Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder.

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.

Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder.

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).

Decreasing the Use of Restraints on Children Admitted for Behavioral Health Conditions.

OBJECTIVES: Pediatric behavioral health admissions to children's hospitals for disposition planning are steadily increasing. These children may exhibit violent behaviors, which can escalate to application of physical limb restraints for safety. Using quality improvement methodology, we sought to decrease physical restraint use on children admitted to our children's hospital for behavioral health conditions from a baseline mean of 2.6% of behavioral health patient days to <1%. METHODS: We included all children ≥3 years of age admitted to our hospital medicine service with a primary behavioral health diagnosis from July 1, 2016, to February 1, 2020. A multidisciplinary team, formed in July 2018, tested interventions based on key drivers targeted toward our aim. The primary outcome measure was the percent of behavioral health patient days on which physical restraints were ordered. The balancing measure was the percent of patient days with a staff injury event. Statistical process control charts were used to view and analyze data. RESULTS: Our cohort included 3962 consecutive behavioral health patient encounters, encompassing a total of 9758 patient days. A 2-year baseline revealed physical restraint orders placed on 2.6% of behavioral health patient days, which was decreased to 0.9% after interventions and has been sustained over 19 months without any change in staff injuries. CONCLUSIONS: Team-based quality improvement methodology was associated with a sustained reduction in physical restraint use on children admitted for behavioral health conditions to our children's hospital. These results indicate that physical restraint use can be safely reduced in children's hospitals.

Medical Etiologies of Secondary Psychosis in Children and Adolescents.

This is an updated review of child and adolescent somatic disorders associated with psychosis/psychotic symptoms, organized into neurologic, infectious, genetic, inborn errors of metabolism, autoimmune, rheumatologic, endocrine, nutritional, metabolic, and iatrogenic categories. When possible clinical manifestations or types of psychotic symptoms and proposed neuropathogenesis causing the neuropsychiatric symptoms are included. In some cases, the psychiatric symptoms may be the first presentation of the disease. The authors hope that this review will aid child and adolescent psychiatrists in considering alternative etiologies of youth presenting with psychosis and encourage appropriate physical examination, history, and further work-up when suspected.

Anti-N-Methyl d-Aspartate Receptor Encephalitis and Electroconvulsive Therapy: Literature Review and Future Directions.

Despite the majority of patients with anti-N-methyl d-aspartate receptor (NMDAR) antibody encephalitis presenting with catatonic symptoms, the literature has not focused on well-known treatments for catatonia, such as electroconvulsive therapy (ECT). The authors review the literature identifying case reports that document the effective use of ECT for anti-NMDAR encephalitis. They also identify gaps in the literature regarding use and documentation of ECT and review possible mechanisms of action for ECT. The authors propose identifying catatonia as a syndrome with multiple potential causes (including anti-NMDAR encephalitis) and suggest a standardized treatment approach using evidence-based catatonia treatments such as ECT and benzodiazepines.