Oxytocin for Male Subjects with Autism Spectrum Disorder and Comorbid Intellectual Disabilities: A Randomized Pilot Study

Abstract

Approximately half of autism spectrum disorder (ASD) individuals suffer from comorbid intellectual disabilities (IDs). Oxytocin (OXT) receptors are highly expressed in temporal lobe structures and are likely to play a modulatory role in excitatory/inhibitory balance, at least based on animal model findings. Thus, it is feasible that in the highly representative group of Kanner-type ASD subjects, OXT could have a beneficial effect on social communication and social interaction. The aim of this pilot study is to investigate the feasibility and adverse events, such as epilepsy, of the long-term administration of intranasal OXT for adolescent and adult ASD subjects with ID because such patients frequently have seizures. We also addressed the question on how to scale the OXT effects to the core symptoms of social deficits because of the relative difficulty in obtaining objective measurements. Twenty-nine males (aged 15-40 years old) participated in a randomized, double-blind, and placebo-controlled crossover study (each for 8 weeks) with OXT (16 IU/day). Except for seizures experienced by one participant, other serious adverse events did not occur. The primary and secondary outcomes measured using the Childhood Autism Rating Scale and several standard scales, respectively, revealed no difference between the OXT and placebo groups. Instead, in an exploratory analysis, the social interactions observed in the play sessions or in daily life were significantly more frequent in the initial half period in the OXT-first arm of the crossover trial. There were also significant correlations between the plasma OXT concentration and subscale scores for irritability on the Aberrant Behavior Checklist. In conclusion, this pilot study demonstrates that long-term administration of intranasal OXT is tolerable in a representative cohort of ASD individuals with ID and suggests that future multicenter trials of OXT are warranted and should include measurements of reciprocal social interactions based on daily life under closer surveillance for epilepsy.

Trial registration: UMIN000007250.

Keywords: Kanner type; autism spectrum disorder; intranasal administration; oxytocin; social behavior.

Figure 1

Schema of the study. Prior to study enrollment, participants, and their caregivers visited Kanazawa University Hospital every 2 weeks during the preparatory period. Each visit consisted of a play session with a participant and an interview session with the caregivers. After the study began, the participants and caregivers visited the hospital eight times every 2 weeks and engaged in the same activities.

Figure 2

CONSORT 2010 flow diagram.

Figure 3

Sequential changes in the outcome measures. (A) The Childhood Autism Rating Scale (CARS). (B) The Clinical Global Impressions – Improvement scale (CGI-I). (C) The Aberrant Behavior Checklist (ABC). (D) The Global Assessment of Functioning (GAF). (E) The Interaction Rating Scale Advanced (IRSA). (F) Plasma oxytocin (OXT) concentrations. Solid and dashed lines indicate the OXT-first and placebo (PLB)-first groups. Black and white bars indicate the first treatment period and second treatment period, respectively (8 weeks for each period). Error bars indicate the SEM values. Response rates in the CGI-I show the percentages of participants assessed at 1 (very much improved) or 2 (much improved). There were no significant main effects of the treatment on any of the outcome measures.

Figure 4

Sequential changes in the percentages of participants with at least one episode of social interaction. (A–C) Percentages indicate the proportions of all participants who had at least one episode that was regarded as reciprocal social interactions every 2 weeks. Solid and dashed lines indicate the oxytocin (OXT)-first and the placebo (PLB)-first groups. Black and white bars indicate the first treatment period and second treatment period, respectively. (A) There were significant main effects for time and order, but not for treatment (P = 0.090). However, during the first treatment period, there was a significant main effect of treatment (P = 0.029). Moreover, there was a significant interaction between treatment and time (P = 0.041). (B) Sequential changes of episodes regarded as reciprocal social interactions in participants (n = 20) with plasma OXT concentrations below 250 pg/ml. There were significant main effects for time and order, but not for treatment (P = 0.109). However, during the first treatment period, there was a significant main effect of treatment (P = 0.028). Moreover, there was a significant interaction between treatment and time (P = 0.038). (C) The same as in B, except participants (n = 7) with OXT concentrations over 250 pg/ml. A generalized mixed regression analysis not including ID showed no significant main effect of treatment (P = 0.983) during the first treatment period. (D,E) Scatter plots portraying the relationships between plasma OXT concentrations and baseline scores on the Aberrant Behavior Checklist (ABC) (D) and the ABC irritability subscale (E). The slopes of the dotted linear regression lines indicate a correlation trend [P = 0.079 (D)] and a significant correlation [P = 0.020 (E)] in all of the participants.