This podcast provides general information, not a substitute for professional medical advice. Please consult your physician for personalized guidance. Hello, hello, welcome back to PsychRounds, a resident-run educational psychiatry podcast. I'm Dr. Tanner Hewitt, and while Dr. Bradley Miller is out today, I'm joined by our other co-host, Dr. Larry Weigh. Now today we will be talking about the anti-psychotic clasping, also known by its brand name, Closeroil. And who better to have on than the man who spearheaded the efforts to get clasping approved in the United States? With his monumental paper in 1988 titled "Closoping, the Treatment Resistant Schizophrenic," a double-blind comparison with chlorpromising. So I'd like to introduce Dr. John Kane, who completed medical school at NYU and residency training at Zucker Hill's side hospital, where he stayed on subsequently as chair of psychiatry for over 34 years. He's also done extensive research in the field and has nearly 900 scientific papers published in peer-review journals. Now, Dr. Kane, is there anything else you'd like to say to introduce yourself? Oh, thanks. I'm very pleased to be able to join you today and appreciate the opportunity to talk to some of your colleagues. Thank you. Thank you for joining us. So to quickly give our listeners a backstory on this medication to those who are not familiar, clasping is widely considered the first atypical anti-psychotic. And in layman's terms, it's a fairly old medication first being synthesized in 1958. They're really not all that much newer compared to something like chlorpromising. Of note, it did not receive FDA approval in the United States until 30 plus years later in 1989. So why was there such a big gap in time from development to approval? While going over the history, clasping did receive approval in some European countries in the 1970s, but there were some problems that arose related to its propensity for causing a granulose atosis. Specifically, I believe there was a case in Finland which resulted in the death of over eight patients. And so clasping status in the United States became uncertain. So I was wondering what it was about clasping that major doctor Kane wanted to look back into this medication. And I was wondering if you could walk us through the history of how you published the paper and eventually helped get this medication approved in the United States. Sure. Thanks for the question. So I had read some of the data that came out of Europe. As you mentioned, there were some countries that had approved the use of clasping. Professor Hippius in Germany had done a study in treatment, resistant patients. So I was aware of some of that work. And I was interested in the possibility that clasping could be at least studied in the United States. As you said, there were a series of deaths in Finland as a result of severe neutropenia. And that led the FDA to be extremely cautious about approving clasping. The company that at that point was manufacturing clasping was Sandos, a Swiss pharmaceutical company. They did have some IND, some investigational new drug permissions for a few investigators in the United States to use clasping. And one of those investigators was a man named Nathan Klein in New York. What happened was Dr. Klein, I guess, had not been keeping up with the paperwork that was necessary to support his IND. Sandos basically told him that they were no longer going to share permission to use the drug and they asked me to take over his patients with the goal of actually getting them off clasping. Because at that point, they did not think that clasping had a future in the US. So I was very young at that point. I had recently finished my residency in in touch with the company. They were aware of me because I had expressed interest in clasping. So I took over a group of patients that had been treated by this gentleman. I did try to discontinue clasping in some of them and with not very good results, we put them back on clasping. We're very, very impressed with the efficacy that it had and these people who were quite ill. We then had a conversation with the FDA about and with the company about how much potential we thought that this drug had. The FDA said that really were not enough data on which to base an approval. But if we were to conduct a very well designed and well executed study that showed clasping to be superior over available anti-psychotic drugs in treatment, resistant patients that they would consider approving it. We met at that time with Paul Lieber, who was the head of the psychopharm drugs division at the Food and Drug Administration. He participated very closely with us in the design of a study. That was what became known as study 30. We worked very hard to design a study that we thought would obviously satisfy the FDA and be credible in the field. It was a very conservative study. We required that patients have a lead in prospective documentation of failure to respond to anti-psychotic medication. This is what you see if you look at the literature of studies in treatment resistance, schizophrenia, you often see a surprising amount of response even in the control condition. These were allegedly treatment resistant patients. When they go into a study, there's often a surprising amount of improvement. It's akin to what we see with placebo in patients who are acutely psychotic. We had a lead in phase where patients had to be treated with haloparital prospectively and continue to demonstrate a lack of response. They were randomly assigned to Closopinocloropromazine on a double blind basis. The study was successful. Many people were surprised that Closopin worked under that strict protocol. It was successful. We published that paper in the archives. It was then called the Archives of General Psychiatry in 1988. Dr. Lieber representing the FDA, as I said, had been involved in the design of that study. I think the FDA was sympathetic because the study had been conducted with their guidance. The challenge, though, was the great concern that they had about monitoring patients for the development of agonol cytosis, which we now refer to as severe neutropenia. Because of the deaths in Finland, not a lot was known about the extent of that risk. The FDA wanted to be sure there was some way to ensure that patients would have weekly blood tests. That a policy was implemented of no blood, no drug. People had to have a blood test in order to have their prescription filled. There was a lot of controversy surrounding that, but it was executed. The plan worked ultimately over the ensuing years. We realized that the risk of severe neutropenia could be managed much better. Probably the estimates are that the, to about 0.4 percent and the death rate, the related death rate is about 0.05 percent. The death rate is very, very low. We are much better able to manage severe neutropenia when it does occur. I think it's much less of a risk than it was in the late 1970s or early 1980s. The package labeling still requires monitoring, weekly monitoring for the first six months and then bi-weekly between month six and 12 and then monthly thereafter. But continuous, there's no cessation. Perhaps later in this conversation, we're going to talk about the recent FDA meeting on the REMS program. But, I think everyone was very pleased to have a medication that the FDA had approved for the treatment of those patients who had failed to respond to first-line treatments. The problem has been in all honesty that Closopene continues to be grossly underutilized. More than several decades later, it still is the only drug that has FDA approved.
approval for treatment resistant patients, which is kind of a sad commentary on our inability to develop new medicines that are more effective. And ironically, we still don't really know how close a pain works. We know that it binds to a lot of different receptors in the brain. We used to say it was a dirty drug. Now we like to say it's a drug with a rich pharmacology. The reality is we still don't understand how it works. The approval of cobency is an Olamine Trust Plus Trosvium. M1M4 agonist has renewed interest in the muskronic agonist and the role that they might play in facilitating treatment response, but a lot of unanswered questions there. And that's sorry if that was a long-winded answer to your question, but that's a little bit of the history of close and pain. And it is unusual in the sense that many people question the desirability of collaborating with pharmaceutical companies. This is something that's not recommended to young academicians. The reality is that that study would never have been funded by NIH. I think we were very fortunate to have a manufacturer that was interested in trying to develop a medicine that could work in that situation. Once it was approved and once we demonstrated that it did have superior efficacy, then NIMH started funding studies with close-up treatment. So they have funded a number of studies. But I don't think they would have funded that initial investigation. We really need to rely at times on the pharmaceutical industry to develop new treatments and provide the initial data going forward. Well, thank you for going over that. Pisc, it was very helpful. And I will never say dirty drug ever again. Every drug is going to be a drug with rich pharmacology that binds to a lot of receptors. But you kind of already touched on some of this. You mentioned how for treatment resistance likeosis in particular, close-upena is vastly more superior than the other antipsychotics, such as Hallopardol or chloropromazine. And you talked about some of the muscaronic agonism and we're not exactly sure how close-upena works. But are there any other guesses? So for example, I hear a lot about its potential actions on glutamate receptors, things like that, especially because of the antipsychotics. It's a very, very poor D2 blocker. Yes, you're absolutely right. I honestly cannot comment, though, on the mechanism. I think we still have a lot of unknowns there. There are a number of hypotheses that have been suggested to what extent the muscaronic agonism plays a role. We don't really know, in my opinion. So with an olemine introspeum, it will be interesting to see if that medicine works when other medicines have failed. We don't know yet what we've seen so far are some very well-conducted studies against placebo in acutely psychotic patients with good effect size. So we know that it works in acute psychosis. We know that it's a different mechanism of action, that it's muscaronic agonists rather than doke-meet receptor antagonists. But whether or not that mechanism will provide superior efficacy in comparison to other drugs remains to be determined. There is a study underway where cobenphe is the brand name. I prefer to use generic name so it's an olemine introspeum is being added to other anti-psychotic drugs in patients who have failed to respond adequately to those drugs. They may not be, they may not meet criteria for treatment resistance, but they are patients who still have residual positive symptoms. So that's an adjunctive study. We expect that study to read out within the next few months, I think. And we'll see if that study's positive that might suggest that zenolemine plus trospium might be helpful in patients who might be treatment resistant. So we'll have to see. There's a lot more work that needs to be done. Yeah, absolutely. Now Dr. Kane, I want to take just a brief moment we touched on the severe neutropenia, which is one of the main things that's often tested on our board exams as young residents. But there's also things like weight gain, constipation, tealuria, a decrease in seizure threshold, orthostatic hypertension, and even some reports of myocarditis. But specifically, I want to talk about constipation first since this is one of the things that I run into. And I believe there are actually higher rates of death due to peri-litic ilias rather than the severe neutropenia. So what are some ways in which we can combat some of these side effects? Well, you're absolutely right. First, let me just comment in general that yes, chlosopene has a number of adverse effects, some of which are potentially fatal. Aralytic ilias is one of them. So gastric hypermortility is a serious concern on pneumonia, aspiration pneumonia is another phenomenon that's associated with the death rate. So there are other causes of death associated with chlosopene side effects besides severe neutropenia. But yet, severe neutropenia gets perhaps more attention because it's easier to do a blood test and measure neutrophils than it is to monitor all of these other things, which I think is a mistake. I think we need to focus more attention, as you said, on monitoring for some of these other potentially serious adverse effects. Despite all of this, though, it's fascinating that when you look at mortality rates among schizophrenia patients being treated with anti-psychotic drugs, the mortality rates among patients receiving chlosopene are significantly lower than those receiving other medication. So that in a way that's counterintuitive, it just shows that the advantages of chlosopene really do outweigh some of the concerns about these potentially serious adverse effects. As far as constipation goes, it is one of the most common adverse effects. So most patients are going to experience some degree of constipation as a result of chlosopene. And as you suggested, it can lead to paralytic ilius, which is potentially fatal. So I think it's probably advisable that anybody who's starting on chlosopene also be, well, first to be screen to understand whether they're already having gastrochemical motility and rule out other medicines that might be contributing to that. Those medicines should be discontinued if at all possible. It should be advised on hydration and exercise and things like that. But even with that, patients should probably be started on medications to counter the constipating effects of chlosopene. And by that, you know, stool softer and osmotic agents and potentially as stimulant. And even all three together to try to prevent severe constipation. So as you said, I think it's very important that clinicians be aware of that as a risk and do everything they can to minimize it. Great. So speaking of side effects, there's also salaria or excessive drooling. Maybe it doesn't sound as bad as some of the other side effects we've talked about. But I have had patients actually request to get off this medication because the salaria was that bad. So I guess one, what are some ways we can combat this to I was always curious myself, why constipation salaria? Because that's a colonergic side effects. Whereas we were always taught that chlosopene is the most anticholinergic of the antipsychotics. I think upon my reading as an intern, I was reading how the it was the active metabolite, nor chlosopene that is heavily pro colonergic that causes a salaria. And we're kind of touching on coben fee a lot. But I was also reading a study where they tested just nor chlosopene by itself, I believe, for schizophrenia. And I think that data wasn't all that effective, actually. So I'm just confused why now we have this new drug that's perhaps very similar to nor chlosopene that is now approved. Well, I think it's different. I mean, these are complicated phenomena. And I'm certainly not an expert on the musklerinic agonist, et cetera, et cetera. So it is counterintuitive. There's no question that we're, you know, it's a little puzzling why we see hyper salivation as such a salient adverse effect. But be that as it may in terms of mechanism, it is a very real phenomena. It's one of the most frequent reasons for people wanting to discontinue chlosopene, as you said. And the solution is another one, wakane is another one, but hyper salivation or seealuria is a very common reason. It's very troubling to patients. It's embarrassing. It's also, but it's another potentially very serious side effect because it can lead to aspiration pneumonia, which is potentially fatal. So I think we need to take hyper salivation very seriously as an adverse effect for all of those reasons.
And it affects most patients. You know, the overwhelming majority of patients are going to have some degree of hyper salivation. So, you know, in terms of all of these things, I guess I want to make sure that we emphasize that talking to our patients and monitoring for adverse effects is absolutely critical. And because Chlozapine has some potentially fatal adverse effects, it becomes even more important. We, you know, as I said earlier, we've been forced to monitors severe, for severe neutropenia, perhaps even more than is necessary, but we're not being forced in the same way to monitor for some of these other potentially lethal side effects. So it's very important that your colleagues understand that they need to evaluate their patients. They need to be talking to them. They need to be warning them about these things, guiding them as to, you know, what to look for, et cetera. So as far as say, Allaria, the treatments that are, you know, basically recommended are atropine drops now sublingually. But botulinum tops and B injections have become, I think, a go to treatment for a lot of patients with hyper salivation. So it's something that, you know, residents should identify a colleague in neurology or who is prepared to give such injections and consider that as a potential treatment. So yeah, it's certainly an adverse effect that needs to be addressed. Cool. And I believe actually the botulinum tops as a treatment for salivaria, that's now a pride question. Yeah. So, you mentioned it already many times how there's strict monitoring, no blood, no drug, right? So I did want to discuss the REMS protocol. Right now in the United States, I believe it's mandated that when you first start the medication for the first six months, it's required to get weekly blood work done. After that, the next six months, you need to get it done every two weeks. And then after that, even if you're on it for 30 years, 30 years later, you still have to get it done monthly. And I think the initial intention was good. It was to maximize safety because there was that fear of agraniosytosis, neutropenia, things like that. But this strict monitoring schedule has caused some issues such as delays in getting delays in patients receiving medications sometimes, which can lead to retitration, relapse of symptoms, as well as things like provider and patient resistance to starting the medication in the first place. And however, I think November of last year, the FDA Advisory Committee voted 14 to 1 to dismiss this REMS protocol. But I don't think anything's been made concrete yet. So I wanted to hear your thoughts on the REMS protocol and what you foresee happening in the future. Sure. Yeah, I was fortunate to be at that meeting, to be one of the speakers and to be able to listen to the discussion. As you said, the vote was two separate committees that were meeting together. The vote was 14 to 1. The one person who did not vote with the majority was basically not saying that we should preserve the REMS program in its current form. He was basically saying, maybe we should consider having a REMS program for the first six months, but not after. So he certainly wasn't in major disagreement with the rest of the advisors. The FDA does not have to follow the advice of its committees. It usually does. So we haven't heard from them exactly what they're going to do and when. But this is not going to change the package label it. So I think there's some confusion that people have at times, you know, is the REMS program what determines the frequency of the monitoring? No. The REMS program was really a requirement for reporting the results and that was problematic for a lot of people. It wasn't always being adhered to. It did create some of the concerns that you raised a moment ago. But there's no indication that the FDA is going to change the package label. I think some of us would like to encourage a review of the label and that it's probably not necessary to continue monitoring for severe neutropenia after, let's say, two years if the patient's done well. The majority of the cases occur in the first 18 weeks. So it's understandable that we would want to monitor weekly for 18 weeks. After that, I think the yield declines. The risk, and some people have suggested that the risk of closepine induced severe neutropenia goes away. It doesn't really go away. It does diminish over time, but it does remain higher than what we see with other anti-psychotic drugs. However, it's, I think, it does become low enough that to require continued monitoring is not really necessary. Given the context that we've talked about earlier, other adverse effects that actually are associated with a greater likelihood of fatality, we should be focusing more attention on some of those adverse effects. But as you said, the committees did vote. They recommended that the REMS program no longer be a requirement. So there was a lot of, I think, a lot of people were very pleased to hear that recommendation. Yeah, absolutely. I think that's an exciting development, and we're all looking forward to seeing what happens with that. One of the things that I've heard going through training, not even just as a resident, but also as a medical student, is candidates for those patients where you feel like they may be a closepine candidate, but then we hear that there's no long acting injectable of this medication. And that always begs the question of medication adherence. So I'm wondering if you think Dr. Kane that there will ever be in the future a development of something like a closepine long acting injectable, or if you can speak to adherence, maybe anecdotally, or just educationally, if this is a valid concern? Sure. And I think adherence is always a valid concern. What's fascinating though about closepine is we see higher adherence rates with closepine despite all of these problems that we've been talking about, the need for blood tests, et cetera. Because patients when closepine is helpful, it's something that they personally recognize and appreciate. So they are much more interested in willing to take the medicine than they might with other medicines that are not working as well. So it would be great if we had a long acting injectable formulation. I don't think that's likely. I wouldn't, you know, one never rules things out in science, but I don't think it's likely in the near future. However, if somebody responds well to closepine, they are likely to be adherent. That's the good news. The other thing that I'd want to emphasize is since the publication of that paper that I mentioned in 1988, there had been many, many other studies of closepine showing its advantages. For example, suicide, the reduction of suicidality, the FDA did approve that. So that is now in the package label that closepine can be used to reduce the risk of suicidality. In addition to that, closepine has been shown to be better at preventing relapse. We just published a paper in Lancet's psychiatry within the last few weeks showing from a large database in Scandinavia that for those patients who relapse, putting them back on the same drug is not very efficacious. That closepine is more efficacious in preventing relapse and re-hospitalization than other medicines. So one question is, you know, when somebody relapses, particularly if they've been taking their medicine, is that a form of treatment resistance? We haven't considered it as such, but it may be if somebody breaks through medication. We've been doing studies, for example, of patients who are receiving long-acting and jeopardable medications. We know that they're getting their medicine. It's not confounded by non-atherence. And we're trying to understand why do those patients relapse? They clearly have adequate dopamine receptor antagonism, but they're relapsing. So that may be a form of form for us of treatment resistance. And I think these data coming out of Scandinavia reinforce that. The other thing that we've seen is closepine can be particularly helpful in reducing aggressive and violent behavior. We mentioned earlier the studies of mortality that patients taking closepine are surviving longer than patients not taking closepine. So it has some very interesting characteristics. Unfortunately, we can't predict who's going to respond to closepine. And I think it's really a shame if somebody for whom closepine is indicated doesn't get a trial. right now in the US, the estimates, and this was presented at the FDA at the end of the
advisory committee, the estimates are that only one out of eight patients who should get a trial of closepine is actually getting a trial of closepine. And we're basing that on the prevalence of treatment resistance schizophrenia, which may be as high as 40% when you follow people over time. Even in the very first episode of schizophrenia, about 20% are treatment resistant, meaning they fail to respond to trials of two different anti-psychotic drugs. Those patients should get a trial of closepine and by and large, they are not. So there's really an eightfold gap in the utilization of closepine. We could talk a lot about the reasons for that. Some people blame the REMS program. I think that was a minor obstacle. I don't think it was the major obstacle. But we don't have good predictors of closepine response. We know that about half of the patients will have a clinically meaningful response and a smaller subgroup will have a potentially life-changing response. And it's unfortunate if patients don't have the opportunity to see that. And what we tell patients and families is we can't predict how you or how your loved one is going to respond to closepine. The only way we're going to know is if we do a therapeutic trial, which means that you need to take this medicine for a few months and see how you do. That will then give you an opportunity to make an informed decision as to whether the benefits outweigh the risks. You will also have had the opportunity to see what side effects you might experience from closepine. And then you can have a balanced view to make an informed decision without that experience, without that trial. It's totally abstract. And I think that's a very important message to get across to patients and families. We really have to increase the utilization of closepine until we find something that works as well, which I hope we do. But right now, it's the best that we have. And it's a shame. I mean, this is true in medicine in general. We see that evidence-based practice is not always implemented. I think it's important for your colleagues also to be part of the solution. And what we've seen is that if you don't have experience using closepine as a resident, there's a good chance you won't feel comfortable doing it later on in your career. So I think the training component is very important. And I think those of you who are working in programs that don't have that opportunity should try to ask your training directors to make sure that you get that experience. Yeah. And I like to call that colloquial medicine, actually. So that's my term for non-evidence-based practices. But as a last question, we already talked about it a bunch. But where do you see Kobenfi or the normally trozbium in the pantheon of antipsychotics? And also, where do you see the future of treatment for schizophrenia? There's another drug I believe you load around. It's a tar one agonist. It looked promising, but ended up failing the Phase III trials. The pharmacology looks pretty rich, though. Do you see future developments for non-doping mean blockers for the treatments gets occurring? Yeah. Well, I think Zenolymine trozbium is certainly a success story. I think they did very good trials. They got approval. It's a different mechanism of action. They have a different label, if you will, different, you know, no boxed warnings in that sense. So that's very good news. That's very exciting. I think that's led to a lot of enthusiasm in CNS drug development. However, as you said, the tar one compound looked very promising, but then failed. We still struggle with placebo response. And so when we see these failed trials, or in this case, a negative trial, and let me just point out what the difference is, when we compare a new medicine to placebo and it is not superior to placebo, that's a negative trial. When we have a third arm of an approved effective medication, we have that to ensure the validity of the study. You know, was this a patient population that's capable of responding to medication, et cetera, et cetera? So you have the experimental drug. You have an active control drug that's already approved. And then you have placebo. If the approved medication doesn't beat placebo, that's a failed study. That means there's something wrong with the study itself. Why did this drug that usually works, not work in that particular context? So what we saw with the tar one agent was a negative study. And you know, that was disappointing because their previous study had been positive. We also saw a negative study with MRACLADINE, which was a Master in the M4 agent. And that was disappointing. The company that sponsored those studies was purchased by a larger pharmaceutical company and then these negative studies came out. In addition, within the last few weeks, we had an announcement by Beringer Ingelheim that they're agent, which was being developed for the treatment of cognitive dysfunction in schizophrenia. Also failed to replicate the earlier positive study that they had seen. So we've had a number of disappointments along with the excitement that we've seen with Zanolamine. There are several other muscarinic agonists under development. So in all likelihood, we will see some further progress in that arena, but it's going to take years. There is, you know, I think there is hope for new mechanisms of action, but as we've seen, it's complicated. The trials are challenging, often because of placebo response that is much higher than anticipated. So we have, you know, we definitely have work to do, but there's this reason for optimism. I must say though that what troubles me more is the lack of our ability to use the medicines that we have now in the most judicious way. I mean, we talked about the underutilization of closeping. We could also talk about the underutilization of long-acting, injectable medicines, which have many advantages, but are also grossly underutilized. We still see patients not receiving any medication at all. And as a result, having a psychotic relapse, we have patients who are struggling with side effects that could be better managed. I mean, so we have a lot of things that we could be doing better while we wait for newer medicines. But I'm optimistic that over time, there will be newer medicines, different mechanisms of action, but it's good to find a tough illness. You know, we still don't have anything approved for negative symptoms. You still don't have anything approved for cognitive dysfunction. These are the major drivers of functional impairment. So Dr. Kane, before you wrap up any last points that you wanted to raise or anything like that? I guess just to you and your colleagues, you know, the future is in your hands. Make sure you try to keep up with recent advances. And I would say be careful to what you pay attention because there are so many demands on your attention now that you really do have to be careful with that. But keep up with your reading, keep up with the literature. Make sure that you're implementing evidence-based practice whenever possible. Make sure that you're teaching your patients and their families in a way that's going to ultimately be helpful to them. It's a tough illness. Also I hope that people will continue to work with underserved populations and, you know, spend some time in that arena regardless of what else you're doing. So, but thank you for the opportunity. All right. So, I think that just about brings today's episode to a close. I want to sincerely thank Dr. John Kane for agreeing to come on today and recording with us. One thing I did want to mention for those of you looking for some resources or anything like that about clasapine. One of my favorites was Dr. Steven Stahl and Dr. Jonathan Mayer's resource, which is the clasapine handbook with this Cambridge series. We do not receive any sponsorship or anything like that for these products, but it's worth a read. As always, feel free to contact us at
[email protected] for questions, comments, or future episode suggestions. If you're a fan of the podcast, please drop us a follow rating review as this helps us reach larger audiences. We will see you next time in Hebegray weekend.
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