Oxytocin (OT) circuitry plays a major role in the mediation of prosocial behavior. Individuals with autism spectrum disorder (ASD) are characterized by impairments in social interaction and communication and have been suggested to display deficiencies in central OT mechanisms. The current preregistered meta-analysis evaluated potential group differences in endogenous OT levels between individuals with ASD and neurotypical (NT) controls. We included 18 studies comprising a total of 1422 participants. We found that endogenous OT levels are lower in children with ASD as compared to NT controls (n = 1123; g = −0.60; p = 0.006), but this effect seems to disappear in adolescent (n = 152; g = −0.20; p = 0.53) and adult populations (n = 147; g = 0.27; p = 0.45). Secondly, while no significant subgroup differences were found in regard to sex, the group difference in OT levels of individuals with versus without ASD seems to be only present in the studies with male participants (n = 814; g = −0.44; p = 0.08) and not female participants (n = 192; g = 0.11; p = 0.47). More research that employs more homogeneous methods is necessary to investigate potential developmental changes in endogenous OT levels, both in typical and atypical development, and to explore the possible use of OT level measurement as a diagnostic marker of ASD.

Background: Intranasal administration of oxytocin is increasingly explored as a new approach to facilitate social development and reduce disability associated with a diagnosis of autism spectrum disorder (ASD). The efficacy of multiple-dose oxytocin administration in children with ASD is, however, not well established. Methods: A double-blind, randomized, placebo-controlled trial with parallel design explored the effects of a 4-week intranasal oxytocin administration (12 IU, twice daily) on parent-rated social responsiveness (Social Responsiveness Scale: SRS-2) in pre-pubertal school-aged children (aged 8–12 years, 61 boys, 16 girls). Secondary outcomes included a questionnaire-based assessment of repetitive behaviors, anxiety, and attachment. Effects of oxytocin were assessed immediately after the administration period and at a follow-up, 4 weeks after the last administration. The double-blind phase was followed by a 4-week single-blind phase during which all participants received intranasal oxytocin. Results: In the double-blind phase, both the oxytocin and placebo group displayed significant pre-to-post-improvements in social responsiveness and secondary questionnaires, but improvements were not specific to the intranasal oxytocin. Notably, in the single-blind phase, participants who were first allocated to intranasal placebo and later changed to intranasal oxytocin displayed a significant improvement in social responsiveness, over and above the placebo-induced improvements noted in the first phase. Participants receiving oxytocin in the first phase also showed a significant further improvement upon receiving a second course of oxytocin, but only at the 4-week follow-up. Further, exploratory moderator analyses indicated that children who received psychosocial trainings (3 or more sessions per month) along with oxytocin administration displayed a more pronounced improvement in social responsiveness. Limitations: Future studies using larger cohorts and more explicitly controlled concurrent psychosocial trainings are warranted to further explore the preliminary moderator effects, also including understudied populations within the autism spectrum, such as children with co-occurring intellectual disabilities. Conclusions: Four weeks of oxytocin administration did not induce treatment-specific improvements in social responsiveness in school-aged children with ASD. Future studies are warranted to further explore the clinical efficacy of oxytocin administration paired with targeted psychosocial trainings that stimulate socio-communicative behaviors. Trial registration The trial was registered with the European Clinical Trial Registry (EudraCT 2018-000769-35) on June 7th, 2018 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-000769-35/BE).

Clinical efficacy of intranasal administration of oxytocin is increasingly explored in autism spectrum disorder, but to date, the biological effects of chronic administration regimes on endogenous oxytocinergic function are largely unknown. Here exploratory biological assessments from a completed randomized, placebo-controlled trial showed that children with autism (n = 79, 16 females) receiving intranasal oxytocin for four weeks (12 IU, twice daily) displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at a four-week follow up session. Regarding salivary oxytocin receptor gene (OXTR)epigenetics (DNA-methylation), oxytocin-induced reductions inOXTRDNA-methylation were observed, suggesting a facilitation of oxytocin receptor expression in the oxytocin compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reducedOXTRDNA-methylation and improved feelings of secure attachment. These findings indicate that four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with autism.

Objectives: Recent magnetic resonance imaging (MRI) studies implicate structural alterations of amygdala, a brain region responsible for processing and experiencing negative emotions, in adolescents with attention-deficit/hyperactivity disorder (ADHD). Here we examined ADHD-related structural correlates of amygdala functional activity elicited during a functional MRI task designed to test behavioural and brain responses to the imposition of delay – an event known to both elicit amygdala hyperactivation and aversity in ADHD. Methods: Structural MRI scans from 28 right-handed male adolescents with combined type ADHD and 32 age-matched controls were analysed. Regional grey matter volumes of ADHD and control participants (P[FWE] < 0.05) were correlated with delay aversion self-ratings and neural activity in response to delay-related cues on the Escape Delay Incentive fMRI task. Results: ADHD was associated with significantly reduced volumes in bilateral amygdala, parahippocampal and temporal gyrus (P[FWE] < 0.05), greater basolateral amygdala activation to delay-related cues (P[FWE] < 0.05) and higher delay aversion self-ratings. Amygdala volume reductions were significantly correlated with, and statistically mediated the pathway from ADHD to, delay-cue-related amygdala hyperactivity (P < 0.01) and self-reported delay aversion (P < 0.01). Conclusions: We provide the first evidence of the functional significance of reduced amygdala volumes in adolescents with ADHD by highlighting its relation to delay-induced brain activity that is linked to delay aversion.

Alterations in the brain’s oxytocinergic system have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse. Here, salivary oxytocin was examined in the morning (AM) and afternoon (PM) in school-aged children with (n = 80) and without (n = 40) ASD (boys/girls 4/1), and also characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR) were obtained. Further, cortisol levels were assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling. Children with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels at AM were associated with lower stress-induced cortisol at PM, likely reflective of aprotectivestress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a significant rise in oxytocin levels from the morning to the afternoon was associated with a higher stress-induced cortisol release in the afternoon, likely reflective of a morereactivestress regulatory release of oxytocin for reactively coping with heightened HPA activity. Regarding epigenetic modifications, no overall pattern ofOXTRhypo- or hypermethylation was evident in ASD. In control children, a notable association betweenOXTRmethylation and levels of cortisol at PM was evident, likely indicative of a compensatory downregulation ofOXTRmethylation (higher oxytocin receptor expression) in children with heightened HPA axis activity. Together, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.