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）是一种高度普遍的疾病，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后的生活，这是2002年全球残疾的第四个主要原因。到2030年，MDD预计将成为该措施评估的残疾第二大主要原因，仅次于艾滋病毒/艾滋病。在美国，MDD已经是15-44岁的残疾的主要原因，估计1990年的年度总成本为437亿美元。最近的估计使美国MDD的年度人口级工作场所成本为366亿美元，不计算医疗费用。增加了疾病负担和MDD中疾病的相关成本是治疗开始与当前可用治疗的治疗作用之间的几周延迟。将这种延迟缩短到临床上显着改善的MDD治疗是一个主要的挑战。研究报告说，即使在耐治疗的MDD中，也可以在小时内完全缓解氯胺酮（NMDA受体拮抗剂）的单一静脉内次动理剂量（NMDA受体拮抗剂）。氯胺酮的治疗作用机制的各个方面已经确定了。已经证明氯胺酮迅速激活雷帕霉素MTOR的哺乳动物靶标。当激活MTOR信号传导时，在几分钟之内突触信号传导蛋白，新的脊柱树突的数量，突触发生以及随之而来的动物模型中的运动活性增加。尽管许多其他途径被激活，但仅当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。这导致了氯胺酮如何激活AMPA受体的问题，AMPA受体是MTOR激活所必需的。我们的初步数据表明，氯胺酮通过阻断NMDA受体，谷氨酸（GLU; NMDA和AMPA受体的内源性激动剂）和γaminobutric Aciric Actoper（GABA）在谷氨酸的内源性激动剂（GABA）水平（ACP CACTENERION CODER（ACC）启发（GABA）的浓度（ACP）（ACP）的浓度（GABA）诱导急性增加（超过60％），以此为1 ACP型（GABA）。 太太）。我们假设不是直接的氯胺酮，而是通过阻断NMDA受体触发的GLU水平的增加是导致AMPA受体的激活以及随后的MTOR信号传导。研究氯胺酮的作用机理可以帮助优化氯胺酮的使用，制定更好的维护策略，并指导其他更容易施用的药物，这些药物通过这些实验结果提出的分子靶标的工作。拟议项目的目的是研究氯胺酮诱导的MDD的改善与GLU和GABA对氯胺酮的反应之间的关系，并比较MDD和健康受试者的GLU和GABA对氯胺酮的反应，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，安慰剂对照的双盲研究，并使用几种不同剂量的氯胺酮研究。

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