DESCRIPTION (provided by applicant): Clozapine remains the most effective agent for the treatment-resistant schizophrenia population. Though clozapine produces fewer extrapyramidal side effects, it is not without side effects, which may include sedation and weight gain. In a five year observational study, we found that 30 of 82 (36.6%) patients treated with clozapine developed diabetes mellitus, and increases in weight, total cholesterol and triglyceride was also observed. We recently completed a study of 36 nonobese schizophrenia patients and found abnormalities in insulin sensitivity and glucose utilization in clozapine- and olanzapine- non-obese treated patients suggesting an impairment of glucose metabolism and increased risk of diabetes. We also conducted a six-week open label study of adjunctive therapy with aripiprazole, an atypical antipsychotic agent, in ten clozapine-treated patients. Significant reductions in fasting triglyceride, total cholesterol, weight and body mass index (BMI) were observed. Method: We propose an eight week, placebo-controlled trial of aripiprazole for adjunctive therapy in 70 clozapine-treated schizophrenia subjects to examine aripiprazole's affect on lipid metabolism, glucose metabolism, and body composition and cardiovascular risk factors. We will perform a battery of symptoms scales to exam clinical correlates of combination therapy. Significance: The results of this study should help clarify the usefulness of adjunctive therapy with aripiprazole in clozapine-treated patients and the relationship of hyperlipidemia to insulin resistance and weight. Clinical adjunctive therapy may establish aripiprazole as a new therapeutic approach in schizophrenia and clozapine-associated medical disorders.