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: 10651847
• 负责人: James Joseph Prisciandaro
• 金额: $ 62.44万
• 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/10651847
• 关键词: Adherence; Adjuvant Analgesic; Adjuvant Study; Adjuvant Therapy; Animals; Anterior; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Automobile Driving; Basal Ganglia; Bipolar Disorder; Brain; Brain region; Cannabis; Characteristics; Cigarette Smoker; Clinical; Corpus striatum structure; 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; Placebo Control; 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; cannabis craving; cannabis cue; 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; multimodal neuroimaging; nervous system disorder; neuroimaging; optimal treatments; pharmacologic; 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 双相情感障碍患者的大麻使用障碍(Cud)患病率增加了8倍。 (BD)相对于一般人群，BD和CUD(BD+CUD)共同出现的个人有 与仅患有BD或CUD的患者相比，临床结果要差得多(例如，自杀率上升)。 对传统的稳定情绪药物的反应很差，但对最佳治疗方法知之甚少。 到目前为止，还没有针对BD+CUD的随机药物试验。一致的证据支持大脑功能紊乱 γ-氨基丁酸(GABA)/谷氨酸稳态作为一种有希望的药理靶点 干预，加巴喷丁作为额叶和纹状体脑GABA正常化的候选辅助药物 和谷氨酸水平，以BD+CUD表示。在这种背景下，我们最近完成了由NIH/NIDA资助的 (R21DA043917)，双盲、随机、交叉、MRI(即质子磁共振波谱[1H- 在BD+CUD(n=22)中，加巴喷丁(1200 mg/天)与安慰剂(n=22)的研究发现 A)加巴喷丁增加背侧前扣带回(DACC)和右侧基底节(RBG)谷氨酸 水平，后者仅在吸烟者中，b)RBG谷氨酸和dACC GABA水平在 接受加巴喷丁治疗的参与者分别与较低的大麻使用量和情绪症状有关， 以及c)加巴喷丁增加对后中扣带回(PMCC)视觉大麻线索的激活， 这与增加RBG谷氨酸和GABA水平以及减少大麻使用有关， 然而，仅限于吸烟者。尽管这些发现很有希望，但由于这项研究的 小样本量，观察到的随机化顺序效应，以及统计主持人的事后识别，在 部分是由于简单的随机化未能平衡条件顺序对参与者特征的影响； 与谷氨酸相反，加巴喷丁对大脑GABA的影响水平并不像预期的那样强劲。 这项拟议的随机、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线索激活、大麻使用和渴望的变化有关，以及 情绪症状。这项研究将克服我们初步研究的局限性，通过a)平行分组研究 设计，b)纳入BD+CUD患者的更大样本(n=68比22)，c)骨灰盒随机治疗 D)较大剂量的加巴喷丁(1800毫克/天)，持续较长时间(17天对5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 可能支持加巴喷丁辅助治疗更多临床重点RCT的BD+CUD的研究。 这项拟议的研究还将增加有关大脑局部GABA/谷氨酸水平与 与BD+CUD相关的结构，包括线索反应性、大麻使用/渴望以及情绪和焦虑症状。