SBIR-STTR Award

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

Schizophrenia, the most serious of the mental disorders, afflicts 1% of the population, causing suffering to patients and their families and stretching health care resources to a maximum. It is the mission of Gabriel Pharma to improve the treatment and health care for patients with mental illnesses through genetic, pharmacological and other technologies. A primary goal of this grant is to establish a genetic screen for antipsychotic drug response and genetic predictors of outcome of schizophrenia, enabling an individualized approach to treatment and resource allocation. This proposal describes the rationale, design and scientific development of the Interactive Clinical Information and DNA database (CI-DNA) introduced in Phase I. The CI-Database will be expanded to include two pharmacological database components designed for pharmacogenetics analysis and a first-of-its-kind clinical outcome database for schizophrenia designed for genetic predictor analysis. Phase I successfully developed the clinical portion of a database for the pharmacogenetics of clozapine. As part of the Phase I feasibility study Gabriel Pharma established, for the first time, genetic predictors of negative symptom response to clozapine. In Phase II, subjects in the expanded database will be genotyped for a panel of ten functional candidate gene variants. These genes are chosen for their relationship to the central nervous system (CNS), schizophrenia and antipsychotic drug mechanisms. In addition, three recently discovered schizophrenia susceptibility genes will be examined in the database. The fully developed proprietary CI-DNA database system is a unique innovation enabling the establishment of genetic screens for antipsychotic drug response and schizophrenia outcome through internal and collaborative scientific efforts. This work has the potential of impacting the individual patient with schizophrenia as well as broader needs in related health care delivery.

Thesaurus Terms:
antipsychotic agent, genetic screening, mental disorder chemotherapy, psychopharmacology, schizophrenia, therapy design /development catechol methyltransferase, central nervous system, clozapine, dopamine receptor, dopamine transporter, gene expression, genetic susceptibility, human therapy evaluation, mental health information system, pharmacogenetics, serotonin transporter clinical research, human subject, neuropsychological test, patient oriented research