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Addressing Barriers to Clozapine Underutilization
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Hello and welcome. I'm Tristan Grindow, Deputy Medical Director and Director of Education for the American Psychiatric Association. I'm so pleased that you are joining us for today's SMI Advisor webinar, Addressing Barriers to Clozapine Underutilization. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an AAPA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. Now I'd like to introduce you to today's faculty, Dr. Deanna Kelly and Dr. Raymond Love. Dr. Love is Professor and Vice Chair of the Department of Pharmacy Practice and Science and Director of the Mental Health Program at the University of Maryland School of Pharmacy. He also has a secondary appointment as Professor of Psychiatry within the University of Maryland School of Medicine and oversees pharmacy services for the Maryland Behavioral Health Administration. He is a past president of the College of Psychiatric and Neurologic Pharmacists, a board-certified psychiatric pharmacist, and a fellow of the American Society of Health Systems Pharmacists. Dr. Kelly is a Professor of Psychiatry at the University of Maryland Baltimore School of Medicine and Affiliate Professor in the School of Pharmacy. She is currently Director-in-Chief of the Treatment Research Program at the Maryland Psychiatric Research Center. She is the past president for the College of Psychiatric and Neurologic Pharmacists and recipient of the 2017 Maltz Prize for Innovation and Promising Schizophrenia Research from the Brain and Behavior Research Foundation. Deanna and Ray, thank you for leading today's webinar. We're very excited to hear about how you're going to help us all be better in using clozapine and addressing the barriers to its implementation. Thank you very much. Welcome, everyone. At first, I wanted just to start with disclosures that are listed on this slide here for both Dr. Love and myself. I am a consultant for Lunebeck, Saladec, Alkermes, and HLS Therapeutics. Dr. Love, if you would like to mention yours. Sure. I've received honoraria from the American Psychiatric Association, the Nevada Psychiatric Association, the American Pharmacists Association, and the National Alliance of State Pharmacy Associations. I am a consultant to the Maryland Medicaid Pharmacy Program and the Maryland Behavioral Health Administration. And I do have stock that is independently managed by a certified financial planner that may include pharmaceutical stock. Great. Thank you very much. So we're going to go ahead and get started here today. I'm going to start off with discussing the learning objectives for today. So during today's talk, at the conclusion of the presentation, I hope that all of you will be able to discuss the utility of clozapine and the treatment of serious mental disorders, list barriers to the use of clozapine, and discuss collaborative strategies to increase and access and improve utilization of this medication. We'll also hope to explain some of the new guidelines, the working group that we've had, requirements for new monitoring, and I'm also going to be touching on some things in barriers related to benign esophageal neutropenia. Okay, just to begin with, I think all of you are probably familiar with the burden of schizophrenia, but I wanted to point out that, of course, this affects about 1% of the world's population. It's characterized differently in a lot of patients, but hallmark symptoms include positive symptoms, negative symptoms, and cognitive dysfunction. Also, our patients are impaired socially and academically. This disease is one of the top 15 leading causes of disability worldwide, and people who have schizophrenia, of course, are at risk of premature mortality with patients dying almost 30 years earlier than the general population, and the newest estimates related to the financial burden of this disease are now estimated to be about $20 billion in direct and indirect costs annually. So, how do we treat schizophrenia? I think, hopefully, all of you are familiar, but just to kind of lead us into the topic, we do combine both medication treatment as well as, hopefully, counseling and support and therapy. The antipsychotics have been our mainstay with schizophrenia. We have what were the older medications, the first generation, which are still used in some patients. Our second generation antipsychotics, which began in production into the marketplace in the 1990s, and then today, we're moving on to talk about clozapine. So, clozapine, right now, is the only FDA-approved medication and available treatment for treatment-resistant schizophrenia. So, what do we know about clozapine? So, clozapine is our most effective antipsychotic for treatment-resistant schizophrenia. We know that from meta-analyses in many clinical trials that 40 percent of people will have a response to this medication with a mean reduction in rating scales, for example, on the positive and negative symptom rating scale of about 22 points during treatment, and this correlates to almost about a 30 percent reduction from symptoms in the average patient. There is a lot of variability, of course, but, overall, it has a superior efficacy. Several large effectiveness studies, as well, have suggested benefits that are, in addition to its efficacy on positive symptoms of the illness, it's known to have a greater time to treatment discontinuation, and you might be familiar with some of the landmark studies related to the CADI study that show that it's the medication that patients stay on the longest. Significantly greater patient-perceived ratings, and also, clinicians in several studies rate this as the most significant medication for improvement among the medications in the clinical trial. This next slide, then, shows us. This is Stefan Luke's meta-analysis, looking at the comparative efficacy of 15 different antipsychotic medications in a meta-analysis published in Lancet in 2013, and you can see here that, among those that we have listed, clozapine sits farthest to the left and has an effect size. This is the relative difference in effect compared to placebo with clozapine, and then the other medications are listed, and you can see that the effect size is quite larger with clozapine than with the other antipsychotics, so they have all very similar effect sizes, ranging anywhere from about almost 0.4 to about 0.6. And what we know, if you remember your statistics and what an effect size might mean, but a mild effect would be about a 0.3, a moderate effect for treatment would be about a 0.4 to 0.5, and a robust effect would be anything greater than a 0.8. So, we do characterize clozapine as having a robust effect, generally, with symptoms for schizophrenia. So, where is clozapine's place in treatment? There are several guidelines that are out there, and I was involved years ago with the Schizophrenia Patient Outcomes Research Team, or the PORT guidelines, and there have been APA guidelines, which I know are new ones that are coming out as well, hopefully soon, but there are many others, including the Harvard South Shore Program, the BAP, the NEIS guidelines, new Canadian guidelines came out this past year, and the guidelines suggest that clozapine should be used after two failed trials of antipsychotic treatment. So, clozapine, and that is for schizophrenia, but I wanted to point out that clozapine also has a broad range of effectiveness. So, clozapine can be used in a variety of other disorders. It is approved for schizophrenia and for suicide behavior, but it does have efficacy for hostility and aggression towards others, as well as suicide or symptoms towards self. Treatment-resistant bipolar disorder, there are some data also with other diseases like borderline personality, tardive dyskinesia, and psychogenic polydipsia as well. So, it is used mostly in treatment refractory psychosis, schizophrenia, but has been used in other disorders as well. There is growing evidence that people are using it earlier in the disorder. There is data using it as early as first episode. However, it's important to think about clozapine in that sometimes people think about it as a last-line agent, and we like to think of it as the first treatment for treatment-resistant schizophrenia. So, it should be a first-line treatment after there have been two failed trials of antipsychotics. And often, and many of you probably realize this, this happens fairly early on in some patients that we have who are treatment-resistant. So, we do have a fair amount of younger patients who are treated with clozapine. If we are appropriately following guidelines and appropriately using the medication, in fact, those who have treatment resistance would be using this medication earlier in their illness. So, I want to point out, though, before moving on to talking about barriers, to make sure we point out the risk-to-benefit profile of clozapine. So, clozapine is associated with a variety of side effects. Some of them are somewhat serious, and I'll mention those in a second, but common side effects include things like hypersalivation, tachycardia, aneurysis, sweating, eosinophil counts sometimes go up, and metabolic syndrome, weight gain does occur quite commonly, and constipation, which is common but can be a serious side effect as well. So, we often make sure that we're treating early on or prophylactically treat for constipation. But there are serious and rare side effects that probably all of you think about when you think about clozapine. So, there is a risk of myocarditis, and it is a small risk, about a 3% risk, cardiomyopathy as well. Seizure risk is somewhat dose-related, while the other ones are not as much. Cardiomyopathy and myocarditis are more associated with a rapid titration. And so, I know you'll have future webinars that'll be later on in the year where we can talk more about specific side effects and specific pointers around minimizing some of these side effects, but there's just a couple of pointers I'm handing out there. But also, the idea of severe neutropenia. The terminology for agranulocytosis was used with clozapine up until more recently when the newest guidelines came out from the FDA suggesting that a neutrophil count of less than 500 cells per millimeter cubed would be termed severe neutropenia. And we do see that happen rarely, and the rates are from 0.05 to 0.86. So, there is some miscommunication around that. There are publications out there that do suggest it's a higher than 1% risk, but after seven large epidemiologic studies and more recently a meta-analysis show that the risk of severe neutropenia is quite low and that generally all studies would show less than a 0.8% risk of severe neutropenia. So, the decision to use clozapine does require a thorough consideration of this risk-to-benefit profile. There's many things that you'll consider as you make that determination, a risk with the patient, things that they may or may not be able to tolerate, etc. But other things we need to pay attention to is the risk of not using clozapine when it should be indicated. So, Austin and I help work in the Medicaid system in Maryland, but Austin and Ray can also vouch for this, but we see polypharmacy very commonly used, and all of us have patients who have been on a few, if not several, antipsychotics at one time. But polypharmacy in general has very little evidence-based with it. There is some rational polypharmacy decisions, and there are, of course, some patients that do better with some combinations when we use that in a rational fashion. But there are lots of patients who are receiving polypharmacy for treatment-resistant schizophrenia when there's little evidence to suggest that two antipsychotics are effective for treatment-resistant schizophrenia. And, of course, poorly treated psychiatric illness where having polypharmacy only compounds and complicates the medical treatment picture with allowing more side effects potentially to occur. I wanted to point out that clozapine is associated with overall cost savings, so I wanted to make sure that we do mention about cost-effectiveness of clozapine. There's a couple of publications I listed here at the bottom. Dawn Belligan's work from the Medicaid system in the state of Texas that she shows that their overall cost savings to hospitals are estimated to be about $20,000 per patient in the first year alone with fewer hospitalization days with clozapine. So there is some benefits that have been shown in a few publications now with cost-effectiveness of using clozapine. But unfortunately, clozapine, and this is sort of getting to the crux of what we're talking about today, is that clozapine is used quite infrequently. And these are older study dates ranging from 2004 to 2008, but the data for clozapine looks very similar today. So the black lines toward the bottom are rates of clozapine over time. And clozapine in the general system, this is among all antipsychotics used in schizophrenia for the market share, is less than 5%. We're looking at a 4% rate overall, while other antipsychotics are used much more frequently. And this graphic, I do like it. This came out in 2015. Fuller Torrey published this from the Treatment Advocacy Center, and he was showing clozapine Medicaid data by state. And this is showing 10% or over. And then, of course, is the lightest color and the lightest shade of gray. But as you go up to almost the black color, this shows very low utilization of about 2% to 4%. And you can see that there is some variability by state. But overall, all states were under 15%, and the majority of states are then under the 5% range. In Canada, we do see rates about 6% to 7%. Other countries have much higher utilization. But the United States is one of the lowest users of clozapine in modernized countries. So also with clozapine underutilization, I just wanted to point out that there's lots of data that suggests that while we don't use this appropriately when we have two failed trials, but it takes us a long time to use it. So here's three studies that I've listed. But the first is showing that the estimation of starting clozapine after two failed trials was almost 48 months and with five prior trials often used before people go on to clozapine. Other data shows us that almost 70%, so two-thirds of patients, have three trials sometimes before going on to clozapine. And the mean prescribing is eight years. And as I mentioned, polypharmacy is really quite high, with about 20% of our patients using a few medications together instead of using clozapine after the second failed trial. So clozapine in our field, then, is arguably one of the most underused, evidence-based practices in all of psychiatry. As I mentioned, all the guidelines suggest that clozapine has an evidence base, and it is one of the evidence-based recommendations for treatment. So what are the barriers? So all of you, I'm sure, have lots of barriers. And we can talk about lots of barriers today. And I'm going to summarize some of those. But some are real. Some are real barriers. And some we perceive that aren't as big as barriers for our patients as we might think. Barriers include things like mandatory blood testing and the fear of serious side effects, the fear that our patients will discontinue their medication. We have difficulties identifying suitable patients, service fragmentation, inadequate training, or the ability to have trained and use clozapine prior to being out in practice on our own are all some of the barriers. But here's some of the data I wanted to show you. And this was a survey of patient perspectives with clozapine. These are medical risks and side effects, looking at the knowledge and attitudes towards clozapine initiation. And so what we do know from a couple of studies is that prescribers do overestimate patients' unhappiness with many side effects. And you can see here on the right-hand side is a graphic where this particular study looked at patients and the physicians of the patients. And they looked at how unhappy were they with blood draws and other side effects as well. And you can see here that overall, physicians often overestimate the side effects that they think patients will have. And another study I have listed here on the left in the United Kingdom, this is over 1,000 patients at 27 clinics. Patients report that 86% feel better on clozapine. Almost 90% prefer clozapine to other antipsychotics they've been on. Almost 90% as well think the advantages outweigh the risks. And then only less than 30% ranks that the frequent blood work is the biggest disadvantage. When in fact, we often think that that's a large disadvantage or our patients would see that as such. So we performed a study, and this was published in 2018 in the Clinical Schizophrenia-Related Psychoses. But we sent out a survey to 860 psychiatrists around the state of Maryland. And we received a response of about 32%. And we're reporting here data on 255 psychiatrists that returned data. But we asked them about barriers to clozapine. And we listed 28 barriers. And I'm summarizing the data here and summarizing these barriers into things like side effects, clinical and non-clinical barriers. But what you can see here is this is a Ligert scale, 0 to 5, with 5 being the most significant barrier. The psychiatrists around our state of Maryland suggest that non-adherence to blood work and the mandatory regular blood work are the biggest barriers, even more so than the other things I was talking about, like side effects, et cetera. And that's not unusual. There are several other papers that have now been published that replicated these same findings in terms of the blood monitoring being the most significant barrier. Again, many barriers, but those rated as the most significant barrier. So then we also looked at the top-ranked strategies. We did a separate survey to the state of Maryland psychiatrists, those who are currently prescribing clozapine. And we asked them, what would be the strategies to expand clozapine use? And for those who feel comfortable using it, still there's so much to learn. And so there's things that could help them better overcome these barriers. So better blood draw coordination, potentially at the point of care, having less logistical issues around blood drawing. So a finger stick. And Ray will touch upon that. And we'll touch upon that. There's exciting things potentially coming our way in the future. But I think it's worthwhile to mention. So that is one thing that might be helpful to us. The issue of benign estic neutropenia, I'm going to talk about here in my next slide. But how do we understand that? Who has benign estic neutropenia? When do we use it? When do we feel safe using clozapine? And that can help as well. I'm going to mention that, like I said, because we don't get much education around benign estic neutropenia. Also, education for physicians, families, and centralized resources are also things. And Ray will touch upon a couple of these as we move forward. So what is benign estic neutropenia? And that's one of the barriers that I wanted to talk about today. So we know that clozapine utilization is lower in African-American patients than Caucasian patients. And we also know that there's more frequent discontinuations and fewer starts with clozapine in this population. We've published a couple of papers and so have others in this area. So this is what got us about a decade ago or more starting to look at why is clozapine utilization lower in this population? There could be a variety of things. But one is potentially around this idea of benign estic neutropenia. And here's some of the data that I was talking about. But in Maryland, we look at the state system. And we actually found, like I said, lower rates of prescribing and more frequent discontinuations. But in New York Medicaid claims, Florida Medicaid claims, and the VA data, all of these large databases show the same thing. African-Americans are more likely to discontinue and less likely to be started. So then what about neutropenia in African-American patients? So this is a study here to sort of set the stage. So the rates of neutropenia in this study that were examined, this was a large cross-sectional study using the NHANES data between 1999 and 2004. And what they show is that relative to Caucasians, people of African ancestry have lower absolute neutrophil counts while having similar lymphocyte counts. So neutropenia itself, as characterized of being a neutrophil count of less than 1,500, occurred then in almost 5% of people of African-Americans versus less than 1% of Caucasians. So this large study showed us that the normative ANC ranges that were developed in Caucasian samples do not necessarily represent that of our African-American patients. So benign ethic neutropenia, those who then have a lower absolute neutrophil count naturally may then explain why we have the high fluctuations and discontinuations in this group because guidelines are in place at certain ANC levels that required discontinuation of the medication or the lack of ability to start if you weren't at a specific level. And if you had benign ethic neutropenia, or I'll refer to as BEN, then you may never have had the opportunity to have been treated. So BEN occurs in African ancestry patients most likely or most often Sub-Saharan Africa, Middle Eastern ancestry as well, and Yemenite Jewish descent patients also are known to have BEN. We identify BEN as a group of people with low absolute neutrophil counts who do not have an increased risk of neutropenia or do not have an increased risk of agranulocytosis happening or increased risk of infection. So the definition then of BEN is the occurrence of neutropenia defined by normative data that's been available in European ancestry patients. These are our lab values that are generally around white populations. These are in individuals of other ethnic groups who are otherwise healthy and do not have repeated or severe infections. So BEN is diagnosed by these repeated low measurements usually seeing a few measurements of the less than 1,500 without an identifiable cause of neutropenia in this population of African descent or Middle Eastern descent patients. So just to point out I may have a slide coming up here on it but when we register in the REM system if we think our patient has BEN we can check that off. We do not have to have a hematologist confirm that there is BEN it's very difficult and I'll talk a little about what genetics of this but it's not necessarily a blood test or some way we can tell. It's based on the definition that I had mentioned about the determination of ruling out other causes of neutropenia and determining that they may likely have BEN. Other countries you do have to have a hematologist. In our country we do not have to have for FDA guidelines a hematologist sign off to categorize a BEN patient. So what do we know about benign ethic neutropenia? Why does this happen? And so I'll give you a little bit of insight into what we've been doing and what we've been studying. So there's potentially a genetic polymorphism on the dark gene the Duffy antigen receptor chemokine gene that's highly associated with having a low ANC and there's three polymorphisms of this gene. There's what's called the Duffy null or what is the negative negative and then there's the heterozygous and then there's the positive positive. And this graphic or this table here shows us that in a sample of an epidemiologic cohort of 6,000 patients and these are all self-identified African-Americans. This was published in 2008. If you then look to see what their absolute neutrophil count was you can see what I'm talking about with this lower absolute neutrophil count on average. So the ANC on the right hand side in the positive negative and the positive positive group averages about 4,000 on on average. But you can see that if you have the Duffy null gene the negative negative genotype and that's in the majority of African-Americans over 4,000 patients in the sample it's about 1,500 lower as their average. So you can see how this is shifted from 4,000 as a mean down to 2,500. And this graphic here shows you visually what I'm talking about so if you see the three genotypes the blue line represents the distribution of those who have the Duffy null. So those of that genotype then have a naturally occurring white blood cell count that is 1,500 units or cells per millimeter cubed less than all others in the in the population and general and compared to Caucasians as well. So just so you all know that there are new guidelines that came out in 2015 for monitoring BEND patients. So there's two algorithms one for general patients and one for those who you characterize who you think might have benign ethnic neutropenia. And like I mentioned we characterize that as less than 1,500 and you mark that off and then on the in the REM system and then you follow these guidelines. So we do see patients who have BEND and I'll show you some data on that run a lot lower than we traditionally have seen but they don't have to be stopped until they have reached 500. So we see people who do dip into 7, 8 and 900 but then return the next day and generally have those creep back up. So we don't aren't as frightened by that as we used to now that we know that there's guidelines and we understand scientifically how why this might be happening. And some data just to show that we published in 2016 this is before and after clozapine in a population of BEND patients. This was 26 patients that we treated in the state of Maryland open label long before guideline changes. This is over in the last 15 years in the state using clozapine off-label knowing that this is a possibility and following very strict protocols to do so. But what was interesting is that the mean lowest absolute neutrophil count was about 1400 before clozapine and ended after a period of time on clozapine. This is about a six month time period about very similar so no changes. But what was interesting is the mean overall mean absolute neutrophil count actually significantly went up after starting clozapine. We don't we aren't proponents to say that clozapine actually raises absolute neutrophil count but what it does show us and there's another publication more recent that do show us that does not put people at increased risk. In fact we do see often we have a we have a sample in Nigeria also we do see that absolute neutrophil count sometimes increase after starting clozapine in a significant fashion. So I'm going to then go ahead and turn over so I talked about a few barriers today and a little bit of the work that we're doing to identify that but I'm going to turn this over to Dr. Love then to talk a little bit more about other barriers and then strategies in some of our national work groups that we've been working on to look at overcoming and addressing some of the barriers. Dr. Love. Thank you so much Dr. Kelly. In Maryland we've worked to improve clozapine utilization for many years. Our efforts were recognized nationally in 2016 when the National Association of State Mental Health Program Directors or NASHPD asked us to work on a white paper addressing this issue. And my job over the next few minutes is going to be to tell you a little bit about this white paper and the findings in it. So along with a variety of stakeholders from around the country this group systematically examined the issue of clozapine underutilization. We identified 15 categories of barriers to clozapine use and created a series of recommendations for 10 different types of entities and stakeholders to consider. These were published in a NASHPD white paper that was sponsored by SAMHSA and later it was summarized in the journal citation below in psychiatric services. Many of those who participated in these efforts have now started working with the SMI advisor the serious mental illness group to continue these efforts. Dr. Kelly talked about a number of the barriers and we'll discuss some of them again in a little bit different light. But among the barriers that we identified was a lack of centralized resources, centers of excellence, and the funding of unique treatment models. All of those who participated in this work group were convinced that specialized multidisciplinary clozapine clinics had and could play an important role in increasing clozapine utilization. We were also aware that there was a relative lack of resources on how to offer such services and the practitioners needed a central repository of information to assist them with the nuts and bolts of prescribing clozapine. We're now working with the SMI advisor to develop clozapine tips in a centralized location on the CSS SMI website that can help address some of these needs and serve as references for prescribers. These tips address everything from clozapine levels to side effect monitoring and management. And the SMI advisor is also offering a clozapine list serve. Another barrier that was discussed at these meetings was the poorly coordinated interface between the justice system and behavioral health systems. Almost everyone has encountered a patient who was stabilized on clozapine who entered a correctional or forensic facility that was either ill-equipped or unwilling to deal with clozapine. I myself had to deal with three such patients within the past month. Unfortunately, this occurs even with facilities with well-integrated psychiatric services. They just don't want to deal with clozapine. And when you have a patient where the services are marginalized, it's virtually impossible to get and keep a patient on clozapine. Dr. Kelly talked about the hematologic issues with clozapine. And certainly, hematologic monitoring is an off-sited obstacle to clozapine use. Weekly venipuncture may be more acceptable to many patients than we think, but it's still no picnic. In some cases, with some patients, it can be a make-or-break issue as to whether the patient is willing to take clozapine. In addition, getting to the clinic or the laboratory can be difficult financially for patients or even challenge a patient's ability to navigate public transportation systems. So trying to keep patients' adherence to blood work is certainly a challenge. In addition, patients are getting a weak supply of drug at a time and need to get to their pharmacy. Fortunately, pharmacies tend to be a lot more centrally located. Another issue related to hematologic monitoring is that some patients are suspicious about their blood being sent off to some lab or location where they never see it again. They're afraid it's being used for some nefarious purpose. We just don't have an easy method for hematologic monitoring that's widely available at the present time. Dr. Kelly talked about a survey that we had done a few years ago, and this was part of our work in the state of Maryland to address barriers to clozapine use. When we surveyed these individuals, help with blood monitoring was the number one answer that people gave. Modification of monitoring parameters was number two, and fortunately, since we did that survey, the BEN guidelines have come out that have made the monitoring parameters more palatable. Rather than waving the white flag on laboratory monitoring of patients on clozapine, I do want you to know that the future is bright. For many years, device developers have been working on methods to make monitoring easier. In conjunction with an NIH study that Deanna is PI of and that I participate on, we've been fortunate to work with a company called Athelas that has developed a device for hematologic monitoring in oncology. While it's not yet available commercially for use in monitoring clozapine, it has several characteristics that clinicians would favor in any monitoring device. And so some of the characteristics that we think important in any device would be to have a device that's small and portable, and this particular device is about the size of an Amazon Echo. It requires only a small finger stick similar to what a diabetic might use for glucose monitoring, so we have some hope that those patients that are resistant to venipuncture might find it more palatable. It gives results in minutes, integrating with the REMS program to reduce the data entry burden. And for patients that have trouble with you taking their blood and sending it out, the whole process happens locally. Patients can witness it and know that their blood isn't being sent off of the premises. So we're hopeful that devices that contain these types of qualities will help us challenge that or address that blood draw barrier in the future. Another barrier that was discussed quite extensively in our workgroup was the clozapine REMS registry. Initially, each manufacturer of clozapine had its own monitoring system, and these tended to be pharmacist-based, which removed a lot of the reporting barriers from the prescriber. The consolidated clozapine REMS system really forced the prescriber or the prescriber's designee back into data entry. The initial rollout of REMS was kind of buggy. There were several articles about the difficulty in using it. Prescribers, if they called into the system, had long waits on the phone, and some of the notices that the system sent out were incorrect. Others were excessive, and prescribers objected to them. Over the past couple of years, many of the bugs have been worked out, but it still takes more time and effort to use the REMS system than the old manufacturer's system. So there's still a bit of an impediment here. Given the relative infrequency of severe neutropenia and the new BEN guidelines, many still question the need for this centralized monitoring at all. Again, this is from the study that we cited earlier, the survey that we cited earlier, and in this particular presentation of the data, I want to call your attention to the yellow lines. Those yellow bars represent prescribers who were not prescribing Clozapine at the time of the survey. And you can see that the issues that they raised were that many of them did not feel competent in using Clozapine, and many cited a lack of experience with Clozapine in residency training. As our group has continued to work, we found that a number of individuals are working on this item. So for instance, several states have actively addressed education and training. Mass General incorporates their Clozapine clinic into their residency training. Ohio educates about Clozapine through their Advancing Best Practices program. The American Association of Directors of Psychiatric Residency Training are considering adding requirements regarding Clozapine to their curricula. And CSSSMI is playing a valuable role by offering programs on Clozapine. Finally, I want to note that it's important that these educational efforts not only be directed at potential and current prescribers, but they need to be addressed to all of the professionals who work on multidisciplinary teams that operate in Clozapine clinics, or to try and help patients with Clozapine. Other barriers that were enumerated in the white paper include lack of standardized materials for shared decision-making, lack of protocols for treatment monitoring and side effect management. An example here might be, what's the best way to monitor a patient's bowel movement so that one can intervene early before impaction occurs? What's the best way to treat it if something does happen? There's a lack of Clozapine hotline. Given the fact that some of the reactions, the adverse reactions to Clozapine can be serious, wouldn't it be great to be able to pick up a phone and have someone you could discuss a Clozapine issue with? Another issue has been facilities that treat patients with serious mental illnesses but do not have Clozapine on their formularies. We'll talk more about this in a second under the recommendations. Finding resources or funding for transportation for laboratory testing is another issue. Some states may pay for this through Medicaid, but in other states practitioners and health systems need to get creative about how we're going to do laboratory testing. In a few years when portable devices become available that give instantaneous readouts, hopefully this will reduce that barrier. Of course, throughout healthcare we have transition of care issues. With Clozapine we have the issues with corrections we talked about, but even when patients change practitioners, when they switch residences, all of these cause profound transition of care issues with Clozapine because treatment can be interrupted. As we noted earlier, the NASMHPD workgroup made multiple recommendations to multiple groups and stakeholders that could address barriers to Clozapine use. One group that was addressed was prescribers. One could argue that it takes more than one clinician to manage a patient on Clozapine. It's almost like it takes a village. One suggestion made by many experienced clinicians was that they should form relationships with other clinicians who can help when problems emerge during Clozapine treatment. It's reassuring and potentially life-saving to have a relationship with a cardiologist who you can consult when a patient develops myocarditis or a hematologist that can help when a patient exhibits neutropenia or a gastroenterologist who can consult on patients with severe constipation, belly pain, or impaction. Similarly, relationships with experienced clinicians who have addressed the mystery of inadequate blood levels, who've dealt with Ben or other treatment emerging adverse effects can improve confidence. Furthermore, one can form these relationships proactively before we run into problems or emergencies. We wish that state and federal authorities would require that every hospital have Clozapine on the formulary and policies for its use. If a hospital did not have naloxone on its formulary, it's likely that accreditation or licensure authorities would prevent them from operating. Clozapine is a whole lot less expensive than naloxone, but it's just as essential to patients who are maintained on it. Every interruption in Clozapine treatment, for the silly reason that it's not on a formulary, may be devastating for patients. When a patient comes into the hospital stable on Clozapine, it borders on unethical to take them off of Clozapine and discharge them not fully stabilized on another medication. The obvious exception if there were a contraindication to Clozapine. Local and state health authorities must also step up to the plate and accept their roles in assuring appropriate access and use of Clozapine. Clozapine has to become a priority. They can and should develop programs to facilitate its use. They can also adopt existing resources as innovative strategies that assist patients. For instance, ACT teams can assist in monitoring. There are unique programs using pharmacy-based monitoring and respite beds have been used for initiation and titration patients on Clozapine. Along the same lines, payers need to understand that Clozapine is a complex treatment whose use pays off in terms of better outcomes. They need to address the fact that reimbursement for use of Clozapine requires reimbursement not only for the prescriber, but all the members of multidisciplinary teams. Telemedicine can assist with consultation. Pharmacy-based medication management services can provide monitoring that's in close proximity to the patient's resident. Transportation costs need to be addressed by payers. And last but not least, Clozapine should be a preferred or tier one medication with minimal co-pays to encourage patients to continue to fill their prescriptions. We all know that behavioral health services may be lacking in many correctional systems. However, the patient that responds to Clozapine may require less of the services that are in such scarce supply if they respond. By forming partnerships and developing appropriate policies and procedures, Clozapine's use is possible in these systems. Through efforts like the CMI Advisor, we're developing and disseminating toolkits and information that deal with everything from consent to patient education. In addition to posting materials, we soon hope to offer some consultation through CSS-SMI. But we still need assistance in developing multidisciplinary clinics and strategies for bringing Clozapine to patients. There's a need for new funding models and reimbursement for innovative techniques like telehealth, and we need advocacy for the appropriate use of Clozapine. Thank you for your attention. To summarize, Clozapine is a superior medication which tends to be underutilized in the United States. While we have many barriers, these national recommendations challenge every person and system to play a role in improving optimal Clozapine use. If access to Clozapine is improved, millions of patients could benefit, and in turn, their improved care could result in substantial cost savings to the entire healthcare system. Thank you so much for your attention.
Video Summary
In this video, Dr. Deanna Kelly and Dr. Raymond Love discuss the underutilization of clozapine, an FDA-approved medication for treatment-resistant schizophrenia. They highlight the burden of schizophrenia, the effectiveness of clozapine, and its place in treatment. They also discuss barriers to clozapine utilization, such as mandatory blood testing and concerns about side effects. The doctors emphasize the need for education and training on clozapine, as well as improved monitoring strategies. They mention the development of a device for hematologic monitoring that may make the process easier for patients. The video also mentions the importance of centralized resources, multidisciplinary clozapine clinics, and better coordination between the justice system and behavioral health systems. The doctors then summarize the findings of a white paper on clozapine underutilization, which includes recommendations for various stakeholders. They discuss the need for standardized materials, protocols for monitoring and managing side effects, and the creation of a clozapine hotline. They also suggest that hospitals should have clozapine on their formularies and that local and state health authorities should prioritize access to clozapine. The doctors stress the importance of payers supporting the use of clozapine through reimbursement and funding models. They also address the issue of clozapine use in correctional systems and emphasize the need for multidisciplinary clinics and telehealth options. They conclude by highlighting the potential benefits of improving clozapine utilization in terms of patient outcomes and cost savings.
Keywords
clozapine underutilization
FDA-approved medication
treatment-resistant schizophrenia
barriers to clozapine utilization
hematologic monitoring device
multidisciplinary clozapine clinics
clozapine hotline
improving clozapine utilization
Funding for SMI Adviser was made possible by Grant No. SM080818 from SAMHSA of the U.S. Department of Health and Human Services (HHS). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, SAMHSA/HHS or the U.S. Government.
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