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.

项目概要/摘要 双相情感障碍 (BD) 是与大麻使用障碍 (CUD) 密切相关的轴 I 病症； BD 患者的 CUD 患病率是普通人群的六倍。 同时发生 CUD 和 BD (CUD+BD) 的临床结果比任一 BD 的患者要差得多 或单独使用 CUD，对传统情绪稳定药物的反应似乎很差，但对此知之甚少。 CUD+BD 的最佳治疗方法，因为迄今为止还没有针对 CUD+BD 的随机药物试验。 一致的证据支持失调的大脑 γ-氨基丁酸 (GABA)/谷氨酸稳态是一种 临床前和临床研究已证明 CUD+BD 药物干预的候选目标。 CUD 和 BD 均与前额叶 GABA 和谷氨酸紊乱有关，而冲动、 CUD 和 BD 的核心神经行为特征以及关键研究领域标准 (RDoC) 构造是 临床前研究一致表明，与 GABA 能/谷氨酸能功能存在因果关系。 调节人体质子磁共振波谱中 GABA 和谷氨酸传输的研究。 (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。 可能通过其对 CUD+BD 个体的影响直接或间接影响临床结果 拟议的为期两周的双盲交叉概念验证研究将重点关注 GABA，而 探索谷氨酸、CUD+BD 的干扰，并将评估：a) 加巴喷丁（一种药物）是否具有 已被证明可以增加健康对照者和癫痫患者的皮质 GABA 浓度， 可能同样会增加患有以下疾病的个体的背侧前扣带回和基底神经节 GABA 水平 CUD+BD，b) 背侧前扣带回基底和神经节 GABA 水平增加是否相关 随着功能性大脑活动的增加，对反应抑制（“go no-go”）提示（一种经过充分研究的神经行为 冲动的探索）以及加巴喷丁对大麻线索的功能性大脑活动的影响。 将探讨大麻使用、情绪症状（包括焦虑和睡眠）和冲动。 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。 拟议的研究还可能成功证明神经行为、多模式神经影像学 用于评估其他 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。