title: Norepinephrine transporter -3081(A/T) and alpha-2A-adrenergic receptor MspI polymorphisms are associated with cardiovascular side effects of OROS-methylphenidate treatment.
abstract: The purpose of this study was to investigate a possible association between norepinephrine genes and cardiovascular side effects of the Osmotic Controlled-Release Oral Delivery System-methylphenidate (OROS-MPH) in Korean children with attention-deficit/hyperactivity disorder (ADHD). One hundred and one children with ADHD (8.7 ± 1.7 years) were recruited from child psychiatric centers at six university hospitals in South Korea. All participants were drug-naive ADHD children treated with OROS-MPH for 12 weeks. During the treatment period the investigators titrated the OROS-MPH dosage on the basis of symptom severity and side effects. Resting heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were examined before and after treatment. The percentage change score (post-treatment - pretreatment/pretreatment × 100) of each parameter was calculated. Genotyping of SLC6A2 -3081(A/T) and G1287A, and alpha-2A-adrenergic receptor (ADRA2A) MspI and DraI polymorphisms was performed. Clinically significant changes were not found in cardiovascular monitoring during the course of treatment. An increase of HR after OROS-MPH treatment was found to be statistically significant (t = 3.54, p = 0.001). Changes in SBP and DBP were not significant and no specific change was found in the ECGs. However, an additive regression analysis demonstrated a significant association between SLC6A2 -3081(A/T) and percentage change in HR post-treatment (p = 0.01) after controlling for age, gender, dosage of MPH and response and baseline pulse rate. Children with ADHD having the T/T genotype of SLC6A2 showed a 12.5% increase in HR compared to baseline, whereas children with the A/T or A/A genotype showed a 3.5% and 2.5% increase after OROS-MPH treatment, respectively. There was also a significant association between the ADRA2A MspI genotype and percentage change of DBP post-treatment after controlling for age, gender, dosage of MPH and response and baseline DBP (p = 0.009). Children with ADHD having the C/C genotype of ADRA2A MspI showed an 18.5% increase in DBP compared to baseline, but children with the G/G or G/C genotype showed a 0.2% decrease after OROS-MPH treatment. The overall cardiovascular effects of OROS-MPH were modest. However, our findings show a positive association between norepinephrine-related gene polymorphisms and cardiovascular response induced by MPH in Korean children with ADHD. Consideration must be given to such children or adults with specific norepinephrine-related genotypes, especially if they show significant changes in HR or DBP after OROS-MPH administration.
authors.affiliation: Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University, College of Medicine, Seoul, South Korea.
authors.forename: Soo-Churl
authors.initials: SC
authors.lastname: Cho
authors.forename: Bung-Nyun
authors.initials: BN
authors.lastname: Kim
authors.forename: Tarrant D R
authors.initials: TD
authors.lastname: Cummins
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bellgrove
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000150:complications / Q000188:drug therapy; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000150:complications / Q000235:genetics*; D002648:Child; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D039721:Diagnostic and Statistical Manual of Mental Disorders; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D016903:Drug Monitoring; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D056726:Genetic Association Studies; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007723:Korea; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: C547768:ADRA2A protein, human; D003692:Delayed-Action Preparations; D018765:Dopamine Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018341:Receptors, Adrenergic, alpha-2; C493227:SLC6A2 protein, human; D008774:Methylphenidate