Optimization of IV Ketamine for Treatment Resistant Major Depression

项目概述：现有的治疗重度抑郁障碍(MDD)的方法可能需要几周时间才能 几个月来发挥他们的最大利益。氯胺酮是一种高亲和力的NMDA谷氨酸受体拮抗剂，是一种 儿科和成人患者常用的麻醉剂和止痛药。氯胺酮有 动物模型中的抗抑郁特性，并可能对慢性阻塞性肺疾病患者具有快速抗抑郁活性 严重的情绪障碍。最近对耐药单相患者进行的一项安慰剂对照研究 抑郁症(TRD)显示出单次静脉注射亚麻醉剂(IV)的强大抗抑郁效果 氯胺酮(0.5毫克/公斤)，这一发现重复了之前的一项小规模试点试验。令人惊讶的是，有很高比例的 患者对静脉注射氯胺酮的急性反应持续数天或更长时间。在这个为期4年的单一站点中 研究中，我们将进行三面罩、随机、平行臂主动控制急性发作的调查。 静注氯胺酮治疗TRD的疗效和安全性。具体目标：(1)测试单次静脉输注氯胺酮是否 与活性控制剂(静脉注射咪达唑仑)相比，TRD患者具有更好的抗抑郁疗效。 (2)确定受益的持久性，并测试静脉注射氯胺酮是否与优胜者有关 在第7天时间点的抗抑郁作用。(3)检查干预措施的安全性和耐受性。 意向治疗样本由TRD患者组成，保守地定义为对7 3在本期节目中进行足够的抗抑郁试验。在停药7 2周后，患者将 随机接受静注氯胺酮(40分钟内0.50毫克/公斤)或咪达唑仑(0.045毫克/公斤) 超过40分钟)。在接下来的7天内对疗效和安全性进行评估。7天终结点无响应者 退出研究，同时对符合反应标准的患者进行两周一次的跟踪，直到复发或再次出现 4周。主要的疗效衡量标准是蒙哥马利抑郁严重程度的降低- 静脉注射后24小时的Asberg抑郁评定量表(MADRS)；额外的结果测量 包括应答率和缓解率、受益的持久性(7天终点)、副作用和不良事件。

Project Summary: Existing treatments for major depressive disorder (MDD) may require several weeks to months to exert their maximal benefit. Ketamine, a high-affinity NMDA glutamate receptor antagonist, is an anesthetic and analgesic medication commonly used in pediatric and adult patients. Ketamine has antidepressant properties in animal models, and may have rapid antidepressant activity for patients with severe mood disorders. A recent placebo-controlled investigation in patients with treatment-resistant unipolar depression (TRD) showed robust antidepressant efficacy of a single subanesthetic dose of intravenous (IV) ketamine (0.5 mg/kg), findings which replicated a previous small pilot trial. Strikingly, a high proportion of patients maintained the acute response to IV ketamine for several days or longer. In this 4-year single-site study, we will conduct a triple-masked, randomized, parallel-arm active control investigation of the acute efficacy and safety of IV ketamine in TRD. Specific Aims: (1) To test whether a single IV infusion of ketamine has superior antidepressant efficacy compared to an active control agent (IV midazolam) in patients with TRD. (2) To characterize the durability of benefit and test whether IV ketamine is associated with superior antidepressant effects at the 7-day timepoint. (3) To examine the safety and tolerability of the interventions. The intent-to-treat sample is comprised of 64 TRD patients, conservatively defined as insufficient response to 7 3 adequate antidepressant trials in the current episode. After a medication-free period 7 2 weeks, patients are randomized to receive an infusion of either IV ketamine (0.5 mg/kg over 40 min) or IV midazolam (0.045 mg/kg over 40 min). Efficacy and safety is evaluated over the following 7 days. Nonresponders at the 7-day endpoint exit the study, while patients meeting response criteria are followed bi-weekly until relapse or for an additional 4 weeks. The primary efficacy measure is reduction in depression severity as assessed by the Montgomery- Asberg Depression Rating Scale (MADRS) scale 24 hours following IV infusion; additional outcome measures include response and remission rates, durability of benefit (7-day endpoint), side effects, and adverse events.