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

描述(申请人提供)：针对强迫症中的谷氨酸：一项谷氨酸调节剂利鲁唑在治疗难治性强迫症中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出现了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”的人会出现严重的残留症状，生活受到限制。迫切需要新的治疗方法。一些证据表明，强迫症患者大脑中普遍存在的氨基酸神经递质谷氨酸可能存在失调。这导致了一种假设，即针对谷氨酸的药物可能代表了一种新的治疗策略。调节谷氨酸的药物利鲁唑就是这样一种药物，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，尽管接受了药物和心理治疗，但仍患有严重症状和生活质量下降的严重耐药强迫症患者中，有相当一部分人在治疗方案中加入利鲁唑后会有所改善。重要的是，几名患有强迫性囤积症的患者已经对利鲁唑的药理增强有了反应。众所周知，这种囤积症对目前的治疗方法难以奏效。这些初步观察并没有提供足够的证据证明利鲁唑治疗强迫症的有效性，从而证明其临床应用的合理性。一项更严格的对照试验是至关重要的。作为实现这一目标的一步，并探索对设计一项更大的多点试验至关重要的可行性问题，本申请提出了一项试验性安慰剂对照的双盲试验，利鲁唑在强迫症中的增强作用。在为期两周的单盲安慰剂引入阶段之后，60名服用稳定用药方案的难治性强迫症患者将被随机分成接受利鲁唑(标准剂量为每天两次50毫克)或安慰剂的患者。主要的结果测量将是Y-BOCS的改善；抑郁、焦虑、生活质量和其他变量的测量将在次要分析中分析。在探索性分析中，我们将调查遗传和临床变量作为潜在的反应预测因素。将从所有患者身上收集DNA。对5-羟色胺和谷氨酸系统中候选基因的探索性分析以及对症状学特定维度的分析可能有助于确定治疗反应的预测因素。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的试验中进一步探索特定假说的产生。许多患者患有难治性强迫症。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有效性的关键一步。

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.