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: 8158152
• 负责人: Susan Swedo
• 金额: $ 77.07万
• 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/8158152
• 关键词: Autistic Disorder; Excitatory Amino Acid Antagonists

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

据报道，自闭症谱系障碍 (ASD) 影响着每 150 名儿童中就有 1 名，他们的终生残疾会影响社交、沟通和心理功能。自闭症谱系障碍（ASD）影响着数百万儿童，是一个巨大的公共卫生问题。 自闭症谱系障碍症状与医学和精神共病相结合，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，还没有任何药物被证明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）有好处。 尽管据报道一些行为策略对社交和沟通领域有用，但没有任何行为干预措施对自闭症谱系障碍的固定兴趣和重复行为显示出一致的益处。 然而，考虑到这些症状与儿童期发病的强迫症 (OCD) 中的强迫行为非常相似，以及强迫症作为 ASD 合并症的频率，我们推测减少 OCD 症状的药物也可能改善 ASD 的重复行为和固定兴趣。 血清素再摄取阻断药物（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，但许多患者对治疗没有反应。 治疗难治性病例在共病 ASD-OCD 组中尤其常见，这表明单独调节血清素不足以缓解该组的症状。 儿童期发病的强迫症的假设病因表明，谷氨酸拮抗剂（例如利鲁唑）可能会减轻强迫症和强迫症的严重程度，因为该药物的作用是当前药物疗法的“上游”。 使用利鲁唑治疗成人和儿童强迫症已取得一些初步成功。 在 13 名患有难治性强迫症的成年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，耶鲁-布朗强迫量表（Y-BOCS）评分在调查过程中显着改善。 5 名受试者被归类为治疗反应者（Y-BOCS 低于 16，基线评分降低 35% 或更多，临床共识改善）。 六名强迫症儿科受试者中的四名在开放标签给药利鲁唑 12 周后表现出显着改善；在一年的随访中，治疗效果得以维持，没有报告严重不良事件。 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行为有益。 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。据推测，利鲁唑在降低该人群强迫症状严重程度方面优于安慰剂，并且还可能降低与自闭症相关的刻板行为和固定兴趣的严重程度。 随着孩子们因强迫症而变得不那么焦虑和痛苦，整体行为也有望得到改善。 在为期 12 周的双盲、安慰剂对照试验阶段，受试者将接受含有利鲁唑或安慰剂的掩蔽胶囊，然后可以选择接受三个月的利鲁唑开放标签治疗。 儿童将参加总共 12 个月的研究，只有在临床指示和建议的情况下，才会在研究的后半段接受利鲁唑治疗。 在整个研究期间将定期进行临床访问，最终评估将在随机分组后一年进行。 截至撰写本文时，该研究正在积极招募 7 至 17 岁的受试者。如果儿童和青少年患有中重度强迫症和/或强迫行为（重复行为）以及自闭症谱系障碍（自闭症、PDD-NOS 或阿斯伯格障碍），则他们有资格参加研究。 有关利鲁唑试验的更多信息，请咨询 ClinicalTrials.gov：http://clinicaltrials.gov/ct2/show/NCT00251303 除了治疗试验外，一项利用磁共振波谱（MRS）研究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利鲁唑治疗前和治疗期间接受 MRS 扫描（类似于 MRI 扫描）。 将评估大脑中谷氨酸和相关化学物质浓度的变化，并将其与症状严重程度和治疗反应程度进行比较。 试验参与者也可能正在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，有关该研究的更多信息可在 ClinicalTrials.gov 上找到，研究标识符为：NCT01019967