What is the use and dosage of Rexulti (brexpiprazole) in treating schizophrenia and major depressive disorder?

Rexulti (Brexpiprazole): Uses, Dosing, and Clinical Considerations

Rexulti (brexpiprazole) is FDA-approved for the treatment of schizophrenia in adults and as an adjunctive treatment for major depressive disorder (MDD) in adults who have had an inadequate response to antidepressant therapy. 1

Indications and Mechanism of Action

Brexpiprazole is an atypical antipsychotic that works as a serotonin-dopamine activity modulator with the following properties:

• Partial agonist at dopamine D2 receptors and serotonin 5-HT1A receptors
• Antagonist at serotonin 5-HT2A receptors and adrenergic alpha1B/alpha2C receptors
• Less intrinsic activity at D2 receptors compared to aripiprazole, which may contribute to its different side effect profile 2, 3

Dosing Recommendations

For Schizophrenia:

• Starting dose: 1 mg once daily on Days 1-4
• Titration: Increase to 2 mg once daily on Days 5-7
• Target dose: 2-4 mg once daily (maximum recommended dose: 4 mg daily) 1

For Adjunctive Treatment of MDD:

• Starting dose: 0.5 mg or 1 mg once daily
• Titration: Increase to 1 mg once daily, then titrate to target dose at weekly intervals
• Target dose: 2 mg once daily (maximum recommended dose: 3 mg daily) 1

Special Populations:

• Hepatic impairment (moderate to severe): Maximum 2 mg daily for MDD and 3 mg daily for schizophrenia
• Renal impairment (CrCl < 60 mL/min): Maximum 2 mg daily for MDD and 3 mg daily for schizophrenia
• CYP2D6 poor metabolizers: Administer half of the recommended dosage 1

Clinical Efficacy

Schizophrenia:

• Two positive 6-week Phase 3 trials demonstrated superiority over placebo
• Pooled responder rates: 46% for brexpiprazole 2-4 mg/day vs. 31% for placebo (NNT = 7)
• In a 52-week maintenance study, significantly fewer patients relapsed with brexpiprazole compared to placebo (13.5% vs. 38.5%, NNT = 4) 2, 4

Major Depressive Disorder:

• Effective as adjunctive therapy in patients with inadequate response to antidepressants alone
• NNT of 12 for response and 17-31 for remission versus placebo 3, 4

Adverse Effects and Safety Profile

Common Adverse Effects:

• Weight gain: Most common adverse event with incidence ≥4% and at least twice the rate of placebo
  • Approximately 10% of patients on 1-4 mg/day gained ≥7% body weight (vs. 4% for placebo, NNH = 17)
  • More pronounced weight gain observed in longer-term studies 2, 4

Other Adverse Effects:

• Akathisia: 5.5% for pooled doses vs. 4.6% for placebo in schizophrenia trials (NNH = 112)
  • Higher rates in MDD trials (8.6%, NNH = 15) 4
• Metabolic effects: Minimal effects on glucose and lipids
• Prolactin: Minimal effects
• QTc interval: No clinically relevant effects 2, 4

Important Warnings:

• Increased mortality in elderly patients with dementia-related psychosis (not approved for this population)
• Suicidal thoughts and behaviors: Increased risk in pediatric and young adult patients; close monitoring required 1

Administration Considerations

• Can be taken with or without food
• Once-daily dosing
• Dose adjustments needed with concomitant CYP3A4 inhibitors, CYP2D6 inhibitors, or strong CYP3A4 inducers 1

Comparison to Other Antipsychotics

• Lower rates of akathisia compared to aripiprazole and cariprazine
• More weight gain than aripiprazole, cariprazine, or ziprasidone
• Less sedation than aripiprazole but more than cariprazine 3

Brexpiprazole represents a valuable option in the treatment of schizophrenia and as an adjunctive treatment for MDD, with a favorable side effect profile regarding akathisia and extrapyramidal symptoms compared to some other antipsychotics. However, monitoring for weight gain is important, particularly in long-term treatment.