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

谷氨酸拮抗剂治疗强迫症和自闭症的试验

• 批准号: 8556977
• 负责人: Susan Swedo
• 金额: $ 3.4万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8556977
• 关键词: Adolescent; Adult; Adverse effects; Affect; Age; Anxiety Disorders; Autistic Disorder; Behavior; Behavior Therapy; Behavioral; Brain; Child; Childhood; Clinical; Cognitive Therapy; Communication; Comorbidity; Complex; Consensus; Data; Data Analyses; Data Collection; Depressive disorder; Double-Blind Method; Etiology; Evaluation; Excitatory Amino Acid Antagonists; Fluoxetine; Fluvoxamine; Frequencies; Glutamates; Goals; Institutional Review Boards; Investigation; Journals; Liver; Measures; Medical; Medicine; Obsession; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Outcome Measure; Participant; Patients; Peer Review; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Prevention; Public Health; Refractory; Reporting; Resistance; Riluzole; Ritual compulsion; Safety; Scanning; Selective Serotonin Reuptake Inhibitor; Serious Adverse Event; Serotonin; Sertraline; Severities; Stereotyped Behavior; Symptoms; Time Study; Transaminases; Work; autism spectrum disorder; cohort; cost; disability; double-blind placebo controlled trial; follow-up; improved; interest; open label; primary outcome; psychologic; response; reuptake; social; social cognition; social communication; success

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.

血清素再摄取阻断药物（SSRI，例如氟西汀，氟氟众和舍曲雷）已被证明可以有效治疗强迫症（OCD），但许多患者未能应对治疗。 在合并症ASD-OCD组中，治疗难治性病例尤为常见，这表明单独调节5-羟色胺不足以缓解该队列中的症状。 儿童期强迫症的假设病因表明，谷氨酸拮抗剂（例如riluzole）可能会减少痴迷和强迫性的严重程度，因为该药物从当前的药物治疗中“上游”。 在成人和儿童中，在Riluzole使用Riluzole方面取得了一些初步的成功。 对13例耐药性强迫症患者进行了Riluzole增强的开放标签试验。在试验期间继续进行伴随的药物，在整个研究过程中，耶鲁棕色的强迫性量表（Y-BOC）得分显着提高。将五名受试者归类为治疗响应者（Y-BOC小于16，基线评分降低35％或更高，以及临床共识的改善）。 六个患有强迫症的儿科受试者中有四名在开放标签的Riluzole经过12周后显示出显着改善。一年随访的治疗收益持续，没有报道严重的不良事件。 包括简单的重复行为在内的强迫症和更复杂的仪式得到了改善，这表明Riluzole可能对自闭症的刻板印象以及对痴迷和强迫有益。 据报道，自闭症谱系障碍（ASD）影响了150名儿童中多达1个，终生残疾影响社会，沟通和心理功能。 ASD有数百万儿童受到影响，代表了一个巨大的公共卫生问题。 复合了ASD症状与医学和精神病合并症的频率一样，而且成本（以美元和苦难都）巨大。 当前，对于自闭症的三种核心症状（社会缺陷，沟通异常和固定的利益/重复行为）的三种核心症状中的任何一种药物都没有证明的好处。 尽管据报道某些行为策略对于社会和沟通领域很有用，但没有行为干预措施显示出对固定利益和ASD重复行为的一致好处。 但是，鉴于这些症状与儿童强迫症（OCD）中看到的强迫性行为之间的相似之处，以及ASD中强迫症作为合并症的频率，我们假设减少OCD症状的药物也可能会改善重复的行为和ASD的固定利益。 IRB限制将研究参与者限制在未能对以前的认知行为干预措施（特别是针对预防反应的暴露）和SSRI做出反应的儿童和青少年。 大多数参与者在学习时正在服用精神药物，并在整个研究参与过程中继续使用这些药物。 因此，该试验评估riluzole在治疗强迫症症状方面的安全性和功效的能力受到限制。 OCD的60名儿童和青少年（7至17岁）完成了12周的双盲试验。 总体而言，安慰剂和瑞唑之间没有明显差异，以衡量强迫症的变化或整体症状严重程度。 观察到riluzole给药的副作用，包括肝转氨酶的升高。 长期（1年）的随访评估表明，所有受试者都从基线上得到了改善，许多受试者已停止其他精神药物，而采用了Riluzole治疗。 但是，缺乏组间差异显着限制了对riluzole儿童期强迫症进一步研究的热情。