Professor Juan Carlos Kaski, St George’s University of London, UK

Abstract 

  1. Sophie Billioti de Gage, PhD student1,
  2. Yola Moride, professor23,
  3. Thierry Ducruet, researcher2,
  4. Tobias Kurth, director of research45,
  5. Hélène Verdoux, professor16,
  6. Marie Tournier, associate professor16,
  7. Antoine Pariente, associate professor1,
  8. Bernard Bégaud, professor1

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.

Full article in BMJ 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g5205 (Published 09 September 2014) Cite this as: BMJ 2014;349:g520

Cardio Debate Expert Comments

In today’s increasingly digital societies we are constantly aware of the impact of big data on our lives.  It is not always welcome or useful (think of unsolicited offers and advertisements resulting from analysis of internet usage). Examination of health records on a very large scale presents opportunities to test hypotheses that would take many years and millions of pounds to examine using conventional clinical research methods.

Billoti de Gage and colleagues examined the digital prescription records of 1800 people aged over 66 with a diagnosis of Alzheimer’s disease, and six or more years of clinical data prior to diagnosis, and compared the rate of benzodiazepine usage with that of 5176 matched controls. The risk of developing Alzheimer’s was 1.5 time higher in those with exposure to a drug from this class than in those without. Mindful of the possibility of ‘reverse causation’ (in this case, an increased tendency for those in the very early stages of the disease to be prescribed anxiolytic medication), the authors looked for, and found, a modest enhancement of the relative risk in those who had taken the drug for more than six months.

One interpretation is that these widely prescribed, very efficacious, and seldom harmful anxiolytics may accelerate or contribute to the unmasking symptoms of dementia in a vulnerable population.  Yet reverse causation cannot be eliminated, as the prodromal phase of Alzheimer’s disease can last for many years before a diagnosis can be made and are often either ignored, or misinterpreted as depression or anxiety.  Since benzodiazepines act enhance the effects of the inhibitory neurotransmitter GABA, and Alzheimer’s disease is associated with a deficit in the excitatory Acetylcholine pathways, a causative association is hard to support biologically, and this study alone is unlikely to lead to any alteration of prescription policy or guidelines without further evidence from animal, cell culture, or other biological models.