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: 10463535
• 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/10463535
• 关键词: Acute; Address; Adherence; Adjuvant Analgesic; Aftercare; 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 (Psychology); FDA approved; Female; Financial Hardship; Foundations; Frequencies; Fright; Glutamates; Goals; Hour; Individual; Infusion procedures; Intervention; Interview; Joints; Ketamine; Measures; Medial; Memory; Mental Depression; Methodology; Midazolam; Military Personnel; Modeling; Mood Disorders; Moods; N-Methylaspartate; Neuronal Plasticity; Neurons; Nootropic Agents; Outcome Measure; Paroxetine; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Placebos; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Property; Proteins; Psychotherapy; Randomized Clinical Trials; 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 symptoms; associated symptom; base; cognitive performance; comorbid depression; comorbidity; conditioned fear; depressive symptoms; diagnostic criteria; fear memory; follow-up; improved; learning extinction; medication administration; military veteran; pre-clinical; pre-clinical assessment; primary outcome; 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.

目前只有舍曲林和帕罗西汀获得 FDA 批准用于治疗创伤后应激障碍（PTSD）。 在 2017 年的 VA 环境中，这种功效差距可能特别大。 VA/DoD 创伤后应激障碍 (PTSD) 和急性应激障碍管理临床实践指南建议 个体化、以创伤为重点的手动操作，例如长期暴露（PE）而不是其他药物 然而，最近对基于创伤的临床试验进行了回顾。 对军人和退伍军人群体的治疗表明，30% 至 50% 的患者没有表现出 临床上显着的症状变化和三分之二的患者在治疗后仍被诊断为 PTSD。 新兴研究表明，PE 治疗可以通过服用靶向药物来改善 氯胺酮是一种经 FDA 批准的具有强效非竞争性的麻醉剂。 谷氨酸能 N-甲基-D-天冬氨酸 (NMDA) 拮抗特性，已被证明可以促进神经可塑性 最近的 PTSD 临床前范例表明，氯胺酮可增强 在不干扰氯胺酮的情况下回忆消退学习并减少恐惧更新。 产生谷氨酸能爆发，导致持久的突触蛋白 (mTORC1) 和神经元激活 因此，氯胺酮可以发挥增强的自上而下的抑制作用。 在 PE 治疗期间从 mPFC 驱动到与恐惧相关的杏仁核。 我们的初步数据显示，经过六次氯胺酮治疗后，PTSD 的缓解率（PCL-5 评分 < 33） 通过临床医生访谈 (CAPS-5) 得出的 PTSD 严重程度也显着降低。 治疗后 PTSD 基线为 39.7 (S.D.=9.3) 至 20.8 (S.D.= 7.2)（Cohen d' = 1.85）。 六次输注后 PTSD 和抑郁症复发的时间分别为 41 天和 26 天。 表明连续氯胺酮具有强大但短期的治疗效果，我们尝试了辅助使用。 4 个月内，12 名退伍军人同意使用氯胺酮来增强标准化 PE 治疗的效果。 其中 10 人参加了该研究，7 名退伍军人在研究时接受了治疗干预 前 3 次体育训练前 24 小时注射一次氯胺酮。 几周的时间被证明是可以接受的，耐受性良好，并且显示出加速减少 PTSD 症状的功效。 根据受试者和治疗师的同意，三名退伍军人在 7 次训练中结束体育治疗，而不是通常的 10 次训练 我们还测量了认知表现，并且有趣的是，我们设定了治疗目标。 转移任务显着改善了干预（氯胺酮和体育运动）。 我们计划进行单中心（弗吉尼亚州明尼阿波利斯）随机对照试验，比较三种氯胺酮治疗与活性安慰剂 （咪达唑仑）对患有 PTSD 的退伍军人进行 PE 治疗的辅助疗法将开始药理学阶段。 与体育训练同时进行 1. 前 3 次输液将在体育训练前 24 小时进行。 PE 完成后（第 10 节），患者将在 3 个月的随访期内接受评估。 我们估计 100 名退伍军人中，有 80 人将达到主要结果的时间点。 测量（第 10 周的 CAPS 评分），并将考虑进行主要分析，包括次要结果。 抑郁和焦虑评分的严重程度、氯胺酮增强体育治疗的安全性和耐受性、认知 治疗期间的表现和 PE 期间的早期改善与退出/完成者率相关 拟议的随机对照试验的结果可以为区分基本的疾病提供科学依据。 该方法的组成部分，增强方法，阐明所涉及的机制，并确定子 最有可能从这种干预措施中受益的 PTSD 人群。