Treating Alzheimer’s Agitation, Not Just Quieting It with Pierre N. Tariot, MD

The Journal of Clinical Psychiatry

Publisher of peer-reviewed research discussed in this episode.

Targeted Treatment of Agitation in Alzheimer’s Dementia: Prioritizing Function and Safety Over Sedation and Other Serious Harms

https://www.psychiatrist.com/pcc/targeted-treatment-agitation-alzheimers-dementia/

The consensus panel report chaired by Dr. Tariot, published in The Primary Care Companion for CNS Disorders.

Dr. Pierre N. Tariot – LinkedIn

https://www.linkedin.com/in/pierre-tariot-13557ba/

The Primary Care Companion for CNS Disorders

https://www.psychiatrist.com/pcc/

Pierre N. Tariot, MD, is director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine. Board certified in internal medicine and psychiatry, with additional training in geriatrics, he has studied agitation and dementia for nearly four decades. He has led more than 50 clinical trials in Alzheimer’s disease and related dementias, published over 400 papers, and co-directs the Alzheimer’s Prevention Initiative. He chaired the consensus panel discussed in this episode.

Ben Everett, PhD, is the creator and host of The JCP Podcast, a series that brings together leading voices in psychiatry to explore the latest research and its clinical implications. Everett earned his PhD in Biochemistry with an emphasis in Neuroscience from the University of Tennessee Health Science Center. Over a two-decade career spanning academia, publishing, and the pharmaceutical industry, he has helped launch more than a dozen new treatments across psychiatry, neurology, and cardiometabolic medicine. His current work focuses on translating complex scientific advances into accessible, evidence-based insights that inform clinical practice and foster meaningful dialogue among mental health professionals.

This transcript has been auto-generated and may contain errors. Please refer to the original audio recording for full accuracy.

00:00 – Introduction and Dr. Tariot’s Path Into Agitation Research

Dr. Ben Everett: Hello, and welcome to the “JCP Podcast.” I’m your host, Dr. Ben Everett. On the podcast, we sit down with leading clinicians, researchers, and educators to explore the science shaping mental health care today with a focus on the insights that matter most in clinical practice.

Dr. Ben Everett: Agitation is one of the most difficult symptoms to manage in Alzheimer’s disease. It can be distressing for patients, overwhelming for families, and challenging for clinicians, particularly when the medications we’ve traditionally used may calm a patient without actually treating the agitation and come at the cost of a- And come at the cost of…

I’m trying to think of how to say this better than I’ve ever written it. And come at a cost of very high side effects, including a burden to alertness, function, safety, and sedation. That’s beginning to change. In April, a panel of experts in psychiatry, neurology, geriatrics, and primary care came together to examine how agitation in Alzheimer’s disease should be recognized, assessed, and treated.

Their consensus report was recently published in the Primary Care Companion for CNS Disorders, a sister journal to the Journal of Clinical Psychiatry. The paper makes a simple but important point. The goal isn’t just a quieter patient. It’s a patient who’s safer, more engaged, and able to maintain as much function as possible.

To talk about the recommendations, I’m joined today by someone who’s been studying agitation and dementia for nearly four decades. Dr. Pierre Tariot is the director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine.

He’s boarded in both internal medicine and psychiatry with additional training in geriatrics. He has led more than fifty clinical trials in Alzheimer’s disease and related dementias. He’s published over four hundred papers and co-directs the Alzheimer’s Prevention Initiative. And importantly, for our conversation today, Dr. Tariot chaired the consensus panel behind this report. We’ll talk about how our understanding of agitation has evolved, why sedation should not be confused with efficacy, and how clinicians can approach assessment and non-pharmacological treatment.

Additionally, we spend some time talking about how there are now actually two FDA-approved options for treating agitation in Alzheimer’s disease and how they fit into this picture.

With that, Dr. Tariot, welcome to the podcast.

Dr. Pierre N. Tariot: Thanks, Ben. Glad to be here.

Dr. Ben Everett: All right. Look, before we get into the paper, I actually want to ask you about something from the fine print in your earlier publications. You first started doing research, trials, and agitation back in the late ’80s and early ’90s, and your affiliation was listed as the Monroe County Hospital in Rochester, which is essentially a long-term care hospital.

You’re also one of a small number of physicians who’s boarded in both internal medicine and psychiatry. So you really started your career at the bedside of patients exactly like the ones in this paper, with a foot in both primary care and psychiatry. So my question really is, how did you end up there, and how did that combination of training in both internal medicine and psychiatry shape the way you think about agitation in this pati- in this patient population?

Dr. Pierre N. Tariot: Oh my goodness, you’re gonna get me to talk for four hours. So the sh- the short version that when I left the National Institute of Mental Health Intramural Research Program, having done experimental therapeutics for Alzheimer’s disease, I wanted to be in an academic setting that both care and study. And I was amazed to be exposed to Monroe Community Hospital, affiliated with the University of Rochester Medical School, which was a s- roughly six hundred and fifty-bed long-term care hospital full of unlucky, complicated, complicated older people with all kinds of neuropsychiatric disorders. So I really felt like I could serve that population as a clinician, but also as a researcher, that, that kind of kicked things off. And in a way, of the context then is pertinent now, which is dementia is really common in that setting and in general in our society. We need to do better and better at recognizing and diagnosing dementia, and most dementias have a very high rate of neuropsychiatric manifestations that we are still learning how to manage as well as pharmacologically. I think I could serve and d- do good science in that setting, and that was our mindset.

04:31 – Why This Consensus Report Was Written for Primary Care

Dr. Ben Everett: So we’ve done a number of these consensus panel reports, and typically w-we like to have one of the authors come on and talk about the paper.

But typically, they are published in the Journal of Clinical Psychiatry, whereas this consensus panel we published in our companion journal, which is the Primary Care Companion for CNS Disorders. And, can you talk to about– can you talk about the intentionality of putting this paper in the Primary Care Companion as opposed to JCP?

Dr. Pierre N. Tariot: Absolutely. So there are millions of Americans with dementias due to Alzheimer’s and other conditions. We put all of the air quotes, “dementia specialists” together in the United States, we probably couldn’t take care of more than 10% of these people. The wait list to see a a specialist a, a brain disorder specialist for a new consultation over a year on average in the United States, but as much as five years in places like the Mountain West or rural South. So it’s it’s not workable, so we need to partner with our specialists in primary care to, to empower them and their practices to be comfortable and taking care of persons with dementia to the extent that they’re able to. And we really think that it, will work for well over half of persons with dementia, including those with complicated neuropsychiatric manifestations.

So it’s really an appeal to our society as a whole and our medical specialties to work together with primary care specialists. I call them specialists in general medicine. I feel very strongly about that. To give them the education and tools that they need to feel comfortable. And if I could, I’ll just elaborate a little bit.

Folks in primary care are ideally suited for this. They have long-term relationships with their patients. used to chronic disease management. They’re used to, all these guidelines that are out there governing practice and treatment and documentation. And their patients are clamoring for support from their primary care colleagues.

So at Banner Health are doing everything we can to help in this regard, including in primary care the primary care setting, a, a ECHO program that we’ve set up, and so on. So that, that’s a long-winded answer, but I’m passionate about it as well that our patients and families and our practitioners can have a very productive relationship dealing with things that are really clinically important and clinically fascinating.

07:15 – Four Decades of Trials: Carbamazepine, Divalproex, and the Atypicals

Dr. Ben Everett: Hey, I couldn’t agree more. I’ve been seeing the same primary care physician since he finished residency. He’s a good friend of mine. We grew up together, but I knew as soon as he finished his residency, he was gonna be my doctor. And yeah, I think back over now, like almost 30 years’ worth of care, and yeah, he– it’s great to be able to have that relationship long-term with your primary care specialist, all right. You’ve served as a PI on a number of trials, including carbamazepine, divalproex, a number of atypical antipsychotics. And what’s interesting is, some of those worked, some of those didn’t in clinical trials. But in the consensus panel, the panel has now moved those to an area where y’all recommend those as not first-line agents.

And so I’m curious, just looking back over that body of work, how has your thinking about the use of different agents changed over time?

Dr. Pierre N. Tariot: Well, eh, we talked about my early days at the University of Rochester. By the way, no thanks for letting people know how old I am. But anyway I look younger than I am, which is a good thing. Imagine being in a setting where you as a clinician are leading a small team responsible for the psychiatric wellbeing of 650 older people, most of whom have chronic neurological illnesses of one type or another, and nobody knows really what to do So we proceeded on several fronts as a clinical service doing, training staff at all levels about recognition and management of dementia and all of its manifestations, also being honest with ourselves and others that we didn’t really know what medications to use.

And so we began using medications empirically in clinical practice, both inpatient and outpatient, from what we knew from other disease states. So for instance if they’re depressive symptoms, let’s try antidepressants. If they’re psychotic symptoms, let’s try antipsychotics, even if the major presentation is, quote, agitation. And we gradually developed a kinda systematic approach to treatment, but also realized that we should set up a systematic clinical research program to assess these things that we were beginning to, use clinically in, in a less systematic way. And so just for instance, carbamazepine popped relatively early as something that might be helpful.

So we did open label studies, then a small placebo-controlled trial, and then a larger placebo-controlled trial with some external funding. And it looked not too pretty bad, shall we say, in terms of efficacy, but pretty terrible in terms of effectiveness. That is to say dosing, laboratory m- surveillance required, tremendous rate of drug-drug interactions, a lot of side effects, really not good for prime time.

And then by analogy we expanded into divalproex sodium, which of course was being used… starting to be used for other conditions as well. And we ended up getting several trials funded, one by industry, two large multicenter trials funded the government, by NIH. and as is typical when you do this type of thing, the smaller the study, the better the effect. But then when we started doing large studies, yeah, we didn’t see a systematic benefit with divalproex. And we even did a very science-y neuroprotection trial with divalproex in people who with probable Alzheimer’s who hadn’t become agitated yet giving it chronically to see if we could stave off the agitation and/or slow down progression of illness measured in other ways. It’s a big study, it was a big deal, and it was a total flop clinically. It did not show benefit, and in fact showed accelerated brain atrophy. It was the first multicenter trial in our world that embedded serial brain MRIs, and it was– it resulted in a change in the prescribing information. So these were not looking good.

We participated in a trazodone study. We participated in the CATIE Alzheimer’s disease trial. We participated in some industry-sponsored trials of atypicals. So atypicals began to loom large as more likely than these boutique drug classes to show benefit. So I call that the, the nineties into the aughties m-most, most of the large studies with the atypicals. And if you want, I can give you the punchline from what we learned, but that, that’s gets us a little closer to the present.

12:17 – Primary Care as the Front Line: Lessons From Depression

Dr. Ben Everett: Well, I certainly didn’t intend to insinuate that you’re an older gentleman, and I will agree that you’re quite well-preserved. I appreciate the background. I think it’s very helpful because it does help to bring to context or bring into context the rationale for this paper and I think why this paper is so important right now.

So let’s come back to this, and we got into this a little bit in the first part of the podcast. But I really wanna come back to this idea of the primary care specialist or primary care physician being the, the main quarterback for these, individuals with dementia and for most Americans.

So the panel estimates that about 80% of people with dementia do have a primary care clinician as their main source of care, and that number actually increases to 90% for those residents who are in long-term care facilities. And you also mentioned just how long it can take to get into a specialist that really has a deep expertise in dementia it can take, quite some time, a year to up to four and maybe even five years to get in to see a specialist. So the consensus panel report really compares this to depression and how primary care has really taken over the treatment of depression over the last few decades, and they’ve become frontline for this.

And you guys argue that really it could be, it, they could do the same for agitation and dementia. What do you think it takes for that shift to happen now?

Dr. Pierre N. Tariot: Yeah, that’s a great question. I I would say, and it’s a good analogy, and it’s one that Leslie Citrome brought up at our meeting. It was great to have his perspective. It took a while for everybody to understand that what you might call bread and butter, I don’t mean to minimize it, but the pretty straightforward, uncomplicated depression in many cases can be managed sensitively and thoughtfully in the primary care setting with non-drug and drug support.

Both are very important. And so it– that is a good analogy for what can happen and I think is happening in the dementia space. It’s really common. These folks are heavily represented in primary care. Primary care providers, doctors, and extend phys– advanced practice practitioners are really well-positioned to deal with chronic illnesses like this, haven’t historically been adequately prepared, so let’s figure out how to help them. And the basics are reassuring. Common condition. Here are the r– you know the simple ways of identifying who’s at risk, a-assessing them, for the presence or absence of a dementia its baby sister, mild cognitive impairment. Assess them for the presence or absence of neuropsychiatric features.

If they’re present, here are the sensible first steps to take. For instance, make sure they’re not delirious. Make sure there isn’t some obvious other like hearing impairment, vision impairment abrupt change in caregiver, environmental problems, too hot, too cold, too noisy safety problems, medication adverse effects.

That’s huge. Huge. So let’s deal with all of those things and then also kinda put on the Sherlock Holmes hat, which primary care docs can do very well. What else could be driving this that we might be able to identify and help mitigate the problem? And then, you know what?

If we’re gonna use medications, here’s the toolbox. Here’s the modern toolbox and how to use it. I think that is redolent of what happened in the depression space, but it took a decade or more for that to actually kinda pan out.

16:08 – Sedation Is Not Efficacy

Dr. Ben Everett: That’s really good that you’re thinking about it this way and I appreciate the setup. Let’s drill into the medications a little bit for a minute. And, you’re talking about medication side effects, and sometimes it’s side effects, but sometimes it’s the, the off-target but maybe intended effect of a medication.

So in the paper, you guys argue that sedation is not efficacy. And there are many medications that are widely used to treat agitation in this population, quetiapine, benzos, trazodone, others, that are used off-label, and their calming effect may car- may largely come from really a his- histaminergic acti- action from sedation rather than actually treating the root cause of the agitation in and of itself.

And that sedation can come at a cost, right? Because these patients who are sedated, they might be more prone to falls, aspiration other cognitive and functional declines, and reduce their ability to engage with others, including their care team at home, as well as their professional care team and their primary care provider.

Can you talk about that a little bit?

Dr. Pierre N. Tariot: Yeah, absolutely. But let me kick it off by saying, and here’s the punchline more or less with the atypicals. you put all the clinical trials together, drug beats p– for agitation, sometimes mixed with psychosis or only psychosis, we can come back to that. But h- most of these studies were for agitation, double-blind, placebo-controlled trials. Drug beats placebo about eighteen percent of the time in terms of a discernible reduction in agitation. However, it comes at the price of over ninety percent rate of toxicity. You featured sedation, I think appropriately but falls metabolic disturbance, Parkinsonian features, peripheral edema marked confusion, even death and unexpected stroke leading to this, this boxed warning for the entire class when used in the elderly.

So eighteen percent efficacy and ninety percent toxicity is not a good formula. There’s a saying in geriatric psychiatry that y-you get painted into the corner. You only use those drugs when you’ve run out of alternatives. And y-you have to say to everybody, “This is off-label. It’s not that great.

Here are the risks. We’re gonna document the risks. We’re gonna document the benefits. We’re not gonna continue if we only cause harm or don’t cause benefit.” I hate to say you hold your nose when you do it. That’s not– It’s not quite that bad, but it’s just not a very good value proposition. we’ve been waiting and waiting for new medications to emerge that have, let’s just say, at least that level of benefit, if not better. and as importantly, don’t have all the other adverse effect baggage. a-and I think sedation is near the top of the list. Historically, we’ve, have– we the royal we prescribers have been lulled into a false sense of security that at least if they’re drowsy, they’re not gonna be shouting or hitting. But imagine calming without drowsiness, without sedation. been a bit of a holy grail, and it’s only relatively recently that we’ve gotten there.

19:33 – Talking With Care Partners and Identifying Unmet Needs

Dr. Ben Everett: Yeah, thanks for that. So when you’re having that conversation maybe with an exhausted care partner or someone who just, you know, it’s really taking an impact on them as well, dealing with their, let’s say their spouse or their, aging parent, y- how do you have that conversation with the patient or again, their care team to help them appropriately put this into context?

Dr. Pierre N. Tariot: Yeah it is a team. And I speak with my patient as well as my family members or other care providers, care partners, as we put it. S- e-explaining the context, explaining the fact that this is very common, very– almost predictable. There are a lot of things we can do. There’s no magic bullet, but there are things that can help. It’s a try and see approach. We’re all gonna be scientists here. We’re gonna try logical interventions and see how they work, and if they work, we’ll change. If they do work a bit, let’s see if we can adjust. that conversation itself is therapeutic, but I think anybody who does any kind of mental health work knows that just sitting down and talking and explaining calmly and being available and understanding the experience g- all of that is therapeutic.

All of that is therapeutic. Even to a confused patient, they can tell that you are meaning to do well by them as best you can. And then it’s almost fun, that could sound weird, but it’s almost fun talk together to try to problem solve the social or environmental triggers that might be relevant.

Let me just give one example. I used to d– run a home visit program for homebound elders who couldn’t get in to see a, a, a doctor. And I remember o-o-one situation where the distraught family was saying, “Mom’s great all day long.” She was in her eighties, quite impaired cognitively. “But when she goes to bed, she starts ranting and screaming and literally tearing the room apart night after night.” So we knew enough about what we were doing to say, “Hey, can we look in the bedroom?” We go in the bedroom, and first thing you see there is the dresser mirror She saw herself in the mirror when she went into her room and thought that image was an intruder and that she needed to defend herself. So we didn’t get into vitamin H, so to speak.

We just got rid of the mirror, and the problem was solved. multiply that anecdote by a hundred. Those things can really work. Now, you don’t always have the time, or you don’t always have, have the good fortune to find things like that, that, that work. Of course, I’ve said already how important it is to look for all these other medical issues that can come up: bad boy medications, hearing loss, and so on.

Pain pain. And while I’m on it, I’m gonna back up a second. I think it’s really important for people to have the headset that a person who’s confused and has a significant dementia and expressing disruptive behaviors, they’re communicating something. They’re communicating that their needs are not being met.

What is the unmet need that’s being represented by the shouting, the hitting, the recoiling, the the, the tears? What is the unmet need? that’s a very… It’s a very generous and therapeutic headset to have. Now, if we get past all of that, and we’re saying, “I think it’s time to start talking about medication options,” it’s important for people to know that there’s no miracle drug. It’s very unlikely for something to work, in minutes or even hours or days, although that sometimes happens. We have to hang in there together to give it time to work. How does that sound to you? And by the way, m- I and my team will be available to you to problem solve along the way and tweak things as, as we go. But that’s where we’re headed now.

23:52 – Revisiting the Evidence for Quetiapine and Trazodone

Dr. Ben Everett: All right that answer really resonates, and I love just the emphasis on the shared decision-making, working with the entire team. A- and also, I’m just w- as you were talking about the investigation there, I was just thinking back to your Sherlock Holmes hat reference earlier.

And yeah, you spend some time doing that, but you can find really the best option for the patient, and it might not necessarily be medication. Let’s dive into medication a little bit more. So I wanna talk just some updates on two very commonly used agents in this field, and maybe not appropriately, right?

So there’s quetiapine and trazodone, and just by way of maybe education for people who haven’t followed this, but quetiapine is very widely used in this patient population. There was a positive trial some time ago, but it was at a much different dose than is what is currently used in practice.

It found that two hundred milligrams a day is where the positive signal came in. But, practically, it’s twenty-five or fifty milligrams are what is typically used in practice, and there’s no evidence for that dose. You wanna comment on that a little bit?

Dr. Pierre N. Tariot: Yeah, I did most, if maybe not all of the quetiapine studies in this space. Did meaning either helped lead or participated in and remember how desperate we were for things that, that could be helpful, and this looked very promising when it came out, and some original unblinded studies were done that were encouraging, leading to double-blind placebo-controlled studies. And the glass is less than half full, is the bottom line. At low doses, it’s heavily sedating. And that can quell agitation, but it’s really a nonspecific effect, and drowsiness and falling and confusion and social withdrawal are not positive outcomes. That’s kinda what we did– There, there’s one study, we were quite right, where we looked at higher and higher doses.

It’s a medication that you, in this population, you get to/have to titrate. You don’t know what’s gonna work. And sometimes you do get lucky at low doses, but at least in the context of a trial, the only thing that worked was the very highest dose of two hundred milligrams a day, which is clinically, I think, infeasible.

It takes too long to get there to much too high a rate of adverse effects. And it’s been a Band-Aid for quite a while, but let’s get past the Band-Aid phase. It’s kinda the same thing with trazodone. A dear colleague named Linda Teri at the University of Washington led an NIH-funded study of trazodone versus haloperidol versus placebo some years ago that I participated in, and everybody was disappointed to, to learn that trazodone just didn’t work. There’s this urban myth, legend that it works pretty well. No, it just sedates people without any specific anti-agitation effect. And again, it’s only recently within the last couple of years that we actually have The, the FDA has actually recognized a neuropsychiatric manifestation of dementia as an approvable indication. It’s like that had never happened before until a couple, three years ago. And they approved the first drug for this indication of agitation associated with Alzheimer’s dementia. What? was a major advance for our field. And, I’ll just keep going unless you interrupt me.

But compared to what we had before with these older agents, we now have therapeutic agents that are FDA-approved with FDA-sanctioned simple criteria for defining what the indication is what do we mean by agitation in dementia and drugs that have anti-agitation efficacy with a very benign adverse effect profile. So it it’s really, it really is a big change, and we all, in this consensus conference, felt like this is a really good time to kinda do a total reset on how to think about this issue in practice.

28:09 – Two FDA-Approved Options: Brexpiprazole and Dextromethorphan-Bupropion

Dr. Ben Everett: I think that’s really important. I really love how you put that. All right, so there are now two approved drugs in this space, and they actually work differently, which, we don’t have to get super into the neurobiology or pharmacology.

But I do think it’s interesting that now we’ve got two medications and they have slightly different MOAs or really very different MOAs. So you’ve got brexpiprazole, which is a partial agonist. It works at both dopamine D2 and serotonin 5-HT1A receptors, and it actually has some 5-HT2A antagonism.

And you’ve got dextromethorphan bupropion, which acts on NMDA and sigma-1 receptors, along with some norepinephrine, some dopamine reuptake. So how do you think about these, these two medications in terms of, you’ve got these different mechanisms of action, pharmacological profiles. How do you think about using these clinically given that, they’re in different classes?

Dr. Pierre N. Tariot: Yeah. First of all, it’s great to have this new FDA recognition of the indication. It’s great to have not one but two FDA-approved therapies. It’s great that they’re in different classes. And without belaboring the details, the, the mechanisms make sense for neural circuits that are damaged in Alzheimer’s disease and probably the source of some of these, neuropsychiatric manifestations.

So they’re mechanistically logical. They are different. think for the practitioner, what matters is it’s FDA approved there’s evidence for efficacy, here’s how to use it. and so brexpiprazole was the first one to gain FDA approval. There were three phase III trials two of which were positive, and it led to the FDA approval. And the trials really were good at informing practice. You over a couple of weeks and it takes some time for the therapeutic to ef- effect to fully emerge but it’s there and with a very low adverse event rate. And we have all the data from these trials that have been published. So that’s great. That’s out there. After the consensus panel met, the FDA also approved a, a drug that we didn’t have as much information on, dextromethorphan/bupropion extended release. It’s a supplemental indication because that drug is already FDA approved as an antidepressant. but there was, I think, I I give the sponsor credit for investing in the agitation space, agitation associated with Alzheimer’s dementia.

That’s true for both of the drugs. And so several trials were done. A couple of them were positive. That led to FDA approval. There’s a bit of a wrinkle here, which at least as far as the panelists know, and that includes me, there haven’t been publications, on these trial programs, so the bulk of the information comes from the prescribing information. but a little bit similar in a way to brexpiprazole, there it, it– at a high level there is a definite anti-agitation effect in most of the trials with a pretty benign adverse effect profile, particularly when compared to the older drugs that we’ve been using so much but don’t need to use anymore. So for instance, essentially no death signal, no stroke signal, no Parkinsonism no significant Parkinsonism no metabolic effects lack of worsening of cognition. These are huge differences, okay? So at a high level, it appears that the two drugs have relatively similar rates of benefit, at least twenty percent or greater compared to placebo, and rates of adverse events that are in the single digits, compared to nearly, ninety percent or higher with the older agents.

32:09 – Older Versus Newer Agents and the Boxed Warning

Dr. Ben Everett: Yeah, I think you’ve really hit on a few really important things in that answer. But I really want to get into now the idea of older versus newer, and those are in air quotes, right?

Older versus newer. You referenced earlier the box warning that these older medications have, became a class effect. And it– the FDA brought together a panel of experts in two thousand twenty-four to take another look at the mortality risk behind the box warning. I’m just curious for you, how do you differentiate older versus newer?

Is there a line in the sand or is there some class effect? How do you think about this idea of older versus newer?

Dr. Pierre N. Tariot: At the risk of oversimplifying, older means low rate of efficacy below twenty percent nearly a hundred percent rate of toxicity, and not FDA-approved, therefore only used off-label and with a a very stern warning from the FDA that if y- if you use these in older persons with dementia, you may increase the risk of death or stroke-like events. Newer agents, i-i-if I was ungenerous, I would say the similar rates of efficacy, although I actually think the rates of efficacy are higher. Adverse effect rate, hugely different, much, much lower, and FDA-approved. People can get confused by the warning with brexpiprazole, which is an antipsychotic. it is FDA-approved to treat agitation associated with Alzheimer’s disease it’s FDA-approved for that. and recently the, the language was clarified to say, and that is with or agitation with or without associated psychosis. you’ve got a path forward for FDA-sanctioned use. And with dextromethorphan-bupropion not in the antipsychotic class, lacking that nuance from a regulatory standpoint, otherwise generally similar. I should hasten to point out that these drugs have not been studied head-to-head. Practitioners have several years of experience with brexpiprazole. Very little experience so far with dextromethorphan-bupropion. No publications yet that I’m aware of. So it’s it remains to be seen how th- this toolbox will be valued in practice, whether one will be favored over another. really too soon to say, but that’s not a bad thing. And we’re gonna learn as we go. And it may be that in a year or two there will be new evidence or new clinical experience to refine the kind of guidance we were trying to give with this consensus process.

35:03 – Preparing Patients and Families for the Primary Care Visit

Dr. Ben Everett: Yeah I think you hit on several very important things there that frankly make this shared decision-making discussion that you’re gonna have with the patient, the carevis-caregivers and others much simpler is we’ve got older options that are off-label and have a boxed warning that can be scary, and you’ve got newer agents that are actually FDA approved for this condition, don’t have that boxed warning, seem to work better, seem to have lower risk associated with them.

So it seems like a pretty easy proposition to choose between these newer agents that are at least approved for this. I shouldn’t say necessarily newer at least for galantamine. So that seems really like just great progress from, where we were a couple of decades ago. So let’s kind of transition into making this real for the primary care practitioner.

We understand that demands on time are very difficult. Sometimes you’ve just got a fifteen-minute meeting or appointment with your primary care collesi-clinician, and so you need to make sure that you capitalize on the time that’s there. So I wanna– you know, i-if you can talk through maybe the patient side of this and then the primary care side of this.

So if you’re counseling patients on what to, what to do, how to have that conversation with your primary care clinician, how are how are you counseling patients on what information they need to take into, to the meeting?

Dr. Pierre N. Tariot: Let me try to say it this way. Alzheimer’s disease, dementia, and related dementias are chronic illnesses. They don’t pop up overnight. so The, the process is actually a chronic one, a long-term one. I-i-is there cognitive im– and functional impairment? Yes, no. Is it mild cognitive impairment or dementia?

If yes, which type? are there have we done the right workup? Routine labs, structural imaging, some objective cognitive testing. is there any reason to consider these new Alzheimer’s biomarkers, which is a whole other separate conversation. if there are neuropsychiatric features there, what are they and what are they most likely to be susceptible to if we need to resort to medication? It doesn’t happen in fifteen minutes. It happens over a year or two, frankly, o-of fifteen-minute discussions. Or if you’re lucky, you could have a brain health assessment paid for b-by a Medicare code, that’s more like forty minutes, thirty, forty minutes, which may be a good investment of time for such a complicated illness. So it’s a conversation that doesn’t happen in fifteen minutes. It happens over a series, it o-o-over time. But I think if I were to identify the most essential element for therapeutic success, is the willingness of the medical practitioner engage with the patient and family on this. “I’m with you. I’ve got your back.” That, sets the tone, that, a-a-and I’m available to you. The anxiety level goes down, confidence goes up, the willingness to tolerate some bumps along the way goes up, the understanding that it’s gonna be a bit of a, a roller coaster ride. There’ll be good days, there’ll be bad days. And then in that context Dorothy, let talk about what we’d like to see better. So he is shouting and he’s hitting you, and he spits at the grandchildren. Are those the things we need to focus on? Okay. That’s what we’re gonna focus on, and I’m gonna be asking you, those things better, worse, or the same as we undertake this therapeutic voyage together? And I can’t promise they’ll get better, but I can promise that we’re gonna… that’s the direction we’re headed in. So what are the target symptoms? How are they doing in response to therapy? and how are we doing in terms of adverse effects.

Dr. Ben Everett: It’s wonderful. I was at a patient conference for patients with a, a very specific rare neuromuscular disorder last week, and just listening to patients talk about what it means for their clinician whoever it is, just to say, “I’ve got your back. I believe you.” That was the single most important thing I took away from that conference, is that oftentimes patients do feel like they, they don’t have the buy-in or that sense of, “I’ve got your back,” as you put it, from their caregiver.

And so I just wanna impress upon people just how important that is from a patient perspective. All right let’s transition to on the provider side now. So as we’ve pointed out, the majority of these patients do have a single primary care provider, managing their care over a long period of time, which is very important.

So on the caregiver side, how do you go about, trying to educate these, these primary care clinicians on how to… Yeah I’m losing my own track. I’m trying to get to, to, to, yeah, essentially managing you can’t measure– you can’t manage what you don’t measure. I’m gonna get there a little bit quicker.

Dr. Pierre N. Tariot: Okay, that’s fine.

40:20 – Measuring Agitation: IPA Criteria, DICE, and Practical Assessment Tools

Dr. Ben Everett: All right all right, so we’ll leave the stuff in there about the patient conference.

We’ll go. All right, so I wanna transition to, guidance for the primary care clinician that’s caring for these patients. So the panel lays out a very specific sequence, right? Confirm that the agitation meets the International Psychogeriatric Association criteria. You wanna make sure it’s measured with a validated tool.

You wanna rule out reversible causes, as you mentioned before, delirium, ur- urinary tract infection, pain, medication side effects. You wanna start with non-pharmacologic care using the describe, investigate, create, and evaluate or DICE approach. And, you make the point, and this is a point that we’ve done in other consensus panels, I think it’s a very important point, is that you can’t manage what you don’t measure.

So there are three separate tools that the panel endorses. There’s the AASC, the Pittsburgh Agitation Scale, and the NPI-Q. I’m just curious, do you use one of these specifically in your own practice? Are they all pretty much the same? Do you think one makes more sense than the other?

Dr. Pierre N. Tariot: As I mentioned to you offline, I’ve spent a lot of time in the primary care setting trying to understand w- h- how things work. It’s a big deal to say, “Here’s another tool for you. Here’s another instrument,” because they’ve already got 100 or so in their hip pocket. So I’m gonna speak out of both sides of my mouth on this one. Yes, tools are valuable but for what purpose? So if I’m talking to my primary care colleagues, even before we get to the agitation problem, I’m gonna be saying, “Here’s what dementia looks like. It’s frequently associated with behavioral manifestations.” And you could do a I’m gonna say roughly one-minute checklist to just survey whether or not, common neuropsychiatric manifestations are there. That’s the Neuropsychiatric Inventory dash Questionnaire. It’s just a yes/no, present/absent, and it’s a way for you to say, “Oh, okay, there are depressive symptoms, there are psychotic symptoms, there are depre– agitated or aggressive features.” So if I were to use any tool in sort of long-term management, that would be it. If I’ve got a red-hot potato in front of me, so to speak, somebody who’s already agitated, I would suggest that there are two approaches here, o-o-one of which wasn’t endorsed by our paper so much, it’s pragmatic, which is what are the target symptoms, as, as I just went through with Dorothy a minute ago. What are the two or three most obvious troublesome behaviors that we wanna talk about going forward? Do they get… Do they change or not? And if they change, is it for better or for worse? If you’ve got– If your practice has the bandwidth for tools beyond that the Agitation in Alzheimer’s Screener for Caregivers, AASC, not widely used, but it’s a very simple sort of screening tool, and it aligns exactly with what the FDA sort of approved of as their definition of agitation in dementia due to Alzheimer’s. I haven’t seen it used a lot, but it is logical to be aware of, to learn about. And then there’s the Pittsburgh Agitation Scale, which is particularly useful for monitoring follow-up response. So at the very, very least, even before anything goes south, understand that neuropsychiatric features are common, and ask about them and prepare, educate families that th-this may be coming down the road. Once features are present, at least describe them in plain language. What are the target symptoms? And if you’ve got the bandwidth to use a, a, a tool, so much the better.

Dr. Ben Everett: Yeah, that’s great. And I want to say there’s four things specifically that y’all mentioned to manage or to check in on at every visit, and that’s safety, alertness, functional engagement, and caregiver well-being. And maybe that’s just the simplest way to talk through this.

Dr. Pierre N. Tariot: Yeah. Yeah. I because they’re all they’re all important. The goal is relief of distress, maximizing safety, maximizing independence, maximizing quality of life, and dare I use the word joy for the patient but also for the care partner. All of those things are important.

45:00 – Switching From Off-Label Agents: Cross-Tapering and Practical Barriers

Dr. Ben Everett: Let me maybe shift gears a little bit. So let’s say there’s somebody who’s listening today and they’re like, “You know what? I’ve got a lot of patients on quetiapine or trazodone,” or whatever else they’ve got patients on. And based on the information they’ve heard today, they’re like, “Hey I really think I want to look into one of these two FDA-approved options.”

Is there a, an off-road that you think about in terms of is a gradual taper needed? Is it, you know what, brexpiprazole might have a little bit longer half-life. Do you need that, that gradual taper before you add in one of the newer drugs?

Maybe somebody’s listening today, and based on the information, they’re thinking, “You know what?

I’ve got a lot of patients in this population, and they’re on quetiapine, trazodone, maybe a benzo, and maybe it makes more sense to get them on one of the two FDA-approved options.” How do you think about transitioning away from, a quetiapine, a trazodone, a benzo, onto brexpiprazole or dextromethorphan/buprenorphine?

Dr. Pierre N. Tariot: A very– It’s actually a, a very sophisticated question with no clear answer because we don’t have data. So not all medical providers understand that the FDA approves medication with phase three trials that don’t necessarily fully define practice. that’s, you have to learn how to use these medications, and so that’s the learning phase we are in. Our field has more experience with brexpiprazole, and so more– there have been more opportunities to deal with things like cross-tapering, which I think is the, the commonest approach. Not much experience with dextromethorphan-bupropion extended-release in that regard yet. But I think I think it will come.

A sort of old-timey psychopharmacologist. In my day the, the old guard would say, “You know what, Pierre? You don’t know how to use a newly approved drug until you’ve used it at least thirty times.” There’s a bit of that going on right now. But I think at a high level yeah, let’s try to get somebody… I-I– Let’s try to get somebody off a drug that’s mostly causing adverse effects and onto something that can be associated with benefit without that degree of adversity. we know all the details about how to do that? No, but we know from general practice that you don’t, whack-whack go cold turkey on something and then start something else the same day. Cross-tapering is a very common way to go. I think prescribers will have the reality that the off-label drugs don’t require prior auth. Some of the new ones are likely to, so that’s, it’s a practical consideration to bear in mind. on the other hand there’s, there is documentation burden associated with the using the older agents that’s very serious.

You really have to document carefully that you’ve discussed all of these issues, and there’s liability exposure that we don’t need to dwell on today, and it varies a lot by state, but… And then there, there are regulations, for instance, in the long-term care setting, that if you use one of these older agents you’re likely to incur a penalty for the facility, if not even yourself. There, there’s really a, a pretty elaborate context. And in general, I would en- I would encourage us all to become more and more familiar with the newer agents and learn together the value-added proposition them.

48:30 – What’s Next: Novel Mechanisms, Disease Modification, and One Takeaway

Dr. Ben Everett: That’s a, a very important nuanced answer, and I think you nailed it. It’s just not that easy in clinical practice, but, sometimes that’s why it’s called practice, and not every patient is going to be the same with the way they respond to to a cross taper or whatever else. All right.

Look, we’re coming to the end of our time together, and I know this has actually become a very exciting time to be doing this research. So maybe just thirty-thousand foot view, is there something coming that you’re especially excited about? I know there’s a lot more going on with muscarinics in this space, some other MOAs that might be coming down.

Is there something you’re really excited about here?

Dr. Pierre N. Tariot: gosh, there’s a, a lot going on. I think the message to real-world practitioners is stay tuned because there will be a bunch of new agents reporting out over the next few years. There are four different muscarinic agonist development programs, some further along than others. Cannabinoids are being looked at. Management of e-emergent agitation is a hot topic, and that was being studied with dexmedetomidine successful phase two program, but I think the phase three program sort of foundered. But still, that’s a pretty– That– What an ambitious goal that was to see if we could immediately manage severe agitation and aggression with a medication.

So there’s, yeah, there’s a lot coming. And, there are disease-modifying therapies for Alzheimer’s disease that, used properly and early, have the potential to stave off this problem in the first place. If we can preserve brain structure and function maybe we can prevent this, this exact clinical picture from emerging.

And there’s at least one study with a monoclonal antibody against amyloid that has shown that type of effect in a preliminary way. So the disease modifiers are coming. Goodness gracious, we even have preclinical Alzheimer’s prevention trials going now that will read out over the next couple of years.

And if we can prevent or delay the onset of the disease in the first place, maybe we don’t need this, this toolkit fifty years from now.

Dr. Ben Everett: What a lofty and aspirational way to close. So maybe one final question, if you will. We’ve covered a lot of ground today. If there’s one thing that primary care specialist is listening to that you want them to take back into clinic today that they aren’t doing, or maybe if you want them to think about different, what would that one thing be?

Dr. Pierre N. Tariot: It would be really two. Dementia is really common, bear that in mind, and it’s really frequently associated with neuropsychiatric features, so bear that in mind and don’t be scared of looking for them.

Dr. Ben Everett: It’s excellent. Dr. Tariot, it’s been a terrific conversation today. I really appreciate you coming on and sharing your wisdom, all your experience with us on the podcast. We really covered quite a bit of ground today. Really wanna thank you for sharing your perspective with us. I know this is gonna help in the real world.

Dr. Pierre N. Tariot: Thanks, Ben. It was a, it was really great speaking with you.

Dr. Ben Everett: I appreciate it. And for listeners, the full consensus article, all the clinical decision pathways, documentation is available online at psychiatrist.com. We’ll have citations for all the research we’ve discussed today in the show notes as well. With that, this has been the JCP podcast. Insightful, evidence-based, human-centered.