Bupropion and Rexulti (Brexpiprazole) Interaction
Bupropion and Rexulti (brexpiprazole) can be safely used together without dose adjustment, as bupropion does not significantly affect brexpiprazole levels or require dosing modifications. 1
Pharmacokinetic Interaction Profile
The FDA-approved prescribing information for Rexulti explicitly addresses this combination. Bupropion is a CYP2B6 substrate, and no dosage adjustment is required for either bupropion or brexpiprazole when administered concomitantly 1. This is based on pharmacokinetic studies demonstrating that brexpiprazole does not meaningfully alter the metabolism of CYP2B6 substrates like bupropion 1, 2.
Key Mechanistic Points:
- Brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, not CYP2B6 1
- Bupropion is metabolized by CYP2B6 and acts as a CYP2D6 inhibitor 3
- While bupropion inhibits CYP2D6, the FDA label specifically notes that in clinical trials for major depressive disorder, brexpiprazole dosing was NOT adjusted for strong CYP2D6 inhibitors (like fluoxetine and paroxetine), meaning CYP considerations are already factored into standard dosing recommendations 1
Clinical Implications
For patients with major depressive disorder taking an antidepressant (including bupropion), add brexpiprazole at standard dosing without adjustment:
- Start brexpiprazole at 0.5-1 mg daily
- Titrate to target dose of 2 mg daily (maximum 3 mg daily) 1
- No dose reduction needed when combined with bupropion
Evidence from Clinical Practice:
A 2018 case series specifically examined patients who switched from bupropion to brexpiprazole due to insufficient outcomes, demonstrating that brexpiprazole was well-tolerated and effective in this population 4. This supports the safety of transitioning between these agents and suggests they occupy different therapeutic niches without problematic interactions.
Important Safety Considerations
Seizure Risk with Bupropion:
While not an interaction per se, bupropion lowers seizure threshold with a 0.1-0.48% seizure risk depending on dose 5, 6. This risk is:
- Dose-dependent (keep ≤450 mg/day) 6
- Contraindicated in patients with seizure disorders, bulimia, anorexia nervosa, or abrupt alcohol/benzodiazepine discontinuation 6
- Particularly relevant if brexpiprazole is being added for treatment-resistant depression in patients with these risk factors
Monitoring Parameters:
When combining these medications, monitor for:
- Akathisia/restlessness (common with brexpiprazole, especially at higher doses)
- Metabolic effects (weight gain, glucose changes with brexpiprazole)
- Neuropsychiatric symptoms (both agents carry warnings, though serious events are rare) 5
- Activation/agitation (particularly when initiating combination therapy)
Clinical Context
This combination is clinically relevant because brexpiprazole is FDA-approved as adjunctive therapy to antidepressants for major depressive disorder 1, and bupropion is a commonly used antidepressant. Recent evidence shows brexpiprazole is effective when added to antidepressants in patients with minimal or partial response 7, 8, making this a rational combination for treatment-resistant depression.
The bottom line: Prescribe both medications at their standard therapeutic doses without adjustment for the drug-drug interaction, as none exists that requires dosing modification.