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Characterization of a Treatment-Response Biomarker in Patients with Schizophrenia

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This application addresses broad Challenge Area (03): Biomarker Discovery and Validation, 03-MH- 101 Biomarkers in mental disorders. The research proposed continues investigation of a new treatment-response biomarker (antipsychotic-biomarker) identified in paired samples of lymphocytes collected from consecutively enrolled patients with schizophrenia. The first blood sample is collected after a person is being admitted to the hospital for acute psychosis. A second blood sample is collected once the patient is stable on medication. The antipsychotic-biomarker was found at high levels during acute psychosis and low levels after treatment using two methods of analysis (microarray expression analysis and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The antipsychotic-biomarker is increased 3-23 fold during acute psychosis in 10 of 11 paired samples (p=0.037, using a paired T- test, 2 tailed). Relapse is a primary contributor to schizophrenia disease burden. Relapse is not entirely due to noncompliance and 27-50% of patients on injectable antipsychotic medication relapse each year into acute psychosis consistent with a need to monitor and adjust medications in accordance with a variable disease course. To date, unbiased biological markers that indicate fluctuation of disease course or markers of response to therapy do not exist. The hypothesis that the level of the antipsychotic-biomarker is decreased in lymphocytes in response to treatment with antipsychotics is tested in patients (Aim 1) and in cultured lymphocytes (Aim 2). Aim 1 is to verify differential gene expression of our novel antipsychotic-biomarker through the analysis of 42 more paired samples collected during the 2-year project period. In Aim 2 peripheral blood lymphocytes will be incubated with an antipsychotic with the intent of generating a dose response curve. Aim 3 is to verify 45 other putative treatment response biomarkers related to the same dopamine pathway using genomics and qRT-PCR. Identifying treatment-response biomarkers is the first step toward developing a tool that can be employed to optimize antipsychotic dose, predict treatment response, monitor the course of illness and ultimately prevent relapse. Treatment- response biomarkers are essential to relieving the primary burden of schizophrenia disease.

PUBLIC HEALTH RELEVANCE; Progress in understanding and effectively treating diseases like schizophrenia is dependent on identifying reliable objective measures of disease in readily accessible tissues such as blood. This proposal will verify and characterize a novel gene expression biomarker of antipsychotic treatment response in patients with schizophrenia. Additional blood based biomarkers will be sought.

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