Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism

Abstract

Autism spectrum disorder is a prevalent neurodevelopmental disorder with no established pharmacological treatment for its core symptoms. Although previous literature has shown that single-dose administration of oxytocin temporally mitigates autistic social behaviours in experimental settings, it remains in dispute whether such potentially beneficial responses in laboratories can result in clinically positive effects in daily life situations, which are measurable only in long-term observations of individuals with the developmental disorder undergoing continual oxytocin administration. Here, to address this issue, we performed an exploratory, randomized, double-blind, placebo-controlled, crossover trial including 20 high-functional adult males with autism spectrum disorder. Data obtained from 18 participants who completed the trial showed that 6-week intranasal administration of oxytocin significantly reduced autism core symptoms specific to social reciprocity, which was clinically evaluated by Autism Diagnostic Observation Scale (P = 0.034, PFDR < 0.05, Cohen's d = 0.78). Critically, the improvement of this clinical score was accompanied by oxytocin-induced enhancement of task-independent resting-state functional connectivity between anterior cingulate cortex and dorso-medial prefrontal cortex (rho = -0.60, P = 0.011), which was measured by functional magnetic resonance imaging. Moreover, using the same social-judgement task as used in our previous single-dose oxytocin trial, we confirmed that the current continual administration also significantly mitigated behavioural and neural responses during the task, both of which were originally impaired in autistic individuals (judgement tendency: P = 0.019, d = 0.62; eye-gaze effect: P = 0.03, d = 0.56; anterior cingulate activity: P = 0.00069, d = 0.97; dorso-medial prefrontal activity: P = 0.0014, d = 0.92; all, PFDR < 0.05). Furthermore, despite its longer administration, these effect sizes of the 6-week intervention were not larger than those seen in our previous single-dose intervention. These findings not only provide the evidence for clinically beneficial effects of continual oxytocin administration on the core social symptoms of autism spectrum disorder with suggesting its underlying biological mechanisms, but also highlight the necessity to seek optimal regimens of continual oxytocin treatment in future studies.

Plasma Oxytocin and Arginine-Vasopressin Levels in Children with Autism Spectrum Disorder in China: Associations with Symptoms

“…Human studies have focused on pharmacological administration and the measurement of plasma neuropeptides, mainly of OXT. It has been suggested that intranasal OXT is beneficial for the remission of autistic symptoms by improving cooperation and sense of trust [15] as well as by enhancing social responsiveness [16] and social reciprocity [17].…”

Intracellular Pathways Associated with the Etiology of Autism

“…In a recent small double-blind study, those taking OXT spray therapy had significantly reduced autism core symptoms specific to social reciprocity [162].…”

The Social (Neural) Network: Towards a Unifying Endophenotype Between Genes and Behavior

“…For example, intranasal OT commonly increases functional connectivity from the amygdala to areas such as the insula 91 , mPFC 12,92,93 , anterior cingulate 92 , and a number of additional brain regions relevant for social perception 9 and emotion regulation 11 . OT administration may also enhance connectivity between mesolimbic and prefrontal regions important for social motivation 9 and social evaluation 94 .…”

“…Importantly, several of these reports suggested a potential therapeutic role for OT administration in cases of trauma 95 , social anxiety 92 , and autism 9,12,94 .…”

“…Despite the controversy surrounding intranasal oxytocin research, a number of studies have consistently found that OT administration increases functional connectivity across regions relevant for social perception, motivation, and cognition more broadly 9,11,12,[91][92][93][94] . Still, these effects are highly-acute, and furthermore, it is unclear whether (or to what extent) baseline connectivity (i.e.…”