Clinical pearls of early use of Xanomeline–Trospium in the in-patient setting with Michael Halassa MD, PhD

Journal of Clinical Psychiatry: psychiatrist.com/jcp/

Dr. Halassa’s Substack: michaelhalassa.substack.com

The Halassa Lab: https://halassalab.tufts.edu/

Preliminary real-world predictors of response to muscarinic targeting in psychosis: https://www.nature.com/articles/s44220-025-00529-w

Real-World Implementation of Xanomeline-Trospium in Schizophrenia: A Consensus Panel Report: https://pubmed.ncbi.nlm.nih.gov/41201439/

Ben Everett, PhD, is the Senior Scientific Director for The Journal of Clinical Psychiatry and Psychiatrist.com, where he oversees editorial strategy, content development, and multimedia education initiatives. He 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. Dr. 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 recording for full accuracy.

00:00 – Welcoming Back Dr. Mike Halassa

Ben Everett: Welcome to The JCP Podcast, where we explore the science and stories shaping modern psychiatry. I am your host, Ben Everett, Senior Scientific Director with Physicians Postgraduate Press, publisher of the Journal of Clinical Psychiatry. Today, I am delighted to welcome back Dr. Mike Halassa. He is the first guest to return for a second appearance on the podcast. Dr. Halassa is a psychiatrist and neuroscientist at Tufts University where his work spans from the micro circuitry of cognition to the real-world treatment of severe psychiatric illnesses.

In his last visit, we discussed algorithmic psychiatry, a framework for connecting computational neuroscience with clinical psychiatry. Today we are going to pivot toward the bedside and really focus on his clinical experience treating schizophrenia in the inpatient setting. He has been an early adopter of xanomeline and trospium, which we will just call XT or Cobenfy. He has had some really good success and, in fact, he has written up more than a handful of patients. His first set of patient experiences using XT in the inpatient setting has just been accepted to Nature Mental Health. That will be out in press hopefully before too much longer. So, Dr. Halassa, welcome back.

Dr. Michael Halassa: Thank you. Thank you, Ben. It is great to be here.

Ben Everett: I have seen some parts of the paper and it is really exciting. I cannot wait for it to get out into press and share it with a whole bunch of other people. We will keep the show notes updated so when that comes out, if anybody listens to this later, they will be able to find the link to PubMed where they can go get it.

Dr. Michael Halassa: So, I have a publication date. It is November 6th.

Ben Everett: Oh, so we are talking next Friday.

Dr. Michael Halassa: Yes, it is next Thursday. Next Thursday.

01:46 – ‘Spending a Day in Someone Else’s Brain’

Ben Everett: All right. So, we start with some icebreaker questions, but I had to rethink these because I am not going to ask you the same question twice. My good friend Chad from ChatGPT, we will just call him Chad GPT, I asked him to write me some new icebreaker questions, and I have not even read them myself. So let us see what it has got. If you could spend a day inside any brain, living or historical, whose would you pick and why?

Dr. Michael Halassa: That is a difficult question to nail down because being inside somebody’s brain, using their way of viewing the world or using, well, this becomes philosophical pretty quickly.

Ben Everett: It gets very philosophical very quickly. But you have still got your way of thinking about things. But it is like, all right, how is Albert Einstein thinking about things? Or it could be Carl Jung or it could be Gandhi.

Dr. Michael Halassa: I think about this stuff a lot. I have not thought about this particular question for a while. I would say probably Charles Darwin.

Ben Everett: Nice.

Dr. Michael Halassa: I feel like the amazing thing that he did was put things together that do not look like a theory of something into a theory of something. Why would you look at different fossils and then come up with a story that these have common origin and that they are particular adaptations to their local environments? I mean that is a very difficult thing to think. And I would love to know what was going throughout his brain at that time to come up with that kind of generative process. Because he generated that entire mechanism out of fossils. That is remarkable.

Ben Everett: Absolutely. Evolution. I have spent a good bit of time doing things like evolutionary biology and nutritional biochemistry. I think a lot about this sort of stuff. People look at natural selection like, oh well, it is broken, it does not work. Well, what a lot of people do not understand about Darwin, which you may, is that after he published On the Origin of Species, he was really fascinated with this idea and this theory, but he knew his theory was flawed and he really spent the latter part of his life trying to refine his theory.

But as we have discussed before, I think every scientist, anthropologist, whatever it is, in every generation, we are all confounded by the tools and the scientific resources we have at our disposal. I have always thought that the genetic evidence would really be the key and I think that is proving to be true. So, very interesting.

Psychiatry requires equal parts science and empathy. So what is something outside of medicine that helps you stay grounded on the human side of what you do?

04:21 – Empathy, Parenting, and Staying Grounded in Psychiatry

Dr. Michael Halassa: My kids, absolutely.

Ben Everett: So tell us a little bit about your kids.

Dr. Michael Halassa: I have two kids, an almost 15 year old boy and an 11 year old girl. They are very different from one another. They have different interests, different strengths, and different areas of improvement. I do not know if the question is about how or where do I find empathy sometimes when it is difficult to do it or how do I stay grounded or whatever. But sometimes when in difficult situations, I do think about my kids a lot and they keep me grounded. They are my window into empathy and they are my window to being grounded. They really keep me going in ways that I do not think I would know how to without them.

Ben Everett: That is excellent. I feel the same thing about my children. So do you like music? Do you listen to music when you are writing or in the lab?

Dr. Michael Halassa: I do not. Which is a very bizarre thing. I like music. I do not know. This is a very good question, because I think I have a personality that is very, I do not know what the right term for it is, but I am focused on the thing that I do. If I am driving, I am just driving and thinking about stuff. If I am listening to music, that is just what I am doing. It is hard for me to listen to music in the background. It is just not a thing I do.

Ben Everett: I found that lyrics distract me. So I listen to a lot of jazz and some classical, sometimes really more jazz, but all non vocal. If I am writing or really ideating on something, I need some kind of white noise in the background. Silence just does not work for me. I become uber distracted by every little creak or whatever. And I kind of go back to the classics, like the Blue Note guys, you know, Coltrane, Davis, and Thelonious Monk. Love that stuff. All right, well, thanks for that background and some thoughts into how you think about things and whose mind you might want to spend some time in. All right, so we are going to switch to clinic. So your clinical focus right now is entirely inpatient.

Dr. Michael Halassa: It is.

Ben Everett: Which is different from a lot of people. There are certainly people who do outpatient and inpatient, but a lot of our listeners probably just do outpatient work. Let us start with, what is it about inpatient psychiatry that interests you? I think there are parts of it that are probably more challenging, but there are parts of it that might be more rewarding as well.

06:37 – Why Inpatient Psychiatry Works: Acuity, Speed, and Team-Based Care

Dr. Michael Halassa: I would say the biggest difference between inpatient psychiatry and outpatient psychiatry, well, I guess there are two different things. One is the acuity level. People inpatient are generally more acute. They require more support and more management. You have to do things quickly. I happen to do well in these types of environments. I do not know if it is because I played different types of sports in the past, and therefore I like to do things very quickly on my feet and think about rapid moves.

But inpatient psychiatry allows you, well, it demands that you do better if you can do these things well and you can be calm and contained. I do like the aspect of being able to be in charge of managing the inpatient team. I also enjoy the aspect of being able to talk to the nurses, to the staff, and to other providers. When things look like they are falling apart on the inpatient unit and you have a code or you have some kind of emergency, you know things are going to be fine. We know how to manage things like that. I like to do that.

Ben Everett: I am sure it is a different type of stress, but some people really thrive at it. It sounds like the way you are describing it is almost like a critical care type of setting where I have got a number of friends that are pulmonary critical care trained.

Dr. Michael Halassa: Exactly.

Ben Everett: And they just love it. They are just like, I always enjoyed taking care of really sick patients. It is a different skill set. But I think it is great that you found an area of clinical medicine that really fits your skill set.

Dr. Michael Halassa: I can tell, the days that I am on the unit, people tell me that they find it calming because they feel like things are under control.

Ben Everett: That is really nice.

Dr. Michael Halassa: That is really nice. I do not get that from a lot of aspects of life, so I enjoy that. But you do not always get that, right? In science, for example, it is kind of the opposite. I ask a lot of tough questions and things of that nature, and I think it balances that out.

Ben Everett: Science is certainly mostly failure. You get really good at delayed gratification. And when you have got an experiment that finally works right, you are really excited. But it takes typically a lot of failure before you get to the result that you are really happy about or excited about.

Dr. Michael Halassa: Absolutely. And with inpatient psychiatry, if you are lucky enough to find the right thing for the patient, then you see the results right away. And that is super gratifying.

Ben Everett: And I think there are not a whole lot of areas of medicine where you really have that. I always think, like, anesthesiology is probably one where it is a great interplay of physiology and psychopharmacology. You can push a drug and you can see, okay, somebody has got some tachycardia, I am going to give them this and it can resolve. If their pressure is up, you give this, you can balance with fluid. But a lot of medicine is just outpatient. It is lab based. It is like, okay, your LDL cholesterol is a little high, we are going to put you on a statin and you will come back in three months.

Dr. Michael Halassa: Exactly.

09:31 – Evaluating Acute Psychosis: Intake, Chronicity, and Treatment Decisions

Ben Everett: So you do not really see the changes. But to that end, and I think that is something that is probably unique about inpatient psychiatry as well, is, all right, so you have got a decompensated schizophrenia patient admitted to the unit. Talk us through what that intake looks like and sort of how you go about evaluating a patient.

Dr. Michael Halassa: You know, the patient comes in from some emergency department somewhere, they get referred, they show up on the inpatient unit. It is a locked facility. They usually do the search and make sure that everything is secure. And then if I am there and I am doing the intake myself, I usually do it with the intake nurse. And we are sort of tag teaming, sometimes asking different types of questions with somebody who is acutely decompensated.

Psychosis is not very like, once you have enough experience seeing enough people with that condition, you recognize it right away. Somebody is delayed in responding, they are internally preoccupied, they are looking, well, kind of not there. I mean there is a not plugged in look that people can have when they are having these experiences. And that is obvious in an inpatient setting.

You are just trying to figure out the usual stuff that results in this type of decompensation. The high level thing is, how chronic is this? Have you been in a place like this before? That is kind of like the basic type of determination that you make. Or sometimes you have that information from the ED, sometimes you get it from the patient, sometimes from the family if you have spoken to the family already.

But at the end of the day you are trying to make the determination of is this a new onset thing, is this a first episode, for example, that has its own type of workup. But by and large most of the people that we see have some degree of chronicity. A lot of the times it is non compliance, some substance related decompensation, or both. And a lot of it is just sorting those through different determinations, either putting them back on the medication that they were on that they had lapsed, figuring out a way to transition them to a long acting injectable, or trying to figure out if they need a different type of medication because of side effects, efficacy, or both.

Ben Everett: That is very helpful for me because I have never done that. So in terms of, let us go with the more frequent, which is your patients that have some chronicity. They might even have a patient history or chart in your facility, might be known to you or some of the staff. They are in. So, you know, okay, this is a person who, all right, so substance use is an issue with this person. And they are probably off their meds trying to figure that out.

At what point do you think, okay, we tried the long acting injectable, they just lapsed on their last appointment or whatever it is, maybe we need to try something new? We have got this new drug. It is the first novel mechanism. It is really novel. We have gone from typical to atypical. We have got the partial agonist versus the full antagonist, but this is really the first thing that is completely different in like 70 years for psychiatry.

12:46 – Discovering XT as the First Novel Schizophrenia Mechanism in Decades

So talk us through. I mean, you have been following this in the literature. Had you been following through clinical development and whatnot?

Dr. Michael Halassa: Yeah.

Ben Everett: Were you excited to try it?

Dr. Michael Halassa: Well, I do not know if I told you the story, but I was at Steve Brannan’s talk. He was giving a talk at some pharma meeting. I do not know why they invited me to that meeting, because I am a basic scientist. Up until that point, I had done clinical work, but all of my research was animal research at that point. Then I got invited by these folks, the Hanson Wade Group. They run a lot of pharma related conferences and they are like, would you like to come and give a talk about animal models that would be relevant to psychiatric illnesses? Sure, yeah, why not?

So I go and actually end up organizing one of their symposia, which was a great experience. And then as part of that meeting, there was Steve Brannan giving his talk. So he is talking about the Emergent trials and showing all of that data. And I had been familiar with XT from just doing my CMEs, which is a good way to learn about new stuff too. So I had been following it a little bit, but then I saw the data. I was like, whoa, this looks pretty amazing. Like, if this is true, this is potentially a really big deal.

I walk up to Steve after his talk and this was like, September 23rd or something like that, 2024. He was basically saying, the FDA has got a rule on this tomorrow. And I am like, okay, so what do you think? And he goes, I am not sure. We are hopeful, but I am not 100 percent sure. And then the next day, it is all over the news. FDA approves Cobenfy , blah, blah, blah.

And I am like, whoa, I just talked to the guy who did all of these, who is the PI on all these grants. And I am at the facility the next day, and I have a pharmacist, Andrew. He is great. He is like the best pharmacist ever. I tell him, Andrew, have you heard of this thing before? I forwarded it to him. And he is like, no, but I know the BMS sales reps. I said, okay, can you call them and see if they would be willing to give us samples? I would like to try this thing.

So he says, yeah, sure, we will do that. So he calls the sales rep, this guy Mark Silva, who is also really great, and Mark shows up to the facility. We meet with him and he is like, it is really cool that you want to try this. I am like, yeah, can you give us samples? He is like, sure. So he gives us like two suitcases worth of stuff. And I am like, this is awesome. It is great to have that. I do not know if it was two suitcases. I am embellishing a little bit, but it is a nice story.

He gave us enough to get started. So then the question becomes, well, who do we give it to? You cannot just give it to anybody. There has got to be some rationale for this. So I am like, all right, now I did not answer that question. So I am going to go back to your original question of why do I like inpatient psychiatry? Well, there is a component of inpatient psychiatry that is similar to a lab. But now you have to make decisions that balance kind of a scientific question with ethics.

These are people. If these were your family, what would you give your brother, your sister or your cousin or your mother or whatever? What are the trade offs that you would consider in a situation like this? The very first thing that I thought about is, we should probably try this when everything has failed, because what else are you going to do?

16:19 – A Remarkable XT Case Study

So I had a patient. This was a story that was just so remarkable. I had a patient who I admitted the first time in the, so we are in 2024, right? This is like, right at a year ago, this patient. I admitted her in the summer of 2020 to this short term inpatient facility. So she comes in, such a wonderful person, was just in a psychotic state, some maybe stimulant use. But I would say over the course of the summer of 2020, we stabilized her on olanzapine. She did great. Her hospital stay was probably like two months or so.

If you would talk to her at that point, you would think that she is completely fine, she can go out in the community and potentially maybe even get a job. She looked very, very good by the time that she left. She comes back in the summer of 2021, similar presentation. I am like, do you remember me? And she was not very clear at that point. She looked a lot more acute than what she was in 2020.

And I am like, all right, well, olanzapine worked. She probably was not compliant. That is fine. We will try her back, stabilize her, and then figure out what would be a stable regimen other than olanzapine. Olanzapine, I think she was discharged on like a relatively low dose, like a five milligram twice a day. It is not low, but it is half the max dose of what people go up to. So I thought, that is probably going to work out. It did not work.

She was still very, very acute and had a lot of psychotic episodes, self dialogue. So we titrated up to a maximum dose. It did not work. She was very, very psychotic. I am like, all right, well, something has changed. She is not responsive to the same medication. So you do the things that we know how to do, which is you switch to another antipsychotic, you cross titrate to some other drug. Olanzapine is not a very strong D2 blocker. You try the D2 blockers and it was not working. And weeks go by while you’re trying these different approaches.

Nothing was working. So we ultimately decided, all right, what is clozapine? What else are you going to do? This is 2021, right? We are doing all of this and clozapine and we are going up on clozapine. And all throughout there is new aggression and she is beating people up. At some point, she assaulted me. We did all of the things that you would do. Is this something new? Should we get brain imaging? We got brain imaging. We did all kinds of neurological investigations. I sent all the neuroinflammatory blood markers, everything that you can think of.

I was like, this is not what I saw a year ago. Maybe there is something else going on. Ruled all of these things out. Nothing that we can see with what we know how to measure was showing up. So this is now 2021 to 2024 on an acute inpatient unit. And the disposition has been, well, she is going to go to the state hospital because she is not sick. Oh, there was one time she was court committed at some point because she was found incompetent to make decisions.

We ended up putting her on the wait list for a state hospital because this was not appropriate for a short term inpatient stay anymore. And this is kind of the tragedy of our health system right now. Massachusetts is one of the most progressive states for mental health care. I would say she was on the wait list for three years. And we were calling the Department of Mental Health every week to try to figure out where she is. And at the end we realized she is really never close to being transferred.

With all of that said, we get Cobenfy. I have this situation with this patient who I have known her now for a long time. These people that you end up seeing in repeated admissions, they become like familiar people, you really, absolutely care about them. My wife was asking me, why are you interested in this clinical work so much and what kind of drives you and motivates you to do it?

Honestly, there was this scientific part of it, but there is also this part in which I cannot believe that people with psychotic experiences have this level of, I do not know what the right word is, the level of purity that they can share this stuff with you and tell you about how they are actually thinking. And on average, I find I just like these people. There is something really good about that manifestation of the human condition and people who do not hold back.

Like, I am hearing things, I am seeing things, I believe somebody is controlling my thoughts or people can read my thoughts. And I am just telling you, a complete stranger, about that in hope that you would be able to help me.

Ben Everett: Complete vulnerability.

Dr. Michael Halassa: It is unbelievable. Complete vulnerability. And you are in a position where you know something about how to manage these conditions and you are able to help, but somebody can trust you enough to do it. I find this unbelievable. This is such a privilege, but I do not take it for granted. I really like my patients.

Back to this particular patient with clozapine, we are up to 800 milligrams of clozapine. That is a whopping dose this poor lady has. When I first met her, she was young and a very charming person. She clearly cared about her figure, she cared about how she looks. And after three years of being on all these medications, this is really tragic. She has gained all this weight, and it cannot be easy. It cannot be easy.

So I am like, I have got to do something about this. There is this new thing, XT, that, I mean, if this was my sister, I would want to do that. That is patient zero, I would say. I can tell you, Ben. We went from her being on the state hospital list to sending her to a group home on XT. It was a remarkable thing. She stopped being aggressive. She became a lot more social. She was joking with me. She was not completely normal or free of psychosis, but she was redirectable enough to exist in a group home setting rather than requiring a continued locked facility.

Just an amazing thing. I was at a BMS thing the other day, and there was a completely different hospital that was sharing their experience. They said something very similar. Got a patient on clozapine. We put them on Cobenfy because there was nothing else to do. And this was two weeks ago, and I am like, that is my story. What are you doing stealing my story? I thought it was pretty cool.

23:26 – XT Dosing Tolerability and Early Clinical Results

Ben Everett: That is a great story. So when you started this first patient on Cobenfy, did you just follow essentially what they did in the EMERGENT trials, where you did the initiation dose of 50 over 20 for like three or four days? Or do you go up pretty quickly?

Dr. Michael Halassa: In the beginning it was three or four days, then 100, then 125. And she tolerated it very well. She had very few side effects. She did not have any side effects, to be honest.

Ben Everett: All right. So a couple of things I want to come back to. You have mentioned one of the things that you like about being in the unit is the multidisciplinary nature. You are doing intakes with your nurse. So it seems like you have a lot of trust and faith in your healthcare team. And then you mentioned Andrew. I want to make sure we give Andrew a shout out, PharmD extraordinaire.

Dr. Michael Halassa: He is awesome. There are so many people I want to give shouts out to. Nicole, she is the NP on the unit. She is definitely a nurse practitioner extraordinaire. Sherry, the unit manager, she is great. All of the social workers, Dion, Cindy, and Ashley are fantastic. I could go on and on.

Ben Everett: It is a great team and it is very important in schizophrenia. I have written about it, I have read a lot about it. But it is an area of medicine where it seems that having that coordinated care where you have to involve a lot more people is key. You can treat hypertension without involving social work. It is very difficult to do these things without involving the entire healthcare team and having a commitment and that continuity of care. To help get someone into a state hospital or into a group home, you have got to have people that know the context and know the resources. Social workers are just amazing, wonderful people for the work that they do. So, great first example with XT. Where did you go from there with using XT in the unit? Now you have had this one really good experience with a very sick, intractable patient that you have just really been struggling with what to do with. What happens after that? You have a good experience. It is always good to have a win the first time you try a new agent.

Dr. Michael Halassa: There is a subset of patients where you feel like they are treatment resistant in some way. There are some patients that cannot go on clozapine for various reasons. They do not want to, or they do not want to do blood draws. That was back when we had to do REMS. Now it is not that big of a deal because the REMS is gone. But we still need to monitor and some people do not like to have frequent blood draws.

Ben Everett: It is not a benign drug. It has got some baggage that comes with it, and that is why it is considered a last resort. It certainly seems effective for a lot of patients. But it is not just like, okay, we have got to worry about some metabolic issues or maybe some TD or something down the road. It has got some other baggage that comes with it.

Dr. Michael Halassa: Oh, you just reminded me there is Steve Brannan and there is also Steve Paul who was involved in these trials. I saw him at another meeting and we were talking about this and he said, hey Mike, have you ever taken risperidone or olanzapine? I said no. He said, I have. They make you feel like shit. It is a miracle that patients take those types of things every day. They can make you feel awful.

Ben Everett: That is certainly what we hear from the bipolar disorder patients. My sister has bipolar disorder. She trends manic and like a lot of those patients that live sort of hypomanic, they do not like the medication because it does not make them feel like themselves. But there is also just this feeling of, yeah, I just feel awful. Just don’t. And that people are willing to do that to try and help deal with their hallucinations or negative symptoms or whatever else they are dealing with is a testament to people wanting to feel closer to, and I will put it in air quotes, normal, whatever normal means, but certainly not wanting to feel like they are feeling when their symptoms are full blown.

Dr. Michael Halassa: Oh, yeah, absolutely. So it is a trade off. If you feel a little bit terrible but you are not hearing voices, that is an appropriate trade off for some people. For some people, they just do not want to feel like that at all. They would rather hear voices or be dysfunctional or whatever it is. That is another type of patient that I felt like, all right, if you are really not going to take anything, then why don’t we go with this new drug that should help and it has none of those other side effects?

That ended up being like the gateway approach. You give them a little bit of Cobenfy , they kind of are okay. They feel a lot better. All right, how about a little bit of risperidone? Or how about a little bit of Abilify? Or how about a little bit of olanzapine? Because I think we can get you there faster. Whatever. I should say, is it possible to put people on monotherapy of Cobenfy ? I am sure it is.

I actually have done this with a couple patients, but because we have a short, relatively short stay, we are really supposed to stabilize and send people out within two to four weeks. Taking down the positive symptoms as fast as possible is important. I think that D2 blockers like risperidone and olanzapine can do that fast. But I think where Cobenfy works in that setting is that it is definitely dose sparing. You can get away with a lot less typical or traditional antipsychotic than you would without it. And then maybe ultimately they would transition off of it completely and be on monotherapy on an outpatient basis. That is certainly possible.

Ben Everett: But even if they are on a lower dose of an atypical on top of XT for the duration, I would think, and this is completely hypothetical, we won’t know until we have had this medicine out for decades, you could potentially see a benefit. If you are on an antipsychotic long enough, you are going to develop something. Every class kind of has its own issues. These are associated with metabolic problems, weight gain, glucose, or whatever it is, or TD and movement.

So there are things we have to worry about. And hey, look, if this allows people to take lower doses of their D2 blockers long term, hopefully we can at least push some of these other untoward side effects further down into the future. Again, that is more hypothesis generating. We will have to see. But I think that is certainly a treatment option that I would be more comfortable with. I think that is one of the really good things about having a new class of medicine. Right now it is just one agent. There are a bunch of M1, M4 candidates, mostly people looking to M1 or M4. There are some other combos that are in development. So hopefully in another handful of years we will have multiple options available.

Dr. Michael Halassa: There are like five companies. There is MapLight, there is Neurocrine, there is Neumora just got into a phase one-

30:15 – From Observation to Evidence: Identifying XT Response Patterns

Ben Everett: There are several. All right. So let us transition to the paper. You have got, at this point, you are a year in, you might have a hundred total patients, but you started with about 50 patients worth of data. You collected all the data and you are like, all right, I am going to write this up and get it submitted somewhere. So just tell me about your process for thinking. It is not prospective, but early on in drug development, I think the more real world experience data that we get published, the more it can help people inform their own treatment decisions and how they are treating patients in the clinic. So just tell me about your process for pulling this data together. What were you looking to accomplish?

Dr. Michael Halassa: I am a scientist, so it is natural for me to want to make observations and then come up with, as we started off with Darwin, the generative process behind these observations. What is going on in the brain that would ultimately manifest itself in the way that we are observing? So the first thing is making the right observation, making sure that you are seeing something that is reproducible.

I remember patient two or three, again, a clozapine woman. She was this lady who came from a group home with aggression on clozapine. The nicest lady in the world, but gets these experiences and becomes aggressive. The group home sends her to inpatient psych to be evaluated. Medication adjustment, sent back. So this was another case. She is on a high dose of clozapine. What, are we going to keep increasing the clozapine? I do not want to do that. Let us try something else. Let us try Cobenfy.

I give her Cobenfy. And I remember I went into the club room. I looked at her. She raised her head and looked at me and she had this smile on her face. I do not know how to describe it. What is so obvious is that you can see a glow around the eyes. You look at the forehead and the eyes and they look different. I saw her when she came. I did the intake. I have a sense of what she looked like then. And then I look at her in the club room. She is looking at me. She is smiling.

There is something different about that look. It looks like there was a light bulb that turned on. It lit up her eyes and lit up her forehead. That is kind of how I saw it. That is different. I have not seen that. And that is not a placebo effect. That is not how placebo works because people are taking all kinds of other medications. I have never seen that. In systems neuroscience, you are also sometimes data limited and you get some measurement or something about the brain and you have to then figure out if this is true. Can we see it again? Can we see it under other measurements, in other patients, or whatever?

So I made note of that. I did not think this was worth writing up or anything, but I thought it was okay. And then I started seeing it in other people. The same kind of thing. You look at them and they are back from whatever state they were in. They are plugged in. They are plugged in in a way that I have not seen before. Then the thing that struck me is that, is this related to what we would think of as negative symptoms? Are people now kind of more socially connected in a way that is revealing to us that what we had seen before is not really who the person is? Is that person plus negative symptoms?

That is the hypothesis. So then I am like, all right, are other people in the staff seeing those things? And I started asking. You do not want to bias them in any way. So you basically say, all right, what do you think of X? Well, yeah, X is out of their room more. They are definitely talking more. They seem more social. So when people start saying stuff like that, I am like, all right, it is not just me. I am not just making that stuff up. Other people are seeing it.

And then Nicole started seeing this too. We were talking about this offline and discussing it and she is saying, Dr. Halassa, is it possible that patients have some degree of negative symptoms we just do not know them well enough and on XT they are just more themselves? I think that is a very reasonable thing. And then over time, she and I built this intuition for patients we think would benefit from XT.

35:12 – Testing Negative Symptoms in Real Time on the Inpatient Unit

But before we started formally doing that, let me tell you another anecdote where she and I were evaluating a patient who had these classical negative symptoms where they are just in bed and they do not initiate conversation. You can go into their room, you can sit down next to their bed, and they will not engage with you. It is as if you are part of the furniture. People with profound negative symptoms are like that.

I remember the first time it was Nicole’s patient. So I went with her into the room and Nicole wanted to engage the patient, say hi or whatever. I just basically signaled to her not to say anything. She and I sat in the corner for a little bit and she was looking at me like, you are not going to say anything? I said no, this is actually part of the clinical exam. You will see what negative symptoms are. And for five minutes, the patient would not say anything.

And then we engaged him. Super nice guy, would like to answer questions, do all of that stuff. And then we asked a few simple things, like, generate a list of 10 words that start with P. And he would go, pizza, pepperoni, pizza, that kind of stuff. So you are like, all right, there is definitely some profound kind of phenotype here that, we did not do any PANSS or anything, but that is kind of what we would consider poverty of thought. That is all consistent with negative symptoms.

So we said, all right, this patient is medicated well with traditionals, there is no obvious self dialoguing, there is not a ton of positive symptoms that we can see. Why don’t we try XT and see what happens? Two doses. After two doses we walk into the room and we just do the same thing that we did the day before. He perks up and he basically says, how can I help you? I looked at Nicole and she was flabbergasted. I mean she was like, this is unbelievable.

Ben Everett: The first time we talked, I was asking you just how do you evaluate for negative symptoms? And you were like, oh I have got a great test. And it was just this. You say you just walk into a room, you do not interact with the patients, you just sit down, and you see if they treat you like furniture.

Dr. Michael Halassa: Yeah, exactly.

Ben Everett: And you told me, I think it was this same patient. You were like, yeah, two doses and you walk in and the guy starts an interaction. It is profound.

Dr. Michael Halassa: And then I would say he generated a list of 6 or 7 words right away. There were no repeats. So this cannot be placebo. This is a real phenomenon. So then at that point I realized, okay, before we really go for modifying our approach and prescribing this when we see a degree of negative symptoms or social isolation, let me just take a look at the medical records.

So I went ahead and looked at all the patients that had been on Cobenfy. Some of them I knew, some of them I did not. So I reviewed the medical record, the notes of the provider, notes of the social workers, the nursing staff, and the staff on the floor. And then I got a sense of whether there were multiple notes indicating improvement. A lot of times they would all say something like, the patient is more visible on the unit, interacting with peers, or reduced psychotic symptoms.

Any of these things would be considered a response. The lack of that, or if the patient is getting worse, is a non response. And when the notes disagree with one another, it is an equivocal kind of case. And I used that and then went back to the history, the mental status exam, all the pertinent things about the patient and figured out if there are predictive features.

Is there something about the features of the patient that correlates with the outcome? There were some features that were common enough across patients that we would be able to do these types of analyses. And those included things like the presence or absence of aggression, negative symptoms, stimulant use, bipolar symptoms, or intellectual delay.

There were enough common features that we were able to take these features and ask through quantitative methods whether those features are predictive of a response. And at the end, in this first set of patients, negative symptoms were hugely predictive. Unsurprisingly, past stimulant use like Adderall or methamphetamine, this was not anything that I would have predicted, but it just came out of the analysis that it was predictive of a response.

And then we said, all right, practically speaking, I think there is a reasonable approach for our next cohort of patients. Whenever we see negative symptoms we will prescribe Cobenfy if there are no side effects or other things that are prohibitive. And we did that and our response rate actually went up. It was very obvious. And then we did a replication of that and that is where we are.

40:33 – XT vs D2 Blockers for Positive and Negative Symptom Control

Ben Everett: We talked a lot about negative symptoms. Obviously, it is great that you are having this impact on negative symptoms because that has been one of the struggles in schizophrenia. Positive symptoms have been a little bit easier to try and get to, but negative symptoms and cognitive impairment have remained largely intractable with things that we have had available in the armamentarium. How are you finding it works on positive symptoms as well as you would like? Not as well as a D2 blocker or good enough? What is your assessment for the ability to control positive symptoms with Cobenfy?

Dr. Michael Halassa: It is definitely effective in the inpatient setting. I think that the level of acuity for positive symptoms is very high on the inpatient unit. Usually higher than what was in from the Emergent trials. I understand that the Emergent trials were inpatient, but the patients themselves were more of an outpatient type of patient.

Ben Everett: You wean them off, they have to have had an inpatient stay within like the past three months or something like that. So they are maybe still vulnerable, but they are on medication now. They are stable enough to where the individual investigator thinks that they could wean off of what they were on to go inpatient into this placebo controlled study. So I get your point. Yes, they have a recent history of a hospital stay, but it is not like what you’re dealing with as an inpatient psychiatrist.

Dr. Michael Halassa: Some of our patients cannot be weaned off medications for two weeks. They are going to be breaking stuff. That is the difference. I think at that level, XT alone may not be the right choice for those patients. But I do think that when patients do not want to be on a high dose of a high efficacy antipsychotic like risperidone or olanzapine, you can supplement it. You can have a dose sparing effect with Cobenfy and it works much, much better even in situations like that.

Ben Everett: And then I know that there was one phenotype that emerged as a negative predictor and that was intellectual disability. Tell us about that finding.

Dr. Michael Halassa: I do not know that this is something that I would hang my hat on. The total number of patients is five in the group that I have seen. I would take it with a huge grain of salt. That definitely needs to be expanded and replicated. The psychosis that is associated with intellectual delay and neurodevelopmental disorders like autism may just be different than the type of psychotic experiences that people have due to other causes. It is possible that XT just does not work in some of these settings. It is possible that I am just wrong and it is a small sample size and you never know. That is part of the reason why this is a preliminary study. I thought it was still worth communicating because there are other things that I am a lot more confident about, like the negative symptoms. I am very confident about that.

Ben Everett: I felt like it was important to bring it up just because it was something that you found. I do not want anybody to think that we are just cherry picking the negative symptoms amazing type of stuff.

Dr. Michael Halassa: Yeah, fair enough.

Ben Everett: So side effects. We know the pro-cholinergic peripheral effects seem to be the most common thing. So how are you finding managing nausea and vomiting? And are you seeing anticholinergic side effects? Is it maybe too much muscarinic sometimes?

Dr. Michael Halassa: Yes, sometimes. The biggest issue with the medication can be anticholinergic side effects. Like men with prostate problems, for example, and urinary retention. I have definitely seen that is a problem. Elevated heart rate and tachycardia, I have seen it in one or two. There is definitely elevated heart rate, but a lot of times people do not feel it. Hypersalivation, diarrhea, or constipation, it is luck of the draw, basically.

Ben Everett: Again, inpatient is different from outpatient. For anybody considering this for outpatient, a good bowel regimen can be very helpful. Think about the fact you could end up on one side of this or the other. So just hydrate and mind your fiber intake. Back to the nausea and vomiting. I just want to make sure we hit on this because it is the most common thing that people are concerned about. It is the most common thing that came out of the clinical trials.

Dr. Michael Halassa: It can be a problem. Some people cannot tolerate XT because of nausea and vomiting. What we try to do with most people is give them Zofran. Prophylactic Zofran. I do not do it with every person, but we try it once. If they develop nausea and vomiting, then we give them Zofran 30 minutes before their XT dose and then usually it is self resolving. Once they get used to it, you do not need Zofran anymore. But it can be a problem.

Ben Everett: BMS has put out some additional studies looking at this now and it seems to be kind of this initial two to four week acclimation period when you are going from the starting dose up to 100. But the majority of patients are able to get through that and then they seem to be self limited and self resolving by the time they get to week six to eight. So yeah, if you can do some prophylactic Zofran and set your patient up for success. That is what we want to do. We do not want your patient to call back and be like, what is this medicine you gave me? I cannot function when I feel like this.

Dr. Michael Halassa: I think letting patients know about this beforehand is extremely important. People do not want to be blindsided and they appreciate it. The last thing that one wants to do is not tell them that the nausea and vomiting is a side effect.

Ben Everett: I absolutely agree with that. Let us be straightforward and it is all part of our informed consent. Hey, this is what might happen with this medicine. It does not happen to everybody. We have ways to manage this. I wanted to come back to M1 and M4 for any of our listeners that might not be as well read with all these different systems as you are. What is it about M1 and M4? Can you talk through how we think this is maybe a little bit better for psychosis and this is a bit better for negative symptoms?

Dr. Michael Halassa: In terms of expression, M1 is expressed in the cortex and a lot of it is in the frontal cortex. That is the part of the brain that is involved in executive function like working memory, task switching, and attention. M4 is subcortical, specifically the thalamus and basal ganglia have a lot of M4. So that is kind of the division of expression profiles. M4 is mostly brain expressed while M1 is expressed in the periphery.

I think a lot of the companies that have developed muscarinics have opted to go for M4 specific pharmacology. One of them is emraclidine from AbbVie. That did not work out very well. There were a lot of issues with that particular clinical trial where placebo effects were super high. We do not know if that was run very well. There were questions about how well run those trials were and if Brannan and Steve Paul and those people had run it, maybe it would have been successful.

Although I do think that the possibility that you do need M1 and M4 is out there at this point. Maybe you do need both. Given the receptor expression profile, is it possible that you need kind of direct prefrontal pharmacological engagement? Maybe. I do not know. The thing is that in the striatum and the thalamus, you are like one synapse away from the frontal cortex. So I do not know what the big deal is about M1. It is possible that there is something very particular about how the combination of M1 and M4 works. But we probably need a little bit more basic science to understand what kind of circuit and behavioral engagement this combination buys you over M4 alone.

Ben Everett: It makes for a fun discussion for a self described nerd such as myself. I think a lot of times we end up with new drugs and in how many drugs in the package insert it says the mechanism of action of X drug is not completely understood? It still ends up on the market. It helps patients in some way or another. And then years and years later, we kind of figure out exactly what they are doing. Statins we did not understand completely for a long time. Aspirin we did not understand for a long time.

This is how clinical medicine comes along. And then sometimes it is translating backwards to the lab to help inform what we are seeing. I think it is an exciting time to be doing research in schizophrenia after decades of not a whole lot of movement other than a few atypicals and partials. It has been pretty much different ways to skin the same cat of D2 blockade. And this is an entirely different thing, at least in your experience and I know in some others, seeing some profound changes with negative symptoms. I think you guys have a really good new tool to offer patients. Anything that offers somebody a chance, if nothing else, is where we want to be. When you are at a place where clozapine is not working, it is not a good place to be as a patient or the person trying to care for that patient. And we are going to have more and more of these choices here in the next few years. I think that is a good place to be with schizophrenia.

Anything else, parting words of wisdom or anything else that we did not talk through with Cobenfy inpatient?

50:28 – Redefining Success in Schizophrenia Through Functional Recovery

Dr. Michael Halassa: I will just maybe leave you with one thing. A lot of times people kind of wonder what I am so excited about when it comes to Cobenfy. It is just another drug. We have had a bunch of other things, Latuda and some other things. And I am just going to say Cobenfy is not Latuda. It is a different class of medication. Why am I excited about a different class of medication? Many reasons. One is that we want to help people and some people respond to it and do not want to take traditional antipsychotics, which is great. I think that is really, really important. Latuda is not going to work for somebody who is not responding to risperidone or olanzapine.

It is kind of a good medication in other ways, specifically weight loss and the metabolic side effects, but it is not a fundamentally different way of engaging the system. XT is a fundamentally different way of engaging the system. It is not acting in dopamine directly and has a different mechanism of action. But I think what is really important about all of this is that now we went from a single dial, how much D2 can we block, to a very different type of dial. Now we can actually engage a different system, the muscarinic system. If we think that negative symptoms have to do with frontal control of social behavior or emotional expression, then we are engaging that system in a way that the D2 blockers cannot. So that is great.

What I think these drugs, and I am involved in more preclinical and phase one collaborations that involve drugs with completely different mechanisms of action that work on the GABAergic system with a company called Ovid, for example. The way I see it is we have this umbrella term of schizophrenia and we are really just calling probably a number of different entities schizophrenia. Our measurements are not particularly precise because we are just talking to people and we do not have other ways to kind of characterize their behavior and the brain correlates of that. If we did, we probably would have other things instead of schizophrenia. We just do not have names for them right now. And my guess is that those things probably respond to different modalities of treatments.

People can ask at some point, okay, you want to divide up schizophrenia into five different things that you want to call based on brain behavior relationships, what is that going to do? If you have five or six different types of medications that you can nudge the system with, that is one, a way to validate these entities, and two, is to really do precision medicine for psychosis.

Ben Everett: Absolutely. And I think the other thing is just the more we can phenotype or have any kind of biomarkers to help guide decision making when it comes to pharmacotherapy. It is like both my kids have ADHD, with very different presentations. I just know going through when we started my daughter on medication without any kind of guidance other than clinical experience, and we trust our pediatrician explicitly, it was just painful. We tried stimulants with her first, and she literally just turned into a zombie. But it is like three months before you decide you need to change classes or try a different one.

Three months is a long time. And so if you are dealing with a decompensated patient with schizophrenia, three months is a very long time. I think anything that we can do to get closer to precision medicine or a better informed guess as to where to start is more patient friendly. This is definitely better for the patient.

Let me just close up with, is there one thing that you hope clinicians take away from your paper? If you had one way of summarizing your experience or one thing that you are really excited about that this offers, what would that one thing be?

54:15 – The Future of Precision Psychiatry and Treating the Whole Person

Dr. Michael Halassa: This experience in general, seeing that you can get people to engage more, has made me really think through what psychiatry is or what it can aspire to be. We can certainly think of ourselves as people who can reduce psychotic symptoms. I do not like to think about myself that way. I like to think about myself as somebody who society trusts with our most vulnerable, that we can not only reduce their suffering, but also give them a life that would be full and fulfilling.

If we are able to not only reduce psychotic symptoms or positive symptoms, but also get people well enough to go back into the job market to be full functioning adults, I think that is what we should be aspiring to do. And I think that it is so easy for psychiatrists, including myself, to forget that we become part of this big machine that has lost its compass or lost the philosophy why it exists in the first place. Sure, part of it is if some of the people are not medicated, they may be dangerous or they may hurt themselves or they may hurt other people. I think that is a low bar though.

Ben Everett: I think the idea of functional recovery is very important. And I mean just look at the data. The data are very clear. It is not the positive symptoms that delay functional recovery for most patients. There are plenty of patients that really function without pharmacotherapy, but just with some CBT, some psychosis related CBT, they get to where they understand the voices and they live with them just fine. But it is the negative symptoms and the cognitive impairment that drive the functional impairment.

That is what keeps people in bed. It keeps them not engaged with society, with their peers and all these different things. I love your philosophy on psychiatry and the type of psychiatrist that you strive to be. That is why I like spending time with you, Mike. So this has been fun again.

Dr. Michael Halassa: Thanks man.

Ben Everett: Thanks for another fascinating discussion. Dr. Halassa, congratulations on your Nature Mental Health paper.

56:42 – Up Next: Dr. Avi Bhar

I do want to set up our teaser for the next episode. I hope everybody joins us. We are going to shift away from psychosis. I will be joined by Dr. Avi Bhar. He is a longtime friend I have known since his pulmonary critical care fellowship. Avi is a triple board certified physician in pulmonary medicine, critical care, and sleep medicine.

He brings a remarkable mix of clinical expertise, innovation, and leadership to the table. He is the founding physician of Virtual Sleep and Pulmonary Telemedicine platform. He spent years practicing in high acuity ICU and pulmonary settings across Georgia and South Carolina. Along the way he picked up an MBA from the University of Chicago Booth School of Business. He has led multiple hospital committees focused on safety and quality. He has also served in national leadership roles with the American College of Chest Physicians.

It is going to be a great conversation. We are really going to talk about sleep and how disordered sleep can be a magnifier for so many other psychiatric as well as general health related morbidities. I hope you join in for that. You are not going to want to miss it. This has been the JCP Podcast. Thanks for joining us. As always, we strive to be insightful, evidence based and human centered.

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