Oxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown. The current study explored metabolites representing the molecular mechanisms of oxytocin’s efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N = 106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial. Among the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P = 0.043, d = 0.74, N = 83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (PFDR = 0.004, d = 1.13, N = 60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (PFDR = 0.006, r = − 0.485, N = 43) and deteriorations between 2 and 4 weeks (PFDR = 0.032, r = 0.415, N = 37). The metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes. Our findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin’s efficacy. Trial registration: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703 ) (UMIN000015264).

中文翻译：

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催产素诱导的 N，N-二甲基甘氨酸的增加和催产素对自闭症社会核心症状疗效变化的时间过程

催产素有望成为自闭症谱系障碍 (ASD) 核心症状的新型治疗剂。然而，先前关于重复施用催产素的功效的结果是有争议的。最近，我们报告了重复给药引起争议性影响的神经肽功效随时间的变化；然而，潜在的机制仍然未知。目前的研究使用高通量代谢组学分析对 ASD 成年男性（N = 106）重复鼻内施用催产素（48 IU/天）或安慰剂前后 6 周收集的血浆，探索代表催产素功效分子机制的代谢物谁参加了一项多中心、平行组、双盲、安慰剂对照、随机对照试验。在测量的 35 种代谢物中，与给予安慰剂的受试者相比，给予催产素的受试者在中等效应量下检测到 N,N-二甲基甘氨酸显着增加（错误发现率 (FDR) 校正 P = 0.043，d = 0.74，N = 83）。此外，对显示催产素功效显着时程变化的参与者进行的亚组分析显示，催产素对 N,N-二甲基甘氨酸水平有显着影响，效应量很大（PFDR = 0.004，d = 1.13，N = 60）。N,N-二甲基甘氨酸的增加与催产素诱导的临床变化显着相关，评估为自闭症面部表情可量化特征的变化，包括基线和 2 周之间的改善（PFDR = 0.006，r = - 0.485，N = 43）和 2 至 4 周之间的恶化（PFDR = 0.032，r = 0.415，N = 37）。使用外周血对催产素给药引起的代谢物变化进行量化，因此可能不能直接反映中枢神经系统的变化。我们的研究结果表明，N,N-二甲基甘氨酸上调与催产素对自闭症社交障碍疗效的时间过程变化有关。此外，目前的研究结果支持 N-甲基-D-天冬氨酸受体和神经可塑性对催产素功效随时间变化的影响。试验注册：一项针对自闭症谱系障碍参与者鼻内催产素的多中心、平行组、安慰剂对照、双盲、验证性试验（注册日期：2014 年 10 月 30 日；UMIN 临床试验注册：https://upload .umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703 ) (UMIN000015264)。