GENETIC SCREEN FOR ANTIPSYCHOTIC DRUG RESPONSE

DESCRIPTION (provided by applicant): Screening for antipsychotic drug response is a research priority to identify new drugs with long-term efficacy and minimal side effects for drug resistant individuals. Schizophrenia, a major public health problem afflicting approximately 1% of Americans, costs over $40 billion annually. The discipline of pharmacogogenomics utilizes genetic information to predict therapeutic drug response. New atypical antipsychotic drugs enhance therapeutics and outcomes of schizophrenia, but differences in individual patient response exist. Other treatment barriers include undesirable side effects impeding medication compliance, an important public health priority. Pharmacogenetics' promises to identify a priori response predictors guiding informed pharmacotherapeutics, enabling patient screening for tolerance and medication compliance. Key NIMH clinical studies of schizophrenic patients yielded unique longitudinal clinical information. We propose to combine this clinical information with contemporaneous patient DNA samples (Cl-DNA database) to test feasibility of a new genetic screen for pharmacogenetics of antipsychotic drug response. This Cl-DNA database has longitudinal behavioral ratings of antipsychotic treatment, placebo washout and treatment with the current gold standard stypical antipsychotic, clozapine (limited due to small but real risk of death). This study will provide preliminary validation for pharmacogenomic investigation by screening drug response to clozapine in relation to variants for the gene coding for catechol-O-methyl transferase, a known marker for dopamine. Phase II will modify, refine and expand the Cl-DNA database for full-scale validation with additional data from other antipsychotic treatments. This proposal will create a unique screen with broad and immediate research application including drug development and clinical practice and important preliminary information regarding gene variants in relation to clozapine treatment. The goal is a commercial individualized treatment screen to identify genetic of antipsychotic drug response.