Analysis of the QTc interval during olanzapine treatment of patients with schizophrenia and related psychosis.
BACKGROUND
There may be a temporal association between some antipsychotics and prolongation of the heart-rate-corrected QT interval (QTc) representing a delay in ventricular repolarization. QTc prolongation significantly exceeding normal intra-individual and interindividual variation may increase the risk of ventricular tachydysrhythmias, especially torsade de pointes, and therefore, sudden cardiac death.


METHODS
Electrocardiogram recordings obtained as part of the safety assessment of olanzapine in 4 controlled, randomized clinical trials (N = 2,700) were analyzed. These analyses were conducted to characterize any change in QTc temporally associated with olanzapine, compared with placebo, haloperidol, and risperidone, in acutely psychotic patients (DSM-III-R and DSM-IV) and to characterize variability and temporal course of the QTc in this patient population. Changes from baseline to minimum and maximum QTc were tested for significance, and baseline to acute-phase endpoint change in mean QTc was tested for significance within treatments and for differences between olanzapine and comparators. The possibility of a linear relationship between dose of olanzapine and mean change in QTc, as well as incidence of treatment-emergent prolongation of QTc (change from < 430 msec at baseline to > or =430 msec at endpoint), was tested.


RESULTS
The incidence of maximum QTc > or = 450 msec during treatment was approximately equal to the incidence of QTc > or =450 msec at baseline.


CONCLUSIONS
Results of these analyses suggest that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute to QTc prolongation resulting in potentially fatal ventricular arrhythmias.
Czekalla
J
J
Medical CNS Division, Lilly Deutschland, Bad Homburg, Germany.
Beasley
C M
CM
Dellva
M A
MA
Berg
P H
PH
Grundy
S
S
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000453:epidemiology; D001569:Benzodiazepines; D004562:Electrocardiography / Q000187:drug effects* / Q000706:statistics & numerical data; D005260:Female; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015994:Incidence; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D010890:Pirenzepine / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D010919:Placebos; D018967:Risperidone / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy*
D014150:Antipsychotic Agents; D010919:Placebos; D001569:Benzodiazepines; D010890:Pirenzepine; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine