title: Association of tardive dyskinesia with variation in CYP2D6: Is there a role for active metabolites?
abstract: BACKGROUND
  The aim of this study was to examine whether there was an association between tardive dyskinesia (TD) and number of functional CYP2D6 genes.
  
  
  METHODS
  A Caucasian sample of 70 patients was recruited in 1996-1997 from South London and Maudsley National Health Service (NHS) Foundation Trust, UK. Subjects had a DSM-IIIR diagnosis of schizophrenia and were treated with typical antipsychotics at doses equivalent to at least 100 mg chlorpromazine daily for at least 12 months prior to assessment. All patients were genotyped for CYP2D6 alleles*3-5, *41, and for amplifications of the gene.
  
  
  RESULTS
  There were 13 patients with TD. The mean (standard deviation (SD)) years of duration of antipsychotic treatment in TD-positive was 15.8 (7.9) vs TD-negative 11.1 (7.4) (p=0.04). Increased odds of experiencing TD were associated with increased ability to metabolize CYP2D6, as measured by genotypic category (odds ratio (OR)=4.2), increasing duration in treatment (OR=1.0), and having drug-induced Parkinsonism (OR=9.7).
  
  
  CONCLUSIONS
  We found a significant association between CYP2D6 genotypic category and TD with the direction of effect being an increase in the number of functional CYP2D6 genes being associated with an increased risk of TD. This is the first study to examine the association between TD and CYP2D6 in Caucasians with this number of genotypic categories. In the future, metabolomics may be utilized in the discovery of biomarkers and novel drug targets.
authors.affiliation: Clinical Research Program, Sheppard Pratt Health System, Baltimore, MD, USA majujuju@yahoo.com.
authors.forename: Maju M
authors.initials: MM
authors.lastname: Koola
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
authors.forename: Evangelia M
authors.initials: EM
authors.lastname: Tsapakis
authors.affiliation: Takeda Development Centre, Europe, London, UK.
authors.forename: Padraig
authors.initials: P
authors.lastname: Wright
authors.affiliation: Department of Forensic and Neurodevelopmental Science, King's College London, London, UK.
authors.forename: Shubulade
authors.initials: S
authors.lastname: Smith
authors.affiliation: Clinical Neuropharmacology Section, King's College London, London, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Kerwin Rip
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland, Baltimore, MD, USA.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Nugent
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK Department of Psychiatry and Medical Genetics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Aitchison
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000378:metabolism; D016009:Chi-Square Distribution; D003430:Cross-Sectional Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008131:London; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D012307:Risk Factors; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D000071057:Tardive Dyskinesia / Q000139:chemically induced / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D013997:Time Factors; D044465:White People / Q000235:genetics
chemical_list: D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6
keywords: Cytochrome P450; Parkinsonism; antipsychotic; genotype; tardive dyskinesia