The Antidepressant Action of Ketamine:Brain Chemistry

氯胺酮的抗抑郁作用：脑化学

• 批准号: 8658471
• 负责人: MATE ISTVAN MILAK
• 金额: $ 56.64万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658471
• 关键词: AIDS/HIV problem; AMPA Receptors; Acute; Adjusted Life Years; Adult; Affect; Age; Agonist; American; Anesthetics; Animal Model; Anterior; Antidepressive Agents; Behavior; Biological Psychiatry; Brain; Brain Chemistry; Chemicals; Cost of Illness; Data; Dendritic Spines; Depressed mood; Development; Disease; Disease remission; Dose; Double-Blind Method; FDA approved; Functional disorder; Glutamates; Hamilton Rating Scale for Depression; Health Care Costs; Hour; Human; Infusion procedures; Intravenous; Ketamine; Laboratories; Magnetic Resonance Spectroscopy; Maintenance; Major Depressive Disorder; Measures; Mental Depression; Molecular Target; Motor Activity; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Nature; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Population; Protocols documentation; Protons; Randomized; Reporting; Research Design; Research Project Grants; Resistance; Saline; Sampling; Series; Signal Transduction; Signaling Protein; Sirolimus; Symptoms; Synapses; Therapeutic; Work; Workplace; World Health Organization; abstracting; base; burden of illness; cingulate cortex; clinically significant; cost; depressive symptoms; design; disability; gamma-Aminobutyric Acid; healthy volunteer; human FRAP1 protein; innovation; kinase inhibitor; mTOR protein; meetings; pre-clinical; research study; response; single episode major depressive disorder; synaptogenesis; treatment strategy; volunteer

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a highly prevalent illness, affecting over 14 million American adults annually. It was the fourth leading cause of disability globally in 2002, as assessed by disease-adjusted- life years according to the World Health Organization. By 2030, MDD is projected to become the second leading cause of disability as assessed by this measure, second only to HIV/AIDS. In the US, MDD is already the leading cause of disability for ages 15-44, with estimated total annual costs of $US 43.7 billion in 1990. A more recent estimate puts the annual population-level workplace cost of MDD in the US at $36.6 billion, not counting healthcare cost. Compounding the disease burden and the related cost of illness in MDD is the several week delay between initiation of treatment and onset of therapeutic action of currently available treatments. Shortening this delay to clinically significant improvement in antidepressant treatment of MDD is a major unmet challenge. Studies report that a single intravenous sub-anesthetic dose of ketamine (an NMDA receptor antagonist) can bring about full remission in hours, even in treatment-resistant MDD. Aspects of ketamine's mechanism of therapeutic action have been fairly well established. It has been demonstrated that ketamine rapidly activates the mammalian target of rapamycin, mTOR. When mTOR signaling is activated, within minutes a rapid increase in synaptic signaling proteins, the number of new spine dendrites, synaptogenesis, and increased motor activity in animal models of depression ensues. Although many other pathways are activated, these ketamine-induced changes are only stopped when either the AMPA receptors or the downstream mTOR signaling is blocked. This leads to the question of how ketamine activates the AMPA receptors, which are necessary for the activation of mTOR. Our preliminary data suggests that ketamine, by blocking NMDA receptors, induces a robust acute increase (more than 60%) in glutamate (Glu; the endogenous agonist of NMDA and AMPA receptors) and gamma aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) as measured by proton magnetic resonance spectroscopy (1H MRS). We hypothesize that not ketamine directly, but this increase in Glu levels, triggered by blocking the NMDA receptors, is responsible for the activation of AMPA receptors and subsequently mTOR signaling. Studying ketamine's mechanism of action could help optimize the use of ketamine, develop better maintenance strategies, and guide development of other more easily administered medications working through the molecular targets suggested by the results of these experiments. The objective of the proposed project is to study the relationship between the ketamine-induced improvement of MDD and the Glu and GABA responses to ketamine and to compare the Glu and GABA responses to ketamine in MDD and healthy subjects to further elucidate the pathophysiology of MDD. To study this we designed a randomized, placebo-controlled, double- blind study with several different doses of ketamine.

描述（由申请人提供）：重度抑郁症 (MDD) 是一种高度流行的疾病，每年影响超过 1400 万美国成年人。根据世界卫生组织的疾病调整生命年评估，2002 年，它是全球第四大残疾原因。根据这一指标评估，到 2030 年，MDD 预计将成为第二大残疾原因，仅次于艾滋病毒/艾滋病。在美国，MDD 已经成为 15-44 岁年龄段人群残疾的主要原因，1990 年估计每年造成的总费用为 437 亿美元。最近的一项估计显示，美国 MDD 在工作场所造成的每年人口成本为 36.6 美元亿，不包括医疗保健费用。目前可用的治疗方法从开始治疗到发挥治疗作用之间有几周的延迟，这加剧了重度抑郁症的疾病负担和相关疾病成本。缩短MDD抗抑郁治疗临床显着改善的延迟是一个尚未解决的重大挑战。研究报告称，单次静脉亚麻醉剂量的氯胺酮（一种 NMDA 受体拮抗剂）可以在数小时内实现完全缓解，即使是难治性 MDD。氯胺酮的治疗作用机制已相当明确。已证明氯胺酮可快速激活雷帕霉素的哺乳动物靶标 mTOR。当 mTOR 信号传导被激活时，抑郁症动物模型中的突触信号蛋白、新树突数量、突触发生和运动活动在几分钟内就会迅速增加。尽管许多其他途径被激活，但只有当 AMPA 受体或下游 mTOR 信号传导被阻断时，这些氯胺酮诱导的变化才会停止。这就引出了氯胺酮如何激活 AMPA 受体的问题，而 AMPA 受体是激活 mTOR 所必需的。我们的初步数据表明，氯胺酮通过阻断 NMDA 受体，诱导前扣带皮层中谷氨酸（Glu；NMDA 和 AMPA 受体的内源性激动剂）和 γ 氨基丁酸 (GABA) 水平急剧增加（超过 60%） (ACC)通过质子磁共振波谱(1H MRS)测量。我们假设不是氯胺酮直接作用，而是通过阻断 NMDA 受体引发的 Glu 水平升高，负责激活 AMPA 受体以及随后的 mTOR 信号传导。研究氯胺酮的作用机制可以帮助优化氯胺酮的使用，制定更好的维护策略，并指导开发其他更容易给药的药物，这些药物通过这些实验结果所建议的分子靶标发挥作用。该项目的目的是研究氯胺酮诱导的MDD改善与Glu和GABA对氯胺酮的反应之间的关系，并比较MDD和健康受试者对氯胺酮的Glu和GABA反应，以进一步阐明MDD的病理生理学。为了研究这一点，我们设计了一项随机、安慰剂对照、双盲研究，使用几种不同剂量的氯胺酮。

项目成果

Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder.

• DOI: 10.1038/s41398-021-01541-1
• 发表时间: 2021-08-05
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Kantrowitz JT;Dong Z;Milak MS;Rashid R;Kegeles LS;Javitt DC;Lieberman JA;John Mann J
• 通讯作者: John Mann J