BERLIN – Chronic use of benzodiazepines by elderly patients is associated with a 43%-51% increased risk of being diagnosed with Alzheimer’s disease 5-10 years later, according to a large case-control study. “Considering the extent to which benzodiazepines are prescribed in the elderly population and the growing incidence of dementia, unwarranted chronic use of benzodiazepines in the elderly should be viewed as a public health issue,” Sophie Billioti de Gage said at the annual congress of the European College of Neuropsychopharmacology.
Her case-control study used the Quebec health insurance database. The subjects were 1,796 elderly individuals diagnosed with Alzheimer’s disease, each matched with 4 controls based upon age, gender, and duration of follow-up. The Quebec database permitted identification of all subjects with prescriptions for benzodiazepines during 2000-2009, a period 5-10 years prior to diagnosis of Alzheimer’s disease. This substantial time lag was chosen because previous studies reporting a link between benzodiazepines and dementia have often been criticized for possible confounding due to reverse causality. That is, because many earlier studies featured a shorter interval between medication use and dementia diagnosis, skeptics argued that benzodiazepines might not have caused the dementia but rather were prescribed to treat early manifestations of the disease, such as anxiety, depressive symptoms, and insomnia, explained Ms. Billioti de Gage, a PhD student at the University of Bordeaux (France).
Sophie Billioti de Gage
The database enabled her to determine how many cumulative days worth of benzodiazepine prescriptions participants filled during the study years, as well as whether the medications had a short or long half-life.
In a multivariate analysis adjusted for stroke, MI, hypertension, diabetes, and use of antiplatelet agents or anticoagulants during the period 5-10 years prior to diagnosis of Alzheimer’s disease, the use of benzodiazepines was independently associated with a 51% increased risk of subsequent Alzheimer’s compared with nonusers.
A dose-response relationship was apparent. Individuals with prescriptions for up to 90 days worth of benzodiazepines were not at significantly greater risk for future Alzheimer’s disease than nonusers. Those with a cumulative 91- to 180-day exposure had a 32% increased risk, compared with nonusers, however, and patients with more than 180 days of benzodiazepine use had an 84% increased risk.
The association with later Alzheimer’s disease was stronger in patients who used benzodiazepines with a half-life of 20 hours or longer. In a multivariate analysis they had a 70% greater risk of Alzheimer’s, compared with nonusers. Patients who used a benzodiazepine having a half-life of less than 20 hours had a 43% increase in risk.
When the multivariate analyses were further adjusted for anxiety, depressive symptoms, and insomnia – all of which can be prodromes of dementia – the results were not meaningfully altered, she added.
This case-control study confirms the results of an earlier prospective population-based study by Ms. Billioti de Gage and coworkers. That French study also found a roughly 50% increased risk of dementia in elderly patients who initiated chronic benzodiazepine therapy (BMJ 2012;345:e6231 [doi: 10.1136/bmj.e6231]). However, with only 1,063 participants, 253 of whom were diagnosed with dementia during 15 years of follow-up, the sample size was too small to draw firm conclusions. The current case-control study, with 8,980 subjects representative of the Quebec community-dwelling elderly population, is more persuasive, the investigator said.
Guidelines recommend preferential use of short half-life benzodiazepines and short durations of use in the elderly; however, in clinical practice the medications are often used long-term.
The biologic mechanism by which chronic use of benzodiazepines by elderly individuals might predispose to Alzheimer’s disease hasn’t been worked out, but the medications’ short-term adverse impact on memory and cognition are well recognized.
The case-control study was funded by the French Ministry of Health and the Funding Agency for Health Research of Quebec as well as by university grants.