A pharmacogenetic human laboratory investigation of brexpiprazole in Alcohol Use Disorder

布瑞哌唑治疗酒精使用障碍的药物遗传学人类实验室研究

基本信息

批准号：
10022084
负责人：
JOSEPH P. SCHACHT
金额：
$ 48.99万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022084
关键词：
Achievement Address Advanced Development Adverse effects Affect Affinity Agonist Alcohol consumption Alcohols Alleles Blood Tests Brain Brain Diseases Corpus striatum structure Cues Data Data Analyses Decision Making Dopamine Dose Environment Evaluation FDA approved Functional Magnetic Resonance Imaging Genes Genetic Polymorphism Genotype HTR2A gene Homozygote Human Individual Inferior frontal gyrus Investigation Laboratories Laboratory Study Measures Mediating Minisatellite Repeats Modeling Molecular Target Mus National Institute on Alcohol Abuse and Alcoholism Neurotransmitters Outcome Participant Patients Pharmaceutical Preparations Pharmacogenetics Placebos Population Predisposition Randomized Rewards Self Administration Serotonin Serotonin Receptor 5-HT2A Severities Signal Transduction Subgroup System Testing Training Translations Variant Ventral Striatum alcohol abuse therapy alcohol cue alcohol seeking behavior alcohol use disorder aripiprazole cognitive function cue reactivity dopamine transporter drinking drinking behavior glutamatergic signaling improved neuroimaging neurophysiology noradrenergic novel pharmacogenetic testing pre-clinical precision medicine prospective receptor recruit relating to nervous system response

项目摘要

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.

抽象的只有三种药物获得 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因此，精准医学中新药物的评估仍然难以捉摸。需要框架来推进 AUD 治疗在最严重的阶段，AUD 的特点是失调。皮质抑制纹状体奖赏信号，导致沉迷于酒精和失去对酒精的控制这种现象伴随着多种神经递质系统的变化，包括。多巴胺 (DA) 和血清素 (5-HT) 多种血清素/多巴胺活性调节剂 (SDAM)，作用于 D2、 D3、5-HT1A 和 5-HT2A 受体已被探索作为 AUD 治疗药物，其中阿立哌唑。（APZ）表现出了最大的希望，但疗效的可变性和对其耐受性的担忧已经减弱在我们的初步数据中，我们对 APZ 进行了人体实验室研究。编码基因中可变数量串联重复序列（VNTR）多态性的变异 DA 转运蛋白 (DAT)、DAT1/SLC6A3、调节 APZ 对酒精提示引起的大脑激活的影响具体来说，APZ 仅在 DAT1 9R 携带者（即，那些倾向于较高基础 DA 音调的人）然而，对研究结果的解释是有限的，因为参与者。是较低严重程度的非治疗寻求者，DAT1 基因型不用于前瞻性随机分组，并且此外，尽管 APZ 引起了更多的不利影响，但尚未测试 APZ 对皮质处理的影响。使用比之前测试的剂量更低的剂量。该项目旨在基于我们的初步数据，测试新型 SDAM（布瑞哌唑）的效果（BREX），在药物遗传学人类实验室范例中，BREX 是 FDA 批准的具有类似的 SDAM。分子靶标为 APZ（D2、D3 和 5-HT1A 激动作用和 5-HT2A 拮抗作用），但增强了血清素能和去甲肾上腺素能效应和不良反应改善的一组非寻求治疗的个体。将招募严重程度较高的 AUD，并根据其 DAT1 VNTR 基因型进行前瞻性随机分组，服用两剂 BREX 中的一剂或匹配的安慰剂，持续十四天，我们的主要目的是评估效果。 BREX 对 1) 与反应抑制和酒精提示反应性相关的大脑激活以及 2) 饮酒自然环境和酒吧实验室范式，并确定 DAT1 基因型是否预测这些其次，我们将探讨 BREX 是否对抑制相关的皮质激活或提示诱发的影响。 VS 激活介导其对饮酒的影响。这些目标的实现将有可能推动 BREX 成为一种新的药物。 AUD 的治疗方案，指出可能最有效的亚组，和/或提供有关的信息 BREX 减少饮酒的潜在作用机制。