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Antipsychotics and Risk for Sudden Cardiac Death

Typical antipsychotics and the newer atypical agents pose similarly elevated risks.

Epidemiologic studies have shown dose-related increases in sudden cardiac death with typical antipsychotic drugs. Less is known about the risk with the newer atypical agents, which have mostly supplanted older agents and are increasingly used off-label for medication-refractory depression and, in low doses, for sleep, anxiety, and agitation. In a careful epidemiologic study of Tennessee Medicaid data, researchers examined the risk for sudden cardiac death in 93,300 users and 186,600 nonusers of antipsychotic drugs. Typical agents were haloperidol and thioridazine; atypical agents were clozapine, olanzapine, risperidone, and quetiapine.

Overall, the risk for sudden cardiac death was 17.9 per 10,000 patient-years, higher in men and older individuals. In analyses limited to users of a single antipsychotic, the risk was greater in current users than in nonusers. Typical and atypical agents posed similarly elevated risks (incidence-rate ratios [IRRs], 2.00 and 2.27). Elevation in risk increased with higher doses and was present for each agent, but was not seen in former users.

To control for group differences (e.g., psychosis diagnoses), the researchers employed propensity score matching. This analysis also showed similarly increased IRRs (typical agents, 1.84; atypicals, 1.99) and dose-response relationships. The risk remained elevated in analyses of short-term (<1 year) and new users.

THE JOURNAL WATCH PSYCHIATRY PERSPECTIVE

This study extends previous findings of increased risk for sudden cardiac death with typical antipsychotics to atypical agents and is consistent with a recent study documenting increased mortality in Alzheimer patients using these medications (Lancet Neurol Jan 9 2009 [e-pub ahead of print]). This risk, which occurs with very short-duration use and at low doses, is distinct from the well-known risk for metabolic syndrome that evolves with longer-term use of atypical agents. Editorialists note that the cardiac risk might not be acceptable where the drugs’ benefits have not been demonstrated and advocate an "age-dependent justification for their use." So far, only one atypical agent, aripiprazole (not included in this study), has been approved to treat refractory depression. Clinicians should be highly cautious when considering other atypical agents with less compelling data for this indication or for other off-label uses.

— Peter Roy-Byrne, MD

THE JOURNAL WATCH CARDIOLOGY PERSPECTIVE

Both the typical and atypical antipsychotics were associated with a doubling in risk for sudden cardiac death. For this outcome, newer did not prove safer; the risk is small but real. The sudden cardiac death associated with these agents likely results from their blockade of potassium channels, which can prolong the QT interval and thus put susceptible individuals at risk for life-threatening arrhythmias. These data support pre-administration electrocardiogram screening of individuals prescribed antipsychotics. However, whether such screening would ultimately lower these patients’ risk for sudden death is not clear. Finally, we should keep in mind that this study included only antipsychotic agents, not other psychopharmacologic medications.

— Mark S. Link, MD

Ray WA et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2008 Jan 15 ; 360:225.

Schneeweiss S and Avorn J. Antipsychotic agents and sudden cardiac death — How should we manage the risk? N Engl J Med 2008 Jan 15 ; 360:294.

— Peter Roy-Byrne, MD and Mark S. Link, MD

Published in Journal Watch Psychiatry January 14, 2009

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