Psychiatry & Psychotherapy Podcast - Anticholinergic Burden

Episode Date: November 10, 2020

There are medications that worsen cognitive function and all mental health providers should be aware, and work on optimizing sensorium. In this episode, we'll cover a spectrum of sensorium disruptions and medications that you need to look out for.  By listening to this episode, you can earn 1 Psychiatry CME Credits. Link to blog. Link to YouTube video.

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Hello, welcome back to the podcast. Today I'm joined with four. medical students. The episode is called medications that cause cognitive impairment, sundowning, and delirium. On this episode is Carl Wallen Kampf, Kyle Logan, Adriana Alvarez, and Ryan Hollis. And we are doing this episode really because this is something that is a personal pet peeve of mine or a passion of mine. Either way, you know, it's a pet peeve when some person, often middle age or elderly, is on a medication for years that takes away some of their cognitive function and doesn't allow them to live a vibrant life. That's probably the pet peeve.

It's passion because it's a quick win, right? So whether you're a therapist who has patients on medications, likely, or a psychiatrist or someone in training, this will be a deep dive. and it started a couple years ago I was on Constable Liaison covering the hospital we have a huge hospital you know eight floors nine floors

ER and so when you're covering you're covering all those floors and I had a good team of medical students and I gave them each little projects and Carl man Carl came through he came through big I'd like to think so he came through very impressed

trying to convert him to psychiatry I have one week left. He's going into internal medicine. And so yeah, me and Carl hit it off. He came over to the pewter gym, got some workouts done, improved his squat for him. It's a lot better now. It's a lot better, yeah. He's about as big as I am.

He's about maybe a little bit bigger, six, seven. And so really what our, the initial clinical question was on, like, I think LASX, if I can remember right, fluoresceide, like, and how anticholinergic that is, a couple other meds. So, you know, we were, I was teaching, I was teaching them how to look at a med list to see if any of the meds that they're on

are a culprit to the worsening cognitive function. And so guys, welcome to podcast. Carl, you wanna say anything? Sure. I just wanted to say that I really appreciated this project because being on consult, liaison. We were being called frequently to patients who were a little altered, possibly had some delirium. And so oftentimes we would have to review the medication list, as you were saying,

to see if there were any special causes. And so I remember you handed me a paper on anticholinergic effects, and that just sort of ran down the rabbit hole that created this project of looking up different medications with anticholinergic burden. And so that's kind of where we find ourselves. So we just got done doing an episode on conscientiousness. You know, it's one of the big five. And I would, Carl, I would put you probably about three standard evasions above the mean for order, specifically for conscientiousness. So there's a subdomain called order.

Because number one, you give someone a project and they actually executed on day one. And then number two, they find other articles and then create and start to create an Excel sheet. And so, you know, I've kind of overseen Carl's. development of that. And that's something I've talked about in prior episodes. So this is really fun to finally have you on so we can finally officially release it. And this is an Excel sheet that looks at a bunch of papers and summarizes it all on one place where you can kind of do a, you know, you can go up to edit, find, and you can look up the med or it's alphabetical, and you can find the med that you're curious about. And you can see which ones cause cognitive

issues. And so how the format of this episode is going to go is we're going to introduce some of the terms, some of the problems that we're facing. We're going to go through some of the studies that informed this Excel sheet that we put together. And then we're going to give some examples. So where do we begin? Sensorium, right? So maybe I'll all introduce it from my perspective and then I'll ask you guys about some of the definitions here. So I did a series on Sensori. four parts and I went through like all the different things that kind of can change global brain function right so I was thinking about like sundowning sundowning is is uh maybe a light issue with total brain function where you know the person has enough uh either medications or

you know they have um maybe a light dementia or heavy dementia and so sundowning is where they have kind of worsening of their cognitive function later in the day, and it's pretty much every day that they'll experience that. That's why it's like when the sun goes down, this will happen. And then some people come in with low energy, fatigue, and those people have a sensorium issue. If the energy and fatigue is from maybe the medication burden or medical burden that they're having. And then you can have mild cognitive impairment,

which is on the way to dementia. And we're going to talk about hypoactive delirium, which is a diagnosis that we give, usually in consulate and psychiatry. But really, as I've run this partial program, this IOP program for people with medical and psychiatric issues, it's pretty much every new patient I'm considering which medications are worsening their brain function,

which medical issues that aren't optimized are worsening their brain function. How do I get them out of potential hyperactive delirium or just a low cognitive functioning compared to where they should be, right? And then kind of like the one where everyone knows about it, like it's even the surgeon's going to call psychiatry at this point is hyperactive delirium. Lines are being pulled out. They're seeing things. You know, all of a sudden they're psychotic.

They don't have a history of schizophrenia. They don't have a history of bipolar. This is the first time they've had this. it's usually in the ER, or not in the ER, it's usually in the ICU after surgery. It's usually in the ICU after, you know, multiple medical issues have hit them hard. So we'll go through these a little bit more. Let's start with Kyle, you want to tell me about sundowning specifically? Yeah, so sundowning refers to neuropsychiatric symptoms that either manifest or worse

than around sunset in patients with dementia. These neuropsychiatric symptoms can include confusion, anxiety, agitation, wandering, screaming, visual and auditory hallucinations. And there are factors associated with having a more severe sundowning, like being on an anticholinergic pharmaceutical medication, or even being fatigued or hungry, having a sleep disorder, or even environmental factors such as inadequate light exposure. That's good, and we'll link in the article, Cannevelli 2016, a deep dive on that. What about mild cognitive impairment? So the National Institute of Aging defines mild cognitive impairment due to Alzheimer's disease as the symptomatic pre-dementia phase of the trajectory of cognitive decline. And what differentiates this from dementia is patients with mild cognitive impairment are still able to perform

the activities of daily living. And we all know, like the medical students know MoCA, the Montreal cognitive assessment, and a score from 18 to 25 is graded as mild cognitive impairment on that rating scale. This is a really good board question. So they love definitions. You know, does this person have full-fledged dementia? Do they have mild cognitive impairment? 18 to 25, that's a good thing to remember.

also that they can do activities of daily living still at this stage. And so diving into dementia, that's a clinical syndrome characterized by progressive cognitive decline that does interfere with the ability to function independently. And classically, you think of the symptoms of dementia as like kind of gradual and slowly progressing over time. And Alzheimer's dementia is characterized by an early short-term memory impairment and then executive functioning declines later in the stage or later on yeah yeah yeah yeah so Alzheimer's is a type of dementia dementia is a sort of broader category and it's a slow decline so they have

executive function you know that doesn't decline as fast unlike um maybe a frontal temporal temporal dementia which has the executive function that frontal lobe declines first and if you have strokes leading to dementia that's like a stepwise decrease in function so all of a sudden like a big drop in function and then another big drop in function often the strokes are are going on and not fully recognized and so it's not like every time they're getting a diagnosis of a new stroke because some are small but it's a stepwise decrease in function okay so we're going to turn a little bit to delirium remember this delirium is the waxing and waning sort of issues with cognition focus, attention. Delirium is usually acute onset. It usually resolves when the predisposing issue

is treated like an illness or an infection, but some people have prolonged delirium. It continues, and some people have that hypoactive delirium that looks like depression. So tell me a little bit about this, Carl. What did you find in this study that we looked at? Yeah, so I think a few of the things that we were just talking about really help us frame the context for delirium, because you can Think of delirium as one article that I read that was very helpful for this. It was published in the New England Journal by someone named Mark Hintoneo called Delirium in Hospitalized Adults. And one of the phrases that I really appreciated was you can think of delirium almost as like

an acute brain attack, sort of similar to acute heart attack, cardiovascular situation. And it has predisposing factors as well as precipitating factors. So in what we were just talking about with mild cognitive impairment, dementia, sundowning, those may all be part of a predisposing picture for a person with who will later be diagnosed with delirium. And so you can think of delirium as this brain attack, this waxing and waning occasion. And one of the things that is really surprising to me is how common delirium is, if you think about if you take patients over the age of 70, about a thing, third of them during an acute inpatient stay will have delirium. And 15% overall or half of that,

30%, probably already had it on presentation to the hospital based on medical illness that had already developed before they came to the emergency department. It's a very common complication also of surgeries. It's the most common surgical complication among older adults. It can happen in up to 25% after elective surgeries and some close to half after high risk things like a hip fracture repair cardiac surgery is another example that was in that study in that paper even higher rates will also occur if you have someone who needs to be admitted to the ICU or has mechanical ventilation well there and then it's tricky because it can last for different time periods certainly it can last for days, but it can last even longer into the months. A systematic review that was cited

there noted that delirium persisted after discharge and almost half of all the patients who were diagnosed with it and continued on for a month and a third of patients who had that diagnosis. That's really important to note is that some of these persist. And there's actually delirium clinics that have started in some institutions where they specifically. specifically will follow anyone with delirium upon discharge. And I think that's really wise because there's things that you can do, you can manage. It's very scary for the families.

I've had a lot of families that come in with their loved ones. They're still having symptoms of delirium, either hyperactive, hyperactive or both. And it can be very jarring to the family unit, you know, that they're elderly ones waking up in the middle of the night. What are they doing? They're seeing things, they're hearing things, right? And, you know, a lot of times they don't even know that there is this thing called delirium.

It's like they just know that their family member came home from the hospital changed. Yeah, so keep going. Yeah. I think this is one of the things that I've really appreciated learning a little bit more about this because just on my internal medicine sub-eye a couple months ago, I had a patient who had delirium like this. So this was really helpful. And it was like that. The wife was able to come in and visit through a minor act of God,

able to get her into the hospital. And she, when present with him, he improved somewhat in his sensorium. You could see him a little bit more with it. He was communicating more effectively, which kind of demonstrates that waxing and waning we see. And she was very surprised to see him acting in that way. Well, it demonstrates the power of connection too, because, you know, one of the things we want to do for patients in the hospital who are having this is recreate a home environment as accurate to home as possible. You know, and there was this guy Maltanado when Stanford was building the brand new hospital. He put these huge, he wanted to put these huge lights in the rooms that would turn on and turn off, turn on during the day, turn off at night.

And they would, like, you could not change the setting on these so that it gave people consistent feeling of day and night. And even that is very powerful. So it's, but especially the power of connection, you know, the connection being, you know, you have your wife who's there. and now in COVID season, it's like no family can visit, right? This is very, very hard. The social withdrawal is a huge stressor, and any stressor can promote delirium, you know? Yeah.

Okay, keep going. I think we were talking a little bit before about hyperactive versus hypoactive delirium, and I think this is a really important thing to talk about in terms of delirium because the statistics, are interesting in that only about a quarter of cases of delirium are hyperactive, which is easy to notice and diagnose. Different staff will notice people getting agitated, while three quarters of

these patients are hypoactive and much less likely to be diagnosed or noticed, which is scary because delirium has been linked with not necessarily causal, but there's a link there with a 10 times increased risk of death and a three to five times increased hospital associated complications with delirium and also an increased likelihood of complicated or worsened functional and cognitive recovery and increased risk of death after leaving the hospital. There have been these interesting reviews that have followed patients for years after leaving the hospital and they can continue to have side effects if they had had delirium in an inpatient environment.

Yeah. And so, you know, as an outpatient psychiatrist, it's like you get these patients there. They're discharged, they're still not back to normal, and then they finally get sent to psychiatry, thinking that they might be depressed. And when you really pull out the history, these people are not depressed. They were delirious in the hospital,

sometimes even hyperactive. And sometimes upon discharge, it didn't go away. The hypoactive delirium continued. And so when they come and see you, this is not someone who needs psychotherapy. This is someone who needs you. to pull off the medications that might be worsening this situation. And I think this is where, like, as providers, if you're a therapist listening to this,

I congratulate you because I don't think therapists think in these terms often because these are very medical things. You know, it's not like therapists are doing C&L rotations, if they are, that's great. They're not usually thinking delirium, not delirium, you know, hypoactive delirium. It takes a little bit of nuance to get that diagnosis. Okay. One of the studies I found that kind of like illustrated how difficult this is to tell a part is an observational study on inpatient adults over the age of 60. And of the 67 patients that were referred for evaluation of depressive episode, 42% were found to have hypoactive delirium and not a depressive episode.

Yep. Yeah. Yeah. So, yeah, let's... So having talked a little bit about that epidemiology and some of those risks that have been associated with it and how it easy it is to confuse, just turning back to our beloved DSM-5, some of the criteria for delirium and how you might notice these patients are seeing a disturbance in their attention. They lack an ability to focus on you as an interviewer. Different hospital staff may report that, oh, this patient doesn't seem to be listening well or the OT or P. say they weren't very compliant. It didn't seem like they could follow along with what was going on.

Usually this disturbance will, well, it has to develop over a short period of time. Now, note, this may occur before the hospital. So it may involve talking with friends and family to see how they were at home before their inpatient stay, but may change, their baseline may change well in the hospital. You'll usually see different cognitive changes, memory deficits, language deficit. People might have like sparsity of speech. They're not able to conjure up the words like they were they were able to before. And usually, this is key in delirium is it's reversible. So usually there will be some kind of acute change intervention or in the case of this podcast where we're really going to focus on some change in their medications that we need to be attuned to. And that's kind of

where we're headed with this. One of the things that can be important is sometimes this is hard to see. especially the hypoactive form. So some have suggested using the confusion assessment method, the CAM, as a way to just screen patients whom you may be concerned about delirium with. Given the morbidity associated with delirium, it may be a good idea to screen. If you're interested in that, I would recommend looking up the confusion assessment method or also the three-minute diagnostic interview for delirium using the CAM or 3D CAM. And both of these are pretty brief. Clearly, they don't take long with three-minute interview.

Generally, you're just looking for presence of both an acute change in mental status with a fluctuating course and in attention that you can have during the interview. And then you either want to also look for disorganized thinking or an altered level of consciousness. And if you see those things, you can be alerted towards delirium and then move forward in your assessment. Yeah. And I would say that the quick way that I, the quick way that I, I teach medical students is can they spell world backwards? Can they draw a clock? And so I actually want to physically see the clocks for the day, you know? I remember that. So every patient, every day, every console, let's see a clock. You know, how I do that is I draw the circle for them. And I say to the patient, hey, can you put the numbers around the clock, one to 12? Okay, like you would see it on a wall.

And then I would say, hey, can you put it at like 10 till 11, which is a little bit tricky, right? And what you're doing is you're also observing for how they put the numbers on, where they put the numbers, how they're thinking through the process. Are they confused? Does it take them a long time? Are they, when they put the 10 to 11, like how do they put the big hand, the little hand? Where do they put them? Often they're like, they're not connected to the middle of the clock, which is unusual. So usually those two questions are a quick assessment. And then of course we can do, you know, more detailed assessments like the mocha, like the, like the cam, you know, and stuff like that. But that's my quick and easy way. That in the history. The history is crucial. You get it from the nurses. You get it from the chart.

You know, is this a fluctuate, is, is there a fluctuating nature to this? You know, the nurse will say, oh, he just sleeps most of the day. Okay. That's interesting. Yeah. Okay. That's kind of a more of a risk factor. He's just kind of heavily sedated, it seems.

but he's not on a sedating medication. Okay, keep going. Now, if you're a psychiatric provider or other kind of provider, a clinician, I mean, you assess this, you will likely need to look into the history, as you were saying, Dr. Puder, or you need to look at different interventions

that may have caused this acute change of delirium. So there was a nice demotic in that New England Journal article that actually just spells out delirium. So the first is drugs, and we're going to be focusing on that here. electrolyte disturbances, a lack of drugs can also cause it, infections, reduced sensory input, intracranial disorders, urinary and fecal disorders, and myocardial and pulmonary disorders. I love pneumonics with big buckets at the end of the mnemonic, but I think that can be a helpful

way of thinking about different causes. But yes, so we're going to transition here. Our focus has been on medications, but... Let me say one thing about that. Basically, it's broken down into drugs, you know, like which which medications are making this worse, potentially? Electrolite disturbances, like, does this person, is, you know, if you look at their, like, blood gas, and that's all whack, you know, whack, that's such slang for, you know, this person's acedotic or this person's severely alcoholic or maybe a multiple, multiple things, you know, their anion gap is huge, you know, do they have a lot of, is there glucose in the 400s?

Like, that's one thing I look at with, like, a lot of the patients I see in outpatient. It's like, okay, this person is glucose in the 400th. Like that increases your risk of depression fourfold if it's out of control. Maybe that's not depression. Maybe that's something else. Maybe that's a sensorium issue. And then for the lack of drugs, really you're thinking about maybe the lack of drugs to treat an infection or the lack of drugs to treat pain. Because if you have very, very high pain, that can also cause it.

In terms of, you know, it goes through like reduced sensory input. isolation man and what are we having right now in this season we're having huge amounts of isolation so you know i think about this as well with the huge rates of you know suicidality that are going on in our country increased suicidal thoughts stuff like that and then they go through different disorders and they pretty much any body organ can cause this so you really have to start at your head and go all the way down the body and think like okay where where where are all this person's issues and do this, does a person have any issues in their brain? Does it have any chest? Does it have any stomach? Does it have any bladder? Does it have any groin? You know, and going all the way down,

and it could be things like open wounds, stuff like that, like just ulcers that are open. So really kind of, that's the big picture for how to assess what might be the underlying issues that are causing the sensorium and delirium. Right. Yeah, I liked what you were saying about the reduced sensory input. Now, of course, respecting social distancing boundaries. Sometimes in the first time I see a patient, I like to stand back in the corner of the room, so I'm a good 10 feet away, just sort of remove my mask for a second or two, just so they can see my face.

I obviously try not to breathe in that moment, but I think sometimes it's nice to, nothing's coming out at that moment. I'm not going to pass anything along, but I think it's sometimes it's valuable to show a patient like my face, especially given this COVID time, just so they're able to have a better recognition of who they're talking to. But our focus for today is going to be on medications. That's what this table that we prepared. I think one of the things that we need to remember are these different medications that can have these cognitive effects that often I, as a student, of course, have forgotten about, but I think it's easy to forget the effects that these drugs can

have. And one of the biggest types of drugs is drugs with an anticholinergic burden. So these are drugs that don't necessarily have an anticholinergic mechanism of action, but may have a burden on that system and then can lead to different symptoms such as drowsiness, can lead to problems with body regulation and lead to delirium. A few different drug types that we often look for, clearly anticholinergic drugs. But this can also happen in benzodiazepines, can happen in opioid analgesics. It happens in antihistamines which have a lot of anticholinergic overlap. And I think that's a lot of benzodiazepines. some of the surprising ones that we'll talk about in a little bit, including metaclopramide and furosomide even has some anticholinergic burden. So I think we want to transition a little

bit to some of the steps that we have for delirium. We've talked a little bit already about what to look for. You've covered that pretty well and talked about a couple of the different scales that you can use to screen for it. Maybe it's worth mentioning here that in this one study they found 75% of admissions with delirium were not appreciated by the admitting team, meaning that these are just missed. It's really interesting how underappreciated this is. It reminds me as someone who's applying to internal medicine. Yeah, you have a week to convince me. But as someone applying to internal medicine, it does remind me that often the night team may be admitting a patient and may not have the time or resources to find delirium and a patient. at night, and it would be natural at nighttime to be a little altered, to be a little drowsy.

So it just reminds me of the responsibility of the day team to do their own full assessment. We talked about using the cam and other screening methods, but we're going to focus here on reviewing the medication list. So after noticing delirium or hypoactive delirium, it's important to just look at the patient's medication list. Part of this has to do with checking their outpatient medications and their inpatient medications, trying to make sure there's stability between those two. But notice when a patient became agitated, when they became admitted or when they became hypoactive, and try to assess the medications that may have been present there. Some of the drug types to look for that we've talked about are purely anticholinergic meds. Those with the

anti-cholinergic overlap, like antihistamines, have that heavily. Antidepressants also have some anticholinergic burden that can lead to delirium, including tricyclic antidepressants, and even some SSRIs, which we use commonly, have some anticholinergic burden. Antipsychotics are an interesting case in which they can improve delirium in some cases, but they still have some anticholinergic effect. Also, you must remember benzodiazepines, non-benzodiazepine sedatives, and opioid analgesics. So jumping into how we created this Excel sheet, this was a little interest and passion project of mine. Going back to a couple of years ago. So during this rotation that I did on consult and liaison, Dr. Peter first handed me

a couple papers. And I just, I must note that a lot of this table just comes directly from the work of others, but I think we made a few edits to it, and I think we added a little extra information that makes it a really practical and helpful tool. But the basis of this table is from an article by Salahuddin at all in 2015, who had considered the anticholinergic burden of different medications, and they had just ranked it as high, moderate, or low anticholinergic burden. And then I looked at another paper from Duran at all from 2013 that was a different systematic review of anticholinergic risk scales. And this Duran paper includes a very long list of medications, and each are plotted against seven different papers that each did their own

assessment of anticholinergic effect. And while these papers did not quantify every drug, not all papers commented on every drug. They often provided complementary assessments of drugs so that a single drug you'd have multiple inputs from different papers in their anticholinergic effect. So what I did is I just used that basis and just created a table using every single one of those drugs that was listed in the Salahudin article, the Duran article, and then there's also an article by Carnahan at all in 2006. I used their appendix.

So just essentially input every one of those drugs. And then I mapped across in these eight different papers, including the Bustani 2008 paper, and then created this input their scales, which are on a zero to three scale, so four different possible scores. And then what I did is I color-coded it, green being zero and red being the score of three with intermediate yellow and orange. and that allowed a nice visual contrast to look across for a specific medication and kind of see what burden was present. And then I went on to add in this table, I added some of the common drug names, for instance, Xanax for Alprazolam, so it'd be easier to look up both of them. And then added also the drug class when I could. And then some of the drug indications so that it's possible

to look up just common indications for drugs. With the end of the end. of course, to have a practical tool that allows a provider to look up a drug quickly and then see what kind of anticholinergic burden it has, and then to possibly look for other drugs that are treating for the same indication and maybe be able to switch for a different one. So it was a little labor intensive, but I've had a, I've had some help from others. My colleagues here in the room have been helping to look into these papers as well, and will help us kind of understand what each paper is doing and what it was assessing for, because I'll just reiterate in these seven or eight different papers, each one used a scale of

zero to three to assess the anticholinergic burden, but these were sometimes divided into a cognitive outcome or an anticholinergic specific outcome going even so far as to assess serum anticholinergic activity. So that was one of the benefits of mapping against these. these eight different studies is they provide an assessment of like, is this an active anticholinergic in the serum all the way to was memory performance worsened? Yeah, and this is just, this has been a real pleasure to work with you, Carl, on this,

because Carl is, like I said, very orderly, and it also makes me a little bit of proud, you know? Like, this is like Carl's brain, kind of executing the best it can, and now potentially providing a lot, a lot of patients with that. So, you know, my role was more getting you started, double-checking your work, giving you some input here and there, but you really did the bulk on this table.

And we'll write up a paper that goes with this on our website and all the other medical students that I talked about before are part of that. And getting this done right before your ERA's submission needs to be done. So that's be good. Excellent timing. Yeah. Okay. So my name is Ryan Holus, and the following studies that Adriana and I will discuss a little bit are expert opinion-based rating scales developed with the intention of providing clinicians with a simple score that identifies the severity of anticholinergic effects on cognition of prescribed and OTC medications. Adriana.

Oh, I'm Adriana Alvarez. So a rating scale of anticholinergic burden could potentially be useful in the management of elderly patients in order to, you know, minimize the anticholinergic induced adverse effects. So the first study is the Carnahan study, which was done in 2006. So basically the study attempted to replicate a pilot study that associated anticholinergic drug scale scores or ADS scores with serum antichester. anti-cholonergic activity or SAA. So this was done by using subjects from a one-month cross-sectional observational study of delirium and 201 long-term facility residents who were not included in the pilot study. So serum was drawn on the 14th day, which was the midpoint of the study, and radio receptor assay was used to measure serum anticholinergic activity against rat muscarinic

brain receptors. Atropine was then used as a reference compound, and the anticholinergic action of each drug was rated on a scale of zero to three, as Carl mentioned earlier, using the anticholinergic drug scale scores and total anticholinergic scores were then calculated based on the sum of the scores of all the medications that each subject was receiving. So simple and multiple linear regression models were then used to determine whether or not the ADS scores could be modified and used to more accurately predict the serum anticholinergic activity in all of these subjects. So according to the results of the replication and modification analysis, ADS scores were significantly associated with and predicted the serum anticholinergic activity, and the P value was

less than 0.001 for each of those. However, they found that the modifications did not appear as useful in optimizing the ADS. Ryan? And the first one I'll talk about is the Ancelin study in 2006. This was a cohort study. They took subjects. They were greater than 60 years old without dementia at the time of recruitment. The classification scale that they used for this,

was the anti-colonergic burden classification. This was based on serum anticholinergic activity and expert opinion. The outcomes that they looked at for this was cognitive performance and mild cognitive impairment. Cognitive performance was measured by ECHO, which is a computerized neuropsychometric examination, and mild cognitive impairment was defined by the Stockholm Census Group 2004, and that is a definition that has to do with cognitive deficit in performance that is about 1.5 standard deviations below average. So in this study, when they looked at cognitive performance, they were comparing cognitive performance in those who were using anticholinergic drugs and those who weren't. So in those who were using, they did worse in aspects such as reaction time, attention,

delayed nonverbal memory, narrative recall, visospatial construction and language tasks. Which basically is like all the things that you would want as you get older. You know, you want like all of those things. You want attention. You want reaction time to be good. You know, you want to be able to do basic language things. Okay. Right.

And then the other outcome, mild cognitive impairment, they found that about 80% of anticholinergic users, and we're showing that as opposed to 35% in non-users. That's really important because those on anticholinergic scored worse on all of these things that would lead to them to score worse on things that would lead to a diagnosis of mild cognitive impairment, which makes me wonder, did they have mild cognitive impairment, or were they just on meds that were slaying their brain and not allowing their brain to function as well. Right.

Okay? Right. Important to note also that they found follow up after eight years, both of these groups had no difference in developing dementia. Both groups, as in those on anticholinerg and those not on anticholinergies. Okay, that's really good. That's important. The next study I wanted to talk about quickly was Han 2008.

Unlike the previous one that was done in France, this particular study was done in the U.S. It's Hahn, 2008. He developed a clinician-rided anticholinergic score scale, another four-point scale. This one was based on expert opinion and pre-existing published anticholinergic scales that he was also involved in in 2001. So this looked at outcomes such as short-term memory and executive function. Short-term memory was scored based on Hopkins Verbal Recall. test and executive function was looked at at baseline and also during follow-up, and it was looked at using the instrumental activity of daily living school. Results that we saw there was that

cumulative exposure to anticholinergic medications over the last 12 months was associated with poor performance on memory and executive function, and on average, one unit increase in the total anticholinergic burden per three months was associated with. with a 0.32 decrease in short-term memory and a 0.1 decrease on the executive function scores, respectively. That's really important. It's important to quantify that because often we're not just talking about a one-point increase in antical lineage burden.

We're talking about like a six or 10-point increase, right? because maybe they got put on two meds or three meds, right, that are threes. And so sometimes it's not just, you know, you put someone on one med, it's barely recognizable, but you put someone on the second, the third, the fourth, sometimes even the fifth. And that's when all of a sudden now they look like they're, and, you know, they have dementia, practically. They're, mild cognitive impairment. So it's good.

Not good, not good, but good that we can. good that we can learn about this, right, as a group. That's good. Yeah, Adriana, tell us about this Rudolph 2008 study. Sure. So the Rudolph 2008 study, this was a double cohort study that retrospectively reviewed medical records of 132 geriatric evaluation and management or GM patients looking for antich colonelergic medications. They also prospectively enrolled 117 primary care patients that were 65 years of age and older and performed medication reconciliation and asked about anticholinergic adverse effects. They then developed the anticholinergic risk scale, or ARS, which is a ranked categorical list of the 500 most commonly prescribed

medications within the Veterans Affairs Boston health care system with possible anticholinergic effects in order to assess whether stratifying the anticholinergic activity could be used to predict the risk of adverse effects of anticholinergic drugs. The medications were ranked on a scale from zero to three based on anticholinergic potential. The patient's ARS score was then calculated using the sum of the ARS rankings assigned to each of the medications the patient was taking. The relationship between ARS score and the risk of anticholinergic adverse effects was assessed using FOSAN regression analysis. According to the results, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM and the primary care cohorts.

And both of those were statistically significant. Yeah. So basically saying pretty similar things. that as you increase the number of anticholinergic medications, you have continued increased risk of developing adverse effects. All right. Tell me about this Chew-2008 study. Right.

So the Chew-2008 study was a study that measured the anticholinergic activity of 107 medications that were commonly used by older adults. This was accomplished by using a competitive radio receptor binding assay, and a specific muscarinic receptor antagonist was used as the radial ligand, and atropine was used for the standard curve. The assay was then used to measure anticholinergic activity at six clinically relevant concentrations of each medication, and a rodent forebrain was used for the analysis.

So for the medications that showed a detectable anticholinergic activity, average steady state peak plasma and serum concentrations in older adults were used to estimate relationships between emboucher dose and anticholinergic activity. Why I think this one is specifically important is because they actually looked at the rodent's brain. because, you know, what's actually going on inside the brain of these people? And of course, you can't do that to humans. You can't, like, take out the human's brain. You know, and so we want to know what's going on at the level of the brain

because that's where the dysfunction takes place. All right. Ryan, there's a couple more studies. Anything you want to summarize from them that they're saying that's new? Right. So we have the Bustani one in 2008. I just want to mention this one because it's one of the more popular ones that I've seen used in studies. And I think that is probably because it's based on a lot of published data.

They did an analysis from all of the articles on this topic from 1966 to 2007. So I thought it was worth mentioning for that reason. And they also kind of had a pretty clinical approach to it where basically you can add the total score this is one of the additive scales where if you add the total score of all of the anticholinergic burden and if it's over three then you can start considering alternative medication so that was kind of neat about that particular one yeah adrian anything you want to add about this eret 2010 article um sure so the ert 2010 study uh was basically a study of 235 patients that they looked at over eight years. And what they found was the results of the linear regression analysis,

adjusting for age, baseline cognition, and depression showed significant associations between decline on the mini mental state examination and anticholinergic activity load, as well as the duration of the anti-colonergic activity drug use. Right. So it showed that both the duration of the use of anticholinergic drugs and the total load had an impact. I think that's important to note. And the last study we'll talk about briefly is Citeranerat. This was in 2011 in Australia. So they came up with the anticholinergic loading scale.

And this one was interesting. The outcomes were psychomotor speed and executive function. The part that was interesting about this one is it had the largest N of any of the studies we looked at. This had 1,112. And they looked at subjects who were healthy, some had Alzheimer's, and some had mild cognitive impairment. And the interesting thing is that it was only in the healthy control that anticholinergic load was associated with slower response speeds for the struped color and incongruent trials. Okay. So those are the studies that we compiled in our Excel sheet that you can get Psychiatrypodcast.com in the resource library. We compiled all those studies, and Carl did a great job of spearheading this Excel sheet. And we're going to take a couple examples and discuss them from the Excel sheet. So let's talk about amatryptylene or Ellaville. So this is a tricycic. antidepressant. We recently talked about this in the episode on nortripylene with Dr. Cummings,

sometimes used for pain, for fibromyalgia, for tension headaches or migraines, interstitial cystitis, neuropathic pain. And I often have a patient who's doing pretty good and then they get this thrown on to them by some other doctor and that can cause potential issues or they come into me with, you know, some cognitive issues, but they're on this for some reason. Sometimes they really have benefited from it. So it's like this kind of cost benefit analysis. We can talk about that a little bit. What did you find in the studies on this medication? So this is one of the few medications on the list that every single study gave a three out of three score for anticholinergic burden. So every study that was assessing cognitive outcomes, every study that was assessing anticholinergic

specific or in vivo or serum activity every single one of them rated is a three out of three yeah and if you remember from my nortriptiline episode this is a good a good thing to know is that if you have a 2d6 blocker you can really increase the level of amatriptylene nor triptriptylene any tricyclic endopressin so a 2d6 blocker fluoxetine paroxetine buproprion right these are all two These are all potent 2D6 blockers will increase the level of amatryptylene. And because of this tricyclic anticholinergic effect, you can have acutely worsening of your cognition just from making these changes. So the next one is nortryptylene. It scored a little bit different in some different studies.

You want to mention what we found here? So again, nortriptylene still has some significant anticholinergic effect. But a few of the studies, for example, Ert and Rudolph who were looking, Ert was looking at the long-term cognitive decline. Rudolph was looking at frequency of anticholinergic events. Also, Chew in the just anticholinergic in vivo study in rodents, found that they scored this as a two out of three rather than a three out of three. Several of the other scales still rated it as a three out of three,

but you can notice here how you can compare different medications using this table and see that some of them may be slightly less anticholinergic or have a lesser burden. I think this is fairly dose-dependent. Both of these are, by the way. Amatriptylene, more anticholinergic than norotryptylene. Norotiptriptylene has more anticholinergic that you go to higher doses. So sometimes at lower doses you can get away without having any cognitive dysfunction now in someone who's older, in someone who may be having, you know, like you need to optimize everything you can. This wouldn't be a good option in my mind. But in a healthier person at a low dose, it might help them with whatever you're trying to treat

with not causing too many problems. That being said, this is something you have to watch for, right? As a provider, you have to have enough ego strength so that if you were to cause some side effect, you could notice that you were the cause of it and then get them off of that. You know, it's actually really hard as providers to think that we would be causing harm to our patients, right? and so we have to kind of be okay with the thought that, you know, if there's a new change after you started a medication, it's probably from the medication. And see the patient back, you know, a week after you start these meds and see if they've had changes.

You know, don't let them go a couple months. Let's go over the next one, diphenhydramine, which, of course, you know, Benadryl, it's in tons of different medications, over-the-counter sleep medication. I can't tell you how many patients have come in taking this with some sleeping medication and it helps them sleep, but it also makes them confused. And it's like the patient doesn't realize how these two things are connected. Like I'm confused during the day. I don't know why. And I'm taking this medication, but it's helping me sleep.

Again, this is just another medication that has a lot of anticholinergic activity. Han, who was reviewing memory performance and executive function, rated this as a three out of three. Carnahan, the serum anticholinergic activity, three out of three. And then Bustani, with their sort of pragmatic, add the scores and try to not go above three, rates this as a three. So this would also be another medication at which point you kind of have that cutoff there. You want to start looking for alternatives. Let's talk about promethazine, fenegrin.

This is another antihistamine, often given. in a hospital setting for things like nausea, right? This is one of those interesting cases in which there is some conflict. So in those anticholinergic specific outcomes, Rudolph looking for anticholinergic events, Carnahan and serum anticholinergic activity, both of those rate this as three out of three in Bustani also rates this as three. But Citeronorot, which was looking for psychomotor speed and executive function rate. did this as a zero. So they did not find anticholinergic effects in this medication in their

review of psychomotor speed and executive function. Yeah, that's interesting to me. This is still on my radar as something that could be worsening the overall global picture. It doesn't quite make sense to me why this huge discrepancy. I don't know, does that make sense to you? There, you know, a few of the different studies, for example, the Duran at all 2013, which is the basis for this table, they actually have in their paper, which I encourage you to read, certain sub-tables. For example, they'll have a table of just the most highly active anticholinergics. And they also have a table that demonstrates those medications which have sort of different scores based on the different studies. So this would be one of those occasions where there isn't like a terrific explanation, but it may come down to the

methodologies of the studies as well, which to me is one of the reasons why to use them all in accord with each other. Yeah, I think it's good to look at them all together. Okay, let's talk about metaclopromide, reglin. You know, not only can this cause aceshesia, okay, internal restlessness, external restlessness, but it can also cause sensorium issues. So, you know, this is a medication that's used for gastroporesis. There aren't a lot of good options for gastropriesis, so that this helps get the stomach moving moving.

Like, let's say someone has diabetes and their stomach isn't moving very much. It helps keep the stomach moving. Yeah, in this medication, there are some subtle anticholinergic effects, not peaking out some of the scores, as we've seen before. But Han, whom I'll just remind was looking at memory performance and executive function, did rate this a three out of three. Cideronorite looking at psychomotor speed, Rudolph looking at other anticholinergic effects. Both of them rated this as a one on the scale of zero to three.

And then Ert, 2010, with a long-term cognitive decline, rated this as a zero, though. So this is another one of those mixed pictures, but one that you should be aware of. All right, let's move on to antipsychotics. There's two on the list we wanted to highlight quatypine and olanzapine. interestingly these are both studied to decrease delirium because of some of their other mechanism of actions but they have some antich colonergic side effects so yeah what did you find with this one i think this is an interesting case and i think one that's worth contemplating a little bit quatyapine and alanzepine were both rated as having anticholinergic activity for example quatiopein

was rated by Han as a two for the memory performance, Ert, Rudolph, and Chu, all rated it as a one. Bustani also rated it as a three. For Alanzapine, the scores were a little bit higher, actually. Ert, Rudolph, Chu, all rated this as a two. Han and Carnahan rated as it a one, and Bustani also rated it as a three. So both of these medications all have some substantial and noticeable anticholinergic effect.

So in summary of the antipsychotics, you know, some of these are anticholinergic. You know, when someone's having delirium, they have other things that can improve the delirium like, you know, bringing the level of dopamine down, stuff like that. So things like olanzapine, quatyapine are probably more focused on that, also helping the sleep-wake cycle. You know, it's interesting when I thought about Clozapine, which is also three across the board.

Clozapine is an antipsychotic. It's very anticholinergic. I was actually surprised that long-term cognitive function can actually increase. And it's because there's other things going on, right? There's other receptors going on. There's a, you know, glutamate, right? And stuff like that.

So we have to look at the big picture. And, you know, there could be an argument for using a less, cholinergic medication, but these meds side to side usually do about the same. I think it's, I think it's worth noting though, like if we're trying to reduce the anticholinergic burden, like maybe picking something a little bit different. Okay. I'm just going to run through a couple here and give a couple of clinical pearls that I know of peroxatine, you know, its anticholinergic effect may actually help with anxiety early on. But, you know, as a lot of, you know, as a

someone's been on these antidepressants for a lot longer, you know, then they start to get the serenergic benefit. It takes six weeks, remember to get that antidepressant benefit to decrease the anxiety. And then they have the side effect that's still there. They'll get used to it a little bit, but the side effect will still cause an issue. So instead of peroxitine, I try not to use that one. You know, I try to use things like serchylene. I try to use things like fluoxetine. And if I really need to decrease the anxiety early on. I might use the hydroxazine for the first couple weeks, but then move away from that. Another one that I often see is oxybutinin. This is used for bladder issues. This has an anticholinergic effect and it's often overlooked. What's the option for urgency?

It's wearing a diaper or something like that, which for some patients, I would argue that it's probably better than the cognitive dysfunction. So you have to kind of weigh these different things, right? Or can we reduce the dose a little bit at least? Okay. And then interesting, Florosomide. That had some, that had a three and a couple ones across the board. So that might be something to think about. What effect is, what effect is that plane? That's a loop diuretic. Okay, Baclyphan is another one I think about often. It's got some twos. We can switch to Robaxin.

I often do that outpatient. Robaxin being a safer alternative in my mind. And then the benzodiazepines. You know, these don't have the antichlinergic effects, but they do have the cognitive effects. And Selin scored at a three for cognitive effects. So in summary, guys, this was awesome. Thank you for helping me put this together.

I've been wanting to get this episode out for literally like a year. I've flipped it like, Carl, we got to get this episode out. It's going to help so many people. Here we are. Please go on my website, download this, share it with your colleagues, maybe listen to this with some colleagues, go over it. I think it's worth just going down the list. If you're a provider and just kind of being surprised or being like kind of confirmed, right, okay, I knew that that one was bad. Yeah.

it's pretty it's pretty bad so yeah i i really really really appreciate you guys sticking through listening to this episode if you're a therapist i'm going to give you some gold stars let me know if you're getting to the resource library and you're a therapist who just wants to be educated on these things that really excites me you know so many people are not seeing the full picture and we want to give you every hammer there is you know we want to give you strength training and the benefits of that on depression we want to give you um the benefits of of optimizing their sensorium, you know, reducing their risk of delirium. And all of these things together, I think, make a really powerful, powerful impact on people's lives. So that's what we're

about. If you're for that, let me know. You probably are if you're listening to the very end of this episode. And it's been great having you guys on. I don't know. Any like pearls that you guys took away from maybe just real quick Carl anything that you came through with like okay this has really helped me in my rotations as I moved away from CNL I think it was really helpful to recognize delirium as a dangerous side effect of our interventions as physicians and is something to look for just as part of the disease process on internal medicine and I think it really helps to have this background of having done all this reading and looking through all these medications so that I'm a little more attuned to my patients and what they might be going through with delirium. And even if I didn't do

this much reading on some of the other causes, that it keeps that in mind and I'm able to look for other resources as necessary. Adriana, anything you want to say? I just think this has been really enlightening. And especially, it's a really good reminder to us students who maybe haven't seen all of this in person yet, that we need to be fully aware of all of the kinds of medications that can be, that can cause, you know, side effects that you would not think. For example, like baclophon or furosomide, as a student, I would not think that those could cause something like delirium, but it can. So I just think it's really important for us to think outside the box and go the extra mile to try to find.

the hidden issues as we're learning. All right. Well, I think we'll leave it there for today. Thank you guys for coming on. Thank you for listening. It's been excellent. This has been excellent to see this all in one place, to put this together. Really happy to do that.

All right, we'll leave it there.