1 Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan 2 Department of Physiology, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan 3 Institute of Cognitive Neuroscience, University College London, 17 Queen Square, London, WC1N 3AR, UK.
4 Department of Child Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Brain. 2015 Nov;138(Pt 11):3400-12. doi: 10.1093/brain/awv249. Epub 2015 Sep 3.
Autism spectrum disorder is a prevalent neurodevelopmental disorder with no established pharmacological treatment for its core symptoms. Although previous literature has shown that single-dose administration of oxytocin temporally mitigates autistic social behaviours in experimental settings, it remains in dispute whether such potentially beneficial responses in laboratories can result in clinically positive effects in daily life situations, which are measurable only in long-term observations of individuals with the developmental disorder undergoing continual oxytocin administration. Here, to address this issue, we performed an exploratory, randomized, double-blind, placebo-controlled, crossover trial including 20 high-functional adult males with autism spectrum disorder. Data obtained from 18 participants who completed the trial showed that 6-week intranasal administration of oxytocin significantly reduced autism core symptoms specific to social reciprocity, which was clinically evaluated by Autism Diagnostic Observation Scale (P = 0.034, PFDR < 0.05, Cohen's d = 0.78). Critically, the improvement of this clinical score was accompanied by oxytocin-induced enhancement of task-independent resting-state functional connectivity between anterior cingulate cortex and dorso-medial prefrontal cortex (rho = -0.60, P = 0.011), which was measured by functional magnetic resonance imaging. Moreover, using the same social-judgement task as used in our previous single-dose oxytocin trial, we confirmed that the current continual administration also significantly mitigated behavioural and neural responses during the task, both of which were originally impaired in autistic individuals (judgement tendency: P = 0.019, d = 0.62; eye-gaze effect: P = 0.03, d = 0.56; anterior cingulate activity: P = 0.00069, d = 0.97; dorso-medial prefrontal activity: P = 0.0014, d = 0.92; all, PFDR < 0.05). Furthermore, despite its longer administration, these effect sizes of the 6-week intervention were not larger than those seen in our previous single-dose intervention. These findings not only provide the evidence for clinically beneficial effects of continual oxytocin administration on the core social symptoms of autism spectrum disorder with suggesting its underlying biological mechanisms, but also highlight the necessity to seek optimal regimens of continual oxytocin treatment in future studies.
自闭症谱系障碍是一种普遍的神经发育障碍，目前尚无针对其核心症状的既定药物治疗方法。尽管先前的文献表明，催产素单次给药可以暂时缓解实验环境中的自闭症社交行为，但仍存在争议，即在实验室中观察到的潜在有益反应是否能在日常生活中产生临床积极影响，而这些影响只能通过对接受持续催产素治疗的发育障碍个体进行长期观察来衡量。在这里，为了解决这个问题，我们进行了一项探索性、随机、双盲、安慰剂对照、交叉试验，纳入了 20 名高功能自闭症谱系障碍成年男性。完成试验的 18 名参与者的数据显示，6 周的鼻内催产素给药显著降低了自闭症核心症状中与社交互惠相关的特定症状，这一临床评估是通过自闭症诊断观察量表（P = 0.034，PFDR < 0.05，Cohen's d = 0.78）来完成的。重要的是，这种临床评分的改善伴随着催产素诱导的前扣带回皮层和背内侧前额叶皮层之间任务无关的静息状态功能连接的增强（rho = -0.60，P = 0.011），这是通过功能磁共振成像来测量的。此外，我们使用与我们之前的单次催产素试验相同的社会判断任务，证实了当前的持续给药也显著减轻了任务中的行为和神经反应，而这些反应在自闭症个体中原本是受损的（判断倾向：P = 0.019，d = 0.62；目光注视效应：P = 0.03，d = 0.56；前扣带活动：P = 0.00069，d = 0.97；背侧内侧前额叶活动：P = 0.0014，d = 0.92；所有 P 值，PFDR < 0.05）。此外，尽管给药时间更长，但 6 周干预的这些效应大小并不大于我们之前单次干预的效应大小。这些发现不仅为持续催产素给药对自闭症谱系障碍核心社交症状的临床有益效果提供了证据，并提出了其潜在的生物学机制，还强调了在未来研究中寻求持续催产素治疗最佳方案的必要性。
