International Meeting for Autism Research (May 7 - 9, 2009): A Pharmacogenetic Study of Escitalopram in Autism

A Pharmacogenetic Study of Escitalopram in Autism

Friday, May 8, 2009
Northwest Hall (Chicago Hilton)
12:00 PM
T. Owley , Psychiatry and Pediatrics, University of Illinois at Chicago, Chicago, IL
C. Brune , Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL
J. Salt , Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL
L. Walton , Psychiatry, University of Illinois at Chicago, Chicago, IL
S. J. Guter , Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL
N. Ayuyao , Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL
R. Gibbons , Statistics, University of Illinois at Chicago, Chicago, IL
B. Leventhal , Psychiatry, University of Illinois at Chicago, Chicago, IL
E. H. Cook , Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL
Background: The Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders characterized by qualitative impairments in reciprocal social interactions, language and communication, and the presence of restricted, repetitive, and stereotyped behaviors and interests. The definitive usefulness of selective serotonin reuptake inhibitors in this population has not been determined, but some studies have suggested that SSRIs may be useful in the treatment of certain symptoms of subjects with ASDs. These symptoms include repetitive behaviors, anxiety, irritability, aggression and self-injurious behavior and more global behavior. In an attempt to determine who might have a positive response to medication, as well as help discover better dosing strategies and predict adverse effects, this study used a pharmacogenetic approach to these questions. The serotonin transporter (5-HTT) was focused on as a logical possible determinant of outcome for two reasons. First, the primary site of action of the SSRIs is the 5-HTT, where these medications act to decrease the reuptake of serotonin, increasing serotonergic signaling at the synapse. Second, polymorphisms in the promoter region of the transporter (5-HTTLPR) have been discovered that are thought to be play an important role in 5-HTT gene expression. Objectives: To assess the effect of escitalopram and to determine the effect of serotonin transporter polymorphism promoter region (5-HTTPLR) genotypic variation (low, intermediate, and high expression groups) on response to escitalopram treatment of children and adolescents with Autism Spectrum Disorders (ASDs). Methods: The study used a forced titration, open label design, with genotype blind until study completion. Participants were children and adolescents aged 4 to 17 years of age with a confirmed ASD (Autistic Disorder, Asperger’s Disorder, or Pervasive Developmental Disorder, Not Otherwise Specified). Results: The interaction between genotype groups and time on the Aberrant Behavior Checklist Irritability Subscale (primary outcome variable) showed a significant decrease (improvement) in scores for the intermediate and high expression genotype groups compared to the low expression group (s/s 5-HTTLPR genotype) (MMLE = -4.84, Z = -2.89, SE = 1.67, p = 0.004) followed by a plateau in ratings for all groups (MMLE = 2.01, Z = 3.09, SE = 0.65, p = 0.002). Refined expression groups based on diplotypes including intron 1 markers further clarified the low expression group and response to treatment. Conclusions: This genotype-blind, prospective pharmacogenetic study found the following differences in response as a function of 5-HTTLPR genotype: 1) The group of subjects with higher expressing 5-HTTLPR genotypes had a better response to pharmacotherapy than subjects with a low expressing genotype group and 2) there was a difference in the final dose by genotype groupings, with the lowest expressing genotype group having a lower final dose when compared with higher expressing genotype groups.
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