Can I prescribe bupropion (Wellbutrin) and brexpiprazole (Rexulti) together for a patient with major depressive disorder who has no contraindications?

Can You Prescribe Bupropion (Wellbutrin) and Brexpiprazole (Rexulti) Together?

Yes, you can safely prescribe bupropion and brexpiprazole together for a patient with major depressive disorder who has inadequate response to antidepressant monotherapy, as brexpiprazole is FDA-approved specifically as adjunctive therapy to antidepressants including bupropion. 1, 2

FDA-Approved Indication for This Combination

• Brexpiprazole received FDA approval in 2015 specifically for adjunctive treatment of major depressive disorder in patients with inadequate response to antidepressant therapy. 1, 3
• Bupropion is FDA-approved for major depressive disorder, and the combination represents a legitimate evidence-based augmentation strategy. 2, 3

Evidence Supporting Efficacy

• Meta-analysis of four randomized controlled trials demonstrates that adjunctive brexpiprazole produces a mean reduction of -1.76 points (95% CI: -2.45 to -1.07) on the Montgomery-Åsberg Depression Rating Scale compared to placebo when added to ongoing antidepressant therapy. 3
• The response rate (≥50% reduction in MADRS) shows a risk ratio of 1.57 (95% CI: 1.29-1.91), and remission rate shows a risk ratio of 1.55 (95% CI: 1.22-1.96) favoring adjunctive brexpiprazole. 3
• Pooled analysis of three Phase 3 trials (n=1,171) confirms efficacy across patients with and without anxiety symptoms, with least squares mean differences ranging from -1.38 to -3.00 points on MADRS. 4

Critical Safety Screening Before Prescribing

Before initiating this combination, verify the patient does NOT have:

• Dementia-related psychosis (brexpiprazole carries a black box warning for increased mortality in elderly patients with dementia-related psychosis). 1
• Seizure disorder or conditions predisposing to seizures (bupropion lowers seizure threshold; risk is approximately 0.1% at 300 mg/day). 5, 2
• Current or recent MAOI use (within 14 days—contraindicated with bupropion). 5, 2
• Uncontrolled hypertension (bupropion can elevate blood pressure and heart rate). 5
• Eating disorders (bulimia or anorexia—bupropion increases seizure risk in these populations). 5
• Concurrent opioid use if considering naltrexone-bupropion formulations (not applicable to standard bupropion monotherapy). 5

Dosing Protocol

Bupropion Dosing

• Start bupropion SR at 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) if tolerated. 5
• Maximum dose is 400 mg/day for SR formulation or 450 mg/day for XL formulation. 5
• For older adults, start at 37.5 mg every morning and increase by 37.5 mg every 3 days as tolerated, with maximum 300 mg/day. 5
• Administer the second dose before 3 PM to minimize insomnia risk. 5

Brexpiprazole Dosing

• Initiate brexpiprazole at 1 mg/day for days 1-4, then increase to 2 mg/day on days 5-7, with a target dose of 2-3 mg/day. 1
• The FDA label supports doses of 1-3 mg/day as adjunctive therapy for MDD. 1
• Most clinical trial data support 2-3 mg/day as the optimal therapeutic range. 3, 6, 4

Mandatory Monitoring Parameters

Week 1-2 Monitoring

• Assess for suicidal ideation, agitation, irritability, or unusual behavioral changes within 1-2 weeks of initiation, as the risk for suicide attempts is greatest during the first 1-2 months of antidepressant treatment. 7, 5
• This monitoring is particularly critical in patients younger than 24 years, who have increased risk of suicidal thoughts with all antidepressants. 7, 5

Ongoing Monitoring

• Monitor blood pressure and heart rate periodically, especially during the first 12 weeks, as bupropion can cause elevations in both parameters. 5
• Assess for akathisia and extrapyramidal symptoms (EPS), as the incidence of akathisia with adjunctive brexpiprazole is 9% versus 2% with placebo. 1, 3
• Monitor weight, as brexpiprazole causes clinically relevant weight gain (≥7%) in 10.5% of patients, with mean weight increase of 4-7% in clinical trials. 1, 3, 8
• Evaluate for metabolic changes including blood glucose and lipids, as atypical antipsychotics carry risk of metabolic syndrome. 1

Expected Timeline for Response

• Allow 6-8 weeks at therapeutic doses before determining treatment response. 7, 5
• Bupropion may produce more rapid improvement in energy levels within the first few weeks compared to SSRIs. 5
• If no adequate response occurs by 6-8 weeks, modify the treatment approach by adjusting doses or considering alternative strategies. 7, 5

Common Adverse Effects to Counsel Patients About

Brexpiprazole-Related

• Akathisia (9% vs 2% placebo), weight increase (7% vs 2% placebo), and somnolence (5% vs 0.5% placebo) are the most common adverse effects when brexpiprazole is added to antidepressants. 1, 3
• Headache (21.3%), restlessness (3%), and fatigue (3%) are also frequently reported. 1, 8
• The incidence of akathisia is dose-related, increasing from 4% at 1 mg/day to 14% at 3 mg/day. 1

Bupropion-Related

• Insomnia, headache, dry mouth, and nausea are common with bupropion. 5
• Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs, making this combination advantageous for patients concerned about sexual side effects. 7, 5
• Bupropion is associated with minimal weight gain or even weight loss, which may partially offset brexpiprazole-related weight gain. 7, 5

Discontinuation Rates and Tolerability

• The discontinuation rate due to adverse events with adjunctive brexpiprazole is 3% versus 1% with placebo, indicating generally good tolerability. 1
• Meta-analysis shows a risk ratio of 3.44 (95% CI: 1.52-7.80) for discontinuation due to adverse events with brexpiprazole versus placebo. 3
• The combination is well-tolerated in young adults (ages 18-35) in work or school environments, with most common adverse events being headache (21.3%), weight increase (17.0%), and somnolence (17.0%). 8

Clinical Advantages of This Specific Combination

• Bupropion's norepinephrine-dopamine reuptake inhibition combined with brexpiprazole's partial dopamine D2 and serotonin 5-HT1A agonism provides complementary mechanisms for treatment-resistant depression. 5, 1
• This combination may be particularly beneficial for patients with depression characterized by low energy, apathy, or hypersomnia, as bupropion has activating properties. 5
• Patients concerned about sexual dysfunction or weight gain may benefit from bupropion's favorable profile in these domains. 7, 5

Special Population Considerations

Hepatic Impairment

• For moderate to severe hepatic impairment, reduce bupropion to maximum 150 mg daily. 5
• Brexpiprazole dose adjustment is not required for hepatic impairment per FDA labeling. 1

Renal Impairment

• For moderate to severe renal impairment (GFR <90 mL/min), reduce bupropion total daily dose by 50%. 5
• Brexpiprazole maximum dose should be 3 mg/day in severe renal impairment. 1

Elderly Patients

• Brexpiprazole is contraindicated in elderly patients with dementia-related psychosis due to increased mortality risk. 1
• For elderly patients without dementia, start bupropion at lower doses (37.5 mg daily) and titrate slowly. 5

Critical Clinical Pitfalls to Avoid

• Do NOT exceed bupropion 450 mg/day total, as seizure risk increases significantly above this dose. 5, 2
• Do NOT skip the intensive monitoring window in weeks 1-2, as this period carries the highest risk for emergent suicidal ideation. 7, 5
• Do NOT administer bupropion's second dose late in the day, as this increases insomnia risk; give before 3 PM. 5
• Do NOT discontinue bupropion abruptly; taper gradually to reduce withdrawal symptoms. 5
• Do NOT combine with MAOIs or within 14 days of MAOI discontinuation. 5, 2