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名患有自闭症谱系障碍（ASD），终生残疾影响社交、沟通和心理功能。由于数百万儿童受到影响，自闭症谱系障碍代表了一个巨大的公共卫生问题。将ASD症状与医学和精神上的共病相结合，这种情况经常发生，而且成本（包括金钱和痛苦）是巨大的。目前，对于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），还没有任何药物显示出疗效。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显示出一致的益处。然而，鉴于这些症状与儿童期强迫症（OCD）的强迫行为非常相似，以及强迫症作为ASD的合并症出现的频率，我们假设减轻强迫症症状的药物也可能改善ASD的重复行为和固定兴趣。

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