Imaging Framework for Testing GABAergic Drugs in Bipolar Alcoholics

项目总结/摘要 双相情感障碍（BD）是与酒精使用障碍最密切相关的轴I精神疾病 （AUD）.合并AUD和BD（AUD+BD）的个体的临床结局显著差于 只有BD或AUD的患者。尽管如此，对于患有糖尿病的患者的最佳治疗方法知之甚少。 AUD+BD。一种选择和理想开发AUD+BD治疗试验药物的新方法将 针对AUD和BD患者的神经化学功能障碍特征。我们的实验室 证明了独特的干扰前额叶γ-氨基丁酸（GABA）和谷氨酸 使用质子磁共振波谱（1H-MRS），使用AUD+BD GABA和谷氨酸水平显著降低的个体，这与渴望的升高有关 和冲动性，相对于单独患有BD、单独患有AUD或健康对照的个体。我们正在进行的双盲， 随机交叉研究正在评估：a）已被证明能使 皮质GABA（即，加巴喷丁）和谷氨酸（即，N-乙酰半胱氨酸[NAC]）水平在其他疾病中， 类似地作用于使AUD+BD中前额叶GABA和谷氨酸水平正常化，和B）是否正常化 这些水平将与功能性大脑活动对反应抑制和酒精的改善有关 线索反应任务，以及饮酒和情绪症状。积极的结果可能支持调查 加巴喷丁和/或NAC在大规模临床试验中作为AUD+BD的连续治疗，以及提供 成功展示了用于评估GABA能和 治疗AUD和/或BD的药物。不幸的是，经过3年的成功，大约80%的 的年终招生目标达到和参与者保留的期望超过，我们的研究是带来了一个 新冠肺炎疫情的影响大流行病严重阻碍了研究的进展， 在过去的2年里，威胁到我们的结果的有效性以及新的/早期研究者的生存能力 博士Prisciandaro在BD+AUD个体治疗开发方面的研究生涯。因此，博士。 Prisciandaro（PI）与其项目官员协商后，申请为期1年的行政补助金 (i.e.,“有资金的延期”），以减轻这一流行病否则将造成的重大损害 我们的研究和他的职业生涯，允许他延长一年的参与者登记。如果得到资助， 本补充材料将恢复我们研究的统计能力和有效性，从而促进成功 Prisciandaro博士的第一个R 01补助金的竞争性延续（更新）。

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.