Quantitative facial expression analysis revealed the efficacy and time course of oxytocin in autism

Abstract

Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder’s core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, −0.57; 95% CI, −1.27 to 0.13; P = 0.023) and confirmatory trials (−0.41; −0.62 to −0.20; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen’s d = −0.78; 95% CI, −1.21 to −0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen’s d = −0.46; 95% CI, −0.90 to −0.01) and 6 weeks (P = 0.10, Cohen’s d = −0.35; 95% CI, −0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen’s d = −1.24; 95% CI, −1.71 to −0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals’ facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment.

Oxytocin-Induced Increase in N,N-dimethylglycine and Time-Course of Changes in Oxytocin Efficacy for Autism Social Core Symptoms

“…Although the bene cial effects of single-dose oxytocin on measures of ASD core symptoms have been consistently reported across studies (3)(4)(5)(6)(7)(8), previous studies on the repeated administration of oxytocin have reported inconsistent ndings, impeding further development of oxytocin as an approved medication (9). Recently, we found a progressive deterioration in the e cacy of oxytocin (10,11), and proposed that this phenomenon may account for the reported inconsistencies in the effect of repeated administration. Elucidating the mechanisms underlying the time-course change in the e cacy of repeated oxytocin administration may help advance the development of oxytocin-based therapy for ASD core symptoms.…”

“…The trial sites were the University of Tokyo Hospital, Nagoya University Hospital, Kanazawa University Hospital, and University of Fukui Hospital in Japan (UMIN000015264) (14). The details of this trial are described elsewhere (11,14). Brie y, the inclusion criteria of this trial were as follows: (1) 18-54 years of age; (2) male; (3) diagnosis of autistic disorder, Asperger's disorder, or pervasive developmental disorders not otherwise speci ed (PDD-NOS) based on DSM-IV-TR; (4) score exceeding the cut-off value (i.e.…”

“…To examine their relationship to metabolite concentrations, we also included six additional outcomes found to be signi cant effects of oxytocin in this trial (11,14) as well as in previous trials (11,18). The six clinical and behavioral indices of oxytocin e cacy were as follows: (i) ADOS repetitive behavior = changes in the ADOS repetitive score between baseline and 6-week endpoint of oxytocin administration (endpoint − baseline).…”

“…The repeated administration speci cally impacted the glutamatergic system, including the N-Methyl-D-Aspartate (NMDA) receptor (10,13). In addition, the time course change in the e cacy of repeated oxytocin was detected with our unique dataset employing 2-week longitudinal assessments of objectively quanti ed measures of ASD social de cits (11). However, to the best of our knowledge, the relationship between the time-course change in e cacy and oxytocin-induced changes in molecular pathways have not yet been examined.…”

“…In the present study, we explored the interaction between oxytocin and molecular systems by analyzing oxytocin-induced changes with high-throughput metabolomics, which can quantify various metabolites related to the glutamatergic system as well as other molecular systems such as cholinergic or serotonergic systems. Metabolite concentrations were quanti ed using plasma samples collected from the participants before and after repeated administration of oxytocin or placebo in our previous multi-center, parallel-group, placebocontrolled, double-blind, con rmatory trial of intranasal oxytocin in adult males with high-functioning ASD (11,14). Furthermore, by utilizing repeatable and quanti able behavioral outcome measures, we explored the molecular mechanisms underlying the time-course change in oxytocin e cacy on ASD.…”