Optimization of IV Ketamine for Treatment Resistant Major Depression

描述（由申请人提供）：现有的重度抑郁障碍（MDD）治疗可能需要数周至数月才能发挥其最大效益。氯胺酮是一种高亲和力的NMDA谷氨酸受体拮抗剂，是一种常用于儿童和成人患者的麻醉镇痛药物。氯胺酮在动物模型中具有抗抑郁特性，对严重情绪障碍患者可能具有快速的抗抑郁活性。最近一项针对难治性单极抑郁症（TRD）患者的安慰剂对照研究显示，单次亚麻醉剂量静脉注射氯胺酮（0.5 mg/kg）具有强大的抗抑郁疗效，这一发现与之前的一项小型试点试验结果一致。引人注目的是，很大比例的患者对静脉注射氯胺酮维持了几天或更长时间的急性反应。在这项为期4年的单点研究中，我们将对静脉注射氯胺酮治疗TRD的急性疗效和安全性进行三盲、随机、平行组主动对照研究。具体目的：(1)检测单次静脉输注氯胺酮是否比活性对照药物（静脉咪达唑仑）在TRD患者中具有更好的抗抑郁疗效。(2)评价获益的持久性，并在7天时间点检测静脉注射氯胺酮是否与较好的抗抑郁效果相关。(3)检查干预措施的安全性和耐受性。意向治疗样本由64名TRD患者组成，保守定义为对当前发作的3项适当抗抑郁药物试验反应不足。在无药期= 2周后，患者随机接受静脉输注氯胺酮（0.5 mg/kg / 40分钟）或静脉输注咪达唑仑（0.045 mg/kg / 40分钟）。在接下来的7天内评估疗效和安全性。在7天的终点无应答者退出研究，而满足应答标准的患者每两周随访一次，直到复发或再随访4周。主要疗效指标是在静脉注射后24小时通过Montgomery- Asberg抑郁评定量表（MADRS）评估抑郁严重程度的降低；其他结局指标包括缓解率和缓解率、获益持续时间（7天终点）、副作用和不良事件。

DESCRIPTION (provided by applicant): 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 = 3 adequate antidepressant trials in the current episode. After a medication-free period = 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. Non responders 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. PUBLIC HEALTH RELEVANCE: There is an urgent public health imperative to develop safe, well-tolerated, and rapidly-acting treatments for MDD. This research application seeks to benefit the public health by identifying a novel therapy for highly symptomatic and treatment-resistant patients that may decrease the morbidity and mortality associated with this common and serious illness.