OPTIMIZATION OF IV KETAMINE FOR TREATMENT RESISTANT MAJOR DEPRESSION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 假设： 现有的重度抑郁症（MDD）治疗方法通常需要数周至数月才能发挥其最大效益。鉴于未能及时治疗抑郁症状导致的发病率和死亡率，迫切需要开发快速起效的治疗方法，以及确定最佳的持续治疗方法。氯胺酮是一种高亲和力N-甲基-D-天冬氨酸（NMDA）谷氨酸受体拮抗剂，多年来一直用作儿科和成人患者的标准静脉（IV）麻醉剂，IV剂量为2 mg kg-1，可在30秒内产生手术麻醉，持续5-10分钟。除了在麻醉和疼痛管理中的既定作用外，有新的证据表明氯胺酮可能对严重情绪障碍患者具有快速抗抑郁作用。两项已发表的研究表明，在难治性MDD患者中，单次给予0.5 mg kg-1剂量的氯胺酮在2小时内产生了强大的抗抑郁作用，许多患者随后在数天内保持了情绪改善（尽管所有患者均在2周内复发）。然而，氯胺酮治疗抑郁症的有效性仍然被认为是一个初步的发现，特别是考虑到先前描述的两项研究在组内RCT中使用了非活性安慰剂（IV盐水），其中很难保持盲态。在第一个输注日接受氯胺酮的受试者中，将受试者从一种治疗交叉到另一种治疗是有问题的。在本研究中，我们建议在组间RCT中使用活性对照（IV咪达唑仑）。这将提供急需的额外证据，证明氯胺酮确实有效治疗抑郁症。 本研究方案将在双盲条件下在TRD患者中检测IV氯胺酮给药与IV咪达唑仑给药相比的抗抑郁疗效。因此，本研究旨在： 具体目标1：在TRD患者中检测单次IV氯胺酮输注是否比活性对照药物（IV咪达唑仑）发挥上级抗抑郁作用。 假设1a：根据输注后24小时MADRS评分的变化确定，与随机接受IV咪达唑仑的患者相比，随机接受IV氯胺酮的TRD患者的抑郁症状改善更大。 假设1b：随机接受IV氯胺酮的TRD患者在24小时的缓解率高于随机接受IV咪达唑仑的患者。 具体目标2：表征抗抑郁获益的持久性，并检测IV氯胺酮治疗是否与随后7天间隔内的上级抗抑郁作用相关。 假设二：随机分配至氯胺酮组的TRD患者的抗抑郁反应的持久性高于随机分配至咪达唑仑组的患者。 具体目标3：检查干预措施的安全性和耐受性。 假设3：中度或重度副作用或不良事件将不常见或不存在。研究干预与需要中止研究的副作用或不良事件的发生率无明显差异。

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.