Anticholinergic Burden in Schizophrenia: Impacts on Cognition and Late Life Diagnoses

Philip D. Harvey, PhD
Professor of Psychiatry
University of Miami Miller School of Medicine
Miami, FL

Philip D. Harvey is a Professor of Psychiatry and Behavioral Sciences at the University of Miami Miller School of Medicine. An internationally recognized expert in cognitive impairment and functional disability associated with severe mental illnesses, his research primarily focuses on schizophrenia, mood disorders, and neuropsychiatric aspects of aging. Dr. Harvey’s extensive publications have significantly advanced the understanding of cognitive deficits and their impact on daily functioning.

In this video, Professor Harvey discusses anticholinergic burden in schizophrenia, highlighting its cognitive impact, particularly memory impairments linked to M1 receptor blockade. He underscores the heightened dementia risk from anticholinergic use, especially in older patients, and emphasizes the clinical importance of managing anticholinergic burden due to its iatrogenic effects on cognition, independent of genetic dementia risk factors.

This presentation is part of the Emerging Approaches in Schizophrenia Editorial Focus collection from Psychiatrist.com News. The collection focuses on the latest advances in schizophrenia treatment, with an emphasis on emerging therapies that go beyond traditional dopaminergic approaches.

To learn more and watch more videos, visit our Emerging Approaches in Schizophrenia collection.

Transcript

[00:12 – 00:44] Introduction: Anticholinergic Burden and Its Relevance in Schizophrenia

Hi, I’m Professor Philip Harvey from the University of Miami Miller School of Medicine. I’m going to talk about anticholinergic burden in schizophrenia, impact on cognition and late-life diagnoses. Anticholinergic effects on cognition have been studied for several decades.

In early work focused on anticholinergics primarily administered to treat EPS caused by first-generation antipsychotics. But there are many other drugs that have anticholinergic properties. Some are psychotropics, which means that people with schizophrenia may have the risk of being exposed to them.

[00:45 – 01:34] Memory Impacts and Cognitive Decline Associated with Anticholinergics

The primary adverse impacts are on working memory and episodic memory, including encoding of newly presented information. And this is likely due to these drugs blockade of the M1 cholinergic receptor system. There have been several recent anticholinergic burden studies that have been conducted.

The older studies and the newer studies yielded similar results. Reduced cognitive performance, interference with cognitive training, and correlations with increased risk for dementia diagnoses. And that may just be diagnoses, not necessarily dementia.

This is some new data on anticholinergic burden. This comes from the COG study, where it shows that there’s a very high level of anticholinergic burden seen on the part of some people with schizophrenia. And when you look at the slide on the right, you can see that a lot of the burden comes from antipsychotic medication.

[01:35 – 02:36] Cognitive Training Interference and Longitudinal Findings in Older Patients

But there are many other medications that are associated with increased anticholinergic burden in people in the schizophrenia spectrum. There are multiple adverse impacts of anticholinergic burden, including interference with cognitive training. Since computerized cognitive training is one of the very few things that we have that improves cognition in people with schizophrenia, interfering with that by administering anticholinergics is a real challenge.

Also, what we’ve seen is there have been a number of studies recently that have suggested chronically institutionalized patients with schizophrenia commonly have very poor cognitive performance. It can worsen precipitously after age 65, and clinical chart reviews suggest high prevalence of dementia diagnoses, although we’re going to evaluate that to see if that is actually accurate. In a longitudinal six-year study that we did, we looked at the six-year course of cognitive functioning in chronic schizophrenia patients, patients with Alzheimer’s disease and healthy controls.

[02:37 – 03:49] Dementia Risk and Neuropathology Insights in Schizophrenia

They were matched on age, and the schizophrenia and Alzheimer’s patients were matched on global cognitive performance. As you see, six-year follow-up data on younger patients with schizophrenia suggests very little conversion toward the more severe CDR scores that are consistent with dementia. And when you look at the course of mini-mental scores, what you see is that Alzheimer’s patients, no matter how old they are when they’re diagnosed, have a significant worsening over six years in their mini-mental scores, while healthy controls don’t, and schizophrenia patients worsen by less than one point on the mini-mental over the course of a six-year follow-up until they’re over the age of 65.

So there appears to be a point of inflection for this worsening. It may be dementia, but it’s not Alzheimer’s disease. In a longitudinal study that we did where we identified people with schizophrenia in life and assessed them, and then did post-mortem neuropathology on them after they died, we found that although the majority of people with schizophrenia showed cognitive impairments, Alzheimer’s disease was only present in 9% of this 100 cases.

[03:50 – 04:47] Broader Implications of Anticholinergic Burden in Mental Health Disorders

A 9% rate of Alzheimer’s diagnosis at post-mortem would be common in the general population. So the proportion of people with schizophrenia who had cognitive impairments but not an Alzheimer’s diagnosis, we see that there are basically 70% who have significant impairment but no AD neuropathology. So what could it be? Well, one of the things that we have discovered is that anticholinergic burden is very common in naturalistic studies.

If you look at the graphic on the left here, this is from our large-scale longitudinal study of people with schizophrenia and bipolar disorder who are in a VA study called CSP572. Basically, 35% of schizophrenia patients are above the cutoff of anticholinergic burden identified previously in the slides we looked at before. And again, the sources of anticholinergic burden are diverse.

[04:48 – 05:28] Role of Age and Medication Diversity in Anticholinergic Burden

It’s not that they’re all getting treated with benzatropine. So lots of people have anticholinergic burden, and it comes from lots of different medications. One of the things that’s really concerning about this is the interaction of anticholinergic burden and age.

Everyone knows that older people are more vulnerable to anticholinergic burden, but what we’re seeing here is that ACB in our sample is higher the older you are. And if you look over to the left side, you’ll see there’s a tremendous diversity of different anticholinergic medications that are delivered to these patients. So despite the need for caution, people’s anticholinergic burden is getting worse as they get older.

[05:29 – 06:04] Veteran Studies on Dementia Risk and Anticholinergic Levels

And if you take a look at the risk of newly incident dementia diagnoses in veterans, there are a lot of risk factors that are quite unusual there. Basically, what we see is in our sample of 65,000 veterans whose medical records we reviewed and on whom we had genotyping information, the highest anticholinergic burden strata has an 11% risk for a newly incident dementia diagnosis in the next 10 years. And if you look at the right side, the risk factors for the dementia diagnosis, strangely, age has nothing to do with it.

[06:05 – 06:36] The Limited Role of Genetics and Age in Dementia Related to Anticholinergics

Age is the single biggest predictor of risk for developing dementia. And genomic predispositions for cognition, Alzheimer’s disease, and schizophrenia, defined by polygenic risk scores, are not correlated with the risk of a dementia diagnosis. But when you look at the significance level for anticholinergic burden, what we’re seeing is that people are getting a newly incipient dementia diagnosis because they have high levels of anticholinergic burden.

[06:37 – 07:10] Clinical Observations: Managing Anticholinergic Burden and Dementia Link

This is iatrogenic. It’s caused by treatment and not caused by the standard risk factors for dementia. So what this means is that anticholinergic burden is a major factor in the naturalistic, clinical, and cognitive presentation with people with schizophrenia.

Despite the wide knowledge that ACB should be managed, particularly in older people, it looks like it’s increasing with age. Diagnoses of dementia are more strongly correlated with ACB than age, which is really informative. Genomic risk scores for AD, intelligence, and schizophrenia are not predictive.

And the APOE4 genotype is not correlated with newly incident diagnoses. With drugs on the horizon that directly and beneficially impact M1 cholinergic receptors, a lot more attention to anticholinergic burden management is likely critical.