Brexpiprazole is a serotonin-dopamine activity modulator that is a partial agonist at 5-HT_1A and dopamine D₂ receptors at similar potency, and an antagonist at 5-HT_2A and noradrenaline alpha_1B/2C receptors.

Evaluating the efficacy, safety, and tolerability of flexible doses of brexpiprazole compared with placebo in patients with acute schizophrenia.

Primary endpoint was change from baseline to week 6 in PANSS total score and key secondary endpoint was change from baseline to week 6 in CGI-S score.

Phase 3, multi-center, randomized, double-blind, placebo-controlled, active reference, trial (NCT01810380). Hospitalized patients were randomized to brexpiprazole (2 to 4mg/day), placebo, or quetiapine extended release (400 to 800mg/day) for 6 weeks. Quetiapine was included as an active reference. Changes from baseline were analyzed using an MMRM approach.

Mean change in PANSS total score was −20.0 and −15.9 in the brexpiprazole (n=150) and placebo (n=159) groups, respectively (P=0.056). Sensitivity analyses suggested treatment effect (e.g., ANCOVA, LOCF: P=0.025; ANCOVA, OC: P=0.026). Mean change in PANSS total score (−24.0) with quetiapine (n=150) was significantly greater than that with placebo (P<0.001), demonstrating sensitivity of the assay. Brexpiprazole separated from placebo on the mean change in CGI-S score (−1.2 vs. −0.9, P=0.014). The proportion of patients reporting TEAEs were similar between the brexpiprazole and placebo treatment groups (54% versus 54.7%).

Treatment with brexpiprazole showed a clinically meaningful improvement in patients with acute schizophrenia. While the difference between brexpiprazole and placebo only approached statistical significance, sensitivity analyses and secondary endpoints supported a treatment effect of brexpiprazole.