Topiramate as a treatment for Co-occurring AUD and PTSD

摘要 酒精使用障碍(AUD)和创伤后应激障碍(PTSD)高度共存， 提出了一个临床挑战，现有的治疗方法对其疗效有限。现有临床证据 建议同时解决创伤后应激障碍和AUD症状的治疗应 比单独治疗任何一种疾病都有效。创伤后应激障碍和AUD的神经生物学基础重叠 (涉及激励显著、压力/负面情绪和执行控制网络功能的变化) 这表明可能有有效治疗这两种疾病的治疗方法。然而，没有 对这两种疾病都明显有效的药物治疗或心理治疗。 托吡酯是FDA批准的一种抗惊厥药物，对GABA能和谷氨酸能信号有影响， 已经在几个随机临床试验(RCT)中证明了对AUD的治疗效果，并 已经在几个开放标签和小型随机对照试验中用于治疗创伤后应激障碍，并有一些有效的证据。 一项开放标签试验和一项小型随机对照试验对并发PTSD和AUD的患者的阳性结果 提示托吡酯可能对该人群中的创伤后应激障碍和AUD的症状有有益的影响。 临床前研究也支持托吡酯在改善焦虑样行为和改变的压力方面的有效性。 应激和慢性酒精暴露动物模型的反应。最近的一项临床研究表明， 托吡酯对酒精使用的影响受到GRIK1基因(编码 海氨酸受体GluK1亚基)，从而仅在rs2832407 C等位基因中发现显著益处 纯合子。 拟建中心的项目2是一项双盲、两组随机对照研究 与安慰剂对照，评价托吡酯对合并创伤后应激障碍和 中至重度AUD。拟议中的试验将提供第一批严格测试之一，以确定 托吡酯在AUD中推广到伴发创伤后应激障碍的患者，以及首批严格的测试之一 托吡酯对这一人群的创伤后应激障碍症状有有益的影响。这将是第一个测试 Rs2832407基因可预测托吡酯对AUD和PTSD患者的临床疗效 精神错乱。此外，这将有助于理解托吡酯在共病中的作用机制。 AUD/PTSD人群，以及治疗反应预测因素的发现。支持总体目标 该试验将作为研究托吡酯对脑化学和功能影响的平台 通过磁共振波谱、功能磁共振成像和EEG进行测量(项目3)。来自项目2的数据也将有助于 总体中心旨在研究项目2中的血浆生物标记物与 项目1，以及项目2的血浆生物标记物与项目3的神经影像标记物的关系。

Summary Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, and present a clinical challenge for which existing treatments have limited efficacy. Existing clinical evidence suggests treatments that simultaneously address symptoms of both PTSD and AUD should be more efficacious than treating either disorder in isolation. The overlap in the neurobiological basis of PTSD and AUD (involving alterations in incentive salience, stress/negative affect, and executive control network functioning) suggests that there could be treatments that would effectively treat both disorders. However, there is no pharmacotherapy or psychotherapy treatment that is clearly effective for both disorders. Topiramate, an FDA-approved anticonvulsant with effects on GABAergic and glutamatergic signaling, has demonstrated efficacy in the treatment of AUD in several randomized clinical trials (RCTs), and has also been tested in several open-label and small RCTs for treatment of PTSD with some evidence of effectiveness. Positive results in one open-label trial and one small RCT in patients with co-occurring PTSD and AUD suggest that topiramate may have beneficial effects on symptoms of both PTSD and AUD in this population. Preclinical work also supports the efficacy of topiramate in ameliorating anxiety-like behavior and altered stress response in animal models of stress and chronic alcohol exposure. A recent clinical study demonstrated that the effects of topiramate on alcohol use were moderated by a polymorphism of the GRIK1 gene (coding for the kainate receptor GluK1 subunit), such that significant benefit was found only among rs2832407 C-allele homozygotes. The proposed study, Project 2 of the proposed center, is a double-blind, 2-group randomized controlled trial evaluating the effects of topiramate, in contrast to those of placebo, in patients with comorbid PTSD and moderate-to-severe AUD. The proposed trial will provide one of the first rigorous tests of whether the effects of topiramate in AUD generalize to patients with co-occurring PTSD, and one of the first rigorous tests of whether topiramate has beneficial effects on PTSD symptoms in this population. It will be the first study to test whether the rs2832407 genotype predicts clinical response to topiramate for AUD and PTSD in patients with both disorders. Further, it will contribute to the understanding of topiramate’s mechanisms of action in the co-morbid AUD/PTSD population, and to the discovery of predictors of treatment response. In support of the overall aims of the center, the trial will serve as a platform for studies of topiramate’s effects on brain chemistry and function as measured by MR spectroscopy, fMRI, and EEG (Project 3). Data from Project 2 will also contribute to Overall Center Aims investigating the relationship of plasma biomarkers in Project 2 to plasma biomarkers in Project 1, and the relationship of plasma biomarkers in Project 2 to neuroimaging markers in Project 3.