Good afternoon, and welcome to the SMI Advisor webinar. I'm Megan Arrett. I'm the Professor of Pharmacy Sciences, Practice, and Health Outcomes Research at the University of Maryland School of Pharmacy. I'm pleased you're joining us today for our webinar, Clozapine and the Gastrointestinal Track. Next slide, please. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need for the care for your patients. Next slide, please. Today's webinar has been designated for one AMA PRA Category 1 credit for Physicians and one Nursing Continuing Professional Development credit hour. Credit for participating in today's webinar will be available until April 24 of this year. Next slide, please. Slides from the presentation today are available now in the handout area found in the lower portion of your control panel. Select the link to download the PDF. Next slide, please. Additionally, please feel free to submit your questions throughout the presentation by typing them in the question area found in the lower portion of your control panel. We're going to reserve 10 to 15 minutes at the end of the presentation for question and answers. So, please, as they come up throughout the presentation, go ahead and jot those into that area and we will get those to Dr. Everie Palmer at the end of the presentation. Next slide, please. So, now I'd like to introduce you to our faculty for today's webinar, Dr. Susanna Everie Palmer, Dr. Everie Palmer is an academic psychiatrist who is passionate about using multidisciplinary research collaborations to inform the highest quality evidence-based care for people with mental illness. She is concurrently employed at the Central Regional and Forensic Services. She has worked in a number of different areas across the mental health sector, including as Clinical Director and Director of Area Mental Health Services for the Forensic and Rehabilitation Services, covering courts, prisons, and inpatient and community forensics across New Zealand's Lower North Island, and as New Zealand's Acting Director of Mental Health at the Ministry of Health. I'm so grateful that she's leading us today in this webinar. So, thank you, Dr. Everie Palmer, and I will turn it over to you for your presentation. Kia ora and ngā mihi nui from Wellington. Thank you. Thank you, Megan. So, just to start off, I've got no disclosures to make today about the subject matter in this presentation, and I'm just going to orientate you to start off with the learning objectives today. So, we're going to be talking about constipation or gastrointestinal hypomotility and the gut, and what I'm hoping at the end of this presentation, that you will be able to recognise the five S's of clozapine-induced gastrointestinal hypomotility, which we call CIGH or slow gut. Importantly, you'll be able to identify and act on the red flags of serious CIGH complications like bowel obstruction, and apply strategies to best manage and prevent constipation and its complications. So, I'm going to start off by telling you a little bit about myself. So, I work in Wellington. This is a picture of Wellington from pretty close to my house, and that's the capital city of New Zealand, a city that's famous for its wind, occasional earthquakes, excellent coffee, and great views. And in this slide, this is what we call Wellington on a good day, the locals. So, it's not always like that, and looking out my window today, it doesn't look like this. So, we're in the Pacific at a latitude of 40 degrees south, an area that's known as the Roaring Forties. And New Zealand is currently, actually, in a national state of emergency. I'm not sure if this has been in the news in the States, but we were hit pretty hard by Cyclone Gabriel in the last week. So, although my city, Wellington, is fine, there's been a huge amount of destruction and disruption across the North Island, and we're still trying to make contact with some of our medical students who've been in regional centres. So, this is the area that I work in. So, my clinical job is out in Porirua, which is about 30 minutes' drive away, and it's a large forensic and general rehabilitation service where we have over 100 medium to long stay inpatient beds catering for the lower half of the North Island. Most of our patients here have psychotic illnesses, usually schizophrenia, and half of the people that we have in this service are prescribed clozapine. So, I've had a lot of clinical experience with clozapine over the last couple of decades. And back in 2008, when I was a resident, I had a patient called Kate. Kate was not her real name, but she was a real person, and she died of an iatrogenic complication that was unknown to her treating psychiatrist, and that psychiatrist was me. So, I was a junior clinician at that time in the forensic and rehabilitation service, and I was prescribing a lot of clozapine. New Zealand has the second highest clozapine prescribing rates in the world, so about 30% of people who have been diagnosed with schizophrenia in New Zealand are on clozapine. Yet, at that time, not only was I oblivious to Kate's constipation, but I'd also not realised that constipation could be a life-threatening complication of the medication that I was most commonly using. So, at that stage, I was not regularly screening my patients for constipation in any form, and I had no evidence-based strategies in place for managing it. So, enquiring about bowel motility problems amongst the people in our service after Kate's death revealed that constipation was widespread amongst patients in our service, but it was really poorly identified and managed by us. And it was this clinical question that actually led me into an academic career. So, figuring out some of the answers about antipsychotic-induced constipation was the road that led me into academia, and I'm now a professor and head of department in my local – in the university here, University of Otago, but it was an interest in trying to find out answers to questions that I did not know in my clinical work that led me down that path. And it's been really motivating to conduct part-time research into a problem with high relevance to the people that I'm working with clinically. So, this presentation is going to cover what I know now, and wished I had known then, about antipsychotic-induced constipation, and specifically about clozapine-induced gastrointestinal motility, or SLOGUT, or as our patients sometimes call it, cloz-tipation. I imagine that you do not use clozapine as much as us, but that you'll have a number of patients who are taking clozapine, and also people who may be receiving polypharmacy and high anticholinergic loads, who are also at risk of developing SLOGUT problems related to their antipsychotics. So, we're going to talk in a minute about how this is an antiserotonergic and anticholinergic effect, for which clozapine causes the greatest problems, but these can also be seen with other medications, like olanzapine in particular. So, we talked about the learning objectives, and we're just going to start getting into the five S's of CIGH first. So, there are five things that I want you to remember, and they all start with S, conveniently, and because I made them do that. So, there's four key points about clozapine-induced gastrointestinal hypomotility, first of all. So, SLOGUT, clozapine can cause the GI system to slow to reduce motility, right from the beginning to the end, the esophagus to the rectum. This is a significant problem, so SLOGUT is probably clozapine's most common side effect. I'm going to tell you about the motility studies and the prevalence of SLOGUT, and clozapine uses in a minute, but at this stage, I just want you to remember this is a really significant problem. It's often silent, so people may not report any symptoms, and I'm going to talk to you more about why this might be, but what we found is that of those people who ended up with life-threatening SLOGUT, only 55% had ever reported constipation, so constipation is not a good signal, necessarily, for detecting SLOGUT. And fourth, SERIOUS, so your clozapine-treated patients are much more likely to die of GI complications than other better-known side effects, such as a granulocytosis. And you're thinking I told you that there were five S's, and these are only four, but the last one has a page all to itself, because it's probably the most important thing to remember in terms of practicing, and this is speed things up. So when starting clozapine, a laxative should also be prescribed prophylactically. You don't wait for problems to develop, but you front-foot this right at the moment that you start clozapine. So my suggestion is to reduce the morbidity and mortality of SLOGUT, all people starting on clozapine or already on clozapine are also prescribed prophylactic laxatives in exactly the same way you would if you were working in end-of-life care and you were studying someone on an opiate. So let's just chat for a little bit about clozapine, which is a classic antipsychotic. So I reckon if clozapine was a rock band, it would be the Rolling Stones. Developed in the 1960s, getting big in the early 70s, then off the market for a while, but with a comeback in the late 1980s. So clozapine's progress, much like the Stones, has also been marred with controversy. And look, you can see that unlike the Stones, it hasn't changed a bit. So here is 100 milligrams of clozapine in 1963 and 100 milligrams of clozapine here today in 2023. And here is Keith Richards in 1963 and Keith Richards in the last year or so. So clozapine maybe has stood the test of time particularly well. So if we rewind to the 1940s and early 1950s, there were no antipsychotics and schizophrenia was managed by a combination of containment, institutionalization, neglect, and controversial interventions like insular chromotherapy and prefrontal lobotomy, which had gone in and out of vogue over that first half of the 20th century. And none of these treatments had notable benefits and many caused significant harm. Then in 1952, it was noted purely by chance that a post-anesthetic agent, chlorpromazine, had significant antipsychotic properties. This prompted the development of a number of other similar agents such as thioridazine, stalazine, haloperidol, and these were game changers allowing many chronically institutionalized people to leave the asylums in which they'd been detained for decades. Here we see a typical advertisement of that age and the start of big pharma in psychiatry. However, all these antipsychotic agents had marked and disabling extrapyramidal side effects, which included the various movement disorders such as the acute dystonias, pseudoparkinsonism, akathisia, and tardive dyskinesia. Chloropramine was patented in 1960 and unlike the other antipsychotics of that time, it did not cause extrapyramidal side effects, which is a good thing, right? Well, ironically, no, not at that time. This was a major obstacle in its marketing. Despite early data showing that it was a potent antipsychotic, Clozapine's appearance was initially greeted with skepticism from the psychiatric community. According to medical historian Hans Hibbius, the prevailing dogma at that time was that there was this inseparable connection between antipsychotic efficacy and extrapyramidal effect. People believed if Clozapine didn't possess the requisite extrapyramidal side effects, then it couldn't be any good. So initially, it star faulted. However, the proof was actually in the pudding. And what do you know? Despite the absence of extrapyramidal side effects, Clozapine worked and was shown to work. And there was a bit of a silent revolution, particularly in Europe, with Clozapine increasingly being used through northern Europe and Scandinavia in the early 1970s with good therapeutic effect. But as you know, this good run wasn't to last and soon Clozapine was out of favor again. In 1974, reports emerged from Finland that Clozapine's use had been associated with 16 cases of agranulocytosis, associated with eight deaths. And in most countries, Clozapine was withdrawn from the market or wasn't registered onto the market due to concerns about this adverse effect. But as you know, this changed after 1988, when the pivotal study by Kane et al unequivocally demonstrated Clozapine superiority for treatment resistance. So much like the Rolling Stones, despite the many limitations, there's nothing as good as the original. Clozapine does things that no other medications can do. And as that famous 1988 study shows, it is best in class for treatment resistant illness. It reduces the mortality rate, largely due to the reduction in suicide rate. It does not cause extrapyramidal side effects. And there's some benefit in negative symptoms as well as positive. And overall, we see better cognitive responses compared to other medication and reduction in psychiatric admissions in terms of frequency and duration. And these advantages are important to remember. I want you to hang on to these as I go through the rest of the presentation and you wonder, is Clozapine worth it? Because the answer is generally, yes, yes. Although Clozapine is guilty of many sins for which other medications would be instantly voted off. It is a high risk, high reward medication. And as you know, clinically, and I'm sure you've seen this yourself, for many people, it's the best that we've got. And I'm reminded of this every day working in the forensic unit. So we've talked about the good, now the bad. Despite Clozapine's advantages, it remains a third line treatment, limited by its side effect profile. So the best recognized serious side effects include delirium, agranulocytosis, cardiomyopathy, myocarditis and seizures. And of course, metabolic syndrome, which is a major contributor to premature mortality and to morbidity and the antipsychotic treatment group. Clozapine, or constipation, sorry, we used to regard as an irritating but fairly mild side effect. It was seen as something that was common within the wider population and a bit of a prosaic sort of boring thing to happen. Not something that we gave a lot of attention to. but we were wrong. After my patient Kate had died of CIGH, I was talking to a surgical colleague who had been involved in four other very serious and similar cases in which another person had died and the other three had had their bowel resected. And to me, this was pretty scary stuff at that time. Looking in the Clozapine prescribing information, while the drug regulator's data listed this as an extremely rare side effect occurring in less than one in 10,000 people, it just didn't seem that could be right. I went through a Medline search, so this was back in 2007-2008, and at that time there were only isolated case studies and no guidance on what to do about slow gut with Clozapine. So I started searching much more rigorously through the available literature. This is an example of some media that appeared a few years ago in New Zealand about people dying of Clozapine-related constipation with the provocative headline of Aucklanders die from medication side effects as doctors bungle care. And the bungling that they talked about was a man who was on Clozapine who was not receiving sufficient regular monitoring of his bowel motions and he and his family had not been informed about the risk of Clozapine-related slow gut. And so he'd started complaining of a sore stomach, the complaints had continued, and 12 days later he had died without receiving any medical investigation, and it turned out that the cause of death was bowel obstruction. So why do people die of constipation when they're on Clozapine, when many people in the wider community deal with constipation all the time but they don't die of it? Well, there's some possible patient-related factors that enhance severity, which might include low-fibre diets, limited exercise, and poor bowel habit. But I'm going to explain in some minutes that these are not as significant as you may think they are. Then there's other medication-related factors, such as the side effects, so with obesity, hypersalivation, sweating, dehydration, people have thought maybe this exacerbates things. There's interesting theories about schizophrenia raising the pain threshold so that people don't complain of discomfort in the way that they might otherwise if they didn't have a schizophrenic illness. And it could also be that co-prescription of antidepressants, neuroleptics, or anticonvulsants, is also affecting the sensation of pain, with some of these agents having analgesic properties. Very interestingly, it seems that Clozapine's antiserotonergic properties also reduce intestinal sensitivity, and so that you may get the bowel being stretched in a way that would be very uncomfortable for someone not on Clozapine, but because of the antiserotonergic pharmacological action of Clozapine, people don't experience that. And lastly, clinicians and patients often aren't aware of the potential seriousness of these problems, and so they're not acted on early. So if you can think back and remember what the five S's were, the first two are slow, insignificant, and we're going to talk a little bit about those. So Clozapine belongs to the family of dibenzodiazepines. It is its combination of dopamine D2 receptor and serotonin 5HT2A receptor blockage, which made it novel when it was first developed, becoming the prototype for this class of antipsychotics, which was called atypicals, a word I don't like, but it was the first of that class. But Clozapine is a particularly complex drug. Its array of actions are responsible for its advantages in treatment resistance, schizophrenia, but also for its unique and considerable adverse side effect profile. So the binding properties of Clozapine are more extensive than of its other antipsychotics classmates in terms of its relatively high affinity for dopamine D1 and D4 receptors versus D2 receptors, alongside a particularly powerful degree of serotonin 5HT2 antagonism. It also has actions at a lot of other serotonergic receptors, 1, 2A, 2C, 3, 6 and 7, and it antagonizes a variety of muscarinic, histaminic, alpha adrenergic receptors and has less well characterized effects on other receptors, including neurokinin, opioid, prostaglandin and MDMA receptors. So, let's talk first about its anticholinergic properties and how this relates to the gut. So acetylcholine is the primary excitatory neurotransmitter in the enteric nervous system. It is what makes the gut tick. We all know that Clozapine is anticholinergic, but we sometimes forget just how anticholinergic it is. It's incredibly potently anticholinergic, sufficiently anticholinergic to induce an atropine-like poisoning on overdose. And so by blocking the acetylcholine receptors, Clozapine disrupts autonomic mediation of the intestine. It inhibits intestinal smooth muscle from contracting, delays intestinal transit, and may cause functional bowel obstruction. However, probably the acetylcholine hypothesis alone does not account for the prevalence of GI hypomotility with Clozapine than compared with other very anticholinergic agents. So then this brings us to the combo, the anticholinergic plus antiserotonergic mechanisms. We, as people working in mental health, we focus on serotonin as a neurotransmitter working up here in the brain. So sometimes it comes as a surprise to realize that 80% of serotonin receptors in the brain are serotonin-induced. So sometimes it comes as a surprise that 80% of serotonin receptors are located in the gut. And serotonin plays a complex and crucial role in the normal motor and secretory function of the gut. So thinking of the different serotonin receptors, the 2s are involved in visceral sensation, the 7s in relaxation and GI smooth muscle, and 5-HT3, those receptors, the 3s may be particularly relevant with the GI effects of antagonizing the 5-HT3 receptor, including slow colon transit, reduced gastrocolic reflexes, increased colonic compliance, and possibly this reduced intestinal sensitivity to distention. Little has been known of clozapine's effects on the various patterns of contractile activity exhibited by different segments of the human gut, and studying this experimentally is difficult. Most studies of human colonic motility have been performed on short strips of tissue or surgically resected segments of diseased colon, and it's difficult to do this study on people. So I was interested in looking at the direct effects of clozapine on the GI tract, and what we did is we examined the effects of clozapine on colonic contractile functioning in depth using fairly novel what's called spatiotemporal mapping techniques. Spatiotemporal mapping sounds very Einsteinian, it's looking at movement over space and time, but essentially what this means is that under the right experimental conditions, a section of the gut can be removed and it will continue to function autonomously governed by the enteric nervous system. So the gut is a bit like a heart that you might see, you know, still beating outside the body. So the gut continues to contract like this, remaining viable for several hours, and you can manage, measure the baseline contractile activity and vary the experimental conditions and see how that affects motility. So we used rabbit colon and set up this autonomously functioning gut model, identifying different contractile patterns, and here you can see this is what the gut looks like, and here is a mass peristalsis traveling through the gut, and you can see this watching it in the organ bath that the gut looks like it contracts like this with the contractions moving through it. So then we added clozapine to the bath, and I wish that I had a video of this and of the technician's face just after we did that, because the gut was contracting, the clozapine went in, and the gut just froze. It stopped, it stopped working. So this is what it looks like in terms of the pacemaker of the gut. So you can see in these, these are the contractions moving through, normal ripple contractions and mass peristalsis, and then at this point here we add clozapine and all those contractions that we were seeing regularly before are abolished. What I would say about that is I was working with a gastroenterological technician in the lab there who had no experience with clozapine but had been working in a lab like that for, you know, 20 years or so, and when this happened he was staggered, and he just looked at this, uttered an expletive, and said, you give this stuff to people? Because he had never seen anything have as profound effect on gastrointestinal motility in all his experience before. So let's talk about the people. This was in an animal model. Do we think that this happens to people as well? So I want you to just do a little bit of a thought experiment in your head and think about people treated with clozapine. What percentage do you think of these people that you're treating have slow gut? Now if you said something like 25, if you're thinking something like 25 to 30 percent, that's what a systematic review, I've given you the reference for that at the end, by Shirazi et al., published in 2017, found that constipation was reported in about 25 to 30 percent of all clozapine treated patients. So just over a quarter of people were complaining of constipation. But remember I told you that silence was one of the S's. Not all people who end up dying of slow gut reported constipation. So we were interested in studying this objectively and started doing some bowel motility studies. This was in the forensic service that I showed you before. And the participants in the study, half were on clozapine and half were on other antipsychotics. And we excluded anyone with known slow gut because we wanted to pause any laxatives that people were on. We couldn't do that if they had any known difficulties. So this was in people for whom there was no history really of CIGH, but some were on some prophylactic laxatives. So we paused these and we measured bowel motility using these little things down the bottom, which are called radio opaque markers. They're in a capsule and over three days you swallow capsules with different patterns of the radio opaque markers. We used a validated method called the Metcalf technique and essentially the patient swallows a series of these radio opaque markers in a scheduled protocol and then using two abdominal x-rays and some mathematical formula you can calculate the time it passes for these markers to pass through the colon transit time. What did we find? For patients not prescribed clozapine, the median colonic transit time was 23 hours, completely normal. A normal average colon transit time is 28 hours, just over a day. So our patients might have been slightly faster because they were generally younger and more males. All sorts of different antipsychotics they were on, but no one who was on an antipsychotic that was not clozapine had an abnormal transit time. For patients prescribed clozapine, the median transit time was about 105 hours. 105 hours, over four times longer than those on other antipsychotics and this was definitely not normal. Over here you can see the clozapine treated patients are in green compared with the non-clozapine treated patients and their survival curves. So 80% of our clozapine treated patients had colonic hypomotility. So if when I asked that question a couple of slides back you thought 80% you're probably going to be right. And what we found was that right colon, left colon and rectosigmoid transit were all abnormal. Wasn't affected by age, gender, ethnicity, smoking status or duration of clozapine treatment. But the one factor this was correlated with was serum levels. So higher clozapine serum levels were associated with longer transit times. Here you can see on the right a pretty standard image of a clozapine treated patient at the end of the monitoring time. You can see those radiopape markers are still here all in the bowel and this is compared with another patient who was taking a lanzapine at the same time. We did the same studies using a smart pill or wireless motility capsule. We wanted to just examine here which parts of the GI tract were affected. So what we found using the wireless motility capsule was that only 18% of people had normal studies within this different method. Most of them had dysmotility in multiple regions of the gut. And what we could see as well in using the wireless motility capsule which also measured gastric emptying is almost half had significantly delayed gastric emptying called gastroparesis. 71% delayed small bowel transit and 50% delayed colonic transit. And again hypermotility was not correlated with ethnicity, sex or the duration of treatment. This is the printout from the wireless motility pill in which you can see from changes in pH and pressure which part of the GI tract the pill is moving through. Okay, the next S is serious. What we have found putting all the data together is that overall it appears of a thousand people treated with clozapine, three to six hundred will complain of constipation and around four will develop life-threatening slow gut complications of which one will die. The mortality of serious complications is high at 27.5%. And we found mortality amongst anyone taking clozapine aged between 17 to 30. 73% and an additional anticholinergic load, so co-prescription of other anticholinergic agents increases the risk. There are three mechanisms where morbidity and mortality caused, sort of helps if you think of the GI tract and plumbing as terms as pipes which can get blocked. So you can have obstruction leading to distention, perforation or sepsis. You can have obstruction leading to kind of a GI traffic jam with the feces backing up causing vomiting and aspiration or fecal stasis leading to infection. This is an important slide because looking at the signs and symptoms that indicate someone's developing life-threatening slow gut, the most common is severe abdominal pain. So we've identified this as the number one red flag in our screening and treatment protocol, which we'll come to in a minute. So yes, severe abdominal pain lasting over an hour. Another question we had was given this was a serious and fairly common side effect, why wasn't it identified earlier? And it might be because CIGH splits the vote in terms of pharmacovigilance reporting in a way that other side effects like agranulocytosis doesn't. So different CIGH negative outcomes were reported in a variety of different ways. So you didn't get one skyscraper standing out. I'm not going to go through this, but I will if you're interested, I will refer this to you for reading after this presentation because it's just been published last year showing the same trends in a large UK data set and also has useful summaries about how to manage. So with Silent, we did a diagnostic accuracy study asking people about constipation and using the Rome criteria and comparing that to the objective bowel motility studies. So these were the methods and this is what we found. I'll skip through the diagnostic accuracy test, but what we found was that only about a quarter of our participants self-reported constipation and we were specifically asking them, but three quarters had CIGH on bowel motility testing. And what we wrote on this paper was that inquiring about constipation had a sensitivity of 18% for diagnosing CIGH, a grim performance for a diagnostic test, worse even than a toss of a coin. So what should we do? Management can be difficult in this population group because a variety of reasons including whether people are good historians, compliance, where they're cited at the time, the lack of medical expertise amongst mental health group staff. So this is what we recommend and this is for all people in your care, people who are on other antipsychotics aside from clozapine, but paying attention to GI function. Consider something like the Bristol stool chart and beware of the red flags. And particularly urgent medical review is required for anyone on clozapine or polypharmacy with moderate to severe abdominal pain lasting over an hour. Use the lowest clozapine dose and minimize anticholinergic load. And this is a recent paper which talks about clozapine dosing that is personalized with lower doses being required in people depending on their gender, smoking status and ethnicity. Don't get caught in the trap of lifestyle interventions. So in some of our review of pharmacovigilance, we saw cases in which clozapine-induced gastrointestinal hepatitis was being attributed to the person not drinking or having a poor diet. This is not the case. We saw from those excised bits of GI tract in the organ bath that if you add clozapine, it stops the gut working. And so adding more water or fibre is not going to work in and of itself to correct that. What we need to do is speed things up. So that's with a pharmacological treatment. What works? I've done a Cochrane systematic review looking at this topic, considering all published and unpublished trials on antipsychotic-related constipation. I've written quite a few boring things in my time, but this systematic review really is the most boring thing that I've ever written. It took me weeks to proofread it because I just kept losing focus in the end. So that you don't have to read it, and I don't recommend it, I have succinctly summarized the answer to the question in one word of what works, which laxative is best. We don't know. So simply put, there have been no good studies. There's no good evidence to guide us or our patients. And given how important the side effects spectrum is, that's a real shame. So my recommendations are a bit pragmatic and taken from other literature in, for example, opioid-induced constipation. So here a stimulant and stool softener are often recommended, although I'd have to say there is not good evidence to support the stool softener, but there is good evidence to support the stimulant laxative. Fibre is not recommended. The reason is that it can cause greater risk of bowel obstruction. There is good evidence for polyethylene glycol, known as PEG or Macrogol, and there are new agents becoming available which are not well tested yet in this population. So first-line treatment, what we use is Senna, two to four tablets daily, and we avoid bulk laxatives, and we liberally add Macrogol. So we use the Porirua protocol, and that basically entails giving all clozapine-treated patients Senna and changing the dose related to their symptoms. So for example, if they develop diarrhoea, we reduce it. If we're still concerned about bowel function, we add Macrogol sachets. Does this work? The answer is yes. We did pre- and post-treatment comparisons with the Porirua protocol, and when we used that, we found that in the original group, the pre-86% had gastrointestinal hypermortality, which was severe in 64%. And once we used the Porirua protocol, median transit time reduced to 62 hours, significant reduction of two days, and hypermortality dropped, severe hypermortality going down to 21%. But interestingly, there was no change in self-reported constipation or Rome 3 symptoms. So people didn't complain less or more. And the other probably most important thing is we found that the cases of serious CIGH in our service reduced significantly with a risk reduction of 0.13. So since Kate's death, I'm pleased to say that I've had no other patients subsequently die of CIGH. So we're coming to the end, but I just quickly want to alleviate some of the fears that you might have about Senna. So we use Senna medium to long term in our patients, starting with two at night. There have been historic fears about chronic use, but these are probably unsubstantiated. And if you want to read more about that, I've got a reference at the end. So don't worry too much about using this chronically. Some of the concerns about cathartic colon dependency and habituation have not been supported by contemporary data. This is also a reference document for you from the British Journal of Psychiatry paper, which has more about the recommendations. So just to wind up, we're going back to the learning objectives to make sure that we're focused on those again. So we've talked about the five S's of CIGH. We've talked about the signs and symptoms of a serious CIGH spectrum, and particularly the red flag of the moderate to severe abdominal pain lasting for over an hour. And we've talked about how best to manage and prevent constipation through assertive monitoring and supporting patients and their families and using a prophylactic laxative. This recommendation of the speed it up. Now, there's lots of new agents that are becoming available like linaclitage and lupiprostone. And we also need to keep an eye on the evidence coming out for their use within the clozapine treated group. So in summary, for every thousand patients treated with clozapine, 300 to 600 will suffer constipation and at least four will develop serious GI complications from which one will die if we are not assertive in treating this group. Iatrogenic mortality is much higher from GI complications than from a granulocytosis. Self-reported constipation has low sensitivity in predicting hypermotility. Prophylactic laxative treatment is recommended in all clozapine treated people. And what I like you to do is to speed things up by using prophylactic laxatives for all clozapine treated people. This may include Senna, Macrogol, or one of the newer agents. Here is the bibliography for reference and you'll find that in your slides. And I'm now going to welcome questions and discussion. Excellent. Thank you. As a reminder, any questions that you guys may have, please drop those in the question box. We are happy to answer those today. So thank you very much. This was a very thorough presentation. I think one of the things that's here in the chat box that's interesting is one of the participants has noted that during their training and career as a treating these patients with schizophrenia, that sometimes the insight into the mental illness can extend to some of the physical side effects of constipation. Could you speak at all to people's insight into the illness and understanding their ability to explain maybe the side effect and what that might be useful to help us with? Yeah, that is interesting and it's a great point, isn't it? That it is both sometimes to do with the positive and the negative symptoms that people don't report or report things in different ways than we might expect. So I've certainly had patients who've had delusional beliefs about bowel function or patients with negative symptoms who've seemed to struggle to articulate some of their physical experiences. I will share something that was interesting though and that I've worked with a consumer advisor, so a woman who developed schizophrenia in her early 30s. Prior to that, she was an oncology charge nurse who worked in oncology and had a ton of experience with managing constipation and had also experienced it herself in the past. She then experienced a very difficult illness in her 30s from which she got in the end good relief with clozapine. But she developed an ileus and she said that what was staggering was that she went for something like 20 days without passing a bowel motion and she felt nothing. She felt no discomfort. So she knew intellectually that this was a really significant problem and was able to speak out. But she said compared to other experiences of being constipated when she hadn't been on clozapine, it was a very, very different experience. And so that's interesting. We sometimes think that maybe it is the schizophrenia that's stopping people from articulating some of the symptoms that we expect them to, but maybe actually it's the clozapine, that reduction in intestinal sensitivity that people don't feel the same level of discomfort when they're on clozapine. So I think that's an interesting thing to be mindful of as well. Which is very timely for our second question. Do you use the Bristol and how often? And if constipation isn't always a complaint, what do you ask? Yeah, that's why I use the Bristol, I think, rather than the Rome criteria because we found that asking about constipation, I don't know, people didn't remember when their bowel motions were, they didn't experience this constipation. We just, like I said, we got that woeful kind of sensitivity. So yes, I really like the Bristol because it's pictorial and people who don't have good ability to articulate things, or maybe don't remember when their last bowel motion was, can still kind of point to where they think they were most likely to be. So that's the tool that I find most helpful. But I do take it with a bit of a grain of sand as well, in that I know that often people won't realise that they're constipated and so I am usually willing to prescribe Senna fairly generously unless people say it's causing them side effects and problems. Excellent. Thank you so much for taking the time. I know it is very early where you are, so we appreciate the time today. I want to make all the participants aware that I inadvertently skipped the SMI advisor app slide. So there is the SMI advisor app to access resources, education, upcoming webinars, complete mental health rating skills, submit questions directly to our SMI experts. So please interact with us on the app and as we'll continue to move through the slides, we'll skip to the consult slide. So if there are topics that were covered in this webinar that you would like more information on that we didn't get an opportunity to talk to our experts today, please post a question or comment on our roundtable discussions board. This is an easy way to network and share ideas with other clinicians who participated in this webinar. And if you have other questions about the webinar or other topics related to evidence-based care for SMI, you can get an answer within one business day from our team of national experts through the consult service. This service is available to all mental health clinicians, peer support specialists, administrators, and anyone else in the mental health field who works with individuals who have SMI. It's completely free and confidential service. So please utilize that. SMI advisor is just one of the many SAMHSA initiatives that are designed to help clinicians implement evidence-based care. We encourage you to explore the resources available through the Homeless and Housing Resource Center, the Center for Excellence for Behavioral Health Disparities and Aging, the Suicide Prevention Resource Center, the Peer Recovery Center of Excellence and Mental Health Technology Transfer Centers. And these initiatives cover a broad range of topics relevant to everyone's practice. To claim credit for participating in today's webinar, you'll need to meet the requisite attendance threshold for your profession. Verification of attendance may take up to five minutes. Then you'll be able to select next to advance and complete the program evaluation before claiming your credit. And please join us next week on March 3rd as Dr. Deborah Pinals presents Competence to Stand the Trial and Competence Restoration, The Basics. This is a free webinar on March 3rd from 12 to 1 p.m. Eastern time. And thank you everyone, especially Dr. Everey Palmer for joining us and presenting us with this webinar today. Until next time, everyone take care.

webinar

Dr. Susanna Everie Palmer

gastrointestinal side effects

antipsychotic medication

clozapine

constipation

complications

life-threatening

proactive monitoring

treating constipation