Good morning everyone. Thanks for joining us this morning. My name is Brian Barnett. I'm a psychiatrist at Cleveland Clinic and today we're going to be talking about catatonia. We've got a great panel here so we're going to start off with Andrew Francis talking about the diagnosis of catatonia and then that will be followed by Scott Beach who is at MGH and has published some very interesting work on the neurobiology of catatonia and so he will be talking about management. After that I will discuss a variety of other things related to catatonia including morbidity, mortality, and economic data related to the costs of caring for patients with catatonia. And then our discussant for today is Greg Frischone who did the first Ativan challenge in a patient with catatonia and so he'll help us wrap things up and so we'll get started now and so I'm going to hand it over to Andy. Thank you Brian. It's my pleasure to be here and to present today. So I'll be talking about, is this mic working all right? I'll be talking about recognition of catatonia and diagnosis of catatonia. I have no disclosures or financial relationships to talk about today. So in the case of catatonia we hearken back to the German psychiatrists of the former era and in this case to a predecessor of Emil Kraepelin whose name was Karl Calbohm who was basically an academic dropout and bought a hospital, an asylum in Eastern Germany where he worked for 35 plus years as the superintendent. Oh, in 1874 he published a monograph on some unusual patients that he'd seen over the past 10 years or so at this asylum in Eastern Germany. And most of the important things about catatonia were described by Calbohm in his beautiful case history. There's 26 case histories in this monograph translated in English in 1973, 100 years later. And these are sequential paragraphs on the introduction. Patient remains motionless without speaking, rigid face, blank stare, can be fully developed or only partial. So this is still true today. Catatonia can be full blast and I'm going to show you gross examples of severely affected patients with catatonia. But it can be, they're milder forms as well and it can also fluctuate. General impression of mental shock or anguish, which you may only hear about later because mutism, not speaking, is a common catatonic sign. Tends to be persistent, although in some patients it can come and go. So that's an important aspect of catatonia, it can fluctuate. And it can fluctuate between a retarded or stuporous form and an excited form. That does happen. And Calbohm, who's writing in the 1870s, makes note that catatonia is associated with medical and what he's calling muscular, we would call them now neurological disorders. So really very important aspects of catatonia, they've been conferred multiple times in clinical experience and also in research studies, were expressed by Calbohm, who first described it. A very underappreciated figure in psychiatry. So I got involved 20, almost 30 years ago in catatonia. And it started with a resident project and that resident's name was George Bush. He was a second-year resident. We had a catatonic patient on the inpatient unit at SUNY Stony Brook, where I worked and Greg Fritsch-Jone worked at the time. And we struggled with this patient, how to treat her. Max Fink, who by the way has turned 100 years old, a couple of months back, and we'll be having the Max Fink Centennial Symposium on Tuesday of this week here at the APA. Anyway, Max Fink suggested we give this patient ECT because he knew that ECT will usually treat people with catatonia. So we were able to do ECT with that patient, who did very well, as many patients with catatonia will. And Dr. Bush approached me and Max Fink, both of us on the faculty at the time, at SUNY Stony Brook and said, I want to study catatonia. We didn't know a lot about this, it's so interesting. And I told him, you can't study something unless you have a way to measure it. And the result was the Catatonia Rating Scale. And as we're about to publish, Dr. Fink recommends that we have a name for it. And we rejected the obvious things like the Catatonia Scale or the New York Catatonia Scale or the Stony Brook Catatonia Scale. And somehow we arrived at the Bush-Francis Catatonia Scale. So we published this in a two-page set, two page per set. The first paper described where we got the rating scale and the items on it. Mostly they came from Calbom. And it's psychometric properties, things you do when you're creating a rating scale. Integrated reliability, CAPAs for agreement, Crombach's alpha. We also operationalized 23 catatonic signs from the literature and designed the rating scale to be used for both diagnosis and to monitor treatment. The second paper was a prospective treatment outcome of a cohort of 28 patients that we collected on the adult inpatient unit. And that paper had the first presentation of quantitative outcome data for Catatonia. And the first presentation of what is now known as the Lorazepam Challenge Test. So this paper has been cited many times. It's approaching a thousand citations, burgeoning literature on Catatonia in its various manifestations. And that rating scale has been used worldwide to translate into several languages. It's incorporated into many electronic medical record systems. Perhaps some of you have that in your hospital. So the structure of this rating scale has 23 items. And as I mentioned, we got most of them from Calbom and some later workers. And the way the scale is structured, the first 14 items are used as a screening, presence, or absence to find a case. So in psychiatry we have clinical syndromes that are characterized by a collection of signs and symptoms. In our research we wanted to collect, we wanted to be able to recognize mild cases. So we set a very low bar. We set a bar of, and by the way this rating scale is commonly available on the web, if you just search Catatonia rating scale you will find it. And you will see the operational definitions of all of these signs. And our rating scale is also anchored in the sense that we give you exemplars of a score of 0, 1, 2, or 3. Three points for each item. So we wanted the rating scale to be used to make a diagnosis. And we used a low bar of two signs out of 14 being present. The current DSM-5 has a standard of three signs out of 12. And those are listed here with an asterisk. It's a similar list. The DSM left off a couple of important signs which are rigidity and, the DSM left off a couple of important signs which are rigidity, sorry about that, rigidity and staring. So again diagnosis is made by the presence of at least two signs. This is for psychiatric patients. For medical patients, especially those in the intensive care unit, a higher standard has been found to be needed for better sensitivity and specificity, which is four signs out of the 14, or four signs on the DSM list. Most of the catatonic signs are observational. That is to say the observer, the examiner does nothing except observe the patient for the observational signs. So for example, immobility and stupor. They don't move. They don't seem to react, they stay in the same place without moving. Grimacing, they have repetitious movements usually of the lower part of the face. Stereotypy and mannerisms, these are repetitious movements that you can observe and I'm going to show video examples of what they look like. Some of the catatonic signs are elicited, that is to say the examiner does something to elicit the sign. A classic example would be echophenomena, echopraxia and echolalia. The patient, without being bidden to do so, mimics the speech or movements of the examiner, or someone in the room, or even someone on the TV. And I'm going to show examples of that on the video. Verbigeration is another observational sign. Verbigeration is the repeating of a phrase, the repeating of a phrase, the repeating of a phrase. Okay, I guess maybe I should keep repeating. And some of the catatonic signs, not very many, are by physical exam. So for example, rigidity would be an increased muscle tone, commonly measured by flexing and extending the elbow, both slowly and also more rapidly. And so that's the nature of the signs. We've included nine additional signs, so the total scale has 23 items. And each one can be rated on a three point scale for severity. So caseness is a number of signs, always true in psychiatry for clinical syndromes. And severity is rating all 23 items on a three point scale. So the maximum would be 23 times 3, 69. I don't think I've ever seen a patient with that high a score. The typical patient that you might meet in a hospital psychiatric unit or medical floor would be in the range of 15 to 25. I think I've seen as high as 35. And that's the nature of the Catatonia rating scale. Here's the list of signs on the DSM. And again, the DSM criteria currently are three signs out of 12. Our original research was two out of 14, a similar list. The DSM-5 was an advance because it now gives a definition of the signs, which the previous one did not. However, the definitions don't have a severity criterion like our rating scale does. And some of the definitions overlap, I think. So for example, their DSM definition of stupor, not actively relating to the environment. To me, it overlaps with how they've defined negativism, no response to external stimuli. So I think our definitions are better. But for most purposes, with psychiatric patients at least, you could diagnose a patient by the DSM, three out of 12, or the Bush-Francis, two out of 14. In medical populations, use a stricter bar. We also included in our publication of the rating scale a systematic assessment, a systematic standardized way to observe and detect Catatonia. And that was to increase the integrated reliability and also the ease of doing it. And it was designed so that a patient could be examined in five minutes, so that rapid response to treatment could be conducted. And that's also available online, on the web, freely available. These are in the public. They're not copyrighted. So that scale has been available for 25 plus years now. And how are we doing in recognizing Catatonia? Well, so a colleague, Mark Oldham at the University of Rochester, and a resident who was in his program, Joshua Wurzel, who's perhaps in the audience, he's at this meeting. He was a resident interested in Catatonia. He's now doing a fellowship at Brown. And together, and in collaborating, they invited me to collaborate, we wanted to find out how well the field is working on recognition of Catatonia. So this first study that we did, we created an online survey. So a informational test, multiple-choice test, about Catatonia, and also some simulated patient videos. Dr. Wurzel was the actor in these simulated videos, acting out various aspects of various catatonic signs. And so there were two parts of this online survey, a quiz, so to speak, that people could take. One was answering multiple-choice questions about Catatonia and its signs, only diagnosis, not treatment. And the second one was watching some of these simulated patient videos of Dr. Wurzel acting out catatonic signs. And the question was, people who identified as psychiatrists, as residents, and as medical students, in this online survey. And there were 482 who engaged in that online survey. The question was, how well do they do? And we exerted, we spent a lot of time creating the right answers for the, and designing the questions. So here's how they did on the first 14 items. And again, these are the items needed for a diagnosis. So again, diagnosis is going to be 2 out of the first 14, and for GSM, 3 out of 12, similar list. So the first, so here are the 14 items on the left column, the middle column is on the multiple choice of knowledge, verbal knowledge of the signs, and on the last column on the right is scores on the recognizing the signs from the video, from the sample patient, artificial patient. So what you see is, there are several instances where below 50% is the score for the people taking this online survey. And on average, 53% for the multiple choice question, and 64% for the standardized patient. But several of the signs were below 50%. And for the remaining nine items, and 14 plus 9 is 23, similar. There were a couple of signs below 42%, below 50%, for both the multiple choice and for the video. So it seemed that, at least based on this survey, and the scores, by the way, were not that different between people who identified as psychiatrists, people who identified as residents, and people who identified as medical students. So in the next wave of this project, we created a teaching module. And that module consists of the complete 23 sets of simulated patient videos, acting out all 23 catatonic signs, and additional information of more detail about how to use the Bush-Francis Catatonia Rating Scale to make a diagnosis of catatonia. And so this was now a new sample, online survey, again looking at psychiatrists, residents, and medical students self-identified on this online research. And we published that a couple of years ago. And the way this part of the study, this phase of the study was designed, was there was a pre-test using the multiple choice and the videos. Then the respondents who were participating were invited to read the literature on how to use the Bush-Francis Scale, and also to watch the videos, and then do a post-test. And then we had a follow-up period a couple of months later to see if information was retained. It's a new sample. So what this complex graph is, here are all 23 signs across the x-axis, horizontal, and on the y-axis is the percent correct of the scoring. And this is for the multiple choice questions. So in each case, the black bars are the percent accurate answers to these multiple choice questions about each of these catatonic signs before the persons who were in the survey looked at the training modules. The white bars are after they did the training module. They read about the use of the catatonia scale and also watched the patient videos or so they said. And the stippled bar is the three-month follow-up with some dropouts of course. So what's interesting is that in every single case the white bar is bigger than the black bar. So what that tells you is that the performance, at least on this multiple choice aspect of the survey, improved with the training module. So the training module works or has a positive effect in terms of improving knowledge and diagnostic ability related to catatonia. And there was fair retention, some drop-off over the three-month period. But it's also true that the scores here are in the range of 60 to 70 percent on average. So there's still perhaps more work to do. And then looking now at the videos, this is again the same part of the survey, the second survey, where the respondents did a baseline exam of looking at the videos and making a diagnosis of the catatonic signs, which is the black bars. Then the white bar after they did that and read the manual. So it's effective training. And then the stippled bar is the three-month follow-up retention of training. So again you see that the white bar is generally higher than the black bar for each of these 23 catatonic signs. That is to say their knowledge of recognizing catatonic signs when seen in a simulated patient video improved. And there was a very good retention. Actually the retention looked better here than for the multiple choice. So what the studies and the results again were similar in that psychiatrists performed slightly better than residents who were slightly better than medical students, but not big differences between these groups. So the implication from these studies is that there's room to improve recognition of catatonia and interventions to do that, which consists of reading material and sample videos do help. At least that's the conclusion I drew. So let me show you some examples from video. How am I doing on time? Okay. So this first example is a historical example from the early 1930s. It's a case, a real patient, and this is available from the National Library of Medicine. It's publicly available. This is a real patient severely affected with catatonia. We do see such severe cases. This is something that no one would miss, that there is something very abnormal with this patient. There's a question about the video. It's the AV person. Oh, I don't know how to turn the lights. There's some switches back here. Okay. Request to dim the lights if that's possible, because I'm going to be showing a few videos. So this first patient, again, is from the early 1930s. A very severely affected person with classic, severe, stuporous, or retarded form of catatonia. The doctor is William Blequin, who was at the University of Wisconsin, and is considered the father of psychopharmacology because he invented the amobarbital treatment of catatonia, which the videos go on to show, but I'm not showing the treatment part. Also known as sodium amytal, which was the first effective treatment for catatonia, and some would say the first psychopharmacological agent for a psychiatric disorder. So I'll show the video. I have a narration attached to this video. So his arm remains in an upright posture where it was previously placed, and you can see that the examiner moves the limbs and they stay in unusual postures, which may persist for long periods of time. And notice how the whole body seems to be rigid. There's no fluidity at all to the man's posture. He may remain in this unusual rigid posture for extended periods of time. He's not talking to the examiner. He also shows mutism, another catatonic sign, and he's blankly staring, not really engaging with the examiner, who is moving him around. We'll see a close-up of his face here. And you'll notice that he's blankly staring, he's mute, he doesn't engage with the examiner. So it's staring, mutism, withdrawal, rigidity, and catalepsy. Multiple catatonic signs that are... Okay, so that's an example of a severely affected person with catatonia, the stuporous or retarded form. So there is an excited form of catatonia as well, and I have some examples of that. Again, historical examples that are publicly available. This is from the 1940s, it's a little bit later. So this man is showing some repetitious movements. And there are two kinds of repetitious movements, stereotopies and mannerisms. We struggle to operationally define the difference. Mannerisms look odd the first time you see them. They often involve parts of the body used for communication, like the hands or the face. Stereotopies, the abnormalities in the frequency. So a classic example is rocking. Nothing unusual about rocking or rubbing your hands together. But if you keep doing that, then that's unusual. So stereotopies, it's more the frequency. Mannerisms, it's more the oddness, so to speak. So this man is going to have a series of repetitious movements that he does in sequence. He's touching his lapel, touching his coat, doing something with his fingers. So he's got a sequence that he does. He's also moving a piece of paper between his hands. Touches his jacket, touches his mouth, touches his tie and lapel in a sequence that looks odd the first time you see it. He's also got grimacing. This was in the pre-neuroleptic era. We would think this is tardive dyskinesia now. Not as well shown, but it is there. So this is sort of a sequence of movements that looks odd the first time you see them. And he repeats them. They keep repeating. So this would be a very typical example of mannerisms. Echopraxia, as I mentioned, the patient, without being bidden to do so, repeats the movements or the postures, in this case as well, of the examiner. So here's a galso from the 1940s. A female patient sitting on a bench outdoors with a doctor next to her. And you'll see she sits in the same posture as he is, and he makes certain movements and she mimics those movements. So she sits in the same posture, had her chin in her hand like he did. He puts his hands across, she does the same. He does a movement with his arms, she does the same. He taps his foot, his leg rather, and she does the same. Perhaps overly enthusiastically. Okay, so perhaps she's manic, actually. And many people who have catatonia are in fact manic. So this would be an example of echopraxia. And I'll show one more. No, I'm not showing one more. Okay, more videos are on our website, which is catatonia.org. And this is the homepage of that website. There's additional videos with narration describing catatonic signs. These are real patients from historical sources. This is the website from the University of Rochester that Dr. Oldham and Wurzel created. It has a lot of information about catatonia, how to use the catatonia rating scale. It has those educational videos with the simulated patient. Details about subtle differences between various catatonic signs are also included in this. It's a very good teaching module. And it's been shown to be very helpful. And it's been shown to be effective in the study that we did. And this is freely available. You just search Catatonia University of Rochester and you'll find this. So to conclude, clinical recognition is suboptimal despite increases of diagnosis and publications. Improvements occur with training and experience. Online resources are available to improve recognition. I'll stop there. Thank you very much. APPLAUSE Dr. Barnett advises we'll do questions at the end. Hi, everyone. Thanks for coming. As I'm getting my slides set up, I just want to say what a treat this is. Thank you, Brian, for organizing it. But you are getting to hear about catatonia from two giants in the field, Dr. Francis and Dr. Frischione. And so it's an honor to be up here with them. I'm going to talk a little bit about management and treatment of catatonia. I don't have any relevant disclosures. Let me just switch to presenter mode. So one of the first questions that is worth thinking about is why do we care about treating catatonia? And Brian's going to talk a little bit about some of the complications that can occur with catatonia. But one thing that I think is really important for us to recognize, which goes under recognized, is how uncomfortable and frightening the experience is for the patient. So we think about fear being the primary affect in catatonia. And if you talk to people after they've had an episode of catatonia, many of them will remember that experience. And the main theme that you'll hear is how terrifying and frightening that experience is. And so treating and managing the catatonia really not only prevents complications, but can be incredibly emotionally relieving for the patient. A couple of principles to keep in mind. Dr. Francis talked about this fact that catatonia is best thought of as a syndrome. And I like to think about it as similar to delirium in many ways, where you not only want to recognize that catatonia is present, but you also want to think about the underlying ideology. We know now that at least 50% of cases of catatonia probably have a neuromedical ideology underlying them. So there's a lot of neuromedical catatonia in addition to psychiatric catatonia. In some cases of psychiatric catatonia, just treating the catatonia is going to be sufficient. But in many cases of psychiatric catatonia and most cases of neuromedical catatonia, you also have to treat the underlying cause in order to prevent recurrence. We heard about the Bush-Francis Rating Scale. Not only is it a great tool to diagnose, but it's also a really important tool to track the course of catatonia, particularly if you're on a service where you're going to have multiple providers, right, on consults, in the emergency room. If you've got multiple people who are going to be following somebody with catatonia, you really want to have a rating scale so everybody knows what they're talking about and what they're looking for in terms of improvement with regards to specific signs. A little bit about historical treatment. So one of the first things that was used for catatonia was actually cocaine. That was back in the 1920s. And then as Andy mentioned, in the 1930s, people started using sodium amytol to unlock catatonia. ECT has actually now been used for almost 90 years, so as early as 1934, to treat catatonia. For a while, there was a phenomenon described as periodic catatonia, where people sort of alternated between a stuporous and excited form. We might call that recurrent idiopathic catatonia now. There's some overlap in terms of those definitions. But lithium was used a lot in case reports and case series for periodic catatonia. And then, of course, neuroleptics were used, often haloperidol, but often without great success. And as we'll talk about, one of the major risks with neuroleptics is this potential for people converting to malignant catatonia, developing malignant features, and that becomes a psychiatric emergency. Anticholinergic agents and amantadine were also occasionally used prior to the 80s as well. And then in 1983, on Christmas Eve, Dr. Fershione and this guy, who's Ned Kassam, had a case of a patient at the MGH with NMS, and they tried intravenous lorazepam. And it liced the patient's catatonia in a pretty dramatic fashion. This is the letter that Ned wrote to Greg after that. And then subsequent to that, there was a series of reports of benzodiazepines being used to lice and to treat catatonia in both malignant and nonmalignant forms. Lorazepam and diazepam were the two main benzodiazepines that were reported, and these reports continued through most of the 80s in larger case series with pretty good response. So one case series of 15 catatonic episodes, 12 responded completely and dramatically within two hours, one responded partially, and two had no response. In another series of 21 patients, 76% responded. And in those who failed, ECT was helpful. That is sort of where we've remained for most of the past 40 years, that our two major treatments for catatonia are benzodiazepines and ECT, and I want to talk a little bit about each of those. Benzodiazepines, there's a nice review by Pelzer and colleagues from 2018 kind of looking at the evidence, including 17 studies, a total of over 500 patients. The efficacy ranges, pretty much the full range, from 0% to 100%, but the average is about 65% efficacy in those studies. I want to highlight the 0%. So I've actually heard two people say in the past year who are very well versed in catatonia that we don't really know if benzodiazepines treat catatonia, and I would argue with that because I think we do know that they do, but what they're pointing to is the fact that there's never actually been a randomized controlled trial showing that, and the only randomized controlled trial that's been attempted is where we get the zero response rate from. That was unpublished data. It was a study done in China that had a lot of significant methodologic flaws, but it's important to recognize that we don't have a randomized controlled trial, but I think we have many, many experiences of people who are severely catatonic not responding to other agents and then receiving a dose of intravenous lorazepam and suddenly improving. So overall the response rate is thought to be around 65% for benzodiazepines. There is some older evidence that suggests for patients with schizophrenia underlying their catatonia they may have lower response rates to benzodiazepines, and we're going to talk about dose and routes of administration, but it's important to keep in mind that benzos are pretty safe in catatonia. Sedation is the main effect, and you watch for respiratory depression, but often not an issue. So if we think about the treatment of catatonia using benzodiazepines, I'm not going to dive deeply into the pathophysiology except to say in a very simplified way it may seem counterintuitive. We think about a catatonic patient, and we think about somebody who's not moving, not speaking. Why would we give them a drug that's going to inhibit them? And the idea is that perhaps the brain is receiving so much stimuli at once that the catatonic patient sort of locks or freezes and can't process and can't make sense of that stimuli. And so giving them an inhibitory agent like a benzodiazepine actually helps them to slow down and unlock and improve. That's a very simplified version of the theory. The two benzodiazepines that have been shown to be most effective for catatonia are lorazepam and diazepam. They have some interesting features, including some features unique to the inflammatory response, and there is a theory that catatonia may be an inflammatory disease. And in addition to that, lorazepam and diazepam also have a pretty long effective clinical activity, and lorazepam specifically has a higher binding affinity for the GABA-A receptor, and we think that's the receptor that's most important in catatonia. Intravenous lorazepam is greatly preferred over other routes of administration. So if you are in a facility where you can give IV lorazepam, please give that preferentially. It's quick-acting, it's easy to administer, it has a quick onset of action, but probably most importantly, despite obviously having the same half-life as other forms of lorazepam, the effective length of action may be longer for the intravenous form. If IV is unavailable, your hierarchy is IM better than sublingual, better than PO, but with an important caveat. Most patients with catatonia will require repeated benzodiazepines, and I would not give somebody with catatonia repeated IM injections for two reasons. One, you're going to worsen that fear response, and that's going to be important to the patient experience. But two, you're going to elevate the CK with multiple IM injections, and then you get into this gray area of whether you're seeing malignant features or whether you've just elevated the CK because of repeated IM injections. So if IV is not available, we prefer to give sublingual. If lorazepam is not available, we'd use diazepam. You've probably heard about the lorazepam challenge, and the nice thing about benzodiazepines and catatonia is that in addition to being helpful as a therapy, they can also be diagnostic. And so the lorazepam challenge is meant to be 2 mg of intravenous lorazepam given to the patient to determine the response and guide further treatment. We almost never give less than 2 mg. In a child or in a very frail elderly patient, we might give a lower dose, but even in a robust 85-year-old, I'm still going to give 2 mg of lorazepam because I don't want that challenge to be equivocal. So 2 mg, IV preferred. And then we think about where to go next on kind of a sliding scale. I like to think about it as a 2 by 2 grid. So on one axis, you have the response to the lorazepam, and on the other axis, you have your degree of suspicion. So if you had a low suspicion for catatonia in the first place and you don't see a response to the Ativan, then you can sort of move on and say, okay, this probably isn't catatonia. But if you had a low suspicion and you do see a response, then you definitely want to consider catatonia more strongly and probably give additional doses of benzodiazepines. If you have a high suspicion and you see a response, then you've made the diagnosis and you should figure out your course of treatment. If you have a high suspicion and the test is negative, and this is where it gets tricky, don't stop. So if your suspicion is high and the patient doesn't respond to the initial 2 mg, we would recommend giving repeated doses of 2 mg spaced a few hours apart because some patients will need more than one dose to respond. So a negative response does not rule out catatonia. Conversely, a positive response doesn't rule in catatonia. Remember, there are other conditions that we see in psychiatry that respond to benzodiazepines. The two most important ones to keep in mind are status epilepticus and alcohol withdrawal. So if those are on your differential, recognize that they will also get better with benzos. Once you've given the 2 mg, the response is typically seen within the first 30 minutes. How many people in the audience have seen a so-called Lazarus response within seconds to a minute? Okay, so you may see that. If you see it, it's probably the most dramatic thing that you'll see in psychiatry, but that's not the typical response. The typical response is a gradual improvement over about 30 minutes, and in some patients it may take up to a couple of hours. You'll sometimes hear about zolpidem being used for catatonia. Where it's used, it's most commonly used as a challenge agent, but then people are usually converted to lorazepam for actual dosing. Because we don't have IV zolpidem in the U.S., we tend to stick with lorazepam. So if you've given the Ativan challenge, then your next step is to determine what you're going to do subsequently. And if you're going to continue to give benzodiazepines, you'll want to think about how to dose them. So again, if you've had no response but your suspicion is high, we would recommend a couple of repeat doses, usually spaced about 2 to 3 hours apart. We've given up to 20 mg in divided doses before ruling the challenge a failure, so don't be afraid to go to higher doses as long as the patient seems to be tolerating it. But if your suspicion is lower, then obviously you may not need additional doses. In terms of the next steps, the standard approach is to then start standing lorazepam. And we usually start a dose of 2 mg, typically between every 6 to 8 hours, but sometimes as frequently as every 3 hours, depending on the severity of the catatonia and whether malignant features are present. One really important thing when you write the order or when you ask the primary team to write the order, it should be written as Q8 hours rather than TID or Q6 hours rather than QID because you really want patients to get it around the clock. That spacing is important. Also ask that the order be written specifically to include a note to not hold for sedation. Nurses are not used to giving people who appear to be asleep a sedating medication. You do want them to get the Ativan regularly, even if they appear to be asleep. Sedation is not a reason to hold the dose of Ativan. If people go for longer amounts of time without Ativan, they're going to be at higher risk for recurrence and worsening of their catatonia. So you want that regularity. Obviously you would hold the dose for any signs of respiratory distress, but you don't hold for sedation. Generally we recommend if you're in a facility where you can give IV that you continue the IV for at least 24 to 48 hours after initiation and ideally for 24 to 48 hours after symptoms begin to improve and then you think about a conversion to PO. There's no good data on tapering. We recommend going very slowly. When you do convert from IV to PO, remember that the potency may be as high as 2 to 1, so we will often double the dose when we're moving from IV to PO before starting the taper by no more than 25% a day in the hospital and probably no more than 25% per day outside of the hospital. I think particularly as patients move towards discharge, there's this hesitancy to give them benzodiazepines when they leave. We all have this mantra, benzos are bad now. And this is a case where patients may in fact need a short prescription for benzodiazepines when they leave the hospital so they can taper gradually and that would seem to reduce their chance of recurrence. If patients have had multiple episodes of catatonia, they may in fact need to be on standing lorazepam at a low dose indefinitely. So we've definitely seen patients who end up on 0.5 of Ativan BID because they've had several episodes of catatonia. And obviously you want to screen for other risk factors. But in that sense, the risk of prescribing a benzodiazepine is likely lower than not prescribing a benzodiazepine. So let's shift a little bit and talk about ECT, which is the main second-line treatment for catatonia. It has a higher success rate than lorazepam. It's effective in 85 to 90% of cases, including 60% of those that fail medication. And any time you see signs of malignant catatonia, that should guide you to move swiftly towards ECT. We start thinking about ECT the moment we lay eyes on a patient with catatonia because that process is going to take at least a couple of days. And we're in a state where it's relatively easy to get ECT. If you're in a state where it's harder, you want to start thinking about that as early as possible in the event that benzodiazepines do not lyse the catatonia. There's a nice review from Leroy in 2017 about ECT, basically showing that it has an average efficacy of about 77% across studies. The side effects are the same that we would expect for ECT in general, with some anterograde memory loss being most common. Bitemporal placement is usually done, sometimes daily treatments or at least three times a week treatments. Most patients require at least six treatments of ECT for catatonia, though you may see some improvement after only two or three treatments. And just like some patients require maintenance benzodiazepines, some patients will require maintenance ECT. That's where we've been at for a long time, and in the last couple of minutes I just want to talk about some advanced cases and what we do in cases where patients don't respond to benzodiazepines and you can't get to ECT or the family has declined ECT and what are some other options. We published this algorithm in 2017 to think about third, fourth, and fifth-line agents. The next thing that we would do is to add an NMDA antagonist, either memantine or amantadine. We usually supplement benzodiazepines with that, and there's some evidence. It's all case-reporting, case-series evidence for NMDA antagonists in the setting of catatonia. We would add either amantadine at a starting dose of 50 mg twice a day, titrating up to a max dose of 400 mg daily, or memantine at a dose of 5 mg BID, increasing to a dose of 10 mg BID. Each has its own advantages and disadvantages. Amantadine has a dual mechanism of action, so in addition to being an NMDA antagonist, it's also a dopamine agonist, and that might be good in catatonia, though it might also worsen any psychosis that underlies catatonia. Amantadine also has some evidence in akinetic mutism, which can overlap with catatonia and look a lot like catatonia, but it can lower the seizure threshold. So most commonly in our hospital, we'll supplement first with memantine, but amantadine is a very reasonable choice as well, and sometimes you'll get some additional improvement with the addition of that agent. The next thing that—I'll just mention dopamine agonists really quickly. They have also been reported in case series and case reports, but almost every case report using a dopamine agonist, either a stimulant or carbidopa levodopa, has noted worsening of psychosis, so we tend to steer away from those, though they are an option. But we would next think about anti-epileptic drugs, usually specifically valproate, which again has some case report, case series literature for help in catatonia, may be particularly helpful for cases of excited catatonia, and particularly if patients have an underlying bipolar disorder that is driving the catatonia. And remember that bipolar disorder is the most common primary psychiatric diagnosis in patients with catatonia. And then finally, we might think about atypical antipsychotics, but with a high degree of caution. So we remember from the 70s that typical neuroleptics did not really seem to be that helpful in catatonia and often made patients have malignant catatonia. Atypical antipsychotics are thought to work by a different mechanism of action. Maybe it's the serotonin, maybe it's the anticholinergicity. They're quite dirty drugs, so we don't really know what they're doing in somebody who's catatonic. But a lot of them do have case reports suggesting some improvement with atypicals. These are the five listed here that have case report evidence. They may be most useful in a couple of cases. One when somebody has catatonia with an underlying psychosis or an overlapping delirium. And if I was compelled to choose an atypical antipsychotic, I would probably go with aripiprazole because I think it's likely the safest as a dopamine agonist. It actually has the most case report literature backing it as well. Interestingly, catiopine and some of the newer agents have no convincing data, so I'd steer clear of them. But I'd want to go with a low-potency agent, so aripiprazole or maybe olanzapine, and give in combination directly with a benzodiazepine. A list of other agents that have been tried, including anticholinergics, minocycline, and I mentioned zolpidem and lithium earlier. And so this is your final algorithm if you get into cases that aren't responsive to benzodiazepines and you can't use ECT. And I'll end with that, so we have a little bit of time, hopefully, for questions at the end. Thank you. All right, before I get started, just out of curiosity, how many of you have treated a case of catatonia in the last month? All right, fair number. All right. These are my disclosures. None of them are relevant to catatonia directly. So I'm going to talk about complications and placing catatonia in a broader healthcare economic context. All right, so there are a number of important complications of catatonia that I think many services outside of psychiatry often miss the connection. So there's a nice review here that looked at them, showed increased odds ratios, some of them quite high for a variety of conditions, including rhabdomyolysis, pneumonia, urinary retention, DVT, pulmonary embolism. And many of these, their onset is just a couple days after the onset of catatonia, although some of them can occur weeks afterwards, such as sepsis, decubitus ulcer, and DIC. One that I really want to highlight is DVT and pulmonary embolism in patients with catatonia. So this was a study by Ishida and colleagues in 2016, where they looked at the rate of DVT prevalence in catatonic patients versus patients who didn't have catatonia who were restrained. And they found that the odds ratio was more than three in favor of the catatonia group. They found that this was primarily patients with retarded catatonia, so the odds ratio there was four. They didn't find a statistical significance for the excited form of catatonia. But I have seen cases of DVT in those patients as well. With this in mind, one important question that comes up from a pragmatic perspective is what do you do in terms of ECT if a patient with catatonia has DVT? So there's a nice case series published here in 2018 of five patients who had DVT and who received ECT. In four of them, there were no complications. However, in the fifth patient, the patient did develop a pulmonary embolism. And the authors noted that that patient had a proximal DVT, and they had only received anticoagulation for a day prior to starting ECT, whereas the other patients had typically received it for anywhere from one to three weeks before starting ECT. So the authors there recommend at least several days of anticoagulation to the point where the DVT breaks up before you start ECT. And as I mentioned before, patients with excited catatonia do also get pulmonary embolism and DVT. That's because catatonia can shift between the retarded form and excited form. And there's also evidence of elevated D-dimer in these patients and inflammatory state that probably raises the risk for DVT in the excited patients as well. Pressure ulcers can be a problem in patients with ECT, so you have to make sure nursing staff are moving these patients regularly to prevent that. A couple cases here of patients who developed catatonia with severe bronchorrhea, and I've actually seen a case. It was a milder case, but it was sort of perplexing at first. The patient had a pretty significant amount of secretions in addition to their catatonia, was having trouble clearing them. And once we started treatment with ECT, that went away. And so at first we were wondering if the patient had some sort of pneumonia or respiratory issue, but it was actually, it seemed to be related to the catatonia itself. Contractures are something that you see periodically with these patients, especially if they've had untreated catatonia for long periods or they've had recurrent catatonia. And typically you'll treat the catatonia and everything else will get better, and then the contracture will remain. And so it's important for nurses to help these patients do stretches if they're able while on the inpatient unit to try to prevent this. I've not seen this, but I thought this was worth mentioning. A case report here of a patient who had catatonia and developed a vitamin K deficiency. They were being treated for pneumonia with an antibiotic, and they developed a vitamin K deficiency, which responded to treatment, but just something to think about since oral intake is such a problem in patients with severe catatonia. All right, just a little bit on neuroleptic malignant syndrome. So we don't have a lot of good data on the prevalence of this, but it looks like in the prospective studies of any type of patient treated with antipsychotics, up to 2% will develop NMS, and it has a mortality of approximately 10%. So it's something you have to be very cautious about. There is one abstract from 1996 showing that 4% of patients with catatonia treated with antipsychotics went on to develop NMS, and so it looks like there's double the risk there. Scott mentioned malignant catatonia, so this is always something we're on the lookout for, especially when we're having to treat patients who have catatonia and psychosis, where it needs treatment because they're causing behavioral problems on the unit. And so these are the diagnostic criteria here. And the incidence of malignant catatonia in psychiatric inpatients is estimated to be about a quarter of a percent, with a pretty high mortality of 15% in one cohort. And the severity really seems to be linked to mortality, so it's about double in patients with severe malignant catatonia compared to moderate. And there was a paper published last year that talked about classification of malignant catatonia into moderate and severe forms. And so it's based on these three criteria here, rigidity, hyperthermia, and impaired consciousness. And if they have just one of those criteria, it's moderate, and if they have two or three, it's considered severe. There was a nice paper published in 2014. I don't think it's gotten a lot of attention. I think it was attached to a case report, and maybe that's why. But the authors published guidelines for complication prevention in catatonia, covering many things I've discussed here. So for example, using prophylaxis to prevent DVT, talking about pressure ulcers there, muscle contracture, nutritional deficiencies. And so I recommend everybody take a look at that paper. I think one particularly interesting question about catatonia is recurrence rate. And we have some data that help us have a better handle on this, because it's an important question that a lot of patients and their families have when the patient does experience an episode. You know, what is the likelihood that this is going to come back? So this was a study done in London using registry data on 1,500 patients with catatonia. They found that in their catchment area, there were about 10 episodes of catatonia per 100,000 years, and about a third of that in children compared to adults. The number of episodes over this follow-up period, which was seven years, ranged from 1 to 27 episodes. So that's very severe recurrent catatonia there. And after the first episode, they found that the rate of recurrence was 0.035 per year. And that translated into about a quarter of patients experiencing at least two episodes of catatonia in the follow-up period. So it's a minority of patients who experience catatonia, but it's still a pretty big chunk. So I think it's important to talk to patients about the possibility of recurrence, what signs families should look for so that they can get patients into treatment quickly. And the authors there noted that in patients who had five episodes, further episodes occurred a majority of the time. And so if you've had five episodes, it's likely that you're going to keep having recurrent episodes unless you get appropriate treatment. All right. So talk about mortality now. We have a few pieces of evidence that indicate that catatonia is linked to excess mortality. So this was a seven-year study of patients with catatonic schizophrenia from 1974, showing that the mortality rate was somewhere between three and four times the general population. And about 1% of those patients completed suicide, and then 6% of the cohort died from all-cause mortality. So suicide is a significant portion of deaths related to catatonia, which you don't often think about in the moment because the patient is, you know, typically ones we see are pretty stuporous and would have a hard time attempting suicide. But in the end, a lot of these patients have bipolar disorder, schizophrenia, other mood disorders that really put them at risk for suicide. This was another study looking at a couple thousand patients with schizophrenia in Japan, and 8% of those patients had catatonic schizophrenia. They had much longer lengths of stay, about 100 days there, compared to 70 for the non-catatonic patients. The odds ratio for increased mortality was five, so quite high. About 7% of those patients with catatonia died while they were in the hospital. And the most common causes of death were pneumonia, tachyarrhythmia, DIC, and sepsis. So it's really important to try to prevent those complications. And then there's a study here that looked at mortality among adolescents who had a history of catatonia. So it's a small study, 35 patients who were followed up prospectively, and they followed them up for about four years. A few were lost to follow-up, so the data are based on 31 subjects, most of whom had schizophrenia. So three of those patients died during the follow-up period, including two suicides, and that yielded an increased rate of premature death of a factor of 60 when compared to the general population. Now I suspect, you know, if they did a larger study, bigger samples, that number would probably come down, but it would still be dramatically higher than the general population. And so this is important to know when we see young patients who have catatonia, you know, that they really are at a very increased risk of dying young. All right, I'm going to wrap up talking about economic costs of catatonia. And so this is based on work coming from Lucarelli and colleagues. Scott Beach has been working with that group. And so they've been using national databases to look at patients who are diagnosed with catatonia and to see how those patients fared while they were in the hospital and how much the costs of caring for them were. And so here they found that catatonia was diagnosed in 0.05 percent of discharges. So this is just a general sample of hospitals across the country. We know that catatonia is dramatically underdiagnosed, so this is just capturing a small part of the patients who actually have catatonia. But about half of them went home and then about 40 percent went to another facility. And more than 1 percent died in the hospital. So these patients are very vulnerable during treatment. And they stayed on average 10 days, so it was about $45,000 for their hospital stay. And when you put those numbers together, it was about a billion dollars that year to care for the patients who were just diagnosed with catatonia. And more than a third of them got a procedure while they were in the hospital. Unsurprisingly, the most common one was ECT and then diagnostic procedures that we often use in patients with catatonia, such as lumbar puncture, EEG, and there's several procedures related to ICU stays there, such as central line insertion and mechanical ventilation. That group did a similar study looking at the cost of catatonia in children during the 2019 year. And they found that catatonia was diagnosed less frequently in children, so it was less than 0.02 percent of discharges. Most of those patients went home, but still a significant number were transferred to another health care facility. Average length of stay was comparable to adults, so it was about nine days. Costs were pretty similar, a little bit more expensive, about $50,000 for the hospitalization. Strikingly, it was among the most, catatonia was among the most costly pediatric mental health disorders on a per case basis. And almost half of those patients got a procedure. And the most common ones there were diagnostic procedures, with ECT being a little bit lower on the list since it's used less frequently in children. And that's it for me. I'm going to hand it over to Greg now. So I do have a disclosure. I just became a consultant to Revival Therapeutics, a start-up, and well, it is a real pleasure to be here. I want to thank Brian for inviting me. These are three special people I really enjoy being with. First of all, Andy, that was a wonderful talk. It makes me nostalgic. At Stony Brook in the late 80s and 90s, it was a golden age of catatonia research, and we had such wonderful people looking into catatonia. And of course, when Brian asked about how many of you have seen catatonia recently, almost all of you raised your hand. And it reminded me of the great contribution of the Bush-Francis Catatonia Rating Scale. People are using it. And remember, it wasn't that long ago people were saying, Catatonia's disappeared. Why has it disappeared? Well, maybe because we didn't have a Bush-Francis-Catatonia Rating Scale to help us. So that's wonderful. And then Scott, very gratified to see Scott up here, one of our fellows who really has developed a passion for Catatonia research. And Andy and I were on this British Association of Psychopharmacology Task Force looking at treatment of Catatonia, which just came out. And it owes a real debt of gratitude to Scott's work looking at how we can treat patients who do not respond to lorazepam. That's really brilliant work. And then Brian, it's so important what you're showing in terms of morbidity and mortality and cost associated with Catatonia. And I particularly liked how you stratified death due to pneumonia, VTAC, V-fib, and hypercoagulability. And I'll mention some of that as we go along. So what I'm going to try to do, I'm going to try to get through this in 15 minutes to open it up for questions. I do have some slides. I'll mention some things about workup. Andy was really positioned us to understand the phenotype of Catatonia. And we'll talk a little bit about workup, looking at etiologies. I'll talk about some special challenges in management, perhaps. And then, as I said, focus on that hypercoagulability, which is kind of interesting. And then perhaps I'll have some time for some personal thoughts and reflections. First of all, I just want to plug Andy's celebration of Max Fink, who turns 100, and that's on Tuesday. What time is it, Andy? 345. And Max Fink really was the kind of godfather of that golden age at Stony Brook, just a brilliant psychiatrist, neurologist. So I would recommend, if you have time, to take that in. And he made so many seminal contributions to our understanding of Catatonia and really helped correct that nosological error, which probably resulted in multiple adverse effects from the use of neuroleptics in patients with Catatonia. So in terms of workup, EEG, this paper just came out from UCL in London not too long ago. And so features of limbic encephalitis, epileptiform discharges, focal abnormalities, status epilepticus, highly specific to neuromedical etiologies. And then, of course, features of encephalopathy, generalized slowing, et cetera, is not as specific. And so you're going to see it in about a quarter of cases that are psychogenic etiologies. Neuroimaging, this paper also from UCL, Jonathan Rogers group, 34% of cases of Catatonia had MRI abnormalities. Most had bilateral abnormalities and frontal lobe changes and atrophy. Routine bloods, white count, CPK. Serum iron, iron is a co-factor of importance for dopamine receptors. Ceruloplasm in terms of the potential for Wilson's disease if indicated by the clinical situation. Other blood work is mentioned. You'll have these slides. I'm not going to go through them chapter and verse. The Emil Barbertal interview, it's fallen into disuse because of lorazepam with its great response rate, 65% to 70%. Andy pointed out a paper of McCall that Emil Barbertal had a 50% response rate. And then in terms of neurological changes, we don't really do this, but it is interesting in terms of colicoloric testing that there are changes that you can pick up in neuromedical causes of Catatonia versus psychogenic causes. When we go to the intensive care unit in particular, we're trying to tease apart causes of encephalopathic stupor versus Catatonia. So you want to try to tease out negativism. Going to the patient, seeing whether you're going to get active resistance to mouth opening or eye opening if their eyes are closed will give you a hint. Also, speech latency, decreased eye blink, it tells you that the brain is already starting to downregulate in terms of dopamine. And so it should give you some pause about using neuroleptics in that condition. And Andy has done one of the first papers on Catatonia and delirium. And again, here was a nosological mistake that we should never make at the diagnosis of Catatonia in a patient with delirium. And as Andy's paper pointed out, no, you're going to see Catatonia nested in delirium. And here are just some hints about trying to find those cases of Catatonia nested in delirium. Might be helpful to you. And there's a lot we've learned about encephalitis, perineoplastic limbic encephalitis, autoimmune limbic encephalitis. And as I say, you can take a look at this slide. I'll make it available to you. But you've been reading an awful lot about it. And of course, I think about the mistakes that I made as a young psychiatrist not knowing about these types of encephalitis in treating patients with psychosis in Catatonia, usually with neuroleptics. So we've come a long way, and we have a long way to go. There are probably many more conditions, as I point out here. We now know that you might see anti-NMDAR encephalitis with neurotropic viruses like herpes simplex, Epstein-Barr virus, and also with mycoplasma pneumonia and others. And I'm sure we'll find more conditions that are sending antibodies up to the limbic system. So we have to stay tuned. And immunotherapies are effective in these encephalitis. However, we've also found, and this sometimes happens when you may send off your assay panel, and it's not back yet. And you treat the patient with ECT, and the patient gets better. And then it comes back, and you find out that the patient has autoimmune limbic encephalitis. So don't forsake the use of our psychiatric treatments. And that includes intravenous lorazepam. Serotonin syndrome. Some people include serotonin syndrome in with subtypes of catatonia. I'm not so convinced that it is, but it is going to be part of the differential sometimes. So you can keep these factoids in mind when you're evaluating a patient. Usually, it's a patient who's just started on a serotoninergic drug, or the dose has been increased, and just go back. So 60% of serotonin syndrome cases start within six hours of the beginning of the drug, or an overdose, or an increased dose. So that should be a big clue to us about whether serotonin syndrome is in the differential. And also, you may wind up wondering whether this is anticholinergic delirium, NMS, malignant hyperthermia. And there are ways to kind of distinguish foul sounds, hyperactive foul sounds in serotonin syndrome, hypoactive in malignant hyperthermia, and usually in NMS, and rigidity changes. And hyperreflexia in the lower extremities in serotonin syndrome, hyporeflexia, malignant hyperthermia. Now, Scott went over treatment. So management-wise, early recognition, close observation, frequent vital signs, supportive care is essential. De-seeing antipsychotics or other drugs, such as metoclopramide. Keep in mind, when you go to the ICU, in an algorithmic way, oftentimes the patient is on Reglan post-surgery. And so it's very important to keep that in mind if you're called and you see a patient who might have catatonia. Restart withdrawn dopaminergic agents, anticholinergic benzodiazepines, especially in patients with Parkinsonism. Supportive measures, high index of suspicion for the development of those medical complications that Brian was talking about. Remember, this literature, simple catatonias treated with neuroleptics often go on to NMS. That's the famous Denise White paper. Once malignant, mortality risk goes way up. We've known that since the 30s. Steve Mann did a good paper on it in 1986. And malignant catatonia patients who are on neuroleptics have an even higher mortality risk. So after lysis of the catatonia, as Scott says, you can switch to sublingual or a PO in divided doses. Psychosis may emerge even after you've lysed the catatonia. And after a period of time when you're satisfied that the catatonia is lysed, as the patient's psychosis is in evidence, you may decide to try an atypical antipsychotic. We always try to keep the patient on the Razopam when a catatonic patient winds up on an atypical. Because even a minor, unprotected dopaminergic blockade can throw the patient back into catatonia. And the Razopam does a pretty good job buffering against that. So we keep the patient on the Razopam when we're using antipsychotics. As Scott said, aripiprazole is a good one. There's a special case of clozapine. You're going to have patients with schizophrenia, catatonic schizophrenia, who the clozapine does a great job with the psychosis and with the catatonia. And for some reason, maybe they have small bowel obstruction and the clozapine has stopped. They're going to become catatonic. Whereas sometimes the Razopam could be helpful. Oftentimes the key that unlocks the door is going to be clozapine, restarting the clozapine. OK. One thing that has occurred to me is that when you have a patient who has a brisk lysis of their catatonia with the Razopam, it makes you wonder, right? Because the Razopam, as Scott mentioned, is a GABA-A drug. GABA is, and I'll talk briefly about this, is usually inhibitory, most often inhibitory. So you wonder, why did they wake up? And this has a lot to do with the pathophysiology of catatonia. But then if this patient is on the Razopam for a while, you'll get a report, oftentimes the patient's at home from the family. The patient's sleeping all the time now, right? Whereas the Razopam was keeping the patient alert. Over time, now they're responding like a normal patient would to the Razopam. They're starting to become sedated. That's a clue that they're, in terms of their system, it's rebalanced. And so that may be a clue to start tapering the Razopam down. Lignin catatonia. Let me just sort of say that Scott mentioned that original case for the use of the Razopam at Mass General. My mentor, the late Dr. Kassam, used the Razopam. It was his choice. He went into the nurse's station, rummaging around. He told me later he was looking for diazepam as a muscle relaxant. My big contribution, as Andy knows, because I wrote this up, is that I was the guy who made the patient catatonic. Because I was a fellow, and the patient had post-cardiotomy delirium. And I went up, and I filled him full of haloperidol. And the surgeons were pissed at me because he was supposed to go home. He was on the eight-day post-cardiotomy plan. And it was really, really hard to get him to go home. And I was the guy who made the patient catatonic. Dr. Kassam, who saved my butt, went up at like 8.30 at night. And he's the one who spritz the patient with the Razopam. And as he was leaving, he was amazed. I was amazed. The nurses were amazed. That was the Lazarus response. And I don't know. You may not know, but Dr. Kassam was a Jesuit priest. And all the nurses knew this. And as he was walking out, he whispered to me, first of all, we have to do this again. And then the nurses said, Dr. Kassam, what did you give him? What did you give him? And he just said, well, holy water, and just walked out. So anyway, that was a case of malignant catatonia responsive to the Razopam. One of the challenges is that, and this stems from the great work of Stan Karoff at NMS and the use of dopaminergic agents in NMS. And you can see why they're still used and so on. I mean, I'm not doctrinaire about saying no dopaminergic agents. Every doctor is there on the particular case and thinks it might be helpful. And there's a rationale for why it would be helpful. But intravenous Razopam, and if that doesn't complete the job quickly with malignant catatonia, then expeditious rapid ECT is the way we go with treating NMS and malignant catatonia. I happen to think that malignant catatonia, NMS, is just a toxic version of malignant catatonia, which you can get from many other etiologies. I don't think it, there are certain special features because it's the neuroleptic that's causing the malignant catatonia. But I think the similarities outweigh the differences. And that's why I think Razopam and ECT work with NMS as they do with malignant catatonia. Scott mentioned achinitic mutism. Oh, I better stop soon. Achinitic mutism, it's very interesting. Achinitic mutism is a problem because there's some blockage in the medial forebrain bundle that brings dopamine and norepinephrine to the anterior cingulate and the ventromedial prefrontal cortex. And you can override some of those lesions with dopaminergic agents, bromocryptine, glyceride, bromopexol, and amantadine, et cetera. So we had a wonderful neurologist, C. Miller Fisher at MGH. And he tried to figure out, well, why does it look like catatonia? And why does it have slight differences? I'm convinced, and we don't have time to talk a lot about it today, but I'm convinced that achinitic mutism is a window, will give us some information about the pathophysiology of catatonia. For one thing, while lorazepam is not great for achinitic mutism, zolpidem is. And zolpidem is also used in catatonia as a test for lysine catatonia. And it has a special GABA A1 receptor effect. And those receptors hang out in the globus pallidus more than any place else. So the question is, is that what makes zolpidem work in both catatonia and achinitic mutism? So there are a lot of mysteries yet to be figured out there. And so this is pure speculation, but I just throw this out there. We think that one reason why lorazepam works is the GABA A agonist, right? And if you spend a lot of time, if you're obsessive and you look at the direct, indirect, and hyperdirect basal ganglia tracks, the striatal thalamocortical circuits, you can convince yourself that if you affect GABA A in those systems, you can unlock a catatonia. You can overcome a hypodopaminergic state. You can change the thalamic filter and all of those things. So GABA A agonists may be helpful. One that hasn't been tried is nasalam, which is intranasal midazolam. So that's something I'm looking out to see whether people try that. And then, of course, you know that zaranolone is coming on the market. And it's a neurosteroid allopregnolone drug. And it's a positive allosteric modulator of GABA. And so who knows? Maybe that will have an effect in catatonia. And then propofol, we know is a GABA A drug, can lyse catatonia. And we've done that and published on that. NMDA antagonists, dextromethorphan, so Nudexta and Alvalti, ketamine. Magnesium sits in the NMDA track and can be helpful, perhaps. And then dexmedetomidine. Now we have agalmi, sublingual dexmedetomidine. Of course, if the patient is in the unit, we can give it IV. And that drug, as an alpha-2 adrenergic receptor drug, may have an effect, and there is a paper out about its use in catatonic excitement. And then this drug, bumetanide, which is a loop diuretic, this brings up this very interesting thing that we don't learn enough about in psychiatry, is that there are certain states related to autism, related to TLE, related to neurotrauma, where GABA in certain parts of your brain can become excitatory. So I think that we haven't really looked enough into, is that playing a role in catatonia? And a professor of child neurology who I've gotten to know at MGH, Kevin Staley, has been looking at autism and seizures in children, because we all start life with GABA excitatory neurons, and then we mature out of it. It has a lot to do with intracellular chloride concentrations, whether it becomes hyperpolarized or depolarizing. So this is an area I think we need to spend more time if we want to try it, because so much in those tracts has to do with excitatory-inhibitory balance. And Dr. Bryan talked about hypercoagulation, and I think you mentioned the D-dimer story. So that I think is important for us clinicians. It might be good for us to be getting D-dimers on patients to see how at risk they are for DBTs and pulmonary emboli, since, as Bryan said, 10% of patients are going to wind up with excess mortality from hypercoagulability. I want to bring up, we haven't talked a lot about trauma, post-traumatic stress, and catatonia. The question is, is primitive defense, sometimes you may not need trauma, but the primitive defense, think about shell shock in World War II. These were really cases of catatonia. And then there's more being written about the subjective experience of catatonia. Fear is what we think is a major one. Max and Ned Shorter have a book about the madness of fear in catatonia. I would suggest that book to you. So I'll end with this, pathophysiology. I think, and the achinitic mutism story helps us understand this, we're talking about a dissolution, as Hughlings Jackson would say, between motivation and movement in catatonia. It's a psychomotor condition. So there are going to be motor problems, but there are also going to be problems in affective experience. And a lot of that is going to emanate from the anterior cingulate, the mid cingulate, the orbofrontal cortex. And getting that message in normal people through to the motor system is very involved. And I would suggest the work of Leonard Heimer and Suzanne Haber. We've worked it out really in intricate ways how the part of your brain with the loop that goes from anterior cingulate to nucleus accumbens to ventral tegmental area moves the message. If you have an affectively driven decision to make to move, moves that message through from ventral striatum to the cognitive part of your dorsal striatum to the motor part of your dorsal striatum. And this is a kind of map that is reflecting the message that's going from your anterior cingulate to your premotor cortex to your supplementary motor area to your motor cortex. So you make a decision you want to move, but you have a fail-safe system subcortically which works on prediction. And if the prediction is don't move because that initial decision you made was fraught with danger, then that initial decision that you sent up the road to M1 is not going to take place. So a lot of what you're doing when you're spritzing a patient with the Razor Pen is unlocking that system and it's working in that paralympic area, but also subcortically to the basal ganglia. All speculation, but it's fun to think about. So I'll leave it there and take questions. Brian, do you want to? Thank you so much for the symposium. I'm working a lot in outpatient settings with adult autistic patients with no intellectual disabilities and who have been, for the last few decades, sometimes misdiagnosed with schizophrenia, women with personality disorders and so on. And we know that 25-30% present catatonia, it's more than schizophrenia. Listening to you, I think the second cause of death is suicide. They live in general 15-20 years shorter life than the general population. So I was curious with all of your experience combined, is through either the initial testing, looking at symptoms, the response to medication, or the evolution, and is your clinical sense built with the years, you have an instinct if it's, maybe it's more someone on the autistic spectrum, maybe it's a mood disorder, maybe schizophrenia, and I was curious what you experience if any at all, and thank you again. I'm so sorry. And thank you for speaking about the terror and the fear, because that's what brought so much when people come out of them. I think you raise a really good question, which is, you know, we all talked about catatonia as a syndrome, and one of the challenges is figuring out how it overlaps with other ideologies, right? And I always think about catatonia as not being the only thing present. So there's something else present, and we know that a lot of psychiatric illness and a lot of neuromedical illness can present with catatonia. You mentioned autism, which is a story we didn't talk much about, but 17% of adults with autism will have an episode of catatonia at some point in their lifetime. So there's a huge overlap between autism and catatonia as well, and sometimes parsing that out can be really challenging. I think what I think about is sometimes treating and managing the catatonia can help you start the process of gathering more information, right? Because it allows the patient to participate more in your interview, to participate more in your exam, and sometimes that's the most important first step in terms of figuring out what else may be part of the mix or what else may be underlying things. Thank you for the wonderful session. I have two quick questions. One is, Andrew, is the Bush-Francis scale can be useful in diagnosing catatonia in severely autistic nonverbal kids, given that they are already nonverbal, and so the item of mutism will not be applicable. And also, they normally don't respond to orders, and so we will not be able to give them orders and expect them to respond in a specific way. My second question is about if both lorazepam and diazepam are not available in a country from Egypt and we don't have both of them, we have midazolam, clonazepam, and other benzodiazepines, would it be beneficial to try to treat patients with these agents? So in general, if a patient is mute for another reason, then we wouldn't count mutism as a catatonic sign. So it's a syndrome, look for other signs. And the purpose of the rating scale was to be comprehensive, give you a long list of items to pick from. And your second question? Oh, other benzodiazepines. Sorry that you don't have lorazepam or diazepam available. There's some evidence that other benzodiazepines can be helpful, there's something peculiar about lorazepam, that it's superior to others, but sometimes the other benzodiazepines do in fact work. I had a point about how to elicit the catatonic features in the nonverbal autistic, given that they don't respond to questions or orders, they don't normally respond to orders. Look for other signs. Thank you. I've successfully treated several cases of catatonia, lethal catatonia, malignant catatonia, catatonic delirium, or whatever you want to call it. To much amazement myself and others, but I have one now, she's approximately 25 years old, suffering from an eating disorder, was brought to the hospital around eight years ago. Her last words to her parents were, if you put me in the hospital, I'll never talk to you again. She has not spoken since. She is a tall, very strikingly beautiful young lady, who now communicates through texts, gesturing, and I've tried Klonopin, I've not tried Ativan, or I've not tried Valium quite yet. So I call this elective mutism versus selective mutism. We've sent her for ketamine treatment, no luck. I have TMS in my office, we're going to move to that next. We've sent her for ECT, unfortunately, I don't know if someone's from the Rochester area, there's a big barrier to get ECT there. I trained under Max Fink, we did a lot of ECT up in Poughkeepsie, New York. If I had her in Poughkeepsie, we would have had ECT, she would have been done by now. I can't find anyone to treat her, and I'm quite frustrated. This is the kind of patient that in the old days, Greg and I would be using sodium amytol. Using what? Sodium amytol. Okay. As a diagnostic. But I can't find somewhere to do that. I'm in an outpatient office, I don't have any medical backup. I even tried the infusion center at the local hospital, they won't do it. In view of the other people with questions, send me an email and we'll have an offline conversation about ideas. Thank you. Hi. First of all, thank you all for speaking today. I think your work has been really influential for me personally and for my trainees, and I really appreciate all the work that you've done. I think one of the things that I run into from time to time is patients where it's difficult to get a full Bush-Francis-Catatonia rating scale complete for whatever reason, they won't allow physical examination, and I was curious what you do in those situations of how you indicate that it was observational or how you use a scale or scoring mechanism to reflect that. I'm not sure I totally grasped the question, but Catatonia is a clinical syndrome, so you look for what it travels with. Every single patient will have an average of five or six catatonic signs out of that first 14. So if you have a person who is showing one thing, look for other things. I'm not sure that answers your question. I can add to it in the sense that I've had patients for whom the negativism is so profound that you have a hard time getting other features. And to Andy's point, there's a lot on the Bush-Francis that is observational, right? So the first principle of our Catatonia exam is place yourself in a position where you can see the patient and the patient doesn't know that they're being observed. If they're in a room with a monitor, that's easy, but otherwise put yourself kind of diagonal to the window and try to observe them. And just watch them for a couple of minutes, and that will tell you about repetitive movements. It'll tell you about immobility. It'll tell you about a lot of those things on the Bush-Francis, even if you can't get them to engage with Gaggen-Halton and Mitgain and some of those that require their participation because they're so negativistic, you can still get a lot by observation. And then in some cases, that may be a case where you try an out-of-band challenge. Does that help with the negativism specifically, and then does that allow you to gather more information? Great. I appreciate both of that. And just a quick follow-up. I know there's more people. Is there any way that you reflect that in your documentation that it was strictly observational and why it might not be a most accurate scale? So I can add to that. What I do in situations like that is I will put the total score for what I've been able to gather, but then after that, I'll put a note saying this was a partial exam. The patient wouldn't cooperate with the physical exam. And I've had some luck teaching nurses about what to look for because they're our eyes when we're not on the unit. And so I tell them about things like mannerisms, stereotypes, so they can be on the lookout for that so you can gather that information if the patient's not cooperating. But for me, if a patient is so negativistic that they're not going to allow a physical exam, catatonia basically moves to the top of my differential in those cases. I think a lot of people just treat it as psychosis and those patients get antipsychotics, but for me, that pretty clearly looks like catatonia most of the time. Thank you. Good morning. So I wanted all thoughts, as you guys mentioned, clozapine after being on kind of induced catatonic response. And if y'all have had experience with that, other antipsychotics, I have a second or two. Female with no psychiatric or medical history who was based on olanzapine-10 for what was presumed steroid-induced psychosis back in early fall. She came to me with a pretty severe Parkinson's from the antipsychotic and we took her off over a couple of weeks. But then after maybe two weeks, she started to develop herpes, what seemed to be a severe So I ended up going to an outside location facility, responded to the out-of-van-shall-and-got-in-to-the-counselor. But I thought it was pretty peculiar. Send me an email and I'll help you with the case. Sounds good. Let's have another question. Thank you all for today. My question has to do with the data on the transition from catatonia to malignant catatonia. And it looked to me like the data was mostly from the 90s. And I'm wondering what your thoughts are when you're on an antipsychotic, what your thoughts are about atypical antipsychotics versus typical antipsychotics and the risk of transitioning to malignant catatonia. So I would say a couple of things. I do think atypicals are probably safer than typicals because they have other effects. But for me, it's more importantly, I think, an issue of potency. So low potency is probably safer than high potency. So if I am in a situation where I'm compelled to use an antipsychotic, I'm going to probably use a low potency atypical, erpiprazole, olanzapine probably being my first two choices. I will always give that directly in combination with benzodiazepine. So at the same time as a benzodiazepine to really safeguard against the potential. And then you've just got to really watch for malignant features. Got to know what you're looking for. I'd probably trend to CK in a situation like that, just to make sure. Look for iron. Do iron studies because we know that low iron is a factor for transition to malignant catatonia. I just want to point out the work of Philip Seaman, clozapine, to a lesser extent, olanzapine, fast on and off the D2 receptor. That may give them a special advantage in this regard. But still, I think the safest approach is to keep the receptor and keep an eye on it. Thank you very much for the excellent talk. Of all the great work that you guys have done to this field and particularly to this topic. I have a quick question being geriatric psych. Do you have any data or limitation on the amin-81 challenge test in geriatric population? Because sometimes what I find difficult is to inject that two milligram IOE followed by another two milligram IOE. Is there any evidence to have a lower dose, one amin-MGI-OE followed by one amin-MG or something like that in the particularly older population? So one of the predictors of response is what else they have. So Greg and Scott mentioned most patients with catatonia have something else. They have bipolar disorder, they have a neurological underpinning, or they have a toxidrome commonly. So it's probably going to depend on what else they have would be a factor in the example that you're talking about. If this is an elderly patient with new onset catatonia that you're speaking about. So what we are usually seeing, we suspect catatonia, but since the elderly patient could be a little more fragile, medically complex. And sometimes we are reluctant to use that two milligram IOE test. So can we go with the lower dose in terms of the amin-IOE test rather than the two MGs? So the question is, you know, in somebody who you're reluctant to use two milligrams of IV Ativan, could you go with a lower dose? The answer is you could, but you just have to be prepared for the fact that you're going to more likely have an equivocal response. So unless you really have evidence that this person is not going to do well with two milligrams of IV Ativan, if they're in a monitored setting, obviously as an outpatient, but if they're in a monitored setting, I'd probably still give them two milligrams just so you have a better chance at seeing the response. Yeah. Monitoring them closely, I would say, right, in the hospital, because we have had patients being unresponsive to a tiny bit of aminolazepines and other stories out there. So if you have a patient that you're concerned about is too medically frail or physically frail to tolerate the racepam, as Dr. Beach is saying, have flumazenil available? Flumazenil is a benzodiazepine reversal agent that rapidly works IV. So that might reassure you that you have that option. Thank you. All right. That's our last question. But if you want to come up and talk with us, feel free to do so.

Cleveland Clinic

catatonia

diagnosis

management

Andrew Francis

Scott Beach

Greg Frischone

Bush-Francis Catatonia Rating Scale

benzodiazepines

electroconvulsive therapy

lorazepam challenge

NMDA antagonists

economic burden

GABA receptor