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

3/3-利鲁唑治疗难治性抑郁症的疗效和耐受性

• 批准号: 7884843
• 负责人: MAURIZIO FAVA
• 金额: $ 24.55万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884843
• 关键词: Acids; Address; Adverse effects; Adverse event; Age; Amino Acid Neurotransmitters; Aminobutyric Acids; Amyotrophic Lateral Sclerosis; Antidepressive Agents; Anxiety; Anxiety Disorders; Bipolar Depression; Case Series; Citalopram; Clinical; Clinical Treatment; Clinical Trials; Clinical trial protocol document; Collection; Conduct Clinical Trials; Controlled Clinical Trials; DNA; Data Analyses; Data Collection; Databases; Disease; Double-Blind Method; Drug Delivery Systems; Event; FDA approved; Feedback; Functional disorder; Funding; Future; Generalized Anxiety Disorder; Genes; Genetic; Genetic Materials; Genetic Polymorphism; Glutamatergic Agents; Glutamates; Human Subject Research; Hydrochloride Salt; Industry; Institution; Investigation; Knowledge; Leadership; Legal patent; Life; Link; Major Depressive Disorder; Manuscripts; Measurement; Measures; Medical Economics; Mental Depression; Mental Health; Mental disorders; Modeling; Montgomery and Asberg depression rating scale; Mood Disorders; Moods; Multi-Institutional Clinical Trial; National Institute of Mental Health; Neurobiology; Neuronal Plasticity; Neuroprotective Agents; Neurotransmitters; Obsessive-Compulsive Disorder; Orphan Drugs; Outpatients; Patient Recruitments; Patients; Persons; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Policies; Population; Positioning Attribute; Preparation; Procedures; Property; Public Health; Publishing; Randomized; Reporting; Research; Research Design; Research Personnel; Research Project Grants; Resistance; Resources; Retrieval; Rilutek; Riluzole; Role; Safety; Sample Size; Sampling; Selective Serotonin Reuptake Inhibitor; Site; Structure; System; Teleconferences; Testing; Training; Translational Research; Treatment Protocols; Voting; base; clinical practice; cost; data management; depressive symptoms; design; double-blind placebo controlled trial; drug development; experience; fighting; improved; innovation; interest; jun Oncogene; meetings; member; metabolomics; monoamine; neuropsychiatry; novel; open label; pre-clinical; preclinical study; programs; public health relevance; response; statistics; translational study; treatment response

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.

描述（由申请人提供）：该协作R01调查了在随机的双盲安慰剂对照临床试验（RCT）中，谷氨酸调节和神经保护剂riluzole在耐药抑郁症患者中的安全性和功效。 Star*d研究的最新发现强调了一个事实，即我们当前的抗抑郁药的武器库是由单胺假说开发的，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）系统也可能有助于主要抑郁症（MDD）的病理生理，并且针对这些系统的药物可能具有有效的抗抑郁剂特性。 Riluzole目前已获得美国FDA的批准，用于治疗肌萎缩性侧面硬化症（ALS）。已显示它对与药物的神经保护性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。现在已经进行了两项开放标签的研究，表明Riluzole在TRD中有效，并显示了Riluzole在躁郁症抑郁症，普遍焦虑症和强迫症中的功效。但是，在TRD中没有进行RCT。这项使用顺序平行比较设计的随机，双盲，安慰剂对照试验评估了riluzole增强选择性5-羟色胺再摄取抑制剂西耐普兰在18-65岁的门诊患者中的疗效和安全性。对公共卫生的意义：在这一独特的5年提案中，来自四个机构[YALE，MSSM，MGH和NIMH（MAP）]的研究人员将进行RCT，以检查TRD中辅助性Riluzole治疗的功效，安全性和耐受性。 Riluzole益处的证明将代表难以治疗抑郁症患者的重大进步，并可能有助于阐明我们对MDD病理生理学的理解和抗抑郁作用的机制。大多数情况下，由于Riluzole已经是FDA批准的药物，已安全地向数千名ALS患者开了处方，因此这项研究的阳性发现可能会迅速传播到临床实践中，并鼓励对该策略进行进一步研究。证明Riluzole在TRD中的功效将为发现针对谷氨酸能系统的未来药物打开大门，该药物可用于抵抗这种常见和毁灭性的疾病。 公共卫生相关性：尽管美国现在有20多种不同的抗抑郁药可用，但耐药抑郁症仍然是一个普遍的问题，并带来严重的医疗和经济后果。较高的耐药抑郁症率可能反映了以下事实：现有的抗抑郁治疗几乎完全是由抑郁症病理生理学的单胺能假设开发的，因此很大程度上具有共同的作用机制。这种方法对抗抑郁药物开发的越来越公认的局限性为探索具有独特作用靶标的新型抗抑郁治疗（例如本研究中提出的）提供了强大的动力。