Dissecting Heterogeneity of Treatment Response of First Episode Schizophrenia

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Description (provided by applicant): There is now considerable evidence that anatomic pathology is present at the first episode of schizophrenia. Little research has been directed at understanding whether these anatomic deficits and their longitudinal course can be used to predict treatment response and neuropsychological and functional outcome measures. The identification of patients early in the course of illness who are nonresponsive to standard antipsychotic treatment could have significant implications for pharmacologic intervention and strategies for improving subsequent prognosis. Neurobiological predictors of treatment response in schizophrenia have not been well defined, however, and this phenomenon has no clear neurobiological basis, although a defect in the brain gray matter has been implicated. Moreover, recent empirical and theoretical work suggests that a defect in the brain white matter may be a contributing factor to antipsychotic nonresponse in schizophrenia. The investigation of neurobiological predictors in schizophrenia has been limited in large part due to the lack of controlled clinical trials from which to recruit patients and test hypotheses regarding response. Our preliminary data suggest that prefrontal gray matter deficits, as assessed via cortical surface mapping methods, predict treatment response in patients with first episode schizophrenia. Additional preliminary data suggest that lower fractional anisotropy, as assessed via diffusion tensor imaging, in frontotemporal regions is associated with treatment nonresponse in these patients. In the present study we propose scanning a unique group of 75 antipsychotic drug-naive, first episode schizophrenia patients. Patients will be drawn from an NIMH-sponsored (2R01-MH60004) double-blind randomized 12-week trial of risperidone vs. aripiprazole, and followed with regular assessments under controlled treatment as part of the CIDAR clinical algorithm for one year. The specific aims of this study are to: (1) determine the relationship between cortical gray matter volume/density and white matter fractional anisotropy in first episode patients with schizophrenia and treatment response/outcome following the 12 week randomized clinical trial and after 52 weeks of controlled treatment; and (2) examine changes in gray matter volume/density and white matter fractional anisotropy in first episode patients over the 12 week randomized clinical trial and after 52 weeks of controlled treatment in relationship to treatment response/outcome. The identification of these abnormalities at the first episode of illness may be useful for identifying indicators of vulnerability, which may lead to improved early identification of individuals at risk for schizophrenia.