Schizophrenia is a major public health concern. Almost 40 percent of patients with schizophrenia have poor outcome despite the best current treatment efforts, indicating a need for new therapeutic approaches. This Mentored Clinical Scientist Development Award (SDA) application describes a training and research program aimed at clarifying the role of membrane deficits in schizophrenia, a novel and promising area of research with significant potential for a new hypothesis-driven therapeutic approach to improving outcome. There is accumulating and consistent evidence that membrane deficits, particularly reductions in polyunsaturated fatty acids (PUFA) are seen in schizophrenia and that reversal of these deficits by essential fatty acid supplementation have positive clinical effects. If this area of research is found to have pathophysiological relevance for schizophrenia, then PUFA supplementation strategies may be useful adjuncts to current empirically derived treatments. However, a number of questions must be addressed before this area of research can gain wider acceptance. Therefore, careful and systematic assessment of the notion that membrane deficits are relevant to schizophrenia is needed; this can be achieved by developing and testing heuristic models and establishing clinical parameters by, which to assess therapeutic efficacy of essential fatty acid supplementation. Because of Dr. Reddy?s clinical experience with schizophrenia, his previous research on membrane biochemistry, he is ideally positioned to further the research in this emerging area. Moreover, the mentorship in separate but overlapping areas of expertise that is central to this SDA is available at his institution. In addition to the structured training plan that includes course work, tutorials and supervision, Dr. Reddy will conduct related studies that will, (I) examine the clinical and biological effects of repairing putative membrane deficits by conducting an open-label adjunctive treatment trial with an omega-3 fatty acid in 40 early-course schizophrenic patients; (2) examine whether PTJFA levels in red blood cells (RBC) parallel central phospholipid metabolism as determined by 31P magnetic resonance spectroscopy; and, (3) examine in a rat model whether RBC PUFA levels parallel brain PUFA levels, a critical issue in determining whether RBC PUFA levels can serve as surrogate for brain PUFA levels. By completing these training and research goals, Dr. Reddy will be ready to independently engage in the future development and application of interventions targeting membrane deficits in schizophrenia. Further, the training will provide versatility and flexibility in applying his expertise to other neuropsychiatric disorders where membrane deficits may play a role, and being able to evaluate emerging treatments focused on membrane repair.
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