Early Pharmacotherapy Guided by Biomarkers in Autism

我们小组以前在5-羟色胺的发育测量中显示出明显不同的时间进程 自闭症儿童与非自闭症儿童在PET成像中的合成(由NICHD资助 RO1 HD34942)。这些数据与5-羟色胺合成异常的观点是一致的 自闭症儿童的大脑发育阶段。具体到这个项目，我们展示了5-羟色胺的合成 6岁以下儿童的能力值显著低于非自闭症儿童。 由于5-羟色胺被认为是参与出生后突触发生的一个重要因素，我们假设 治疗自闭症核心特征的药理学方法之一是使用5-羟色胺激动剂 6岁以下儿童。这种治疗的目标是提供一种更正常的调节 自闭症儿童早期突触可塑性的研究。在这项研究中，我们选择了5HT1A 羟色胺激动剂丁螺环酮。选择丁螺环酮的理由是基于基础研究 显示了5HT1a受体在调节出生后突触发生中的重要作用。 我们的长期目标是在自闭症中使用神经成像标记物，这种标记物可以用于 自闭症儿童分组治疗的合理设计。这项研究的目标是测试 此外，丁螺环酮在一大群幼儿中的安全性和有效性。本试验以先导研究为指导 结果由NICHD通过儿科药理学研究单位(PPRU)网络提供资金。在我们的试点中 研究表明，我们在社交、重复行为、感觉障碍和焦虑方面有所改善 用丁螺环酮治疗3个月。其中一部分儿童继续进行为期6个月的开放式标签研究， 在开放标签研究结束时显示出进一步的改进。此外，5-羟色胺的合成能力 用α[11C]甲基L色氨酸(AMT)正电子发射断层扫描(PET)测量的结果与 在先导研究中，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。

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.