Abstract and Introduction
Abstract
Objectives To investigate the relation between the risk of Alzheimer’s disease and exposure to benzodiazepines started at least five years before, considering both the dose-response relation and prodromes (anxiety, depression, insomnia) possibly linked with treatment.
Design Case-control study.
Setting The Quebec health insurance program database (RAMQ).
Participants 1796 people with a first diagnosis of Alzheimer’s disease and followed up for at least six years before were matched with 7184 controls on sex, age group, and duration of follow-up. Both groups were randomly sampled from older people (age >66) living in the community in 2000-09.
Main outcome measure The association between Alzheimer’s disease and benzodiazepine use started at least five years before diagnosis was assessed by using multivariable conditional logistic regression. Ever exposure to benzodiazepines was first considered and then categorised according to the cumulative dose expressed as prescribed daily doses (1-90, 91-180, >180) and the drug elimination half life.
Results Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51, 95% confidence interval 1.36 to 1.69; further adjustment on anxiety, depression, and insomnia did not markedly alter this result: 1.43, 1.28 to 1.60). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density (1.32 (1.01 to 1.74) for 91-180 prescribed daily doses and 1.84 (1.62 to 2.08) for >180 prescribed daily doses) and with the drug half life (1.43 (1.27 to 1.61) for short acting drugs and 1.70 (1.46 to 1.98) for long acting ones).
Conclusion Benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.
Introduction
Dementia is currently the main cause of dependency in older people and a major public health concern affecting about 36 million people worldwide. Because of population growth and demographic ageing, this number is expected to double every 20 years and to reach 115 million in 2050, resulting in tragic human consequences and social costs. As there are no effective treatments, the search for putative modifying factors remains a priority. Several studies have shown that benzodiazepine use could be one of these. This class of drugs is mainly used to treat anxiety or insomnia. Prevalence of use among elderly patients is consistently high in developed countries and ranges from 7% to 43%. International guidelines recommend short term use, mainly because of withdrawal symptoms that make discontinuation problematic. Although the long term effectiveness of benzodiazepines remains unproved for insomnia and questionable for anxiety, their use is predominantly chronic in older people.
While the acute deleterious effects of benzodiazepines on memory and cognition are well documented, the possibility of an increased risk of dementia is still a matter of debate. The frequency of symptoms highly correlated with prescription of benzodiazepines (anxiety, insomnia, and depressive disorders) increases in the years before a diagnosis of dementia. Hence, benzodiazepines might not cause the disease but rather be prescribed to treat its prodromes. Adjustment for such a reverse causality bias is not easy in observational studies as prodromes are often not recorded as such. It might consist in the demonstration of a delayed risk or in the censoring of information on exposures started during the suspected prodromal phase. Moreover, few studies published on the topic have had sufficient power to investigate a cumulative dose relation, which is a compelling argument in the assessment of a potentially drug induced outcome.
We evaluated the association between past benzodiazepine use and the risk of Alzheimer’s disease using an administrative claims database with a long follow-up period and investigated the potential dose-effect relation.