All right. Hello everyone. Welcome. Good to see everybody. The topic here is Clozapine. And this talk is actually focused on everything that you need to know how to start a new patient on Clozapine. Now we're going to be hearing from our other presenters about more of this data, but you know essentially if you look at first episode patients prospectively, about 23% of those individuals are going to meet criteria for treatment-resistant schizophrenia at some point in their life. Also about 25 to 50 percent of people with schizophrenia have a suicide attempt and maybe between 5 to 10 percent die by suicide. So despite all that, in the United States we're only using Clozapine for around 4 to 5 percent of people with schizophrenia. This gap I like to think of as the Clozapine underutilization gap. It's maybe 18% or so. So the only way that we remedy this gap is by starting new patients on Clozapine. We would love to have a talk in the future about what do you do if you've been working with someone who's transferred to your care that's on Clozapine. You know there's some specific considerations. This is really focused on identifying appropriate Clozapine candidates, coming up with a plan, a titration plan, and then initiating Clozapine for them and then monitoring things. Okay so this talk is sponsored by SMI Advisor, also known as the Clinical Support System for Serious Mental Illness. Our initiative is funded by SAMHSA and it is administered by the American Psychiatric Association. We are in year six of our grant. We have a bunch of free resources for you on how to use Clozapine. We have a Clozapine Center of Excellence. You can write a consultation to us free of charge and we'll get back to you with an evidence based response within 24 business hours. So Friday afternoon consult we will respond to on Monday probably or a Friday afternoon depending on the complexity. Sometimes we can do an organizational consult as well. So if people are interested in you know starting a new Clozapine clinic, other sort of questions regarding Clozapine, we're happy to help with that as well. Okay so our distinguished faculty for the afternoon. We have Dr. Oliver Freundreich from Mass General. He's the co-director of the MGH Psychosis Clinical and Research Program. We have Fred Nusifora from Johns Hopkins. He directs the Clozapine clinic there and he is also the co-director for the Schizoaffective Disorder Precision Medicine Center of Excellence. And I'm Rob Cotez. I am an associate professor at Emory University. I direct the Clinical and Research Program for Psychosis there which includes a Clozapine clinic and an early psychosis program. And I serve as physician expert for SMI advisor. The learning objectives for today pretty straightforward. After you walk out of this talk hopefully you'll be able to list three tips for identifying a patient who may benefit from Clozapine. You'll be able to describe an initial titration strategy for starting a new patient on Clozapine. You'll be able to state how to use a Clozapine level early on in a titration. And then finally you'll be able to list and describe strategies to mitigate the most common serious side effects of Clozapine including neutropenia and myocarditis. Here is the list of our disclosures. They're also available in the slides. As far as the agenda goes we're going to be together for 90 minutes. First we'll do a little bit of an introduction. Well we're in the middle of the introduction. Then we'll have Dr. Nusifora talk about Clozapine efficacy. Some tips on how to identify Clozapine candidates. I'll then go into how to have a conversation with people who are considering Clozapine. Talk a little bit about various rates of titrating Clozapine for new patients. And a little bit about therapeutic drug monitoring using Clozapine. And then after that Dr. Freundreich is going to talk about how to manage Clozapine side effects. If we have time I'm going to talk a little bit about how to efficiently manage Clozapine REMS. And then we'll have about 10 minutes for question and answer. So with that I will go ahead and hand it over to Dr. Nusifora. Thank you. Great. Well thank you for everyone coming. I'm going to mainly focus on the idea of treatment resistant schizophrenia and what that means and how that will help in deciding what patients should be on Clozapine. So about 70% of patients respond to treatment with standard antipsychotics. And their term non-treatment resistant schizophrenia. About 30% of patients have treatment resistant schizophrenia. And that means that they don't respond to the standard antipsychotics. And the only FDA approved medication for treatment resistant schizophrenia is Clozapine. And then unfortunately about 30% of patients with treatment resistant schizophrenia do not respond to Clozapine. And they're considered to have ultra treatment resistant schizophrenia. And so the idea of defining treatment resistant schizophrenia is important because Clozapine is indicated for treatment resistant schizophrenia. And the way to define that is essentially that a person fails two full trials of antipsychotics. And there was a group that got together to decide on what the criteria should be. And those are mainly for research studies. But I think they're useful to think about clinically. And really the key elements are that you've confirmed the diagnosis. That they've had adequate pharmacological treatment. So you want full failure of medicine. You want people on medicine for at least six weeks. They were receiving the proper dose and they were getting about 80% of the dose throughout the time they were on it. And that they continue to have persistent symptoms usually of moderate or above. And so if we think about treatment resistant schizophrenia, I think that it's interesting and kind of important to think that it may possibly be a subtype. So there may be a different pathophysiology between treatment resistant schizophrenia and non-treatment resistant schizophrenia. So it's possible that there's just a continuum of severity between non-TRS and TRS. But it's also possible that there's a different pathophysiology. And so I'm going to describe some evidence that compares non-TRS and TRS and give you a sense of why they might be different. So if we look at the clinical characteristics, when comparing TRS to non-TRS, patients with treatment resistant schizophrenia tend to have an earlier age of onset. The ratio of men to female is equal, whereas it's usually higher within males. It's associated with more rural residents. And at the time of diagnosis, you're more likely to have been inpatient, require more medications, and spend greater than 30 days in a psychiatric hospital. It also is likely a more familial form of the disease. So patients with treatment resistant schizophrenia are more likely to have first or second degree relatives with schizophrenia. If we look at what's known about the cognitive performance, this is two studies. The first one on the left, it looked at a number of battery of tests, cognitive tests. And as we know, patients with schizophrenia perform significantly worse on all cognitive measures compared to controls. But if you notice in the non-broken line, the TRS, with verbal learning and memory, is the only cognitive domain that's separated from non-TRS and TRS. And this was replicated in another study that looked at verbal memory, working memory, processing speed, executive functioning. And they saw the same thing, in that verbal memory was the only one that's separated from control and non-TRS. So suggesting that there may be a different pattern in their cognitive abilities. The patients with treatment resistant schizophrenia also respond to clozapine as opposed to the other antipsychotics. Clozapine is the only medicine FDA approved for treatment resistant schizophrenia. It's the consensus choice as the most efficacious antipsychotic. And TRS is often defined as including any patient on clozapine. There's not a lot known about the biology. So clozapine, it's thought that it binds weakly to the D2 receptor. And it also binds to many other receptors, including the serotonin receptor and muscarinic receptor. But unfortunately, to date, we don't know why clozapine is superior. And I'd like to show this. This is a meta-analysis. And what's nice about it is the way it was done is it's a ranking. So as you go up, the medications are more efficacious. They were able to take a meta-analysis but actually rank them. And as you can see, all the antipsychotics, including some of the first and second generation medicines, are about equally efficacious. But clozapine is the only one that separates from all the medicines available in the United States. What do we know if we look at some imaging data? So this was a study done in a small number of patients, about 12 patients. And this is a PET scan looking at DOPA. And so what they found is that healthy controls and treatment-resistant schizophrenia patients had about equal levels of dopamine synthesis, whereas non-treatment-resistant schizophrenia, they actually had increased levels of dopamine. And so that that would make sense, right? If you're giving in a D2 antagonist, that would lower the dopamine and then the patients respond. But if you have treatment-resistant schizophrenia and your dopamine levels are already comparable to controls, taking that medicine may not help. So then the same group looked at the same patients that came back. It's not quite the same number, but you have 10, 8, and 6 patients. But these are the same patients from the study I just showed. And here they looked at glutamate concentration. And what they saw is healthy controls and responders had equal levels of glutamate, whereas the treatment-resistant patients had increased levels. And this was replicated in another study. So suggesting that maybe there's different neurotransmitters that are involved in treatment-resistant schizophrenia. If we look at what's known about the genetic loading, it seems that in some studies that they've shown increase in polygenic risk scores. This study shows that their proportion of individuals having at least one disruptive mutation in genes coded by antipsychotics, there was significantly more in patients with clozapine, suggesting possibly a greater genetic risk burden. And then we did a study where we wanted to understand what genes and pathways were differentially regulated between clozapine and patients on other antipsychotics. And interestingly, we found that there was a number of genes and pathways that were differentially regulated, suggesting that this provided some insight into treatment resistance and possibly why clozapine was better. So just a summary of the data for treatment-resistant as a subtype. There are clinical differences, such as earlier age of onset, equal ratio in male and female. There's possible specific cognitive deficits. It's more familiar and greater genetic risk burden. Patients respond to clozapine, but not other antipsychotics. TRS patients may have dopamine levels comparable to healthy controls, but elevated glutamate levels. And so I think the hypothesis that this is a different pathophysiology, it remains inconclusive, but it's certainly suggestive that these patients are different. And I think this is important, you know, as you think about identifying patients and using clozapine, you know, the idea of continually using another antipsychotic one after the other may not be helpful since these patients may have a different pathophysiology that responds to clozapine and not other medicines. The other issue I wanted to bring up a little bit is the idea of ultra treatment resistance. We talked about, unfortunately, about 30% of patients on clozapine won't respond. They're often, interestingly, they're often grouped together with treatment-resistant schizophrenia, and they too may have a different pathophysiology. So we wanted to understand what clinical features distinguish UTRS from other patients. And to do that, we wanted to determine the difference between treatment-resistant schizophrenia and ultra-treatment-resistant schizophrenia in a functional capacity and cognitive performance. And so we utilized simulations of real-world tasks critical for life functioning and compared clozapine responders to non-responders. So clozapine responders would be treatment-resistant and non-responders are ultra-treatment-resistant. And so this was a small cross-sectional study, sort of a basically a sort of a pilot study, but I think the results are interesting. So we had 27 patients with treatment-resistant schizophrenia on clozapine, ages 21 to 72. The clozapine levels were above 350, so at least suggesting if you had ultra-treatment-resistant schizophrenia, you were likely on a high enough dose and you were taking the medicine. The patient was considered a responder if their PANS score was less than 58. So less than 58 could be considered mild, and so the idea is that since this was cross-sectional and we couldn't determine who responded to clozapine, it's unlikely that you're going to start someone on clozapine if they have mild illness, so they were likely moderate or more severe. And so if they were below 58, they likely responded. And so 18 patients were responders and nine were non-responders, which is a roughly the ratio you would expect. And what we did is we performed these computer simulations. So there were three simulations, ATM, medication refill, and ticket purchase, as well as we performed the brief assessment of cognition and schizophrenia for cognitive functioning. And so the tasks were you would go up to a computer screen and an ATM, a picture of an ATM would appear, and you would follow commands. So it's really very much like doing this in the real world, and we also did that for medication refills and for purchasing a ticket. And the questions get harder as you go on. For example, one question might be you've been on 10 milligrams of a medicine for five days, your doctor increases you to 20, how many more days of medicine would you have left? And interestingly what we saw is the patients who responded to clozapine did significantly better in essentially every test that we looked at. And we looked at completion time, we looked at percent of correct responses, and then we looked at efficiency, which was correct responses over time. And so as you can see, so for example if you look at a portion of correct responses for refill, the patients who didn't respond to clozapine got about 40% of the questions right, whereas the patients who responded to clozapine got about 80% right. So quite a big difference. And if you look at the cognitive from the backs in D here, you see that patients who respond to clozapine did almost a standard deviation better on these tests. So what this says to me is that clozapine responders perform better on cognitive and functional capacity assessments. I think this further supports the use of clozapine in treatment-resistant schizophrenia, not only for greater that it improves their positive symptoms, but it also may improve their real-world functioning and cognitive abilities. Now it's unclear, because this was cross-sectional, it's unclear if the patients who responded to clozapine did better at the outset or whether clozapine improved it. But either way, it's an important information. If clozapine can increase their cognitive capacity and functional capacity, again that's a really great reason to use it more. And if they sort of start out different, then this may suggest who would respond and not respond to clozapine. And also the study highlights the problems of confounding these two groups. If we combine treatment resistance with ultra-treatment resistant, we have patients who are significantly worse in cognitive ability, positive symptoms, and functional capacity. And so it's possible that UTRS is driving a lot of the differences we see. So a summary, patients with treatment-resistant patients may differ and clozapine may have unique pharmacological properties that benefit TRS. So again, I think it's important to try to recognize the treatment-resistant patients and to utilize clozapine. Patients with UTRS do not respond to any antipsychotics, including clozapine. No biomarkers currently to determine who will be TRS or UTRS. And identifying candidates can be challenging, but it's really necessary to optimize care. And so in this case, I tried to kind of make a list. We're going to talk about when you should have high suspicion versus when you should really consider using clozapine. And so what I would say for high suspicion, a lot of these things we kind of talked about, but if you have a patient who presents with a younger age of onset, they have a first degree or second degree relative with schizophrenia, they have a longer duration of untreated psychosis, prominent negative symptoms, lower premorbid functioning, those are patients you should start to be thinking about. They may become treatment-resistant and possibly need clozapine. In my opinion, if you see someone who fails one antipsychotic, you should start thinking about the possibility of clozapine. And it's not uncommon for me to start to bring up, when I'm suggesting a second antipsychotic before clozapine, is to discuss, well, there is this other medicine, to just start introducing clozapine as a possibility so they're not kind of surprised, you know, when you're bringing it up if they fail another medicine. And then there was this sort of preliminary interesting study suggesting that possibly that the sum of three baseline pans on conceptual disorganization, difficulty in abstract thinking, and unusual thought content that may predict that if they had high scores in those, and those are pretty easy to assess for, that they may be more likely to develop treatment resistant schizophrenia. And so now, what I would say as high priority starts is if you fail two antipsychotics, you should absolutely be started on clozapine. And, you know, there are a number of barriers, but often those can be addressed. But the reasons that a person should be started is clozapine's superior efficacy. Polypharmacy in itself has medical risks. So many people will use multiple antipsychotics, high doses of antipsychotics, high doses of multiple antipsychotics, and the patients aren't doing better, and you're still exposing them to harm by doing that. So we know that clozapine decreases hospitalizations. It's actually a decreased discontinuation rate. And from personal experience, most of my patients who go on clozapine, they stay on it and they stay out of the hospital. And so I think it's really important to consider these things. There's an overall cost to the health care system, and there's potential improvements in other domains, as we talked about, like cognitive functioning and real-world functioning. Another high-priority start that I think is often overlooked is the idea of suicidality. Clozapine actually has an FDA indication for suicidality, and that came from the first study up top, which was the INTERCEPT study, and this was a two-year prospective multinational study, and it looked at several outcomes for suicide, including patients with significant suicide attempts, hospitalizations, actual suicidality, and the understanding of suicide thoughts. And this was compared to olanzapine, and what they saw was that there was a significant improvement in all of those domains except actual suicides, but there were only a handful of suicides in the study. And so actually, Rob and I and Paul Nestat and a number of us just published a paper recently where we wanted to look at, that clozapine may reduce these suicidal thoughts, but we wanted to know if that actually led to changes in suicidality. And so we were able to get autopsy data from the state of Maryland, and in the state of Maryland, if you die of unknown causes, they actually do toxicology, and they actually obtain clozapine on olanzapine levels, and so we were kind of able to mirror the INTERCEPT study. And what we saw is that descendants with clozapine were significantly less likely to have died by suicide than by accidents, and this odds ratio was .47. So it suggests, you know, further suggestion that clozapine could be beneficial for your suicidal patients. The other time to think about using clozapine is if a person has tardive dyskinesia. And so there are now medications to treat tardive dyskinesia, but in my experience, I think if a patient's developing tardive dyskinesia, I'd rather get them off of the medicine than have it progress and have to consider using another medicine. And so clozapine is one of the least likely medicines to cause tardive dyskinesia. This is probably likely due to its weak binding at the D2 receptor, whereas Haldol binds tightly and is more likely to cause tardive dyskinesia. So often if I have a patient presenting with tardive dyskinesia that's developing, or even if they have it, I consider switching to clozapine. And then talking about clozapine non-responders. Obviously more research is needed to understand clozapine responders versus non-responders. It's possible that these cognitive and functional capacity assessments may help to distinguish it, but it's too early to say. And, you know, there's some evidence that delaying starting clozapine is more associated with ultra-treatment-resistant schizophrenia. So, you know, again, I think the case is to be made to use clozapine and to use it as soon as it's warranted. And so the recommendations from this is clozapine is vastly underutilized in the United States. Delaying initiation of clozapine is associated with poor outcomes. At least 30% of patients should be on clozapine if you consider, again, tardive dyskinesia, suicidality, failure of other medicines. Clozapine should be initiated after two trial failures. Clozapine, and the point is the clozapine side effects can be monitored and mitigated. And data suggests that patients are less bothered by the mandatory blood draws than prescribers tend to think, and patients actually prefer to be on clozapine. So, you know, I always tell my team, I don't want us or the psychiatrist to be the barrier. I think we have to really think about using it and, you know, often I hear, oh, they won't get the blood drawn, or, oh, we can't start clozapine. But, in fact, you know, often that's not the case and that patients do better, and with wraparound services and a supportive team, people can get on clozapine and do quite well. So, thank you. All right. Thank you so much, Dr. Nusifora. So, I think, really, in one of these days, we're going to have a biomarker that's going to help us to develop, to understand who has TRS, and maybe even to understand who has ultra-tremor-resistant schizophrenia as well. But right now, we do not have that. And I think that when we do, there's going to be some really interesting conversations to be had with our patients about saying, like, okay, we think that you may have this particular phenotype and we think that clozapine may benefit you, and there's, I think, a really interesting discussion to be had when we get there. But right now, we're at this point where we have to identify clozapine patients and then we are going to be talking to them about clozapine and sort of explaining its potential life-changing benefit. So, the first thing we're going to do is talk a little bit about some tips on how I like to talk to people about a discussion about clozapine. And, you know, by virtue of running a clozapine clinic, sometimes people think that I have some sort of magical powers. And they'll say, Dr. Kotez, why don't you go and talk to this person about clozapine? And their expectation is that we're going to walk out of that meeting and this person is going to go on clozapine. And that is just a wild expectation. And I don't know. I've never been successful. But one way to think about it is this is a conversation that's going to take time, most of the time. Sometimes, some people might just say yes. But really, I mean, the other day, I started a patient on clozapine. We've been talking about it for three years. And then, yes, just one month ago, he started clozapine. He's having a beautiful response. So it takes time. And, you know, on inpatient settings, it's very difficult because often you have a very abbreviated time to work with people. Still, very, very difficult. But even over the course of that admission, you can talk to people multiple times, potentially, about clozapine. I work on an early psychosis team, a coordinated specialty care model. And like Dr. Nusifor was saying, like with early psychosis patients, after someone has had one antipsychotic failure, maybe even on a long-acting injectable, we're beginning the discussion about clozapine. We don't want to get into a situation where people have been on five to nine antipsychotic trials before they have an opportunity to be on clozapine. So some tips on how to make an effective case here. Know, first of all, where you are with clozapine. And in a study that we did, a national study, about 40% of respondents actually preferred to combine two antipsychotics versus use clozapine. And if you're not sure how to use clozapine or if you don't believe it's going to be helpful, in that discussion you have with someone, that might come through. I think it's important to balance the amount of time you spend with someone talking about the potential benefits versus the potential risks. Some of our most talented residents at Emory ever have had conversations with patients 45, 50 minutes long, and they have explained the five black box warnings for clozapine plus other side effects. Priapism, rare side effects. And at the end of that meeting, that patient's like, get me out of here. I don't want to talk to this. This is too much. So you have to really think about balancing what is the potential benefit versus the risks. Also, save yourself some time. If you use an electronic medical system, medical record system, we have a number of dot phrases that talk about the consenting process for clozapine. So it's like, dot, start clozapine. And the five black box warnings come up, and also the additional potential side effects. And we just sort of go through and talk about those with folks. We have developed sort of a systematic approach called Team Up, which really underscores the partnership that we're having with our patients when we're starting clozapine. It stands for, BARD didn't come up with this. It's not CHAT-GBT acronyms before all that. The acronym is Team Up, which stands for time and setting. Think about, you know, this is going to be an ongoing conversation. The setting is really, really important. This isn't sort of a doorknob kind of conversation. You want to elicit the goals and priorities of that individual. Sometimes the case for coming back to functioning is much more effective than the case of, you know, sort of reducing symptoms. I have a hunch that some people who are doing great on clozapine probably don't believe the idea that they have schizophrenia. But the medicine can really be helpful for them. So you also have to anticipate possible barriers, which we'll talk about. Have some facts in your mind about what the medical side effects might be. One fact, one in 7,700 people that are exposed to clozapine actually die due to severe neutropenia. It's fairly rare. And also, family members can be incredibly valuable. And I like to use a decision matrix kind of that you can see over here. Write it up on the whiteboard. Benefits. Pros. Cons. Okay. Be prepared for certain kinds of responses. This is a really nice piece that kind of goes over some potential statements that you may say based on the types of barriers that people often have. So some of this is here. I can't get blood work weekly. Yeah, blood work can be a pain, but it gets more spaced out over time. You may consider using point-of-care technology. There's a point-of-care home device now that can be utilized. If you find the burden isn't worth it, we can change to a different drug. If you don't like getting your blood drawn, we can do a finger stick. Clozapine has too many side effects. So I think having some of this stuff in your mind can be helpful. But really, the most powerful advocates for clozapine are patients themselves who are taking clozapine. I really think that the patients are their own best ambassadors for clozapine. When people see someone who's been recovering and doing great because of clozapine, that's a very, very compelling story. More compelling than anything I can say. So this is an example of a young man that I interviewed in his family. He was started on clozapine. This is on the SMI Advisor website. Watching these patient testimonial videos can be really, really helpful. The anecdotal evidence can be powerful. Okay, how to titrate clozapine. My wife accuses me often of trying to overcomplicate things. And I don't want to overcomplicate things in this section. But I do want to give you some practical guidance on how to titrate clozapine. First, you have to have an initial monitoring rubric set up. There's a lot of different ways that people can do the initial monitoring. Obviously, you have to monitor the absolute neutrophil count for the first six months that people are taking clozapine. Then the variability kicks in. Some people do a myocarditis screening protocol. It's never been shown that a myocarditis screening protocol actually reduces the risk of myocarditis. But many people find it quite valuable, especially if you've seen people with myocarditis. And Dr. Freundreich will talk more about myocarditis in the next section. I like to do a pretty simple one. I don't like to get a baseline echocardiogram. I like to get a baseline EKG if I can. I do troponin, CRP for the first eight weeks, particularly in an outpatient. I also like to do serum creatinine for the first eight weeks to screen for interstitial nephritis. Vital signs, as often as you can get them. If somebody can get access to vital signs at home, have them do them at home. You may not have the luxury of deciding where to do the clozapine titration. Let's say you work in the inpatient unit. You might not be able to say, but I think in general, outpatient titrations are typically slower. Somebody might have good support. There's an urgent but not immediate need. Maybe you don't have access to a voluntary hospitalization in your setting. Inpatient titrations can be done a little bit more rapidly. And we'll talk a little bit about titration rates, particularly with high clinical acuity, suicidality, instability with housing, and then difficulties following the titration schedule, failed attempts at prior outpatient titration. The majority of the clozapine in the United States is probably started on the inpatient unit. The inpatient to outpatient transition is a common place where things often fall apart in a clozapine sort of initiation. So you really have to have good partnerships with outpatient sort of clozapine folks in order to get this right. I presented this poster last weekend at a research meeting in Toronto that kind of takes a little bit of a dive into what do different guidelines say about the target clozapine dose at 2 weeks based on 14 different sort of published titration schedules. What's shocking is if you look at the package insert, the package insert says, titrate clozapine, get to a target dose up to 2 weeks of 300 mg to 450 mg, as you can see here, kind of on the extreme side. So, in general, slower titrations could possibly be a little bit more, I think it would be safer. There's a lot of different options that you can use. There is no such thing as one clozapine titration to kind of end all. It really depends on the patient that you're working with. We published this recent paper that defeats the hair, the case for slow clozapine titrations with CRP monitoring. I like to use, again, CRPs the first 8 weeks, slow titration, slower titration outpatient versus inpatient. Part of the issue is that rapid clozapine titrations are most likely associated with myocarditis. There's an increased risk of myocarditis if you titrate to somebody who has 300 mg at 2 weeks versus 300 mg at 2 weeks. That difference right there might put your patient at an increased risk for myocarditis. Plus, going slow can help to minimize the overshoot that sometimes you might see on an inpatient unit if you're doing a very rapid titration. You don't know what the minimally effective dose of clozapine is. Then also, early discontinuation based on side effects the patient might stop clozapine. If you don't use a lot of clozapine and you see somebody develop side effects, then you might be less likely to use it the next time. Going slow can be helpful. This is a sample of what we do at Grady. Relatively slow titration, we get to 200 mg at 16 days. That's give or take. You have to really have some flexibility once you have set a titration schedule. I like to use this one for the inpatient setting. For the outpatient setting, there's been some nice resources from the North Carolina Clozapine Network. This is an outpatient titration that's on their website. You can see 100 mg at 2 weeks. At week 5, these are folks who are on 250-300 mg of clozapine. In an outpatient titration, you really have to think about how frequently can this patient get vital signs, particularly in the first 2 weeks. Is the titration schedule feasible based on the complexity of the titration? If you have a lot of dose adjustments over the week, is it really feasible to do that? If somebody's at a board and care home or a personal care home or they're doing it on their own. I really implore people to have a mechanism in place for the patient to reach you directly or early in that titration if something goes wrong. If you look at the package insert, I know I'm picking on the package insert because reasonable people might actually look at this. The titration schedule on the package insert is divided into 1 third in the morning and 2 thirds at bedtime. The majority of clozapine in North America is given at bedtime. Many times I like to just dose all the clozapine at bedtime. It's easier. It's very difficult to wake up in the morning taking clozapine and then functioning the rest of the day. Sometimes when people get orthostatic hypotension, I might split up the dose a little bit. Next slide here is this idea that personalized dosing is important. There's an increasing emphasis on the ethno-psychopharmacology of clozapine. There was an international guideline published by Jose de Leon and another number of authors including me and probably some of these guys here too that looked at rates of titration for people who are of different racial and ethnic backgrounds. I think that one of the key takeaway points from here is that individuals of Asian ancestry may need about half the clozapine prescribed to Caucasian patients. On this slide I've highlighted one of the different six clozapine titrations. This is of someone with Asian DNA ancestry on an inpatient unit with average metabolism, not a poor metabolizer. Genetic testing is sort of irrelevant right now in the United States for us in trying to figure this out. I think they have some other options in the UK and elsewhere in Europe to do a little bit more sophisticated genetic testing. It's hard to know actually if someone has average metabolism. You can see here at the end of week three this particular patient has gotten to 150 mg per day. Again, pretty slow. It's sort of highlighted in the green text and then it's highlighted in that little green arrow there on the graph. People always talk about well somebody is on three other antipsychotic medications and we want to start clozapine. Well what do we do first? Difficult, but typically you want to probably discontinue the most clozapine like medication first like quetiapine or olanzapine. They're very anticholinergic and antihistamatic medications. Those are usually the ones I target. I usually leave ones on with a little bit more D2 blockade especially if there's like three antipsychotics. You don't want to get rid of the anticholinergics, the benztropine. Clozapine is highly anticholinergic on its own. Don't give people more problems than they really need to have with the anticholinergics. And just so you can get a sense, non-smokers, 50 milligrams of clozapine equals one milligram of venstropine. The other thing, when you're thinking about the medications to start clozapine, you want to avoid, as much as you can, other constipating medications. Clozapine is gonna be highly constipating. Avoid other sedating medications. Clozapine's gonna do that on its own. This is not an evidence-based strategy, but this is something that we've been doing at Emory now for a little while. What happens if people miss a dose or two of clozapine? Caution when using this, not been studied. This is just practical wisdom. I don't know if it's wisdom, but it's a plan. And if people miss a couple of doses, you have to think about how are you gonna restart clozapine for that patient. Sometimes, if you restart at 25 milligrams and you do a very slow titration, that patient is gonna be quickly in the hospital. So there's a risk to restarting too quickly. Sorry, restarting not quickly enough. Okay, clozapine levels in a titration. We've really come to rely on clozapine levels to help guide our prescribing. You see just here the relative contribution of various CYP isoenzymes in clozapine's metabolism to its main metabolite, noreclozapine. CYP1A2 does the majority of the heavy lifting. Inducers are things like aerohydrocarbons, and then also omeprazole. Inhibitors, things that increase the level include fluvoxamine and ciprofloxacin. When you start somebody on clozapine, tell them if you get started on ciprofloxacin, contact me immediately. Don't, you know, like, talk to us. Try not to take it. You can get an elevated level of clozapine that can sometimes cause toxicity. So I usually give people a list of things that I don't want them to take. If they go to an emergency room and they get an antibiotic and they're not sure what it is, call me. If they get COVID-19, call me, okay? Most people don't think, call the psychiatrist with COVID-19, but gotta do it. Okay, clozapine levels. So most people think of 350 nanograms per mil as sort of the magical number. And there's no, again, no magic. I think, you know, to get you a little bit perspective on this, there was a recent meta-analysis that came out by Northwood and colleagues and Dan Siskind this year. And they found that the median clozapine dose that was effective was 372 nanograms per mil with an interquartile range of 223 to 558. So that means 25% will respond to less than 223 nanograms per mil. 25% will respond to more than 558 nanograms per mil. Sorry, bear with me. But what I'm saying is 350 is a pretty good starting plate. Risk of ADRs increase over a thousand nanograms per mil. So when do you get the first level if you get levels? Well, it depends. There's two ways that clozapine levels are measured right now. The first is the LC-MS-MS technology. This is a send-out lab that takes between five to seven business days to get back. The SMI Advisor Consultation Service is only one business day, shameless plug. Okay, the other way that clozapine levels are measured is by an immunoassay. And this is produced by Saladex Biomedical and it can be done at the same speed as you get your CBC with DiffBac. So you can actually, it's called a rapid clozapine level. So we have the immunoassay at our facility. We use it all the time. We have people get their clozapine, you know, their blood work in the morning, do a group and then come see us in the afternoon and we have a clozapine level back and we can do something. Particularly if the level is low and then we do a little retitration based on what people have been doing. A couple of pharmacology concepts. The concentration dose ratio is something to think about. It varies based on a couple of different factors like male, female, smoker, nonsmoker. And there's a two-fold difference between the dose that's expected to reach 350 nanograms per mil just based on those two factors alone. So one size definitely does not fit all. At SMI Advisor, we develop a clozapine dose planner where there's two different ways that you can look at this. Number one, maybe you'd like to predict the level based on the clozapine dose, smoking status, sex, weight and age. Or maybe you'd like to predict the clozapine dose that's needed to give you a certain clozapine level. So this is an example of how it works. You just kind of select smoking status, sex, weight in kilograms. We recently added pounds for US and age and then the clozapine level that you desire. And then you'll get a recommended clozapine dose. Use this as a rough approximation. But it's a cool tool and as you kind of move around the weight and the age, you can see how it sort of affects the predicted clozapine dose. There's another concept called the metabolic ratio that I'm not gonna spend too much time talking about but it's basically the clozapine level divided by the noreclozapine level. If you get the LC-MS clozapine level, you'll get a noreclozapine level as well. You are interpreting the clozapine level, not the total clozapine level, okay? So the clozapine level is what matters, 350 clozapine level. Noreclozapine, yeah, you can do some interesting stuff to kind of think about the kinetics. Okay, the expected metabolic ratio for a non-smoking male is 1.32. So that's clozapine level divided by noreclozapine level. It remains unchanged during periods of poor adherence and except if somebody takes clozapine right prior to the level. The levels also, just as a convention, are taken 12 hours after the bedtime dose. So if somebody's on BID dosing, you gotta watch that. This is just sort of a little bit on interpreting the metabolic ratio. Sometimes you can tell if the metabolic ratio is low, somebody might have an inducer on board. Smoking is the most common culprit. If the metabolic ratio is high, like really high, like three or more, I start to think about an infection or maybe somebody has, maybe the ciprofloxacin has somehow slipped through. All right, so just to kind of sum this up, there's sort of a planning phase, an initial titration phase, and then you're kind of doing some fine-tuning. The planning phase, consider the patient-specific factors. Where are you doing this? You know, the sort of demographic factors. I like to approximate a target clozapine dose using the dose calculator. You wanna set a goal titration rate. You can choose any of the ones that are sort of in the literature, but like kind of have a plan. Establish a communication system so the patient can reach you or somebody else on call, especially in the first two weeks. And then you wanna sign up for REMS. You wanna have the patient enrolled in REMS, and you wanna kind of get that going. And if we have time, we'll talk a little bit more about REMS. But we could talk a lot about REMS, and we won't have enough time. And then, so during the titration phase itself, you wanna start clozapine, initiate the monitoring protocol, consider early TDM, gradually reduce the other antipsychotics. The way I like to think about this is like, in the event somebody's on two antipsychotics, I'm probably gonna make a 25% reduction of the other antipsychotic when somebody is, you know, typically at 25% of my clozapine target dose. I guide the levels with this much more, but when I'm starting the dose titration, I usually wait a little bit before peeling the other antipsychotics off. Others may have other sort of thoughts about it. So, you know, again, I don't wanna overcomplicate things, but you can always consult us, free clinician-to-clinician consult. And then we also have a virtual learning collaborative on clozapine through SMI Advisor, which is a 12-week deep dive into clozapine. It kind of involves asynchronous and synchronous components. So it's 12 weeks, we have office hours that are virtual every other week. And then at the end, there's an optional deliverable that you can develop on sort of measuring the clozapine side effects, like using a scale. So you can see sort of what the agenda is there. And it kind of goes through system by system, you know, the potential side effects of clozapine and how to mitigate them. All right, with that, I will turn it over to Dr. Freundreich. Thank you. Okay, good afternoon. Thank you, Rob. So the Tourism Bureau in Boston asked me to put in a slide about Heroic Boston, which goes back to a book about my favorite architecture, Brutalism. I actually worked in a clinic, the Eric Lindemann Mental Health Center on the right side that is built in this style of architecture. I'm in the minority. Most patients absolutely hate this building, Paul Rudolph building. And just like City Hall, it usually gets voted as the worst building in Boston. MGH has a more traditional in the middle here, more traditional look with our ether dome. So I'm telling you a little bit, not the story of a clinic, but what we've done in a clinic over the last 20 years and related really to my experience, how to manage the side effects of clozapine. And a little bit, you'll see repetition does create truth. I'm going to reemphasize a few points that were already made by my colleagues. The two disclosures that are relevant here, so I am on the APA's SMI advisor group, and I do write, so I get royalties. Hint, by the way, writing is good, but anything web-based is even better for royalties. So I do write the section on clozapine, one of the sections with up-to-date, which some of you may actually use for other purposes, not just for clozapine. So big picture here. Number one, I want to tell you about my favorite philosopher, Sir Winston Churchill, who says, however beautiful the strategy, you should occasionally look at the results. If you have children, it always works. Oh, over here and over there, I couldn't study, the test was too hard. Well, it does apply. So this applies a little bit to managing the side effects from clozapine. And I'm telling you that it's actually complicated, because if we think about why our patients die, those patients with treatment-resistant schizophrenia, it's actually, they die from so-called natural causes more likely than from suicide, which we really focus on. And we focus on it rightly, the numbers differ a little bit. Sometimes I think it's 80-20 is really the breakup. So we often, as psychiatrists, focus on the 20% of people, and that's not wrong. And clozapine may actually play a really good role in addressing those 20%. The other issue is that people die from the usual causes, that the general population also dies from, number one being cardiovascular disease. And there's two problems. Number one is not prescribing clozapine for those who need it, because you get the worst medical outcomes for people who are psychotic. They are unable to take care of their medical needs. And then on the other hand, once you prescribe clozapine, and I'll repeat this at a later point, you will actually have to manage the iatrogenic complications that we also introduce in this equation. So it's really tricky, this part. But it is, I think, a paradigm for being a psychiatrist, because it really matters for us to remind ourselves occasionally that we are MDs. And there's a reason for that, because we may be able to not just work on the efficacy side with medicines, but also to manage the side effects in a way that will help the medical morbidity from having actually a psychiatric-controlled illness. Sorry to belabor this point a little bit, but I wanted to emphasize this, because sometimes people say, and this is the discussion, I think, that you need to have with patients, that your outcome, if you need clozapine, is actually worse from not taking clozapine, because people think, you know, oh, I'm going to get this side effect and everything will be worse. The clinical trials or the population-based studies really don't show this to be true. So, you already mentioned, I think, was it you, Rob, the five black box warnings. I always tell my residents, whatever medicine you use, you've got to know, for better or worse, the black box warnings. It's really only four, if you think about it. Forget the fifth one here, the general class warning for increased mortality in elderly patients. So, I'm going to talk about agonist, cirrhosis, seizures, myocarditis, and orthostatic hypertension as the four key ones. There's one that's not listed, but I want to start out with not to forget neuroleptic malignant syndrome, because that will, if you miss it, sorry to be so blunt here, it will kill your patient. So, it's certainly something to keep in mind. To keep it in mind, because people, I think, are not fully aware sometimes that, because they think clozapine is different, milder D2 blocker, so it couldn't really happen. That's not true. If anything, there is the concern that the typical EPS findings that you will have with neuroleptic malignant syndrome, the rigidity may not be so visible in those people on some second generation endocarditis, specifically actually with clozapine. There's a nice website, the Neuroleptic Malignant Syndrome Information Service, and a fairly recent meta-analysis that really looked at all of this, making the point, I used the French word for frustrier, to always consider a somewhat modified version, so it may not always look that typical. So, keep that in mind when you start clozapine. Now, clozapine agonist psittacosis has a complicated history that led to a complicated approval process, and in the end to our registry-based prescribing, and I do hope we have some time for the REMS discussion, because REMS really only makes sense if you understand the history of how clozapine got approved in a country that is very much based on, in the end, on bad outcomes leading to lawsuits. Nobody is going to put you to court if you don't prescribe clozapine. A patient who then dies because you didn't prescribe it, if you prescribe clozapine and something goes wrong, you bet somebody is going to sue you immediately. So, this is the context of REMS and agonist psittacosis. At least at this point, we do have a somewhat separate pathway for so-called benign ethnic neutropenia, probably not the best term anymore to use, and it is actually an example of structural racism in lab values that we even have to start, that they have to, at some point, enshrine it to make people ineligible. Now, with the modified REMS for a few years now, at least it has been somewhat alleviated, that concern. There are also very large, I think it was within the last year or so, a review in, I want to say, JAMA psychiatry, about guidelines or viewpoint pointing out that the guidelines for monitoring vary across the world. And one interpretation of this is it can't be all evidence-based, right, if the guidelines vary so much. So, why are we having something that is really problematic? Let's just say that. In any case, I think the thing that you need to remember or need to know about agonist psittacosis, yes, it can happen. It's clearly less than 1% of cases, and the highest risk is really the first six months, maximum one year. And then you approach the population-based risk, okay? And I say this because every now and then you have a patient who has been on clozapine for 20 years and develops agonist psittacosis and people want to take off clozapine. It is highly unlikely, at least if we think about the agonist psittacosis from clozapine being a really toxic effect early in the course of treatment and an immune reaction, okay, it's highly unlikely that clozapine is directly causally related in such a patient. This fact alone helps you a lot. If you have problems with your blood work, it's going to happen at the beginning of treatment when you start somebody and not after a year or longer. It still can happen, but at least the first question if I get a call that the patient's A and C is low, my first question is always, how long has the patient been on it? That changes everything. This changes your decision tree, okay? Second, black box organ seizures happens to be a German, so my accent, I always say this, by the way, in case you get confused, it's not a Brooklyn accent from the East Coast. I am from Germany originally. In a German drug safety program, it actually did have the highest seizure rate, and you know, you will, if you prescribe it enough, you will see it. And I think what often happens is that using a risk factor model that some people, you mentioned COVID, you know, people may be stably controlled on clozapine and whatever the dose and the blood level is, and then they develop an infection that increases clozapine levels, having basically a spike, and there may be some people who biologically may not be able to tolerate this. So then the vulnerabilities toward seizures come in. So that's why it can happen and everybody seems surprised. After years of treatment, it is actually something that really with a careful titration should not, and in therapeutic drug monitoring should not happen at the beginning of treatment. I think, unfortunately, I look at my experience, when it happens, it comes as a surprise to everybody, and then it is usually people with some where I think, you know, I think of autism spectrum, maybe some brain, different brain, maybe a little bit higher blood level in general, probably, and then something else happened to that patient to have an increased level all of a sudden. The clinical red flag, if you see myoclonus in the patient, think about perhaps being more careful with clozapine and getting a blood level. So the prevention, titration, therapeutic drug monitoring, and then paying attention to clinical comorbidities that increase the seizure risk. Depakote is a good choice because it actually is fairly specific and effective for myoclonus, but there are many other of the newer ones, broad-spectrum anti-epileptic drugs that work really well. Capamazepine you want to avoid, right, because it affects the bone marrow and it's also a pun inducer of P450 enzymes, so you're going to have a much harder time increasing clozapine levels. Myocarditis risk is the third black box warning. The myocarditis risk is probably, and you'll see different numbers, it's probably 5.3%, at least in one analysis. Have you paid attention, right, agranocytosis, where we do a lot of stuff because it's demanded of us, it's 1% or less. So here we actually have the question, are we monitoring for the wrong thing? I think you still need to monitor for both, but keep that in mind. Just because you follow the REMS, if you don't pay attention to this, you probably will be, if you start enough patients on it, you will probably miss a few people. The problem with the diagnosis of myocarditis is that the symptoms are completely nonspecific, so you need to have a high index of suspicion. And the problem is that it's tachycardia, for example, and sedation. Now, anyone you start on clozapine will actually have these early side effects, so it's really, really tricky. The highest risk period is usually considered about four weeks, and I think we actually changed our monitoring from four to eight weeks. I think the four weeks really only start when you have a little bit of a blood level. And Fred has a very nice reference here where he looked at the protocol. It's very complex. I just gave you a little snapshot, so please look it up. What to actually add on and for how long. So at this point, I think not to make things too complicated. If you only want to do one thing for eight weeks, and that's troponin. Troponin is key. You want to add some other stuff, too, but the problem is if you just look at CRP, for example, it's not specific enough. And you'll basically stop prescribing clozapine if CRP goes up a little bit. So it really is very important to add the troponin to whatever else you do. Now, some cardiologists will also advise you to add five other things, to just keep that in mind. And just like I think you said it, Rob, if I did all the things that our European or Australian colleagues do, like an echo, nobody would start in our clozapine clinic. So I do try to get an EKG, not because I'm worried about long QTC, although if you see it, you say, oh, great, glad I got it. Because you want to have something to compare to, okay, if there's a problem that develops. The read challenge may come up. It is, and here I wanted to say one thing, it's sometimes still, despite my best efforts, not clear if somebody actually had myocarditis or not. It is a little bit of a messy field. And I'm on a working group for treatment-resistant schizophrenia. We're actually one of those Delphi procedures. I'm curious to see, you know, so-called experts in the field, like us here, you know, trying to agree what we really should do. So I'm actually curious to see what people think once that comes out. Orthostatic hypotension is actually a black box warning. It goes back to the early days of clozapine, so just keep that in mind. Titration was a lot more aggressive, and they had people die during initial titration from clozapine. It turns out a lot of people were actually on benzodiazepines as well. Okay, so let's be realistic, though. Are you going to manage people without benzodiazepines? No, just be aware, be smart. You know, how you use it, look at the patient. Okay, what is the patient being able to tolerate? You know, if it's a healthy patient, the patient may be able to tolerate a drop in blood pressure a little bit. And the titration issue comes in yet again. And there was... At least I found one review that points out the relative safety of using benzodiazepines, because, I mean, it becomes a problem if you look at guidelines, and then you realize, okay, I'm doing something here that I ought not to be doing, but then everybody else does it. So just keep it. It's good to know about this, I guess is my point. Then we have what I call nuisance side effects, clozapine and sialaria. It's a little bit of a nuisance for patients, but it's also a serious issue. It is either the number one or number two cause of side... Usually in many surveys, the number one or number two side effect that people report. It's not just a cosmetic problem. People may get aspiration pneumonia from it. It's stigmatizing. If I stood here and drooled, you would think, what's wrong with this guy? It's natural that we look at what people present to us. It stigmatizes people on the train. You always think, why does somebody look psychiatrically ill? Maybe it's because the patient is Parkinsonized and drools. And then parotid swelling and parotitis are other side effects that can occur. It's only seemingly paradoxical, because clozapine is very endocrinogenic, so you would think it should cause a dry mouth, but it's more complicated with the muscarinic receptors that actually activate some of those having to do with drooling. And then clozapine causes, because it's endocrinogenic, a so-called slow gut, so everything is slower, including your swallowing. You swallow less. That's why sialaria is a problem at night. We naturally swallow less at night. The wet pillow sign I put up here, patients will complain about it, and one of my colleagues, not those two here, always jokes about the treatment, with putting a towel on your pillow. Well, that is good treatment for the towel, but not for the patient. Honestly, I know there's this idea that the topical preparations like ipertropium, the spray for under the tongue, or the atropine eye drops are preferred, and I use them occasionally, but I often end up using glycopyrrolate, despite its problems, because it is the most effective one, and it is a very tricky issue. What's not on this list is Botox, which is actually FDA-approved for drooling, not from clozapine, but drooling from neurological conditions, and if you have access, you could consider it. In some patients, I think in group homes, it may actually not be a bad thing. Clozapine-associated constipation is really important, another cause of mortality for this group of patients. The FDA recently strengthened their warning about it, because untreated constipation can progress to serious bowel problems, including obstruction and death. We have a large clozapine clinic, about 200-300 patients, and each year we have one or two people in the hospital with it, despite our best efforts, because, as I said earlier, clozapine slows the gut reliably and predictably. So the idea is really, and it turns out that just asking people if they feel constipated actually does not capture the severity of this problem. So there is the idea to really manage this proactively with the bowel regimen for chronic constipation, regardless of patient complaint or not. And I gave you one example here from one of those clinical pearls that I put together with the resident. There's two medicines, or the medicine classes, newer ones I haven't put on there yet. I probably should, but they're so expensive, it's really hard for us to get them. And I really would work with a primary care doctor. Those medicines, lupiprostone for example, that really affect the apical cells in the gut lumen, and they basically increase water in the gut. So basically if you all had diarrhea from some sort of infection, they basically mimic this mechanism by blocking certain chloride channels, for example, in the CGMP. Actually the two major ones have different actions, but in the end they all increase the water in the gut. So they're very effective medicines if these things fail. Now, again, however beautiful the strategy, you should occasionally look at the results. I was in the hometown of Arlington, Massachusetts, and I don't know, maybe they had some extra concrete, or there was a switch from the metric system to the imperial system. But the problem is this, and this is the Lindemann again. My previous boss, Dr. Henderson, did a five-year study in the early days, 20 years ago now, where he just looked at blood work regularly over five years, specifically at diabetes. And after five years, 30% of the clinic cohort had diagnosed diabetes. Now, some of those patients would have gotten diabetes anyways, but not all of them. And as you know here in this group, I don't have to tell you that clozapine is a so-called metabolically high-risk medication. So usually I tell people, you know, metabolic prevention you choose wisely, use a low-risk medicine if you can. Then you screen and monitor, and at some point, whatever you do, I mean, do take some action if you discover a problem. And the Irish metformin guidelines here, I put this in because it's a very nice review of the use of metformin to prevent perhaps the development of diabetes if you use it really early or from the get-go in patients with schizophrenia who start on clozapine. The now not-so-new medication class is always increasingly in the news, the incretin mimetics, the GLP-1 receptor agonists, right, because, you know, we can use a lot of weight if we use those. We're not quite there yet in our clinic to use them routinely, but I do think we're going to be shifting, at least in problematic patients, from using metformin to these newer medicines. Cost is, of course, an issue. There are differences between them. I've actually lost, at this point, the big picture. But the big picture I get, but there are so many now, and there's also the twin cretins, as one of them is called, because it does not only affect the GLP-1 receptor, but also the, I think it's called GIP receptor. So, I mean, it gets complicated fairly quickly, and, you know, we are not GI doctors here. But keep an eye out for, as guidelines, you know, get developed in what people are doing. I'm going to summarize here what I think are really important broad principles. So, whatever you do, think about a population-based approach. And even if you have only three patients on clozapine, you could approach a population-based approach. Our medical records has never helped me with anything with regards to managing groups of patients. So we have, somewhat illegally, it's between us here, right, a spreadsheet where we literally keep track of a lot of stuff. So, you know, spreadsheet is always a poor man's version of, you know, electronic medical record that, in theory, could do all kinds of things for you. But there always seem to be other priorities that IT has, not just, not what you need. So, and one other thing that is also a poor man's version, I think, of really making sure you don't forget this, add a medical prevention bullet point to your problem list that every visit you think about. So, for example, I just cut and paste the most recent, let's just say we do something annually, the annual, you know, labs, and then I see every time the patient comes in, we haven't done this for two years, you know. It does happen that people fall through the cracks. And then we talked about the ANC, you have to use the REMS protocol, troponin and CRP for at least four, and I said we're actually doing it eight weeks. I weigh people when they come in. I actually still, I don't do it quarterly, I really do it every time they come in. It's really part of what we do, including also getting vital signs. And then, you know, perfect is the enemy of good. I'd rather you figure out a way that you get something at least yearly when it comes to metabolic monitoring as opposed to thinking about, oh, I've got to do this. And then earlier makes some sense when you start somebody on it, but at some point it's at least you make sure you have a system to do something annually. You're not going to believe how fast a year goes by, and you look around, and yet again you didn't get the hemoglobin A1C on a patient. And let's never forget what Don Berwick, who was in charge of CMS for a while, ran for governor in Massachusetts, didn't make it. All organizations are perfectly designed to get the results they get. If you have an organization that does not focus on this, don't be surprised that you don't have a hemoglobin A1C. That is up to us. This is where we as physicians need to show leadership to also insist, you know, to meet with IT and say, you know, this is not okay. If this were another specialty, you wouldn't ignore us, to really become advocates for optimal management of those patients who will die if we don't treat them correctly, die because, you know, if we don't use it because we are worried, or if we use it incorrectly because of the iatrogenic morbidity that we may ask. You cannot do this alone, though. So this is the Lindemann again, now from the inside. So there is this team-based approach, and it's really hard to do this if you're just a single practitioner. And you've got to look. All problems are local, all solutions are local, Tip or Neil. Look in your system how to do it. And maybe you can have a virtual close-up clinic as one way of creating a group of people in your system who actually apply some of those principles that I spoke about. Okay? And now we're going to come to my favorite topic, REMS. Thank you. APPLAUSE All right, thank you. Thank you so much, Dr. Freundreich. We're going to talk a little bit about clozapine REMS. Clozapine REMS is, you know, REMS stands for the Risk Evaluation and Mitigation System. Clozapine REMS is under what's called an ATASU from the FDA, which means that you have to do something in order to get the medication to you. So you have to basically upload the absolute neutrophil count in order to get the medication. I just want to put here a kind of timeline of the events of clozapine REMS that have occurred. And really, like, before any of this, there was a change to clozapine REMS in 2015 in which we went from each pharmaceutical manufacturer having their own sort of REMS system to a shared REMS system, which actually was a helpful advance. And in that 2015 change, there was a new algorithm that was developed for benign ethic neutropenia. And in some ways, the U.S. guidelines are maybe a little bit ahead of other countries in terms of, you know, the certain aspects of hematologic monitoring for clozapine. The new clozapine REMS system was initiated in November 2021, and five days after it was started, certain provisions were immediately suspended and still remain suspended. So it was a very chaotic week. For those of you who prescribe clozapine, it was really, really rough. And I think that there were a number of people who couldn't get their medication, who had, you know, the kind of problems that happen when people stop taking their clozapine for a little while. And it often did not go well. So, you know, the new user interface, you know, there may be some advantages, but I think that overall the clozapine REMS system really I think makes it difficult, I'm just speaking for myself here, to get clozapine to patients who may need it. And it really helps to have a system in place. Like I have a full-time clozapine REMS manager that's sort of sponsored by philanthropic funds because I run a clozapine clinic and have, you know, it's like most clinics can't do that. That's just not possible. And I, you know, did it on my own for many, many years and then finally got this person to manage the interface. I've gotten so much time of my life back. It used to be a big thing. I used to have a fax machine in my house. I was the last person to have a fax machine in my house. The phone company was like wondering, like, why do you still have this? You know, they looked at my age, they were confused. But there's advantages now to actually having, you know, this sort of electronic system. And this is just sort of a timeline of the sort of events. Again, certain provisions of the REMS are suspended, including the need for a REMS dispense authorization. So some tips for managing clozapine REMS. You know, when you get started, there is a 12-item multiple choice knowledge assessment to be certified in REMS. It was the same knowledge assessment that was there in 2015. You have to get a patient status form in order for someone to continue clozapine or start clozapine. The problem, though, is some pharmacies will actually require you to fax the lab values themselves to them in addition to updating clozapine REMS. And to me, that is one of the most difficult problems with all of this. Because let's say you're doing what you need to do, you update clozapine REMS, and then the patient's at the pharmacy on Saturday morning at 5 a.m. and they're like, we can't get the clozapine. This happens to me every Saturday morning at 5 a.m. So anyway, I think that what we do now is for generally chain pharmacies, we are sending the fax directly to the pharmacy every time, and it's sort of inconsistently, you know, some pharmacists will take it, some pharmacists, you know, don't need it, but really, you don't need it. I think some pharmacies have procedures in place in which they have to get it, so it's not their fault, it's just sort of a bigger problem, and there's a lot of advocacy work being done. I like to use a lot of screenshots, and use digital faxing for the pharmacies that do require the fax itself. And then just a couple of final points about, you know, what can advocacy do to help improve the Clozapine REM system? I think number one, there's like a couple tweaks that could happen, kind of on the user interface level, that would be nice. You know, one advance, actually, of the new Clozapine REM system is, you can specify a reason for missing the lab, like patient refused, or extrinsic factors, or clinician distression, and then that should be enough to get a patient status form. But sometimes that doesn't, you know, it doesn't work. And now, actually, to save yourself some time, you can just click that the, you know, that the patient has a normal range ANC, instead of actually putting in the absolute neutrophil count value itself, so you kind of cut down on transcription errors. But, you know, basically, the REM system itself is impermeable to study, you know, it's not meant to be a database for researchers to figure out, sort of, what's the risk for neutropenia. It's really more of a, you know, sort of a regulatory thing. So, number one, you know, what can we do to advocate? Yes, I think that, you know, some tweaks to the UI might make sense. Number two, I really think it would be useful to convene, sort of, a scientific review to really understand if lifelong hematologic monitoring is necessary, you know. Maybe people only had to be in the REMs for the first 12 months they were taking the medication, and then, you know, responsible prescribers were left to their own on then, sort of, doing the monitoring as they saw fit. The risk of neutropenia after a year, like Dr. Freundreich was saying, really drops to similar rates than other antipsychotic medications. For many people, the idea of starting a medicine and having lifelong hematologic monitoring is a non-starter. And, you know, that was one of the things that took me three years to kind of get over the finish line and with a patient, I finally started taking it. Okay, and then, I guess the other, the other, sort of, big point of advocacy is, you know, maybe we could make the REM system an educational REMs rather than the ATASU system. So, this would mean that rather than us actually uploading the labs into a system, we take a test and a quiz in the beginning and get trained, you know, on how to use clozapine, and then we monitor the labs as we kind of see like would be necessary. You know, the REMs, I think, really has done a real number on reducing access to clozapine. And I think that there is a perception that REMs is this big thing and it's really difficult to work with, and I think that that's true in some part, but the perception really helps drive down the clozapine utilization itself. Okay, so, we could go on and on about clozapine REMs, but we do wanna take some questions in our remaining time. This is Dr. Freundreich's slide here with the feet, so I'm not sure exactly what he intended here. But... Well, how quickly we forget, you know, lining up in front of a grocery store during the pandemic outside. All right, thank you. So, with that, we'll take some questions. I had one question about use of clozapine in children, and, you know, I'm sure you're not child psychiatrists, but for chronic suicidality, can you comment on that? Chronic suicidality in kids. Yeah, so I'm not a child psychiatrist, but I do work with child psychiatry, and, you know, clozapine is actually a broad-spectrum psychotropic. Now, I wouldn't use clozapine in an uncomplicated child, and, you know, if there's suicidality by definition, I guess it's complicated. But I think there are groups of multiply-impaired children here in many domains, developmental disorders, maybe some paranoia, suicidal ideation, where I think it's one of those life-saving interventions. Now, you know, it is a serious psychiatric intervention, but it also is for a serious condition. So we have a significant minority of our patients who don't really fit into the typical treatment-resistant schizophrenia paradigm, because they are younger kids. The diagnoses are often not as clear as we would like them. But one side effect that is really minimal, let's never forget this, is actually EPS with clozapine. And that, for those who are sensitive to EPS, for those patients, makes an enormous difference. And I think, didn't you, Rob, do a study where you looked at people's opinion about clozapine compared to other medicines that they've been on before? Many will say, this is the best medicine I've ever been on. I can't believe you waited so long for this one. Yes, next question. Yeah, thank you for an amazing talk and for validating all my feels about clozapine REMS. I wanna talk about treatment-resistant schizophrenia as it relates to someone who's chronically using clozapine, let's say a client who has not been able to, is continuing to have positive and negative symptoms, despite multiple antipsychotic trials, but is also chronically using cannabis. Would that, would you consider clozapine for that client if they? So, yeah, so actually there's some data that clozapine can help with addictions, people with smoking and some other things. So, I mean, in my opinion, if someone is failing medicine, then you should consider clozapine either way. I mean, I try to get them help to stop using, but I think more and more with marijuana, that's gonna be a bigger issue, but it wouldn't stop me from using clozapine. Yeah, and also what's interesting, too, about cannabis use, you know, it depends on the way that people are using cannabis, but if they are smoking cannabis, it's going to produce aerohydrocarbons, which could drive the clozapine levels down slightly. It hasn't actually been studied as much as the aerohydrocarbons that are produced with cigarette smoke from tobacco, but there is some suspicion that, you know, there's a lot of ways that people can use cannabis now, so you wanna ask how they're doing it, and if there is aerohydrocarbons that are being produced, it can kind of drop the level a bit. Yes. Great, thank you so much for this excellent talk. And I forget the rationale, but I'm curious about your opinion of people who prefer to start Luvox with clozapine, kind of what your comment is on that. Yeah, so, you know, Luvox or fluvoxamine is a strong CYP1A2 inhibitor. Some people like to use Luvox in order to increase the clozapine level. You know, I think that, just sort of speaking for myself, there are some situations where that actually may be appropriate. Like, for example, you have somebody who's on the FDA maximum dose of clozapine, 900 milligrams, you're in a state hospital setting, the person is an ultra-rapid metabolizer, the state hospital actually won't let you increase beyond 900 milligrams. So then, you know, kind of considering a pharmacokinetic helper might be an option. For many people, you know, we really tend to tell people to not use fluvoxamine, because once you start to use fluvoxamine, the, it no longer, clozapine no longer follows linear pharmacokinetics. So you can't actually get, you know, as you increase the dose, you're not gonna get a predictably increase in level, proportional increase in level. So I think that it is, you know, you see it sometimes, some people like to use fluvoxamine to affect the metabolic ratio, and there's some ideas that maybe an ideal metabolic ratio is around two, although that needs to be, you know, better replicated. And, you know, typically, my thought is not to, I don't like to use pharmacology to get to a metabolic ratio that is not completely, you know, studied so far. It really needs replication. Thanks all for the stellar talk. I'm primarily an impatient guy, and so I realize that maybe my population's a bit skewed towards the treatment-resistant folks. My question is about defining treatment resistance in a population which, for us, we have a fair number of people who either first episode psychosis, or for a variety of reasons, we're not able to establish that they've had antipsychotic trials, but under the luxury of keeping them for 12 weeks to do, you know, two full medication trials, do we get to then shorten the time that qualifies for treatment resistance? People who I'd like to start on clozapine in the hospital and don't want to wait 12 weeks can't wait 12 weeks. Yeah. So your question is, what do you do in this situation if you don't have time to get them on, or determine if they have two failures? I mean, I think there's some evidence that suggests that if you fail one medicine that you're better off going on clozapine. I mean, you know, the recommendation is to fail two failures but there's nothing saying that you can't start sooner. I do think it's hard to make the case for first line given that if you respond to something without so much side effects, that's great. At least with not more evidence that it improves other areas, as I suggest it might. So, you know, I think you kind of have to go with the situation, but I think if it's looking like they're failing one, it's possible that they're gonna fail another and it's worth considering if that's the only option you have. I think it's an important point that you're making though and it does have to do with the people. If they're treatment resistant, the vast majority are biologically different and they're treatment resistant from the get-go, probably around 80%. The other 20% are those that develop treatment resistance over time related to occurrences and things like that. So if somebody does not respond in an inpatient setting to the first treatment, it's a really bad sign. And there are some European studies that really show switching in people, you know, continuing the thing that doesn't work longer doesn't turn people treatment resistant. I think the only reason why we wait longer is because sometimes we don't really know. Was the trial enough? You know, did they take the medicine? So we often, for that reason, on the outpatient side at least, insist on a kind of long-acting injectable trial just to make sure that the medicine was actually taken. You know, one other point to that. I agree with everything that's been said. And then sometimes in these situations, I used to work on an inpatient unit for many years and we would have somebody who was having a partial response to antipsychotic number one or number two and we would say to ourselves, okay, we are gonna get an antipsychotic blood level of this particular patient as they're leaving the hospital. And we're not gonna get the level back for the next five to seven business days. It's not gonna help us in that setting. But sometimes you wanna make sure that people aren't having sort of a kinetic failure. And then, you know, on the inpatient unit you have sort of limited ability. So we've sometimes gotten levels for people who we think may ultimately need clozapine. And it kind of helps us to say, okay, let's not do the same thing again that makes no sense, yeah. A bit of a political question. We've seen some movement on the federal level for some regulations that maybe don't make empirical sense like the X waiver. You know, why do you, your opinion of why this hasn't happened with something like REMS, you know, with agranulocytosis rates maybe similar to other antipsychotics? I'm sorry, could you repeat the first part of the question? Oh, just your opinion on why there hasn't been sort of the same political movement with clozapine REMS maybe versus some other regulations at the federal level. Okay, yeah, I can take that. Yeah, great question. I think that, you know, there have been conversations with, you know, organizations like the American Psychiatric Association and other professional organizations with the FDA in order to advocate, I think using some similar lines of argument. The other pieces of argument have been, you know, sort of patient level data on their experiences after clozapine REMS, the new system kind of took over, the catastrophic sort of failures. And then there's been some work on looking at clinician perspectives on what happened during the new, you know, rollout. So there's a lot of work done in that area and hopefully next year we'll be having a different conversation. I do think part of the issue elephant in the room is that the FDA is a very conservative, you know, federal agency and to them there's no harm in keeping it. And as long as, you know, we're dealing with a stigmatized group of patients and, you know, in psychiatry we're not cardiology, I think it is harder for us to get hurt despite everybody's, NAMI is an example, you know, families despite everybody's efforts. Hi, if you have someone who's been on a certain dose of clozapine for a while and they're on monthly maintenance blood draws and then you finally convince them that it would be worth giving a try to a higher dose, do you need to increase the frequency of the blood draws or can you leave it at monthly? Yep, you can leave it at monthly. Yep, it's all about the amount of time after clozapine initiation. So if somebody's been on clozapine for a year, 12 months, in our clinic we have like a kind of celebration kind of thing because it's a big milestone. And by that time people are usually doing quite well. You can do whatever you want with the dose afterward. You don't have to go back down to other sort of monitoring. My question is for adolescents with treatment-resistant schizophrenia when started on clozapine, if a different approach would be for monitoring side effects and titration. Yeah, I mean, again, you know, like I'm an adult psychiatrist, work with some, you know, sort of adolescents and consult with some child and adolescent psychiatrists on clozapine. I would say that, you know, if somebody has TRS and they're, you know, less than 17, 18, some of these people may even have childhood schizophrenia, clozapine is the treatment of choice for these folks. I mean, getting people on clozapine early who have sort of early onset schizophrenia I think is a real benefit to them. As far as specific monitoring, I don't really do anything all that differently. There may be some evidence that, you know, just sort of in general in the antipsychotic-induced weight gain sort of world that, you know, younger folks may be more vulnerable to cardiometabolic side effects. So in that case, you would probably wanna continue to, you know, do your monitoring. Every visit, you know, hemoglobin A1C lipid panel more frequently than the APA-ADA guidelines. And then, you know, I work with a number of these people who are actually on GLP-1 agonists or trizepatide. And the nice thing about clozapine is that you can actually use therapeutic drug monitoring. So if you're worried also about, is dosing a little different, you know, because the metabolism may actually be higher, you know, in younger, as you know, in children, but it depends a little bit on the age. I think it helps you to just use that even more explicitly perhaps. Thank you. Thank you. Thoughts on using lithium for clozapine-induced neutropenia? So I've used that many times in the past. I think it's, I mean, it's valuable if you need to keep someone on it. Interestingly, since they've dropped the, it's now 1.5 instead of two, I've had most of my patients that no longer need that and I was able to take them off of lithium. So that was a big improvement for me, but I use it if I need to. Yeah. I also used to use it and even wrote, you know, case reports in the time when this was still the thing to do. It's a health disparity, by the way, that you have to do this in a patient who doesn't need it except for regulatory purposes. So I am glad that at this point, you know, with the benign ethine neutropenia, it's actually no longer an issue. Just be aware. If you use lithium, you may be covering, if you use it early, for example, you may be covering up developing neutropenia by doing this. So it's really nothing you should do at the beginning of treatment. And just keep that in mind, actually, for people who are on lithium because the WBCs or ANCs are slightly up. Thank you. Yeah, and just to follow up on that point. So if somebody is on lithium, you know, it can be sort of temporarily to boost the absolute neutrophil count. Like lithium is interesting because it causes demargination of absolute neutrophils. But the other thing is it actually stimulates GCSF as well so it actually causes neutrophil production. And there's a handful of people who they have been started on lithium prophylactically to minimize the risk of severe neutropenia if they have already had severe neutropenia. And in that situation, we once did this review. We found that when you try to stop the lithium for these people, it can be kind of risky. That's very different than if you have somebody who has an ANC of 1.3 and you kind of put lithium on board, like a very different situation. So sometimes people will have somebody on lithium and they will, you know, they'll just be like, they don't need the lithium. I'm gonna stop it. You know, most of us probably aren't that cavalier, especially if they had severe neutropenia. Yeah, lithium is a poor man's GCSF. Yes. Hi, great talk. Can you just speak to using clozapine in treatment resistant bipolar disorder, your experience, special considerations? Yeah, I consider clozapine a broad spectrum antipsychotic, like a broad spectrum, you know, antibiotic, which has efficacy beyond just a very narrowly, you know, FDA approved indications to, you know, aggression in the setting of particular psychosis that comes to mind. Poor stabilization in bipolar disorder, it's absolutely a consideration. And I think it can be a life course altering for a lot more people with difficult to treat conditions. Yeah, may even be able to go away with lower doses sometimes. Great study by one of my mentors, Alan Green, on lithium for treatment resistant mania. People who've had multiple sort of manic episodes without resolution can really benefit from clozapine. Efficacy for bipolar depression, kind of a little iffy. Other questions? Well, thank you all. Thank you, really great questions. Thank you.

Clozapine

treatment-resistant schizophrenia

TRS

suicidality

side effects

underutilization

psychiatric drug

patient-centered approach

blood monitoring

agranulocytosis

REMS program

Dr. Rob Cotez

Dr. Oliver Freundreich