A pharmacogenetic study of escitalopram in autism spectrum disorders

Abstract

Scientific AbstractObjective-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).Method-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-There was an interaction between genotype group and time on the Aberrant Behavior Checklist Irritability Subscale (primary outcome variable) (linear MMLE = −4.84, Z = −2.89, SE = 1.67, p = 0.004). Examination of baseline to last-observation carried forward scores revealed that a genotype grouping based on a previous study of platelet 5-HT uptake revealed less response in the genotype group that had S/S genotype for 5-HTTLPR and did not have a diplotype in intron 1 previously shown to be associated with increased platelet 5-HT uptake.Conclusion-This genotype-blind, prospective pharmacogenetic study found the group of subjects with associated with the lowest platelet 5-HT uptake from previous study had the smallest reduction in ABC-Irritability scores after open label treatment with escitalopram. Replication is necessary to confirm these findings.Lay Abstract-Many children with Autism Spectrum Disorders have problems with anxiety, obsessions, compulsions, and insisting that things stay the same. When other interventions are not adequately helping the child deal with these difficulties, sometimes medication is considered a treatment option. There continues to be some difficulties associated with the use of SSRIs for a substantial proportion of individuals. A substantial minority of children with ASDs will become activated (drug-induced insomnia, hyperactivity, and/or general disinhibition) on these medications, even at low doses McDougle et al., 2000;Owley et al., 2005). Dosing is also complicated by the fact that there appears to be no relationship between weight and final dose, and only a weak correlation between age and final dose (Owley et al., 2005).A pharmacogenetic study was conducted to determine if variation in the gene that codes for the primary protein target of SSRIs, the serotonin transporter, would be related to escitalopram response or final dose. A complex insertion/deletion/single nucleotide containing polymorphism in the promoter region of the transporter (5-HTTLPR), thought be related to 5-HTT gene expression, was chosen as the primary candidate polymorphism (Heils et al., 1996;Hu et al., 2006).Only one study has looked at the SSRI treatment as a function of 5-HTTPLR in ASDs. In a double-blind study of outcome using the SSRI fluvoxamine in a group of 18 children diagnosed with autism using DSM-IV (APA, 1994) criteria only, Sugie and colleagues (Sugie et al., 2005) found the L/L and S/L groups to have superior ou...

Pharmacogenetic Study of Serotonin Transporter and 5HT2A Genotypes in Autism

“…In contrast, participants in the SS group showed significant improvement in delayed speech or peculiar or inappropriate speech. In an open label study (blind to genotype) with escitalopram (n = 58), the LL and SL groups showed a greater reduction in the Aberrant Behavior Checklist-Irritability factor (Aman et al 1985) scores than did the SS group (Owley et al 2010). The direction of these findings is generally consistent with those found in pharmacogenetic studies of major depressive disorder (Serretti et al 2007).…”

“…Our study is the first study to look at the response to SSRI in ASD as a function of both 5HTTLPR and HTR2A genotypes. Owley et al (2010) observed smaller decreases (less response) in irritability on the ABC-CV in the 5HTTLPR SS group than in the SL and LL groups. Sugie et al (2005) not only identified that subjects with SS genotypes had less response as measured by the CGI Severity scale, but also that the S allele was associated with significant improvement in language on the Behavioral Assessment Scale (BAS).…”

“…The reasons for this are unclear. However, our study sample represented slightly older patients than those in the previous studies, and had a higher proportion of subjects of non-Western European ancestry than the Owley et al (2010) study, and a higher proportion of subjects of Western European ancestry than Sugie et al (2005), who examined Japanese patients. Additionally, baseline irritability symptoms were lower in the 5HTTLPR not-SS group, which may have influenced the trajectory of response in that measure, and the magnitude of change that was observed over time.…”

“…Two previous studies (Sugie et al 2005;Owley et al 2010) have also investigated response to SSRIs in ASD as a function of genetic variation. These investigations only examined the 5HTTLPR.…”

The Autism Treatment Network and Autism Intervention Research Network on Physical Health: Future Directions

“…For example, studies using pharmacogenomics and clinical trials would allow clinicians todetermine which medication in a certain class would be best for treating specific symptoms. 8,9 …”