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

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。 5-羟色胺再摄取阻断剂（SSRIs，如氟西汀、氟伏沙明和舍曲林）已被证明对治疗强迫症有效，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。 目前正在进行一项为期12周的安慰剂对照研究，以评估利鲁唑治疗30名患有自闭症谱系障碍（ASD）和强迫症（OCD）的儿童和青少年（7至17岁）强迫症状的安全性和有效性。假设利鲁唑在降低该队列的强迫症状严重程度方面优于安慰剂，并且它还可以降低与自闭症相关的刻板行为和固定兴趣的严重程度。 随着孩子们对强迫症的焦虑和痛苦减少，整体行为也有望得到改善。 受试者将在为期12周的双盲、安慰剂对照试验期间接受含有利鲁唑或安慰剂的盲态胶囊，然后可以选择接受利鲁唑的三个月开放标签治疗。 儿童将参加总共12个月的研究，仅在有临床指征和建议的情况下，在研究的后半段接受利鲁唑。 将在整个研究期间进行定期门诊访视，最终评价将在随机化后一年进行。 在撰写本文时，该研究正在积极招募7 - 17岁的受试者。如果儿童和青少年有中度至重度强迫症和/或强迫行为（重复行为）和自闭症谱系障碍（自闭症，PDD-NOS或自闭症障碍），则有资格参加研究。 有关利鲁唑试验的更多信息，请访问www.example.com：www.example.com 除了治疗试验外，正在利用磁共振波谱（MRS）对利鲁唑治疗的神经化学作用进行小型研究。 参与研究的儿童和青少年在开始利鲁唑治疗前和治疗期间将接受MRS扫描（类似于MRI扫描）。 将评估谷氨酸和相关化学物质的脑浓度变化，并与症状严重程度和治疗反应程度进行比较。 试验的参与者也可能参加利鲁唑的双盲安慰剂对照试验;服用安慰剂的儿童的扫描将与基线和开放标签利鲁唑治疗期间获得的扫描进行比较，以区分扫描间变异性导致的MRS变化与药物治疗相关的MRS变化。 MRS研究也在招募患者，有关研究的更多信息可参见www.example.com，研究标识符为：NCT 01019967

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. The serotonin reuptake blocking medications (SSRIs, such as fluoxetine, fluvoxamine and sertraline) have been demonstrated to be efficacious in the treatment of 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. A 12-weeks long, placebo-controlled investigation is currently underway to assess the safety and efficacy of riluzole for the treatment of obsessive-compulsive symptoms among 30 children and adolescents(ages 7 to 17 years), with autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD). It is hypothesized that riluzole will be superior to placebo in reducing obsessive-compulsive symptom severity for this cohort and that it may also decrease severity of the stereotyped behaviors and fixated interests associated with autism. Overall behavior is also expected to improve as the children become less anxious and distressed by their OCD. Subjects will receive masked capsules containing riluzole or placebo during the 12 weeks long double-blined, placebo-controlled phase of the trial and then may opt to receive three months open-label treatment with riluzole. Children will participate in the study for 12 months total, receiving riluzole during the second half of the study only if clinically indicated and advisable. Periodic clinic visits will occur throughout the study period, with the final evaluation occurring one year after randomization. At the time of this writing, the study is actively recruiting subjects aged 7 - 17 years. Children and adolescents are eligible for study inclusion if they have moderate-severe obsessions and/or compulsions (repetitive behaviors) and an autism spectrum disorder (Autism, PDD-NOS or Asperger disorder). For further information about the riluzole trial, please consult ClinicalTrials.gov at: http://clinicaltrials.gov/ct2/show/NCT00251303 In addition to the treatment trial, a small study of the neurochemical effects of riluzole treatment is underway, utilizing magnetic resonance spectroscopy (MRS). Children and adolescents who participate in the investigation will undergo an MRS scan (similar to an MRI scan) before starting treatment with riluzole and during treatment. Changes in brain concentrations of glutamate and related chemicals will be assessed and compared with symptom severity and degree of treatment response. Participants in the trial may also be participating in the double-blind placebo-controlled trial of riluzole; scans from children taking placebo will be compared with those obtained at baseline and during open-label riluzole treatment to distinguish MRS changes that result from inter-scan variability from those related to drug treatment. The MRS study is also recruiting patients and further information about the investigation can be found at ClinicalTrials.gov with study identifier: NCT01019967