Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD

Mol Psychiatry. 2018 Sep;23(9):1929-1936. doi: 10.1038/mp.2017.234. Epub 2017 Dec 12.

Abstract

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 interaction with dopaminergic, adrenergic and serotonergic system components; it is therefore likely that catecholaminergic molecular components influence the effects of ADHD treatment. Using meta-analysis, we sought to identify predictors of pharmacotherapy to further the clinical implementation of personalized medicine. We identified 36 studies (3647 children) linking the effectiveness 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 (OR): 1.40; confidence interval: 1.04-1.87), rs5569 SLC6A2 (odds ratio: 1.73; confidence interval: 1.26-2.37) and rs28386840 SLC6A2 (odds ratio: 2.93; confidence interval: 1.76-4.90), and, repeat variants variable number tandem repeat (VNTR) 4 DRD4 (odds ratio: 1.66; confidence interval: 1.16-2.37) and VNTR 10 SLC6A3 (odds ratio: 0.74; confidence interval: 0.60-0.90), whereas the following variants were not statistically significant: rs1947274 LPHN3 (odds ratio: 0.95; confidence interval: 0.71-1.26), rs5661665 LPHN3 (odds ratio: 1.07; confidence interval: 0.84-1.37) and VNTR 7 DRD4 (odds ratio: 0.68; confidence interval: 0.47-1.00). Funnel plot asymmetry among SLC6A3 studies was identified and attributed largely to small study effects. Egger's regression test and Duval and Tweedie's 'trim and fill' were used to examine and correct for publication bias. These findings have major implications for advancing our therapeutic approach to childhood ADHD treatment.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Attention Deficit Disorder with Hyperactivity / drug therapy
  • Attention Deficit Disorder with Hyperactivity / genetics*
  • Biomarkers, Pharmacological / blood
  • Catechol O-Methyltransferase / genetics
  • Catechol O-Methyltransferase / metabolism
  • Child
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Female
  • Genotype
  • Humans
  • Male
  • Methylphenidate / pharmacology*
  • Minisatellite Repeats
  • Norepinephrine Plasma Membrane Transport Proteins / genetics
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Receptors, Dopamine D4 / genetics
  • Receptors, Dopamine D4 / metabolism
  • Treatment Outcome

Substances

  • ADRA2A protein, human
  • Biomarkers, Pharmacological
  • DRD4 protein, human
  • Dopamine Plasma Membrane Transport Proteins
  • Norepinephrine Plasma Membrane Transport Proteins
  • Receptors, Adrenergic, alpha-2
  • SLC6A2 protein, human
  • SLC6A3 protein, human
  • Receptors, Dopamine D4
  • Methylphenidate
  • COMT protein, human
  • Catechol O-Methyltransferase