Trial of a Glutamate Antagonist in the Treatment of OCD and Autistic Disorders

5-羟色胺再摄取阻断剂（SSRIs，如氟西汀、氟伏沙明和舍曲林）已被证明对强迫症（OCD）的治疗有效，但许多患者对治疗无效。 治疗难治性病例在ASD-OCD共病组中特别常见，这表明单独调节5-羟色胺不足以缓解该队列的症状。 儿童期发作强迫症的假设病因表明，谷氨酸拮抗剂，如利鲁唑，可能会降低强迫症和强迫症的严重程度，因为药物的工作“上游”从目前的药物治疗。 在成人和儿童中使用利鲁唑治疗强迫症已经取得了一些初步的成功。 在13例难治性强迫症成人患者中进行了一项利鲁唑强化治疗的开放标签试验。试验期间继续使用伴随药物，研究期间耶鲁-布朗强迫症量表（Y-BOCS）评分显著改善。5例受试者被归类为治疗应答者（Y-BOCS小于16，基线评分降低35%或以上以及临床一致性改善）。 6名患有强迫症的儿童受试者中有4名在利鲁唑开放标签给药12周后显示出显著改善;治疗收益在一年随访时持续存在，未报告严重不良事件。 包括简单重复行为在内的行为改善程度与更复杂的仪式一样多，这表明利鲁唑可能对自闭症的刻板行为以及强迫症和强迫症有益。 据报道，自闭症谱系障碍（ASD）影响多达1/150的儿童，终身残疾影响社会，沟通和心理功能。由于数百万儿童受到影响，ASD是一个巨大的公共卫生问题。 ASD症状与医疗和精神并发症的复合，经常发生，成本（美元和痛苦）是巨大的。 目前，没有药物对自闭症的三个核心症状（社交缺陷，沟通异常和固定兴趣/重复行为）中的任何一个都有明显的益处。 虽然一些行为策略被报道对社交和交流领域有用，但没有行为干预对ASD的固定兴趣和重复行为表现出一致的益处。 然而，考虑到这些症状与儿童期发作的强迫症（OCD）中的强迫行为之间的密切相似性，以及OCD作为ASD合并症的频率，我们假设减轻OCD症状的药物也可能改善ASD的重复行为和固定兴趣。 IRB限制将研究参与者限于对先前认知行为干预治疗（特别是暴露于反应预防）和SSRI治疗无效的儿童和青少年。 大多数参与者在进入研究时正在服用精神药物，并在整个研究参与期间继续服用药物。 因此，该试验评估利鲁唑治疗强迫症症状的安全性和有效性的能力有限。 60名患有强迫症的儿童和青少年（7至17岁）完成了为期12周的双盲试验。 总的来说，安慰剂和利鲁唑在强迫症或总体症状严重程度的变化方面没有显著差异。 观察到利鲁唑给药的副作用，包括肝转氨酶升高。 长期（1年）随访评价显示，所有受试者均较基线改善，许多受试者已停用其他精神药物，转而使用利鲁唑治疗。 然而，缺乏组间差异显著限制了进一步研究利鲁唑治疗儿童期发作的强迫症的热情。

The serotonin reuptake blocking medications (SSRIs, such as fluoxetine, fluvoxamine and sertraline) have been demonstrated to be efficacious in the treatment of obsessive-compulsive disorder (OCD), but many patients fail to respond to therapy. Treatment-refractory cases are particularly common among the comorbid ASD-OCD group, suggesting that modulation of serotonin alone is not sufficient for symptom relief in this cohort. The hypothesized etiology of childhood-onset OCD suggests that glutamate antagonists, such as riluzole, might reduce the severity of obsessions and compulsions because the drug works "upstream" from current pharmacotherapies. There has been some preliminary success in the use of riluzole for OCD among both adults and children. An open label trial of riluzole augmentation was conducted in 13 adult patients with treatment-resistant OCD. Concomitant medicines were continued during the trial and Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores improved significantly over the course of the investigation. Five subjects were categorized as treatment responders (Y-BOCS less than 16, and 35% or greater reduction in baseline score as well as clinical consensus improvement). Four of six pediatric subjects with OCD showed significant improvements after 12 weeks of open-label administration of riluzole; the treatment gains were sustained at one year follow-up with no serious adverse events reported. Compulsions, including simple, repetitive behaviors were improved as much as more complex rituals, suggesting that riluzole might be of benefit for the stereotyped behaviors of autism, as well as for the obsessions and compulsions. Autism spectrum disorders (ASD) are reported to affect as many as 1 in 150 children, with lifelong disabilities affecting social, communication and psychological functioning. With millions of children affected, ASD represents a tremendous public health problem. Compound the ASD symptoms with medical and psychiatric comorbidity, as frequently occurs, and the costs (in both dollars and suffering) are immense. Currently, there are no medications with demonstrated benefits for any of the three core symptoms of autism (social deficits, communication abnormalities and fixated interests/repetitive behaviors). Although some behavioral strategies are reported to be useful for the social and communication spheres, no behavioral interventions have shown consistent benefits for the fixated interests and repetitive behaviors of ASD. However, given the close similarity between these symptoms and the obsessive-compulsive behaviors seen in childhood-onset obsessive-compulsive disorder (OCD), and the frequency with which OCD is present as a comorbidity in ASD, we postulated that medications which reduce OCD symptoms might also improve the repetitive behaviors and fixated interests of ASD. IRB restrictions limited study participants to children and adolescents who had failed to respond to previous therapy with cognitive-behavioral interventions (specifically, exposure with response prevention) and an SSRI. Most participants were taking psychotropic medications at the time of study entry and continued the drugs throughout study participation. Therefore, the trial was limited in its ability to assess safety and efficacy of riluzole for the treatment of obsessive-compulsive symptoms. 60 children and adolescents(ages 7 to 17 years)with OCD completed the 12-weeks double-blind trial. Overall, there were no significant differences between placebo and riluzole for measures of change in OCD or overall symptom severity. Side-effects of riluzole administration were observed, including elevations of liver transaminases. Long-term (1 year) follow-up evaluations revealed that all subjects were improved from baseline, and many had stopped other psychotropic medications in favor of riluzole therapy. However, the lack of between-group differences significantly limits enthusiasm for further investigations of riluzole for childhood-onset OCD.