Early Pharmacotherapy Guided by Biomarkers in Autism

自闭症生物标志物指导的早期药物治疗

• 批准号: 8231524
• 负责人: DIANE C CHUGANI
• 金额: $ 199.61万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231524
• 关键词: Early; Pharmacotherapy; Guided; Biomarkers; Autism

DESCRIPTION (provided by applicant): The investigators have previously shown a different time course in the developmental values of brain serotonin synthesis in children with autism using positron emission tomography (PET). These data are consistent with the notion that serotonin synthesis is abnormal during critical periods of brain development in autistic children. Specific to this project, the investigators demonstrated that serotonin synthesis capacity in children less than the age of six years showed significantly lower values than non- autistic children. Since serotonin is known to be an important factor involved in postnatal synaptogenesis, they hypothesized that one approach to the treatment of autism pharmacologically is the use of serotonin agonists in children less than the age of six years. The goal of this treatment is to provide a more normal serotonergic modulation of synaptic plasticity in autistic children during the early childhood years. For this study, they chose the 5HT1A serotonin agonist buspirone. The rationale for the choice of buspirone was based upon basic studies demonstrating a prominent role of the 5HT1A receptor in the regulation of postnatal synaptogenesis. The long-range goal is to utilize biochemical and genetic factors in autism that can be used in the rational design of treatment in groups or subgroups of children with autism. This study is to test further the safety and efficacy of buspirone in a large group of young autistic children. This trial is guided by pilot study results funded by NICHD through the Pediatric Pharmacology Research Unit (PPRU) network. In their pilot study, the investigators demonstrated improvement in social interaction, repetitive behavior, sensory dysfunction, and anxiety with three months of buspirone treatment. A subset of the children continued in a six-month open label study and showed further improvement by the end of the open label study. In addition, serotonin synthesis capacity measured with a-[11C]-methyl-L-tryptophan (AMT) PET was related to the response to buspirone in the pilot study, while plasma serotonin was not. Thus AMT PET will be tested as a biomarker for drug response.

描述（由申请人提供）：研究人员先前使用正电子发射断层扫描（PET）显示了自闭症儿童大脑5-羟色胺合成发育价值的不同时间过程。 这些数据与自闭症儿童大脑发育关键时期血清素合成异常的观点一致。 具体到这个项目，研究人员证明，小于六岁的儿童的血清素合成能力显示出明显低于非自闭症儿童的数值。 由于5-羟色胺已知是参与出生后突触发生的重要因素，他们假设治疗自闭症的一种方法是在6岁以下的儿童中使用5-羟色胺激动剂。 这种治疗的目的是提供一个更正常的突触可塑性在自闭症儿童在童年早期的多巴胺能调制。 在这项研究中，他们选择了5 HT 1A血清素激动剂丁螺环酮。 选择丁螺环酮的理由是基于基础研究，证明了5 HT 1A受体在调节出生后突触发生中的重要作用。 长期目标是利用自闭症中的生物化学和遗传因素，这些因素可用于自闭症儿童群体或亚群体的合理治疗设计。 这项研究是为了进一步测试丁螺环酮的安全性和有效性在一个大的年轻自闭症儿童群体。 本试验由NICHD通过儿科药理学研究单位（PPRU）网络资助的试点研究结果指导。 在他们的初步研究中，研究人员证明了三个月的丁螺环酮治疗对社会互动，重复行为，感觉功能障碍和焦虑的改善。 一部分儿童继续进行为期六个月的开放标签研究，并在开放标签研究结束时显示出进一步的改善。 此外，在初步研究中，用-[11 C]-甲基-L-色氨酸（AMT）PET测量的5-羟色胺合成能力与丁螺环酮的反应有关，而血浆5-羟色胺则无关。 因此，AMT PET将作为药物反应的生物标志物进行检测。