Topiramate as a treatment for Co-occurring AUD and PTSD

托吡酯治疗同时发生的 AUD 和 PTSD

• 批准号: 10473681
• 负责人: Michael Parks Bogenschutz
• 金额: $ 43.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473681
• 关键词: Acute; Address; Alcohol consumption; Alcohols; Alleles; Animal Model; Anticonvulsants; Apoptosis; Biological Markers; Brain Chemistry; Chronic; Clinical; Clinical Research; Clinical Treatment; Code; Data; Disease; Dose; Double-Blind Method; Effectiveness; FDA approved; Genes; Genetic Polymorphism; Genotype; Glutamates; Homozygote; Human; Kainic Acid Receptors; Magnetic Resonance Spectroscopy; Measures; Methods; Neurobiology; Neurocognitive; Neuropeptides; Outcome; Oxidative Stress; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Plasma; Population; Post-Traumatic Stress Disorders; Prediction of Response to Therapy; Probability; Psychotherapy; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Research; Rewards; Sampling; Stress; Symptoms; Testing; Work; alcohol abuse therapy; alcohol cue; alcohol effect; alcohol exposure; alcohol response; alcohol use disorder; anxiety-like behavior; biological adaptation to stress; clinical predictors; clinically relevant; comorbidity; drinking; executive function; functional magnetic resonance imaging/electroencephalography; glutamatergic signaling; hypothalamic-pituitary-adrenal axis; incentive salience; negative affect; neuroimaging; neuroimaging marker; neuroinflammation; neurotrophic factor; open label; personalized medicine; pre-clinical; response; topiramate; treatment group; trial design

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.

概括 酒精使用障碍（AUD）和创伤后应激障碍（PTSD）高度合并，并且 提出临床挑战，现有治疗的有效性有限。现有的临床证据 建议仅解决PTSD和AUD症状的治疗方法应该更多 这比孤立地治疗任何一种疾病都是有效的。 PTSD和AUD的神经生物学基础的重叠 （涉及激励显着性，压力/负面影响和执行控制网络功能的改变） 表明可能会有有效治疗这两种疾病的治疗方法。但是，没有 药物疗法或心理治疗对两种疾病显然有效。 托吡酯，一种经FDA批准的抗惊厥药，对GABA能和谷氨酸能信号的影响， 在几项随机临床试验（RCT）中，已经证明了AUD治疗的效率，并且也已有 我们在几个开放标签和小的RCT中进行了测试，用于治疗PTSD，并具有一些有效性的证据。 一项开放标签试验的阳性结果和同时发生的PTSD和AUD患者的一个小RCT 表明topramate在该人群中可能对PTSD和AUD的症状产生有益的影响。 临床前工作还支持topramate在改善动画样行为和改变压力方面的效率 在压力和慢性酒精暴露的动物模型中的反应。最近的一项临床研究表明 通过Grik1基因的多态性，可以调节甲胺对饮酒的影响（编码 海藻酸盐接收器gluk1亚基），因此仅在RS2832407 C-Allele中发现了巨大的益处 纯合子。 拟议中心的拟议研究2是双盲，2组随机对照 与安慰剂相比，在合并症患者和安慰剂的患者中，评估甲板酸酯的影响 中度至重度音频。拟议的试验将提供第一个严格的测试之一 topramate在AUD中概括了同时发生的PTSD患者，这是第一个严格的测试之一 托吡酯对该人群中的PTSD症状具有有益的影响。这将是测试是否的研究 RS2832407基因型预测对AUD和PTSD的Topramate的临床反应， 疾病。此外，它将有助于理解托普拉梅特的合并症中的作用机制 AUD/PTSD人群，并发现治疗反应的预测指标。支持总体目标 在该中心，该试验将作为研究topramate对大脑化学和功能影响的平台 通过MR光谱，fMRI和EEG测量（项目3）。项目2的数据也将有助于 总体中心旨在研究项目2中等离子体生物标志物与等离子生物标志物的关系 项目1，项目2中的等离子体生物标志物与项目3中的神经成像标记的关系。