Topiramate as a treatment for Co-occurring AUD and PTSD

总结 酒精使用障碍（AUD）和创伤后应激障碍（PTSD）高度共病， 存在临床挑战，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PTSD和AUD症状的治疗应该更多 比单独治疗任何一种疾病都有效。PTSD和AUD神经生物学基础的重叠 （涉及激励显著性、压力/负面影响和执行控制网络功能的改变） 这表明可能存在有效治疗这两种疾病的治疗方法。但没有 药物治疗或心理治疗对这两种疾病都明显有效。 托吡酯，FDA批准的抗惊厥药，对GABA能和谷氨酸能信号传导有影响， 在几项随机临床试验（RCT）中证实了治疗AUD的疗效， 在几个开放标签和小型RCT中进行了测试，用于治疗PTSD，并有一些有效性证据。 在PTSD和AUD并存患者中进行的一项开放标签试验和一项小型RCT的阳性结果 提示托吡酯可能对这一人群中PTSD和AUD症状具有有益作用。 临床前工作也支持托吡酯在改善焦虑样行为和改变压力方面的疗效 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GRIK 1基因多态性的调节（编码 红藻氨酸受体GluK 1亚基），因此仅在rs 2832407 C-等位基因中发现显著益处 纯合子 拟定研究（拟定中心的项目2）是一项双盲、2组随机对照研究 一项评估托吡酯与安慰剂相比对共患创伤后应激障碍（PTSD）患者的影响的试验， 中度至重度AUD。拟议中的试验将提供第一个严格的测试， 托吡酯在AUD中的应用可推广到合并PTSD的患者， 托吡酯对这一人群的PTSD症状有有益作用。这将是第一个测试是否 rs 2832407基因型可预测托吡酯治疗AUD和PTSD的临床疗效 紊乱此外，它将有助于了解托吡酯的作用机制，在共病 AUD/PTSD人群，并发现治疗反应的预测因子。为了支持总体目标， 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、功能磁共振成像和脑电图测量（项目3）。项目2的数据还将有助于 总体中心目的：研究项目2中的血浆生物标志物与 项目1中血浆生物标志物与项目3中神经影像学标志物的关系。

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.