Epigenetics of Methylphenidate Adverse Effects and Pharmacokinetics in Children with ADHD
Principle Investigator: Tanya Froehlich, MD, MS
Robust data support the American Academy of Pediatrics’ recommendation to prescribe stimulant medications as first-line treatment for Attention Deficit Hyperactivity Disorder (ADHD). The stimulant methylphenidate (MPH) is the most commonly prescribed ADHD medication worldwide with more than10 million MPH prescriptions dispensed at U.S. pharmacies in 2010 to children. Unfortunately, when MPH is prescribed, there is marked individual variability in adverse effects with no consistent predictors of those effects. Since adverse effects are the leading reason that families stop using stimulant medications, this dosing strategy leads to many children NOT receiving the most effective ADHD treatment available.
One strategy for understanding individual variability is to identify genetic moderators of adverse effects. But to make more rapid progress, an expanded perspective on pharmacogenomics is required. Specifically, gene expression regulation through epigenetic mechanisms plays an important role in drug response via influencing drug absorption, metabolism and distribution as well as drug targets. Since epigenetic studies have improved our understanding of ADHD etiology, we propose that they will be useful in predicting and understanding ADHD medication response.
Therefore, we are testing for associations between baseline whole-blood DNA methylation at CpG sites proximal to candidate genes for the MPH adverse effects of appetite suppression, sleep problems, and irritability. In addition, we are looking for an association between epigenetic profiles and MPH plasma levels in a group of MPH responders to determine if methylation profiles at CpG sites proximal to CES1 (the enzyme which metabolizes MPH) will be linked to specific MPH pharmacokinetic profiles and if those will mediate the association between CES1 methylation profiles and MPH adverse effects.