title: Terminal illness and the increased mortality risk of conventional antipsychotics in observational studies: a systematic review.
abstract: BACKGROUND
  Numerous large observational studies have shown an increased risk of mortality in elderly users of conventional antipsychotics. Health authorities have warned against use of these drugs. However, terminal illness is a potentially strong confounder of the observational findings. So, the objective of this study was to systematically assess whether terminal illness may have biased the observational association between conventional antipsychotics and risk of mortality in elderly patients.
  
  
  METHODS
  Studies were searched in PubMed, CINAHL, Embase, the references of selected studies and articles referring to selected studies (Web of Science). Inclusion criteria were (i) observational studies that estimated (ii) the risk of all-cause mortality in (iii) new elderly users of (iv) conventional antipsychotics compared with atypical antipsychotics or no use. Two investigators assessed the characteristics of the exposure and reference groups, main results, measured confounders and methods used to adjust for unmeasured confounders.
  
  
  RESULTS
  We identified 21 studies. All studies were based on administrative medical and pharmaceutical databases. Sicker and older patients received conventional antipsychotics more often than new antipsychotics. The risk of dying was especially high in the first month of use, and when haloperidol was administered per injection or in high doses. Terminal illness was not measured in any study. Instrumental variables that were used were also confounded by terminal illness.
  
  
  CONCLUSIONS
  We conclude that terminal illness has not been adjusted for in observational studies that reported an increased risk of mortality risk in elderly users of conventional antipsychotics. As the validity of the evidence is questionable, so is the warning based on it.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of General Practice, Groningen, The Netherlands.|Department of Geriatric Psychiatry, BAVO Europoort, Rotterdam, The Netherlands.
authors.forename: Hendrika J
authors.initials: HJ
authors.lastname: Luijendijk
authors.affiliation: Laurens Alzheimer's Care Research Center, Rotterdam, The Netherlands.|Novicare Geriatric Care Inc, Best, The Netherlands.
authors.forename: Niels C
authors.initials: NC
authors.lastname: de Bruin
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of General Practice, Groningen, The Netherlands.|Department of Health Sciences, VU University, Amsterdam, The Netherlands.
authors.forename: Tessa A
authors.initials: TA
authors.lastname: Hulshof
authors.affiliation: Department of Health Sciences, VU University, Amsterdam, The Netherlands.
authors.forename: Xander
authors.initials: X
authors.lastname: Koolman
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects*; D006801:Humans; D009026:Mortality / Q000639:trends*; D064887:Observational Studies as Topic / Q000379:methods; D012307:Risk Factors; D013727:Terminal Care / Q000379:methods / Q000639:trends*; D019452:Terminally Ill
chemical_list: D014150:Antipsychotic Agents
keywords: conventional antipsychotics; elderly; mortality; observational studies; pharmacoepidemiology; systematic review