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 ).

Keywords: Autism spectrum disorder (ASD); Oxytocin; Randomized controlled trial; Social responsiveness.

Fig. 1

Trial design (panel A) and CONSORT flow diagram of participants in the trial (panel B). Participants first underwent a double-blind phase (phase I) during which they were allocated to administer either oxytocin or placebo (4 weeks of twice daily intranasal administration). In phase I, nasal spray administration effects were assessed immediately after the last administration of the 4-week administration period (post, T1) and at a follow-up session, four weeks after cessation of the daily administrations (follow-up, T2). Phase I was immediately followed by a single-blind phase (phase II, during which all participants received four weeks of intranasal oxytocin. Also in phase II, nasal spray administration effects were assessed immediately after the four-week administration period (post, T3) and at a follow-up session, four weeks after cessation of the daily administrations (follow-up, T4) (panel A). The CONSORT flow diagram (panel B) visualizes the number of participants throughout the trial, indicating completed assessments at each session, separately for parent informant- and child self-reports

Fig. 2

Effects of oxytocin nasal spray administration on social responsiveness. Visualization of changes from baseline in caregiver-reported social responsiveness (SRS-2 total raw scores) of the double-blind phase (phase I) and the single-blind phase (phase II), separately for each original nasal spray group (oxytocin-first, placebo-first) and assessment session (immediate post (T1 and T3)and four-week follow-up (T2 and T4)). Lower scores indicate improvement. Vertical bars denote ± standard errors

Fig. 3

Change in treatment responses according to the presence of concomitant psychosocial training. Visualization of changes from baseline in parent-reported social responsiveness (SRS-2 raw total scores) of the double-blind phase (phase I), separately for children receiving only the oxytocin (n = 28) or placebo (n = 30) nasal spray and children receiving oxytocin (n = 10) or placebo (n = 8) nasal spray in combination with concomitant psychosocial trainings (pooled across the immediate post and four-week follow-up sessions of phase I). Lower scores indicate improvement. Vertical bars denote ± standard errors