Imaging Framework for Testing GABAergic Drugs in Bipolar Alcoholics

项目摘要/摘要 双相情感障碍(BD)是与酒精使用障碍关系最密切的轴心I精神疾病 (澳元)。同时患有AUD和BD(AUD+BD)的患者的临床结果比 那些单独患有BD或AUD的人。尽管如此，人们对慢性阻塞性肺疾病的最佳治疗知之甚少。 AUD+BD。为AUD+BD治疗试验选择并理想地开发药物的一种新方法是 BE针对AUD和BD患者特有的神经化学功能障碍。我们的实验室有 前额叶γ-氨基丁酸(GABA)和谷氨酸的独特紊乱 用AUD+BD的质子磁共振波谱(1H-MRS)测定该人群中的浓度 GABA和谷氨酸水平明显较低的个体，这两种物质与饥饿感的增强有关 以及冲动，相对于单独患有BD、单独AUD或健康对照组的人。我们正在进行的双盲， 随机交叉研究正在评估：a)已被证明可正常化的药物 在其他疾病中，皮质GABA(即加巴喷丁)和谷氨酸(即N-乙酰半胱氨酸[NAC])水平可能 类似地，AUD+BD的前额叶GABA和谷氨酸水平正常化，以及b)是否正常化 这些水平将与对反应抑制和酒精的大脑功能活动的改善有关 提示-反应任务，以及饮酒和情绪症状。积极的结果可能支持对 加巴喷丁和/或NAC作为AUD+BD的大规模临床试验的辅助治疗，以及提供 一个多模式神经成像平台的成功演示，用于评估GABA和 治疗AUD和/或BD的谷氨酸能药物。不幸的是，在三年的成功之后，大约有80% 在达到年终招生目标和超出参与者保留预期的情况下，我们的研究被带到了 新冠肺炎大流行让这一切戛然而止。这种大流行严重阻碍了研究的进展。 过去两年，威胁到我们结果的有效性以及新的/早期调查人员的生存能力 Prisciandaro博士在BD+AUD患者治疗开发方面的研究生涯。结果，Dr。 Prisciandaro(PI)在与其方案干事协商后，要求提供为期一年的行政补编 (即“用资金延长”)，以减轻大流行病否则将造成的重大损害 通过允许他将参与者的注册延长一年，对我们的学习和他的职业生涯产生影响。如果得到资助， 这份副刊将恢复我们研究的统计力量和有效性，从而促进成功 Prisciandaro博士的第一笔R01赠款的竞争性延续(续签)。

Project Summary / Abstract Bipolar disorder (BD) is the Axis I psychiatric condition most strongly associated with alcohol use disorder (AUD). Individuals with co-occurring AUD and BD (AUD+BD) have substantially worse clinical outcomes than those with either BD or AUD alone. Nonetheless, little is known about optimal treatment for individuals with AUD+BD. A novel approach to selecting, and ideally developing, medications for AUD+BD treatment trials would be to target neurochemical dysfunctions characteristic of individuals with both AUD and BD. Our lab has demonstrated unique disturbances in prefrontal gamma-Aminobutyric acid (GABA) and glutamate concentrations in this population using proton magnetic resonance spectroscopy (1H-MRS), with AUD+BD individuals having significantly lower levels of GABA and glutamate, which were associated with elevated craving and impulsivity, relative to individuals with BD alone, AUD alone, or healthy controls. Our ongoing double-blind, randomized, crossover study is evaluating: a) whether medications that have been demonstrated to normalize cortical GABA (i.e., gabapentin) and glutamate (i.e., N-Acetylcysteine [NAC]) levels in other diseases, may similarly act to normalize prefrontal GABA and glutamate levels in AUD+BD, and b) whether normalization of these levels will be associated with improvements in functional brain activity to response inhibition and alcohol cue-reactivity tasks, as well as drinking and mood symptoms. Positive results may support investigation of gabapentin and/or NAC as adjunctive treatments for AUD+BD in large-scale clinical trials, as well as provide successful demonstration of a multimodal neuroimaging platform for evaluating the promise of GABAergic and glutamatergic drugs for AUD and/or BD. Unfortunately, following a 3-year period of success, with roughly 80% of year-end enrollment targets met and participant-retention expectations exceeded, our study was brought to a screeching halt by the COVID-19 pandemic. The pandemic has severely impeded the progress of the study over the past 2 years, threatening both the validity of our results as well as the viability of New/Early-Stage Investigator Dr. Prisciandaro's research career in treatment development for individuals with BD+AUD. As a result, Dr. Prisciandaro (PI), in consultation with his Program Officer, is requesting a 1-year Administrative Supplement (i.e., “Extension with Funds”) in order to mitigate the substantial damage that the pandemic will otherwise inflict on our study and his career by allowing him to extend participant enrollment for one additional year. If funded, this Supplement will restore the statistical power and validity of our study, thereby facilitating successful competitive continuation (renewal) of Dr. Prisciandaro's first R01 grant.