Benzodiazepine use and risk of dementia: prospective population based studyBMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e6231 (Published 27 September 2012) Cite this as: BMJ 2012;345:e6231
- Sophie Billioti de Gage, PhD student12,
- Bernard Bégaud, professor123,
- Fabienne Bazin, researcher12,
- Hélène Verdoux, professor124,
- Jean-François Dartigues, professor153,
- Karine Pérès, researcher15,
- Tobias Kurth, director of research167,
- Antoine Pariente, associate professor123
- 1Université Bordeaux Segalen, F-33000 Bordeaux, France
- 2INSERM, U657, F-33000 Bordeaux
- 3CHU de Bordeaux, F-33000 Bordeaux
- 4Centre Hospitalier Charles Perrens, F-33000 Bordeaux
- 5INSERM, U897, F-33000 Bordeaux
- 6Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- 7INSERM, U708-Neuroepidemiology, F-33000 Bordeaux,
- Correspondence to: S Billioti de Gage or B Bégaud, Université Bordeaux Segalen, INSERM U657, 146 rue Léo Saignat, F-33076, Bordeaux cedex, France or
- Accepted 4 September 2012
Objective To evaluate the association between use of benzodiazepines and incident dementia.
Design Prospective, population based study.
Setting PAQUID study, France.
Participants 1063 men and women (mean age 78.2 years) who were free of dementia and did not start taking benzodiazepines until at least the third year of follow-up.
Main outcome measures Incident dementia, confirmed by a neurologist.
Results During a 15 year follow-up, 253 incident cases of dementia were confirmed. New use of benzodiazepines was associated with an increased risk of dementia (multivariable adjusted hazard ratio 1.60, 95% confidence interval 1.08 to 2.38). Sensitivity analysis considering the existence of depressive symptoms showed a similar association (hazard ratio 1.62, 1.08 to 2.43). A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia. The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46 (1.10 to 1.94). Results of a complementary nested case-control study showed that ever use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia (adjusted odds ratio 1.55, 1.24 to 1.95) compared with never users. The results were similar in past users (odds ratio 1.56, 1.23 to 1.98) and recent users (1.48, 0.83 to 2.63) but reached significance only for past users.
Conclusions In this prospective population based study, new use of benzodiazepines was associated with increased risk of dementia. The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study. Considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects of this drug class in the general population, indiscriminate widespread use should be cautioned against.
We thank Catherine Helmer (INSERM U897 and Université Bordeaux Segalen, Bordeaux, France) for her valuable comments on the results and manuscript and Marie Tournier (INSERM U657 and Université Bordeaux Segalen, Bordeaux, France) for her comments on the protocol and analytic approach.
Contributors: SBdG did the statistical analysis, interpreted the results, and drafted the manuscript. BB contributed to the design of the study, interpreted the results, and participated in the writing and editing of the manuscript. FB oversaw and contributed to the statistical analysis. HV contributed to definition of benzodiazepine exposure and depressive symptoms and critically revised the manuscript. J-FD and KP provided all necessary information about the PAQUID cohort, prodromal dementia, and diagnosis of dementia and revised the manuscript. TK and AP equally contributed to the study design and protocol development, interpretation of results, and manuscript writing and editing. All the authors made a significant contribution to the research and the development of the manuscript and approved the final version. SBdG and BB are the guarantors.
Funding: This research was conducted by the INSERM U657 research team co-funded by INSERM (Institut National de la Santé et de la Recherche Médicale) and Université Bordeaux Segalen. Additional support was provided by a 2010 grant from IRESP (Institut de Recherche en Santé Publique) acting on behalf of the French Ministry of Health (Direction Générale de la Santé, Direction de la Recherche, des Études, de l’Évaluation et des Statistiques); by a 2011 grant from the French Ministry of Health (Direction Générale de la Santé); and by Caisse Nationale des Travailleurs Salariés, Régime Social des Indépendants, Caisse Nationale de Solidarité pour l’Autonomie, and Institut National de Prévention et d’Education pour la Santé.
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 this study has been funded only by academic research funds; no financial relationships with any organisation or company that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. SBdG is a part time researcher in the INSERM 657 Unit, and her salary is paid by IRESP. BB has received investigator initiated research funding from the French Health Ministry (2011); he is chair of the scientific committee for two pharmacoepidemiological studies conducted by the contract research organisation LA-SER (London): one on medicines used in osteoarthritis, the other on the use of homeopathic remedies by French practitioners. HV has received funding from the French Association de Recherche sur le Cancer (ARC) for a research project on psychotropic drugs and breast cancer. J-FD has received grants from IPSEN and Novartis and honorariums from Merck, Serono, Novartis, and Ipsen. TK has received investigator initiated research funding from the French National Research Agency, the US National Institutes of Health, the Migraine Research Foundation, and the Parkinson’s Disease Foundation; he has received honorariums from Allergan, the American Academy of Neurology, and Merck for educational lectures and from MAP Pharmaceutical for contributing to a scientific advisory panel; he receives honorariums from the BMJ for editorial services. AP has received investigator initiated research funding from the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS) and from IRESP; he has participated in research funded by the Fonds de la Recherche en Santé du Québec (FRSQ), the Réseau Québécois de Recherche sur l’Utilisation des Médicaments (RQRUM), the European Union (FP7 grants), the Innovative Medicines Initiative (IMI grant), and Sanofi-Aventis.
Ethical approval: The PAQUID study was approved by the ethics committee of the University of Bordeaux Segalen (France) in 1988, and each participant provided written informed consent.
Data sharing: No additional data available.
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