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

描述（由申请人提供）：虽然抗精神病药物（apd）对许多精神分裂症患者的症状改善有效，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仍有症状。缺乏药物反应的预测因子，指导临床医生进行预后和临床决策的经验数据也很少。药物遗传学有望提供一种有用的工具，提供具有最佳疗效的个性化治疗，同时最大限度地减少副作用。然而，迄今为止的药物遗传学研究尚未提供临床可用的数据，使这一承诺无法实现。在这次K23申请中，我提出了一个结构化的培训计划，在我经验丰富的导师团队的指导下，我的目标是在临床试验研究设计、药物基因组学分析和apd诱导体重增加的机制方面进行高级培训。目标是成为一名独立的研究者，可以在随机临床试验中测试实际的药物遗传学假设。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，研究药物遗传学检测在指导AP治疗中的临床应用。具体而言，将招募精神分裂症患者并对CYP2D6进行前瞻性基因分型。CYP2D6代谢不良或中度代谢不良的患者将随机接受利培酮治疗，分为常规治疗组（TAU）和低剂量滴定组（LDT）。主要假设是，这些患者由于药物清除率较差，可能对副作用更敏感，与TAU组相比，被分配到LDT组的副作用更少。本研究将为药物遗传学检测在精神分裂症治疗中的临床价值提供首批前瞻性数据之一。在Project 2中，我建议分析来自多个首发或未用药队列的大型药物遗传数据库，以建立具有高灵敏度和特异性的预测APD反应的遗传模型，特别是APD诱导的体重增加。这个庞大的数据集由1200多名患者组成，他们的既往药物暴露最小，并确保药物依从性，克服了先前药物遗传学研究的许多局限性。总的来说，这个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，也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，我将能够很好地设计一个随机试验来测试药物遗传学

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.