Feb 01, 2006

Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005;353:2335-2441.

Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005;353:2335-2441.


A retrospective study of 22,890 persons aged 65 years or older who were enrolled in a state-sponsored drug benefit program was conducted using Medicare data from January 1, 1994, through December 31, 2003. The study's purpose was to compare the short-term (180 days) risk of death between elderly patients starting therapy with a conventional antipsychotic agent and those beginning treatment with an atypical antipsychotic agent.

In April 2005, a black-box warning was approved by the FDA for atypical antipsychotics, but not conventional antipsychotics, concerning use of the atypical agents in elderly patients with dementia. The findings of this study are important, especially in light of the concern that clinicians may switch their elderly patients who are taking atypical antipsychotic agents to conventional antipsychotic medications because of the black-box warning.

Elderly persons who began receiving a conventional antipsychotic agent were less likely than those beginning treatment with an atypical antipsychotic to have cerebrovascular disease, dementia, delirium, psychoses, or other psychiatric disorders; rather, congestive heart failure, ischemic heart disease, and cancer were more likely.

Persons receiving conventional antipsychotic drugs had a significantly higher risk of death than those receiving atypical agents. Risk of death was increased in persons receiving higher doses of conventional agents and within the 40-day period after treatment initiation.

Results suggest that conventional antipsychotic agents merit an FDA warning on use in elderly patients with dementia, that they are at least as likely as atypical antipsychotics to increase risk of death in elderly patients, and that they should not be substituted for atypical antipsychotics that were discontinued after the black-box warning.


There is great concern about the emergent adverse-effect profile of antipsychotic medications. That concern, coupled with the initial results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study showing comparable efficacy between most second-generation antipsychotics and the first-generation antipsychotic perphenazine, has made the question of whether we should continue to use first-generation antipsychotics--from an economic and tolerability perspective--a "hot" topic.

It is surprising how relatively little comparative information is available to cogently debate this issue, especially in light of the significance of and public interest in this topic. There are even fewer data available regarding antipsychotic medication use in elderly persons, for whom these medications are used primarily to reduce agitation-aggression rather than manage psychosis per se.

The use of antipsychotic medication in elderly persons has come under scrutiny because of analyses of studies that reported a higher rate of deaths from cardiovascular incidents in patients receiving second-generation antipsychotics. The FDA responded to this concern by requiring all second-generation antipsychotic agents to have a black-box warning stating that such medications are not approved for use in elderly patients with dementia.

This timely study by Wang and colleagues provides comparative data for first- and second-generation antipsychotic medication use in elderly patients. Surprisingly, the investigators found that the mortality rate was 37% higher among elderly patients receiving first-generation antipsychotics than among those receiving second-generation antipsychotics. This effect was most pronounced early in treatment and was more evident when higher doses of the first-generation agent were used.

A drawback of this study is that it does not report cause of death. Thus, the factors contributing to the differences in mortality are unknown. The findings of increased mortality early in treatment and with higher doses of first-generation agents could reflect that these agents were used in a sicker and perhaps more delirious elderly patient group. The results could be a consequence of patients' medical state, in which death was more likely during the time that these medications were prescribed. The article also outlines other potential explanations, including cardiovascular effects of antipsychotic medications.

The article poses the question of whether the FDA's black-box warning for all second-generation antipsychotics should be extended to first-generation agents. Whether this occurs or not, it further complicates the decision- making process for clinicians trying to ease suffering and the burden of care in agitated elderly patients.

Peter F. Buckley, MD Professor and Chairman Department of Psychiatry Medical College of Georgia Augusta