title: Methylphenidate side effect profile is influenced by genetic variation in the attention-deficit/hyperactivity disorder-associated CES1 gene.
abstract: OBJECTIVE
  A naturalistic, prospective study of the influence of genetic variation on dose prescribed, clinical response, and side effects related to stimulant medication in 77 children with attention-deficit/hyperactivity disorder (ADHD) was undertaken. The influence of genetic variation of the CES1 gene coding for carboxylesterase 1A1 (CES1A1), the major enzyme responsible for the first-pass, stereoselective metabolism of methylphenidate, was investigated.
  
  
  METHODS
  Parent- and teacher-rated behavioral questionnaires were collected at baseline when the children were medication naïve, and again at 6 weeks while they were on medication. Medication dose, prescribed at the discretion of the treating clinician, and side effects, were recorded at week 6. Blood and saliva samples were collected for genotyping. Single nucleotide polymorphisms (SNPs) were selected in the coding, non-coding and the 3' flanking region of the CES1 gene. Genetic association between CES1 variants and ADHD was investigated in an expanded sample of 265 Irish ADHD families. Analyses were conducted using analysis of covariance (ANCOVA) and logistic regression models.
  
  
  RESULTS
  None of the CES1 gene variants were associated with the dose of methylphenidate provided or the clinical response recorded at the 6 week time point. An association between two CES1 SNP markers and the occurrence of sadness as a side effect of short-acting methylphenidate was found. The two associated CES1 markers were in linkage disequilibrium and were significantly associated with ADHD in a larger sample of ADHD trios. The associated CES1 markers were also in linkage disequilibrium with two SNP markers of the noradrenaline transporter gene (SLC6A2).
  
  
  CONCLUSIONS
  This study found an association between two CES1 SNP markers and the occurrence of sadness as a side effect of short-acting methylphenidate. These markers were in linkage disequilibrium together and with two SNP markers of the noradrenaline transporter gene.
authors.affiliation: 1 School of Psychological Sciences, University of Melbourne , Australia .
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Johnson
authors.forename: Edwina
authors.initials: E
authors.lastname: Barry
authors.forename: David
authors.initials: D
authors.lastname: Lambert
authors.forename: Michael
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Fiona
authors.initials: F
authors.lastname: McNicholas
authors.forename: Aiveen
authors.initials: A
authors.lastname: Kirley
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bellgrove
authors.forename: Ziarih
authors.initials: Z
authors.lastname: Hawi
mesh_terms: D000293:Adolescent; D001066:Appetite / Q000187:drug effects; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human