This study is a multi-site, randomized controlled trial that will enroll 60 patients who began antipsychotic treatment for schizophrenia or schizoaffective disorder less than five years prior to study entry and who are currently in treatment for a recent or ongoing psychotic exacerbation. After baseline assessments have been completed, patients will be randomly assigned to olanzapine, perphenazine or aripiprazole. Patients assigned to olanzapine will receive concomitant treatment with metformin and patients assigned to perphenazine will receive concomitant treatment with benztropine from day one of treatment. Any patient, regardless of treatment assignment, whose non-HDL cholesterol rises to greater than 190, will receive simvastatin. Metformin and benztropiill also be available for all patients according to clinical need, regardless of treatment assignment. In addition for patients with elevated triglycerides for whom simvastatin is not indicated fenofibrate will be added. Patients will be followed for up to 28 weeks. All patients will receive a manualized behavioral therapy intervention focused on diet and exercise. All treatments will be open label, but raters of psychopathology and EPSE will be blinded to treatment assignment.

Weight gain, insulin resistance, and non-HDL cholesterol elevations that are not addressed lead to accelerated cardiovascular morbidity and mortality. Acute EPSE (parkinsonian rigidity and akathisia) that are not addressed may lead to tardive dyskinesia. Strategies are available to address these adverse effects of olanzapine and perphenazine. The study will determine if olanzapine, with its metabolic effects addressed, is more efficacious than perphenazine and aripiprazole; and, if aripiprazole is a more successfully tolerable treatment than olanzapine and perphenazine even if the adverse effects of the latter drugs are addressed.