title: The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment.
abstract: OBJECTIVE
  The genetically polymorphic enzyme cytochrome P450 (CYP) 2D6 contributes to the biotransformation of the antipsychotic drug haloperidol. The impact of the polymorphism on haloperidol pharmacokinetics, adverse events, and efficacy was prospectively evaluated under naturalistic conditions in 172 unselected psychiatric inpatients with acute psychotic symptoms.
  
  
  METHODS
  Serum trough levels of haloperidol and reduced haloperidol of patients receiving clinically adjusted doses were analyzed on days 3, 14, and 28 after hospital admission. Adverse events such as extrapyramidal symptoms were assessed by standardized rating scales. Efficacy was documented by recording the change in positive and negative schizophrenic symptoms. These parameters were correlated with the CYP2D6 genotype determined by polymerase chain reaction analysis for alleles *1 to *15 and *17.
  
  
  RESULTS
  The serum concentrations showed wide interindividual variation. Reduced haloperidol trough levels and haloperidol total clearance correlated significantly with the number of active CYP2D6 genes. In addition, body weight and smoking had significant effects on haloperidol kinetics, whereas age, gender, and comedication showed only slight effects. The ratings for pseudoparkinsonism were significantly higher in poor metabolizers of substrates of CYP2D6. On the other hand, there was a trend toward lower therapeutic efficacy with increasing number of active CYP2D6 genes.
  
  
  CONCLUSIONS
  Treatment with haloperidol should be avoided in extremely slow and extremely rapid metabolizers of CYP2D6 substrates. Both genotyping and blood concentration measurement explained only a fraction of the adverse events; about 20 patients would have to be genotyped to achieve a significant benefit in 1 patient. It is interesting that genotyping was at least as good a predictor of adverse events as the measured drug concentrations.
authors.affiliation: Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University, Berlin, Germany. jurgen.brockmoller@med.uni-goettingen.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
authors.forename: Julia
authors.initials: J
authors.lastname: Kirchheiner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schmider
authors.forename: Silke
authors.initials: S
authors.lastname: Walter
authors.forename: Christoph
authors.initials: C
authors.lastname: Sachse
authors.forename: Bruno
authors.initials: B
authors.lastname: Müller-Oerlinghausen
authors.forename: Ivar
authors.initials: I
authors.lastname: Roots
mesh_terms: D000328:Adult; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006220:Haloperidol / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D016014:Linear Models; D008297:Male; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D019389:Cytochrome P-450 CYP2D6; D006220:Haloperidol