The Antidepressant Action of Ketamine:Brain Chemistry

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寿命年评估，2002年，它是全球第四大残疾原因。到2030年，MDD预计将成为该措施评估的第二大残疾原因，仅次于艾滋病毒/艾滋病。在美国，MDD已经是15-44岁残疾的主要原因，1990年估计每年总成本为437亿美元。最近的一项估计显示，美国每年因MDD而造成的人口级工作场所成本为366亿美元，这还不包括医疗保健成本。MDD患者的疾病负担和相关疾病成本的复合是目前可用治疗的治疗开始和治疗作用开始之间的数周延迟。将这种延迟缩短到MDD抗抑郁治疗的临床显著改善是一个主要的未满足的挑战。研究报告称，单次静脉注射亚麻醉剂量的氯胺酮（一种NMDA受体拮抗剂）可在数小时内完全缓解，即使是治疗抵抗性MDD。氯胺酮的治疗作用机制方面已经相当完善。已经证明氯胺酮快速激活雷帕霉素的哺乳动物靶标mTOR。当mTOR信号被激活时，在几分钟内，突触信号蛋白的快速增加，新的棘树突的数量，突触发生，以及抑郁症动物模型中运动活动的增加。尽管许多其他途径被激活，但这些氯胺酮诱导的变化只有在AMPA受体或下游mTOR信号传导被阻断时才停止。这就引出了氯胺酮如何激活AMPA受体的问题，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，诱导一个强大的急性增加（超过60%）谷氨酸（Glu;内源性激动剂的NMDA和AMPA受体）和γ-氨基丁酸（GABA）水平在前扣带皮层（ACC）的质子磁共振波谱（1H MRS）测量。我们假设，不是氯胺酮直接，而是通过阻断NMDA受体触发的Glu水平的增加，负责AMPA受体的激活和随后的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，制定更好的维持策略，并指导开发其他更容易管理的药物，通过这些实验结果所建议的分子靶点发挥作用。本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。 公共卫生相关性：氯胺酮，在一个单一的，低剂量的使用，可以带来完全缓解的症状，在严重的抑郁症，持续一个星期。该项目旨在通过测量大脑化学物质的变化，并研究这些变化与氯胺酮抗抑郁作用的关系，从而更好地了解氯胺酮的作用机制。

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. PUBLIC HEALTH RELEVANCE: Ketamine, used in a single, low dose, can bring about complete remission of symptoms in major depressive disorder that lasts a week. This project is designed to gain a better understanding of ketamine's mechanism of action by measuring changes in brain chemicals and studying the relationship of these changes with ketamine's antidepressant effect.