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

据报道，每150名儿童中就有1人患有自闭症谱系障碍(ASD)，终身残疾会影响社交、沟通和心理功能。由于数百万儿童受到影响，自闭症是一个巨大的公共卫生问题。就像经常发生的那样，将自闭症症状与医学和精神疾病的共病混合在一起，成本(无论是在金钱上还是在痛苦中)都是巨大的。目前，还没有对自闭症的三种核心症状(社交缺陷、沟通障碍和固定兴趣/重复行为)中的任何一种显示出疗效的药物。虽然一些行为策略被报道在社会和交流领域是有用的，但没有行为干预对ASD的固定兴趣和重复行为显示出一致的好处。然而，鉴于这些症状与儿童期起病的强迫症(OCD)中的强迫行为非常相似，以及强迫症在ASD中作为共病出现的频率，我们推测，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-羟色胺再摄取阻断药物(SSRIs，如氟西汀、氟伏沙明和舍曲林)已被证明在治疗强迫症方面有效，但许多患者对治疗无效。难治性病例在合并ASD-OCD组中尤其常见，这表明在这个队列中，仅靠调节5-羟色胺还不足以缓解症状。儿童期强迫症的假设病因学表明，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，因为这种药物的作用是在当前药物疗法的“上游”。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成功。对13例成人难治性强迫症患者进行了利鲁唑强化治疗的开放标签试验。在试验期间继续服用伴随药物，在调查过程中耶鲁-布朗强迫量表(Y-BOCS)的得分显著提高。5名受试者被归类为治疗有效者(Y-BOCS<16，基线评分下降35%或以上以及临床共识改善)。在6名患有强迫症的儿科受试者中，有4人在开放服用利鲁唑12周后有显著改善；治疗成果在一年的随访中保持不变，没有报告严重的不良事件。强迫行为，包括简单、重复的行为，与更复杂的仪式一样得到改善，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好处。 目前正在进行一项为期12周的安慰剂对照研究，以评估利鲁唑对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)治疗强迫症症状的安全性和有效性。据推测，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，还可能降低与自闭症相关的刻板印象行为和固执兴趣的严重程度。随着孩子们对他们的强迫症变得不那么焦虑和痛苦，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阶段接受含有利鲁唑或安慰剂的面膜胶囊，然后可能选择接受三个月的利鲁唑开放标签治疗。儿童将参与总共12个月的研究，只有在临床指征和建议的情况下，才在研究的后半部分接受利鲁唑治疗。在整个研究期间将进行定期的诊所就诊，最终评估将在随机分组一年后进行。在撰写本文时，这项研究正在积极招募7-17岁的受试者。如果儿童和青少年有中-重度强迫症和/或强迫症(重复行为)和自闭症谱系障碍(自闭症、PDD-NOS或阿斯伯格障碍)，则有资格纳入研究。欲了解有关利鲁唑试验的更多信息，请访问ClinicalTrials.gov：http://clinicaltrials.gov/ct2/show/NCT00251303。 除了治疗试验，利用磁共振波谱(MRS)对利鲁唑治疗的神经化学效应的小型研究正在进行中。参与调查的儿童和青少年将在开始使用利鲁唑治疗之前和治疗期间接受MRS扫描(类似于MRI扫描)。将评估大脑谷氨酸和相关化学物质浓度的变化，并与症状严重程度和治疗反应程度进行比较。这项试验的参与者可能还参加了利鲁唑的双盲安慰剂对照试验；服用安慰剂的儿童的扫描结果将与基线和开放标签利鲁唑治疗期间获得的扫描结果进行比较，以区分扫描间变异导致的MRS变化与药物治疗相关的变化。MRS研究也在招募患者，有关这项调查的更多信息可在ClinicalTrials.gov上找到，研究编号：NCT01019967

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