Breaking the Therapeutic Ceiling: Emerging Treatments for Schizophrenia Care

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Breaking the Therapeutic Ceiling in Schizophrenia Care: What’s New?

Disclosures

Dr. Leslie Citrome (New York Medical College): Thanks very much for the introduction. Thank you, everybody, for joining us today. We are going to talk about something that actually is new, interesting, and revolutionary.

Learning Objectives
For years, we have been treating schizophrenia by blocking dopamine receptors in the striatum. We think that there is too much dopamine in the striatum, that part of the brain that produces hallucinations and delusions. For years, we have been blocking those dopamine receptors that exist there. By blocking the dopamine receptors, we manage the hallucinations and delusions because there is just too much dopamine.

We are going to learn about differentiating dopaminergic and muscarinic mechanisms of action of therapies, and explain a bit more about what we have to do in terms of unmet needs in people with schizophrenia. We will evaluate the clinical evidence that supports other ways of treating schizophrenia. We are going to look at efficacy, safety, and some limitations of the information we have so far.

We are going to think about strategies to integrate these new novel approaches into treatment plans and figure out how to best offer it, and how to manage different side effects.

What’s Old? Dopamine Hypothesis of Schizophrenia
What is old? What is old is the dopamine hypothesis of schizophrenia. The early models that we have had for years have been that we have excess dopaminergic activity in the mesolimbic pathway. That is the pathway going from the ventral tegmental area to the ventral striatum. That is supported by models using psychostimulants like amphetamines that produce psychotic‑like symptoms when administered to people, as well as antipsychotic efficacy being correlated with D2 receptor antagonism.

Animal models show mesolimbic hyperactivity induced psychosis‑like behaviors. We have an animal model for psychosis. We also have recognized hypoactivity in the mesocortical pathway. Ventral tegmental area with connections to the cortex. That is old. It explains a lot of things, but not everything. It turns out that is incorrect in terms of what applies to people.

Humans Differ From Rodents: The New Dopamine Pathway Story
Humans are different from rodents. Yes, it is true, humans are different from rodents. The new dopamine pathway story involves a different part of the deeper structures in the brain, and is not the ventral tegmental area in people; it is part of the substantia nigra, which is very confusing to people because substantia nigra has been always associated with a pathway for the control of motor movements, not psychosis. However, it appears that part of the substantia nigra in human beings goes and projects to a part of the striatum called the associative striatum, and excess dopaminergic activity there explains psychosis in people.

Refinement of the Dopamine Hypothesis
We can refine the dopamine hypothesis by looking at the pathways in people, which turns out to be somewhat different than rodents. In particular, we still see this increased dopaminergic activity, which explains psychosis. That is the important part. Too much dopamine leads to hallucinations and delusions.

It is not really important for our story to know exactly where this pathway is located, simply to remind ourselves too much dopamine in the striatum produces hallucinations and delusions.

Dopamine Pathway Problems Remain
The problems of dopaminergic pathway issues remain with us, and I should go over this in a bit more detail. The mesocortical pathway I mentioned earlier from what we thought was the ventral tegmental area in the midbrain to the frontal cortex. That pathway will explain issues in people with schizophrenia in terms of negative symptoms, cognitive impairment, and depression. The mesolimbic pathway, we originally thought from the ventral tegmental area goes to the ventral striatum, olfactory tubercle, parts of limbic system, that has explained in the past positive symptoms of schizophrenia. However, now we have a better recognition that this really explains a bit about negative symptoms only.

The key pathway that we now appreciate is nigrostriatal pathway number one, going from the substantia nigra, a special part of it, and innervates the associative striatum. That is the refinement of the model. Nigrostriatal pathway two is still there. Goes from the substantia nigra and innervates the sensory‑motor striatum or dorsal striatum. Blocking dopamine receptors there causes no end of problems motorically. The tuberoinfundibular hypothalamic pathway explains hyperprolactinemia.

But Wait, There’s More: Potential Association Between Non-D₂ Receptor Blockade and Tolerability
However, there is more, unfortunately. There is an association between other receptor blockade and tolerability. Our second‑generation antipsychotics typically have affinity to all sorts of other receptors: alpha‑adrenergic receptors, which may lead to postural hypotension, increased blood pressure; histaminergic receptors, whose blockade can lead to sedation and weight gain. Muscarinic pathways blockade there leads to cognitive impairment. 5‑HT₂C antagonism, those serotonin receptors are responsible for control of appetite, and so blockade of those receptors can increase appetite. Along with the dopamine D2 blockade of our antipsychotics, we have a whole assortment of other receptor blockade and, consequentially, tolerability issues.

Problem: D₂ Antagonists Are Not Selective
The big problem is D2 antagonists or antipsychotics are not selective. Although there is too much dopamine in the associative striatum causing psychotic symptoms block those D2 receptors and decrease hallucinations and delusions, it does not stop there. Blocking postsynaptic dopamine D2 receptors where we want to is accompanied by D2 blockade where we do not want to, causing motor adverse events, drug‑induced parkinsonism, akathisia, dystonia, ultimately tardive dyskinesia. Elevation of prolactin can also occur by blocking dopamine D2 receptors elsewhere in the hypothalamic pituitary pathway.

Another way to treat psychosis is perhaps decreasing the amount of dopamine released in the first place. Do it presynaptically. If we can do that selectively only in those circuits that modulate dopamine where we want to, maybe we can treat psychosis without causing all sorts of other collateral damage. Maybe muscarinic receptors will fit the bill here. That is the story we will talk about today.

Future Directions: Novel Mechanisms
Presynaptic dopamine dysregulation needs to be addressed. One way is just decreasing the amount of dopamine that is either synthesized or released. Intervening upstream of the dopamine D2 receptor is a strategy that can possibly work. However, up to now, we really have not had anything in the clinic that we can use to treat psychosis that works that way. We have been stuck with dopamine receptor blockade.

There are other ways, though. Muscarinic receptors can be targeted. We will talk about a specific agent called xanomeline. It comes combined with trospium and can be used to treat people with schizophrenia. Xanomeline targets muscarinic M1 and M4 receptors and modulates dopaminergic circuits. I am going to explain this in much more detail in a few moments.

There have been other approaches to address the release and action of dopamine. Releasing dopamine can be modulated by glutamate. Glutamate is involved in this story here, and it is thought that one model of schizophrenia has been the NMDA receptor hypofunction hypothesis, leading to dopamine dysregulation. I will explain that as well.

Trace amine receptor agonists have been explored as a potential treatment of schizophrenia by regulating dopamine release. We have had a drug candidate there. Unfortunately, it failed the initial trials. However, it is still going to be evaluated. As we speak, clinical trials are still going on.

There is also another way of addressing these NMDA receptors. These glutamate receptors are very complicated. They need to be activated, of course, by glutamate, an excitatory neurotransmitter, but also by a co‑agonist called glycine. Glycine needs to be there as well. If we can increase the amount of glycine at the synapse, maybe these NMDA receptors would work better. That strategy has been used to address negative symptoms and cognitive deficits. However, so far, we have had no successful agent reaching the point of FDA approval.

Central to the Story: Evidence for Glutamate Hypofunction and Symptoms of Schizophrenia
Let us talk about this glutamate hypofunction and how it can explain some symptoms of schizophrenia that we see. NMDA receptors are very complex. They are really present in many places in the brain, and they are activated by glutamate, the brain's most commonly encountered excitatory neurotransmitter. NMDA receptors do not work alone. You need other glutamate receptors called AMPA or kainate. The important point is, in people with schizophrenia, there may be hypofunctioning of this NMDA receptor.

We know that we can develop mice models that explain this quite nicely. Transgenic mice with reduced NMDA receptor expression exhibit hyperactivity and reduced social interactions. That is a model of psychosis. NMDA receptor antagonists can induce cognitive disruption. In humans, NMDA antagonists at high amounts can induce hallucinations and delusions. NMDA antagonists also induce cognitive deficits, that we know in people and nonhuman primates. However, in the end, NMDA receptors are complicated, so regulating them directly is complicated. Maybe there is another way.

The Sick GABA Interneuron
The other way is addressing that interneuron. You know that glutamatergic neurons give a positive signal to wherever it connects to. It increases activity in circuits, and it is held back by GABA. GABA is the brain's ubiquitous inhibitory neurotransmitter. GABA interneurons are also all over the brain, and they control the glutamate neurons. GABA puts the brakes on glutamate.

In people with schizophrenia, there is insufficient excitation of this GABA interneuron. If this GABA interneuron is not working because the NMDA receptor on it is not working, then you are going to have a problem. This is actually an interesting story here. You need that negative signal to stop glutamate. However, if there is insufficient glutamate, you are not going to be able to stop excessive glutamate later down on the chain. Excessive glutamate ultimately will result in excess dopamine and ultimately result in hallucinations and delusions.

This NMDA receptor on the GABA interneuron is really important. When activated, it will excite the GABA interneuron, allowing it to inhibit glutamatergic neurons next down the chain. It is a regulatory process here. You really need that GABA interneuron to put the brakes on things. However, it does not happen in people with schizophrenia, and the relevant glutamatergic neuron down the chain is disinhibited. Too much dopamine is ultimately released in the circuit responsible for psychosis. If I drew a little picture of this GABA interneuron, he is supine in bed, thermometer in his mouth, ice pack on his head. He is sick. Can we make him better?

Muscarinic Agonism Can “Treat” a Sick GABA Interneuron
Yes, we can. Muscarinic agonism can treat this sick GABA interneuron. How does it do that? Muscarinic M1 receptors exist on the GABA interneuron. They also excite the GABA interneuron. A fix here for NMDA receptor hypofunction is to increase the activity of this muscarinic M1 receptor located on that very same GABA interneuron. When we activate that M1 receptor, it will excite the GABA interneuron, allowing it to inhibit glutamate. That is good because we want to decrease glutamatergic activity so that we decrease dopaminergic activity. We want less dopamine released in the striatum that is responsible for hallucinations and delusions. We can call this M1 ‘chicken soup for the brain’ for people with schizophrenia to fix their GABA interneurons.

Muscarinic Agonism for Psychosis Rediscovered
Muscarinic agonism is actually an old story. In 1957, arecoline was found to actually modulate these symptoms we see in rats that are a model of schizophrenia. We have also noted in the 1950s, if you look back in the history books, that arecoline can actually treat psychosis. However, they measured it by lucid intervals. Can you have conversations with patients with schizophrenia for longer than a few seconds? If you can have more lucid intervals, you are actually treating psychosis. You can do that with arecoline injected under the skin. Arecoline is a muscarinic agonist. By the way, arecoline is found in betel nuts. In some cultures, chewing betel nuts is pretty common. That may be a treatment for people who are psychotic.

In 1992, xanomeline was synthesized. It is a relative of arecoline. It was synthesized with the purpose of improving cognition in people with Alzheimer's dementia. Xanomeline has no direct D2 receptor blocking activity.

In 1997, this study in people with Alzheimer's disease – a double‑blind, placebo‑controlled xanomeline – revealed that, yes, cognition improved. Surprise, surprise, it seemed to also improve psychotic symptoms associated with Alzheimer's dementia.

This got to be very interesting. Further developments revealed that xanomeline actually will reverse some of the issues found with mice when we knock out their M1 and M4 receptors. We have this dysregulation in these mice that looks like psychosis. We can address some deficiency in M1/M4 receptor activity with agonists that appear to reverse the psychosis that we induce. This is interesting, supported by animal models.

More About Muscarinic Receptors
A little bit more about muscarinic receptors that you need to know about. There are excitatory muscarinic receptors and inhibitory muscarinic receptors. The excitatory muscarinic receptors are M1, M3, M5. You will notice that they are odd numbers. Inhibitory muscarinic receptors are M2 and M4. They are even numbers.

These muscarinic receptors are located throughout the body, in the brain and in the periphery. They operate by G‑protein cascades. There is a whole bunch of events that occurs when these receptors are activated. It helps us control neuronal excitability, learning and memory, but also cardiac function and smooth muscle contraction and exocrine gland secretion or saliva, as well as insulin.

The excitatory muscarinic receptors M1, M3, and M5 are postsynaptic. They are activated by agonists or positive allosteric modulators that actually work by increasing activity without going to the actual site where the acetylcholine goes, but another site on that receptor. That seems to work as well.

The even‑numbered muscarinic receptors are presynaptic. What does that mean? It means they are inhibitory. Presynaptic receptors are the important link in regulation in terms of decreasing the amount of neurotransmitter that is ultimately released. Muscarinic receptors, M2, M4, presynaptically will dial things down. The excitatory muscarinic receptors postsynaptically will ramp things up. We can target those receptors as well.

The “Top Down” M₁ Story: How Muscarinic Stimulation of PFC GABAergic Inhibitory Interneurons Decreases VTA Dopamine Release
Let us go through some circuits. There is the top‑down story of the control of hallucinations and delusions. How does that happen? Muscarinic M1 receptors are excitatory. They exist on GABA interneurons. We talked about that. GABA interneurons control glutamate neurons. If you do not have inhibition of the glutamate neuron you are going to have too much glutamate being released resulting in excitation in the ventral tegmental area, or where dopamine neurons live. You are going to have more dopamine neurotransmission if you excite those dopamine neurons. We do not want to do that. We want to put the brakes on that glutamatergic neuron that connects to the dopaminergic neuron. We can do that by increasing the activity of this GABA interneuron in the cortex.

M1 receptors live on that GABA interneuron. By agonizing or exciting that M1 receptor, we make that GABA interneuron works better. It inhibits glutamate, that glutamatergic neuron, to the point that it does not excessively excite the dopaminergic neuron that it connects to. You will have less dopamine released in that part of the striatum that explains psychosis. This downstream effect does the job. Instead of blocking those D2 receptors in striatum, we just reduce the amount of dopamine that is released in the first place. That is the top‑down story because it starts in the cortex with GABA interneurons.

But Wait, There’s More! What Is an Autoreceptor?
However, there is also the bottom‑up involving autoreceptors. Just as a reminder, autoreceptors are receptors on nerve cells that respond to the same neurotransmitters released by that cell. It is a negative feedback loop. If you have too much of that neurotransmitter, it bounces back to the presynaptic neuron and shuts down or decreases the amount of neurotransmitter being released.

We have many examples of this in medicine, and there is a recent example in the treatment of agitation associated with schizophrenia or bipolar disorder, with an old drug reformulated called dexmedetomidine, which actually decreases norepinephrine release in the locus coeruleus. Decreasing norepinephrine release there reduces agitation simply by agonizing the right autoreceptor.

But Wait, There’s More! “Bottom Up” M₄: Midbrain Input Decreases Dopamine Release in Psychosis Related Areas
We can do that with muscarinic receptors: the even‑numbered muscarinic receptors, particularly M4. In the hindbrain exists a nucleus of acetylcholine cells. It is in the lateral dorsal tegmentum. We abbreviate it as LDT. The LDT controls ultimately the part of the brain that projects to the striatum. That part of the brain, we will call it the ventral tegmental area. If you can control the VTA, you can control the amount of dopamine that is being released in the striatum. You can do that not only top‑down but bottom‑up.

This LDT is a nucleus of cells that release acetylcholine. Acetylcholine is excitatory. When connected to the VTA, which is where dopamine neurons live, you are going to increase the activity of these dopamine neurons. You are going to influence the amount of dopamine that is released in the striatum. Maybe we can slow things down. Maybe we can inhibit that circuit. The LDT to the VTA, that acetylcholine release can be decreased, hence decreasing the excitation of the dopaminergic neuron that goes to the striatum. Less dopamine there means less hallucinations or delusions. That is the bottom‑up approach.

Healthy Brain
M1 top‑down. Starts in the cortex with the GABA interneurons – the M1 receptor lives there – and it connects to the glutamate neuron, which is excitatory, which connects to the VTA, which is our dopamine neurons, which goes to the striatum. In a healthy brain, this works well. You have good control of the amount of dopamine that is released in the striatum. You do not have hallucinations and delusions.

The bottom‑up circuit is also well regulated in a healthy brain. In the hindbrain is that LDT, lateral dorsal tegmentum. That is a nucleus of acetylcholine neurons which connects to the VTA, where the dopaminergic neurons are, which of course connects to the striatum. This all works well. The M4 receptor works fine. You have a good amount of dopamine, not too much, not too little, and you have a healthy brain.

Psychotic Brain
Unfortunately, in the psychotic brain, those GABA interneurons are sick. You have too much glutamate being released ultimately. Why? Because you are not putting the brakes on that glutamate neuron. That glutamate neuron works excessively, and you have too much excitation in the VTA where the dopaminergic neurons live, and hence too much dopamine being released in the striatum, and you have psychosis.

Bottom‑up, similar story here. You do not control the release of acetylcholine. You have too much being released and exciting the VTA dopaminergic neurons. Too much excitement there, too much dopamine released ultimately in the striatum because that M4 receptor is not adequately inhibiting this pathway. That is the psychotic brain.

What do we do with dopamine receptor blocking agents? We create a shield that prevents the excitation of that neuron by blocking those dopamine receptors that exist in the striatum and those neurons there. We control the signaling not by reducing dopamine release, but by blocking dopamine action with the DRBA shield.

Both top‑down and bottom‑up pathways are controlled not directly, but really are managed by blocking the dopamine receptors, finally, in the striatum. That is one way of doing it. We have been doing it for years. It helps psychosis, but there has got to be a better way.

That better way is M1/M4 agonism, because they can selectively target those circuits that explain psychosis. GABA interneurons can be excited by M1 receptor agonism, which results in inhibition of the glutamatergic neuron. Remember GABA is inhibitory. If you increase inhibitory tone, you are going to decrease, ultimately, glutamate excitation. The glutamatergic neuron releases less glutamate, resulting in less excitation of the dopaminergic neuron, leading to less dopamine being released in the striatum.

Bottom up, we can increase the activity of the M4 autoreceptor, dial down that LDT release of acetylcholine, thus dialing down the dopaminergic neuron, thus dialing down the amount of dopamine released in the striatum. Top‑down, bottom‑up are controlled selectively by muscarinic agonism M1 and M4.

Xanomeline as a Muscarinic Agonist: In Vitro Binding and Functional Activity
That is the explanation we think, what is going on. That is the heavy lifting here in understanding this new approach to addressing schizophrenia.

Xanomeline fits the bill here in terms of M1/M4 agonism. It goes to, of course, all muscarinic receptors, but functionally it works more at M1/M4 receptors in terms of agonism.

2008 Pilot Study: Xanomeline vs Placebo
We know that it partially worked in Alzheimer's dementia in improving their cognition and, surprise, their psychosis. It was thought that maybe we can use this for schizophrenia.

A pilot study was done in 2008. It was reported that xanomeline, double‑blind, placebo‑controlled, four‑week trial resulted in a decrease in psychosis for those randomized to xanomeline, much more so than a decrease in psychosis observed with placebo. Brief Psychiatric Rating Scale, BPRS, showed improvement for those on xanomeline superior to that seen with placebo. Moreover, cognition also seemed to improve.

What is the catch? The catch was the tolerability. The problem here is excessive GI side effects because muscarinic agonism is going to increase GI activity. Vomiting occurred in 60% of the patients randomized to xanomeline. That is a deal breaker when developing a drug; 60% of patients had experienced vomiting. What can we do about that?

Can We Mitigate the Peripheral Procholinergic Effects of Xanomeline?
How can we mitigate the procholinergic activity of xanomeline? Perhaps by blocking muscarinic receptors in the periphery that otherwise xanomeline excites too much. How do we do that? We find in anticholinergic that does not go into the brain. We find an anticholinergic that just will be distributed in the periphery. Trospium fits the bill here. Trospium is an anticholinergic agent, does not cross the blood‑brain barrier, has no central effects, but has peripheral effects. It manages excessive muscarinic agonism, or at least addresses some of that.

This drug, trospium, has been approved in the US for more than 20 years for overactive bladder. It has been around since the 1970s, and it actually will serve as an antidote, so to speak, to xanomeline activity in the periphery.

Xanomeline-Trospium in Acute Schizophrenia: PANSS Total Score Change From Baseline
Does this actually work, xanomeline-trospium combination? Actually, it does. It was studied in people with schizophrenia, and in three studies that recruited patients with acute exacerbations of schizophrenia, patients were randomized to either receive xanomeline and trospium or placebo and observed for five weeks. It was found that psychotic symptoms decreased more with xanomeline-trospium than with placebo. Not only that, a whole lot more. The effect size is large. What do I mean by effect size?

What Is an Effect Size?
Basically, effect size is the way to look at a clinical trial and see if it is clinically relevant or not. That p‑value will not tell you anything about the importance of the clinical trial result. All it tells you is that it is probably true because it is statistically significant and not due to chance.

How do we know if it is important? The size of the treatment effect has to be important. The point differences need to be relatively large, and we can express that in a standardized way by looking at the point change difference and translating that into standard deviation units.

This is how it is done statistically. It is called the Cohen's d standardized mean difference. We can look at the point change in the results of the Positive and Negative Syndrome Scale total score. We can take a look to see how large it is in a standardized way. A Cohen's d of 1 would mean one standard deviation difference, which would be huge. 0.2 standard deviations would be small. 0.5 in the middle.

We can also calculate number needed to treat. How many patients needed to be randomized to the drug of interest compared to placebo before expecting one additional patient to be a responder.

Those are effect sizes. They will tell us the importance of a clinical trial and really address what the p‑value cannot.

Xanomeline/Trospium and Cohen’s d
Let us take a look at the Cohen's d. The differences between drug and placebo in standard deviation units. An effect size of 0.3, yes, you will notice that, but it is not dramatic. 0.5, yes, we will notice that. That is generally what we see with the drugs we have on hand to treat our patients. Greater than or equal to 0.6 is very noticeable, and more than what we would expect. The Cohen's d for xanomeline‑trospium combination in addressing the Positive and Negative Syndrome Scale total score was 0.65. It was more than expected. It works.

When we think about this, xanomeline is a muscarinic receptor agonist. It does not block dopamine D2 receptors, yet it reduces psychosis. That is fascinating because this is the first time that we have in our hands a drug to treat psychosis that does not block D2 receptors and works by decreasing dopamine release in the first place and works well.

It works in terms of positive symptoms. There is also an effect on negative symptoms, possibly because the positive symptoms are improved. In terms of the Clinical Global Impression-Severity, that is the overall marker of a drug working, the effect size 0.63 means this works.

Efficacy Pooled Acute Studies: NNT
We can also look at number needed to treat. What we want to see is an NNT less than 10. The number of patients randomized to drug versus placebo before seeing one extra responder. Placebo is not no treatment, by the way. Placebo in a clinical trial means that someone is not getting the active drug, but they are still being seen frequently and involved in the research process.

If we calculate or define a response as greater than or equal to 20% improvement on the Positive and Negative Syndrome Scale, that is noticeable. The number you need to treat was five. That is way less than 10. Greater than or equal to 30%, our standard in measuring response in these trials, the NNT was still five. Still good. If we go higher and see more robust reductions in the PANSS total score for greater than or equal to 40%, it is still a single digit. It is eight. It is less than 10. That is rather unusual. If we go for the gold here and look at the NNT for improvements of at least 50%, which does not happen often, but it happened twice as often with xanomeline-trospium than with placebo. The NNT was 15, so we will not necessarily expect it every day, but it can happen.

Indirect Comparisons of Acute Efficacy
When we compare these NNTs with other drugs we use to treat schizophrenia, it is either as good as or better than the alternatives. They have NNTs ranging from 4 to 10. In order to really know if xanomeline-trospium is really better than the others, we will really need to do a head‑to‑head clinical trial to test that. However, I can say that it is either as good as or better than what we have. This is really interesting because this does not work by blocking postsynaptic D2 receptors in the striatum. It works through muscarinic agonism. It is a different way.

Tolerability and Safety Outcomes: NNH
Now, the tolerability, we need to look at the GI side effects in particular. When we look at the adverse events occurring in at least 5% of those people randomized to xanomeline‑trospium versus placebo, nausea occurred in 18.5% for those on xanomeline‑trospium, and about 4% for those on placebo. That results in a number needed to harm of seven. We can expect nausea on a regular basis in day‑to‑day use. We can also expect vomiting. 13.5% for xanomeline‑trospium versus about 2% for placebo number, needed to harm of nine. It took nine patients to be randomized to xanomeline‑trospium versus placebo before encountering one additional patient with that side effect.

Did that cause a problem? If you warn patients about it and manage it, and it does seem to go away, then they remain on the drug. In the clinical trial, very few patients stopped because of nausea, dyspepsia, or vomiting. The rate of discontinuation was 2.1%, dose reduction 0.6%. These are low numbers. That is the bottom line there. Took about 50 patients to be randomized to xanomeline-trospium versus placebo before having to stop the patient because of nausea, dyspepsia, or vomiting. In this regard, we can manage this, but we need to know more about it, and I will talk about it in a moment.

Long-Term Change in PANSS Total Score
Long‑term change in the Positive and Negative Syndrome Scale is observed. This was an open‑label study and an open‑label phase of another study. It shows that patients who are on xanomeline‑trospium for a longer period of time continue to improve. Patients received a placebo at the beginning in the double‑blind study, and were given xanomeline‑trospium in the open‑label portion of the study, and they caught up with their fellow patients who received xanomeline‑trospium from the beginning. In the end, everyone was improving slowly over time with PANSS score reductions that are clinically relevant, of 30 points.

Pooled Long-term Trials: Safety and Tolerability During the 52-Wk Open-Label Treatment Period
In terms of long‑term treatment, we look at side effects that may occur. There are really no surprises here, but let us take a look. The duration of nausea, vomiting, is less than a week. We can also look at the intensity. Generally mild, sometimes moderate. I am not dismissing it. We have to warn patients about it. We have to strategize. One way of dealing with that is proactively. If you want to use more trospium, you can do that. It is available generically, you can add it on. You can do something. Actually, when we talk about xanomeline‑trospium dosing, we can do something that is pretty obvious. I will talk about that in a moment.

Xanomeline/Trospium Chloride: FDA Approved (September 2024)
The indication of xanomeline‑trospium as FDA‑approved in September 2024 was schizophrenia in adults. It is the first schizophrenia approval for a muscarinic agonist. The word antipsychotic actually does not appear in the product label, and hence there is no box‑bolded warning about elderly, demented patients with psychosis, because it does not block dopamine D2 receptors. There is no box‑bolded warning. And there are no class‑level warnings and precautions that include dysphagia and seizures and so on that we find in the antipsychotic drug labels. It is not in the xanomeline‑trospium drug label because it is not a D2 blocker.

The dosing is really very important here. It was studied in the following way. Patients received 50 mg of xanomeline together with 20 mg of trospium in a single pill. We will call that 50/20 BID for two days. Then they were given 100/20 twice a day for five days. Then they went to 125/30 BID. Almost everybody went to 125/30 BID. Very few patients were stuck at 100/20.

It turns out that 30 mg BID of trospium works better than 20 mg BID of trospium in countering procholinergic effects. Getting to 125/30, that dose is really important, and going higher more quickly is what I generally recommend.

We did not know this for sure at the beginning when we had this in our hands, and we tended to dose this drug too slowly. If you do that, you are going to have more GI side effects. I have heard some clinicians go from 50/20 right away to 125/30. I have not done that, but I was told this, and it seemed to work at least for that clinician. The idea here is you want to get to 125/30.

You want to take it on an empty stomach. One hour before a meal or two hours after a meal, because trospium is not absorbed with food in the stomach. What happens if you take it with a meal? Trospium is not absorbed, and you will have more nausea, maybe vomiting. Actually, it is interesting. When you eat, you will feel worse. I suggest to patients, make sure you are on an empty stomach or you really just may get into a problem here. The product label tells us to test, at baseline and during treatment, heart rate and liver enzymes and bilirubin.

Practical Guidance for Xanomeline/Trospium
There are contraindications. You cannot give it to people with urinary retention because of the trospium. That will be a problem. You do not give it to moderate or severe hepatic impairment. That is a contraindication. With mild hepatic impairment, it is not recommended but not a contraindication. You do not want to give it to someone with gastric retention because the trospium would make it worse. You do not want to give it in people with untreated narrow‑angle glaucoma, and of course, you do not give it to people who are allergic to it.

In terms of renal impairment, you do not need to adjust the dose with mild, but you do not want to give it to someone with moderate or severe renal impairment.

Remember the bottom line here: taking xanomeline‑trospium with a meal may increase procholinergic adverse effects because trospium absorption will not occur as it should.

Caution: Anticholinergic Agents
A word of caution here. Anticholinergic agents. Trospium is anticholinergic. We do not want to add to it without realizing that we may increase the anticholinergic burden, increase the risk for urinary retention, increase the risk of constipation, increase the risk of dry mouth. We need to also be mindful about those anticholinergics that cross the blood‑brain barrier, and theoretically, that may interfere with xanomeline's mechanism of action.

What are some examples of drugs that have anticholinergic activity? Clozapine, olanzapine, chlorpromazine, tricyclic antidepressants, diphenhydramine, and of course, benztropine. We need to be mindful about those drugs. We can anticipate more peripheral side effects and possibly a decrease in the therapeutic effects of xanomeline, although I say that theoretically, because the binding affinities play into this. That is another topic for another presentation.

Potential Place of Xanomeline/Trospium in Clinical Practice?
What is the potential place of xanomeline‑trospium in our hands in the clinic? Those with residual positive symptoms, I would give it a try. Adding it to what their current treatment is sounds logical. It was tested in a double‑blind randomized clinical trial, found that there was no advantage there, but at least it was tolerated. That was done in groups of people. We treat individual people, so it is something that we do consider. Early switch from olanzapine or risperidone after their hospital discharge to avoid ultimately long‑term adverse effects, metabolic, motoric, and so on. Maybe this is useful for those with cognitive dysfunction, but more data is needed.

We do know that secondary cognitive and negative symptoms due to postsynaptic D2 blocker treatment can be addressed by not blocking those D2 receptors. We do not block them with xanomeline. Early‑phase patients may be interested in this drug because we can avoid long‑standing antidopaminergic effects, as well as the other effects of the other receptor‑blocking activities of these traditional antipsychotics.

We may want to think about it for those who have continuing problems with dystonia, akathisia, parkinsonism. We may think about it for those with prolactin elevation leading to problems. We may think about it for those who have problems with weight gain. We may think about it with those who are easily sedated. Xanomeline, I did not mention, is not sedating at all. If you are looking for something that is not sedating, that fits the bill.

Not everyone is going to respond to every drug we give, so I like having these alternatives. We can address some of these adverse effects by switching the antipsychotic for another second‑generation antipsychotic. We can certainly do that. However, xanomeline‑trospium provides another avenue here. The treatment‑resistant schizophrenia story has not been solved yet. More data is needed.

Bottom Line: Xanomeline/Trospium Combination Is Different
The bottom line is xanomeline‑trospium is different. The mechanism of action is central muscarinic M1 and M4 receptor agonism thanks to xanomeline, which selectively decreases dopamine in that part of the human striatum responsible for hallucinations and delusions. By avoiding dopamine D2 receptor blockade, we avoid the collateral damage of drug‑induced movement disorders and prolactin elevation. We can also avoid blockade of serotonin, adrenergic, and histamine receptors, and that reduces the risk of sedation, weight gain, and metabolic abnormalities that can be problematic with our traditional treatments.

The prescribing information of xanomeline‑trospium does not contain the class‑level warnings and precautions that we find in the traditional antipsychotic drug labels. It has a different array of tolerability concerns that we need to learn to manage, and those are the pro‑muscarinic peripheral effects that lead to gastrointestinal issues such as nausea and vomiting.

Trospium's peripheral anticholinergic actions can cause constipation and urinary retention. We want to be careful with trospium, but we are getting more facile with dealing with this trospium dose. The prescribing information for xanomeline‑trospium also includes recommendations to assess heart rate at baseline and as clinically indicated during treatment, as well as liver enzymes and bilirubin prior to initiating treatment and as clinically indicated.

Updated Heat Map for Rx Schizophrenia
There are adverse events that we commonly think about when treating people with schizophrenia. Weight gain of at least 7%. Adverse events of somnolence or sedation and adverse events of akathisia. Green means go. Orange or yellow means caution. Red means no go. Red number needed to harm values are less than 10. It means that we are going to be expecting to encounter, let us say, weight gain for olanzapine, sedation for lumateperone. With orange, we are going to see this from time to time, including akathisia for cariprazine, lurasidone, or risperidone.

Basically, we look for drugs that are all green. Aripiprazole is well tolerated. It may not work with everybody, so we need alternatives. Xanomeline‑trospium combination is best in terms of no difference between drug and placebo in weight gain and not associated with sedation or somnolence or with akathisia.

Other Muscarinic Agonists/Positive Allosteric Modulators
There are other muscarinic receptor agonists and positive allosteric modulators in development. There is one called emraclidine. The first studies showed NNT of five and four for improvement from baseline on the PANSS in terms of 20% and 30% improvement. Robust decreases in terms of point change.

Emraclidine: Phase II 6-Wk Trials Yielded Negative Findings
Unfortunately, the subsequent studies yielded negative findings.

Emraclidine: Next Steps
However, it is not gone. More studies are being planned or in place.

Other Muscarinic Agonists/Positive Allosteric Modulators
There is another one being developed that has some data supporting one of the doses, and that is being pursued.

Other Emerging Novel Therapeutics in Schizophrenia
There are other drugs. Keep in mind that muscarinic agonism is not the only way to decrease dopamine release. We can do it through different receptors that we have not talked about and different channels and so on. Stay tuned.

Summary
Let us summarize Human dopaminergic pathways differ from rodents'. Muscarinic agonism can decrease the dopaminergic tone where we want to and not where we do not want to. This is a paradigm shift. Stay tuned for more about xanomeline and other muscarinic receptor modulators.

Thank you!
I want to thank you for your attention. This is new information, and you are going to have to hear it over and over again before it sticks. I know. That happened to me. I needed to hear it over and over again.