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Pharmacogenetics of methylphenidate response and tolerability in attention-deficit/hyperactivity disorder

Abstract

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder. However, a considerable interindividual variability exists in clinical outcome, which may reflect underlying genetic influences. We analyzed 57 single-nucleotide polymorphisms in 9 dopamine-related candidate genes (TH, DBH, COMT, DAT1 and DRD1-5) as potential predictors of MPH efficacy and tolerability, and we considered prenatal and perinatal risk factors as environmental hazards that may influence treatment effects in a gene-by-environment analysis. Our results provide evidence for the contribution of DRD3 (P=0.041; odds ratio (OR)=4.00), DBH (P=0.032; OR=2.85), TH (P=5.5e-03; OR=4.34) and prenatal smoking (P=1.7e-03; OR=5.10) to the clinical efficacy of MPH, with a higher risk for treatment failure in genetically susceptible subjects whose mother smoked during pregnancy. Adverse events after MPH treatment were significantly associated with variation in DBH (P=6.4e-03; OR=0.28) and DRD2 (P=0.047; OR=3.76). This study suggests that the dopaminergic system together with prenatal smoking exposure may moderate MPH treatment effects.

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Acknowledgements

Mireia Pagerols and Iris Garcia-Martínez are recipients of a predoctoral fellowship from the Vall d'Hebron Research Institute (PRED-VHIR-2013 and PRED-VHIR-2012). Cristina Sánchez-Mora is a recipient of a contract from the 7th Framework Programme for Research, Technological Development and Demonstration, European Commission (AGGRESSOTYPE_FP7HEALTH2013/602805). Marta Ribasés is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain (CP09/00119). This work was funded by Fundación Alicia Koplowitz and Instituto de Salud Carlos III (PI11/00571, PI11/01629, PI12/01139, PI14/01700) and cofinanced by the European Regional Development Fund (ERDF), Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (2014SGR1357, 2014SGR0932), Ministerio de Economía y Competitividad (MINECO, SAF2012-33484), Spain, the European College of Neuropsychopharmacology (ECNP network: 'ADHD across the lifespan') and Departament de Salut, Government of Catalonia, Spain.

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Correspondence to M Ribasés.

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Professor Casas has received travel grants and research support from Eli Lilly, Janssen-Cilag, Shire and Laboratorios Rubió. He has been on the advisory board and served as a consultant for Eli Lilly, Janssen-Cilag, Shire and Laboratorios Rubió. Dr Ramos-Quiroga has served on the speakers' bureau and acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Lundbeck, Shire, Ferrer and Laboratorios Rubió. He has received travel awards from Eli Lilly, Janssen-Cilag and Shire for participating in psychiatric meetings. The ADHD Program chaired by Dr Ramos-Quiroga has received unrestricted educational and research support from Eli Lilly, Janssen-Cilag, Shire, Rovi and Laboratorios Rubió in the past 2 years. The other authors declare no conflict of interest.

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Pagerols, M., Richarte, V., Sánchez-Mora, C. et al. Pharmacogenetics of methylphenidate response and tolerability in attention-deficit/hyperactivity disorder. Pharmacogenomics J 17, 98–104 (2017). https://doi.org/10.1038/tpj.2015.89

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