Pharmacogenetic Analysis of Topiramate Treatment of AUD

描述(申请人提供)：酒精依赖(AD)在美国非常普遍，很少有FDA批准的药物治疗。促进使用FDA批准的三种治疗AD的药物的共同努力取得的成功有限，主要是因为它们的疗效不高。抗惊厥药托吡酯(TOP)虽然未被批准用于治疗AD，但在四项安慰剂对照试验和两项开放标签研究中，显著减少了大量饮酒(HD)的频率。基于这些发现，TOP越来越多地被非标签处方用于治疗AD(例如，在VA医疗系统中)。最近，我们发现TOP降低HD的能力仅限于rs2832407的CC基因型的个体，rs2832407是编码红藻氨酸受体GluK1亚单位的基因GRIK1的单核苷酸多态(SNP)。对TOP的这一发现增加了治疗AD的另外两种药物的类似药物遗传学研究结果，这两种药物的有益效果因遗传调节剂而大大增强：纳曲酮(受u-阿片受体基因OPRM1中的SNP调节)和恩丹西酮(受5-羟色胺转运体基因SLC6A4中的两种基因调节)。与AD个性化治疗的目标一致，这些发现将使临床医生提前确定哪些患者可能会有反应 对于这些药物中的每一种，都应该避免可能伴随着治疗无效的不必要的不良反应。值得注意的是，这三个药物遗传学的发现将使选择最好的药物来降低约75%的欧洲美国人的HD成为可能。方法：为了推动酒精使用障碍(AUDS)个性化药物治疗的努力，我们提议进行一项为期12周的前瞻性随机临床试验，研究rs2832407对200名患有DSM-5 AUD的欧洲血统患者使用TOP的调节作用。我们将对基因型进行分层，并对rs2832407*C纯合子进行过抽样，以确保四个用药x基因型组的患者数量具有可比性。我们将使用日常数据收集来检查相关过程变量的变化(例如，酒精预期)及其与基因和药物组的交互作用，作为HD的预测因素。这项拟议的研究具有创新性，因为它将是涉及TOP的药物遗传学假说的第一个预期TES：它将使用每日报告来检查预期，以及它们如何与药物和基因相互作用来预测HD~，它将纳入目标是减少或停止饮酒的DSM-5 AUD患者，这将增加研究的外部有效性。对公共健康的影响：提前区分可能的应答者和无应答者的能力将极大地提高酒精治疗的疗效，避免不必要的不良反应，并提高AUD的护理质量。它还可能增加对高效药物的使用 用于治疗AUD的药物，目前治疗不足，循证治疗也未得到充分利用。

DESCRIPTION (provided by applicant): Alcohol dependence (AD), which is highly prevalent in the United States, is rarely treated with medications approved by the FDA. Concerted efforts to promote the use of the three FDA-approved medications for AD have had limited success, largely because of their modest efficacy. The anticonvulsant topiramate (TOP), though not approved to treat AD, substantially reduced the frequency of heavy drinking (HD) in four placebo-controlled trials and two open-label studies. Based on these findings, TOP is increasingly being prescribed off-label to treat AD (e.g., in the VA Healthcare System). Recently, we found that the ability of TOP to reduce HD was limited to individuals with the CC genotype of rs2832407, a single nucleotide polymorphism (SNP) in GRIK1, the gene encoding the kainate receptor GluK1 subunit. This finding for TOP adds to similar Pharmacogenetics findings for two other medications to treat AD, the beneficial effects of which are substantially enhanced by genetic moderators: naltrexone (which is moderated by a SNP in the mu-opioid receptor gene, OPRM1) and ondansetron (which is moderated by two genotypes in SLC6A4, the serotonin transporter gene). Consistent with the goal of personalized treatment for AD, these findings would allow clinicians to identify, in advance, which patients are likely to respond to each of these medications and which should be spared the unnecessary adverse effects that may accompany treatment in a likely non-responder. Of note, together, these three Pharmacogenetics findings would make it possible to select the best medication to reduce HD in ~75% of European Americans. METHODS: To advance the effort to develop personalized pharmacotherapy for alcohol use disorders (AUDs), we propose to conduct a 12-week, prospective, randomized clinical trial of the moderating effect of rs2832407 on the efficacy of TOP in reducing HD in 200 individuals of European descent with DSM-5 AUD. We will stratify the randomization on genotype and oversample rs2832407*C homozygote's, the most TOP-responsive genotype, to ensure comparable numbers of patients in the four medication x genotype groups. We will use daily data collection to examine changes in relevant process variables (e.g., alcohol expectancies) and their interaction with genotype and medication group as predictors of HD. The proposed study is innovative in that it will be the first prospective tes of a Pharmacogenetics hypothesis involving TOP: it will use daily reports to examine expectancies and how they interact with medication and genotype to predict HD~ and it will enroll DSM-5 AUD patients whose goal is either to reduce or stop drinking, which will increase the study's external validity. PUBLIC HEALTH IMPACT: The capacity to differentiate, in advance, likely responders from non-responders to a medication such as TOP would substantially enhance the efficacy of alcohol treatment, avoid unnecessary adverse effects, and improve the quality of care for AUD. It would also likely increase the use of a highly efficacious medication to treat AUD, which is currently undertreated and for which evidence-based treatment is underutilized.