LAUSR

Background Stimulant medication has long been effective in treating Attention-Deficit Hyperactivity Disorder (ADHD) and is currently the first line pharmacological treatment for children. Both methylphenidate and amphetamine modulate extracellular catecholamine levels through interactions with dopaminergic, adrenergic, and serotonergic system components; it is therefore likely that catecholaminergic molecular components influence the effects of ADHD treatment. Methods We conducted a PubMed search to identify all peer-reviewed publications examining efficacy response to methylphenidate in the treatment of childhood ADHD. Using meta-analysis, we sought to identify predictors of pharmacotherapy to further the clinical implementation of personalized medicine. We used meta-regression to examine the effects of gender ratios, cohort ethnicity, study quality, and mean participant age. Egger's test and Duval and Tweedie's 'trim and fill' were used to examine and correct for publication bias. Results We identified 35 studies (3,698 children) linking the efficacy of methylphenidate treatment with DNA variants. Pooled-data revealed a statistically significant association between Single Nucleotide Polymorphisms (SNPs) rs1800544 ADRA2A (odds ratio: 1.69; confidence interval 1.12–2.55), rs4680 COMT (odds ratio: 1.40; confidence interval: 1.04–1.87), rs5569 SLC6A2 (odds ratio: 1.71; confidence interval 1.22–2.38), and, repeat variants VNTR 4 DRD4 (odds ratio: 1.64; confidence interval: 1.15–2.33), VNTR 7 DRD4 (odds ratio: 1.47; confidence interval: 1.00–2.15), and VNTR 10 SLC6A3 (odds ratio: 1.26; confidence interval: 1.11–1.67), whereas the following variants were not statistically significant: rs1947274 LPHN3 (odds ratio: 0.95; confidence interval: 0.71–1.26) and rs5661665 LPHN3 (odds ratio: 1.07; confidence interval: 0.84–1.37). Funnel plot asymmetry amongst SLC6A3 studies was identified and attributed largely to small study effects. Discussion This meta-analysis supports an association between genetic variants - within the ADRA2A, COMT, SLC6A2, and DRD4 genes - and efficacy response to methylphenidate for the treatment of childhood ADHD. These findings have major implications for advancing our therapeutic approach to childhood ADHD treatment.