Bonus Episode: Lessons from Early Adopters of XT in Schizophrenia with Ilan Melnick, MD

Journal of Clinical Psychiatry

Publisher of peer-reviewed research discussed in this episode.

Real-World Implementation of Xanomeline-Trospium in Schizophrenia: A Consensus Panel Report

https://www.psychiatrist.com/jcp/real-world-implementation-xanomeline-trospium-schizophrenia-consensus-report/

The JCP consensus panel report chaired by Dr. Melnick and discussed throughout this episode.

Dr. Ilan Melnick – LinkedIn

https://www.linkedin.com/in/ilan-melnick-516b4468/

#Schizophrenia #XanomelineTrospium #MuscarinicAgonist #FirstEpisodePsychosis #Psychopharmacology

Ilan Melnick, MD, is chief medical officer of Passageway in South Florida, which he describes as the largest forensic community control program in the US, serving patients found not guilty by reason of insanity or incompetent to proceed as they transition back into the community. He also runs a private concierge practice, rounds with psychiatry residents, chaired a JCP consensus panel of early xanomeline-trospium adopters, and recently presented two posters at Psych Congress.

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: Revisiting the XT Consensus Panel

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: Today on the JCP podcast, I’m joined by Dr. Ilan Melnick for a conversation about one of the more significant changes we’ve seen in the treatment of schizophrenia in recent years, the emergence of xanomeline-trospium chloride or XT, it acts differently by activating the M1 and M4 muscarinic receptors rather than by directly blocking dopamine D2 receptors. But this conversation really isn’t about the mechanism alone. What interested me was what happens when a new treatment moves from clinical trials into everyday practice.

XT was approved almost two years ago, and about a year ago, Dr. Melnick chaired a consensus panel that brought together a group of early XT adopters to share their experience using a first-in-class medication. We thought this would be a great time to revisit that conversation and see what we’ve learned since then.

We talked about several different practice settings, what group learned about putting the treatment into practice from appropriate patient selection to managing the early GI side effects to titration, cross-titration, and the possibility of using XT alongside other antipsychotic treatments.

We also talked about what has happened since that paper was published, including the fact that Dr. Melnick just recently presented two posters at Psych Congress that provide a look at how clinicians are using XT now. So we covered all that in what I think was a really good conversation. It gets particularly interesting in how much we’ve learned in the real world and how much that enforces or reinforces what the original consensus recommendations were.

So rather than looking simply at XT as a new mechanism or another antipsychotic option, this was really a conversation about what it takes to make a fundamentally different approach to treating schizophrenia work in clinical practice. I hope you enjoy my conversation with Dr. Melnick. With that introduction, Dr. Melnick, welcome to the podcast.

Dr. Ilan Melnick: Thank you for having me, Ben.

02:04 – Forensic Community Care and a Concierge Practice

Dr. Ben Everett: Well, look, you know, we got to know each other working on this project just over a year ago, and we stayed in touch for a little bit. But I wanna start away from the paper. I wanna start with your area of practice because you kinda have a couple of different types of practice, and I think it’s very interesting.

But it probably also really informs a lot of both who you are as an individual, but also how you practice as a clinician. And i- it- it’s unusual to me. So on the one hand, you’re the chief medical officer of Passageway, which as I have it, is one of the largest forensic community programs in the country.

You care for a lot of patients that have been found not guilty by reason of insanity or been judged incompetent to proceed to trial, and they’re transitioning back into their community. And on the other hand, ’cause you’re in South Florida, you, you run a private practice, kind of a concierge practice, where you’ve got a lot of the more South Florida famous model type people.

It’s pretty interesting. I’d just like to hear you kinda talk about these, these two different practice as- aspects and how they influence, you know, how you think about psychiatry.

Dr. Ilan Melnick: Yeah, no. So when I first started out, I realized quickly that I wanted to do things a little differently. I was never one to just walk down the same path that everybody else has walked by. When I started off in my private practice. I decided I was gonna not go down the path of insurances, and this was back before anybody decided they wanted to do concierge cash offices. So it was a little different in that aspect. Got involved working with athletes and models and some celebrities. I work with CEOs from some of the bigger companies, so I do a lot of that work. We’re– in that I’ve learned also that in Miami Beach, you learn that there’s a lot of worried well. But one of the challenges I’ve always had since I was a little kid, and my dad will attest to that, is that I have very little patience when it comes to doing the same thing for long periods of time. So doing the fact that I got bored, I worked one of my friends was retiring and ended up getting placed into this program where I was just one of the psychiatrists who came to Passageway. Met with Tom Mullen and Lillian Menendez, and both of them were the ones who started this program back in the late ’90s. And when I took it over we decided that we were gonna expand this exponentially, and we went from about 25 patients to now close to about 150 patients.

And we are the largest forensic community control program in the US. Most of our patients that got brought in get brought in through the the criminal justice system and where they’ve committed a first-degree felony like rape, arson, and murder. And what we did is develop this paradigm in transitioning them from the forensic psychiatric facilities into the community, and we follow them for a, a long period of time, usually even most of their lives. So this idea of being able to treat a more difficult population, whether it’s the worried well of my concierge practice or the forensic facility, both of them give me that excitement that makes me go to work every day and love what I do.

05:26 – From Postsynaptic Blockade to Presynaptic Modulation

Dr. Ben Everett: That’s awesome. I, I also or my wife would probably tell you that, yeah, if I– she doesn’t want me to get bored. If I get bored, then I start deciding maybe I wanna do something different, and that drives everybody crazy, so. Well, look, we wanna spend the majority of our time today talking about this consensus panel that we did last year.

We got together, I guess, about 14 months ago. This was published late last year, and I’m excited to have you on to talk about it now. But we’re gonna be talking about xanomeline-trospium chloride. The trade name is called Cobenfy. We’ll say Cobenfy, we’ll say XT, ’cause xanomeline-trospium chloride is a bit of a mouthful.

But we were approached with BMS with a grant to develop this consensus panel to bring together a handful of early adopters for XT. So this is on-label use for XT, and really just figure out, you know, what were the challenges, what were the best practices, what were the pearls that you would learn, ’cause this was a brand-new first-in-class medication.

And a lot of people, you know, might not have been comfortable with switching to a first-in-class medication if they’ve been out of training for a few years or maybe a lot of years, and they’re, you know, just used to your typical D2 blockers, atypicals, things like that. This is a little bit different. So maybe let’s just set the stage.

For some reason, almost two years since it was approved, if someone’s not familiar with it, can you just kinda give us that 30,000-foot view of what XT is and, and how you think about it?

Dr. Ilan Melnick: Yeah. XT was a first-in-class muscarinic agent. So basically since the 1950s all the medicines that we’ve been using have been basically blocking postsynaptic dopamine receptors. And that’s how they really worked. They didn’t change the amount of dopamine going into the synapse.

They just blocked them. And by doing so, it did help with certain things like positive symptoms. But in exchange for that, you would also block those receptors in the the, prefrontal cortex. You would block it in the nigrostriatal, where we control movements, and also you’d block it in the in the tubular and fimbriate area of the brain, where we deal with things like prolactin, the pituitary. And so this was always this trade-off. And even though we had a lot of medicines that did the more or less the same thing, the question I always had, even before XT came out, was, if you block one receptor with a medicine, does it matter what name you give it, right? So whether you block or even partially block, at the end of the day, they do the same thing. They do a little bit of things on the side, but mostly that’s one of the main things it does. With the coming out of XT, what’s been different is the fact that we now have an agent that doesn’t work postsynaptically where everything else has worked, but actually worked presynaptically by trying to lower the amount of dopamine going into the areas of the brain where they’re overstimulated by controlling the amount of dopamine there through a mechanism of the muscarinic world.

08:34 – M1/M4 Agonism and the Role of Trospium Chloride

Dr. Ben Everett: Yeah, I think I remember you used the, the kind of the classic accelerator versus brake pedal analogy. And so xanomeline is both an M1 and an M4 agonist that I think they might say an allosteric r- modulator. I can’t remember exactly what, what nomenclature they use. But how do you think about M1 versus M4 agonism with xanomeline?

Dr. Ilan Melnick: Yeah, it’s interesting because, when this was coming out and one of the things that I was– found really fascinating was the fact that, one, we never really learned much about the muscarinic system. And when xanomeline when we were taught a lot– a little bit about xanomeline and I talked to some of the MSLs when they were studying it in the ’90s one of the things that I learned about it was that it helps control the VTA or the ventral tegmental area. And by doing so, it actually modulates the amount of dopamine that goes into the striatum or the mesolimbic area of the brain. It’s interesting to see how, when you talk about muscarinic receptors that the even ones are things when you activate them, they turn something off. When you activate an odd one, they turn something on. Depending on where they are in the brain, they can modulate dopamine differently. So, for example M1 being that it’s odd, when you activate it, it turns on the area of the GABA interneuron. So increasing GABA, it then goes and then GABA being the most abundant inhibitory neurotransmitter the amount of glutamate, and if you lower the amount of glutamate, it affects the VTA by lowering the presynaptic dopamine. The M4 receptor is an autoreceptor, and when you activate it, being that it’s even, it turns off that autoreceptor, and b- by doing so, it lowers the production of dopamine at the VTA. So you basically have two mechanisms in where you’re able to lower the amount of presynaptic dopamine by activating these two receptors at M1 and M4.

Dr. Ben Everett: Yeah, thanks for that background. So what’s really interesting in doing research for this, I found out that Eli Lilly and Company had actually developed xanomeline for psychiatric disorders back in, I think it was the 1990s, but they abandoned it because you’re giving people a whole bunch of, of procholinergic essentially, and you’re gonna have some GI side effects.

And trospium is also an older medication but Karuna Therapeutics, they just had the idea that, hey, we’re gonna put both of these together. And so what does that solve, in your opinion?

Dr. Ilan Melnick: Yeah. Just very simplistically xanomeline, although mostly and intrinsically work on M1 and M4, it still is a pancholinergic medicine, as it does activate M1, M2, M3, M4, and M5. Now, M2 and M3 live in the periphery, and because you activate them, even though slightly, can increase the cholinergic activity, which can cause things like upset stomach, acid reflux, can move your intestines a little faster, can cause things like diarrhea or salivation. And so when they gave this to patients, especially in the early trials where they were actually studying it for psychosis in people with dementia, what they found is that it really wasn’t really well-tolerated. And then they looked at schizophrenia, and similarly, it didn’t really work well. Now, trospium chloride originally created in the early 2000s for bladder spasms. What it does is that it’s a pan-anticholinergic medicine as it blocks M1, M2, M3, M4, and M5. Now, thing about trospium chloride is that it on- it is too big to cross the blood-brain barrier, just simplistically. So by doing so, it only blocks it in the periphery. So by blocking the M1, M2, M3, M4, M5 in the periphery while leaving alone the M1 and M4 in the brain then what you get is a net effect of xanomeline’s M1, M4 activation.

13:03 – EMERGENT Trial Results and Early Cognitive Benefits

Dr. Ben Everett: That’s a great explanation. I really appreciate that. I’m sure the listeners will as well. All right, well, let’s transition into the EMERGENT program. So this was a, a, a large undertaking that Karuna Therapeutics started, BMS finished. And essentially that was the clinical development program for getting xanomeline-trospium chloride approved in schizophrenia.

I know you’ve lectured a lot on this, so if you can just– it’s, it’s a comprehensive trial, but if you can kind of just break it down for us a little bit and essentially who were the patients that were, that were followed and, you know, what evidence has been generated that you think is really most appropriate a couple of years now since or coming up on a couple of years since its approval?

Dr. Ilan Melnick: EMERGENT-1 was actually a phase 2 study. EMERGENT-2 and 3 were phase 3 studies and, encompassing almost 1,200 patients total. They were all rel- roughly the same, about five-week studies that were all inpatient of these acutely psychotic patients between the ages of 18 and 60 years of age.

The primary endpoint was actually to look at something called the PANSS or the Positive and Negative Syndrome Scale. It’s a research tool that kind of gives us a good understanding of how the disease progresses on three different spheres, on positive symptoms, negative symptoms, but also something called general psychopathology, which is a lot of what prevents our patients with schizophrenia from being able to function in the real world. And what they found in this study, as they pooled all three of those together, is that you found twice the improvement in positive symptoms. Now, be honest, most of the D2 blockers that have come out before have done a decent job of fixing positive symptoms. But for the first time, we now have a molecule that was able to help and give twice the improvement in negative symptoms and twice the improvement in general psychopathology. And that data is something that I found just really interesting because we now had something that not only controlled the symptomatology, that is what people in society fear when they interact with people with schizophrenia, but we now have a molecule that also helps in those negative and general psychopathology subscales in helping them integrate back into society.

Dr. Ben Everett: Yeah, I agree. That was kind of my read on the data. And really for the first time, it seems we had a medication that really seemed to help with negative symptoms. And of course, it’s the negative symptoms, the cognitive impairment, they really drive the dysfunction in those patients. Because a lot of times patients can learn through psychotherapy, psychosocial things to deal with positive symptoms e-even if they’ve got some residual symptoms.

But it’s the other things that really impact function. And this was pretty quick, at least the way I read it. I think positive symptoms emerged very quickly from placebo. I can’t remember exactly when the first check-in was, one week or two weeks after. Negative symptoms about three weeks.

But in an era where like an SSRI or other medication, a lot of times we’re giving patients something or the prescriber is, and you’re saying, “Okay, this could take, you know, three months to work,” I think seeing something work two to three weeks is really pretty rapid and different. It’s definitely unique from an antipsychotic perspective.

Dr. Ilan Melnick: Yeah. As an antipsychotic, most of them are measured in months, not in weeks. And so people start seeing some separation, but to where we start seeing an improvement like we saw this double the improvement you don’t really get to see very often in, in such a short period of time.

Dr. Ben Everett: That’s exciting. So we talked about positive symptoms, negative symptoms. What about cognitive improvement? So that data has been harder to get to. There’s been a number of failures in, in schizophrenia research over the past couple of years. But in the panel, there was a lot of… And of course, it was early days, but a lot of anecdotal evidence where people some of the panelists talked about they really saw some frank differences in in cognitive improvement in their patients once they got started.

Is that something that, that you’ve seen in practice as well?

Dr. Ilan Melnick: Yeah. Now having a little over almost two years of experience using this XT product one of the things that we’ve noticed is definitely the ability for them to retain more information. In our forensic community control program, it’s all about teaching and learning life skills. And one of the things that we’ve noticed is that those that we started on XT definitely were able to grasp concepts a little faster. They weren’t as clouded as they were maybe with some of the other medicines that they had taken before. So we were pretty, We found it very interesting that we were able to get these patients not only better with their symptoms, but actually able to think a little clearer. And I think we’re starting to see some changes here too.

I think as we start using more XT in society, I think we’re gonna start seeing bigger changes in the overall treatment of psychosis with schizophren- patients with schizophrenia.

18:17 – Inside the Panel: Early Adopters and Experiential Evidence

Dr. Ben Everett: I think that is an amazing line right there that yeah, if we can continue to see improvement, that’ll be great. All right. Well, look, let’s really get into the panel itself. So can you tell us, you know, who was in the room? Well, I guess we did this one virtually, right? So who all was on the computer?

And, you know, spoiler alert, but I liked that it was really a, a, a varied group of clinicians that, that we brought together, all of whom had been early adopters. Can you give us a little flavor for, for who all participated in the panel?

Dr. Ilan Melnick: Yeah, absolutely. I acted as chair and led the panel. But I brought in a couple of friends Erin Crown, who’s a PA out of of Pennsylvania, and she’s amazing, bright but really gives a good perspective through the mid-level world. She also does a lot of research and has been really much in the forefront of all new medicines. Manish Zinzuvadia from New York City a premier psychiatrist out here and just really really caring to his patients. And then also Michael Halassa brilliant researcher, writer, one of the smartest people I’ve actually ever interacted with, and I think overall he’s really gave a lot of clinic– background information and really gave some really great tone to the way that our panel was set up.

So I think overall, we had such a great varied panel and really did I think we came out with some really good ideas from it.

Dr. Ben Everett: Yeah, I agree. And what I like what Mike really brought into it was at that point in time he was at Tufts, and he only saw patients in the inpatient setting. So he was only dealing with patients, you know, admitted to his service who were, you know, acutely decompensated. And actually, he wrote up I think a retrospective analysis of like the first twenty patients he put on.

I’ll talk about that later. All right. So I love the paper. It’s very candid and the recommendations come from early experience. At that point in time, between the four of you, y’all had treated about two hundred patients, which is pretty remarkable. I’m curious, you kind of alluded to, do you have any idea how many you’ve got on therapy now or a lot more than, the fifty or sixty that you had to start with, I’m sure?

Dr. Ilan Melnick: Yeah. So it’s interesting. So our forensic facilities we check in… We don’t have that much turnover. So we do have quite a bit. Where I’ve started noticing is higher usage in my private practice, where I’ve started using it in some of the patients that come in with schizophrenia in my private office now that I’ve gotten a lot more hands-on. Also, I’ve been working with residents from two of the bigger programs, and we’ve also been rounding and really focusing on how we can get some of our patients that unfortunately, we don’t practice medicine in the United States, insurance companies do. And so oftentimes using a D2 blocker is our first line, but what we’ve done is started to move towards the XT being a good second line as we’re starting to see where we can get our patients better.

Dr. Ben Everett: It’s awesome. All right, in an era of evidence-based medicine, this is not evidence-based so much as experiential learnings from a handful of people. How do you put a piece like this into perspective with, with that backdrop?

Dr. Ilan Melnick: So one of the things I teach a lot to my residents is understanding what clinical trials are. They’re not natural in any way, shape, or form, and unfortunately, our patients don’t read journal articles, and our patients don’t read the the inclusion/exclusion criteria, and they don’t match up with what you would normally find in a clinical practice. So although we get a lot of guidance from clinical trials, especially in the early interventions of when medicines come to market, what we start noticing is what we see in clinical practice, anecdotal, the write-ups that Michael did the patterns of seeing a lot of patients on XT, we start getting ideas of how to best manage the, the symptoms of schizophrenia with XT.

22:35 – Early Use in First-Episode Psychosis and Dose Titration

Dr. Ben Everett: I, I agree. I think that’s great. All right, so let’s get into the paper now. So the way we do these is we bring people together. There’s a discussion guide. You kind of walk everybody through the discussion guide, and then collectively you come up with a, a series of consensus statements, and you present evidence.

Sometimes it’s anecdotal and based on experience and it- it’s opinion, but certainly we looked at the clinical research as well. But the first consensus statement from the paper was that XT should be considered early in the course of illness, particularly in first episode psychosis.

What was the, the rationale for, for that recommendation?

Dr. Ilan Melnick: So one of the things that we, when we talk about newer patients is, one is the ideal world and the other is the practical world. We believe that we’re gonna start seeing big changes in how we treat schizophrenia into the future. Challenge is obviously the payer systems usually want some failures before we go down that path, and it’s not universal, and every state’s a little different and… But more likely than not, you’re gonna have to go down the path of a D2 blocker. Challenge with the D2 blockers or partial agonists are the fact that they actually go in, they block the receptors postsynaptically, but they don’t change any of the any of the, the problems that are arisen by the disease state itself. So we start seeing consequences in that, in dealings with movement disorders, or we may have some metabolic issues that we see that become more of a class effect with these medicines. With the addition of XT, what we started seeing in the muscarinic system is that now we’re starting to fix the underlying issue, the over- secretion, the overburdening of the striatal system the mesolimbic system, in which we’re now able to hopefully fix, correct, and help the patients improve while not touching the other areas of the brain that we normally have to deal with, like the mesocortical or the tuberoinfundibular or the nigrostriatal area of the brain.

Dr. Ben Everett: Yeah. And so the issue with blocking dopamine so broadly in these others is side effects, right? And, and those side effects can be quite burdensome from patients. We know there’s some metabolic side effects that can be associated with them. And then more long-term you know, TD certainly becomes an issue for, for patients.

All right. So kind of follow up on this first episode, psychosis. So with XT, there is a starting dose of fifty milligrams of xanomeline fixed with twenty milligrams of the trospium chloride, so that’s fifty/twenty.

And then patients would then escalate up to one hundred over twenty, and then finally, if necessary, they could go to the one twenty-five over twenty-five. But Erin noted that she had a lot of her earlier disease patients, she would start them on fifty over twenty, and they really did remarkable, and she would leave patients there if their symptom control was good enough.

Is– I’m, I’m curious if, have you seen any research on that come out to date? And, you know, is that something that, that you’ve heard of other people having that type of success with fifty over twenty?

Dr. Ilan Melnick: So like I was saying earlier, I think that understanding clinical trials is important. The way they do these things in clinical trials isn’t the way we practice medicine oftentimes. It’s rare that we get somebody that’s completely clean, has never used any drugs, has, not been in a state hospital, has never tried or failed more than two antipsychotics, has… That’s not what we normally deal with. Now, in the earlier population, they weren’t– they were also excluded, first episode, were also excluded from the clinical trials. So these are uncharted territories. Now, we do know that people in the early stages of their disease state, they actually do well with less medicine and even get better outcomes. So what I would say is that the challenge with this molecule is that if you stay at the lower dose, there is a good chance that you may have breakthrough symptoms, and oftentimes clinicians refuse to go up higher to the doses that they actually need due to fear that the patient may experience side effects. Now, the advantage of the XT is that you can somewhat predict what those adverse events will be, whether cholinergic or anticholinergic, and being able to see where you stand. My advice to the clinicians are stay at fifty twice a day for a little while, but if the patient even has a little bit of breakthrough symptoms, definitely push up to that one hundred milligram dose quickly. The medicine has a fairly short half-life. You reach steady state within about five days, so there is no reason to wait much longer than a week or two before you start seeing whether or not that dose is working for them. So in our office, we usually use about one week of fifty. We go up to the hundred, is an effective dose as per the clinical trial. And at that point, we can make a determination of whether or not they’re having maybe some side effects where we can always go back down, we keep them at that one hundred and see where they stand.

Dr. Ben Everett: Yeah. And that, that’s really good. And I think the other thing I, I kind of alluded to it, but I didn’t say it maybe clear enough, is that per the, per the label for Cobenfy, the fifty over twenty is, is labeled as a starting dose, not as a maintenance dose. Only the one hundred over twenty and the one twenty-five over twenty-five are considered maintenance doses.

So just important I just felt like I needed to put that in there.

28:28 – Patient Selection and Prophylactic Ondansetron

Dr. Ben Everett: So you mentioned that in your private practice you’re starting to use this more as aside from just the, the forensic practice. I’m curious if there’s a, a patient type that jumps out to you or is it, you know, something else that you’re looking for that makes you think, “You know, I think XT could be a good, a good medi- a good medicine for this patient”?

Dr. Ilan Melnick: So I believe that my thoughts in my private practice are one, tend to be a little higher functioning and oftentimes are much more susceptible to adverse events, side effects, and discontinuation. So when I started using it in the forensic facility and started realizing pretty quickly that it was well-tolerated, I was pretty quick to start moving it into my private practice.

And so although we have had I’d say about twenty, thirty patients extra since the last time, most of them had come from my private practice. I started noticing is that the earlier the intervention, the better the outcome. I started patients that were already on other medicines, whether they were having breakthrough symptoms or they were having adverse events, in where they didn’t tolerate it very well, Cobenfy tended to be my next option. And so I started using more and more of it, and I’ve seen some really great outcomes, similar to what we discuss in the c- in the consensus panel guidelines, but similar also to what we’ve been seeing in the real world. And as I travel the country and talk to a lot of different clinicians, these are the same ideas that most people have had. A little hesitant at first, but now starting to realize where it all fits in, and if not the first line, definitely a second-line option.

Dr. Ben Everett: That’s great. I think a lot of the hesitation at first when it came out in my mind it was really twofold. One, it’s the first-in-class agent, and so people don’t have any experience with it. And then number two is you do have these GI side effects, and they can be pretty scary you know, to have to walk a patient through.

But the panel came up with a recommendation just to go ahead and co-prescribe ondansetron for every patient. Can you walk through a little bit about how you think about using ondansetron concomitantly with it and how you counsel patients?

Dr. Ilan Melnick: Yeah, absolutely. So one of the things to keep in mind is ondansetron works on the serotonin system, not the anticholinergic or the or the dopamine system at all. And, by doing so, it actually slows down the sto- the intestinal tract, which helps with some of the activation that may happen from the cholinergic adverse events. One of the things we know about ondansetron is that it’s a better preventer than it is a fixer. In other words, using it prophylactically and even before you actually give the XT, you get a better chance of the medicine working versus just giving it once they start getting nauseous. If you’ve ever used it for, seasickness or when you’ve got nauseous, or you’ll know that if you take it before you get on the boat, it will work much better than if you’re already on the boat and already seasick.

31:47 – Empty-Stomach Dosing and Cholinergic vs Anticholinergic Effects

Dr. Ben Everett: That’s that old ounce of prevention versus a pound of cure. The other thing that comes up repeatedly is just dosing on an empty stomach. Can you just give a little bit of the rationale for why it needs to be dosed on an empty stomach, and has that been a barrier in your practice at all?

Dr. Ilan Melnick: So one thing I learned is that most of the cholinergic adverse events usually happen at the very beginning when you’re first starting the medicine. And so what we do is we usually will order the ondansetron early on, and we’ll have them take it while they’re either titrating up or at the very beginning. Then the next thing is we really have to educate our patients to not take it with food, especially at that very beginning stage, it will– in– food will increase the absorption of xanomeline while it will decrease the absorption of trospium chloride. It increases the thing that causes nausea, it lowers the thing that’s meant to protect it, and that oftentimes leads to a recipe of disaster. So the best thing to do is, one, take it on an empty stomach about an hour before, two hours after food, or you wanna take it with ondansetron before you start taking the medicine to minimize any of those adverse events, especially while early on or titrating up.

Dr. Ben Everett: Yeah, and I know there’s been a good bit of, of follow-up data and even some individual just studies that BMS did just looking at the, the GI side effects over time and trying to get the timing down around when do you titrate up, you know, how do you manage that? Can you maybe give us a sense of where the data are on that now, and then just personally what you’re doing in clinic and what, what’s been working for you and your patients?

Dr. Ilan Melnick: So like I said, at the very beginning is where you have most of the food effect. Actually, the data has shown that if you once you stabilize the patient, the food effect becomes less and less of a burden. It is something still as a recommendation, but it is something that if a patient occasionally eats on the medicine, there’s less likelihood once they’ve reached a period of time, a few months of being on the medicine and staying on it. One of the biggest challenges with that, though, is that if they even miss a dose, it could reset that clock. The other thing is that knowing the cholinergic versus anticholinergic adverse events plays a big role in nausea. Words, we know that nausea is caused by the cholinergic adverse events, and that’s protect– What protects that is the trospium chloride. If at a hundred milligrams the patient is having a lot of nausea c– or vomiting, consider increasing the dose to the one twenty-five as that will increase the trospium chloride from twenty up to thirty milligrams, and by doing so usually eliminates that nausea And vomiting. And actually, as per the clinical trials and what we’ve seen in clinical practice, that’s exactly what happens. So it’s important to recognize those cholinergic adverse events usually once you’re at the hundred-milligram dose.

Dr. Ben Everett: I think that’s important to understand that the trospium dose is not linear ’cause you’ve got 20 milligrams for the 50 over 20 and then 20 for the 100 over 20, but the trospium does not go up until you get up to that 125 milligram dose. Well, since we’re talking here, so talk about anticholinergic burden and what are you seeing in practice and how are you managing, you know, patients that might have like you know, bladder retention issues or, or things like that?

Dr. Ilan Melnick: I tell this to my students, and I tell this to my patients quite a bit. The nausea is something that’s manageable. And for clinicians that fear that aspect of it, is understanding, where the cholinergic medicine is coming from and what we can do to counteract it, whether by increasing the dose to increase the trospium chloride. But the anticholinergic effects are actually a lot more complicated, and that’s because it’s harder to manage. In other words, if you have somebody that gets urinary retention, it’s kinda hard to undo that other than just going to the, a clinic to get your bladder rel- relieved of its pressure. The idea of going up to a hundred milligrams twice a day then seeing where your adverse events are. If they’re cholinergic in nature, go up to the one twenty-five. But if they’re anticholinergic in nature then we have to see what other medicines are causing that extra anticholinergic effect. And that’s something that we’ve noticed quite a bit. Usually, people don’t recognize that there are certain sleeping medicines or there are certain allergy medicines that might interfere with that anticholinergic effects. And the few times in where we’ve had people have constipation or other things that were anticholinergic, oftentimes it was not caused specifically by XT, but actually the combination of XT with other medicines that they didn’t realize had some anticholinergic effects. And at that point, you definitely don’t wanna go to the one twenty-five until you’ve real- realized or have corrected that anticholinergic effect that the patient is having.

37:15 – Cross-Titrating From Dones, Pines, and Partial Agonists

Dr. Ben Everett: I think the history is really important here to make sure the patient is telling you all of their OTC meds and, “Oh yeah, I take a little Tylenol PM.” They have no idea that that’s diphenhydramine, right? And, and these things can make a difference, so really important. All right, so I think the other thing to consider is you’ve talked about some kind of cross-titration starting you know, we’ve talked about new starts or maybe if a patient comes in, they’re off of their meds, maybe they’re decompensated.

But, you know, think about cross-titration in a patient who is already on, let’s say, an atypical but has got some residual positive symptoms, has some negative, some cognitive impairment, and you’re thinking, “Okay, I wanna add XT onto this.” How do you have to think about you know, down titrating what they’re currently on?

Do, do you need to think about a washout or anything like that? Obviously, we wanna maintain our patient’s you know, ability to, to, to function appropriately and, and have as little symptom burden as possible.

Dr. Ilan Melnick: Yeah. One of the things that we’ve learned is that most of the times polypharmacy is not the best answer. But unfortunately, it is what happens in a lot of clinical practices. So when you’re trying to switch from one to the other, a couple things to keep in mind. The first thing is that you want to try to de- prescribe, right?

You want to try to do what we can to get on the lowest dose necessary of whatever agent they’re on. But the next thing you want to do is know what you’re switching from so that you can make proper assessments. So I always talk about the dones, the pines, and I’m gonna switch it up. I used to say azoles, but at the end of the day, they’re the partial agonists.

And the partial agonists include things like cariprazine and also lumateperone, which is this hybrid-ish kind of medicine. So the dones include the typical antipsychotics, right? So those include things like haloperidol and fluphenazine because they all react very similarly as they’re very tight binding to D2. What ends up happening is that for those medicines, it’s actually a fairly quick transfer off. You can get them off the dones usually about over two weeks. Now, with the pines, the challenge with those is the histaminergic burden. So all these medicines are– Most of the pines, they all have some anticholinergic effects, but they also have histaminergic effects in where if you block the histamine receptors, it’s gonna cause bulk sedation, and it also may cause some insomnia with the rebound if you take them off too quickly. For those, we recommend doing about a four-week titration over that period of time. And with the partial agonists most of them have a very long half-life, and by doing so, what you’re able to do you’re able to get the patient off that partial agonist very quickly and then be able to titrate up the Cobenfy at your speed, knowing that the other, the– knowing that the partial agonist may just take a long time to get out due to its very long half-life.

40:33 – Antipsychotic Dose Sparing, the ARISE Trial, and LAIs

Dr. Ben Everett: Yeah, there was a table four in the paper that really broke this down very well. I think it was one of those tables, and we put it together. I was like, “This is one that somebody can cut out and, like, put in a, in, in the sample closet.” You know, a really good very accessible type of table. Right, so one last thing that we really…

Another thing that we talked about at the consensus panel was the ability or the potential, I should say, for XT to be antipsychotic dose sparing. And I think you’ve kinda talked about it just there, where, you know, okay, maybe with polypharmacy, sometimes it just is what it is, but maybe we don’t have to have that really high dose of our traditional donepeen or azole when a patient gets to 100 or 125 milligrams of xanomeline.

I’m curious what you’re seeing now, you know, long term, you know, two years into, into using this. Is that something that you think is holding up? And are you excited or happy about this, you know, moving forward?

Dr. Ilan Melnick: Yeah. So a couple things to keep in mind. First, by using XT you’re lowering the presynaptic burden. As you’re lowering presynaptic dopamine release, you need much less of that postsynaptic blockade. One of the things that I do is as I titrate from one medicine to another, is I actually look for Parkinsonism features as I lower the presynaptic burden, and if I’m still over-blocking the postsynaptic receptors oftentimes it does lead to some Parkinson’s features.

And that’s one of the things I look for as a hallmark to see that if I’m going a little too slow in my titration. But it has worked out quite well despite… There was a study called the ARISE trial which was actually a study in which they compared X- XT with an antipsychotic as using them together, and they wanted to see how it compared it to the antipsychotic with placebo. And what they basically found in this study is similar to what we find in clinical practice, is that with most medicines, it actually worked a little better. The only exception to that is exactly counter to what we see in my clinical practice and what I’ve discussed with a couple of my friends and colleagues, is the fact that risperidone did not separate out from placebo mixed with risperidone. So the main thing here is that we actually use it quite a bit with an LAI, and that’s actually worked really well, especially in our forensic facility where we are required to keep a lot of our patients on an LAI at the same time of using an oral.

Dr. Ben Everett: Well, that begs the question of, you know, how do you bridge if a patient is on an LAI? What’s your strategy there for starting XT? Is it try and lower the dose a little bit or, you know, h- how do you go about doing that?

Dr. Ilan Melnick: One of the things that we’ve been able to do by adding XT is we’ve been able to use almost microscopic doses of those LAIs. We’ve been able to use most, especially on the risperidone LAI, we’ve been able to use very small amounts and still get very good outcomes despite that combination failure in the ARISE trial.

Dr. Ben Everett: I remember reading the ARISE trial when it came out. It was maybe not the most well– I think it was very well-intentioned, but I don’t think it was the most well-designed study. So I think there were a lot of commentaries about that when it came out. All right. Well, look, I know Psych Congress was just happened recently, and you had a couple of new posters there, so I want to transition and talk about a couple of these new posters that you presented there.

44:17 – Psych Congress Poster: Real-World Prescriber Survey

Dr. Ben Everett: ‘Cause I think it gives us a more practical approach to how the evidence has evolved and what people are looking at. So the first one was actually doing a prescriber survey, and I love these types of surveys because you get real-world evidence or real-world data from practicing clinicians.

In this case, it was mostly psychiatrists that completed the survey. It was about a hundred clinicians. What were you really trying to get to with this study?

Dr. Ilan Melnick: The main thing that we were looking for was trying to get a good sense of how people actually use this in the real world and how people can go from one medicine, to XT over a titration period, and what is like best practice of what– how people do this in their clinical practice. So this was not a…

This was like asking a survey of people that have used XT in their clinical practice. They had to have at least two prescriptions written. It had to be some confidence with the the use of it. And they wanted to get a good sense of wh- how they viewed XT in comparison to other molecules in the space. What they basically found and what I thought was interesting is that effectiveness was found to be higher in olanzapine and risperidone. When you talk about tolerability, when you talk about metabolics, when you talk about weight, xanomeline trospium chloride matched up and was like at the top of the list for pretty much everything else. And that was one of the things that I also noticed, is that even though olanzapine and risperidone did did rank a little higher, the error bars all overlap. So there really wasn’t any significant difference between XT and those, despite them being on the higher end.

Dr. Ben Everett: Yeah, that’s nice. I also liked that when, you know, the most common reason that clinicians gave for prescribing XT was either improving overall quality of life or functioning for their patients, so they’re really thinking beyond just positive symptoms Which was followed by avoiding cardiometabolic side effects.

What does that tell you about how people are thinking about this, and is that consistent with, you know, your conversations as you go around and lecture across the country?

Dr. Ilan Melnick: So one of the things that I was saying early on in our podcast today was this general psychopathology, right? This is the stuff that people are able to go back into the real world. And when you start thinking about quality of life measurements, it’s all about functionality. What you’re able to do with XT and even what they showed here in this study and what these 100 clinicians all went out and discussed was the fact that quality of life measurements were one of the main reasons why they felt that XT was their top choice. And also, when talking about number one cause of death in patients with schizophrenia, it’s cardiovascular disease. And knowing that’s the second reason why, it just, again, was something that we didn’t find surprising because this is exactly what we do in clinical practice. But I was really happy to capture that information and seeing how by giving XT to patients, it actually is able to get them to become more functional, improve their quality of life, and lower the metabolic burden that we’ve been causing for, all these years.

Dr. Ben Everett: Yeah, I think that’s great. The other thing that I caught a-about this in terms of findings was when clinicians were asked to rate xanomeline, trospium against the other agents xanomeline, trospium scored highest for safety and also for ability to help improve negative and cognitive symptoms, which I think really gets directly into that part you were just talking about, about function and quality of life.

But, you know, I think you mentioned earlier, olanzapine, risperidone still did a little bit better for positive symptoms and then partial agonist a little bit better for tolerability. Is that kinda consistent with, with how you’re seeing the field these days? Any surprises there, I guess, would be maybe a better way to put it.

Dr. Ilan Melnick: It’s not an issue of surprise. It’s an issue of realizing that when you look at the error bars, they are all overlapped. So even though numerically they were higher, there really wasn’t any real significant difference between one and the other, and that’s more or less what we’ve seen. I got to tell you, I think that xanomeline-trospium chloride combination, or XT really does a great job of helping those positive symptoms. But what you’re not seeing is that it’s not just the vacuum of the positive symptoms. It’s the fact that you’re able to fix the overall picture. You’re able to get these patients back to the real world and functional.

49:07 – EMERGENT-5 Retention Data and the Future of Muscarinics

Dr. Ben Everett: I think that’s amazing. Something that, you know, frankly, we’ve been working on for, you know, a century or more. So that’s great. All right, I wanna transition to this other patient, and then we’ll, we’ll start to close things out. You’ve been very gracious with your time today. So the second poster was a post-hoc analysis of EMERGENT-5.

That was the fifty-two-week open-label outpatient study, and it looked at GI side effects on patients who stayed on treatment. So if I didn’t set that up well enough, please give us a little bit more detail. And then just what was the headline finding from the, from the open label study?

Dr. Ilan Melnick: Yeah, so this was really interesting. So one of the things that we wanted to look at were how people discontinued. And what they found was, is that if patients stayed at the 100 milligram dose, that it didn’t improve retention. So those that stay there and don’t move up to the 125 milligram dose ended up usually dropping out due to higher GI issues. So the goal here is to try to figure out how we can manage their symptoms. So again, at 100 milligrams, recognize whether it’s cholinergic versus anticholinergic, and if it’s cholinergic, definitely go up to that next dose so that you can minimize any of those adverse events. One thing also that’s important to keep in mind is that you really don’t want to stay at the 50 unless it’s one of those special populations and where staying at that 50 makes sense. But the vast majority of your patients are gonna be between 100 and the 125 milligram dosings.

Dr. Ben Everett: Yeah. I think the other thing, and you’ve made that point multiple times today, so hopefully people are listening, is let’s go ahead and get up to that higher dose. Is– And, and to me, this is just another one of these things that just kind of makes sense. We have tools, let’s use our tools. But patients who receive medication to manage nausea were less likely to stop treatment.

I think that comes right back to the recommendations from the consensus panel is at start, everybody gets a co-prescription for ondansetron. Like, go ahead and start the medicine and take away the, the potential obstacle that the GI side effects could potentially cause.

Dr. Ilan Melnick: Absolutely.

Dr. Ben Everett: So some really exciting work. Congratulations on these two recent posters. I’m curious, what do you think is next for, for the muscarinics? I know this has become a, a pretty active area of research for a number of different companies, but not just schizophrenia.

People are starting to look in, in other types of, of mental illness, psychosis, et cetera. What are you excited about in the future for muscarinics?

Dr. Ilan Melnick: I can tell you that BMS has definitely got a really strong pipeline when it comes to the world of muscarinics and what they’re going to be doing with this molecule. But AbbVie, Neurocrine, are all in the same process of trying to find the next muscarinic. As I said at the very beginning, I believe in the next five to 10 years, we’re going to be prescribing muscarinic agents as a first-line agent, not as a second-line agent.

Dr. Ben Everett: All right, final question. If a clinician is listening today and hasn’t found a patient to prescribe XT for yet, what would you tell them to be on the lookout for in terms of finding that right patient to try the first time?

Dr. Ilan Melnick: The first thing I’d tell you is that don’t be fearful of the medicine. If you understand the medicine, it becomes a very easy medicine to use, to dose, and to have your patients accept. If you don’t understand the medicine, then it becomes a little bit more complicated where you need to gain your knowledge. My advice for those that have never prescribed, educate yourselves. There’s tons of resources out there, tons of articles that have been written. The reality is that we need to start thinking differently about the world of psychosis, and the muscarinic agents are definitely gonna be there long term. Understanding the mechanism of disease, mechanism of action, and how these medicines work in that space is vital to the success of your patient’s well-being. But for those that have never tried XT, courageous. Go out there, give it a chance. You’ll see some pretty amazing things when you get down to the point of getting your patient smiling, functional, and able to go back into society.

Dr. Ben Everett: Appreciate that. That’s a really strong close. I like the hope that comes with that. So Dr. Melnick, it’s been great connecting again. This has been a terrific combination. We’ve really gone all the way from conceptual in the brain, how this medicine works, the mechanism behind it, the panel approaches, cross-titration, new data that you just presented.

I know this is gonna be a really good episode for our listeners. I really thank you for taking the time to share your perspective with us.

Dr. Ilan Melnick: Thank you so much. Appreciate it.

Dr. Ben Everett: For our listeners, we’ll have relevant disclosures for Dr. Melnick and myself, as well as citations for the research, all the re- sources for the references today in the show notes. With that, this has been the JCP podcast.

Insightful, evidence-based, human-centered.