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Assessing QT Interval Prolongation and its Associated Risks with Antipsychotics

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Abstract

Several antipsychotics are associated with the ventricular tachycardia torsade de pointes (TdP), which may lead to sudden cardiac death (SCD), because of their inhibition of the cardiac delayed potassium rectifier channel. This inhibition extends the repolarization process of the ventricles of the heart, illustrated as a prolongation of the QT interval on a surface ECG. SCD in individuals receiving antipsychotics has an incidence of approximately 15 cases per 10 000 years of drug exposure but the exact association with TdP remains unknown because the diagnosis of TdP is uncertain. Most patients manifesting antipsychotic-associated TdP and subsequently SCD have well established risk factors for SCD, i.e. older age, female gender, hypokalaemia and cardiovascular disease.

QT interval prolongation is the most widely used surrogate marker for assessing the risk of TdP but it is considered somewhat imprecise, partly because QT interval changes are subject to measurement error. In particular, drug-induced T-wave changes (e.g. flattening of the T-wave) may complicate the measurement of the QT interval. Furthermore, the QT interval depends on the heart rate and a corrected QT (QTc) interval is often used to compensate for this. Several correction formulas have been suggested, with Bazett’s formula the most widely used. However, Bazett’s formula overcorrects at a heart rate above 80 beats per minute and, therefore, Fridericia’s formula is considered more appropriate to use in these cases. Several other surrogate markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled in its measurement.

A QT interval >500 ms markedly increases the risk for TdP and SCD, and should lead to discontinuation of the offending drug and, if present, correction of underlying electrolyte disturbances, particularly serum potassium and magnesium derangements. Before prescribing antipsychotics that may increase the QTc interval, the clinician should ask about family and personal history of SCD, presyncope, syncope and cardiac arrhythmias, and recommend cardiology consultation if history is positive.

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Acknowledgements

The work was supported by the Tryg Foundation but the foundation has not been involved in the preparation of the manuscript. J. Nielsen has received research grants from H. Lundbeck, Chempaq and Pfizer for clinical trials and received speaking fees from Bristol-Myers Squibb, Astra Zeneca, Lundbeck, Janssen Pharmaceutica and Eli-Lilly. J.K. Kanters, E. Toft and C. Graff hold patents on a T-wave morphology method. J.K. Kanters is on the advisory board for UCB Pharma. Prof. Taylor has received consultancies fees, lecturing honoraria and/or research funding from AstraZeneca, Janssen-Cilag, Servier, Sanofi-aventis, Lundbeck, Bristol-Myers Squibb, Novartis, Eli Lilly and Wyeth. Dr Meyer reports having received support from HIH (as GCRC support), NIMH, Bristol-Myers Squibb and Pfizer, Inc. Dr Meyer reports having received speaking or advising fees from AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Dainippon Sumitomo Pharmaceuticals, Inc., Schering-Plough (now Merck), Vanda Pharmaceuticals, Wyeth Pharmaceuticals Inc. (now Pfizer, Inc.), Janssen Pharmaceuticals, Novartis, Organon and Pfizer.

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Authors and Affiliations

  1. Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospital, Mølleparkvej 10, P.O. Box 210, Aalborg, 9100, Denmark

    Jimmi Nielsen

  2. Medical Informatics Group (MI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark

    Claus Graff

  3. Department of Cardiology P, Gentofte University Hospital, Gentofte, Denmark

    Jørgen K. Kanters

  4. Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), Laboratory of Experimental Cardiology, University of Copenhagen, Copenhagen, Denmark

    Jørgen K. Kanters

  5. Center for Sensory Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark

    Egon Toft

  6. Pharmacy Department, Maudsley Hospital, London, UK

    David Taylor

  7. Institute of Pharmaceutical Science, King’s College, London, UK

    David Taylor

  8. Department of Psychiatry, University of California San Diego, San Diego, California, USA

    Jonathan M. Meyer

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  1. Jimmi Nielsen
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Correspondence to Jimmi Nielsen.

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Nielsen, J., Graff, C., Kanters, J.K. et al. Assessing QT Interval Prolongation and its Associated Risks with Antipsychotics. CNS Drugs 25, 473–490 (2011). https://doi.org/10.2165/11587800-000000000-00000

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