This application provides the candidate with the expertise and skills needed to study metabolic disorders, as well as psychopathology and cognitive function in patients with schizophrenia. The candidate proposes a career development plan that consists of coursework, directed learning and mentored research projects in the early years of the award, and emphasizes follow-up studies and preparation of manuscripts and grants in the later years. The training and the proposed projects will serve as a foundation for the candidate's independent clinical research in the future. The candidate proposes a series of studies to be conducted over the 5-year award period. These studies will focus on two major themes: 1) exploring the mechanisms of antipsychotic-induced metabolic disturbances in schizophrenia patients as well as in healthy subjects; 2) interventional studies to address metabolic disturbances, psychopathology, and cognitive impairment in schizophrenia patients. Ultimately these proposed studies will lead to the development of innovative interventional strategies to treat medical comorbidity and possibly to improve psychiatric symptoms and cognitive deficits in patients with this devastating mental illness. As a representative study, the candidate proposes a 12-week, randomized, double-blind, placebo-controlled trial of telmisartan 80 mg/day, as an adjunctive therapy in 70 clozapine or olanzapine treated schizophrenia patients. The primary aims are to examine the efficacy of telmisartan in: 1) improving insulin resistance and glucose metabolism based on changes in insulin sensitivity index (SI), glucose effectiveness (SG) and the acute insulin response to glucose (AIRG) using the frequently sampled intravenous glucose tolerance test (FSIVGTT) and Bergman's minimal model analysis; 2) reducing fasting plasma triglycerides and LDL; 3) improving positive symptoms, negative symptoms and cognitive impairment. Obesity, diabetes and cardiovascular disease are much more common in schizophrenia patients compared with the general population. The high prevalence of these serious medical problems apparently contributes to the high mortality rate of this patient population, which is approximately twice that of the general population. The research area proposed by the candidate addresses a critical yet under studied public health issue. ? ? ?
