What are the considerations for using bupropion (Wellbutrin) and brexpiprazole (Rexulti) together?

Bupropion and Brexpiprazole Combination: Clinical Considerations

The combination of bupropion (Wellbutrin) and brexpiprazole (Rexulti) is pharmacologically compatible and can be safely administered together without dosage adjustments, as brexpiprazole requires no dosage modification when used with bupropion. 1

Pharmacological Compatibility

Bupropion and brexpiprazole can be used together without significant pharmacokinetic concerns:

• The FDA label for brexpiprazole specifically states that "no dosage adjustment for substrates of CYP2D6, CYP3A4, CYP2B6 (e.g., bupropion), BCRP, or P-gp is required when administered concomitantly with brexpiprazole" 1
• Brexpiprazole is a major substrate of CYP2D6 and CYP3A4, while bupropion is a CYP2B6 substrate 1

Therapeutic Rationale and Benefits

This combination may be particularly beneficial in several clinical scenarios:

1. Treatment-resistant depression:

   • Bupropion is FDA-approved as an antidepressant that works through dopamine and norepinephrine reuptake inhibition 2
   • Brexpiprazole is approved as an adjunctive treatment for major depressive disorder 3
   • Research suggests that patients with inadequate response to previous adjunctive therapies may benefit from switching to brexpiprazole 4

2. Depression with cognitive symptoms:

   • The combination has shown improvements in cognitive functioning in patients with depression 4
   • Mean changes from baseline in Cognitive and Physical Functioning Questionnaire scores showed significant improvement (-9.2, P<.0001) when brexpiprazole was added 4

3. Depression with comorbid conditions:

   • For patients with depression and comorbid obesity, naltrexone-bupropion ER is conditionally recommended 2, but brexpiprazole could be considered as an alternative adjunctive agent

Clinical Evidence for Efficacy

Research supports the potential benefits of this combination:

• A study examining patients switched to brexpiprazole after insufficient outcomes with aripiprazole or bupropion showed that the majority exhibited good tolerability of brexpiprazole with reduction in PHQ-9 scores 5
• Another study demonstrated that the combination of brexpiprazole with SSRIs (fluoxetine) promoted rapid antidepressant effects through BDNF-TrkB signaling 6
• In a 6-week open-label study, patients switched to adjunctive brexpiprazole showed significant improvements in depressive symptoms (Montgomery-Åsberg Depression Rating Scale change: -17.3, P<.0001) 4

Safety Considerations and Monitoring

When using this combination, monitor for:

1. Seizure risk:

   • Bupropion lowers the seizure threshold and should be avoided in patients with epilepsy or elevated seizure risk 2
   • Use caution in patients with brain metastases or history of seizures 2

2. Cardiovascular effects:

   • Monitor vital signs as bupropion can cause elevated heart rate and blood pressure 2
   • Avoid in patients with uncontrolled hypertension 2

3. Common side effects:

   • For bupropion: dry mouth, insomnia, headaches, nausea 2
   • For brexpiprazole: dizziness, headaches, insomnia, somnolence 7
   • For the combination: potential fatigue (14.8%) and akathisia (8.2%) 4

4. Special populations:

   • In patients with moderate to severe renal or hepatic impairment, brexpiprazole dosage adjustments may be required 7
   • Avoid bupropion in patients requiring opioid therapy, as it may be combined with naltrexone which antagonizes opioid effects 2

Dosing Considerations

• Start with standard doses of each medication and adjust based on response and tolerability
• For bupropion, typical dosing is 150-300 mg daily 2
• For brexpiprazole as adjunctive therapy in MDD, dosing typically ranges from 2-3 mg daily 7
• If a patient has not shown improvement after 12 weeks on maintenance doses, consider discontinuing or modifying the regimen 2

Potential Advantages Over Other Combinations

This combination may offer advantages over other adjunctive strategies:

• Unlike some atypical antipsychotics, brexpiprazole has a more favorable metabolic profile 3
• The combination may be particularly beneficial for patients with depression and comorbid anxiety or cognitive dysfunction 4
• For patients who cannot tolerate aripiprazole, brexpiprazole may be better tolerated due to its different pharmacological profile (less intrinsic activity at D2 receptors) 3, 5