Author Affiliations: Departments of Psychiatry
and the Behavioral Sciences (Dr Schneider and Ms Dagerman), Neurology (Dr
Schneider), and Department of Preventive Medicine (Mr Insel), Keck School
of Medicine, and Leonard Davis School of Gerontology (Dr Schneider), University
of Southern California, Los Angeles.
Context Atypical antipsychotic medications are widely used to treat delusions,
aggression, and agitation in people with Alzheimer disease and other dementia;
however, concerns have arisen about the increased risk for cerebrovascular
adverse events, rapid cognitive decline, and mortality with their use.
Objective To assess the evidence for increased mortality from atypical antipsychotic
drug treatment for people with dementia.
Data Sources MEDLINE (1966 to April 2005), the Cochrane Controlled Trials Register
(2005, Issue 1), meetings presentations (1997-2004), and information from
the sponsors were searched using the terms for atypical antipsychotic drugs
(aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), dementia, Alzheimer disease, and clinical trial.
Study Selection Published and unpublished randomized placebo-controlled, parallel-group
clinical trials of atypical antipsychotic drugs marketed in the United States
to treat patients with Alzheimer disease or dementia were selected by consensus
of the authors.
Data Extraction Trials, baseline characteristics, outcomes, all-cause dropouts, and
deaths were extracted by one reviewer; treatment exposure was obtained or
estimated. Data were checked by a second reviewer.
Data Synthesis Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration,
including 16 contrasts of atypical antipsychotic drugs with placebo met criteria
(aripiprazole [n = 3], olanzapine [n = 5], quetiapine
[n = 3], risperidone [n = 5]). A total of 3353 patients
were randomized to study drug and 1757 were randomized to placebo. Outcomes
were assessed using standard methods (with random- or fixed-effects models)
to calculate odds ratios (ORs) and risk differences based on patients randomized
and relative risks based on total exposure to treatment. There were no differences
in dropouts. Death occurred more often among patients randomized to drugs
(118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence
interval [CI], 1.06-2.23; P = .02; and
risk difference was 0.01; 95% CI, 0.004-0.02; P = .01).
Sensitivity analyses did not show evidence for differential risks for individual
drugs, severity, sample selection, or diagnosis.
Conclusions Atypical antipsychotic drugs may be associated with a small increased
risk for death compared with placebo. This risk should be considered within
the context of medical need for the drugs, efficacy evidence, medical comorbidity,
and the efficacy and safety of alternatives. Individual patient analyses modeling
survival and causes of death are needed.
Schneider LS, Dagerman KS, Insel P. Risk of Death With Atypical Antipsychotic Drug Treatment for Dementia: Meta-analysis of Randomized Placebo-Controlled Trials. JAMA. 2005;294(15):1934–1943. doi:10.1001/jama.294.15.1934
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