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: 10153592
• 负责人: James Joseph Prisciandaro
• 金额: $ 52.06万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153592
• 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; optimal treatments; 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.

项目摘要 /摘要 双相情感障碍（BD）是轴I精神病，与药物使用障碍最密切相关 （SUD）;在BD和酒精使用障碍（AUD）之间，诊断性共发生尤其高。个人 与同时发生的SUD和BD（SUD+BD）相比，临床结果要差得多 或单独使用SUD。尽管如此，对于SUD+BD的个体的最佳治疗知之甚少。对 锂似乎很差，只有一个双盲，随机，安慰剂对照试验的丙戊酸试验 在这个人群中表现出了改善的饮酒结果。传统上，SUD+BD的治疗试验具有 调查了已批准FDA治疗BD或SUD的药物，希望这种药物 对于患有SUD+BD的人来说，证明有效。选择，理想发展的一种不同的方法， SUD+BD治疗试验的药物将是针对神经化学功能障碍的特征 具有BD和SUD的人。我们的实验室最近显示了前额叶γ- 使用质子磁共振，该人群中氨基丁酸（GABA）和谷氨酸浓度 光谱法（1H-MRS），具有显着性酒精依赖（AD）的个体具有显着的依赖性（AD） 较低的GABA和谷氨酸相对于单独具有BD，AD或健康对照的个体。降低 前额叶GABA和谷氨酸的水平反过来又与冲动性和渴望升高有关。 拟议的3周，双盲，跨界，概念验证研究将评估：a） 已证明可以使皮质GABA（即加巴喷丁）和谷氨酸（即N-乙酰半胱氨酸）归一化 [NAC]）分别具有癫痫和可卡因依赖性个体的浓度可能会类似地作用于 将AUD+BD的个体中的前额叶GABA和谷氨酸水平归一化，b）是否正常化 前额叶GABA和谷氨酸水平将与任务的功能性脑活动改善有关 该评估AUD和BD的核心神经行为缺陷（即抑制作用，酒精提示反应性），为 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的研究 大规模，随机临床试验中AUD+BD的辅助处理。最重要的是，拟议的研究 可以成功演示用于评估的神经行为，多模式神经影像平台 GABA能和谷氨酸能药物对AUD和/或BD的潜在希望以及其他条件 由GABA能/谷氨酸能功能障碍标记。