A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome

Abstract

Background Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS. Methods Eighteen children aged 5–17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period. Results There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann–Whitney U = 50, p = 0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events. Limitations The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results. Conclusion Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084.

Utilizing Genomically Targeted Molecular Data to Improve Patient-Specific Outcomes in Autism Spectrum Disorder

“…A small study of 18 children with SHANK3 haplotype insufficiency (Phelan-McDermid syndrome) has also been published using intranasal oxytocin with a p-value approaching, but not quite reaching, the threshold for significance at 12 weeks (p = 0.055). Changes on the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) was the endpoint measured in this study [39]. All of the above findings, along with the published studies of intranasal oxytocin being used and having a demonstrated benefit in children with ASD [40], made oxytocin qualify to be listed as a potential intervention for SHANK3 for the genomic CDS described.…”

Effects of multiple-dose intranasal oxytocin treatment on social responsiveness in children with autism: A randomized, placebo-controlled trial

“…The results of earlier continual OT trials in children with ASD have been equivocal: some with beneficial outcomes (Parker et al, 2017; Yatawara et al, 2016), while others without significant effect (Fastman et al, 2021; Guastella et al, 2015; Sikich et al, 2021). While it is difficult to pinpoint the different factors contributing to variability in study results, several key differences in adopted dosing schema, trial design, and participant demographics have been put forward as important moderators.…”

“…Two initial trials reported a consistent pattern of results, indicating improvements in the social domain (parent-reported social responsiveness) after five weeks of intranasal OT treatment in 3-to-6-year-old children (n = 31; cross-over; Yatawara et al, 2016) and after four weeks of treatment in 6-to-12-year-old children with ASD (14 OT / 18 placebo; Parker et al, 2017). No significant improvements on core autism symptoms were demonstrated, however, after an eight-week OT treatment in adolescent boys with ASD (26 OT / 24 placebo; 12-18 years; Guastella et al, 2015) or in a preliminary 12-week administration trial encompassing a broad age range of 5-to-17-year-old children (8 OT / 10 placebo) with Phelan-McDermid syndrome (characterized by ASD symptoms; Fastman et al, 2021). Also, in a recent confirmatory trial including 3-to-17-year-old children with ASD (139 OT / 138 placebo) and an age-adjusted dosing scheme ranging from 8-80 IU, no improvements on outcomes of social functioning were evident after 24 weeks of OT treatment (Sikich et al, 2021).…”

Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome

“…Thus, individuals with high ABC-SW scores display reduced levels of expression for these genes. Given the interest in the ABC-SW as a clinical outcome assessment of treatment efficacy in clinical trials of PMS, 68 , 69 peripheral biomarkers that scale ABC-SW severity may serve as a valuable resource to monitor treatment responses and outcomes in PMS and other disorders that present with social withdrawal phenotypes. However, further follow-up of these genes and their dynamic expression profiles following administration of such therapeutic agents is warranted.…”