Topiramate as a treatment for Co-occurring AUD and PTSD

托吡酯治疗同时发生的 AUD 和 PTSD

基本信息

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
项目类别：
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

项目摘要

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) 是高度共病的，并且提出了现有治疗方法疗效有限的临床挑战。建议同时解决 PTSD 和 AUD 症状的治疗方法应该更有效 PTSD 和 AUD 的神经生物学基础的重叠比单独治疗任何一种疾病都有效。（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）表明可能存在可以有效治疗这两种疾病的治疗方法。对这两种疾病明显有效的药物疗法或心理疗法。托吡酯是 FDA 批准的一种抗惊厥药，对 GABA 能和谷氨酸能信号传导有影响，多项随机临床试验 (RCT) 已证明治疗 AUD 的疗效，并且还已在多项开放标签和小型随机对照试验中对治疗 PTSD 进行了测试，并取得了一些有效性证据。一项针对同时发生 PTSD 和 AUD 的开放标签试验和一项小型随机对照试验取得了积极结果表明托吡酯可能对该人群的 PTSD 和 AUD 症状都有有益的影响。临床前工作也支持托吡酯在改善焦虑样行为和压力方面的功效最近的一项临床研究表明，压力和长期酒精暴露的动物模型的反应。托吡酯对饮酒的影响通过 GRIK1 基因（编码红藻氨酸受体 GluK1 亚基），因此仅在 rs2832407 C 等位基因中发现显着益处纯合子。拟议的研究，即拟议中心的项目 2，是一项双盲、两组随机对照研究该试验评估了托吡酯与安慰剂相比，对合并 PTSD 和拟议的试验将提供首批严格的测试之一，以确定是否有影响。 AUD 中的托吡酯适用于同时患有 PTSD 的患者，并且是第一个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作用，这将是第一项测试是否具有有益作用的研究。 rs2832407 基因型预测托吡酯对 AUD 和 PTSD 患者的临床反应此外，它将有助于了解托吡酯在共病中的作用机制。 AUD/PTSD 人群，并发现治疗反应的预测因子以支持总体目标。该中心的试验将作为研究托吡酯对大脑化学和功能影响的平台通过 MR 光谱、功能磁共振成像和脑电图测量（项目 2 的数据）也将有助于中心总体目标是调查项目 2 中的血浆生物标志物与项目 1，以及项目 2 中血浆生物标志物与项目 3 中神经影像标志物的关系。