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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.

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.

From the Division of Pharmacoepidemiology, Department of Preventive Medicine (Drs Ray and Meredith and Ms Hall), and the Divisions of Cardiology and Clinical Pharmacology, Departments of Medicine and Pharmacology (Dr Murray), Vanderbilt University School of Medicine, Geriatric Research, Education, and Clinical Center, Nashville Veterans Affairs Medical Center (Dr Ray), Nashville, Tenn; the Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock (Dr Thapa); and the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, NC (Dr Meador).

Corresponding author and reprints: Wayne A. Ray, PhD, Department of Preventive Medicine, Medical Center North, Room A-1124, Vanderbilt University Medical Center, Nashville, TN 37232 (e-mail: wayne.ray{at}mcmail.vanderbilt.edu).

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