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: 7696269
• 负责人: DIANE C CHUGANI
• 金额: $ 120万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7696269
• 关键词: Adverse effects; Aftercare; Age; Anxiety; Autistic Disorder; Behavior; Behavioral; Biological Markers; Brain; Buspirone; Child; Complex; Data; Development; Dose; Functional disorder; Funding; Goals; Image; Incidence; Label; Measures; National Institute of Child Health and Human Development; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Placebos; Plasma; Positron-Emission Tomography; Range; Rate; Regulation; Research; Role; Safety; Sensory; Serotonin; Serotonin Agonists; Social Interaction; Subgroup; Synaptic plasticity; Testing; Time; Tryptophan; autistic children; base; critical developmental period; early childhood; improved; neuroimaging; pediatric pharmacology; postnatal; receptor; response; synaptogenesis; therapy design; uptake

Our group has previously shown a markedly different time course in the developmental measures of serotonin synthesis in children with autism as compared to non-autistic children using PET imaging (Funded by NICHD RO1 HD34942). 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, we showed that serotonin synthesis capacity in children less than the age of 6 years showed significantly lower values than non-autistic children. Since serotonin is known to be an important factor involved in postnatal synaptogenesis, we hypothesized that one approach to the treatment of core features of autism pharmacologically is the use of serotonin agonists in children less than the age of 6 years. The goal of this treatment is to provide a more normal modulation of synaptic plasticity in autistic children during the early childhood years. For this study, we 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. Our long-range goal is to utilize neuroimaging markers in autism, which can be used in the rational design of treatment in groups or subgroups of children with autism. The goal of this study is to test further the safety and efficacy of buspirone in a large group of young children. This trial is guided by pilot study results funded by NICHD through the Pediatric Pharmacology Research Unit (PPRU) network. In our pilot study, we demonstrated improvement in social interaction, repetitive behavior, sensory dysfunction and anxiety with 3 months of buspirone treatment. A subset of the children continued in a 6-month open label study and showed further improvement by the end of the open label study. In addition, serotonin synthesis capacity measured with alpha[11C]methyl-L-tryptophan (AMT) positron emission tomography (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.

我们的研究小组先前已经显示了一个显着不同的时间过程中的发展措施的血清素 使用PET成像（由NICHD资助），自闭症儿童与非自闭症儿童的合成比较 RO1 HD34942）。这些数据与以下观点一致，即在关键性发育过程中，血清素合成异常。 自闭症儿童的大脑发育时期。具体到这个项目，我们发现血清素合成 6岁以下儿童的能力值明显低于非自闭症儿童。 由于5-羟色胺是已知的参与出生后突触发生的重要因素，我们假设， 治疗孤独症核心特征的一种方法是使用5-羟色胺激动剂， 6岁以下儿童。这种治疗的目的是提供一个更正常的调节， 自闭症儿童早期的突触可塑性。在这项研究中，我们选择了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。 我们的长期目标是利用自闭症的神经影像学标记， 合理设计自闭症儿童的治疗方案。这项研究的目的是测试 进一步证实了丁螺环酮在一大群幼儿中的安全性和有效性。本试验以试点研究为指导 NICHD通过儿科药理学研究单位（PPRU）网络资助的结果。在我们的试播集里 在一项研究中，我们证明了社交互动，重复行为，感觉功能障碍和焦虑的改善 三个月的丁螺环酮治疗一部分儿童继续进行为期6个月的开放标签研究， 在开放标签研究结束时显示出进一步的改善。此外，血清素合成能力 用α [11 C]甲基-L-色氨酸（AMT）正电子发射断层扫描（PET）测量的 对丁螺环酮的反应，而血浆5-羟色胺没有。因此，AMT PET将作为 药物反应的生物标志物。