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

项目概要/摘要 双相情感障碍（BD）是与大麻使用障碍（CUD）最密切相关的轴I病症; 相对于普通人群，BD患者中CUD的患病率增加了6倍。个人 合并CUD和BD（CUD+BD）的患者的临床结局显著差于BD 或单独使用CUD。对传统的情绪稳定药物的反应似乎很差，但对 CUD+BD的最佳治疗，因为迄今为止还没有针对CUD+BD的随机药物试验。 汇聚的证据支持脑γ-氨基丁酸（GABA）/谷氨酸稳态失调是一种神经系统疾病。 药物干预CUD+BD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， CUD和BD的核心神经行为特征以及关键研究领域标准（RDoC）结构是 与GABA能/谷氨酸能功能有因果关系。加巴喷丁在临床前研究中一直表现出 研究调节GABA和谷氨酸传输。在人体质子磁共振波谱中 （1H-MRS）研究表明，急性和慢性加巴喷丁给药均可增加大脑GABA水平， 然而，很少有研究调查加巴喷丁对谷氨酸水平的影响。我们建议加巴喷丁 可能直接和间接影响CUD+BD个体的临床结局， 冲动拟议的2周、双盲、交叉、概念验证研究将重点关注GABA， 探索谷氨酸，CUD+BD的干扰，并将评估：a）是否加巴喷丁，一种药物， 已被证明可以增加健康对照组和癫痫患者的皮质GABA浓度， 可能类似地增加背侧前扣带回和基底神经节GABA水平， CUD+BD，以及B）背侧前扣带回和基底神经节GABA水平的增加是否与 随着对反应抑制（“去不去”）线索的功能性大脑活动增加（一种被充分研究的神经行为学方法）， 冲动的探针）以及大麻线索的功能性大脑活动减少。加巴喷丁对 大麻使用，情绪症状（包括焦虑和睡眠）和冲动将被探讨。积极成果 可能支持在大规模随机临床试验中研究加巴喷丁治疗CUD+BD。 拟议的研究也可能提供一个神经行为，多模式神经影像学的成功证明 评估其他GABA能药物治疗CUD和/或BD以及其他 以GABA/谷氨酸功能障碍为标志的病症。

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.