Good morning and good afternoon to where you are from. My name is Vishal Madan. I serve as the Chief of Education and Deputy Medical Director for the American Psychiatric Association. I will be serving as a moderator for today's APA Emerging Topics webinar on treatment as prevention improving the outcome of schizophrenia. Thank you all for joining us today to learn about the latest advances on this exciting topic for us. I'd like to introduce our speaker now, Dr. Oliver Freudenreich, who's the co-director of the MGH Psychosis Clinical and Research Program, as well as a professor of clinical psychiatry at the Harvard Medical School and a psychiatrist, obviously, at the MGH Hospital. Dr. Freudenreich is board certified in general psychiatry, as well as in consultation liaison psychiatry. His academic interests lies in improving schizophrenia care across all states of illness, as he will be talking about, including the development of innovative and accessible treatments for treatment-resistant psychosis, as well as better integration between psychiatry and medicine. In addition to his clinical expertise and clinical trials expertise in schizophrenia research, Dr. Freudenreich also provides psychiatric consultations for medically complex patients with serious medical illness, serious mental illness, and for diagnostically difficult cases with psychosis, who are often cared for in state hospitals. Dr. Freudenreich has also published extensively in his areas of interest, and one of the bigger publications that I'm very well aware of is the Handbook on Psychotic Disorders, the second edition of which was published in 2020. He teaches and speaks on a regular basis, and without taking all the time, he has such a long and accomplished career. I would like to go over a couple of quick housekeeping items, and then I'll hand it over to him. The first is obviously the CE, or the Continuing Education Credit, in support of improving patient care. The APA is jointly accredited, as you all may be aware. This live webinar is designated by the APA for a maximum of one and a half AMA category credits. Next slide, please. And the second thing I wanted to share was, you know, please feel free to submit your questions throughout the presentation by typing them in the questions area, which is found in the lower portion of your control panel. We will reserve 10 to 15 minutes at the end of the presentation for these Q&A. And without any further delay, I'd like to hand it over to our speaker, Dr. Freudenreich. Oliver, please take them. Thank you. Thank you, Dr. Mardan, for the kind introduction. Thank you to the APA for inviting me to give this talk. Treatment as Prevention, it's actually a slogan from HIV medicine, Treatment as Prevention, Improving the Outcome of Schizophrenia, something that I've really tried to define in my own mind for the last 25 years that I've been a public sector psychiatrist. And as you may remember from Dubai, I'm also trained in CL, so you will get a dose of med psych integration with this talk as well, because I do think this is actually critical. I am giving this talk as a physician, hence Treatment as Prevention. I will focus mostly on psychopharmacology, but I'm going to also step back and give you my view of the role that psychopharm, why psychopharmacology, expert psychopharmacology actually matters with regards to having a good outcome in psychiatry, specifically in this case for people with schizophrenia. My disclosures, there's really nothing specific that I need to highlight. I think I have a very brief slide and mention of the new medicine that was just approved Co-Benfi, and otherwise my other disclosures really have to do mostly with my teaching engagements such as this one. The Tourism Bureau of Boston asked me to put in a few slides, so I put in Heroic Boston, which really comes from a title about a book on brutalist architecture. I'm a huge fan. On the right bottom, you see Boston City Hall. It usually gets voted one of the ugliest buildings in the United States. I tend to disagree. We also have buildings by Walter Gropius and Le Corbusier here in Boston, the JFK Federal Building and the Harvard Center for the Visual Arts. If you're ever in Boston, please come and visit those. After this webinar, I hope you'll be able to do four things. Apply a stage-based prevention approach to the care of your patients. Using two tools specifically that I'll discuss in great detail, long-acting injectable antipsychotics and Clozapine. Both, I think, are really critical in this treatment as prevention paradigm. And then also, the CLPs, being a physician also needs to worry about medical illness, the role of the new GLP-1 agonists in reducing antipsychotic-induced weight gain. Those are the kind of four things that I'll be discussing, and I rearranged it a little bit so we have three parts to this talk. We're going to talk about stage-based care, we're going to talk about medical prevention, and then we're going to put it all together in a section that I called Outcome of Schizophrenia. So let's reflect for a second here. How are we actually doing when it comes to outcome of schizophrenia? You know, here in the shadows of a great institution of Mass General and Harvard Medical School, if you pay attention, this is the subway stop here at Harvard Square. There's actually a human being that's sitting there between his or her belongings. And not to just, you may recognize by my accent, I'm not from Brooklyn, New York. I'm from Germany. Not to just criticize the United States, on the right, you have images from Paris, this tent there, the person lying there is in Frankfurt, Germany, and then the underpath is actually from Atlanta, Georgia. So I'll come back to this slide because I think this is why this matters, that we do a good job, because bad outcomes are a real possibility for this serious mental illness that we call schizophrenia. So stage-based care. Let me spend a few minutes on this slide here. It's very schematic, does not apply to all patients, doesn't capture the heterogeneity of patient outcomes and patient course. So for example, on this slide, you're not going to see the people who just have one episode in their lives and none. This, on the other hand, I think is a fairly typical course for many people with chronic schizophrenia. If you see them 10, 15, 20 years in their illness course and you go back and look at the number of hospitalizations and the X-axis is the time and the Y-axis is kind of a hodgepodge of mostly really symptoms, but you can also think about function, disability, kind of a global assessment of how they are doing. And we have really three phases. We have a pre-psychotic phase where everything seems to be okay. Then we have a critical phase where things go terribly wrong. And for most people with schizophrenia, that's in their late adolescence, young adulthood. And then at some point people enter a, and I stick with this term, even though it's not a great term because it has chronicity in it, but for pedagogical purposes, let's call it the chronic phase. And if you just follow along, you see that at some point people start to become ill and develop a prodrome of the illness. It's not really clear what it is until they have the first episode of psychosis. So this is his first steep decline. With treatment, on the other hand, it is really important. You also see that the first episode really resolves very nicely and gets almost back to baseline. And then the problem, there's going to be a second episode. And the second episode, you see, it's no longer this sharp recovery period, but there's already a little bit plateau. May take a little bit and they only, instead of having this almost full of the full recovery, they're going to only have partial recovery. And subsequent episodes for a lot of people, they enter what I labeled on this slide here, stable disability, where if they have another episode, you know, they do recover. It may take a while, but otherwise they're certainly never going to return to their pre-psychotic, pre-morbid level of having no symptoms and functioning. So let's keep this in mind as we think about various ways of maybe bending this curve, changing the trajectory for individual patients. And this is where the idea of treatment as prevention comes in. Providing psychiatric treatment may perhaps avoid that people go deeper and deeper into these illness stages. The rationale for staging, which I think is underused in psychiatry, clearly widely used in medicine, for example, in cancer care. The rationale for staging there is you want to avoid progression to disease stages, and where only amelioration is possible. And as a general rule, there's a better treatment response to treatment in earlier stages. And another general rule is also that the earlier treatments tend to be less aggressive. Reframing this a little bit into some principles, we want to have early intervention to treat patients as early as possible in the disease course. We want to have stage-specific care. One size does not fit all. We want to tailor our interventions to the patient's need at that illness stage. And then this is really critical. We want to step up care, or we're going to use step care to adjust the treatment intensity based on the response. Now, people have criticized the staging model of treatment as really not applicable to chronic schizophrenia in particular, because that's an end-stage disease, end-disease stage already. So it really works best probably for transdiagnostic psychiatry in the early stages. But I still think it's a valuable way of thinking about our interventions. Now, when we think about prevention, you may remember from medical school, you may have heard or remember first, primary, secondary, and tertiary prevention. I think we have really shifted now towards different types of prevention. And there's a question sometimes, what is prevention? What is actual treatment as depicted here in this nice spectrum of interventions for mental disorders? And the early intervention piece here, it includes a type of what's called indicated prevention, and then includes early treatment, case detection, and early treatment before then moving on to higher disease stages and continuing care for chronic disease. Universal prevention means everybody gets it. People have no symptoms whatsoever. Selective prevention is a helpful term when we think about intervening in specific groups, also no symptoms yet, but they have certain risk factors, such as a family history. And so they get selected based on certain risk factors. And indicated prevention that I already alluded to as really the beginning of early intervention suggests that you also already have a clinical suspicion that something is not right. And we're using this particular scheme here mostly for psychiatric prevention. But of course, we also will have medical prevention as part of prevention. So I'm not going to spend too much time on this slide. This is a talk in and of itself. There's this whole idea of prodromal research. Basically, different terms for this are used today. Clinical high risk, for example, is a term that's used for the prodromal phase. And clinical high risk, as the name indicates, suggests to you that people seem to be heading into a problem. So they may have attenuated symptoms of psychosis, but they have not crossed this severity threshold yet into syndromal psychosis. Often very unspecific symptoms, such as anxiety and depression. And the idea here really has been over the last 20 years, maybe we can use our benign interventions. This would be a case for indicated prevention. People have symptoms, right? To delay the conversion potentially to syndromal schizophrenia. And sadly enough, we have made some progress, really focused on the idea to offer needs based care based on we treat what we see. But hopes to really alter the course of illness using antipsychotics, for example, to basically prevent conversion to schizophrenia have really not panned out. And there have been many other attempts to show, like omega-3 fatty acids and acetylcholine and minocycline, who really in the end have not been shown to work, at least not at the population level. So we often end up using antipsychotics, should we load those second generation antipsychotics if there is severe symptomatology and if you have your concerns, but you're not using those for the primarily preventive purpose. And just a reminder here, when you see a college student who complains about ADD, never had anything like it before, probably pseudo-ADD could be the prodromal period of schizophrenia. So don't treat this with stimulants. Now, this is where I think it gets interesting, the question of early case finding or reducing DUP, DUP standing for the duration of untreated psychosis. If you think about the last patient that you saw, if you work in this area with the first episode of psychosis, and you just ask them, well, when did it actually start? A shocking number of people will tell you, excuse me, I have to move my thing here, a shocking number of people will tell you, it didn't start yesterday or the day before yesterday or last month, but many, many months, weeks and months before the index episode, which is often the hospitalization. And on the right, you see a box here from a recent meta-analysis that shows, I'm just going to look at North America here, the duration of untreated psychosis in this meta-analysis was 49 weeks, really, really long time. And it, I think it's common sense to think, well, you know, if you're a quietly psychotic, you're probably not functioning. So here, the idea is that, and it has been shown in meta-analysis, that a prolonged duration of untreated psychosis has a worse outcome in the end, if you look longitudinally, and it has a poor response to your treatment. It can be reduced with a sustained information campaign, and that's the problem, which is really hard to do. We've shown it, a group at Yale, that if you have a long duration of untreated psychosis, a group at Yale in Connecticut, that it is feasible to do it in the United States. But as opposed to people knowing when they have chest pain, I think it's still really hard for people to know what to do with their child if he or she complains about hearing voices. It's also problematic, I think we miss outliers, we miss people who are just sitting in their basement for years at times. And there's a statistical problem that is called lead time bias, if you want to read up on that, that kind of makes the whole assessment how effective reducing the duration of untreated psychosis actually is in the end, makes it a little bit harder to be sure about. I just want to say, though, that it makes a lot of clinical sense, I think, to identify people as early as possible and get them into treatment as early as possible. The RAISE trial that I'm going to be talking about in the next slide, the DUP, was 74 weeks, for example. And here we are, stage-specific care, first episode psychosis care. And RAISE stands for the recovery after an initial schizophrenia episode. It was a very large NIH project with the goal to develop an early intervention system in the real world of the fragmented U.S. healthcare system. Okay, so they really tried to figure out what are critical ingredients, if you have a first episode of psychosis or schizophrenia, critical treatment ingredients to have a good outcome. And they developed core services to be offered as a package, family education, resilience training, supported employment or supported education, and medications that were given based on a consensus best practice algorithm. Over 400 people, they used 34 clinics in 21 states, they called it NAVIGATE versus usual care or community care. And they found that NAVIGATE improved the primary outcome variable, which was quality of life more than the usual care. And the benefits persisted in five-year follow-up. Effects were better for those with the shorter DUP, which is consistent with what we just discussed. You want to get people as early as possible. Now, the term that's used today for this package of treatment is called coordinated specialty care. And you may have one of those clinics in your neighborhood somewhere. Now, if you think about, it's on the left side of the slide, a few things to know about first episode care, a lot of things are surprisingly unresolved. For example, should you get an MRI in first episode, psychosis workup, the German guideline, which I put here because it's the most recent one, says yes, you should. The treatment, the optical pharmacotherapy, we're going to discuss a little bit more, basically just says, choose wisely, choose a metabolically safe one, and think about the mode of delivery. And then the APA guideline does suggest if you have access to this coordinated specialty care approach. And of course, you integrate this with the proactive medical monitoring. So in the end, I would argue this is actually just very good psychiatric care, but it's good, I think, that we as a field have spent time to work this out. And the prognosis here, I did say this already, we want to really get people into treatment early, effective treatment early, that is. We want to address the comorbidities, and non-adherence is obviously a big issue. It is interesting that we actually do not know after a first episode of psychosis how long we need to treat. So the duration of maintenance treatment remains unresolved. And the German guideline, for example, states just explicitly that it's a case-by-case discussion how long to continue the antipsychotic after the first episode is resolved. It does have to do with this vexing problem that a significant minority of patients, about 20%, will recover after the first episode and not need maintenance treatment. And this is really important now, the idea of step care for treatment-resistant schizophrenia. Schweitzer, you know, the humanitarian theologian and physician, said it nicely, the tragedy of life is what dies inside a man while he lives. The death of genuine feeling, the death of inspired response, the death of the awareness that makes it possible to feel the pain or the glory of other men in oneself. I think it's a beautiful description of really being disconnected from society and having negative symptoms and perhaps being psychotic. Here's the dirty little secret. 20 to 30 percent of patients with schizophrenia have a limited response to first-line antipsychotics. And first-line antipsychotics are actually any antipsychotic other than clozapine. And even worse, at least 10 percent of patients with schizophrenia have no response to clozapine. That's an issue, a topic in and of itself. We're going to skip for the purposes of this talk what to do with this group. Treatment-resistant schizophrenia is probably a biological subtype or, referencing Bleuler here, the schizophrenia is plural. People have suggested to really think about treatment-resistant schizophrenia as not just one neurobiology. There are clinical differences to kind of run-of-the-mill schizophrenia, the age of onset is earlier. It is not more common in males, so you will have female representation and a little bit circular reasoning admittedly, but the outcome is worse. The biological differences, you can look at studies, there are studies suggest greater genetic loading, there may be possibly more specific cognitive deficits. And this is one of the disorders where we actually use a treatment response, a response to clozapine, but not other antipsychotics as part of diagnostic criteria. And the pathophysiology is clearly not dopamine-driven, otherwise our first-line treatments would work. The majority of patients, the majority of patients who you will see in the first episode of psychosis who do not respond to your first-line treatments are going to be treatment-resistant. They're treatment-resistant at presentation. This is where the 80%, 20% comes from. 80% of patients that you will see, if they're treatment-resistant, they will be treatment-resistant from the get-go, so when you see them, and it's really important to come back to that point to use effective treatment, meaning clozapine, for these patients and not spend years and years with ineffective treatments shifting from one antipsychotic to the next. Conceptually, if you think about it, this makes sense, doesn't it? If it's not dopamine-driven, the pathophysiology, and it's genetically based and based in brain development, you wouldn't expect people to somehow be resistant at the beginning and then only over time become treatment-resistant. Those 20%, that is a group that does happen, a second pathway for late-onset treatment-resistance where there's a relationship to the number of episodes that has been described with the crude disability and development of treatment-resistance over time, and there may be mechanisms that do have to do with the dopamine system at play, such as dopamine super-sensitivity, an effect that you may have heard about coming from dopamine blockade, ultimately, for example, you can see it in the form of tardive dyskinesia in some patients, but there may be an aspect of this for some people who become treatment-resistant over time. The diagnosis of treatment-resistant schizophrenia is pretty straightforward. Number one, always think about, do I actually have the diagnosis correct, or is this a secondary form of psychosis based in some neurological problem? So you want to rule out medical and other psychiatric problems, and of course, as always, substance use. And then, I'm going to be critical about this, by the way, but here, I put it there, has there been an adequate trial of two antipsychotic medications, want to be sure there's no pseudo-resistance, is the dose adequate, is the duration adequate, is there adequate adherence, all of this. You're going to be using blood levels to be sure, and ideally, we actually would insist on a trial of a long-acting injectable antipsychotic, just to remove this variable of insufficient adherence. And then, most people, just by default and by the way the disease is, will have persistently moderate to severe illness and functional impairment for long periods of time, unless you institute effective treatment. And so, you end up with at least a working diagnosis of treatment-resistant schizophrenia. And here, it's pretty clear in terms of the APA Schizophrenia Guideline Recommendations. I put it here in red. The psychopharmacology is obviously a close-up for treatment-resistant schizophrenia. So, I want to highlight here the last bullet point in terms of psychosocial intervention. The so-called Coordinated Specialty Care for First Episode Patients, based on the RAISE initiative by NIMH, has found entry into the Schizophrenia Guideline. Now, clinically, these are the patients you want to prioritize for clozapine. Just pointing this out as well. Anyone with chronic schizophrenia and poor illness scores and function. I think it's always worthwhile asking somebody who has been in your clinic, perhaps, for many, many years, if they've ever had a clozapine trial. And you'll be surprised how many patients were never offered one. It's not just limited to people with schizophrenia, but refractory severe bipolar disorder. And we can argue if this is actually a separate illness or not. Also worthwhile considering clozapine, which can have real course-stabilizing, let's just say course-stabilizing properties. I did talk already about the first episode patients with this early treatment resistance, which is the majority of people. Anyone with a forensic history due to psychosis and aggression. Patients with the schizophrenia spectrum disorder and suicidality. Increasingly there's a recognition that patients with comorbid substance use, particularly cannabis, may benefit from a clozapine trial. And anyone where there's a suggestion that they're very sensitive to EPS and catatomic symptoms may be one of those markers. Anyone with established title dyskinesia really ought to be considered for clozapine maintenance. Now, these are clinical recommendations and not based on FDA approvals. The one FDA indication for clozapine you may recall is actually a suicide in the setting of schizoaffective disorder. There is, talking to a group that knows there's a high risk of suicide and schizophrenia and the risk is elevated in the early course of illness. Remains high throughout a person's life, but it is another example where this early intervention during this early illness period providing effective treatment. Treatment as prevention, psychiatric treatment as suicide prevention is really critical. And the highest risk is for untreated patients. We do have a lot of pharmacology interventions, long-acting injectables and clozapine. We'll be discussing this a little bit more. So it was an autopsy study in Maryland that really showed that clozapine has clear benefits. There's an interesting design of the trial, of the study. They looked at people who had died, who were either on clozapine or olanzapine. And they found that people on clozapine had a much lower risk of having died from suicide and a much higher rate, ratios, if you will, from just other accidents compared to olanzapine, suggesting that this is really, you know, we don't know the exact numbers, you know, for each group. So not really directly comparing, but the ratios is interesting, suggesting that there's really been a shift away from suicide to accident in a ratio type of way. Not sure if I explained this well, but please go look at this autopsy study. Consider clozapine for the prevention of violence in patients with psychosis, particularly if conduct disorder is present. It has been shown very nicely in a randomized controlled trial with clozapine being more effective than olanzapine, being more effective than haloperidol. Why am I emphasizing this? Because I do consultations on inpatient units, forensic inpatient units, and it is shocking how many people are getting treated with haloperidol, forensic inpatient units. As you can imagine, aggression and violence is a big problem. So they're not using the most effective pharmacotherapy for this group of people. Now, the most dangerous group of people that you may encounter are young males with traits, not sure if that's an elegant way of saying it, but with sociopathic traits who are psychotic. And maybe you have encountered some of those. And it is interesting that this is not a marker of a poor response to clozapine, but it is interesting that that difficult to reach and treat group of patients actually does improve with clozapine if there's conduct disorder, or even if there's conduct disorder. And just the last bullet point here, clozapine has anti-aggressive properties independent from psychosis, been pretty well established now. Not saying that we are going to be using clozapine indiscriminately, any forms of aggression or violence, but it is worth keeping that in mind. So briefly, to summarize this section here, we have treatment-resistant schizophrenia diagnosed, again, and it's maybe a young patient. And after two failed antipsychotic trials, we need to step up to a clozapine trial that is timely and optimal. And then for those people who don't respond, it's a different talk, but we need to think about the judicious use of add-on treatments. Now, this is one of my favorite slides because it really calls into question the whole idea of switching medications around in somebody who is treatment-resistant to first-line treatment. And again, it's this idea that if you have a biology that we end up calling treatment-resistant, it shouldn't make any difference if you switch medications around. The most important switch will be the switch to clozapine. And this trial from the European Union did exactly show using imisorpride as the first-line treatment for four weeks and then a double-blind phase, either just sticking with it or switching to olanzapine. And for those who didn't respond, ultimately to clozapine, it showed very nicely that number one, imisorpride induced a overall very good remission rate after 10 weeks of treatment, about two-thirds of patients. So the expectation is people really ought to do well, most of them, when treated appropriately in the first episode of psychosis. And most responded actually pretty quickly over the course of four weeks. And there was no added benefit from switching to olanzapine as opposed to just waiting. And finally, for those who did not respond after which is 10 weeks of treatment, switching to clozapine really did make a difference for those who switched. But it was not as good, the outcome, as those people who did respond to the first-line treatment, suggesting you are dealing with a more difficult-to-treat illness or stage of illness. So to be very clear, sorry if I belabor this point, but it has been really one of my career missions to improve the use of clozapine. Clozapine is not a treatment of last resort. Ineffective treatment given over long periods of time is still ineffective treatment, even if given with great sincerity. So clozapine has broad benefits. It reduces mortality best. It has real-world real-life prevention, a lot of things I could list with individual studies that are at the bottom of your slide here. So do please move to clozapine quickly. Some of the majority of TRS, treatment-resistant schizophrenia patients are so at presentation. And waiting and or switching is really not an effective strategy. There's a risk of not prescribing clozapine, you accrue psychosocial toxicity, you end up with end-stage brain disease with poor functioning, you end up with polypharmacy, and in the end with higher mortality from that approach. Let me also highlight one quote by Brooke Chisholm, a psychiatrist, the first director general of the World Health Organization, there is no health without mental health. If you're psychiatrically ill, you're going to have a really hard time managing your medical needs optimally. So clozapine in clinical practice, you want to have a time-limited clozapine trial. It should be done early and routine, needs to be done safely, and you need a team for this. Colleagues have written about this at the time, a long time ago now, training in a clozapine clinic for psychiatry residents, something that we have as a mandatory part of our training. But more recently, colleagues have written about clozapine proficiency as a milestone in psychiatric training. And for those of you who speak Polish, by the way, on the right here, you see clozapine, the king of schizophrenia. I didn't include a slide, but it has been an exciting development. You may have seen that the FDA actually essentially rescinded the REMS requirements. We're going to be learning over the next few days and weeks exactly how to actually implement this in our clinics, what that means. But it basically means that it's really up to us physicians, again, to manage clozapine optimally and safely. It doesn't mean that we will completely abandon all blood work, but the REMS, a relevant obstacle to wider clozapine utilization, is gone as of two days ago. It's an example, by the way, of physician advocacy making an enormous difference for patient care, physician advocacy and grassroots advocacy. Shout out to the angry moms, as this group was called, unhappy family members because of the big, big hurdles imposed to clozapine prescribing. So we've talked about Prodrome, one slide. We've talked about how to optimally treat the first episode. Now if you think about just looking at this slide, what do you want to prevent? What do you want to focus on next? You absolutely want to prevent relapse. You want to prevent the second episode and subsequent episodes. Because the cost of relapse is really significant, and I call this psychosocial toxicity. People may lose their job, their education gets derailed, they'll end up with criminal problems, suicide is a risk, they lose their reputation, might even be biologically harmful. And I did allude to this, I rounded up to 20%, the emergent treatment non-response in some patients. Sustained remission is the basis for accrued treatment benefits over time. So relapse prevention is a key goal of schizophrenia care. This applies really for those forms of schizophrenia with a remitting relapsing course. I got this from Dr. Venner, one of our old-time neurologists, when we talked about this he said, well this does sound like multiple sclerosis, doesn't it? So there's this idea of remitting relapsing illness course and really trying to prevent another episode. This is where it comes from. Endosarcotics are highly effective to prevent relapse. The number needed to treat NNT is three, which is really up there with highly effective treatments in medicine. But the reality really is first episode psychosis, one-fifth is not using services at all and the majority is not using endosarcotics following the first episode. So non-adherence is really part and parcel of the illness and it's a system failure. We have suggested to really think about team-based prescribing. It's another talk for another day, including patient-centered solutions, prescribing hope for recovery, or even thinking about the consumer perspective to increase this. But we actually have something that would make an enormous difference if used more widely, long-acting injectable endosarcotics. Many studies have shown that you reduce the relapse risk by 20 to 30 percent compared to oral antipsychotics, which I think anyone who treats this disease knows this to be true. And interestingly enough, if you look at so-called mirror image studies, it's kind of a pre-post design before you start the long-acting injectables, you find an even higher reduction in relapse, which makes sense. This is probably the group where you really, really want to use long-acting injectables. They also can be lifesaving. There's a 30 percent lower risk of dying from all causes when you use long-acting injectables compared to oral antipsychotics. I should repeat this sentence because that is incredible news. I spoke with an oncologist once and he said, well, do you realize if we had medicine that would lower our risk of dying by 30 percent, it would be a first-line treatment. And we would really emphasize this. I don't think we emphasize this enough with patients. Long-acting injectables really help you with shared decision-making that is based on facts. It gives you real-time, accurate information about adherence. I alluded to this briefly earlier when I said, you know, you want to have a long-acting injectable trial to determine if somebody is actually treatment-resistant. Because if they are pseudo-resistant, they would not necessarily need to be on clozapine. It also avoids family conflict. It is so nice to have family being parents and siblings and not the medication police and everything is just centered around, you know, the nagging, did you take your pill today? Long-acting injectables are not a panacea. They need to be best employed as part of a comprehensive care program. And I do think, I'll have another slide, we still need to maintain frequent clinical contacts with patients and not just give them a shot every six months. And breakthrough symptoms of hospitalizations is still surprisingly high with a 30 percent incidence despite long-acting injectables. Who are we going to select for a long-acting injectable? Any patient who prefers a long-acting injectable. And if you discuss it with people as a good first-line treatment, as a good choice, many may actually say yes. Clearly trials have shown this, the so-called prelapse trial, early use of long-acting injectables actually lower the risk of death, reduces suicide by half, better efficacy in patients with short illness duration if given then just like other medicines and could make an enormous difference. Also reduces a different group now, arrest rates and incarcerations if the offending is part of being psychotic. And I already, I think, mentioned with clozapine, cannabis use, long-acting injectables as well. So it is interesting that in those comorbidities that makes sense, right, that not having to think about an oral pill in a chaotic life potentially does work. Now this is the one slide that you are always told to never show, a slide nobody can read. I just want to show you that it's gotten complicated, the use of long-acting injectables because it's no longer just Haldol or Heloperidol and Flufenazine, but we have a whole host of other long-acting injectable preparations, not just IM but also subcutaneous and now stretching out all the way to three months or six months injections. And you do want to ask yourself here, how long is too long? The best injection interval is actually a clinical decision and less frequent clinic visits is not automatically better. I think I'm not telling you anything that you don't know, but you will have an opportunity to engage patients in many other discussions about the quality of life, about substance use, about medical stuff if they come regularly enough. There are some things that you need to know about injection technique. Some behave like a Newtonian fluid, ketchup is a Newtonian fluid, you know when you try to get something out of the bottle and nothing comes out and then all of a sudden everything comes out. So do seek consultation or refer to a clinic if you have somebody who would be a good candidate for a long-acting injectable and consider setting up an injection clinic if you have a specialty clinic that focuses on serious mental illness. The problem is really despite a clear recommendation from the APA in general, long-acting injectables are underused. They are often considered, there was a recent utilization study from Canada, even in Canada only third-line treatment, 6.5% only overall use. And the biggest barriers to long-acting injectable use may actually not be your patient, but you and John Kane in particular has really talked a lot about we need to figure out how to do the shared decision-making well, training, having support and everybody on the same page in a team to really help people make a good decision with regards to long-acting injectables, seeing it as a really good first-line choice as early as possible actually in the course of treatment. Inpatient units play a role in real-life prevention. Seth Palberger, you may not know, is a fabled coach for the German soccer team from 1954. He said after the game, it's before the game, this idea, you know, once you have somebody in the hospital, they recover from their episode of psychosis, you now need to prevent the next episode. So real-life prevention is a key goal of schizophrenia care, really begins with discharge, begins in the hospital, and here I put discharge planning, begins with the admission. Keep the long goal here in mind, and ideally, long-acting injectables in the discussion happens in the inpatient unit. Somebody is already sent out with the inpatient unit having started the long-acting injectable. So to summarize this section here, we have stage one, two, and three clinical high-risk first-episode psychosis, and then stage three and four, the chronic disease where you have different goals and different tools to manage this, and we just highlight here stage two. We want to reduce the duration of untreated psychosis using low doses of antipsychotics to minimize side effects. I didn't talk about this. We want to offer the coordinated specialty care if we can, and we want to offer long-acting injectables and clozapine if no symptomatic remission in three to six months. I think that's a good general guideline. So medical prevention. Why do we need to focus on mortality here? This reminds me of a story of a patient in our clozapine clinic who played the harmonica. Didn't play it well. He only knew one song, but we really missed him when he stopped playing because he had died from a massive heart attack. He was a smoker, and here's a reminder how times have changed. This is me. Same bad hairstyle, same tie, it looks like, on a smoke break maybe in a John Amstead Hospital in Butman, North Carolina, a state hospital where I began my training in the 90s. And we've come a long way. Patients with schizophrenia still have a higher rate of smoking, but they do want to quit. It's more difficult, but we have tools, and it's really Dr. Eden Evans from Mass General who has done study after study after study to show that psychopharmacology is not only needed for this group, but it's effective. Virenicline is better than the patch. It is safe in our patients, but also that maintenance treatment may be needed, which may be different from patients not with serious mental illness. He also has shown that provider education alone is insufficient. So just the medical detailing, me telling you, oh, you need to do more, will actually not lead to an increase in Virenicline prescriptions, for example, in your patients. So a little bit more effort is needed. And I think the one conceptual shift that I've seen in the field is an opt-out nudge as the default for smoking cessation. We're really now de-emphasizing the pre-contemplation phase. The idea, are you ready to quit smoking, and then people prepare forever in this pre-contemplation phase. So instead, we're going to basically say, well, I have here a medicine that may help you quit smoking, and people have to opt out. I think just conceptually that makes a difference. By the way, there's a phrase, there's a phase that's never in any textbook, it's the anti-contemplation phase. Some people get really angry if you bring up smoking with them. So tiptoe around the issue in those patients. The patient I described with harmonica that died was in our CLOSUPING cohort. Here on the right is the Eric Lindemann Mental Health Center, a beautiful buddhist building by the famous Paul Rudolph, famous architect. And this is Dave Henderson's work from 25 years ago, but I think it really makes a great point. The idea is, if you take patients in the CLOSUPING clinic and you just follow them over five years, five years of naturalistic follow-up, 30% of that patient group will be diagnosed with diabetes. So this was one of the first studies that really put on the map for us this issue of medical morbidity and mortality and schizophrenia. And you know that it is greatly decreased compared to the general population. I don't want to go over this slide in great detail, only to make the case that while we correctly, don't get me wrong, while we focus so much on suicide prevention, it's actually natural causes, meaning medical causes, that causes death in the majority of our patients. So the idea of focusing on reducing medical mortality and morbidity as a psychiatrist is not absurd to me, just looking at what's actually at stake. We need to manage the medical stuff proactively. So we could, using antipsychotic-induced weight gain and subsequent problems like diabetes as an example, we've got to choose wisely, if we can, to prevent metabolic syndrome by using metabolically low-risk antipsychotics. May not work if we need CLOSUPING, but it may be possible in some people, and switching to low-risk antipsychotics if possible, discontinuing also contributing medicines. Then we want to detect and treat guideline-concordant monitoring and treating identified medical morbidities, and then blunting and mitigating any antipsychotic-induced weight gain. I'm going to talk about this some more. I always like this quote here by Teddy Roosevelt in a speech that he gave at the Saban Citizenship in the Republic. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood. The point here is, as a physician, you've got to be active, got to do stuff, got to think about, you know, do I need to switch, do I need to add, did I do all the blood work? So just having patients come in and rewrite their scripts, I think, is actually no longer, if it ever was, is no longer good care. For a while, we used metformin, and there's an Irish metformin guideline. Shout out to Ireland here and our Irish colleagues, also from Boston, where everybody seems to be from Ireland, really found its way into guidelines to manage antipsychotic-induced weight gain. Specifically, in my mind, guidelines say any antipsychotic, but I think specifically for the high-risk antipsychotics like clozapine and olanzapine, we use it routinely, but metformin is not a weight-loss drug. And here now we have the, in creatinine mimetics, so the GLP-1 agonists, the classic one, exenatide, liraglutide, delaglutide, semaglutide, and then more recent ones, the dual agonists and the triagonists, that would be a talk in and of itself, I just put a slide here that shows how complex it is. It stimulates insulin release, decreases glucagon secretion, decreases hepatic gluconeogenesis, delays gastric emptying, and it promotes also central satiety and reduces appetite. So it acts at many different peripheral and central pathways to lead to a very substantial weight loss, potentially. It's also interesting now, you know, Zempig was one of the early ones, the Atlantic wrote goodbye with Zempig, because now we are onto so-called dual agonists, for example, Tuzepatide, which is GLP-1 plus GIP, and unfortunately, you know, they have hard-to-remember names, I put it in the box here, GIP stands for glucose-dependent insulinotropic polypeptide, and the triagonist also adds a glucagon receptor agonist with possibly even more efficacy. So I do think they do represent a shift, a paradigm shift for psychiatry in that the end-of-the-coding-induced weight gain, we are already managing it, but we must manage it better, particularly on people, in people who use high-risk medicines like olanzapine and clozapine, and who will gain a lot of weight. They are effective medicines, the GLP-1 agonists, they are psychiatrically safe, which matters since they are CNS-active, if you will, got to pay attention to potential drug-drug interaction because they actually change the absorption of medicines, and we really have no experience with newer GLP-1 agonists in schizophrenia, but there are some being studied right now, semaglutide, where the results are pending. It is a fast-moving field, a lot of things to be figured out, you may have read a question of expanding indications like obstructive sleep apnea was just a proof, and interestingly also alcohol or other substance use disorders. So keep an eye on those, think about what it means for you and your practice, and sometimes one image really shows you more than any study. This is a patient who was started on clozapine and metformin at the same time, by the way. Remember I said metformin is not a weight-loss drug, was titrated up and over the course of one year gained 60 pounds, and then something was started and you see the weight drop precipitously and what was started was a dual-GIP-GLP-1 receptor agonist, terzapotite in this case, and he basically lost all the weight that he had gained from clozapine, he was a young first-episode patient. Now unfortunately because of insurance issues, terzapotite had to be stopped and despite efforts with phentermine and topiramate, he regained his weight until they could figure out how to get terzapotite again, and you see the most recent point in this curve is actually below his starting weight of 190 when he started clozapine. So I think this is clearly something we need to keep in mind. Now our life has, just a reminder here, has not been smooth. These are the pandemic years, you see I'm still struggling with my hair, but it was great because I had an excuse to not go to get a haircut so often. This was our headline here in Boston, shut down. Six hours later the stores were empty, and you may remember, or you may not want to remember, but here our intrepid nurses in the clinic moved the chairs six feet, nicely six feet apart and the first group of patients immediately put all the chairs back together so they could talk to each other. What we did, this is again the Lindemann Paul Rudolph Goodlist building, I showed you Dave Henderson's cohort there, the clozapine cohort, and the diabetes development over five years. We used the same cohort basically with a concerted effort, and we wrote about it, to increase the COVID vaccination rates by taking this on as a task for us as physicians and as a clinic. In our cohort we actually exceeded the very high as a comparison vaccination rate of adults in Massachusetts. In a group of patients where I think people would have thought that's not really possible, and then we did some subsequent work, Dr. Van Elfen with mobile vaccine clinics, and I find this as a CL psychiatrist an intriguing aspect of care for us. So the next frontier I do believe is actually pulmonary health, it already is, but we need to really think about this lung cancer, there's actually screening guidelines given the high rates of smoking, asthma and COPD, there's a link to climate change with air pollution, obstructive sleep apnea, a very common problem in our patients, and I said already that GLP-1 agonist actually is a proof for that, and then the pulmonary infections, COVID-19 just one example, but of course many, many others. Here are three things you can do if you want to focus a little bit in your clinic on the medical morbidity, become an expert in smoking cessation, make it a treatment goal for every patient to smoke, smoking cessation that is. Become an ambassador, thank you Dr. Ling for this phrase, become an ambassador for vaccine preventable illnesses. I do think infection control is part of our job, at least since COVID, and infectious diseases because of climate change are an increasing threat. And then do become a champion of reverse care integration, meaning figure out ways to care for our patients with serious mental illness in the non-medical psychiatric setting, like in a community mental health center. If you have doubts, the World Health Organization guideline from 2018 is labeled management of physical health conditions in adults with severe mental disorders, and it makes it very clear that at least the World Health Organization considers this our task. And there's a book on medical psychiatry that I think emphasizes this. So what about outcome? Remember this slide? What is actually a good outcome in serious mental illness? This is sobering. And the quote here is from Churchill actually, however beautiful your strategy, you should occasionally look at the results. What it means is sometimes we do something, we pat ourselves on the back, another job well done. But the thing that keeps you honest in medicine is long-term follow-up. And that's why I really love this epidemiological long-term first episode study from Long Island actually, that's Suffolk County, Long Island, the Suffolk County Mental Health Project. It also started kind of when I was in training, they recruited over 500 first episode patients from 12 inpatients units, and then they followed them up over many years, publishing variously. And the most recent follow-up, it's actually 25 years. And the most common outcome pattern for this group of patients in the real world of U.S. health care was no remission and no recovery for schizophrenia. Now, if you didn't have schizophrenia, but other non-schizophrenia psychoses, you had some intermittent remissions and recoveries, but it usually was also not sustained. There was also some racial disparities and mortality actually 20% was fairly high. So why is that? Well, the problem is that we have antipsychotics, we focus on the positive symptoms, but the functional outcome is actually not driven by psychosis, but by negative symptoms and cognitive impairment for which we really have, let's just say, no approved treatment at this point. And focusing just on the middle here for the new treatments for schizophrenia, we have, and let me be very clear, we have no disease-modifying antipsychotic. So you could argue the whole idea of a stage-based approach is to have a medicine that modifies actually your disease trajectory. While we don't have that, on the other hand, hopefully I convinced you a little bit, but by intervening at different stages with appropriate tools, you can still overall potentially improve the outcome. Even if you do not modify the disease course per se. We also have no substitute for cosepine and we have no drugs for negative symptoms and cognition. We'll have to see the new non-dopaminergic antipsychotic, Zenoniline, which is a muscarinic acetylcholinesterase receptor, M1M4 agonist, as you know, was just approved, give you a talk in a year to tell you what we think. It's too new to be sure. I just want to show on the right side, it's clearly, you don't need statistics. This is one of the registration trials, the placebo, and then the active drug. Really a striking, nice difference of an effect size of 0.75 for the Zenoniline trospium and the trospium is the peripheral muscarinic antagonist approved for overactive bladder that is co-formulated to avoid the side effects, the poor tolerability of Zenoniline alone causing the cholinergic syndrome. I do believe we must continue to invest in psychiatric clinical trials. This is probably the most important slide in a way. It summarizes my thinking about how to truly actually improve the care and outcome of people with schizophrenia. Let's look at the two gray boxes. On the rest, on the left, we have unresponsive biology. That's a problem. We need innovation, new treatments, treatments that are better than clozapine for those who do not respond to even clozapine, and certainly it would be nice to have a medicine that is clozapine-like but devoid of the many side effects. On the right, we have time spent psychotic in the hospital or homeless with poor access to treatment or no care at all, with poor engagement in ongoing care. We have the social determinants of health, substance use, and we also have substandard psychiatric care and comorbid medical disorders, all impacting on causing a poor outcome. For example, we talked a little bit about the iatrogenic morbidity with anti-induced weight gain, and here's the harmonica, as a cause of death, which is the ultimate bad outcome in medicine. Here's the point. We actually had existing treatments that could have a real meaningful impact on patient outcomes, but they are not used enough. They're underutilized clozapine and long-acting injectable antipsychotics, and I hope I convinced you a little bit. If you use those using the stage-based paradigm, you would make a difference for your patient, and I could put here, just since I had included it in this talk, the next frontier, really the GOP1 agonist, figuring out how we're going to incorporate those into our practice. Social interventions have a greater impact on outcome than molecular advances. Paul Farmer said this. Here's a book that he wrote with Gutierrez in The Company of the Poor. He makes the point that we often have treatment, but we don't have a treatment system or society that makes it possible for everybody to benefit from those treatments. That's why the social interventions, how we arrange our treatment system, makes a much bigger difference. Now, I always take a molecular advance leading to a cure or a disease-modifying drug, don't get me wrong, but short of that, the problem really is access to treatment and people using the available treatments optimally. There are other non-medical treatments that we do have. Think about how easy it is for your patient to access those clubhouses, psychological treatments like CBT for psychosis. Let me also be clear, though, here, that optical pharmacotherapy is usually critical. We also have effective mental health care providers that are better and cheaper than us, psychiatrists. They're called peers. But let's also not demedicalize the medical aspects of care. I think we have to be careful in the pendulum, and it has at times swung too far in the direction of questioning any expertise that we may bring to the table. And ultimately, the system must become human-centered so real people can actually navigate it. But it's hard. The system has too many networks. It's basically a disorganized journey for patients. and maybe in a conceptual way. We really want to, I like this term by Jeste, positive psychiatry, not just positive psychology, but really positive psychiatry and emphasizing the recovery as a goal as well. So we have no more excuses. We kind of know how to do it. Herbert Marcuse, the German leftist, you know, who really thought very hard about the utopias in what it means. But Wilhelm said it best, I think, and I'm translating here, medicine is a social science and politics is nothing more than medicine at a larger scale. That's literally translated. And you see it today, you know, when we have discussions about Medicaid cuts, you know, who's in power, who determines who has access to what treatment. And Don Berwick, who ran CMS for a while and others basically said all organizations are perfectly designed to get the results they get. I think that's the naked truth right here. So we shouldn't be shocked if we have people with no insurance that they can't access any treatments. Now, I look worried, right? Is the crisis over? Well, I don't know. Toilet paper is back. Yes. And you know, my card here, my vaccine card is filled out. But it still feels like a crisis and maybe more than one crisis. On the right, you have in Berlin, the Ukraine, a welcome center. So we have a war in Europe, we have a social movement, Black Lives Matter, and the backlash now against diversity initiatives, or DEI initiatives. And we have, of course, there's no plan B, the whole issue of climate change, that does feel like a poly-crisis or permanent crisis, permacrisis, or even a meta-crisis of systems, maybe a crisis even of late-stage capitalism. And certainly, global warming is dangerous for humans. I have a nice talk about this if I get invited again. Just the whole issue in this case for our patients, actually increasing heat-related deaths for people with schizophrenia has been shown now in studies that our patient population is at a higher risk. Andrew Nuremberg pointed out, in this age of turmoil, we have the opportunity and privilege to do everything we can to relieve our patients' suffering and to maintain our ability to care for our patients. It's imperative that we take care of ourselves. We can do this by living as full a life as we can by cultivating relationships, curiosity, interest inside and outside work, and finding opportunities to be kind and generous. And this is really, in a way, also one of my key slides. If you feel helpless in this day and age, and if you don't know what you could do for your patients, because everything seems to be getting even more complicated, and climate action here is, this is where it comes from, from Dr. Johnson's TED talk about climate action, but it's really any type of professional action or non-professional action, but let's stick with professional action. Always think what works needs to be doing, what are you good at, and what brings you joy. And if those things come together, there's a lot of things you can do in disaster psychiatry with med-psych integration that we talked about, immigrant health as another example, medical education, which I kind of do here, this is really brings me joy, or political advocacy. And I do believe picking something even small, doesn't have to be large scale, just a small, will give you some sense of control, and that you're actually contributing. So when it comes to climate change, some small thing that we did, here's the term again, not just vaccine ambassador, but climate change ambassador, doing a provider and patient education, shelters, group homes, inpatient units, in services, to help them prepare for heat waves. And this is up here, up here in Boston. So obviously, some people listening to this from other parts of the country have been doing this forever. But for us, it's a kind of a newish, newish thing. And just one example of how to prepare, prepare our organizations to respond to the challenges of climate change. There's something that's dear to my heart, sounds dramatic now, the lessons from Nazi Germany, but the values of compassion in society can get eroded. Health of a society and prevention can supersede individual welfare. And atrocities are possible. You know, there may be medical theories of the time, ideologies that are just wrong in hindsight, social and peer pressure and simple careerism. And anti-humanistic forces always exist in any society. I don't want to point fingers at this point in time, but I do believe we live right now at a time where some vigilance is necessary and perhaps some willingness to defend the weak. So do please use your professional voice to speak up for people with serious mental illness, so they can benefit from the approach treatment as prevention, improving the outcome that are outlined, including creating the societal conditions under which some flourishing can actually happen. And in a way it's, you could call it a commitment to professionalism if you do this, considering primacy of patient welfare. So reject the patient's commodity, patient autonomy, give patients a voice and to think about social justice issues, offer asylum in a broad sense when you have a clinic where people come to you. And I do like the ideas of accompaniment and solidarity as the basis for a lot of things that we can do. And I hope it makes sense that I include this in a talk that, you know, I could just talk about the psychopharmacology itself, but there is no psychopharmacology without a commitment to professionalism, I believe, and a sense of trying to truly help our patients. So here are some references. If you're more interested in semaglutinin psychiatry opportunities and challenges, so the whole issue of GLP-1 agonists, pay attention to this. I had an opportunity to summarize our second opinion consultation service. Dr. Lim is the lead author here and the last one in psychiatric services last year. And it really does discuss the stage-based care that was the topic of my discussion today. And please do read Torian Lieberman's editorial, The Underuse of Clozapine in Long-Acting Ejectable Antipsychotics. So I was in a way in psychiatric services recently. So in a way, I was very pleased to see this. I should have written this because this is a talk I've given in some form or another for many, many years, and it confirms that I must be onto something. So with this, I'll leave you with a photo of Arlington, Massachusetts, and of Cambridge, Massachusetts. Thank you for your attention. And let me stop sharing so we can have a little bit of question and answers. Dr. Magan, yeah, I see him. Hi. Thank you so much, Dr. Freidenreich, for this very, very thought-provoking talk in an area that is close to our hearts. And I would also remind our attendees to add any questions in the Q&A section in the meantime. Now, you noted very clearly, and we are aware, as you mentioned, we are aware, as you mentioned a few times about Clozapine continuing to be underutilized in our clinical settings forever. And, you know, you talked about how many, many years ago you had written this paper, and we just referred to the 2025 article, kind of reflecting on the same issues. Now, I just wanted to, and you've shared this, but just wanted to reiterate for our attendees that one of the big news that we received yesterday, and I'm going to quote from the FDA website on this, is that FDA does not expect prescribers, pharmacies, and patients to participate in the risk evaluation and mitigation strategies, called RAMS, program for Clozapine anymore, or to report results of the ANC, or absolute neurofil counts, before pharmacies can dispense Clozapine. FDA still recommends that prescribers monitor patients' ANCs according to the monitoring frequencies described in the prescribing information. Now, this is something that APA has strongly worked on advocating together with the patient groups that you noted, and we will continue to work on, you know, enhancing education for members and non-members. But wondering if you had any additional thoughts on this, on how to, you know, move forward. This is obviously something that's very, very close to you, as you've shared. Yeah, I think you kind of said it in so many ways. I mean, this is incredible news. It also, to tie it back a little bit to, at the end, what I talked about, the issue of, you know, pick something that you want to fight for to help our patients. Advocacy, it may not happen overnight, but, you know, collective action, it may actually happen. You know, the APA has been very instrumental, NAMI, Angry Moms, and at some point, the FDA just couldn't ignore this anymore. The next few months, I think, it's going to be interesting. There's a European guideline, actually a consensus guideline already that you can, if you Google it, you'll find it about Clozapine use. They try to harmonize this in the EU, which has a different system, and their guidelines is basically, they just, you know, they really reduce the monitoring frequency and the possibility of them not monitoring at all at some point. I think we'll come up with something. We're going to follow the package insert, whatever that will say in the end, with the possibility that, you know, in a discussion with your patient and the family, to come up with a reasonable plan that actually makes sense for the patient. I think the big news here is that the decision-making is actually put back on us as physicians, together with patients and families, as opposed to just some system where the patient goes with the script and the pharmacy says, well, we don't have your blood work, but I did give it. I mean, the runaround, and this is what really, I think, where Angry Mouse was so impactful, the runaround that our patients and families have gotten from a clunky system that didn't save any lives, by the way, the way it was set up. If anything, it probably prevented people from ever starting. So, this is encouraging. It is just one example, I believe, where ongoing advocacy for our patient groups will eventually make a difference. And the internal vigilance, if we don't pay attention, you know, things may go backwards as well. Absolutely, absolutely. That's very well stated. I think I didn't answer your question, so keep an eye out for, you know, APA. I do believe there's going to be some guidance coming out over the next few months, how exactly to implement this. It will require, I already heard that some pharmacies are obviously not aware of this, refuse to actually acknowledge, you know, even if you show, the family shows, you know, the printout from the FDA, they don't believe it. So, I think there's going to be a confusing few months. Yeah, absolutely. And I think, again, we'll be working with our pharmacy colleagues as well, you know, the society, the associations for, you know, psychiatric pharmacists and others. I think that's something, again, we'll need to keep working on. Now, there are a couple of questions in the chat. One is about Clozapine again, and that's, that talks about, you know, thank you for your important emphasis on Clozapine, but what about when it does not work or when patients cannot tolerate it, even at 150 milligrams? Yeah, there's two dirty little secrets of Clozapine. I'm a big proponent, and I think I made the case, at least on a theoretical level, why it really is potentially life-saving and, of course, altering, if not modifying at least altering. The two dirty little secrets is, number one, the medical illness burden is substantial, potentially. That's why we have to be good at the med psych piece, the GLP-1 agonist, that's, I talked about this. And you raised the other problem that it's not effective for everybody. Most people have a meaningful response, not great, but meaningful, and there's a group of patients who really has no response. The one intervention, and I acknowledge that it may be extremely difficult depending where you live, what your setup is, the one intervention that would make potentially a difference is actually ECT. ECT. And, and there you see the problem, right? How easy is it? But it is an example of stepped care, where however beautiful your strategy, you should occasionally look at the results. If Clozapine doesn't work, what's the next step, right? And in an algorithm-based approach, it is actually ECT. Short of that, we always end up then trying stuff, adding other antipsychotics, and none of, none of this really works that well. Aripiprazole, we've done a study, may help a little bit. It's also nice, it actually does blunt some weight gain, so you have some, some, some dual benefit here. But none of these add-on approaches are really convincing. Now, we never give up, don't get me wrong. We still support people, and this is something we didn't talk about much. I had one slide. We actually have other psychosocial treatments. Maybe instead of just focusing on, well, which antipsychotic can we use next as an add-on therapy? Why not stepping back and saying, well, what is it about the patient's group home that doesn't seem to work? Maybe with some training, despite not a big change in psychopathology, maybe the management could be improved. And so the, the patient's experience in the group home, and then you set up a virtuous cycle, if you, if you will. I also am a strong believer in not focusing, despite my talk, focusing in some ways on symptoms, really focus on function. There's probably nothing more salutary than work. You know, work could mean different things to different people. Clearly, some people are not able to work in any meaningful capacity. But boy, the whole idea of clubhouses is that people, if given a chance, a niche, a little bit, a small job, you know, they can be part of the community. And I do believe we underestimate the importance of such things and just focus on the, what seems to be a low-hanging fruit is just trying another medicine. So I do encourage you in those situations to really step back and think, and I think I alluded to this, to think really more broadly. Absolutely. I think those are, those are great points. Now, our next question is, how soon should we consider starting metformin in patients? Should it be prophylactically in patients on antipsychotics who have a higher chance of metabolic side effects, or should it only be when they start getting considerable weight? Yeah. Well, the reality is that most people will gain considerable weight. So weighting doesn't really make much sense. And even those people who don't gain that much weight, at least not visible weight, may gain, you know, the invisible weight and develop the metabolic syndrome with seemingly normal weight. So that's a, that's a problem. And you really use the metformin, not for weight management, but to reduce the risk of the metabolic syndrome. And the metabolic syndrome is not just from weight gain. It's, it's also a direct effect having to do with insulin metabolism. What do I do in reality? I hate to start it at the same time that I start closing pages because then you have a problem, you have side effects, and then you know, you know what comes from what. So I do, I do wait a little bit, but I don't wait, you know, month after month or week after week, they come in, you weigh them and it keeps going up. So, so please do do it earlier rather than later. In a way, it is a little bit of a clinical decision. And some of my colleagues just started at the same time. That's interesting. Now, the next question we have in the chat touches on some of the unmet needs you were discussing, right? And one of the biggest ones being cognitive functions and schizophrenia. And, you know, the question is, do we know if Clozapine is protective for cognitive functions? That's one. And that's a multi-part one. The second one talks about how do you stage care with long acting injectables and advancement to Clozapine or do you do it the other way around vice versa? So maybe let's start with those two and then there's a third part to it, but Clozapine and cognitive function. The staging is interesting because in a way I kind of told you what I do, right? I do consider long acting injectables as a first line treatment. So ideally if people agree, you know, that's what they're on. That also solves the problem then if they are treatment resistant, the pseudo-adherence that I mentioned or the pseudo-resistance because of poor adherence. So you already have, you don't lose too much time. And then it's very easy to just, why do you keep the long acting? Just pharmacokinetics thinking to have a Clozapine trial. So this is kind of the order. If I answer your question with this, there are some people on Clozapine where you end up adding a long acting injectable that I mentioned eripiprazole is possibly having some benefit from an add-on. It is interesting that there's a small group of patients from this combination treatment seem to be doing better overall. And if they are partially adherent only to Clozapine, they still do okay. And the rapidity of relapse is not as pronounced. As you may see otherwise, you know, unfortunately the truth is you can look at many studies and you will find some that make claims about cognition. Would you use Clozapine to improve your cognition? I know the answer. It's not a pro-cognitive agent. And even if there's some aspect of it, um, because it's very endocolinergic, you have this problem that the, the, the, the, the receptor profile is such it's just not a good drug. That's why it would be ideal to have a better Clozapine drug that works like Clozapine with regards to efficacy, but with better tolerability. And I didn't really discuss the possibility of actually impacting, impacting cognitive function with Clozapine. Now it gets complicated. You'll see, if you look it up, Clozapine, no Clozapine, the metabolites and all kinds of things. But, but I think it's a drop in the, in the bucket. I mean, treatment resistant schizophrenia is actually a neurocognitive disorder. And, and so, so we, we, we desperately need, need pharmacotherapy for this. And I recall, you know, there was, there were some initial clinical trials with the Glycine inhibitor, right? That didn't quite go well. Yeah. I mean, we'll, we'll see it. It's not, none of this is out. So maybe there, there's going to be a game changer if the FDA actually approves a drug like Glycine, you know, transporting inhibitors. But we'll, we'll, we'll have to see, you know, and it would not be actually specific for schizophrenia. That would be really a trans-diagnostic approach. Absolutely. And I think the third part for this question, we are almost out of time, is what's your experience with Amyosulpride? I don't know if you want to? Zero. I'm not in the, I am from Germany originally, but I mostly trained here and practiced here. My colleagues in Germany, so I always ask, you know, what are they doing? Amyosulpride in Germany is first line treatment. And the experience is, it's excellent because it's really fairly safe. It's fairly clean. And it is just unfortunate that the drug is old, so there's no interest in bringing it to market here. There's one company that is modifying this drug, adding a methyl group, I think, so they can claim it's something new, but, but I don't know, it's a small company if they ever will, will make it. Awesome. I'll do one last question and then we'll wrap it up. Is there any role for pharmacogenomics at this time in making treatment choices in managing first episode schizophrenia or even treatment resistant schizophrenia? I can, I can only say, answer this wrong and make people unhappy, but I wish we, I wish we couldn't just order it. Okay. Think about when we think, and then people don't get, they order pharmacogenomic testing, but they forget we actually have therapeutic drug monitoring for clozapine, for example. I'm really only interested in how high the clozapine level is, not about the genetic composition of the person. The clozapine level is actually what I'm interested in. So, so, so why not just go where I'm actually interested in? It's expensive. It doesn't really predict. Does it, do I, do I order in cases where I'm really surprised that somebody has such a low blood level? Yeah. Then it could confirm, well, it is because of pharmacogenomics, but it's the other way around. It's not the starting point. Thank you so much. Thank you for your time, Dr. Rodenreich. It was amazing conversation. Like I said, very thought provoking on, on multiple levels. And I thank our audience for, for joining us and we look forward to our next emerging topic webinars here soon. Thank you again. Take care. Thank you for guiding me here, Dr. Madan. And thanks, thank you to the audience and APA for this opportunity. Have a good rest of the day.

schizophrenia

stage-based care

early intervention

long-acting injectables

clozapine

treatment-resistant

metabolic side effects

antipsychotics

GLP-1 agonists

integrated care

REMS program

public health disparities

patient outcomes