Antidepressants

Bupropion offers distinct tolerability advantages:

• Lower rates of sexual dysfunction compared to SSRIs (fluoxetine, sertraline, paroxetine), making it particularly valuable for patients experiencing SSRI-induced sexual side effects 1.

• Less somnolence and weight gain compared to many other antidepressants 4, 5.

• May be particularly beneficial for patients with comorbid symptoms of fatigue, low energy, or cognitive slowing given its dopaminergic and noradrenergic mechanisms 4, 5, 6.

Clinical Scenarios Favoring Bupropion Augmentation

Consider bupropion augmentation specifically when:

• The patient has SSRI-induced sexual dysfunction that is limiting adherence 1.

• Prominent symptoms include fatigue, hypersomnia, or psychomotor retardation 6.

• The patient has comorbid nicotine dependence, as bupropion has established efficacy for smoking cessation 1.

• Weight gain on the current SSRI is problematic 4, 5.

Common Pitfalls to Avoid

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

• Avoid late-day dosing to minimize insomnia risk 1.

• In patients with moderate-to-severe renal impairment, reduce the total daily dose by half; avoid in end-stage renal disease 1.

• In moderate-to-severe hepatic impairment, do not exceed 150 mg/day 1.

• Discontinue if the patient has not lost 5% body weight after 12 weeks when using naltrexone-bupropion combination (this applies to the combination product for obesity, not MDD treatment) 1.

Drug Interactions

Important CYP2D6 considerations:

• Bupropion is a CYP2D6 inhibitor and can increase levels of drugs metabolized by this pathway (e.g., desipramine, other TCAs, some SSRIs) by 2-5 fold 2.

• Drugs that induce metabolism (carbamazepine, phenobarbital, phenytoin, efavirenz) may reduce bupropion levels and efficacy 2.