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: 10626710
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626710
• 关键词: Acceleration; Acoustics; Affect; Alzheimer' s Disease; Anesthetics; Anhedonia; Antidepressive Agents; Clinical; Clinical Treatment; Clinics and Hospitals; Data; Development; Dose; Electroencephalography; Excitatory Amino Acid Antagonists; Exposure to; Extinction; Foundations; Fright; Glutamate Receptor; Glutamates; Goals; Home; Hour; Human; Individual; Intervention; Ketamine; Life; Measures; Medial; Mediating; Mental Depression; Mental disorders; Metabolic; Metabolism; Motivation; Mus; N-Methylaspartate; Nature; Outcome; Parkinson Disease; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Actions; 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; abuse liability; clinically relevant; combat veteran; conditioned fear; conditioning; drug development; endophenotype; experience; experimental study; improved; inhibitor; neurotransmission; novel; pharmacologic; pleasure; pre-clinical; preference; prevent; response; side effect; sleep abnormalities; stress related disorder; suicidal; suicidal risk; traumatic stress

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.

压力带来的有害精神后果困扰着许多最近部署的战斗退伍军人。 最近的证据表明，小剂量的麻醉剂氯胺酮可以迅速缓解抑郁， 创伤后应激障碍(PTSD)、快感缺乏(体验快乐的能力降低)和自杀 在一次给药后的几个小时内。这些影响延伸到对治疗有抗药性的人群， 暗示氯胺酮是治疗精神疾病的一种新的和独特的药理选择， 不成比例地影响了我们的退伍军人。尽管有这些有希望的结果，氯胺酮作为一种治疗方法的使用 医院或诊所外的环境受到限制，因为它即使在低电压下也能产生解离效果 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)，因此该药物的所有精神影响(包括负面和治疗性)， 假设有类似的潜在作用机制。氯胺酮被迅速代谢成许多 代谢物，包括对NMDAR的抑制作用要弱得多的羟去甲基氯胺酮(HNK)。我们 最近(《自然》，2016)证明了(2R，6R)-HNK代谢物在 临床前试验可预测快速和持续的抗抑郁药物疗效。有意义的是，我们发现即使是 极大剂量的(2R，6R)-HNK缺乏麻醉和解离作用，以及临床前的滥用倾向 测试。我们的目标是开发一种改进的干预措施，用于治疗退伍军人的应激相关障碍， 鉴于我们对氯胺酮相关药理作用的了解。 我们的初步数据表明，在人体内产生的(2R，6R)-HNK代谢物 给予氯胺酮，可能是治疗遭受创伤后应激障碍和快感障碍困扰的退伍军人的理想方法。 压力。在特定的目标#1中，我们将定义氯胺酮与(2R，6R)-HNK在小鼠试验中的作用 创伤后应激障碍领域包括条件性恐惧反应和恐惧消退，用声学测量高度觉醒 惊吓反应和脑电睡眠异常，无论是在控制条件下还是在以下情况下 压力。我们将测试症状前和症状后给药的效果，预测(2R，6R)-HNK将 充分充分发挥氯胺酮在不同领域/内表型的治疗作用 与创伤后应激障碍有关。在特定目标#2中，我们将确定氯胺酮及其(2R，6R)-HNK的作用 代谢物对快感缺乏症的消耗性、预期性和激励性亚型的影响，这与 快感缺乏是创伤后应激障碍患者的一种症状；以及抑郁症、精神分裂症、 帕金森氏症和阿尔茨海默氏症。 我们预计(2R，6R)-HNK将在几个重要的实验措施中被证明是有效的，并且 该项目的成功完成将提供(2R，6R)-HNK所需的临床前证据 作为创伤后应激障碍和快感缺乏症的临床治疗方法的评估进展。这项工作可能会有一个 直接影响，鉴于(2R，6R)-HNK目前正在开发治疗抑郁症的药物。因此，我们认为 拟议中的实验的完成将为一流的 我们可以为退伍军人提供治疗，他们受到创伤后应激障碍的影响不成比例， 快感缺乏症。

项目成果

Ketamine metabolite (2R,6R)-hydroxynorketamine reverses behavioral despair produced by adolescent trauma.

• DOI: 10.1016/j.pbb.2020.172973
• 发表时间: 2020-09
• 期刊: Pharmacology, biochemistry, and behavior
• 作者: Elmer GI;Tapocik JD;Mayo CL;Zanos P;Gould TD
• 通讯作者: Gould TD

Experimenters' sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor.

• DOI: 10.1038/s41593-022-01146-x
• 发表时间: 2022-09
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Georgiou, Polymnia;Zanos, Panos;Mou, Ta-Chung M.;An, Xiaoxian;Gerhard, Danielle M.;Dryanovski, Dilyan, I;Potter, Liam E.;Highland, Jaclyn N.;Jenne, Carleigh E.;Stewart, Brent W.;Pultorak, Katherine J.;Yuan, Peixiong;Powels, Chris F.;Lovett, Jacqueline;Pereira, Edna F. R.;Clark, Sarah M.;Tonelli, Leonardo H.;Moaddel, Ruin;Zarate, Carlos A., Jr.;Duman, Ronald S.;Thompson, Scott M.;Gould, Todd D.
• 通讯作者: Gould, Todd D.

Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration.

• DOI: 10.1038/s41398-022-01941-x
• 发表时间: 2022-05-02
• 期刊: TRANSLATIONAL PSYCHIATRY
• 影响因子: 6.8
• 作者: Moaddel, Ruin;Zanos, Panos;Farmer, Cristan A.;Kadriu, Bashkim;Morris, Patrick J.;Lovett, Jacqueline;Acevedo-Diaz, Elia E.;Cavanaugh, Grace W.;Yuan, Peixiong;Yavi, Mani;Thomas, Craig J.;Park, Lawrence T.;Ferrucci, Luigi;Gould, Todd D.;Zarate, Carlos A., Jr.
• 通讯作者: Zarate, Carlos A., Jr.

Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects.

• DOI: 10.1038/s41380-018-0028-2
• 发表时间: 2019-07
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Nugent AC;Ballard ED;Gould TD;Park LT;Moaddel R;Brutsche NE;Zarate CA Jr
• 通讯作者: Zarate CA Jr

Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects.

重度抑郁症和健康对照受试者的氯胺酮和安慰剂跨界试验的血浆代谢组分析。

• DOI: 10.1007/s00213-018-4992-7
• 发表时间: 2018-10
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Moaddel R;Shardell M;Khadeer M;Lovett J;Kadriu B;Ravichandran S;Morris PJ;Yuan P;Thomas CJ;Gould TD;Ferrucci L;Zarate CA
• 通讯作者: Zarate CA