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

 描述(由申请人提供)：近60%的创伤后应激障碍(PTSD)患者患有共病酒精使用障碍(AUD)。这种共病与更严重的创伤后应激障碍症状、更高的心理社会和医疗问题发生率、更高的复发率和更差的治疗结果有关。临床前研究表明，创伤后应激障碍和AUD具有共同的分子基础，相互作用。特别是，大脑神经递质系统对慢性过量饮酒的适应在戒酒期间表现得很明显，这与创伤后应激障碍B和E类症状(特征是重新体验和高度唤醒的症状)有相似之处，后者引发了反复饮酒和创伤后应激障碍症状恶化的循环。在PTSD/AUD共病患者的不同脑区，发现谷氨酸过多和GABA神经递质浓度降低。抗惊厥药托吡酯通过抑制谷氨酸和促进GABA神经传递来调节皮质中缘多巴胺神经元，并已显示出减少饮酒和大量饮酒的疗效。到目前为止，已经发表了两项小型试验，显示托吡酯对PTSD/AUD的治疗有好处。为了更好地评估托吡酯对创伤后应激障碍患者AUD的影响，研究必须利用具有足够统计能力的更大样本来确定托吡酯是否同时减少酗酒和创伤后应激障碍症状。样本还必须在所代表的创伤类型方面多样化，并应包括来自社区和退伍军人管理局的参与者，这些参与者既有战斗创伤，也有非战斗相关创伤。此外，加强AUD治疗的一项重要战略是使用个性化药物方法，通过选择可能与特定药物治疗“匹配”的个体来优化治疗效果。最近的一项研究表明，编码红藻氨酸受体GluK1亚单位的GRIK1基因的单核苷酸多态(rs2832407，在欧洲血统的个体中常见)缓和了托吡酯对酒精依赖的欧洲美国人的治疗效果(Kranzler等人)。2014年)。托吡酯200 mg/天只在rs2832407：C等位基因纯合的个体中减少大量饮酒。我们建议在一项3×2、双盲、安慰剂对照的16周临床试验中测试托吡酯在减少AUD和PTSD B或E类疾病方面的有效性，并设定饮酒目标戒烟日期(TQD)。我们将利用大量和多样化的欧洲血统个人样本，其中包括性别和有不同类型创伤的个人。我们将根据GRIK1 SNP rs2832407的三种基因型(即CC与AC与AA)对参与者进行随机分组，以分别测试托吡酯在三组中的不同疗效。然后，我们将使用递增剂量的托吡酯-50毫克/天至300毫克/天和安慰剂，从基线到第6周；TQD将设定在第8周。分裂设计(TQD后和TQD前)将允许我们分别检查托吡酯的抗谷氨酸作用是否减少饮酒和防止戒酒后复发，以及停止饮酒是否导致特定rs2832407基因携带者的PTSD B或E组症状改善。所有参与者将接受标准化的两周一次的简明行为遵从性强化治疗和后续治疗，并进行3个月的评估。

 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.