Setting the Stage: Unmet Needs in Schizophrenia Management

And then we will press on to setting the stage of unmet needs in schizophrenia management.

[00:02:48]

The Dopamine Hypothesis of Schizophrenia: Positive, Negative and Cognitive Symptoms

So just like in those movies where everything gets blurry in a flashback scene, pretend we're getting blurry in a flashback scene. I bet you, you were taught at some point in your training, and you may even have taught others in your training the idea that schizophrenia is a problem with dopamine, and that in certain parts of the brain there's too much of it which causes psychosis. And in other parts of the brain, there's too little of it which we think causes negative symptoms.

I know I was taught that. I confess I have taught others that. And it's partly true. It's just partly also not true. So what's true?

Well, here are the - the primary circuits in the brain that we think are dysfunctional in schizophrenia. Like I just said, in the midbrain we have the - the mesolimbic dopamine pathway. That's what goes from the ventral tegmental area to the nucleus accumbens. And there's also circuits that go to another area now called the associative striatum.

We think that too much dopamine in that circuitry probably contributes to, if not directly leads to, psychosis. And so traditional antipsychotics block dopamine transmission. There is kind of a blunt instrument just block dopamine. And likewise, if we look over here from the ventral tegmental area out to the prefrontal cortex, here we think there's not enough dopamine going on. And so low tone of dopamine transmission in the mesocortical pathway, we think plays a role in negative and positive - negative symptoms, not positive symptoms.

So avolition apathy, anhedonia and some of the cognitive symptoms, attentional processing, executive dysfunction, working memory probably is just too little dopamine there. And if we had a perfect brain and a perfect world, we'd crank up dopamine in the mesocortical pathway and we'd bring it down in the mesolimbic pathway if we had such a perfect world. Oh, and if we really had a perfect world, we would spare any collateral damage to the other innocent bystander dopamine pathways shown here, the tuberoinfundibular pathway that's from the hypothalamus to the pituitary gland.

If you block dopamine there, prolactin levels go up. You get gynecomastia. you get amenorrhea, galactorrhea, and maybe even depression and osteoporosis and other problems of high prolactin. So we want to leave that pathway alone.

And then lastly in the nigrostriatal pathway, we don't want to imitate Parkinson's disease by blocking dopamine there. And then you get, in the dorsal striatum as it's called the collateral damage of extrapyramidal symptoms, akathisia, EPS and so on.

[00:05:31]

Domains of Cognitive Dysfunction in Schizophrenia

So - so - so let's go back in sort of conceptually thinking of schizophrenia as - as a complex syndrome that really was named dementia praecox based on the fact that it involved pervasive cognitive symptoms across just about all major domains of cognitive functioning shown here. For instance, attention, executive functioning, processing speed, verbal learning, different kinds of memory, working memory, visual memory.

And it may well be a progressive or neurodegenerative that starts in youth, hence the term dementia praecox. It's a neuro-progressive dementia that starts out in youth and there's loss of brain tissue. And so it's not just psychosis and it's not just positive symptoms and negative symptoms, but you also have the cognitive symptoms of schizophrenia.

So we've been going at this complex syndrome for decades mainly by blocking dopamine receptors, and in particular, D2 receptors.

[00:06:26]

How D₂ Antagonists Work

In an oversimplified nutshell, dopamine D2 receptors are certainly prominently found in all the areas that we just talked about. And if you block them, you can interfere with transmission. So there are 2 kinds of D2 receptors we think, presynaptic and postsynaptic. The presynaptic ones shown here on the axon terminal are autoreceptors. Binding there may regulate the outflow of dopamine. And postsynaptically, you've got like catcher's mitts, like just like the pitcher's - the catcher's waiting for the pitcher to throw the ball catches the ball.

And we think that in schizophrenia, the problem, at least for positive symptoms. And I say with my baseball analogy, since it's October, if you don't mind, is the pitching machine is throwing a lot of pitches at the catcher, and the catcher is trying to catch them all, but there's just so much transmission of these dopamine baseballs going across the mound to the catcher's mitt, it's hard to keep up with.

So what do you do? You block the catcher's mitt, you block the receptor, you block the D2 dopamine receptor postsynaptically. And that is one way to try to downregulate positive symptoms. Unfortunately, if you do that in the mesocortical pathway, well, you don't want to downregulate dopamine there. You're going to aggravate if not even cause negative symptoms - secondary negative symptoms.

If you do that in the dorsal striatum, you get parkinsonism. So these D2 blockers, you know, it's true that they have their effect, but they really are very non-surgical and imprecise as - as a way to try to manage things.

And then last but not least in terms of side effects, if it's not enough to say we don't have the perfect mechanism to make the pitching machine slow down, these collateral pathways, we also, in the case of atypical antipsychotics, in particular, can have other kinds of side effects too.

[00:08:22]

Pretest 2

So this brings us to this pre-test question. In clinical trials of the combination of olanzapine/samidorphan, what was the key differentiating safety outcome compared with olanzapine alone? Was it:

1. A lower rate of akathisia;
2. Reduced prolactin elevation;
3. A 50% lower risk of gaining more than 10% - more - gaining at least or more than 10% of your body weight over 6 months; or
4. Improved glycemic control.

What was the key differentiating safety outcome in those studies? And we will come back to this momentarily. But take a moment. Let's let you vote. We'll look at the polling. And as the votes are coming in, we're going to see the results on the back end when we post-test you. So okay, well, let's move on from here.

[00:09:18]

D₂ Blockade Can Also Cause Adverse Endocrine Effects

So dopamine blockade does lots of things, as I just mentioned. And one thing dopamine blockade does, believe it or not, is it also interferes with normal glycemic regulation. So who knew, you have D2 dopamine receptors in your pancreatic beta cells. And if you're giving somebody a first-generation or even a second-generation antipsychotic, block those dopamine receptors and you can actually interfere with the effects of insulin.

So while we often think of atypical antipsychotics as disrupting insulin signaling as one reason for metabolic syndrome, you can get weight gain, you can get high blood sugar, you can get dyslipidemias, particularly from atypical antipsychotics, and some more than others. You can even get them from first-generation antipsychotics because of these D2 receptor blockades.

[00:10:15]

Long-term Olanzapine Is Superior to Many Other Antipsychotics . . .

So with that in mind, there are differences among all antipsychotics in how much they disrupt insulin signaling, which plays this role in metabolic regulation. And likewise, there's also differences among antipsychotics and efficacy. And as is so true in all of psychopharmacology, if not all of medicine, we're always doing risks and benefits.

I have a really efficacious, terrific drug, but it's got side effects. Everything has side effects, even placebos. So we're trying to get a balance.

Now, what if I've got a really hard to treat form of an illness, say, schizophrenia, especially if it doesn't get better with a first or second treatment? Are all other antipsychotics treated equal in their chance of success? And then how does that fit in against risk? So this is a kind of a nice meta-analysis that says in long-term treatment of psychosis and schizophrenia patients, as it turns out, olanzapine actually has certain advantages over other antipsychotics. The ones at the bottom that go to the right of - of the zero vertical line.

So as compared to ziprasidone, asenapine, iloperidone, paliperidone, haloperidol, quetiapine, aripiprazole, risperidone, a lot of these agents are actually not - not as effective as olanzapine in terms of long-term relapse prevention of positive symptoms as well as negative symptoms in schizophrenia patients. So that's an important point as you're thinking to yourself, well, but these medicines also may differ in metabolic profiles or even other side effects, right? Because again we're always weighing risks versus benefits.

[00:11:52]

. . . but Has Significantly More Weight Gain

So here the same meta-analysis says, sure, you might say olanzapine kind of leads the pack in terms of efficacy, but it also tends to lead the pack in terms of weight gain, at least as compared to a number of these medicines compared to ziprasidone, compared to a first-generation drug like perphenazine and compared to quetiapine, asenapine, aripiprazole, risperidone.

So what a risk benefit that is, right? Here is superior efficacy but a greater weight gain liability.

[00:12:24]

Samidorphan + Olanzapine: 24-Wk Outcomes

Well, enter the drug samidorphan, an opioid receptor antagonist, in particular a mu opioid receptor antagonist, which when added on to olanzapine, creates a proprietary molecule that's main outcome was around mitigating weight gain in the course of treating positive and negative symptoms in schizophrenia.

So this slide shows us over the course of half a year people with schizophrenia who were taking olanzapine alone, and that's the - oh, forgive me, I'm colorblind. I think it's a reddish orange line at the top compared to the blue line below it. That's the trajectory of weight gain that you see with just olanzapine alone over half a year. And after 6 months, you've gained about 6.5% of your body weight as compared to if samidorphan was added on to the olanzapine as this proprietary molecule, where it's about little over 4% weight gain. That's a little more than a 33% lesser chance of having weight gain.

So there's 2 kind of takeaways that are important here. One is that when you add samidorphan onto olanzapine, it's not a weight loss strategy. It's a weight mitigation strategy to reduce the chances of seeing weight gain over the course of time.

Notice from this graph, by the way, that the difference between these 2 drugs, olanzapine and olanzapine plus samidorphan is not evident at the get go. It's after about the first month that you start to see separation, where any weight gain that may have occurred with the combo plateaus out, whereas olanzapine continues on.

So first point, about a little more than a third less amount of weight gain with the combo than with olanzapine alone.

Second is for significant weight gain, and that got defined here as at least 10% of your - your body weight that's shown in the box up here. You were about 50% less likely to have significant weight gain over the course of 6 months with olanzapine/samidorphan than with olanzapine alone.

In case anybody might ask you that question, about 34 minutes from now, major difference that was seen a 50% less chance of significant weight gain.

Okay. Good to know that. Let's press onward from here.

[00:14:32]

GLP-1 Agonists to Counter Antipsychotic-Induced Weight Gain

There's other ways to try to manage weight gain. This is one way to try to mitigate it. And it's always - prevention is always a better strategy than, you know, after that the damage has occurred. So I was saying before about insulin and insulin resistance.

There's different ways people can gain weight with many antipsychotics, including olanzapine and other atypical antipsychotics. One is appetite stimulation. By the way, we think that's how the samidorphan part works is it reduces - we think the mu opioid receptor blockade reduces the reinforcing or craving effects of food, which olanzapine can stimulate.

You have mu opioid receptors in your nucleus accumbens, your reward circuitry. And so if you block them, you might downregulate the likelihood of the reinforcing effects of food. So it may help with the appetite part.

But we also have another way to try to overcome what will be called insulin-resistance caused by drugs like olanzapine. That is to say, you need insulin to transport sugar out of your bloodstream and into your organs so you can burn it and use it as fuel. And atypical antipsychotics, to varying degrees, can interfere with insulin doing its job. We call that insulin resistance.

So there are ways to try to overcome insulin resistance. And this is separate from the appetite stimulation part that we were talking about a moment ago. This is like how efficiently does your body burn fuel.

So we often nowadays use metformin in some practice guidelines advocate adding metformin to some atypical antipsychotics very much sooner than later and not waiting until someone started to gain weight. But almost the simultaneous inception of treatment to try to overcome insulin resistance. And now we have this class of medicines called glucagon-like peptide-1, or GLP-1 agonists, you know, tirzepatide or semaglutide.

So these were drugs that were first studied and developed to treat diabetes because by stimulating glucagon-like peptide-1, which is found in various parts of the body, you make insulin work better. In fact, they're called insulin mimetics or incretins is the other name for these drugs. They basically turbocharge insulin to make it do a better job at bringing sugar out of your bloodstream into your organs so you can burn it.

They also may help with satiety. They can slow gastric emptying. And they're just now starting to get looked at as antidote strategies for drug-induced weight gain. And there’s a handful of studies, this is shown on the slide here of patients who have taken one of these compounds to overcome weight gain or obesity that's caused by a drug like, say, olanzapine or clozapine.

So there are indications from the FDA at the moment are for diabetes, or some forms of these drugs are just for obesity and overweight, which means if your body mass index is over 30 and sometimes you need to have an associated problem, like a dyslipidemia or hypertension, or being pre-diabetic or diabetic.

But increasingly, we are looking at these drugs as potentially having value as a potential strategy to help manage weight gain. So we're not - we're not without options in ways to try to balance the risk benefits.

[00:17:48]

Antipsychotics Approved for Schizophrenia Before 2024

Let's go back to what we said at the very beginning about mechanisms and dopamine blockade being part of the story, but not the full story. So ever since chlorpromazine came along in the 1950s, to varying degrees, we've been blocking dopamine D2, block D2, block D2 through the first-generation drugs in the 60s and the 70s to the second-generation or atypical drugs like clozapine, olanzapine, risperidone through the 90s, and then the atypical partial agonist drugs aripiprazole, brexpiprazole and cariprazine are a little bit like thermostats.

So those are drugs that will, interestingly, block dopamine where it's too high, like in your ventral tegmental area to your associative striatum for psychosis, and raise it where it's too low, like in your prefrontal cortex for negative symptoms. So the - the partial agonists, those 3, aripiprazole, brexpiprazole and cariprazine were thought to be a real big breakthrough in terms of mechanism beyond just full antagonists.

And those drugs may work a little more like agonists at lower doses, a little bit more like antagonists at higher doses, which means you may see a little more oomph for depression symptoms and - at the lower doses than the higher doses.

Anyway, they've been in advance, but they haven't - they haven't exactly solved the problem. And so we're still trying to manage schizophrenia and psychosis through tweaking dopamine.

[00:19:11]

5HT2A Blockade and Dopamine Transmission

We can do it indirectly also, if you give a 5-HT2A blocker, which is what atypical antipsychotics are. There's an inverse relationship between serotonin 2A receptors and dopamine receptors. You have a lot of them in your prefrontal cortex. And so one reason people were very hopeful and optimistic that some atypical antipsychotics might help positive - negative symptoms and cognitive symptoms is because if you block 5-HT2A in your prefrontal cortex, you actually would raise dopamine where you want it.

So you might even get like a - like a methylphenidate type of effect of increasing dopamine transmission in your attention network. That's a good idea. It doesn't necessarily pan out that much. And - and if you block dopamine in - in the ventral striatum, you could get an antipsychotic effect directly.

Heck, if you give a 5-HT2A agonist like psilocybin, well that's complicated. You can get psychosis. I mean, that's how LSD and ayahuasca and psilocybin work. You get hallucinations and psychosis by 5-HT2A agonism, but you may also get an antidepressant effect. Boy, this is getting complicated.

And you could block the antipsychotic effect of psilocybin by giving any 5-HT2A blocker. Of course, at the same time, 5-HT2A blockers, like quetiapine or aripiprazole or lumateperone also can have antidepressant effects. So the 5-HT2A story is pretty complicated. Agonizing, it can lead to psychosis. Blocking, it can have an antipsychotic effect. It might have a pro-cognitive effect, but not always.

And as to whether or not you get your antidepressant results from an atypical antipsychotic by virtue of agonizing 5-HT2A with, say, a hallucinogen or antagonizing it with a 5-HT2A blocker is still up for grabs. But I've confused you at this point. That's okay. That's okay. Because the takeaway from this vantage moment is we're not fully getting entire success with schizophrenia for all that we're doing with D2 dopamine blockade, partial versus full agonism.

[00:21:20]

Dopamine Partial Agonists Regulate Ambient DA Tone

Here's a graph that shows what I said just a moment before. If you give a drug that is a partial agonist, like aripiprazole or brexpiprazole or cariprazine at higher doses, it behaves more like a full antagonist, like risperidone or - or ziprasidone. But at lower doses, you might capitalize on this agonist-like effect. And so there's interest in using some of these drugs for depression treatment, especially at lower doses.

But - but then we're still not getting to the fuller strategy of trying to manage schizophrenia.

[00:21:57]

Overall Acute Symptom Change Across Antipsychotics

And if we look at non-refractory populations, this is a graph that says on an overall basis, there's not a gigantic difference among atypical antipsychotics in terms of efficacy in non-refractory populations. There are differences in refractory populations. I showed you those data with long-term with olanzapine before. There's data with clozapine and olanzapine in previously non-responsive patients. And of course there's differences in terms of tolerability and side effects.

[00:22:26]

Limitations of Existing Antipsychotic Medications

So here's a quick summary of all these limitations. Tweaking dopamine doesn't fully help ameliorate the problems in schizophrenia. You get collateral damage in the pathways. You don't want it. Eh, we're not great with negative symptoms with any of these drugs. There's a metabolic liability. They’re neurological - neurological liability. Gee, we don't have a lot of add-on treatments, right?

I mean, people sometimes put together poly anti-psychotics, but that's not as evidence-based as one might wish, at least outside of augmenting clozapine in a lot of treatment-resistant patients.

[00:23:01]

Posttest 2

So with that, let's come to our - revisiting the first pretest question. You've seen this before. In clinical trials of olanzapine/samidorphan, what was the key differentiating safety outcome as compared to olanzapine alone? Was it:

1. A lower rate of akathisia;
2. Reduced prolactin elevation;
3. A 50% lower risk of gaining at least 10% of your body weight over 6 months; or
4. Improved glycemic control.

Have a look at that. Give you a hint. The answer is one of these 4. Okay. So we have our results. Okay. So first go around. Most people - 62% had said answer C, which is correct. And in the post-test, 80% of you got it right. And for the 20 - that's answer C. So adding samidorphan to olanzapine reduces significant weight gain by about 50%. Remember, the 20% of you who did not get that right. Well, we'll talk to - we'll talk to ourselves more at the end of this. Okay.

So let's press on.

[00:24:27]

Breaking the Mold: Exploring Novel Mechanisms of Action in Schizophrenia Treatment

If we could go beyond the dopamine hypothesis and look at novel mechanisms, could we do more than we're doing right now?

[00:24:34]

Higher-up Control: GABA/Glutamatergic Regulation of Mesostriatal Dopamine Circuitry

Well, you know what? Everybody has a boss, right? Even dopamine has a boss. And dopamine is just doing its job, spritzing out lots and lots of dopamine, like the pitching machine that keeps throwing out lots of balls. But who - who tells the pitching machine to pitch out lots of balls? Ah, who's in charge here? It's not dopamine. Dopamine is just doing its job. So who's giving dopamine its marching orders?

Acetylcholine enters the picture, in particular muscarinic cholinergic receptors, and in particular of the 5 different kinds of muscarinic receptors, M1 and M4 muscarinic receptors are dopamine’s boss. And in particular, particular, particular, there's 2 circuits of M4 and M1 muscarinic cholinergic oversight of dopamine that kind of runs the show.

I'm going to show you this in a couple of different ways. Here's the first way. So in this little cartoon of the brain, here you got the ventral tegmental area going to the - the associative striatum, spritzing out lots of dopamine here makes for positive symptoms. But there's a little structure here in your pons that's called the lateral dorsal tegmental nucleus. It is the - the seat of the cartel of dopamine boss hood.

The lateral dorsal tegmental nucleus here in the pons in your - in your hindbrain. This nucleus sends out M4 inhibitory neurons to the ventral tegmental area. And that circuitry seems to be not working so well in schizophrenia. So if you had a way to boost that signal of these M4 inhibitory neurons that are coming from this lateral dorsal tegmental area in your pons to the ventral tegmental area, these M4 inhibitory neurons, if agonized, would do a better job at shushing down the overactivity of the ventral tegmental area as dopamine release. Got that? Maybe not. You'll see it again in just a second.

So that's kind of one, first way to do this, is to agonize M4 inhibitory neurons that go to the ventral tegmental area.

Let's look at the next slide for a little more clarity on this.

[00:26:48]

Glutamate Hypofunction at the NMDAR and Symptoms of Schizophrenia

If your ventral tegmental area is spitting out too much dopamine, you get positive symptoms. If you could downregulate that, you'd spit out less dopamine. So I just told you one way to do that with these M4 inhibitory muscarinic neurons. There's a second way to do that with M1 excitatory neurons. M1 excitatory neurons are found in the prefrontal cortex, and they make 2 stops before they get to the ventral tegmental area. Kind of like a train. We have to change trains or buses. You have to change buses twice.

So these M1 excitatory cholinergic neurons in your prefrontal cortex make their first pit stop onto a GABAergic neuron in the circuitry in your prefrontal cortex. GABA remember is inhibitory. So if M1 is excitatory and you agonize that, it's going to make these GABA inhibitory neurons inhibit all the more.

And then the second stop in this circuit is from GABA to glutamate. You have these glutamate circuits going from your prefrontal cortex down to your ventral tegmental area, the inner sanctum of - of psychosis and positive symptoms.

And these glutamate neurons are excitatory. Now think about this. If I could turn on GABA inhibition that would shut down glutamate excitation that's going to the ventral tegmental area. I'll say that one more time. If I could stimulate GABA inhibition in your prefrontal cortex to swish down glutamate excitation as the next circuit in the pathway, shutting down the glutamate is going to shut down, or at least diminish the release of dopamine in your ventral tegmental area, leading to less in the way of positive symptoms.

Well, that's where M1 excitation comes in. M1 excitatory neurons excite or amplify the effects of GABA inhibition. So now I've told you 2 ways that dopamine circuitry in schizophrenia has a boss, M4 inhibition to the ventral tegmental area directly, and M1 excitation that makes 2 pit stops, first to GABA inhibition shutting down glutamate excitation, turning down dopamine release. Interesting stuff.

[00:29:01]

Evidence for Glutamate Hypofunction and Symptoms of Schizophrenia

There are theories that glutamate functioning is directly impaired in schizophrenia. And so there's been a lot of interest in drugs like - well, you can - you can mimic psychosis with NMDA receptor antagonists like phencyclidine and ketamine. And now you may get an antidepressant effect from this as well, right. That's something that's known about ketamine and maybe other NMDA receptor antagonists like dextromethorphan.

But if glutamate circuitry is broken in schizophrenia and it's sort of doing its own thing, if you could bypass it, if you could tweak it, if you could do something with these M1 excitatory neurons in the prefrontal cortex that will stimulate GABA to inhibit glutamate, you might better regulate the signaling.

So again, modulating glutamate, modulating GABA through the effects of M1 excitation cholinergic neurons is one way to try to show dopamine who's boss.

[00:30:03]

Ulotaront: TAAR1 Agonist in Schizophrenia

There's another whole new novel approach in schizophrenia that's called TAAR1 agonist. I'm going to just say a quick word about this because they're more experimental. Trace Amine Associated Receptor 1 proteins. They're intracellular components in the presynaptic neuron. And they seem to play a role in the release and modulation and transmission of monoamines like dopamine. And so some initial research said, you know, if you could agonize these TAAR1 proteins, you might be able to spiff up the efficiency of neuronal transmission in these brain circuits that are involved in schizophrenia.

It's a good idea because we don't have robust data, because the initial phase II positive studies were followed by negative phase III studies. So darn, darn, darn. An interesting idea. But so we're still - we're still - we're still looking at that.

[00:30:52]

Pretest 3

So let's go back to what we were talking about with muscarinic receptors just a moment ago. Here's a quick check yourself question. Which of the following mechanisms best explains - and we just talked about this. Which of the following mechanisms best explains how muscarinic agonism modulates striatal dopamine release in schizophrenia? Is it:

1. Anticholinergic effects from trospium to the ventral tegmentum;
2. M4 excitatory input to the ventral tegmentum;
3. M4 inhibitory input to the ventral tegmentum, or
4. M1 inhibitory modulation of GABA and glutamate circuitry to the ventral tegmentum.

If you're confused, you'll have more chance to see this again. Let's have a quick vote. We'll come back to this, I promise. The correct answer is one of these. All right. We're letting you take your poll. We're going to come back to this in just a bit. Let's press onward. Oh.

[00:31:51]

Pretest 4

Here's - here's - here's another question for you. You're going to hear about this in a second. In phase IIb, phase IIIb EMERGENT trials of the drug xanomeline-trospium, what was the efficacy outcome? Was it:

1. A pooled effect size of 0.65 on the PANSS total score;
2. Superiority only in negative symptoms;
3. No difference from placebo; or
4. Efficacy limited to cognitive symptoms.

Vote now on this one and we'll come back to it too. Okay. Trust me, this will all come together, if it hasn't yet. It will gel. Let's have you vote on this. And now, while you're voting and we'll see your results a little later, let's review.

[00:32:34]

The Role of CNS Muscarinic Receptors

Remember what I said? Muscarinic cholinergic receptors are the boss of dopamine. There's 5 different kinds in the brain and - in body, actually, but 2 in particular that are thought to be important in schizophrenia. This is review folks. Okay. So remember these words. M4 inhibitory - M4 inhibitory. Just memorize it, M4 inhibitory and M1 excitatory.

And these M4 inhibitory neurons are the ones that are coming directly into the ventral tegmental area. And when you agonize M4, you say, shut down dopamine or stop sending out too much pitching machines. Stop sending so many pitches. M4 inhibition to the ventral tegmental area downregulates dopamine release.

And M1 excitation of the prefrontal cortex makes those 2 stops to GABA and glutamate as a more indirect route to try to also say to the ventral tegmentum pretty please with sugar on top, stop spitting – spitting out so much dopamine.

[00:33:29]

Even Higher Higher-up Control: Muscarinic Circuitry Regulates Presynaptic Dopamine Release

Here's a graphic of that. So here's that lateral dorsal tegmental nucleus that I showed you before. This is the seed of these M4 inhibitory neurons. So take a drug that's an M4 agonist. It will inhibit release of dopamine from the ventral tegmental area into the associative striatum through M4 excitation amplifying that effect. And M1 - M1 excitation, which is in the prefrontal cortex does that’s 2-step process to get there.

[00:34:02]

Mechanism of Action Video

So let's now look at a mechanism of action video that further says what I just showed you. Have a look.

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 2 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. Goldberg: Got that? Better? M4 inhibition downregulates dopamine release in the ventral tegmentum. M1 excitation, 2-step process through GABA and glutamate to downregulate dopamine release in the ventral tegmentum.

[00:36:29]

Posttest 3

Okay, well, if only we had a drug that could do those things. Oh, look, here's a question. Maybe you've seen this one before. Which of the following mechanisms best explains how muscarinic agonism modulates striatal dopamine release in schizophrenia? You are all experts in this right by now. Is it:

1. Anticholinergic effects from trospium to the ventral tegmentum;
2. M4 excitatory input to the ventral tegmentum;
3. M4 inhibitory input to the ventral tegmentum; or
4. M1 inhibitory modulation of GABA and glutamate circuitry in ventral tegmentum.

And let's see how people do. All right. So on the pre-test - on the pre-test, 66% of you said M4 inhibition inputs to the ventral tegmental area and is responsible for modulating striatal dopamine release. And - oh, that was the post-test. Okay, good. 66% of you. Heck, on the first go around, yeah, you were in the wrong place. So only 30% got that answer right on the first go round, and a majority of you thought that it was M1 inhibition. So now M - M1 is excitation, M4 is inhibition, M1 is excitation, M1 - say it over, say it and say it and say it and say it because this is explaining what it's doing in the brain, right?

[00:38:03]

Posttest 3: Rationale  

So M4 inhibition downregulates dopamine release. It's dopamine's boss.

[00:38:13]

EMERGENT Trials: Change in PANSS Total Score

So there's this drug that's the combination of - of xanomeline and trospium. And xanomeline is - wait for it. Xanomeline is an M1, M4 agonist. It's dopamine's boss. So M1, M4 agonism is all the stuff we were just talking about, right. And xanomeline is a drug that does that. Problem, problem. If you give a very pro-cholinergic drug, that could be a good thing for tweaking M1 and M4 control over dopamine in the brain, but it's not so good below the neck, because if anyone's ever taken a high potency pro-muscarinic drug, donepezil, for instance.

You get a lot of GI side effects. In fact, if xanomeline was used all by itself, you'd have a lot of nausea and maybe diarrhea and vomiting. So if you had some clever way to be able to offset the agonism of muscarinic receptors below your neck, especially in your GI tract, well, you make xanomeline much more tolerable. And that's what trospium is.

Trospium is a peripheral anticholinergic. It doesn't seem to cross the blood brain barrier, and so it counteracts the undesirable pro-muscarinic effects of GI hypermotility. That means that nausea, vomiting, or diarrhea is markedly reduced. It's not gone, but it's markedly reduced from over half of people to maybe less than or equal to 20% of people.

So xanomeline is an M1, M4 agonist, and trospium is just there to counteract the unwanted pro-muscarinic effects below the neck. Xanomeline-trospium, XT is the name of this drug.

The 3 FDA trials that looked at it were called the EMERGENT trials. And collectively, they all work better than a placebo in treating positive, negative symptoms. The size of their effect – effect, how big was the difference from placebo, was it medium to large effect. It's expressed here. Pooled effect size, 0.65.

In case anybody was to ask you in about 10 minutes, what was the main finding from the EMERGENT-3 trials? There was an effect size of 0.65. That means a very substantial clinically meaningful differences compared to - to placebo. So it didn't just be placebo. It did it in a very important, meaningful kind of way.

[00:40:23]

EMERGENT Trials: Long-term Change in PANSS Total Score

So over the short term, we saw this medium to large effect size with xanomeline-trospium compared to placebo. And then over the course of a year of open-label treatment, notice that positive, negative symptoms during open-label treatment kept going down. Down is good. So boy, if you - if you could - if you could order around dopamine's boss by agonizing M1 inhibition and M4 excitation, look what you could potentially do.

You could actually get a really significant and sustained improvement in positive and negative symptoms without touching dopamine. This drug is not an antipsychotic. It doesn't touch dopamine. It touches dopamine's boss. That means no extrapyramidal side effects, no abnormal movement disorders, no tardive dyskinesia, no QT prolongation, no issues with use in the elderly dementia-related psychosis patients that's not involved here. No weight gain. No metabolic dysregulation.

Oh my God. The only thing you really think about is that you still could get some GI upset and nausea from the xanomeline, because the trospium isn't 100% perfect in offsetting that.

[00:41:35]

EMERGENT Trials: Onset and Duration AEs

Here, in fact, were the main side effects that we're seeing. So GI-wise, nausea, constipation, dyspepsia, vomiting mostly in the first week or 2. It tended to Peter out after that.

[00:41:48]

EMERGENT Trials: Polled Safety and Tolerability

And then over the course of the 52 weeks, again, the GI side effects were most common. And the look of these side effects, we're not seeing motor side effects, we're not seeing metabolic side effects. We're not really seeing much in the way of cognitive or sedating kinds of side effects. We're not seeing sexual dysfunction. So this is a substantially different way of treating schizophrenia through M1, M4 agonism than anything else.

[00:42:10]

EMERGENT Trials: CANTAB by Cognitive Subgroup

There's some research that says that people with schizophrenia have very substantial cognitive symptoms at the outset. Not all do, not all do, but many do. And often it's progressive. Xanomeline trospium seems to improve various measures of cognitive functioning. This is a paper that was published in the American Journal of Psychiatry earlier this year, which showed that in the cognitively impaired group, there was a significant improvement with xanomeline trospium as compared to with placebo.

[00:42:39]

ARISE Trial: Adjunctive Xanomeline + Trospium

There was another study that was not published, but it was posted online earlier this year in the spring, which said, “Well, what if you take a patient who's on an antipsychotic drug and you add xanomeline trospium, what happens?” And the results are a little bit mixed. The researchers looked at doing this augmentation to either aripiprazole or risperidone. Their hope was to say anything you added this drug onto would have an advantage. But it turned out it only was beneficially more helpful if you added it on to aripiprazole and not to risperidone. And no one quite knows why that might be, or if that's a real finding. And why didn't it work in both groups?

I think there's a few - so we don't - we don't know. The drug was studied all by itself, but there's no mandate that says you must use it by itself. However, you might not want to mix xanomeline trospium with any other drug that has a very high anticholinergic load to it, like olanzapine or quetiapine or clozapine, because now you're going to amplify the peripheral anticholinergic effects of the trospium. Plus, if you give an anticholinergic antipsychotic like quetiapine or clozapine or olanzapine, you might, at least, in theory, undo the pro-muscarinic effects with antimuscarinic effects. Right?

You want the pro-muscarinic effects of the xanomeline, but if I mixed it with quetiapine or perphenazine or Thorazine, well, it's possible that they might - they might be working at cross purposes in the brain. So augmentation approaches still have yet to be worked out.

[00:44:07]

Xanomeline-Trospium Dosing

Dosing with this molecule. It's a BID drug. 50 milligram worth of xanomeline paired with 20 milligrams of trospium BID on an empty stomach because you don't really absorb the trospium very well unless you have an empty stomach. So unlike all those times you tell patients with nausea, take this drug with food. Not here. Take this drug on an empty stomach. The trospium is better absorbed on an empty stomach.

Once someone is tolerating that initial dosing, you can then go on up from 50 to 100 milligrams of the trospium and the - of the xanomeline and trospium stays at 20. It can then go as high as 125 of xanomeline and as high as 30 twice a day on the trospium.

Ondansetron is sometimes recommended as an augmentation for nausea if it's needed.

[00:44:56]

Posttest 4

Okay, let's press on. Question. You saw this before. The phase III - phase IIb, phase III EMERGENT trials of xanomeline trospium demonstrated which efficacy outcome? Was it:

1. A pooled effect size of 0.65 on the PANSS score;
2. Superiority only on negative symptoms;
3. No difference from placebo; or
4. Efficacy limited to cognitive symptoms.

You've seen this before. Think of this as a short-term memory test. Let's see what people think. All right, so in our pre-test, 35% of people identify choice A that medium to large effect size on the PANSS. In our post-test, 77% of you got that correct. So yay, terrific. Learning has occurred. That is right.

[00:46:01]

Is M₁ Receptor Stimulation Necessary? M₄ Selective Agents in Development

So let's press onward. So do you need both the M1 excitation and the M4 inhibition? That's an interesting question.

[00:46:08]

EMPOWER Trials: Negative Findings With Emraclidine

There was this drug called emraclidine that was studied earlier this year. And emraclidine is just an M1 selective drug. It doesn't know anything with the M4. It's just the M1 excitation. Okay. That's one way to get to the ventral tegmental area. It didn't work, as you can see here. It didn't separate from placebo, and so it's - it’s hard to know if that means, aha, you really need both the M1 excitation and the M4 inhibition to get this kind of effect.

Or maybe this study just had some flaws. Maybe the placebo response was high, maybe it was underpowered. So we - we don't know what this means. All we know is we currently have one and only one M1, M4 agonist. And that's the class that it's called. It's not an antipsychotic. So stay tuned. There'll be more kinds of studies of these coming along.

[00:47:04]

NBI-1117568: An M₄ Selective Agonist

Here's another study that was looking at just a selective M4 agonist. Remember the M4 inhibition route? And here it looked like it was a positive finding for the study. There's now a phase III trial that's underway. So keep your radar looking at NBI-1117568, and we'll learn more about M4 versus M1. But in years to come, you'll be - you'll be incorporating this language into your treatment of schizophrenia more and more and more. M1, M4, both agonism, the loss of dopamine.

[00:47:36]

Muscarinic M₁ or M₄ Agonists/PAMs in Development

And there's even more drugs that are in development that look at not just agonizing, but something called a positive allosteric modulator. That means a molecule that binds to a site that's different from the ligand binding site on a receptor and turns the receptor on. PAMs, as they're called, positive allosteric modulators.

So look at this alphabet soup. You got this ML, blah, blah, blah thing, this NBI thing. These are all molecular entities that are under investigation right now, playing off the same rationale and mechanism, there’s M1, M4 agonism. So what an exciting time to tell your patients that we're truly having the first kind of breakthrough approach in modulating the circuitry in schizophrenia in 70 years? I find that really exciting.

[00:48:18]

Other Emerging Novel Therapeutics in Schizophrenia

There are other antipsychotics that are in development as well. Just for the sake of completeness, some of these are variations on partial agonists, like brilaroxazine, which is oxaripiprazole. There's methylamisulpride antagonist that seems to have some unique binding properties at D2 and D3 receptors. There's other ways to get at this through sodium channels. So again, the spirit of this is there's real development going on. And I think xanomeline trospium represents kind of the tangible payoff of that in real time.

[00:48:51]

Bridging the Gap: Role of Novel Mechanisms and Agents in the Treatment Paradigm

So let's kind of finish up.

[00:48:53]

Poll 2

Here's a case. I'm going to ask you to think about this in your head. We're not going to really pull you, but just think about this one. Victoria, 57-year-old postmenopausal woman, 25 year history of schizophrenia, hypertension and tardive dyskinesia. Now on quetiapine 600 milligrams and risperidone 1 milligram. She's on valbenazine, VMAT2 inhibitor optimally dosed. She takes doxepin at bedtime, zolpidem at bedtime, losartan and hormone replacement therapy. Which of the following should be modified before you were to give her xanomeline trospium. Should you:

1. Taper down the quetiapine;
2. Taper down the risperidone;
3. Taper down the valbenazine; or
4. Taper down the doxepin.

Don't vote. Think about this. I will tell you the reasoning for the answer being both A and D is that quetiapine is a very potent anticholinergic drug. And doxepin, that is Silenor is brand name for it, is sometimes used for, for sleep. And that's very anticholinergic as well. It's a tricyclic antidepressant.

So remember, you're not thrilled about giving xanomeline and trospium together to someone who's already on a potent anticholinergic drug. Risperidone has no anticholinergic properties, so maybe it's redundant. Maybe it's a little inelegant. Maybe you don't need it and it didn't work in that ARISE study, which I showed you before. So you can make an argument if it didn't work in the ARISE study, why keep it? But it doesn't pose the anticholinergic risk.

And the valbenazine VMAT2 inhibitor is sort of neither here nor there. So if you're going to tweak her regimen, just try to slim down the anticholinergic effects.

[00:50:27]

Poll 3

So you give her xanomeline trospium and she's nauseated. So what would you want to not do? Would you:

1. Say take it with food;
2. Lower the dose;
3. Add ondansetron: or
4. Just tell her, well, in clinical trials, nausea was transient.

Well, you wouldn't do A. Remember, like I said, trospium is not very well absorbed to begin with. And on a full stomach, it's really not well absorbed. So make sure Victoria is taking this medicine on an empty stomach. And meanwhile, for nausea, you could keep the dose on the lower side. You can certainly add ondansetron 5-HT3 antagonist that's used for nausea. And it is true that nausea usually does pass. So not all side effects are transient. This one - this one tends to be.

[00:51:09]

Key Summary Points

All right. So hey, we're getting to the end. Let's wrap up. Key points. Muscarinic M1/M4 agonism offers a new and novel strategy to treat schizophrenia by downregulating excessive presynaptic dopamine transmission in the associative striatum. You should by now all feel very comfortable, or at least more comfortable with that language.

Xanomeline trospium is an M1/M4 agonist. No D2 binding. Its FDA approval is in schizophrenia in adults does not seem to have the metabolic effects of antipsychotics, doesn't seem to have D2 effects in terms of movement problems, prolactin problems, the collateral pathway damage. If patients have prominent cognitive dysfunction, that paper in The American Journal this past January says, you might see some leveraging of that.

Beware of drugs that have central anticholinergic effects, benztropine, doxepin, amitriptyline, Benadryl, quetiapine, etc. could amplify the unwanted anticholinergic effects from the trospium and maybe counteract the pro-muscarinic desirable effects of the xanomeline.

And if you're using a just an M4 positive allosteric modulator like emraclidine. It didn't seem to work as well as having both the M4 inhibition with the M1 excitation, so we - we may well need both, or at least we need more studies. Stay tuned and we'll find out.

[00:52:32]

Patient Communication Resource

Here's a nice little summary thing that I wrote up. You can't read this. Don't even try. But you can download it from Clinical Care Options websites. It's a handy thing that sort of explains a lot of these things to patients with schizophrenia. And I think in such a way, if I may say so myself, since I wrote this, it really just tries to explain what's going on in the brain. There's an optical illusion here.

Your brain can misperceive things. Brains play tricks on us. When you're sleeping at night, you don't know you're awake or asleep. So our brain can play tricks on us. And this idea of dopamine dysfunction is maybe just the small piece of the story. The bigger piece is how do you modulate dopamine?

[00:53:12]

Posttest 1

So with that, let's go back to these pre-test, post-test questions. First, after participating in this educational activity, how knowledgeable do you feel about the safety, efficacy, and clinical use of new medicines with novel mechanisms of action for the treatment of schizophrenia?

1. Very knowledgeable - unknowledgeable – sorry, very unknowledgeable.
2. Unknowledgeable;
3. Neutral;
4. Knowledgeable; or
5. Very knowledgeable.

Let's have a vote. And as you vote, I am going to turn things back to Jennifer. Dr. Payne, I think.

[00:53:42]

Q&A

Dr. Payne: Awesome. Thank you so much, Joe. That - that was fantastic. I - I really enjoyed learning about this today. And we have a number of questions which I'm going to get to. But as a mood disorder specialist, you well know that we use antipsychotic medications as mood stabilizing medications for bipolar disorder. And so I'm wondering what you think about some of these agents in bipolar disorder or schizoaffective disorder bipolar type?

Dr. Goldberg: Sure. So plenty of opportunity for more improvement in that domain as well beyond schizophrenia. At the moment, the studies with M1/M4 agonists have just been in schizophrenia. So we don't know about mood disorders. There's extrapolation obviously. We also don't know about mood symptoms in schizophrenia patients. I'll tell you a secret, Jennifer. Schizophrenia patients get depressed.

Dr. Payne: Yes, they do.

Dr. Goldberg: Maybe some people didn't know that. But you're allowed to get depressed. And unfortunately, these xanomeline trospium studies didn't measure depression. Now, here's a crinkle. We don't really know what the effect of a pro-muscarinic drug is on depression. Many years ago, there was this old theory called the cholinergic adrenergic hypothesis of depression.

Dr. Payne: Remember

Dr. Goldberg: Some of us who are of a certain age - remember that?

Dr. Payne: Yes.

Dr. Goldberg: This guy named David Janowsky wrote that up in the 1970s, and it was played out. Get this by giving people an anti-muscarinic drug to treat depression, the drug scopolamine. At your old stomping ground, NIMH, I think Wayne Drevets gave people intravenous scopolamine, a potent antimuscarinic to treat depression. And it worked better than placebo.

And so he said, “Aha!, Dr. Janowsky's theory was right. An antimuscarinic could have an antidepressant effect.” That never quite made it. I mean, I was for a while giving people these scopolamine ear patches and never got anywhere with that. But - but it raises the question of, you know, beware and be careful until we have data with xanomeline or for that matter, any other M1, M4 agonist or positive allosteric modulator, that it does not induce depression.

Dr. Payne: Right.

Dr. Goldberg: Because it's the opposite of scopolamine. And if it could help, well, take that Dr. Janowsky and take that Wayne Drevets. You know, we - we just don't know. But I wouldn't take it for granted. I would expect that these drugs would be helpful for mania and for psychotic mania, but I - I - I want to see some data on depression before we go further.

Dr. Payne: I think that's a - those are great points. And I remember the scopolamine data myself. And - so, all right, I will get to some audience questions for you.

Does insurance require you to prescribe olanzapine before prescribing Lybalvi?

Dr. Goldberg: So it depends on the person's insurance, if it's commercial, if it's non-commercial. You know, clinically speaking, you want to give olanzapine/samidorphan before the patient has gained weight because the whole point of it is to prevent it from happening. So you wouldn't want to find yourself saying, “Well, I gave the person olanzapine. They gained 20 pounds. So now I'd like to give them olanzapine/samidorphan.” Because that's not going to reverse the gaining of weight.

So I don't know, an insurance plan per plan if they require that. Some of them do require, you know, generic things before that. In my opinion, 2 important things. One, if your patient is taking olanzapine and they don't gain weight, they - lucky them. Such things happen. They may not need this. However, if they are gaining weight, I wouldn't wait until they've had a lot of weight gain. That'd be like saying I'm not going to give you aspirin if you're at risk for heart attack until you've had your heart attack.

I'm not going to give you a statin until you've had an MI, right? So if someone's showing signs of weight gain, I would intervene sooner than later. And, you know, some people - I'm going to add to this. Some people would say, “Well, could you give other opioid antagonists besides samidorphan?” So naltrexone was actually studied. And the thing with naltrexone, it's about 5.5 times less potent at the mu opioid receptor than naltrexone than - than samidorphan is. So I think that prompted the manufacturer to not want to study naltrexone as their go to.

I mean, one could certainly try that if one wanted to, but I wouldn't make it, in my mind, comparable to a 5.5 times more potent mu opioid receptor antagonist - antagonist like – like samidorphan. So takeaway, I wouldn't wait until the bad stuff has happened before intervening. And also if someone has high risk - high cardiometabolic risk or hyperlipidemia to begin with, they have a family history of heart disease, or you do one of those, you know, Framingham pooled cohort things that, oh my gosh, heart attack is high.

I would use that in my prior authorization saying this drug could really help this person, but they're at risk for cardiovascular or cerebrovascular disease. So let's - let's not make them have a heart attack. Let's prevent one.

Dr. Payne: Yeah, I think that sounds - that sounds great. And this is a slightly mixed question. The audience is asking, what is the effect of adding GLP-1 meds to antipsychotics to decrease weight gain? So they've already gained weight. And does GLP-1 work there? And I'm going to add to that question with how's insurance doing with GLP-1s?

Dr. Goldberg: Oh, we were going so well until you added that last part.

Dr. Payne: Sorry.

Dr. Goldberg: So what studies have been done so far? Christoph Correll published a study with liraglutide. There was an open case series with semaglutide. I think there is a body of literature that is emerging, but conceptually, it is the smartest thing in the whole wide world to do. Because if you think that the atypical antipsychotic is causing insulin resistance, and if metformin is not a sufficient strategy to overcome the insulin resistance, GLP-1 agonists do that for their day job. They overcome insulin resistance. So it's not only a good idea. It plays right exactly to the mechanism, which is brilliant.

So I would not wait until bad things have happened in terms of ballooning weight or metabolic sequelae before doing that.

Now, as to the insurance question. Insurance has not said, “Sure, feel free to use as an antidote.” So we're still left with 2 things. One, in the world of diabetic type 2, not type 1 diabetic patients, some of these drugs have branded formulations that are intact for - for diabetes patients.

But if you're not diabetic, let's see, 2 things. One, there's a version of semaglutide that does have an FDA indication saying it will reduce the risk of heart disease by 20%. I have actually gotten that approval for patients who happen to have hypertension and a history of cardiovascular disease. And I don't mean to impersonate a primary care doctor, but I will say to the patient, you know, if we add semaglutide, it could accomplish what we wanted to for weight. But since you have heart disease, I will focus on that. And I've had that happen.

The other is for non-diabetic non-cardiovascular patients who have a BMI over 30 or over 27-plus at least 2 risk factors like hypertension and hyperlipidemia is usually covered. But then you sort of get into the nuances sometimes with insurance. Gosh, I had one insurance company that the patient's BMI was like 29.8 or something. And they said, ‘Well, if she gains another 8 points, we'll pay for this.” And she called them and said, “You mean to tell me that if I gain 8 more pounds, you'll give me a drug so I can lose most of it?” And they said, “Yeah.”

So I think these are very expensive medicines and they have to be feasible and affordable. But I think as we are - as healthcare providers, taking into account the totality of risks and benefits for our patients, we should know what their cardiovascular risk is. We wouldn't want to avoid a drug with high metabolic liability if it could be life-saving. Heck, clozapine, the only drug that's approved to reduce suicide, geez, in schizophrenia.

I mean, I'd hate to forego that because of the metabolic, so I would - I would go to the mat for the patient to try to get a GLP-1 covered if it can overcome the metabolic dysregulation, because I think that makes me a better healthcare provider and renders better care for the patient.

Dr. Payne: Yeah, completely agree with you. I think psychiatrists are going to need to know how to prescribe these medications.

Dr. Goldberg: And nurse practitioners and other prescribers.

Dr. Payne: Absolutely.

Dr. Goldberg: And also to make our colleagues in primary care medicine as conversant about these risk benefit discussions as we are. I don't think we just want to punt it to the primary care people, because they may not be able to have the dialogue in the conversation of this is somebody with really hard to treat psychosis, for whom a drug like, say, olanzapine or clozapine is really uniquely beneficial. We bring that perspective to bear.

Dr. Payne: I - I think that's great. Okay. I think we have time for another question. If you have nausea but are following the diet precautions with Cobenfy, can you give additional trospium?

Dr. Goldberg: Yes. So, in the studies, the augmenting dose of trospium went as high as 30 twice a day. You could give another 10 or 20 milligrams. And quite frankly, that - that's done in the overactive bladder literature with - with trospium. It - it's a pretty benign drug, unless you're worried about things like urinary retention or prostatism in a guy.

So you know, you are giving a peripheral anticholinergic and you also get some vagolytic effects meaning a reflex tachycardia. So if you're monitoring those things and men don't like to be put into - into prostatism, it's very unpleasant. And they go get straight cath in the ER. They don't like that. And you know if somebody's tachycardic. So I would just keep an eye on those things. But yes, you certainly could.

And the dietary restrictions just means no food. And I would not be shy about ondansetron. It's not perfect, but you know it - or for that matter, Phenergan or your favorite anti-nausea drug, especially the first 2 weeks seems to be where the risk window is greatest.

Dr. Payne: Okay. All right. One last question.

Dr. Goldberg: Sure.

Dr. Payne: Do we have any information on studies about treating psychosis with - how do you say this? Xanomeline trospium.

Dr. Goldberg: Xanomeline.

Dr. Payne: Yes. Okay. In adolescents or younger children?

Dr. Goldberg: No, not yet. 18 and above. Stay tuned. The drug just came out a year ago, folks. Give them a little time. I mean, make sure drug, for heaven's sakes. September of 2024 the drug first came out. In 70 years, we haven't had anything besides D2 blockers. So little catch up time. Okay? Just patience. It's coming. It's coming.

Dr. Payne: Yes. We need more - more research.

Dr. Goldberg: For sure.

Dr. Payne: Okay. We have 30 seconds remaining. If a patient's been on a long-term clozapine but has only shown partial efficacy, is there a cross-titration strategy to another agent?

Dr. Goldberg: The best data for augmenting clozapine is aripiprazole.

Dr. Payne: Okay.

Dr. Goldberg: You could try xanomeline trospium. But now you're playing in the anticholinergic territory.

Dr. Payne: Right. It’s complicated.

Dr. Goldberg: And so a little more - you know, now if you want to be a researcher, I'm a researcher. Hey, write that as a case report and let the patient know we're doing something that's a little mechanistically - we'll have to see. But there is a pretty good literature on adding a dopamine partial agonist. Aripiprazole is the best studied. I sometimes use brexpiprazole or even cariprazine because you're playing off the mechanism.

Remember that - that partial agonist, full agonist thing. So it's - it's - it's a little more mechanistically acceptable, I think, to use that as an augmentor for an incomplete response to clozapine, assuming their clozapine level is over 350. There's also some data with lamotrigine augmentation of clozapine in refractory psychosis. There's a few tricks up the sleeve. But if you're going to say let's try xanomeline trospium, just kind of keep an eye on the pro-cholinergic, anticholinergic side of things. And that - that is a study awaiting to be done by somebody.

Dr. Payne: Excellent. Always good - good. More research to be done. So thank you, Joe. That was really fabulous. And…

Dr. Goldberg: Thank you.