CONTINUATION RILUZOLE IN PREVENTION OF RELAPSE FOLLOWING KETAMINE IN 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来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 11/28/2006 现有的重度抑郁症（MDD）治疗通常需要几周到几个月才能发挥其最大的益处。鉴于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麻醉剂，剂量高达2 mg/kg IV。 除了其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在动物模型中具有抗抑郁和抗焦虑作用，并且可能对严重情绪障碍患者具有快速抗抑郁特性。 事实上，最近的一项安慰剂对照研究复制了一项早期的初步研究（Berman et al 2000），并证明了氯胺酮（0.5 mg/kg）单次给药在难治性单相抑郁症患者中的稳健抗抑郁疗效（Zarate et al 2006）。 这些患者中有很高比例的患者对IV氯胺酮的急性反应维持了数天或更长时间。 为了利用IV氯胺酮治疗MDD的治疗前景，这项新研究将解决几个问题。 首先，确定IV氯胺酮后安全有效的持续和维持治疗策略至关重要。 第二，我们需要开发减轻IV氯胺酮的急性神经认知副作用的药理学策略，以提高患者的整体可接受性。 最后，需要在较大样本量中IV氯胺酮治疗难治性MDD的临床经验，以确定缓解的调节因素，最终确定最合适的干预候选者。 本研究方案将测试利鲁唑（100 mg/天）在对单次静脉（IV）外消旋氯胺酮（0.5 mg/kg，40分钟内）给药表现出急性持续反应的难治性单相重度抑郁障碍（MDD）患者中的疗效。 还将检查拉莫三嗪预处理减轻IV氯胺酮副作用的疗效。 我们计划在一项为期4周的随机、双盲、持续期研究中，将约50例急性IV氯胺酮应答者随机分配至利鲁唑组（n=25）或安慰剂组（n=25）。 主要的结果测量是抑郁症复发的时间。

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. 11/28/2006 Existing treatments for major depressive disorder (MDD) generally take several weeks to several months to exert their maximal benefit. Given the morbidity and mortality resulting from depressive symptoms, 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 anesthetic agent for many years in both pediatric and adult patients, with doses as high as 2 mg/kg IV. Beyond its well-established role in anesthesia and pain management, there is emerging evidence that ketamine has antidepressant and anxiolytic effects in animal models, and may have rapid antidepressant properties for patients with severe mood disorders. Indeed, a recent placebo-controlled investigation replicated an earlier pilot study (Berman et al 2000), and demonstrated robust antidepressant efficacy of a single dose of ketamine (0.5 mg/kg) in patients with treatment-resistant unipolar depression (Zarate et al 2006). A high proportion of these patients maintained the acute response to IV ketamine for several days or longer. To capitalize on the therapeutic promise of IV ketamine for MDD, several issues will be addressed in this new study. First, it is crucial to identify safe and effective continuation and maintenance treatment strategies following IV ketamine. Second, we need to develop pharmacological strategies that attenuate the acute neurocognitive side effects of IV ketamine, in order to enhance overall patient acceptability. Finally, clinical experience with IV ketamine in treatment-resistant MDD in larger sample sizes is necessary to identify moderators of response, to ultimately target the most appropriate candidates for this intervention. This research protocol will test the efficacy of riluzole (100 mg/day), in patients with treatment-resistant unipolar major depressive disorder (MDD) who exhibit an acute, sustained response to a single dose of intravenous (IV) racemic ketamine (0.5 mg/kg over 40 minutes). The efficacy of pretreatment with lamotrigine to attenuate IV ketamine's side effects will also be examined. We propose to randomize approximately 50 acute IV ketamine responders to riluzole (n=25) or placebo (n=25) in a 4-week, randomized, double-blind, continuation-phase study. The main outcome measure is time to relapse of depression.