Clinical efficacy of intranasal administration of oxytocin is increasingly explored in autism spectrum disorder, but to date, the biological effects of chronic administration regimes on endogenous oxytocinergic function are largely unknown. Here exploratory biological assessments from a completed randomized, placebo-controlled trial showed that children with autism (n = 79, 16 females) receiving intranasal oxytocin for four weeks (12 IU, twice daily) displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at a four-week follow up session. Regarding salivary oxytocin receptor gene ( OXTR) epigenetics (DNA-methylation), oxytocin-induced reductions in OXTR DNA-methylation were observed, suggesting a facilitation of oxytocin receptor expression in the oxytocin compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reduced OXTR DNA-methylation and improved feelings of secure attachment. These findings indicate that four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with autism.

Background: RASopathies are associated with an increased risk of autism spectrum disorder (ASD). For neurofibromatosis type 1 (NF1) there is ample evidence for this increased risk, while for other RASopathies this association has been studied less. No specific ASD profile has been delineated so far for RASopathies or a specific RASopathy individually. Methods: We conducted a systematic review to investigate whether a specific RASopathy is associated with a specific ASD profile, or if RASopathies altogether have a distinct ASD profile compared to idiopathic ASD (iASD). We searched PubMed, Web of Science, and Open Grey for data about ASD features in RASopathies and potential modifiers. Results: We included 41 articles on ASD features in NF1, Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Individuals with NF1, NS, CS, and CFC on average have higher ASD symptomatology than healthy controls and unaffected siblings, though less than people with iASD. There is insufficient evidence for a distinct ASD phenotype in RASopathies compared to iASD or when RASopathies are compared with each other. We identified several potentially modifying factors of ASD symptoms in RASopathies. Conclusions: Our systematic review found no convincing evidence for a specific ASD profile in RASopathies compared to iASD, or in a specific RASopathy compared to other RASopathies. However, we identified important limitations in the research literature which may also account for this result. These limitations are discussed and recommendations for future research are formulated.

Background Clinical efficacy of chronic intranasal administration of oxytocin is increasingly explored in autism spectrum disorder (ASD), but to date, little is known regarding its biological effects and in particular how chronic administration regimes impact endogenous oxytocinergic function. Methods To fill this gap, this double-blind, randomized, placebo-controlled study explored chronic oxytocin administration effects on endogenous salivary oxytocin levels and oxytocin receptor gene ( OXTR ) epigenetics (DNA methylation) in 8-to-12-year-old children with ASD (n = 79, 16 females). Biological sampling was performed at baseline (pre-treatment), immediately (24 hours) after the four-week oxytocin administration period (12 IU, twice daily) and at a follow-up session, four weeks after the last nasal spray administration. Results Compared to placebo, children receiving the oxytocin nasal spray displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at the four-week follow up session. Regarding epigenetics, oxytocin-induced reductions in OXTR methylation were observed, reflecting a facilitation of oxytocin receptor expression in the oxytocin, compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reduced OXTR DNA methylation and improved feelings of secure attachment. Conclusion Four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with ASD, as evidenced by increased salivary oxytocin levels and reduced OXTR DNA methylation (indicating increased receptor expression).

BACKGROUND:Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication and interaction. Crucial for efficient social interaction is the ability to quickly and accurately extract information from a person's face. Frequency-tagging electroencephalography (EEG) is a novel tool to quantify face-processing sensitivity in a robust and implicit manner. In terms of intervention approaches, intranasal administration of oxytocin (OT) is increasingly considered as a potential pharmacological approach for improving socio-communicative difficulties in ASD, through enhancing social salience and/or reducing (social) stress and anxiety.METHODS:In this randomized, double-blind, placebo-controlled, mechanistic pharmaco-neuroimaging clinical trial, we implemented frequency-tagging EEG to conduct an exploratory investigation into the impact of repeated OT administration (4 weeks, 12 IU, twice daily) on neural sensitivity towards happy and fearful facial expressions in children with ASD (8-12 years old; OT: n = 29; placebo: n = 32). Neural effects were assessed at baseline, post-nasal spray (24 hr after the last nasal spray) and at a follow-up session, 4 weeks after the OT administration period. At baseline, neural assessments of children with ASD were compared with those of an age- and gender-matched cohort of neurotypical (NT) children (n = 39).RESULTS:Children with ASD demonstrated reduced neural sensitivity towards expressive faces, as compared to NT children. Upon nasal spray administration, children with ASD displayed a significant increase in neural sensitivity at the post- and follow-up sessions, but only in the placebo group, likely reflecting an implicit learning effect. Strikingly, in the OT group, neural sensitivity remained unaffected from the baseline to the post-session, likely reflecting a dampening of an otherwise typically occurring implicit learning effect.CONCLUSIONS:First, we validated the robustness of the frequency-tagging EEG approach to assess reduced neural sensitivity towards expressive faces in children with ASD. Furthermore, in contrast to social salience effects observed after single-dose administrations, repeated OT administration dampened typically occurring learning effects in neural sensitivity. In line with OT's social anxiolytic account, these observations possibly reflect a predominant (social) stress regulatory effect towards emotionally evocative faces after repeated OT administration.

In the past decade, intranasal administration of the neuropeptide oxytocin is increasingly explored as a new treatment for reducing the core symptoms of autism spectrum disorder (ASD). The efficacy of continual oxytocin treatment in school-aged children with ASD is, however, not well established. Using a double-blind, randomized, placebo-controlled, parallel design, the current trial explored the effects of four weeks of intranasal oxytocin treatment (12 IU, twice daily) on social functioning in pre-pubertal school-aged children (aged 8-12 years, 61 boys, 16 girls). The double-blind phase was followed by a four-week single-blind extension phase during which all participants received intranasal oxytocin. In the double-blind phase, no treatment-specific effects were identified in the primary outcome assessing social functioning (parent-rated Social Responsiveness Scale), as well as on secondary outcomes assessing repetitive behaviors, anxiety, and attachment. Exploratory moderator analyses revealed that children who received the oxytocin treatment in combination with concomitant psychosocial treatment displayed a greater benefit than those who received psychosocial treatment or oxytocin alone. A modulating effect of parents’ beliefs about allocated treatment was also identified, indicating that parents who believed their child assigned to the active treatment reported greater benefit than those who believed their child received placebo, particularly in the actual oxytocin group. Finally, participants who were allocated to receive the placebo treatment during the double-blind phase of the trial and later crossed-over to receive the active treatment during the single-blind extension phase, displayed a significant within-group improvement in social responsiveness, over and above the placebo-induced improvements noted in the first phase. While no overall treatment-specific improvements were identified, our results provide important indications that clinical efficacy can be augmented when oxytocin administration is paired with targeted psychosocial interventions that similarly stimulate socio-communicative behaviors. Future trials are urged to further elucidate the potential of embedding oxytocin treatment within a socially stimulating context.

Two semi-structured parental interviews are available with algorithms developed to measure DSM-5 criteria of ASD, namely the Developmental, Dimensional and Diagnostic Interview (3di) and the Diagnostic Interview for Social and Communication Disorders (DISCO-11). The main aim of this study was to examine the agreement between classification according to both interviews, and their convergence with the clinical diagnosis. Therefore, the 3di and DISCO-11 were administered from three groups of parents of a 4-18 year old. Results showed 75% agreement between both instruments, but in the ASD group only 16% of the children scored above threshold on both instruments. Exploratory analyses suggested that the 3di failed to detect rigid and repetitive behaviors, whereas the DISCO-11 was insufficiently sensitive in detecting socio-communicative problems.

AIMS Despite longstanding recognition of significant age‐dependent differences in drug disposition during childhood, the exact course and the underlying mechanisms are not known. Our aim was to determine the course and determinants of individual relative dose requirements, during long‐term follow‐up in children on tacrolimus. METHODS This was a cohort study in a tertiary hospital with standardized annual pharmacokinetic (PK) follow‐up (AUC0–12hr) in recipients of a renal allograft (≤19 years), between 1998 and 2015. In addition, the presence of relevant pharmacogenetic variants was determined. The evolution of dose‐corrected exposure was evaluated using mixed models. RESULTS A total of 184 PK visits by 43 children were included in the study (median age: 14.6). AUC0–12h corrected for dose per kg demonstrated a biphasic course: annual increase 4.4% (CI: 0.3–8.7%) until ±14 years of age, followed by 13.4% increase (CI 8.7–18.3%). Moreover, exposure corrected for dose per m2 proved stable until 14 years (+0.8% annually; CI: −3.0 to +4.8%), followed by a steep increase ≥14 years (+11%; CI: 7.0–16.0%). Analysis according to bone maturation instead of age demonstrated a similar course with a distinct divergence at TW2: 800 (P = 0.01). Genetic variation in CYP3A4, CYP3A5, and CYP3A7 was associated with altered dose requirements, independent of age. CONCLUSIONS Children exhibit a biphasic course in tacrolimus disposition characterized by a high and stable drug clearance until a specific phase in pubertal development (TW2: 800 at age: ±14 years), followed by an important decline in relative dose requirements thereafter. Pharmacogenetic variation demonstrated an age/puberty independent effect. We suggest a critical reappraisal of current paediatric dosing algorithms for tacrolimus and drugs with a similar disposition.