Antipsychotics and the Risk of Sudden Cardiac Death
Wayne A. Ray, PhD; Sarah Meredith, MBBS, MSc; Purushottam B. Thapa, MBBS, MPH; Keith G. Meador, MD, MPH; Kathi Hall, BS; Katherine T. Murray, MD


Arch Gen Psychiatry. 2001;58:1161-1167.

ABSTRACT

Background Case reports link antipsychotic drugs with sudden cardiac deaths, which is consistent with dose-related electrophysiologic effects. Because this association has not been confirmed in controlled studies, we conducted a retrospective cohort study in Tennessee Medicaid enrollees, which included many antipsychotic users; there were also computer files describing medication use and comorbidity. The study was conducted before the introduction of risperidone and, thus, did not include the newer atypical agents.

Methods The cohort included 481 744 persons with 1 282 996 person-years of follow-up. This included 26 749 person-years for current moderate-dose antipsychotic use (>100-mg thioridazine equivalents), 31 864 person-years for current low-dose antipsychotic use, 37 881 person-years for use in the past year only, and 1 186 501 person-years for no use. The cohort had 1487 confirmed sudden cardiac deaths; from these, we calculated multivariate rate ratios adjusted for potential confounding factors.

Results When current moderate-dose antipsychotic use was compared with nonuse, the multivariate rate ratio was 2.39 (95% confidence interval, 1.77-3.22; P<.001). This was greater than that for current low-dose (rate ratio, 1.30; 95% confidence interval, 0.98-1.72; P = .003) and former (rate ratio, 1.20; 95% confidence interval, 0.91-1.58; P<.001) use. Among cohort members with severe cardiovascular disease, current moderate-dose users had a 3.53-fold (95% confidence interval, 1.66-7.51) increased rate relative to comparable nonusers (P<.001), resulting in 367 additional deaths per 10 000 person-years of follow-up.

Conclusions Patients prescribed moderate doses of antipsychotics had large relative and absolute increases in the risk of sudden cardiac death. Although the study data cannot demonstrate causality, they suggest that the potential adverse cardiac effects of antipsychotics should be considered in clinical practice, particularly for patients with cardiovascular disease.





ANTIPSYCHOTIC AGENTS, the primary treatment for schizophrenia and other psychoses,1 long have been suspected to increase the risk of serious ventricular arrhythmias and, thus, sudden cardiac death.2, 3 The literature includes numerous case reports of torsades de pointes and sudden death in patients taking thioridazine,4, 5, 6 haloperidol,7, 8 risperidone,9, 10 and other antipsychotics.3 Users of antipsychotic medications are overrepresented in registries of sudden deaths.11 Cohort studies12, 13, 14, 15 of schizophrenic patients have reported a persistent excess of cardiovascular disease–related mortality. Several3, 16 have speculated that this is, at least in part, attributable to antipsychotic use.

An increased risk of sudden cardiac death is consistent with the dose-related effects of antipsychotic medications on cardiac electrophysiologic properties. Haloperidol and sertindole block repolarizing potassium currents in vitro,17, 18 hypothesized to be the mechanism underlying drug-induced torsades de pointes.2 In an isolated feline heart model, haloperidol, risperidone, sertindole, clozapine, and olanzapine produced dose-dependent prolongation of the QT interval.16 In isolated spontaneously beating guinea pig Purkinje fibers, chlorpromazine and thioridazine induce early "after depolarizations,"19 a hypothesized trigger for torsades de pointes.16 Approximately 25% of patients taking phenothiazines and other antipsychotics have electrocardiographic abnormalities, including prolongation of the QT interval,3, 20 which is thought to increase the risk of serious ventricular arrhythmias.

Although these data suggest that antipsychotic medications might increase the risk of sudden cardiac death, this question has not been addressed in controlled epidemiologic studies. Thus, we conducted a large retrospective cohort study of the risk of sudden cardiac death among antipsychotic users. The study was conducted in a Medicaid population, which included many antipsychotic users; there were also computerized files from which study data could be obtained.21 The study was conducted before the introduction of risperidone, olanzapine, and quetiapine fumarate and, thus, did not include the newer atypical agents.