Is it safe to use Vraylar (cariprazine) with Rexulti (brexpiprazole) together?

Combining Vraylar (Cariprazine) with Rexulti (Brexpiprazole) is Not Recommended

Using two dopamine receptor partial agonists (DRPAs) together—Vraylar (cariprazine) and Rexulti (brexpiprazole)—is not supported by evidence and should be avoided due to overlapping mechanisms of action, increased risk of adverse effects, and lack of demonstrated additive benefit.

Rationale for Avoiding This Combination

Overlapping Pharmacological Mechanisms

• Both cariprazine and brexpiprazole are dopamine D2 receptor partial agonists with similar mechanisms of action, functioning as serotonin-dopamine activity modulators (SDAMs) 1, 2.
• They both act as partial agonists at dopamine D2 and serotonin 5-HT1A receptors, and as antagonists at 5-HT2A receptors 3, 1.
• Combining drugs with similar mechanisms provides no therapeutic advantage and increases the risk of cumulative side effects 2.

Increased Risk of Adverse Effects

• Both medications can cause extrapyramidal symptoms (EPS), akathisia, weight gain, and metabolic effects 1, 4.
• Cariprazine and brexpiprazole both carry risks of akathisia, with cariprazine showing higher rates compared to placebo 1.
• Combining these agents would amplify dopaminergic effects, potentially increasing akathisia, restlessness, insomnia, and agitation 3, 2.
• The cumulative dopamine receptor occupancy could paradoxically worsen psychotic symptoms or cause unpredictable motor side effects 1.

Lack of Evidence for Combination Therapy

• No clinical trials have evaluated the safety or efficacy of combining two DRPAs 2.
• There are no head-to-head comparisons between aripiprazole, brexpiprazole, or cariprazine, let alone studies of their combination 2.
• The absence of evidence for benefit, combined with predictable increased risks, makes this combination unjustifiable in clinical practice 1, 2.

Clinical Alternatives

If Current Monotherapy is Inadequate

• Switch from one DRPA to another rather than combining them, as each has distinct pharmacokinetic and pharmacodynamic properties that may offer different clinical responses 1, 2.
• Consider augmentation with a medication from a different class (e.g., mood stabilizer, antidepressant, or non-DRPA antipsychotic) depending on target symptoms 2.

Specific Considerations

• If negative symptoms are the primary concern, cariprazine has demonstrated specific efficacy for primary negative symptoms of schizophrenia 2.
• If akathisia is problematic with one DRPA, brexpiprazole may have relatively lower incidence compared to aripiprazole, though still present 3, 1.
• For treatment-resistant cases, consider clozapine or augmentation strategies with evidence-based combinations rather than dual DRPA therapy 2.

Common Pitfalls to Avoid

• Do not assume that "more is better" with partial agonists—excessive D2 receptor stimulation can worsen outcomes 1.
• Avoid polypharmacy with mechanistically redundant agents, which increases pill burden, costs, and side effects without proven benefit 2.
• If a patient is on both medications, taper one off while monitoring for symptom changes rather than continuing the combination 1.