Anticholinergic use and dementia
I am going to take a quick break from the Lyme series to discuss something that has a lot of people concerned: whether or not antihistamines cause dementia.
A paper released online this week (“Cumulative use of strong anticholinergics and incident dementia,” by Gray and colleagues, JAMA Internal Medicine) was widely interpreted by the general media as proving that anticholinergic use causes dementia. It doesn’t. Studies like this get a lot of attention by the media – including reputable media – and they get sensationalist headlines. This is generally not helpful. I think I have established well my distaste for tactics that scare the general public and this is a good example. Whether it is misinterpreted or intentionally misrepresented, news articles reporting on papers like this usually get it wrong.
Let’s look at what the paper actually says.
I actually like studies like this, because they have huge data sets to work with, and scientists usually like big data sets. (I’ll explain why that is in another post.) The study included 3434 patients 65 years of age or older who had no history of dementia when the study began. They were recruited to the study from 1994-1996 and then again from 2000-2003. Patients were followed up with every two years.
The purpose of this study was to determine if cumulative anticholinergic exposure over 10 years was linked to dementia, including Alzheimer’s disease. What is also interesting about this study is that the researchers had access to computerized pharmacy records for all these patients. This is important because it removes the uncertainty associated with patient reported information. The researchers developed values for anticholinergic medications so that different medications could be compared meaningfully.
A lot of medications are anticholinergic. The more common medications include some antihistamines, tricyclic antidepressants, some antipsychotics, antispasmodics for the GI tract, bladder antimuscarinic medications, and medications used to treat Parkinson’s disease. In various studies, 8-37% of adults over the age of 65 have been found to regularly use anticholinergics. Cognitive disturbances (with memory, attention, “feeling slow,” etc) are well known side effects of anticholinergic medications. Older adults are thought to be more sensitive to these effects because of age related changes to the central nervous system.
Most researchers feel that these cognitive deficits are reversible by discontinuing the offending medication. However, some researchers have found that these deficits may be sustained, culminating in a range of effects from mild cognitive impairment to dementia. These studies had some noted limitations: they did not have solid proof of medication dosages or usage; they did not have information regarding dose or duration of therapy; the follow up periods were short; and they did not account for anticholinergic use to manage insomnia and depression, which can be seen in early, undiagnosed Alzheimer’s. This last one is very important because then the association would not be that anticholinergics cause dementia, but that they are used to manage symptoms of dementia.
The researchers also tried to control for health status, like a self-reported “poor” health status; hypertension; diabetes; APOE gene status; coronary heart disease; depressive symptoms; and benzodiazepine use, among other things. Some of these data were self-reported and some used a proxy, like the use of benzodiazepines for sleep or anxiety disorders.
78.3% of patients filled at least one anticholinergic prescription in the ten years before the study started. Antidepressants, antihistamines and bladder antimuscarinics accounted for more than 90% of all anticholinergic exposure. The most common medications from each of those categories were doxepin, chlorpheniramine and oxybutynin.
23.2% of patients (797 people) developed dementia in a mean period of time of 7.3 years from entry into the trial. 79.9% of those patients (637) were diagnosed with Alzheimer’s disease. This study found that patients in the highest exposure category had a statistically significant increased risk for dementia or Alzheimer’s. Participants in the next highest exposure category had a slightly elevated risk for dementia and Alzheimer’s compared to people who did not use any anticholinergics.
This is the take home message: this study found that people who used higher amounts of anticholinergics had an increased risk of dementia. They found that people with the most exposure took at least one of the following medications daily for more than three years: oxybutynin chloride, 5mg; chlorpheniramine maleate, 4mg; olanzapine, 2.5mg; meclizine hydrochloride, 25mg; doxepin hydrochloride, 10mg.
However, the study does not find that the medications CAUSED dementia. This is really important. It’s important because it’s possible that the conditions that required these medications may be linked to dementia. Or that these medications taken in conjunction with other medications to treat specific conditions might cause the increased risk of dementia. This study found an association. It found that high use of anticholinergics was correlated to increased risk of dementia. It did not find that high use of anticholinergics CAUSED increased risk of dementia. Associations like this are called correlative, not causative.
This study was well done. This was good science. I am a big believer in reducing anticholinergics where possible. I have a lot of lower GI problems and my need for huge doses of anticholinergics pretty much ground my motility to a halt. So I think it’s a good idea to examine medication regimens and reduce anticholinergics if possible, simply for the fact that they cause a lot of side effects.
The reality is that mast cell patients generally cannot avoid taking high doses of anticholinergic medications. I did a previous post on anticholinergic activity of antihistamines, so feel free to refer there. This is a topic I will keep an eye on, but I want to be clear: there is not yet any proof that anticholinergic medications cause dementia or Alzheimer’s disease.
Grey, Shelley L., et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015.
Campbell, Noll L., Boustani, Malaz A. Adverse cognitive effects of medications: Turning attention to reversibility. JAMA Intern Med. 2015.
Cai X, et al. Long-term anticholinergic use and the aging brain. Alzheimers Dement. 2013; 9(4):377-385.
Fox C, et al. Anticholinergic medication use and cognitive impairment in the older population: the Medical Research Council Cognitive Function and Ageing Study. J Am Geriatr Soc. 2011;59(8):1477-1483.