Intranasal vasopressin treatment in children with autism

项目总结 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 并保持有意义的关系。目前，抗精神病药物是唯一被批准用于治疗自闭症的药物， 但它们针对的是相关症状，有不利的副作用，而且不能治疗自闭症的核心社会缺陷。 因此，开发专门针对社会功能的新药将解决一个重要的未得到满足的需求。 大量研究表明，神经肽精氨酸加压素(AVP)在 促进社会行为和AVP信号通路的实验性失调产生社会行为 动物模型的缺陷。虽然鼻腔注射AVP改善了大鼠的社会认知和记忆 在神经典型个体中，还没有发表的研究测试AVP治疗ASD患者的效果。几个 一连串的证据突显了此类研究的必要性。例如，我们最近报道了血液中的AVP 水平可以预测ASD儿童的心理理论能力，因此AVP水平最低的儿童具有 最显著的心理缺陷理论。这一发现与我们的临床前研究一致，表明社交 与对照猴子相比，受损猴子的脑脊液AVP水平显著降低。 同样，首次对灵长类动物死后脑组织进行的神经肽受体图谱研究的数据显示 AVP V1a受体广泛分布于延伸的杏仁核神经通路，提示 AVP管理可以直接针对已知的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，鉴于ASD的男性偏向流行， AVP缺陷可能与了解ASD的风险和治疗特别相关。我们最近测试了 在双盲随机安慰剂中，4周鼻内注射AVP治疗儿童ASD的效果。 受控飞行员试验(R21 MH100387；MPI：Parker&Hardan)。在这个小样本中，AVP总体上耐受性良好， 重要的是，AVP治疗改善了ASD儿童的社会能力，根据父母对 社会反应性量表第二版(SRS-2)。当我们考虑到 治疗前血AVP水平。在这里，我们试图将这些发现扩展到更大的ASD研究队列中(N=100)， 在这项为期8周的双盲随机安慰剂对照试验中，年龄在6到17岁之间。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交能力的改善。我们还将测试 AVP治疗的安全性和耐受性，以及治疗前血AVP水平是否个性化 治疗效果的预测因子。最后，我们将测试AVP治疗是否如评估的那样改善ASD症状 根据临床医生的印象，额外的父母报告措施，以及儿童在社交网络实验室测试中的表现 认知和交流。我们预测AVP治疗将改善ASD儿童的社会能力， 根据我们的初步数据，这一AVP将被很好地容忍。这项研究具有很大的领先潜力 到开发第一种有效的药物来治疗自闭症目前难以治愈的社会缺陷。

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.