Gabapentin for Bipolar & Cannabis Use Disorders: Relation to Brain GABA/Glutamate

加巴喷丁治疗双相情感障碍

• 批准号: 9456182
• 负责人: James Joseph Prisciandaro
• 金额: $ 22.43万
• 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: 2017-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9456182
• 关键词: Acute; Anterior; Anxiety; Basal Ganglia; Bipolar Disorder; Brain; Cannabis; Characteristics; Chronic; Clinical; Clinical Research; Cues; Data; Dorsal; Dose; Double-Blind Method; Epilepsy; Functional Magnetic Resonance Imaging; Functional disorder; General Population; Glutamates; Homeostasis; Human; Impulsivity; Individual; Intervention; Investigation; Magnetic Resonance Spectroscopy; Measures; Moods; Outcome; Pharmaceutical Preparations; Pharmacology; Placebos; Population; Prevalence; Protons; Randomized; Randomized Clinical Trials; Research; Research Domain Criteria; Sleep; Therapeutic; Visual; cue reactivity; gabapentin; gamma-Aminobutyric Acid; marijuana use; marijuana use disorder; mood symptom; multimodality; neurobehavioral; neurochemistry; neuroimaging; pre-clinical research; preclinical study; response; transmission process

Project Summary / Abstract Bipolar disorder (BD) is the Axis I condition most strongly associated with cannabis use disorder (CUD); there is a six-fold increase in the prevalence of CUD in individuals with BD relative to the general population. Individuals with co-occurring CUD and BD (CUD+BD) have substantially worse clinical outcomes than those with either BD or CUD alone. Response to traditional mood stabilizing medications appears to be poor, yet little is known about optimal treatment for CUD+BD as there have been no randomized medication trials for CUD+BD to date. Convergent evidence supports dysregulated brain γ-Aminobutyric acid (GABA)/glutamate homeostasis as a candidate target for pharmacological intervention in CUD+BD. Preclinical and clinical studies have demonstrated that CUD and BD are each associated with prefrontal GABA and glutamate disturbances and that impulsivity, a core neurobehavioral feature of both CUD and BD and a key Research Domain Criteria (RDoC) construct, is causally related to GABAergic/glutamatergic functioning. Gabapentin has been consistently shown in preclinical research to modulate GABA and glutamate transmission. In human Proton Magnetic Resonance Spectroscopy (1H-MRS) studies, both acute and chronic gabapentin dosing have been shown to increase brain GABA levels, however, few studies have investigated gabapentin effects on glutamate levels. We propose that gabapentin may impact clinical outcomes in CUD+BD individuals both directly and indirectly through their impact on impulsivity. The proposed 2-week, double-blind, crossover, proof of concept study will focus on GABA, while exploring glutamate, disturbances in CUD+BD and will evaluate: a) whether gabapentin, a medication that has been demonstrated to increase cortical GABA concentrations in healthy controls and individuals with epilepsy, may similarly act to increase dorsal anterior cingulate and basal ganglia GABA levels in individuals with CUD+BD, and b) whether increased dorsal anterior cingulate and basal ganglia GABA levels will be associated with increased functional brain activity to response inhibition (“go no-go”) cues (a well-studied neurobehavioral probe of impulsivity) as well as decreased functional brain activity to cannabis cues. Effects of gabapentin on cannabis use, mood symptoms (including anxiety and sleep), and impulsivity will be explored. Positive results may support investigation of gabapentin for the treatment of CUD+BD in large-scale, randomized clinical trials. The proposed study may also provide successful demonstration of a neurobehavioral, multimodal neuroimaging platform for evaluating the potential promise of other GABAergic drugs for CUD and/or BD, as well as other conditions marked by GABA/glutamate dysfunction.

项目摘要/摘要 双相情感障碍(BD)是与大麻使用障碍(CUD)关系最密切的轴心I型疾病； 与普通人群相比，BD患者的CUD患病率增加了6倍。个人 同时发生CUD和BD(CUD+BD)的患者的临床结果明显比任何一种BD患者差。 或者孤身一人。对传统的情绪稳定药物的反应似乎很差，但人们对此知之甚少 CUD+BD的最佳治疗，因为到目前为止还没有关于CUD+BD的随机药物试验。 一致的证据支持大脑γ-氨基丁酸/谷氨酸平衡失调是一种 CUD+BD药物干预的候选靶点。临床前和临床研究表明 CUD和BD都与前额叶GABA和谷氨酸紊乱有关，而冲动， CUD和BD的核心神经行为特征和关键研究领域标准(RDoC)结构，是 与GABA能/谷氨酸能功能有因果关系。加巴喷丁在临床前一直被证明是 研究调节GABA和谷氨酸的传递。在人体质子磁共振波谱中 (1H-MRS)研究表明，急性和长期服用加巴喷丁都能提高大脑GABA水平， 然而，很少有研究研究加巴喷丁对谷氨酸水平的影响。我们建议加巴喷丁 可能直接或间接地影响CUD+BD患者的临床结局 冲动。拟议的为期两周的双盲交叉概念验证研究将侧重于GABA，而 探索谷氨酸，CUD+BD的紊乱，并将评估：a)加巴喷丁，一种具有 已被证明可以增加健康对照组和癫痫患者的皮质GABA浓度， 可能类似地作用于增加背侧前扣带回和基底节GABA水平 CUD+BD，以及b)背侧前扣带回和基底节GABA水平的增加是否会相关 大脑对反应抑制(“GO-NO-GO”)提示的功能性活动增加(一种研究很好的神经行为 对冲动的探测)以及对大麻线索的功能性大脑活动减少。加巴喷丁对血管紧张素转换酶的影响 课程将探讨大麻的使用、情绪症状(包括焦虑和睡眠)和冲动。积极的结果 可能支持大规模随机临床试验中加巴喷丁治疗CUD+BD的研究。 这项拟议的研究还可能提供神经行为、多模式神经成像的成功演示 评估其他GABA能药物治疗CUD和/或BD以及其他药物的潜在前景的平台 以GABA/谷氨酸功能障碍为标志的疾病。