Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial

Abstract

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18-48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P < .001) but placebo also reduced the score (8.3 to 7.2; P < .001), no between-group difference was found (effect size -0.08; 95% CI, -0.46 to 0.31; P = .69); however, plasma oxytocin was only elevated from baseline to endpoint in the oxytocin-group compared with the placebo-group (effect size -1.12; -1.53 to -0.70; P < .0001). Among the secondary endpoints, oxytocin reduced ADOS repetitive behavior (2.0 to 1.5; P < .0001) compared with placebo (2.0 to 1.8; P = .43) (effect size 0.44; 0.05 to 0.83; P = .026). In addition, the duration of gaze fixation on socially relevant regions, another secondary endpoint, was increased by oxytocin (41.2 to 52.3; P = .03) compared with placebo (45.7 to 40.4; P = .25) (effect size 0.55; 0.10 to 1.0; P = .018). No significant effects were observed for the other secondary endpoints. No significant difference in the prevalence of adverse events was observed between groups, although one participant experienced temporary gynecomastia during oxytocin administration. Based on the present findings, we cannot recommend continuous intranasal oxytocin treatment alone at the current dose and duration for treatment of the core social symptoms of high-functioning ASD in adult men, although this large-scale trial suggests oxytocin's possibility to treat ASD repetitive behavior.

Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up

“…The current study provides preliminary evidence that multiple-dose OT treatment may relieve an individual from this increased "need for sameness" and the resulting need for engaging in repetitive and restricted behaviors. Overall, these observed effects on repetitive behaviors are in line with previous trials with adult men with ASD showing beneficial effects of OT on repetitive behaviors after 4 h of intravenous OT administration [4] and after 6 weeks of daily administrations [8,10]. Note however that one 1-week trial with adult men with ASD did not show OT-specific improvements on informant-based reports of repetitive behaviors [9].…”

“…Similarly, Parker et al [14] investigated whether a 4-week intranasal OT treatment could improve core autism characteristics in 32 children (6-12 years old) with ASD and showed an increase in parentreported social responsiveness. Taken together, findings of these initial multiple-dose trials provided indications for a more consistent (positive) pattern of results for OT trials with adults with ASD [8][9][10], compared to trials with children with ASD [11][12][13][14].…”

“…In another study with 20 adult men with ASD, Watanabe et al [9] studied the effects of 6 weeks of intranasal OT administration on core autism characteristics and showed significant improvements in social reciprocity and social functioning (social-judgment task). In a more recent large-scale trial, Yamasue et al [10] also assessed the effects of 6 weeks of intranasal OT treatment on core autism symptom domains in 106 adult men with ASD and showed significant improvements in repetitive behaviors.…”

Role of oxytocin in the control of stress and food intake

“…279,280 The physiological roles of these receptors in the actions of oxytocin remain to be clarified. Further studies are also necessary to facilitate therapeutic potentials of oxytocin 281,282 or oxytocin-related treatments including diet ingredients 283…”

Genotype and dose-frequency determine acute and chronic effects of oxytocin on amygdala fear responses in humans: therapeutic implications

“…To date the functional effects of intranasal OT administration have been based primarily on a single dose and there is evidence that a 24IU dose may be optimal [6]. However, initial clinical trials reporting some therapeutic efficacy have typically used twice-daily treatment protocols lasting a number of weeks [1,[7][8][9][10][11], even though no studies have investigated if this is an optimal strategy. This is an important issue since clinical trials to date have reported relatively modest or inconsistent effects of chronic daily intranasal OT treatment and there is evidence from animal studies for rapid desensitization of OT receptors in some brain regions [12], most notably in the amygdala which mediates many of OTs functional effects on social cognition and anxiety [1].…”