title: Autonomic signs and dosing during the initial stages of clozapine therapy.
abstract: BACKGROUND
  Recent reports implicate clozapine in heart rate variability, QTc prolongation, torsade de pointes and sudden death at therapeutic doses, even in physically healthy patients. This study aims to examine whether autonomic (vital) signs are correlated with clozapine dose titration and blood levels of clozapine and nor-clozapine during clozapine therapy.
  
  
  METHODS
  Thirty-seven consecutive patients with diagnosis of schizophrenia treated with clozapine were included in this prospective longitudinal study. The study was restricted to only the first 8 weeks of treatment. After obtaining informed consent, serum concentrations of clozapine and nor-clozapine were determined weekly at trough, as doses were administered q12h and adjusted according to clinical guidelines for clozapine use. Autonomic signs including BP (supine and erect), pulse (supine and erect) and temperature were monitored daily each morning before and one hour after the morning's dose of clozapine was administered.
  
  
  RESULTS
  We calculated analyses of covariance (ANCOVAs) to evaluate the changes in vital signs parameters, from baseline to week 8, with clozapine variables as covariates (i.e, the dose of clozapine, as well as the levels of serum clozapine and nor-clozapine). The blood pressure and pulse did not change significantly (p<0.01) from baseline to weeks 8. The temperature was inversely related to clozapine dose (p<0.003). Higher nor-clozapine to clozapine ratios were associated with higher BP measures (p=0.002). The magnitude of these relationships is weak (r<0.30).
  
  
  CONCLUSIONS
  There is a tendency to autonomic dysregulation during clozapine use. This has cardiac function implications, justifying cautious dose adjustment with frequent monitoring of vital signs.
authors.affiliation: Queen's University, Hotel-Dieu Hospital, 166 Brock Street, Kingston, Ontario K7L 5G2, Canada. oyewumik@post.queensu.ca
authors.forename: L Kola
authors.initials: LK
authors.lastname: Oyewumi
authors.forename: Zack Z
authors.initials: ZZ
authors.lastname: Cernovsky
authors.forename: David J
authors.initials: DJ
authors.lastname: Freeman
mesh_terms: D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects*; D003024:Clozapine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D011446:Prospective Studies; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; C058272:norclozapine; D003024:Clozapine