A Pilot Study of Oxytocin in Children and Adolescents with Autistic Disorder

Friday, May 18, 2012
Sheraton Hall (Sheraton Centre Toronto)
9:00 AM
L. Sikich1,2, T. C. Bethea1,2 and C. Alderman2, (1)Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, (2)Department of Psychiatry, ASPIRE Research Program, UNC-CH, Chapel Hill, NC
Background:  Oxytocin and high densities of oxytocin receptors in the nucleus accumbens have been implicated in bonding, prosocial behaviors, social memories and social rewards
in primate and nonprimate animals.  Mice with reduced or absent levels of oxytocin receptor gene (OXTR) expression show reduced social responses to separation from the mother as infants with less remarkable social differences seen in older animals.  Given the critical importance of aberrant social interactions and reciprocity in autism symptomatology, several investigators have examined the oxytocin gene (OXT) and oxytocin receptor gene (OXTR) among people with autism.  Oxytocin plasma levels are reduced in some individuals with autism.  Recent work suggests associations between the chromosomal region containing OXTR and autism in multiple populations.  Individuals with autism who have deletions in OXTR have been identified.  One study revealed epigenetic modification of OXTR (e.g. greater methylation of the promoter and intron 3) in 20 individuals with autism (~70%) as compared to 20 controls (~40%) and replicated this finding in postmortem temporal cortex samples from 4 individuals with autism.

Objectives: Our study is highly innovative in that it combines efforts to advance our understanding of the epigenetic phenomena of OXTR methylation in autism, to develop proof of concept
data for translating these findings into useful biomarkers of diagnostic homogeneity and/or oxytocin treatment response, and to obtain pilot data that is essential to design and implement
a pivotal trial of supplemental oxytocin therapy in autism.

Methods:  Twenty-four youths between the ages of 3-17 year old with autistic disorder were randomized to 2 months of treatment with intranasal oxytocin or placebo.  Subsequently all participants will receive open-label oxytocin for 2 additional months.  Oxytocin will be titrated weekly to target doses of 24IU or 32IU depending on age and tolerability.  Safety assessments include systemic adverse event surveillance, electrocardiograph, vital signs and electrolytes.  Efficacy outcomes include behavioral and developmental assessments including the clincal global impression scale, social reciprocity scale, Vineland adaptive behaviors, pervasive developmental disorder behavioral inventory, caregiver strain questionnaire, aberrant behavior checklist and Stanford-Binet.  Post-treatment assessments will be done 3-15 months after treatment is discontinued.  We will also determine OXTR methylation status at baseline to explore potential relationships with baseline severity of social problems and treatment response.

Results:  Enrollment goal met in October 2011.  All youth will complete treatment by March 2012 when initial study outcomes and OXTR data will be available. Mean age of currently randomized participants (n=15)  is 10.0 (SD 4.1) yrs range 3 -18 years, mean ABC-SW score is 11.3 (SD 7.8) range 2-33, 53% are nonverbal and 60% have intellectual disability.  

Conclusions:  We anticipate that oxytocin will be safe and well-tolerated for sustained treatment of youth with autism and may become the first agent with clinically important efficacy for core social impairment.

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