Intranasal vasopressin treatment in children with autism

自闭症儿童鼻内加压素治疗

• 批准号: 9893009
• 负责人: ANTONIO HARDAN
• 金额: $ 60.39万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893009
• 关键词: Adaptive Behaviors; Address; Adverse event; Aftercare; Amygdaloid structure; Animal Model; Animals; Antipsychotic Agents; Argipressin; Autopsy; Biological Markers; Biology; Blood; Blood specimen; Brain region; Cerebrospinal Fluid; Child; Clinical; Cohort Studies; Comprehension; Cooperative Behavior; Cues; Data; Development; Diagnostic; Dose; Double-Blind Method; Dropout; Emotional; Emotions; Exhibits; Eye; Face; Family member; Female; Financial Hardship; Gene Expression; Human; Impairment; Individual; Laboratories; Lead; Measures; Memory; Mind; Monkeys; Neural Pathways; Neuropeptide Receptor; Neuropeptides; OXT gene; Outcome Measure; Oxytocin; Oxytocin Receptor; Parents; Participant; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phenotype; Placebos; Play; Prevalence; Primates; Publishing; Quality of life; Randomized; Receptor Gene; Receptor Signaling; Reporting; Research; Risk; Rodent Model; Role; Sampling; Severities; Signal Pathway; Social Behavior; Social Functioning; Social Identification; Societies; Symptoms; Testing; Treatment Efficacy; V1a vasopressin receptor; Vasopressins; Vasotocin; aged; arginine treatment; associated symptom; autism spectrum disorder; autistic children; base; blood treatment; brain tissue; design; dosage; efficacy testing; gaze; impression; improved; innovation; male; medication safety; novel; open label; personalized predictions; pilot trial; pre-clinical research; primary outcome; randomized placebo controlled trial; receptor; relating to nervous system; repetitive behavior; safety testing; secondary outcome; side effect; social; social cognition; social communication; social deficits; social learning; symptom treatment; symptomatic improvement; theories; treatment response; trial design; week trial

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.

项目概要 自闭症谱系障碍 (ASD) 的特点是核心社交障碍，限制了患者的形成能力 并维持有意义的关系。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，具有不利的副作用，并且不能治疗自闭症谱系障碍的核心社交缺陷。 因此，开发专门针对社会功能的新药物将解决一个重要的未满足的需求。 大量研究表明，神经肽精氨酸加压素 (AVP) 在 促进社交行为并且 AVP 信号通路的实验性失调会产生社交行为 动物模型的缺陷。尽管鼻内 AVP 给药可改善社会认知和记忆 对于神经典型个体，尚无已发表的研究测试 AVP 治疗对 ASD 患者的效果。一些 一系列证据强调了此类研究的必要性。例如，我们最近报道了血液 AVP AVP 水平可预测 ASD 儿童的心智理论能力，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一致，表明社交 与对照组猴子相比，受损猴子的脑脊液 AVP 水平显着降低。 同样，第一个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 V1a 受体广泛分布在整个扩展神经杏仁核通路中，这表明 AVP 管理可以直接针对已知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，并且考虑到自闭症谱系障碍的男性患病率偏高， 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 双盲随机安慰剂试验中 4 周鼻内 AVP 治疗对 ASD 儿童的影响 受控试点试验（R21 MH100387；MPI：Parker & Hardan）。 AVP 在这个小样本中总体耐受性良好， 重要的是，AVP 治疗提高了自闭症儿童的社交能力，根据家长对 社会反应量表，第二版 (SRS-2)。当我们考虑到 治疗前血液AVP水平。在这里，我们寻求在更大的 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，受试者年龄为 6 至 17 岁。我们的主要成果 衡量标准是通过家长对 SRS-2 的评分来评估儿童社交能力的提高。我们也会测试 AVP 治疗的安全性和耐受性，以及治疗前血液 AVP 水平是否个性化 治疗效果的预测因子。最后，我们将测试 AVP 治疗是否可以改善评估的 ASD 症状 根据临床医生的印象、额外的家长报告措施以及儿童在社交实验室测试中的表现 认知和沟通。我们预测 AVP 治疗将提高自闭症儿童的社交能力， 根据我们的初步数据，AVP 具有良好的耐受性。这项研究具有很大的引领潜力 开发第一种有效药物来治疗自闭症谱系障碍目前棘手的社会缺陷。