title: The impact of cytochrome P450-2D6 genotype on the use and interpretation of therapeutic drug monitoring in long-stay patients treated with antidepressant and antipsychotic drugs in daily psychiatric practice.
abstract: OBJECTIVE
  This retrospective follow-up study investigates whether cytochrome P450-2D6 (CYP2D6) genotype explains variability in plasma concentrations of psychotropic drugs in daily psychiatric practice.
  
  
  METHODS
  The study population consisted of 62 hospitalised psychiatric patients genotyped for CYP2D6. Primary endpoint was the normalised plasma concentration ratio which was defined as the [measured concentration]/[mean therapeutic concentration] allowing comparison of plasma concentrations of different substrates. Secondary endpoint was a plasma concentration above the therapeutic range. The determinant was CYP2D6 genotype classified as ultrarapid metaboliser (UM), extensive metaboliser (EM), intermediate metaboliser (IM), or poor metaboliser (PM). The relation between CYP2D6 genotype and the normalised plasma concentration ratio was assessed with a linear mixed-effects model after adjustment for the Prescribed Daily Dose (PDD). The risk of having a plasma concentration above the therapeutic range was assessed with a logistic mixed-effects model.
  
  
  RESULTS
  For antidepressants, CYP2D6 genotype PM (1.68 (95%CI: 1.01-2.28)) and IM (1.09 (95%CI: 0.77-1.29)) were associated with higher normalised plasma concentration ratios of antidepressants compared to EMs (0.56 (95%CI: 0.26-0.74)). In addition, the risk of a plasma concentration above the therapeutic range was increased for PMs (OR 33.1 (95%CI: 2.0-544.6)) and IMs (OR 8.2 (95%CI: 1.1-60.3)) relative to EMs using antidepressants. CYP2D6 genotype could not clearly explain variability in plasma concentrations of antipsychotics possibly due to a low frequency of therapeutic drug monitoring (TDM) in antipsychotics primarily metabolised by CYP2D6 in daily psychiatric practice.
  
  
  CONCLUSIONS
  CYP2D6 genotype contributes to clinically relevant variability in plasma concentrations of antidepressants but probably not antipsychotics in daily clinical practice.
authors.affiliation: Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Mulder
authors.forename: Anita
authors.initials: A
authors.lastname: Herder
authors.forename: Frederik W
authors.initials: FW
authors.lastname: Wilmink
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Tamminga
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Belitser
authors.forename: Antoine C G
authors.initials: AC
authors.lastname: Egberts
mesh_terms: D000928:Antidepressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006778:Hospitals, Psychiatric; D006801:Humans; D007297:Inpatients; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009426:Netherlands; D010597:Pharmacogenetics / Q000379:methods; D012189:Retrospective Studies
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6