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

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(OCD)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。 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。IRB限制将研究参与者限制为对先前通过认知-行为干预(特别是接触反应预防)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，并在整个研究过程中继续服用药物。因此，该试验评估利鲁唑治疗强迫症的安全性和有效性的能力受到限制。 60名患有强迫症的儿童和青少年(年龄从7岁到17岁)完成了为期12周的双盲试验。总体而言，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。观察利鲁唑的副作用，包括肝转氨酶升高。长期(1年)随访评估显示，所有受试者都比基线有所改善，许多人已经停止了其他精神药物的治疗，转而使用利鲁唑治疗。然而，组间差异的缺乏大大限制了利鲁唑治疗儿童期强迫症的进一步研究的热情。

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.