What is the new medication to treat agitation in people with Alzheimer’s

foreign [Music] good afternoon and welcome to ask the doc this is the monthly show where we invite our audience to ask questions of our experts in Alzheimer's disease and dementia my name is Dr Megan with Brock I'm the associate director of Education here at UCI mind and the co-host for this program just as a reminder UCI mind is one of 38 Alzheimer's disease research centers federally designated by the National Institutes of Health um and uh today's topic is going to be about the new agitation drug to treat Alzheimer's disease my guest is Dr David salzer he has been on the show once before at least once before about two years ago and so we're excited to have him back Dr salzer is the clinical research director for UCI mind he leads the clinical core at the UCI Alzheimer's disease Research Center uh he's a physician a psychiatrist and a professor in the department of Psychiatry and human behavior in the school of medicine Dr Salto received his medical degree from the University of Northern of North Carolina and um completed a psychiatric residency at UCLA after a long tenure at UCLA we were fortunate enough to get Dr Salter at UCI and UCI mind he studies the Neuropsychiatric symptoms that occur in Alzheimer's disease or that promote the risk for Alzheimer's disease welcome to Dr seltzer good afternoon Megan nice to join you today yes thank you for coming back okay earlier this year uh brex piprazole a drug to treat agitation in people with Alzheimer's disease was granted FDA approval and this is the first drug approved to treat agitation ever um so I brought you on to tell us a little more about it but maybe we can start with the basics can you can you tell us what agitation is and why it's difficult to manage sure absolutely agitation is one of the non-cognitive symptoms of Alzheimer's disease we think of memory perception problem solving as being the core symptom cluster in people with Alzheimer's but we now know that there are a whole host of Neuropsychiatric or behavioral symptoms that are that are fundamental parts of the illness itself so things like agitation irritability anxiety Etc are parts of um the Alzheimer's syndrome the agitation is generally defined as either motor symptoms or physical or verbal aggression so angry outbursts for example or sometimes physical aggression and increased motor activity folks who are really aggressive Pacers if you will lots of motor movement that isn't really particularly goal oriented can be pretty distressing um this occurs in you know 30 to 40 percent of older adults with Alzheimer's disease usually more um later on in the course of illness and although there may be some early symptoms interestingly even before people have memory difficulty and um what causes people to experience agitation and Alzheimer's yeah it's complicated there's been a lot of recent work trying to understand this because our ability to develop treatments for anything really depend on understanding what's causing it in both brain and environment wise and that agitation is caused you can think of it as being sort of a constellation of both brain function and we've done some work as well as others demonstrating that when certain parts of the brain and Alzheimer's disease aren't working properly that group is more susceptible to behaviors like agitated and aggressive behaviors but there's also other important contributions as well everything from environmental issues that particularly in places like long-term long-term care facilities where the environment can be really frustrating for people and when folks respond to frustration sometimes it comes with some agitated behaviors as well and then there's psychological issues interestingly people who have a lifelong history three of being more aggressive if you will are more susceptible to developing agitation late in life with Alzheimer's as well so it's this constellation of um different kinds of contributors to the syndrome you know I think most importantly is the the brain contributions are important because those are opportunities to develop treatment targets and there's been a fair amount of work done recently to better understand what specifically is going on in the brain with agitated behaviors to identify opportunities for intervention yeah that's a nice segue so prior to 2023 What treatments were available for agitation in people with Alzheimer's disease shares as most are aware that the treatments the medication treatments for Alzheimer's disease have not been particularly robustly effective over the years and that traditionally atypical antipsychotics medicines like risperidone olanzapine Quetiapine have been used to treat agitated or aggressive behaviors and Alzheimer's disease and you know we've learned over you know many studies now going back two decades that the magnitude of benefit from from atypical antipsychotics of the ones I mentioned the magnitude is not huge that it's a modest response on average and we've also learned more over time about the side effect profile that is not as benign as as folks used to believe as well that there can be a fair number of side effects that contribute to additional morbidity with the illness so it's kind of the balance balance The Meta atypical antipsychotics have been shown to be effective but only modestly so and come with some side effects so you know this is now a change where a medicine has been FDA approved brex pip result 2 is an atypical antipsychotic and it's not clear right now how much more benefit there will be from brex petrosol compared to other atypical antipsychotics that have been used over the years the general sense is that the side effect profile may be a little bit more benign and that would be a distinct Advantage but there haven't been head-to-head trials we don't know exactly and clinical experience with the medicine is still pretty limited because it's not it's only been recently available for General use in in the community so how does an atypical antipsychotic work are they do they have the same mechanism or they each one work a little differently each one's a little different and it's a good question because that's really the key to identifying those that are most beneficial and least harmful um in general the atypical antipsychotics have effects on neuroreceptors in the brain that include two primary classes one is serotonin receptors and the other is dopamine receptors and each of those categories of receptors has a whole bunch of different subcategories and each one of the atypical antipsychotics has slightly different effects on the different subclasses of receptors so one may have more dopamine effects one may have more serotonin effects some may have more serotonin reuptake um effects Others May block certain kinds of Serotonin or dopamine receptors so there's some heterogeneity across them but as a class we kind of lump them all together and for back Rex piprazole um who do we expect who do we expect it to help in terms of what uh at what stage in the disease and who who's the target population here yeah I mean the trials were done in people with Alzheimer's disease and who met a certain threshold of agitated Behavior so you know in clinical practice we're going to be looking for you know folks who have significant agitated or aggressive behaviors so this is not to include people who have you know everybody gets frustrated sometimes including people with Alzheimer's disease and and you know with the challenges in responding and coordinating um behavioral responses people with Alzheimer's disease may be more susceptible but we're going to identify those that have kind of um and not just short-lived symptoms but those who have had significant symptoms that have an impact on safety or reflect a lot of distress that have gone on for a period of time we're also going to want to look at particularly if it's new onset I.E somebody who's not previously been affected by such symptoms to be able to make sure there's not a medical cause promoting the agitation um that's treatable things like pain for example somebody with alzheimer's disease May lack the capacity to ideally Express themselves and may not be able to explain pain for example and that can come out as agitated behavior when they're really attempting to get their needs met um so we're looking for any medical things infections bladder infection Etc that may be contributing to behavioral symptoms in Alzheimer's disease and then we're starting with each of the medicines in brexiprazole as well starts with a titration with a lower dose than increasing over a couple of weeks to get up to a more effective dose later on so we're looking for people who you know the kinds of symptoms that may respond um include things like physical aggression verbal aggression and the excessive motor behaviors that I described previously in the more recent uh the most recent trial indicated or suggested really that those with um more severe agitation particularly physical physical aggression may be the most responsive to brex Peppers all treatment although there was some response to all of the symptoms that I've just described over the course of treatment so that's kind of what we're looking for yeah that that's really important that's great I mean if it could alleviate some of those symptoms of physical aggression that has to be very difficult to manage absolutely we need to remind ourselves that you know these symptoms are really um significant parts of the Alzheimer's disease syndrome and when you think about what promotes caregiver burden caregiver distress institutionalization it's not memory problems memory I don't mean to trivialize it memory problems are obviously important but things like agitation anxiety irritability are really important aspects of the illness so we actually have a question from the audience that I think fits nicely so um Mark Applegate is asking would this drug be appropriate for someone with a Lewy Body dementia yeah it's a good question that um there there haven't been controlled Trials of Rex pipazole for Lewy Body Dementia or behavioral symptoms in Lewy Body dementia that said and and the the neurobiology of Lewy Body dementia is different than Alzheimer's disease so it's certainly possible if the response would be somewhat different but it may be it certainly is a reasonable consideration just based on clinical practice and that's something that you know clinicians will need to figure out over time that the um a challenge with Lewy Body dementia is they tend to be folks with Lewy Body dementia tend to be particularly susceptible to some of the side effects of um atypical antipsychotics particularly A syndrome called extrapyramidal symptoms with rigidity Tremor can be associated with Falls as well and obviously that's something that's not good it seemed that in the brexit result trials in Alzheimer's disease that the extra pyramidal symptoms were not that common they weren't non-existent but they may be less than other um antipsychotics so it's possible that Parkinson's dementia with behavioral problems or Lewy Body dementia may may be that Rex pepper Zone may be a reasonable consideration although at this point that's a clinical guess and certainly worth trying and considering but we just don't know the answer to that yet and so as far as you know there are no current political trials being done with this drug in people with Lewy Body or Parkinson's no not to my knowledge it's possible there's something going on that I'm not familiar with but the you know breakfast every every drug has its history of the drug development program it's part of and brexiprazole has already been FDA approved for people with schizophrenia it's an atypical antipsychotic so it's been on the market for symptoms associated with schizophrenia for quite some time now uh so there they the trials were done for agitation and Alzheimer's disease identifying that as a particular Target and then it took you know three trials that included just over a thousand participants to develop the data set that was um submitted to the FDA for agitation and Alzheimer's disease so that's where sometimes drugs are very good for other symptoms but we just don't have the trials data and there's not an opportunity to have robust trials data for every clinical syndrome so you know that's where you know clinical wisdom comes to play a role and identifying candidates who may be reasonable to consider then it would be an off label on treatment and obviously you need to be cautious then but to uh identify those candidates who may have a response and it wouldn't be an unreasonable clinical approach mm-hmm um and then what are what are some of the side effects associated with taking brexiprazole yeah I've mentioned some of them overall in the trials the side effect profile was reasonably benign at the doses used in the study um there was a little bit of sedation a little bit of dizziness a little a bit of GI symptoms diarrhea in particular and those are things those are happening in less than 10 percent are usually dose related as well and that's where the medication is started at a lower dose and then increased over a period of two to three weeks like I mentioned to make sure that folks will be tolerating the medicine reasonably the other symptom profile that we're concerned about is the extra pyramidal symptoms I've already mentioned and won't belabor but that's something that can really have an impact on things like rigidity Falls and things that are medically compromising um and brex peppers all the signal for extra pyramidal symptoms in the trials was was relatively low so I think that's a good sign we also need to keep in mind that all atypical antipsychotics carry a warning from the FDA about the mortality risk and coming from the older evidence from um atypical antipsychotics that have been prescribed over the past two decades there's evidence that taking an atypical antipsychotic an older adult with dementia and psychosis or agitation is at risk for mortality or death over the next period of time that may be extended the magnitude of that risk is relatively small but obviously when it comes to mortality we want to be very very careful about that so that's something that was there there weren't enough people in the brex pepresol trials to know was that risk higher lower about the same than other atypicals one would presume just based on the molecular structure and clinical practice that would be about the same so we we want to be aware that medicines including brex Peppers all can have some uncommon but serious side effects hence the importance of choosing people wisely to treat with the medication because it comes with some risks and why is the mortality risk higher in these atypical um neuropsychotics yeah it's a great question Megan and people have tried been trying to understand that if you look at you know again it's not that common so the evidence that we have the evidence-based is not um huge to be able to say aha it looks like this is what's happening that the the causes of mortality have varied mostly across um infectious illnesses like like pneumonia and and that's what older people die from unfortunately so it's not clear that there's sort of a Smoking Gun for atypical antipsychotics some people believe that you know folks taking these medicines tend to be activated and that's part of the the treatment goal is to reduce that excessive activation movement Etc and and older people when they're when they're sitting more actually are at risk for stasis um Venous stasis in their legs Etc so it's possible that that's related but that's pure respect calculation the short answer is nobody really knows and it looks like the causes of death have been um quite varied and typical for for the mortality of older adults in general so it's not a clear specific antipsychotic mechanism so then when would you typically start and stop a patient on brexit result yeah I think I've alluded already to selecting people who may be appropriate for treatment we're going to again identify those who have persistent significant agitated or aggressive behaviors that are contributing to safety concerns that are contributing to distress that are contributing to basic care needs that people are trying to provide and then we're going to consider um the medical evaluation and also to identify those who may respond to a behavioral intervention as I mentioned at the top of the hour that environmental factors can play a role in contributing to agitation so um looking at are there things going on in the environment that are agitation ogenic if that's a word to be able to you know to to help improve the uh the situation there's also evidence that working with caregivers including in uh nursing assistance and skilled nursing facilities to understand what the behaviors are and how to how to man handle them in a behavioral way a non-pharmacologic way is um can be really beneficial and that's an area that's really going to be important going forward because the solution of these behaviors isn't always medications and that all medication trials should be treatment should be um done alongside be partnered with these behavioral interventions as well so we're going to select people who we have tried have provided a reasonable behavioral intervention and and symptoms persist if the if the behaviors improve of the behavioral intervention then meds aren't needed so we're going to select wisely and those who clearly need it and haven't responded to non-pharmacologic interventions and then stopping it's a little I think you mentioned stopping you don't want to catch off there yeah shopping is a little bit less known because most of the trials you know look at they're about you know two to three month treatment studies to look at benefit not what happens later on and The Field's been because risk is also related to length of time on drug we want to be able to discontinue meds in the general sense is if people have been symptom-free for a period of time like several months it's probably reasonable consider treatment for a few months depending on the case but if somebody gets better in the first week of treatment it probably wasn't the medication anyway um so to be thinking about those kinds of issues and consider a trial for a few months and if somebody is doing much much better over that period of time than to taper them off the drugs so people aren't on these medicines forever but nobody really knows and we published a study going back a bit looking at discontinuation and you know when you discontinue these meds some people will have the agitation recur but it's certainly not everybody so it's worth the consideration and those who did well in that trial were those who really had no residual symptoms you know they were really substantially improved on the medication but we'll need to know more about that again based on how clinicians experience that as now more people will be treating folks with these medicines um you mentioned behavioral interventions what are some common behavioral interventions that are being done now yeah we think of them as really focusing on uh three things if you will one is the the patient the person with Alzheimer's disease the second is the caregiver and the third's the environment and in each of those domains for the for the patient we really think the person we're thinking about um recognizing um what things are distressing to them and to call be be as calming as possible there's a tendency as you can imagine when somebody a loved one is agitated there's there's an interest appropriately in trying to calm them but it can be really distressing and if you look at um Care Partners of people with Alzheimer's disease with uh agitation they're a very stressed group and so we can talk about be calming but it's a little it's very difficult to do so we really work with um patients and caregivers to understand what can be calming environments for the for the the person with Alzheimer's disease it may be just separating them from a situation that tends to be um cause problems for them and like I mentioned earlier for for Care Partners to be able to talk about what symptoms are some educational interventions so they understand what the nature of these behaviors are and what some strategies can be for example distracting somebody who's caught up in something that's really upsetting to them just separating them from that environment can be helpful um and then the environment I've mentioned already that just to be able to identify those things that may be contributing so we're thinking about things in those three domains and there's good evidence that putting together a thoughtful plan that involves looking at those three domains this patient-centered everybody has their own issues and to be able to identify what's best for an individual uh person and then Implement that plan check it out see how it's doing over a period of a couple of weeks for example before moving to medication unless there's huge safety issues in which case it's almost impossible to implement some behavioral interventions but that's far and away the minority of people with agitation is this medication available broadly now yes yes great and um I guess my next question is and probably my last question um are there other treatments or medications for other symptoms that people should look into or can we talk a little bit more about that just to kind of finish us off sure it's it's been a complex landscape as we've both alluded to now over the past decade or so for agitation or for other Neuropsychiatric or behavioral symptoms in Alzheimer's disease in the agitation realm there's been work done looking at um ssris or serotonin reuptake Inhibitors that are typically used as anti-anxiety or antidepressant medications and there's a large trial with escitalopram going on right now for agitation and Alzheimer's Disease an earlier version of similar work looked very promising so we'll likely hear more about that going forward this is now agitation a couple other medicines like dextrin with orphan is a compound that's been in trials for a while now Pim of answering is another compound that's been approved for psychosis in Parkinson's disease and has been explored in other dementias as well so there's it's it's a rich area for treatment development although you know many of these treatment trials have not been ideally driven by understanding the molecular pharmacology of agitation so that you know developing understanding of how the brain works in medication development go in parallel and that's been less than ideal thus far partly because we haven't had good treatment targets based on brain Imaging for example also some work with cannabinoids for example cannabidiol has been looked at for uh um agitation and Alzheimer's disease then for other symptoms like irritability anxiety depression there's been a handful of Trials there's no medication that's FDA approved for those circumstances in Alzheimer's Alzheimer's disease specifically but clinicians have historically tinkered with those treatments and had modest success have been a few Trials of antidepressants for depression in Alzheimer's disease interestingly not showing dramatic benefit and suggesting that depression and Alzheimer's disease is probably different than depression in in other circumstances traditional DSM major depressive episode for worry uh a final syndrome that's been interesting is apathy that we tend to think of um apathy is not often a focus of treatment but particularly early on in Alzheimer's disease there's this interesting observation that apathy may be one of the first and most significant symptoms early on in the development of Alzheimer's disease in some people perhaps before they develop memory problems and that you know family members will describe being sort of emotionally widowed if you will they're not sad they're not depressed they're not hopeless helpless Etc but just a bit of emptiness and less connected to the world around them and that too has been um it promotes a lot of additional morbidity with the illness just less engagement and less opportunity to connect with things that tend to be emotionally stimulating in a good way in providing good brain health rather than um being sort of isolated and the apathy can contribute to the isolation and there's been some work in that domain with stimulants interestingly um to look at with some evidence of benefit so that's something with uh when when when people with Alzheimer's disease have significant apathy we'll consider a stimulant trial for example to see if that can be helpful to them and it tends to be fairly benign that too is off label it's not FDA approved so again it's a rich area for treatment development acknowledging that you know we're currently in 2023 at a place where we're going to have a whole host of new medicines online for treating Alzheimer's disease per se perhaps even before symptoms develop and developing symptomatic treatments for memory impairment for example it's a whole new world right now but you know High proportion of people there's still you know six and a half million people in the United States with this illness who have these symptoms that really drive a lot of the the morbidity of the illness and institutionalization and caregiver distress so it's really going to be an important area going forward and there continue to be thoughtful trials so I'm hopeful about that particularly as we can develop a better understanding of optimal treatment targets absolutely and you know this I think the approval of this drug sort of got buried in the like canamab dynamab add you can you map story but this is a really important medication uh to help people exactly exactly and we'll see you know as the brex peppers all trials show not everybody was cured of their agitation for sure and that's what we'd expect actually but anything we can do to improve the the magnitude the severity of these symptoms or their frequencies is a huge benefit particularly when it comes to quality of life and allowing people to um institutionalization decisions are made based on behaviors not memory um that's the broad statement but I think you can appreciate why that might be so they remain really important treatment targets so we actually had a few questions pop up on the chat if you have a little more time absolutely and you talked about this previously but maybe you can reiterate it um one woman is asking my mother has anxiety and grinds her teeth and has facial pain from TMJ is this treatment useful to deal with agitation and anxiety yeah that's a great question um you know I think similar to like I mentioned earlier that the goal there would be to treat the TMJ and the pain that can be difficult I acknowledge but um it doesn't make a whole lot of sense to use a medication to treat the consequences of of a primary underlying medical issue so without knowing what her experience has been with uh treating the TMJ in pain that would be the first start you know if it turned out that that persisted regardless of optimal medical treatment for TMJ and pain then it'd be worthwhile considering it but I again I'd really be cautious in that for example if there are any extra pyramidal symptoms that could potentially exacerbate the TMJ because of the rigidity in the jaw that's that's out there a bit but it's something that just comes to mind so there I think the focus is on TMJ and pain and considering medication treatment for the anxiety or behavior to be or the sleep challenge which I'm guessing is is a problem as well to be secondary considerations uh you would mention cannabinoids can you talk a little bit more about cannabinoids as a treatment in Alzheimer's disease and what symptoms specifically they're targeting yeah that too is a great question and it's been an interesting history in that um there have been off label and just you know people have con considered cannabinoids remember there's kind of two different kinds the THC kind that has psychoactive effects that are more notable and then the cannabid iol that that has more some some uh anxiolytic effects without the the traditional psychotropic high of THC so and there's been some work done in both areas most recently and probably most importantly it's been either a combination or with cannabidiol the latter category of medicines and you know cannabinoids we call it that because there are somewhere around 100 different psychoactive compounds included in the cannabinoid umbrella so um it's been messy to identify you know which which of those to best consider as a treatment opportunity a study that's going on that's sponsored by the Alzheimer's clinical trial Consortium it's just getting started is looking at people with um very um late late um stage Alzheimer's disease who are at hospice care um with a combination I believe of uh of cannabinoids in order to look at beneficial effects there so at this point there's not been a consistent um cannabinoid candidate that has been tested and demonstrated to be safe and effective it's still a bit of the Wild West unfortunately but because of some evidence of benefit based on either clinical experience that people have had or some smaller trials it's an area for development so we'll be hearing more about that I think at this point it's hard to say gee they work or they don't work but that to understand it and not to just in future we'll know more about that and particularly what what um can species if you will are most beneficial so it's still it's just a work in progress great thank you so Dr salsa Salter thank you so much for joining us again on the program this was a fantastic episode I learned so much about this uh medication and I hope our audience learned a lot as well that's great it's been great to be here Megan as always and uh I hope the the attendees got what they wanted out of it so um um we'll continue on yes I think they did and I want to thank our audience too uh for joining us and asking so many great questions you can um access this ask the doc and others by visiting mind.uci.edu backslash mindcast next month we'll be chatting with Karen Dr Karen Lincoln about health disparities and in the meantime to learn more about research at UCI mind you can visit our website or consider signing up for the UCI consent to contact at C2C .uci.edu take care and we'll see you next month bye [Music] thank you

Channel: UCI MIND

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Id: ntpc_W-8V_U

Length: 34min 57sec (2097 seconds)

Published: Thu Sep 28 2023