Effects of multiple-dose intranasal oxytocin administration on social responsiveness in children with autism: a randomized, placebo-controlled trial

Abstract

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).

At the Head and Heart of Oxytocin’s Stress-Regulatory Neural and Cardiac Effects: A Chronic Administration RCT in Children with Autism

“…Future trials should therefore be directed at identifying optimal daily dosing schemes, administration length, and intervals. Indeed, it is noted that while some associations were identified in the current trial between oxytocin-induced neural changes at T2 and improvements in social functioning, specifically on the Social Cognition subscale of the SRS-2, the overall 4-week administration regime did not induce comprehensive clinical-behavioral improvements across primary or secondary clinical-behavioral scales, as previously described in Daniels et al [39]. Given the relatively brief administration period of 4 weeks, longer administration periods and/or alternative dosing regimes, such as intermittent dosing [15], may have greater potential to elicit significant clinical-behavioral improvements.…”

“…Further, as outlined in Daniels et al (2023) [39], compared to the placebo group, children receiving oxytocin did notas a groupdisplay stronger improvements in social functioning, as assessed using the Social Responsiveness Scale-Children, second edition (i.e., SRS-2, comprising five subscales examining social awareness, social cognition, social communication, social motivation and restricted interests and repetitive behavior) [50].…”

“…The neural assessments were conducted at the Leuven University Hospital (registered at the EU Clinical Trials Register: EudraCT 2018-000769-35 and the Belgian Federal Agency for Medicines and Health Products). As indicated in the EudraCT registration, fMRI data collections were part of a broader assessment including clinical-behavioral characterizations [39], as well as other (neuro)physiological (electroencephalographic) [40] and biological assessments [41]. The trial was monitored by the Clinical Trial Center at the University Hospital of Leuven; all trial staff had Good Clinical Practice certification and was trained in the study protocol.…”

Can repeated intranasal oxytocin administration affect reduced neural sensitivity towards expressive faces in autism? A randomized controlled trial

“…As registered at the European Clinical Trial Registry (https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-000769-35/BE), the EEG recordings were part of a larger assessment protocol, evaluating clinical efficacy of OT administration on distinct autism symptoms questionnaires, including the parent-rated Social Responsiveness Scale-Children, second edition (SRS-2; Constantino & Gruber, 2012) as primary behavioural outcome, see Daniels et al (2023) for a detailed report. In short, in terms of behavioural assessments, no OT-specific improvements were identified, since both the OT and the placebo group displayed significant behavioural improvements in constructs assessing social responsiveness, Ó 2023 Association for Child and Adolescent Mental Health.…”

Chronic oxytocin administration stimulates the oxytocinergic system in children with autism

“…However, while initial single-dose administration studies yielded promising acute effects of oxytocin on pro-social behaviour 2 , subsequent multiple-dose, chronic administration studies (i.e. administrating the oxytocin nasal spray over a course of multiple weeks) have yielded a more mixed pattern of results, with some studies demonstrating beneficial outcomes, while others did not 8 – 12 (see 13 for a full review on chronic oxytocin administration trials).…”