Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based studyBMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i90 (Published 02 February 2016) Cite this as: BMJ 2016;352:i90
- Shelly L Gray, professor1,
- Sascha Dublin, associate scientific investigator2,
- Onchee Yu, senior biostatistician2,
- Rod Walker, biostatistician2,
- Melissa Anderson, senior biostatistician2,
- Rebecca A Hubbard, associate professor3,
- Paul K Crane, associate professor4,
- Eric B Larson, executive director2
- 1School of Pharmacy, University of Washington, Seattle, WA 98195-7630, US
- 2Group Health Research Institute, Group Health Cooperative, Seattle, WA, US
- 3Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, US
- 4University of Washington Department of Medicine, Division of General Internal Medicine, Seattle, WA, US
- Correspondence to: S Gray
Objective To determine whether higher cumulative use of benzodiazepines is associated with a higher risk of dementia or more rapid cognitive decline.
Design Prospective population based cohort.
Setting Integrated healthcare delivery system, Seattle, Washington.
Participants 3434 participants aged ≥65 without dementia at study entry. There were two rounds of recruitment (1994-96 and 2000-03) followed by continuous enrollment beginning in 2004.
Main outcomes measures The cognitive abilities screening instrument (CASI) was administered every two years to screen for dementia and was used to examine cognitive trajectory. Incident dementia and Alzheimer’s disease were determined with standard diagnostic criteria. Benzodiazepine exposure was defined from computerized pharmacy data and consisted of the total standardized daily doses (TSDDs) dispensed over a 10 year period (a rolling window that moved forward in time during follow-up). The most recent year was excluded because of possible use for prodromal symptoms. Multivariable Cox proportional hazard models were used to examine time varying use of benzodiazepine and dementia risk. Analyses of cognitive trajectory used linear regression models with generalized estimating equations.
Results Over a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia, of whom 637 developed Alzheimer’s disease. For dementia, the adjusted hazard ratios associated with cumulative benzodiazepine use compared with non-use were 1.25 (95% confidence interval 1.03 to 1.51) for 1-30 TSDDs; 1.31 (1.00 to 1.71) for 31-120 TSDDs; and 1.07 (0.82 to 1.39) for ≥121 TSDDs. Results were similar for Alzheimer’s disease. Higher benzodiazepine use was not associated with more rapid cognitive decline.
Conclusion The risk of dementia is slightly higher in people with minimal exposure to benzodiazepines but not with the highest level of exposure. These results do not support a causal association between benzodiazepine use and dementia.
We thank Susan McCurry, Wayne McCormick, and James Bowen, who participated in multidisciplinary consensus committee meetings that determined study participants’ dementia status. This paper was presented at the 20th Annual HMO Research Network Conference in Phoenix, AZ, on 3 April 2014.
Contributors: SLG, MA, SD, RW, RAH, OY, and EBL contributed to study conception and design; all authors contributed to acquisition, analysis, or interpretation of data; SLG and OY drafted the manuscript; all authors revised the manuscript for critical intellectual content; OY conducted statistical analyses; and SD, EBL, and PKC obtained funding. All authors had full access to all of the data (including statistical reports and tables) in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. SLG and EBL are guarantors.
Funding: This work was supported by National Institute on Aging (NIH Grants U01AG00678 (EBL), R03AG042930 (SD)) and by the Branta Foundation (SD). The sponsors had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; or in preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that SD received a Merck/American Geriatrics Society New Investigator Award; EB receives royalties from UpToDate; RW received funding as a biostatistician from a research grant awarded to Group Health Research Institute from Pfizer; OY received funding as a biostatistician from research grants awarded to Group Health Research Institute from Amgen and Bayer.
Ethical approval: The research protocol for this study was approved by the institutional review boards of Group Health and University of Washington. Written informed consent was obtained from all participants.
Transparency declaration: SLG affirms 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 (and, if relevant, registered) have been explained.
Data sharing: No additional data available.
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