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Benzodiazepine use and risk of Alzheimer’s disease: case-control study

BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g5205 (Published 09 September 2014) Cite this as: BMJ 2014;349:g5205
  1. Sophie Billioti de Gage, PhD student1,
  2. Yola Moride, professor23,
  3. Thierry Ducruet, researcher2,
  4. Tobias Kurth, director of research45,
  5. Hélène Verdoux, professor16,
  6. Marie Tournier, associate professor16,
  7. Antoine Pariente, associate professor1,
  8. Bernard Bégaud, professor1
  1. 1INSERM, U657-Pharmacoepidemiology, Université de Bordeaux, F-33000 Bordeaux, France
  2. 2Research Center, University of Montreal Hospital Center, Montreal, Canada
  3. 3Faculty of Pharmacy, University of Montreal, Montreal, Canada
  4. 4Inserm Research Center for Epidemiology and Biostatistics, U897-Team Neuroepidemiology, F-33000 Bordeaux, France
  5. 5University of Bordeaux, College of Health Sciences, F-33000 Bordeaux, France
  6. 6Centre Hospitalier Charles Perrens, F-33000 Bordeaux, France
  1. Correspondence to: S Billioti de Gage sophie.billioti-de-gage{at}u-bordeaux.fr
  • Accepted 4 August 2014

Abstract

Objectives To investigate the relation between the risk of Alzheimer’s disease and exposure to benzodiazepines started at least five years before, considering both the dose-response relation and prodromes (anxiety, depression, insomnia) possibly linked with treatment.

Design Case-control study.

Setting The Quebec health insurance program database (RAMQ).

Participants 1796 people with a first diagnosis of Alzheimer’s disease and followed up for at least six years before were matched with 7184 controls on sex, age group, and duration of follow-up. Both groups were randomly sampled from older people (age >66) living in the community in 2000-09.

Main outcome measure The association between Alzheimer’s disease and benzodiazepine use started at least five years before diagnosis was assessed by using multivariable conditional logistic regression. Ever exposure to benzodiazepines was first considered and then categorised according to the cumulative dose expressed as prescribed daily doses (1-90, 91-180, >180) and the drug elimination half life.

Results Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51, 95% confidence interval 1.36 to 1.69; further adjustment on anxiety, depression, and insomnia did not markedly alter this result: 1.43, 1.28 to 1.60). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density (1.32 (1.01 to 1.74) for 91-180 prescribed daily doses and 1.84 (1.62 to 2.08) for >180 prescribed daily doses) and with the drug half life (1.43 (1.27 to 1.61) for short acting drugs and 1.70 (1.46 to 1.98) for long acting ones).

Conclusion Benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.

Footnotes

  • Contributors: SB, BB, YM, AP, HV, and TK contributed to the conception and design of the study. TD and YM contributed to data acquisition. SB and TD did the statistical analyses. All authors contributed to interpretation of the results. SB and BB drafted the manuscript. All authors critically revised the manuscript for important intellectual content. SB and TD had full access to all of the study data and take responsibility for the integrity of the data and the accuracy of the data analysis. TK and BB supervised the study. All the authors made a significant contribution to the research and the development of the manuscript and approved the final version for publication. SB and BB are guarantors.

  • Funding: This research was conducted by the INSERM (Institut National de la Santé et de la Recherche Médicale) and University of Bordeaux. Additional support was provided by unconditional grants from IRESP (Institut de Recherche en Santé Publique); the French Ministry of Health (Direction Générale de la Santé); and the Funding Agency for Health Research of Quebec (Fonds de la Recherche en Santé du Québec, FRSQ).

  • Competing interests: All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that TK has received investigator-initiated research funding from the French National Research Agency and the US National Institutes of Health within the past two years and honorariums from BMJ and Cephalalgia for editorial services; MT received honorariums as a speaker from Astra Zeneca, BMS, and Janssen; AP participated in studies conducted by the Clinical Research Center of the Bordeaux Teaching Hospital and funded by Novartis, Sanofi-Aventis, Lundbeck, and Vivatech, none of which were related to the present study.

  • Ethical approval: Protocol was approved by the research ethics committee of the Research Center of the University of Montreal Hospital Center (CRCHUM).

  • Data sharing: No additional data available.

  • Transparency declaration: SB and BB affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

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