Brexpiprazole, a serotonin-dopamine activity modulator, is a partial agonist at 5-HT1A and dopamine D2 receptors, and antagonist at 5-HT2A and noradrenaline α1B and α2C receptors, all at similar potency. Efficacy of brexpiprazole was evaluated in patients with acutely exacerbated schizophrenia in three short-term, randomized, double-blind, placebo-controlled studies.
In a Phase 2 study, patients were randomized to brexpiprazole 0.25 mg (fixed dose), 1.0 ± 0.5 mg, 2.5 ± 0.5 mg, 5.0 ± 1 mg (flexible-dose ranges), placebo, or aripiprazole 15 ± 5 mg. In two Phase 3 studies, patients were randomized to fixed-dose brexpiprazole 0.25 mg, 1 mg, 2 mg, or 4 mg, or placebo. For this review, brexpiprazole 2 mg and 4 mg arms from the Phase 3 studies were combined. Primary efficacy endpoint was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline at week 6; key secondary endpoint was change in Clinical Global Impression-Severity of illness (CGI-S) score at week 6. Primary outcome moderator analyses explored effects of sex, age, race, and illness duration.
There were no statistically significant differences vs. placebo in the Phase 2 brexpiprazole and aripiprazole groups for primary and key secondary endpoints. Combined brexpiprazole 2 mg (n = 359) and 4 mg (n = 359) were superior to placebo (n = 358) in change in PANSS total score (least square mean difference from placebo: − 5.46, p = 0.0004, and − 6.69, p < 0.0001, respectively) and CGI-S (− 0.25, p = 0.0035, and − 0.38, p < 0.0001, respectively). Changes from baseline in efficacy endpoints were minimal in the 0.25 mg group, while the 1 mg group exhibited suboptimal improvement. No relevant moderators were identified.
Meta-analysis of the pivotal studies indicates brexpiprazole 2 mg and 4 mg are effective in treating acute schizophrenia.
