September 9, 2014

expert reaction to benzodiazepine use and Alzheimer’s disease

Researchers publishing in the British Medical Journal investigated a link between the use of benzodiazepine and Alzheimer’s disease in older patients.

Dr James Pickett, Head of Research at Alzheimer’s Society, said:

“With 1.5million people in the UK being prescribed benzodiazepines at any one time, evidence that their long-term use increases the risk of dementia is significant, and raises questions about their use. This research should not be used to condemn benzodiazepines completely, since their short-term use can have an important role in the management of anxiety and insomnia, but people and doctors should be aware of the longer-term risks associated with these drugs.”

“This report comes the day before the G7 Global Dementia Legacy Event in Canada where leaders will discuss how we tackle dementia through research. There are currently 850,000 people living with dementia in the UK, and with so few drugs available to treat Alzheimer’s disease, these findings show the need for us to look at how we might change prescription habits to reduce people’s risk of developing dementia.”

Dr Liz Coulthard, Consultant Senior Lecturer in Dementia Neurology, University of Bristol, said:

“This work provides yet another reason to avoid prescription of benzodiazepines for anything other than very short term relief of insomnia or anxiety. In addition to short term cognitive impairment, falls and car accidents already known to be associated with benzodiazepine use, there is a hint from this study that these drugs might in some way increase the risk of developing Alzheimer’s disease.”

“However, we know that Alzheimer’s disease pathology accumulates for up to 17 years prior to diagnosis and this study looked at benzodiazepine use well into the course of the pathological cascade in the disease. In addition, retrospective studies such as this cannot prove causation. Therefore there is still a possibility that, rather than causing Alzheimer’s disease, benzodiazepines tend to be prescribed to patients presenting with anxiety or insomnia as part of an as yet undiagnosed dementia.”

“To investigate further, future work should seek a plausible neurobiological mechanisms for the effect of benzodiazepines on Alzheimer’s pathology and, more broadly, the ongoing focus on earlier diagnosis of dementia will help associations to be teased apart from causative factors.”

Dr Eric Karran, Director of Research at Alzheimer’s Research UK, said:

“This study shows an apparent link between the use of benzodiazepines and Alzheimer’s disease although it’s hard to know the underlying reason behind the link.”

“One limitation of this study is that benzodiazepines treat symptoms such as anxiety and sleep disturbance, which may also be early indicators of Alzheimer’s disease. We know that the processes that lead to Alzheimer’s could start more than a decade before any symptoms show. This study looks at benzodiazepine use five to ten years before diagnosis, and so the disease is likely to have already been present in some people.”

“Benzodiazepines have been shown to cause memory problems as part of their side effects and so it is difficult to tease out cause and effect in studies such as this. We need more long-term research to understand this proposed link and what the underlying reasons behind it may be.”

Prof Gordon Wilcock, Emeritus Professor of Geratology, University of Oxford, said:

“This carefully conducted study provides convincing evidence that the use of benzodiazepines may contribute to the development of Alzheimer’s disease, and importantly may be another factor we could modify to reduce the occurrence of dementia. However, these drugs would have been given to treat symptoms and it is possible that the latter may have been the earliest signs of unrecognised Alzheimer’s disease, although the authors have tried to control for this as far as was possible in their study.  Ideally more research needs to be undertaken, but it will be difficult to do this prospectively as most clinicians would avoid long term prescription of these drugs in older people.”

Prof Guy Goodwin, President of the European College of Neuropsychopharmacology (ECNP), said:

“Many treatments can look bad because they are given to sick people. This is “Confounding by indication”, and is the bane of all epidemiological studies of drug exposure. This publication recognizes the problem but may not have an adequate solution. The finding that benzodiazepine exposure is associated with the diagnosis of Alzheimer’s disease 5 years or more later could mean that the drugs cause the disease, but is more likely to mean that the drugs are being given to people who are already ill. In other words, we are seeing an association, rather than a cause.”

“Non-specific symptoms arise in the 14 years before an Alzheimer diagnosis, so a 5 year study, as in this paper, may not be long enough to exclude what we call reverse causality; in other words symptoms in the early phases of Alzheimer’s disease may increase the probability of being prescribed a benzodiazepine. It is very difficult to control for this in most databases because the detail is insufficient to reconstruct the clinical reality.”

“Nevertheless, benzodiazepines can impair memory by their direct effect on the brain (unrelated to dementia), and their use in the elderly always merits caution and care to balance side-effects with benefits.”

Prof John Hardy, Professor of Neuroscience, UCL, said:

“The apparent association between benzodiazepines and Alzheimer’s disease is interesting and deserves further investigation.  There are many possible explanations: it could be a true association in that it reflects benzodiazepine use in the early stage of disease (this is the reverse causation discussed by the authors), it could be caused by benzodiazepine causing minor brain damage which is clinically additive to Alzheimer disease, there could be a direct relationship between benzodiazepine drug action and the disease process, or it could be a false positive, a statistical fluke.  Clearly more work is needed before any firm conclusions are drawn.  Clinicians are already careful about benzodiazepine prescribing so I would not regard this unexplained and as of yet unreplicated study as cause for any alarm.”

‘Benzodiazepine use and risk of Alzheimer’s disease: case-control study’ by Billioti de Gage et al. published in The BMJ on Tuesday 9th September.

Declared interests

Prof John Hardy consults for Eisai Pharmaceuticals on the biology of Alzheimer’s disease

Prof Guy Goodwin has acted as a consultant to most large pharmaceutical companies (but not in relation to benzodiazepines).

Dr Liz Coulthard has received grants from ARUK, BRACE and NIHR and her research group have one industry study with Takeda (the TOMMORROW study into early stage Alzheimer’s disease).

Dr Eric Karran, Prof Gordon Wilcock & Dr James Pickett have no interests to declare.