In a patient with major depressive disorder currently taking bupropion (Wellbutrin) 300 mg daily who remains severely depressed, can brexpiprazole (Rexulti) be added as an adjunct?

Can You Add Rexulti to Wellbutrin 300mg for Severe Depression?

Yes, you can add brexpiprazole (Rexulti) to bupropion (Wellbutrin) 300mg for treatment-resistant major depressive disorder, as this is an FDA-approved indication and supported by clinical trial evidence. However, proceed with heightened caution regarding neuropsychiatric monitoring given the patient's severe depression and bupropion's existing antidepressant properties.

FDA-Approved Indication and Dosing

Brexpiprazole is FDA-approved as adjunctive treatment to antidepressants for major depressive disorder 1. The drug label explicitly states that no dosage adjustment is required when brexpiprazole is combined with bupropion, as bupropion is a CYP2B6 substrate and brexpiprazole does not significantly interact with this pathway 1.

Standard dosing approach:

• Start brexpiprazole at 0.5-1 mg daily for days 1-4
• Increase to 1 mg daily on days 5-7
• Target dose: 2 mg daily (can increase to 3 mg if needed)
• Titrate based on response and tolerability 1

Evidence for Efficacy

Multiple randomized controlled trials demonstrate that adjunctive brexpiprazole significantly improves depressive symptoms when added to antidepressants:

• Pooled analysis of 4 studies (n=1,853) showed adjunctive brexpiprazole 2-3 mg/day produced greater improvement in MADRS scores compared to placebo (effect size 0.33, p<0.0001) 2
• Response rates at 6 weeks: Number needed to treat = 17 for response, 25 for remission 3
• Benefits appear as early as Week 1 and are maintained through 6 weeks 4
• Effective across multiple symptom clusters including anhedonia, dysphoria, and lassitude 4

Importantly, brexpiprazole showed efficacy in patients with minimal response (<25% improvement) to antidepressants, with a Cohen's d of 0.41 (p<0.001) 5, which is relevant for your patient with "serious depression."

Critical Safety Considerations

Neuropsychiatric Monitoring (HIGHEST PRIORITY)

You must implement intensive monitoring for worsening depression and suicidal ideation, particularly in the first 1-2 months 6:

• Weekly visits for the first 4 weeks, then biweekly through week 8
• Use structured assessment tools (e.g., C-SSRS) at each visit
• Educate patient and family about warning signs: agitation, irritability, unusual behavioral changes
• Document baseline suicidality before starting brexpiprazole

The FDA drug label carries a black box warning for suicidal thoughts and behaviors, especially in patients under 24 years old 1. While clinical trials of brexpiprazole showed low rates of suicidality (0.03% vs 0.2% placebo) 7, your patient's severe depression warrants heightened vigilance.

Depression-Specific Concerns

Critical caveat: The AACE/ACE guidelines specifically state that naltrexone-bupropion ER (which contains bupropion) should be used with caution or avoided in patients with depression 7. While this refers to the combination product for obesity, it raises the question of whether adding ANY medication to bupropion in severe depression requires extra caution.

However, the brexpiprazole drug label notes that patients with depression were not excluded from MDD trials, and the combination showed no increased depression rates compared to placebo 7, 1.

Common Adverse Effects to Monitor

Most frequent side effects with adjunctive brexpiprazole (≥5%) 1:

• Akathisia (8.0%) - may worsen agitation in severe depression
• Weight gain (5.8%)
• Headache (5.8%)
• Somnolence - monitor for excessive sedation

When to Modify Treatment

Following ACP guidelines for treatment-resistant depression 6:

Reassess at 6-8 weeks:

• If inadequate response: Consider dose increase to 3 mg daily or switch strategies
• If partial response: Continue current regimen
• If no response: Discontinue brexpiprazole and pursue alternative augmentation

Alternative considerations if brexpiprazole fails or is not tolerated:

• Switch antidepressant class entirely (per ACP Recommendation 3) 6
• Consider psychotherapy augmentation (CBT, interpersonal therapy)
• Evaluate for treatment-resistant depression protocols

Common Pitfalls to Avoid

1. Don't delay intervention: Your patient has "serious depression" on adequate bupropion dosing (300mg). Waiting longer than 6-8 weeks without modification increases morbidity 6

2. Don't assume bupropion is optimized: Verify adherence, timing of doses, and whether 300mg is truly the maximum tolerated dose before adding brexpiprazole

3. Don't overlook seizure risk: Bupropion lowers seizure threshold; brexpiprazole doesn't significantly add to this, but document seizure history 8

4. Don't forget metabolic monitoring: Baseline weight, glucose, lipids, then periodic monitoring given atypical antipsychotic class effects 1

Bottom Line Algorithm

For your patient with severe MDD on bupropion 300mg:

1. ✓ Verify adequate trial duration (≥6-8 weeks at 300mg)
2. ✓ Assess baseline suicidality with structured tool
3. ✓ Start brexpiprazole 0.5-1 mg, titrate to 2 mg over 1 week
4. ✓ Weekly monitoring weeks 1-4 for worsening depression/suicidality
5. ✓ Reassess efficacy at week 6-8
6. ✓ Continue if response achieved; adjust or discontinue if inadequate

The combination is evidence-based, FDA-approved, and appropriate for treatment-resistant MDD, but requires vigilant neuropsychiatric monitoring given the severity of your patient's depression 1, 5, 3, 2.