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. 2012 Sep 27:345:e6231.
doi: 10.1136/bmj.e6231.

Benzodiazepine use and risk of dementia: prospective population based study

Sophie Billioti de Gage  1 , Bernard Bégaud, Fabienne Bazin, Hélène Verdoux, Jean-François Dartigues, Karine Pérès, Tobias Kurth, Antoine Pariente
Affiliations

Benzodiazepine use and risk of dementia: prospective population based study

Sophie Billioti de Gage et al. BMJ. .

Abstract

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.

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Conflict of interest statement

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.

Figures

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Fig 1 Follow-up scheme and study design for primary cohort analysis
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Fig 2 Identification of participants from PAQUID study followed up at T5 (follow-up at year 5 of PAQUID study) and eligible for main cohort analysis (no dementia and no prevalent benzodiazepine use)
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Fig 3 Dementia-free survival in PAQUID study, in new benzodiazepine users and non-users at baseline (T5)
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Fig 4 Pooled associations between new benzodiazepine use at follow-up years 5 (cohort T5), 8 (cohort T8), 10 (cohort T10), 13 (cohort T13), and 15 (cohort T15) and risk of subsequent dementia. Results adjusted for age, sex, schooling duration, singleness, wine consumption, use of antihypertensive drugs, use of antidiabetic agents, use of statins, use of platelet inhibitors or oral anticoagulants, depressive symptoms, and mini-mental state examination evolution between inclusion (T0) and 3 year follow-up visit (T3)
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Fig 5 Identification of participants from PAQUID study eligible for nested case-control analysis
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