title: Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Published and unpublished randomized placebo-controlled, parallel-group clinical trials of atypical antipsychotic drugs marketed in the United States to treat patients with Alzheimer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.
  
  
  METHODS
  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.
  
  
  RESULTS
  Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo met criteria (aripiprazole [n = 3], olanzapine [n =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.
authors.affiliation: Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, USA. lschneid@usc.edu
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
authors.forename: Karen S
authors.initials: KS
authors.lastname: Dagerman
authors.forename: Philip
authors.initials: P
authors.lastname: Insel
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects*; D002561:Cerebrovascular Disorders / Q000139:chemically induced* / Q000401:mortality; D003704:Dementia / Q000188:drug therapy* / Q000401:mortality*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D012306:Risk
chemical_list: D014150:Antipsychotic Agents