Alternative Medications to Rexulti (Brexpiprazole)
For schizophrenia or major depressive disorder augmentation, aripiprazole is the most direct alternative to brexpiprazole, as both are dopamine D2 partial agonists with similar mechanisms of action, though aripiprazole has higher intrinsic D2 activity and may cause more akathisia. 1, 2, 3
Primary Alternatives Based on Indication
For Schizophrenia Treatment
Second-generation (atypical) antipsychotics are the preferred alternatives, with selection based on side effect profile and patient-specific factors:
Aripiprazole is the closest pharmacological alternative, sharing the D2 partial agonist mechanism but with higher intrinsic activity at D2 receptors, potentially leading to more activating effects and akathisia 3, 4, 5
Risperidone starting at 0.25 mg daily at bedtime, maximum 2-3 mg daily in divided doses, is effective for psychotic symptoms with lower risk of extrapyramidal symptoms than typical antipsychotics 6
Olanzapine starting at 2.5 mg daily at bedtime, maximum 10 mg daily, is generally well tolerated but carries higher metabolic risk 6
Quetiapine starting at 12.5 mg twice daily, maximum 200 mg twice daily, provides more sedation and requires monitoring for orthostatic hypotension 6
Cariprazine is another D2 partial agonist with lower akathisia rates than aripiprazole but higher than brexpiprazole 4, 5
Ziprasidone offers minimal weight gain and metabolic effects, making it preferable when these are concerns 4
For Major Depressive Disorder Augmentation
When brexpiprazole is used as adjunctive treatment for depression:
Aripiprazole is FDA-approved for depression augmentation and represents the most evidence-based alternative with similar mechanism 1, 4
Quetiapine (extended-release formulation) is also approved for depression augmentation but carries higher sedation and metabolic burden 6
Selection Algorithm Based on Clinical Priorities
When Minimizing Akathisia Risk:
- Choose olanzapine or quetiapine over aripiprazole, as brexpiprazole's lower D2 intrinsic activity (compared to aripiprazole) was designed specifically to reduce akathisia 3, 4, 5
- Brexpiprazole has akathisia rates of 5.5% in schizophrenia and 8.6% in depression, with NNH of 15 for depression 2, 4
When Minimizing Sedation:
- Choose aripiprazole or ziprasidone, as these have the lowest sedation profiles among atypicals 1, 4
- Avoid olanzapine and quetiapine if sedation is problematic 6, 1
When Minimizing Metabolic Effects:
- Choose aripiprazole, ziprasidone, or cariprazine over olanzapine or quetiapine 6, 4
- The 2025 INTEGRATE guidelines recommend switching to antipsychotics with more benign metabolic profiles when weight gain or metabolic syndrome develops 6
When Minimizing Weight Gain:
- Aripiprazole and ziprasidone cause less weight gain than brexpiprazole 4
- Brexpiprazole causes more weight gain than aripiprazole or cariprazine but less than olanzapine 4, 5
Important Clinical Considerations
Dose adjustments are required for elderly patients, those with hepatic impairment, or poor CYP2D6 metabolizers when using any of these alternatives 1, 4
Monitoring requirements before starting any alternative antipsychotic should include: BMI, waist circumference, blood pressure, HbA1c, glucose, lipids, prolactin, liver function tests, electrolytes, full blood count, and ECG 6
Common pitfall: Switching directly between antipsychotics without considering cross-titration strategies can lead to symptom exacerbation or withdrawal effects. When switching from brexpiprazole, gradual cross-titration is generally preferred over abrupt discontinuation.
Cardiovascular considerations: Aripiprazole is preferred when QTc prolongation is a concern, as it has not been associated with significant QT prolongation 1
Hyperprolactinemia management: If switching due to prolactin-related side effects, aripiprazole or other D2 partial agonists are preferred, as they typically lower prolactin levels 6