Is Rexulti (brexpiprazole) effective in treating psychosis, particularly in adults with schizophrenia or major depressive disorder?

Does Rexulti Help with Psychosis?

Yes, Rexulti (brexpiprazole) is FDA-approved and effective for treating psychosis in adults with schizophrenia, with proven efficacy in reducing positive psychotic symptoms such as hallucinations and delusions. 1

FDA-Approved Indications

Brexpiprazole is specifically indicated for:

• Treatment of schizophrenia in adults (as monotherapy) 1
• Adjunctive treatment of major depressive disorder in adults (not primarily for psychosis) 1

The drug received FDA approval in 2015 based on robust clinical trial data demonstrating efficacy for psychotic symptoms. 2

Efficacy for Psychotic Symptoms

In acute schizophrenia, brexpiprazole at the recommended dose of 2-4 mg/day demonstrates clear superiority over placebo:

• Response rate: 45.5% vs 31.0% for placebo 3
• Number needed to treat (NNT): 7 (95% CI 5-12), meaning approximately 7 patients need treatment for one additional patient to respond 3
• Significantly reduces positive symptoms including hallucinations, delusions, and thought disorder 4, 3

For relapse prevention, the evidence is even stronger:

• Relapse rate: 13.5% vs 38.5% for placebo 3
• NNT: 4 (95% CI 3-8), indicating robust maintenance efficacy 3

Mechanism of Action

Brexpiprazole works as a serotonin-dopamine activity modulator with a unique receptor profile: 4, 2

• Partial agonist at dopamine D2 receptors (antipsychotic effect)
• Partial agonist at serotonin 5-HT1A receptors
• Antagonist at serotonin 5-HT2A receptors
• Antagonist at noradrenergic α1B and α2C receptors 2

This mechanism places it in the category of atypical (second-generation) antipsychotics, which are generally preferred over traditional neuroleptics due to lower risk of extrapyramidal symptoms. 5

Dosing for Psychosis

For schizophrenia treatment: 1

• Starting dose: 1 mg/day
• Target dose: 2-4 mg/day
• Maximum dose: 4 mg/day
• Administer once daily with or without food 1
• Allow at least 4 weeks at therapeutic dose before determining efficacy 6

Safety and Tolerability Profile

Brexpiprazole demonstrates favorable tolerability compared to many antipsychotics:

Common adverse effects: 3, 7

• Akathisia (5.5% in schizophrenia trials, modest difference from placebo with NNH of 112)
• Weight gain (modest in short-term, but more outliers with ≥7% increase in long-term studies)
• Discontinuation due to adverse events was actually lower than placebo in schizophrenia trials 3

Metabolic effects are relatively modest: 3

• Small effects on glucose and lipids
• Minimal prolactin elevation
• No clinically relevant QT prolongation 3

Critical Warnings

Black box warnings apply: 1

• Increased mortality in elderly patients with dementia-related psychosis (not approved for this use)
• Suicidal thoughts and behaviors in pediatric and young adult patients (though primarily relevant for MDD indication)

Other important warnings: 1

• Neuroleptic malignant syndrome (manage with immediate discontinuation)
• Tardive dyskinesia (discontinue if clinically appropriate)
• Metabolic changes require monitoring
• Orthostatic hypotension and syncope
• Seizure risk in susceptible patients

Place in Treatment Algorithm

Based on current guidelines, brexpiprazole represents a reasonable first-line option for schizophrenia: 6

• First-line antipsychotics include amisulpride, risperidone, paliperidone, olanzapine, and aripiprazole 6
• Brexpiprazole shares pharmacological similarities with aripiprazole (both are D2 partial agonists) 6, 4
• Selection should be based on individual side-effect profiles 6

If brexpiprazole fails after 4-6 weeks at therapeutic dose: 6

• Switch to an antipsychotic with different pharmacodynamic profile
• Consider clozapine for treatment-resistant cases 5, 8

Comparison to Other Antipsychotics

While head-to-head trials are limited, brexpiprazole appears to offer: 3, 7

• Similar efficacy to other atypical antipsychotics for positive symptoms
• Lower akathisia rates compared to some alternatives
• More favorable metabolic profile than olanzapine or clozapine
• Efficacy comparable to aripiprazole but potentially better tolerability in some patients 4

Common Pitfalls to Avoid

• Do not use inadequate trial duration: Allow full 4-6 weeks at therapeutic dose before concluding lack of efficacy 6
• Avoid polypharmacy as initial strategy: Monotherapy is preferred unless multiple trials have failed 6
• Do not neglect metabolic monitoring: Despite modest effects, regular monitoring of weight, glucose, and lipids is essential 1
• Dose adjustments required: Reduce dose by half with strong CYP2D6 or CYP3A4 inhibitors; reduce to quarter dose with combined inhibitors 1