Imaging Framework for Testing GABAergic/glutamatergic Drugs in Bipolar Alcoholics

项目摘要/摘要 双相情感障碍(BD)是一种与物质使用障碍关系最为密切的I型精神疾病 (SUD)；BD和酒精使用障碍(AUD)之间的诊断重现率特别高。个人 伴发SUD和BD(SUD+BD)的患者比任何一种BD患者的临床结果都要差得多 或者独自一人苏德。然而，对SUD+BD患者的最佳治疗方法知之甚少；对 锂似乎很差，只有一项双盲、随机、安慰剂对照的丙戊酸盐试验 在这一人群中证明了饮酒结果的改善。传统上，SUD+BD的治疗试验有 调查了FDA批准用于治疗BD或SUD的药物，希望此类药物 将被证明对患有SUD+BD的个体有效。一种不同的方法来选择和理想地发展， SUD+BD治疗试验的药物将针对以下特征的神经化学功能障碍 同时患有BD和SUD的个体。我们的实验室最近证实了前额叶伽马的独特干扰- 用质子磁共振技术测定该人群的氨基丁酸和谷氨酸浓度 波谱(1H-MRS)，同时存在酒精依赖(AD)和BD的个体具有显著的 与单纯BD、单纯AD或健康对照组相比，GABA和谷氨酸水平较低。更低的位置 前额叶GABA和谷氨酸水平依次与冲动增强和饮酒欲望相关。 拟议的为期3周的双盲交叉概念验证研究将评估：a)药物是否 已经证明可以使皮质GABA(即加巴喷丁)和谷氨酸(即N-乙酰半胱氨酸)正常化 [NAC])浓度分别在癫痫和可卡因依赖者中可能起类似的作用 使AUD+BD患者的前额叶GABA和谷氨酸水平正常化，以及b)正常化 前额叶GABA和谷氨酸水平将与任务时大脑功能活动的改善有关 评估AUD和BD的核心神经行为缺陷(即反应抑制、酒精提示反应性)，AS 以及酗酒和情绪症状。阳性结果可能支持对加巴喷丁和/或NAC AS的调查 AUD+BD的大规模随机临床试验中的辅助治疗。最重要的是，拟议的研究 可提供神经行为、多模式神经成像平台的成功演示 GABA能和谷氨酸能药物治疗AUD和/或BD以及其他疾病的潜在前景 以GABA能/谷氨酸能障碍为特征。

Project Summary / Abstract Bipolar disorder (BD) is the Axis I psychiatric condition most strongly associated with substance use disorder (SUD); diagnostic co-occurrence is particularly high between BD and alcohol use disorder (AUD). Individuals with co-occurring SUD and BD (SUD+BD) have substantially worse clinical outcomes than those with either BD or SUD alone. Nonetheless, little is known about optimal treatment for individuals with SUD+BD; response to lithium appears to be poor, and only one double-blind, randomized, placebo-controlled trial of valproate has demonstrated improved drinking outcomes in this population. Traditionally, treatment trials for SUD+BD have investigated medications that have been FDA approved to treat either BD or SUD in hopes that such medications would prove efficacious in individuals with SUD+BD. A different approach to selecting, and ideally developing, medications for SUD+BD treatment trials would be to target neurochemical dysfunctions characteristic of individuals with both BD and SUD. Our lab recently demonstrated unique disturbances in prefrontal gamma- Aminobutyric acid (GABA) and glutamate concentrations in this population using proton magnetic resonance spectroscopy (1H-MRS), with individuals with co-occurring alcohol dependence (AD) and BD having significantly lower levels of GABA and glutamate relative to individuals with BD alone, AD alone, or healthy controls. Lower levels of prefrontal GABA and glutamate were in turn associated with elevated impulsivity and alcohol craving. The proposed 3-week, double-blind, crossover, proof of concept study will evaluate: a) whether medications that have been demonstrated to normalize cortical GABA (i.e., gabapentin) and glutamate (i.e., N-Acetylcysteine [NAC]) concentrations in individuals with epilepsy and cocaine dependence, respectively, may similarly act to normalize prefrontal GABA and glutamate levels in individuals with AUD+BD, and b) whether normalization of prefrontal GABA and glutamate levels will be associated with improvements in functional brain activity to tasks that assess core neurobehavioral deficits of AUD and BD (i.e., response inhibition, alcohol cue-reactivity), 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, randomized clinical trials. Most importantly, the proposed study may provide successful demonstration of a neuro-behavioral, multimodal neuroimaging platform for evaluating the potential promise of GABAergic and glutamatergic drugs for AUD and/or BD, as well as other conditions marked by GABAergic/glutamatergic dysfunction.