Hydroxynorketamine for the Treatment of PTSD and Anhedonia

羟基去甲氯胺酮治疗创伤后应激障碍和快感缺失

• 批准号: 9561714
• 负责人: Todd D Gould
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9561714
• 关键词: Acoustics; Affect; Alzheimer' s Disease; Anesthetics; Anhedonia; Antidepressive Agents; Clinic; Clinical; Clinical Treatment; Data; Development; Dose; Electroencephalogram; Excitatory Amino Acid Antagonists; Exposure to; Extinction (Psychology); Foundations; Fright; Glutamate Receptor; Glutamates; Goals; Home environment; Hospitals; Hour; Human; Individual; Intervention; Ketamine; Lead; Life; Measures; Medial; Mediating; Mental Depression; Mental disorders; Metabolic; Metabolism; Motivation; Mus; N-Methylaspartate; Nature; Outcome; Parkinson Disease; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Actions; Pharmacology; Population; Post-Traumatic Stress Disorders; Pre-Clinical Model; Preclinical Testing; Prefrontal Cortex; Prevention; Property; Receptor Activation; Reporting; Research; Resistance; Role; Schizophrenia; Series; Severities; Startle Reaction; Stress; Sucrose; Suicide; Symptoms; Testing; Therapeutic; Therapeutic Effect; Therapeutic Uses; Translational Research; Treatment Efficacy; Veterans; Work; clinically relevant; combat; conditioned fear; conditioning; drug development; endophenotype; experience; experimental study; improved; inhibitor/antagonist; neurotransmission; novel; pleasure; pre-clinical; predictive test; preference; prevent; response; side effect; sleep abnormalities; stress related disorder; suicidal risk

Deleterious psychiatric outcomes following stress afflict many recently deployed combat Veterans. Recent evidence has shown that low doses of the anesthetic ketamine rapidly ameliorate depression, posttraumatic stress disorder (PTSD), anhedonia (a reduced capacity to experience pleasure), and suicidality within hours following a single administration. These effects extend to treatment-resistant populations, implicating ketamine as a novel and unique pharmacological option for treating psychiatric illnesses that disproportionately impact our combat Veterans. Despite these promising results, ketamine's use as a treatment outside of a hospital or clinic setting is limited due to its capacity to produce dissociative effects even at low doses and abuse liability. Ketamine's anesthetic effects are likely mediated by inhibition of the NMDA glutamate receptor (NMDAR) and as a consequence all of the drug's psychiatric effects (both negative and therapeutic), were assumed to have a similar underlying mechanism of action. Ketamine is rapidly metabolized into a number of metabolites, including hydroxynorketamines (HNKs) that are much less potent inhibitors of the NMDAR. We recently demonstrated (Nature, 2016) that the (2R,6R)-HNK metabolite exerts actions identical to ketamine in preclinical tests predictive of rapid and sustained antidepressant efficacy. Of significance, we found that even very high doses of (2R,6R)-HNK lack anesthetic and dissociative effects, as well as abuse liability in preclinical tests. Our goal is to develop an improved intervention for the treatment of stress-related disorders in Veterans, given what we know of ketamine's relevant pharmacological actions. Our preliminary data indicates that the (2R,6R)-HNK metabolite that is produced in humans after ketamine administration, may be an ideal treatment for PTSD and anhedonia afflicting Veterans exposed to stress. In Specific Aim #1, we will define the actions of ketamine compared to (2R,6R)-HNK in mouse tests of PTSD domains including conditioned fear responses and fear extinction, hyperarousal measured by acoustic startle responses, and electroencephalogram sleep abnormalities, both under control conditions and following stress. We will test effects of both pre- and post- symptom administration, predicting that (2R,6R)-HNK will be necessary and sufficient to exert the therapeutic effects of ketamine on different domains/endophenotypes associated with PTSD. In Specific Aim #2, we will determine actions of ketamine and its (2R,6R)-HNK metabolite on consummatory, anticipatory, and motivational subtypes of anhedonia, which has relevance to anhedonia observed as a symptom in patients with PTSD; as well as those with depression, schizophrenia, Parkinson's, and Alzheimer's disease. We anticipate that (2R,6R)-HNK will prove efficacious in several important experimental measures, and that successful completion of the project will provide the preclinical evidence that is needed for (2R,6R)-HNK to move forward in assessment as a clinical treatment for PTSD and anhedonia. This work could have an immediate impact, given that (2R,6R)-HNK is currently in drug development for depression. Thus, we believe that completion of the proposed experiments will provide a strong foundation from which a first-in-class treatment could be made available for our Veterans who are disproportionately affected by PTSD and anhedonia.

压力遭受了许多最近部署的战斗退伍军人的压力后，有害的精神病结果。 最近的证据表明，低剂量的麻醉氯胺酮迅速改善抑郁症， 创伤后应激障碍（PTSD），ANHEDONIA（体验愉悦的能力降低）和自杀性 单个管理后的几个小时内。这些影响扩展到耐药的种群， 将氯胺酮牵连为一种新颖而独特的药理学选择，用于治疗精神病疾病 不成比例地影响我们的战斗退伍军人。尽管这些有希望的结果，但氯胺酮用作治疗 医院或诊所环境之外的限制是由于其产生分离作用的能力，即使在低处 剂量和滥用责任。 氯胺酮的麻醉作用可能是通过抑制NMDA谷氨酸受体介导的 （NMDAR），因此所有药物的精神病作用（均为阴性和治疗）都是 假定具有类似的基本作用机理。氯胺酮迅速代谢成许多 代谢物，包括羟基甲胺（HNK），它们对NMDAR的有效抑制剂差得多。我们 最近证明（自然，2016年），（2R，6R）-HHNK代谢物在与氯胺酮相同的作用 临床前测试可预测快速和持续的抗抑郁功效。重要的是，我们发现甚至 非常高剂量的（2R，6R）-HHNK缺乏麻醉和分离效应，以及临床前的滥用责任 测试。我们的目标是开发改进的干预措施，以治疗退伍军人的压力相关疾病， 鉴于我们对氯胺酮相关的药理作用的了解。 我们的初步数据表明（2R，6R）-HHNK代谢物在人类之后产生 氯胺酮给药，可能是PTSD和Anhedonia的理想治疗方法 压力。在特定的目标＃1中，我们将定义氯胺酮与（2R，6R）-HHNK在鼠标测试中的作用 PTSD域，包括条件恐惧反应和恐惧灭绝，由声学测量 在控制条件下和以下 压力。我们将测试症状前和症状后的效果，预测（2R，6R）-HNK将是 必要且足够的足以发挥氯胺酮对不同结构域/内型型的治疗作用 与PTSD相关。在特定的目标＃2中，我们将确定氯胺酮及其（2R，6R）-HNK的动作 与阿尔多尼亚的完整，预期和动机亚型有关的代谢产物，这与 在PTSD患者中，Anhedonia视为症状；以及患有抑郁症，精神分裂症的人， 帕金森氏症和阿尔茨海默氏病。 我们预计（2R，6R）-HHNK将在几种重要的实验措施中有效，并且 该项目的成功完成将提供（2r，6r）-HNK所需的临床前证据 作为PTSD和ANHEDONIA的临床治疗进行评估。这项工作可能有一个 鉴于（2R，6R）-HHNK目前正在抑郁症的药物开发中，直接影响。因此，我们相信 拟议的实验的完成将提供一个强大的基础 可以为受PTSD和PTSD影响不成比例的退伍军人提供治疗 阿内多尼亚。