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Office of Mental Health

APA Guidance on the Use of Antipsychotic Drugs and Cardiac Sudden Death

Prepared by Jeffrey A. Lieberman, M.D. 1, David Merrill, M.D. 1, and Sharat Parameswaran, M.D. 1, for the APA Council on Research

In the January 15, 2009, issue of the New England Journal of Medicine, Wayne A. Ray, PhD, and colleagues reported findings of a study investigating the risk of sudden cardiac death (SCD) associated with the use of antipsychotic medications (Ray et al., 2009). The researchers used a Tennessee Medicaid database to retrospectively calculate the incidence of SCD among 44,218 users of typical (i.e. first-generation) agents, 46,089 users of atypical (i.e. second-generation) agents and 186,600 nonusers of antipsychotic drugs. The patients included in the study were 30 to 74 years of age, and predominantly women, white and residing in urban areas. The individual drugs that were analyzed were haloperidol, thioridazine, clozapine, olanzapine, quetiapine and risperidone.

Ray and colleagues found that both antipsychotic classes were associated with an approximate doubling of the risk of SCD, relative to the baseline rate among nonusers of antipsychotics. In absolute terms, the incidence of SCD among patients prescribed antipsychotics was approximately three events per 1000 patient-years. This risk was dose-dependent in both medication classes, with doses equivalent to 300 mg or more of chlorpromazine per day posing the greatest risk.

That first-generation antipsychotics are associated with SCD is well established (Ray et al., 2001; Straus et al., 2004), but the finding that second-generation agents were associated with a comparable risk was new information and surprising as the newer medications have been considered to be generally safer.

Careful examination of the study methodology, however, raises questions about the validity of the results. Ray and colleagues used a retrospective analysis of death certificates to evaluate mortality by SCD, which may overestimate SCD incidence. Multiple studies using a prospective, multiple-source surveillance method (Chugh et al., 2004; Byrne et al., 2008; Vaillancourt et al., 2004) have shown rates of SCD in the general population between 51 and 56 per 100,000 person-years, compared to 143 per 100,000 person-years in the study by Ray and colleagues. A direct comparison between the prospective and retrospective methods showed a positive predictive value of only 19% with the latter method (Chugh et al., 2004). In addition, Ray and colleagues utilized an unvalidated cardiovascular risk score to assess patients' risk for SCD, noting a non-significantly lower baseline risk score in patients receiving antipsychotic medications than in those not receiving them. This finding is inconsistent with existing evidence regarding high rates of cardiovascular morbidity and mortality in patients with mental illness, particularly severe mental illness (Newcomer et al, 2007; Osborn et al., 2006; Goff et al., 2005). Indeed, a lower calculated cardiovascular risk in patients taking antipsychotic medication may actually reflect the well-known low rates of detection and treatment of cardiovascular risk factors in patients with mental illness (Nasrallah et al., 2006), which may account for the higher rate of cardiac-related mortality among antipsychotic users in this study. Neither cardiovascular risk nor primary mental illness was controlled for in the primary cohorts analyzed by Ray and colleagues; a secondary set of cohorts, while better matched for mental illness, specifically excluded patients with schizophrenia. Without controlling for these potentially confounding variables, it is unclear whether the high rates of cardiac mortality reported in this study were attributable to antipsychotic medications or other causes.

Ray and colleagues suggested that the most likely mechanism of SCD among antipsychotic users is a drug-induced blockade of repolarizing currents in cardiac myocytes, leading to a prolongation of the electrocardiogram (ECG) rate-corrected QT interval (QTc), and ultimately to the potentially fatal ventricular tachyarrhythmia torsades de pointes (TdP). An accompanying editorial (Schneeweiss and Avorn, 2009) proposed that an ECG be obtained before and shortly after initiation of treatment with an antipsychotic drug. According to the editorial, when QT interval prolongation is detected, the antipsychotic dose should be reduced or the drug discontinued, other risk factors for SCD should be addressed, and follow-up ECGs should be obtained.

Instituting a policy of routine serial measurement of the QTc interval in all patients initiating treatment with antipsychotic medication may be premature. While some antipsychotics are known to substantially prolong the QTc, others do so to only a modest degree (Harrigan et al., 2004). Furthermore, although prolongation of the QTc is the best available clinical surrogate for the development of TdP, it is an imperfect biomarker (Shah, 2005; Sager, 2008). The QTc generally has low specificity for predicting arrhythmias, and for some drugs a dissociation exists between QTc prolongation and TdP risk (Sager, 2008).

Given the methodological limitations of the study by Ray and colleagues, and the lack of data regarding the utility and cost-effectiveness of serial QTc measurement in antipsychotic-treated patients, clinicians should continue to observe extant practice guidelines for the work-up and management of psychotic patients. With regard to cardiac safety, these include obtaining a medical and medication history, a thorough physical exam, vital signs and routine laboratory tests (APA, 2006). Thioridazine, mesoridazine and pimozide should not be prescribed for patients with cardiac risk factors of known heart disease, a personal history of syncope, a family history of sudden death under age 40, or prolonged QTc syndrome (Marder et al., 2004). If these agents are prescribed, serum potassium and an ECG should be checked before drug initiation; serum potassium and an ECG should also be checked in the presence of the above cardiac risk factors prior to treatment with ziprasidone (APA, 2004). An ECG should be checked again following a significant change in dose of thioridazine, mesoridazine, pimozide or, in the presence of cardiac risk factors, ziprasidone, or following the addition of another QTc-prolonging medication (APA, 2004), or if a patient presents with symptoms associated with a prolonged QTc interval (e.g., syncope) (Marder et al., 2004). An absolute QTc interval of >500 msec or an increase of 60 msec from baseline may be associated with an increased risk of TdP (Haddad and Anderson, 2002) and should prompt reduction or discontinuation of the offending agent.

When prescribing antipsychotic medication, clinicians are encouraged to use the lowest dose effective for any given patient in order to minimize dose-dependent adverse effect risks.


  1. The authors are from the Columbia University Department of Psychiatry and New York State Psychiatric Institute

References

American Psychiatric Association, APA Practice Guidelines. Psychiatric Evaluation of Adults, 2nd Edition (May 2006).

American Psychiatric Association, APA Practice Guidelines. Treatment of Patients with Schizophrenia, 2nd Edition (April 2004).

Byrne R, Constant O, Smyth Y, Callagy G, Nash P, Daly K, Crowley J. Multiple source surveillance incidence and aetiology of out-of-hospital sudden cardiac death in a rural population in the West of Ireland. Eur Heart J. 2008; 29:1418-1423.

Chugh SS, Jui J, Gunson K, Stecker EC, John BT, Thompson B, Ilias N, Vickers C, Dogra V, Daya M, Kron J, Zheng ZJ, Mensah G, McAnulty J. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J Am Coll Cardiol. 2004; 44:1268-1275.

Goff DC, Sullivan LM, McEvoy JP, Meyer JM, Nasrallah HA, Daumit GL, Lamberti S, D'Agostino RB, Stroup TS, Davis S, Lieberman JA. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophr Res. 2005; 80:45-53.

Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsades de pointes and sudden death. Drugs. 2002; 62:1649-1671.

Harrigan EP, Micelli JJ, Anziano R, Watsky E, Reeves KR, Cutler NR, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol. 2004; 24:62-69.

Marder SR, Essock SM, Miller AL, Buchanan RW, Casey DE, Davis JM, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry. 2004; 161:1334-1349.

Nasrallah HA, Meyer JM, Goff DC, McEvoy JP, Davis SM, Stroup TS, Lieberman JA. Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. Schizophr Res. 2006; 86:15-22.

Newcomer JW, Hennekens CH. Severe mental illness and risk of cardiovascular disease. JAMA. 2007; 298:1794-1796.

Osborn DP, Nazareth I, King MB. Risk for coronary heart disease in people with severe mental illness: cross-sectional comparative study in primary care. Br J Psychiatry. 2006; 188:271-277.

Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009; 360:225-235.

Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry. 2001; 58:1161-1167.

Sager PT. Key clinical considerations for demonstrating the utility of preclinical models to predict clinical drug-induced torsades de pointe. Br J Pharmacol. 2008; 154:1544-1549.

Schneeweiss S, Avorn J. Antipsychotic agents and sudden cardiac death – how should we manage the risk? N Engl J Med. 2009; 360:294-296.

Shah RR. Drug-induced QT dispersion: does it predict the risk of torsades de pointes? J Electrocardiol. 2005; 38:10-18.

Straus SM, Bleumink GS, Dieleman JP, van der Lei J, ‘t Jong GW, Kingma JH et al. Antipsychotics and the risk of sudden cardiac death. Arch Intern Med. 2004; 164:1293-1297.

Vaillancourt C, Stiell IG; Canadian Cardiovascular Outcomes Research Team. Cardiac arrest care and emergency medical services in Canada. Can J Cardiol. 2004; 20:1081-1090.