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

项目概要/摘要 双相情感障碍患者大麻使用障碍 (CUD) 的患病率增加了 8 倍 (BD) 相对于一般人群，同时患有 BD 和 CUD (BD CUD) 的个体 与单独使用 BD 或 CUD 的患者相比，临床结果要差得多（例如，自杀率升高）。 对传统情绪稳定药物的反应很差，但人们对最佳治疗知之甚少，因为 迄今为止还没有针对 BD CUD 的随机药物试验。一致的证据支持大脑受到破坏 γ-氨基丁酸（GABA）/谷氨酸稳态作为有前景的药理学靶点 干预，加巴喷丁作为候选辅助药物，使额叶和纹状体大脑 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 资助的一项研究 (R21DA043917)、双盲、随机、交叉、MRI（即质子磁共振波谱 [1H- MRS]、功能性 MRI [fMRI]）在 BD CUD (n=22) 中加巴喷丁（1200 毫克/天）与安慰剂的研究发现 a) 加巴喷丁增加背侧前扣带皮层 (dACC) 和右基底神经节 (rBG) 谷氨酸 水平，后者仅存在于吸烟者中，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， c) 加巴喷丁增加了后中扣带回（pMCC）对视觉大麻线索的激活， 这与 rBG 谷氨酸和 GABA 水平增加以及大麻使用减少有关， 但仅限于吸烟者。尽管很有希望，但由于该研究的结果，必须谨慎解释这些发现 小样本量、观察到的随机化顺序效应以及统计调节因素的事后识别， 部分以简单随机化未能平衡参与者特征的条件顺序为指导；效果 加巴喷丁在大脑中的 GABA（与谷氨酸相反）的水平也没有预期的那么强。 拟议的随机、安慰剂对照、双盲、平行组 MRI 研究旨在评估是否 加巴喷丁增加 BD CUD 中的 dACC 和 rBG GABA 和谷氨酸水平，以及是否正常化 这些水平将与大脑大麻提示激活、大麻使用和渴望的变化有关，以及 情绪症状。这项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) 登记的 BD CUD 个体的更大样本（n=68 vs. 22），c) 随机化治疗 d) 在较长时间内（17 天与 5 天）给予更高剂量的加巴喷丁（1800 毫克/天） 天/条件）以增加我们观察加巴喷丁对大脑 GABA 水平影响的可能性。积极的结果 可能支持在更多以临床为重点的随机对照试验中研究加巴喷丁辅助治疗 BD CUD。 拟议的研究还将增加关于区域大脑 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。

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.