Targeting Glutamate in OCD: A Placebo-Controlled, Double-Blind Augmentation Trial

以谷氨酸治疗强迫症：安慰剂对照、双盲增强试验

• 批准号: 7589314
• 负责人: Christopher John Pittenger
• 金额: $ 21.23万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589314
• 关键词: Address; Adult; Adverse effects; Affect; Amino Acid Neurotransmitters; Amyotrophic Lateral Sclerosis; Anxiety; Asthenia; Brain; Candidate Disease Gene; Case Series; Cerebrospinal Fluid; Childhood; Clinic; Clinical; Clinical assessments; Communities; Compulsive Hoarding; DNA; Data; Databases; Development; Dimensions; Dose; Double-Blind Method; Exhibits; FDA approved; Fatigue; Functional disorder; Future; Generations; Genetic; Glutamates; Homeostasis; Intramural Research Program; Laboratories; Lead; Life; Magnetic Resonance Spectroscopy; Measures; Morbidity - disease rate; National Institute of Mental Health; Nausea; Neurobiology; Neuroprotective Agents; Obsessive-Compulsive Disorder; Outcome Measure; Outpatients; Patient Recruitments; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pilot Projects; Placebo Control; Placebos; Population; Population Study; Prevalence; Publications; Quality of life; Randomized; Recruitment Activity; Refractory; Reporting; Research Design; Residual state; Resistance; Riluzole; Risk; Safety; Sampling; Serotonin; Site; Symptoms; System; Testing; Therapeutic; Treatment Efficacy; Treatment Protocols; Uncontrolled Study; base; control trial; cost; depression; depressive symptoms; design; double-blind placebo controlled trial; efficacy trial; experience; genetic analysis; improved; multi-site trial; neurotransmission; novel; novel therapeutics; open label; placebo controlled study; primary outcome; productivity loss; psychologic; repository; response; treatment response; treatment strategy

DESCRIPTION (provided by applicant): Targeting glutamate in OCD: a placebo-controlled, double-blind augmentation trial of the glutamate-modulating agent riluzole in treatment-refractory OCD. Obsessive-compulsive disorder (OCD) affects approximately 2.5% of the population worldwide. About a quarter of patients have symptoms that are resistant to available medications and psychotherapeutic approaches. Many of those described as `responders' to existing treatments suffer substantial residual symptoms and lead constricted lives. New treatment approaches are urgently needed. Several lines of evidence suggest that the ubiquitous amino acid neurotransmitter glutamate may be dysregulated in the brains of patients with OCD. This leads to the hypothesis that medications that target glutamate may represent a novel treatment strategy. The glutamate-modulating medication riluzole, which has been FDA approved for over ten years for use in amyotrophic lateral sclerosis, is one such agent. Preliminary open-label data suggest that a substantial fraction of patients with profoundly treatment-resistant OCD, who suffer severe symptoms and impaired quality of life despite medication and psychological treatment, improve when riluzole is added to their regimen. Importantly, several patients with compulsive hoarding, which is notoriously refractory to current treatments, have responded to pharmacological augmentation with riluzole. These preliminary observations do not provide adequate evidence of the efficacy of riluzole in OCD to justify its general clinical use. A more rigorous, controlled trial is essential. As a step towards this end, and to explore feasibility issues essential to the design of a larger, multi-site trial, this application proposes a pilot placebo-controlled, double-blind trial of riluzole augmentation in OCD. 60 outpatients with treatment-resistant OCD on stable medication regimens will be randomized to receive either riluzole (at the standard dose of 50 mg twice daily) or placebo, following a two-week single-blind placebo lead-in phase. The primary outcome measure will be improvement in Y-BOCS; measures of depression, anxiety, quality of life, and other variables will be analyzed in secondary analyses. In exploratory analyses, we will investigate genetic and clinical variables as potential predictors of response. DNA will be collected from all patients. Exploratory analyses of candidate genes in the serotonin and glutamate systems and of specific dimensions of symptomatology may help identify predictors of treatment response. While this study is not powered to definitively identify the predictors of response to riluzole, it will allow the generation of specific hypotheses to be further explored in a larger future trial. Many patients suffer from treatment-resistant OCD. This trial is a critical step towards exploring the efficacy glutamate modulating agents such as riluzole as a new alternative to alleviate their suffering.

描述（由申请人提供）：在强迫症中靶向谷氨酸：谷氨酸调节剂利鲁唑治疗难治性强迫症的安慰剂对照、双盲增强试验。强迫症（OCD）影响着全球约2.5%的人口。大约四分之一的患者有对现有药物和心理治疗方法有抵抗力的症状。许多被描述为对现有治疗有“反应”的人都有严重的残余症状，生活受到限制。迫切需要新的治疗方法。一些证据表明，普遍存在的氨基酸神经递质谷氨酸可能在强迫症患者的大脑中失调。这导致了一种假设，即靶向谷氨酸的药物可能代表了一种新的治疗策略。谷氨酸调节药物利鲁唑（riluzole）就是这样一种药物，它已经被FDA批准用于肌萎缩侧索硬化症超过十年。初步的开放标签数据表明，相当一部分患有严重治疗抵抗性强迫症的患者，尽管接受药物和心理治疗，但症状严重，生活质量受损，当利鲁唑加入他们的治疗方案时，情况有所改善。重要的是，几名患有强迫性囤积症的患者，这是众所周知的难治性目前的治疗，已响应与利鲁唑的药理学增强。这些初步观察结果未提供利鲁唑治疗强迫症疗效的充分证据，以证明其一般临床使用的合理性。更严格的对照试验至关重要。作为实现这一目标的一个步骤，并探索设计一个更大的，多中心试验的可行性问题，本申请提出了一个试点安慰剂对照，双盲试验的利鲁唑增加强迫症。在为期两周的单盲安慰剂导入期后，60名接受稳定药物治疗方案的难治性OCD门诊患者将随机接受利鲁唑（标准剂量为50 mg，每日两次）或安慰剂。主要结局指标将是Y-BOCS的改善;抑郁、焦虑、生活质量和其他变量的指标将在次要分析中进行分析。在探索性分析中，我们将研究遗传和临床变量作为缓解的潜在预测因素。将从所有患者中收集DNA。探索性分析5-羟色胺和谷氨酸系统中的候选基因和特定维度的神经病学可能有助于确定治疗反应的预测因子。虽然这项研究不能明确确定利鲁唑反应的预测因素，但它将允许在未来更大规模的试验中进一步探索特定假设的产生。许多患者患有治疗抵抗性强迫症。这项试验是探索谷氨酸调节剂（如利鲁唑）作为减轻他们痛苦的新替代品的功效的关键一步。