title: Quantifying the role of adverse events in the mortality difference between first and second-generation antipsychotics in older adults: systematic review and meta-synthesis.
abstract: BACKGROUND
  Observational studies have reported higher mortality among older adults treated with first-generation antipsychotics (FGAs) versus second-generation antipsychotics (SGAs). A few studies examined risk for medical events, including stroke, ventricular arrhythmia, venous thromboembolism, myocardial infarction, pneumonia, and hip fracture.
  
  
  OBJECTIVE
  1) Review robust epidemiologic evidence comparing mortality and medical event risk between FGAs and SGAs in older adults; 2) Quantify how much these medical events explain the observed mortality difference between FGAs and SGAs.
  
  
  METHODS
  Pubmed and Science Citation Index.
  
  
  METHODS
  Studies of antipsychotic users that: 1) evaluated mortality or medical events specified above; 2) restricted to populations with a mean age of 65 years or older 3) compared FGAs to SGAs, or both to a non-user group; (4) employed a "new user" design; (5) adjusted for confounders assessed prior to antipsychotic initiation; (6) and did not require survival after antipsychotic initiation. A separate search was performed for mortality estimates associated with the specified medical events.
  
  
  METHODS
  For each medical event, we used a non-parametric model to estimate lower and upper bounds for the proportion of the mortality difference-comparing FGAs to SGAs-mediated by their difference in risk for the medical event.
  
  
  RESULTS
  We provide a brief, updated summary of the included studies and the biological plausibility of these mechanisms. Of the 1122 unique citations retrieved, we reviewed 20 observational cohort studies that reported 28 associations. We identified hip fracture, stroke, myocardial infarction, and ventricular arrhythmias as potential intermediaries on the causal pathway from antipsychotic type to death. However, these events did not appear to explain the entire mortality difference.
  
  
  CONCLUSIONS
  The current literature suggests that hip fracture, stroke, myocardial infarction, and ventricular arrhythmias partially explain the mortality difference between SGAs and FGAs.
authors.affiliation: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, Massachusetts, United States of America; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Jackson
authors.affiliation: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, Massachusetts, United States of America; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schneeweiss
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: VanderWeele
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America; Gerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Deborah
authors.initials: D
authors.lastname: Blacker
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000401:mortality; D003704:Dementia / Q000188:drug therapy* / Q000401:mortality; D006620:Hip Fractures / Q000209:etiology / Q000401:mortality; D006801:Humans; D011014:Pneumonia / Q000209:etiology / Q000401:mortality
chemical_list: D014150:Antipsychotic Agents