Breaking the Therapeutic Ceiling in Schizophrenia Care

Schizophrenia Is a Complex Psychiatric Disorder
Schizophrenia can be confusing to a lot of people, but it is essentially three different pillars or domains. The first of that is going to be positive symptoms.

Positive symptoms tends to be what people think about when they think about schizophrenia. They think about hallucinations; they think about delusions. I am going to give you a good way to remember these symptoms. If you think of a flat line, a stable person, positive symptoms think it is positive. It is above the stability, it is adding to the reality things that were not supposed to be there: delusions, hallucinations, so on and so forth.

Whereas negative symptoms are things detracting from the reality: avolition, anhedonia, blunted affect, poverty of speech—all of those things that should be there, but are detracted.

Then finally, but equally important is cognitive symptoms, which is another symptom domain that I feel like people just forget about, but it is so important because that is the ability to think, to problem‑solve, to pay attention to things. A pivotal area for things like going to work and going to school, so definitely something we want to keep in mind because our patients are truly all three of these domains, not just one. We want to make sure that they are being attended to in all of these areas.

Schizophrenia Pathophysiology
The pathophysiology of schizophrenia is complex. Here is what we do understand about it.

The pathophysiology is centered around what is called the dopamine hypothesis. If you are not aware of this, this is an imbalance of dopamine in different areas of the brain. Specifically in the mesolimbic pathway, there is too much dopamine. That is what yields positive symptoms things adding to the reality. If you think those extra neurotransmitters flying around creating the hallucination.

Then the mesocortical area, which is more in the prefrontal cortex, it is running a little bit low, and that is what is thought to lead to negative or cognitive symptoms, meaning those things that are detracting from the reality that are missing.

Another way to think about this as well is if you think of like Parkinson's disease is a great example for a quick remembrance of the schizophrenia pathophysiology, because it is in some effect, at least for the positive symptoms in inverse disease. In Parkinson's disease, we have too little of dopamine. You give L‑DOPA; a side effect is psychosis or psychotic side effects.

Whereas for schizophrenia, for the positive symptoms, you have too much dopamine. If you give a typical or atypical antipsychotic, a side effect is going to be movement disorders or parkinsonism. Kind of an inverse you can think to help remember that pathophysiology.

Schizophrenia Clinical Reality
What is the prevalence of schizophrenia. It is estimated to be 0.3% to 0.7% worldwide. That is not just in the United States but that is across the globe, which does equate to 20 million individuals globally. That is quite the disease impact. There is also a 4% to 10% lifetime suicide risk. This is a inclement population; we want to make sure we are screening for this, and keeping that in mind, it is a chronic relapsing illness with a variable functional outcome. What that means is some people can completely be rehabilitated back into their job and be leaders in the industry, be successful. That is 100% a possible thing for this population. However, there are variable functional outcomes. Some people will struggle to maintain stability. It is quite the continuum and depends on the person and their treatment.

The current treatment paradigm is going to be antipsychotics, whether it is first‑generation, second‑generations, which are also termed typical or atypical. We will talk a lot about those today. Those are the mainstay of treatment. However, functional recovery can still remain limited despite some of these medications.

Antipsychotic Medication
Antipsychotics: what is an antipsychotic. Let us just touch on the MoA of really what makes an antipsychotic an antipsychotic.

When something is deemed an antipsychotic by the FDA, whether it is a first‑generation or an or a second‑generation, typical or atypical, it is going to block dopamine. Specifically, it is going to antagonize at the D2 receptor. If we think about what we just talked about with the pathophysiology, too much dopamine flying around. Those are representing our psychotic symptoms; blocking it will stabilize that. Therefore, antipsychotics are going to block dopamine D2 receptors.

Now, between first‑generation and second‑generations, which are also typical and atypical, the delineating difference from a mechanistic standpoint is going to be that our second‑generation atypicals have greater 5‑HT2A antagonism, that is, serotonin 5‑HT2A. It is going to have that serotonin action, which it varies them from the first‑generations.

Old vs New Pathways in Schizophrenia Treatment
Now we will touch on the old versus new pathways in schizophrenia. We are here today to talk about new mechanisms for this disease state, just to compare and contrast where we have been ‑ dopamine model that we just touched on ‑ versus where we are going, the muscarinic model.

As we mentioned, the old model involves our first and second‑generation antipsychotics involves D2 receptor blockade. Therefore, it is going to suppress dopamine signaling. They are for targeting those positive symptoms. Remember too much flying around the D2 receptor. A side effect of that is going to be EPS or movement side effects; prolactin, can raise metabolic side effects, so A1C, cholesterol, weight gain. All of those metabolic ones. Then there is a limited cognitive benefit that has been shown.

Conversely, our new muscarinic models. This is going to be M1/M4 receptor agonism. As you can see, I did not mention the D2 receptor at all. This is unique that we are not going to directly touch the D2 receptor at all. We are going to indirectly modulate dopamine through these muscarinic receptors, specifically M1/M4. We will talk about what those do momentarily.

This is going to target multiple symptom domains. Therefore, it is going to have a lower EPS risk because we are not blocking dopamine directly. We are also seeing a potential cognitive benefit for those with more cognitive dysfunction. We will touch on that as well.

Setting the Stage: Unmet Needs in Schizophrenia Management
Unmet Needs in Schizophrenia: Limitations of Current Therapies
Let us talk about the unmet needs in schizophrenia for the current therapies that we are using. This is alluding to our first and second‑generation antipsychotics; the limitation of current therapies that are widely used.

There can be potential persistent symptoms, or might not be full efficacy. There could still be some hallucinations or positive symptoms. As mentioned, there is a lack of cognitive benefit that has been shown since the D2 receptor mainly targeting is in relation to the psychotic and positive symptoms.

Likewise, there is limited negative symptom efficacy, so that low mood, anhedonia, and avolition type of symptoms. Then also, there are safety and tolerability concerns. With the movement side effects and the metabolic side effects, some people cannot tolerate those things and need other options available to them.

Schizophrenia MoA Comparison
Just to compare and contrast the MoA. Something to keep in mind is, as the antipsychotics are straight up antagonizing, they are blocking the dopamine receptors; that is a very direct blockade, whereas the muscarinic receptors are indirect modulation.

I will give you an example. For these cholinergic receptors, when these are agonized, it is going to indirectly turn up or down the volume of dopamine in different areas of the brain, and is going to be very targeted in areas where we see psychosis, where we see those more negative cognitive symptoms, and it is not going to go anywhere else aside from those M1 and M4 receptors. It is a little more targeted. It is essentially going to turn down the volume of the dopamine before it gets to that area. Meaning you do not have to block the D2 receptor because there is less dopamine that got there from your brain to begin with, if that makes sense.

I will give you an example. If someone is sitting in a room and that person represents schizophrenia patient, and there is really, really loud music just blasting in the room, and that represents their positive symptoms or hallucinations. Our prior model would have been direct blockade would have been handing them some earplugs. If their ears are blocked, they cannot hear the loud music; they cannot hear the psychosis. It is technically still there, but they cannot hear it because it is blocked. Just like if we were to block the D2 receptor. Whereas the muscarinic indirect modulation would be, instead of blocking that, let us just turn down the volume and going and turning down the volume of that radio or music box. You do not have to get earplugs; you do not have to block if less is getting there to begin with. That is a good example. I do actually use that example with my patients, so feel free to steal it. I love a good analogy.

With that, since it is a more targeted area, we are having a totally different side effect profile. There is minimal EPS risk, neutral for the prolactin being affected, and then potential and emerging benefits for our cognitive and negative symptoms.

Efficacy Differences in Antipsychotics
A review meta‑analysis that compared the efficacy and tolerability of 32 oral antipsychotics. Essentially, what it found for our existing agents was that there was some efficacy differences, but most were pretty gradual rather than discrete. The most prominent or marked difference between the existing agents were their differences in ease or adverse effects.

As clinicians, we just need to weigh those pros and cons accordingly.

Adverse Effects: Mechanisms
Other antipsychotics. As mentioned, when we talked about the inverse of Parkinson's disease, we will see these movement side effects: tardive dyskinesia, parkinsonism; all of those things fall under the EPS umbrella. That is directly from D2 blockade in the nigrostriatal pathway, because remember our first and second‑generations are not just blocking dopamine where psychosis is; it is blocking all over. Some of those are off‑target dopamine blockade. EPS is a great example of that off‑target dopamine blockade in the nigrostriatal pathway, causing the movement issues and the motor symptoms that result from that.

Likewise, sedation. A lot of these medications have H1 blockade and that H stands for histamine. There is going to be some central nervous system depression, which can overall cause this sedating lethargy or fatigue. A lot of people can be very tired on these medications.

Hyperprolactinemia: Another example of a result of dopamine blockade in a different area. In this case, it is the tuberoinfundibular pathway. When this occurs, we can see an increase in prolactin, and is why we get prolactin labs on those on these medications.

Weight gain: This one is really multifactorial. It is from blockade of H1 that’s our histamine receptor, serotonin 5‑HT2C. That one, 5‑HT2C, is a serotonin receptor. A good way to memorize that one is they theorize that that receptor is associated with satiety, meaning where that is affected, people tend to be less satisfied after they eat as opposed to feeling full after they eat. A great way to memorize that is that subscript 2C is to think of two cookies. After you have one cookie, you are not satisfied; you want a second cookie.

Why Do Atypical Antipsychotics Cause Weight Gain?
I usually want a second cookie, but great way to remember that, amongst other hypothalamic effects, an increase in appetite, between our histamine, which can increase appetite, serotonin 5HT2C, which is the loss of satiety I just mentioned. Hypothalamic effects, which is more so our leptin/ghrelin changes. That has to do with our hunger as well.

Insulin resistance more of a downstream effect can occur early though, and decreases insulin sensitivity. Then, along with the sedation, that one is more indirect in terms of if you are more sedated and tired, you are probably less active, less caloric burn or energy expenditure, but all collectively can contribute to weight gain, although the prominent ones are going to be the blockade of these two receptors.

Psychotropic Drug‑Related Weight Gain
Now, weight gain is in general a class‑wide side effect to these medications. However, that does not mean they are all producing the same amount of weight gain. If you guys have ever experienced patients on these medications, there is some that people will just gain 10 pounds just like that and some where it is less of an issue. It is just important to weigh the pros and cons. They can all be associated with weight gain, but just knowing the differences between them is important.

Antipsychotic Adherence: Related Adverse Events
I actually love to talk about adherence because the number one reason for hospital admission across the country is lack of adherence, meaning people just stop taking their pills; they think they do not need them. That is not just psychiatry; that is across medicine in general, primary reason for hospital admission.

Now, what is the main reason for lack of adherence? Is going to be adverse events/side effects. Here are the primary ones that affect that for our existing agents, meaning our antipsychotics. It is going to be EPS or agitation which is our movement side effects we mentioned. Metabolic: that could be weight gain, that could be A1C or high cholesterol, prolactin, endocrine effects. As we mentioned, it can raise prolactin, sedation, or cognitive effects, or GI.

Limitations of D2‑Based Therapies: Negative and Cognitive Symptoms
Negative Symptoms: How Common Are They?
Let us just touch on the negative cognitive symptom limitations. Negative symptoms can be very common. As we can see, like I mentioned, a lot of people do think schizophrenia as positive symptoms, but it is important to not forget about our negative symptoms because they are not rare. A lot of people do struggle with poor motivation, blunted affect, a study with 7,678 patients with schizophrenia, and 41% had over two negative symptoms. That was in general associated with being male, younger age, single marital status, and was correlated with an increased likelihood of hospitalization and a longer duration of hospitalization, and an increased likelihood of readmission post being released. Definitely something we want to pay attention to as these are important.

Looking Forward
We talked about the existing agents, what their side effects are. We talked about how negative symptoms can still be very prevalent. Now let us talk looking forward about this new mechanism and how that works and what we see.

Future Directions: Novel Mechanisms
If psychosis and schizophrenia is presynaptic dopamine dysregulation, can we intervene upstream of the D2 receptor? I know we already talked about this as intervening upstream before it gets there. I gave you the example of the music, but I am going to give you another example. If you think of a house, and all of the sinks are just going crazy, they are all on, and the house is flooding because showers, sinks, everything is just on, and there is water spilling everywhere. Let us have that water represent the symptoms of schizophrenia, positive symptoms and so forth. Our existing agents would be like, "Let us get some tape and put it on top of the faucet," and maybe a little bit of water still comes up the side, or maybe you put your hand there and some still coming off the side. That represents our off‑target side effects. Some that is still coming out here and there. Whereas our new agent, we are intervening upstream before that occurs. The example here would be: why don't we just turn off the faucet? We will just turn off the sink. Again, just intervening before it occurs.

Muscarinic Receptors
That brings us to our muscarinic receptors. There are several muscarinic receptors. We are going to be focusing on M1 and M4 today, but just for completion, here are some others that we will see. M1, M3, and M5 are excitatory; M2 and M4 are inhibitory. They signal via G‑protein cascades and are truly involved in a variety of bodily functions beyond just the brain. In general, they are going to be associated with other things such as learning and memory, cardiac function, smooth muscle concentration.

Central Muscarinic Receptors (M1‑M5): Functional Overview
Then, specifically, we are focusing on M1 and M4 because M1 is going to be in the cortex and hippocampus. Primary function is going to be cognition memory, attention. It is going to improve those cognitive and negative symptoms. That is the target we are going for there. M4 in the striatum is going to decrease dopamine release to reduce positive symptoms. One for each. M2, M3, M5 in other areas and having to do with other functions that we are not targeting because we are M1, M4 selective for this agent we are going to discuss.

Anticholinergic = “Mad as a Hatter,” so PROcholinergic...
If you guys remember this from school or your medical training, whatever it may be, if you can recall anticholinergic toxicity. I just love to connect these things to other things, whether it is psychosis or anticholinergic toxicity, because it is so fascinating that we have learned about this in other ways, and it is just clicking it to connect it here.

Our anticholinergic toxidrome: it is the mad as a hatter, dry as a bone, red as a beet. Maybe that is ringing some bells. Specifically, if anticholinergic toxicity, meaning too much anticholinergic is mad as a hatter, hallucinating, if we are procholinergic, which this is a muscarinic agonist, so promuscarinic, procholinergic is the medication we are talking about, wouldn't that make sense that it is less mad as a hatter, so to speak. There is another way to remember the mechanism.

Balancing Muscarinic Activation and Cholinergic Tolerability
In general, procholinergic was showing a therapeutic signal, and there was a tolerability trade‑off, it is going to have a totally different set of side effects that we are going to get into. This is going to be a central M1/M4 activation. By central, we mean in the CNS, the central nervous system, to help modulate those dopamine circuits. Key word is modulate, not block, not antagonize, but modulate, which is therefore going to reduce those psychosis related symptoms.

However, this medication is not just for the xanomeline/trospium. The xanomeline is not just central. There is some that goes into the periphery more cholinergic in the periphery. What would those side effects mean? That would be like GI effects, especially nausea and vomiting.

A good way to memorize procholinergic/anticholinergic is procholinergic is like are more juicy side effects: nausea, diarrhea. Anticholinergic is more dry: dry as a bone, dry mouth, constipation. Yes, we want that cholinergicness in the brain because that is what is going to give the efficacy that we are looking for. We do not necessarily need the procholinergic in the periphery, because that is just going to be the nausea and vomiting. Therefore, trospium was added ‑ this as a combo medication of xanomeline and trospium ‑ because trospium is going to do its best of ability limit those peripheral procholinergic effects.

Xanomeline/Trospium
Just to split that up here again, trospium is that peripheral muscarinic antagonist. It is going to have limited penetration of the blood‑brain barrier, so it will let the xanomeline still function in the CNS. We want that central agonism. We do not particularly want that peripheral agonism. Therefore, this is added to simply undo it in the periphery, meaning to undo it for tolerability for side effect purposes, to have it be more tolerable to hopefully help reduce the nausea and make it have better adherence. That is the goal of trospium. Whereas the goal of the xanomeline is going to be the agent for efficacy, because that is the one that is going to agonize in the CNS and do these things we just mentioned: the M1/M4 agonism. The trospium is just the peripheral antagonist in the periphery only.

You might recognize trospium. This medication has existed in pharmacies. You might notice it in perhaps men's health or other fields. Since 1974, it was used for overactive bladder. That medication, although existing, xanomeline was the new agent that was not in pharmacies before this combo medication. Xanomeline is a new one and they are like, "Okay, trospium is a good peripheral antagonist. Pair it together for tolerability."

Xanomeline MoA
Let’s talk about xanomeline because this is our agent for efficacy. As mentioned, it is going to be an M1/M4 agonist. Each of these has its own thing it is geared towards. The M1 agonism is going to increase that prefrontal cortex signaling. That is often what is associated with things like attention, working memory, some of our perhaps negative-esq symptoms, anhedonia, things like that. That is going to try to target those, enhance our attention, working memory, and modulate glutamate transmission. Overall, being the agent that is more so geared towards the cognitive and negative symptoms.

Conversely, M4 agonism, as you can recall, the M4 was inhibitory, and the M1 was excitatory. It makes sense that if we are agonizing M4, it is going to decrease dopamine release. This is going to be specifically in the mesolimbic pathway. That is going to affect the presynaptic regulation kind of before it occurs. It is going to, from there, reduce the dopamine signaling before it gets there, as we have mentioned. That is going to be targeting the positive symptoms because that is going to reduce dopamine. Remember, too much dopamine is associated with psychosis, so reduce that to target our positive symptoms.

EMERGENT Trials: Change in PANSS Total Score
Given that, we are now going to move forward on our data for xanomeline/trospium. The studies that got us medication approved, as an only interest is in pharmacies today. Those were called the EMERGENT trials. The primary endpoint, meaning the thing they look at to get that FDA indication for schizophrenia, was change in PANSS total score.

Has anyone ever done a PANSS? Probably not. It is not really used in clinical visits. It is more so done in clinical studies as opposed to outpatient visits, so if you are not familiar with it, it is essentially the marker that is used for schizophrenia. The PANSS score involves positive, negative, and cognitive symptoms and looks at that from a global measure.

They looked at that specifically at the end of five weeks to see the difference from placebo.

EMERGENT Trials: CANTAB by Cognitive Subgroup
The EMERGENT trials got it approved. let us look at the cognitive data. Here is what they found; it was pretty interesting. The full pooled sample versus when you are splitting it between people that originally had impaired cognition and how much their cognition improved versus if their cognition started off fine; they did not see some brand‑new improvement.

Essentially, there was more marked cognition improvement if they were already having issues; if they were not having issues, it ended up being about the same.

Effect Size

Effect size is a nice way to look at the magnitude of efficacy from a given study. The pooled effect size across all three EMERGENT trials was 0.65. That is one of the highest effect sizes, with the only one being higher being clozapine. Clozapine, if you are aware, is a second‑generation or atypical antipsychotic. It is seen as a more later‑line one. Lots of side effects. However, it does have a very profound effect size, so again, just another food for thought on this new MoA. Why would clozapine's effect size be so high? Then we have our xanomeline/trospium. Then all of our other agents are seen below that.

Clozapine relative binding affinity
Most of our second‑generation antipsychotics are really D2‑centric; we talked about that it is the definition that makes an antipsychotic, but uniquely, clozapine's relative binding affinity for muscarinic is actually much higher than that for its relative binding affinity to D2. Perhaps now we do not know for sure, but maybe that contributes to its higher effect size, and xanomeline/trospium focusing in on muscarinic perhaps could be why we are seeing those effect sizes. Just food for thought, just something to consider and think about.

EMERGENT Trials: Pooled Safety and Tolerability
Back to our EMERGENT trials. These are what got the xanomeline/trospium agent FDA‑approved. Our pooled safety and tolerability, which was done during a 52‑week ‑ that is a year ‑ open‑label treatment period. When you are doing safety trials, there is often not a placebo anymore. It is open‑label because the primary endpoint is no longer efficacy, but it is safety.

Here is what they found. The most common adverse effect was nausea, followed by vomiting, which makes sense because remember, we want that procholinergic in the CNS, procholinergic in the periphery is going to be more associated with those juicy side effects: nausea, vomiting.

Now, we do have the trospium affecting the periphery, trying to undo it, but remember it is undoing it to the best of its ability. It does not mean it is going to zip, zero, zilch; there is still going to be some that breaks through, but it is making it more tolerable. Without the trospium, this was higher. The trospium is bringing it down to this amount of incidence to make it more tolerable for people.

Now you are also seeing things like constipation; you are like, "Wait, is that not a dry side effect? Is it not an anticholinergic side effect?" Yes, because we do have the trospium that is undoing that side effect of those juicy side effects. With that, some people might have diarrhea if it is not undone enough, and if it is undone too much, you are going to have constipation. You will see pro and anticholinergic side effects.

However, what I do want to focus on is what we are not seeing here. We are not seeing weight gain. We are not seeing those metabolic things. We are not seeing prolactin. We are not seeing akathisia or EPS. Yes, we have some nausea, but it is a totally different side effect profile than what we are used to from our existing first‑generation and second‑generation antipsychotics.

It is definitely a good tool in the tool belt for if people do not want weight gain or have an underlying metabolic disorder, or want to avoid a creation of a metabolic disorder or struggle with EPS, or just do not want to have that be something that can be an issue. So, totally different side effect profile. Make sure you are aware of those differences.

Next‑Generation Muscarinic M1/M4 Therapeutics in Development
This is an area in development. It is super exciting for psychiatry. We have not had a new mechanism for schizophrenia in decades. The last beginning of a new MoA for schizophrenia was with the dawn of clozapine in 1989. Super exciting that we have another tool in our tool belt to reach for.

These muscarinic agonists, as we call them, there are several in development, all in different phases, and some are targeting different things one is going to be M4 selective. Others are dual, others are M1‑preferring, so as you can see, it is definitely an area where we are seeing a lot of advancement in studies.

Direclidine: An M4 Selective Agonist
Direclidine is an M4‑selective agonist. If we can recall, the M4 is the one that was more so indirectly modulating the positive symptoms. Just targeting one and seeing how that goes. So far, it is in phase III, and this has shown to have a decent effect size. They were doing some dose‑finding, the different doses, and at the 20 mg, 0.61 effect size. This is not approved. This is still going through studies, but just something to keep an eye on, as this is an area that is being looked at.

Integrating Into Your Practice
If you were to see a patient tomorrow and you are like, "I want to try this medication on them." We are going to talk about how you would exactly do that.

Xanomeline/Trospium: How to Initiate
Okay so how to initiate. The recommended starting dose is 50/20. It is a medication where you need to start at lower and then titrate it up for efficacy, so the 50/20 the 50 is xanomeline, and the 20 is trospium is going to be twice daily. Once in the morning on empty stomach, once at night on empty stomach. That could be an hour before breakfast and two hours after dinner. They are going to do that for at least two days.

Then you are going to go to the 100/20; you may stop there. The 100/20 is efficacious, is a theoretical stopping dose, or you may optionally go up to the 125/30, which is also an efficacious dose you may stop at. Going up has been shown to actually reduce side effects. You are like, that is interesting, but the reason for that is the ratio of trospium is going up. As you see 50/20, 100/20, the trospium stays the same. When you go up again, there is more trospium, which, remember, is the side‑effect‑undoing part of the combination medication, so going up can help with side effects, and it can also obviously increase efficacy.

Something that is counterintuitive with medication is a lot of times, in psychiatry or medicine in general, if people get side effects, we want to go slower; you want to be conservative, but in this one, going up can reduce that between our two efficacious doses. However, if you go up, you can also go back down if you like this one better, but in general, needing to stop at either the 100/20 or the 125/30. Those are both going to be twice daily they are both going to be on an empty stomach.

Why is it on an empty stomach? Again, counterintuitive here. A lot of people think, take your pill with food, and that is going to help you reduce nausea; not the case here. The food is going to bind with the trospium, which is our nausea side effect, helping part of the medication, and it is going to eliminate it. Taking it with food will actually make them more nauseous than not, so the empty stomach is a helpful counselling point. You can also give it with a prophylactic antiemetic 5‑HT3 antagonist such as ondansetron.

Then, finally, our anticholinergic adverse reaction. Since we have an anticholinergic in this medication, you want to note use of other anticholinergics are using, whether it is other overactive bladder medicines and other things that are on that can potentially exacerbate that.

Then also the maximum dose for geriatric patients. We have two efficacious doses: 100/20 or 125/30. For geriatric patients, we are going to want to stop at the 100/20, and it is contraindicated in urinary and gastric retention, which makes sense because trospium is used for overactive bladder. Contraindications for urinary retention; it would make that worse because of that agent added on.

Practical strategy here is use a slower titration, taper off other anticholinergics there on, and ask about urinary symptoms. Just like, "Hey, do you have any issues with urinating?" For those that do, this is going to make it more difficult to urinate, especially older males with prostate issues; someone you want to take consideration for this might not be the medication for them, but more common in older females is more of incontinence. This could even help just some things to keep in mind there.

Where This Could Fit in Your Treatment Algorithm
So where this could fit into your treatment algorithm. It could be positioned either after intolerance to D2 agents. They might be having EPS sensitivity, akathisia, or movement side effects. They might have metabolic concerns. I do want to delineate that could be an underlying metabolic disease, whether it is diabetes, hyperlipidemia, obesity; or they could not have those things, and their previous agents ‑ these antipsychotics ‑ can create a metabolic disease or metabolic concern where they were not existing previously, so someone who wants to avoid those. Then, if they have poor adherence to their second‑generation antipsychotics due to any of these adverse effects, or perhaps want more efficacy, are not having full stability of their positive symptoms, or maybe wanting to attempt to target negative and cognitive symptoms more.

It is not yet first‑line, but things you can consider if these are occurring, reasons to swap them and try out xanomeline/trospium, which is a totally different side effect profile.

Tolerability Practical Tips
Here is just some tolerability practical tips. If they were to get nausea, you can prophylactically give an antiemetic, meaning ‑ and I do this with my patients. I will prescribe the prophylactically an antiemetic when I enter prescribing xanomeline/trospium, meaning they have not already tried it and said, "Hey, Rebecca, I have nausea." Before they even get it. I am giving them a prophylactic antiemetic. You know what? A lot of my patients do not even feel it. They do not even use it, but I would rather them have it if they do need it. That way, they do not have to do an add‑on visit call message. All the things they are just equipped and prepared for if this is to happen.

Now, remember, nausea does not happen in everyone. A lot will not need the prophylactically antiemetic, but good to have in case they need it.

Constipation. Another side effect we see. What are some strategies for that? Could be hydration. Make sure they are adequately drinking enough water. Fiber can also help dry mouth, sugar‑free lozenges as well. Just some tolerability tips. I like to have my patients be equipped for if these things happen, but it is also important. I want to equip them, saying "If this is to happen," but I also do not want to fearmonger them into, like, manifesting that it is going to happen. The mind is powerful.

Every study always has a placebo response for a reason. The mind can do a lot. I do not want them to manifest these things either. I want to equip them without convincing them it is definitely going to happen because it is not definitely going to happen. The study did not show it with 100% of people. It did not even show it of 51% of people. With that, we want to be like, it is very possible this does not happen, but just in case wants you to be prepared.

Xanomeline/Trospium: Drug–Drug Interactions and Monitoring
Here are some of the monitoring interaction things to consider. Monitoring LFTs is something that you want to do. Just obtain baseline LFTs, like bilirubin. Then, as clinically indicated during treatment, it is not specified that you have to at any certain interval, but in the absence of clinical symptoms relating to this, you could repeat it after one month and document lack of effect in the raising of that.

Now, a lot of medications can raise ALT/AST. Just something that you want to get in your baseline labs.

Monitoring heart rate: the difference was 9.8 beats per minute of which it went up, just getting heart rate as a part of your vitals at baseline and periodically during treatment, which a lot of people are doing for vitals anyway.

Drug interactions: There are no contraindicated specific agents we want to consider when they are on anticholinergics, things like that, but there is no contraindicated specific agents. However, CYP2D6 contributes to xanomeline metabolism. However, the PI package insert does not recommend a dose adjustment, more so just monitoring for adverse reactions.

Again, no specific agents that are contraindicated. There is actually also no black box warning to this medication which is very rare. Just monitoring for side effects accordingly. In those cases, CYP2D6 agent, you can consider a slower initial titration and perhaps a lower maximum dose if they are on an agent that is also inhibiting that.

Hepatic and renal dysfunction: It is contraindicated in these populations as it will create a higher xanomeline exposure.

Case Study: Muscarinic Agonists, but for Whom?
Finally, we will touch on a case study. This patient presentation is going to be a 29‑year‑old man with a five‑year history of schizophrenia, diagnosed at age 24 with a psychotic episode with hallucinations and delusions. Those things add into our reality. There is no history of substance use disorder. However, there was a strong family history of schizophrenia. There is a genetic basis to that.

He is currently on olanzapine 15 mg at bedtime for the past two years. He has good positive symptom control. The hallucinations are stable. However, he is having persistent negative and cognitive symptoms: emotional blunting, lack of motivation, social withdrawal, those things detracting from the reality, slower processing speed, the executive functioning skills, planning things having to do with those cognitive symptoms, and then metabolic complications.

He has gained 40 pounds over the past 18 months. I have seen that happen unfortunately; that type of weight gain can occur in these other agents. Elevated fasting glucose and triglycerides, hypertension, sedation, increased appetite. Common side effects we see with these agents.

Is This a Candidate for a Muscarinic Agonist?
Is this candidate a good one for this muscarinic agonist, xanomeline/trospium?

The potential benefits he could have are the negative and cognitive symptoms might be a little bit more targeted through the muscarinic M1/M4 agonists have shown they can improve those areas, reducing the social withdrawal and helping with the memory and motivation.

The metabolic profile: He is having weight gain. He is having metabolic issues. Unlike olanzapine and the other atypicals, these are not associated with significant weight gain or metabolic disturbances. There is potential to reduce appetite and improve glucose homeostasis.

Then finally, tolerability. There is a lower risk of sedation and EPS movement, akathisia symptoms. No known risk of increased heart dyskinesia because this medication is not blocking the D2 receptor. Those movement side effects are from blocking of the D2 receptor off‑target, so he could have improvement in these areas. A lot of potential benefits to be gained. The risks would be those GI side effects nausea, dry mouth. Make sure you are advising him, giving him tools, and then potential for transient bradycardia or hypotension.

This is really an ideal candidate profile because he can have these other areas, other domains of improvement, and does not have history of GI motility issues, things like that, and potentially weighing the risks and benefits has more benefits to gain, so it could be an option for this patient.

Key Summary Points
Then, finally, our key summary points here is dopamine is not the whole story.

Muscarinic agonism does offer a new and novel strategy to treat schizophrenia by downregulating excessive presynaptic dopamine.

There is no direct D2 receptor binding. It is now approved for schizophrenia and in pharmacies for treatment in adults 18 and up.

It does not have metabolic or D2‑related adverse effects, is not directly antagonizing D2 receptor. We are not going to see our stereotypical weight gain and movement disorders.

Data suggest improved cognition in patients that had higher levels of cognitive dysfunction.