FAQ
Antipsychotics and risk in patients with dementia
In 2005, the Food and Drug Administration (FDA) issued a warning regarding the use of atypical antipsychotics in elderly patients with dementia, which led to the addition of a boxed warning in the labeling of these agents. This warning was based on the results of an analysis of 17 placebo-controlled trials of atypical antipsychotics in 5106 elderly patients with dementia. A 1.6- to 1.7-fold increase in mortality was seen in these trials, primarily from cardiovascular and infectious causes.
Recently, the FDA has expanded this boxed warning to include all antipsychotics, adding the warning to conventional or first-generation agents. This most current warning is based on the analysis of 2 large, observational trials involving 27,000 to 30,000 patients. A summary of these 2 trials is given below.
Epidemiologic studies on the risk of mortality with antipsychotics
Gill and colleagues conducted a retrospective cohort study of patients 66 years of age and older with dementia to compare the effects of atypical antipsychotics, conventional antipsychotics, and no antipsychotic use on mortality. Antipsychotic use among patients with a diagnosis of dementia was identified using the Ontario Drug Benefit program. Only new antipsychotic use was included in the analysis; patients with a history or diagnosis of psychiatric disorders were excluded. The primary outcome of the study was all-cause mortality, assessed at 30, 60, 120, and 180 days after initiation of antipsychotics. Patients were stratified by place of residence—either community or long-term care facilities. A propensity score was utilized to match users of antipsychotics with non-users. A total of 27,259 matched pairs were included in the study. Based on multivariate analysis (which adjusted outcomes for factors such as age, sex, and comorbidities [e.g., cerebrovascular disease, pulmonary disease, heart failure, and diabetes]), new use of atypical and conventional antipsychotics was associated with an increase in mortality in both the community and long-term care settings at all timepoints compared to no antipsychotic use. For atypical antipsychotics, hazard ratios for mortality ranged from 1.29 to 1.32 for patients in the community and from 1.23 to 1.55 for those in long-term care (p=significant for all comparisons). Similar results were seen for conventional antipsychotics; hazard ratios for mortality among the community cohort ranged from 1.23 to 1.55 and 1.26 to 1.27 for long-term care (p=significant except for 180 day mortality in the community cohort [95% confidence interval (CI) 1.00 to 1.50]). The authors concluded that use of atypical antipsychotics may increase the risk of mortality among elderly patients with dementia, beginning at 30 days after initiation of treatment and persisting for up to 6 months. This effect may be more pronounced with conventional antipsychotics.
A similar study was conducted by Schneeweiss and colleagues. A prescription and medical services database was used to identify patients 65 years and older who received a new prescription for an antipsychotic, either an atypical or a conventional agent. All-cause mortality at 180 days was compared between patients taking atypical and conventional antipsychotics. A total of 37,241 patients were included in the analysis—12,882 given conventional antipsychotics and 24,359 an atypical antipsychotic. At 180 days, the mortality ratio for conventional versus atypical antipsychotics was 1.47 (95% CI 1.39 to 1.56). After adjustment for confounders such as age, sex, race, presence of comorbidities, other medication use, nursing home stays, and hospital admission, the risk of mortality remained higher with conventional antipsychotics (1.18 [95% CI 1.06 to 1.31]) compared to atypical agents. The authors concluded that the risk of mortality with conventional antipsychotics was comparable to, and likely greater than, that seen with atypical antipsychotics.
A third epidemiologic study was conducted to evaluate the risk of serious adverse events with short-term use of antipsychotics. Serious adverse events included extrapyramidal symptoms, cerebrovascular events, falls/hip fractures, acute care hospital admissions, and death. Using a population-based, retrospective cohort design, Rochon and colleagues reviewed data from medical records of elderly patients with dementia living in the community or long-term care setting who received antipsychotics. These outcomes were compared to a matched group of patients with no antipsychotic exposure. Over 40,000 patients (cases and controls) were included in the trial. Short-term use of antipsychotics, in either setting, was associated with a significant increase in the risk of a serious adverse event over no use. The odds ratios of an event were 3.19 (95% CI 2.77 to 3.68) and 1.92 (95% CI 1.68 to 2.21) for atypical antipsychotics compared to no use for community and long-term care settings, respectively. For conventional antipsychotics, the corresponding odds ratios were 3.81 (95% CI 3.31 to 4.39) and 2.38 (95% CI 2.08 to 2.72).
Summary
Based on the findings of 3 large epidemiologic studies, antipsychotics—atypical and conventional—may increase the risk of mortality as well as serious adverse events among elderly patients being treated for dementia. This increase in risk appears to be evident with short- and longer-term use, and can occur in both the community and long-term care settings. Although antipsychotics have some efficacy in the treatment of dementia in elderly patients, the risks of treatment should be considered. Current guidelines from the American Psychiatric Association recommend that, if antipsychotics are used, the lowest effective dose should be employed, with periodic attempts made to reduce the dose or discontinue the antipsychotic.
References
Gill S, Bronskill S, Normand S, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med. 2007;146(11):775-786.
Schneeweiss S, Setoguchi S, Brookhart A, Cormuth C, Wang P. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ. 2007;176(5):627-632.
Rochon P, Normand S, Gomes T, et al. Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Intern Med. 2008;168(10):1090-1096.
Work Group on Alzheimer’s Disease and Other Dementias. Practice guideline for the treatment of patients with Alzheimer’s disease and other dementia. 2nd edition. American Psychiatric Association. http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=AlzPG101007. Accessed June 25, 2008.