Optimization of IV Ketamine for Treatment Resistant Major Depression

描述（由申请人提供）：现有的重度抑郁症（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NMDA谷氨酸受体拮抗剂，是一种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情绪障碍的患者具有快速抗抑郁活性。最近在难治性单相抑郁症（TRD）患者中进行的一项安慰剂对照研究显示，单次亚麻醉剂量静脉注射（IV）氯胺酮（0.5 mg/kg）具有稳健的抗抑郁疗效，这一结果复制了先前的小型初探性试验。引人注目的是，高比例的患者对IV氯胺酮的急性反应维持了数天或更长时间。在这项为期4年的单中心研究中，我们将对IV氯胺酮治疗TRD的急性疗效和安全性进行一项三盲、随机化、平行组活性对照研究。具体目标：（1）测试在TRD患者中，氯胺酮单次IV输注是否具有优于活性对照药物（IV咪达唑仑）的上级抗抑郁疗效。(2)表征获益的持久性，并检测IV氯胺酮是否与7天时间点的上级抗抑郁作用相关。(3)检查干预措施的安全性和耐受性。意向治疗样本包括64例TRD患者，保守定义为当前发作中≥ 3项充分抗抑郁药试验应答不足。停药期= 2周后，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，40 min）输注。在接下来的7天内评价疗效和安全性。在7天终点时无应答者退出研究，而满足应答标准的患者每两周随访一次，直至复发或再随访4周。主要疗效指标是IV输注后24小时通过蒙哥马利-阿斯伯格抑郁评定量表（MADRS）量表评估的抑郁严重程度降低;其他结局指标包括应答率和缓解率、获益持久性（7天终点）、副作用和不良事件。 公共卫生相关性：迫切需要开发安全、耐受性良好和快速起效的MDD治疗方法。这项研究申请旨在通过确定一种用于高度症状和治疗抵抗患者的新疗法来造福公众健康，该疗法可能会降低与这种常见和严重疾病相关的发病率和死亡率。

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.