Optimization of IV Ketamine for Treatment Resistant Major Depression

项目摘要：现有的治疗重度抑郁症（MDD）可能需要几周的时间， 几个月来发挥最大的效益。氯胺酮是一种高亲和力的NMDA谷氨酸受体拮抗剂，是一种 通常用于儿科和成人患者的麻醉和镇痛药物。氯胺酮 在动物模型中具有抗抑郁特性，并且可能对患有 严重的情绪障碍最近在难治性单极患者中进行的一项安慰剂对照研究 抑郁症（TRD）显示出单次亚麻醉剂量静脉（IV） 氯胺酮（0.5 mg/kg），结果重复了先前的小型试点试验。令人惊讶的是， 患者对IV氯胺酮的急性反应持续数天或更长时间。在这个为期4年的单中心 研究中，我们将进行一项三盲、随机、平行组的急性 IV氯胺酮治疗TRD的有效性和安全性。具体目的：（1）检测单次静脉输注氯胺酮是否 与活性对照药物（IV咪达唑仑）相比，在TRD患者中具有上级抗抑郁疗效。 (2)表征获益的持久性，并检验IV氯胺酮是否与上级 在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64例TRD患者组成，保守定义为对7例 当前事件中有3项充分的抗抑郁药试验。经过7 - 2周的停药期，患者 随机接受IV氯胺酮（0.5 mg/kg，40 min）或IV咪达唑仑（0.045 mg/kg）输注 超过40分钟）。在接下来的7天内评价疗效和安全性。7天终点时的无应答者 退出研究，而符合反应标准的患者每两周随访一次，直至复发或额外的 4周主要疗效指标是抑郁严重程度的降低，由蒙哥马利- IV输注后24小时的Asberg抑郁评定量表（MADRS）;其他结局指标 包括反应和缓解率、益处持久性（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.