The relationship between atypical antipsychotics drugs, QT interval prolongation, and torsades de pointes: implications for clinical use

ABSTRACT

Introduction: Increased mortality has been observed in patients with mental health disorders. Specifically, exposure to antipsychotic medications conveys a greater than 2 fold risk of sudden death, thought to be mediated through effects on QT prolongation and risk of torsades de pointes.

Areas covered: We review the association between antipsychotic drugs and sudden cardiac death, the physiologic basis for these associations, assessment of patients at risk, and strategies to minimize risk of sudden cardiac death.

Expert opinion: Despite the prevalence of antipsychotic medication use for many decades, there remain considerable challenges in reducing the associated risk of sudden cardiac death. A structured algorithm that incorporates patient clinical factors and antipsychotic drug factors may improve risk assessment and reduce the risk of adverse cardiac events. Future advancements in genetics and artificial intelligence may allow for enhanced risk stratification and predicting response (efficacy and adverse effects) to therapy.

KEYWORDS:

• Antipsychotics
• arrhythmias
• atypical antipsychotics
• first generation
• QT interval prolongation
• second generation
• sudden cardiac death
• torsades de pointes
• typical antipsychotics

Article highlights

• Patients with mental health disorders, and in particular those with schizophrenia, have an increased mortality compared to the general population.

• Antipsychotic drugs confer a >2 fold increased risk of ventricular arrhythmias and sudden cardiac death.

• The mechanism for this risk is due to inhibition of the inward rectifying potassium current. This results in prolonged cardiac myocyte repolarization which manifests as a prolonged QT interval on an electrocardiogram.

• Prolongation of the QT interval is associated with increased risk for torsades de pointes and sudden cardiac death.

• Lurasidone, aripiprazole, paliperidone, and asenapine appear to result in no significant QTc prolongation.

• Additional clinical risk factors have been recognized as contributing to the risk of drug-induced torsades de pointes. These include inherent risk of the drug, higher doses, rapid upward titration, rapid IV infusion, female gender, electrolyte disturbance (hypokalemia, hypomagnesemia), bradycardia, CHF, concomitant QT prolonging drugs, ion-channel polymorphisms, and those with congenital long QT syndrome caused by ion channel mutations.

• Prior to the initiation of an antipsychotic medication, it is important to obtain a comprehensive history focusing on the presence of any risk factors that can promote QT prolongation and/or torsades de pointes. This should include patient’s medical history, family history of cardiac disease, or sudden death (consider unrecognized inherited disease), and concomitant medication use (some may prolong QT, affect electrolytes, or impact drug metabolism and elimination).

• For those patients with risk factors, it is reasonable to obtain a baseline electrocardiogram for QT evaluation if one is not available. Further ECG monitoring monthly for the first 6 months and then once or twice a year is also advised to monitor the QT interval.

• Prolongation of the corrected QT interval to a duration greater than 500 ms or of 60 ms or more from baseline has been linked to an increased risk of torsades de pointes and should prompt a modification in the patient’s regimen.

• Crediblemeds.org is a useful resource for up-to-date drug safety information and information on the risk of QT prolongation and torsades de pointes.

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Declaration of interest

None of the authors have any conflicts of interest to disclose. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Additional information

Funding

This article was not funded.