Negative symptoms are a key feature of schizophrenia that pose a strong limitation on the real-life functioning of patients. In order to establish whether antipsychotic drugs are truly effective on primary negative symptoms (as opposed to negative symptoms secondary to positive, extrapyramidal or depressive symptoms), studies in specific populations are needed. To this end, a phase III, multinational, randomised, double-blind, active-controlled trial was conducted with a 26-week treatment duration in 460 adults (18-65) with schizophrenia eliciting predominant negative symptoms. Cariprazine (4.5 mg once daily) was shown to be superior to risperidone (4.0 mg/day) in reducing the negative symptoms (P=0.0022) and improving PSP total score (the secondary efficacy parameter, P<0.0001). Cariprazine’s additional effect size on negative symptoms vs. risperidone (0.31) was comparable to the effect size of other antipsychotics vs. placebo (0.42) in this patient population, thus almost doubling the total effect size vs. placebo (although this is an indirect comparison). An increased percentage of patients responded to the cariprazine treatment with ≥20% and ≥30% decrease in PANSS-FSNS, resulting an NNT26wk of 9 and 8, respectively. These improvements occurred independently of those in positive, depressive, or extrapyramidal symptoms. The advantages of cariprazine on primary negative symptoms are thought to be associated with its preference for D3 (vs. D2) receptors, along with a considerable affinity for the 5-HT1A receptor.

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