Repeated Ketamine Treatment to Accelerate Efficacy of Prolonged Exposure in PTSD

重复氯胺酮治疗可提高 PTSD 患者长期接触氯胺酮的疗效

• 批准号: 10578751
• 负责人: Paulo R. Shiroma
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578751
• 关键词: Acceleration; Acute; Address; Adherence; Adjuvant Analgesic; Aftercare; Agreement; Amygdaloid structure; Anesthetics; Anxiety; Area; Biological Process; Blood; Brain; Clinical; Clinical Data; Clinical Practice Guideline; Clinical Trials; Complex; Consent; Data; Diagnosis; Disease; Disease remission; Dose; Dropout; Drops; Enrollment; Extinction; FDA approved; Female; Financial Hardship; Foundations; Frequencies; Fright; Glutamates; Goals; Hour; Individual; Infusion procedures; Intervention; Interview; Joints; Ketamine; Manuals; Measures; Medial; Memory; Mental Depression; Methodology; Midazolam; Military Personnel; Modeling; Mood Disorders; Multicenter Studies; N-Methylaspartate; Neuronal Plasticity; Neurons; Nootropic Agents; Outcome; Outcome Measure; Paroxetine; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Property; Proteins; Psychotherapy; Recommendation; Relapse; Research; Residual state; Rodent; Safety; Sertraline; Severities; Site; Standardization; Symptoms; Synapses; Therapeutic; Therapeutic Effect; Time; Training; Trauma; Trust; Veterans; active duty; acute traumatic stress disorder; anxiety reduction; anxiety symptoms; associated symptom; cognitive performance; comorbid depression; comorbidity; conditioned fear; depressive symptoms; diagnostic criteria; efficacy evaluation; fear memory; follow-up; improved; learning extinction; medication administration; military veteran; patient retention; pharmacologic; pre-clinical; pre-clinical assessment; primary outcome; randomized, clinical trials; reduce symptoms; response; secondary outcome; side effect; social; trauma exposure

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.

目前，仅FDA批准用于治疗PTSD。其他精神技术同样是 限制提供最佳响应。在VA环境中，此效率差距可能特别大。 2017年 PTSD和急性应激障碍管理的VA/DOD临床实践指南建议 个人手动创伤的个人，例如其他药理学的长时间暴露（PE） 主要治疗PTSD的干预措施。但是，最近对基于创伤的临床试验的回顾 军事和退伍军人人口的疗法表明，有30％至50％的患者没有证明 治疗后，临床上有意义的症状改变，三分之二的患者保留了PTSD诊断。 新兴研究表明，通过靶向的药物可以改善PE疗法 一种或多种治疗机制。氯胺酮，一种由FDA批准的麻醉剂，具有潜在的非竞争力 谷氨酸能N-甲基-D-天冬氨酸（NMDA）拮抗特性已证明可以促进神经可塑性 情绪障碍和PTSD。 PTSD最近的临床前范例表明，氯胺酮可以增强 召回扩展学习并减少恐惧的续约，而不会干扰扩展培训。氯胺酮 产生谷氨酸能爆发，导致持久的突触蛋白（MTORC1）和神经元激活 在媒体前额叶皮层（MPCF）中。因此，氯胺酮可以施加增强的自上而下抑制 在PE治疗期间，从MPFC开车到与恐惧相关的杏仁核。 我们的初步数据表明，经过六种氯胺酮治疗后，PTSD的缓解率（PCL-5分数<33） 是80.0％。通过临床访谈（CAPS-5），PTSD严重程度也证明了A 治疗后的PTSD基线为39.7（S.D. = 9.3）至20.8（S.D. = 7.2）（Cohen's D'= 1.85）。但是，中位数 六次输注后的PTSD和抑郁症中继的时间分别为41天和26天。这个发现 提出了连续氯胺酮的强大但短期治疗的作用。我们试用了辅助用途 氯胺酮可提高标准化PE疗法的效率。十二名退伍军人在4个月内同意 他们中有10名参加了研究，而7名退伍军人在 提交这项研究。第3个PE会议前24小时给药的单个氯胺酮输注 几周被证明是可以接受的，耐受性且表现出的效率，以加速减少PTSD症状。 三名退伍军人结束了7次课程的体育治疗，而不是通常的10次课程，因为受试者和治疗师同意 该治疗目标已经实现。我们还测量了认知表现，有趣的是 在整个干预过程中，转移任务得到了明显改善（氯胺酮和PE）。 我们计划进行单个部位（Minneapolis VA）RCT，以比较三种氯胺酮治疗与活动安慰剂 （咪达唑仑）与PTSD的退伍军人中PE治疗的辅助。药理阶段将开始 类似地，与PE会话1同样。输注液将进行24小时。在第3个PE会话之前 几周。 PE完成后（会议10）后，将在3个月的随访期内评估患者 各种时间点。我们估计，在100名退伍军人中，有80位将达到主要结果的时间点 测量（第10周的上限得分），并将考虑进行初级分析。次要结果包括 抑郁和焦虑评分的严重程度，氯胺酮增强体育疗法的安全性和耐受性，认知 治疗期间的性能和PE期间的早期改进与辍学率/完成者的速度有关 在体育治疗期间。拟议的RCT的结果可以提供科学基础，以区分基本 这种方法的组成部分，增强方法论，阐明所涉及的机制，并确定子 - PTSD种群很可能受益于这种干预措施。