The Antidepressant Action of Ketamine:Brain Chemistry

描述（由申请人提供）：重度抑郁症（MDD）是一种非常普遍的疾病，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寿命年评估，在2002年，它是全球第四大致残原因。根据这项措施的评估，到2030年，抑郁症预计将成为仅次于艾滋病毒/艾滋病的第二大致残原因。在美国，重度抑郁症已经是15-44岁人群致残的主要原因，1990年估计每年的总费用为437亿美元。最近的一项估计显示，不包括医疗成本在内，美国每年因重度抑郁症造成的工作场所成本为366亿美元。加重重度抑郁症疾病负担和相关疾病费用的是，从开始治疗到目前可用的治疗措施开始治疗之间的几周延迟。缩短这种延迟到临床显著改善的抗抑郁药物治疗重度抑郁症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）可以在数小时内完全缓解，即使对治疗难治性重度抑郁症也是如此。氯胺酮的治疗作用机制的各个方面已经相当确定。已经证明氯胺酮能迅速激活哺乳动物雷帕霉素靶蛋白mTOR。当mTOR信号被激活时，在几分钟内突触信号蛋白迅速增加，新的脊柱树突数量增加，突触发生，抑郁症动物模型中的运动活动增加。虽然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信号被阻断时才会停止。这就引出了氯胺酮是如何激活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（ACC）中谷氨酸（Glu； NMDA和AMPA受体的内源性激动剂）和γ氨基丁酸（GABA）水平的急性增加（超过60%），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有助于优化氯胺酮的使用，制定更好的维持策略，并指导开发其他更容易施用的药物，这些药物通过这些实验结果提示的分子靶点起作用。本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和健康受试者对氯胺酮的Glu和GABA反应，以进一步阐明MDD的病理生理。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。

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.