title: Effects of Oral Ziprasidone and Oral Haloperidol on QTc interval in patients with Schizophrenia or Schizoaffective disorder.
abstract: OBJECTIVE
  To characterize the effect of oral ziprasidone and haloperidol on the corrected QT (QTc) interval under steady-state conditions. Design. Prospective, randomized, open-label, parallel-group study.
  
  
  METHODS
  Inpatient clinical research facility. Patients Fifty-nine adults (age range 25-59 yrs) with schizophrenia or schizoaffective disorder who had no clinically significant abnormality on electrocardiogram (ECG) at screening. Intervention. During period 1 (days -10 to -4), antipsychotic and anticholinergic drugs were tapered. On the first day (day -3) of period 2, the drugs were discontinued, and placebo was given for the next 3 days (days -2 to 0). On the last day (day 0) of period 2, serial baseline ECGs were collected. During period 3 (days 1-16), patients received escalating oral doses of ziprasidone and haloperidol to reach steady state. Period 4 (days 17-19) allowed for study drug washout and initiation of outpatient antipsychotic therapy; safety assessments were also performed during this period.
  
  
  RESULTS
  At each steady-state dose level, three ECGs and a serum or plasma sample were collected at the predicted time of peak exposure to the administered drug. Point estimates and 95% confidence intervals (CIs) were determined for the mean QTc interval at baseline and for the mean change from baseline in QTc at each steady-state dose level. Mean changes from baseline in the QTc interval (msec) for ziprasidone were 4.5 (95% CI 1.9-7.1), 19.5 (95% CI 15.5-23.4), and 22.5 (95% CI 15.7- 29.4) for steady-state doses of 40, 160, and 320 mg/day, respectively; for haloperidol, -1.2 (95% CI -4.1-1.7), 6.6 (95% CI 1.6-11.7), and 7.2 (95% CI 1.4-13.1) for steady-state doses of 2.5, 15, and 30 mg/day. Although no patient in either treatment group experienced a QTc interval of 450 msec or greater, the QTc interval increased 30 msec or more in 11 and 17 ziprasidone-treated patients at 160 and 320 mg/day, respectively, and in 3 and 5 haloperidol-treated patients at 15 and 30 mg/day, respectively. Most treatment-emergent adverse drug reactions were mild in intensity, and none were severe.
  
  
  CONCLUSIONS
  The QTc interval in ziprasidone- and haloperidol-treated patients increased with dose. Treatment with high doses of ziprasidone or haloperidol did not result in any patient experiencing a QTc interval of 450 msec or greater.
authors.affiliation: Pfizer Global Research and Development, New London, Connecticut, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Miceli
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Tensfeldt
authors.forename: Thomas
authors.initials: T
authors.lastname: Shiovitz
authors.forename: Richard
authors.initials: R
authors.lastname: Anziano
authors.forename: Cedric
authors.initials: C
authors.lastname: O'Gorman
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Harrigan
mesh_terms: D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006220:Haloperidol / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011618:Psychotic Disorders / Q000188:drug therapy*; D012559:Schizophrenia / Q000188:drug therapy*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D013844:Thiazoles; C092292:ziprasidone; D006220:Haloperidol