Transcript:
Christoph Correll, MD: Hello, welcome to a roundtable discussion on “Muscarinic Pathways in Schizophrenia: Unlocking New Therapeutic Targets.”
Isn't that something we've all been waiting for for a long time? My name is Christoph Correll. I'm professor of Psychiatry and Molecular Medicine at the Zucker School of Medicine at Hofstra/Northwell in New York, and I'm also a professor and chair of the department of Child and Adolescent Psychiatry at the Charité University in Berlin, Germany.
I'm really happy to be the moderator of this very exciting program. I'm also happy to be joined by 2 friends and colleagues who are really at the top of the clinical and research knowledge and will enrich our discussion greatly. Do you want to start, Les?
Leslie Citrome, MD, MPH: Sure. My name is Leslie Citrome. I'm a psychiatrist, and I'm a clinical professor in the Department of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York.
CC: Peter.
Peter Weiden, MD: I'm Peter Weiden, and I'm a clinical professor at SUNY Stony Brook, Stony Brook, New York, where I went to medical school, and also a principal investigator at Richmond Behavioral Associates, which is a clinical trials site, looking at other new medications for schizophrenia and other disorders.
I also had the privilege and honor of working for the company Karuna that developed a muscarinic. Not now, I'm not affiliated with that now, but I was affiliated with the development of one of these muscarinic agents.
CC: Yeah, and that will come in very handy and also maybe getting into the meats and wheats of what needs to be done in order to enrich our treatment. But let's start at the beginning. Whenever we talk about schizophrenia or think about it, I think the first thing if we surveyed like 200 psychiatrists or clinicians, maybe even patients and family members, would be the word “dopamine.”
We've tied schizophrenia to dopamine very closely, and that has to do obviously with the serendipitous discovery of chlorpromazine because that works not only as a major tranquilizer, but it also works for psychosis when people actually ask patients and didn't only feel relief that they weren't so agitated anymore.
Then basically, there was reverse engineering looking at “How does this medication work?” and it seems that postsynaptic dopamine blockade was the name of the game. So today, we'll be starting to discuss that, also the limitations of dopamine and the hypothesis and coming up with a, what I would still say is a revolution, because we've had the first agent approved on 26th of September 2024—the drug that Peter, you worked on and that is xanomeline-trospium.
We'll discuss what that is and what it fits into in terms of a class, then talk about challenges and future treatments. So, this will be a very well-rounded and exciting program, and I'm really eager to hear also what you all have to say.
So, let's go back to dopamine, and maybe I'll start again with you, Les. What comes to mind when you link dopamine and schizophrenia?
LC: So, what comes to mind is for the past 70 years, our treatments for schizophrenia have consisted of dopamine receptor blocking agents. They all essentially work, at least part of the time, in terms of blocking postsynaptic D2 receptors in the part of the striatum that explains hallucinations and delusions.
Now, some of our antipsychotics also do other things as well with other receptors, but principally, the control of psychotic symptoms is thanks to dopamine D2 blockade. To my mind, that's a huge limitation because when we block dopamine D2 receptors where we want to, we also block it where we don't want to, such as in the motor striatum, and thus, we see drug-induced Parkinsonism and ultimately TD, tardive dyskinesia, with some of our patients.
We can also encounter dopamine blockade in the tuberoinfundibular pathway and encounter elevations in prolactin, and it's unavoidable when you block D2 receptors 'cause there's that collateral damage that's there when we use our traditional agents.
CC: Peter, dopamine, yes, we have too much in some area, but it grows further.
PW: You know, a theory is as good as it works and as bad as it doesn't work, so I view the dopamine hypothesis in its various forms as a blessing and a curse. It is a blessing that we have and had effective treatments for schizophrenia, and they have gotten better. The linchpin of that has been developing drugs based on, at least to some extent, blocking dopamine.
The curse has been the same thing, that we have all the toxicities related to messing with the dopamine receptor, as well as if you only have one mechanism in any chronic disease, it sort of is logical to think that you're limited. Then other diseases, you have other mechanisms, and that has really improved outcomes in other diseases.
Now, I would like to say one thing about what the dopamine hypothesis has done to us. We are all, I'll speak for myself, we've all spent our careers in schizophrenia. It sort of brainwashed me. So, I ignored anything in my teaching or in my reading that showed that anything besides dopamine worked.
I had a huge bias that way, and it affected my thinking, kind of a brainwashing of that's, you know, linking the illness with the side effects and the medications. I think that is actually as big a problem as anything else with the medications. It's really, I think, limited our collective thinking as clinicians.
LC: You know, Peter, we've all been brainwashed with the idea that the only way to combat psychosis is by blocking D2 receptors. But when you think about it, why do we block D2 receptors? Because there's too much dopamine where we don't want it. So, that's been our mechanism of action of choice there. We hadn't really thought through, maybe there's some way that we can selectively decrease dopamine output where we want to.
I'm sure we're going to get into this in some detail, but it escaped us because we're so used to, “Well, let's see, how else we can block D2 receptors without too much blockade in the motor striatum?” or “Maybe there's some mitigating receptor binding activity that can help with that,” and hence the second-generation antipsychotics and 5-HT2A receptor antagonism.
This has led to actually a product available to us today that is actually much more in terms of affinity to 5-HT2A than D2, but the bottom line, still binds to D2. So, maybe there's another way to modulate dopamine. All roads lead to dopamine, but maybe there's some roads that we have not taken until now.
CC: So, to sum this up, we've had a primacy of postsynaptic dopamine blockade, a postsynaptic answer to what we think is more a presynaptic problem, where we have too much dopamine release and synthesis in certain areas of the brain currently understood as the associative stratum, different from the limbic system in rodents, where actually in humans, the limbic system is underproductive in terms of dopamine transmission, as is the frontal lobe.
So, we have reward issues, negative symptoms, cognitive symptoms, and those can actually be made worse when you block dopamine indiscriminately everywhere, in addition to having maybe sexual side effects due to the prolactin elevation and also neuromotor side effects. That means although we've talked about dopamine in somewhat a unilateral way, it's been more complex and complicated because there are other areas where we have too little dopamine, and by just pumping down the dopamine on one end, we didn't really get a handle on negative and cognitive symptoms at all.
So, this revolution we'll be talking about is not only that we will hopefully have a series of medications that tap into the presynaptic dopamine problem without blocking too much dopamine postsynaptically, but maybe also providing an answer for more than just positive symptoms because we know that negative and cognitive symptoms are part of the game.
So, do you want to sum up this theory of the dopamine hypothesis and where it might have led us or misled us?
PW: The thing is, is that nothing succeeds like success. The dopamine hypothesis worked. It explained our medicines, but if you go back in a time machine back to that era, there were many other treatments that were tried and worked. I know for myself, I ignored those. You know, it was like, okay, this works. I'm a young psychiatrist. I'm joining this.
I think if you take a step back, I think that the people who were better than me in understanding this would say, “Hey, schizophrenia is too complicated an illness to narrow down to one receptor, one neurotransmitter.” I would pay lip service to that and say, “Yeah, right, I agree.” But then I would go about teaching my residents about all about dopamine.
So, I think that let's start back with the basics. Schizophrenia is too complicated an illness to be in one receptor. We have just focused on what works, what had worked. I think the other opportunity we have with different mechanisms is it forces us to rethink some of the principles back to, I think, the more accurate understanding of complicated illnesses and also the urgent need to have more than one way of treating something.
LC: If I go back in time. I'm sorry. You know, all our medicines that we had until very recently available today, as approved by the FDA, have been postsynaptic D2-blocking agents. In the past, though, we had reserpine, a dopamine neurotransmitter depleter, so to speak, that decreases dopamine presynaptically and actually worked in some patients with schizophrenia.
I recall in my first job in a large VA hospital, there was an entire ward of people on reserpine who had not responded to traditional, at that time, first-generation antipsychotics. That's kind of interesting; we kind of forget about that. So, an entire ward in this large 1000-bed hospital of people on reserpine, but it was difficult to deal with. It has all sorts of tolerability challenges and ultimately was superseded by all our traditional dopamine D2-blocking agents, which are far easier to administer and more accepted by patients.
CC: Yeah, so tolerability was very important. Obviously, reserpine is an irreversible VMAT2 inhibitor, vesicular, monoamine, transporter inhibitor. Whoever has heard that word, VMAT2 inhibitor, can now think forward to tell 2017 when 2 non-irreversible, but reversible VMAT inhibitors were approved for the treatment of tardive dyskinesia and Huntington's chorea. Actually, one of them, valbenazine, is currently being tested as maybe augmentation for postsynaptic dopamine blockers by depleting a little bit the, or reducing the presynaptic dopamine availability.
We had that, and we even had arecoline, which was the first panmuscarinic agonist that in 1950s also worked, but it was all put to the side because of the better tolerability of chlorpromazine and what will come afterwards, although we then suffered from the lack of tolerability.
So, let's go into that. What were the limitations and have been the limitations of the current schizophrenia treatments? Although they've been very helpful in actually opening wards, getting people out of straight jackets, yes, but what are also limitations that we want to overcome by maybe having more of a crosstalk across different neurotransmitters, because they do interact with each other, and we might do a better job by honoring that and actually modifying several neurotransmitters in concert.
LC: Well, if I can take a stab at it, our second-generation antipsychotics have mitigated, to a large extent, drug -induced Parkinsonism, but it can still emerge. It has not eliminated akathisia. Akathisia remains a significant obstacle to the use of, in particular, some dopamine receptor partial agonists. Then we have sedation. This is certainly an issue with some of our medicines. It's difficult to function if you're sleeping all day.
Then lastly, it's weight gain and metabolic disturbances that have stymied a lot of us in terms of, well, it turns out some of our treatments that are associated with the most weight gain seem to be the most efficacious. So, what do we do there? So, sedation, weight gain, akathisia are my three main obstacles in finding the ideal drug amongst the second-generation antipsychotics.
CC: Peter, any other side effects or limitations?
PW: Side effects are very important, as we all know, and it's very important for us to minimize side effects, no matter what medicine they're on. I think we've made great progress with that. You know, it's easy to forget how bad it was when we were all young, and we see people shuffling and drooling down the hall, their lives ruined, not just by their schizophrenia, but by the medicine.
So, it's been a big change, but we had to tell our patients that because we don't cure schizophrenia. We don't come close to curing schizophrenia. So, you know, more treatments were needed. I would like to take one point before, you know, a lot of researchers and some brave drug companies knew this, and over the years, they would come up with different mechanisms aside from dopamine.
Now, we're celebrating muscarinic as the first success, but there have been so many failures that that was also another pressure to stay with dopamine. It's just, you know, if you were a betting man, you wouldn't be betting on muscarinic or anything else because the chances were it wouldn't work. So, my sense of it is we've made this great progress, but I think we've hit the point of diminishing returns. We can't get more juice out of dopamine drugs with fewer side effects. We've done that.
I think, you know, it's sort of been like, okay, we're getting very limited with this. We really need something different. I'd like to think we were smart and figured this out. I'm not so sure we were. We kind of bumbled our way into this one, but we'll take it. You know, I think the story is yet to be told about how changing a mechanism will change the face of an illness or not, or how we will rethink what we can treat or not treat.
I don't think we're going to cure schizophrenia still, but I think we have a good chance at really making some inroads that we didn't simply because it's a different mechanism.
CC: So, we've discussed limitations. Some of them are side effects: neuromotor, weight gain, cardiometabolic, also arousal can go either way, sedation or insomnia, sexual side effects, but we've also had limitations based on efficacy. No big efficacy signals for negative and cognitive symptoms, but even residual positive symptoms, up to 40% of people, and treatment resistance, 20% of patients in the first episode and onwards, and another 20% getting up to 40% when you have residual symptoms and relapses.
So, in that sense, except for clozapine, which was actually marketed first 50 years ago, we haven't made any strides on coming back up to efficacy of olanzapine or risperidone, same way with better side effect profile or even getting treatments for treatment-resistant patients who may not respond to postsynaptic dopamine blockade. So, isn't that also a gap we need to fill?
PW: To say the least, Christoph, and I would like to say something to the audience here that's, I think, to me very important. The standard teaching is we do pretty well with positive symptoms, but I'd like to ask the audience a question, if you're treating patients. If you have a patient who has no positive symptoms, but they are not going out in life, they're not going to school or dating, because if they do, they're going to get positive symptoms. So, their lives have collapsed, have involuted to prevent that from happening. Is that really not positive symptoms?
To me, the problem is even worse because there are many patients who don't have overt positive symptoms, but whose lives are very restricted because they limit themselves so they don't get it. I think this is still a huge problem. Yeah, negative symptoms, cognitive, we've got a lot of work to do.
CC: Les?
LC: I agree. So, the remaining symptoms that we absolutely have no ways of dealing with well are negative symptoms and cognitive impairment. Both of those actually impact functioning a whole lot more than positive symptoms.
I often give the example of, let's say the greeter at Walmart. They may be psychotic, I don't know, but their psychosis is under reasonable control, and they could maybe ignore some of the internal stimuli they're having, and they can greet people.
However, you can have someone who doesn't have those symptoms but has negative symptoms and doesn't want to work, has no interest in being with people. And then people with cognitive impairment who may want to work, may not, but can't figure out how to get to work. If the bus comes, they don't know which bus to take, or if the bus doesn't come, what to do to get to work, and once at work, what do you do next? Punching a time clock and following instructions are beyond their capacity at that time.
So, negative symptoms and cognitive impairment are extremely impactful on functioning, and we don't have any good treatments for them.
CC: Yes, and now let's go back to the neurobiological drawing board. We have dopamine. It's not in isolation. We know there's also a glutamate problem, too much glutamate in some areas that feeds into the dopamine presynaptic synthesis and release. We have too little GABA, which might keep the glutamate in check, but we also have too little glutamates in the frontal lobe. So, it's a real issue between glutamate, GABA.
You've talked about serotonin already. 5-HT2A may be helpful to balance some of the neuromotor side effects, hence the serotonin-dopamine antagonists, second-generation agents. It might even by itself convey some antipsychotic efficacy, pimavanserin being at least efficacious for psychosis in Parkinson's disease and the psychedelic agents that simulate 5-HT2A can cause psychotic-like experiences.
Now let's talk about the cholinergic system. Five years ago, I would have thought, "Okay, cholinergic system that has only to do with countering EPS. What else do I have?" And I don't like it if it gives me or the patient dry mouth and some bladder issues. But why are we now talking about the cholinergic and especially the muscarinic system? Tell us about that.
LC: You know, I'll take a stab at it. Peter could fill in the details. So, you know, in the 1950s, as you mentioned earlier, arecoline is a procholinergic agent, promuscarinic agent. It's contained in betel nuts, and those who chew betel nuts who happen to be psychotic may be less psychotic. That observation led to trying arecoline in those who were hospitalized long-term, and it was very poorly tolerated, but those experiments demonstrated an increase in lucid moments.
That was the outcome measure, lucid moments. Can you have a conversation with someone? And you could, but it was so poorly tolerated, and at the same time, as you mentioned, chlorpromazine came to be, and that was far easier to administer, far easier to tolerate. That was the winning strategy at the time, and here we are today, 70 years later.
But someone thought about muscarinic agonism, again, when they figured, “Well, maybe it'll help with cognition in Alzheimer's disease.” So, xanomeline was tested in Alzheimer's disease, and it turned out not only did it help with cognition, it seemed to reduce any associated psychotic symptoms. That led to a small study that looked at xanomeline in people with schizophrenia. It seemed to work, but very poorly tolerated.
That led to, “Well, what can we do to make it more tolerable?” And I'll toss it over to Peter because Karuna came up with a solution.
PW: Well, yeah. By the way, I worked there, I had nothing to do with figuring this out. For those of you listening now, some of you will be familiar with this, but if you're scratching your head saying, “What are these people talking about?” Let me take a step back and kind of do muscarinic 101 because we never focused on that.
Acetylcholine is our most primitive neurotransmitter. It does everything. You know, it's everywhere. It does a lot of stuff. There are 2 receptor systems that receive acetylcholine in the brain and the body. One is nicotinic, as in smoking, and I'm going to ignore that for the rest of it. There had been drugs developed for nicotinic receptor in schizophrenia, but just put that aside.
The muscarinic receptor is the other one, and there are 5 of these guys. They are cleverly named 1 through 5, muscarinic M1 through 5. These are the receptors we're talking about. And very important, I want you to listen to, if you're new to this, muscarinic receptors live in the brain and in the body, in the periphery. The brain is where we're going to talk about the good stuff happening. The periphery is where the bad stuff happens. So, one of the things we're going to be talking about is that the other thing is that because they're everywhere, selectivity of these has wound up being very important.
Then the third point I want to make is that the sort of science of muscarinic receptors kind of lag behind the others because it was just harder for a variety of technical reasons. But as Christoph said, many years ago, there was a hint that if you take the drug that stimulates the muscarinic receptor. Now, last point about muscarinic 101. If you are treating patients with cogentin or you're using drugs with anticholinergic activities, those inhibit the muscarinic receptor. Those make them go down. We're talking about muscarinic agonists that directly stimulate the muscarinic receptor.
Now, one last point, you may be used to using aricept or drugs for Alzheimer's that also raise acetylcholine, but they do that indirectly by messing up the metabolism of acetylcholine, so it raises. We're now talking about therapeutic use of direct muscarinic agonists, and that's the opposite of what we're used to seeing the side effects, their muscarinic antagonists. Okay, I'm done with 101. I'll give the floor to one of my colleagues.
LC: So, let me pick it up where you left off. One of the thoughts of why people have schizophrenia is that this GABA interneuron is not functioning very well. The GABA interneuron is supposed to dampen down glutamatergic signaling that ends up encouraging dopamine release in the part of the striatum where we don't want it.
Well, that would explain hallucinations and delusions. It all goes back to that GABA interneuron way back in the cortex. Now, if we can increase the activity of that GABA interneuron, then we can inhibit that glutamatergic circuit and decrease the amount of dopamine ultimately released.
But we can do that with muscarinic M1 agonism, which will ramp up the GABA activity so that it works better in inhibiting that glutamatergic circuit, that very specific circuit that goes to a very specific part of the striatum that explains hallucinations and delusions. So, that's one avenue that we can do now. There's M1 receptors elsewhere as well, but that's the circuit that we think is in play here in ultimately reducing psychotic symptoms with M1 agonism.
PW: Was that the theory when it was first found, or what? Was it not then?
CC: No, the idea there was that it helps cognition because M1 stimulation on the frontal cortex also stimulates acetylcholine by itself, which then stimulates dopamine in that circuit and helps cognition. So anyway, it helps just to tell people again that there are 5 muscarinic receptors, and the odd-numbered ones, 1, 3, 5, are actually postsynaptic. When you stimulate them, it's a go. Stimulate, go.
As you said, Les, in the frontal cortex, it sits at the GABA receptor. You stimulate M1, it says go to GABA. GABA inhibits because it's the break in the system and then reduces glutamate, which reduces dopamine. But there's also M2 and M4, the even-numbered muscarinic receptors, and they actually are presynaptic receptors. You may remember from your pharmacology class that presynaptic receptors are the autoreceptors. Autoreceptors are the brake in the system. So, as you stimulate M2 or M4, you're reducing and dampening the acetylcholine input.
Maybe, unless you wanna pick up, you said M1 is one top-down mechanism to reduce glutamatergic input into the stratum, which then decreases dopamine output. But what about simulation, again, direct simulation of M4, which actually means you're simulating a brake? What happens there with the M4 pathway?
LC: Yeah, so, the M4 pathway is very interesting. Now, the M1 pathway, I kind of understood from the get go, because we always were talking about GABA interneurons and glutamatergic circuitry in our models of schizophrenia. We never really talked much about the LD, lateral dorsal tegmentum, in the hindbrain. Now, no one has ever mentioned this to me before. This was news to me, and actually my first reaction was, “Who the hell cares about the LDT? It's irrelevant.”
I was convinced otherwise because the LDT is where acetylcholine neuron cell bodies live in the hindbrain. It's a very old part of the brain if we think about evolutionary changes over time, and its job is to actually interface with dopaminergic neurons directly. If you actually stimulate that dopaminergic neuron, it's going to release more dopamine where you don't want it in the striatum.
So, how do we put a stop to this? Well, the autoreceptor, the M4 autoreceptor lives on that acetylcholine neuron that originates from the LDT, and it's an M4 autoreceptor that very selectively addresses that circuit to the part of the striatum that we care about for psychosis. So, the LDT was introduced to me some years ago, and I didn't fully appreciate it. I needed to hear this story over and over again before I kind of sort of understood it and was able then to tell other people about it.
People always ask, “Well, why isn't there some problem there with decreasing dopamine in the motor striatum because that would lead to drug-induced Parkinsonism, right?” And we don't see that with M1, M4, that business. And why not? Well, the motor striatum is dealing with another acetylcholine nucleus in the hindbrain, the PPT. I even forget what it stands for, but it's stopped by an autoreceptor, M2. Not M4, M2. So, if you develop an M1, M4 agonist and avoid M2, you avoid all the motor side effects that have plagued us for the past 70 years.
So, really kind of interesting how it all played out. Now, of course, it all came from the observation that Peter, as you said, “Hey, this stuff works. So, let's try to find an explanation for it.” Now we have an explanation that kind of makes sense, but you have to hear it over and over again in order for it to gel, 'cause it's so new, so revolutionary, and so different.
PW: I think the thing that was staring the brighter people in the room in the face when they thought about it, and I certainly was not one of them, was, hey, if you go back 20, 30 years, you have very strong clinical evidence that a direct muscarinic agonist helps psychosis, both in Alzheimer's and then later in schizophrenia, and it did not read the textbook. It did not read that it was supposed to be a dopamine antagonist.
That was the foundation of everything else coming on in terms of then furthering drug development, but there was a problem, a big problem, even though you have this promising treatment of a new mechanism, the holy grail of schizophrenia. Houston, we have a problem. I don't know, Christoph, do you know what that problem was?
CC: So, that problem is that obviously the receptors that you're talking about, the acetylcholine receptors, are not just in the brain, they're also in the periphery. We have to add another concept, and that is that these 5 receptors have basically a so-called orthosteric pocket where the acetylcholine goes and the agonist would go.
That pocket is pretty much preserved across the five receptors. So, if you just have an orthosteric agonist, it might spill over into other receptors that give side effects, procholinergic side effects, in the periphery. Also, M1 is in the periphery, can cause nausea, vomiting, even syncope, and had the problem that people dropped out of these studies enormously, and that needed to be mitigated.
Now, there's an allosteric pocket at these receptors, which is like a bystander pocket. When you have an agonist there, it actually strengthens the binding of endogenous, physiologically occurring acetylcholine and then also strengthens the transmission. So, it would have a preserved both temporal and local transmission of acetylcholine, but it's a potential problem because we know that people with schizophrenia have too little M1 and M4 receptors. That's post-modern data.
We know when we knock out M1 and M4 receptors in mice, they become psychotic in the sense that they basically wander around and don't take care of themselves anymore and also have a heightened response to amphetamine. So, in that sense, we may need an additional factor to stimulate M1 and M4 receptors but also clean up the peripheral act. One way of doing it is maybe developing an M4 positive allosteric modulator that just stands by and doesn't spill over into the periphery.
Or, and that's something you can talk about, Peter, what did actually Karuna come up with? Andrew Miller had an ingenious idea.
PW: The founder really thought this through. Let's take a step back. What really was a big problem with any drug, and this is true of any drug that directly stimulates a muscarinic receptor in the brain, is that the good stuff is in the brain, but if you stimulate the stuff in the body, you get side effects. So, for some drugs, those can be very serious, dangerous side effects. For some, it can just you know make you, turn you off to treatment. So, stimulating peripheral muscarinic receptors is bad, and xanomeline and all the others have the same characteristic.
Now, I'll give you a way to remember this or at least most of the problems that you get with peripheral stimulation. Remember our autonomic nervous system. We have the sympathetic nerves, fright, flight, that's the noradrenergic, so on, and we have the parasympathetic system, rest, digest, or couch potato, right, that calms things down.
So, the parasympathetic system ends the nervous system, the very last stop is picked up by muscarinic receptors. If you stimulate muscarinic receptors in the periphery, you're basically putting the parasympathetic nervous system in overdrive. Or, if you're used to seeing patients with vasovagal or excessive vasovagal activity, you're going to see it as nausea, sweating, peeing, diarrhea, throwing up, dyspepsia, that kind of thing. You can have theoretically cardiac problems, although the one that's out, these do not.
The point is, you buy into over-stimulation of the parasympathetic system. That is the problem. So, the solution or the partial solution that all the drug companies need to figure out is, “How do you preserve the good stuff in the brain while dampening down or getting rid of this peripheral over-stimulation?"
Drug development is now figuring this out in different ways. So, the way that Dr Miller figured this out is, “Hey, if it's peripheral over-stimulation, peripheral means peripheral nervous system, but the central in the brain is the good stuff. Why don't we just find a medicine that counteracts this stimulation in the periphery but doesn't travel into the brain?”
And where did he find that? He went to your local urologist, “u” with a “u” urologist, because urologists have such a drug that is used to treat overactive bladder. So, overactive bladder, you can give an anticholinergic or antimuscarinic, and some of these drugs go into the brain, and we don't want that. One of them is called trospium. The brand name is Sanctura, available by prescription for overactive bladder, is now combined with one of these direct muscarinic agonists.
So, the one that is approved is trospium, xanomeline-trospium. Xanomeline is the direct agonist going into the brain, and trospium is the stuff that is kind of dampening down, mitigating, not completely eliminating, some of these overactive peripheral side effects. That was the very clever solution that worked, or worked in part. I mean, there's still those side effects. There are other ways that, you know, Christoph is saying, technically, but it's the same thing. It's kind of fine, you know, how do you get the benefits and minimize these? This is a problem across all direct muscarinic agonists.
Let's shift gears and actually talk about the data with xanomeline-trospium, both for efficacy and safety and then also some of the other drugs in that class that are being assessed right now and see where this takes us.
LC: Before we do that, let's learn what we can from the xanomeline monotherapy trials.
We learned that 60% of those randomized to receive xanomeline vomited, 60. So 6 out of 10, actually; there were only 10 subjects receiving xanomeline, and 6 of them vomited. Now, this is a problem, right? It's a problem offering a medicine to someone and say, oh, over half will vomit. It's not a winning strategy to convince someone to take something. So, can we dial that down? And we can, with trospium, dialing it down to a fraction of that, not to zero, but to a fraction of that. So, that's good, but what do we get from this?
Well, we actually get very good efficacy. So, this was studied, xanomeline-trospium combination, was studied in patients with acute schizophrenia in 5 week-long randomized placebo-controlled trials. One was a phase 2 trial, so early on, and 2 were the definitive phase 3 trials.
Now, I was very surprised with the phase 2 trial being so successful in demonstrating robust efficacy with an effect size larger than what we'd ordinarily expect when looking at second- or first- generation antipsychotics and similar studies. So, that was very interesting, and the rate of vomiting was a fraction of that observed with xanomeline alone. The phase 3 trials essentially replicated the phase 2 trials in terms of statistical separation from placebo and a very reasonable effect size, still larger when pulled together than what we ordinarily would expect from equivalent meta-analyses of older drugs.
So, that was a winner. When looking at side effects and tolerability short-term, and I'll let Peter talk about longer-term efficacy and tolerability from what we know so far. So, the tolerability short-term is actually not so bad. You didn't see actually any weight gain or sedation to speak of, no akathisia to speak of. There was GI side effects as would be expected, and they are at rates that are higher than anything else we've had, but it did not necessarily lead to discontinuation from the clinical trial.
Actually, very few people actually stopped because of adverse events. Very few people actually had a dose reduction because of adverse events. So, these studies were not fixed-dose studies. People were actually forced up in their titration relatively rapidly, different from what we would do in real-world practice. This is how it was studied, and basically was reasonably tolerated. Not perfect, but reasonably well tolerated. And the trade-off is, hey, no motor side effects, no sedation, no weight gain, no elevation in prolactin, no QT prolongation. So actually, that's good.
When you look at the product label, and I want everyone listening to this, look at the product label for xanomeline-trospium combination. I dare you to find the word "antipsychotic" in it. It's not in there. I challenge you to look for box-bolded warnings that we're used to seeing with antipsychotics. It's not there, and the usual class-level warnings and precautions, they're not there. This is a whole new approach that has a whole different tolerability profile, but I think overall, it's very promising. But does it continue to work? Does it continue to be well tolerated? I'm going to toss it over to Peter.
PW: Well, let me just say the relapse prevention or the maintenance of effect studies have not been done. So, if you want to be technical, we have to say we don't know. But if you have schizophrenia and you stay on open-label xanomeline-trospium, and you don't relapse after a year, most of us, I included, would feel that that's good evidence of efficacy, and indeed that's what happened in the what are called long-term extension, open-label, long-term safety studies.
So, what I would say with the long-term studies, we need to know more, but in long-term safety studies, the way I say it, think of it, is surprise is not your friend. You don't like surprises in long-term safety studies. You don't want to see new stuff, and there were no surprises. There was, you know, the short-term safety played out long-term the way everyone thought. There was no monster in the closet in terms of a big problem.
Furthermore, because other drugs have sometimes had hypertension or other issues, this drug and all the ones coming down the pipe pretty much are doing cardiac studies just to make sure it's safe, and that's fine, that all passed. So, the safe the long-term safety seems to be within the number of subjects, is good, and the long-term effectiveness. Effectiveness means, “Do your symptoms still improve slowly over time?” and the answer is yes, it does.
Now, there were 2 studies, the long-term safety studies. One has been criticized because the retention was quite poor, and the other, the retention was sort of schizophrenia standard, about 50%. So, let me focus on the one that was criticized because the retention was poor. What I can say having kind of been there is, to me, that was an artifact of patients being discharged from a hospital and then being re-titrated onto the same drug at sites that might not have been as tuned into outpatient treatment as inpatient.
I can't say that for sure. I am speculating, but I think that the, that is called the rollover, where patients who were acutely ill kind of graduated, hey, you can stay on. There is another, the other safety study was called “de novo,” meaning a potential subject was an outpatient kind of hanging out, so if you will, and then switched to the xanomeline-trospium.
That is the one I would look at if you're going to be a nerd about this and kind of look at what the long-term is on that, and that's pretty good. It's not amazing retention, but it's not bad. So, that's my opinion. I think there is a very active clinical trials program with xanomeline-trospium now going on, and you know, we're gonna learn a lot more in the years to come.
CC: Great. I would like to bring us back to the acute studies that led to approval and put some numbers on this. So basically, these were 5-week studies, you've heard it. Three of them, and they were with a fixed-force titration, 2 days of 50 mg xanomeline plus 20 mg trospium BID, followed by another 5 days of 100 mg xanomeline with 20 mg trospium. Then as of day 8, it was 125 mg xanomeline plus 30 mg trospium.
This was a pretty fast titration. As you've said, Les, this is not necessarily what we would do in clinical care, it's BID dosing, but we could now do it every week as is done in a study that is running right now, the Arise study, which looks at the addition of xanomeline-trospium to an atypical antipsychotic treatment that is still with ongoing positive symptoms. So here, maybe weekly titration, but it's BID dosing.
Since trospium is actually not well-absorbed when food is in the stomach, actually 85% to 90% less area under the curve, it has to be given either 1 hour before food or 2 hours after the food. Now, with that prospect or also process in the studies, there was an effect size when you pool everything together by the company of about 0.65. The average across acute studies is 0.42, when you look at risperidone, 0.55, olanzapine, 0.56. When you reanalyze the data, it actually comes down to 0.56.
So, it's roughly similar to olanzapine, but higher than the overall pooled results. When we look at the side effects, yes, there was only 1% greater risk of stopping for side effects, but there was basically 17.5% of people had nausea, 13.5% of patients had vomiting, about 14.5% had dyspepsia. So, that's like the pressure in the stomach, which is more of an anticholinergic side effect, and again, about 17% had constipation.
So, they were both procholinergic side effects, nausea, vomiting, and anticholinergic side effects, that's dyspepsia, and also constipation. Interestingly, this actually emerged in the first 2 weeks, and then most of it was done by 3 weeks. So, there seems to be an attenuation process or tachyphylaxis against the side effects, and that is when bumping up the dose within 8 days.
So hopefully on the outpatient side, that will be less so, and when we add xanomeline-trospium to dopamine antagonists, that actually can be given for motion sickness and nausea, we would expect this hopefully to be even less so. So, we will have to learn, can we give this with some anti-nausea or vomiting medications and sensitive patients? Will it go down over time in terms of side effects? Then we don't have these lingering long-term side effects that our current dopamine antagonists have really been limited by.
That's, as we've discussed, the neuromotor side effects, cardiometabolic, sexual side effects, and also arousal problems. Les, you also wanted to add something to that before we then go into maybe the positive allosteric modulation and also M4 agonists.
LC: Yes, I'd like to share with our listeners what is meant by effect size. So, we often bandy around numbers 0.65, 0.45. What does that actually mean?
It means a difference from placebo in standard deviation units, and 0.5 is considered a moderate effect size, 0.88 large effect size. So, 0.8 of a standard deviation unit would be large, and very few of our treatments in psychiatry have that effect size so large. Most have actually small to moderate effect sizes.
So, this is really exciting that this generally, xanomeline-trospium combination comes up at the upper end of what we ordinarily would expect with drugs to treat schizophrenia. So, I wanted to make that comment. I also want to make a plug for another effect size, and you know what's coming now, number needed to treat and number needed to harm, which we won't get into today, but I'm sure you'll hear about in a not-too-distant future. That's easier to understand in patient units.
Lastly, I want to add something about the importance of not taking it with food. So, this is actually encouraging to me because patients will soon learn not to take it with food. Because if you take it with food, your chances of vomiting are much higher because the trospium won't be on board. It won't be absorbed. So, actually, this is something that won't be silent if patients don't listen to the instructions to take it 1 hour before breakfast and 2 hours after dinner.
CC: Great. So, let's go on from xanomeline-trospium to emraclidine, which is an M4 positive allosteric modulator. So, the idea was, okay, let's put it at the side and not allosteric pocket so that you don't stimulate other muscarinic receptors. Then phase 2...
PW: I'm sorry, is that hard to do this selectivity?
CC: Well, it's not so easy to do, and it was actually done with emraclidine in a phase 1B study, where they had almost no side effects, but a good effect which was similar to xanomeline-trospium in a very small study. But then, what was done after that in the phase 2 studies?
LC: Yeah, so you know, positive allosteric modulation is very tantalizing, although hard to find an allosteric positive allosteric modulator. Once you find one, it's very valuable because it'll only go to that receptor. One of the receptors, so a very specific M4 PAM, was found, and you don't have any of the other off-target muscarinic tweaking that we would otherwise see. That's excellent.
CC: And no need for postsynaptic or peripheral anticholinenergic either?
LC: No. No. Very, very clean. It reduces the signaling of dopamine to that part of the striatum we care about, but only in one way. So, we thought it would work out based on the initial study that was done. Unfortunately, the large phase 2 studies failed to show a difference between drug and placebo, much to our disappointment.
We thought it should work, but maybe M4 alone is insufficient. Maybe M4 PAM is insufficient. So, we don't know about M4 direct agonists. We don't know about M1 alone. All we know is M1, M4 is a winning strategy. So, this opens the door to trying other things out. I think M4 PAMs, in my book, are history, and I would put my money on direct agonists for M4, in particular, based on the emraclidine experience.
PW: Les, it's very funny because a year ago, I would get calls saying, "M1 is history." So, things change. I think what the audience should know if they're not really into this is of these 5 receptors, there are 2 that are really associated with therapeutic efficacy and schizophrenia, it looks like. If you haven't figured that out, it's M1 and M4.
There is debate as to whether it’s, you know, could it be only M1, could it be only M4, can it be only, or does it have to be combined, or does it have to be a certain kind of binding? The good news is that just like when clozapine came out, there was a slew of research on atypicals after clozapine came out. That is happening now as we speak.
So, we're going to see pure M1s, we're going to see pure M4s, we're going to see all of these different things, and we're going to all learn together what the differences are, which ones do well, which ones don't. I think we're going to have a very interesting ride in the next few years.
Or, put it another way, with xanomeline-trospium, it is the first. Just like clozapine was the first. But it's not the last. It'll be far from the last, and I think it's ultimately very good news for our patients, where it'll take us.
LC: In terms of the mechanism, though, we'll hear more about the mechanism too and then we'll hear more about muscarinic receptors in the striatum, which complicates the story somewhat, but stay tuned for that too.
CC: Yeah, I think the jury is still out. How much M1 or how much M4 and how delivered you need, because there's NBI 568, which is basically the M4 orthosteric agonist that Neurocrine studied, and out of 4 different doses, the lowest dose, the 20 milligrams, worked, and at a similar effect size as xanomeline-trospium, as also emraclidine did the M4 positive allosteric modulator.
It might also be true that certain subgroups of patients might meet the M1 tweaking because they have this excitation inhibition imbalance, too little GABA, too much glutamate from the top down, and others might have really more this LDT to ventral tegmental area, too much acetylcholine input, and then that ends up being hyperstimulated in the stratum so that there's too much dopamine output.
So, I think we will learn much more about this, but it's interesting that now the field is looking into acetylcholine, but I also want to broaden this briefly into other symptoms, because as we've heard, xanomeline was tested for cognition in Alzheimer's disease. What about some of the early data in the acute studies where, granted, also positive and negative symptoms improved with xanomeline-trospium? Did we see anything for either cognition or negative symptoms?
LC: I think we saw a signal for cognition in the phase 2 study. I recently looked at that, actually yesterday, and saw that in an analysis that was, I think, post-hoc; it was not pre-specified, I don't think. Anyhow, they looked at improvements in cognition in those who had impairments from the start, and they actually showed an improvement in a 5-week period. Is 5 weeks long enough? Probably not.
What I would want to do is a prospectively conducted study of patients selected because they have cognitive impairment associated with schizophrenia over a longer period of time with the right neuropsychological testing and the right measurements of functioning like everyone else does in terms of determining whether something is good for cognitive impairment associated with schizophrenia. The negative symptom signal is also looking interesting, but then there's this whole issue of pseudo-specificity.
When you improve positive symptoms, you will improve the secondary negative symptoms that comes with it. Does it have an effect on enduring or persistent negative symptoms? Well, we need to do a specifically designed study that's longer that selects patients with persistent negative symptoms, and over the long haul. That way, we'll answer that question, but it looks like these initial signals are promising.
CC: At least we're not dampening too much dopamine that could cause secondary negative and cognitive symptoms. There's potential that it might actually improve cognition, and in the 3 studies, there was each a signal, but only in the subgroup, the half of the patients that had at least 1 standard deviation of cognitive performance.
PW: So, if you use schizophrenia, as most people with schizophrenia, if you compared them to their, if you did the thought experiment of comparing them to themselves without schizophrenia, most people will have cognitive impairment. You take the more impaired half of those people, if you will. Those seem to, in a kind of post-hoc way, respond better with medication, xanomeline-trospium.
I think the nice thing also, the analysis, they did try it as best they could, look for pseudo-specificity, and it wasn't explained just by reduction voices and so on. So, you know, this is pretty promising. I don't think we can go say that it is, but there's a lot of reason to be optimistic about that given, you know, given the mechanism makes sense and there is some evidence and, you know, we'll see. I mean, I think people who use this drug a lot will probably be telling us what they think.
CC: So, we've talked about the promise. We've also talked about the challenges being specific, not having too much in terms of stimulation of peripheral cholinergic receptors that can give us these side effects, not having to buffer it, which gives us anticholinergic side effects, and then maybe finding also a combination of pro- and anticholenergic drugs that have similar pharmacokinetics so that there is not sometimes an over-stimulation of one side, which is the procholinenergic side effects, and then an over-stimulation of the blockade on the other side.
Are there any other challenges before we go into the future of where will we use these agents and what other agents are on the horizon?
LC: I think we need to take a step back actually also as what we call schizophrenia. It's based on the symptoms, not based on the pathophysiology. What we've talked about are some patients may need this kind of agonism or the other kind of agonism, or the D2 blockade doesn't work for them. We'll need to find some other way of addressing their symptoms. That actually is because we're kind of ignorant on how to segment the population based on exactly what's going on in their brains.
So, I'm looking forward to the future when we'll be able to identify what kind of schizophrenia someone has. The schizophrenia is really the schizophrenias. There are many different types of psychopathologies that end up with the same kind of symptoms but treated very differently. So, we're going to learn more about that. Then once we can do clinical trials with that segmented population that have an identifiable pathophysiology, we’ll be way ahead of the game.
CC: We are.
PW: Yeah. You know, there's some obvious things. I mean, we're still not curing schizophrenia. We have a lot of challenges in formulation, especially with this. So, when you combine these or there's no long-acting, we don't have predictors, so we don't know. There's going to be the concern about, well, when a drug or a new mechanism is released, are we going to get blindsided? That happened with tardive dyskinesia with the old drugs and then with weight gain with the atypicals.
So, there's a lot, there are gonna be challenges. I'll tell you where I lose sleep, okay? I lose sleep over, let's assume that this is a drug that will have real benefit in a meaningful way for a subpopulation that wouldn't have had that opportunity before. This is just, let's make this up. I can't say that's, I don't know if that's true, but let's say that's true.
If we look at the history of what our profession has done with medications that are better, we have to look at clozapine, and it's under used. We have to look at long-actings, and they're under-used. We have to look at a treatment system that is broken with fragmented care. I worry a lot about, well, what's going to keep—if it is really better or we have a new class of medicines that’s really better—what's going to keep that from happening again I'm not seeing much that makes me optimistic about that. So, that's really one thing that I worry about.
On a more boring technical level, the other thing I worry about is what I call success at launch, meaning if you are a prescriber and you like to do things like go double the usual dose, or half the dose, or consolidate it or whatever, right? You feel that that's the way to go. I think the chances are you're going to cause more problems than help because the new mechanism that's not known and the tricks of the trade that you've done with the other medicines may not apply here. Then, if you get bad results, the patient will blame you, you will blame the drug, and it won't do well.
I think this is a time, until there's better understanding, to play it straight, go by the book, go by the prescribing information, look at it. It's BID, don't go once a day. Use the dosing guide, get a sense of what this drug is, and come to your own conclusions. I think the only way to do that, given what we know, is to stay within label. Also, what comes up a lot is “Do I combine and leave them there, or do I go to monotherapy?” meaning just xanomeline-trospium.
At least from an understanding of what a drug can do or not do, I think it's a lot more informative to go to monotherapy. You're going to understand this drug much better than if you combine it and then try to figure out, well, what the heck is going on here? So, I mean, I'm concerned about these things in terms of what we used to call the difference between efficacy and effectiveness.
So, that’s my soapbox. I've said it, and you may want to think about it if you're enthusiastic about using this drug. I am enthusiastic about using this drug, now that I'm back out in practice, but I would play it straight. I would really try to respect the prescribing information and not go too far field on that until we know more, until we know more.
CC: Les?
LC: So, the thing that keeps me up at night is the ubiquitous use of anticholinergic drugs. Lots of people are on them for no good reason, and I happen to dislike them intensely because they actually impair cognition. If any one of our listeners takes benztropine, for example, they won't be thinking as clearly as before. That's clear. Imagine that if our patients already have a reduction in their cognitive abilities, it will make it worse.
PW: Well, how come trospium doesn't do that?
LC: It doesn't cross the blood-brain barrier. You weren't listening, Peter. It doesn't cross the blood-brain barrier.
PW: Okay, got it. Thank you.
LC: But benztropine and trihexyphenidyl and diphenhydramine do, and that could actually interfere, supposedly, with the purported mechanism of action of M1, M4 agonism. We don't want to do that. Besides the fact that anticholinergics are no good to begin with under most situations, we really, really don't want to use them together with xanomeline-trospium, and the peripheral side effects can be made even worse.
So, imagine if someone is taking xanomeline-trospium, and on top of that, another anticholinergic. Well, their bowels may shut down, and they may have urinary retention. That's a huge problem. We know that some of the drugs we use besides benztropine and trihexyphenidyl also have anticholinergic properties like olanzapine, and clozapine, and quetiapine.
Anecdotally, I've heard people who are adding xanomeline-trospium to clozapine. I think that's particularly risky in terms of creating someone with an ileus which is potentially fatal. So, more people die of an ileus with clozapine than with agranulocytosis. So, I'm worried about that. We need to be very mindful about on-board additional anticholinergic drugs, and we have to ask patients too.
Do you take Benadryl that you bought at the drug store to help you sleep? Because that's anticholinergic too. So, I think we need to be very careful.
CC: So, I hear from both of you that we need to learn more about xanomeline-trospium, but this class of medication, we will learn more because it will be studied. Hopefully there will be other agents that can be given once a day, may not have a food effect. We might also get long-acting injectables in the long run because treating psychosis may not really change illness insights all that much. We will also have to see that.
That brings up the question, “Where will this class of medication be used?” So, I think one low-hanging fruit is switching people who are stable on higher side effect drugs. So, risperidone or olanzapine, and they have either sexual side effects or weight gain or other things, and you want the oomph. You want enough effects or people who are just discharged after having been started on olanzapine, risperidone, and you may not want to give a drug that may not have exactly the same efficacy at least in your hands or in the meta-analysis, so that might be a go-to drug.
Then we've talked about the Arise program and adding xanomeline-trospium to other agents, and Les, you make the point, don't use this together with anticholinergic drugs. That's other “pines,” olanzapine, quetiapine, chlorpromazine, because they have anticholinergic side effects, and you might be adding the trospium unless you give xanomeline-trospium with food because then you actually don't have trospium on board.
That might mitigate the doubling up of the anticholinergic side effects. But then, what about the central dampening of the xanomeline-trospium effect because of central anticholinergic effects of those “pines”? I think we will also have to learn much more about it. Would, in the future, this class of medication be good for either negative or cognitive symptoms, or even psychosis in other conditions?
Parkinson's psychosis, at the moment, xanomeline-trospium is tried for dementia with Alzheimer's dementia related-psychosis. What about mania? What about agitation and aggression in psychosis in bipolar disorder, maybe associated with autism? We'll have to learn much more, but there are a couple of newcomers, and one of them I already mentioned. That's NBI 1117568. The short form would be NBI 568, which is an M4 agonist. There's also another M1, M4 agonist, which is called MLO7. Does anyone want to talk about that one?
LC: Well, we hardly know anything about it. The first one you mentioned, we know something about it because an early-stage clinical trial was reported out. It turns out that separation from placebo occurred counterintuitively at the lowest dose, if I remember correctly, not the higher doses, but otherwise reasonably well tolerated.
Then there's the other one you mentioned. I don't think we have anything in people in terms of schizophrenia and efficacy.
CC: Yeah, so ML007, MAPLite07 is also an M1, M4 agonist which has a peripheral anticholinergic added, supposedly being tightly correlated with the pharmacokinetics of the M1, M4 agent. In terms of affinity and intrinsic activity, it seems to be more M1 agonist than M4, whereas xanomeline-trospium ultimately is more M4 agonist than M1. Whether that makes a difference, what it means, this drug will soon go into phase 2. It's interesting.
We also have NMRA-266, which is a selective M4 receptor PAM, like emraclidine that failed in phase 2 because of high placebo response. I mean, this was really high, up to 19 points, which we've never seen before, and the drug also went down. So, we really have to look at this, what happens with the placebo effect. Neumora’s drug is on hold because in rabbits, it caused some seizures, also telling us, well, maybe not all drugs are created equal, even though they hit the receptors on the surface in terms of safety.
There's also something we haven't talked about, just a brief excursion, which is called biased agonism. Even though you might bind to the receptor, even though you might have either more or less intrinsic activity, what happens below that G protein-coupled receptor, which is M1 and M4, is different, which cascade of second messenger system stimulates.
So, we may really learn about multiple drugs that have different effects. I think like with second- and first-generation agents, there will be a lot of room for different agents that we then will have to try because these drugs will also not work in all patients, which was even evident in the acute studies.
My big question is whether this could be the new clozapine, this class, because clozapine has an M1, M4 agonist activity as norclozapine, and it would be obviously beautiful if this could be used before clozapine or on the roll to clozapine, but these studies are also outstanding. We're in an exciting time where after 7 decades, a new class of medication enters the scene.
Hopefully, Peter, you're not entirely right that people will hold back and not try it because it's, I think, easier to use than the examples you gave.
PW: I think you should. I mean, I think you should just make sure you do it within, at the beginning, within label. We will all learn together. I think also I'd like to make one point. I don't know if you've seen this, but I think that there's often a prevailing belief among the atypicals that if you want efficacy, you have to put up with more tolerability problems, and if you want the absence of tolerable problems, maybe the drug isn't gonna be quite as effective.
Do not have that belief with this drug. This is an effective antipsychotic. That is hard when every bone in your body says you need to block dopamine to do this, when every bone in your body says you can't have a safe, well-tolerated medicine that is a heavy hitter within schizophrenia and stuff like that.
Psychologically, it's going to be hard, but it is an effective antipsychotic. I plan to use it for people I call on the road who have persistent positive symptoms, which is many of my patients, I wouldn't hesitate or worry about, you know, if they need to clozapine, they need clozapine. I'm not talking about that. Until then, if the person is right in other ways, I think it's one to consider for persistent positive symptoms.
CC: Absolutely. I just want to make one comment. You said, stay within label, I agree. Just read the label carefully because it doesn't say you have to get 2 days of the 50/20 and 5 days of the 120. It's no faster, then, but you can be slower, and that's been done now quite a bit of doing it once a week. So, we can deviate in that sense.
LC: I just want to say, and you don't have to go to the highest dose either. So, there was no fixed-dose study that was done that informs us about dose response. So, what you see in your patient is going to determine how you're going to increase the dose.
PW: Absolutely. So, I think if you had to remember one dose that works, it's the 100/20 twice a day seems to be therapeutic. It's not clear whether you're going to get more bang for your dose if you push beyond there. So, I think unless there's some drug-drug interaction where you might go lower or higher, that seems to be a nice go-to dose.
As my colleagues have said, the trade-off is, if you start lower, that's fine. It just may take you longer to get to therapeutic, you might need another medicine to cover. The faster you go, the more quickly you get to therapeutic, but then potentially more side effects you're going to have, along the lines of what we've been talking about.
CC: Well, I think that depends on setting. If you go inpatient, you may want to go faster, and you have nurses around that can help with separating the dose from food and also respond to some nausea or vomiting. On the outpatient side, like what you said, this residual positive symptom patient that all of us have, you have time.
Just to make the point, 90% of patients actually did go up to the 125/30 twice a day, so we don't know whether 120/20 is really more efficacious or equally efficacious. It's certainly something we can all find out, and patients might be very different in their tolerability and efficacy experience.
Let's wrap up here and give each of you just the role of giving some summary and clinical pearls to our audience. And I again start with you, Les.
LC: Well, I'm pretty excited about having something new. In my entire career, I never really had something new. Okay, clozapine came about, that was kind of new, but it came with a lot of baggage, and so it was reserved for my sickest patients. Now, we have something completely different.
I feel like, hey, this is like cardiology. Finally, we have different treatments for the same disease that work differently. The cardiologists in treating hypertension have all sorts of different ways of addressing it, calcium channel blockers and beta blockers and so on. Finally, today, for schizophrenia, I have something different. I'm excited about that.
I agree with Peter. Read the label carefully or understand the pitfalls of deviating from the label, and then don't rely on only your anecdotal and of one experience and give it a fair shot at it. I'm rather tantalized by the prospect of offering this to first-episode patients. It may decrease ultimately their risk of developing tardive dyskinesia in the future.
That certainly needs to be looked at. Will it work in first episode? I think it will. Will it be tolerated in first episode? I think it will. Will it be accepted by those in first episode? I'm not sure, but we need to try to find out.
CC: Peter?
PW: I think I've said many things. I think if you're thinking about this, you may be asking, is this really different? I think it's a fair statement. This is really different.
I think it's fair to say that different prescribers and different patients will have different risk tolerances. Do you aggressively go on it, or do you wait and see what happens with other people? I think there are different approaches, but I do think it's one that you should be discussing with your patient and not blowing it off as, oh, you know, yet another false alarm and learn a bit about it.
For those of you who are using it, brush up on this muscarinic stuff. There's a lot written about it, and both the basics and the fine points, and then it'll come to you. It's like learning a new, or relearning, a new transmitter.
CC: Yes, so thanks so much to the 2 of you for this very lively and engaging discussion, and I also am very excited about having something new and different because some patients really need something different. We've been trying to switch from 1 drug to another, from same drugs to other drugs.
We've really done well, I think, in improving safety. That's been a great journey from the 1950s until now. But on efficacy, we haven't really made a dent for negative and cognitive symptoms, for treatment-resistant patients, or patients who are just not getting enough out of the current treatment. So, the hope is that this can be complementary, fit into these pockets where there is not enough efficacy with the current agents, which will still be our reality and will also help patients.
There are also used second-generation agents for other conditions, depression, mania, and we'll see where this class of muscarinic agonists and positive allosteric modulators will land. Whether M1 or M4 or the combination, and which combination is most important, which subgroups of patients can benefit the most, what combinations are most efficacious. We’ll hopefully get data on cognitive and negative symptoms, will get data on treatment resistance.
It's just an exciting time, and we want you all to try it out. Just don't sit back and let other people do it because you have patients who could benefit from something new. We hope that this program today can stimulate some of this exploration and also getting used to something new that can be helpful for your patients.
So, we wanna thank you for your attention and hope that this was engaging and helpful. And I thank you, Les and you, Peter, for really a terrific program.
Thank you, both of you, I learned a lot today.
LC: Yes, thank you. Same here.
CC: Take care.