Transcript:
Greg Mattingly, MD: Welcome, everyone, to this really interactive discussion on the Spectrum of Schizophrenia Symptoms. We're going to be joined today by 2 of my very good friends, colleagues, world leaders in the field of mental health disorder. We are dedicated today to talking about psychiatry made practical.
Joining me today are going to be my good friend Andy Cutler, my good friend Roger McIntyre, and we're going to be talking about the Spectrum of Schizophrenia Symptoms. I'm Greg Mattingly, an Associate Clinical Professor at the Washington University School of Medicine and the President of the Midwest Research Group here in St Louis, Missouri. Andy, why don't you go ahead and introduce yourself?
Andy Cutler, MD: Sure, Greg. I'm really happy to be here. I'm Dr Andy Cutler. I'm Clinical Associate Professor of Psychiatry at SUNY Upstate Medical University and Chief Medical Officer of the Neuroscience Education Institute. Been doing clinical trials like you for many, many years and have worked on the development of many of our psychiatric medications.
GM: And our friend from up north, Roger, introduce yourself to the audience.
Roger McIntyre, MD: Well, first of all, Greg, always fun to work with you. Andy, ditto, great to work with you guys and have this conversation. I'm a psychiatrist by training, over 25 years in the area. I'm a practitioner, also an academician. I divide my time between seeing patients and also I have a—as you guys know, kind of a lot of curiosity and especially interested in mechanisms. Hence, I'm called the translational researcher.
I’m particularly interested in inflammation and metabolism, what role it might play causing serious mental illness. So, it’s— that's my academic endeavors. I see myself primarily as an advocate of people with mental illness. And I think today we're going to be doing a lot of advocating, and we have some really innovative and very helpful things to talk about.
GM: So, Andy and Roger, we know that schizophrenia is not a one-size-fits-all illness. It can present in a lot of different ways. It can come on very slowly. It can come on with a bang. It can kind of smolder over time. It's very easy to miss at first. So, today, we're going to talk about the various domains of schizophrenia, positive symptoms, negative symptoms. Something we tend to overlook, Roger, and I know it's an area you've done a lot of research, but cognitive symptoms, the cognitive domains of schizophrenia. How do we kind of put those together? How do we think about new mechanisms, treatment options, when we're trying to optimize and individualize our treatments for patients.
So, let's start out by just talking about, Roger, when you think about the onset of schizophrenia symptoms, what are some of the things you look for in that very early onset? What are things, prodromal symptoms, even pre-prodromal? What do you tend to think about when you're teaching or looking for it?
RM: Well, you know, Greg, what's so interesting about the way you just prefaced the question is prodrome and onset of symptoms. My question, in my mind, is how do we define the onset of schizophrenia? I like your comment, Greg. These are schizophrenias. These are plural. There's not one singular disease or disorder state. If, in fact, we're declaring the onset of schizophrenia as the presence of DSM-5 Text Revision criteria and that, you know, for 6 months or longer, I think most epidemiologic studies in North America would converge late teens, early 20s. Nobody in the field believes that's when schizophrenia begins. No one believes that diabetes begins overnight. There's usually a prediabetic stage before you become diabetic.
Right now, I suppose in many ways, Greg, you could in fact say that the prodrome, so to speak, begins in utero. This is a highly genetic disorder. Its heritability approach is 70 to 90%, depends on the study. In studies after study after study has shown that in children who later declare themselves as having schizophrenia, there is in fact so-called soft signs, soft psychiatric signs, soft neurologic signs. For example, maybe some learning problems or some social problems. But, of course, this kind of is not really picked up clinically. There's no reason to have really necessarily a lot of concern. But, in retrospect, as they say, vision's 20/20.
What begins to happen is—not in all cases, but in many cases in the early teens, certainly post-pubertal, you start to see emergence and amplification of symptoms that, again, could be conceptualized, something you mentioned as cognitive. Maybe some school problems. Maybe there's some behavioral problems. This could manifest in different ways. For example, it could manifest in drug and alcohol misuse for the first time being imbibed on. Or, for example, there may be some, maybe reactions to drugs, maybe psychosis. Many clinicians are seeing young people smoking cannabis, and for the first time having psychosis. Or it doesn't have to be mobilized by an exogenous substance, but there could be some other idiosyncrasies or stereotypic behaviors beginning to manifest.
Certainly, my experience has been, Greg, is that it's highly heterogeneous, not uncommon to see some of these so-called positive symptoms. In other words, aspects of reality testing could be slightly altered. But what I've noticed in people that I'm referred, which is often a clarification question—is this first-episode schizophrenia, first-episode mania—a lot of negative symptoms, withdrawal, disengagement, almost a depressive type syndrome, that very often is the precursor to the overt phenomenology that we declare as sort of more typical schizophrenia symptoms.
GM: Andy, I know your practice has been very similar to mine. You've been both a researcher and a clinician, and you see kids and adults. When you see those pre-prodromal kids, you know what Roger described, what are some of those soft signs we see early in the illness before we have our first formal psychotic symptoms? What have you seen?
AC: Yeah. First of all, I'd like to say Roger set the stage beautifully. This is a very heterogeneous disorder. And while there is a genetic component, there also are environmental factors. For instance, we know that infections or injuries in utero, birth complications, even viral infections, and so on. So, it is a very heterogeneous illness, both neurobiologically, etiologically, and also in the clinical presentation. The problem with the prodrome, Greg, is it is nonspecific.
GM: One hundred percent.
AC: Before I go into the details of it. You know what I mean? This prodrome, many people who have what looks like a prodrome don't go on to declare as having schizophrenia. They go on to have bipolar disorder, major depression, ADHD, autism, and so on. The real Holy Grail would be if we could identify these people before they have that first overt psychotic break and do something to head it off.
But Roger said it really well. You can see, first of all, there's evidence in retrospect of people performing cognitively lower, perhaps one and a half standard deviations lower in their IQ testing. But again, that doesn't necessarily prove anything. And then, the prodrome often does look like depression and withdrawal. And then some—we call them attenuated psychotic symptoms. Roger mentioned reality testing. They just get a little paranoid or have some strange thoughts that are not fully necessarily psychotic.
One of the things I want to say is I'll never forget a patient I saw a few years ago who, you know, his first diagnosis, of course, was, I believe, in his early 20s. But he had this moment when he said something to me, which, of course, is the highlight of all of our days, when he said, "I've never told anybody this before, but..." And he said, "I've been hallucinating since I was 14." And so, sometimes they won't talk about this, but I think those are the issues with the prodrome. And then, of course, by the time the first full psychotic break happens, as Roger knows very well, this is probably an inflammatory and neurodegenerative event. And so, relapse is really to be prevented at all costs.
RM: Just on that note, just a comment, just on the theoretical pickup on Andy's comment, is that I think that the prevailing view in psychiatry today as it relates to prodrome, maybe is really stepping back a step in things. Schizophrenia represents a complex confluence of both neurodevelopmental aspects and, maybe in some cases, neurodegenerative aspects later on. Alzheimer's disease is clearly a neurodegenerative disorder, and autism is clearly a neurodevelopmental disorder. And schizophrenia seems to have elements of both. There's a neurodevelopmental trajectory that's gone awry behaviorally and neurobiologically, probably beginning in utero. And we know that people with lived experience later in their life begin to show elements of neurodegeneration. But so, the prodrome to this point is probably mapping on to a complex neurodevelopmental trajectory that's gone awry.
GM: Yeah, it almost feels like it's during that time when we're having synaptic pruning during late adolescence, early adulthood. We're pruning back pathways in the prefrontal cortex we're not using. We should be myelinating and reinforcing pathways we are using. And it feels like the onset happens right at that time with a lot of patients. Right?
AC: Yeah, you’re exactly right.
RM: Yeah.
GM: So, Roger, I like your kind of genes times environment, you know, they have the risk. There's then an alteration in synaptic pruning, neurodevelopment That then it has break onset of the condition. I think another common misperception is everybody thinks about the psychotic man they've seen on the street.
AC: Yeah.
GM: But schizophrenia is almost equal in prevalence between men and women. Women have a little later onset. So, it's easier to miss it. It may show up a little slower in our female patients. But it's easy to think about that guy that's out there, frankly, psychotic on the street. And you forget about the person who's withdrawn, isolated, paranoid, has more negative symptoms, maybe has more cognitive symptoms in the presentation. Let's talk about the various domains.
Today, I'm going to kind of set up 3 different domains to talk about. We're going to talk about positive symptoms. We're going to talk about the negative symptom domain. We're going to talk about the cognitive symptom domain. And let's kind of walk through each of those as we kind of think about diagnosis, as we think about recognition, as we think about following symptom trajectory, and then as we think later on about different treatment options that may be a little more targeted for one of those versus another.
So, Andy, I'll throw it to you this time. When you think about positive symptoms, you see somebody that has that first psychotic break, they've now been ill for 6 months. What kind of symptoms are you looking for? How do you track their symptom progression? In research trials, you and I use the PANSS or the SCI-PANSS, but that takes an hour. Probably not many clinicians are going to sit down with the PANSS and do the 90 questions and rate it all. So how do you measure symptom progression, and how do you measure improvement? What do you look for with positive symptoms?
AC: Yeah, great question, Greg. And I love how you framed this as the 3 domains. And some people would add mood as another domain, of course, but that's really helpful. So, the positive symptoms have always been fascinating to me, and I would say is probably part of what got me interested in psychiatry to begin with, this really interesting, altered perception of reality. So positive symptoms are symptoms we think of as kind of increased beyond normal. So, classically, it's hallucinations, which are false perceptions, delusions are false beliefs, and then disorganized thoughts and disorganized behaviors is sort of a classic thing.
One of the things that I've always been struck by, Greg, is that there is no one generic hallucination or delusion. Hallucinations and delusions always seem to have some relevance, some personalization to that person. And there's often a kernel where you can see where they originally came from, and then they just go really kind of off the rails. So, I think it's always interesting to individualize. And to your point, what I like to do is establish a baseline of what are the specific kinds of hallucinations and delusions for that patient. So, that becomes my baseline.
Now, another thing we have to make sure of, Greg, is that we are not at cross purposes with our patient. I'll tell you a quick story about that. I have a patient who actually works as a toll collector and is hallucinating all the time. But what he said to me was, which really shaped my thinking about our treatment goals, is he said, "Doc, whatever you do, don't get rid of the voices. They're my friends. Just make them nice." So, you see eradicating the hallucination is not the right goal for him. It's taking them from terrifying persecutory command hallucinations to friendlier voices that keep him company. So, I think those are some of the things. You're right, the PANSS does take a very long time. But if you establish some of those anchor points that are specific and unique to that patient—and the other thing, of course, is I have families all the time trying to get me—can't you just convince him that this isn't true or that this isn't happening? And no, you can't. So, I take a stance of not necessarily agreeing with the person, but acknowledging, wow, okay, that must be a little scary to have those kind of thoughts. And I think if you create the right environment, you're going to get them more comfortable sharing some of these things that they may be used to hiding because they get negative reaction from people.
GM: I love that approach about personalizing it. Which symptoms are bothersome to you? Which symptoms are bothersome in your relationships with other people? Which symptoms tend to get you in trouble when you don't want to get in trouble? Are intrusive. I take care of a nurse, Andy, and she described it as a fan in the background. She goes, "Dr Mattingly, when I'm doing well, the voices are kind of like that fan over there. It's in the background. It doesn't bother me. You know, it's not a big deal. When I'm not doing well, it's overwhelming. I can't tune it out. I can't filter it out.” That filtered noise ratio just isn't quite the way it should be for my— for my patients.
Roger, anything else you'd add when we think about the positive symptom domains? How do you—how do you tease out paranoia? You know, paranoia, it can be tough. Some people want to endorse it, and some people are very reluctant to endorse anything when they're having paranoid delusions.
RM: Well, that's right. You know, and I think that, you know, that there's a phrase that even paranoid people have enemies. So, not all paranoia is paranoia. And the point only is, is that I think, as a clinician, we know firsthand that many people lived experience because of insecurity of finance and insecurity of housing often live in neighborhoods that are less than ideal with respect to high unemployment, low net income, high crime neighborhoods, things of that nature. That is the clinician to be familiar with, and I bring that up because that represents a large percentage of people I've seen in my career who say, "Guess what? I'm paranoid living in my environment." Well, that's understandable in many respects. The paranoid belief systems, I think we have—we're talking about spectrum here, Greg.
And there's a spectrum of belief system, ranging from an idea that then becomes preoccupied, then becomes an overvalued idea, then becomes a—almost a—like an evanescent transient psychotic belief that patients are not entirely clear whether in fact it's true or not, that there's some harm coming towards them from some person or agency or what have you. Then, it becomes a fixed false belief system that's not amenable to any kind of external data. And that's the definition of delusion, as Andy described. And certainly, paranoia would be one example of a delusional system.
To pick up also on Andy's comment about mood symptoms, I completely agree. about. Emil Kraepelin coined the phrase dementia praecox. It was Eugen Bleuler that coined the word schizophrenia. And when Eugen Bleuler coined the word schizophrenia, he became also probably better known for the so-called 4A's of schizophrenia. And they referred to affect, association, autism, and ambivalence. And what Bleuler was trying to capture is that he saw the essence of schizophrenia not so much in the positive symptoms, but in the cognitive symptoms and the negative symptoms. What we would call negative symptoms today, ambivalence being an aspect of psychosis, autism being an element of social cognition. Altered association of thought is a cognitive problem. But he also emphasized the affect.
And so, in my clinical experience, again, what I'm typically asked to see is young people in their teens, 20s, with first-episode psychosis, which is often paranoid, but not always. And the question is, is this best explained by bipolar I disorder or schizophrenia? That's often the question I'm being asked to address here by Saturn Toronto. And there's no feature about a paranoid delusional system or, for that matter, any delusional system that is pathognomonic, in other words, that makes the diagnosis of schizophrenia bipolarity. But it's also true that, on the whole, people living with schizophrenia tend to have more paranoid, in many ways, in many cases, bizarre delusional belief systems, more so than perhaps someone living with bipolar disorder.
One final comment about that, Greg, is that I like what you said about that salience is that the prevailing view right now in psychiatry is that the reason why people report, you know, hallucinations and so on, is there's something that's gone awry with the brain's salient system. Our brain is always being asked to do 2 things: identify what's relevant and screen out what's not relevant. In fact, we're screening out what's not relevant most of the time.
And in people living with schizophrenia, there seems to be a lesion in the brain, so to speak, with respect to ruling out or screening out what's not relevant. So, the relevant and the irrelevant get all mixed together. And so, what's salient gets confused and gets attributed to some kind of external voice or what have you or an internal voice. So, it's—and again, many would say that's a problem with with—with brain circuit connectivity and brain reciprocity between circuits. So, again, it goes back to this neurodevelopmental theory around schizophrenia involving parts of the brain subserving cognition, but also affect, motivation, motor function, which we call positive, cognitive, and negative symptoms, respectively.
GM: You know, it's interesting, Roger, listening to you, especially when you talk about Bleuler and autism and affect. Many of my autism patients, you know, they have sensory filtering issues—a tactile sensation, a tag, a noise, a sensation they just can't filter it out. And I think you're right. I think with many of my schizophrenia patients, it's similar. But they can't filter out a thought, an emotion, a delusion, or perception. They may even have an idea that this isn't quite right, but they can't filter it out. So that's a very interesting thing when you think about the lesion of being able to—kind of that filter-to-noise ratio, but for emotions and thoughts. I think that's an interesting way to think about it.
Let's move into the negative symptom domain, and I'll throw something up and we can just discuss it and debate it. I think one of the reasons we've talked so much about positive symptoms when it comes to schizophrenia, first of all, you see them. They're obvious. They're there in your face. But I think our original tools, our original treatments that block dopamine may have been more effective for that class of symptoms, those positive symptoms. We tend to talk about things we have tools to fix.
AC: That's right.
GM: Positive symptoms can be horribly disabling. They kind of come on more slowly. They can be much harder to fix sometimes for our patients. So, how do you tease out those difficulties with motivation, difficulties with social interaction, difficulties with reward and positive emotional valence.
So, how do you—Roger, you're a mood disorder expert. You know, you're one of the world's leaders when it comes to bipolar disorder. The difficulties with reward and motivation that we see in schizophrenia versus mood disorders, are there differences or similarities or both?
RM: I think this could be both. And it's an area, frankly, I have struggled throughout my entire career to find that line between so-called negative symptoms in schizophrenia and what's in quotes a mood symptom. I remember many years ago, Samuel Sears had in New York, very much an expert in depression and schizophrenia, left and etched in my mind a statistic that 1 in 4 people with schizophrenia will experience a depressive episode at some time in their life. And that's probably on the—on the lower end of the estimate. But 1 in 4 always stuck with me. And as—and I am referred commonly. Many of my colleagues are no different than me, the patients where it's not clear. Is this a mood symptom? Is this negative symptoms?
The phenomenology, as you mentioned, Greg, does overlap aspects of amotivation, anhedonia. In some cases, there's a sort of disengagement. We're limited by, to some extent, the literacy of how we do business in psychiatry and the extent to which our language adequately disambiguates all this phenomenon.
I would say, though, that it's an important exercise because we do know, for example, if you do have a depressive episode that is meeting the DSM-5-TR criteria during, you know, living with schizophrenia, the set of considerations therapeutically would be maybe overlapping, but different than or not identical to, I should say, if you have negative symptoms. And for me, there's not one specific symptom that jumps out, but I would say that suicidality is not a negative symptom of schizophrenia necessarily. Self-reproach, self-criticism, aspects of utter hopelessness, and these types of experiences fit more to the realm of a mood symptom to me than negative symptoms for me.
But as you guys know, depression is not just a disturbance in mood. It involves the striatum, both the ventral and the dorsal. Therefore, depression involves aspects of incentive, motivation, salience to be motivated, psychomotor activity. And all of this is probably overlapping neurobiologically in schizophrenia with negative symptoms. Not the same thing, but I can't believe it's totally dissociable neurobiologically. There's probably some overlap.
So, for me, it's a bit like going back to, you know, Greg, you know that in ADHD, your area of, and you know, Andy are obviously experts, well, the experts in ADHD. If a kid came to me with ADHD and described sexual preoccupation, I don't think that's part of ADHD. Or the kid has grandiosity. That's not part of ADHD. That's sounds more like bipolar to me. Or, of course, in the case of sexual preoccupation, we have to rule out sexual abuse.
So, there's some features that get you thinking more towards one direction. But for me, suicidality, hopelessness, self-reproach and this rumination of self-failure and self-inefficacy. Could that be part of schizophrenia negative symptoms? Possibly. But for me, over the years, my instinct has been that's more explained by mood symptoms on top of what could be also negative symptoms.
GM: It certainly raises the alarm bells about suicidality. As you were describing that patient, Roger, we've all dealt with those patients in our practice. Those are the people that, all of a sudden, the hairs on the back of your neck start to rise. You start to worry about safety with the patient. You start worrying about wraparound services. Instead of seeing you back in a month, I'd like to see you in a week. Are there any guns in the household, you know, talking to family members, making sure we ensure safety for that patient. So, I think you're right. That patient that has those negative symptoms but now develops depression on top of it. That's a warning sign, and we will all see that in our practice.
Andy, let me flip it to you as somebody who's done a lot of clinical trials. You know, you and I have spent many, many hours doing the PANSS with patients at various stages of schizophrenia. PANSS is 30 questions, 30 items. The SCI-PANSS is an extended version of that, but it's 30 questions. Seven of those are positive symptoms. Seven of those are negative symptoms. Then we have what we call 16 associated symptoms, right? You think the PANSS itself, those 7 negative symptoms on the PANSS, does that do a good job of capturing negative symptoms? Or are we still missing kind of the flavor of negative symptoms?
AC: Well, the answer is definitely yes. But let me just first, Greg, mention something that Roger said that has particularly relevance to you. And that is when Roger mentioned grandiosity and sexual preoccupation as a differentiator from ADHD and being more bipolar. That comes from Barbara Geller and colleagues at WashU in St Louis, right, where you work. I know that literature.
I want to just get to that question by saying a couple of quick things. You're 100% right that positive symptoms are much more obvious. That's what gets people admitted to the hospital, gets them in trouble. But interestingly, the degree of functional impairment much more highly correlates with the negative symptoms and cognitive impairment that we'll be talking about. And I love Roger's discussion of the neurobiology. It's completely intertwined, and I totally agree.
Now, to your point, no, I really don't think that the 7 items on the PANSS really well capture the experience of negative symptoms. Clearly, negative symptoms are a disturbance of the motivation reward system and, you know, connecting with other people. What has sometimes been described though is that patients with schizophrenia have—when we're talking about anhedonia in particular—have more of a problem with anticipatory anhedonia than consummatory or experiencing. They can actually, if they're in a fun or pleasurable situation, they can tell you that they're enjoying it, but they just don't get to that point.
There are, as you know, many other rating scales and instruments to assess negative symptoms that I think do a better job. And we know that for—and the other thing I wanted to mention that leads up to this, you said about the medications, you're 100% right that our standard D2 antagonist antipsychotics work much better on the positive symptoms than negative or cognition, even our newer atypicals.
So, I agree with you that I think clinicians have adjusted their expectations to what our drugs can do. We're not as skilled at assessing negative symptoms and cognitive impairment. So—and we'll talk about the challenges with cognitive impairment in a minute. But there are other scales, and one of the Holy Grails has been defined treatments that work on the negative symptoms of schizophrenia. And there have been some newer antipsychotics, but also some newer medications specifically directed at negative symptoms that we would add to an antipsychotic. And, as you know, you've done these trials as I have, unfortunately, they've so far failed. So, it really is a big challenge, both in drug development, but also in assessing the symptoms. And I think, again, since a clinician is not going to do a PANSS, it would be helpful for us to help them understand how to assess and what you're looking for with the negative symptoms.
GM: Yeah, social engagement, you know, looking forward to pleasure, feeling joy. And I love your comment about anticipatory. You know, do I look forward to things in the future? Does it motivate me? Does it reward me?
I just had a patient, Roger, his dad's a paramedic. It's a young man who's developed schizophrenia. Had become horribly isolated, was living in the family's basement, came back to see me this last week. And I asked him how he was doing and he said, "Uh, I'm fine." And we talked a little more. “How are you doing?” “I'm fine.” And finally, his dad elbowed him. He goes, "Tell him." I go, "Tell me what?" And the young man goes, "Dad wants me to tell you that we went bowling last week." And I said, "Wow." And I said, "What?" He goes, "Yeah, that's what Dad and I used to do before I got sick. It's the first time we've gone bowling in 2 years." And now, he's starting to look forward to bowling. Being able to enjoy those things in his life, being able to be able to want to be with people, being able to anticipate that, hey, this may have a positive valence when you think about those in your life.
Let's move to an area that's very intertwined, but somewhat different, and that's cognition. And there's a lot of ways to think about cognition, Roger. You and I and Andy, I know we've all done studies looking at, you know, working memory, processing speed, declarative memory, verbal memory. How do you look for cognitive deficits in schizophrenia? They tend to be an early onset symptom. They can be there in that pre-prodromal phase. We may have missed it. But quite often, looking backwards, you realize things were starting to change when it comes to subtle cognitive biomarkers. How do we look for that and how do we measure the improvement in that in our patients?
RM: Yeah, that's a great question, Greg. And I think that the short answer is function. When we think about cognition, because it is a reflection of underlying brain function, we wouldn't know what the patient's cognitive functions are just by looking at the patient. Secondly, subjective cognitive performance and objective cognitive performance don't always correlate. So, we are—unless we do a pencil and paper or nowadays, of course, digitalized or computer-based cognitive assessments, we would never have a precise quantitative estimate of the overall or the domain-specific cognitive function of the patient.
However, if a patient comes to my clinic and says, "Guess what? I'm struggling at school. I'm struggling at my work," or not uncommonly, someone will be described as, usually they’re described this way rather than they describing it in the first person as socially aloof, socially disengaged. Their timing is off socially. That's social cognitive problems. And it's not uncommon for someone to be on their journey of life, they're in their teenage years, maybe even off to college, everything's, for the most part, seemingly okay. And then, there's this deterioration, in this case, academic function. So, it comes down to function. And when we think about cognition in schizophrenia and positive symptoms and negative symptoms, they all contribute to the overall loss of function. There's no doubt about that.
And you guys know that study after study after study has shown that when you try to precisely estimate to what extent does cognition contribute to impaired function, it is a lot. In fact, it's even more so than the positive symptoms in many cases. And Andy's patient that he described earlier, I think reminds us of that. In other words, I've always said in the depression area, you can work sad, but you can't work if you can't think.
And many of our patients can find ways to maneuver or work with positive symptoms, not always, but sometimes you can't, Andy's patient was a great illustration of that. But when you've got cognitive problems interwoven with negative symptoms, that really reduces human capital in the first degree. These folks can't function. So that's when they start to show loss of academic trajectory, they’re starting to drop out of courses, see guidance counselors, something's not quite right.
And then, along with that, there's a lot of social cognitive problems. And their friends will say, “Oh, so and so is, I think he might be depressed. What's going on? He doesn't hang out with us anymore.” He's hanging out in his room just watching TV but just staring at the same channel for 14 hours a day. And so, there's this level of social cognition deficit that becomes very prominent. And also, you see the overall function especially when people are engaged in some type of activity, such as school or volunteering, that depends on their cognition to be a participant. So, I think it manifests functionally in our patients, and that's how I think cognition raises its head.
GM: So, Roger said something really important, Andy, and I know we all believe this. There's cognition like processing speed, reading a book, doing your homework. There's also social cognition.
AC: Yes, I agree.
GM: Interacting with others, being able to go on a date, pick up interpersonal cues, all those things. And Roger, I think that becomes a big impairment for a lot of our patients with schizophrenia. I subtly don't pick up on interpersonal cues, social cognition. And once again, it reminds me of the flavor of some of my patients I take care of with autism spectrum. It's not the same illness, but it does have some of the same impairments. My guess is it’s some of the overlapping similar circuits in the brain.
RM: That's exactly right. And what we're talking about today are so-called hard cognitive deficits, executive functions, processing, speed learning, memory, and attention, but also social cognition. And these deficits are transdiagnostic. You mentioned autism spectrum. Narrowly defined autism would be the sort of prototype, so to speak, of impairment in social cognition or so-called theory of mind deficit. But this is not specific to autism spectrum. This is seen in other conditions, e.g., schizophrenia, bipolar disorder, and so on.
And for many of our patients, these deficits in social cognition—again, hindsight's 20/20. Parents will often tell us, you know, in retrospect so-and-so when he was 10 he was very aloof. We weren't sure what was going on with him and not that participatory other kids. We would have him assessed for autism spectrum. We have assessed for ADHD, which was going on here.
And what makes the picture even more mucky is that, of course, no one's unaware of the amount of cannabis people are smoking, and in cannabis itself has deleterious effects on cognition, in some cases irreversible, and also amplifies cognitive deficits in the social area and, of course, reward and motivational areas. So, and that makes it even more complicated, but that's a real-world patient.
So, I think social cognition is a real critical issue. It's one that, as you mentioned, Greg, it's one that really impairs people clearly in their interpersonal and their social lives, obviously. And for a lot of these patients, again, that may be one of the early tips. We'll get calls from family or friends concerned about so-and-so being very aloof. His timing's off. We don’t know if he's taking drugs, but he's just not the same person he used to be. It's “the lights are on, but nobody's home” kind of phenomena. He's just not there. And this is a very common complaint, especially from family and loved ones.
AC: Yeah, guys, I love how we're framing this. And, Roger, you mentioned the term earlier, dementia praecox, what Bleuler called it. These people are not actually demented in the sense the deficits aren't exactly the same, although they overlap. But you also mentioned—and, Greg, your story of your case really well illustrates one of the things I hear again and again from families is how devastating it is that here's this relatively normal kid, they're on their trajectory.
As a parent myself, and you Greg know, you start thinking in the future what's going to happen, your hopes and dreams of this kid, and then they just sort of fade away. They disappear, and they're just sitting, watching TV, smoking cigarettes. And so, these negative symptoms and cognitive we're talking about are so devastating not only for the patient, but for the family.
GM: So, let's move from—and we've already touched on it, we've talked about these 3 major domains of schizophrenia, symptoms, some of the neurobiology behind them, positive symptoms, negative symptoms, cognitive symptoms, the overlap of all of those neurobiologically. Let's talk about function. So, we have some functional rating scales that we use in trials these days. You can measure patient-reported outcomes for function. You can do scales that we sit down with our patients and drill into function.
How do we talk about functional impairments in schizophrenia? If we want to track that. Is it a biomarker for an improvement or a biomarker that things aren't improving? How do we track function? Andy, let me throw it to you this time.
AC: Yeah, let me start. Well, first of all, just one quick thought is, you know, technology is going to revolutionize medicine. It's already revolutionizing clinical trials, as you know. And there are things like wearables. There are real-time ways to monitor some of these things.
There's something called ecological momentary assessment or EMA that is starting to be used in trials. Our cell phones, which really, most of our patients have cell phones and can be technologically savvy. Don't assume because they have schizophrenia, they can't manipulate these things. They can be collecting a lot of information about our patient. For instance, how often are they getting out of the house and moving around? We have GPS tracking. They can monitor, are you going on the internet or social media, you know, connecting with people digitally, if you will, texting, calling, things like that. So, that may be a part of this, but I love Roger's assessment.
I think a lot of our colleagues are very intimidated by the idea of cognitive impairment. They think somehow we have to do these complicated neuropsychological tests. And I love boiling it down to what really matters, which is aspects of everyday function, whether it's traditional cognitive functions or the social cognition that we've been talking about. But one of the ways is, simply ask a patient, what do they do throughout the day? Tell me what you do throughout the day. Tell me what your goals are. For many of our patients, as we know, it's going back to school or it's getting a job or it's having a meaningful relationship. So, these are definitely things we can track and we can use as treatment goals, frankly.
So, those will be some of the things that I would say about how to monitor function is really, again, it comes down to individualizing. First, understand who this person is. I love, Greg, what you said about premorbidly. What did they enjoy or what was their function like? And then, you really have a basis for tracking that things that are meaningful to that patient rather than a generic scale, which, you know, may or may not be relevant for them.
RM: Andy, you guys might remember—you guys might remember a number of years ago, back in 2008, the great Lehman Brothers financial collapse, that led to this declaration of some financial institutions as too big to fail. I've remember too big to fail. And they became known as systemically important financial institutions or SIFI. So, I thought, hmm, interesting, SIFI. A SIFI is what cognition is. I changed it to, it's a systemically important functional index. So, cognition is the SIFI of all mental disorders. And so, for me, it manifests as function. And when someone is deteriorating in function or off trajectory or not maintaining the progressive gains, something's gone awry with cognition. That's the best index that cognition is not quite right.
GM: Yeah. Andy, I loved your techie kind of answer for us about how to measure function. And where that's exciting is that is the world we live in. We live in a digital world. And as you know, there are a lot of studies going on. We're part of a number of studies where we're seeing digital interventions to help with negative symptoms.
AC: It's not just digital tracking, Greg, but digital interventions, I think.
GM: Digital interventions, prosody of your voice to measure relapse detection, because our voice has its own little fingerprint. And what happens when people start to get ill, that changes. It becomes spiky or flat. Actigraphy, social interaction, all of those types of things. Some of the biomarkers we may have in the future to look at function.
AC: That's a good point. We call those—people think biomarkers, they think blood tests. But you can have a digital biomarker. So, I love what you're saying.
GM: One hundred percent. And then, Roger, I loved your talk about cognition and function. It's, you know, it is the capital these days. Can I hold a job? I was thinking about, I sat on the—I've sat on the board of one of our clubhouses here in St Louis. When I first got on that board, I assumed everybody wanted a job. I wanted to get everybody in job training. And I realized about half the patients did, or half the people wanted to try to get a job, get job skills, job training. But about half just wanted to fit in. Because that's social cognition. I'm interacting with people. I don't pick up personal cues.
So, looking at what is personalized, as you said, Andy, to the person, on what do you want your functional capacity to be? What do you wish was different? What would you like that next chapter to be? Maybe that's having a friend, maybe that's listening to music, maybe that's being able to go for a walk, maybe that's having a part-time job and earning some money.
AC: Yeah, if I can make one other comment about cognition. I believe that all patients with schizophrenia are cognitively impaired to some degree, but there's a real gradient. And our good friend Jonathan Meyer has showed me some really interesting data that about 25% of patients with schizophrenia have really significant cognitive impairment, and that's actually been shown to have some biologic correlates. They're shown to have much lower levels of the M1 muscarinic receptor, for instance, in their prefrontal cortex.
So, you know, and as I mentioned, my patient earlier that Roger alluded to. I spoke to his boss one time. He said, "He's my best employee." And he's hallucinating constantly. So, the positive symptoms are not impairing him. If he had more cognitive impairment, of course, he wouldn't be able to hold that job. So, that's another point, too, to realize the heterogeneity of cognition as well.
RM: Andy, it's such a nice point because one of the questions I've been asked, especially in bipolar and major depression, which I think would be copy and paste into schizophrenia is, can I use the Mini Mental Status Exam or the MoCA, the Montreal Cognitive Assessment as a screening tool for schizophrenia? And the answer is, we wouldn't recommend that because a person can have lived experience of schizophrenia and have considerable cognitive impairment that's not going to be detected by those instruments.
AC: That's right.
RM: And so, we would not recommend a, in quotes, more traditional dementia rating instrument for the cognitive deficits in schizophrenia and bipolar and depression for what Andy just so beautifully articulated.
AC: Yeah. I mean, they are often oriented. Orientation is not necessarily a problem. It's also abstract thought is a big problem for these people. They can be very concrete. Greg, you know, on the PANSS, some of the—what you test is proverbs and abstraction and things like that, you know.
GM: Yeah. So, it's interesting as we kind of talk about function. Let's set the bar though. How are we doing right now? So, we've come a long way in the last 30 years, Andy. You and I have been investigators in hundreds of clinical trials, as has Roger. We've come a long way, but we still have a long way to go. What percent of people right now with schizophrenia hold a job?
AC: I would say it's quite low, maybe 10 percent.
GM: OK, what percent ever get married?
AC: Oh, gosh, very low, also probably 20%, 30%.
GM: I think the number is 15%.
AC: Yes, that's minority.
GM: If you think about those things that define us, having a job with purpose, having an interpersonal relationship with ongoing action and commitment. We all know some patients were able to get there. But we know for a lot of our patients, Roger, that's an ongoing deficit. So, you know, we've come a long way, but we still have a long way to go with this condition, right?
AC: Greg, you just said something beautiful. Freud said to be mentally healthy is to be able to work and to love. And I translate that into having purpose and having meaningful relationships. I really think that's the goal here.
GM: Yeah. So how do we, before we go into medications and treatments, how do we use psychosocial supports to help increase structure for people that maybe their brain is not, you know, functioning in a way that that comes to them very easily at this point in their illness and their condition. I've become a big fan of the community support programs, you know, the various clubhouse models, places where you show up and have purpose, where you have interaction, you have daily structure. Circadian rhythm can get upside down in our patients.
So, how do we use those kind of, you know, lifestyle interventions before we go to medicines? What else do we do holistically for our patients? Roger, what are some of the thoughts up there in Canada? What do you guys use?
RM: Well, I think this point is very well taken. And I think first and foremost, what I might say is, is that individuals who are living with schizophrenia can benefit from these psychosocial interventions. Let's start with that. Secondly, is that we know from a literature from the '70s and '80s from parts of Asia, including not limited to India, that outcomes in schizophrenia can be considerably improved when there are supports put in place from family and community resources and so on.
Now, look, let's just have a heavy dose of reality, not to be dour, but just reality. Our patients often don't have appropriate housing or security of health care or food or finance. So, these are aspects—and this really laid bare during the pandemic. Our patients were so vulnerable during the pandemic for a variety of reasons, notably social economic determinants. But that aside for a moment, because that's more in the systems and structural approach to managing schizophrenia at the general population level. But for individuals, there's no question.
I remember vividly many, many years ago, the expressed emotional literature. In other words, people living with schizophrenia who are living in environments of high expressed, negativistic environments, hypercritical environments, did more poorly. And when interventions were done to target these family or group level ways of communicating, schizophrenia outcomes were significantly improved to the same extent that antipsychotics would improve outcomes in schizophrenia. So, I think we're not just talking about it's something nice to do or cosmetic. The effect sizes of social interventions are similar to the effect assizes of pharmacology in managing schizophrenia. So, 1 plus 1 can at least equal 2, sometimes 3. And so, I think that's something we need to be aware of.
The other part is, is that there is a whole literature on manualized based psychotherapies like CBT in helping aspects of schizophrenia. And that's an interesting area itself, but that's been also looked at. And then, also, Greg, something I'm not gonna forget to mention, I hope, is we need to also be counseling patients on lifestyle and diet and exercise. And people have said to me, they don't think people with schizophrenia can benefit from that because of cognition problems and so on. Well, the literature actually tells us that the benefits that people living with schizophrenia can obtain with exercise, diet, lifestyle changes is not a whole lot different than the general population. I'm not going to overstate the benefit because the benefit is not the greatest anyways. But this is a critical, critical part. So it's psychological, it's emotional, it's interpersonal, it's targeting the loneliness of our patients. But it's also targeting their weight and their diet.
And again, I'm cognizant of social and economic issues. It's very expensive to eat well, I got that. But it's also something given the hazards of the physical health morbidity in schizophrenia. Cardiovascular disease, number 1 cause of premature mortality—2020, about 20 years of life lost, my goodness. So, this has to be considered as well as part of a coherent, comprehensive psychosocial management plan.
GM: Roger, I started with the clubhouse that I worked with here, and we started introducing exercise. And at first, everybody was like, “Oh, people don't want to exercise. That's too hard.” I'm like, “Let's make it fun. Let's play music.” Everybody likes to exercise different. Some people like to stretch. Some people like to do yoga. Some people want to do—go for walks.
AC: Let's just dance.
GM: Let’s find different ways to engage people. That's right. Now everybody looks forward to coming, playing some music, wiggling a little bit, stretching, yoga, whatever they do. I then said, okay, how about nutrition? Something we overlook. You know, when was the last time many of our patients ate a meal with others?
RM: Yes.
GM: The last time they cooked a meal with purpose. We started every Friday. The different members could bring a recipe, and they could make the recipe for the other members. And we gave an award for the best recipe of the week. It's now the favorite day of the week for people to come to the clubhouse. You know, they all get to eat a little something. They get to make meals together. They get to give rewards to each other, and it makes them go home and think about that with purpose in their life. So, those kind of—
RM: Yeah. You know, it's such a nice point. I think that when it comes to many roles that we have as healthcare providers, with people with schizophrenia, living with schizophrenia, I think literacy enhancement as it relates to their illness and their treatment is paramount. And secondly is literacy around food. Again, economics is often a juggernaut. It's a big issue. Our patients are often indigent, not resourced economically. My goodness, you’ve got to be well off to eat well nowadays. But I got that. But there are ways that you can eat, but this was literacy and educating people on this. I never would have thought when I started my career, I would have spent so much time on this aspect, but I do. And I just firmly believe it's as important as everything else in terms of their overall brain health.
AC: I like to call it therapeutic nihilism. I think some of our colleagues think, "Well, they can't benefit from nutritional counseling or exercise." As that’s, as you said, Roger, there's a whole literature on that that it's not true.
RM: Right, and—
AC: If I could just make a couple of other points real quickly. Let's not forget that this illness interrupts the trajectory of someone's development in every possible way, intellectually, socially, skills acquisition. So, part of when you get somebody better, and you really do have to stabilize the chemistry to some degree, let's not forget you have to pick up where they were. They have to learn what we call adulting, if you will, but they have to start relearning or learning for the first time skills such as socialization and how do I balance a checkbook or, you know, figure out a train or bus schedule and all these sort of things. So those are, to me, psychosocial interventions, too.
We all are familiar with vocational rehab, but I want to tell another quick story, Greg, to your point. Boy, this is such a good one. I'll never forget in my residency, we had a recreational therapist. That was actually a title on the unit. And I remember getting friendly with this man who was a recreational therapist. He actually had a degree from college in recreational therapy. I said, "You just play games. You play sports. You have fun with these people all day. I don't get it." He said, "Andy, think about it. When people get mentally ill, they lose the ability to have fun, and they lose, they forget, or they never learn recreational activities, which can be social.
So, Roger, it goes to your point about loneliness. So, we have these evidence-based therapies and interventions, but we need the political will and the financial support to employ them. And so, it's hard to talk about this without talking a little bit about some of the systemic issues and the stigma.
GM: One hundred percent. One of my families here in St Louis, they had 2 twin boys that developed schizophrenia. They were some of the founders of the original NAMI Family-to-Family training program. So, I love using those support systems that don't cost our patients money that we can wrap around. Boys and Girls Club of St Charles, NAMI, and NAMI Family program where you can get support, learn about the illness. As Roger, you said, learn how to parent someone who has a mental condition in a way that's possible versus negative, getting upset, getting frustrated, feeling overwhelmed. It's tough enough to be out there and have somebody that has this condition. It's even tougher if you feel all alone. Let's move into treatments.
So, we've set up kind of the groundwork that function is still impaired for the majority of our patients. That function can be symptomatic function, that function can be cognitive function, it can be psychosocial interactions. How do we think about the treatments? So, Roger and I grew up in the old days of D2 blockade. And I can remember on our Schizophrenia Research Unit at WashU, we would titrate our dose of high potency dopamine antipsychotic to where we made somebody slightly parkinsonian.
RM: Yes.
GM: When they had a little bit of a tremor, we knew we had about 80% dopamine receptor blockade. We thought we were doing a great job of blocking their positive symptoms. But people didn't function. They sat in the unit. They weren't as disturbed, they weren't as violent, they weren't as agitated, but they sat there and were pretty apathetic and didn't do much. So, walk us through kind of the evolution of dopamine, antagonists, atypical antipsychotics, clozapine, partial agonists, and now we have a new group of medicines that are muscarinic, or I think of them as presynaptic treatments instead of postsynaptic.
RM: Yeah, well, first of all, Greg, I think it starts off with a comment, and that is that the use of medications to treat schizophrenia is the standard of care. Just recently, I was reading an article in The New York Times where there was some descriptions of people who were attempting to live with schizophrenia without medication. I would say that's not the standard of care. Standard of care is to treat schizophrenia with medication. We start with that.
To your point on the chronology, it begins way back in 1950, really 1952, when chlorpromazine and aliphatic phenothiazine was first introduced into psychiatry. We poached it from anesthesia. We liked poaching medications in psychiatry. We poached many drugs in many areas. The atypical antipsychotic drugs then came out not too long, much later. In fact, clozapine, which we didn't really know clozapine until the ‘90s here in North America, it actually was synthesized in 1958. So, it's actually an old drug as well.
But I think when most of us think about atypical antipsychotics, we think about Paul Janssen's discovery, not of haloperidol, which he discovered, and then droperidol, but he also discovered risperidone. And risperidone came out in the very, very early ‘90s as a, in quotes, atypical antipsychotic for schizophrenia. I think that now we've got over a dozen definitions of what atypical means. It might be accused of being slightly more of a marketing moniker. But there was, in fact, a view that rather than only binding to D2, if you could bind to the serotonin system, that may obviate some of the dopamine side effects. And that was the hope, that was the aspiration. That was essentially followed, as you said, Greg, by so-called dopamine partial agonists.
That was inspired by a consideration at the theory level that the problem in schizophrenia is not so much too much or too little dopamine but rather a view that dopamine may be altered differently in different parts of the brain. So, what we needed was more of a kind of a—kind of a rheostat to put that all back together. So, Goldilocks' porridge was required, where—where dopamine’s too hot and we want to cool it down, and where it's too cold we want to warm it up. That was the whole theory behind that. And also, the theory held that if we weren't blocking the D2 receptors aggressively postsynaptically, we may have less so-called D2 side effects.
I think during this time, beginning with chlorpromazine all the way through the so-called typicals and atypicals, there were other lightbulb moments that happened. And other light bulb moments that happened was, well, people started looking at glutamate and looking at other systems. We mentioned inflammation earlier, and there's many other academic areas that people are still looking at. But then, the muscarinic system came into our consideration, but there was another sort of more sort of cellular observation made. And that is that there is a consensus, at least in schizophrenia, that there is an increase in the presynaptic production of dopamine. And what we're doing is we're giving postsynaptic drugs to block the dopamine effect.
Now, it would make a lot more sense, wouldn't it, to target our drugs where—where the trouble is, which is presynaptically. And so, this has inspired a variety of different efforts to look at interventions to target the presynaptic dopamine synthesis or presynaptic dopamine packaging or presynaptic dopamine release. But the point is, it's presynaptic. And so, we have efforts that really, in fact, are kind of deja vu all over again, looking at VMAT inhibition, which we think of as a treatment for TD, but it may also be a treatment yet again—it was an old treatment for schizophrenia, presynaptically, to affect dopamine availability.
And then, to your point, Greg, muscarinic systems, which have been well known to modulate presynaptic dopamine differently in different parts of the brain as another therapeutic approach. And the hope is, by targeting presynaptic, that's where the problem is, so that makes a lot more sense, but it's more than that. If we're not blocking postsynaptic D2 receptors, that means maybe less D2 problems such as tardive dyskinesia, akathisia, prolactin elevation, apathy, and so on and so forth. So, it's not just a sensible approach, but also has reasons to believe it may get closer to the lesion—that may have implications for efficacy—and also may have implications for better safety and tolerability.
GM: Andy, let me throw it to you and I'll pose a question. So, the old traditional dopamine antagonists, the haloperidols, the fluphenazines, the chlorpromazines, is there a place for them anymore? So, is there a place for just pure dopamine blockade, or should we move past that, or is that an either/or question? Go ahead.
AC: Yeah. Well, like many of these things, it's not so black and white. But my short answer is, yes, in certain situations, but I love how Roger framed this. Basically, for 70 years, we have been treating a presynaptic problem for most patients. There might be a subset who don't necessarily have that, and they may be patients who respond better to Clozaril, for instance, which is a weak D2 blocker. But for 70 years, we've been treating this presynaptic problem with postsynaptic D2 blockade. And the problem with that, of course, is a couple. One is it works best for positive symptoms, but not so well for negative symptoms or cognition, which we highlighted earlier.
But also, there's all this collateral damage Roger alluded to. And Roger, of course, will tell us, because he's the metabolic expert, there are D2 receptors in your pancreas. And so, you can get metabolic dysregulation even without weight gain, so to speak. But, you know, also, Roger said what's old is new again.
And of interest—and, Greg, you love trivia questions. You love asking these questions. Do you guys know that the first drug FDA approved to treat schizophrenia was not chlorpromazine. It was reserpine, to Roger's point, a VMAT2 inhibitor, which decreased the presynaptic release of dopamine. But of course, it was intolerable because of the incredible orthostatic hypotension, people passed out. And so, we now use reserpine more for recalcitrant hypertension, but that's when people went over to the D2s.
But another thing is, the muscarinic system has been recognized since the '50s, and there was a medicine called arecoline, which is derived from the betel nut, B-E-T-E-L. And arecoline is a muscarinic agonist, and that was shown in the 1950s to be an effective antipsychotic, again, working presynaptically. It was never FDA approved in the US and very hard to tolerate because of peripheral gastrointestinal side effects.
So, to your question, there are some patients who still do need some D2 blockade. And what's nice is especially this muscarinic agonist may be a complementary mechanism to D2 blockade. So, it does make sense to do this rationally rather than adding 2 D2 blockers perhaps, although the atypicals all have different fingerprints, different other receptors that they bind to. So, it may actually not be irrational to combine some of those that have different profiles other than D2 blockade.
But you know, Roger, you do a lot of work in Asia and China. I was just on, actually this morning, a virtual meeting to prepare. I'm doing a webinar for our Chinese colleagues on tardive dyskinesia, and they presented data to me on prescribing patterns. And in China, Greg, over 50% of the antipsychotics used are still the first-generation antipsychotics.
And as you mentioned, well, all 3 of us trained in—we were taught to do rapid neuroleptization was the actual term. And we would often start concomitantly an anticholinergic medication, which also has a lot of collateral damage. So, we have to monitor for that. So, I guess there are situations when they still have a role. They're, of course, very inexpensive. There are LAI versions of 2 of them, fluphenazine and haloperidol, that sometimes are used and very effective and may, in fact, be a little better tolerated because of better pharmacokinetics. So, Greg and Roger, of course, if it was our child, I think we would agree. We would want them on a newer atypical antipsychotic that perhaps has less of the risk of the D2 collateral damage by blocking it.
GM: Yeah, I would say that when I think about the old traditional dopamine antagonists, you know, there are emergencies. There are times when you have to treat someone in an emergency, and I think there is still a realm for those in an emergent situation. They're not just dopamine antagonists, they're also major tranquilizers. So, I think in an emergent situation.
AC: That's a really good point.
GM: But I don't think it's your long-term strategy. I think your long-term strategy then moves into the atypicals. I'm a big fan of the dopamine partial agonist class of medicines, Roger. You and I and Andy have all been part of the development of many of those molecules looking at partial agonism versus antagonism. And then, I pick and choose based on various other side effects. Extrapyramidal side effects, metabolic side effects, weight gain. Are they sedating versus energizing? So, when I think about the various atypicals—and then, never forget about clozapine, some of my very best outcomes in my practice. Some of my people that hold jobs are people on clozapine. So, we think about being the refractory patients, but quite often it's the lucky patients that are offered clozapine.
AC: Yeah. You know, I had a professor who told me, "Ah, dirty drugs are better." And what he meant was multimodal drugs, and of course, clozapine’s the best example. So, it's a risk-benefit analysis. And Greg, I love your point about sometimes I choose the medicine not based on the diagnosis, but on the clinical presentation, the cluster of symptoms, the profile, what am I trying to do? I think we do sometimes put drugs into more calming or more energizing kinds of buckets. You know, I agree with you about the D2 partial agonists, but of course, they're not entirely free of so-called EPS and akathisia. So, we sort of sometimes have to pick our poison with these drugs.
GM: My gut feeling is that the partial agonists in clozapine probably come out a little more favorable when it comes to some of the negative symptoms, social interaction. I know the data is mixed about it. We've all seen it's hard to show that when you do meta-analysis. But I think clinically, we've all seen that some of those tend to be more favorable when it comes to some of the negative symptoms. Let's talk about the whole new—
AC: Well, hang on Greg. You're 100% right. There is a landmark study done in Europe of cariprazine actually being superior to risperidone for negative symptoms. It didn't quite catch on in the US, but I think you're right. I would agree with you.
GM: I agree. So, cariprazine is a perfect example, slightly energizing, D3 more than D2, and partial agonists for both. Let's talk about the pre- and postsynaptic. And so, we've been touching on it, and there's a lot of presynaptic mechanisms. There's VMAT, there's muscarinic, there's glutamate. It's a fascinating area of research right now. And it's why it's exciting to be, I think, in mental health and in psychiatry, where we are right now. Roger, I've taught, for years, my medical students. I would teach psychosis by drugs of abuse. And if a drug of abuse can make you psychotic, then we may be able to develop treatments that pull the brain together.
AC: That's right.
GM: So, I talk about dopamine psychosis, you know, methamphetamines, you know, it's the flavor of that type of psychosis. I talk about serotonin psychosis, LSD, a different flavor of psychosis. I talk about anticholinergic delirium, Osler's triad, a different flavor of psychosis. And then, I talk about glutamate psychosis, you know, PCP. And so, when now we're developing tools that hit different parts of that cascade about how the brain can become psychotic, right? So not just dopamine anymore, not just dopamine plus serotonin, which was the atypicals.
We're now developing cholinergic treatments that work through the muscarinics, but they also work through—and Andy, you know this, they come down through that GABA glutamate cascade. So, we're touching muscarinic receptors, but we're also modulating glutamate to modulate dopamine release. So, in some ways, I think it's a unified theory about why the brain is getting psychotic.
RM: Yeah, I agree, Greg. I like that unification theory or unification hypothesis. 2019, the FDA approved esketamine for the people living with treatment-resistant depression, and that ushered in the glutamatergic modulators for depression. And now, we have a combination dextromethorphan-bupropion.
And again, it's a new chapter in psychopharmacology in mood—that being glutamate. We're not throwing the old chapter out. Chapter 1 on monoamine still exists. Similarly in schizophrenia, just to your point, that's a really nice way, that round the horn you just did, Greg, with respect to different ways to conceptualize psychosis.
And I agree, these are not mutually exclusive. I think what's happened is you had unification. And some might say, well, obviously, Greg and Andy and Roger have got too much time on their hands. Why do they spend all their time wasting—thinking about this? Well, this brings in a dropdown menu. If, in fact, we have reasons to believe that these other neurotransmitter systems directly or indirectly are relevant to the target, for example, psychosis, then that introduces new therapeutic considerations that up until now either we haven't considered, or we did many years ago, and now we’re reconsidering. And a lot of this is sort of deja vu all over again. So, I think it's exciting. It's hopeful. It's neuroscientifically interesting, but it's hopeful for patients.
AC: Yeah, Greg, I also loved your formulation with respect to—it's not too much or too little of a chemical or of something. It's really the interplay, it's modulation, it's regulation. As Roger always says, it's circuits, nodes, and networks. You know, CNN, if you will. And I really believe that because schizophrenia is heterogeneous, as we said before, it's really important that we have different modes, different mechanisms of action that might perhaps work better for some patients than others. It might work better on some circuits or clusters of symptoms than others.
And I think, of course, we need to talk about the possibility that some of these newer treatments, glutamatergic, modulating muscarinic, might help for those Holy Grail symptoms of negative symptoms and cognitive impairment.
GM: So, we had a breakthrough moment last year. We had a breakthrough moment where we had a medicine approved for schizophrenia treatment. It's no longer called an antipsychotic.
AC: Yeah.
GM: Helping to remove stigma. And I love that that we get rid of the stigma by not calling it an antipsychotic. It's a treatment for individuals living with schizophrenia, but they described it based on its mechanism. It's a muscarinic treatment for individuals.
AC: Muscarinic agonist, that's right.
GM: Muscarinic agonist. So, we have a muscarinic agonist approved for the treatment of individuals with schizophrenia. First of all, it points out that it's new. It's different. It's novel. It's not a direct dopamine postsynaptic treatment. It's a muscarinic presynaptic treatment. And it makes you think about the emerging world of how you touch the brain. There's a big debate right now, and we'll just touch on it briefly. We don't have a lot of time left for this segment. I think we'll get together and do this again sometime. This is an emerging world about the muscarinic world. And the treatment we have approved now is a muscarinic agonist both at the M1 and the M4 receptor.
AC: That's right.
GM: We kind of think that as top-down and bottom-up control of dopamine release, working through different pathways.
AC: That's right.
GM: There's a real debate about whether it's better to be M1, better to be M4, or better to be both together. What's your thoughts there, Roger? You've done a lot of work looking at some of these neuropathways and the neural networks involved. Any thoughts?
RM: Well, I think right now we've got reasons to believe that both are relevant. And I've become very pragmatic about this in the sense that until recently, many folks thought M1 was where the action was, and part of this was a derivation of clozapine's metabolite and its effect perhaps at M1 and its role in cognition. Others, in fact, began to look at M4. And there was also a belief system, that's where the action's at. I think, frankly, this is not meant to be kind of humility. I think that at the end of the day, they say you dance with the one that brings you. And so, if you have a treatment that's M1 only and it makes patients significantly better, that's the winner. M4, that's the winner. If you have a combo, M1, M4, and it gets people, as I say, over the wall, in other words, it gets them better. Then that, to me, substantiates the concept. So, I think, for now, the debate is still going on.
For our colleagues who are joining us who don't spend their day-to-day life in medicinal chemistry and so on, psychiatry has known for a long time that muscarinic receptor modulation may have therapeutic opportunity in psychosis. The challenge has been that the field hasn't really had a consensus. Which one is it? And do you bind to the orthosteric site? Do you bind to the allosteric site? And it gets kind of complicated very quickly.
This reminds me a lot of glutamate. A lot of glutamate drugs are not antidepressants, but some glutamate drugs are. So, the details do matter at the medicinal chemistry level. And this has become very sophisticated. And elegant work is now shown. Some of this is in silico in computers. Some of this is done in animals, of course, in pharmacologic studies, that M1 and M4 gave people a reason to believe. I've not ruled out M1 or M4 on its own. But for now, we have, as you alluded to, Greg, September 2024, the FDA approved an M1 and M4, and it worked. At the end of the day, does it work? And that's all that matters. And so, for now, M1 and M4 combined seems to be the leading view at this point.
AC: To boil it down to what's clinically relevant, guys, there's preclinical evidence that both M1 and M4 modulation can have antipsychotic effects. And Greg, you said it beautifully because I conceptualize the brain as working through top-down and bottom-up regulation.
Whoever designed our brain, guys, did something incredible. M1 and M4 receptors are exactly where we want them for psychiatry, but not where we don't. So, for instance, M1 is heavily concentrated in the prefrontal cortex. M4, more down in the limbic system, and even lower areas that control the release of monoamines, especially dopamine.
So, in a way, we're still, as you said, Greg, indirectly, still modulating dopamine. My research training was dopamine receptor pharmacology. So, I'm loathe to completely give up my friend dopamine. And many clinicians—we have to meet folks where they're at. We're steeped in the dopamine theory of schizophrenia. And for 70 years, we've treated it by blocking dopamine receptors, and this drug does not.
But I think real quickly, it's very interesting that you have this top-down bottom-up. And what's really interesting, Greg—I'm a little bit drinking the M1 Kool-Aid, I'll be honest here. Because the original raison d'etre for xanomeline, which is half of the xanomeline-trospium combination, was stimulating M1 receptors, which were known to be procognitive. And the first study, as you know, was done in Alzheimer's dementia, and it did work for cognition. It separated on the rating scales, the ADAS-Cog and the CIBIC-C for cognition. But it was found to especially work for the neurobehavioral and psychotic-y kinds of symptoms, so they pivoted to schizophrenia.
But I believe, to wrap this in a bow, Greg, I believe that these muscarinic agonists, especially M1, may have the potential to help with the negative symptoms and the cognitive impairment. There is some preliminary evidence that's true derived from subanalyses of the clinical trials with this combination. So, that's another reason, I think, to be hopeful and maybe even excited about this.
GM: Let me thank you all for joining me—Andy, Roger, good friends, colleagues, always learn from you—to the audience that's joined us today. Let me thank everybody that's joined us out there. And let me just say this is an exciting time to be in mental health. Thirty years to the day of when clozapine was first FDA approved. This September, Roger, we had our first muscarinic treatment now approved, a presynaptic treatment for schizophrenia. We're learning more all the time. It's an exciting time to be where we are.
So, let's review. We talked about the positive symptom domain, the negative symptom domain, the cognitive symptom domain. We talked about those symptoms not living in a vacuum, but their importance when it comes to functional relevance. And then, we talked about the neurobiology of some of our treatments being a little more targeted for specific areas of the brain in those neural networks.
Let me thank you all for joining us. Hopefully, we'll get back together again and share a little more knowledge. Till then, be well.
RM: Thank you. Great job.
AC: What a pleasure. Thank you.