ROSIGLITAZONE FOR CLOZAPINE INDUCED GLUCOSE METABOLISM IMPAIRMENT

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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 cause fewer extrapyramidal side effects than conventional neuroleptics but have a variety of other side effects. Obesity is a known side effect of neuroleptics and recent reports in the literature have linked clozapine with weight gain. By increasing a patient's risk of obesity, antipsychotic agents may be placing patients at risk for associated morbidity and mortality. Patients who gain greater than 10% of their total body weight are at risk for developing weight associated conditions such as hypertension and non-insulin dependent diabetes. Clozapine remains the most effective agent for treatment-resistant schizophrenia, developing interventions to prevent serious clozapine-related medical morbidity is critical. Diabetes is a devastating disease with complications including cardiovascular disease, renal disease, neuropathy, and retinopathy. In addition to schizophrenia, diabetes significantly impacts the health, quality of life, and life expectancy of this population. Furthermore, in a population with chronic mental illness and subsequent difficulty in following up with medical care, the economic impact of type 2 diabetes mellitus is profound. We propose an eight-week, double-blind, placebo-controlled trial of rosiglitazone in schizophrenia subjects treated with clozapine using Bergman's MINMOD FSIVGTT for examination of glucose metabolism. The MINMOD determines the relationship between insulin sensitivity, insulin secretion and the degree of obesity and can be used to study drug effects upon these variables. The computer program estimates glucose effectiveness (SG), insulin sensitivity index (SI), and the acute insulin response to glucose (AIRG). (see below). These parameters will be calculated from glucose and insulin values measured during the FSIVGTT. The Specific Aims are to: 1. Compare the effects of treatment with rosiglitazone to placebo in schizophrenia subjects treated with clozapine on insulin SI, SG, and AIRG by performing baseline and 8-week follow-up FSIVGTT. 2. Correlate the findings on SI, SG and AIRG with change in BMI, body composition, family history, age, sex, race, diet, exercise, weight gain, and lipid abnormalities. 3. Determine if rosiglitazone, compared to placebo, improves other variables associated with insulin resistance such as biochemical makers for cardiovascular disease (plasminogen activator inhibitor-1 [PAI-1], LDL particle size, C-reactive protein, soluble intercellular adhesion molecule-1 [sICAM-1], and von Willebrand factor [vWF]) and cognitive deficits. 4. Examine the effects of insulin resistance and hyperglycemia on cognition in subjects with schizophrenia 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. Fifty clozapine-treated subjects will be recruited from the Freedom Trail Clinic. Patients must be between the ages of 18-65, with the diagnosis of schizophrenia, schizoaffective disorder or schizophreniform disorder. Patients will be matched according to baseline fasting glucose. They will be stratified into two groups: normal fasting glucose (glucose <100 mg/dL) and impaired fasting glucose (glucose =100 mg/dL and < 126 mg/dL).