A pharmacogenetic human laboratory investigation of brexpiprazole in Alcohol Use Disorder

摘要 只有三种药物获得FDA批准用于治疗酒精使用障碍(AUD)，并且可在患者水平上复制 药物反应的预测指标仍然难以捉摸。因此，对精准医学中的新药进行评价 需要框架来推进AUD的治疗。在其最严重的阶段，澳元的特点是不受监管 纹状体奖赏信号的皮质抑制，导致对酒精的专注和失去控制 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)。一些在D2起作用的5-羟色胺/多巴胺活性调节剂(SDAM)， D3、5-HT1a和5-HT2a受体已被探索为AUD的治疗方法。在这些化合物中，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 继续深造的热情。在我们的初步数据中，我们对APZ进行了一项人体实验室研究，在研究中，我们 证明编码该基因的可变数目串联重复序列(VNTR)多态的变异 DA转运体(DAT)，DAT1/SLC6A3，缓和APZ对酒精诱导的脑激活和 在酒吧实验室里喝酒。具体地说，APZ仅在DAT19R携带者中降低了这些结果(即， 那些倾向于更高的基础DA音调的人)。然而，对结果的解释是有限的，因为参与者 严重程度较低的非治疗寻求者，DAT1基因不用于前瞻性随机分组，以及 未测试APZ对皮质加工的影响。此外，APZ引起的不良反应增加，尽管 使用比先前检测的剂量更低的剂量。 该项目旨在通过测试一种新型SDAM--布雷克哌唑的效果来建立我们的初步数据 (Brex)，在药物遗传学人类实验室范式中。Brex是FDA批准的SDAM，具有类似的 分子靶点为APZ(D2、D3和5-HT1A激动剂和5-HT2A拮抗剂)，但增强5-羟色胺能和 去甲肾上腺素作用和改善的不良反应情况。一群没有寻求治疗的人 将招募严重程度较高的AUD，并根据他们的DAT1 VNTR基因型进行前瞻性随机分组， 两种剂量的Brex或匹配的安慰剂中的一种，为期14天。我们的主要目标是评估效果 Brex对1)与反应抑制和酒精线索反应性相关的大脑激活以及2)饮酒 自然环境和BAR-LAB范式，并确定DAT1基因是否预测这些 效果。其次，我们将探索Brex对抑制相关的皮质激活或线索诱导的影响 VS激活在其对饮酒的影响中起中介作用。这些目标的实现可能会推动英国作为一个新的 AUD的治疗选项，指明可能对其最有效的子组，和/或提供以下信息 Brex在减少饮酒方面的潜在作用机制。

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.