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.

项目摘要 自闭症谱系障碍（ASD）的特征是核心社会障碍，这些障碍限制了患者形成的能力 并保持有意义的关系。目前，抗精神病药是唯一批准治疗ASD的药物， 但是它们针对相关的症状，具有不利的副作用，并且不治疗ASD的核心社会缺陷。 因此，开发专门针对社会功能的新药物将满足重要的未满足需求。 大量研究表明，神经肽精氨酸加压素（AVP）在 促进社会行为以及AVP信号通路的实验失调会产生社会 动物模型中的缺陷。尽管鼻内AVP管理可以改善社会认知和记忆 神经典型的个体，没有发表的研究测试了AVP治疗对ASD患者的影响。一些 证据线突显了此类研究的必要条件。例如，我们最近报道了血液AVP 水平预测ASD儿童的心理能力理论，使AVP水平最低的儿童具有 大多数明显的心理缺陷理论。这一发现与我们的临床前研究一致，表明社会上 与对照猴子相比，猴子受损的脑脊液AVP水平显着降低。 同样，来自第一个神经肽受体受体图研究的数据显示，尸体灵长类动物脑组织的数据显示 AVP V1A受体在整个扩展的神经杏仁核途径中广泛分布，表明 该AVP给药可以针对已知可以调节社会功能的直接神经途径。有趣的是， AVP的药物作用在雄性动物中尤其是证据，并且鉴于ASD的雄性偏见患病率， AVP定义可能与了解ASD的风险和治疗尤其重要。我们最近测试了 4周鼻内AVP治疗对双盲随机安慰剂中ASD儿童的影响 受控试验试验（R21 MH100387； MPI：Parker＆Hardan）。在这个小样本中，AVP总体上容忍了 重要的是，AVP治疗提高了父母评级评级评级的ASD儿童的社会能力 社会响应量表，第二版（SRS-2）。当我们考虑到这个结果时，这个结果更为明显 治疗前的血液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（n = 100）， 在这项双盲随机安慰剂对照的8周试验中，年龄在6至17岁之间。我们的主要结果 根据父母评级对SRS-2的评分评估，措施是改善儿童社会能力。我们还将测试 AVP治疗的安全性和耐受性，以及治疗前的血液AVP水平是否为个性化 预测治疗效率。最后，我们将测试AVP治疗是否改善了评估的ASD症状 通过临床印象，其他父母报告措施以及在社会实验室测试中的儿童表现 认知和交流。我们预测，AVP治疗将改善ASD儿童的社会能力， 与我们的初步数据保持一致，该AVP的耐受性很高。这项研究具有很高的领导潜力 开发第一种有效的药物来治疗ASD目前棘手的社会缺陷。