What are the next steps for partial responders to bupropion (Wellbutrin) for depression, specifically regarding the use of augmenting agents?

Augmentation Strategies for Partial Responders to Bupropion (Wellbutrin)

Primary Recommendation

For patients with partial response to bupropion after 6-8 weeks at adequate doses, augment with an SSRI (such as citalopram, sertraline, or escitalopram) rather than switching to another antidepressant. 1, 2

Evidence-Based Augmentation Approach

First-Line Augmentation Strategy

• Add an SSRI to existing bupropion therapy when partial response occurs after 6-8 weeks of treatment at therapeutic doses (typically 300 mg/day). 1, 2

• The STAR*D trial demonstrated that augmenting citalopram with bupropion achieved 30.3% remission rates, with significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone augmentation (20.6%, P < 0.001). 1, 2

• Bupropion augmentation of SSRIs reduces depression severity more effectively than buspirone augmentation in patients who failed initial SSRI monotherapy. 1, 2

• A prospective randomized controlled trial showed that adding bupropion to SSRIs in partial responders resulted in 60% remission rates (per HDRS) and 63% (per MADRS) compared to only 24-27% with SSRI continuation alone (p < 0.05). 3

Alternative Augmentation Options

• Augmentation is equally effective as switching to another antidepressant but may be preferred to avoid discontinuation symptoms and preserve any partial benefit already achieved. 1, 2, 4

• If switching is chosen over augmentation, the STAR*D trial showed no significant differences in response or remission when switching from one antidepressant to another (bupropion SR, sertraline, or venlafaxine XR), with response rates of 21-28%. 1, 2

• For patients who smoke, combine bupropion with nicotine replacement therapy (NRT) to address both depression and smoking cessation simultaneously, with 12-month abstinence rates of 35.5% for the combination versus 30.3% for bupropion alone. 2

Clinical Trial Evidence Summary

Bupropion as Augmenting Agent

• A prospective, randomized, controlled, single-blind study of 60 patients with major depressive disorder and partial response to SSRIs (HDRS ≥16 after 4 weeks) demonstrated that SSRI plus bupropion achieved significantly higher remission rates (60-63%) compared to SSRI plus placebo (24-27%). 3

• The mean decrease in depression scores (HDRS, MADRS, and ADI) was significantly greater in the bupropion augmentation group compared to placebo augmentation. 3

Switching to Bupropion

• An open-trial study of 29 patients with MDD refractory to 8-12 weeks of fluoxetine showed that switching to bupropion SR resulted in 35% full responders, 25% partial responders, and 30% remitters using completer analysis. 5

• Approximately 60% of patients with MDD resistant to fluoxetine experienced a full or partial response when switched to bupropion SR. 5

Clinician Practice Patterns

• A survey of 466 clinicians (mean 16.6 years in practice) showed that bupropion was the most widely chosen augmenting agent (30%), followed by lithium (22%), when managing partial SSRI response. 6

• More experienced clinicians preferred bupropion as a first-choice augmenter, whereas less experienced clinicians showed a slight preference for lithium. 6

Critical Timing and Monitoring

When to Modify Treatment

• Reassess diagnosis and treatment if no improvement occurs after 6-8 weeks of bupropion at adequate doses (typically 300 mg/day for depression). 1, 2

• Begin monitoring patient status, therapeutic response, and adverse effects within 1-2 weeks of initiating any treatment modification. 1, 2

• The risk for suicide attempts is greatest during the first 1-2 months of treatment, requiring close monitoring especially in patients under 24 years of age. 1, 2

Response Expectations

• Response rates to antidepressant therapy may be as low as 50%, with 38% of patients not achieving treatment response and 54% not achieving remission during 6-12 weeks of treatment. 1, 2

• Do not discontinue treatment prematurely before 6-8 weeks unless significant adverse effects occur. 2

Safety Considerations for Augmentation

Maximum Dosing

• The maximum dose of bupropion must not exceed 450 mg/day (for XL formulation) or 400 mg/day (for SR formulation) to maintain seizure risk at 0.1%. 2

• When augmenting with an SSRI, monitor for serotonin syndrome, though this is rare with bupropion combinations. 1

Monitoring Parameters

• Assess for neuropsychiatric adverse effects including agitation, restlessness, and behavioral changes, particularly when combining medications. 2

• Monitor blood pressure and heart rate periodically, especially in the first 12 weeks, as bupropion can cause elevations in both parameters. 2

• Watch for increased suicidal ideation, especially during the first 1-2 months after treatment modification. 1, 2

Common Pitfalls to Avoid

• Do not switch antidepressants prematurely before allowing 6-8 weeks at adequate doses, as this may result in loss of partial benefit already achieved. 1, 2, 4

• Do not combine bupropion with MAOIs or use within 14 days of discontinuing MAOIs due to serious drug interactions. 2

• Avoid exceeding maximum daily doses when augmenting, as seizure risk increases significantly above 450 mg/day. 2

• Do not use naltrexone-bupropion combination products in patients on any opioid therapy, including buprenorphine/naloxone (Suboxone), as naltrexone will precipitate severe withdrawal. 2

Special Populations

• For patients with moderate to severe hepatic impairment, reduce the total daily dose by half and do not exceed 150 mg daily. 2

• For patients with moderate to severe renal impairment (GFR <90 mL/min), reduce the total daily dose by 50%. 2

• Avoid bupropion in patients with seizure disorders, eating disorders (bulimia/anorexia), or those abruptly discontinuing alcohol, benzodiazepines, or antiepileptic drugs. 2