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Do anticholinergic medications increase the risk of long-term cognitive decline and dementia? In this podcast, we will review the latest research examining the relationship between anticholinergic medication use and cognitive decline.

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Published On: 05/02/2022

Duration: 15 minutes, 58 seconds

Referenced Article: “Anticholinergic Drugs and Risk of Cognitive Impairment and Dementia,” The Carlat Hospital Psychiatry Report, October/November/December 2021

Victoria Hendrick, MD, Zachary N. Davis, BS, and Shelly Gray, PharmD, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

Transcript:

Dr. Hendrick: Do anticholinergic medications increase the risk of long-term cognitive decline and dementia? We discussed this topic with Dr. Shelly Gray in the October/November/December 2021 issue of The Carlat Hospital Psychiatry Report. Dr. Gray is a Professor and Plein Endowed Director at the Plein Center for Geriatric Pharmacy Research at the University of Washington School of Pharmacy. In this podcast, we will review the research examining the relationship between anticholinergic medication use and cognitive decline.

Welcome to The Carlat Psychiatry Podcast

This is a special episode from The Carlat Hospital Psychiatry Report.

I’m Dr. Victoria Hendrick, the Editor-in-Chief of The Carlat Hospital Psychiatry Report, and a clinical professor at the David Geffen School of Medicine at UCLA. I’m also the director of inpatient psychiatry at Olive View — UCLA Medical Center.

Zachary Davis: And I’m Zachary Davis. I graduated from UC Santa Cruz with a BS degree in neuroscience, and I’m a content-coordinator at Carlat Publishing. I write CME questions, podcast scripts, and I edit podcasts too. I’m also a pre-med student who’ll be applying to medical school next year, and I’ll be joining Dr. Hendrick on this podcast.

Dr. Gray’s research mainly focuses on the risk of adverse events, like dementia, falls, and fractures, associated with medication use in elderly patients. What has she found in her research about the use of  anticholinergic medications and the development of dementia/long-term cognitive decline in the elderly?

Dr. Hendrick: She found that elderly patients with a higher cumulative exposure to anticholinergic agents were significantly more likely to receive a dementia diagnosis after an average of seven years of anticholinergic use, compared to nonusers. The elderly subjects involved in this study did not have a diagnosis of dementia prior to entering the study. 

Zachary Davis: Have other studies found similar results?

Dr. Hendrick: Yes! To give an example, a case-control study, by Richardson and colleagues, of over 40,000 older adult patients reported that certain classes of anticholinergic medications were strongly associated with higher risk of new-onset dementia. 

Zachary Davis: Another study, which looked at nearly 300,000 subjects (ages 55 and above), found a nearly 50% increased risk of dementia associated with three years of daily use of strong anticholinergic medications.

It sounds like most research on anticholinergic agents and cognitive impairment has focused on older adults. 

Dr. Hendrick: These studies usually involve older patients because they’re at a greater risk for cognitive decline and are more prone to side effects. However, we also have some evidence linking anticholinergic exposure with deteriorating cognition in younger patients, even in subjects younger than age 50.

Zachary Davis: Do younger patients experience negative cognitive outcomes related to anticholinergic use?

Dr. Hendrick: Yes, they do but these studies in young patients are not assessing the same outcome variables as the ones in elderly patients. For instance, a recent study looked at the relationship between anticholinergic medication exposure and cognitive performance in patients as young as age 18 with schizophrenia or schizoaffective disorder and found that higher anticholinergic burden was significantly associated with worse cognitive performance. However, this study focused on cognitive performance, not long-term cognitive decline or risk of dementia. More studies with better methods are needed to determine the long-term cognitive risks in younger people.

Nevertheless, whenever possible, we should use the fewest number of anticholinergics as possible when treating people with schizophrenia to minimize effects on cognition.

Zachary Davis: That’s an important distinction you mentioned: cognitive performance versus long-term cognitive decline or rates of dementia. Unlike dementia, it is well known that anticholinergics are associated with lower performance on tests of cognition. Keep in mind, with cross-sectional studies you cannot determine that the anticholinergics are the reason for poor cognition. There may be other factors that explain the poorer performance. 

Let’s move on to the factors and limitations of these anticholinergic medication studies. 

How much should these studies affect clinical care? After all, for years it was thought that benzodiazepines increased the risk for dementia, but, according to new data, they don’t seem to increase this risk.

Dr. Hendrick: Right. The results of recent research using high-quality study designs do not support a link between benzodiazepines and dementia. There are a lot of issues that can complicate these pharmacoepidemiology studies—and that’s true for studies that have examined anticholinergics too.

Zachary Davis: Yeah, these studies rely on pharmacy prescription refills, and patients don’t always adhere to their prescribed medications. Patients may take over-the-counter meds that aren’t included in studies’ analyses, and they may inaccurately estimate their alcohol and nicotine use. 

Dr. Hendrick: And protopathic bias is another important concern. 

Zachary Davis: What’s protopathic bias?

Dr. Hendrick: Protopathic bias is when a drug is used to treat early symptoms of a disease that has not yet been diagnosed. Patients take benzodiazepines and anticholinergics in the years leading up to a dementia diagnosis for treatment of prodromal symptoms such as anxiety and insomnia. If researchers don’t take this use into account, their studies will show spurious positive associations.

Zachary Davis: Okay, that makes sense. You also touched on another point that we should probably discuss further. Patients often believe that if a medication is classified as over-the-counter then it’s most likely safe. Although, many commonly used over-the-counter medications, such as Benadryl, have strong anticholinergic properties. We asked Dr. Gray about this topic. Here’s what she had to say.

Dr. Gray: So, I’m particularly concerned with over-the-counter medication use because many of these anticholinergics might be hidden in a product to promote sleep, for example, and people might not be aware at all that that medication includes an anticholinergic. Many people think if a medication is available over the counter it’s safe, and they may also not volunteer that they’re using an over-the-counter medication to their health care provider, so their health care provider has no idea that they may be taking, you know, in addition to their prescribed anticholinergic they may also be taking over-the-counter anticholinergics. And these anticholinergics are considered strong. Diphenhydramine is considered a strong anticholinergic. So I am concerned that many older adults in particular are not aware that the sleep aid they are taking includes a strong anticholinergic medication.

Zachary Davis: So, Dr. Hendrick, when researchers take these limitations into account, is there still a positive relationship between anticholinergic use and dementia or long-term cognitive decline?

Dr. Hendrick: Yes, the relationship still holds up, but we can’t 100% rule out that biases are not an issue. Yet, several studies have done a good job addressing these issues.

Zachary Davis: Is the research consistent in finding a link between anticholinergics and cognitive impairment?

Dr. Hendrick: There are some discrepancies in the research. For example, in the Richardson and colleagues study I mentioned earlier, the risk of cognitive impairment was linked with anticholinergic antidepressant, urological, and antiparkinsonian drugs, but not gastrointestinal medications. But as a whole, the literature supports an association.

Zachary Davis: We know that acetylcholine is important for memory and learning, so it’s reasonable to worry that medications that reduce cholinergic activity might adversely affect cognition.

Dr. Hendrick: Right, and the main drugs approved for dementia are cholinesterase inhibitors, which increase levels of acetylcholine.

Zachary Davis: Okay, so if cognitive impairment is associated with reduced cholinergic activity and dementia is treated with cholinesterase inhibitors, then shouldn’t discontinuation of anticholinergic medications return cholinergic activity back to baseline and reverse cognitive deficits?

Dr. Hendrick: Unfortunately, this question hasn’t received a lot of attention. A study of older adults who were followed over four years reported that the risk of cognitive decline was about 1.5–2 times higher for continuous anticholinergic users but not for those who discontinued the medications. However, Dr. Gray’s 2015 study revealed that the dementia risk was similar among people with past heavy use of anticholinergics and people with recent heavy use, suggesting that the risk for dementia with anticholinergic use persists despite discontinuation.

Zachary Davis: So, what should clinicians do with all of this information?

Dr. Hendrick: Well, the best thing clinicians can do is to identify the strength of anticholinergic activity associated with each patient’s medications including over-the-counter medications. Make sure to take note of any medications that are classified as strong anticholinergic agents. For example, medications that have a score of 3 on scales of anticholinergic activity, like the Anticholinergic Cognitive Burden Scale, are considered strong anticholinergic agents. In our Oct/Nov/Dec issue, you’ll see a table listing common examples of strongly anticholinergic medications, including diphenhydramine, clozapine, olanzapine, and quetiapine.

Zachary Davis: We discussed these scales with Dr. Gray during our interview, and this is what she had to say. 

Dr. Gray: So, this is a pretty tricky area. There are several different scales that researchers have used to try to determine the overall anticholinergic burden from all medications a patient might be taking. But estimating the anticholinergic effect of individual drugs on the human brain is very difficult. Many times the people who have developed these scales have relied on expert consensus and also based on literature review of side effects to come up with the scoring for these different scales. Some of the medications that are included in this scale are medications that we typically don’t think of as having anticholinergic effects based on the pharmacology. 

Some of these medications were found to have serum anticholinergic activity, but they really don’t have clinically relevant negative cognitive effects. So it’s difficult when you include those types of medications in this overall scale. And just to take this a step further, in some of these large, well-conducted studies that have looked at these scales and dementia risk, they really haven’t found an association with those drugs that have unknown anticholinergic effects based on pharmacology, but have tested positive according to this serum anticholinergic activity assay. 

So the bottom line is, all these scales I think there is good consensus among the medications that we know have strong anticholinergic properties, and these are ones we know based on the pharmacology of the drug. So I think that the scales are pretty aligned on those that have strong anticholinergic effects, but what becomes a little bit unclear are those medications that are scored as 1 that might have possible effects.

And there are some drugs like furosemide and warfarin that you know if you look at the pharmacology of the medications there is really not an effect at the acetylcholine receptor, but because of the test tube assay that was done they were found to have serum anticholinergic activity.

But we really don’t know what that means clinically, but because of the positive effect on this assay, many of those drugs have been included in these scales as having a 1, which is possible anticholinergic activity with 3 being strong anticholinergic activity. 

And so even in some of the more recent studies they really found the association of those drugs that were highly anticholinergic or moderate that those drugs were associated with dementia risk, not those ones that were scored as 1 that had possible anticholinergic effects.

I think where there is the most alignment on the drugs that are scored as 3 because those are really clearly the ones that have strong anticholinergic effects, and those align well with what you will find in the American Geriatric Society Beers Criteria. They have a table of strongly anticholinergic medications that should be avoided in all older adults, not only because of the effect on cognition, but because of their effects on many other symptoms such as constipation and those types of adverse events.

Dr. Hendrick: We must pay close attention to the number and dose of strong anticholinergic medications that our patients are taking. We should try to reduce the use of strong anticholinergics in all of our patients, especially in the elderly. 

Before we go, here’s Dr. Gray’s bottom-line message for clinicians.

Dr. Gray: I think the general message is just for providers to ask about over-the-counter medication use, especially if patients are using something to help them sleep so that they are aware of the overall burden of anticholinergic medications a patient might be taking. 

It’s not possible sometimes for patients to discontinue their anticholinergics. They might need it for control of their medical condition, but I think providers should be mindful of the number of strong anticholinergic medications that their patients might be taking.

There are non pharmacological measures and also medications that have lower anticholinergic effects or none that patients might be able to transition to, in order to reduce their overall burden of anticholinergic effects.

And if prescribing a new medication, just having that awareness that of the choices of antidepressants or of the choices for antipsychotics, there are medications that have lower anticholinergic properties, and in older adults it would be prudent to select one that has the lowest anticholinergic effects just for brain health. 

Dr. Hendrick: Our interview with Dr. Gray is available for subscribers to read in The Carlat Hospital Psychiatry Report. Hopefully, people will check it out. Subscribers get print issues in the mail and email notifications when new issues are available on the website. Subscriptions also come with full access to all the articles on the website and CME credits. 

Zachary Davis: And everything from Carlat Publishing is independently researched and produced. There’s no funding from the pharmaceutical industry. 

Dr. Hendrick: That’s right, the newsletters and books we produce depend entirely on reader support. There are no ads and our authors don’t receive industry funding. That helps us bring you unbiased information you can trust. 

Zachary Davis: Go to www.thecarlatreport.com to sign up. You can get a full subscription to any of our four newsletters for $30 off using the coupon code LISTENER.

Dr. Hendrick: As always, the links you need are in the episode description. Thanks for listening and have a great day!