Pharmacogenetics of Antipsychotic-Induced Side Effects with a Focus on Weight Gai

抗精神病药物引起的副作用的药物遗传学，重点关注体重增益

• 批准号: 8281140
• 负责人: Jianping Zhang
• 金额: $ 18.09万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281140
• 关键词: Address; Adverse drug effect; Adverse effects; Adverse event; Akathisia; Antipsychotic Agents; Attention; Award; Biological Assay; Blood; CYP2D6 gene; Candidate Disease Gene; Chronic; Clinical; Clinical Trials; DNA; Data; Data Set; Databases; Disease remission; Dose; Double-Blind Method; Drug Exposure; Drug Receptors; Drug effect disorder; Ensure; Exposure to; Funding; Future; Genetic Markers; Genetic Models; Genetic screening method; Genotype; Goals; Heterogeneity; Individual; Individual Differences; Intervention Studies; Left; Measurement; Mentorship; Metabolic syndrome; Methods; Molecular; Molecular Genetics; Molecular Target; National Institute of Mental Health; Outcome; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phenotype; Pilot Projects; Positioning Attribute; Predisposition; Psychotropic Drugs; Randomized; Randomized Clinical Trials; Recruitment Activity; Refractory; Relative (related person); Research; Research Design; Research Personnel; Research Project Grants; Research Training; Risperidone; Saliva; Sample Size; Sampling; Schedule; Schizophrenia; Sedation procedure; Sensitivity and Specificity; Strategic Planning; Structure; Symptoms; Testing; Titrations; Training; Weight; Weight Gain; base; clinical decision-making; clinical practice; cohort; cost; design; drug clearance; drug discovery; drug efficacy; drug-induced weight gain; experience; first episode schizophrenia; genetic variant; genome wide association study; high risk; improved; innovation; medication compliance; outcome forecast; pharmacogenetic testing; predictive modeling; programs; prospective; randomized trial; receptor binding; response; tool; treatment as usual; treatment trial

DESCRIPTION (provided by applicant): Although antipsychotic drugs (APDs) are effective in improving symptoms for many patients with schizophrenia, they can also induce serious side effects and a large proportion of patients remain symptomatic despite treatment. Predictors of drug response are lacking and there is little empirical data available to guide clinicians in prognosis and clinical decision-making. Pharmacogenetics holds the promise of providing a useful tool to provide personalized treatment with optimal efficacy while minimizing side effects. However, pharmacogenetic studies to date have not yet provided clinically usable data, leaving this promise unfulfilled. In this K23 application, I proposed a structured training plan with the goals of gaining advanced training in clinical trial study design, pharmacogenomic analysis, and mechanisms of APD-induced weight gain, under the guidance of my experienced mentorship team. The objective is to become an independent investigator who can test practical pharmacogenetic hypotheses in randomized clinical trials. To accompany the training plan, I will conduct two separate but related pharmacogenetic research projects. Project 1 is a randomized, double-blind clinical trial, in which the clinical utility of pharmacogenetic testing in guiding AP treatment will be examined. Specifically, patients with schizophrenia will be recruited and genotyped for CYP2D6 prospectively. Patients who are poor or intermediate CYP2D6 metabolizers will be randomized to treatment with risperidone in either a treatment-as-usual condition (TAU) or a low-dose-titration condition (LDT). The primary hypothesis is that these patients, who may be at heightened vulnerability to side effects due to poor drug clearance, will have fewer side effects when assigned to the LDT condition compared to those in TAU group. This study will provide one of the first prospective data regarding the clinical value of pharmacogenetic testing in schizophrenia treatment. In Project 2, I propose to analyze a large pharmacogenetic database from several first-episode or drug-na¿ve cohorts to build a genetic model predicting APD response, particularly APD-induced weight gain, with high sensitivity and specificity. This large dataset consists of more than 1200 patients with minimal prior drug exposure and ensured medication adherence, overcoming many limitations in prior pharmacogenetic studies. Taken together, this application aims to utilize these data to better inform treatment decisions for schizophrenia patients, and also potentially provide molecular targets for new drug discovery. At the end of the combined training and research plan outlined in this application, I will be well positioned to design a randomized trial to test pharmacogenetic strategies aimed at minimizing APD-induced weight gain, for submission as an independent R01 application. PUBLIC HEALTH RELEVANCE: Many schizophrenia patients discontinue antipsychotic drug treatment due to lack of efficacy or intolerable side effects, and predictors of drug response are lacking. In this study, we seek to examine the clinical utility of pharmacogenetic testing in guiding treatment and attempt to identify genetic markers to predict antipsychotic drug response. These results may help to provide personalized treatment with these patients.

描述（由申请人提供）：虽然抗精神病药物（APD）可以有效改善许多精神分裂症患者的症状，但它们也会引起严重的副作用，并且很大一部分患者尽管接受治疗但仍然有症状。缺乏药物反应的预测因素，并且几乎没有经验数据可以指导临床医生进行预后和临床决策。药物遗传学有望提供一种有用的工具，以提供最佳疗效的个性化治疗，同时最大限度地减少副作用。然而，迄今为止，药物遗传学研究尚未提供临床可用的数据，使这一承诺未能实现。在这个 K23 申请中，我提出了一个结构化的培训计划，目标是在我经验丰富的导师团队的指导下获得临床试验研究设计、药物基因组分析和 APD 引起的体重增加机制方面的高级培训。目标是成为一名独立研究者，能够在随机临床试验中测试实用的药物遗传学假设。为了配合培训计划，我将进行两个独立但相关的药物遗传学研究项目。项目1是一项随机、双盲临床试验，将检验药物遗传学检测在指导AP治疗中的临床效用。具体来说，将前瞻性地招募精神分裂症患者并进行 CYP2D6 基因分型。 CYP2D6 代谢能力较差或中等的患者将被随机分配到常规治疗 (TAU) 或低剂量滴定治疗 (LDT) 下接受利培酮治疗。主要假设是，这些患者可能由于药物清除率差而更容易出现副作用，因此与 TAU 组相比，分配到 LDT 组时，副作用会更少。这项研究将提供关于药物遗传学测试在精神分裂症治疗中的临床价值的首批前瞻性数据之一。在项目 2 中，我建议分析来自多个首发或未接触药物队列的大型药物遗传学数据库，以建立一个具有高灵敏度和特异性的遗传模型，预测 APD 反应，特别是 APD 引起的体重增加。这个大型数据集由 1200 多名患者组成，这些患者既往药物暴露程度极低，并确保用药依从性，克服了先前药物遗传学研究中的许多限制。总而言之，该应用程序旨在利用这些数据更好地为精神分裂症患者的治疗决策提供信息，并有可能为新药发现提供分子靶点。在本申请中概述的联合培训和研究计划结束时，我将能够设计一项随机试验来测试药物遗传学 旨在最大限度地减少 APD 引起的体重增加的策略，作为独立的 R01 申请提交。 公共卫生相关性：许多精神分裂症患者由于缺乏疗效或无法忍受的副作用而停止抗精神病药物治疗，并且缺乏药物反应的预测因素。在这项研究中，我们试图检验药物遗传学测试在指导治疗中的临床效用，并尝试识别遗传标记来预测抗精神病药物的反应。这些结果可能有助于为这些患者提供个性化治疗。