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

描述(申请人提供)：这项合作的R01在一项随机、双盲、安慰剂对照的临床试验(RCT)中调查了谷氨酸调节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研究的最新发现突显了这样一个事实，即我们目前的抗抑郁药物是从单胺假说发展而来的，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)系统也可能在抑郁症(MDD)的病理生理学中起作用，并且针对这些系统的药物可能具有强大的抗抑郁特性。利鲁唑目前被美国FDA批准用于治疗肌萎缩侧索硬化症(ALS)。它已被证明对谷氨酸能功能具有多种神经生物学效应，与药物的神经保护和增强可塑性特性有关。最近有两项开放标签的研究表明利鲁唑对TRD有效，还有几份报告表明利鲁唑对双相抑郁、广泛性焦虑症和强迫症有效。然而，在TRD中没有进行随机对照试验。这项随机、双盲、安慰剂对照试验采用顺序平行对照设计，评估了选择性5-羟色胺再摄取抑制剂西酞普兰在18-65岁中度TRD门诊患者中增强利鲁唑的有效性和安全性。对公共卫生的意义：在这项独特的5年计划中，来自四个机构[耶鲁大学、MSSM、MGH和NIMH(MAP)]的研究人员将进行一项随机对照试验，以检查辅助利鲁唑治疗TRD的有效性、安全性和耐受性。证明利鲁唑的益处将代表着难治性抑郁症患者的重大进步，并可能有助于阐明我们对MDD的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，已经安全地开给了数千名ALS患者，这项研究的积极结果可能会迅速传播到临床实践中，并将鼓励对这一策略的进一步研究。证明利鲁唑在TRD中的疗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和毁灭性的疾病。 与公共健康相关：尽管美国现在有20多种不同的抗抑郁药物，但耐药抑郁症仍然是一个常见的问题，会带来严重的医疗和经济后果。耐药抑郁症的高比率可能反映了这样一个事实，即现有的抗抑郁药物治疗几乎完全是从抑郁病理生理学的单胺能假说发展出来的，因此在很大程度上共享共同的作用机制。越来越多的人认识到这种方法在抗抑郁药物开发中的局限性，这为探索具有独特作用靶点的新型抗抑郁药物治疗提供了强大的动力，如本研究中提出的那样。

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. PUBLIC HEALTH RELEVANCE: Although there are now more than 20 different antidepressant medications available in the US, treatment resistant depression remains a common problem, with serious medical and economic consequences. The high rates of treatment resistant depression likely reflect the fact that existing antidepressant treatments were almost exclusively developed out of the monoaminergic hypothesis of depression pathophysiology and therefore largely share a common mechanism of action. The increasingly recognized limitations of this approach to antidepressant drug development provides a strong impetus for exploration of novel antidepressant treatments with unique targets of action such as that proposed in this study.