11th Annual Psychopharmacology Update 2025

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Introduction

Dr. Jonathan Meyer (University of California, San Diego): Good morning. Welcome to day two of the 11th Annual Psychopharmacology Update. And thank you to everyone who joined us at the reception last night. I hope that was a lot of fun for you. And it was great to relax, unwind, and drink blue cocktails. For those of you who drank too much last night, my name is Jonathan Meyer. I'm a Voluntary Clinical Professor of Psychiatry at UC San Diego. You can see my affiliations up there, and I'm your moderator again for today. 

And of course, everything we're doing today is sponsored by a lot of nice people, all run by CCO now doing business as Decera, but I want to thank our sponsors, AbbVie, Intra-Cellular, BMS, and Neurocrine Biosciences. And you all know how to do this in terms of responding to the polling questions. And please, we like to see you engage as much as anything.

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Polling & Questions: In-Room Learners

For those of you out in the virtual audience who might not be in the East Coast, everything is going to be on Eastern Time Zone. As always, if you're here, use your iPads to respond. You can submit questions using Ask a Question.

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Polling and Questions: Virtual Learners

And for the online learners, the polling questions will appear on your screen and you can put in questions for the Q&A using the questions window on the slide.

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Resources: In-Room Learners

As we've talked about before, most of the content is available for you to download and share. If you're here in person, there's QR codes at the table.

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Resources: Virtual Learners

For the virtual people, there's a resources tab on the left side of your screen.

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Closed Captioning

And if you need it, you can do closed captioning for the virtual learners using the transcription tab.

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Ask the Experts!

If you're having problem in the virtual world, use the Request support button and somebody will get back to you.

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Poll 1

So let's try out the polling thing to see if and when you might still be awake. Okay, so number one, what region of the US do you live in? I'm not going to read the answers. There's only one correct answer, which is A but you put what you want.

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Poll 2

So number two, what is your profession? Pick one, even if you have more than one.

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Poll 3

Okay. Number three, your primary specialty or area of clinical focus.

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Poll 4

And your practice setting.

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Poll 5

And lastly, how many years have you been in practice?

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Dopamine Detours: New Paths for Positive, Negative & Cognitive Symptoms

Okay, here we go. So I'm happy to introduce our next speaker, myself. Well, it's really a pleasure to be here, and I hope you enjoy this lecture on schizophrenia.

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Disclosures

Here are my disclosures.

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Learning Objectives

And here's a learning objectives. We're going to talk about I think a model for understanding schizophrenia. I'm not going to get too much into the science, but to give you a sense that we may have a better way to understand schizophrenia and look at new treatments. We're going to talk about some of the new and emerging treatments, especially the muscarinics, which hopefully many of you have heard about, now that we've had xanomeline/trospium out now for over a year, and look at what the future might be. 

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Let's vote!

Before we get into the content, I do have some more polling questions. These will not be asking you where you live.

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Poll 1

Okay. First one, how many people with schizophrenia do you provide care for in a typical month? Is it: 

A. One to four, 

B. Five to 10; 

C. 11 to 15; 

D. 16 to 20; or 

E. More than 20;

Okay. Next question. Okay, but looks like many of you provide a lot of care, some quite a bit, which is great.

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Pretest 1

Okay. First content question. The mechanism of action of the novels xanomeline/trospium combo involves: 

A. Muscarinic M2/M3 partial agonism;

B. Muscarinic M1/M4 agonism;

C. Muscarinic M4 positive allosteric modulation; or

D. M4 negative allosteric modulation;

Okay. And the answer is [inaudible] . People do have some insight, but we'll go over this. You'll do very differently in the post-test.

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Pretest 2

Okay. Question two. Compared with first-generation antipsychotics, the greatest effect of serotonin 2A antagonism with the SGAs relates to what? Is it:

A. Enhanced efficacy for negative symptoms - enhanced efficacy for - sorry, cognitive symptoms; 

B. Negative symptoms; or 

C. Positive symptoms; or does it 

D. Deduce the risk of drug-induced movement disorders;

Dr. Meyer: Okay. And question - seems like there's some uncertainty there. There'll be clarity later.

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Pretest 3

And then lastly, question three. The phase IIb and III EMERGENT trials of xanomeline/trospium demonstrated which efficacy outcome? Was the: 

A. Pooled effect size 0.65 or 0.56 using the meta-analysis method; did it 

B. Show superiority only for negative symptoms; 

C. No significant difference from placebo; or 

D. Efficacy limited to cognitive symptoms;

Okay. You guys are good test takers, I'll say that.

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The Pathophysiology of Schizophrenia

All right, so this slide I put together. You can see it's very dense.

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What Underlies Schizophrenia?

And let's talk about what underlies schizophrenia. The concept is, in particular, if you have positive symptoms of schizophrenia and you're not treatment-resistant, you have too much dopamine being released in some part of your striatum. And that's why for many years, dopamine blockade works. We'll talk about how xanomeline works in a second.

The question then comes, why is there too much dopamine being released? And really, that's a fundamental issue if we accept the fact that too much dopamine overproduction underlies the positive symptoms. 

Well, these very smart people at Pittsburgh have created this model in rats, which has given us insight into how that occurs. And there's simply an issue with the normal regulatory process which governs dopamine release in the striatum being broken. And the way they've done this is by exposing rats who are pregnant to a toxin. But we think this is the better neurodevelopmental model of schizophrenia and - than what we used to do in the old days, which is to give rats as a model of psychosis, a bunch of amphetamines or PCP. This gave us an answer to why there's a problem. And there's a lack of these what we call GABAergic interneurons, which normally put a brake on dopamine release. And they are insufficient, and that is why you have too much dopamine release.

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What Underlies the Negative and Cognitive Symptoms of Schizophrenia?

I think the idea is we have an interesting model for studying this, and it also gave us insight into cognitive and negative symptoms as well. Because as we come to appreciate, schizophrenia is not just positive symptoms. We focused on that heavily for decades because to be honest, that's all we could really treat. You know, if I'm giving you most agents, all I'm doing, if I'm lucky, is making positive symptoms better. And I have limited impact on negative symptoms or cognition.

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What About Treatment-Resist and Schizophrenia?

Now, I made the point that if you're treatment-resistant, maybe things are different. And this is what we've come to appreciate that if you're not treatment-resistant, you have too much dopamine release in a certain part of your striatum. If you're a rat, that's called the mesolimbic pathway or the VTA. In humans, it's actually a slightly different pathway.

But the point is that there's too much dopamine release. And that's why either postsynaptic blockade might make your positive symptoms better, or xanomeline, which reduces dopamine release presynaptically might also make your positive symptoms better. But when you image people who are treatment-resistant, we don't see that dopamine overproduction underlying their positive symptoms. 

 So they have a slightly different form of schizophrenia. And now once you understand that it makes sense. You think, "Man, I gave this guy all the haloperidol he could handle. Why didn't he get better?" Because he doesn't have a dopamine overproduction problem underlying his positive symptoms. And that's why, at least in this day and age, the only drug with evidence to remediate this problem is clozapine.

We don't fully understand why it works, but it's pretty clear whatever it's doing has nothing to do with its efficacy - I'm sorry, its affinity for D2 receptors, but its efficacy lies in doing other things which moderate other signals involving glutamate. 

But this is important to understand because as we'll get into the muscarinic agent, xanomeline, it's still working on that same dopamine pathway. And so if you ask me, would it necessarily work in resistant schizophrenia? I would say, for one thing, there's no data. That's one - data trumps everything. If you need - if you have data, that's fine. But in the absence of data, theoretically it might not because it's still working on that dopamine pathway. And these people don't have a dopamine problem.

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Muscarinic M1 and M4 Receptors and Schizophrenia Pathophysiology

We're going to talk about a lot about muscarinics. And the reason I want to show you this is to let you know that there are problems in people with schizophrenia related to certain muscarinic receptors, predominantly M1. But we delved into the both the M1 and M4 story, really because of the fortuitous discovery that xanomeline and antipsychotic properties and xanomeline, which is part of the xanomeline/trospium combo, was an M1, M4 agonist. So people did all these animal studies to try to understand how this works, and how do problems in the muscarinic system relate to psychosis?

There was also human studies as well. There's probably not a huge contribution of variations in M4 expression or polymorphisms to schizophrenia, but that's not true for M1. And I'll show you in a second how important that is, especially for cognitive symptoms and negative symptoms as well.

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Cognitive Impairment Associated With Schizophrenia: Course and Impact

And cognition is one of the big unmet needs. I've already talked about negative symptoms, but this is a huge unmet need in schizophrenia. What's the most impairing aspect of the disorder? Yes, we're all very impressed with positive symptoms. People have interesting things to say. Their behavior may be disorganized, but we're often pretty good at moderating those symptoms. Why do people not be able to function independently? Because they have cognitive deficits, which is exceedingly common, and none of our agents really effectively address this, at least until recently.

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Muscarinic Dysfunction in Schizophrenia

This is one thing which is underlying the cognitive deficits in people with schizophrenia is that their expression of muscarinic M1 receptors in roughly 25% is really, really low. And these people are actually called having the muscarinic receptor deficit syndrome. But the point being is those folks on the left, the MRDS folks, not surprisingly, have a lot of cognitive deficits and also some negative symptoms as well.

When we look at some of the data for xanomeline/trospium, we will see that it did improve cognition, but not necessarily for everybody and now you understand why. Because not everyone has really low M1 expression. Those who did, we hypothesized are the ones who really got that cognitive boost.

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Limitations of D2-Based Therapies Antipsychotics Approved for Schizophrenia Before 2024

But for decades this is what we've done. So these are the agents which have been approved since 1957. All of these, for the most part, are D2 blockers, except one old, old drug which is called reserpine, which actually worked presynaptically. It was a non-selective VMAT1 and VMAT2 inhibitor.

And the whole point was, you think, "I've heard of VMAT2 inhibitors. I heard somebody talk about TD yesterday." Yes, you could use reserpine for TD, but it was non-selective. It also blocked VMAT1. So when you cranked up the dose, it lowered people's blood pressure, which is one of its uses as an antihypertensive. And then eventually because it reduced so much dopamine outflow and it was non-selective, you gave people parkinsonism and akathisia and folks just stopped using it.

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How D2 Antagonists Work

This is how a D2 antagonist works. You think, "Okay, I want to block postsynaptic D2 receptors with a D2 antagonist." That's correct. But in case you didn't know, on the presynaptic side, we have what are called inhibitory autoreceptors. Their job is to act as a brake on dopamine release. So dopamine, which is released into the synapse, some of which will come back to that auto receptor and tell the presynaptic side, stop releasing dopamine.

Well, we actually block that break with a D2 antagonist. And so when you give D2 antagonist, you're actually working against yourself - literally working against yourself.

And that may be why we have to give so much antagonism to treat the positive symptoms of schizophrenia, because we're actually blocking that presynaptic braking mechanism. But the biggest issue, as much as anything is not only are we doing this and we're blocking things at a fairly high level, it's non-selective. I - does anyone here treat rats, by the way? Anyone? No. What if they have many, many? No. All right.

If you're treating your animals, you know, I want to reduce dopamine VTA mesolimbic pathway. Okay. The problem is my antipsychotic doesn't just go there. It goes everywhere. And that's the problem.

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D2 Blockade Can Also Cause Adverse Endocrine Effects

It goes to the motor area of the striatum. It goes to the pancreas. In case you didn't know, you have D2 receptors in the pancreas. Why do people living with schizophrenia have two times higher rates of cardiometabolic disorders? This may be part of it. And then of course the drugs do other things as well.

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Antipsychotics Heat Maps: Impact on Weight, BMI and Metabolic Parameters

Some of our agents induce weight gain. Some of them directly impair glycemic control by other mechanisms or cause dyslipidemia. Here's the heat map of some of the cardiometabolic effects that we see from a variety of antipsychotics. It's a big problem.

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Frequency of Antipsychotic Toxicities in Schizophrenia

But most specifically to what we're talking about, here's the D2-related adverse effect. So they're coded in red. In case you didn't know that - is anyone here new in practice, by the way? In case you didn't know. Okay. Just this is a general rule of thumb. People don't like side effects. So you learn something. Oh, that's why I got up at 8:00 in the morning.

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What did 5-HT2A Antagonism Really Do For Us?

Okay, now, the second generations have a built in mechanism, which is serotonin 2A antagonism. And so these are the things which were designed after clozapine was discovered to be relatively special to, in theory, mimic clozapine. None of them ever did, by the way. And you probably know that nothing works in resistant schizophrenia except for clozapine.

But serotonin 2A antagonism was very intriguing, and people thought it might give a whole bunch of different properties to these compounds. What it did do, and this is absolutely true, is that having serotonin 2A antagonism reduced the rates of drug-induced movement disorders.

In this day and age, I just want to say, we try not to use that three letter acronym movement disorders. It begins with an E and ends with an S. Not sure what the middle letter is. Your job going - don't say it. Your job going forward when you see patients on Monday is not to write those three letters in the chart ever again. I'm just saying your job is to call it what it is. You think - I think this lady has drug-induced parkinsonism. You know, how you can abbreviate that in the chart? DIP, D-I-P. I think this person has DIP.

 If somebody has tardive dyskinesia, what do you write in the chart? TD. And akathisia, you know what you write in the chart? Akathisia. The point is don't use those three letters ever again. And please stop giving people benztropine. Okay. You heard that yesterday. You're hearing it again today. Stop using that stuff. Stop using diphenhydramine.

Okay, small rant aside, this is what serotonin 2A antagonism did. It reduced the rates of movement disorders. It did not, however, make these drugs very effective for negative symptoms or cognitive deficits. Despite what you may have heard. Here's the data. Here's the meta-analysis. Those are the references down below. It did not. And this has been a huge unmet need.

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Antipsychotic Adherence: Related Adverse Events

And the problem is when people get a lot of adverse effects, motor or otherwise, they don't take their meds. And one thing I've learned in studying psychopharmacology is that when the pill sits in the bottle, it's less effective. It has to do with the plastic inhibits the action at the receptor. But the point is people don't take this stuff. It doesn't work. And that's one of the huge problems for a lot of our agents. They actually were effective for - for a good chunk of people, but they didn't want to take them because of all of these adverse effects.

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The Unmet Need in Schizophrenia: Limitations of Current Therapies

And then there was other unmet needs, in particular for negative symptoms and cognitive deficits. But now we're in a new era where you don't have to rely on D2 modulation for people who aren't treatment-resistant.

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New Muscarinic Mechanisms for Schizophrenia

And the muscarinic era began on September 26th of 2024, with the approval of xanomeline/trospium. And what was ironic, and I thought very cool is that, that approval date was exactly 35 years after the approval of clozapine, also revolutionary drug.

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Xanomeline In Vitro Binding and Functional Activity

This is the activity of xanomeline. And as you see, if you look at the binding numbers in the middle, if you just look at that, you'd think, "I don't know, Where does this drug work?" It looks like it binds to all the muscarinic receptors kind of equally. Where the difference is, is the intrinsic activity. Xanomeline is an M1 and M4 agonist.

And if you look at the numbers in the parentheses in the right column, you can see the activity at M1 is almost 80% of what you get from acetylcholine. And for M4 it's 96%. It does have a little bit of activity at some of the other muscarinic receptors. But we think all of what we're doing for psychosis and maybe other aspects of cognition or negative symptoms is from the M1, M4 activities.

The downside, though, of some of these muscarinic activities were high rates of peripheral procholinergic, not anti. Procholinergic adverse effects, which people experienced as nausea and vomiting if you gave xanomeline just by itself, which they did. And people didn’t tolerate it, and you had to find a way to mitigate these procholinergic adverse effects.

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Managing the Peripheral Procholinergic Effects of Xanomeline

And the solution problem was trospium. Trospium is a medicine which has been available in the US for over 20 years, and outside the US for maybe 50 years. It's been around for a long time. It's an anticholinergic. So I know you're thinking I just told you not to give people anticholinergics. Yes. This anticholinergic doesn't get into your brain. It has very, very low CNS penetration.

So it does exactly what you want. It blocks xanomeline from stimulating things in the gut, for example, and giving people some of those GI side effects. But it doesn't get into your brain and act like Cogentin, for one thing. 

And also, if it did act like Cogentin, it would interfere with the action of xanomeline. Xanomeline is trying to stimulate those receptors, and something which is strongly anticholinergic would totally block it. The whole point is trospium stays in the periphery largely, and there it helps drastically reduce the rates of procholinergic adverse effects by 65% to 70%. They are not absent. I'm not going to say otherwise, but it is much better tolerated. And that's why we actually have a marketed drug.

Now, if you always wanted to know how xanomeline really works with schizophrenia, we have this nice video.

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Mechanism of Action Video

So I'll go ahead and show that to you, and then we'll take it up with some of the clinical data. So go ahead and play the video.

Speaker: Positive symptoms of schizophrenia, such as hallucinations and delusions, are related to the associative and limbic striatum and are caused by excessive dopamine release by VTA neurons.

First and second-generation antipsychotics manage excessive dopamine release by blocking postsynaptic dopamine receptors. A new approach to schizophrenia involves limiting dopamine release from VTA neurons. VTA neurons are regulated by two neuronal circuits in which the muscarinic system plays an important role. 

First, the midbrain pathway, the LDT, which modulates VTA dopamine release via acetylcholine. Second, the glutamate pathway arising from the prefrontal cortex also regulates VTA neurons. Both pathways can be addressed using an acetylcholine receptor agonist specific for M1 and M4 receptors like xanomeline. LDT neurons have inhibitory M4 autoreceptors. Activating these receptors reduces acetylcholine, thereby reducing VTA stimulation and dopamine release. 

Prefrontal cortex pyramidal neurons are regulated by inhibitory GABAergic interneurons, which express M1 receptors. Stimulating M1 receptors releases GABA, an inhibitory neurotransmitter which reduces glutamate output in pyramidal neurons, reducing VTA stimulation, and striatal dopamine release.

M1 and M4 receptors are highly expressed in brain areas relating to positive, negative, and cognitive symptoms of schizophrenia, but are uncommon in areas that relate to adverse effects of current antipsychotic medications. Treatment with M1, M4 agonists, like xanomeline, is a new approach to schizophrenia by reducing dopamine levels at the source.

Dr. Meyer: If you've never heard about this mechanism, it does look a little daunting. But in a nutshell, again, using the animal terminology. If you have positive symptoms, you have too much dopamine release in the mesolimbic pathway. I'll use the - the term VTA. That VTA neuron gets a couple of different inputs. If we think the problem really is a presynaptic problem with positive symptoms, what I'd like to do is turn off the flow of dopamine at the source, so to speak, rather than blocking it postsynaptically and doing it non-selectively. You know, doing it in the pituitary, doing it in the motor area, and that's what xanomeline does. 

Both M1 and M4 agonism reduce inputs to the VTA, and therefore we have less dopamine release. And most importantly, it's happening selectively where we have the positive symptoms of schizophrenia. We're not reducing dopamine release in the motor pathway. We're not affecting the pituitary. And that's just the revolution of muscarinic agonism.

I now have a non-D2 mechanism which is also selective, and that is what's so exciting about having this type of treatment for schizophrenia.

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EMERGENT Trials: Safety and Efficacy of Xanomeline/Trospium

For those of you who've looked in the package insert for xanomeline/trospium, you probably know there's a word missing in there. Does anyone know what that word is which is not in that package insert? Antipsychotic. It's a drug approved for schizophrenia. It's not an antipsychotic. Yes, it has antipsychotic properties, but the FDA was making a point. This is its own new class of medicines which treats people living with schizophrenia. It has nothing to do with the whole generation of D2-binding agents.

Here's the studies that got it approved. The EMERGENT studies were all double-blind, placebo-controlled, inpatient five-week study. 

You can see the standard titration. I'll talk about the dosing a little bit later. But I will say two things. It is a BID drug, and most importantly, you cannot take it with food. Because the purpose of trospium in the combo is to mitigate the pro-cholinergic adverse effects of xanomeline. When you take trospium with food, you lose almost all of it. And so these people would take it first thing in the morning and then usually at bedtime, two hours after their evening meal.

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EMERGENT Trials: Change in PANSS Total Score

Here's the standard titration. And this is the exciting findings that these people got better in all the studies. In fact, there's not been a study of xanomeline/trospium by itself for schizophrenia, which is not separated from placebo. Even small studies done over 20 years ago. So you see the effect size here, which may have been a question, of 0.65. And that's using modern statistical methods. We'll put that into a context in a second.

Here's the long-term changes in the positive and negative syndrome scale. Generally, we believe as long as you take your antipsychotic it continues to work. But you know, here's a novel mechanism for all we knew, maybe you'd get tolerance. We had no idea. But it's pretty clear, as long as people take it, they continue to get better and they get better and better over time.

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A Historical Perspective on Effective Size

I mentioned before that using the modern statistical methods, the effect size was 0.65. But to put that into context, we have to use a slightly different statistical technique when we do meta-analyses. And allows us to compare modern data sets to drug study 30 and 40 years ago.

Here's the effect size for xanomeline/trospium. I think the point is that it's not more effective than we've had, but it's as effective as anything we've had approved over the last 32 years. The effect size using the meta-analysis method is 0.56.

Is it clozapine? No, but nothing is clozapine. That's fine. So what? Here's a drug which is not going to give you weight gain, which is not going to give you, what's those three letters? Don't say it. I'm not going to give you akathisia or DIP or TD. Not going to give you endocrine problems. That's a big deal. You're treating somebody who's 20 years old with her first episode of schizophrenia. Wouldn't it be nice to offer her a medication that's not going to cause weight gain or menstrual irregularities, or gynecomastia, or weight gain?

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EMERGENT Trials Onset and Duration AEs

These are the things that we do have to deal with, which are some of the adverse effects. The procholinergic stuff is what people really have trouble managing sometimes. I will give you a couple of pointers later on about initiating this, but they tend to be fairly short in duration. You know, things like constipation. We're very good at managing. It's a pro-cholinergic stuff that folks had a little bit of trouble with, but it tended to be fairly time limited. And usually it happened when we went from the first dose, which was 50/20.

When I give you two numbers, or if I say 50/20, the first number is the xanomeline and the second number is the trospium. The standard titration was 50/20 BID for a couple of days, and then you went to 100/20 or 100-20 BID. Well, that was the problem we realized in retrospect, because you're doubling the xanomeline, but the trospium remains the same. And that's when people tended to have their problem.

But once they got over the hump, there was tolerance for that, and it tended not to recur.

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EMERGENT Trials: Pooled Safety and Tolerability

So here's the pooled data from the long-term study. So this is over a year. And you can see there is some nausea and vomiting, but these numbers are not too dissimilar to the short-term studies. So the point is that if people had an episode, it was usually a one-time event. And that was it. And then they developed some tolerance and we didn't see it thereafter. But it's an important part about talking to people about this, and as we'll discuss, finding ways to mitigate this so that people can get the benefit of a really novel mechanism that we've never had before to manage adverse effects.

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EMERGENT- 1-3: Impact of Baseline Negative Impairment on Improvement in Marder Negative Symptom Factor

What was exciting is, in these studies, they did some post-hoc analyses looking at negative symptoms. As I argued before, we've really never made much inroads in negative symptoms. If anything, we've often made them worse. You know, if I give you all a whole lot of D2 blockade, you're probably not going to be the most motivated person in the world, among other things.

But we saw a signal here for improvement in negative symptoms, and especially on the right, if you had a lot of negative symptoms at baseline. You know, there's a lot of hypotheses for why this might be true. But as I alluded to before, the M1 agonist properties of xanomeline might be contributing to some of these unique aspects. But it won't be for everybody. You can see the biggest effect is for people who had a lot of negative symptoms at baseline, and the hypothesis is that if we actually could image these people or take their brains even though they're using them, we might see that this is the subgroup with really low M1 expression. That's just a hypothesis.

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Cognitive Benefit From Muscarinic Stimulation? EMERGENT-1 Analysis

But that's also the hypothesis for the benefit and cognition. Again, it didn't make everyone better. But if you remember that earlier graphic I showed you, there's only a fraction of people, maybe 25%, who have really low M1 expression. And those are the people who have the more significant cognitive deficits.

Well, here again, if you look at people who had minimal cognitive impairment, xanomeline didn't make them a whole lot smarter. But those who had a lot of cognitive impairment, admittedly, is a small study. Now we're seeing a pretty big effect size. So this is in the earliest study. You can see the sample sizes are kind of small, but this exact signal was replicated in the next two studies which were much larger.

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EMERGENT Trials: CANTAB by Cognitive Subgroup

Again, the benefit on cognition accrued to those who had really more significant baseline impairments. And that's very exciting because, you know, we had to make cognition better before this. Nothing.

Now, this is not a dedicated cog study, which is usually done in stable outpatients. And so we would say this is a very exciting signal. You may have seen this as you've treated patients but don't promise it to everybody for one thing. And we would like to see some more data, maybe in stable outpatients. But the fact that it's been replicated a couple of times. We think this is probably a real finding. But again, it's going to be beneficial if it is to anyone in those who have significant impairment at baseline.

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Adjunctive Study of Xanomeline/Trospium

Now you think, okay, I'm using drugs that work postsynaptically, right? What if I added this on top of it? Now I'm working both sides of the synapse. I can block D2 postsynaptically and then I can turn off the spigot presynaptically. Sounds wonderful. An adjunct study was done. It was called the ARISE study.

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What Can We Learn From the ARISE Adjunctive Trial Findings?

Well, it didn't quite work out. As you can see in the upper left, the change in the PANSS score very hard to see, but it really didn't separate much from placebo. The idea was that for a lot of people, if they're getting a ton of D2 blockade, turning off dopamine release presynaptically, maybe it doesn't change things a whole lot. You've already reduced dopamine neurotransmission so much. You've essentially gotten what you're going to get from reducing dopamine activity postsynaptically. But they did some subanalyses. And there's a couple of things they found. 

So if you look at that graphic in the middle there, that little table, you can see that the people who are on aripiprazole actually got some benefit when xanomeline was added in a way that we didn't see from stronger D2 antagonists like risperidone or paliperidone. So that's kind of exciting. And you say, "Well, I got somebody who's on LAI aripiprazole and I want to add this. Might it make them better?" It might.

I don't want to dissuade you from adding it to another D2 antagonist. I just say you should moderate your expectations based upon this data. 

 Also, one thing we saw is that if we just look at the positive symptoms, there probably was some separation overall, regardless of what drug you were on. It wasn't dramatic, but there probably was some benefit. But a lot of the benefit devolved to those people who weren't the sickest of the sick, and these were people who had PANSS scores under 90 at baseline. The point is that some of these people who are already getting a D2 antagonist, who had PANSS scores or 90 above need another drug. And what is that drug? Clozapine. This drug isn't clozapine. 

 On the other hand, you've got some of these folks who, as we kind of say, are partial responders. Euphemistically, we sometimes refer to them as the walking wounded. Look, they're better on drug than there are - than nothing, right? It's like, "Okay, I got this guy, and he's better on that than on nothing, but he ain't great."

I don't want to say adding xanomeline shouldn't be done. But you should know, maybe it might not work out. But, you know, I don't think there's a reason not to consider it, because at least you'll have convinced yourself and maybe the patient and the patient's family and caregivers, whether or not they need clozapine as the next step.

And if this works out adjunctively, great, problem solved. If it doesn't, now you know the answer. That brain probably needs the special properties of clozapine.

[00:37:29]

Is M1 Receptor Stimulation Necessary? M4 Selective Agents in Development

Well, as I mentioned, the procholinergic stuff we think comes a lot from the M1 side of the xanomeline. And so the question was, even though both M1 and M4 receptor stimulation contributes to the efficacy, if I can get rid of the M1 stuff, I can get rid of all the procholinergic adverse effects, and maybe I'll lose a little bit of efficacy, but I'll be swapping it out for ease of use and tolerability. Maybe I won't have to titrate. I don't have to have a second drug to manage the side effects.

[00:37:58]

Orthosteric and Allosteric Binding: Relevance for Muscarinic Receptors

How do I do that? Well, the muscarinic receptor system is kind of tricky. There are five subtypes of receptors. Just so you know, I showed you the binding profile of xanomeline. It bound to all of them in some way.

The problem is where acetylcholine binds, which is called the orthosteric site. This is true for all receptors where the natural neurotransmitter or ligand binds is called the orthosteric site. Well, where an agonist binds, it's usually stimulating that orthosteric site. The problem is for the five muscarinic receptors those orthosteric sites are highly conserved. They're very, very similar. So it's hard to make a very selective agonist. 

 What people have figured out, though, is that there's another way to stimulate activity at these muscarinic receptors is by binding at what we call the allosteric site.

Now, some of you out there are actually giving positive allosteric modulators to some of your patients in the form of benzodiazepines. So when you put your patients on benzodiazepines, not that you do it all the time, but every once in a while, what you're doing is not giving a GABA agonist. It's not stimulating the orthosteric site. What it's doing is it's binding to a slightly different site, which changes the configuration of the receptor a little bit, and it makes the GABA more active.

So a positive allosteric modulator increases the activity of the endogenous neurotransmitter. In theory, there's also negative allosteric modulators. I can't think of one. They might exist in the pharmacopeia, but we have a PAM in the form of benzodiazepines and that's what they do. They modulate the activity at that receptor and they increase what GABA does in terms of its activity.

Well, it turns out the allosteric site on the muscarinic receptors is different across all the five subtypes, and therefore I can make a very selective M4 acting agent by acting as an M4 PAM or positive allosteric modulator, in a way that will be very difficult to do as an agonist.

[00:40:13]

Emraclidine, M4 PAM: PANSS-Based Efficacy Results Phase1B Study

Well, that all sounds good. And people created a compound called emraclidine. And here's a phase I study. So look at those effect sizes. You can see 0.59, 0.68. Sounds a whole lot like xanomeline/trospium, right? Right in that range looked very exciting.

The company that created that was called Cerevel and they were purchased by a bigger company called AbbVie for many billions of dollars. And what was exciting is not only did it work, you thought, "Man, if I can get the effect size of xanomeline/trospium and without some of its side effects, wouldn't that be nice?"

[00:40:50]

Emraclidine: Safety in Phase IB Study

You know what word you don't see on this? You don't see vomiting. Again, is there anyone here who's new in practice? Is there anyone within, like, new prescribers? Okay, you're all very seasoned, so you probably have appreciated the point patients don't like to throw up, so you learn something. You had no idea. Zero. Zero. And that was great. And people would have accepted again, I'll swap out some efficacy. I'm losing the M1. That's fine. But maybe I have something which is much easier to use.

[00:41:19]

EMPOWER Trials: Negative Findings With Emraclidine

And so two big, big phase II studies were done. And the sad truth was they didn't work. What do you mean? This is a huge bummer on many, many levels. I mean, people hoped we'd have another muscarinic agent. We'd hope we'd have one. Even if the efficacy wasn't quite the same as the xanomeline/trospium, that would be one which is free of some of those pro-cholinergic adverse effects and it didn't work.

So the folks who control this compound, emraclidine, are kind of going back to the drawing board, and really what they're looking at is dosing.  That maybe the max dose that was studied early on was too low overall, and we may just need to explore other doses.

So this is not dead. But it was a setback and it was an unfortunate one, but a lot of other people were plowing along.

[00:42:07]

NBI-1117568: An M4 Selective Agonist

So I live in San Diego. Neurocrine Biosciences is very close to where I live. They have an M4 agent, which they swear up and down as a selective agonist.

Now, I just gave you that a whole lecture about orthosteric sites and being, you know, very, very similar across the five muscarinic receptors. So how can they have a selective M4 agonist? All I can say is people say many things. It's possible that this drug actually does two things at the same time. That it does bind to the orthosteric site, but it may also bind at the same time to the allosteric site. 

 So it might be a two for one. You know, what's another two for one at the M4 receptor? Xanomeline. Xanomeline is both an agonist and a PAM. So - so they say it's an agonist. That's fine. I'll take them at their word. I'm a little skeptical. I suspect it's more of a PAM than an agonist. Not that it matters. It's M4 selective.

And here's the early phase data. Now you're looking at this and you're thinking, "All right, this is really weird. Some of these doses don't separate." They think they have figured it out from these early phase study what the best dose is and they're moving along. 

 But I think the point is that this is an exciting time to be in the world of muscarinics for schizophrenia. As I alluded to before, we think that the M1 property is very important for both positive symptoms and also maybe for the cog and negative symptom. So we have a combination of different agents. We have some M4 selective ones which are PAMs. We have MapLight-007, which is exactly the same model as xanomeline/trospium.

MapLight-007 is a combination of an M1, M4 agonist with a peripherally acting anticholinergic. It's the exact same model. We think it should work. They're doing later phase studies right now and you have other people moving along. 

And then lastly, emraclidine, like I said, they went back to the drawing board and they're trying to work on the dose. But we hope that in the next few years maybe we'll have another muscarinic strategy. But I can say, in case you forgot what day it is, because you had too much to drink last night, it's not 2030. I'm just saying that right now.

[00:44:23]

Starting Xanomeline/Trospium

And so you got to know how to use this guy because this is it. This is it, at least for a few years. And you want to be good at using it because if your patients don't tolerate it or don't like it, you don't have an alternative, which is like this. And like I say, again, here's an agent which doesn't give you weight gain, which doesn't give you movement disorders, doesn't give you hyperprolactinemia. Doesn't that sound good? But only - you can only give a patient those benefits if they'll take it.

[00:44:51]

Our Patient

So here's a patient we got here. 21-year-old. Heritage is Latina. She has schizophrenia. She's been on risperidone four, and of course they had to give her Cogentin, right? Because, you know, just because you have a cognitive disorder, let's make it much worse by giving you Cogentin, which you probably - as you know, probably never needed for one thing and is going to do nothing good for her except impair her cognition.

For prophylaxis, for EPS. I don't know what EPS means. Anyhow. That's a joke. So she comes here. She says, "Look, my positive symptoms were controlled," but she's not happy with the weight gain. She's not happy with gynecomastia. She's not feeling real smart. We kind of know what's going on with there. 

She says she's taking her medicines. I believe no one. Believe. But anyhow, but she's not going to put up with it much longer because of all these adverse effects. And so the big question really is if I wanted to give her the benefit of xanomeline/trospium, will she be adherent with an oral medication?

And then the other thing is because some unfortunate person put her on benztropine, which you're never going to do ever again, ever.

[00:46:04]

Xanomeline/Trospium: Thoughts on Initiation

How do I get rid of it? Okay, a couple of things. I work with a first episode program in San Diego. The big question we always have when we see people is will they take oral meds? It's a coin flip. A lot of folks won't, and then we want them on an LAI. And I love LAIs and I wish we had more, but that's - that's where you have to go. There's no question. Because every time people relapse, you lose drug responsiveness. And that's why people who have a chronic form of schizophrenia look like that, because they've relapsed five or 10 times.

You'll never have more brain than after your first episode of schizophrenia. You'll never have more drug responsiveness than after your first episode of schizophrenia. 

So you just have to kind of, you know, assess your patient and see whether this person can take an oral medicine reliably and follow instructions.

Now, if the person is on an antipsychotic, which is anticholinergic, there's some thinking to do about how I transition them. And part of it has to do with trospium in the periphery, which is anticholinergic. That's its job. But if the person is also on a whole bunch of olanzapine, well, maybe I'll make them really constipated. Or if it's somebody like me, you might give me urinary retention given my - the fact that I'm a male and I'm not 25 years old. 

Now, if the antipsychotic is not anticholinergic, I would say "Just leave it alone. It's not going to harm xanomeline. It's not going to cause any problems if they remain on the risperidone or aripiprazole or cariprazine. Just leave it alone." It gives you time to get the xanomeline to a therapeutic dose, and then you can peel away, if you want to, the underlying antipsychotic.

And again, I mentioned the fact that for some people, the adjunct study wasn't overwhelmingly positive, but occasionally we see people who we cannot trust them to take all medicines reliably, and we're never going to take them off in LAI. As I joke, they're going to get their last shot at the time of their funeral, just in case. Just in case. And that's fine. You'll leave it alone. And, you know, the LAIs we have are not anticholinergic.

[00:48:10]

Xanomeline/Trospium: How to Initiate

Okay. A couple of things. The PI said 50/20 for at least two days. One thing we are starting to learn now that we have a years’ worth of experience with this, is that leaving people on 50/20 doesn't accomplish a whole lot, because it's not therapeutic, and seemingly it doesn't mitigate the procholinergic adverse effects they might get when they go to 100/20 BID. Just, you know, so don't leave people on 50/20 BID forever. You're not doing them any favors whatsoever. The issue is often once you get to 100/20 BID.

And here's a couple of strategies I will give you. The first thing is ondansetron is cheap. It's readily available. Give people lots of it. And also, as much as anything, you should do the thing which many people don't want to do, which is talk to your patient. I think you can bill for that. And find out how nervous they are about these side effects. I mean, there are some people, if they get anything, they're not going to take it. There’s other folks will say, "Well, if I throw up, I'll give you a call." That's great. But, you know, I want to know where they are on that spectrum and how concerned they are. 

If they're really concerned, everyone's going to get ondansetron regardless, but the people who are really concerned, I'll probably tell them, "You know what? Take it before your first dose, at least an hour before." That means they're going to be taking it a couple of times a day.

The other thing to consider, and this is in select patients, is the big problem is when you go from 50/20 BID which is 40 milligrams of trospium total for the day, right? To 120 BID, which is 40 milligrams of trospium again, but you've now doubled the xanomeline. So how can you solve that problem?

Well, the max dose of trospium a day is 60 milligrams, so you might want to consider in some instances having an extra prescription for trospium 20 milligrams. This is not going to be for everybody, and you don't want to give anyone urinary retention. But if the people are that nervous about, especially if you're treating a younger individual that you - say, "Look, you have this available." Because what we know is that when you get to the highest dose, which is 125/30 BID, you're now on 60 of trospium and that's going to give you all the trospium you can handle. But that intermediate dose doesn't quite give you that exposure, and that may be one way to solve the problem.

The other way to solve the problem is just to go all the way up to 125/30 BID. That might be a hard sell for some patients, and that's just kind of something to bear in mind as you're talking to your patient. I know in my mind, if I can go to 125/30, I'm now giving them 60 milligrams of trospium, but the patient may not be thrilled with that. So you've got to be flexible and you have to know how to work with this so you can get people over the hump. Because what we have found out from a lot of studies is that once they have, if they have any pro-cholinergic adverse effects, that's it. 

And they typically don't have other episodes if they ever did throw up, which is only one out of seven. It probably is not going to happen again. And the reason we know this is that in the long-term extensions, they took people who were on the max dose and they stopped them abruptly from their xanomeline/trospium. And then when they put them back on it, only a few percent after a week had any pro-cholinergic adverse effects. So it really speaks to the concept of tolerance.

You just got to get them over the hump. Once they're on it, they're on it. And then they can get all the benefits from this novel mechanism. 

So here's the food issue. You can see it right here. You have to instruct people. "Do not take this with food," because they're going to lose all their trospium. And if they lose their trospium, what are they going to lose? Possibly their last meal. It's important. You got to let people know what not to do, because what will happen is if somebody gets a little nauseated, they think, "Oh, you know, if I take it with food, maybe that'll mitigate it." No, it's going to make it much worse, much worse. 

So the way I write this prescription is first thing in the morning, an hour before breakfast and then two hours after dinner. I don't write at bedtime because, you know, some of these group homes, they give the HS medicines at 6:30 PM so all the staff can go watch TV. Right? Am I right? Yeah. So you have to write very specifically two hours after dinner. And that's really important because if people give it too close to dinner, they're going to lose the trospium. And then you've defeated the whole purpose. So they've got to get it right. You have to educate patients and caregivers about all these - all these things. 

Lastly, if people are on other anticholinergics, do not stop them abruptly. Most of what we're talking about is benztropine and diphenhydramine. And the reasonable thing to do is just taper those off over the first month as you're adding the xanomeline/trospium.

So this poor unfortunate lady, she's on one milligram BID. You could probably taper off the benztropine by 0.5 milligram a week, and it'll be gone at the end of the month. But if you stop that stuff abruptly, what's going to happen? People get cholinergic rebound. They'll sleep poorly. They'll have vivid dreams and nightmares. And what are they going to do? They blame the new drug, of course, and then they blame you. And even worse, they're going to call you. And that's the worst outcome possible. They'll call you.

[00:53:38]

Xanomeline/Trospium: Drug-Drug Interactions and Monitoring

Okay. There's a couple of little monitoring things. There's not a lot. Get baseline LFTs with bilirubin. There are some transient bumps in the first month, almost all of which resolve except for a very tiny percent and you should check it again. If the patient has no complaints, just check it again after a month or so once you finish your titration, so you can say you've done it.

The heart rate change is nominal, 5.9 beats per minute. This is not clozapine. I don't think you'll ever have to monitor - or I’m sorry, treat this, but you should monitor it. 

If people are on 2D6 inhibitors, you're going to get higher drug exposure. So factor that in into your dosing. And also if people have some renal dysfunction, they will get higher exposure as well. You can't give it to people with cirrhosis. So you heard yesterday some comments about hepatic impairment. Let me just say very specifically, when we say hepatic impairment, this has nothing to do with inflammation, which is measured by AST and ALT or GGT.

What we're talking about is cirrhosis. And cirrhosis is measured by different labs using what's called the Child-Pugh scale. Most of you don't see people with cirrhosis. If people have cirrhosis and it's more advanced Child-Pugh B and C, you can't use this. You'll never see these people. You might have a few people who are Child-Pugh A and just be very cautious. Just go more slowly the way you will do with people who have subnormal renal function.

[00:55:07]

Our Patient

So here's our patient. She doesn't like a whole lot of the stuff she's getting from her current drugs. And we talk about we have a new option, which is not going to give her weight gain, not going to give her gynecomastia. Doesn't get movement disorders. I shouldn't care about that. And we explained to her, look, you do have to take it twice a day. You cannot take it with food. Here's the right way to take it. We give her some ondansetron and we give her instructions because she wasn't as concerned. You don't have to take it, but if you want it, you have it. And if it's not enough, you will give me a call. So here's a suggested titration for this person. 

The reason I say a week for 50/20 is they have sample cards which have a week's worth of medicines, and I'm not going to touch that risperidone. The risperidone is not the problem here, right? What's the problem? It's the Cogentin. It's the benztropine. It's going to interfere with the xanomeline. And it's going to give me additional peripheral side effects with the trospium. And so I'll taper it off slowly. I'm going to go down by roughly 0.5 milligram a week, knowing that after a few weeks it'll be completely gone. She never needed it to begin with. Certainly if she's on risperidone, very unlikely she ever needed it. 

And here I went up to 120 BID with food and, again, the same issues. I say, "Look, if you've got a problem, use ondansetron." And if that's not enough, you give me a call because I got my one other thing I can do is either I can go up to 125/30, which sometimes the patients won't always buy, but I know I'll get max trospium exposure, or I can give her the extra 20 as a separate prescription of trospium. So you got a couple of options there. 

When did I touch the risperidone? Once I got her to a therapeutic dose of xanomeline/trospium. I don't care if she stays on risperidone forever. She's not going to want to stay on it, but it's not anticholinergic. It's not going to interfere with the xanomeline. There's no hurry in getting rid of it. And I don't want to yank away the other drug, which is effective until the second one, I think is at a therapeutic dose. It doesn't make a whole lot of sense. You take the other one away too soon, and now you'll have a sick lady who's on a subtherapeutic dose of xanomeline/trospium. It's not a good way to do it.

[00:57:19]

Can We Target Hippocampal Hyperactivity?

Okay. Lastly, I talk about this animal model for hippocampal hyperactivity.

[00:57:26]

Evenamide: A Novel Agent to target Hippocampal Hyperactivity due to Loss of GABA-ergic Interneuron Inhibition

And I know you're thinking, well, what the hell is all this? I mentioned that we now understand the biological basis for the dopamine overactivity underlying positive symptoms. Now that we have an accurate animal model or really good animal model, now we can study drugs which work on. So I mentioned xanomeline really kind of works on the source of the problem so to speak, which is the dopamine release. But that's actually the second or third step in the process, right?

Why is there too much excessive dopamine release? Because there's a problem way back in the hippocampus with lack of control. Well, talk about treating the problem at the source. This is it. 

 And so people have studied a lot of different molecules. This is really exploratory. But this stuff is now being given to human beings right now. So think about it. We may have something, which really goes back really to the source of the biology of schizophrenia, which may treat the positive symptoms and perhaps the downstream negative and cognitive side effects as well in some people. That's very exciting. This is still very early on. You can read the slide.

I mean, they've given it to people this drug, evenamide. It works. Whether it works in large phase III studies? Who knows. But this might really be the future, and wouldn't that be exciting that we actually are treating schizophrenia not just at the dopamine problem source, but upstream from that where all arises way back in the hippocampus and a lack of control over a lot of things just due to loss of these GABAergic inhibitory interneurons.

It might be the future, and you might be one of the few people who've actually heard about this. Will you get into your hands? I don't know, but man, it will be exciting if it happens.

[00:59:17]

Key Summary Points

Okay, some summary points. We think we have a better understanding of the pathophysiology of schizophrenia based on that animal model. We hope it will yield new treatments, but certainly we now have an alternative to the D2-binding solution to a presynaptic problem. We were never happy with the non-selective postsynaptic solution, but guess what? It was better than what we had before, because before chlorpromazine was fortuitously found to work for schizophrenia, you know, we had before that? Yes, you said it. Nothing. There you go. You said nothing. That's what I heard. Nothing. 

We have large state hospitals. That was it. Large state hospitals. ECT works, but, you know, it's - it's not easy to implement and you have to keep giving it. So it was a revolution in and of itself. But we really didn't have much for a lot of people, especially for those who are having negative and cognitive deficits. And the limitations of therapies, I think, were evident to everyone in this room. You've all used them, but we are now in a whole new era of schizophrenia treatment. It's not going to be that we're going to abandon D2 blockade. 

Again, if somebody needs an LAI, the only LAI I got my hands on is one that's going to bind to the D2 receptors, but we're hoping more and more. This will be the future of schizophrenia treatment. I mean, this really is a dawn of a new era that I can make schizophrenia better and maybe make it better across all the symptom clusters without the need for non-selective D2 binding.

Your job is to not be afraid of xanomeline/trospium. Learn how to use it. Most importantly, talk to your patient. If they understand your excitement about this, maybe they might be willing to put up with a little inconvenience or some adverse effects to get something which no other drug before this has ever given them.

[01:01:08]

Let's Vote Again!

So at this point, I'm going to stop talking. So thank you all very much. Appreciate it.

[01:01:16]

Posttest 1

And let's see how you do on the post-test. So I think everyone's going to get this one correctly, even the virtual people. The mechanism of action of xanomeline/trospium involves: Is it:

A. Muscarinic M2/M3 partial agonism; 

B. Muscarinic M1/M4 agonism; 

C. Muscarinic M4 positive allosteric modulation; or 

D. Muscarinic M4 negative allosteric modulation;

Okay. And the correct answer is you all know is B. Very good. 92.9%. I'll take that.

[01:02:08]

          Posttest 1:Rationale

Yeah. It's an M1/M4 drug. All the drugs being developed going forward on the muscarinic side are either M4 or M1 plus M4. So that is great.

[01:02:18]

Posttest 2

Question two. Compared with the first-generation agents. I gave you a whole big thing about serotonin 2A antagonism. But what did it really do for us? Did it: 

A. Enhance efficacy for cognitive symptoms; 

B. For negative symptoms; 

C. For positive symptoms; or did it 

D. Reduce rates of drug-induced movement disorders;

[01:03:05]

          Posttest 2: Rationale

And the correct answer is D. Yeah, it really did not. I'll just say this again. You have the references on that slide. It didn't make negative symptoms better. It did not make cognitive symptoms better. All it did - which is a big deal by the way. I don't want to minimize this. It really improved motoric tolerability, reduce the rates of akathisia, drug-induced parkinsonism and TD several fold, which was a big win, but it really didn't solve the problems for those other aspects of schizophrenia that weren't previously addressed.

[01:03:33]

Posttest 3

Okay. Question three. Across all the studies for xanomeline/trospium, what was true about them in terms of efficacy outcome? Was it that the 

A. Pooled effect size was 0.65 or 0.56 using the meta-analysis method: 

B. That it only shows superiority for negative symptoms versus placebo; was there 

C. No difference from placebo, or was 

D. The efficacy just limited to cognitive symptoms; 

You're all going to get this one. Okay. And the correct answer. Oh, 96%. Excellent. Really good. Okay, so we have about six minutes for questions. So let me get into some of these and see what we got.

[01:04:32]

Q&A

Can xanomeline be taken with an antidepressant? Absolutely. The only issue would be it's not been studied formally, but my only concern is drug-drug interactions. I would try to avoid things which are 2D6 inhibitors. So I would say, you know, the antidepressants we use commonly like sertraline, citalopram probably not an issue. I probably would avoid fluoxetine, paroxetine, or bupropion.

So the question is, why can't we give separate doses of both medicines instead of a combo? Because the combo is what was approved by the FDA. You cannot get xanomeline into your hot little hands. I don't know how - you can't. You just - it's not available out there. So, yes, I understand sometimes people have frustrations with fixed dose combos, but it is what it is. 

As I said though, you can manipulate the trospium exposure independently and you may have to do that in some circumstances. You know, again, one option is to go up to the highest dose, which gives you the max trospium exposure. Or if they're stuck at 100/20 BID, you could give them an extra 20. But you can't manipulate those.

Can this agent be used for bipolar disorder with psychotic features? Has it been studied? They are going to look at mania indications. So we will see. I don't know that it will address the mania or if it will do it in a way that a D2 blocking agent might. I just don't know. It might. It might because blocking dopamine seems to make mania better. I just can't give you any insights onto that. 

So is there a benefit to transferring individuals who have been on other agents for a while to xanomeline/trospium for cognition? Well, the big question really comes down to what don't they like about their current drug? And can they take oral medicines reliably. If the person can take oral medicines reliably, I would absolutely offer them a transition. For one thing, you'll lose whatever the adverse effects are that they don't like currently, weight gain, endocrine stuff, movement disorders, sedation, things of that sort. Might it benefit their cognition? 

Again, that benefit only really applied to a fraction of the people. Maybe we'll call it 25%. If they do have significant cognitive impairment and you've finally taken them off the Benadryl and the Cogentin and the benzos and the trazodone, and they still have cognitive impairment, I would give it a try. I don't think you have a lot to lose, and you might really help some people, but not everybody. You know, if the patients are high functioning, they're doing well on their cariprazine, and they say, "Hey, well, this make me smarter?" "I don't know, you're living independently. You have a volunteer job. You know, you pay your bills. I can't promise you that." 

But the people who have significant cognitive impairment, I have more hope that it might really make a difference.

So the question is really, when - when getting to xanomeline/trospium, and I think it's realistic that many insurance companies will not allow it as the first drug. Why? Because it's expensive. It's a brand name product. But to be honest, the case I presented is often the way it goes is that you're going to get this person in your outpatient practice who's already been on at least one agent. 

 And in many places, that's all you need to get to it. Sometimes you have to fail a couple of agents. Well, you know how to play the game. So maybe the case I showed you shouldn't like a risperidone. And you're like, "This is the drug I really want to give you. But we have to fail one more agent, so we're going to give you something. You're not going to like it. And then we will transition you." So you just pick something else. I would say, though, make your life easy. 

If I want to switch something to xanomeline/trospium, it's much easier if the underlying antipsychotic is not anticholinergic. So let me cover that real briefly. So let's say this lady was on olanzapine, which is not a great choice for a 20-year-old, especially a 20-year-old who's non-White. Let me tell you, unless your goal is to make her gain a whole lot of weight.

So - but she responds to 20 of olanzapine, how would I switch her to xanomeline/trospium? Well, my only concern really is peripheral anticholinergic effects. 

Again, I don't want to be in a hurry yanking away that olanzapine too soon because it might take me a week or two to get up to the higher dose of xanomeline and trospium, which is 120 BID. So I would probably leave it alone for the first week while she's on 50/20 BID. Then when she goes to the next dose 120, if she tolerates it, then that's the point where I'd start reducing the olanzapine with the goal of over the next couple of weeks, tapering it off. 

But again, don't yank away the other drug on day one because 50/20, we don't think it's therapeutic for - for anybody really. And you want to give yourself some chance to kind of get the person again over the hump up to that 100/20 BID dose, which we think is more likely to be effective before we start pulling away the other drug.

Again, if the other drug is not anticholinergic, all that discussion is moot. Just leave him alone. "I don't know, I don't like my Vraylar. Fine, take it for another month and I'll get rid of it. Okay. Or your risperidone or paliperidone or aripiprazole." There's no issue in overlapping them. There's no additive adverse effects.

Now let me see if I can do one more quick question. Is it safe to use in people on GLP-1 drugs? So the only question there really comes down to if people are new on their GLP-1s, the issue for them is nausea, right? Is that the time to start xanomeline/trospium? Probably not. On the other hand, if you have somebody who comes in and she says, "Look, I've been on tirzepatide or semaglutide for a year and I'm great. No nausea, no vomiting, nothing. I'm fine." That's fine. But don't want to do two things at once. 

If they're still titrating up their GLP-1 or their tirzepatide, I don't think that's the time you want to give another agent, which may have some GI side effects. Wait till they're stable and then you can take it from there. Okay, so it looks like we're not out of time. Thank you so much.