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Pharmacogenomics J. 2017 Jan;17(1):98-104. doi: 10.1038/tpj.2015.89. Epub 2016 Jan 26.

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

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Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.


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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