Pharmacogenetic Treatment with Anti-Glutaminergic Agents for Comorbid PTSD & AUD

使用抗谷氨酰胺能药物治疗共病 PTSD 的药物遗传学治疗

• 批准号: 9901406
• 负责人: MELANIE E. BENNETT
• 金额: $ 55.91万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901406
• 关键词: Address; Adverse event; Aftercare; Alcohol dependence; Alcohol withdrawal syndrome; Alleles; American; Anticonvulsants; Arousal; Behavioral; Brain; Brain region; Chronic; Clinical; Clinical Trials; Communities; DSM-V; Data; Dose; Double-Blind Method; European; Future; Gender; Genetic; Genotype; Glutamates; Heavy Drinking; Individual; Joints; Kainic Acid Receptors; Mediation; Medical; Mental Health; Military Personnel; Molecular; Neurobiology; Neurotransmitters; Outcome; Participant; Pathway interactions; Patient Recruitments; Pharmaceutical Preparations; Pharmacogenetics; Pilot Projects; Placebos; Post-Traumatic Stress Disorders; Public Health; Publishing; Randomized; Randomized Controlled Trials; Relapse; Running; Sample Size; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Standardization; Subgroup; Symptoms; System; Testing; Therapeutic; Trauma; Treatment Efficacy; Treatment outcome; Veterans; Withdrawal; alcohol abuse therapy; alcohol comorbidity; alcohol use disorder; base; combat; comorbidity; design; dopaminergic neuron; drinking; effective therapy; efficacy testing; experience; follow-up; gamma-Aminobutyric Acid; genetic variant; genome-wide; improved; neurotransmission; open label; personalized medicine; preclinical study; prevent; psychosocial; public health priorities; public health relevance; topiramate; treatment arm; treatment effect; treatment optimization; week trial

 DESCRIPTION (provided by applicant): Nearly 60% of individuals with posttraumatic stress disorder (PTSD) have a comorbid alcohol use disorder (AUD). This comorbidity is associated with more severe PTSD symptoms, higher rates of psychosocial and medical problems, higher relapse rates, and poorer treatment outcome. Pre-clinical studies have indicated that PTSD and AUD share common molecular underpinnings that feed in to each other. Particularly, the adaptations in the brain neuro- transmitter systems to chronic excessive drinking that are evident during alcohol withdrawal share similarities with PTSD cluster B and E symptoms (characterized by symptoms of re-experiencing and hyper-arousal), which initiate a cycle of relapse into excessive drinking and worsening of PTSD symptoms. Excessive glutamate and reduced gamma- aminobutyric acid (GABA) neurotransmitter concentrations were found in various brain regions in individuals with co- morbid PTSD/AUD. The anticonvulsant topiramate modulates cortico-mesolimbic dopamine neurons by inhibiting glutamate and facilitating GABA neurotransmission and has shown efficacy in reducing drinking and heavy drinking in AUD. To date, there have been two small published trials showing benefit of topiramate for the treatment of PTSD/AUD. To better evaluate the impact of topiramate on AUD in PTSD, studies must utilize larger samples with sufficient statistical power to determine whether topiramate reduces both heavy drinking and PTSD symptoms. Samples must also be diverse in terms of the types of trauma represented and should include participants from community and VA settings with both combat and non-combat-related traumas. In addition, an important strategy to enhance treatment of AUD uses a personalized medicine approach to optimize treatment effects by selecting individuals who may be a therapeutic "match" for a specific medication. A recent study showed that a single nucleotide polymorphism (rs2832407, common in individuals of European ancestry) in GRIK1, encoding the GluK1 subunit of the kainate receptor, moderated the treatment effect of topiramate in alcohol-dependent European Americans (Kranzler et al. 2014). Topiramate at 200mg/day reduced heavy drinking only in individuals homozygous for the rs2832407: C allele. We propose to test the efficacy of topiramate in reducing both AUD and PTSD Clusters B or E in a 3 x 2, double- blind, placebo-controlled 16-week clinical trial with a set target quit-date (TQD) for drinking. We will utilize a large and diverse sample of European ancestry individuals that includes both genders and individuals with different types of trauma. We will randomize participants based on the three genotypes of GRIK1 SNP rs2832407 (i.e., CC vs. AC vs. AA) to test the differential efficacy of topiramate within the three groups separately. We will then use an escalating dose of topiramate -50mg/day up to 300mg/day and placebo, from baseline up to week 6; the TQD will be set at week 8. The split design (post-TQD vs. pre-TQD) will allow us to separately examine both whether topiramate's anti-glutaminergic effects reduce drinking and prevent relapse post cessation and whether the cessation of drinking results in improved PTSD cluster B or E symptoms in carriers of specific rs2832407 genotypes. All participants will receive standardized bi-weekly Brief Behavioral Compliance Enhancement Treatment and follow-up post treatment and 3 month assessments.

 描述（由适用提供）：近60％的创伤后应激障碍患者（PTSD）患有合并症酒精使用障碍（AUD）。这种合并症与更严重的PTSD症状，更高的社会心理和医疗问题，更高的继电器率以及治疗结果较差有关。临床前研究表明，PTSD和AUD共享彼此进食的常见分子基础。尤其是，脑神经神经递质系统对慢性过量饮酒的适应性与PTSD群集B和E症状相似（以重新体验和过度体验的症状为特征），这引发了相关循环，从而导致了过度饮酒和PTSD症状的过量饮酒和担忧。过度谷氨酸和降低的γ-氨基丁酸（GABA）神经递质浓度在患有PTSD/AUD的个体的各个大脑区域中都发现它们。通过抑制谷氨酸并支撑GABA神经传递，抗惊厥药的抗曲张调节皮质 - 溶质脱糖多巴胺神经元，并显示出在减少AUD饮酒和大量饮酒方面的有效性。迄今为止，已经进行了两项小型发表试验，显示了Topramate对PTSD/AUD治疗的好处。为了更好地评估Topramate对AUD PTSD的影响，研究必须利用具有足够统计能力的较大样品来确定topramate是否既降低饮酒又减少了PTSD符号。样本在代表的创伤类型方面也必须是多种多样的，应包括与战斗和非战斗相关创伤的社区和VA环境的参与者。此外，增强AUD处理的重要策略采用个性化医学方法来优化治疗效果，通过选择可能是特定药物治疗的“匹配”的个体。最近的一项研究表明，在Grik1中，单个核丁基多态性（rs2832407，在欧洲血统的个体中常见），编码海藻酸盐受体的GLUK1亚基，调节了托吡酯对酒精依赖性欧洲美国人的治疗效果（Kranzler等人（Kranzler等）（Kranzzler等人，2014年）。托吡酯的含量为200mg/天，只有在纯合rs2832407的个体中减少了大量饮酒：C等位基因。我们建议在3 x 2中测试topramate在降低AUD和PTSD群集B或E中的效率，双盲，安慰剂对照的16周临床试验，并进行固定目标退出日期（TQD）进行饮酒。我们将利用包括性别和具有不同类型创伤的个体在内的欧洲血统的大量样本。我们将根据GRIK1 SNP RS2832407（即CC与AC与AA）的三种基因型进行随机分组参与者，以分别测试这三组中主题amamate的差异效率。然后，从基线到第6周，我们将使用升级剂量的主题仪-50mg/天至300mg/天和安慰剂； TQD将在第8周设置。拆分设计（TQD与TQD与TQD）将使我们能够分别检查TopicAmate的抗谷氨酰胺能效应是否会减少饮酒和防止饮酒后饮酒后是否导致PTSD PTSD集群B或E症状是否会导致特定RS282407 Genotypes的PTSD集群B或E症状。所有参与者将获得标准化的两周简短行为合规性增强治疗和后续治疗后的随访以及3个月的评估。