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.

项目概要/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 （南苏丹）； BD 和酒精使用障碍 (AUD) 之间的诊断共现率特别高。个人 同时发生 SUD 和 BD (SUD+BD) 的临床结果比任一 BD 的患者要差得多 或单独 SUD。尽管如此，对于 SUD+BD 患者的最佳治疗知之甚少；回应 锂似乎效果不佳，只有一项丙戊酸双盲、随机、安慰剂对照试验显示 证明该人群的饮酒结果有所改善。传统上，SUD+BD 的治疗试验 研究了 FDA 批准用于治疗 BD 或 SUD 的药物，希望这些药物能够 证明对 SUD+BD 患者有效。采用不同的方法来选择和理想地开发， SUD+BD 治疗试验的药物将针对神经化学功能障碍特征 同时患有 BD 和 SUD 的人。我们的实验室最近证明了前额叶伽玛的独特干扰 使用质子磁共振检测该群体中的氨基丁酸 (GABA) 和谷氨酸浓度 光谱 (1H-MRS)，同时患有酒精依赖 (AD) 和 BD 的个体具有显着的 与单纯 BD 患者、AD 患者或健康对照者相比，GABA 和谷氨酸水平较低。降低 前额叶 GABA 和谷氨酸的水平反过来又与冲动和酒精渴望的增加有关。 拟议的为期 3 周、双盲、交叉、概念验证研究将评估：a) 药物是否 已被证明可以使皮质 GABA（即加巴喷丁）和谷氨酸（即 N-乙酰半胱氨酸）正常化 [NAC]）分别在患有癫痫和可卡因依赖的个体中的浓度可能类似地作用于 使 AUD+BD 个体的前额 GABA 和谷氨酸水平正常化，以及 b) 是否正常化 前额叶 GABA 和谷氨酸水平与任务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、酒精提示反应性），如 以及饮酒和情绪症状。阳性结果可能支持加巴喷丁和/或 NAC 的研究 大规模随机临床试验中 AUD+BD 的辅助治疗。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 以及其他病症的潜在前景 以 GABA 能/谷氨酸能功能障碍为特征。