CONTINUATION RILUZOLE IN PREVENTION OF RELAPSE FOLLOWING KETAMINE IN DEPRESSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 11/28/2006 现有的治疗严重抑郁障碍(MDD)的方法通常需要几周到几个月的时间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的N-甲基-D-天冬氨酸(NMDA)谷氨酸受体拮抗剂，多年来一直被用作儿科和成人患者的标准麻醉剂，静脉注射剂量高达2 mg/kg。除了在麻醉和疼痛治疗中已被公认的作用外，越来越多的证据表明，氯胺酮在动物模型中具有抗抑郁和缓解焦虑的作用，并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重复了早期的初步研究(Berman等人，2000年)，并证明了单剂量氯胺酮(0.5 mg/kg)对难治性单相抑郁患者的强大抗抑郁效果(Zarate等人，2006年)。这些患者中有很高比例的人对静脉注射氯胺酮保持了几天或更长时间的急性反应。 为了充分利用静脉注射氯胺酮治疗MDD的前景，这项新的研究将解决几个问题。首先，在静脉注射氯胺酮之后，确定安全有效的继续和维持治疗策略至关重要。其次，我们需要开发药理学策略来减轻静脉注射氯胺酮的急性神经认知副作用，以提高患者的整体接受性。最后，在更大样本量的耐药MDD中静脉注射氯胺酮的临床经验是必要的，以确定反应的调节因素，最终针对这种干预的最合适的候选者。 这项研究方案将测试利鲁唑(100毫克/天)在单剂量静脉注射(IV)外消旋氯胺酮(40分钟内0.5毫克/公斤)出现急性持续反应的单相严重抑郁障碍(MDD)患者中的疗效。此外，还将检查预先应用拉莫三嗪减轻静脉注射氯胺酮副作用的效果。我们建议将大约50名急性静脉注射氯胺酮的应答者随机分为利鲁唑(n=25)或安慰剂(n=25)，进行为期4周的随机、双盲、持续阶段研究。主要的结果衡量标准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.