Ketamine for Treatment Resistant Late-Life Depression

 描述（由申请人提供）： 超过1100万（45.7%）的美国退伍军人至少65岁，高达20%患有抑郁症。晚年抑郁症是一种常见的疾病，通常诊断不足和治疗不足，并且与增加的功能障碍有关，无论症状严重程度如何。抗抑郁药的实际疗效在高达三分之二的难治性抑郁症患者中是次优或不完全的（Trivedi，2006; Rush，2006）。此外，治疗难治性抑郁症的常用方法，如电休克治疗和单胺氧化酶抑制剂，不被老年患者很好地接受或有显著的副作用。然而，最令人担忧的是未经治疗的抑郁症与退伍军人自杀风险之间的关联，69%的退伍军人自杀者年龄在50岁及以上。面对老龄化的人口特征，老年退伍军人的比例更高，迫切需要对患有晚期难治性抑郁症（LL-TRD）的退伍军人进行循证，有效，安全和高效的干预。 与西奈山医学院（MSSM）的研究人员合作，研究小组最近完成了一项NIMH赞助的对难治性抑郁症患者的随机试验，比较了单次输注氯胺酮（KET）的即时抗抑郁特性，一种开放通道非选择性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂;咪达唑仑（MID），一种苯二氮卓类麻醉剂。这项试验的结果明确肯定了KE的快速抗抑郁疗效。一项数据子分析显示，老年受试者的反应和缓解率与年轻队列相当。然而，该研究没有把握度回答固定KET剂量的老年人群特有的问题。这些发现为目前提出的单中心、随机、三盲（患者、评定者和 麻醉师）研究。这一新策略尚未得到充分的测试。 根据自适应随机化设计，72名55岁或以上的退伍军人将随机接受KET（0.10 mg/kg、0.25 mg/kg或0.5 mg/kg）或MID（0.03 mg/Kg）单次输注。主要目的是确定和评价3种亚麻醉剂量KET和咪达唑仑在4周内对LL-TRD退伍军人的最佳表现的获益持久性。创新的探索性目的是测量KET输注对神经认知、细胞可塑性和炎症的外周生物标志物以及药物脑电图的影响。作为首项针对LL-TRD老年退伍军人的氯胺酮输注治疗的随机对照试验，该提案有可能对临床实践产生变革性影响。不论 结果，该项目将产生有价值的数据，支持发现研究的NMDA受体调节剂的严重情绪障碍。

 DESCRIPTION (provided by applicant): Project Summary/Abstract: More than eleven million (45.7%) U.S. Veterans are at least 65 years of age with up to 20% suffering from depression. Late-life depression is a common disorder which is often under-diagnosed and under-treated and has been associated with increased functional impairment regardless of symptom severity. Real-world effectiveness of antidepressants is sub-optimal or incomplete in up to two-thirds of patients with treatment resistant depression (Trivedi, 2006; Rush, 2006). Furthermore, common approaches for treatment resistant depression, such as electroconvulsive therapy and monoamine oxidase inhibitors, are not well accepted by elderly patients or risk significant side effects. Most alarmig, however, is the association between untreated depression and risk of suicide among the Veteran population with 69% of Veteran suicides are among those age 50 years and older. Faced with an aging demographic profile towards a higher proportion of elderly Veterans, evidence-based, effective, safe, and efficient interventions for Veterans with late-life treatment resistant depression (LL-TRD) are critically needed. In collaboration with investigators at the Mount Sinai School of Medicine (MSSM), the study team recently completed a NIMH-sponsored randomized trial in patients with treatment resistant depression, comparing the immediate antidepressant properties of a single infusion of ketamine (KET), an open-channel nonselective N-methyl-D-aspartate (NMDA) receptor antagonist; to midazolam (MID), a benzodiazepine anesthetic. The results of this trial definitively affirmed the rapid antidepressant efficacy of KE. A data sub- analysis showed that older participant's response and remission rates were comparable to those of the younger cohort. However, the study was not powered to answer questions unique to the elderly population of a fixed KET dose. These findings provide the rationale for the current proposal of a single-site, randomized, triple- blind (patient, rater, and anesthesiologist) study. This novel strategy has not been adequately tested. Seventy two Veterans age 55 or older will be randomized to receive a single infusion of KET (0.10 mg/kg, 0.25 mg/kg, or 0.5 mg/kg) or MID (0.03mg/Kg), following an adaptive randomization design. The primary aim is to identify and evaluate the durability of benefit of the best performing of the thre sub- anesthetic doses KET and midazolam Veterans with LL-TRD over a 4-week period. Innovative exploratory aims measure the effects of KET infusion on neurocognition, peripheral biomarkers of cellular plasticity and inflammation, and Pharmaco-electroencephalography. As the first randomized controlled trial of ketamine infusion therapy for elderly Veterans with LL-TRD, this proposal has the potential for a transformative impact on clinical practice. Irrespective of outcome, this project will generate valuable data supporting discovery research on NMDA receptor modulators for serious mood disorders.