Oxytocin-based Pharmacotherapy for Autism Spectrum Disorder: Behavioral and Neural Effects of a Promising Intervention Approach

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by difficulties in social interaction and communication, and restricted interests and repetitive behaviors. Considering the increasing prevalence and high clinical, social and financial burden of ASD on society, there is a strong need for effective treatments. To date, therapeutic interventions mainly comprise behavioral social skills trainings, for which evidence is mixed. In addition, the only approved pharmacological therapies do not target the core characteristics of ASD. However, during the past 15 years, the neuropeptide oxytocin (OT) has gained increasing interest as a potential therapeutic approach for improving the core social impairments characteristic of ASD. OT is a neuropeptide with a dual function. As a hormone, OT is released into the bloodstream where it is known to affect bodily functions such as lactation and uterine contractions. Within the brain, OT acts as an important neuromodulator for modulating complex social behaviors such as interpersonal bonding, reciprocity and face processing, and the ability to establish trust and social attachment. The current doctoral project aimed to gain insight into the behavioral and neural effects of single-dose and multiple-dose administration of OT both in the neurotypical population and in individuals with ASD. Before initiating the clinical trial designed to assess the behavioral and neural effects of single-dose and multiple-dose intranasal OT administration in adult men with ASD (that forms the core of the current doctoral project), we first tested (parts of) the study procedure and outcome measures in a sample of typically developing adult men. In a first study, we assessed the immediate effects of single-dose OT treatment (compared to placebo (PL)) on emotion recognition from point-light biological motion and found that a single dose of intranasal OT had a significant, medium-sized effect on emotion recognition from point-light biological motion regardless of the emotional valence of the presented stimuli. Albeit moderate, these findings of OT-induced improvements in emotion recognition provided further support for a link between OT and the processing of social information. A complementary line of research has also highlighted the beneficial effects of intranasal OT administration on feelings of attachment, yet evidence on the effects of multiple-dose OT treatment in typically developing individuals was limited. Accordingly, in a subsequent study, we assessed the effects of two weeks of daily OT administration (compared to PL) on measures of attachment feelings, social responsiveness, quality of life and mood. Participants reported significant reductions in attachment avoidance and increases in reports of attachment toward peers after two weeks of OT treatment. In addition, treatment-induced changes were most pronounced for participants with less secure attachment towards their peers, indicating that normal variance at baseline modulated treatment response. OT treatment also improved participant's reports of mood with respect to tension and (tentatively) anger. Further, at the end of the two-week trial, both treatment groups (OT, PL) reported increased social responsiveness and quality of life, indicating that these effects were not treatment-specific. Again, the reported improvements in feelings of attachment after the multiple-dose treatment with OT provided further evidence in support of a pivotal role of OT in promoting social behavior and, in particular, the experience of attachment. After finding these beneficial effects of both single-dose and multiple-dose OT administration in typically developing adult men, we adopted the aforementioned outcome measures in a clinical trial with adult men with ASD. We investigated the immediate and long-term effects of multiple-dose OT treatment on a behavioral and neural level. To assess the behavioral effects of multiple-dose OT treatment, autism characteristics (social responsiveness, and restricted and repetitive behaviors (RRBs)), feelings of attachment and quality of life were assessed up to one month and one year post-treatment. To assess the neural effects of multiple-dose OT treatment, we performed functional magnetic resonance imaging (fMRI) in order to study the changes in task-related brain activity of the posterior superior temporal sulcus (pSTS) and amygdala up to one month and one year post-treatment. To do so, we adopted a double-blind, randomized, placebo-controlled, parallel design (clinical trial) during which we tested participants (i) at baseline, (ii) after a single dose of OT, (iii) immediately after four weeks of continual OT treatment, and at two follow-up sessions, (iv) one month (four weeks) and (v) one year post-treatment. A key question was to evaluate whether any beneficial effects of continual OT treatment would outlast the period of actual administration until one month or even one year post-treatment. On a behavioral level, results revealed that the four-week, multiple-dose OT treatment did not improve social responsiveness, but did induce medium- to large-sized improvements in RRBs, reduced feelings of avoidance towards others and increased feelings of vigor, which outlasted the period of actual administration until one month and even one year post-treatment. On a neural level, results revealed that the four-week, multiple-dose treatment attenuated activity in bilateral amygdala and induced sustained higher levels of task-related activity within (right) pSTS. Anew, these treatment-induced neural changes were shown to outlast the intervention until one month and even one year post-treatment, indicating that continual OT treatment induced long-lasting neural changes in core regions of the social brain circuit. Importantly, we also showed that the extent of amygdala attenuation was associated with the extent of (long-term) improvements in self-reports of social functioning (social responsiveness). This dissertation provides evidence that intranasal administration of OT, albeit in single-dose or multiple-dose form, is effective for inducing behavioral and neural changes in typically developing adult men and adult men with ASD. In particular, for the first time, we show that these changes outlast the administration period until one year post-treatment. These findings provide first indications for the anxiolytic role and social salience boosting effect of OT in adult men with ASD. However, in order to generalize these findings, more research replicating these findings in larger and more diverse samples is necessary.

Jaar van publicatie:2019

Toegankelijkheid:Open