Given the frequent prescription of benzodiazepines (BZDs) as adjunctive treatment to antipsychotics, this study aimed to uncover how BZD use affects treatment outcomes with cariprazine (CAR). This post-hoc analysis used pooled data from four placebo-controlled trials in patients with acute schizophrenia. Efficacy evaluations involved changes from baseline to Week 6 on PANSS Total Score, Marder Positive Factor Score, Excitement Component Subscale Score, and Marder Anxiety Single Item Score. Safety evaluations focused on extrapyramidal symptoms and akathisia. Comparisons were made between CAR alone vs. placebo (PLB) alone
CAR+BZD vs. PLB+BZD
CAR alone vs. CAR+BZD
and PLB alone vs. PLB+BZD. Data from 1643 patients were analysed (CAR only=943
CAR+BZD=132
PLB only=475
PLB+BZD=93). CAR alone yielded significantly greater improvement on all measures than PLB alone. CAR+BZD yielded significantly greater improvements in overall schizophrenia symptoms than PLB+BZD. CAR alone showed greater improvements in overall, positive, and anxiety symptoms compared to CAR+BZD. PLB alone yielded significantly greater improvements in positive and anxiety symptoms than PLB+BZD. Anxiety and agitation were the leading reasons for BZD administration. CAR was associated with more akathisia and EPS in both the non-BZD and BZD-user groups than PLB. The results support the superior efficacy of CAR with or without BZD co-treatment for total and positive symptoms of schizophrenia compared to PLB with or without BZD use. These findings suggest BZDs should be used for emergent symptoms like anxiety or agitation, rather than core schizophrenia symptoms.