Gabapentin for Restoring GABA/glutamate Homeostasis in Co-occurring Bipolar and Cannabis Use Disorders: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Clinical MRI Study

加巴喷丁用于恢复双相情感障碍和大麻使用障碍同时发生的 GABA/谷氨酸稳态：一项随机、双盲、安慰剂对照、平行组临床 MRI 研究

• 批准号: 10276615
• 负责人: James Joseph Prisciandaro
• 金额: $ 62.26万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10276615
• 关键词: Adherence; Adjuvant; Adjuvant Analgesic; Adjuvant Study; Animals; Anterior; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Automobile Driving; Basal Ganglia; Bipolar Disorder; Brain; Cannabis; Characteristics; Cigarette Smoker; Clinical; Corpus striatum structure; Cues; Dangerousness; Diagnosis; Dorsal; Dose; Double-Blind Method; Enrollment; Epilepsy; Equilibrium; FDA approved; Failure; Functional Magnetic Resonance Imaging; Functional disorder; Funding; General Population; Glutamates; Homeostasis; Hospitalization; Human; Impairment; Individual; Intervention; Investigation; Literature; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manic; Moods; National Institute of Drug Abuse; Outcome; Participant; Pharmaceutical Preparations; Pharmacology; Placebos; Population; Prevalence; Protons; Randomized; Randomized Controlled Trials; Reporting; Research Design; Residual state; Safety; Sample Size; Sampling; Sleep; Sleep Disorders; Smoker; Smoking Status; Stimulus; Suicide; Symptoms; Therapeutic; United States National Institutes of Health; Visual; anxiety symptoms; attentional control; behavioral response; cigarette smoking; cingulate cortex; cost; craving; cue reactivity; depressive symptoms; disability; efficacy trial; gabapentin; gamma-Aminobutyric Acid; improved; marijuana use; marijuana use disorder; mood symptom; multimodality; nervous system disorder; neuroimaging; optimal treatments; recruit; response; suicide rate; symptomatology; treatment group

Project Summary / Abstract There is an 8-fold increase in the prevalence of cannabis use disorder (CUD) in individuals with bipolar disorder (BD) relative to the general population, and individuals with co-occurring BD and CUD (BD+CUD) have substantially worse clinical outcomes (e.g., elevated rates of suicide) than those with either BD or CUD alone. Response to traditional mood-stabilizing medications is poor, yet little is known about optimal treatment as there have been no randomized medication trials for BD+CUD to date. Convergent evidence supports disrupted brain gamma-Aminobutyric acid (GABA)/glutamate homeostasis as a promising target for pharmacological intervention, and gabapentin as a candidate adjuvant medication to normalize frontal and striatal brain GABA and glutamate levels, in BD+CUD. Against this background, we recently completed an NIH/NIDA-funded (R21DA043917), double-blind, randomized, crossover, MRI (i.e., proton magnetic resonance spectroscopy [1H- MRS], functional MRI [fMRI]) study of gabapentin (1200mg/day) vs. placebo in BD+CUD (n=22) which found that, a) gabapentin increased dorsal anterior cingulate cortex (dACC) and right basal ganglia (rBG) glutamate levels, the latter only in cigarette-smokers, b) relative elevations of rBG glutamate and dACC GABA levels in gabapentin-treated participants were associated with lower cannabis use and mood symptoms, respectively, and c) gabapentin increased activation to visual cannabis cues in the posterior midcingulate (pMCC) gyrus, which was associated with increased rBG glutamate and GABA levels, as well as reduced cannabis use, however only in smokers. Though promising, these findings must be interpreted with caution due to the study's small sample size, observed randomization order effects, and post-hoc identification of statistical moderators, in part guided by a failure of simple randomization to balance condition orders on participant characteristics; effects of gabapentin on brain GABA, as opposed to glutamate, levels were additionally not as robust as anticipated. The proposed randomized, placebo-controlled, double-blind, parallel-group, MRI study aims to evaluate whether gabapentin increases dACC and rBG GABA and glutamate levels in BD+CUD, and whether normalization of these levels will be associated with changes in brain cannabis-cue activation, cannabis use and craving, and mood symptoms. This study will overcome the limitations of our preliminary study via, a) parallel-group study design, b) a larger sample of enrolled BD+CUD individuals (n=68 vs. 22), c) urn-randomization to treatment group, and d) a higher dose of gabapentin (1800mg/day) delivered over a longer period (17 days vs. 5 days/condition) to increase our likelihood of observing gabapentin effects on brain GABA levels. Positive results may support investigation of gabapentin for the adjuvant treatment of BD+CUD in more clinically-focused RCTs. The proposed study will also add to the literature on associations of regional brain GABA/glutamate levels with constructs related to BD+CUD, including cue reactivity, cannabis use/craving, and mood and anxiety symptoms.

项目总结/摘要 在双相情感障碍患者中，大麻使用障碍（CUD）的患病率增加了8倍。 (BD)与一般人群相比，BD和CUD（BD+CUD）并存的个体 实质上更差的临床结果（例如，自杀率升高）。 对传统的情绪稳定药物的反应很差，但对最佳治疗知之甚少， 迄今为止，尚无BD+CUD的随机药物试验。汇聚证据支持大脑受损 γ-氨基丁酸（GABA）/谷氨酸稳态作为药理学的有前途的目标 干预，加巴喷丁作为一个候选的辅助药物，以正常化额叶和纹状体脑GABA 和谷氨酸水平。在这种背景下，我们最近完成了一项由NIH/NIDA资助的 （R21 DA 043917）、双盲、随机、交叉、MRI（即，质子磁共振波谱[1H- 加巴喷丁（1200 mg/天）与安慰剂治疗BD+CUD（n=22）的MRS [，功能性MRI [fMRI]）研究发现 a）加巴喷丁增加背侧前扣带皮层（dACC）和右侧基底神经节（rBG）谷氨酸 B）rBG谷氨酸和dACC GABA水平的相对升高， 加巴喷丁治疗的参与者分别与较低的大麻使用和情绪症状相关， 和c）加巴喷丁增加后中扣带回（pMCC）脑回中对视觉大麻提示的激活， 这与rBG谷氨酸盐和GABA水平增加以及大麻使用减少有关， 但仅限于吸烟者。尽管这些发现很有希望，但由于研究的局限性， 小样本量，观察到的随机化顺序效应，以及事后确定的统计主持人， 部分由简单随机化的失败指导，以平衡参与者特征的条件顺序;影响 加巴喷丁对脑GABA（与谷氨酸相反）的作用水平也不像预期的那么强。 拟定的随机、安慰剂对照、双盲、平行组MRI研究旨在评估 加巴喷丁增加BD+CUD中的dACC和rBG GABA和谷氨酸水平， 这些水平将与大脑大麻线索激活、大麻使用和渴望的变化有关， 情绪症状本研究将通过以下方式克服我们初步研究的局限性：a）平行组研究 设计，B）入组BD+CUD个体的较大样本（n=68 vs. 22），c）接受治疗的非随机化 组，和d）在较长时间内（17天对5天）递送较高剂量的加巴喷丁（1800 mg/天 天/条件），以增加我们观察加巴喷丁对脑GABA水平影响的可能性。积极成果 可能支持在更多临床关注的RCT中研究加巴喷丁对BD+CUD的辅助治疗。 这项拟议的研究还将增加关于局部脑GABA/谷氨酸水平与脑缺血相关性的文献。 与BD+CUD相关的结构，包括线索反应，大麻使用/渴望，以及情绪和焦虑症状。