Repeated Ketamine Treatment to Accelerate Efficacy of Prolonged Exposure in PTSD

目前只有舍曲林和帕罗西汀被FDA批准用于治疗创伤后应激障碍。其他精神药物也是一样的 仅限于提供最佳响应。这种疗效差距在退伍军人管理局的设置中可能特别大。2017年 VA/DoD创伤后应激障碍和急性应激障碍管理的临床实践指南建议 以个人、手动创伤为重点，如长期暴露(PE)，而不是其他药物 创伤后应激障碍初级治疗的干预措施。然而，最近对创伤为基础的临床试验的回顾 在军人和退伍军人中的治疗表明，30%到50%的患者没有表现出 临床上有意义的症状变化和三分之二的患者在治疗后保留了PTSD的诊断。 新的研究表明，通过使用针对以下目标的药物可以改善PE治疗 一种或多种治疗机制。氯胺酮，FDA批准的麻醉剂，具有强大的非竞争性 谷氨酸能N-甲基-D-天冬氨酸(NMDA)的拮抗作用，已显示出促进神经可塑性。 情绪障碍和创伤后应激障碍。最近的创伤后应激障碍的临床前范例表明，氯胺酮增强了 在不干扰灭绝训练的情况下回忆灭绝学习并减少恐惧更新。氯胺酮 产生谷氨酸能爆发，导致长效突触蛋白(MTORC1)和神经元激活 在内侧前额叶皮质(MPCF)。因此，氯胺酮可增强自上而下的抑制作用 在体育治疗期间，从mPFC开车到恐惧相关的杏仁核。 我们的初步数据显示，经过六次氯胺酮治疗后，创伤后应激障碍的缓解率(PCL-5评分和33分) 为80.0%。临床医生访谈的创伤后应激障碍严重程度(CAPS-5)也显示出比 治疗后PTSD基线为39.7(S.D.=9.3)~20.8(S.D.=7.2)(Cohen‘s d’=1.85)。然而，中位数 6次注射后PTSD和抑郁症复发的时间分别为41天和26天。这一发现 表明一系列氯胺酮具有强大但短期的治疗效果。我们试行使用…的附加语。 提高氯胺酮标准化体育治疗的疗效。12名退伍军人在4个月内获得同意 其中10人参加了研究，7名退伍军人在#年接受了治疗干预 本研究的意见书。前3次PE前24小时单次输注氯胺酮 几周的治疗显示可以接受，耐受性良好，并显示出加速减轻创伤后应激障碍症状的效果。 三名退伍军人在7个疗程内结束体育治疗，而不是通常的10个疗程，这是受试者和治疗师商定的 这一治疗目标已经实现。我们还测量了认知表现，有趣的是，我们设置了 在整个干预过程中，任务转移显著改善(氯胺酮和PE)。 我们计划进行一项单一地点(明尼阿波利斯，弗吉尼亚州)随机对照试验，比较三种氯胺酮治疗和活性安慰剂 在患有创伤后应激障碍的退伍军人中使用咪达唑仑辅助体育治疗。药理学阶段将开始 与第一次PE同时进行。输液将持续24小时。在前3个月的PE会话之前 几周。在完成PE(第10节)后，患者将在3个月的随访期内接受评估 不同的时间点。我们估计，在100名退伍军人中，有80名将达到主要结果的时间点 测量(第10周的CAPS评分)，并将被考虑用于初步分析。次要结果包括 抑郁和焦虑的严重程度评分、氯胺酮强化体育治疗的安全性和耐受性、认知 治疗期间的表现和PE期间的早期改善与辍学率/完成率有关 在体育治疗期间。随机对照试验的结果可以为区分本质 这一方法的组成部分，加强方法论，阐明所涉及的机制，并确定次 最有可能从这种干预中受益的创伤后应激障碍人群。

Only sertraline and paroxetine are currently FDA‐approved to treat PTSD. Other psychotropics are equally limited to provide optimal respond. This efficacy gap may be particularly great in VA settings. The 2017 VA/DoD Clinical Practice Guideline for The Management of PTSD and Acute Stress Disorder recommends individual, manualized trauma-focused such as Prolonged Exposure (PE) over other pharmacologic interventions for the primary treatment of PTSD. However, a recent review of clinical trials of trauma-based therapies in the military and veteran population showed that 30% to 50% of patients did not demonstrate clinically meaningful symptom change and two-thirds of patients retained PTSD diagnosis after treatment. Emerging research indicates that PE therapy may be improved by administration of medications that target one or more therapeutic mechanisms. Ketamine, an FDA-approved anesthetic with potent non-competitive glutamatergic N-methyl-D-aspartate (NMDA) antagonistic properties, has shown to promote neuroplasticity in mood disorders and PTSD. Recent preclinical paradigms of PTSD demonstrated that ketamine enhances the recall of extinction learning and decrease fear renewal without interference of extinction training. Ketamine produces a glutamatergic burst that leads to a long-lasting synaptic protein (mTORC1) and neuronal activation in the medial prefrontal cortex (mPCF). Therefore, ketamine could exert an augmented top-down inhibitory drive from the mPFC to fear-related amygdala during PE therapy. Our preliminary data showed that after six ketamine treatment, the remission rate for PTSD (PCL-5 score < 33) was 80.0 %. PTSD severity by clinician interview (CAPS-5) also demonstrated a significant reduction from a PTSD baseline of 39.7 (S.D.=9.3) to 20.8 (S.D.= 7.2) after treatment (Cohen’s d’ = 1.85). However, the median time to relapse for PTSD and depression after six infusions were 41 and 26 days, respectively. This finding suggests a powerful but short-term therapeutic effect from serial ketamine. We piloted the adjunctive use of ketamine to enhance the efficacy of standardized PE therapy. Twelve Veterans were consented in 4 months with 10 of them enrolled in the study, and 7 Veterans received treatment intervention by the time of submission for this study. Single ketamine infusion administered 24 hours prior to PE session for the first 3 weeks showed to be acceptable, well-tolerated, and showed efficacy to accelerate reduction of PTSD symptoms. Three Veterans ends PE therapy in 7 sessions instead of the usual 10 sessions as subjects and therapist agreed that therapeutic goals were already achieved. We also measured cognitive performance and, interestingly, set shifting tasks remarkably improved throughout the intervention (ketamine and PE). We plan to conduct a single site (Minneapolis VA) RCT comparing three ketamine treatment vs. active placebo (midazolam) adjunct to PE therapy among Veterans with PTSD. Pharmacological phase will start simultaneously with PE session 1. Infusions will be administered 24 hrs. prior to PE session for the first 3 weeks. After PE is completed (session 10), patients will be assessed during a 3-month follow-up period at various time points. We estimate that out of 100 veterans, 80 will reach time point for primary outcome measure (CAPS score at week 10) and will be considered for primary analysis. Secondary outcomes include severity of depression and anxiety scores, safety and tolerability of ketamine-enhanced PE therapy, cognitive performance during treatment and early improvement during PE related to the rate of dropouts/completers during PE therapy. Results of the proposed RCT could provide scientific foundation to distinguish the essential components of this approach, enhance the methodology, elucidate the mechanisms involved, and identify sub- PTSD populations that most likely benefit from this intervention.