Week 7 Geriatric Psychopharmacology Transcript PDF

Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... Geriatric Psychopharmacology And welcome to week 7. We're almost done. I can't believe it. One more week after this. So thi...

Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... Geriatric Psychopharmacology And welcome to week 7. We're almost done. I can't believe it. One more week after this. So this week, we're going to talk about geriatric psychopharmacology. And not entirely unlike pediatric psychopharmacology that we talked about last week, it's still the same medications that we've talked about all along. It's just that now, we need to think about the impact of normal age-related physiologic changes, how those changes impact absorption, distribution, metabolism, and excretion. And so, we'll look at that !rst. And the other thing that we need to think about here, speci!cally in this slide set, is the pharmacologic management of neurocognitive disorders. Not that they can't occur in younger people because they absolutely can. But statistically speaking, the signi!cant majority of neurocognitive disorders does occur in the older adult population. And so, we have just a couple of medications that we use to try and improve symptoms in that population, and I've chosen to include that in this discussion. So with that said, you know what happens now. I turn o" the video, so we all don't have to stare at me for the next hour. I turn o" the video and turn on the discussion. So how do I turn o" the video? Let's see. It's not going nearly as easy as I would have hoped. There we go. OK, so issues in geriatric psychopharmacology. First up, like I said, all of the medications that we use to treat psych mental health disorders in our older adult population are the same things that we've talked about all along. And they're all listed here. Things like antidepressants, mood stabilizers, et cetera. There are, of course, some that are preferred in the older population for a variety of reasons, and those reasons are typically based on normal age-related change and normal age-related physiology. And do keep in mind that-- sometimes, I will have students say, you know why are you-- like, do we really have to pick these medications for the !rst time when someone is quote geriatric or an older adult? Who has new onset of a psychiatric disorder in older age? And the answer is, it 1 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... happens more than you might ever imagine. Sometimes, people just develop their disorders at a later date. Anxiety and depression are big ones. Sometimes, people go through the entire life span and maybe they've had a tendency to anxiety or a tendency to dysthymia, but it was never actually a disorder. It never met criteria for a disorder. And then, when they retire-- for some people, I mean, it is a complete loss of identity when they retire from their profession. Other people, it's about when they lose a spouse. So anyway, the short answer of which you know, I am rarely capable. But the short answer is, yes, sometimes, these things do onset in older age. And other times, they have been there all along. But for whatever reason, it just never interfered with social or occupational function to the extent that the patient sought care. Bipolar disorder is a classic example of this. There are those who cycle through episodes of depression and mania through the lifespan or depression and hypomania through the lifespan, and they self-medicate. They self-medicate they're depressed times. They even may self-medicate if they have hypomanic episodes to try to calm down. And then, when they're manic, I mean, truly, mania, most people think that's fun. Most patients that have bipolar disorder are really reluctant to manage their mania. And if it just evolves, that the patient is able to self medicate when they need to and then incorporate their symptoms into their lifestyle, they just never present for care. I'll give you an example. I have a patient right now who is 67 years old, and he is under my care as a court order. It's part of a condition of his probation. And what happened was, this gentleman was having some-- it was a football season, I think. He was having a party at his condo, and I guess things got exciting. And it was a happy day. And all of a sudden, he decided it would be a good idea to take o" all of his clothes and go streaking through his neighborhood. And so, he did. And he was having a great time, but his neighbors didn't really appreciate it. So they saw this 67-year-old man running around naked. I guess, one of the neighbors tried to approach him and suggest that he should go in the house and put some clothes on, and that didn't go well. So eventually, the police were called, and that didn't go very well because the patient genuinely didn't understand what the problem was. Remember, in a manic state, you really lose your ability to properly process emotion, and reason, and things like that. So anywho, he, of course, was arrested. And then, as 2 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... part of his initial intake into the county jail, he had a psych evaluation. And he had, very clear, bipolar disorder. And so, of course, he was started on medication. And then, like I said, as a condition of his parole, he was required to seek psychiatric care in the outpatient setting. And in talking to the man, who now is medicated and doing well, in talking to him, it's clear that he has had this for his entire adult life, but he was a casino host for his profession-- because I live in Las Vegas-- and casino hosts, it's their job to be fun. It's their job to be available at all hours, and late into the night, and early mornings when necessary. And it's their job really to facilitate the party. So it just so happened that his manic episodes made him very successful at his job. And when he had depressive episodes, he would self-medicate with whatever unprescribed substance of abuse of choice was available. And that's just-- I mean, I'm not saying it wasn't a problem for him, but he managed it on his own. And then in retirement, he's suddenly not a casino host anymore. So the next thing you know, he's running around naked in the condo association, and that's how he came to psychiatric care at the age of 67. So it de!nitely does happen. So whatever the disorder, whether it is-- and there is a late onset schizophrenia as well. So with all sorts of disorders, it is possible that you'll see them for the !rst time in the older adult. And we have all the same drugs that we have for everybody else, all the same drugs that we've talked about all along. But now, we have some signi!cant di"erences in how we reason through them. Remember, every time we pick a medication, the question always is, among my drug choices, which one has the least o"ensive adverse e"ect pro!le to my target population? I mean, that's what it always comes down to in the end. So in the geriatric population, we have to consider normal age-related changes that impact the absorption, distribution, et cetera of medication. And a few of them are listed here. As a consequence of aging, we have decreased renal perfusion. I mean, none of these are representative of illness, or disease, or anything wrong. This is just normal age- related change. Remember, the human organism, from the time of conception, grows, and develops, and builds reserves. From the time it's a conceptus and a zygote-- I don't know-- all the stages of embryonic development. But cells just divide, divide, divide, and then they become an embryo. And then, rudimentary organ systems develop. And then they become a fetus, and then it 3 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... becomes a neonate, and an infant, and toddler, and all the way through the lifespan. And for the !rst 30 years of that lifespan, we are constantly growing, developing, and building reserves. We're building our optimal physiologic reserves that we can live on for the rest of our life. And at about the age of 30, we begin to stop building and start living o" our reserves. It really is all downhill after the age of 30, physiologically speaking. I know it's not always the easiest thing to absorb. Believe me, 30 is looking pretty good from where I'm sitting. But it's true. We build, grow, build, grow. We have two lungs, two kidneys. We have an awesome ejection fraction-- 70%, 75% in our prime. We build all these reserves that we don't need. People live just !ne on one kidney. People live just !ne with a lesser cardiac output. We build to a peak at about the age of 30. And then we stop building, and we begin the slow, steady decline of the organism. And I mean, all things being equal, this will go on for many decades, but that's what happens. And you start to see the physiologic impact of that decline, certainly, by the age of 60 or 65. The glomerular !ltration rate is just not what it was 20 or 30 years ago. And this is hugely important because the majority of medications are excreted by the kidney. So decreased renal perfusion means that our mechanism of excretion is just going to be di"erent. It's suboptimal. Most drugs are metabolized by the liver, and age-related decreased liver e#ciency means that it's just going to be a little less e#cient with respect to drug metabolism. So those are two big ones. The organs that metabolize meds and excrete them do have decreased function as a consequence of aging. I mean, it doesn't mean we can't use these medications. It just means we need to consider these things when we choose particular medications and doses. Another one is decreased GI peristalsis. I mean, this is very commonly known. I mean, we know that constipation is a big problem in the older adult because GI peristalsis is just not what it was 30 years ago. But remember that GI peristalsis also impacts how drugs are mixed and absorbed. Remember that mixing of oral contents occurs in the stomach. There is acidotic breakdown. There's the introduction of enzymes, and then the chyme moves into the duodenum so that it can be absorbed. And in the optimal physiologic specimen, the timing for this is all pretty precise. 4 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... As we get older, because of decreased peristalsis, oral contents will sit longer in the stomach, so it is more exposed to acidotic degradation. It will sit longer in the duodenum, so it has a greater opportunity for absorption. And so in some cases, this means that we will absorb drugs more e#ciently or more readily. In other cases, less so. It just depends on the nature of the drug. If sitting in the stomach exposed to acid for longer than normal breaks it down more, then, maybe by the time it gets to absorption in the duodenum, it's not the actual product or molecule that we need. On the $ip side, maybe GI acid doesn't really impact it, and the molecule sits in the duodenum for extra long, and it gets absorbed more. So the decrease in GI peristalsis can either increase or decrease absorption of medication. And then decreased cardiac output as a function of age-related decline. I mean, when you get to be 60, 70 years old, your cardiac output has typically dropped by about 30% of what it was in your prime. And so, that impacts how blood and its contents, like everything it's transporting, is delivered to peripheral tissues. So they all matter. Again, I mean I'm not saying that this is illness, or disease, or bad, or it means that you can't use certain medications. These are just things that we need to consider. Other-- oh, dear, under age-related physiologic changes, there certainly are quite a few of them, aren't there? It's just all downhill, like I said, after the age of 30. Another one that actually does have signi!cant impact for this general topic of conversation is age-related decrease in neurological e#ciency. There's this theory in the geriatric population that-- well, I mean, it's not a theory, I guess. It seems to be factual-- as a consequence of age-related decline, there are certain body systems that are more vulnerable than others to insult. I mean, everybody system demonstrates some decline, but a few of them are just more vulnerable to impact. Remember that the body is a series of organ systems that are all interdependent and all play o" each other. They all function together. And so, an insult in one system can produce symptoms in another. Now, in the young and middle aged population, this is not so overt because we tend to compensate and compartmentalize very well. But as we get older, the consequences of age-related decline become just more apparent. And one of the body systems that is extremely vulnerable to age-related decline is the neurologic system. So what this translates to is that you can have an insult in any body system, and it's more likely to manifest neurological symptoms as we age. Those of you that work with 5 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... the older population know what I'm talking about when I say this. And those of you that don't work with the older population, this is actually a really useful point to keep in mind. Urinary tract infection is the single most common cause of acute mental status change in the older adult. And the reason is, their neurologic system is more vulnerable to insult, so infection in any part of the body, but it's just more common in the urinary tract, infection there manifests as an acute mental status change. Like I said, if you work with the older adults, you know what I'm talking about. If you have a patient with an acute mental status change, the !rst thing you do is urinalysis. Because more than half the time, you'll !nd that the patient has UTI, and that's why they're delirious. And we treat it, and the delirium resolves. Now, you or I-- notice I group myself with you, young and middle aged people-- if we have UTI, we get things like urinary frequency, urgency, dysuria, the usual suspects, maybe suprapubic discomfort. But in the older adult, they are much less likely to complain of those things. And what you will see is an acute mental status change. And it's true of any infection or pretty much any insult, and it's because of decreased neurologic e#ciency with aging. Another thing that we have to consider when we choose medication is cardiac electrical hyperexcitability. So in other words, in the myocardium-- remember the heart is just a huge pump that is driven by electricity, and the heart can generate its own electrical impulses, give or take 60 times a minute in the sinoatrial node. And then, that electrical impulse is transmitted through myocardium in a very speci!c uniform way through various pathways, electrical pathways, that allow for smooth, uniform contraction of all the cells of the atria at the same time and then all the cells of the ventricles at the same time. And this is necessary so that we get smooth, uniform cardiac output, the greatest push of blood out of the heart to the rest of the body. And that happens because of specialized conduction pathways that move in a very precise fashion-- from the SA through the atria. They all feed back into the atrioventricular node, where the impulse is arrested for a fraction of a second, allowing blood to get from atria to ventricle. And then, the impulse goes down the His bundle, and then depolarizes the intraventricular septum from left to right. And then the left and right ventricles are depolarize simultaneously. And this all occurs by way of very speci!c pathways, which is great until we get older. And as a 6 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... consequence of normal age-related change, our cells start to shrink just a bit, just like fractions of a micron. But it's just enough that the cell membranes of the cardiac myocytes are not as tightly packed together, and this causes interruption of those electrical pathways. And so, they are very vulnerable to insult. So if you take a medication that has any unintended adverse e"ect of impacting myocardium, you can throw the patient into AFib, which is very common in the older population, and/or, perhaps even worse, ventricular dysrhythmia. And it's just because of normal age-related change. Yet, another age related change we have to look forward to is a proportional increase in body fat. And I know that you might be thinking, but wait, the elderly or the older adult, they don't have more weight. The problem, usually, is that they will lose weight. And I suppose that's true. I'm not implying that our older adults gain weight. But proportionally, there's less water and less protein as compared to what they had in youth or middle age. And so, even though, overall, there might be weight loss, proportionately, there's more body fat than there was a young or middle age. And the reason that's signi!cant is because fat is fat. And medications will all have some degree of lipophilia, which allows them to interact with cell membranes-- cross cell membranes. I mean, drugs can't do their job unless they can cross a cell membrane and have some action in the intracellular space. And they can only do that if they have some degree of lipophilia. And so, if we have a proportional increase in body fat, then we have more places for drugs to go, which means they tend to be stored for the longer haul. They hang around longer. So a drug that has a long half life in anybody is going to have even a longer half life in the older adult because of its ability to store in body fat of which they have more. So it's just another consideration when we're selecting drugs. Decreased baroreceptor function. This is another thing that is very prevalent in the older adult. And I mean, it can slip your mind unless you really think about what's going on. But remember, under normal circumstances, we all have baroreceptors in our carotid. We have baroreceptors in our-- what do you call it? The aorta. And those are mechanoreceptors that sense changes in pressure. And so, when we change position and gravity suddenly impacts blood $ow to those superior areas, the baroreceptors will sense an increase or decrease in volume and send out the 7 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... appropriate messages to the autonomic nervous system to either produce vasodilation or vasoconstriction to make sure that the brain gets perfused. That's why, we don't pass out every time we get up. That's why you can see something exciting, jump out of your chair, and run to it. That's why you can wake up in the morning, realize you're late for work, bolt out of bed and not pass out every time you do it. But as a consequence of normal age-related decline, the older adult just does not have as e#cient baroreceptor function. So that population is more vulnerable to getting lightheaded or passing out if they bolt out of bed or jump up from a chair. Throw in a medication, that can produce orthostasis, and it can, for sure, produce some clinically-relevant symptoms. So all of those are just normal age-related things. And then, of course, the longer we live, the more likely we are to develop some chronic illness. I mean, it is just-- remember, we peak at 30, and then it's all downhill. The next 80, 70, 80 years of our life is just a slow, steady insidious degradation. Nothing will be as e#cient as it was in our prime, which means we are more vulnerable to insult. We are more vulnerable to chronic illness. And then, polypharmacy is the last thing we have to consider here. The older adult population, statistically, is typically reported as being on six prescription medications on average and two over-the-counter medications. So on-average, our older adult population reportedly takes eight medications a day. I mean, it's almost inevitable that one of those meds is going to have some impact on another med or on chronic illness in some way. And these are just all things we have to consider when it's time to prescribe. So it's a lot. I mean, I know it's a lot. You look at this and go, OK, here's the answer. Let's never prescribe medication again. I will tell you that the more you learn about pharmacology, the less likely you are to be very liberal with the prescription, which is as it should be. Because my favorite line, all drugs are poisons. The only question is, does the bene!t of that poison outweigh the risk? And in the older adult, we just have to consider all of these things. I mean, don't worry. Once you get past the initial immersion here, when you get some clinical experience with it, you will just !nd that there are certain drugs you avoid, and there are certain drugs you use more often. And then, it'll all depend, too, on what the patient's insurance will pay for. So it's not like you have to make a decision from every drug in class every time you prescribe, but 8 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... these are the things, early in the learning curve, that we really have to think about. So for instance, drugs that a"ect cardiac conduction really should be used very carefully, if at all, because of age-related cardiac hyperexcitability. So just for example, the selective serotonin reuptake inhibitors, these are medications that we always think of as being very benign, very safe, really well-tolerated, no real dangerous adverse e"ects. And for the most part, when you compare them to other antidepressants and anxiolytic, that's true. But they're still drugs. They're still poisons, and there are still things we have to consider. For instance, citalopram. Citalopram is the only SSRI that has an FDA Black box warning about a prolonged QT interval and the risk of dysrhythmia. All of the SSRIs can potentially prolong the QT interval. I mean, they've all been studied for it, believe me. But the only one that demonstrates a statistically signi!cant prolongation of the QT interval is citalopram. In fact, it is dose limited to 40 milligrams for the general population and dose limited to 20 milligrams for the geriatric population. And so, you just don't use it. I mean, there's almost no reason where you have to use citalopram and can't use anything else as an SSRI. I mean, the only time that occurs to me that this might be an issue is if the patient has no insurance at all and has to pay out of pocket for every medication they take. Citalopram, I believe, is the one that is what do you call it on the $4 list of most places that have a $4 list. So I mean, I guess that could become an issue at some point. But really, I mean, there's so many-- oh, just so many programs and so many samples that are available and even when you consider costs. If you're not familiar yet with GoodRx, you'll probably learn about it in clinical. And probably, I should mention it in some lecture in the future. But GoodRx is a program where you, as the provider, have access to coupons that you can give your patient. And even a cash pay patient can take the coupon on a device. I guess you could print it, but I just text it to them. And they will get certain medications for various prices. So just while we were talking about this, I looked up Zoloft on GoodRx-- Sertraline, 100 milligrams tablets. And without insurance, with a GoodRx coupon, you can get it for as little as $6.52 a month. So scratch that. There's no circumstance where you would have to use citalopram. One thing I will say about GoodRx while we're on the topic, though, is, the prices can hugely vary from one pharmacy to the other. So if resources really are a concern, and 9 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... you want to use GoodRx for your patient, discuss with them that they might want to consider di"erent pharmacies for di"erent things. Just for example, as I'm looking now at Sertraline on GoodRx, there is a pharmacy called AHF, which I've never even heard of. But a AHF Pharmacy will prescribed you a 30-day supply for $6.52, Costco $10.99. Whereas, Walgreens, it's $27.20. So I mean, that's like what? Almost !ve times more than this a AHF pharmacy and 2 and 1/2 times more than Costco or Vons. So it really does matter. But anyway, I know I digress from my point, which was, when do you have to use citalopram and no other. And the answer is never. So just avoid it in the older adult. Another thing to consider. Remember, I said that the older adult has proportionately more body fat? So long half lives become even longer in our older adults-- Fluoxetine. This is marketed as Prozac. This was the !rst SSRI that was put on the market, I believe, back in the 1980s. And I remember-- I know I've said this to you before because I say the same thing every time I present these kind of topics is that the !rst drug in a class, the !rst drug in a new class of medications, is always going to be safe and e"ective by FDA standards, but, usually, there are some issues with it. But pharmaceutical houses just want to be the one to get the !rst one to market. And then, other pharmaceutical houses, take that molecule and try to !x what's not great about it and make their own products. And we can plainly see that with $uoxetine. Fluoxetine-- I mean, it's a good drug. It remains a good drug all these years later, but it does have one or two issues. And one of them is that it has a markedly longer half-life than any other SSRI. All the other SSRIs, you're looking at a day, a day and 1/2, 24 to 36 hour a half-life. And $uoxetine is 84 hours. So this really does have an impact. I mean, sometimes, it's helpful. If you're treating a younger patient who will, from time to time, forget to take their meds or maybe they work shifts and sometimes forget or get messed up, long half-lives can be a really good thing. But in an older adult, long half-lives aren't a good thing. Because of that proportional increase in body fat, long half-lives become even longer. The downside of a long half- life drug is that if you want to change it, it's a very slow washout titration period. If you try somebody on an SSRI, and they're not doing well, or they're doing well, but the adverse e"ects are intolerable, or for whatever reason you want to change them to another SSRI, most of the other ones you can just sub them out because they have all 10 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... more or less the same half-lives. But with $uoxetine, if you're coming o" $uoxetine and going on something else, you need to account for that very long half-life and titrate it-- wait days with it o". So anywho, that's the implication there. Another thing in the world of considerations in the geriatric population are drugs with signi!cant cytochrome P450 impact. We have, of course, talked about this. And in the world of the safe benign SSRI, we have two drugs that are pretty powerful inhibitors of, at least, one of the P450 enzymes. The two drugs are paroxetine, which is marketed as Paxil, and $uoxetine, we just talked about, is marketed as Prozac. And they are signi!cant inhibitors of the 2d6 ISO enzyme. And the reason that matters is because lots of psychiatric medications, lots of-- what you call it-- antipsychotics are substrates of the 2D6 family. So if you have a patient who's taking an antipsychotic, who's metabolized by the 2d6 ISO enzyme, and then you want to put them on an antidepressant, if you put them on one of these, these drugs inhibit the enzyme that metabolizes the antipsychotic. So the antipsychotic levels go up, up, up, and the next thing you know, you have side e"ects. You have extrapyramidal symptoms. You have prolactin symptoms. You have 80 pounds weight gain. It just depends on which drug you're on. But that's the signi!cance of this. And so, that's just the example. And I use the SSRI class because we do tend to think of SSRIs as very safe and just not a lot of side e"ects and easy to use. And that really is true as you compare them to others. But even still, in the geriatric population, you can really see readily how those normal age-related changes do impact selection of medications. So that's that. Consider it for every drug class you lose-- you lose? Not you lose. Consider it for every drug class that you use. All right, time to change the topic a little bit. Neurocognitive disorders. As I trip over my own words and can't even get them out the right way, let's talk about cognitive impairment. Let's talk about word !nding di#culties. But seriously, neurocognitive disorders, like I said, they certainly can occur anywhere in the lifespan, but statistically are more common in the elderly population. So what we're really talking about here are conditions that we used to call dementia. And I know that you still hear the term dementia a lot. In fact, sometimes, even in this lecture, I'll use it. But I will explain why one of the things that it's my job to do as a professor is to present 11 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... you with the, quote, "right way," the textbook way, the evidence-based terminology and discussions. And neurocognitive disorders is one of those new-ish terms. We used to talk about dementia all the time-- Alzheimer's dementia, Lewy body dementia, vascular dementia. I mean, that was the terminology. And like I said, a lot of your-- especially your more experienced clinicians will still use those terms. But in 2013, when the DSM-5 came out, they reclassi!ed these conditions. And now, they call them neurocognitive disorders. So the neurocognitive disorders as a group of disorders includes delirium, mild neurocognitive disorder, and major neurocognitive disorder. Well, I mean, we will talk about the disorders in terms of assessment, treatment, et cetera, in nursing 69-70 next semester. But with respect to the medications, what we're really talking about are medications to treat the symptoms of major neurocognitive disorder, which is the artist formerly known as dementia. Now, the way we're supposed to look at it is, neurocognitive disorders are characterized by a series of cognitive symptoms. And there's many things that can make that happen, like Alzheimer's disease, like target organ damage from vascular disease, like Lewy body disease. See where I'm going with this? So the proper terminology now is that we look at many of these disorders that cause neurocognitive impairment, and that's the thing that we used to call dementia. So I hope that makes sense a little bit. I mean, it's a much bigger conversation, and it really belongs in the assessment and management course. But in the framework of looking at medication, I do want you to understand that when I refer to neurocognitive disorders, what I'm really referring to are what you might more normally think of as a dementing disorder or a dementia. And so, with that said, pharmacology of neurocognitive disorders is truly centered on symptom improvement. We don't have anything that can cure a neurocognitive disorder. We don't have anything that can stop the progression. We don't have anything that can reverse symptoms. I mean, I wish we did. There's lots of research into trying to !nd a way, especially with Alzheimer's disease, speci!cally as a cause of neurocognitive impairment. There is lots of privately funded research going on to try to !nd a way to stop that, or cure it, or keep it from happening because there's people with lots of money who are afraid of 12 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... getting it. And there have been of things studied. It's really very interesting. But to date, nobody has found any way to actually treat the disease itself. All we have are a couple of medications that can help with symptom control. Now, the other thing I should probably mention is when I talk about pharmacologic management of neurocognitive disorders, I will highlight very speci!c causes of neurocognitive disorders. There are a ton. I mean, there are a ton, including things like traumatic brain injury, organic lesions, things like that. But when we talk about pharmacotherapy for the symptoms of neurocognitive disorders, we are usually talking very speci!cally about just a couple of the underlying diseases. And the one that has been best studied, the one that we have the most is for a neurocognitive impairment due to Alzheimer's disease. We know the pathophysiology of Alzheimer's disease pretty well. It is characterized by, among other things, neuro!brillary tangles and a loss of acetylcholine-producing neurons in various functional areas of the brain, including the hippocampus, which is where memory is stored. So while we do have some medications that can help improve some symptoms in speci!c types of neurocognitive disorders, we don't have anything really that across the board is used for symptom management. But I mean, we have a few. But really, for the most part, the study of pharmacotherapy for neurocognitive disorders really centers on the study of pharmacotherapy for just a couple of causes of neurocognitive impairment, and Alzheimer's disease is number one. And then, there are some classes of drugs that we will use across the board just to try to calm patients down because sometimes patients with neurocognitive impairment, they have trouble processing emotion and can have behavioral dysregulation. And another concern in some forms of neurocognitive impairment is hypersexuality, especially as the cerebral cortex starts to atrophy and deteriorate. In some forms of neurocognitive impairment, you will see patients start to revert back to more basal instincts, more childlike, and less able to control certain drives, and the sex drive is one of them. And in some dementing disorders, we do see hypersexuality as a symptom, and it needs to be medicated. So !rst up is Alzheimer's disease. So like I said, Alzheimer's disease, we know that it is associated with a loss of acetylcholine-producing neurons. It is the single most 13 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... common cause of neurocognitive disorder. So for many reasons, it is a popular area of study. And recognizing that loss of acetylcholine-producing neurons is a big problem, earliest pharmacotherapy centered on trying to increase the acetylcholine concentration. So remember, from week one, like your second bullet point says, hearkening back to week one, if you can even remember it now, we talked a lot about synaptic transmission. And I mentioned that, virtually, all psychiatric disorders are a result of some insult or some impairment in the process of synaptic transmission, and acetylcholine is a chemical transmitter. So we have presynaptic neurons. We have postsynaptic neurons, and we have the synaptic cleft, which is the extracellular space in between. And a presynaptic neuron, when appropriately stimulated, will release a neurotransmitter that binds to a receptor on the postsynaptic receptor. And in the hippocampus, acetylcholine is that neurotransmitter that helps us to process and store memory. And we know that in Alzheimer's disease, there is a loss of that. So some scientists at somewhere, sometime, said, hey, perhaps we can improve the memory loss and the cognitive impairment of Alzheimer's disease if we !nd a way to increase the acetylcholine concentration in those relevant pathways. And that's where the cholinesterase inhibitors are born. So recall that when a presynaptic neuron releases a neurotransmitter, the neurotransmitter then binds to the postsynaptic receptor, does its job, does whatever it's supposed to do, and then that neurotransmitter has to be neutralized. We have to get rid of it. I mean, we can't have it hanging around all the time. We can't have it doing extra work. I guess, in the case of memory, we'd never forget anything if we had too much acetylcholine. And remember the three ways that we neutralize neurotransmitters. Sometimes, they just di"use away from the synapse as a consequence of Fick's !rst law of di"usion. Stu" will go from an area of high concentration to an area of low concentration. Sometimes, neurotransmitter is re-uptaken by the presynaptic neuron. And sometimes, it is enzymatically degraded. And in the world of acetylcholine, it is enzymatically degraded by the enzyme acetylcholinesterase or cholinesterase. Remember that, in science, when you put "ase" on the end of a word, it breaks down the !rst part of the word. So lipases break down lipids. Proteinases break down proteins. And 14 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... cholinesterases, a.k.a. acetylcholinesterase, break down acetylcholine. And so, like I said, some research pharmacologist somewhere said, hey, if we block the action of acetylcholinesterase, we are blocking the breakdown of acetylcholine, so we will have more acetylcholine hanging around the synapse to do its job and maybe we can improve memory that way. So in neurocognitive disorders with symptoms related to an acetylcholine de!ciency, this is logically not a bad idea, keeping in mind that Alzheimer's disease, the most common cause of neurocognitive disorder is a condition-- excuse me. Thought I could get through that slide without the sneeze, but it didn't work out that way. Anywho, Alzheimer's disease is the most common cause of neurocognitive disorder, and we know that there is a signi!cant impact in there of decreased acetylcholine. So it would stand to reason that cholinesterase inhibitors could improve the symptoms of Alzheimer's disease. And so, the cholinesterase inhibitors were born. They do have the greatest documented e#cacy for symptom control or symptom improvement in patients with Alzheimer's disease. And for a very long time, they were indicated only for Alzheimer's disease. You would hear a lot of people in the mental health world and the geriatric world tell you that they don't work. And the reason they probably appear not to work is because they were being used in patients whose cognitive impairment was not the consequence of a cholinesterase de!ciency. It wasn't Alzheimer's disease. Just in more recent years, they have been advocated for Parkinson's psychosis or, a.k.a., Parkinson's dementia. But they really aren't going to help people who don't have an acetylcholine problem. So Alzheimer's disease, for sure, maybe Parkinson's dementia. But if the problem is vascular disease causing, or cognitive impairment, or traumatic brain injury stu" like that, it's really not. I wouldn't expect these to make a big di"erence. And even in patients with Alzheimer's disease, I should probably point out that these drugs, they do have documented improvement in cognitive symptoms. Obviously, they're FDA approved, so they have to have some e#cacy. But it's not hugely impressive. You really do want to manage expectations in the patient and the family. I mean, it's not like taking these medications are going to suddenly restore them to their pre-dementia baseline. So you want to be clear that while there may be some improvement, it certainly isn't going to get mom or dad back to the way they were. And they have the greatest utility 15 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... in patients with Alzheimer's disease. It's not always so easy to get a sense of what the cause of neurocognitive impairment is, but you can often come pretty close. I mean, de!nitively, you can't diagnose Alzheimer's disease until autopsy. At which point, medication really becomes a moot point. But a good neurocognitive assessment or neuropsychiatric assessment really can help you nail it down. The common causes of neurocognitive impairment really do have a symptom collection that makes them distinguishable. And again, we'll talk about that more in a nursing 69-70. So when we talk about cholinesterase inhibitors, !rst up is Aricept. Actually, the very !rst cholinesterase inhibitor was not Aricept. I don't even discuss it anymore. It's been o" the market for a long time, and it really was ludicrous. Another example of how drug companies really want to be the !rst one to get a new class of medication to market. You'll probably never hear this again. But just for the sake of illustrating the timeline and how this stu" goes sometimes, the very !rst cholinesterase inhibitor indicated for Alzheimer's disease was marketed under the brand name Cognex. The generic name was tacrine, and the brand name was Cognex. And it was a QID drug. It had to be taken four times a day, which is really ludicrous. I mean, it's hard enough for anybody to remember to take anything four times a day. But this is a drug for Alzheimer's disease. The primary symptom presentation in these patients is memory loss. So to expect them to take it four times a day, I mean, it's just crazy. And in addition to that, there were some other issues with respect to cytochrome P450 Interaction and stu" like that. So as is often the case, subsequent companies came up with better formulations. And I don't even think-- I think Cognex has been o" the market for a long time now. Anyway, what we have now are drugs that are more user- friendly. Still have some issues, but again, all drugs are a poison. Every drug has an adverse e"ect pro!le. The question really is just, which one best matches your patient? So !rst up is Aricept. This is the most commonly used medication for patients with Alzheimer's disease. So it's got pros and cons. One of the pros is it's a once-a-day drug. So that's nice. I mean, you can-- except for the most severe progression, patients with Alzheimer's disease will often live with prompts, signs, and routine, and things like that. So they often can be prompted to take it once a day. And if not, then there is usually a caregiver 16 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... that can help with that. Anyway, once daily is a pretty good. It's a pretty good plus. Also, it is available by orally disintegrating tablet, which is a plus for people that have trouble swallowing pills. So they're easy, and they are convenient. The downside is that this is a substrate of a couple of di"erent cytochrome P450 enzymes. So for the polypharmacy patient, which you are more likely than not to encounter in this population, it may be a concern. There's that 2d6 enzyme. Again, remember, I said many psychiatric medications are substrates of the 2d6 ISO enzyme, and this is one of them. So there are some pros and cons. It certainly better than Cognex that you had to take four times a day. Then we got Exelon. Exelon is another cholinesterase inhibitor. And typical of the pharmaceutical trajectory, it needed to !nd a way to be di"erent from Aricept, so it could !nd its niche in the market. And there are a couple of them. One of them is that it is available not just orally, but also in patch form. So if oral ingestion is an issue or a concern, this can be put on as a patch. So that's nice. It's real pro, though, is that it is not metabolized by the liver. So cytochrome P450 metabolism and even liver function is not an issue at all. So this really is the best choice for people with signi!cant liver disease or liver impairment. And if you are really worried about polypharmacy and drug interactions, this may be one to consider. Now, on the $ip side, this is very potent. And this medication class, in general, does have a tendency to an adverse e"ect pro!le. You know, some meds, people take them and never have any adverse e"ects at all. That's not usually the case here. The thing with cholinesterase inhibitors is that while we're trying to block acetylcholine breakdown in the brain and increase acetylcholine activity in the brain, which is great, the problem is, we're not so sophisticated that we can make a drug that just does it in the brain. So the trade-o" here is that you're going to block metabolism of acetylcholine all over the rest of the body. And remember, acetylcholine, I mean, it is the neurotransmitter of the parasympathetic nervous system or the cholinergic system. And so, cholinergic adverse e"ects are fairly common with cholinesterase inhibitors and can be most pronounced with this particular medication. So pros and cons. You've got to pick your poison. Now, Razadyne is yet another cholinesterase inhibitor. And again, trying to !nd its place in the world, like what makes it di"erent from the others. So here's the story with 17 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... this class of drug, which really hasn't caught on as well. So like Aricept, it is metabolized by cytochrome P450 enzymes, so it can't claim any particular utility when there's concern about drug interactions. It is dosed twice daily, which is not as good as once daily. But their claim to fame is, with this particular drug, is that the long term e#cacy is better than donepezil. That you get quality symptom improvement for a longer time, and that's its claim to fame. It has some study to support that. I'm a little bit skeptical of that. Although, I mean, I'm no cholinesterase inhibitor research expert, so I don't claim to have any evidence to back up that impression. But I just !nd it di#cult. I mean, you can almost-- you can support almost anything with the right study design. But the thing is that Alzheimer's disease is a degenerative disorder. It just gets worse and worse over time, and none of these drugs will impact that. And keeping in mind that if a cholinesterase inhibitor is going to be e"ective, there has to be some acetylcholine production. As Alzheimer's disease progresses and you lose more and more acetylcholine-producing neurons, there will come a time when these drugs won't help at all because the patient's just not making any acetylcholine to begin with. If you don't have acetylcholine, blocking its breakdown is not likely to help. So I !nd it hard to get my hands around any one of these drugs can give you better long term e#cacy than the other when they all are just treating a disease that's going to continue to deteriorate. But I don't know. I report. You decide. If you !nd that you have a patient for whom you want to consider a cholinesterase inhibitor, these are the ones that are available. And you have to go through the pros and cons and decide what's the best one for your patient. But what you can count on with virtually all of them are cholinergic adverse e"ects. You should be familiar with them. And so, I have a conveniently located slide here to tell you all about the cholinergic side e"ects. Remember, acetylcholine is the neurotransmitter of the parasympathetic side of the autonomic nervous system. Autonomic nervous system has two branches, right? Sympathetic and parasympathetic or sympathetic and cholinergic. The sympathetic nervous system is your fear $ight-!ght response. It's your stress response. It's what makes you physiologically ready to manage a stressor. And I mean, it's the sexy one. It's the tachycardia, the dilated pupils, the increased respirations, 18 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... increase cerebral perfusion, blood pressure goes up. You are ready to !ght, $y, or whatever you're going to do. And when you have a sympathetic discharge, it all happens at once, right? You don't even control it. This isn't under voluntary control. It just happens when you perceive a stressor. Well, the cholinergic side, the parasympathetic side of the autonomic nervous system is not nearly as exciting. The parasympathetic side is the side that maintains just day to day life functions. The cholinergic side, the parasympathetic side, this is just like the old reliable workhorse. This is like the signi!cant other that your mother and father might have said, well, it might not be the most exciting person, but this person is going to be solid, rock steady, be good to you, be faithful, and not lie, contribute to the household !nances. That's the cholinergic system. The sympathetic nervous system, that's the exciting one. That's the one that's exciting, and gorgeous, and lots of fun, but doesn't last very long, right? It's only around for the extreme, and then is gone. So the cholinergic side, the parasympathetic side, we don't think about it a whole lot because it's just not as exciting it's just happening, day in and day out, but it's keeping us alive. So the parasympathetic or cholinergic symptoms are often discussed with the use of the mnemonic SLUDD. Salivation, lacrimation, urination, defecation. And I threw through bradycardia in here because we do need to mention it, but it doesn't !t the mnemonic. So I don't know about all that. Well, let's just say SLUDDB. Salivation, lacrimation, urination, and defecation, these are things that are driven by acetylcholine. In order to eat, you have to salivate, right? Because saliva has enzymes in it that begin food degradation. You don't think a whole lot about saliva, so you don't have any. You don't really appreciate it until it's gone, walk around with perpetual dry mouth. Try taking a diuretic for a week. And all of a sudden, you'll appreciate how important saliva is. Same thing with lacrimation. This is how we keep our cornea lubricated. Most of us take it for granted. But if you suddenly can't lubricate your eye, you will totally realize how important it is. And not being lacrimated-- not being lacrimated, that's not grammatically correct. The inability to lacrimate can lead to dry eye, which can lead to iatrogenic corneal abrasions, which can be exceedingly uncomfortable. I guess it's just a day-to-day vegetative kind of function. Urination and defecation, I 19 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... mean, what can I say? No real explanation is needed here. We need to be able to urinate. We need to be able to defecate. And these are things that are driven by the cholinergic system. Bladder contraction is driven by acetylcholine. Smooth muscle contraction of the gut is driven by acetylcholine. And the parasympathetic nervous system, remember, is the one that helps control heart rate. The sympathetic system speeds it up when you have to !ght a stressor, but the parasympathetic system is what controls heart rate, so when you're sleeping, you're not tapping away at 120 beats a minute. So under normal circumstances, we certainly need cholinergic activity. We all need to be able to salivate, lacrimate, urinate, and defecate. Fortunately, unlike the sympathetic system, they don't all happen at the same time. I mean, think how exciting every meal would be if every time your cholinergic system discharge every piece of it worked together. You'd sit down. You try to eat. You'd salivate. You cry. You'd urinate. You defecate. It would be a mess. The cholinergic system is just more controlled, more considered, more focused, and that's great until you take a medication that increases the amount of acetylcholine in circulation. And then what you wind up with are excesses in salivation, lacrimation, urination, defecation, and bradycardia. And this is what produces the side e"ect pro!le that people complain of. I mean, I always feel like whenever I try to prescribe these, the patients have more adverse e"ects than they do clinical improvement, but I repeatedly hear complaints about, I feel like I'm going to throw up all the time. My mouth is always watering. People that had any tendency to urge incontinence, this will exacerbate it. This can produce diarrhea, nausea, vomiting, and fatigue because the heart rate slows down. So those are all things that you really need to be on the lookout for. And again, you know my tagline here, risk, bene!t, all drugs are a poison. Are these adverse e"ects worth the clinical improvement that you might see? And I mean, they're not all necessarily bad. We mentioned before that the elderly often struggle with constipation. This can actually crank that up a little bit. If you have an older adult patient who, perhaps, could bene!t from a cholinesterase inhibitor but also has some trouble with urinary retention, whether they have neurogenic bladder or a man with benign prostate hypertrophy, this can facilitate urination. Somebody who is on diuretics or does have perpetually dry mouth, this 20 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... could improve that. So it's not that these things are all bad. It's just to be aware that these are very common side e"ects. And that's it for the cholinesterase inhibitors. Their primary utility is for neurocognitive disorders that are caused by diseases that result in decrease acetylcholine. Then, we have the NMDA receptor antagonist. This is a separate drug class, and there's only one drug in class on the market in the United States. It's called-- what's it called? I can't even believe I just blanked on the name of it. Oh, well, we'll !nd out-- we'll !nd out in the next-- Namenda. The brand name is Namenda. And we'll look at this for the next slide or two. So this is a di"erent class of medication. This does not block the breakdown of acetylcholine. What this class of drug does is actually preserve acetylcholine-producing neurons. One of the theories of Alzheimer's disease is that, for whatever reason, certain acetylcholine-producing neurons are subject to excess excitation, like disproportionate excitation, which then leads them to degrade and self-destruct. And so, if they self destruct, then they're not there anymore, and you don't have enough acetylcholine. So these drugs aim to block the excess excitation by blocking the receptor that is activated by the chemical glutamate. Glutamate is an excitatory neurotransmitter. And when glutamate binds to NMDA receptors, it causes excitation in the receiving or postsynaptic neuron. And the concern is that some of these neurons get overexcited and blow up basically. So the theory was, OK, if we can block some of these receptors, then the neuron doesn't get overexcited, and it won't blow up. And we will preserve our acetylcholine- producing neurons. So this drug works synergistically with cholinesterase inhibitors. They can work together to ultimately both preserve acetylcholine-producing neurons and maximize the utility of the acetylcholine that is actually released. And that's what this slide aims to show you, and I hope I can do justice to this and make it clear. Let's see. Let me get my laser pointer thing here. OK, so we're like we're not looking at the same synapses here. We're looking at two di"erent synapses. So here on the left in blue, what we're looking at is the excitation of an acetylcholine- producing neuron. So here's your acetylcholine-producing neuron. At this synapse, it is the postsynaptic neuron. This is the neuron that will be stimulated. Again, think back to week one. Neurons receive a bunch of stimuli. The stimuli is conducted down to the cell body and 21 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... processed. And if threshold is reached, excitation occurs and an impulse will shoot down to the axon terminal and a transmitter will be released. And for this particular neuron, the chemical transmitter would be acetylcholine. So here, this is the acetylcholine-producing neuron, and it is normally excited or activated by the chemical transmitter glutamate. So glutamate is the little red triangles here. And glutamate will bind to NMDA receptors and cause excitation of this neuron and ultimately release acetylcholine. So one of the theories of Alzheimer's disease is there is too much excitation. So if we give the NMDA receptor antagonist memantine, a.k.a.-- what did I say that was called?-- Namenda, and then you'll block some of the receptors, you will attenuate excitation so that excitation is not out of control. So here, we're trying to preserve the acetylcholine- producing neuron. The picture you see over here is the acetylcholine synapse. So this is the axon terminal of this neuron. This neuron is excited. If it gets excited to threshold, it will release acetylcholine. So acetylcholine is the little purple balls. And when acetylcholine is released, it will bind to an acetylcholine receptor in the hippocampus. It will facilitate memory storage and retrieval. And then, what usually happens is acetylcholine is released. It gets a chance to bind, and then it is enzymatically degraded by acetylcholinesterase, which is visualized here as green triangles. s So acetylcholinesterase is the enzyme that breaks down acetylcholine. But remember, in Alzheimer's disease, we want to try to preserve acetylcholine, so we give a cholinesterase inhibitor represented by blue boxes. The cholinesterase inhibitor blocks the action of cholinesterase. The acetylcholine is not broken down, and it combined all over the place, thus improving memory. So that's how these two drugs work together. This one preserves the acetylcholine-producing neuron. This one blocks the enzymatic degradation of acetylcholine. And if it goes the right way, then, ultimately, you have preserved neurons, and you have more acetylcholine activity. And that's the idea. Like I said, there's one drug in class. It's called Namenda. It is not a cholinesterase inhibitor as we have just described, and there is also improved memory documented in patients with SDAT or-- this is the older terminology-- senile dementia of the Alzheimer's type. Now, we call it Alzheimer's disease. This medication does need to be introduced and in fairly slow titration. It comes with a 22 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... starter pack if you decide to prescribe it. And again, it's very speci!c to acetylcholine- producing neurons. So whether or not it will be helpful in other neurocognitive disorders, there's just really no meaningful evidence to support it. Although, I can tell you that both of these, both cholinesterase inhibitors and Namenda are used o"-label for a variety of dementing disorders or neurocognitive disorders. And that's when they don't work half the time. It's because acetylcholine really isn't the problem. Now, there is one combination agent. It is the standard of care now. If you deduce that the patient will bene!t from a drug that increases acetylcholine concentration and preserves acetylcholine-producing neurons, the standard of care is to start both of these drugs when you start therapy. And so, the combo agent is marketed as a Namzaric. It is a combination of memantine and donepezil. And once you get the patient on it, it's once a day, which is nice. There are still potentially cholinergic side e"ects because donepezil is one of the components here. And it's just another way to introduce another mechanism to try to optimize the cognitive symptoms in the patient with neurocognitive disorder. And that's that. I mean, they were originally designed for Alzheimer's disease. As I said, they are trialed in other dementing disorders or other neurocognitive-- I have to stop saying that-- other neurocognitive disorders. But clinically, they just don't appear to be as e#cacious in other conditions. So that's that. Now, the next symptom control drug, which is a totally di"erent mechanism of action is Nuplazid. Nuplazid is the brand name for pimavanserin, which was put on the market, I don't know, maybe, !ve, six years ago now? So this one, this is a really interesting drug. This is FDA approved for the hallucinations and delusions that are associated with Parkinson's psychosis, which is the artist formerly known as Parkinson's dementia. Psychotic symptoms are not really common in neurocognitive disorders. They are the exception rather than the rule. Usually, you see cognitive decline, but you don't see the onset of psychosis. There are just a couple of neurocognitive disorders that are characterized by psychosis, and Parkinson's is one of them. And it's a particular type of neurocognitive disorder. It's di"erent from Alzheimer's. It's di"erent from vascular dementia, and it is associated with hallucinations and delusions. So this has always been a real challenge because we identify that hallucinations are typically a problem of excess dopamine activity in the mesolimbic pathway, if I can hearken you back to, I think, it's a week four. 23 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... So hallucinations and delusions are typically a consequence of too much dopamine activity Parkinson's disease, the motor Parkinson's disease, the motor symptoms are a consequence of too little dopamine activity in another area of the brain. So it can become a challenge here. How can you manage symptoms of psychosis if you have to block dopamine activity in this patient with Parkinson's disease who already has a dopamine de!ciency problem? So if you treat the psychosis, the Parkinsonian motor symptoms will get worse. So it's a bit of a clinical conundrum. And then, as I said, !ve or six years ago, Nuplazid hit the scene. So this is really an interesting medication in that it controls hallucinations and delusions without impacting dopamine in any way. When we look at the mechanism of action-- but !rst, let's look at the last bullet point. No impact on dopamine, histamine, or muscarinic receptors. This is a big deal. Virtually, every other antipsychotic does have an impact on dopamine. Many have an impact on histamine and have antihistamine-like side e"ects. And many have anticholinergic e"ects because of their impact on muscarinic receptors. This drug doesn't have any of those which is awesome. The mechanism of action, the mechanism of control of hallucinations and psychosis is theorized to be related to its action as both a serotonin 2A receptor antagonist and a serotonin 2A inverse agonist. I know your slide doesn't say antagonist. I should have put it in there. And in fact, I tried to put it in there yesterday, and I wiped out the entire lecture, which is why I'm recording this lecture again. And I'm not making any changes to slides. So work with me here. The mechanism of action of Nuplazid is that it is theorized to be both a serotonin 2A receptor antagonist and an inverse agonist. So what does that mean? Well, you know what an antagonist is. Remember, in week one, we talked about agonists and antagonist. And agonist produces a biologic response. The agonist binds to a receptor and produces a biologic response. And antagonist has no action of its own. An antagonist will bind to a receptor and block the natural response that would occur with an agonist. An inverse agonist binds to a receptor and actually produces the opposite response that the natural agonist would. So in this case, you've got two di"erent ways to impact, to inhibit the e"ect of natural serotonin. So you're actually-- not only are you blocking the action of natural serotonin, but you're also producing the opposite response in the 24 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... postsynaptic neuron that serotonin would produce. So you're really, really dropping serotonin activity at this receptor site, and that's theorized to be the mechanism of action. Markedly attenuating serotonin activity in 5HT2A or serotonin 2A receptors ultimately will decrease dopaminergic activity in a downstream way, like multiple synapses later. So ultimately, you get the same blockade of hallucinations. But we do it without actually blocking dopamine activity. I mean, it's interesting. And I would say it again, but actually, if you need to hear it again, just play this back a little bit, just rewind a few seconds and listen to it again. An inverse agonist does produce a response in the postsynaptic receptor, but the response it produces is opposite that of the natural agonist or the natural ligand. This is cool because it's the !rst clinical inverse agonist that I've ever heard of. I mean, again, I'm no research pharmacologist. There may be others out there. But when I was in school and learning about this stu", we learned the concept of the inverse agonist, but there was not a drug on the market yet that worked that way. And now, we have one, so it's cool. But anyway, the real important thing here is that this can attenuate hallucinations without having any impact on dopamine at all. So it's cool. But like every star, there has to be somebody trying to put it out, right? There has to be something wrong with it. And with Nuplazid, the wrong with it is right here on the screen. I mean, again, these aren't reasons not to use it. These are just things to be aware of. This medication, too, will prolong the QT interval. And so, it is either contraindicated or use very cautiously in people that already have underlying cardiac dysrhythmia. Like 50% of all prescription medications, it is a cytochrome P4503A4 substrate, so you have to consider that interaction. And there have been reports of patients developing urticaria and angioedema. And the thing about that is that it can occur at any time in treatment. It's not necessarily just when you start it. So you can have somebody who's been on Nuplazid for three years, and they come into your o#ce one day with swollen face, and we have to stop the medication. So be on the lookout for that. Those are the two or the three classes of medications that have been developed speci!cally for symptoms in neurocognitive disorders. Everything else we have is just trying to !nd some more generic way to attenuate symptoms. Before we leave Nuplazid, I did want to mention that it is only indicated for 25 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... Parkinson's psychosis, but it is used o" label in other psychotic disorders like schizophrenia. And there is evidence to suggest that the symptom control is better with a traditional antipsychotic rather than the antipsychotic alone. But it's o" label, so I'm sure you'll discuss more of that when you do your clinical rotations with your preceptors. OK, the rest of the story, the last few slides. It's just what can we do to try to control some of the symptoms that happen when neurocognitive disease progresses. One of the things that we have to consider are the SSRIs, and it's for a few reasons. First of all, older adults do become depressed. And if they are diagnosed with a degenerative neurocognitive disorder like Alzheimer's disease, I mean, it would increase their risk of depression. To be told that you have this neurocognitive disorder that's just going to get worse, and if you live long enough, you won't be the same person anymore, I mean, of course, it can precipitate a major depressive episode, particularly in someone maybe who already has a tendency to that or is vulnerable to that. So any time we make a diagnosis of neurocognitive disorder, we should also screen for depression. And sometimes, depression actually presents as neurocognitive impairment, but it's not really. It's just that they need to have an antidepressant. So SSRI should always be in the top of our arsenal. It's this something to consider when we are seeing patients who have neurocognitive symptoms. We also use SSRIs. I think it comes up in a later slide. But we also use SSRI sometimes to control hypersexuality. We're just capitalizing on the sexual adverse e"ects. A behavioral dysregulation is another concern in patients with neurocognitive disorders. And some causes more than others, but there are circumstances where patients with neurocognitive impairment can demonstrate really signi!cant behavioral episodes or angry outbursts to the extent that they can be a danger to themselves and others. And when that happens, when all else fails, when we try to manage their environment and optimize their other medications, when all else fails, sometimes, we have to put people on antipsychotics to control their behavior. There are a couple of options to choose from. But risperidone seems to be the go-to one for anger management and behavior management across the lifespan. I know we've talked about it in other contexts. And it is frequently used here. You'll especially see risperidone use frequently in patients who have neurocognitive impairment. 26 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... At home, they're managed OK with nonpharmacologic therapies. But then, they become hospitalized for anything, like a hip fracture or UTI or whatever. And when they become hospitalized and taken out of their environment, their behavior just becomes very dysregulated. And they have to be put on risperidone. We see it used commonly for that reason. But risperidone isn't necessarily the drug for everybody. It does have an adverse e"ect pro!le, and there are some patients for whom it is not a good choice. And then, we have to look at others. The beauty of antipsychotics is we have many excellent ones to choose from. Others that are used for behavioral dysregulation include olanzapine. This is marketed as Zyprexa. This is an excellent drug. I mean, it is an excellent antipsychotic. The only problem with it is the dang weight gain, the metabolic symptoms. So if metabolic symptoms are already a concern, it's not the drug for your patient. But if metabolic symptoms aren't a concern, olanzapine can be very e"ective. Quetiapine is also an interesting antipsychotic. I mean, it's an older one, but it's one that's used for all sorts of di"erent things, depending upon the dose. And we can use it for behavior dysregulation in patients who maybe have a comorbid condition that would bene!t from quetiapine. Or for whatever reason, it's the one that's accessible. And sometimes, we have to use haloperidol. Haloperidol is a !rst generation antipsychotic. It's got a much more signi!cant adverse e"ect pro!le than the others. And so, we really only use Haldol when we have to. It's available in all sorts of dose formulations. We can give it by injection. We can get a pretty quick response. And sometimes, it's necessary for that reason. But it is an option, but we generally don't use it if we have other options. Now, before we leave the topic of antipsychotics entirely, let's take a look at the next slide. So there are some neurocognitive disorders that are hugely characterized by hypersexuality, impulse control, and even hyperorality. Just like the name implies, excessive mouth movement, excessive mouth stimulation. Remember that the mouth is the !rst place of comfort at the very beginning of the life cycle. The neonate and the infant, they feel better when they have a breast or they have a bottle, when they are being orally stimulated. The mouth is a very, very primitive mechanism of soothing. And sometimes, when you see these neurocognitive disorders-- like frontotemporal impairment is one example, but even Alzheimer's 27 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... disease, if it manages to progress all the way to the end stage. Most of the time, Alzheimer's takes so long to progress that the patient will usually die of something else before the Alzheimer's gets to end stage. But if it does get to end stage, then you may see hyperorality along with the return of infant re$exes, like the grasp re$ex, even a Babinski re$ex. But hyperorality really is usually symptomatic of a return to a very basal infantile approach to the world. And the patients, they-- I mean, in addition to constant lip smacking and tongue movement, they are forever putting everything in a mouth, it's self-soothing. And it goes back to infancy. For those of you that are really interested in psychiatric disorders in infants and very young children, those that are consequences of attachment problems and things, it's a whole separate area of study. And it's very interesting how infants that are under psychiatric duress self-soothe by stimulating regurgitation and then swallowing it again because it makes them feel better. But again, I'm getting further a!eld here. I just wanted to point out that there are some neurocognitive disorders that really do ultimately culminate in a return to basal instincts and loss of impulse control. And it can be a problem if you're able to walk and talk and do stu", right? So hypersexuality-- not so much of a concern in the infant because it's not going anywhere. But in the geriatric patient, it is. So we do have some drugs that we use speci!cally for that, and they are listed here. Quetiapine-- I don't know why, but this one seems to be especially e"ective in controlling hypersexuality and hyperorality. SSRIs, as I mentioned before, we use them, just capitalizing on these sexual side e"ects. And cimetidine. Yes, this is good old fashioned Tagamet. This is an H2 blocker that we use for GI acidity, re$ux, ulcers, stu" like that. But cimetidine also has an anti- adrenergic property. And remember, androgen are the precursors to most of your secondary sex hormones. And so, when you block androgen synthesis, you can also attenuate some of these hypersexual responses as well. So there are all di"erent options. Every drug is a poison. They all have adverse e"ect pro!les to consider, and you just have to pick the one that's least o"ensive to your patient. And lastly, before we close down this discussion for good this week, the last thing I wanted to call out was Lewy body disease. This is yet another cause of neurocognitive disorder, and it's a very speci!c type. This is, again, one of those neurocognitive 28 of 29 6/26/24, 10:04 PM Geriatric Psychopharmacology Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425040-dt-... disorders that is an exception to the rule and that visual hallucinations are a hallmark symptom. That, coupled with the fact that these patients do tend to be enormously, disproportionately, sensitive to antipsychotics. Many antipsychotics can actually make these symptoms worse. So if you have a patient with Lewy body disease, and that patient is hallucinating and you need to use an antipsychotic, or even if they're not hallucinating but you need to use an antipsychotic for behavioral dysregulation, which is also likely because these patients tend to be very angry, the drug of choice is quetiapine. I don't know why. I've tried to !nd out, and I just can't !nd a good explanation. But quetiapine is readily accepted as the most e"ective and least o"ensive for the patient with Lewy body disease that needs an antipsychotic. And so, that takes us to the end. Lots of takeaway points in this discussion. But one of them is that we cannot, in any way, shape or form, arrest, control, or reverse neurocognitive disorders. All we can try to do is make symptoms a little less disruptive into patients' day-to-day life. We have several di"erent classes of drugs that we use for a variety of symptoms. You always need to consider the risk bene!t analysis. All drugs are poisons. Which poison is least o"ensive to your particular patient. And then, I mean, this is a pharmacology course, so pharmacology is our emphasis. We don't get into the nonpharmacologic aspects of management. We will talk about that in nursing 69-70 and 71 and 72 for that matter. But do keep in mind that with neurocognitive disorders, nonpharmacologic management really is the mainstay of care. Many patients with neurocognitive disorders are not on any medications at all. The best practice management of those disorders really is about lifestyle, environmental management, things like that. We only use medications when we really need to for very speci!c circumstances. So on that node, I'm going to end this discussion, and I'm going to pray that this recording works because I just don't know if I have it in me to do it a third time. Hopefully, all is well. We're closing out this, and I will see you next week for our last week of the semester. Print this page 29 of 29 6/26/24, 10:04 PM