Anticholinergic Drugs Could Account for 10% of Dementia Cases

June 28, 2019

Further evidence showing that anticholinergic drugs are linked to the development of dementia has come from a new, large observational study.

In the case-control study, use of a strong anticholinergic drug at the standard dose for 3 years or more in middle-aged and older people was associated with an almost 50% increased risk of developing dementia.

Associations were strongest for the anticholinergic antidepressants, bladder antimuscarinics, antipsychotics, and antiepileptic drugs. Associations were also stronger in dementia cases diagnosed before the age of 80 years and in cases diagnosed with vascular dementia rather than Alzheimer's disease.

There were no significantly increased risks for antihistamines, gastrointestinal antispasmodics, antimuscarinic bronchodilators, antiarrhythmics, or skeletal muscle relaxants, although the numbers of patients prescribed skeletal muscle relaxants and antiarrhythmic drugs were small.

"All we can say from this data is that there is an association between use of anticholinergic drugs and the development of dementia. We cannot say that this is a causal effect from this observational study," lead author Carol Coupland, PhD, University of Nottingham, United Kingdom, told Medscape Medical News.

"It is possible that there may be other factors that we haven't measured that could explain the association," she added. "However, if the association is proven to be a causal effect, we can estimate from our results that anticholinergic drugs could be responsible for about 10% of new cases of dementia." 

Noting that several other observational studies have shown similar results, Coupland said, "I would suggest that, from what we know so far, clinicians should weigh up the potential benefits and the potential risks of these drugs for their individual patients and consider alternative treatments if possible. For most of these drugs, there are very reasonable alternatives that can be used."

The study was published online in JAMA Internal Medicine on June 24.

The researchers analyzed information from the UK QResearch primary care database, searching for patients who had had one or more of 56 different anticholinergic drugs prescribed and those who had had a diagnosis of dementia. 

They found 58,769 patients with a diagnosis of dementia and these were matched with 225,574 controls age 55 years or older matched by age, sex, general practice, and calendar time. Then, the use of anticholinergic drugs was examined in both cases and controls.

Results showed that individuals in the highest category of anticholinergic drug use (>1095 total standardized daily doses; equivalent to taking one anticholinergic drug daily at the standard dose for 3 years) in the 1 to 11 years before the index date had an adjusted odds ratio for developing dementia of 1.49 (95% confidence interval, 1.44 - 1.54) compared with those who had not taken anticholinergic drugs.

Because some of these drugs may be used for the treatment of early symptoms of dementia, the researchers excluded use of these drugs in the year before dementia was diagnosed in the main analysis. Results were also similar in other analyses where the use of anticholinergic drugs in the 3 or 5 years before dementia diagnosis was excluded.

Prospective "Deprescribing" Study Planned

Authors of an accompanying editorial note that the current study replicates findings from similar studies encompassing various international populations.

Coauthor Noll Campbell, PharmD, Purdue University College of Pharmacy, West Lafayette, Indiana, told Medscape Medical News that the current study adds some incremental new information. "The suggestion that this effect may be responsible for about 10% of new cases of dementia is new. I have not seen that quantified before," he said.

"That might not seem like a lot, but in the US there are about 500,000 new cases of dementia every year, so if this relationship is shown to be causal and we can get patients off these drugs, then that could prevent about 50,000 cases of dementia every year just in the US. To me, that's worth going after," he added. 

Campbell noted that studies in animals have also shown that blockade of acetylcholine causes accumulation of beta-amyloid in the brain similar to that seen in Alzheimer's disease. Similar changes, Campbell added, have been seen in the brains of patients with Parkinson's disease treated with anticholinergic drugs.

However, while the studies to date have shown that people who take anticholinergic drugs are more likely to be diagnosed with dementia, these data do not prove a causal link, Campbell stressed.

"The hypothesis is that there may be a window of time in which we may be able to modify the effects of neurotransmitters on the development of dementia. If this relationship is established to be causal, then it would be relatively easy to modify. Anticholinergic drugs can be stopped or swapped for alternatives," he said.

Campbell’s group is starting a prospective randomized "deprescribing" study to try and investigate causality more fully.

For the study, which is being funded by the National Institutes of Health, 350 patients on anticholinergic drugs are being randomly assigned to continue  taking the drugs or to stop (either stopping medication completely or switching to an alternative with a different mechanism). Patients will undergo cognitive tests at baseline and every 6 months and will be followed for 2 years.

"We know anticholinergic drugs can affect memory in the short term, so we would expect to see an improvement in cognition the first few months after stopping. But if they really do contribute to the development of dementia, we would expect to see a continuing separation of the two groups on performance in cognitive tests over the long term," Campbell explained.

Based on the information currently available, Campbell says he would still advise clinicians to think about preventing exposure to anticholinergic drugs if possible, particularly in older adults at risk of cognitive impairment.

"I would ask whether the drug is working, is it needed, and is it possible to use an alternative instead. This would be a precautionary measure, as we don't know if they are harmful or not yet, but in some cases we don't know if they are effective or not either."

In this study, investigators didn’t show a link between use of anticholinergic antihistamine drugs and dementia. "But many antihistamines are bought over the counter so a study analyzing prescription records is not the best way of measuring their use," Campbell said.

Beware of Confounding

Also commenting for Medscape Medical News, Mahyar Etminan, PharmD, University of British Columbia, Vancouver, Canada, said the major limitation of the current study is confounding by disease severity. "Patients who have conditions for which they take these drugs may already be at higher risk of developing dementia. This type of confounding cannot always be controlled in these studies," said Etminan, who was not involved with the study.

Another limitation is disease latency bias, he noted. "It can take 5 to 10 years for dementia to develop and show symptoms, so it is possible that the dementia/disease mechanism had already started before at least some of these patients took these drugs."

Etminan concluded that it's best to wait for future studies to validate these results and better control for the above biases. "Until then, I think the clinical message is to take these drugs only if patients are getting benefit from them, ie, improving symptoms and quality of life."

The current study was funded by the National Institute for Health Research (NIHR) School for Primary Care Research, and the Faculty of Medicine and Health Sciences Research Board, University of Nottingham.

JAMA Int Med. Published online June 24, 2019. Full text, Editorial

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