Despite progress in pediatric attention-deficit/hyperactivity disorder (ADHD) research over the past decade, no one genetic variant or currently available pharmacogenomics test has predicted with precision which ADHD medications will be most effective for individual patients, according to a review article published in CNS Drugs.
The determination of an ADHD treatment regimen can be time-consuming, requiring gradual upward dose titration and trial and error and often resulting in delays in symptom remission, premature termination of treatment, and frustration. Pharmacogenomics has called attention to a growing interest in examining how an individual’s genetic makeup influences responsiveness to treatment.
Researchers from the division of developmental and behavioral pediatrics at Cincinnati Children’s Hospital Medical Center in Ohio searched PubMed and PsycINFO databases for ADHD pharmacogenomics efficacy studies published between 2009 and 2019. Criteria included studies that enrolled patients age <18 years and that assessed improvements in symptoms or global functioning with medical treatment or used direct observations of inattention or activity level. The studies focused primarily on pharmacodynamic candidate gene investigations of methylphenidate (MPH) response, with a smaller number that addressed atomoxetine (ATX) response, and few to none that evaluated amphetamine, guanfacine, and clonidine.
Recent meta-analyses have reported a small but significant impact on MPH efficacy of variants in the dopamine transporter (DAT/SLC6A3), dopamine receptor D4 (DRD4), adrenergic α2A-receptor (ADRA2A), catechol-O-methyltransferase (COMT), and norepinephrine transporter (NET/ SLC6A2) genes, but results have lacked consistency. Clinical Pharmacogenetics Implementation Consortium guidelines have also been published, which have provided some recommended variations in ATX dosing based on cytochrome P450 2D6 (CYP2D6) genotype. However, to date, the field has yet to identify optimal ADHD medications for individual patients.
The researchers cited a “myriad [of] factors underlying this impasse — including the small effects of individual genetic variants, study design weaknesses and inconsistencies, lack of confirmatory studies in different racial/ethnic populations, and failure to consider gene–gene interactions — which should be addressed when undertaking future ADHD [attention deficit hyperactivity disorder] pharmacogenomics research.”
Elsayed NA, Yamamoto KM, Froehlich TE. Genetic influence on efficacy of pharmacotherapy for pediatric attention-deficit/hyperactivity disorder: overview and current status of research [published online March 4, 2020]. CNS Drugs. doi:10.1007/s40263-020-00702-y