Intranasal vasopressin treatment in children with autism

项目摘要 自闭症谱系障碍（ASD）的特点是核心社会障碍，限制了患者的形成能力， 保持有意义的关系。目前，抗精神病药物是唯一被批准用于治疗ASD的药物， 但它们针对的是相关症状，有不利的副作用，并且不能治疗ASD的核心社交缺陷。 因此，开发专门针对社会功能的新药将解决一个重要的未满足的需求。 大量的研究表明，神经肽精氨酸加压素（AVP）在脑血管病的发生发展中起着关键作用。 促进社会行为和AVP信号通路的实验失调产生社会性 动物模型中的缺陷。虽然鼻内AVP给药可改善患者的社会认知和记忆， 对于神经型个体，没有发表的研究测试了AVP治疗在ASD患者中的效果。几 一系列证据强调了这种研究的必要性。例如，我们最近报道，血液AVP AVP水平预测ASD儿童的心理理论能力，因此AVP水平最低的儿童具有 最明显的心理理论缺陷这一发现与我们的临床前研究相一致，该研究表明， 与对照猴相比，受损猴的脑脊液AVP水平显著降低。 同样，第一次灵长类动物死后脑组织神经肽受体图谱研究的数据显示， AVP V1 a受体广泛分布于整个延伸的神经杏仁核通路，表明 AVP给药可以直接靶向调节社会功能的神经通路。有趣的是， AVP的药理作用在雄性动物中尤其明显，考虑到ASD的男性偏见流行， AVP缺陷可能与理解ASD的风险和治疗特别相关。我们最近测试了 在一项双盲随机安慰剂研究中， 对照中试试验（R21 MH 100387; MPI：帕克和哈登）。AVP在这个小样本中总体耐受良好， 重要的是，AVP治疗改善了ASD儿童的社会能力， 社会反应量表，第二版艾德（SRS-2）。当我们考虑到 治疗前血液AVP水平。在这里，我们试图在一个更大的ASD研究队列（N=100）中扩展这些发现， 在这项为期8周的双盲随机安慰剂对照试验中，年龄为6至17岁。我们的主要成果 衡量标准是通过父母对SRS-2的评分来评估儿童社会能力的改善。我们还将测试 AVP治疗的安全性和耐受性，以及治疗前血液AVP水平是否是个体化的 治疗效果的预测指标。最后，我们将测试AVP治疗是否改善ASD症状， 通过临床医生的印象，额外的父母报告措施，以及儿童在社会实验室测试中的表现， 认知和沟通。我们预测AVP治疗将改善ASD儿童的社会能力， AVP耐受性良好，与我们的初步数据一致。这项研究具有很高的潜力， 第一种有效的药物来治疗ASD目前难以解决的社会缺陷。

PROJECT SUMMARY Autism spectrum disorder (ASD) is characterized by core social impairments which limit patients’ ability to form and maintain meaningful relationships. At present, antipsychotics are the only medication approved to treat ASD, but they target associated symptoms, have unfavorable side-effects, and do not treat ASD’s core social deficits. Developing new medications that specifically target social functioning will thus address an important unmet need. A large body of research has shown that the neuropeptide arginine vasopressin (AVP) plays a critical role in promoting social behavior and that experimental dysregulation of the AVP signaling pathway produces social deficits in animal models. Although intranasal AVP administration improves social cognition and memory in neurotypical individuals, no published research has tested the effects of AVP treatment in ASD patients. Several lines of evidence underscore the necessity of such research. For example, we recently reported that blood AVP levels predict theory of mind ability in children with ASD, such that children with the lowest AVP levels have the most marked theory of mind deficits. This finding is consistent with our preclinical research showing that socially impaired monkeys have significantly diminished cerebrospinal fluid AVP levels compared to control monkeys. Similarly, data from the first neuropeptide receptor mapping study of postmortem primate brain tissue revealed that AVP V1a receptors are widely distributed throughout the extended neural amygdala pathway, suggesting that AVP administration can target directly neural pathways known to regulate social functioning. Interestingly, AVP’s pharmacological effects are especially evident in male animals, and given ASD’s male-biased prevalence, AVP deficits may be particularly relevant to understanding the risk for, and treatment of, ASD. We recently tested the effects of 4-week intranasal AVP treatment in children with ASD in a double-blind randomized placebo- controlled pilot trial (R21 MH100387; MPI: Parker & Hardan). AVP was overall well tolerated in this small sample, and importantly, AVP treatment improved social abilities in children with ASD as assessed by parent ratings on the Social Responsiveness Scale, 2nd Ed (SRS-2). This result was more pronounced when we accounted for pre-treatment blood AVP levels. Here we seek to extend these findings in a larger ASD study cohort (N=100), aged 6 to 17 years, in this double-blind randomized placebo-controlled 8-week trial. Our primary outcome measure is improvement in child social abilities as assessed by parent ratings on the SRS-2. We will also test the safety and tolerability of AVP treatment, and whether pre-treatment blood AVP levels are a personalized predictor of treatment efficacy. Finally, we will test whether AVP treatment improves ASD symptoms as assessed by clinician impression, additional parent report measures, and child performance on laboratory tests of social cognition and communication. We predict that AVP treatment will improve social abilities in children with ASD, and that AVP will be well tolerated, in keeping with our preliminary data. This research has high potential to lead to development of the first effective medication to treat ASD’s currently intractable social deficits.