I hope you're having a good afternoon and welcome to this upcoming exciting update session. The topic of which is an overview of all antipsychotics, how far have we come? My name is Vikas Gupta. I am a member of the Clinical Updates Committee. I'll be moderating this session with my co-moderator, Dr. Mata, who's also a member of our subcommittee. We have our eminent speaker, Dr. Cain, and I'll be talking briefly about him as regards to his background. John M. Cain, MD, served as chair of psychiatry for 34 years at the Zucker Hillside Hospital and is currently the co-director of the Institute of Behavioral Research at the Feinstein Institute for Medical Research. He also served as the inaugural chair of psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra Northwell for 12 years. He's been the principal investigator on 23 U.S. National Institute of Health grants focusing on schizophrenia, psychobiology, and treatment recovery and improvement of quality and cost of care. He's the author of over 925 peer-reviewed papers. Please put your hands together for this very exciting talk by Dr. Cain. Thank you so much. It's a pleasure to be here. And before I get started, I'm always struck by the fact that when we do sports, we stretch beforehand. When we do something intellectual, we don't do that. So I'm going to ask you to do a little stretch with me. I'd like everyone to pick a number between 1 and 10. Now multiply that number by 9. Now take the two digits that you have and add them together. Now subtract 5 from that number. Now take the number that you have and convert it to a letter. So 1 would be A, 2 would be B, 3 would be C, and so forth. So now you have a letter. I want you to think of a country that begins with that letter. Now I want you to take the second letter of that country and think of an animal that begins with that letter. How many people have elephant? Not bad, okay. There are three other countries besides Denmark that begin with D. Dominican Republic, Dominica, and Djibouti. And Dubai is not a country. Also I want to tell you a little story from Times Square since we're very close to Times Square. And there was a man standing in the middle of Times Square going like this. And he was blocking traffic and people were honking their horns and starting to yell. And so finally a policeman comes out and he walks up to the man. He says, what is that? And the man says, it's bullshit. And the policeman says, what are you doing? And he says, I'm making a cop. So obviously the policeman is angry and he arrests the guy and he brings him down to the station house. The next morning he's brought before a judge and he's sitting in the courtroom going like this and the judge says, what is that? The man says, actually your honor, it's bullshit. And the judge says, what are you doing? He says, I'm making a judge. So the judge says, obviously this man is mentally ill. We need a psychiatrist. So we call him the psychiatrist. The man is sitting in the consultation room going like this. The psychiatrist sits down and he watches for a minute. He says, I bet that's bullshit. The guy goes, yeah, yeah. And he says, I bet you're making a psychiatrist. No, I don't have enough bullshit for that. So, um, one disclaimer before I get started, I'm going to be talking about antipsychotic drugs, but I'm really going to be talking about schizophrenia. So I'm sure, I'm sure some of you are very interested in the role that antipsychotic drugs play in the treatment of other disorders, but I'm really going to focus on schizophrenia. So keep that in mind. First my disclosures, I've been a consultant to a number of the pharmaceutical companies involved in developing antipsychotic drugs. This is not a well-known quote from Kafka. To write prescriptions is easy, but to come to an understanding with people is hard. And we, we certainly, I think have come a long way in terms of shared decision-making that we are in a much better position to have very open conversations with our patients, to provide them and their families with the information that they need to make informed decisions and to have them partner with us in terms of making those decisions. But I'm going to be talking about some of the information that we also need to share with our patients in order to enable them to make informed decisions. And it's not as easy as it sounds. So when we talk about schizophrenia, we still struggle with a lot of unmet treatment needs. For example, earlier illness identification. So the duration of untreated psychosis in the US at this moment in time is probably a median of a year. So we have many people in the community experiencing hallucinations, delusions, and other psychotic signs and symptoms and not receiving any treatment for many, many months. And the concern there is that that duration of untreated psychosis has also been associated with poor outcome. The longer the duration, the poorer the outcome on a number of different measures. How do we reduce the duration of untreated psychosis? That is an enormous challenge. A lot of it has to do, I think, with mental health literacy, with access to care, with the stigma associated with mental illness, particularly with an illness like schizophrenia. But we have to do a better job of that. There are enormous efforts underway to try to better understand the prodromal phase of schizophrenia, the adolescents or young adults who are experiencing what appears to be early signs of schizophrenia. They don't yet meet diagnostic criteria. But can we do something to diminish the likelihood that they will develop a full-blown psychosis? We have comorbid conditions. Many of our patients are smoking marijuana. We now have a challenge across the U.S. with some states legalizing marijuana. This is a drug that is not necessarily a good idea for people with a diathesis towards schizophrenia to be using. But this, again, is a challenge. We have high rates of non-adherence to medication taking. And again, that's not just associated with mental illnesses. It's true in every area of medicine. Taking medication on a chronic basis, whether it's diabetes or hypertension or asthma or epilepsy or schizophrenia, is a major challenge. And we do not do a good job of recognizing that. We have negative symptoms in schizophrenia, for which we still do not have FDA-approved treatments. We have cognitive dysfunction. And that, along with negative symptoms, really account for a lot of the disability that we see in patients with schizophrenia. There are treatments under development that hopefully will enhance cognition and improve negative symptoms, but we have no approved treatments yet. We need psychosocial interventions to enhance quality of life and functioning. And many patients, sadly, do not have access to a full range of psychosocial interventions, including supported education, supported employment, individual therapy, family therapy, family psychoeducation, and so forth. Many of our patients struggle with residual symptoms. We'll get into a discussion about treatment-resistant schizophrenia, but this is an enormous challenge. Only 30% or more of our patients would come under the category of treatment-resistant, not responding adequately to antipsychotic drugs. We still have a long way to go in terms of providing the psychoeducation that patients and families need about this illness, which is very complicated, very frightening at times, and about which people need a good deal of psychoeducation. So these are just some examples. Even those patients getting guaranteed medication, by that I mean long-acting injectable formulations, which I'll be talking about, even some of those patients will still relapse. And we don't fully understand why someone who's receiving an adequate dose of a dopamine receptor antagonist, and we know that they're actually getting it, why would they still relapse? That's something we also need to understand. If you have an empty seat right next to you, please raise your hand. So please move forward and take these seats. If you have an empty seat right next to you, please raise your hand. Please come up forward, and there's enough seats for you to seat yourselves. Long talk. Please keep your hands up for folks so they can see the seats available. Thank you so much. Thank you, Dr. King. There's a number right over here. There's quite a few. If you could keep your hands up until you have a neighbor. If you sit close, I promise I won't call on you. Thank you. Thank you, guys. So our goal in treating our patients is to bring about recovery, and by recovery we mean functioning in the community, leading lives that are relatively normal, being able to do many of the things that we all take for granted, having a job, going to school, having friends, having intimate relationships. So this is a systematic review and meta-analysis of recovery in schizophrenia that was done a number of years ago, but I don't think the results have changed very much, and unfortunately only one in seven individuals with schizophrenia met criteria for recovery. So we need to do a much better job in bringing about recovery for our patients. We know that antipsychotic drugs for the last 60 or so years have played a very important role in helping to mitigate some of the signs and symptoms of schizophrenia, preventing relapse, enabling people to live in the community as opposed to in institutions. The 1950s, within about 75 miles of Manhattan, there were about 150,000 people living in psychiatric institutions, really quite extraordinary, and the introduction of antipsychotic drugs really helped to reverse that. We know that antipsychotic drugs are superior to placebo, but in some studies the superiority is not as dramatic or as profound as we would like, and we do see that over the years, response to placebo has increased in the context of clinical trials. So when we develop new medications, we have to do studies to submit to the Food and Drug Administration to show, to demonstrate efficacy and safety, and to demonstrate efficacy we often compare medicines to placebo. The effect of the medicines hasn't changed over decades, but for some reason response to placebo in these trials has gone up and up and up, and we don't fully understand that, and I'll show you, we'll talk about a recent example of that. We have a large array of different antipsychotic medications available to us now, both first and second generation antipsychotic drugs. Some people feel that distinction has outlived its usefulness, but it still is something that you'll see in the literature. The differences between these medications are mostly in terms of tolerability, less in terms of efficacy. The efficacy differences are gradual rather than discrete, but the differences in side effects are more marked. And this is a seminal meta-analysis that was published by Stefan Leut's group in Lancet in 2019. We see that clozapine is the most efficacious antipsychotic drug in this meta-analysis, and we'll talk more about clozapine later on. It still is the only antipsychotic drug that has regulatory approval for the management of patients with treatment-resistant schizophrenia, but it is also grossly underutilized, in my opinion, for a variety of reasons. What do we know about the use of antipsychotic drugs for the prevention of relapse, and in turn re-hospitalization? So this is another meta-analysis from Stefan Leut's group published in The Lancet about 10 years ago, looking at multiple studies comparing antipsychotic drugs to placebo in the context of relapse prevention. The number needed to treat significant superiority for antipsychotic drugs, the number needed to treat is three, which in medicine in general is a very, very powerful effect. Yet we still hear debate about the need to continue antipsychotic medication in patients with schizophrenia, and this is a debate that I personally find a little bit frustrating. I think we have an overwhelming amount of data to suggest the value of continuing antipsychotic medication among patients with a clear diagnosis of schizophrenia. You'll see some studies that include patients with psychotic disorders. I am not talking about people with brief reactive psychosis or substance-induced psychosis or schizophreniform disorder. I'm talking about people with an established diagnosis of schizophrenia when I talk about the indications for antipsychotic drugs, so please keep that in mind. Why are we so concerned about relapse, about preventing relapse? Well, I think it's obvious that a relapse where someone experiences an exacerbation of psychosis and often ends up in a hospital can be not only a traumatic experience but interferes with recovery, interferes with vocational and social adjustment, and increases family burden and impacts people's social relationships, et cetera, et cetera. You think about a young person who has a first episode of schizophrenia, responds well to treatment, goes back to school, stops taking his or her medication, has another psychotic episode, ends up back in the hospital. If this happens a couple of times, think about the implications or the impact of that on that individual's life in terms of disruption of jobs or school, personal relationships, and can you get back to those states once you've had several episodes of psychosis? Your friends might begin to back away, your family becomes discouraged, you no longer find it as easy to get back to school or find a job, and so what I'm suggesting is that in the early phase of this illness that we call schizophrenia, just a couple of relapses I think can be very devastating, so we want to do everything we can to prevent that. Another reason are these data from, this was a study done by Hiroyoshi Takeuchi when he was a fellow at the University of Toronto, where he studied 130 first episode patients who were treated basically with the same medication when they experienced a relapse. The relapses were largely due to discontinuing medication. Patients were then restarted on medication, in most cases the same medication they had the first time, and what we see here is a significant reduction in the likelihood of their responding to that treatment the second time around. Same medication, same patient, not responding as well in the second episode as they did in the first episode. Now is this sort of the trajectory towards treatment resistance? This has not been studied on a long-term longitudinal basis with multiple, multiple relapses, but it is in my opinion very concerning. This is a unique study, no other study has done this on this scale. We hear people talking about the desire to discontinue medication, and of course everyone would love to discontinue the medication that they're taking. The medicines that I have to take, I would certainly rather not be taking them. But we also have to understand the risks associated with medication discontinuation, and it's very appealing, I think, to be able to say to patients, well, let's try to discontinue your medication, or we'll lower the dose significantly, then we'll discontinue it. But we have to also responsibly explain to patients and families the risks associated with that. This study that's on the slide in front of you now represents a 20-year nationwide follow-up of thousands of patients in Scandinavia who were treated for the first time with antipsychotic drugs and then divided into different groups in terms of those who continued to take medication, those who did not take medication, et cetera. And what we see is that those patients who continued to take medication, and we're talking about individuals followed for roughly eight years, it's not just a year or two. The discontinuation of medication was associated with a significant increase in the risk, not just of hospitalization, but also of death. And there was no time where it appeared to be safe for people to discontinue taking their medication. Again, these are people with a diagnosis of schizophrenia. So I think we're hard-pressed to identify a point in time in a patient's trajectory as to when it's safe to fully discontinue medication. And as I said, the outcome measures in this study were psychiatric re-hospitalization or death. There's still a general belief that after the first episode of schizophrenia, the risk of relapse decreases over time in patients who are stabilized. That is not necessarily the case. One of the things that we've seen with antipsychotic drugs is that those patients who are taking them, those patients who are adherent, maybe because they're on a long-acting injectable, but those patients who are currently taking antipsychotic drugs have a decreased risk of discontinuation of other drugs that they need to take for medical reasons, such as statins or antidiabetics or antihypertensive beta blockers, et cetera. So we can promote adherence. And it can have a ripple effect with other medications as well. What about mortality in patients with schizophrenia? I mentioned the Scandinavian data a moment ago where I said one of the outcomes was death. This is a meta-analysis looking at a variety of antipsychotic drugs, including clozapine. What these data suggest is even antipsychotics with elevated cardiometabolic adverse effects, such as clozapine, can reduce overall mortality, which is not counterbalanced by larger but supported by reduced cardiometabolic-related mortality. So earlier use of LAIs and, if indicated, clozapine in individuals with schizophrenia I think is a very important consideration. This is another study utilizing the Scandinavian data. One of the advantages of countries that have national registries and national health insurance is that you can follow large cohorts of patients and interpret findings regarding outcome and factors that contribute to those outcomes. So in this study, which also involved over 20,000 patients, among individuals with first episode non-affective psychosis, antipsychotic treatment with long-acting injectables in particular was associated with about a 30% to 50% lower risk of work disability. So here we're not just talking about relapse and re-hospitalization and death, we're talking about work disability. That is a very, in my opinion, a very important finding. Again, involving first episode patients. Now this is a relatively recent publication, Lancet Psychiatry 2023, where Toby Pillinger and colleagues developed a sort of a heat map which provides summations of side effects scores and efficacy in terms of a variety of different antipsychotic drugs. And if you want to look at this in more detail, as I said, it was published in the Lancet Psychiatry, Pillinger et al, 2023. I'm not gonna go through this in great detail, but for those of you who are interested in comparing the proportion of different adverse effects, whether it's weight gain or Parkinsonism or sexual side effects or anticholinergic side effects, and then overall efficacy, this kind of heat map can give you a sense of where different medications fall. And I think we are not going to, all of us, use all of these drugs. I think you have to identify a handful of drugs about which you are knowledgeable and comfortable and use those most appropriately for the patients that you treat. What are patients and families most concerned about in terms of adverse effects? So I mentioned early on that the differences among many of these drugs in terms of efficacy are not that great, with the possible exception of clozapine, but the differences in adverse effects are more marked. I think as part of the process of shared decision making, we need to be able to talk to our patients about what is their perception of the medication that they're taking, of the adverse effects that they're experiencing, and what adverse effects are most troubling to them. That's a conversation that we should have before we even decide which medication to use, because that can help us, with the patient, make a more appropriate decision. So this slide is adverse effects considered by relatives to have the most negative effect on the patient's quality of life. The relative said sedation and weight gain. What did the patient say? Weight gain, somnolence, and insomnia. So there's a certain amount of concordance between patients and families, but again, it's gonna vary from patient to patient, depending on what their own personal experience is, what their, et cetera, and these are conversations that need to be informed by shared decision making. I wanna comment a little bit, excuse me, on therapeutic drug monitoring. What we mean by that is our ability to draw a plasma level and measure the concentration of a particular medication in that patient's system. We know that antipsychotic drugs vary enormously in terms of absorption, bioavailability, metabolism, et cetera. We all differ, if we all took the same dose of the same drug, I might have a plasma level that is 10 times higher than a plasma level that one of you has. We do not study that as routinely as we should, and I know that some of this has to do with the fact that if we send a laboratory request for a particular blood level, it may take many days for us to get it back. But I think if we were all clamoring for a more rapid turnaround, and we felt this was very important to us clinically, I think we would perhaps see some more opportunities. But what are the indications for therapeutic drug monitoring? Adherence, lack of response. Many patients are labeled as treatment resistant when in fact they weren't taking the medicine as prescribed or they didn't have a therapeutic blood level. Why does a patient relapse when they're supposedly taking medicine? Is it because they're not taking it or because they have a sub-therapeutic blood level? Patients vary enormously in the extent to which they develop adverse drug reactions. There's concern about some generic counterfeits that we understand occurs from time to times. We might wanna check on blood levels. We have genetic abnormalities. Some patients are very rapid metabolizers. Different ethnicity. Changes in biophysiological status, like pregnancy. We have elderly children, et cetera. Hepatic and renal deficits, inflammation, bariatric operations, people who go from a non-smoking to a smoking status or vice versa. All of these things can affect blood levels. So it's something that we should think about more often, in my opinion. And there are some valuable reviews if you want to read more about this. One published in the Journal of Clinical Psychiatry. So motivational interviewing, I think, is a very important component of what we do. We have to help our patients in terms of psychoeducation, but also help motivate them to take the actions that they need to take to improve their quality of life. And that includes taking medication. That includes participating in treatment of various types. Shared decision making, I keep mentioning the importance of that. We want to build a partnership with our patients. We want to elicit what's important to them. You know, what are their goals and objectives? What are their personal desires? We want to give them the right of self-direction, but we also want to provide the guidance that's necessary from a professional who is familiar with the data, which is very, very important. Right now, a lot of our treatment of patients with schizophrenia, let's just focus on in the hospital for the moment. If someone's admitted to hospital in an acute psychotic state, you will try a particular antipsychotic drug. If that doesn't work, what do you do? Do you try another one? How long do you wait before you decide it's not working? These are day-to-day clinical questions that I think many of us still grapple with. Many of our hospitalizations are very brief now. Someone might only be in the hospital for 10 days or two weeks. Do you decide that a medicine isn't working within that timeframe? And if so, what do you do? So I want to talk for a moment about the early-onset hypothesis of antipsychotic drug action. So when I was in training, there was a notion that it took antipsychotic drugs a couple of weeks to work. So-called depolarization blockade was an explanation for that. Turns out that that's not the case. Then antipsychotic drugs actually can show a therapeutic effect very quickly within a day or two days. We can see important improvement in our patients. It also turns out that the response that we see within two weeks is a very powerful predictor of the response that we're gonna see after six, eight, or 12 weeks. And this has not become a clinical guideline yet, but it's something that you should think about. These are data from one of the larger studies that was published by Bruce Kynan in neuropsychopharmacology, where he demonstrated there are two groups of patients, those who respond by at least 20% on a PANS total or BPRS within two weeks, and those who don't. And those who don't, which are the red triangles, never catch up with those patients who are early responders. So the question becomes, what do we do for the early non-responders? Should we switch medication after two weeks? Some people would say we should go to Clozapine after two weeks, but unfortunately, the studies have not been done that we need to better inform us about this issue. But this effect has been shown in multiple studies now, including a meta-analysis that was done by the group in Munich, 34 studies, almost 10,000 patients, showing that patients that are not even minimally improved by week two are unlikely to respond later and may benefit from a treatment change. Of course, then the question becomes, what do you change the treatment to? So this is another more recent study suggesting that it can be efficacious to change from one drug to another drug. Not all studies show this. Some studies show that after early non-response, it doesn't matter whether you keep the person on the same drug or switch to a different drug, the response is the same until you go to Clozapine. This study suggests that there was some advantage to switching medications. Treatment of negative symptoms. As I said earlier, we do not have any approved, any regulatory approved treatments for negative symptoms. There is one study with Cariprazine that showed superiority to Risperidone in negative symptoms, but that is not an FDA approval or an indication. There is a drug in Europe, which has been shown to be helpful in treating negative symptoms in comparison to placebo, Amisulpride. That's in lower doses than is generally used to treat psychosis. That's not a drug that's available in the United States. One of the debates that we've witnessed recently, as I mentioned, is the desire to reduce dosage. Not necessarily stopping medication, but reducing dosage as much as possible. This meta-analysis suggested that continuing antipsychotic treatment at standard doses or switching to a different antipsychotic are similarly effective treatment strategies, whereas reducing antipsychotic doses below standard doses is associated with higher risk of relapse than the other two strategies. So that should be limited to selected cases. For example, patients that are having difficulty tolerating a particular dose of an antipsychotic drug, but to reduce the dose for other reasons may not be appropriate, may not be wise. I wanna share with you a study that we published a few years ago that was funded by the National Institute of Mental Health. This was called RAISE, Recovery After Initial Schizophrenia Episode. This was a very large initiative that NIMH funded to determine whether or not what we call coordinated specialty care or what in other countries is called early intervention services when applied to people in the early stages of schizophrenia, whether that produces a better outcome than other approaches. So what do we mean by coordinated specialty care? Well, we called our model NAVIGATE. It's team-based. It involves shared decision-making. Individual therapy, which focuses on strength and resiliency, motivational enhancement, teaching skills, collaboration with natural supports. In addition, family psychoeducation, psychopharmacology, and employment-supported education, having a specialist who can help the individual get back to school, find a job, and not only get back, but sustain that engagement. So those are the components of NAVIGATE. And this was a treatment model developed with consultation from experts all over the world. And then NIMH wanted us to do a real-world study where we went into clinics across the United States and trained people to deliver this model of care and then did a controlled comparison with usual care, usual care meaning clinicians doing whatever they please. And we did this study in 404 first-episode patients at 34 clinics across the United States. And what we showed is that compared with usual care, those individuals receiving coordinated specialty care, again, we used the term NAVIGATE to describe it, were significantly more likely to remain in treatment. They had significantly better quality of life. That was the primary outcome measure was quality of life. They had less severe psychotic and depressive symptoms. They had more gains in working or going to school. They were more likely to receive a prescription that conformed to treatment guidelines. They experienced significantly fewer side effects. So there were a number of positive results from these early intervention services, coordinated specialty care. We also were able to demonstrate that we could introduce this model of treatment into real-world clinics across the United States without any additional financial reimbursement. They were basically constrained by their usual insurance or Medicaid or what have you. However, there was one caveat here, and that is when we looked at the rate of hospitalization among these young first-episode patients, one out of every three patients was hospitalized within the two years, two years of follow-up. So despite all of those other gains and those superiorities over usual care, we did not see an advantage in terms of hospitalization. And one out of every, if you think about, as I said earlier, a young person with first-episode schizophrenia being hospitalized, what that means, what the consequence of that, one out of every three of these patients were hospitalized within the next two years. That was very disappointing to us. But it also obviously raised some questions. So let me first share with you, this was a meta-analysis that we published with Christophe Carel, where we looked at all of the studies that have been done around the world of early intervention services compared to usual care, like the study that I just described. There were 10 such studies involving over 2,000 patients. And when we combined these studies together in a meta-analysis, we saw that, in fact, early intervention services was superior in reducing the risk of hospitalization. However, what was interesting is if you look at the actual numbers, in the experimental group, which is early intervention services or coordinated specialty care, one out of every three patients was hospitalized within a year and a half or two years. So exactly what we found in our study. The difference in our study is that the control condition did better than the control condition in these other studies that were done around the world. And we could talk about why that might be, but the point I wanna make here is that even with state-of-the-art care, which is what early intervention services represent, even with that, we're seeing one out of every three of these young people hospitalized within a couple of years. That is just not good enough, in my opinion. Why is that happening? Well, we went back and we looked at our data. We tried to identify risk factors for hospitalization. Some of them are not surprising. Substance misuse, substance abuse. Duration of untreated psychosis. But very importantly, patients' beliefs about the value of medication. We did not do any fancy-schmancy measures of adherence, but we did ask the patients some very simple questions about how they felt regarding the taking of medication. And how they responded to those questions was a significant predictor of hospitalization. So again, that's probably not a surprise, right? If patients stop taking their medicine, they're gonna increase their risk for hospitalization. Excuse me. So one of the challenges we have in medicine in general is we don't have good methods to assess adherence. What do we usually do? We usually ask the patient, are you taking the medicine? We may or may not get an accurate answer. Not that the patient is necessarily being dishonest. He or she may not remember the extent to which they missed their medication. I've had situations myself where, you know, one evening or something, I'm asking my, did you take the medicine or not? I'm not even sure. So we rely on patient self-report. Sometimes we'll ask the family. They don't necessarily know. We might observe pill-taking. We might go to the patient's home and count the pills left in the medicine cabinet. There is digital monitoring that's now available. There are smart medications that have been marketed with ingestible event markers that tell you when the medication is swallowed. We can do a drug blood level, but again, that's not something we're gonna do frequently. Or we can use long-acting injectable formulation. So if you haven't gotten a sense yet that I'm a big proponent of long-acting injectable formulations, you are going to get that sense. It seems to me that once we've decided that someone needs medication or should be getting medication, then the question becomes how do we ensure that they're going to get the benefit of that medication? This is not about whether the person needs medicine or not. I still hear people say, well, Dr. Cain, you're recommending a long-acting formulation. What if the patient doesn't need the medicine? That's not the point. The point is we have established the need for the medication. We've established the indication. Now we're just saying, what's going to increase the likelihood that the patient actually gets the medication? So we could talk about many studies that have looked at different methods of measuring adherence. They're usually all wrong. They don't correspond to ground truth. What happens when we don't detect non-adherence? Well, we may change the medicine because we think it's not working. Or we'll increase the dose because we think the patient needs more medicine. Or we'll add a second antipsychotic drug. Or we'll say the patient is treatment-resistant. So it's very important that we have a better grasp on non-adherence. This is a study that we did with Leo Lopez, who happens to be in the audience, looking at patients coming to an emergency room with psychotic relapse. And investigators drawing a blood level to see whether or not the patient had a therapeutic drug blood level, and at the same time asking the attending physician whether or not he or she thought the patient was adherent. And what Leo found was very interesting, that nearly 20% of patients assessed as adherent had undetectable plasma levels. But equally interesting, 25% of the patients who were assessed as non-adherent had therapeutic levels. So here we are with a patient presenting to an emergency room in a psychotic state, and we don't really know whether the patient was taking the medicine or not. That would be an important piece of information, right? If you're deciding what the next step of treatment should be. So long-acting injectable medicines have been available for a very long time. There are a large number of studies. We recently, with Taisho Kishimoto, reported a meta-analysis in Lancet Psychiatry, where we looked at the three different methods of studying long-acting injectable medicines. The randomized controlled trial, the so-called mirror image study, or the cohort study. And regardless of the design that you use, the meta-analysis was consistent in showing significant superiority for the long-acting injectable formulation. Despite that, clinicians primarily use long-acting formulations later in the patient's illness. So we're waiting for patients to experience multiple relapses, and then we say, hmm, maybe this patient would benefit from a long-acting formulation, because they haven't been taking their medicine consistently. That is way after the fact. We should be doing everything we can to prevent those relapses. Instead, I hear clinicians say, well, I'm gonna wait until the patient shows me that he's non-adherent by relapsing, and then I'll start a long-acting injectable drug. That seems a very unfortunate perspective to have. This, I think, was a very impactful study that was also done in Finland by Jari Tohonen's group. Two and a half thousand patients hospitalized for the first time with a diagnosis of schizophrenia. What they reported was that half of the patients were not taking their medicine within a month or two of leaving the hospital. They didn't get their prescription filled. Half the patients within a month or two of leaving the hospital. Those patients who received a long-acting injectable formulation had a significantly lower risk of being hospitalized. The first point is that only a minority of patients are actually taking their medicine after a couple of months, but if you use a long-acting injectable medication, you have a much greater likelihood of being able to prevent a relapse or rehospitalization. So this was another study that we did. This was an investigator-initiated study supported by Lundbeck and Otsuka. And we wanted to do a real-world study to see if we could go into so-called real-world clinics and train the clinicians on how to utilize long-acting medications and also how to have a conversation with the patient. Because this is often where things break down. If I say to my patient, you know, gee, I think you would be better off getting injections, the patient says, no, I don't like injections, I don't wanna do that. What do I say at that point? Do I just give up? And a lot of clinicians do. They just say, okay, never mind. This is a conversation that needs time and a degree of patience and to be able to share data and answer frequently asked questions. So that's what we did. We went into these clinics. We had 39 clinics participating in this study, real-world clinics across the US. In half of the clinics, we went in and trained the staff. And we also did role-playing. You know, I'm gonna pretend to be a patient. You're gonna suggest a long-acting formulation to me and I'm gonna give you a really hard time. That's a lot of fun. And then we're gonna see how you respond to that. And then we're gonna switch roles and you're gonna practice. And the clinicians really enjoyed that. They thought it was a lot of fun. And I think it was very educational because what we saw when we actually did the study is that 86% of the, these were first episode and early phase patients, young people. 86% of them agreed to a trial of a long-acting injectable drug. And people are shocked when we say that. It's like, how did you do that? Well, that's how we did it. We trained the staff. We practiced. We did role-playing. That was only the first phase of the study. That's what made the study possible. Then we looked at hospitalization. So those patients who were in the clinics where we trained the staff had a significant lengthening in the time to hospitalization with a number needed to treat of seven, a 44% reduction in the incidence risk of first hospitalization. That was the primary outcome measure. So this showed that you could go into clinics and train the staff and really produce a very good outcome. Patients will accept the treatment. You could really produce a very good outcome. Now, not every study is positive. In this study, ULAST was published in Lancet Psychiatry. I recommend that you read the letter that we wrote in response to this study because I believe there are some major, major flaws with this study. But they reported they didn't see a difference in the rate of discontinuation between long-acting injectable medicines and oral medicines. Very different design, random assignment. They didn't talk about how many patients refused to participate in the study, which is always a very big deal when you're doing randomized controlled trials because most patients do not want to participate in a randomized controlled trial, et cetera, et cetera. I mentioned earlier that patients who are receiving long-acting injectable medicines are not necessarily free from the risk of relapse. They also can, we don't understand why. As I said, why should someone receiving adequate dopamine receptor antagonism, why should they still relapse? But they do, about 20% of patients will relapse even with a long-acting injectable medicine. But that's much lower than what we would see with oral medication. They are also much less likely to discontinue the medication. One of my colleagues, Jose Rubio, showed that during the time that patients were receiving long-acting injectable medicines, they were 67% less likely to discontinue compared to the time when they were on oral medication. So there are a number of factors that influence the use of long-acting formulations. There's confusion about the evidence. I just showed you a negative study despite all the meta-analyses that are supportive. Clinicians don't necessarily feel comfortable offering this. They think it's punitive. They think it's gonna damage the therapeutic relationship. If I say to my patient, I'm recommending a long-acting injectable formulation, I'm basically saying, I don't trust you. I don't trust you to take your medicine. That's not a message that I wanna give to my patient. Well, that's where the way you have the conversation comes into play. It's not about mistrusting someone. You have to explain what the rationale is. Some clinicians are not comfortable answering frequently asked questions. Doc, so doc, you're giving me this medicine that's gonna be in my system for like a month or two, so that's like a big dose, right? So am I gonna have more side effects than I would if I were taking oral medicine? What's the answer to that question? Answer's no, I'll show you the data in a minute. And then there are logistical considerations. Many of us doctors don't like giving injections for some reason. So if there's not a nurse available to give the injection, perhaps it's not gonna happen. Another example of this, this is a clinic in London where patients were being referred as treatment-resistant candidates for clozapine. The investigators did blood levels on everybody and found that 35% of plasma levels were subtherapeutic and 34% of those were actually undetectable. So these are patients who are gonna be referred for clozapine when in fact they were pseudo-treatment-resistant based on non-adherence. That's something that we really should think about. And in fact, the TRIP guidelines that we published in the American Journal a few years ago recommend a trial of a long-acting injectable formulation before you declare somebody as treatment-resistant to just make sure they actually were getting the medication. Many reasons why people don't use LAIs, particularly in early phase schizophrenia, and I've already articulated some of them. These are data looking at US claims data. So looking at thousands and thousands of young patients, only 4.4% with first episode schizophrenia were treated with a second-generation long-acting formulation. I think, obviously, the rate should be much, much higher than that. I posed the question earlier, what about side effects? These are studies comparing the same drug in a long-acting formulation and an oral formulation to determine whether or not there was any difference in adverse effects, basically no difference. And if anything, this is a conservative bias because there's a likelihood that some of the patients in the oral medication group were not actually taking all of the medication, but still, the LAIs were not associated with significantly more side effects. Another question a patient, a very sophisticated patient or family member might say, well, you know, I've heard about this neuroleptic malignant syndrome, which some people get, and I understand it's potentially fatal, and the guidelines say you're supposed to stop the medication immediately if that happens. Well, what if I'm on a long-acting injectable formulation? So we have looked at this very carefully. There are three publications by Danny Guinart. We do not see any evidence. We've looked at several hundred cases from around the world. We do not see any evidence of a higher mortality rate in patients receiving long-acting formulations in comparison to patients receiving oral medication. In addition, if you look specifically for second-generation long-acting injectable formulations, there are very, very few cases of NMS. So when we talk about the use of long-acting formulations, we are, how am I doing, Tom? 10 minutes, 15 minutes. Thanks. Obviously, shared decision-making is a process here. We need to provide the educational tools. We did an ethnographic study. We had some ethnographers go out into clinics and talk to the clinicians. You know, these are sort of anthropologists. They're not psychiatrists. They're not researchers the way we are. They can have very candid conversations. They met with doctors, nurses, social workers, patients, insurance companies. They did a range of interviews. And what they found was that training needs to be supported and that all the team members really need to be trained. It's not just the prescriber. But if I'm a patient, I'm gonna be spending much more time with my therapist than I am with my prescriber. My therapist needs to understand why someone would recommend a long-acting formulation. They need to be able to have that conversation with the patient as well. And in many cases, that doesn't happen. I talked about the TRIP guidelines. I wanna talk for a moment about clozapine. So one of the sobering realities that we did in the TRIP review was we looked at studies around the world focusing on treatment-resistant schizophrenia. Most of the studies didn't use the same criteria. So one of the first things we wanted to do is really kind of establish universal criteria. What is treatment-resistant? Basically, failure of two drugs given for at least six weeks each at an adequate dose with good evidence that the patient was actually taking the medicine. And then the person could be considered treatment-resistant. And then they should be a candidate for clozapine, in my opinion. Even in first-episode patients, about 20% are treatment-resistant from the get-go. And they rarely get clozapine. So they're tried on multiple different drugs if they ever get clozapine. We have been working with clozapine since 1988 when this paper was published, which led to the FDA's approval of clozapine. It's been more than three decades. We still don't really understand how clozapine works. I think that's embarrassing. We still don't have any other drug that's been approved by regulatory authorities for the treatment of these patients. I think that's also embarrassing. Clozapine is not the easiest drug in the world to use. But as we showed earlier, you can reduce morbidity and mortality with clozapine, even though it has a lot of side effects. Clozapine's shown to be effective in first-episode patients who failed on two prior drugs. Interestingly, we talked earlier about coordinated specialty care or early intervention services. This is a study that was done in Hong Kong where they looked at the impact of early intervention services on the utilization of clozapine on the evolution of treatment resistance. It didn't seem to impact the evolution of treatment resistance. They still got the same proportion of first-episode patients who were considered treatment resistant. The one thing that it did do was it reduced the lag time for them getting clozapine. And there are data suggesting that if you wait too long to give clozapine, so one of the Japanese studies suggests if you wait more than 2.8 years to give clozapine, it's not gonna be as effective as if you give it within the first couple of years. So that's something else to keep in mind. I'm gonna skip some of these data because I know we wanna allow time for questions. Mortality and self-harm associated with clozapine and treatment-resistant schizophrenia. This meta-analysis showed that those patients who received clozapine in comparison to those patients who did not receive clozapine had a significant reduction in mortality and self-harm. In fact, there was some suggestion that the non-clozapine drugs might have had a negative effect. How many patients respond to clozapine? Well, at least 40%. This is one meta-analysis. Some studies suggest it's a little bit higher, but 40% is not bad when we're talking about treatment resistance. Another situation where therapeutic drug monitoring can be important. Patients are significantly more likely to respond to clozapine if they have a therapeutic drug blood level. Delays in prescribing clozapine. So usually patients will get one medicine. If they fail that, they get another medicine. If they fail that, they get a third medicine. They fail that, they probably will get a combination of two different antipsychotic drugs. Then they may go on to another medication. Unfortunately, clozapine is delayed enormously. We could talk about reasons why that is. It's a hassle to use. Some clinicians are afraid of it. Some clinicians don't know how to have a conversation with a patient about it. They are worried about metabolic side effects, cardiac side effects, hematologic side effects, et cetera, et cetera. But this is sobering when you see tremendous variability in the utilization of a particular treatment. This is a map of the United States where the investigators looked at the utilization rates of clozapine from state to state. The lowest was Louisiana at 2%. The highest was South Dakota at 16%. So some of you may wonder, well, South Dakota? What's going on in South Dakota? So interestingly, there was a psychiatrist from New York, from the Bronx, who moved to South Dakota. Who was a huge believer in clozapine. I mean, really, really very passionate, very passionate. I mean, he would put his mother on clozapine. She didn't take it, but anyway. But so he moved to South Dakota and increased the utilization of clozapine across the state. It was really quite impressive. Anyway, but this just suggests there's something wrong in our treatment practices. Why should there be such variability across the country? The patients aren't different in Louisiana and South Dakota. So we can talk about the underutilization of clozapine. There are lots of reasons. This is the Japanese study I referred to a few minutes ago, suggesting that you wanna use it earlier rather than later. So I just wanna leave a message with you also about how do we talk to patients about clozapine? So I've heard clinicians start out with the blood monitoring. It's like, well, you know, we have this drug. It's approved by the FDA for treatment-resistant patients. You're gonna have to get blood tests every week because it might affect your white blood cells, et cetera, et cetera. I don't know that that's the way to begin the conversation. I think what we need to explain to patients is, look, the medicines that we've tried really haven't worked as well as we'd like. We do have this medicine that, you know, there's a reasonable chance it's gonna help you. The data suggests about 40% of patients, maybe more, are gonna get a meaningful clinical response to clozapine. What's interesting, though, is that there are some patients, and I hope many of you have witnessed this, there are some patients who really have a life-changing response to clozapine. It is really incredibly dramatic. Cover of Time magazine, et cetera, et cetera. We can't predict who those people are. We can't even predict who's gonna respond to clozapine, even, you know, to a modest degree, not alone an extreme degree. So what I think we need to say to the patient is, look, we have this medicine. There's a good chance it's gonna help you. We can't predict whether or not it's gonna help you. It does have side effects. The only way you can make an informed decision about this medicine is to try it. You know, if you try it for three months, then you can see what impact it's gonna have on you and your life, and then you can make a decision. Is it worth it to, you know, manage the side effects, et cetera, et cetera? That's a very different kind of conversation, and I think it's a shame if somebody misses that opportunity for a life-changing experience because we haven't really explained that well enough. And that's what, you know, benefit-risk decisions need to, you know, we need to understand, well, what is the benefit? And if you can't tell me what the benefit is, how am I gonna make a decision? So those are the kinds of conversations we need to have. This is another example of disparities across treatment programs. We're involved in this large NIMH-funded consortium called EpiNet, and these are as clinics providing care to first-episode patients. About 101 clinics involved in this program, and we looked at the utilization of LAIs and clozapine across these clinics, across the hubs. There are hubs that represent groups of clinics, and what we saw with LAIs is the utilization rate ranged from 10% to 36%. Patients are not different across these hubs or these clinics. It's the clinicians that are different. In the case of clozapine, it ranged from 3% to 16%. And when we see such, you know, broad variation, it suggests to us that we need to be doing a better job of training and promoting guidelines and algorithms so that people are more consistent in the way they treat patients. I'm going to stop soon, but people ask me about strategies for dosing and switching. I think there are publications in the literature that talk about, you know, you have to have a good reason for switching. We talked about some of the, you know, misconceptions that we often entertain and that lead to switching, whether it's non-adherence or, you know, that we're going to get better efficacy with a different medicine, et cetera, et cetera. But we need to think about receptor profiles, tolerability, safety, patient preference. You know, what side effects are they most concerned about? What side effects have they had in the past, et cetera? Techniques for switching from one antipsychotic formulation to another. Again, the cross titration, I think, is the most common strategy used in clinical practice. I think it makes sense unless you're under tremendous pressure to do something quickly, which is very unusual. We have to be concerned about withdrawal syndromes when we discontinue an antipsychotic drug, particularly abruptly. It can be cholinergic, it can be dopaminergic, it can be rebound psychosis in the case of clozapine. There are some new drugs under development. There was a lot of enthusiasm about a TAR1 agent that looked good in initial trials. This was published in the New England Journal of Medicine. Unfortunately, two subsequent studies had huge placebo response rates, which really mitigated the efficacy of the antipsychotic drug. And we'll see how this plays out. But it's, as I mentioned very early on in the talk, we've seen increasing placebo response rates in these clinical trials. We also have the soon to be available muscarinic agonists. And I'm not gonna go into details here, but we've seen some, I think, exciting results with these agents so far. These are agents that do not directly antagonize dopamine receptors. They impact dopamine from further upstream. But they do appear to have efficacy in psychosis. We're gonna see much more data. CAR-XT is one. Amaraclidine is another one. So you'll be hearing more about these drugs. And I want to conclude, just by reminding you, that we're talking about patients with schizophrenia, but antipsychotic medications are very effective in alleviating psychotic signs and symptoms and reducing the risk of recurrence. They are not 100% effective. So we have to understand what to do when they don't work as well as we'd like. As with all medications, to treat chronic illness, adverse effects can occur and vary among medications, and we need to be sensitive to that. What I see sometimes is sort of a saliency bias among clinicians. You know, you've had someone in the hospital who was very, very ill, was brought into the hospital by the police, responded to antipsychotic medication, and now they're having some side effects, and they're not happy about that. And you're sort of saying to yourself, well, compared to the state that this person is, the state that this person was when he came into the hospital, he's doing really well. That's not necessarily what the patient is thinking about. The patient is thinking about the side effects that are bothering him at that moment. We have to take them very seriously and make sure that we communicate to the patient the seriousness with which we're taking them. We should try to prevent adverse effects as well as reduce them. I made a plea for more therapeutic drug monitoring. I think if we are consistent in making those pleas, we'll probably have better access to them. Patients and families need to be educated about the benefits and risks of treatment, shared decision-making, but they really need information. I still, we still have families coming in and saying, you know, gee, no one ever told me that there was a long-acting injectable formulation in this medication. I would have been very interested in that for my son. Adherence is a challenge. And it's always interesting, we do these surveys and we ask clinicians, so what's your understanding of rates of non-adherence in the literature? And they give us a number. And then we say, what's the rate of non-adherence among your patients? And it's always, their patients are always much less non-adherent than everyone else's patients. And that's, you know, it's like a narcissistic injury for us to think that our patients aren't following our recommendations. But we really should accept the reality of this. It's human nature to have trouble taking medicine. We need to de-stigmatize non-adherence. You are not a bad patient or a bad person if you have trouble taking your medicine. It's human nature. It's just our challenge to figure out what to do about that. So I've made a plea that long-acting injectable medicines and Clozapine are two evidence-based treatments that are grossly underutilized. We do have new agents under development which do not directly block dopamine receptors. I think they show promise. There's a lot more to be learned about these medications. But it's very exciting to have some new medicines, to have more opportunities and a better understanding of some of the neuropharmacologic mechanisms. So I want to thank you for your attention. I appreciate the opportunity to speak to you. With this, we'll be starting a Q&A session. So a few housekeeping points before we get started. We have a number of questions from the online attendees. So we'll be taking turns. One question online and one question from the audience. I want to reiterate, please state your questions in 30 seconds or less. And I'll actually get started with the first question. My first question to you... Before you... Just in terms of the ones that are virtual, you can vote up questions, and there are so many questions. Please vote them up if you like the question. My question to you, Dr. Cain, is... What do you comment about the efficacy and tolerability between comparing between longer long-acting agents, for example, the six-monthly versus the three-monthly versus the bi-monthly compared to the monthly versions of paliparadone? And similarly, Abilify, monthly versus bi-monthly, different formulations. What's your take on the efficacy and tolerability? So I think the efficacy and tolerability are good for those treatments. I think they've been well-developed and well-studied. I think what's nice is that it gives us a menu of options for our patients. I personally would prefer to start with once monthly and then progress from there, maybe once every other month, once every three months. But this is also a patient preference, and it may change over time. So initially, we may want the once monthly, and then we graduate to something else. What I think is the best news in all of this is that we've now got multiple options, and also we have intramuscular, we have subcutaneous, we have different dosage strengths, we have different intervals. So when we sit down with our patient, we can really offer a range of opportunities. When I talk to colleagues in other branches of medicine about long-acting formulations, they often say, gee, I wish I had something like that that I could give my patient. There are very few examples of long-acting formulations in medicine in general, but I think it's a very powerful strategy. Thank you. Hi. Thank you for a great lecture. Can you comment on the use of more than one antipsychotic? I have seen with horror even three being prescribed at once. My second question is comment on clozapril blood levels, the use of noreclozapine plus the clozapine. What's your top level that you would accept? So the first question is combining different antipsychotic drugs. There's sort of mixed evidence on this. There's some meta-analysis that suggests that patients on multiple drugs do better than we thought. In general, I'm not a big believer, because we have to ask ourselves, you know, why would you start a second antipsychotic drug? Does that mean the first one isn't working? If it's really not working, I would, you know, let's do an adequate trial of a second drug and then go to clozapine. If it's a tolerability issue, let's deal with the tolerability issue. And I think combining drugs is not my favorite approach. But there may be some exceptions to that, you know. The second question was, were you asking what the minimum effective blood level for clozapine was? I know what the minimum is, but I've had patients that their levels are all over the place. And of course, I think my patient's very compliant. And Dr. Meyer told me 1,000 would be the point of no return. And I'm just curious about your feelings about that. There's no reason to go that high. Some patients do fluctuate. You want to treat the patient, though not the blood level, right? So that's, you know, that's the other message. And when we talk about therapeutic drug monitoring, it's a tool. It's a piece of information. But we basically want to clinically evaluate the patient and then, you know, use that information. What do you use to combat the enormous weight gain from clozapine? Yeah, that's a complicated question. I think, you know, I certainly start with things like metformin and, you know, but whether or not we're going to be using some of the newer agents, I think that's still a big question. You know, do our patients have access to them? You know, they're very expensive, et cetera. I would assume over time that's going to change. Yeah, one strategy I have to advocate long-acting injectables is that I tell, you know, somebody that you don't want your boyfriend and girlfriend to see this bottle next to you. If Google tells them that you're psychotic, that if you take this, then nobody needs to know unless you feel comfortable telling them about it. Yeah, no, I think that's true. It's a, it is a, it can be a privacy issue. It's also a convenience issue. You know, if you only have to go to a clinic once a month, then you're not, you know, you're not incurring all those, those travel issues, et cetera. Yes, sir. So what are your feelings about psychiatrists prescribing metformin in cases where patients don't have primary care or trouble getting to the doctors? So that's like part two. Can a psychiatrist prescribe metformin? Yeah, I don't see why, I don't see why not. Regarding plug-in closure, I'd like to add that although the database is much smaller, people should remember treatment refractory bipolar disorder would be an appropriate time to consider closure as well. And for those who've been shying away, REM system is very easy to use. I think that intimidates some doctors, particularly the modified, but you're smiling, you disagree. No, I, what are, what are angry moms angry about, you know, what are you talking about? The REM system? The REM system. Yeah. So some people are not happy with it, but you know. But not hard to use is what I'll, at least I think. Yeah. Okay. That's fair. To, about, yes, it's better now, yeah. So two questions about gastro, well, weight gain issues. One is, is there a dose relationship with risk of weight gain with the drugs that are more commonly associated with weight gain? And the other question I would ask is slightly related. How important do you think it is to actually have patients worry about the size of the meal they're having with loracidone? There's already enough burden on scheduling, you know, when you're going to take medication and so forth. After all, if a person is going to be taking their medication a regular time during the course of the day anyway, they'll be in some consistent relationship with their last or next big meal. Yeah. You emphasize that to the patient is what I'm saying. Yeah. No, I think, yes, those things. But again, this is a patient preference, patient discussion, you know, get them on board. And dose relationship with weight gain in general? I think it's inconsistent. Some patients, you know, years ago we studied the MC4R gene, so there are some people who probably have a genetic predisposition to gaining weight. That's not something we use routinely clinically. But I think people vary in their vulnerability to weight gain, even with these drugs like olanzapine or clozapine. And not sure whether or not risk varies with the dose, even within an individual? No, I don't think that's the biggest issue. I mean, that's what I'm saying. I think there may be other, you know, genetic predispositions, et cetera, that will have more of an impact. On an admitted patient in an acute unit refusing any oral medication, would you be okay with giving a long-acting injectable without an oral trial? Yeah, that's a tough one. I would like to see at least, you know, a few doses of an oral medicine to make sure the patient tolerates it. So I would try to do that. Just as a principle, I've often thought it's more, there is more medication you're required to treat the episode than to maintain someone. What are your principles about reduction to avoid relapse, but hopefully keep the patient on side? And another thing, in Australia, we have clozapine clinics, and often trainees are in the clinic, so they get a firsthand good experience of what it's like to treat with clozapine. So if I understood the first question, it's, you know, the question, the dose that you're using in acute treatment may be higher than the dose that's necessary for maintenance treatment. So what kind of rules would you apply? Some of the recent meta-analyses suggest that we don't really, we shouldn't necessarily be lowering the dose for maintenance. This used to be, you know, when I was early in my career, tardive dyskinesia was a very big issue. We were trying to keep doses as low as possible. I don't think that that's as much of an issue now as it was. You know, I think the guidance recently is to keep people on a moderate dose of an antipsychotic, not to try to lower it that much. And there was a second part of the question, which I forgot. Just really a statement that you're talking about clozapine and clozapine use. In Australia, we have clozapine clinics, so all the monitoring is done in the clinic. Trainees get experience in the clinic, so I think that might help with the use of clozapine more broadly. I agree. The same thing applies to long-acting injectable formulations. When you have a clinic, a specialty clinic, it can be very helpful. But that's not always the American way, so to speak. You know, we're all supposed to be able to do everything. And there are pros and cons, but I agree with you. I think having specialists makes things a lot easier for patients and for access. But then, you know, where is the specialty clinic? Is there one near me? What if I live in, you know, South Dakota, et cetera? A patient responds very well to clozapine but develops severe neutropenia even on lithium. What do you suggest in this particular case? Yeah, unfortunately, we don't have a good solution to that problem. If someone develops agranulocytosis, you know, we do not re-challenge them. And you know, those are heartbreaking cases where we have to try other treatments. So I'm a child psychiatrist working in a residential treatment facility. And a couple years ago, I had a 14-year-old who came who was early schizophrenia and was not responding to anything. I tried him on clozapine. He had a dramatic response. The mother thought I was God. The staff thought I was God. He responded so well. So now I have a kid who's a little younger who come. These are kids who, they come to us and they've been tried on all kinds of things. And he looks very similar to this kid, except he looks a little bit more schizoaffective than straight schizophrenia like the other kid. He's only 12. And everybody is saying, why don't you give him a trial of clozapine? I've been reluctant because he's so young and he looks maybe more schizoaffective than schizophrenic. Would you try him on it? I probably would, yes. Great talk. I'm hoping you can comment briefly first on clozapine's impact on non-adherence. I think there's this common element of the psychiatric lore, right, that if a patient has a history of non-adherence, that perhaps clozapine isn't the best choice when I think Dr. Tihonen's data and others suggest otherwise. And then given that we have this captive audience and I want everyone to hear your answer, can you please comment on clozapine's role in suicide prevention in the schizophrenia population? Sure. Suicide prevention, yeah, I think it is a medication that has FDA approval for reducing the risk of suicide. So it's something that should be considered. And what was the first part of the question again? Oh, yeah, adherence, sorry. So it's interesting. I think we have seen that patients are very adherent to clozapine. Now, is that because they're coming in for weekly blood tests? Is that because they feel better on clozapine? I think it's the latter. I think that when you have a treatment that you've experienced as having a positive effect, you want to take it. It makes you more, you know, there are a lot of data with clozapine suggesting that it also facilitates patient engagement in psychotherapy and psychosocial treatment. So there's something to do with the motivation towards self-improvement and da, da, da. So that includes taking the medicine. It's fascinating because it's a medicine with so many side effects, yet the patients want to take it. So I think, unfortunately, we still don't understand what do we attribute these somewhat unique features. So it's not negative. You know, people say, well, it's negative. You're improving negative symptoms. I'm not so sure that's what it is. You have a patient on a long-acting paliperidone who ends up with amenorrhea, negative pregnancy tests, prolactin levels are elevated. Do you think reducing the dose or switching to Abilify Maintena or treat hyperprolactinemia without symptoms? So I think hyperprolactinemia can be an indication to switch medications. I mean, there are, you know, one can add aripropazole or other medications, but I think if it's clinically significant, there are other choices, you know, there are other choices that don't produce prolactin elevation. Okay. We're going to have to stop soon. We'll go ahead and take one more from the audience. I treated a young woman in a school residential setting for quite a while earlier in my career. I'm now no longer treating kids, but she was a true childhood schizophrenic. She went through a trial of medicines at NIMH, received clozapine, came back to western Wyoming where I work, and I worked with the research doctor there whose name escapes me at this time. And it was remarkable what she had in her course of treatment and effect. If that's my mother, don't tell her I'm here. Anyway, what I learned from the researcher was that she encouraged us to make sure we because we were struggling with her relapsing psychotic features. And I'm sorry, sorry to interrupt you. Could you please ask your question? Okay. What we learned is that we had to keep this young lady on the clozapine for at least a year before we saw optimal results. Is that well understood in the literature? So I think in general you should see some response after three months. You're not going to see the full response. And some patients continue to improve even for a year. So it's not unreasonable to think that you want to wait to see the full improvement. But when I was talking earlier about how we present clozapine to patients and I'm asking for a three-month trial, I think that's enough time to get some sense of whether or not it's going to help. That's why she was able to come back. Next question, please, just for the moment of time. Thank you. Thank you. First, thank you for a very thoughtful and practical talk. It was very helpful as a clinician. I just want to ask you, the other Dr. Cain at Vanderbilt did a study a number of years ago on refractory schizophrenia where he defined refractory schizophrenia as failure of two or more antipsychotics that didn't include zyprexa and risperidone. Do you remember that study? And then he, it was a very big sample size. And then if they failed, those who failed risperidone and zyprexa, he then put them on either Trilofan or Abilify with very good results. Was that an efficacious study in your opinion? Because it convinced a lot of us to start using Abilify and or Trilofan. So that's question one. Two is, what do you think of Trilofan? As he called it the gold standard at the time, I use a lot of it. And what do you think of Loxapine as well? So those are my questions. So I'm actually not familiar with the study that you referred to. The results are a little bit surprising. We also did a study with Aripiprazole in treatment in poor partial responders and didn't see any superiority. I think Profenazine is a, you know, certainly an efficacious drug. I mean, it was used in Katie, good results. So I don't, I don't have any, you know, any strong feelings one way or another. It's a reasonable medication. Was there another drug that you mentioned? Loxapine also, you know, reasonable medication, not widely used, but efficacious. And I think, you know, we have so many different medicines, we tend to focus on a small group of them. But those are, those drugs certainly are efficacious. Are relapses due to medication noncompliance or should relapses be expected as part and parcel of the disorder? Well, I think there are elements of the disorder. Some patients have anosognosia, you know, they don't necessarily acknowledge that they're ill. That definitely makes it hard to facilitate adherence. We know that probably 70 or 80% of patients with schizophrenia have cognitive dysfunction. So what extent does that contribute to non-adherence? But I also think it's human nature to have trouble taking medicine. So whatever aspects are attributable to the illness itself, we also have to deal with the other, you know, the other dimensions. And it's a vicious cycle in the sense that if we can treat the illness and the non-adherence is due to the illness, then we have a better chance of getting the non-adherence under control. Can you advise a bit on assessing if there's a treatment failure in the inpatient setting where we don't always have, you know, the luxury of time to determine, you know, to give two full weeks on a significant dose of an antipsychotic medication on one medication? Yeah, it's a tough question because I think, you know, we hope that patients are going to derive some benefit within a few days, but if they don't, you know, you have to, and you can't keep them in the hospital, you have to refer them to a facility where they're going to be able to get the necessary management and supervision. If that includes Clozapine, you can start Clozapine as an outpatient, but you need, you know, you need to have the people in place to do that. You need to have a patient who's, you know, got a stable living environment and all of those things, but, you know, I don't know whether you refer patients to state hospitals if they're treatment resistant. These are all challenges. Yeah, I mean, I guess I was kind of referring to like how much time should we give on a certain antipsychotic in the inpatient setting before deeming it, you know, a failure, a failed trial. I think two weeks. Two weeks at like the highest possible dose, for example, or? Two weeks at a moderate dose, you know. And technically, you want to wait six weeks before, you know, before you think about Clozapine, but I think two weeks is at least, from the data I showed you about early response, you get a pretty good signal whether the patient's going to respond or not. And you get a blood level. Yeah, also blood level, thank you. I guess my question is, what is your opinion on the REMS? What should be done with the future of the REMS? There have been studies that have been coming out from a couple of health networks that have shown that the risk of neutropenia after a period of eight months is significantly lower and I guess the other question is, what is the reason we don't have access to the REMS data? It seems like there would be an enormous amount of REMS data that we could use to analyze to give us information about Clozapine, but it seems to be in the ether, if you will. Oh, you're right. I share your concern. I don't have a good answer to that question as to why that's happened. In terms of the future, I think we need to do more risk-benefit calculations of what, you know, what is the incidence after, you know, six months, a year, et cetera. Can we reduce it? You know, what is the logic to doing it once a month? I mean, is that frequent enough to actually detect anything or are we just kind of kidding ourselves? So I think there's got to be more discussion about it and I would hope that we could reduce some of the requirements. Thank you. We only have time for one more question. I'm sorry. My questions are three. I'm sorry. So you'll have to condense them to one. So pick one. It'll be very short. I'm a consultation licensed psychiatrist working in the Queens here. I'm a local. I hear very much about Dr. John Kane. Thank you for all your presentation and the work. So the first question is that ileus, constipation is the biggest problem from the close of pain. Do you stop if there's ileus and obstruction in surgery? And should we continue with the patient comes with the close of pain given that ileus is a problem? Yeah, I think, you know, you want to provide the best possible treatment for that. But that is definitely a concern. That's one of the major concerns with close of pain. No question. So, you know, you want to be prepared to provide adequate management. Should we stop? Yeah, it depends. I think it depends if you, you know, if it's not responsive to other agents, then yes, you probably wouldn't need to stop. Some patients are very sensitive. Thank you all. Thank you so much.

antipsychotic treatments

schizophrenia

Dr. John M. Cain

early illness identification

untreated psychosis

recovery

relapse prevention

long-acting injectables

clozapine

adherence challenges

comorbid conditions

treatment-resistant schizophrenia

new treatments