Effectiveness of the selective D4 antagonist sonepiprazole in schizophrenia: a placebo-controlled trial

Background Selective localization of dopamine D4 receptors in the prefrontal cortex and preferential affinity of clozapine for the dopamine D4 receptor over the D2 receptor led to the hypothesis that the superior efficacy of clozapine may be mediated via blockade of the D4 receptor. This hypothesis was tested by evaluating sonepiprazole, a selective D4 dopamine antagonist, in schizophrenia patients. Methods We treated 467 hospitalized schizophrenia patients with scores of ≥ 60 on the Positive and Negative Syndrome Scale (PANSS) with sonepiprazole, olanzapine, or placebo once daily for 6 weeks. The primary efficacy end point was the mean change from baseline in the PANSS total score at 6 weeks. Secondary efficacy end points were the mean change from baseline in the PANSS factor scores, the Brief Psychiatric Rating Scale score, the Clinical Global Impressions Severity of Illness score, and the Calgary Depression Scale score. Results No statistically significant differences were observed between placebo and any sonepiprazole dose on the primary or any secondary end point after 6 weeks of treatment. Statistically significant differences, favoring olanzapine over placebo, were observed on all efficacy end points but the Calgary Depression Scale. Conclusions Sonepiprazole was ineffective for the treatment of patients with schizophrenia.