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

描述(申请人提供)：尽管抗精神病药物(APD)能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，而且很大一部分患者在接受治疗后仍有症状。缺乏药物反应的预测指标，几乎没有经验数据可用于指导临床医生的预后和临床决策。药物遗传学有望提供一种有用的工具，在最大限度地减少副作用的同时，提供具有最佳疗效的个性化治疗。然而，到目前为止，药物遗传学研究还没有提供临床可用的数据，这使得这一承诺没有实现。在这项K23应用中，我提出了一项结构化的培训计划，目的是在我经验丰富的指导团队的指导下，获得临床试验研究设计、药物基因组分析和APD诱导体重增加机制方面的高级培训。我们的目标是成为一名独立的研究者，能够在随机临床试验中检验实用的药物遗传学假说。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、双盲的临床试验，将检验药物遗传学测试在指导AP治疗方面的临床效用。具体地说，精神分裂症患者将被招募并前瞻性地进行CYP2D6基因分型。在常规治疗(TAU)或低剂量滴定(LDT)条件下，CYP2D6代谢能力差或中等的患者将被随机分成利培酮治疗组。主要的假设是，这些患者可能由于药物清除不良而对副作用的易感性更高，与TAU组相比，当被分配到LDT条件下时，他们的副作用将更少。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第一批前瞻性数据之一。在项目2中，我建议分析几个首发病例或药物对照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度的遗传模型，预测雪崩的反应，特别是雪崩引起的体重增加。这个庞大的数据集包括1200多名患者，他们以前的药物暴露最少，并确保了药物依从性，克服了先前药物遗传学研究中的许多限制。综上所述，这项应用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，并可能为新药发现提供分子靶点。在本申请中概述的综合培训和研究计划结束时，我将很好地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导致的体重增加的策略，作为独立的R01申请提交。

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.