1/3-Efficacy and Tolerability of Riluzole in Treatment-Resistant Depression

描述（由申请人提供）：该合作 R01 在一项随机双盲安慰剂对照临床试验（RCT）中研究了谷氨酸调节剂和神经保护剂利鲁唑在难治性抑郁症（TRD）患者中的安全性和有效性。 STAR*D 研究的最新发现凸显了这样一个事实，即我们目前根据单胺假说开发的抗抑郁药物备库具有严重的局限性。现在有新的证据表明氨基酸神经递质（AANt）系统也可能导致重度抑郁症（MDD）的病理生理学，并且针对这些系统的药物可能具有有效的抗抑郁特性。利鲁唑目前已获得美国 FDA 批准用于治疗肌萎缩侧索硬化症 (ALS)。它已被证明对与药物的神经保护和可塑性增强特性相关的谷氨酸能功能具有多种神经生物学作用。最近有两项开放标签研究表明利鲁唑对 TRD 有效，还有几份报告证明利鲁唑对双相抑郁、广泛性焦虑症和强迫症有效。然而，尚未在 TRD 中进行随机对照试验。这项随机、双盲、安慰剂对照试验采用序贯平行比较设计，评估利鲁唑增强选择性血清素再摄取抑制剂西酞普兰对 18-65 岁中度 TRD 门诊患者的疗效和安全性。对公共卫生的意义：在这项独特的 5 年提案中，来自四个机构 [耶鲁大学、MSSM、MGH 和 NIMH (MAP)] 的研究人员将进行随机对照试验，以检验利鲁唑辅助治疗 TRD 的有效性、安全性和耐受性。证明利鲁唑的益处对于难以治疗的抑郁症患者来说将是一个重大进步，并可能有助于阐明我们对 MDD 病理生理学和抗抑郁作用机制的理解。最直接的是，由于利鲁唑已经是 FDA 批准的药物，已被安全地开给数千名 ALS 患者，因此这项研究的积极结果可以迅速传播到临床实践中，并鼓励对该策略的进一步研究。证明利鲁唑在 TRD 中的功效将为发现未来针对谷氨酸能系统的药物打开大门，这些药物可用于对抗这种常见的破坏性疾病。

DESCRIPTION (provided by applicant): This collaborative R01 investigates the safety and efficacy of the glutamate-modulating and neuroprotective agent riluzole in a randomized double-blind placebo-controlled clinical trial (RCT) in patients with treatment- resistant depression (TRD). The recent findings of the STAR*D study highlight the fact that our current armamentarium of antidepressant medications, developed out of the monoamine hypothesis, has serious limitations. There is now emerging evidence that amino acid neurotransmitter (AANt) systems may also contribute to the pathophysiology of major depressive disorder (MDD), and that drugs targeting these systems may have potent antidepressant properties. Riluzole is currently approved by the US FDA for the treatment of amyotrophic lateral sclerosis (ALS). It has been shown to have a variety of neurobiological effects on glutamatergic function associated with the drug's neuroprotective and plasticity-enhancing properties. There have now been two recent open-label studies showing riluzole to be effective in TRD as well as several reports demonstrating riluzole's efficacy in bipolar depression, generalized anxiety disorder, and obsessive-compulsive disorder. However, no RCT has been performed in TRD. This randomized, double-blind, placebo-controlled trial, using a sequential parallel comparison design, evaluates the efficacy and safety of riluzole augmentation of the selective serotonin reuptake inhibitor citalopram in outpatients ages 18-65 with moderate TRD. Significance to Public Health: In this unique 5-year proposal, investigators from four institutions [Yale, MSSM, MGH and NIMH (MAP)] will conduct a RCT to examine the efficacy, safety and tolerability of adjunctive riluzole treatment in TRD. Demonstration of riluzole's benefit would represent a major advance for patients with difficult-to-treat depression, and may help elucidate our understanding of the pathophysiology of MDD and the mechanism of antidepressant action. Most immediately, since riluzole is already a FDA-approved medication that has been safely prescribed to thousands of patients with ALS, positive findings from this study could rapidly disseminate into clinical practice and would encourage further investigation of this strategy. Demonstrating riluzole's efficacy in TRD would open the door to the discovery of future medications targeting the glutamatergic system that could be used to fight this common and devastating disorder.