Monday, October 25, 2021

Intranasal oxytocin in children and adolescents with autism spectrum disorder

Linmarie Sikich,  Alexander Kolevzon, Bryan H. King,  Christopher J. McDougle, Kevin B. Sanders, Soo-Jeong Kim, Marina Spanos, Tara Chandrasekhar, M.D. Pilar Trelles, Carol M. Rockhill, Michelle L. Palumbo, Allyson Witters Cundiff, et al. Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder. N Engl J Med 2021; 385:1462-1473DOI: 10.1056/NEJMoa2103583    





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. 


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. 


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. 


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. 

Courtesy of:   


Daniel H. Geschwind. Oxytocin for Autism Spectrum Disorder — Down, but Not Out. N Engl J Med 2021; 385:1524-1525 DOI: 10.1056/NEJMe2110158   


Autism spectrum disorder, a common neurodevelopmental disorder with onset in infancy, is characterized by deficits in social functioning and by repetitive–restrictive behaviors, such as repeated body movements, circumscribed interests, or resistance to change in routines. Pharmacologic interventions are limited to the treatment of symptoms, which does not target social deficits. Although behavioral treatments have been effective in improving social and educational outcomes in some persons with autism spectrum disorder, there remains a need for the development of drugs that improve social functioning. The potential of the neuropeptide oxytocin as a “pro-social” hormone has gained attention for the treatment of autism spectrum disorder. Some research suggests that oxytocin modulates the salience and reward properties of social stimuli in animals and humans; however, its effects are diverse and dependent on species, sex, and social context. 

In this issue of the Journal, Sikich et al. present the results of a double-blind, placebo-controlled trial of intranasal oxytocin, administered up to twice daily, in children and adolescents with autism spectrum disorder — the Autism Centers of Excellence Network Study of Oxytocin in Autism to Improve Reciprocal Social Behaviors (SOARS-B). The premise of this trial is based on a reasonably strong mechanistic hypothesis that “[autism spectrum disorder]…decreases the relative value ascribed to social rewards, resulting in limited social motivation” and that oxytocin will increase social reward. The trial design permits the study of potential drivers of variation in outcomes, including oxytocin serum or saliva concentrations and genetic markers that were not reported in this article but that may be assessed in future analyses. The trial involved a large population of children and adolescents, 3 to 17 years of age; frequent evaluations with the use of several scales of social cognition and behavior were conducted, and the trial regimens were all designed to mirror community practice and previous smaller trials. 

Despite these strengths, there was no effect of intranasal oxytocin therapy on the primary outcome — the change in the score on a modified version of the Aberrant Behavior Checklist Social Withdrawal subscale — or on any other measures of social behavior. The inclusion of the participants’ baseline plasma oxytocin levels as a covariate in the analysis did not alter the results. Furthermore, the placebo effect in the trial was small and did not obscure a potential signal of the benefit of treatment. 

What can we conclude from this well-powered, carefully conducted trial? First, we see that oxytocin as administered in previous clinical studies and trials and in a method similar to most off-label use in clinical practice did not improve social function in a generalizable population of persons with autism spectrum disorder. These results do not support the current off-label use of oxytocin in the treatment of autism spectrum disorder. 

Nevertheless, it may be premature to summarily reject the oxytocin signaling pathway (or efforts to increase social motivation in general) as a potential treatment target in autism spectrum disorder. Potential mitigating factors in interpreting the trial results include the following: the age range of the persons studied, particularly around dynamic periods of development, given that the physiologic effects of oxytocin differ over developmental stages and that there may be critical windows for treatment effects; the likely short half-life of oxytocin activity in the brain, which potentially limits the effectiveness of even sustained twice-daily administration; and the insensitivity of current measures to capture social motivation, even though they represent the current standard. In this regard, social dysfunction in autism spectrum disorder is heterogeneous, and human social behavior has many components. There is a need to learn more about the neurobiologic basis of complex social behavior and to create measures that can be used effectively to evaluate its components in clinical trials. 

Moreover, the drug was administered without concomitant standardized behavioral intervention for social skills. Should we expect that increasing motivation alone, without contemporaneous behavioral intervention, would lead to ongoing improvements in social function? Motivation is just one component of the social behavior equation. An analogy would be an attempt to build athletic prowess by the administration of anabolic steroids without simultaneous rigorous physical training. Given these uncertainties and the short half-life of oxytocin, clinical efficacy may require drug administration that is temporally coupled with behavioral intervention. 

Finally, autism spectrum disorder is genetically heterogeneous, including contributions from more than 100 genes with rare mutations with potentially distinct pathophysiological characteristics that may have an effect on treatment responses. Studies of single-gene mutations in mouse models that are based on rare genetic forms of autism spectrum disorder have shown unexpected connections to the oxytocin system. These findings include the reversal of social behavioral deficits by the intranasal administration of oxytocin in mice with POGZ and CNTNAP2 mutations, which supports the hypothesis that certain forms of autism spectrum disorder with deficits in oxytocin-related pathways may be treatable and suggests windows in development during which oxytocin therapy may be effective. However, whether this is applicable to autism spectrum disorder in humans is not clear. Looking ahead, as we enter the era of precision medicine in which treatment may be based on genetically informed disease mechanisms, the hope is that we can leverage genetic and molecular biomarkers in trial design and patient selection to improve outcomes in autism spectrum disorder and other neurodevelopmental disorders. 







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