title: Mediators of First- Versus Second-generation Antipsychotic-related Mortality in Older Adults.
abstract: BACKGROUND
  Observational studies of older adults showed higher mortality for first-generation antipsychotics than their second- generation counterparts, which led to US Food and Drug Administration warnings, but the actual mechanisms involved remain unclear.
  
  
  METHODS
  A cohort of 9,060 initiators of first-generation antipsychotics and 17,137 of second-generation antipsychotics enrolled in New Jersey and Pennsylvania Medicare were followed for 180 days. Medical events were assessed using diagnostic and procedure codes on inpatient billing claims. For the individual and joint set of medical events (mediators), we estimated the total, direct, and indirect effects of antipsychotic type (first versus second generation) on mortality on the risk ratio scale and the proportion mediated on the risk difference scale, obtaining 95% confidence intervals through bootstrapping. We performed bias analyses for false-negative mediator misclassification in claims data, with sensitivity ranging from 0.25 to 0.75.
  
  
  RESULTS
  There were 3,199 deaths (outcomes), 862 cardiovascular events, 675 infectious events, and 491 hip fractures (potential mediators). Mortality was higher for first- than second-generation antipsychotic initiators (adjusted risk ratio: 1.14; 95% confidence interval: 1.06, 1.22). In naïve analyses, that ignored potential misclassification, less than 4% of this difference was explained by any particular medical event. In bias analyses, the proportion mediated ranged from 6% to 16% for stroke, 3% to 9% for ventricular arrhythmia, 3% to 11% for myocardial infarction, 0% venous thromboembolism, 3% to 9% for pneumonia, 0% to 1% for other bacterial infection, and 1% to 3% for hip fracture.
  
  
  CONCLUSIONS
  Acute cardiovascular events and pneumonia may explain part of the mortality difference between first- and second-generation antipsychotic initiators in this analysis.
authors.affiliation: From the aDivision of Pharmacoepidemiology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; bDepartment of Epidemiology, cDepartment of Biostatistics, Harvard School of Public Health, Boston, MA; and dGerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital & Harvard Medical School, Boston, MA.
authors.forename: John W
authors.initials: JW
authors.lastname: Jackson
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: VanderWeele
authors.forename: Deborah
authors.initials: D
authors.lastname: Blacker
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schneeweiss
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000401:mortality; D002423:Cause of Death; D015987:Effect Modifier, Epidemiologic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016015:Logistic Models; D008297:Male; D006278:Medicare; D009515:New Jersey / Q000453:epidemiology; D010414:Pennsylvania / Q000453:epidemiology; D011014:Pneumonia / Q000401:mortality; D012189:Retrospective Studies; D012307:Risk Factors; D014481:United States
chemical_list: D014150:Antipsychotic Agents