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）患者患有酒精使用障碍（AUD）。这种合并症与更严重的PTSD症状、更高的心理社会和医学问题发生率、更高的复发率和更差的治疗结果相关。临床前研究表明，PTSD和AUD有共同的分子基础，相互作用。特别地，在酒精戒断过程中明显的脑神经递质系统对慢性过量饮酒的适应与PTSD簇B和E症状（特征在于重新体验和过度觉醒的症状）具有相似性，其引发复发到过量饮酒和PTSD症状恶化的循环。在患有PTSD/AUD共病的个体中，在各个脑区发现了过量的谷氨酸和减少的γ-氨基丁酸（GABA）神经递质浓度。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-中脑边缘多巴胺神经元，并已显示出减少AUD患者饮酒和大量饮酒的疗效。到目前为止，已经有两个小的发表的试验显示托吡酯治疗PTSD/AUD的好处。 为了更好地评估托吡酯对创伤后应激障碍患者AUD的影响，研究必须使用具有足够统计功效的较大样本来确定托吡酯是否可以减少重度饮酒和创伤后应激障碍症状。样本也必须是多样化的创伤类型的代表，并应包括来自社区和VA设置与战斗和非战斗相关的创伤的参与者。此外，加强AUD治疗的一个重要策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，GRIK 1（编码红藻氨酸受体GluK 1亚基）的单核苷酸多态性（rs 2832407，在欧洲血统个体中常见）可调节托吡酯在酒精依赖的欧洲裔美国人中的治疗效果（Kranzler et al. 2014）。托吡酯200 mg/天仅在rs 2832407：C等位基因纯合子个体中减少重度饮酒。 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降低AUD和PTSD群集B或E方面的功效，该试验设定了饮酒的目标戒烟日期（TQD）。我们将利用大量不同的欧洲血统个体样本，其中包括性别和具有不同类型创伤的个体。我们将根据GRIK 1 SNP rs 2832407的三种基因型（即，CC vs. AC vs. AA），以分别检验托吡酯在三组中的差异疗效。然后，我们将使用托吡酯-50 mg/天至300 mg/天的递增剂量和安慰剂，从基线至第6周; TQD将设定在第8周。分裂设计（TQD后与TQD前）将允许我们分别检查托吡酯的抗多巴胺能作用是否减少饮酒和预防戒酒后复发，以及戒酒是否导致特定rs 2832407基因型携带者的PTSD簇B或E症状改善。所有参与者将接受标准化的双周简短行为依从性增强治疗和治疗后随访以及3个月评估。

 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.