Rexulti (Brexpiprazole) Drug Classification and Clinical Use
Rexulti (brexpiprazole) is a third-generation atypical antipsychotic that functions as a serotonin-dopamine activity modulator, FDA-approved for two specific indications: monotherapy treatment of schizophrenia in adults and adjunctive treatment to antidepressants for major depressive disorder (MDD) in adults. 1
Drug Classification
Brexpiprazole is classified as a third-generation atypical antipsychotic, distinguished by its unique receptor profile as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, combined with antagonist activity at serotonin 5-HT2A receptors and noradrenergic α1B and α2C receptors. 2, 3, 4
The third-generation classification reflects its partial dopamine receptor agonist activity, which differentiates it pharmacologically from second-generation antipsychotics that act purely as dopamine-serotonin antagonists. 5, 6
Brexpiprazole displays significantly less intrinsic activity at D2 receptors compared to aripiprazole (another third-generation agent), which theoretically translates to a lower propensity for activating adverse events and extrapyramidal symptoms. 3
The drug's balanced receptor affinity profile—with actions at 5HT1A, 5HT2A, and noradrenaline α1B receptors that are at least as potent as its D2 receptor activity—contributes to its favorable tolerability profile. 3
FDA-Approved Indications
Schizophrenia (Monotherapy)
Brexpiprazole is approved for the treatment of schizophrenia in adults at a recommended dose of 2-4 mg once daily, with a starting dose of 1 mg/day. 1
The maximum dosage is 4 mg/day for schizophrenia, and the medication should be administered orally once daily with or without food. 1
Clinical trials demonstrated statistically significant and clinically meaningful improvements in overall symptomatology and psychosocial functioning compared with placebo in adults with acute exacerbation of schizophrenia. 3
In relapse prevention studies, brexpiprazole 1-4 mg/day significantly delayed time to relapse compared with placebo in stabilized patients (13.5% vs. 38.5% relapse rate, NNT = 4). 3, 7
Major Depressive Disorder (Adjunctive Therapy)
Brexpiprazole is approved as adjunctive therapy to antidepressants for MDD in adults at a recommended target dose of 2 mg once daily, with a starting dose of 0.5-1 mg/day and maximum dose of 3 mg/day. 1
This indication is specifically for patients who have demonstrated inadequate response to standard antidepressant therapy, not as monotherapy for depression. 7, 8
Pooled data from Phase III trials showed 23.2% of brexpiprazole-treated patients were responders versus 14.5% for placebo (NNT = 12), indicating modest but statistically significant efficacy. 7
Dosage Adjustments Required
Dose reductions are mandatory in specific populations to prevent toxicity:
For moderate to severe hepatic impairment: Maximum dose is 2 mg once daily for MDD and 3 mg once daily for schizophrenia. 1
For renal impairment (CrCl < 60 mL/minute): Maximum dose is 2 mg once daily for MDD and 3 mg once daily for schizophrenia. 1
For CYP2D6 poor metabolizers or patients taking strong/moderate CYP2D6 or CYP3A4 inhibitors: Administer half the recommended dosage; if both inhibitors are present, administer one-quarter of the recommended dosage. 1
Safety Profile and Monitoring
Brexpiprazole carries a boxed warning for increased mortality in elderly patients with dementia-related psychosis (for which it is NOT approved) and for suicidal thoughts and behaviors in pediatric and young adult patients when used for MDD. 1
Common Adverse Effects
For schizophrenia: Weight gain was the most common adverse effect (≥4% and at least twice the rate for placebo). 1
For MDD: Weight increased, somnolence, and akathisia (≥5% and at least twice the rate for placebo) were most common, with akathisia occurring in 8.6% of patients (NNH = 15). 1, 7
Akathisia was frequently reported in MDD trials but less so in schizophrenia trials, representing a key tolerability consideration. 8
Metabolic and Cardiovascular Effects
Brexpiprazole demonstrates a relatively favorable metabolic profile compared to many second-generation antipsychotics, with small changes in metabolic parameters that were not clinically significant in short-term trials. 3
However, more outliers with ≥7% body weight increase were evident in open-label 52-week safety studies, suggesting cumulative weight gain risk with long-term use. 7
Minimal effects on prolactin and no clinically relevant QT interval prolongation were observed in clinical trials. 3, 7
Clinical Context and Place in Therapy
The traditional classification of antipsychotics into generations is clinically misleading and should not guide treatment selection—instead, choose medications based on their specific receptor profiles, side effect profiles, and patient-specific factors. 5, 6
Brexpiprazole represents a viable option for treating acute exacerbation of schizophrenia requiring hospitalization or adjunctive treatment of MDD in patients with inadequate response to 1-3 antidepressants. 8
Head-to-head comparisons with other available agents in real-world settings are needed to definitively establish its place in therapy relative to other antipsychotics. 7