Randomized Clinical Trial
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatr. Dec 22, 2016; 6(4): 442-448
Published online Dec 22, 2016. doi: 10.5498/wjp.v6.i4.442
Influence of different second generation antipsychotics on the QTc interval: A pragmatic study
Roy E Olsen, Rune A Kroken, Sigmund Bjørhovde, Kristina Aanesen, Hugo A Jørgensen, Else-Marie Løberg, Erik Johnsen
Roy E Olsen, Rune A Kroken, Sigmund Bjørhovde, Kristina Aanesen, Erik Johnsen, Division of Psychiatry, Haukeland University Hospital, 5021 Bergen, Norway
Rune A Kroken, Hugo A Jørgensen, Erik Johnsen, Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
Else-Marie Løberg, Department of Addiction Medicine, Haukeland University Hospital, 5021 Bergen, Norway
Else-Marie Løberg, Department of Clinical Psychology, University of Bergen, 5020 Bergen, Norway
Author contributions: Jørgensen HA and Johnsen E designed the original study; Olsen RE and Johnsen E analyzed the data and made the first manuscript draft; all authors made substantial contributions to the conception and design of the present study, helped to draft the article, critically reviewed the manuscript and approved it.
Institutional review board statement: The study was reviewed and approved by the Division of Psychiatry Institutional Review Board.
Clinical trial registration statement: ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/: NCT00932529.
Informed consent statement: The study was approved by the Regional Committee for Medical Research Ethics and the Norwegian Social Science Data Services. The Regional Committee for Medical Research Ethics allowed eligible patients to be included before informed consent was provided.
Conflict-of-interest statement: The study received no financial or other support from the pharmaceutical industry. The authors report no conflict of interest regarding the work.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Erik Johnsen, MD, PhD, Division of Psychiatry, Haukeland University Hospital, P.O. Box 1400, 5021 Bergen, Norway. erik.johnsen@helse-bergen.no
Telephone: +47-55-958400 Fax: +47-55-958436
Received: June 30, 2016
Peer-review started: July 2, 2016
First decision: August 5, 2016
Revised: September 9, 2016
Accepted: October 5, 2016
Article in press: October 9, 2016
Published online: December 22, 2016

To investigate whether differential influence on the QTc interval exists among four second generation antipsychotics (SGAs) in psychosis.


Data were drawn from a pragmatic, randomized head-to-head trial of the SGAs risperidone, olanzapine, quetiapine, and ziprasidone in acute admissions patients with psychosis, and with follow-up visits at discharge or maximally 6-9 wk, 3, 6, 12 and 24 mo. Electrocardiograms were recorded on all visits. To mimic clinical shared decision-making, the patients were randomized not to a single drug, but to a sequence of the SGAs under investigation. The first drug in the sequence defined the randomization group, but the patient and/or clinician could choose an SGA later in the sequence if prior negative experiences with the first one(s) in the sequence had occurred. The study focuses on the time of, and actual use of the SGAs under investigation, that is until treatment discontinuation or change, in order to capture the direct medication effects on the QTc interval. Secondary intention-to-treat (ITT) analyses were also performed.


A total of 173 patients, with even distribution among the treatment groups, underwent ECG assessments. About 70% were males and 43% had never used antipsychotic drugs before the study. The mean antipsychotic doses in milligrams per day with standard deviations (SD) were 3.4 (1.2) for risperidone, 13.9 (4.6) for olanzapine, 325.9 (185.8) for quetiapine, and 97.2 (42.8) for ziprasidone treated groups. The time until discontinuation of the antipsychotic drug used did not differ in a statistically significant way among the groups (Log-Rank test: P = 0.171). The maximum QTc interval recorded during follow-up was 462 ms. Based on linear mixed effects analyses, the QTc interval change per day with standard error was -0.0030 (0.0280) for risperidone; -0.0099 (0.0108) for olanzapine; -0.0027 (0.0170) for quetiapine, and -0.0081 (0.0229) for ziprasidone. There were no statistically significant differences among the groups in this regard. LME analyses based on ITT groups (the randomization groups), revealed almost identical slopes with -0.0063 (0.0160) for risperidone, -0.0130 (0.0126) for olanzapine, -0.0034 (0.0168) for quetiapine, and -0.0045 (0.0225) for ziprasidone.


None of the SGAs under investigation led to statistically significant QTc prolongation. No statistically significant differences among the SGAs were found.

Keywords: Psychosis, QTc prolongation, Antipsychotics, Clinical trial, Pragmatic design

Core tip: Antipsychotic drugs have a bad reputation of prolonging the QTc interval, and thereby possibly leading to fatal incidents of Torsade de pointes arrhythmias and sudden cardiac death. Differential propensities for QTc prolongation among second generation antipsychotics (SGAs) have been claimed, but lack substantial support from pragmatic studies. None of the SGAs was statistically significantly prolonging the QTc interval in the present pragmatic study, and no statistically significant differences among the drug groups were found for this outcome. Even in a situation with a substantial proportion with QTc prolongation at admittance any of the SGAs under investigation seemed to be safe choices in the present study.