A pharmacogenetic human laboratory investigation of brexpiprazole in Alcohol Use Disorder

摘要 只有三种药物被FDA批准用于治疗酒精使用障碍（AUD），并且可复制的患者水平 药物反应的预测因子仍然难以捉摸。因此，在精确医学中评价新药物 需要一个框架来推进AUD治疗。在最严重的阶段，AUD的特征是失调， 皮质抑制纹状体奖励信号，导致对酒精的专注和对酒精的控制丧失。 喝酒这种现象伴随着多种神经递质系统的变化，包括 多巴胺（DA）和5-羟色胺（5-HT）。几种5-羟色胺/多巴胺活性调节剂（SDAM），作用于D2， D3、5-HT 1A和5-HT 2A受体已被探索作为AUD治疗。这些化合物中，阿立哌唑 (APZ)已经显示出最有希望的，但可变的疗效和对其耐受性的担忧已经减少， 对进一步学习的热情。在我们的初步数据中，我们进行了一项APZ的人体实验室研究， 研究表明，在可变数目串联重复序列（VNTR）多态性的基因编码的变化， 多巴胺转运蛋白（DAT），DAT 1/SLC 6A 3，调节APZ对酒精线索引起的脑激活的作用， 在酒吧和实验室里喝酒具体而言，APZ仅在DAT 1 9 R携带者中降低了这些结果（即， 那些倾向于更高的基础DA张力的人）。然而，对结果的解释是有限的，因为参与者 严重程度较低的非寻求治疗者，DAT 1基因型不用于前瞻性随机化， APZ对皮层处理的影响未进行测试。此外，APZ造成的不良影响增加，尽管 使用比先前测试更低的剂量。 本项目旨在通过测试新型SDAM（布雷哌唑）的作用，建立我们的初步数据 （BREX），在药物遗传学人类实验室范例中。BREX是FDA批准的SDAM， 分子靶点为APZ（D2、D3和5-HT 1A激动作用和5-HT 2A拮抗作用），但增强了肾上腺素能， 去甲肾上腺素能作用和改善的副作用特征。一群不寻求治疗的人， 将招募严重程度较高的AUD患者，并根据其DAT 1 VNTR基因型进行前瞻性随机化， 两种剂量的BREX或匹配的安慰剂中的一种，持续14天。我们的主要目的是评估 BREX对1）与反应抑制和酒精提示反应相关的大脑激活和2）饮酒的影响 自然环境和酒吧实验室范例，并确定DAT 1基因型是否预测这些 方面的影响.其次，我们将探讨BREX是否影响抑制相关的皮层激活或线索引起的 VS激活介导其对饮酒的影响。这些目标的实现可能会推动BREX成为一个新的 AUD的治疗选择，指出可能最有效的亚组，和/或提供以下信息 BREX减少饮酒的潜在作用机制。

ABSTRACT Only three medications are FDA-approved to treat Alcohol Use Disorder (AUD), and replicable patient-level predictors of medication response remain elusive. Thus, evaluation of novel medications in a precision medicine framework is needed to advance AUD treatment. At its most severe stage, AUD is characterized by dysregulated cortical inhibition of striatal reward signaling, leading to preoccupation with alcohol and loss of control over drinking. This phenomenon is accompanied by changes in multiple neurotransmitter systems, including dopamine (DA) and serotonin (5-HT). Several serotonin/dopamine activity modulators (SDAMs), which act at D2, D3, 5-HT1A, and 5-HT2A receptors, have been explored as AUD treatments. Of these compounds, aripiprazole (APZ) has displayed the most promise, but variable efficacy and concerns about its tolerability have reduced enthusiasm for further study. In our preliminary data, we conducted a human lab study of APZ in which we demonstrated that variation at a variable number tandem repeat (VNTR) polymorphism in the gene encoding the DA transporter (DAT), DAT1/SLC6A3, moderated APZ effects on alcohol cue-elicited brain activation and drinking in a bar-lab paradigm. Specifically, APZ reduced these outcomes only among DAT1 9R carriers (i.e., those predisposed to higher basal DA tone). However, interpretation of findings was limited because participants were lower severity non-treatment-seekers, DAT1 genotype was not used for prospective randomization, and APZ effects on cortical processing were not tested. Further, APZ caused increased adverse effects despite the use of a lower dose than previously tested. This project aims to build upon our preliminary data by testing the effects of a novel SDAM, brexpiprazole (BREX), in a pharmacogenetic human laboratory paradigm. BREX is an FDA-approved SDAM with similar molecular targets as APZ (D2, D3, and 5-HT1A agonism and 5-HT2A antagonism) but enhanced serotonergic and noradrenergic effects and an improved adverse effect profile. A group of non-treatment-seeking individuals with higher severity AUD will be recruited and prospectively randomized, on the basis of their DAT1 VNTR genotype, to one of two doses of BREX, or matched placebo, for fourteen days. Our primary aims are to evaluate the effect of BREX on 1) brain activation associated with response inhibition and alcohol cue reactivity and 2) drinking in the natural environment and in a bar-lab paradigm, and to determine whether DAT1 genotype predicts these effects. Secondarily, we will explore whether BREX effects on inhibition-related cortical activation or cue-elicited VS activation mediate its effects on drinking. Achievement of these aims will potentially advance BREX as a new treatment option for AUD, indicate a subgroup for whom it may be most effective, and/or offer information about BREX’s potential mechanism of action in reducing drinking.