While there are some FDA-approved medications for dementia, more individuals living with dementia are actually prescribed psychotropic medications. In this episode, Donovan introduces Matt to the concept of the behavioral and psychological symptoms of dementia, which are just as much part of dementia as the memory loss—and are probably a big reason for all this other prescribing.
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The foundation of a good health study is the assessment of important and objective health outcomes. The term outcome is specific to studies of health and health care. It's the same thing as the dependent variable, the end point, or even what some people refer to as the response variable. Frankly, important means that the outcomes matter, measures of things that people actually care about.
An objective refers to measures that are of high quality. In this way they're not based on opinion or bias in some other way. Traditionally health outcomes were bad things, like a disease or a nasty health event. We would basically identify and count them. For instance, how many people develop mesothelioma, a form of cancer following asbestos exposure?
But health outcomes now can really be good or bad things, depending on the context. To know something about health care outcomes for people living with dementia, we have to understand what good and bad care looks like.
This provides us with a pathway by which we can start to study healthcare for individuals living with dementia. Being able to say something about the quality of care allows us to study things like how treatment has changed over time, how care varies across healthcare systems, and identify important potential differences in treatment. Things like disparities.
But getting a handle on the quality of care measures for dementia can be a struggle if you're new to the field. One logical place to assess health care for dementia is the use of medications. From a practical perspective, it's feasible to identify medications too. Every medication is coded in administrative data, using something called a National Drug Code. What people call NDC for short.
As you might imagine, there are a lot of NDCs, but we can link NDCs to other datasets that allow us to identify whole classes of drugs. The list of NDCs continue to grow as new drugs enter the market. You have to keep this in mind if you plan on doing analyses across time.
When we talk about drugs and dementia, it's important to distinguish between drugs that individuals should get. In other words, drugs for which the potential benefits outweigh potential harms versus drugs they perhaps should not get, drugs that are potentially dangerous.
I'm Matt Davis.
And I'm Donovan Maust.
You're listening to Minding Memory, a podcast devoted to exploring research on Alzheimer's disease and other related dementias.
This episode is all about drugs for dementia. We're going to separate the good, the bad, versus the ugly today. We're joined by our very own Dr. Donovan Maust. In addition to being a cohost of a highly acclaimed podcast on dementia, Dr. Maust is an Associate Professor of psychiatry at the University of Michigan and a research scientist in the Center for Clinical Management Research at the Veteran Affairs Ann Arbor Healthcare system.
His research focuses on understanding both the drivers and consequences of potentially inappropriate psychotropic use among older adults with dementia, Dr. Maust has published many articles on drugs and dementia. One prominent recent article was published in JAMA this past year. The study looked at the use of psychotropic and opioid drugs among community dwelling, older adults with dementia. Spoiler alert. He found concerning rates in the use of antidepressants, opioids, sedatives, anti-epileptics, and anti-psychotics, all of which have the potential to cause harm.
Donovan, thanks so much for joining us. I wanted to give you a proper introduction to let you know, we appreciate you coming on. Really wanted to roll out the red carpet for you.
That's my pleasure, Matt. As long as you don't sneak up any surprise cognitive tests, like a couple episodes ago, I'm happy to do it.
So the theme that I introduced leading into this episode is a play on that 1960s film, The Good, the Bad, and the Ugly, alluding to the fact that there are good versus potentially dangerous drugs for people living with dementia. Let's start off talking about the good drugs. What are the types of drugs in broad strokes used to treat dementia?
I guess first I'd say maybe good drugs is being a little bit overly generous. I would say that there are two types of drugs that are FDA approved to treat dementia. And really here by treating dementia, we don't mean that patients who get these drugs are going to improve. What it means is, and we heard a couple episodes ago, dementia is basically a chronic gradually progressing decline in cognition and function. And so what these medications do is they slightly slow the rate of the decline. So just want to be clear that we're not seeing a reversal of the dementia.
So having said that, the two types of medications are cholinesterase inhibitors. The most common one is called Aricept or Donepezil is the generic name. And then this other medication that's sort of in a class by its own called Memantine or the brand name is Namenda.
And again, these medications cause very small declines in the rate of deterioration of cognition. It frankly is very clinician dependent whether a person with dementia will get these medications. If you see a specialist like a neurologist or psychiatrist, you might be a little bit more likely that you would get them. If you see a geriatrician, a little bit less likely that you'll get them. Actually our fearless leader, Dr. Julie Bynum published a paper in JAGS a couple of years ago showing this.
There's also a huge variation across the country where in some parts of the country, it's like only maybe a third of patients will get these meds. In other parts of the country, more like two-thirds will get these medications. So there's really a lot of variation in whether or not folks get these just because the benefit is so small. And again, because of the nature of the illness, it's frankly hard to know if a patient is experiencing benefit because you don't really know what the person would look like without the medication that they're getting.
So when they evaluate the efficacy of a new drug, I assume that they're focused on the cognitive functioning aspect. They're not necessarily trying to reduce plaquing or something like that in Alzheimer's.
Right. So that's a great point and brings up the latest kid on the block with FDA approval, which is this Aducanumab. So the approval of that was largely based on the fact that it did clear these amyloid plaques. Although again, it had like vanishingly tiny benefit, if any, on cognition or function.
These medications, the cholinesterase inhibitors and Memantine were approved based on the impact, albeit small on cognition. They were not looking at, didn't get approval based on any type of change in neuroimaging. No change in the burden of plaques or tangles.
So in a previous episode, we talked a little about the different types of dementia, sort of a primer on that. And obviously there's different. I mean, if you think about dementia as sort of a constellation of signs and symptoms, something you observe in a person, there's lots of different biological underpinnings or etiologies. To what degree do meds vary by the type of dementia?
So I think that's why actually there's been so little progress in this area over decades now is because really dementia is a syndrome. It's a phenotype that can have a whole array of different underlying biological processes leading to this phenotype or syndrome of dementia, which is why I think we've been limited in our ability to really identify effective treatments.
When drug companies were getting these medications approved, they did look in different types of dementia. So for example, cholinesterase inhibitor, one of them is called Rivastigmine. It does specifically have approval for Parkinson's disease dementia or dementia with Lewy bodies. The other two cholinesterase inhibitors don't necessarily have that specific approval.
In general, I think out in the real world, these medications get used, frankly, regardless of the type of dementia, but I don't know that there's really strong evidence to say that they're necessarily more effective for any particular type.
the drugs we've been discussing have been officially approved to treat dementia, even though they may not necessarily be great at doing it. Around when did people start using them?
Yep. So the cholinesterase inhibitors were approved in the mid-90s, and Memantine was a little bit later. Now, nearly 20 years ago in 2003, it got FDA approval. So they've been around at this point for a long time.
And that's something to keep in mind when researchers are looking at some of this stuff in terms of how far back you can really go.
What do you see as the future of treating dementia?
So I think a big part of the concern about this new FDA approval for Aducanumab, and we'll have some episodes on this later, so I won't talk too much now, but I think a concern is that now companies are going to really focus on these amyloid clearing agents since the FDA granted approval to this medication based on its ability to clear amyloid.
The problem is there isn't a great track record for those types of agents having much benefit. So I think there's of course great interests. We need effective treatments for dementia, but I think we're limited based on our understanding or lack of understanding around what are actually the true biological causes of the illness limit our ability to identify treatments to treat the illness. Really the science and research I think is moving further upstream to look at strategies to prevent dementia from developing in the first place.
You know, thinking about the end points that people potentially use to evaluate the effectiveness of new therapies, and coming back to the amyloid thing that we've discussed in previous episodes, it reminds me of other studies that I'm familiar with where... There were studies that looked at back problems with MRIs and those types of things and found very little correlation in terms of how bad things looked on the film versus actual symptoms. Is the formation of amyloid and these tangles and things we talked before, is it correlated with poor cognition? Is that a tight correlation?
That could be a whole next season of our podcast to get into that discussion. So I think the short answer of your question is in the BMJ, they just published. A group just published a meta-analysis looking at the burden of amyloid and cognition and reduction in amyloid and impact on cognition. And essentially the effect was null.
There are also studies, say the religious order studies out of Rush in Chicago where they've done autopsies on folks who've gotten regular cognitive testing in the years proceeding death. And then an autopsy was performed after they die with neuroimaging or a neuropathology done. And the correlation between the burden of neuropathologist and the participants' cognition is really minimal. I think like the R-squared or the amount of variation explained by the neuropathology is something like maybe 0.4. So in the grand scheme of things, the neuropathology has actually relatively little power to explain who does or does not have dementia.
So some of the drugs that we've just been discussing that can be used to treat dementia, say that we're comparing two different healthcare systems. And you start observing that one system is using drugs more, these types of drugs more than another. Does that indicate any kind of quality from your perspective?
So I think the issue of quality for dementia care is particularly challenging because I think it can be very preference sensitive to patients and their families about how aggressive they want to be with the care.
In general, I don't think that you would think of medications like Memantine or these cholinesterase inhibitors. I don't think those are great measures of quality, frankly, because the effects are so small and questionable. And it could be the preference of some families that they're just not interested. The medications have side effects, they have minimal benefit. We don't want to bother with it.
Part of the reason that I have interest in use of these other types of medications, these psychotropics and opioids, because I think maybe it can be a little bit easier to think about quality as potentially inappropriate. So things that potentially are less preference sensitive and it's more straightforward, whether or not it's a good or bad thing for patients to be receiving some of these other medications.
I mean the questionable efficacy of some of these meds, it makes me it heightens the importance of costs from a society standpoint. Are they expensive meds?
Not anymore. I mean, these are all, in particular thinking about the cholinesterase inhibitors and Memantine, at this point, they're all available generic. So cost is much less of a factor at this point than it was when they were first on the block. Of course, costs with the Aducanumab is a whole, whole other issue. But with these meds that we're more talking about today, I think cost is less of a factor in the decision.
You mentioned briefly patient preference in one of your responses. And people think about what drives healthcare use, and people sometimes differentiate between the healthcare providers in the system differing in terms of the likelihood or what have you, in terms of using something versus patients demanding it. I mean, I can imagine that if someone's experiencing dementia, they want to do something for it. And to some degree, that drives utilization, I guess, from your perspective, to what degree are these meds driven by differences in various attitudes and specialists like you've touched on before versus actual differences in patients' demand for them?
I think that is what can be so challenging in this space is these patients and frequently their family members can experience periods of great distress. And so as healthcare providers, you want to feel like you're doing something. You want to feel like active help. It feels like listening and education about the illness is not enough.
That unfortunately I think, leads to prescriptions because that's what clinicians are good at. That's what we know how to do is write a prescription, and it feels like something is better than nothing. Safer antidepressants in particular, where we think of them as being relatively safe. It seems like, oh, well it might not help a lot, but there's probably not much risk. And then it also feels like I'm doing something to help the patient to help the caregiver. The caregiver will perceive it as me being responsive.
What's frustrating is that there's a whole body of work around dementia care. So there are very good evidence-based things we know we could do to support these patients and to support these caregivers, but the healthcare system isn't set up to provide those kinds of support, or most healthcare systems aren't set up to provide that. So what the clinician is left to do is write a prescription because it feels like they're helping the patient and they're helping the family. And my point and concern is that that may not be the case. And I think we need to think more critically about how and why we're using these medications.
Has there been much done looking at how patient preference for the meds might vary among different subgroups and different types of people?
So I guess one answer is it's pretty consistent that you see that white patients are more likely to receive these medications. It's hard to know how much of that is confounded by say, those patients possibly are more likely to have access to specialists, are more likely to even get a diagnosis of dementia in the first place. How much of it is that in general, white patients are more comfortable with the idea possibly of getting psychotropic medications or using psychotropic medications?
Unfortunately, I think it's many times is less about patient preference and is more about the family or caregiver preference and what they're comfortable with and what their expectations are that I think can really drive the care that these folks receive.
I mean, the things that come up in my mind is some of the stuff I'm more familiar with on end of life and just how much that varies amongst certain groups in terms of wanting more intensive types of care. It might be an interesting thing to think about in the future.
Let's shift gears now and talk about drugs that are potentially dangerous for older adults who are living with dementia. Perhaps we could call them bad or even refer to them as ugly drugs. You looked at several different types of medications in your JAMA article. Among the ones you examined from your perspective, which ones are bad or potentially dangerous?
So I'm going to take a step back for just a minute and say, I don't necessarily think of it as dangerous as I think our risk benefit calculation with using them is a little bit out of whack maybe and say we're overbalanced on their risk compared to the benefit side.
And then I just want to take one more step back for folks who are maybe new in the space to talk about this. Why are people getting these medications in the first place? So we've talked a lot primarily about dementia as being a disease of cognition where your memory changes other domains of cognitive function and executive function language. A huge part of dementia, and I would argue possibly the most disturbing and distressing part of the illness are what are called the behavioral and psychological symptoms of dementia.
They used to be called the neuropsychiatric symptoms, but that seems to have fallen out of favor. So it's, BPSD, behavioral and psychological symptoms of dementia. And these include things like apathy, irritability, sleep cycle disturbances, changes in mood, psychotic symptoms, so seeing things that aren't there, hearing things that aren't there, believing that things are going on in the world around you that aren't really happening. These are potentially profoundly distressing to these patients. They're also profoundly distressing to their family members.
And so I just wanted to, we can't really talk about these medication classes without addressing the fact that these are the symptoms that are driving I think a lot of this medication use.
The most common group of use were antidepressants. So we found about 50% of older adults were getting antidepressants. So it makes sense because depression is a really common feature of dementia. Also apathy is a really common feature of dementia where it really looks like the person's depressed. Actually, when you talk to them though, they don't feel sad. They don't feel down. It's more like there's not the initiative there. They're not initiating or engaging with activities.
You would think in a 45 year old, if you saw somebody with symptoms like that, most clinicians would prescribe an anti-depressant or maybe refer to psychotherapy or prescribe an antidepressant. So it's a natural response that if you see an 80 year old with symptoms like that, that you would prescribe a medication. The problem is the evidence isn't really there to support it as being effective. So you're ultimately treating a patient with a medication for which there's no good evidence to support that it helps.
And so then you're only left with side effects for the patient. And antidepressants in general are safe medications. However, they have side effects. Potentially you can feel restless or a little bit jittery. If you have moderate dementia, you might have difficulty articulating that experience, and instead you get more irritable, you might start wandering. You might maybe even have like a little bit of aggressive behavior towards a family member.
And what looks like a bad behavior that might trigger another medication, is in fact a side effect of the antidepressant that you prescribed. And then antidepressants can cause hyponatremia or low sodium in your blood. They're associated with increased fall risk. And another thing I think people don't think of is they actually do adversely impact cognition.
So there was this study where they were looking at citalopram or Celexa to treat agitation in patients with dementia. This was only a nine week trial published in JAMA. Compared to the patients who got placebo, those getting the medication had a one point decline on their mini mental status exam. So again, this is only out of 30 points. They lost a point after only nine weeks of treatment.
And so you're giving people with cognitive impairment, a medication that is further impairing their cognition. And so antidepressants generally seem pretty benign, but you're giving a treatment with really no or very minimal high-quality evidence of benefit. But we know that there's a bunch of side effects associated.
We're giving those to 50% of patients with dementia. And so I could spend the next half an hour going through all of the medication classes, but that's just an example of how I think about why the widespread use of these meds is not necessarily not a good thing for these patients.
I could see though how clinicians. So what you're implying is that they need to shift... When you treat a patient with dementia or severe cognitive issues, you've got to recalibrate in terms of how you think about these meds because it's a different patient population.
Right. That's exactly right. So the brain of a 45 year old with major depressive disorder, whatever is going on, their brain pathophysiology that is leading to the manifestation of depression is a different process than what is happening in an 80 year old, who has dementia, who is also exhibiting symptoms that look like depression. Or the psychosis or the irritability in an 80 year old with dementia is a different brain process, almost certainly is a different brain process than what's happening in younger patients.
So it totally makes sense as principles of pattern recognition, that the things that you use to treat a phenotype in a 45 year old, you would also apply in an 85 year old with dementia. The problem is very little evidence when people have looked, supports the use of those medications.
It sounds complicated. There's a lot of things to consider. It's easier for us to say, "Oh, clinicians should recognize this and treat things differently among this patient population." But it is a continuum, right? Where is that point at which the benefit risk ratio shift in terms of how bad is the cognitive... And changing guidelines and the types of pressures on clinicians, it is a complicated thing, I imagine, in terms of trying to shift how people think about different conditions and how they actually go about it on the front lines.
So one drug I want to touch on just as we wrap things up here is opioids. I mean, all of our listeners are well aware of the amount of research coming out around opioids in the United States, and thinking of pain meds and pain among this population, what are your thoughts about opioids and their use among people living with dementia? And I'm curious too about like having to manage a coexisting pain condition with someone who's having cognitive issues.
So to be perfectly honest, opioids were in the mix in this letter partly because opioids are on everybody's mind in the past decade or even more than that. And so we wanted to look at them.
Of course, pain is super common in this population. I think my geriatrician colleagues would, many of them, most of them would argue that opioids are an appropriate treatment for these older adults because chronic pain is common. We know that untreated pain can actually lead to some of these disturbing behaviors where again, patients might be experiencing pain. They can't articulate or explain that they're in pain, and then they they're acting more irritable. They're wandering, they're agitated. So undertreated pain is definitely a problem.
The other reason I think probably opioids are not so bad is that I would worry potentially about other medications being given as an alternative. Then number one I would think of is Gabapentin, which is in the letter in the anti-epileptic or anti-seizure group.
We know that most of these older adults on Gabapentin are not getting it because they have a seizure disorder. Almost certainly a big chunk of it is being used for chronic pain.
Again, the evidence for that is really minimal, and there are definitely side effects associated with it. So I think most people, most geriatricians would say if you have an older adult with chronic pain who needs medication, probably an opioid might be the most appropriate choice.
I also think some of the questions about potential misuse abuse are less relevant in this population than they might be for younger patients when the topic of opioids or their concerns about opioids come up. Hopefully there would be very low risk of something like an overdose, because generally, hopefully there's somebody else helping manage these patients' medications.
So I think the questions, concerns around opioids are I think, different and perhaps less problematic for this population actually.
So my last question might be a little bit out of your wheelhouse, but some things we've been talking about so far about some of these indirect, maybe associated other things that people are dealing with concurrently with issues with cognition, I started thinking about the caregivers. Has anybody studied some of the medications use and like antidepressants and those types of things among caregivers?
Not medication use in the patient, but medication use by the caregivers?
You know, I should know the answer to that question, but I don't. And that's maybe something you and I need to talk about more. People have definitely looked a lot at things like caregiver burden, caregiver depression. One of the challenges here is frankly, around the what's the right data source to be able to do that. Because for example, in this paper, we used Medicare claims data. We don't have the data for who their caregivers are. You know, a caregiver might be a child, most likely a daughter. Let's be honest, and they maybe are not even in Medicare. So it's hard to get access to the data. So I actually don't know specifically about medication use in the caregivers.
Donovan, thanks for coming on to talk with us about medications and dementia, and as always, thanks to all of you who listened in.
If you enjoyed our discussion today, please consider subscribing to our podcast. Other episodes can be found on Apple podcasts, Spotify, and SoundCloud as well as directly from us at capra.med.umich.edu where a full transcript of this episode is also available.
On our website, you'll also find links to our seminar series and the data products we've created for dementia research. Music and engineering for this podcast was provided by Dan Langa. For more information available at www.danlanga.com.
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The views expressed in this podcast do not necessarily represent the views of the NIH or the University of Michigan. Thanks for joining us, and we'll be back soon.