This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Atypical antipsychotic agents offer significant improvements in side effect profiles relative to conventional antipsychotic agents, particularly concerning extrapyramidal symptoms (EPS). Clozapine, an atypical antipsychotic agent, remains the most effective agent for the treatment-resistant schizophrenia population. Though clozapine produces fewer extrapyramidal side effects, it is not without side effects. Several reports in the literature suggest an association of clozapine with hyperlipidemia, weight gain, hypertension, insulin resistance, hyperglycemia, diabetic ketoacidosis (DKA) and type 2 diabetes mellitus (DM). In a five-year observational study, we found that 30 of 82 (36.6%) patients treated with clozapine developed diabetes mellitus, which was not correlated with weight gain. Significant increases in total cholesterol and triglyceride was observed. We also studied the effects of clozapine, olanzapine, and risperidone in a cross-sectional design, using a frequent sampled intravenous glucose intolerance test (FSIVGTT) which allowed for the measurement of insulin sensitivity index (SI), glucose effectiveness (SG,) and the acute insulin response (AIRG). Results suggested abnormalities in SI and SG in clozapine- and olanzapine- non-obese treated subjects, suggesting insulin resistance and an impairment of glucose utilization, both increasing the risk for DM. Hyperinsulinemia or insulin resistance is thought to impair lipid metabolism and is a precursor to DM. It is possible that the lipid abnormalities observed with clozapine treatment is secondary to insulin resistance induced by the drug. Few interventions have been successful to prevent or reverse the medical complications of clozapine therapy. We 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, comparing baseline to study endpoint. We now propose an 8-week, placebo-controlled trial of the novel antipsychotic agent, aripiprazole, with a 4-week follow-up for adjunctive therapy in 70 clozapine-treated schizophrenia subjects to examine aripiprazole's affect on lipid and glucose metabolism, as well as body composition. We will also perform a battery of symptoms scales to exam clinical correlates of combination therapy. 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 gain with clozapine treatment. Specific Aims: Primary: 1. Examine the efficacy of aripiprazole for reducing fasting lipids, including triglycerides and total cholesterol, by conducting an 8-week placebo-controlled trial of 15 mg aripiprazole in 70 clozapine-treated schizophrenia subjects. 2. Examine the efficacy of aripiprazole for weight loss and BMI reduction. 3. Examine the efficacy of aripiprazole for improving insulin resistance and glucose metabolism measured by examining changes in fasting insulin, homeostatic model assessment-insulin resistance (HOMA-IR), and SI, SG from FSIVGTT. 4. Analyze potential predictors of response for improvements in lipids, weight loss, and insulin resistance, including baseline lipids, weight, age, gender, race, activity levels, and smoking status. Secondary: 1. Examine the aripiprazole's effect on food intake and energy expenditure. 2. Evaluate tolerability and safety of aripiprazole added to clozapine using the SAFTEE and vital signs. 3. Correlate the findings from the FSIVGTT, SI, and SG with age, sex, race, and changes in BMI, body composition, family history, diet, exercise, weight gain, and lipid abnormalities. 4. Correlate improvements in lipid and glucose metabolism with change in biochemical predictors of atherosclerosis by sequential measurements of plasminogen activator moledcule-1 (PAI-1), LDL particle size, C-reactive protein, soluble intercellular adhesion molecule-1 (sICAM-1), and von Willebrand factor (vWF). 5. Characterize the changes of baseline lipid abnormalities using apolipoproteins and lipoprotein density classes. 6. Evaluate the effects of aripiprazole upon negative symptoms (SANS total score), positive symptoms (PANSS total score and positive symptom sub score) and depressive symptoms (Hamilton Depression Rating Scale). The site for subject enrollment, clinical assessment, and collection of blood will be at the Freedom Trail Clinic at the Erich Lindemann Mental Health Center. The FSIVGTT and blood samples will be conducted at the Mallinckrodt General Clinical Research Center at Massachusetts General Hospital.