The impact of individual and methodological factors in the variability of response to methylphenidate in ADHD pharmacogenetic studies from four different continents

Abstract

Several studies have evaluated the association between individual polymorphisms and response to methylphenidate (MPH) in subjects with attention-deficit/hyperactivity disorder (ADHD). There are few replication studies for each polymorphism of interest and results are sometimes inconsistent in this field. Although data collection from multiple international sites would allow large sample sizes, this approach has been criticized for introducing sampling variability due to differences in ethnicity and methodology between studies. To examine these issues, we aggregated nine pharmacogenetic studies from four different continents and conducted a two stage analysis: a) we evaluated the role of methodological aspects in the variability of ADHD symptom improvement between studies using meta-regression analysis; b) we assessed the role of individual characteristics of the subjects in the variability of ADHD symptoms improvement using multivariate regression analysis in the same data sets. At the study level, from five evaluated factors, only the design of the study (open studies versus randomized controlled trials) was significantly associated with heterogeneity of results (p=.001). At the individual level, age (p<. 001), comorbid oppositional defiant disorder (p<.001), and pre-treatment scores (p<.001) were associated with change of ADHD scores with treatment in the final multivariate model. Our results suggest that joint analyses of pharmacogenetic studies are feasible and promising, since fixed variables, such as the site where the study was conducted, were not related to results. Nevertheless, stratified analyses according to the design of the study must be preferentially conducted and the role of individual factors such as demographic data and comorbid profile as confounders should be assessed.

Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD

“…Similar differences of pharmacogenetic effects in ADHD-treated subjects between randomised clinical trials and naturalistic studies have been reported previously. 27 As randomised clinical trials control for placebo effects by including a control group, they are generally considered to be the superior experimental approach to the investigation of pharmacological effects. Even if in the case of the presented pharmacogenetic studies potential placebo effects Overall, however, these results suggest that the often-examined 40 bp VNTR in the 3 0 -untranslated region of the SLC6A3 gene does not significantly relate to quantitative measures of treatment success with methylphenidate in ADHD, with the exception of studies using naturalistic designs.…”

“…26 The reasons for this response variability among patients are unclear, but are likely to be multifactorial. Although interstudy methodological issues may play a role for observed variability in the literature, 27 the present study aims to clarify the role of pharmacogenetics in interindividual response variability. Pharmacogenetics refers to the association between genetic variation and the magnitude of response to treatment.…”

“…Additionally, there have been a number of studies investigating (1) an aetiological role of SLC6A3 in ADHD, 2 (2) dopamine transporter availability in ADHD 43 and (3) the association between the SLC6A3 VNTR and dopamine transporter availability in human striatum. 40 Although some studies have shown that the 9R allele is associated with better clinical response to methylphenidate, 27,[44][45][46][47] other studies have shown the opposite pattern [48][49][50] or have failed to observe a significant effect. [51][52][53][54][55][56][57][58][59] A recent review has summarised the literature on this topic and an early meta-analysis of six studies in childhood ADHD reported that 10R homozygotes showed poor methylphenidate response.…”

Progress and Promise of Attention-Deficit Hyperactivity Disorder Pharmacogenetics

“…Variations in study design may be partially responsible for the disparate findings, since a recent meta-analysis of ADHD pharmacogenetics investigations determined that the design of the study (open-label studies vs. randomized controlled trials) was significantly associated with heterogeneity of results. [47] Concerns raised regarding retrospective, observational pharmacogenetic studies have included biased ascertainment of outcome,[48] as well as a tendency to underestimate environmental contributions and overestimate genetic effects. [49] Therefore, in this article, results of double-blind, placebo-controlled trials are presented separately from those of naturalistic studies for each genetic polymorphism.…”

Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

“…There are concerns that small sample sizes, study design variations (open-label vs. randomized controlled trials), outcome measure differences, sample differences, and varying dosing regimens may be partially responsible for the disparate findings to date. 8,9,41,42 For example, only three ADHD pharmacogenetic studies in school-age children have been randomized, placebo-controlled, and double-blinded. 18–20 Only two school-age 19,33 and one preschool trial 32 have used parent and teacher outcome ratings.…”