Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study

Abstract

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.

Fig 1 Sample for analyses of dementia and cognitive trajectory in Adult Changes in Thought (ACT) study

Fig 2 Scheme for exposure definition for dementia and cognitive trajectory analyses. For analyses of dementia, a rolling 10 year window was used to define our time varying exposures. At each time point during follow-up, the 10 year cumulative exposure for all participants at risk is recalculated by summing all of their benzodiazepine use in the previous 10 years. The most recent year was excluded because of concerns about possible use for prodromal symptoms (shaded area). For analyses of cognitive trajectory, the circle at the far right represents a study visit at which the cognitive test was administered. Here, the year immediately before a study visit is not excluded from the cumulative use measure because by design, no participants could have a diagnosis of dementia at the time of a study visit included in these analyses. Recent exposure is defined as use in the six months immediately before the visit

Fig 3 Hazard ratios for all cause dementia and Alzheimer’s disease for each level of cumulative benzodiazepine exposure compared with no use. Multivariable models adjusted for study cohort, age at study entry, sex, educational level, hypertension, diabetes mellitus, current smoking, stroke, coronary heart disease, BMI, regular exercise, self rated health, and depressive symptoms

Fig 4 Association between cumulative benzodiazepine use modeled as spline and risk of incident dementia or Alzheimer’s disease