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）是与大麻使用障碍最密切相关的轴I条件（CUD）；有 相对于普通人群，BD的个体的CUD患病率增加了六倍。个人 与同时发生的CUD和BD（CUD+BD）相比，临床结局比具有BD的临床结果差得多 或单独使用。对传统情绪稳定药物的反应似乎很差，但对 CUD+BD的最佳治疗方法是迄今为止尚无对CUD+BD进行的随机药物试验。 收敛证据支持失调的脑γ-氨基丁酸（GABA）/谷氨酸稳态作为一种 CUD+BD中药物干预的候选靶标。临床前和临床研究表明 CUD和BD各自与前额叶GABA和谷氨酸疾病有关，冲动性，A CUD和BD的核心神经行为特征以及关键的研究领域标准（RDOC）结构是 与GABA能/谷氨酸能功能的因果关系。加巴喷丁在临床前一直显示 研究调节GABA和谷氨酸传播的研究。在人类质子磁共振光谱中 （1H-MRS）研究，急性和慢性加巴喷丁的剂量均已证明会增加脑GABA水平， 但是，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 可能会直接和间接影响CUD+BD个体的临床结果。 冲动。拟议的2周，双盲，跨界，概念验证研究将集中在GABA上，而 探索谷氨酸，CUD+BD中的灾难，将评估：a）Gabapentin是否是一种药物 被证明可以增加健康对照中的皮质GABA浓度和癫痫病的个体 可能会采取类似的作用以增加背侧扣带回和基本神经节GABA的gaba水平 cud+bd，b）背侧扣带回和基本的神经节gaba水平是否增加 随着功能性脑活动的增加，对响应抑制（“无关”）提示（一种良好的神经行为 冲动性的探针）以及改善了对大麻提示的功能性脑活动。加巴喷丁对 将探索大麻使用，情绪症状（包括焦虑和睡眠）和冲动性。积极的结果 可以支持对大规模的，随机的临床试验中的Gabapentin进行CUD+BD的研究。 拟议的研究还可以成功证明神经行为的多模仿神经影像学 评估其他GABA能药物对CUD和/或BD的潜在承诺的平台，以及其他 由GABA/谷氨酸功能障碍标记的条件。