Pharmacogenetic moderators of methylphenidate and guanfacine response in children and adolescents with adhd

Abstract

Background: Pharmacogenetic influences may explain differential response to commonly prescribed psychiatric medications. The consideration of pharmacogenetic factors has shown clinical utility in medical specialties such as oncology, cardiovascular medicine, and pulmonology, improving patient outcomes and reducing morbidity. An expanded understanding of pharmacodynamic factors moderating response to psychiatric medications will allow rapid treatment matching, avoid morbidity, and guide the design of novel therapeutics. While methylphenidate and guanfacine are effective treatments of hyperactive and inattentive symptoms associated with ADHD, variability in individual treatment response is substantial. We sought to determine whether genetic variation in monoamine drug targets could help explain variable treatment outcomes in a randomized, double-blind, placebo-controlled trial of dexmethylphenidate (d-MPH) and guanfacine for pediatric ADHD. Methods: Subjects were recruited for Project I of the NIMH CIDAR Translational Research to Enhance Cognitive Control (TRECC) Center at UCLA, which aims to develop treatments that specifically remediate executive function deficits as an important path to improve outcomes. Project I was designed to test the short-term efficacy of d- MPH and guanfacine combination pharmacotherapy against standard stimulant or guanfacine monotherapy on both symptom and cognitive endpoints. We further examined the contribution of genetic variation in monoamine candidates on treatment response using the standardized ADHD-Rating Scale IV (ADHD-RS) in this carefully phenotyped sample (n=202). Complete common variation in dopaminergic and adrenergic drug targets was queried, including dopamine (DA) receptors D1-D5 (DRD1, DRD2, DRD3, DRD4, DRD5), alpha-2 adrenergic receptor 2A (ADRA2A), and catabolic enzymes monoamine oxidase A (MAO-A) and B (MAO-B). Known functional and previously associated variants in the DA transporter (SLC3A6), norephinephrine transporter (SLC2A6) and catabolic enzyme catechol- o-methyltransferase (COMT) were also genotyped. Variants were selected using HapMap to identify tag SNPs (tSNPs) that capture the common variability above 10% allele frequency at a minimum r2 of 0.8. Genotyping was performed on the Life Technologies' TaqMan genotyping platform. Results: In children receiving d-MPH, two SNPs in DRD2 and a single ADRA2A variant predicted treatment response. None of the 7 homozygotes for the minor allele of a synonymous SNP (His313His, rs6275) met responder criteria, compared to an 80% response rate in 47 common allele carriers (p=0.0001). The minor (low expression) allele of the DRD2 Taq1A variant (rs1800497) was associated with an allele dosage-dependent improvement in both groups receiving d-MPH, either alone or in combination with guanfacine (p=0.001). Furthermore, haplotypes defined by these 2 DRD2 SNPs showed differential effects on treatment response (p=0.0017). Finally, the minor allele of an ADRA2A promoter variant (rs521674) was associated with poor d- MPH response (p=0.0004). Guanfacine response was predicted by homozygosity for the minor alleles (p<0.0001) of functional variants in DRD1 (rs686) and DRD2 (rs2075654). Conclusions: Common genetic variation in dopaminergic and adrenergic receptors influenced treatment response to standard ADHD drug therapies in our dataset. These results survive correction for multiple testing (adjusted significance threshold p<0.002), and many of these variants have been shown to impact gene expression in functional assays. Monoaminergic candidate genes have been previously examined and received support in small studies of treatment response, though previous studies have not comprehensively evaluated these gene loci. Our study benefits from a randomized, double-blind, placebo-controlled design, an exhaustive genetic approach, a moderate size treatment sample, repeated outcome measures, and the focus on children and adolescents. Pediatric samples may provide additional power given reduced treatment history, comorbidity (including substance use), and polypharmacy. Our results show promise for eventual personalization of ADHD treatment algorithms and warrant replication in larger samples and prospective treatment studies