The Antidepressant Action of Ketamine:Brain Chemistry

描述(由申请人提供)：严重抑郁障碍(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数据，根据疾病调整寿命年的评估，2002年，它是全球第四大致残原因。到2030年，根据这一衡量标准，MDD预计将成为仅次于艾滋病毒/艾滋病的第二大残疾原因。在美国，MDD已经是15-44岁的残疾的主要原因，1990年估计每年的总成本为437亿美元。最近的一项估计显示，美国每年因MDD造成的人口层面的工作场所成本为366亿美元，这还不包括医疗成本。使MDD的疾病负担和相关疾病成本复杂化的是，目前可用的治疗方法在开始治疗和开始治疗行动之间有几个星期的延迟。缩短这一延迟，使MDD的抗抑郁治疗在临床上有显著改善，这是一个尚未满足的主要挑战。研究报告称，一次静脉注射亚麻药剂量的氯胺酮(一种NMDA受体拮抗剂)可以在几个小时内完全缓解，即使是在治疗耐药的MDD中也是如此。氯胺酮的治疗作用机制方面已经得到了相当充分的证实。已有研究表明，氯胺酮可迅速激活雷帕霉素的哺乳动物靶点mTOR。当mTOR信号被激活时，突触信号蛋白在几分钟内迅速增加，在抑郁症动物模型中新的棘树突数量、突触发生和运动活动增加随之而来。尽管许多其他途径被激活，但只有当AMPA受体或下游的mTOR信号被阻断时，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，AMPA受体是激活mTOR所必需的。我们的初步数据表明，通过阻断NMDA受体，氯胺酮可引起前扣带回皮质(ACC)谷氨酸(Glu；NMDA和AMPA受体的内源性激动剂)和伽马氨基丁酸(GABA)水平的强劲急性升高(超过60%)，这是通过质子磁共振波谱(1HMRS)测量的。我们推测，不是直接的氯胺酮，而是这种谷氨酸水平的增加，由阻断NMDA受体，负责激活AMPA受体，并随后的mTOR信号。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，并通过这些实验结果提出的分子靶点来指导其他更容易给药的药物的开发。本研究的目的是研究氯胺酮对MDD的改善作用与对氯胺酮的Glu和GABA反应的关系，并比较MDD和健康人对氯胺酮的Glu和GABA反应，以进一步阐明MDD的病理生理机制。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，使用了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.