Background: Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. This multicenter trial examined the efficacy, safety, and tolerability of aripiprazole in patients with acute exacerbation of schizophrenia or schizoaffective disorder. Methods: In this 4-week double-blind study, 404 patients were randomized to 20 mg/d (n=101) or 30 mg/d (n=101)ofaripiprazole,placebo(n=103),or6mg/dofrisperidone (n=99). Efficacy assessments included Positive and Negative Syndrome Scale (PANSS) scores and ClinicalGlobalImpressionscores.Safetyandtolerabilityevaluations included extrapyramidal symptoms and effects on weight, prolactin, and corrected QT (QTc) interval. Results: Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/d) were significantly better than placebo on all efficacy measures. Separation from placebo occurred at week 1 for PANSS total and positive scores with aripiprazole and risperidone and for PANSS negative scores with aripiprazole. There were no significant differences between aripiprazole and placebo in mean change from baseline in the extrapyramidal symptom rating scales. Meanprolactinlevelsdecreasedwitharipiprazolebutsignificantlyincreased5-foldwithrisperidone.Meanchange in QTc interval did not differ significantly from placebo with any active treatment group. Aripiprazole and risperidone groups showed a similar lowincidence of clinically significant weight gain. Conclusions: Aripiprazole is effective, safe, and well toleratedforthepositiveandnegativesymptomsinschizophreniaandschizoaffectivedisorder.Itisthefirstnon-D2receptorantagonistwithclearantipsychoticeffectsandrepresents a novel treatment development for psychotic disorders. Arch Gen Psychiatry. 2003;60:681-690