So, I want to start by just providing a brief overview of schizophrenia. And, you know, the cool thing about these presentations is we have a lot of different professionals on this call or on this meeting. So, maybe you've had a lot of experience. Maybe you work in community mental health where schizophrenia is your bread and butter. But we may also have people that are new grads or even students that are joining in on this.

So, we'll give a little bit of a level set to make sure that we're familiar with the disease state before we move forward.

So, schizophrenia unfortunately is 1 of the most severe, most debilitating, really sad illnesses within mental health. And it's 1 that has just incredible unmet needs. A lot of areas that we can do better because frankly, these patients are just suffering incredibly.

We see here the prevalence listed, unfortunately, between 4% and 10% of people with schizophrenia die by suicide. On average, a patient with schizophrenia, their lifespan is about 30 years shorter than a healthy comparator. It's a very heterogeneous presentation. And this can be quite challenging. There's unfortunately no singular genetic mutation or anything that we can point to where we have 1 gene, 1 mutation, 1 treatment, but rather many different factors, both genetically and environmentally, that may contribute to the presentation of schizophrenia, which is also why it's been such an elusive illness.

The current treatment philosophy is informed by the recovery model. And so we'll talk about that in a subsequent slide what we actually mean by that. But the key within this is that antipsychotic medications still remain the mainstay in cornerstone of treatment.

[00:06:29]

Schizophrenia Is a Complex Psychiatric Disorder

We can think of schizophrenia as a 3-domain illness. So, we have positive symptoms. These are typically the ones that we think of with schizophrenia. And some of that is Hollywood. Some of it is culture that if we think of someone with schizophrenia, at least in my mind, sadly, I think of someone who maybe is homeless, you know, mumbling to themselves on the street, having hallucinations or paranoia. And those are certainly, I think, the most forward symptoms in the sense that if we have an interaction as a healthcare professional with a patient with schizophrenia, very often what we focus on is the presence or absence of positive symptoms. Those are the most visible to us.

But we don't want to forget the other symptom domains of schizophrenia, which include negative symptoms and cognitive symptoms. So, these symptoms are quite important because negative and cognitive are often overlooked in large part because historically we haven't had many good interventions or treatments for them. And sometimes we only look for our keys where the light is shining, but also with cognitive symptoms. Specifically, the DSM-5 does not include cognitive symptoms in the diagnostic criteria for schizophrenia, not because cognitive symptoms are unimportant, not because cognitive symptoms are not a huge part of schizophrenia, but rather cognitive difficulties are really nonspecific symptoms.

So, in terms of diagnostic clarity, the inclusion of cognitive symptoms, there's too much crossover or cross representation where patients can have cognitive difficulties with depression, with anxiety, with other areas.

So, the reason that cognitive symptoms are not included in the DSM-5 schizophrenia criteria is because of the lack of specificity. But unfortunately, what happens is, in psychiatry, we end up being very often quite focused on diagnostic criteria, and we may overlook the impact of cognitive symptoms in a patient with schizophrenia.

[00:08:15]

Negative and Cognitive Symptoms Drive Disability

We see the importance of cognitive and negative symptoms here, where again, very often we look at schizophrenia through the lens of positive symptoms. And certainly positive symptoms are incredibly distressing. They may cause both the patient and the family a lot of distress or difficulty, but the negative and cognitive symptoms are often the primary drivers of disability.

And this is the case really through much of the lifespan where the negative and cognitive are quite insidious. A, there are things that we just don't treat very effectively, or we don't have a lot of options, but these are also the things that really drive diminished quality of life and functioning for this individual.

[00:08:54]

Treatment Philosophy

We talked earlier about the treatment philosophy. And on the left-hand side we see the medical model. So, the traditional medical model is we identify a symptom, we pick an intervention to then address that symptom and hopefully drive wellness.

Recovery model as we see it a little bit more holistic. It incorporates other aspects. So, we have where the patient is at. We're then going to use shared decision-making to identify goals where the patient wants to go and then we're going to work to identify different strategies to help the patient get there, and that includes identifying and eliminating barriers. Certainly pharmacologic intervention is part of that treatment plan.

But the idea behind this is to work with the patient to figure out what those goals are. Maybe the patient's goal, recovery for that patient may be returning to the workforce or living independently. So, the recovery model is a little bit more inclusive and functionally focused, which I think is a really nice evolution.

[00:09:48]

Antipsychotic Medication

As I said earlier, antipsychotics still remain the mainstay of treatment. So, as we evolve to a recovery model, it doesn't mean that we're diminishing the importance of pharmacologic intervention. Antipsychotics can improve symptoms, functioning, and quality of life. Right now, traditional antipsychotics all work very similarly where they block postsynaptic D2 receptors. Both first-generation and second-generation antipsychotics have roughly comparable efficacy when we're specifically looking at positive symptoms.

And atypical antipsychotics are typically defined by having a higher affinity at the serotonin 5-HT2A. They antagonize the 2A, and this is what defines them as an atypical or second-generation antipsychotic vs atypical antipsychotic. There is considerable heterogeneity amongst mechanism of action, especially in the atypical antipsychotics area, and a lot of those differences end up being more discreet in terms of efficacy and more focused on different mechanisms that may change side effect or tolerability profiles.

[00:10:51]

APA Guideline Supported Treatment Overview

I want to take a minute and look at the American Psychiatric Association guideline for treatment of schizophrenia. And it's a little bit tough to see here, but there is some color coding here. In black, we have the recommended interventions and then in blue we have suggested. So, just reflective of different levels of evidence or certainty.

So, on the left-hand side pharmacology, again, the cornerstone of treatment, we are going to use antipsychotic medications. Consider clozapine for treatment-resistant schizophrenia or suicide risk. We need to address adverse effects such as anticholinergics for dystonic reactions or VMAT2 inhibitors for moderate to severe TD.

But equally as important, we also see on the right-hand side psychosocial interventions. And the recommended guidelines include coordinated specialty care for early psychosis. We want to be very aggressive in our interventions for early psychosis.

We also see CBT, so cognitive behavioral therapy for schizophrenia. And then psychoeducation supported employment and assertive community treatment. So, it's really imperative as we see with this that mental health in general, but certainly within schizophrenia, we need to take in all of the above approach. It is not an effective option to try and treat schizophrenia without medications. This is absolutely a condition that medications make a big difference. But the flip side to that is we can't also expect to have set the patient up for success if we're just giving them a medication and not working to coordinate and support them in other psychosocial aspects. So, really it takes a village. It's an all of the above approach.

One of the challenges with that is, as we all know, resources and mental health are not infinite. We often are trying to do a lot with very little support, very little resources.

[00:12:37]

Barriers to Quality Schizophrenia Care

And there's a lot of barriers to quality schizophrenia care. So, just to highlight a few of them, this is not a comprehensive list. But 1 of the challenges is that antipsychotic efficacy is fairly decent for positive symptoms. But antipsychotics, or at least traditional D2 antagonists, don't really have a ton of efficacy for negative and cognitive symptoms. We just saw earlier that the leading driver of disability is negative and cognitive symptoms.

So, here's the paradigm. We have a ton of medications available to us to treat schizophrenia. But these medications only really have efficacy in 1 domain of schizophrenia and don't really address those 2 other domains that are really driving disability. So, right off the bat, we're kind of between a rock and a hard place in terms of traditional treatments that we have available.

Unfortunately, patients with schizophrenia are often reluctant to engage in care. About 50 to 80% of patients lack insight, so they don't realize that they're sick. And Jeremy always makes fun of me because I cannot pronounce this. I've been in psychiatry for 13 years and I still mispronounce it. Anosognosia is the concept that the patient does not know that they are sick. And unfortunately, a high number of patients with schizophrenia don't recognize that they need care.

And that can make an incredibly challenging, right, if the patient's not buying into care. These are the patients that don't follow up with treatment. They don't make follow up appointments, they don't fill the medication at the pharmacy.

And lastly, we have system challenges. We saw earlier the APA recommendations are quite labor intensive. It's not just a 15-minute med check with this patient and then send them on their way. Care coordination, support, psychoeducation, therapy. These are all things that can have very valuable upside for a patient that's struggling with schizophrenia. But they all take time. They all take resources.

And the mental health system right now just doesn't have a lot in terms of access resources. We're all struggling to do the best we can with very limited options. So, it really is an incredible challenge. And this is kind of the landscape that leads to a very sad state of affairs, where schizophrenia, in my opinion, is 1 of the biggest unmet needs in all of medicine in terms of the quality of care that we're able to provide our patients.

[00:14:51]

Treatment Quality of First Episode Psychosis

One of the most frustrating things within this, as we looked at those barriers, is even though we have good quality evidence demonstrating that, you know, these interventions can provide improvements for these patients, a lot of times that doesn't mean that these are actually being delivered to the patient, and a lot of those barriers prevent it.

Here we see a claims based study that looks at the quality of care in first episode psychosis. And the biggest thing that stands out, 71% of patients with first episode psychosis did not receive psychotherapy, despite the APA recommending that CBT is a key component of psychiatric care for patients with schizophrenia.

Many of these patients failed to even fill their antipsychotic medication, and there was no evidence of integrated care delivery, meaning coordination with care managers, other supported employment, things like that. So, it's hard, right? Not only do we need innovation in this space, we need better options. We need to build a better mousetrap. But at the same time, we have things that we know are evidence-based, that can provide improvements, and we're unable to implement them due to various barriers and systemic problems.

[00:15:58]

Efficacy Differences in Antipsychotics

Moving back to antipsychotics. We talked a little bit earlier that a lot of antipsychotics are roughly interchangeable in the sense of how effective they are for positive symptoms, and a lot of the differences end up being more nuanced. And this systematic review looks at 32 different oral antipsychotics. And this is really what it finds, is that there's some efficacy differences, but it's more gradual than discrete. But the big difference is in adverse effects. And there is more marked difference between this.

So, a lot of times when we're prescribing medications, we may be picking the medication for our patient based on those side effect profiles. If the patient is having a lot of difficulty sleeping, well, then maybe we might pick something that is a little bit more calming or sedating. So, those are the types of things that we may integrate into our treatment decision making.

[00:16:45]

Antipsychotic Drugs vs Placebo for Relapse Prevention

Should we use antipsychotics? I think it's a really interesting time in psychiatry where the psychiatry critical movement or people that are skeptical of psychiatry have had a loud voice and it's been elevated by a lot of our political discourse. And I think this is a really important slide to remember that the use of antipsychotics absolutely does help.

We see here at the top 3 I've highlighted, that patients on antipsychotic drugs compared to placebo have lower risk of relapse in 7-12 months and lower risk of relapse independent of duration and lower risk of readmission to the hospital. So, having patients on medication, again, pharmacologic intervention is the cornerstone of schizophrenia treatment.

[00:17:33]

Limitations of D2-Based Therapies

So, we've alluded to some of the limitations of D2 therapies. But I want to dive into that a little bit deeper to really set the stage of why we need more innovation in this space.

[00:17:44]

Negative Symptoms: How Common Are They?

We talked a little bit earlier about negative symptoms. And negative symptoms unfortunately, are quite pervasive. A majority of patients with schizophrenia struggle with negative symptoms, with about 41% in this study having more than 2 negative symptoms. And this is what negative symptoms can look like. It can be poor motivation, a blunted or flattened or withdrawn affect, inability or unwillingness to make eye contact, emotional withdrawal, poor rapport, social withdrawal, poverty of speech, apathy, concrete thinking.

When you see those symptoms laid out, it makes sense why this is what's driving disability, right? If we use an antipsychotic and we can effectively manage their positive symptoms, maybe they're not hearing voices anymore. They're not having delusions anymore. But if we can't get those patients out from their basement, if they are unwilling or unable to, you know, interact publicly with society and not get a job, this is going to drive a lot of that disability.

So, it makes sense when you start to think it through of why the negative symptoms are driving so much of the disability and trouble here.

[00:18:49]

Impact on Disease Remission and Recovery

So, in addition to disability, negative symptoms matter because patients that have negative symptoms do worse across the board. So, they have greater comorbidities, they have greater difficulty, including prolonged disease course. They're more expensive because of those comorbidities. So, even if we're just looking at this from an economic standpoint instead of a human cost, it's more costly to insurance to the government to insure these individuals. And there's a reduced quality of remission. So, even if we're able to achieve remission or recovery for these patients, if they still have residual negative symptoms, the quality of life will be diminished because of reduced social functioning emotion motivation.

So, it really is imperative that we work hard to try and find avenues to address negative symptoms in our patients with schizophrenia.

[00:19:39]

Negative Symptoms: It's Complicated

Why haven't we done it yet? Right. We've had 70 years in this era of pharmacology for psychiatry and especially for schizophrenia. So what's taking us so long? Why haven't we done it? Well it's complicated. We started earlier by talking about the heterogeneity of schizophrenia. And this is a challenge, right? There's not 1 singular genetic defect that has led to schizophrenia, where we can work our way backwards or kind of it's like, you know, a line of dominoes where we can follow the trail and figure out a solution.

There's a lot of different factors, and negative symptoms are very similar, where there's numerous neurocircuits that are implicated, including the prefrontal cortex, different reward pathways within the striatum, and adjacent structures of the basal ganglia.

As a result, multiple neurotransmitters are also involved, including dopamine, glutamate, serotonin and GABA. So, the underlying neurobiology, we have kind of 2 symptom clusters. We have the avolition apathy cluster and then also the expressive deficit cluster. And the thinking is, is that these probably have separate or different neurobiological components. So, this also makes it incredibly difficult as we're trying to find therapeutic agents to target this because it may be different systems that require different approaches.

[00:20:49]

Cognitive Impairment Associated With Schizophrenia: Course and Impact

So, we've talked a little bit about negative symptoms. I want to just give a moment to cognitive symptoms as well. Unfortunately, cognitive symptoms again drive a lot of the disability. And we see here that through the lifespan we can consider schizophrenia a neurodevelopmental disorder. And from the start from childhood, patients that eventually develop schizophrenia are at a cognitive disadvantage compared to healthy controls. And this deficit carries through the lifespan. So, again, this can lead to incredible amounts of disability even in patients where their positive symptoms are well controlled.

[00:21:23]

The Unmet Need in Schizophrenia: Limitations of Current Therapies

So, let's wrap it up. The unmet needs of schizophrenia include the limitations of current therapy. So, the potential persistence of positive symptoms. We said, yes, antipsychotics do have efficacy for positive symptoms but not for everybody's positive symptoms. A lot of times there's a significant number of people that will receive antipsychotic therapies and still have treatment-resistant positive symptoms or residual positive symptoms.

So, there's an unmet need in terms of our ability to manage those. We have very limited options for negative and cognitive symptoms. Really not a ton in terms of pharmacologic intervention. It's been a huge area of unmet need.

And then we also have safety and tolerability concerns. One of the challenges with traditional antipsychotics is while they can be effective in reducing positive symptoms, they also come with significant trade-offs. So, we need to have more options. There are some things that are coming that may, you know, kind of that don't necessarily innovate. They still work within the basic framework, but can be quite exciting in the sense that we can improve quality.

Long-acting injectables is a good option of that, where we're not, you know, reinventing the wheel with a long-acting injectable, but we're improving compliance. We may be able to mitigate some of those side effect concerns and ultimately make a difference for these patients. There's some other interesting things, such as using digital therapies to maybe provide CBT in an area where we don't have the resources for a counselor to meet with that patient 1 on 1.

So, there's some stuff that's even happening within the current framework that I think is also very exciting.

[00:22:57]

Dopamine Hypothesis of Schizophrenia

All right. So, now let's shift and let's talk a little bit high science. Let's have some fun on this early Friday morning. So, the traditional dopamine hypothesis of schizophrenia, this was developed in the 60s and 70s. And I think this was kind of still in the area of let's try it and see what happens. We had this incredible era of drug discovery in the 50s through the 60s. And a lot of those discoveries were serendipitous, meaning we didn't intend it. So, chlorpromazine, the first antipsychotic, was originally developed. They were looking for an anesthetic. So, they weren't developing it specifically for schizophrenia. Ended up using it in a patient as an anesthetic drug for someone who was manic and the mania went away. And that was kind of the oh, wow, we might be on to something.

So, that era, the 1950s and 60s were kind of defined by just kind of throwing drugs at people to see what would happen. And a lot of drugs that we have were developed in that way. The first antidepressant was actually an antituberculosis agent, that patients were euphoric when they received it.

So, we saw a lot of the discovery happen kind of accidentally without rational design, and as a result, our understanding of the hypothesis or the underlying neuroscience, we kind of worked our way backwards. We said, “Okay, well, we have this drug that works in this way. So, de facto, this must be what's happening.” And this is how we ended up with the dopamine hypothesis.

So, because we had an antipsychotic, chlorpromazine that worked, we knew that it worked by blocking D2 receptors. We kind of worked our way backwards and said, “Okay, well, psychosis and schizophrenia must be a postsynaptic hyper dopaminergic state where we have too much dopamine activity postsynaptically, because that's where chlorpromazine works.”

And this was confirmed in the sense that stimulants which increase dopamine cause psychotic like symptoms. So, that kind of confirmed the theory. And then within that, as that theory evolved, we also then recognized that there was so hyperactivity in the mesolimbic pathway, the ventral striatum, and then hypoactivity in the mesocortical pathway.

So, right off the bat though this is a challenge, right? Because when we have D2 antipsychotics, we don't have a dopamine-modulating antipsychotic that is able to just hit 1 dopamine pathway. So, if within schizophrenia our hypothesis is that there's too much dopamine signaling in the mesolimbic pathway, and not enough dopamine signaling in the mesocortical pathway. If we give dopamine blockade, that's going to block dopamine signaling across the board.

The other challenge that comes with this is we are also blocking dopamine signaling in the motor pathways, and then also in the pathways that regulate hormonal regulation. So, this is why so often with antipsychotics we have movement-related issues. We also can have prolactin-related issues because we don't have a way to just target 1 singular dopamine pathway.

[00:25:50]

Refinement of the Dopamine Hypothesis

So, this is where we started in. The cool thing that's happened is in the '80s to '90s, we started to have functional neuroimaging, where instead of basing all of our models on rat brains or on autopsy, because we couldn't cut into a functional living brain and see what was happening. But as we entered the '80s and '90s, we had the ability to then have functional PET scans, functional MRIs where we could see what a brain was doing and kind of what pathways lit up.

One of the big things that happened with the advancing of PET imaging is our understanding of the dopamine hypothesis within schizophrenia refined. So, we went from seeing this as a postsynaptic excess in dopamine to also changing to recognizing that dopamine synthesis and release are increased in the associative striatum, not just the ventral striatum. So, a little bit of a difference between a rat model and a human brain.

But the big thing, the big evolution here, is that positive symptoms are linked to presynaptic dope - hyperdopaminergic activity. So, the big change was instead of looking at this as a postsynaptic issue, we've now moved upstream and now recognized that it's a presynaptic issue.

[00:27:03]

Antipsychotics Approved for Schizophrenia Before 2024

So, through the years we've had many different antipsychotics, but they all basically were based on chlorpromazine. So, we had chlorpromazine that came on the scene in the 1950s. Again, we kind of accidentally discovered it, and everything was based on that premise that blocking postsynaptic D2 receptors reduce psychosis. So, everything kind of worked off of that.

Interestingly, though, in the 1950s, we had a presynaptic medication. Reserpine is a VMAT2 inhibitor, so it's actually blocking or reducing dopamine release presynaptically. And this was the first FDA-approved antipsychotic. But unfortunately, the path of drug development over the next 70 years all coalesced around the postsynaptic theory.

So, even though we had reserpine, we were looking presynaptically early on because our understanding of neuroscience had not yet evolved, we decided to pursue the postsynaptic theory. So, really quite interesting, just the way that all of those things happen and how we've - our understanding has evolved and changed.

[00:28:03]

How D2 Antagonists Work

So, let's dig in a little bit about how a postsynaptic D2 antagonist works. So, we said earlier that we now know that psychosis is driven by excessive striatal presynaptic dopamine release, and this leads to positive symptoms and psychosis. So, antipsychotics block the D2 receptors postsynaptically.

But 1 of the challenges with antipsychotics is there's also D2 presynaptic autoreceptors. So, we can think about autoreceptors like a circuit where if I'm in my house and I turn on my dishwasher, my washing machine, and my dryer all at the same time, they're all in the same circuit. There's too much electrical load and the circuit will break. That will switch off to protect that electrical line from overheating or causing a fire. So, it's a safety in the system that says there's too much activity here. We need to shut it down.

Autoreceptors work the very same way. They're presynaptically there, and if there is too much dopamine in the synapse, that dopamine will spill out and agonize or activate that autoreceptor. When the autoreceptor is activated, that signals to the presynaptic neuron to shut down release. Okay. There's too much dopamine in the synapse. Shut it down. So, this is the challenge, is we're creating this bad loop where if we're blocking dopamine postsynaptically, we're also blocking the D2 autoreceptor presynaptically. So, we're blocking that shut off switch.

So, we're blocking postsynaptically. That's not changing the presynaptic problem, right? We just said that dopamine release presynaptic is the issue here. It's excessive. So, it's already excessive. And then with a D2 antagonist we're blocking that autoreceptor which is then going to reinforce the loop of presynaptic release of too much dopamine.

So, yes, they work, they can reduce positive symptoms, but they do so in a way that is kind of messy. And this is in large part why we see a lot of side effect concerns within this.

[00:29:57]

Future Directions: Novel Mechanisms

So, let's pause there. So, what is the future. So, we can basically boil it down. If psychosis and schizophrenia boils down to a presynaptic dopamine dysregulation, then instead of focusing our treatments postsynaptically, shouldn't we look for opportunities to intervene upstream of the D2 receptor? Sounds simple, right? It's not simple, but it's exciting that we now have some options.

So, dopamine remains central. This is still it, but there's opportunities to move upstream and address this before we address the dopamine receptors. So, muscarinic receptors are a great option. They target M1 and M4 and this modulates dopamine circuits upstream. We'll talk about that in more detail.

Glutamate modulation is also something that's been identified because NMDA receptor hypofunction is linked to dopamine dysregulation. We also have TAAR1 agonist that can regulate presynaptic dopamine and then novel antipsychotic agents like these. The excitement here is they may be able to address negative and cognitive symptoms better than their current dopamine targets. And we'll see on subsequent slides why that may be.

[00:31:01]

Glutamate Hypofunction at the NMDAR and Symptoms of Schizophrenia

So let's just spend a quick minute on glutamate hypofunction. So, with this slide the visual can be a little bit confusing. So I would draw your attention to the very bottom. The text here is a little bit more descriptive and can help. So in the prefrontal cortex GABAergic interneurons regulate glutamate pathways, the NMDA receptor hypofunction on these interneurons results in inadequate braking. So, we have glutamate dysfunction that then can lead to dopamine dysregulation because the glutamate is upstream and is regulating dopamine release.

So, in some areas of the brain that may release that glutamate dysfunction may lead to increased midbrain dopamine activation leading to positive symptoms. But in other areas that glutamate dysfunction may lead to cortical dopamine decreases, which may contribute to negative or cognitive symptoms.

So, if we're able to target the NMDA receptor dysfunction with glutamate or GABA interventions, that may offer us an opportunity not only to address positive but also negative symptoms.

[00:32:03]

Muscarinic Agionism for Psychosis Rediscovered

So, let's talk a little bit about muscarinic agonism. So, this is not actually a new concept. This is so fascinating. Again so much drug discovery happened in the 1950s. And in 1957 the muscarinic agonist arecoline exhibited antipsychotic properties in rats. And there was clinical evidence that it can lead to lucid intervals in patients with schizophrenia.

Fast forward to 1992, and there was a lot of research on muscarinic system around acetylcholine for Alzheimer's disease, it was identified as a potential therapeutic target. That line of research actually led to several medications that modulate acetylcholine or the muscarinic system that we still use today, donepezil being a great example. And the muscarinic agonist xanomeline was synthesized in 1992 with the goal of addressing cognitive dysfunction in Alzheimer's dementia. Xanomeline did not have any direct D2 receptor blocking activity.

Fast forward to 1997 and there was a study published of using xanomeline for patients with mild to moderate Alzheimer's disease. The study found it did have a positive impact on cognition compared to placebo. It also had an unexpected finding that there was a significant dose-dependent reduction in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. Sadly, a large part of Alzheimer's ends up being psychotic like activity.

So, this study was quite interesting, but it also died. No further development happened after 1997, not because the drug was ineffective, but because the procholinergic side effects of using a muscarinic agonist like xanomeline were a huge issue. Nearly 60% of patients dropped out of the study, the ones that were on xanomeline. And some of the GI side effects were reported with rates as high as 70%.

So, Eli Lilly was the one who was developing this. Even though there was a signal, it was an efficacious medication, they thought it was a dead end, because they did not see it as something that was going to be viable because of those procholinergic side effects.

[00:34:02]

Managing the Peripheral Procholinergic Effects of Xanomeline

So, this leads to a really fascinating question, right? If muscarinic agonism in the central nervous system can lead to, you know, reductions in positive symptoms, potential opportunities to address negative and cognitive symptoms. There's a lot of benefit there. There's a lot of intrigue, especially within schizophrenia. But we can't have those procholinergic side effects peripherally. They're a big problem. So, how do we address this?

What if we paired xanomeline with an anticholinergic that only stays in the periphery, that doesn't have any central penetration? So, enter trospium. So, trospium has been around since the 1970s a very well-known established medication for overactive bladder. Trospium was selected to pair with xanomeline because trospium does not penetrate the central nervous system, it does not cross the blood brain barrier.

So, the idea behind this is we have procholinergic effects in the central nervous system, which is very desired. And then anticholinergic effects to offset those procholinergic effects in the peripheral.

[00:35:04]

Muscarinic Receptors

So, a little bit more about muscarinic receptors. For muscarinic receptors we have 1 through 5. There's 5 different types of receptors. The odd numbered receptors 1, 3, and 5 are primarily postsynaptic and excitatory M2 and M4. So, even receptors are going to be primarily presynaptic and inhibitory.

Muscarinic receptors have a lot of really important and exciting functions in the central nervous system neuronal excitability and neurotransmitter regulation, learning memory. But here's the challenge. Peripherally, the muscarinic receptors have a lot of impact on cardiac function, smooth muscle contraction, and then exocrine gland secretion. So, those peripheral roles is what drives a lot of these tolerability concerns.

[00:35:49]

Mechanism of Action Video

So, now we're going to shift. And we're just going to watch a quick 2-minute mechanism of action video. So, you'll be back with me in 2 minutes. But I'll turn you over to the video.

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

First and second-generation antipsychotics manage excessive dopamine release by blocking postsynaptic dopamine receptors. A new approach to schizophrenia involves limiting dopamine release from VTA neurons. VTA neurons are regulated by 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 Asbach: All right. Thank you. I hope you guys enjoyed that video. I'm very much a visual learner. So, I love when we have animations and an opportunity to see it played out. So, I hope that was as helpful for you as it is for me.

I want to now take just 2 slides and reinforce what you saw in the video. Again, because these are complicated concepts, and I want to make sure that everyone on this call feels comfortable saying that it's complicated and that it may take us some repetition to get to a point where we feel comfortable with it.

[00:38:29]

"Bottom Up" M4: Midbrain Input Decreases Dopamine Release in Psychosis Related Areas

So, to review, from an M4 perspective, keep in mind M4 is inhibitory and presynaptic. So, when we agonize M4, this will decrease its inhibitory. So, it's going to decrease acetylcholine release which is then going to decrease dopamine release from the VTA.

This is important because 1 of the cool things with M1 and M4 is we do not see high distribution of M1 and M4 receptors in the areas of the brain that are related to motor symptoms or hormonal regulation. So, the M1 and the M4 distribute within the brain in the areas that are significant for psychosis. But then we can have some level of selectivity and avoidance of those motor systems and hormonal regulation. That's what makes this so cool.

So, M4 bottom-up, we're going to reduce dopamine through that presynaptic inhibition.

[00:39:23]

The "Top Down" M1 Story: How Muscarinic Stimulation of PFC GABAergic Inhibitory Interneurons Decreases VTA Dopamine Release

Moving on to M1, we can think of this as top-down. So, with this one we're going to activate M1. M1 is excitatory and we're going to excite the GABA. So, GABA is inhibitory. I know this is getting confusing. So, if we have activation, so increased GABA, then we're going to decrease glutamate because GABA and glutamate function in balance with each other. Decreased glutamate which is stimulatory is going to decrease dopamine release. It's a mouthful. I get it.

Both of these, the key to keep in mind is M1 and M4 activation downstream lead to reductions in dopamine in the areas of the brain where psychosis is located. So, that really is the key.

[00:40:10]

How Muscarinic Activation Might Improve Cognition

All right. So, we've talked a lot about positive symptoms. But I want to just take a brief minute and think about cognition. So, this is also where it gets quite cool. One of the reasons that xanomeline was originally synthesized was looking at Alzheimer's disease. And a big part of that is early on, many decades ago, the acetylcholine receptor or muscarinic system was identified as having maybe an important role within Alzheimer's.

And here we see that patients with schizophrenia have lower, on average, M1 receptor levels. So, there is a lower distribution of M1 receptors in patients that struggle with schizophrenia. And those low M1 levels are associated with poor performance in verbal learning task memory task in more severe negative symptoms. So, it's a very interesting finding where we can look at that and say, okay, if there's less M1 receptors in a schizophrenia brain, does that offer an opportunity where if we can increase M1 receptor activation, does that give us a potential path to address some of these cognitive deficits?

[00:41:11]

EMERGENT Trials: Change in PANSS Total Score

So, here's the xanomeline trospium clinical trials. This is the 3 clinical trials, so, EMERGENT-1, 2, and 3. And I'm not a statistician, I do some clinical research at my job but I am not going to be the person that's going to be able to give you the - the breakdown from a stats standpoint.

I always like to look at these studies in terms of does it pass the eyeball test? And the reason I say that is the reason the FDA requires replication, we need multiple studies, is a lot - sometimes something weird can happen in 1 clinical trial. So, we want to see is that result replicable across different clinical trials? And we see in the phase II and the 2 phase III studies that they have very similar response curves.

The other thing to point out here is we see in the grey boxes above, the effect size for EMERGENT-1 was 0.75 for 2, 0.61, and for EMERGENT-3, 0.60.

[00:42:04]

A Historical Perspective on Effective Size

So, for those of you that may not be familiar with effect size, effect size basically is a way that we can indirectly measure the magnitude of difference. So, it's, you know, how big of a difference did this drug have compared to placebo? And while we don't have head to head studies with any of these drugs, effect size because it's a statistical calculation gives us at least an indirect calculation of what was the magnitude of difference.

On the right-hand side here we see effect sizes for other antipsychotics that are available to us to use. So, the pooled effect size for xanomeline trospium was 0.65. We see on the right-hand side here that fares quite well. So, let's put aside some of the excitement that the muscarinic system may give us an opportunity to avoid motor symptoms, to avoid hormonal dysregulation, and maybe avoid some of those side effects that come with that.

This also is a medication that looks like it stacks up fairly well to traditional antipsychotics, just in terms of an effect.

[00:43:05]

EMERGENT Trials: CANTAB by Cognitive Subgroup

So, let's shift back and talk about cognition. We talked about a lower representation of M1 receptors in patients with schizophrenia. And this is where it gets really interesting. So, in the full pool sample of the EMERGENT—and this is the pooled data from EMERGENT-2 an EMERGENT-3. The full pooled sample, you did not see much of a difference in cognition.

But in patients with baseline cognitive impairment, the treatment effect was the most pronounced. So, patients that were already having cognitive difficulties, the xanomeline trospium did have a difference in terms of cognitive performance. So, it kind of ties into maybe that M1 story that there might be a, you know, a there there. So, it's something to definitely watch. This is an area that we want to continue to invest in more research and keep an eye on the journals.

[00:43:49]

ARISE Trial: Adjunctive Xanomeline + Tropsium

So, the ARISE trial looked at xanomeline and trospium as an adjunctive agent. And this is very interesting because on paper this makes sense, right? If I'm using an antipsychotic that is blocking postsynaptic dopamine receptors, then using a muscarinic agonist presynaptically might actually complement.

But unfortunately, the study did not meet primary endpoints at the subgroup post-hoc analysis. It actually found there was significant improvement in the non-risperidone patients, but the risperidone patients did not fare well in this. So, it's a great example where, you know, clinical trials are so important because sometimes the results are unexpected. And it's always important to keep an eye on this.

More to come with this because I think there is going to be more discussion and more interest of how muscarinic agonists fit in with traditional antipsychotics. Whether there is an opportunity for adjunctive use or how we cross taper, there's going to be a lot more that we have to learn, since we truly are on the tip of the spear of this new era, of this different approach.

[00:44:47]

EMERGENT Trials: Onset and Duration AEs

Here we see the side effect profile. We talked earlier that the big thing with this is we have procholinergic effects that can lead to nausea, vomiting. Those are all more procholinergic effects. We also see some anticholinergic effects such as dry mouth. The key though with this is think about xanomeline and trospium. The whole idea behind this is to have a balance. The procholinergic and the anticholinergic balance each other out, almost cancel each other out peripherally.

But as we're initiating this medication, those balances may not be quite right. And that's a lot of what drives these side effects. In part, this is also why we see the duration of many of these side effects is more limited. So, this is something where with time the side effects do seem to get better. Some recent data seems to indicate that the 100-20 dosage of xanomeline trospium seems to be kind of especially problematic in terms of tolerability.

And actually when you get the patients to the higher dosage, which has a 30 mg component of trospium, so a higher anticholinergic load at the higher dose that that settles down some of these side effects. So, it's a little bit counterintuitive where we always talk about low and slow. As more data come out, it does appear that this might actually be a little bit different with this drug, where we want to get people to that higher dosage sooner in the process to get them through that 100-20 where a lot of those side effects occur.

[00:46:07]

EMERGENT Trials: Pooled Safety and Tolerability

So, here we see the safety and tolerability for the long-term trials. So, this is going up 52 weeks. Very similar profile to what we saw in the short-term trials.

[00:46:17]

Is M1 Receptor Stimulation Necessary? M4 Selective Agents in Development

And let's think about this for a second. So, is M1 receptor stimulation necessary. We talked about M1 and maybe some intriguing interest from a cognitive standpoint. But maybe M4 is all we need.

[00:46:29]

Novel Drugs in Development

There's a lot of drugs in development that are kind of pursuing this theory that maybe the M4 is the one that's doing a lot of the heavy lifting. Here, we see emraclidine. Emraclidine is a positive allosteric modulator of the M4. So, a little bit different positive allosteric modulators are enhancing receptor activity as opposed to orthosteric binding which is agonizing or antagonizing. So, blocking, or activating, or deactivating that receptor. So, a little bit different.

And the whole idea is a positive allosteric modulator, you might be able to get a lot of the therapeutic effects, but avoid some of those side effects that come from agonism or antagonism. Unfortunately, we see in November 2024, emraclidine had a readout of their studies, their phase II, and it did not reach the primary endpoint. So, this drug, from my understanding, is not dead. They are still pursuing development. So, it's something to continue to watch.

NBI-1117568 is another one. This is an M4 selective agonist and as of August 24th, there was a positive topline readout of the phase II study. And they are currently in phase III. In the phase II there was an effect size of 0.61. So, a lot of excitement for that one.

And then iclepertin, this is interesting. This is a glycine transporter inhibitor. So, glycine is a co-agonist to glutamate. So when you agonize or modulate an NMDA receptor, you need both glycine and glutamate to have any role. So, the idea behind this is if we can increase glycine circulation that's going to enhance NMDA receptor function. Unfortunately in January 25th the phase III did not meet its primary or secondary endpoint so the company announced the discontinuation of the long-term study.

[00:48:08]

NBI-1117568: An M4 Selective Agonist

So, let's shift back to NBI-1117568. And this is, as I said, a phase II that looks very exciting. The drug is currently doing their phase III trials right now. I believe the readout for the phase III is going to be probably late 2026, early 2027, if I'm remembering correctly. So, this is definitely one that we're still a little bit away from seeing that phase III, but should have a lot of excitement.

[00:48:34]

Muscarinic M1 or M4 Agonists/PAMs in Development

And here we see a lot of stuff in development. So, this is—really the xanomeline trospium I think is the first one. And it's spurred a lot of research and a lot of interest in an area that thankfully, we're finally having some innovation in the schizophrenia space after 70 years of very little outside of the dopamine hypothesis.

[00:48:52]

Case Study: Muscarinic Agonists, but for Whom?

So, let's finish with just a really brief case study. I'm not going to spend a ton of time on this, but I like to use this just as an opportunity to kind of get our creative juices flowing. So, I have here a 29-year-old man with a 5-year history of schizophrenia. He was diagnosed at age 24 after a psychotic episode of hallucinations and delusions. No history of substance abuse. Strong family history of schizophrenia. He's currently taking olanzapine 15. That's reasonable. Right? That's a pretty common drug that we see for schizophrenia.

And the positive symptoms are under fairly good control. He's not having any significant hallucinations or delusions. No recent hospitalizations. But unfortunately he has persistent negative and cognitive symptoms, and these are leading to impaired working memory, poor executive functioning that are affecting daily life.

He's also had significant metabolic complications. He's gained over 40 pounds in 18 months. He has elevated fasting glucose and triglycerides, and he developed mild hypertension. I'd like to remind everyone that the leading cause of death in schizophrenia is cardiometabolic.

[00:49:54]

Is This a Candidate for a Muscarinic Agonist?

So, is this someone who's a potential candidate for a muscarinic agonist? Right? It's a tough question because his positive symptoms are under fairly good control. So, some of the potential benefits a muscarinic agonist may lead to better negative and cognitive symptom improvement. As we've seen, M1/M4 agonists have shown the potential for improving cognition, working memory, motivation may also reduce social blunting and withdrawal. These are the symptoms that are driving disability for this patient.

Moving to a muscarinic agonist might have a favorable metabolic profile. Olanzapine is notorious for the metabolic issues that it may cause. So, switching to that metabolic—or muscarinic agonist don't really have weight gain as an associated issue there.

And tolerability even—we may have lower risk of sedation or extrapyramidal symptoms, because muscarinic agonists are not going to affect the dopamine signaling within the pathways for motor control.

So, what are the potential risks? Well, we have risks of GI upset, adverse effects that way, also the risk for transient bradycardia or hypotension because of muscarinic activity. So, how do we think about this? The ideal candidate for muscarinic agonist. It might be someone who has good control of positive symptoms, but persistent negative and cognitive symptoms that are driving disability, it might be someone who has significant weight gain or metabolic shifts on their atypical antipsychotic, and it's also probably someone that we need to think about that doesn't have a significant history of cardiac arrhythmias or GI motility issues.

[00:51:23]

Case Summary

So, in summary, this is a very classic profile of a patient with schizophrenia where their positive symptoms are under fairly good control on an atypical, but the metabolics are causing significant issue. So, in this case, we may consider a cross taper to a muscarinic agonist.

[00:51:38]

Xanomeline-Trospium: How to Initiate

So, how do we initiate? So, the titration. The PI recommends starting at 50-20 and then staying on that for at least 2 days before then increasing to 100-20, which we stay on for at least 5 days.

The PI does give us the ability to slow it down. As I said earlier, when this first came out a year ago, a lot of the thinking was low and slow. But now there's more data coming out. There's some really interesting posters that actually indicate that it might be better to get these patients up to the 125-30 as rapidly as you can, still following the 2-day, 5-day titration, because the 100-20 dose really seems to be the area where a lot of these side effects are concentrated.

So, just something to think about. A lot of this is going to continue to evolve. This is something where exposure to trospium is decreased if they take it with food. So, the recommendation is to take it 1 hour before or 2 hours after a meal. Because this is a BID dose, I always like to tell my patients first thing in the morning, last thing at night. That seems to help. We want to think about BID dosing may not be for every patient with schizophrenia. So, you need to make sure that if you're considering this, it's a patient that's going to be compliant with treatment.

[00:52:52]

Xanomeline/Trospium: Drug-Drug Interactions and Monitoring

So, drug to drug interactions. Again, we think about this xanomeline trospium as just the right amount of xanomeline to give us procholinergic effects in the brain, just the right amount of trospium to offset the peripheral procholinergic effects. But because of that, we need to make sure that everything's in balance.

So, we're going to have to be very careful using this for anyone that has liver concerns. So, it's contraindicated in moderate and severe hepatic impairment, warnings for mild hepatic impairment. We also see here a recommendation to monitor LFTs. The monitoring of LFTs is not because of the liver impairment concerns, but when we first start the medication, there's a really transient—a small number of patients that have a transient increase in LFTs in biliary response. So, it's just something that we want to keep an eye on with baseline, and then as clinically indicated, LFTs.

We also want to keep an eye on heart rate because cholinergic medications can impact heart rate. So, the average compared to placebo was an increase of 5.9 beats per minute.

And lastly, drug interactions. Again, if we have something that is, you know, through the 2D6 pathway, because normally is primarily metabolized by the liver, anything that may mess with metabolism through the liver, whether that's cytochrome pathway interactions or liver functioning concerns, that's going to be a concern because the level of xanomeline may be different.

Trospium is primarily metabolized through the kidneys. So, if we have any kidney concerns that may mess with the trospium levels as well.

[00:54:26]

Patient Communication Resource

So, we have a really wonderful resource guide here for schizophrenia that's available through the website, I believe. So, this is a nice thing that CCO has put together. I highly recommend it. It gives a lot of really great information on just a 2-page sheet.

[00:54:40]

Key Summary Points

Here are the summary points for you. So, the muscarinic era is just beginning. Xanomeline and trospium is an M1/M4 agonist with no D2 receptor binding. Now approved for schizophrenia, it does not have metabolic or D2-related adverse effects such as movement disorders or hyperprolactinemia.

There is the potential for improved cognition in a lot of excitement there, based on kind of the underlying neuroscience that we talked about, and the use of centrally acting anticholinergics may pose a concern for interference with this mechanism. So, we want to be aware that we're using a procholinergic medication to treat schizophrenia. If we have anticholinergic medications on board that are centrally acting, that may offset. And we've got some exciting stuff in the pipeline.