OPTIMIZATION OF IV KETAMINE FOR TREATMENT RESISTANT MAJOR DEPRESSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 假设： 现有的治疗重度抑郁障碍(MDD)的方法通常需要几周到几个月的时间才能发挥其最大的益处。鉴于未能及时治疗抑郁症状导致的发病率和死亡率，迫切需要开发快速有效的治疗方法，以及确定最佳的持续治疗方法。氯胺酮是一种高亲和力的N-甲基-D-天冬氨酸(NMDA)谷氨酸受体拮抗剂，多年来一直作为标准静脉麻醉剂用于儿童和成人患者，静脉注射剂量2 mg kg-1可在30秒内产生手术麻醉，持续5-10分钟。除了在麻醉和疼痛控制方面的公认作用外，有新的证据表明，氯胺酮可能对患有严重情绪障碍的患者具有快速抗抑郁特性。现已发表的两项研究表明，在难治性MDD患者中，单次0.5 mg kg-1剂量的氯胺酮在2小时内就能产生强劲的抗抑郁效果，许多患者随后会在几天内保持情绪改善(尽管所有患者都在2周内复发)。然而，氯胺酮S治疗抑郁症的有效性仍被认为是初步发现，特别是考虑到之前描述的两项研究在组内随机对照试验中使用了非活性安慰剂(IV生理盐水)，在该试验中很难维持盲人。对于那些在第一天就接受了氯胺酮治疗的人来说，将参与者从一种治疗方法转移到另一种治疗方法是有问题的。在本研究中，我们建议在组间随机对照试验中使用主动对照(静脉注射咪达唑仑)。这将提供亟需的额外证据，证明氯胺酮确实对治疗抑郁症有效。 这项研究方案将在双盲条件下测试静注氯胺酮和静脉注射咪达唑仑的抗抑郁效果。因此，本研究的目的是： 具体目的1：测试单次输注氯胺酮是否比静脉注射咪达唑仑对TRD患者有更好的抗抑郁效果。 假设1a：与静脉注射咪达唑仑的患者相比，随机接受氯胺酮静脉注射的TRD患者抑郁症状的改善更大，这是由注射24小时后MADRS评分的变化确定的。 假设1b：与24小时内随机接受咪达唑仑静脉注射的患者相比，随机接受氯胺酮静脉注射的TRD患者有更高的有效率。 具体目的2：表征抗抑郁药物益处的持久性，并测试静脉注射氯胺酮是否与随后7天的抗抑郁效果有关。 假设2：与随机服用咪达唑仑的患者相比，随机服用氯胺酮的TRD患者将表现出更强的抗抑郁反应持久性。 具体目的3：检查干预措施的安全性和耐受性。 假设3：中度或严重的副作用或不良事件将很少发生或不发生。这项研究的干预措施不会与需要停止研究的副作用或不良事件的发生率有明显差异。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: Existing treatments for major depressive disorder (MDD) generally take weeks to months to exert their maximal benefit. Given the morbidity and mortality resulting from failure to treat depressive symptoms in a timely fashion, there is an urgent need to develop rapidly-acting treatments, as well as to identify optimal continuation treatment approaches. Ketamine, a high-affinity N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, has been used as a standard intravenous (IV) anesthetic agent for many years in both pediatric and adult patients, with IV doses of 2 mg kg-1 producing surgical anesthesia within 30 seconds and lasting 5-10 minutes. Beyond its well-established role in anesthesia and pain management, there is emerging evidence that ketamine may have rapid antidepressant properties for patients with severe mood disorders. Two published studies have now shown that a single 0.5 mg kg-1 dose of ketamine in patients with treatment-resistant MDD causes a robust antidepressant effect within 2 hours, and many patients subsequently maintain a mood improvement for several days (though all had undergone relapse within 2 weeks). However, ketamine s effectiveness in treating depression is still considered a preliminary finding, especially given that the two studies described previously used an inactive placebo (IV saline) in a within-group RCT, in which it was difficult to maintain the blind. Crossing participants over from one treatment to another was problematic in those who had received ketamine on the first infusion day. In the present study we instead propose the use of an active control (IV midazolam) in a between-groups RCT. This will provide much-needed additional evidence that ketamine is indeed effective in treating depression. This research protocol will, in patients with TRD under double-blind conditions, test the antidepressant efficacy of IV ketamine administration in comparison with that of IV midazolam administration. Thus, the study aims: SPECIFIC AIM 1: To test whether a single infusion of IV ketamine exerts superior antidepressant effects compared to an active control agent (IV midazolam) in patients with TRD. Hypothesis 1a: TRD patients randomized to IV ketamine show greater improvement in depressive symptoms compared to patients randomized to IV midazolam, as determined by the change in the MADRS score 24 hours following infusion. Hypothesis 1b: TRD patients randomized to IV ketamine have a higher response rate compared to patients randomized to IV midazolam at 24 hours. SPECIFIC AIM 2: To characterize the durability of antidepressant benefit and test whether treatment with IV ketamine is associated with superior antidepressant effects over the subsequent 7-day interval. Hypothesis 2: TRD patients randomized to ketamine will demonstrate greater durability of antidepressant response than patients randomized to midazolam. SPECIFIC AIM 3: To examine the safety and tolerability of the interventions. Hypothesis 3: Moderate or severe side effects or adverse events will be infrequent or absent. The study interventions will not be associated with distinctly different rates of side effects or adverse events requiring discontinuation from the study.