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.

项目摘要 /摘要 躁郁症患者大麻使用障碍（CUD）的患病率增加了8倍 （BD）相对于一般人群，同时存在BD和CUD（BD+CUD）的个体具有 与单独使用BD或CUD的临床结局相比，临床结果差得多（例如，自杀率升高）。 对传统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。收敛证据支持大脑中断 γ-氨基丁酸（GABA）/谷氨酸稳态作为药理学的有希望的靶标 干预，加巴喷丁作为候选辅助药物，使额叶和纹状体脑gaba正常化 BD+CUD中的谷氨酸水平。在此背景下，我们最近完成了NIH/NIDA资助 （R21DA043917），双盲，随机，交叉，MRI（即质子磁共振光谱[1H-- MRS]，功能性MRI [FMRI]）研究Gabapentin（1200mg/day）与BD+CUD中的安慰剂（n = 22） a）加巴喷丁增加背扣带回皮质（DACC）和右基底神经节（RBG）谷氨酸 水平，后者仅在香烟烟民中，b）RBG谷氨酸和DACC GABA水平的相对升高 加巴喷丁处理的参与者分别与大麻使用和情绪症状分别相关 c）加巴喷丁增加了后中期（PMCC）回合中视觉大麻提示的激活， 这与RBG谷氨酸和GABA水平增加以及大麻使用降低有关 但是只有吸烟者。尽管很有希望，但由于研究的 样本量较小，观察到的随机秩序效应以及统计调节器的事后识别， 一部分是由简单随机化无法平衡参与者特征的条件顺序的部分。效果 与谷氨酸相比，脑gaba蛋白的脑膜化水平也不如预期的那么健壮。 提出的随机，安慰剂对照，双盲，平行组，MRI研究旨在评估是否是否 Gabapentin增加了BD+CUD中的DACC和RBG GABA和谷氨酸水平，以及是否归一化 这些水平将与脑大麻激活，大麻使用和渴望的变化以及 情绪症状。这项研究将通过a）平行组研究来克服我们初步研究的局限性 设计，b）较大的注册BD+CUD个体的样本（n = 68 vs. 22），c）urn随机化治疗 组，d）更高剂量的加巴喷丁（1800毫克/天）在更长的时间内（17天与5 天数），以增加观察加巴喷丁对脑gaba水平的影响的可能性。积极的结果 可以支持对更临床重点的RCT中BD+CUD辅助治疗的Gabapentin的研究。 拟议的研究还将增加有关区域脑GABA/谷氨酸水平与 与BD+CUD相关的结构，包括提示反应性，大麻使用/渴望以及情绪和焦虑症状。