Using Ketamine to enhance memory reconsolidation and extinction of overgeneralized fear in individuals diagnosed with PTSD

使用氯胺酮增强被诊断患有创伤后应激障碍 (PTSD) 的患者的记忆重新巩固和过度恐惧的消除

• 批准号: 10574049
• 负责人: ILAN HARPAZ-ROTEM
• 金额: $ 124.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574049
• 关键词: Acceleration; Affective; Aftercare; Amygdaloid structure; Anesthetics; Animals; Antidepressive Agents; Atrophic; Back; Basic Science; Biological Markers; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cell Proliferation; Chronic Post Traumatic Stress Disorder; Chronic stress; Classification; Clinical; Clinical assessments; Cognitive Therapy; Control Groups; Corpus striatum structure; Cues; Data; Development; Devices; Diagnosis; Dose; Double-Blind Method; Dropout; Effectiveness; Excitatory Amino Acid Antagonists; Exposure to; Extinction; FDA approved; Fright; Functional disorder; Galvanic Skin Response; Harvest; Hippocampus; Human; Impairment; Individual; Industrialization; Infusion procedures; Insula of Reil; Intervention; Ketamine; Learning; Link; Measures; Memory; Midazolam; Moods; N-Methylaspartate; Neurobiology; Neuronal Plasticity; Neurosciences; Participant; Patients; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Psychophysiology; Psychotherapy; Reporting; Selective Serotonin Reuptake Inhibitor; Startle Reaction; Structure; Symptoms; Testing; Therapeutic Intervention; Time; Trauma; Treatment outcome; Visit; Work; antidepressant effect; clinical effect; depressive symptoms; design; effective intervention; efficacy evaluation; experience; fear memory; improved; in vivo; insight; interest; meetings; neural; neurogenesis; neuroimaging; neuromechanism; novel; pharmacologic; placebo group; premature; randomized, controlled study; reduce symptoms; response; severe mental illness; success; symptomatology; synaptogenesis; therapy resistant; treatment response; treatment trial; treatment-resistant depression

Project Summary Posttraumatic Stress Disorder (PTSD) is a debilitating and a chronic mental illness. There are currently only two FDA-approved medications for the treatment of PTSD, both of which may take weeks to months to reach full clinical effects. The rates of nonresponse to these selective serotonin reuptake inhibitor antidepressants are high. Therefore, there is a tremendous need to test novel pharmacological approaches to PTSD. Trauma focus psychotherapies on the other hand require a high level of commitment by attending weekly visits for a substantial amount to time. An average course of Prolonged Exposures therapy (PE) or Trauma focus CBT usually lasts about 3 months until completion with high dropout rate and about 50% of completers being classified as non-responders. Recent studies demonstrated the effectiveness of intensive exposure therapy for PTSD which is being delivered within 1-2 weeks period that are as affective as a 3-month full course treatment but have a lower dropout rate. There are evidences to suggest that fear extinction may be further enhanced with the use of ketamine, an N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist mostly used as anesthetic. Interest in ketamine as a possible treatment for PTSD began when it was found to alleviate depressive symptoms. Two recent studies have reported that ketamine reduces PTSD symptoms during the course of drug administration period and up to 7-day post treatment, but all participants convert to PTSD soon after drug discontinuation. Using a biomarker-informed, double blind placebo-controlled design, the present proposal aims to examine the efficacy of ketamine infusion (0.5mg/kg vs 0.2mg/kg in the R61 phase to established dose; selected superior dose will advance to the R33), as compared to an active placebo (midazolam 0.045mg/kg) in enhancing postretrieval extinction of Criterion A original trauma memory. Pharmacological intervention will be combined with an intensive 4-day exposure therapy, utilizing elevated BDNF levels and increased neuroplasticity, to potentially produce a rapid and sustained reduction in PTSD symptomatology. In addition, we propose use of state-of-the-art neuroimaging assessments at baseline and at the end of treatment trial to gain insight into the neurobiology of PTSD and the neural mechanisms dictating treatment response or resistance.

项目摘要 创伤后应激障碍（PTSD）是一种使人衰弱的慢性精神疾病。目前只有两种FDA批准的治疗PTSD的药物，这两种药物都可能需要数周到数月才能达到完全的临床效果。这些选择性5-羟色胺再摄取抑制剂抗抑郁药的无反应率很高。因此，有一个巨大的需求，以测试新的药物治疗PTSD的方法。另一方面，以创伤为重点的心理治疗需要高水平的承诺，即每周参加大量的访视。延长暴露治疗（PE）或创伤焦点CBT的平均疗程通常持续约3个月，直至完成，脱落率高，约50%的完成者被归类为无应答者。最近的研究表明，在1-2周内提供的PTSD强化暴露治疗的有效性与3个月的全程治疗一样有效，但脱落率较低。 有证据表明，使用氯胺酮（一种主要用作麻醉剂的N-甲基-D-天冬氨酸谷氨酸受体（NMDAR）拮抗剂）可进一步增强恐惧消退。当发现氯胺酮可以缓解抑郁症状时，人们开始对氯胺酮作为PTSD的可能治疗方法感兴趣。最近的两项研究报告说，氯胺酮在给药期间和治疗后7天内减轻了PTSD症状，但所有参与者在停药后不久都转化为PTSD。 使用生物标志物知情、双盲安慰剂对照设计，本提案旨在检查氯胺酮输注（0.5 mg/kg vs 0.2 mg/kg，R61阶段至确定剂量;选定的上级剂量将推进至R33）与活性安慰剂（咪达唑仑0.045 mg/kg）相比在增强标准A原始创伤记忆的试验后消退方面的疗效。药物干预将与为期4天的强化暴露治疗相结合，利用BDNF水平升高和神经可塑性增加，可能会迅速和持续地减少PTSD的发病率。此外，我们建议在基线和治疗试验结束时使用最先进的神经影像学评估，以深入了解PTSD的神经生物学和决定治疗反应或抵抗的神经机制。