Daniel Knoepflmacher, MD (Host): Before I begin today's episode of On The Mind, I want to personally thank you for listening to this podcast. It's been truly exciting for me to see how our listenership has grown over the past several months. We've had tens of thousands of listens and downloads since we first started. It's confirmed my belief that there's an audience out there interested in hearing thoughtful conversations about mental health and psychiatry.

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Welcome to On the Mind, the official podcast of the Weill Cornell Medicine Department of Psychiatry. I'm your host, Dr. Daniel Knoepflmacher. In each episode, I speak with experts in various aspects of psychiatry, psychotherapy, research, and other important topics on the mind.

Our topic today is schizophrenia, a core psychiatric diagnosis that affects more than 24 million people around the world. The World Health Organization identifies it as among the top 10 illnesses contributing to the global burden of disease. Schizophrenia is estimated to cost the U.S. economy hundreds of billions of dollars annually. It's associated with a shortened lifespan and a significant increase in risk of suicide.

The typical syndrome of clinical manifestations includes psychosis, cognitive impairment, and the cluster of features we call negative symptoms, which include deficits in expressiveness, social engagement, and motivational drive. It is a profoundly heterogeneous condition with a spectrum of presentations and outcomes. Though the course of illness can be insidious and chronic for many individuals, research has demonstrated that a significant percentage of people diagnosed with schizophrenia can achieve favorable outcomes with a marked reduction or even remission of symptoms. Research has also demonstrated that early intervention and specific treatment approaches are tied to better outcomes.

In this episode, we'll describe the key facets of this condition, review the leading evidence-based treatments, and look at what new options are emerging to improve the lives of the millions who are living with schizophrenia. I'm happy to welcome our guest, Dr. Leonardo Lopez, who is the Vice Chair of Inpatient Services and Associate Professor of Clinical Psychiatry here at Weill Cornell Medicine. Leo, thank you so much for joining me today.

Leonardo Lopez, MD: Thank you. It's a pleasure to be here. .

Daniel Knoepflmacher, MD: Well, we have a lot to talk about. So, I'm going to begin by asking about you and how you developed an interest in schizophrenia and Inpatient Psychiatry.

Leonardo Lopez, MD: Sure. I'm happy to answer that. So, I was not someone who in my youth had any intention to become a physician. After completing my undergraduate studies, I was high school mathematics teacher, a job I enjoyed very much. But during my time as a teacher, I started to recognize the impact that mental health had on our students and the challenges they had in learning and succeeding that were directly related to mental health. So, I decided to pursue a career in Psychiatry at that time, which meant going to medical school. I didn't anticipate enjoying medical school, actually. I thought it was sort of means to an end, but it turned out I enjoyed it very much and was fascinated by everything I learned and ended up going a different direction from Psychiatry and pursuing a career in Neurology. I was interested in the brain and all its aspects.

But at the time, Neurology, I suppose it was a little more mathematical than what I was used to In Psychiatry. And so, that was the path I chose. When I started my training as a neurologist, part of the training was to rotate on an Inpatient psychiatric floor, sort of a minor requirement for Neurology trainees. And when I got to the psychiatric floor and started to meet patients with schizophrenia, and as we'll probably discuss at some point, a very large percentage of patients admitted to psychiatric facilities have schizophrenia. Well, I mean, I suppose that changed my life, right? So first of all, I'll say that I was just fascinated by the illness. I was fascinated by speaking with people who experienced and understood the world in a completely different fashion than I did, or than anyone I knew did, and trying to understand what was happening to them and what it felt like for them.

And then, secondly, I saw really how transformative treatment for the illness could be. This is not the case uniformly in Medicine. You know, people think of doctors performing miracle cures all the time, but the truth is much of medicine is a real battle against illness and it's a battle that we lose a lot of the time. But it was stunning to see patients come in in tremendous unimaginable distress, really divorced from reality and leave feeling happy and wonderful. There are very few places that I rotated in as an early trainee where I saw physicians be that effective. And so, I became very passionate about Psychiatry and about schizophrenia particularly. I changed my course of study. I pursued residency in Psychiatry. I did a research fellowship in schizophrenia, was very involved in first-episode schizophrenia research in the early part of my career. And since that time, because the easiest place to find patients with schizophrenia is in the Inpatient Psychiatric setting, I sort of dedicated my career to that setting so I could have as much contact and contribute to the lives of those patients to the greatest degree possible.

Daniel Knoepflmacher, MD: It's a great story. And if I'm not mistaken, it's kind of a full circle for you, right? Because that unit that was so formative for you is here at Weill Cornell and is now a part of your portfolio of inpatient services. Is that right?

Leonardo Lopez, MD: It's amazing how life works that way. But that's exactly right, I started as a Neurology resident here at Weill Cornell and rotated on our 11 North Unit. And that was what made me decide to go into Psychiatry. And then, I went my own way for, you know, a decade or so, and ultimately found my way back. One of the social workers when I arrived and was introduced said, "I remember you. You were an intern here."

Daniel Knoepflmacher, MD: We keep pulling people back in. I don't know what it is yet.

Leonardo Lopez, MD: That's right.

Daniel Knoepflmacher, MD: You know, I, I love how you spoke about your specific interest in schizophrenia, developing kind of the interest in the way of thinking that occurs with in schizophrenia and just empathy for the suffering and the potential for help for this population. So, I want to go into a little background. And schizophrenia is a disorder that's been studied for hundreds of years, famously by European psychiatrists in the 19th century. I think of the German psychiatrist, Emil Kraepelin, and the Swiss psychiatrist, Eugen Bleuler, who in 1908 coined the term schizophrenia. So, thinking about this history, can you share with us how our understanding of schizophrenia was founded in that area and then has kind of evolved since the time of Bleuler?

Leonardo Lopez, MD: Yeah, absolutely a topic I am very happy to discuss. So, Kraepelin was the first psychiatrist to sort of identify this illness entity, an illness that was characterized by hallucinations and delusions. We can talk more about what those things mean as we move along. And he called the disease dementia praecox. The term dementia here is different than the way we use it today. In Latin, dementia literally means out of one's mind. So, it was meant to indicate not that people had cognitive dysfunction, but that they were divorced from reality. And praecox means premature. So, the idea was that this was premature madness.

The reason it's premature, by the way, is that in the mid to late 19th century, the majority of people presenting with psychosis in psychiatric facilities had neurosyphilis. And so, they were actually presenting well into their adulthood, which is not the case with this population. They tend to present as adolescents or early adults. So at the time, it made sense to call this premature madness. He and Bleuler both studied the disease extensively. In parallel, they had some disagreements about the fundamental characteristics of the disease. For example, Bleuler thought delusions and hallucinations were sort of secondary, and there were other things that were more fundamental to the disease, like disorganization of speech or difficulties with emotional processing. Bleuler also had a more optimistic view of the disease. Kraepelin felt that it was uniformly terminal, which is to say that people deteriorated over time without question.

Bleuler had a more optimistic view, and it turned out he had a better name, which was schizophrenia, which won the day. It's a name that's caused a lot of confusion until the present time, actually, I think. The term schizophrenia literally means split mind. What Bleuler was trying to indicate was that by that was that the person's will, their desire to do things, was split from the things they actually did. That their will and their volition were split. So if you ask a schizophrenia patient, "Why did you just do that strange thing that you did?" The answer is often, "I was commanded to do it. I was controlled by an outside force. It wasn't me," right? So, that was what Bleuler was trying to indicate with the term schizophrenia, that the person's mind was split off from their ability to act. And we see that in many manifestations of the disease. So, that's sort of the background.

Since that time, I think we've made a lot of progress in understanding. There was a major shift in the 1950s in our understanding for two reasons. One was the work of a psychiatrist named Kurt Schneider, who was the first to sort of very meticulously codify, okay, what are these hallucinations and what are these delusions that people are experiencing. Sure, they believe things that are not true, but what are the things they believe? Sure, that they hear things, but what are the things that they're hearing? And he developed a list of nine symptoms, which he called first rank symptoms. Now, they're known as Schneiderian symptoms that are present in almost all patients with schizophrenia. Upwards of 80% of patients who are ill have one Schneiderian symptom.

The other thing that happened in the 1950s that we'll get to at some point is that antipsychotics were developed. Chlorpromazine, more commonly known as Thorazine, was the first antipsychotic that was made available worldwide. It was made available in the United States in 1954. And for the first time, we had a really rather rapidly in the grand scheme of things effective treatment. And we were able to see what patients looked like when they were treated, right?

So, one of the things that we discovered from that is that when we treated the patients, they stopped hallucinating to the same degree. Often they weren't preoccupied with these sort of beliefs that we call delusions anymore. They were able have reality-based conversations. But they still had some dysfunctions. Specifically, they had difficulty processing emotion, expressing emotion, enjoying pleasurable activities, engaging in sort of basic activities of daily living, so sort of cluster of symptoms that had to do not with what they were thinking or what they were seeing or hearing, but how they were functioning. And these were sort of grouped together in the mid to late 1980s by Nancy Andreasen, a very important psychiatrist, Chair of Psychiatry at University of Iowa for a long time, and referred to as negative symptoms to contrast with them with the positive symptoms of hallucinations and delusions.

So over time, I think we got a much understanding of what the illness looks like. Yes, it has hallucinations and delusions, but it also has these negative symptoms. They come out to varying degrees in different patients. And we just get a broader sense of the heterogeneity that you referenced in your introduction that we see in the disease.

Daniel Knoepflmacher, MD: And with that heterogeneity, I know that the early specialists looking at schizophrenia in Europe were identifying and classifying different aspects of the disease. But as we've had advances in science and research over the past few decades, my sense, I'm not a researcher, but it's that the more we learn about the genetics and neurobiology underlying schizophrenia, the more complex the picture seems. And I'm wondering if you can tell our listeners if you could give them an overview of what we do know at this point about the pathophysiology of schizophrenia.

Leonardo Lopez, MD: Absolutely. So, it's hard to say that we know anything definitively, that's true in most of Psychiatry. In fact, I think the thing that we're most confident about is that schizophrenia is in some way intimately involved with disruptions in the transmission of a neurotransmitter called dopamine. And we know that for a variety of reasons that I will get into. The most important reason is that we know that antipsychotics, which are effective in schizophrenia, work by binding blocking dopamine receptors. That's not something that we knew at the time antipsychotics became available. It took over two decades to make it clear exactly how they worked.

But once that was clear, a number of other things became clear about dysfunctional dopamine transmission in schizophrenia patients. For example, we have since that time learned that the most common genetic abnormality in schizophrenia patients is mutations in the D2 receptor or the locus of the D2 receptor. We've learned that schizophrenia patients overproduce dopamine in certain parts of the brain referred to as the striatum and that there's more dopamine present in synapses in that part of the brain in patients, in untreated patients with schizophrenia. We've learned that medications that enhance dopamine transmission, for example, stimulants, amphetamines, Ritalin, et cetera, enhance it to a greater degree in schizophrenia patients than they do in healthy patients. In other words, if a schizophrenia patient takes a stimulant, the dopamine release is substantially more than it is in an otherwise healthy person.

So, we have a variety of indicators that dopamine transmission is at the root of schizophrenia. And this makes sense because dopamine is a neurotransmitter that's implicated, students are commonly taught that it's implicated in reward pathways. But more importantly than that, it's implicated in the attribution of what we call incentive salience. Essentially, it helps you, me, everybody decide what is significant in their environment and what's not. What should they be paying attention to and what should they not be paying attention to, right? What happens if dopamine is overexpressed is that things that, when you are well, you would consider neutral and significant, et cetera, start to take on meaning, right? They start to either be potentially threatening or potentially rewarding. This is a change for you. All of a sudden there are all these significant things happening. People are paying attention to you. People seem to know things about you. This requires some sort of explanation. Why has this happened all of a sudden? It wasn't the case earlier in my life. And that leads to the formation of delusions.

I will say that there are other neurotransmitters involved in schizophrenia. We know that glutamate is involved in psychosis to some degree. We know that because there are hallucinogenic drugs that work via glutamatergic pathways. We also know that there are genetic abnormalities in schizophrenia related to glutamate transmission. For example, changes related to the NMDA receptor locus. That's particularly interesting because in the last 15 years or so, it's become clear that there's an autoimmune disease that works against the NMDA receptor that actually looks quite a bit like schizophrenia at times. We know that there are differences in acetylcholine transmission in schizophrenia patients. It's not clear to what degree those things are sort of secondary and have impact by downstream affecting dopamine transmission or how much they're independent. But we've definitely made a lot of progress in that area, although there's much to learn still.

Daniel Knoepflmacher, MD: We'll talk a little bit more about some of these mechanisms in the medications later, including, I believe, acetylcholine. But I wanted to transition from talking about the underlying pathophysiology to the actual clinical picture. The course of illness in schizophrenia, which you alluded to earlier when you were talking about Kraepelin, that it's something that in a classical picture, I think, spans this slow insidious onset in late adolescence, early adulthood, leading to a chronic debilitating course. Yet there's also the possibility of a more abrupt onset, which then might result in intermittent symptoms with remission and relapse. So, looking at this spectrum and how the disease course looks, can you tell us what is known at this point?

Leonardo Lopez, MD: Absolutely. So, I mean, I will say that this idea that schizophrenia is uniformly this progressive terminal disease is a very common misapprehension. It's one that we owe in part to Kraeplin. Kraeplin in many ways was the most influential psychiatrist of the 20th Century. But one of the downsides of that is that many of the things that he said were taken as canon law for decades and ultimately turned out not to be true. This was one of them.

I think another reason that misapprehension is present is because when you or I or the average person encounters schizophrenia, they're often encountering it in the public settings, on the street, mass transit, et cetera. And they're seeing the patients who have been the most ill for the longest period of time. That's sort of where their impression crystallizes around the illness. So, they have this idea that this is the uniform outcome. But we know at this point from larger epidemiologic studies, that that's certainly not the case. One of the best conducted studies on this came out of the UK, it was called ASOP10, and that study followed patients who had presented in London for a first-episode of psychosis and collected large volume of data on those patients over the course of 10 years.

And what they found at the 10-year followup, and they had several hundred patients. And so, that was not a trivial schizophrenia study, was that although it was the case that 30% of the patients did have continuous evidence of illness throughout their 10 years, the other 70% did not, and they looked many different ways. So, about 50% of those patients had some sort of long episodes, but then with periods of complete remission in between, with no symptoms. About 15% of them had very short episodes, episodes lasting only a month or so, and then very long remission periods afterwards. And 8% of patients had no further episodes at all over the 10-year followup period. These are treated patients, of course, but nonetheless had no further episodes at all over the 10-year period. So, 8% may not sound like a lot, but 8% is basically the odds of rolling a 10, if you have two dice, right? So like you go home, you play Monopoly with your kids, you're going to end up with some 10s. So, it's not that infrequent. It's not the norm, but there are a lot of different possibilities. And we try to communicate these things to family members when they have a loved one, child, et cetera, who presents for the first time that they shouldn't view this course as written in stone, that there are certain things that will make us more likely to roll a 10, if you will, and have a successful outcome.

Daniel Knoepflmacher, MD: Some other recent research, I mean, in the past 20 years has focused on early recognition and intervention in schizophrenia. I believe that was with one of your mentors who's a pioneer in this area, John Kane. What did this work teach us about how we should treat schizophrenia?

Leonardo Lopez, MD: Yeah, wonderful question. So, I would say that, first of all, to the point of early intervention, one of the things we know with, I would argue, great clarity at this point, is that the longer that a patient is ill before they come to medical attention, the worse the outcome. Or another way of saying that, the shorter they are ill before they come to medical attention, the better the outcome. And we understand that from a very large volume of epidemiologic studies. That period of time where someone is ill before they come to medical attention, in the field, we call it the duration of untreated psychosis or the DUP. And we know that the DUP the shortening of the DUP is associated with a variety of outcomes. So, John Kane and others have shown, for example, that a shorter DUP is associated with more robust response to antipsychotic treatment. It's associated with fewer negative symptoms. It's associated with lower cognitive burden. It's associated with fewer days spent in the hospital over the course of the five years following initiation of treatment.

But beyond that, there are even more sort of tangible benefits. One of the most interesting studies on duration of untreated psychosis was done by Tom McGlashan and colleagues in Denmark and Norway and Scandinavia. It was called the TIPS study. And it essentially looked at four counties in Norway and Denmark and randomized two of the counties to just continue as usual, and then two of the counties had these sort of aggressive public health intervention efforts around education of the public, early identification, how do you know that your loved one might be suffering from a first episode of a psychotic disorder, how do we get them into a clinic quickly, if that's the case.

And what they found not so surprisingly is that the duration of untreated psychosis was shorter in the randomized groups with the aggressive early intervention pathway. But in addition to the outcomes I mentioned before, really tangible, meaningful life outcomes down the road were different. For example, if you were in one of those early identification counties rather than the general county, the odds that five years hence you were employed increased by a factor of three. So, simply recognizing the disease early increase the likelihood that years hence you'd be working. So, this is not a trivial thing. We know that the early identification is absolutely crucial.

The other thing that we know with some certainty now, thanks to a study called RAISE-ETP, which was also conducted by John Kane and colleagues at Hillside Hospital, is that patients who receive specialized care in clinics that are designed specifically to care for patients with the first episode of schizophrenia or psychotic illness do better in the long run and in the medium term than they do if they're managed generally in the community. We know that they have better quality of life outcomes. They have better scores on psychopathology measures. They spend fewer days in the hospital, just like I mentioned before. But all of those things are contingent on them having a shorter duration of untreated psychosis. So, the duration of untreated psychosis is in many ways the fundamental variable here. If we can keep that short, we can get better outcomes.

And if you'll allow me, I want to make a point about what short means. In the United States, in the RAISE-ETP, for example, the median duration of untreated psychosis was 76 weeks, which means that the average person, the person in the middle, had hallucinations and delusions for a year and a half before they were brought to see a doctor. Not that something was a little bit off, not that they weren't hanging out with their friends as much, not that they weren't doing as well at school, that they had frank hallucinations and delusions for a year and a half on average. If you were under a year and a half, the good outcomes came. If you were over a year and a half, they did not. I'm oversimplifying obviously for the purposes of the podcast, but that's the general idea. So, this is not stroke. We don't have to recognize it in four and a half hours, right? But we do have to have it on our minds and be aware of the possibility because if we do, it can change the whole course of the patient's life.

Daniel Knoepflmacher, MD: That's an important point, and I want to pause for a second on that because we haven't really talked about prodromal symptoms. And so, you're saying that these are frank positive symptoms. That is the start of that clock for the untreated period. Now, prodromal symptoms are maybe sometimes harder to ascertain, but this really makes a difference once the symptoms are positive. I just wanted to clarify and emphasize that.

Leonardo Lopez, MD: That's exactly right. It really makes a difference once the symptoms are present. I mean, I have this discussion with our trainees all the time. They will say the parents brought the patient in and he was fine until two weeks ago, but he was not fine until two weeks ago. The fact of the matter is that when you interview those patients, almost uniformly, you find that whatever has been affecting their behavior, concerns about persecution or monitoring or poisoning, or whatever it might be that's the sort of characteristic of schizophrenia, have been present for months and months and months. And it simply didn't occur to parents to ask these questions, right? "Why are you spending more time in your room?" is not as powerful a question as "Are you concerned that something bad is going to happen if you leave your room?" Right? There's no reason a parent would be equipped with that second question. And this is why these things go unnoticed for so long, right? So, this is why I do think that more effort focused towards public health identification campaigns around this could have a massive difference.

As you pointed out at the beginning, just from an economic perspective, it's a very expensive disease. A recent study that came out in the Journal Clinical Psychiatry estimated $87,000 per patient per year for schizophrenia, over two and a half million patients in the United States. So, this is far from trivial. And that could be reduced substantially, likely could be reduced substantially with more early identification.

But to do that, we have to equip parents and caretakers and educators and anyone who interacts with young people on a regular basis, because the disease does typically although not always present in the young, to understand what are the warning signs, but also how they can sort of clarify whether the warning signs are something they should be deeply concerned about.

Daniel Knoepflmacher, MD: I want to get into the public health sphere with this, because it's very important a little later. But the point that you're making about early identification, of course, is the introduction of these medications at an early phase. So, let's start there and talk about antipsychotic medications, which are not the only medications that people with schizophrenia take, but they're obviously at the core of treatment.

So, we have a wide variety of agents. You mentioned dopamine specifically, but there's D2 receptor antagonists. They're more complex than just that, I know, but they clearly decrease psychotic thinking. And that was discovered with chlorpromazine. I'm wondering about there now, just to say there's been multiple antipsychotics since Thorazine was still introduced that have come to market. How do people make decisions about which agent to use over another?

Leonardo Lopez, MD: Yeah. So, it's a great question. And I will say that it's sort of like the tip of the iceberg question because there are a lot of questions that you have to ask as followup. I'm going to stick with the idea that this hypothetical patient is presenting for the first time, because the answer to the question actually shifts a little bit if they're presenting after several episodes of the illness. But if in the first time, how do you make the decision about what to choose? The answer to that mostly has to do around what is favorable from a side effect profile and point of view and what's not. Because from an efficacy point of view, although people will get into spirited debates about this, to a first approximation, with one notable exception, all of the drugs are basically the same. They all work in some way or other. At least up until a couple of months ago, we'll talk about that later, every drug that existed worked in some way or another by blocking D2 receptors. We know that, and we know that they had roughly the same impact on hallucinations and delusions. They have different side effect profiles, and you have to think about those in youth in particular, because they will impact both the functional outcome of the young person and impact the likelihood that they'll continue a medication, which is the single most important thing once treatment has started.

The older medications like chlorpromazine, which is known commonly as Thorazine, as well as haloperidol, which is known commonly as Haldol and was the leading market antipsychotic for decades until the second generation of drugs was produced in the '90s, these are effective drugs, but they cause significant physical side effects related to motor functions, stiffening, slowing of the gait, what we would call parkinsonism, stiffness. And then, over time, somewhere in the vicinity of 25-30% of patients, if they're on it long enough, they cause a condition called tardive dyskinesia, which is a condition characterized by involuntary movements actually really in the entire body. They're most commonly noticed by people in the mouth and in the tongue and in the face, because that's what people are looking at. But if you look everywhere else in the body, it's everywhere else in the body too, this can be very debilitating from a functional point of view. If you can imagine just what it is like to go to a job interview and not have control of your own tongue, your prospects are poor. So for that reason, we tend to avoid the older drugs because they have these side effects to a degree that the newer drugs don't. They work just as well for hallucinations and delusions, but they have these side effects that the newer drugs don't.

The newer drugs, they're not that new anymore, I guess. You know, we're talking Clinton administration era drugs. But nonetheless, the newer drugs, risperidone or Risperdal, olanzapine or Zyprexa, aripiprazole or Abilify don't have the same type of motor effects. They don't have zero, but they have much less and they cause tardive dyskinesia much less than the older drugs. They do have their own side effects though. They cause weight gain. They cause metabolic problems that are associated with weight gain. For example, problems with lipids, they can lead to the development of type 2 diabetes. And they also can have very significant impact on libido and sexual function as a consequence of interference with a hormone called prolactin, which is also under the control of dopamine. This is something we don't talk about enough as psychiatrists, I think, actually, particularly in the young. But some of our drugs, especially Risperdal, which is a very, very commonly used antipsychotic, has a profound and uniform effect on prolactin, which will devastate the libido of the patient, which can be really relevant if the patient is 23 years old and has never been on a medicine before.

So for that reason, most of the field now recommends aripiprazole or Abilify as the first-line treatment. It works just as well as the other drugs. We know that from randomized trials. It has a little less effect on the metabolic derangements than the other drugs. It has no effect on the prolactin at all and doesn't cause those kind of side effects.

That said, other second generation drugs, Risperdal, olanzapine, are certainly effective. I wouldn't choose them first line because of their side effect profile. But they can absolutely be used and people will disagree with me on that. And I would accept, their alternate point of view is also legitimate and reasonable.

Daniel Knoepflmacher, MD: So you alluded to this, you know, being the first episode of treatment. We know that often there's multiple episodes of treatment, and there can be treatment-resistant schizophrenia. I'm wondering if you could tell us about another very important medication, which I think you avoided talking about cause you knew we'd be getting to it, which is clozapine, and speak to how that fits into the treatment of schizophrenia.

Leonardo Lopez, MD: Yeah, I certainly can. So, clozapine is by far the most effective antipsychotic medication. It distinguishes itself from every other antipsychotic medication in trial after trial after trial in all patients. But particularly, in patients who have failed one or two medications, or rather I should say patients whom have not responded to one or two previous medications. In that population, clozapine is dramatically better than the other drugs. Clozapine is also, I would argue, the one intervention we have in Psychiatry that we know definitively and without question lowers the rate of suicide in a specific population. It's very clear, both from randomized trials and from epidemiologic data, that clozapine lowers the likelihood of schizophrenia patients specifically committing suicide. As you alluded to in your introduction, their risk is very high to commit suicide, right? Several orders of magnitude greater than someone in the general population. Clozapine reduces that.

 Clozapine's use has been limited for a variety of reasons that I could spend three hours talking about, so I will avoid. But suffice it to say, some of them have to do with the way it was rolled out and introduced in the United States, where it's particularly underutilized. And then, some of them have to do with side effects. I think most psychiatrists believe that it's because of side effects, but I would argue strongly against that. The scariest side effect from clozapine is something called agranulocytosis, where the patient's immune system shuts down. That was first identified in the 1970s in Finland. And the reason I say that I don't believe side effects are the main reason we don't use this drug is that Finland is actually the country that uses more clozapine than anywhere else in the world, despite being the place that identified this. Finland is also the place with the lowest suicide rate among schizophrenia patients in the world, substantially lower than even the rest of Western Europe. And I think the reason for that is because they use clozapine more aggressively. So, most doctors would not introduce clozapine until the patient has not responded to two previous antipsychotic medications. That's sort of the APA guideline. I think that's in general reasonable with the exception of the person who you believe to be at very high risk for suicide.

If you have a patient who you believe to be at very high risk for suicide, they've had serious suicide attempts in the past, they hear voices telling them that they must commit suicide or the world will end, et cetera, et cetera, those are patients that you would think about putting on clozapine much, much earlier in the course of their disease.

Daniel Knoepflmacher, MD: In talking about these antipsychotics, we're targeting positive symptoms primarily. But as you alluded to earlier, a big feature of schizophrenia are the negative symptoms, the cognitive impairment that ensues. What can we do to address these core features of schizophrenia?

Leonardo Lopez, MD: Right. So, the honest answer to that question is right now, very little. This is a place where I think as a field, we have really failed. We have failed because it is a very difficult problem to solve. But we have not solved the problem of negative symptoms in schizophrenia. We have not solved the problem of cognitive dysfunction in schizophrenia. We shouldn't underestimate the solution to positive symptoms. Those positive symptoms are what lead to suicide and violence and dangerous outcomes and eliminating them is very important. But it's the negative symptoms that lead to inability to participate in work, inability to succeed academically, inability to have meaningful relationships. They have a really long term burden on the patient. None of our medications meaningfully impact these right now. You will see some studies here and there that say this anti-psychotic or that one has an impact on negative symptoms, but the truth is that impact is very, very small and not something that you would notice as the average clinician. The same goes for cognitive side effects.

There are some psychosocial treatments that have shown to have some efficacy for negative symptoms and cognitive symptoms. Again, that efficacy is pretty mild. It's not life-changing by any stretch, but it's not meaningless. The one that's the best studied is called cognitive remediation, which has to do with sort of task practice and developing compensatory methods to overcome cognitive problems. That has some positive data for improving cognitive outcomes and negative symptom burden.

There are other interventions such as social skills training that seem to have some impact. More sort of pragmatic things like supportive employment seem to have some impact. But this is an area that we remain sort of at the frontier of. The solution to that problem is over the horizon.

Daniel Knoepflmacher, MD: I think this points to the fact that the treatments as they are most effective are multimodal and longitudinal given the nature of the disease. Thinking about these treatments taken together, where are they most likely to go wrong for patients?

Leonardo Lopez, MD: Yeah. Well, there's a few ways of thinking about that. So, the first place that they're likely to go wrong is if they're not accepted by the patient, right? If the patient doesn't believe that the treatment is useful or beneficial to them in any way, and they stop their treatment. This almost uniformly leads to relapse. And, you know, if you were to ask me at the beginning, what are the two most important things to avoid in the illness? I would say a long duration of untreated psychosis and repeated relapses. Those are the things that modify that prognosis, right?

You made the point earlier that this is a heterogeneous disease with different outcomes, but the outcomes are not random. The bad outcomes are much more likely to occur in people who were sick for a long time before they came to a doctor and who relapsed over and over again. And the way that treatment often goes wrong, I think, is that doctors are not clear enough often with families or patients about the need to really, really commit to these treatments and, frankly, to commit to them for life because removing the treatment can result in relapse, which can lead to an entirely different course of illness for the patient and a much worse one.

The other place that I think we go wrong as physicians frequently is undertreating patients. So, we know from first-episode research that if you treat these patients consistently and aggressively, the overwhelming majority of them will be symptom-free at the end of it. And yet very often as a.

So in this field, we settle for less than symptom free and there's a variety of reasons why I think we do that. One of them is just our own both lack of knowledge and maybe lack of hope about these illnesses. We sort of accept less than perfect, because we think that's the best we can do. It's definitely not the best we can do. And in fact, we know that when we get patients symptom-free, again, their long-term outcomes are much better.

So, I think that the main places that we go wrong as a field are sort of not going far enough and trying to get the patient completely well and not being clear enough about the need to engage in treatment all the time. It's a lifelong illness. even if the patient is one of those patients that rolls a 10 and doesn't have an episode for five years, that's because the patient has been engaged in treatment, right? And so, that has to stay the case and the patient can have a good outcome.

Daniel Knoepflmacher, MD: So, given the socioeconomic vulnerability of this population, you talked about the need for public programs and systems to intervene early. And there's so much intersectional burden with this most marginalized population. We're talking about people who often are unhoused and don't have the support, you know, and they have the burden of this disease. Can you speak to public policy? Because this is something which is even more important with this diagnosis than many others. And what does that look like both in New York City and nationally?

Leonardo Lopez, MD: That's a great question. You know, I've been talking a lot about need for public policy measures to intervene early to create systems for early detection and early intervention, because I think that's where the long-term benefit comes. Most public policy discussion around schizophrenia is around the patients who have been ill for a long time and clearly are not functioning in an optimal way, and that we haven't found ways to optimize functionally.

So in a way, we need to help those patients, and everyone who's an inpatient psychiatrist helps those patients every day. As an investment, we would be wise try to invest early, so that we don't have to make all these late investments. The public policy discussions in New York City, I think, have accelerated in the last few years. It's been a major initiative of the mayor to try to find some way to address what he and others in the administration see to be the problem of untreated people with psychotic illnesses who, as you say, are unhoused and are on the subway or are in public places and often creating a disturbance. His solution to that problem has been, depending on your viewpoint, to encourage treatment or to encourage confinement. I won't come down on, which is the proper way to interpret that. But certainly, his point of view is that we need to do more to get the patients that we see in public who are clearly struggling into hospitals. There's no question that hospitals can benefit these patients, but I would argue that once we're at the point where we have to drag patients into the hospital for the sixth, seventh, eighth time, that whatever policy measure we have put in place is a failure, right? If we have gotten to that point.

Even more to the point, we know that if we have to aggressively staff our jails and prisons with psychiatrists and psychologists and nurse practitioners, then that is representative of a public policy failure, because it means that many of these patients have found their way to jail or to prison. And we know that that is the case in the United States. I think most people know that the largest provider of mental health services in the United States is the Los Angeles County Jail System. Cook County and New York County are not far behind that. And that's a consequence of the fact that patients have been left untreated and unattended to for a very long period of time and dangerous things have resulted that have put them in prison. We don't have time for that, but once they get to prison, It's a whole different public policy disaster that unfolds.

So, I guess what I would say in summary is most of the public discussion about this has been what to do right now about the people with this illness that we have failed. And I would argue that although that is very important, we should shift some of our attention to what to do to prevent us from failing so many people in the first place.

Daniel Knoepflmacher, MD: I totally agree. What's visible that is attracting the attention, not all of the behind the scenes systems and support and work that has to go in to really making a difference. Leo, we're running out of time, and I'm going to condense a few things into one question.

 You alluded to a new medication that has come out recently. It's called Cobenfy. I don't even know if I'm pronouncing it correctly. I know one of my patients with schizophrenia has been bringing it up in every session and we've talked about how we're going to be cautious and wait in approaching this medication. But I wondered if you could speak briefly about that. And then if you could, in as little time as possible, talk about what other promising things you think may be available for people suffering with schizophrenia.

Leonardo Lopez, MD: Yeah, I will do just that. I'm cognizant of the time. So, xanomeline and trospium or Cobenfy is a new medication for schizophrenia, which is interesting for the most part, because it works via a different mechanism. It does not block D2 receptors. It's actually the first FDA approved antipsychotic that clearly does not interact with the D2 receptors in any way. It acts at M1 and M4 acetylcholine receptors and is agonist at those receptors.

Now, that said, they probably, at least to some degree, work by downstream from that affecting the transmission of dopamine. But nonetheless, they work via a different mechanism and sort of exciting because it opens the door to new research possibilities and perhaps more efficacious drugs or less burdensome drugs in the future. That said, there's not a lot of reason to believe that this drug is more efficacious or less burdensome than any of the drugs that we already have. It was FDA approved on the basis of two randomized trials that were both five weeks in duration. These are very short trials for schizophrenia medications. And as a consequence of that, we have really very little to no knowledge of what these medications do in the long term.

That's relevant for a lot of reasons. One of the reasons it's relevant is that I told you at the beginning that one of the most serious side effects, tardive dyskinesia, of first generation antipsychotics doesn't occur until months after the person has been on the medication. I'm not suggesting that Cobenfy causes tardive dyskinesia. In fact, if I had to bet, I would say it does not. The larger point is we don't really know how this will play out in the long run. We know that it reduces positive symptoms to the same degree that other antipsychotics do. And we know that it works by a different mechanism. So, that's exciting. It's something new after eight decades of the same. So, I think there's reason for optimism there.

There are other treatments, neuromodulatory treatments that are being tested for schizophrenia that also provide some hope for different avenues to success. Transcranial magnetic stimulation, which has been well studied for treatment-resistant depression and also for obsessive compulsive disorder, is starting to make its way into the schizophrenia research field. Focused ultrasound is very on the cusp of treatment that's being researched by some of our colleagues here in New York City and has promise. Older neuromodulatory treatments like ECT, we know to work very well in schizophrenia. So, there are a lot of reasons for optimism about treatment in the future.

But I will also just say in conclusion that we should not focus all our attention on those to the exclusion of the treatments that we know are very effective, right? Clozapine is very effective. Keeping people on medication is very effective. Intervening early is very effective. I would implore psychiatrists to focus on these things, on the things that we know now work and work well and work better than other things. That's how we'll have the greatest impact now while we wait for the next generation to supply us with new tools.

Daniel Knoepflmacher, MD: There's still a lot of work to be done to get us to the point that we're actually doing the things we do now well. So, that's a really important point. Well, Leo, I hate to stop right now because there's so much more we could cover. I mean, you and I are usually talking about much more boring things related to our work as administrative leaders. So, it's nice to have this chance to speak with you about Psychiatry, especially schizophrenia, which I know is a topic you are really interested in and experienced in. So, great to have you on the podcast. Really, thank you so much for joining me today.

Leonardo Lopez, MD: My pleasure. It was a real pleasure being here. I'm always happy to talk about this topic. And you're exactly right, as we move forward in our careers, we somehow managed to talk about psychiatry less and less. So, these conversations sort of remind us why we do this work and why we love it.

Daniel Knoepflmacher, MD: It's a big part of why I'm doing this. No, yeah, absolutely. Well, thank you to all who listened to this episode of On The Mind, the official podcast of the Weill Cornell Medicine Department of Psychiatry. Our podcast is available on many major audio streaming platforms, including Spotify, Apple Podcasts, YouTube, and iHeartRadio.

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