title: Effectiveness of clozapine in neuroleptic-resistant schizophrenia: clinical response and plasma concentrations.
abstract: OBJECTIVE
  To assess the relation between plasma concentrations of clozapine and its 2 main metabolites desmethyl clozapine and clozapine N-oxide, and clinical change in a sample of inpatients with schizophrenia who were resistant to conventional neuroleptics.
  
  
  METHODS
  Thirty-seven patients (27 men and 10 women, mean age 34.8 yr) with treatment-resistant schizophrenia were treated with clozapine for 18 weeks; dosage was adjusted according to clinical response, and plasma concentrations of clozapine and of its metabolites were measured weekly by high-performance liquid chromatography. Clinical status was also assessed weekly with the Positive and Negative Syndrome Scale (PANSS). Patients were considered "responsive" if they showed at least a 20% improvement over their baseline PANSS ratings.
  
  
  RESULTS
  The mean endpoint clozapine dosage was 486.5 mg/day. There was a significant correlation between the daily dosage of clozapine and the plasma levels of clozapine and of its metabolites (p < 0.05). There was no correlation between the clozapine plasma level and the percent improvement on the PANSS. Clozapine plasma levels were not significantly different between those who responded to clozapine (n = 19) and those who did not (n = 18) and were not significantly different between patients who smoked (n = 28) and those who did not (n = 9). Receiver operating characteristic (ROC) curve analysis determined the plasma level threshold (above which a better clinical response was obtained) to be 550 ng/mL. Using the total of plasma levels of clozapine and its metabolites did not lead to a better sensitivity and specificity.
  
  
  CONCLUSIONS
  Our calculated plasma clozapine threshold was higher than that reported by others, but this may be related to the severity of symptoms of our patient sample. Monitoring plasma rates remains a useful tool, together with clinical evaluation, to establish the clozapine dosage for an optimum benefit-risk ratio.
authors.affiliation: Centre Médico-Psychologique B, Centre Hospitalier Universitaire, BP 69, 63003 Clermont-Ferrand, France. pmllorca@chu-clermontferrand.fr
authors.forename: Pierre-Michel
authors.initials: PM
authors.lastname: Llorca
authors.forename: Christophe
authors.initials: C
authors.lastname: Lancon
authors.forename: Béatrice
authors.initials: B
authors.lastname: Disdier
authors.forename: Jean
authors.initials: J
authors.lastname: Farisse
authors.forename: Christophe
authors.initials: C
authors.lastname: Sapin
authors.forename: Pascal
authors.initials: P
authors.lastname: Auquier
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood* / Q000627:therapeutic use*; D001480:Basal Ganglia Diseases / Q000175:diagnosis; D003024:Clozapine / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D012372:ROC Curve; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine; C079149:clozapine N-oxide