A pharmacogenetic study of escitalopram in autism spectrum disorders

The Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders characterized by qualitative impairments in reciprocal social interaction, language and communication, and the presence of restricted, repetitive, and stereotyped behaviors and interests (APA, 1994). It has been suggested that selective serotonin reuptake inhibitors (SSRIs) may be useful in the treatment of certain symptoms of subjects with ASDs (Posey, Erickson, Stigler, & McDougle, 2006) including repetitive behaviors (Hollander et al., 2005; McDougle, Epperson, Price, & Gelernter, 1998; McDougle et al., 1996), anxiety (Buchsbaum et al., 2001), irritability (Owley et al., 2005), aggression and self-injurious behavior (Hellings, Kelley, Gabrielli, Kilgore, & Shah, 1996), and more global behavior (Cook, Rowlett, Jaselskis, & Leventhal, 1992; DeLong, Ritch, & Burch, 2002; Namerow, Thomas, Bostic, Prince, & Monuteaux, 2003; Sugie et al., 2005). However, a recent large controlled trial study by King and colleagues (2009) did not find a reduction in repetitive behaviors by citalopram. 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 (Cook et al., 1992; 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 outcomes compared to subjects in the S/S group. With some exceptions, this finding was in keeping with the studies that had been done examining pharmacogenetic outcomes of SSRIs and 5-HTTPLR in major depression (Kirchheiner, Grundemann, & Schomig, 2006). A previous study by our laboratory revealed that subjects homozygous for a TT diplotype in intron 1 of the serotonin transporter gene who had S/S or S/L genotypes had higher functional uptake more consistent subjects with the L/L genotype (Cross et al., 2007). More recently, a common functional A > G variant found predominately on the L 5HTTLPR allele was characterized (Hu et al., 2006). This LG allele reduces messenger RNA levels to levels very similar that found in the S allele. We have previously reported an open label study of escitalopram in subjects with ASDs (N= 28), in which clinical data were collected independent of genotype (Owley et al., 2005). With the strong qualifier that pertains to open label trials in this population, those data indicated improvement of some symptoms associated with ASDs. In particular, the primary outcome variable, changes in the Irritability Subscale of the Aberrant Behavior Checklist-Community Version (ABC-CV), was reduced (p < 0.001) compared to baseline. The current manuscript extends this study to report on a total of 58 subjects with ASDs between the ages of 5 and 17, who received an SSRI, escitalopram, in a prospective, 10-week, forced titration design. The study was open-label in terms of medication, but all participants and investigators were blind to genotype until all clinical data had been collected. Our primary hypotheses were 1) genotype group would be related to response of ABC-Irritability scores after escitalopram, and 2) genotype group would be related to final dose with the lowest expressing genotype group having a lower final dose when compared with higher expressing genotype groups.