Supplementary Material for: Infrequent Intranasal Oxytocin Followed by Positive Social Interaction Improves Symptoms in Autistic Children: A Pilot Randomized Clinical Trial

<b><i>Introduction:</i></b> There are currently no approved drug interventions for social behavior dysfunction in autism spectrum disorder (ASD). Previous trials investigating effects of daily intranasal oxytocin treatment have reported inconsistent results and have not combined it with positive social interaction. However, in two preclinical studies we established that treatment every other day rather than daily is more efficacious in maintaining neural and behavioral effects by reducing receptor desensitization. <b><i>Objective:</i></b> We aimed to establish whether a 6-week intranasal oxytocin compared with placebo treatment, followed by a period of positive social interaction, would produce reliable symptom improvements in children with ASD. <b><i>Methods:</i></b> A pilot double-blind, randomized, crossover design trial was completed including 41 children with ASD aged 3–8 years. Primary outcomes were the Autism Diagnostic Observation Schedule-2 (ADOS-2) and social responsivity scale-2 (SRS-2). Secondary measures included cognitive, autism- and caregiver-related questionnaires, and social attention assessed using eye-tracking. <b><i>Results:</i></b> Significant improvements were found for oxytocin relative to placebo in primary outcome measures (total ADOS-2 and SRS-2 scores, <i>p</i>s &lt; 0.001) and in behavioral adaptability and repetitive behavior secondary measures. Altered SRS-2 scores were associated with increased saliva oxytocin concentrations. Additionally, oxytocin significantly increased time spent viewing dynamic social compared to geometric stimuli and the eyes of angry, happy, and neutral expression faces. There were no adverse side effects of oxytocin treatment. <b><i>Conclusions:</i></b> Overall, results demonstrate that a 6-week intranasal oxytocin treatment administered every other day and followed by positive social interactions can improve clinical, eye tracking, and questionnaire-based assessments of symptoms in young autistic children.

**引言：**
目前尚无针对自闭症谱系障碍（Autism Spectrum Disorder, ASD）社交行为功能障碍的获批药物干预方案。既往针对每日鼻内催产素治疗效果的临床试验结果存在不一致性，且均未将该治疗与积极社交互动相结合。不过，我们在两项临床前研究中证实，相较于每日给药方案，隔日给药可通过降低受体脱敏反应，更有效地维持神经与行为层面的治疗效果。

**研究目的：**
本研究旨在探讨：相较于安慰剂治疗，为期6周的鼻内催产素治疗联合后续积极社交互动阶段，是否可使自闭症谱系障碍儿童获得可靠的症状改善。

**研究方法：**
本研究完成了一项试点性双盲随机交叉设计临床试验，共纳入41名3~8岁的自闭症谱系障碍儿童。主要结局指标为自闭症诊断观察量表第二版（Autism Diagnostic Observation Schedule-2, ADOS-2）与社交反应量表第二版（Social Responsivity Scale-2, SRS-2）。次要评估指标包括认知功能、自闭症相关及照料者相关问卷，以及通过眼动追踪技术评估的社交注意力。

**研究结果：**
相较于安慰剂组，催产素组的主要结局指标（ADOS-2与SRS-2总分，*p*值均<0.001）以及行为适应性与重复行为相关次要指标均出现显著改善。SRS-2评分的变化与唾液催产素浓度升高呈显著正相关。此外，相较于几何图形刺激，催产素治疗可显著增加受试者对动态社交刺激以及愤怒、快乐、中性表情面孔眼部区域的注视时长。催产素治疗未观察到明显不良反应。

**研究结论：**
整体而言，本研究结果证实，隔日给药的6周鼻内催产素治疗配合后续积极社交互动，可改善年幼自闭症儿童的临床症状、眼动追踪评估结果以及基于问卷的症状评估。