June 24, 2019

expert reaction to anticholinergic drug exposure and risk of dementia

Research published in JAMA Internal Medicine demonstrates that exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia.

Dr Ian Maidment, Reader in Clinical Pharmacy, Aston University, said:

 “This is an important study that adds to the evidence, from two other studies – one in the USA and in the UK – that medications that block a key chemical in the brain (acetylcholine) are associated with dementia. The team appear to have accounted for important confounders, but the possibility of unknown confounders remains; therefore we can’t be 100% sure that the medicines have caused dementia, or about the size of any effect.

“Anyone taking these medications shouldn’t suddenly stop taking the medication, but discuss their concerns with their GP, pharmacist or nurse.

“Regular medication reviews by a doctor, pharmacist or nurse are also important to see if these medication can be safely stopped (de-prescribing), or whether there is a safer alternative medication.”

Dr Justin Sauer, Consultant Psychiatrist, Clinical Lead for Memory Services, Mental Health of Older Adults & Dementia, South London and Maudsley NHS Foundation Trust

 “Drugs with a high anticholinergic burden have long been suspected to increase the risk of dementia in susceptible individuals.  This research has reviewed a large population and demonstrates a link between some of these medications and dementia risk.

“This is an important finding which confirms the need for caution in the use of these medicines, particularly for people in late middle age and beyond.  Additionally, this research adds weight to the need for regular reviews of prescribed medicine by health care professionals.

“All older adults in our services have their medication reviewed at medichec.com with advice to their GPs where there is a high cholinergic burden.  However, it is important that patients do not suddenly stop their medication as this may be detrimental but should seek advice from their doctor if there are any concerns.”

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

“Our own researchers have already shown a strong link between anticholinergic drugs and risk of dementia. This study builds on this information, showing that long-term, high-dose use increases risk of some dementias, particularly vascular dementia.

“A shortcoming of this type of study is that from this information we can’t rule out whether the diseases that cause dementia might have already begun in the brains of people involved before they started taking these drugs. Our ongoing research at the University of East Anglia is exploring whether anticholinergic bladder drugs could increase risk by following people while they take the drug. This research will tell us whether these drugs can cause dementia and how they might be doing it.

“Current guidelines for doctors say that anticholinergic drugs should be avoided for frail older people because of their impact on memory and thinking, but doctors should consider these new findings for all middle aged and older people as we continue to learn more about long-term use and the risk of dementia.”

Prof Parastou Donyai, Professor of Social and Cognitive Pharmacy at the University of Reading, said: 

“This is the latest research to ask if blocking a major brain chemical (acetylcholine), by giving certain medicines, makes patients more likely to develop dementia years later. The main recommendation ties in well with current advice for doctors to be careful when using medicines that block this chemical (anticholinergic drugs) in older people, those who are frail and in others with numerous health conditions. The authors’ advice extends to people who are 55 years of age or older.

“The paper links the prescribing of anticholinergic drugs with higher chances of developing both Alzheimer’s disease and vascular dementia. But the two conditions are very different, so the authors need to give a clear reason on how the drugs might be linked with both; Alzheimer’s disease is linked to proteins gathered in the brain whereas vascular dementia happens because less blood gets to the brain. 

“Importantly, in this type of study researchers give their advice by looking at the prescriptions that doctors were writing over a long period of time. They then imagine that patients genuinely take the medicines as prescribed for them. But we know from other research that people only take medication as prescribed around half of the time – the other half, people either take more or less of their medication or not at all. This problem of ‘non-adherence’ is well-known in people with a range of conditions, including diseases treated with anticholinergic drugs, so we want to be careful not to add to the problem. We have to remember that the paper looked at the ‘prescribing’ of drugs rather than the ‘taking’ of these medicines. Anyone worried about taking their medication as a result of this paper should speak to their doctor or pharmacist first and not suddenly stop their medication.”

Dr Jana Voigt, Head of Research at Alzheimer’s Research UK, said:
“There is a growing body of evidence that suggests certain anticholinergic drugs are linked to an increased dementia risk.

“In this well-conducted study, researchers looked at the information stored in thousands of people’s health records. While finding a link between certain strong anticholinergic drugs and an increased risk of dementia, it doesn’t tell us if these drugs cause the condition.

“Interestingly strong anticholinergic drug use was associated with a higher risk of vascular dementia than Alzheimer’s disease, but the mechanisms behind this observation are unclear.

“Current NICE guidelines for dementia reference the risk of cognitive impairment for those taking strong anticholinergic drugs and recommends doctors try to look for alternatives. Anticholinergics can have beneficial effects that doctors need to carefully weigh against any potential side effects. Anyone who is worried about their medication should seek advice from their GP before stopping any course of treatment.”

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine (LSHTM), said:

“This study has been reasonably well conducted though there are some questions about some of the analysis. The authors are cautious when they say “This observational study has shown associations, but is not able to evaluate causality” but then go on to assume it when they say, “anticholinergic drugs should be prescribed with caution in middle-aged and older people”. Their calculations of absolute effects are to be commended but must be treated with great caution since the size of effect may be exaggerated because of inevitable bias in this type of study.

“There are a number of reasons why the caution is justified, and a non-causal interpretation is not only compatible with these results, but may well be more likely than a causal one. For example, the odds of being aged 95 or over are 1.7 (a greater risk than any of the anticholinergic effects seen, and a dramatically statistically significant result) in spite of matching by age. There is a significantly increased rate of recording of BMI so that the case patients were probably attending their GP practice at a higher rate. The effects are not seen in anticholinergic drugs given for muscle relaxants or gastrointestinal problems (which are not associated with dementia) while the drugs that show an effect are for conditions also associated with dementia.

“While it is certainly possible that there is a causal effect, it is unwise to assume it and to ignore the benefits of these drugs for most patients. Stopping treatments that are providing benefits to patients can have unintended harmful consequences.”

Prof Tara Spires-Jones, UK Dementia Research Institute Programme Lead and Deputy Director, Centre for Discovery Brain Sciences, University of Edinburgh, said:

“This study led by Prof Carol Coupland at the University of Nottingham has found an association between taking anticholinergic medications and increased risk of developing dementia.   This is a robust study examining data from a large number of people – over 55,000 people with dementia and over 225,000 people without dementia.  The scientists observed that using some anticholinergic treatments was associated with an almost 50% increase in risk of developing dementia compared to people who did not use these medications.  This kind of observational study cannot determine whether the increased risk is due to the medications or another related factor. For example, Parkinson’s and depression are both risk factors for dementia so it is possible that the increased risk of dementia was due to these diseases and not the anticholinergic drugs being used to treat them. 

“This study is important because if the observed association between anticholinergic drugs and dementia turns out to be causative, these drugs could be causing around 10% of new dementia diagnoses.  While this is a well conducted study, it is important to note that it is not yet certain that these anticholinergic drugs cause dementia, while it is certain that they help many people with other health problems.  Thus, while this will be important for scientists to study further, it does not support people discontinuing their current medications without consulting their doctors.”

Prof Clive Ballard, Professor of Age-Related Diseases at the University of Exeter Medical School, said:

 “This is a very important finding with enormous and very practical implications that could improve brain health. We do need to consider two important caveats. Firstly, anticholinergics may impair cognition, but from this study it’s more difficult to determine whether this is a potentially reversible problem or a genuine progressive cognitive decline. Secondly, some of these drugs may be more likely to be prescribed to people with emerging problems such as psychiatric symptoms and urinary incontinence – which may reflect people already at increased risk of cognitive decline. Despite those caveats, anticholinergics are clearly damaging cognitive health – and these key implications for prescribing and clinical practice can be taken into account to improve cognitive health.”

‘Anticholinergic Drug Exposure and the Risk of Dementia, A Nested Case-Control Study’ by Carol A. C. Coupland et al. was published in JAMA Internal Medicine at 16:00 UK time on Monday 24th June.

Declared interests

Dr Ian Maidment: A potential conflict of interest – Richardson K, Fox C, Maidment I, Steel N, Loke YK, Arthur A, Myint PK, Grossi CM, Mattishent K, Bennett K, Campbell NL, Boustani M, Robinson L, Brayne C, Matthews FE, Savva GM. 2018. Anticholinergic drugs and risk of dementia: case-control study. BMJ. 361:k1315. doi: 10.1136/bmj.k1315 

Dr Justin Sauer: No conflicts of interest. Justin is a founder of medichec/AEC which is a free to use SLaM tool with no financial gain.

 Dr James Pickett: No conflicts of interest. 

Prof Parastou Donyai: No declarations of interest.

Dr Jana Voigt: No conflicts of interest 

Prof Stephen Evans: I have no conflict of interest to declare other than that I was a co-author of a response to a BMJ paper on this topic.

Prof Tara Spires-Jones: I have no conflicts with this study.

Prof Clive Ballard: No conflicts of interest.

doi:10.1001/jamainternmed.2019.0677