Adding Rexulti (Brexpiprazole) to a Patient Already on Abilify (Aripiprazole)
There is no evidence supporting the addition of brexpiprazole (Rexulti) to a patient already receiving aripiprazole (Abilify), and this combination should be avoided. Both medications are dopamine D2 partial agonists with nearly identical mechanisms of action, making concurrent use pharmacologically redundant and potentially harmful.
Why This Combination Is Not Recommended
Pharmacological Redundancy
Both aripiprazole and brexpiprazole function as dopamine D2 receptor partial agonists—they work through the same mechanism at the same receptor sites 1. Adding one to the other provides no additional therapeutic benefit, as they would essentially compete for the same receptors rather than providing complementary effects.
Guideline Recommendations Against This Practice
The most recent international guidelines explicitly address antipsychotic polypharmacy strategies. When guidelines recommend aripiprazole augmentation, they specifically state this should only be offered "in individuals not already prescribed a D2 partial agonist" 2. This directly excludes adding brexpiprazole to aripiprazole or vice versa.
The 2021 comprehensive guideline on antipsychotic polypharmacy emphasizes that when combining antipsychotics, clinicians should select agents with differing side-effect profiles and mechanisms 3. Combining two D2 partial agonists violates this fundamental principle.
What the Evidence Actually Shows
Switching, Not Adding
The available research examines switching from aripiprazole to brexpiprazole, not combining them 4, 5. A Japanese study found that switching to brexpiprazole from aripiprazole was safe and associated with minimal metabolic changes 4. Another case series showed that patients with insufficient outcomes on aripiprazole could benefit by switching to brexpiprazole 5.
No Drug Interaction Data for This Combination
The FDA label for Rexulti discusses numerous drug interactions but makes no mention of concurrent use with aripiprazole 6. This absence is telling—there's no established dosing, safety data, or rationale for this combination.
Appropriate Clinical Approach
If Aripiprazole Is Insufficient:
Option 1: Switch to Brexpiprazole
- Taper aripiprazole while initiating brexpiprazole
- Evidence supports this approach for patients with inadequate response 4, 5
Option 2: Switch to a Different Mechanism
- Consider cariprazine (another D2 partial agonist with different receptor binding profile)
- Switch to a D2 antagonist antipsychotic
- Trial clozapine if treatment-resistant 2
Option 3: Augmentation with Different Mechanism
- If remaining on aripiprazole, consider augmenting with a D2 antagonist (not another partial agonist)
- The 2025 guidelines note potential benefits of combining clozapine with aripiprazole for specific symptoms 2, 3
Critical Pitfalls to Avoid
Don't combine two D2 partial agonists - This includes aripiprazole + brexpiprazole, aripiprazole + cariprazine, or brexpiprazole + cariprazine
Don't assume "newer is better" - Brexpiprazole is not inherently superior to aripiprazole; they have comparable efficacy with slightly different tolerability profiles 1
Don't add without removing - If considering brexpiprazole for a patient on aripiprazole, this should be a switch, not an addition
Risk-Benefit Analysis
Risks of combining these agents:
- Increased side effect burden without additional efficacy 3
- Higher rates of akathisia, weight gain, and metabolic effects 3
- Increased medication costs
- Reduced adherence due to treatment complexity 3
- No mortality benefit and potential for increased adverse events 3
Benefits of combining these agents:
- None documented in the literature
Bottom Line
The appropriate clinical decision is to either continue aripiprazole alone, switch to brexpiprazole monotherapy, or augment aripiprazole with an antipsychotic having a different mechanism of action. Prescribing both simultaneously lacks scientific rationale, violates evidence-based guidelines, and exposes patients to unnecessary risks without potential benefit.