Imaging Framework for Testing GABAergic/glutamatergic Drugs in Bipolar Alcoholics

用于测试双相酗酒者中 GABA 能/谷氨酸能药物的成像框架

• 批准号: 9329264
• 负责人: James Joseph Prisciandaro
• 金额: $ 48.08万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329264
• 关键词: Acetylcysteine; Alcohol dependence; Bipolar Disorder; Brain; Characteristics; Clinical; Cocaine Dependence; Diagnostic; Double-Blind Method; Epilepsy; FDA approved; Functional Magnetic Resonance Imaging; Functional disorder; Glutamates; Image; Impulsivity; Individual; Investigation; Lithium; Magnetic Resonance Spectroscopy; Moods; National Institute on Alcohol Abuse and Alcoholism; Outcome; Pharmaceutical Preparations; Placebos; Population; Protons; Randomized Clinical Trials; Research; Substance Use Disorder; Testing; alcohol abuse therapy; alcohol craving; alcohol cue; alcohol use disorder; cue reactivity; drinking; gabapentin; gamma-Aminobutyric Acid; improved; mood symptom; multimodality; neurobehavioral; neurochemistry; neuroimaging; novel; problem drinker; randomized placebo controlled trial; response; treatment trial; valproate

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.

项目总结/摘要 双相情感障碍（BD）是与物质使用障碍最密切相关的轴I精神疾病 (SUD)BD和酒精使用障碍（AUD）之间的诊断共现率特别高。个人 合并SUD和BD（SUD+BD）的患者的临床结局显著差于BD 或单独使用SUD。尽管如此，对SUD+BD患者的最佳治疗知之甚少; 锂似乎是穷人，只有一个双盲，随机，安慰剂对照试验的丙戊酸盐 在这一人群中表现出改善的饮酒结果。传统上，SUD+BD的治疗试验 调查了FDA批准用于治疗BD或SUD的药物，希望这些药物 将在SUD+BD患者中证明有效。一种不同的方法来选择，并理想地发展， 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： 患有BD和SUD的人。我们的实验室最近证明了前额叶伽马的独特干扰- 使用质子磁共振测量该人群中的氨基丁酸（GABA）和谷氨酸浓度 1H-MRS，同时发生酒精依赖（AD）和BD的个体具有显著的 相对于单独患有BD、单独患有AD或健康对照的个体，GABA和谷氨酸水平较低。低 而前额叶GABA和谷氨酸的水平又与冲动性和酒精渴望的增加有关。 拟议的3周、双盲、交叉、概念验证研究将评估：a） 已经证明可以使皮质GABA正常化（即，加巴喷丁）和谷氨酸（即，N-乙酰半胱氨酸 [NAC]）浓度分别在癫痫和可卡因依赖个体中可能起类似作用， 使患有AUD+BD的个体中的前额叶GABA和谷氨酸水平正常化，和B）是否正常化 前额叶GABA和谷氨酸水平将与功能性大脑活动的改善有关 评估AUD和BD的核心神经行为缺陷（即，反应抑制，酒精线索反应性），如 还有酗酒和情绪症状阳性结果可能支持加巴喷丁和/或NAC作为 大规模随机临床试验中AUD+BD的连续治疗。最重要的是，这项研究 可提供神经行为、多模式神经成像平台的成功示范， 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γ-氨基丁酸能/谷氨酸能功能障碍为特征。