Genetic Screen for Antipsychotic Drug Response

描述(由申请人提供)：抗精神病药物反应筛查是一项研究重点，旨在为耐药个体确定具有长期疗效和最小副作用的新药。精神分裂症是困扰大约1%美国人的一个主要公共卫生问题，每年花费超过400亿美元。药物基因组学利用遗传信息来预测治疗药物的反应。新的非典型抗精神病药物提高了精神分裂症的治疗效果和结果，但个体患者的反应存在差异。其他治疗障碍包括阻碍服药依从性的不良副作用，这是一个重要的公共卫生优先事项。药物遗传学承诺识别先验反应预测因素，指导知情的药物治疗，使患者能够筛选耐受性和用药依从性。精神分裂症患者的关键NIMH临床研究产生了独特的纵向临床信息。我们建议将这些临床信息与同期的患者DNA样本(CL-DNA数据库)相结合，以测试抗精神病药物反应的药物遗传学新的遗传筛选的可行性。这个氯化脱氧核糖核酸数据库有抗精神病药物治疗、安慰剂洗脱和目前金标准的典型抗精神病药物氯氮平治疗的纵向行为评级(由于小但真实的死亡风险而受到限制)。这项研究将通过筛选氯氮平对氯氮平的药物反应与编码多巴胺的已知标记物儿茶酚-O-甲基转移酶基因变体的关系，为药物基因组学研究提供初步验证。第二阶段将修改、提炼和扩展氯-DNA数据库，以利用来自其他抗精神病药物治疗的额外数据进行全面验证。这项建议将创建一个独特的筛选，具有广泛和立即的研究应用，包括药物开发和临床实践，以及与氯氮平治疗有关的基因变异的重要初步信息。其目标是一种商业个体化治疗筛选，以确定抗精神病药物反应的遗传。

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.