title: Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients.
abstract: BACKGROUND
  Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects and its superior efficacy in refractory schizophrenia. However, an unambiguous concentration-response relationship has not yet been established.
  
  
  OBJECTIVE
  We investigated serum concentrations of clozapine, norclozapine and clozapine-N-oxide in psychiatric in- and outpatients to identify particular metabolic patterns in clozapine responders and non-responders and putative threshold levels for clozapine response.
  
  
  METHODS
  Psychiatric assessments, CYP2D6 genotype, and weekly serum concentrations of clozapine, norclozapine and clozapine-N-oxide were obtained in 34 adult schizophrenic in-and outpatients (18 men, 16 women) during 10 weeks of clozapine treatment with a naturalistic dose design.
  
  
  RESULTS
  Responders (n=21) displayed significantly lower serum concentrations of clozapine corrected for dose compared to non-responders (n=13; P<0.05), while none of the other parameters (absolute clozapine concentration, metabolite ratios, gender) were different. Smokers had significantly lower dose-corrected clozapine concentrations. A positive correlation was observed between age and average steady state clozapine concentrations.
  
  
  CONCLUSIONS
  These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.
authors.affiliation: Department of Psychiatry, University Clinic Charité, Humboldt University, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dettling
authors.forename: C
authors.initials: C
authors.lastname: Sachse
authors.forename: J
authors.initials: J
authors.lastname: Brockmöller
authors.forename: J
authors.initials: J
authors.lastname: Schley
authors.forename: B
authors.initials: B
authors.lastname: Müller-Oerlinghausen
authors.forename: I
authors.initials: I
authors.lastname: Pickersgill
authors.forename: A
authors.initials: A
authors.lastname: Rolfs
authors.forename: R T
authors.initials: RT
authors.lastname: Schaub
authors.forename: J
authors.initials: J
authors.lastname: Schmider
mesh_terms: D000328:Adult; D000483:Alleles; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001711:Biotransformation; D003024:Clozapine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D012563:Schizophrenia, Paranoid / Q000097:blood / Q000188:drug therapy* / Q000523:psychology
chemical_list: D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6; D003024:Clozapine