This transcript has been edited for clarity.
John Kane, MD: Hi. I'm Dr John Kane, professor of psychiatry at The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in New York. Welcome to Medscape's InDiscussion series on schizophrenia. Today we'll be discussing what new antipsychotic drugs are available, what drugs are under development, and what do they potentially offer? First, let me introduce my guest, Dr Jonathan Meyer, voluntary clinical professor in the Department of Psychiatry at the University of California, San Diego. But more importantly, one of our leading psychopharmacology educators and most recently the author of 2 very valuable books, one on clozapine and one on plasma levels. So, Jonathan, thank you so much for joining us. Welcome to InDiscussion.
Jonathan M. Meyer, MD: Thank you so much for having me.
Kane: We have improved greatly on some adverse effects of the antipsychotic drugs, such as metabolic burden. But it's a very interesting history when you think back to how these drugs developed and how they've been used. Could you help review that for us? Then we'll talk a little bit later about some of the drugs that are under development.
Meyer: Well, I fall a little bit behind in certain aspects of my reading, but I finally unearthed my April 1955 issue of the Annals of the New York Academy of Sciences. And in that issue, there was a paper by a famous psychopharmacologist, Manfred Bleuler, talking about 2 compounds, one was reserpine and the other was chlorpromazine. Reserpine, as we now come to realize is a mechanism for modulating presynaptic dopamine release. It is a VMAT (vesicular monoamine transport) inhibitor. Chlorpromazine, as we all know, is a postsynaptic dopamine receptor blocker. At that time, though, these were considered virtually indistinguishable. They didn't know the pharmacological mechanisms. All they knew was they made a certain fraction of schizophrenia patients better. They both caused some sedation, they both caused some orthostasis, and they actually both caused some parkinsonism. But as we all know, the chlorpromazine mechanism won out. And why was that? For one thing, you can synthesize analogs of chlorpromazine, which didn't have the sedation, which didn't have the orthostasis. And so that became a much more tolerable treatment. And then Arvid Carlsson won the Nobel Prize a few years later and really unraveled the common mechanism for antipsychotics at that time. And because they proved so useful, we just continued down that path for the next 70 years and the idea of modulating presynaptic dopamine release just kind of fell by the wayside. And to be honest, I think for a long time people felt like it was necessary to block dopamine receptors postsynaptically and do it quite strongly. But then this other molecule came out and I think somebody wrote a paper in 1989 about this thing called clozapine. Do you know much about clozapine, John?
Kane: That was certainly an interesting development. I guess it was the first medicine that was approved by regulatory authorities for treatment-resistant schizophrenia. It also had a very low incidence of parkinsonian side effects. And what was interesting is that it seemed to have relatively less affinity for the dopamine D2 receptor. The problem with clozapine is we still don't really know how it differentiates itself from other drugs in terms of its mechanism. Because it binds to so many different receptors, we used to say it was a dirty drug. Now we like to say it's a drug with a rich pharmacology, but we still have a lot of unanswered questions.
Meyer: I think that's it. People thought maybe the magic property was 5-HT2A antagonism, it had very high affinity for that and lower affinity for D2. And so we have now synthesized a whole series of atypical antipsychotics, which maybe improved on the tolerability compared to first generation agents. But in some people, they still cause D2-related adverse effects. We still see people who develop parkinsonism and even tardive dyskinesia (TD) from atypical antipsychotics and even the partial agonists still bind to the D2 receptor, and we can still see movement disorders related to them. So really, we've moved along in terms of tolerability. We still are wedded to the D2 receptor. We have been until recently. And the other thing that popped up unfortunately early on in the development of atypicals was significant metabolic adverse effects. We feel like we have less of that with the newer atypicals, but in the end, they are still binding to the D2 receptor, and we get all of those potential D2-related adverse effects as part and parcel of that mechanism.
Kane: Is it the D2 mechanism that really accounts for the weight gain or is there's something else going on there?
Meyer: We figured out that the weight gain was due primarily to histamine H1 antagonism, which causes you to really have impaired satiety. People just keep eating. And so newer compounds of course had much less of that. We would say the newer atypicals are not quite weight neutral, because they never are, but certainly have much lower liabilities. But in the end, they still do something at the D2 receptor, and we recognize that by blocking the D2 receptor, we may get efficacy for positive symptoms. But in that dorsal part of the striatum, there's often a price to pay.
Kane: You mentioned TD a minute ago, there is a sense that some of the newer medicines are less likely to cause TD — but they still can, right?
Meyer: Absolutely. The best meta-analysis was one by Carbone in 2017. It looked at people who had been only on second generation antipsychotics, mostly folks with schizophrenia, and the rate of TD was 7.2%. Now that was still about a fourth of what it was for people who were on first generation agents. But it's not zero.
Kane: And I guess because they're more widely used now in illnesses besides schizophrenia, that we're probably seeing some cases that we might not have seen otherwise.
Meyer: Absolutely. And sometimes people think, well, the partial agonists won't cause TD because they have intrinsic agonism. But guess what? You talk to the movement disorder neurologists, and they see cases of TD in people on partial agonists. Just the population we talk about often being use adjunctively for mood.
Kane: What about this whole issue of is there like a minimum level of dopamine receptor blockade that we need to see efficacy when we're treating patients with schizophrenia?
Meyer: Well, if you're using a D2 antagonist, part of the overall package, when you give D2 antagonism, is it not only blocks the postsynaptic receptor, you're also blocking the autoreceptors presynaptically, which is what we'd prefer not to do because you're removing feedback inhibition; you're essentially disinhibiting that presynaptic neuron. And so the idea that we might need 60% to 80% postsynaptic D2 blockade is because we're also messing with things presynaptically, we're actually working against ourselves a little bit. In order to compensate for that, we need a certain level of D2 blockade postsynaptically. Now some of the newer compounds maybe have less of that issue potentially lumateperone does even act like an antagonist presynaptically. But the party line still is that you need a fairly high level D2 blockade postsynaptically to give effective control of positive symptoms of psychosis.
Kane: Is it your sense that sometimes in the hospital or the clinic that we use higher doses than necessary?
Meyer: I would say we use higher levels of exposure maybe than is necessary. But as we've come to learn, at least until recently, we really only had 2 viable mechanisms for controlling the positive symptoms of psychosis. It was either D2 blockade or modulation or the magic of clozapine. And there are some people who just need it, and their brain seem to require, very high levels of D2 blockade, if you want to call it, to control their positive symptoms. But I think your point is well taken. Often, we would overshoot quite a bit and sometimes incur those neurological adverse effects. We started to get some clues, at least from clozapine and from other things that emerged about 20 years ago, that there might be another path towards treating psychosis and maybe it's a presynaptic one.
Kane: Do you want to tell us a little bit about some of the drugs that are under development and how they look so far and some of the newer medicines?
Meyer: There's a couple of competing mechanisms which are out there, both of which are very exciting and both of which rely fairly extensively on modulation of presynaptic activities. The first one is called TAAR1, which is the trace-amine associated receptor type 1. Most people have never heard of this, and these receptors were only characterized about 20 years ago. But it became clear from genetic studies that people who had certain polymorphisms and these TAAR genes had increased rates of schizophrenia. And then once you could create TAAR1 knockout mice, it became very clear that these mice have the phenotype of schizophrenia and certain abnormalities in dopamine neurotransmission. And what's really cool about that is that a big part of that abnormality in these TAAR1 knockouts was that they would have increased presynaptic dopamine release in that area of the mouse brain, which is the human analog of the parts which have positive symptoms of psychosis. The next step was the synthesis of TAAR1 agonists. When you gave TAAR1 agonists to animals, you saw that one of their big properties was modulating presynaptic dopamine release. They also do something about modulating the postsynaptic signal, but it just turned out to be fortuitous for us that the major effect on presynaptic dopamine release happens in that area of the brain associated with the positive symptoms of psychosis. If they did things equally in the more ventral and the more dorsal areas, well then, we just have another drug which potentially can cause a lot of neurological adverse effects. And it's fortunate that the TAAR1 agonists don't do that. There's now a couple of them in development being used in human studies. So the one leading candidate is called ulotaront (SEP-363856), which already had a phase 2 study published in The New England Journal of Medicine. So when we have an antipsychotic published in The New England Journal of Medicine, you know it's a big deal. And what was cool about that study? Very low rates of neurological adverse effects, low rates of weight gain. And we saw efficacy both in positive symptoms with a signal maybe of something different in negative symptoms. And there's also a lot of really cool pre-clinical stuff in animals, which we'll see how that turns out in human beings, such as effects on metabolic properties. So that's now in phase 3 and that's very exciting. Again, doesn't bind to the D2 receptor, is not blocking D2 neurotransmission per se, but just reducing the amount of dopamine coming out presynaptically and also a little bit modulating the signal postsynaptically but without binding directly to the D2 receptor. There's another TAAR1 drug out there called ralmitaront (RO6889450), which is a little bit further behind in terms of clinical development, but both are very exciting.
Kane: Any sense of a difference between those 2 compounds?
Meyer: Well, ralmitaront is earlier on in development, so I think it's a little premature to say. And I think we'll have a better sense when we see some of their larger data sets in human exposure about how that pans out. But, you know, the other interesting mechanism also relates a little bit to clozapine as well, is that we started to get a sense in the 90s that maybe one of clozapine's special properties had to do with some things we got from the metabolite norclozapine, which was muscarinic agonism.
Kane: You're referring to xanomeline-trospium. Can you tell us a little bit about that?
Meyer: So this is a story which really goes back to people looking for drugs for Alzheimer's disease. And the idea in the 90s was let's find some cholinergic agonists. We're tired of cholinesterase inhibitors. Let's directly stimulate those cholinergic receptors. So they synthesized a compound called xanomeline which was a muscarinic, M4 and M1 agonist and xanomeline was studied in people with Alzheimer's disease, it didn't quite hit the endpoints they wanted to on cognition. But what they noted in a dose-dependent manner is that as people stayed on it for prolonged periods of time, their rate of developing new psychotic symptoms, such as delusions, were lower. So, folks had this idea that maybe this muscarinic agonism does something for psychosis. And then again, people synthesized other compounds to study in animals and they created knockout mice. And lo and behold, the M4 muscarinic, M4 knockout mouse was a good model of schizophrenia. And also the M1 knockout mouse. The problem is xanomeline is a cholinergic agonist. So what do you think that does to your GI motility, John?
Kane: Not good.
Meyer: Not good, not good. High rates of nausea, high rate of diarrhea. But it worked. People did a study published in 2008 in the American Journal of Psychiatry, which showed it worked in schizophrenia. It worked really well, but the GI tolerability was a big problem. And so one company said, well, maybe if we just give a peripherally acting anticholinergic which doesn't cross the blood brain barrier, we can mitigate those adverse effects. And that's where we came up with this combo called xanomeline-trospium. Trospium is there just to mitigate the peripheral adverse effects. The phase 2 trial was so exciting, it also was published in the New England Journal of Medicine this time last year. And when we look at the wiring diagram, how does M4 agonism in particular reduce presynaptic dopamine release in the striatum? Well, it's modulating this system which actually gets cholinergic input from a midbrain nucleus. And guess what? Cholinergic stimulation from this midbrain nucleus onto dopamine pathways facilitates dopamine release. And M4 agonists actually are working on the auto receptors. By stimulating the auto receptor, we reduce acetylcholine release onto these dopamine neurons, and we get fewer positive symptoms of psychosis and again, without the motoric baggage we would get from dopamine, D2 receptor blockade.
Kane: Given the fact that we're now talking about M1, M4 agonism and this story relates back to cognitive functioning, might this particular compound also be helpful for cognitive dysfunction in schizophrenia?
Meyer: Well, that's the hope. We think the M1 properties in particular might contribute to improved cognitive function. But as we know, sometimes you can see a lot of things in laboratory animals that don't always translate to human beings. But I think that's the exciting part. And guess what? The TAAR1 agonist compounds also seem to have some pro-cognitive effects in animal models as well. The big question, is what effect will we see in a human brain with schizophrenia? But as we all know, the more functionally-impairing aspects of the disorder are not necessarily the positive symptoms, but it's negative symptoms and cognitive deficits. And wouldn't it be cool if we could actually mitigate some of those with these newer agents?
Kane: Yeah, that clearly would be fantastic. I guess the other questions are, will these new agents differ from our classical D2 receptor antagonists in terms of will they work better in certain patients? Will they do a better job of preventing relapse or will they work better in treatment-resistant patients? Do you have any thoughts about those?
Meyer: One factor in relapse is nonadherence. That's why I wrote that book on measuring antipsychotic plasma levels, because occasionally you may treat patients on oral antipsychotics who don't take their medications. Not my patients, of course, other people's patients. And the only way you know if people are taking their drug or what their level of drug exposure is, is to measure — in particular if they're on oral agents. Having improved tolerability, we think will translate to improved adherence and therefore improved clinical outcomes. Whether we'll see differential effects, whether we'll see effects in treatment-resistant patients, that remains to be seen. I think there's a lot of excitement, but I don't want to oversell it because as we know, treatment-resistant schizophrenia is a unique animal. And maybe the reason clozapine works is that it has 5 mechanisms, all of which are contributing in different ways to get the clinical picture of efficacy in resistant patients. So I would say at this point, stay tuned. There certainly is interest in these companies in using these compounds both as monotherapy for schizophrenia as well as adjunctively. And that may really help us see can we add these on to existing agents, so we don't lose what we have, but maybe improve on that? And to what extent might we get people who are partial or inadequate responders to be better responders by the use of these novel mechanisms?
Kane: I guess the other question that I have is if we have a novel mechanism, are we going to be able to learn everything that we need to know if we start using that in someone who's already been treated in some cases for years with a D2 receptor antagonist? And wouldn't it be nice to have some patients who've been exposed only to a drug with a novel mechanism so we can see what the long-term consequences are?
Meyer: In terms of the tolerability profile, it would be very hard for me. And again, I know costs will be an issue, but it would be very hard for me to look at a first episode patient and say I should give you anything which is going to act at the D2 receptor when I have the option not to. Because we know, as you mentioned, that first episode patients are very sensitive to the motoric adverse effects of antipsychotics, even atypicals. You know, Steve Marder did this wonderful study with first episode patients with risperidone, which showed in that group 2 mg actually worked out pretty well. And when they got to 4 mg, a lot of them had neurological adverse effects. Wouldn't it be nice to have compounds which really have, almost no risk or very little risk for neurological adverse effects without the burden of the metabolic issues, weight gain, sedation? To me, the prime population really will be the first episode patients because we recognize in that group that they don't take their meds, they do poorly. But most importantly, they've also probably modified the course of their disease. And people in their first episode who become non adherent don't often respond as well the second time around, even to those same medications. And we may have pushed them one step closer to becoming treatment resistant.
Kane: And I guess in terms of influence on the trajectory of the illness, even some patients who continue to take their medicine, let's say they're receiving a long-acting injectable formulation, some of those patients will relapse despite that when they're receiving these D2 receptor antagonists. It's lower than the number of people who would relapse without medicine, significantly lower, but it's still probably in the order of 10% to 20%. So I wonder if these newer medicines with different mechanisms might reduce that risk in some way.
Meyer: It would be interesting to see. And it would be really exciting if we could put these into a long-acting injectable formulation. As you know, the best drug in the world doesn't work well when it sits in the bottle. I think that plastic inhibits the receptor activity in the brain. But that's a big issue. Even if you have literally the best drug in the world, so to speak, and people don't take it, they often do poorly. And we're also dealing with a very sick population with a very serious illness. Even if people take their meds, there are psychosocial stressors or other reasons why patients might relapse despite continuous drug exposure. All we can say is we're trying to offer them a mechanism which we think can control their illness as best we can. And then, you know, will there still be inherent relapse rates? There will, but perhaps less.
Kane: Jonathan, thanks so much. What would you say would be the key takeaways to our listeners?
Meyer: Well, it may not be necessary to have an effective antipsychotic which binds to the D2 receptor. And I think we've improved in tolerability with other compounds, which are antipsychotics in terms of sedation and metabolic issues. But maybe the next step in treating schizophrenia might involve 1 of these 2 strategies, whether TAAR1 agonism or muscarinic, M4, agonism or modulation to treat schizophrenia without blocking the D2 receptor. And I think that will be very exciting if these end up making it into the clinic and into our hands.
Kane: Great. So thanks very much. I want to thank Jonathan for joining us and thank our listeners. This is Dr John Kane for InDiscussion.
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Cite this: What New Antipsychotic Drugs Are Available for Schizophrenia? What Drugs Are Under Development? And What Do They Potentially Offer? - Medscape - Sep 13, 2022.