Clozapine - Beyond the Basics

Dr. O'Leary explores the history of clozapine, highlighting its initial revolutionary impact as the first atypical antipsychotic, followed by a ban on its use, followed by its re-emergences as a strictly monitored medication, and then culminating in new recommendations that greatly encourage its use. The discussion details the severe side effects that led to its initial discontinuation,  and then emphasizes other critical but often overlooked adverse effects, such as metabolic syndrome, sialorrhea, and especially severe gastrointestinal hypomotility, which can be life-threatening. 

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Welcome to Psychedactic. I'm Dr. O'Leary, a second year fellow in child and adolescent psychiatry in the National Capital Region. This is a podcast about neuroscience and psychiatry, and I do it in my free time to help me learn how to be a better psychiatrist. Today I want to talk about a medication that has a long history as being one of the most feared and one of the most effective medications that psychiatrists have ever used for the treatment of things like schizophrenia, suicide, aggression. The name of this medication is clozapine, also called closeryl. Clozapine was developed as what many people refer to as the first atypical or the first second generation antipsychotic. And it seemed to be revolutionary. It seemed to be more effective than the first generation antipsychotics, and it didn't have the same kinds of side effects that were feared at the time, which were mainly the extrapyramidal side effects. So these problems where patients would develop movement disorders, they would get very stiff, they would become agasthetic, which means they had a difficult time sitting still, felt like they constantly had to move. Because of things like this, clozapine seemed to be a great medication. It reduced the positive symptoms of schizophrenia, and it also seemed to help with the negative symptoms of schizophrenia. Also, clozapine did not result in or worsen catatonia, and it sometimes could even treat catatonia. It could also treat aggression. Later on, we'd find out that clozapine is actually effective at reducing suicidality in patients over time. But in the late 1970s, they discovered that clozepine can cause a side effect called agranulocytosis, where your body basically stops producing certain types of white blood cells called neutrophils. If your body's not producing neutrophils, you can get infections, especially bacterial infections, that your body can't fight off. And so quite often they are fatal. Of course, this is not what we want. This is very, very bad. So immediately they stopped using clozapine. It became illegal in the United States, and it wasn't until uh 1990, I think, in the US, that they decided we need to start using clozapine again. But we're going to monitor patients so that if they do develop this side effect, it won't be a big deal. We can stop the medication and we can make sure that they're in a place where they're unlikely to get very, very sick. They created a system to monitor this. It was called the REM system, and providers needed to be part of the system in order to prescribe clozapine. However, because clozapine was so difficult to prescribe, even though it remained the most effective antipsychotic medication out there, it was not prescribed very much. Also, we they noticed that the incidence of agranulocytosis was pretty low, especially if you were to slowly titrate the medication up. Within the first few months of giving the medication, and especially the first year, the risk is the highest. And after about two years of giving the medication, the risk of that is negligible. The same is true for other risks that clozepine has. It has risks for myocarditis and cardiomyopathies, which can kill you as well. And those risks, just like the risks of agranulocytosis, are the highest when you're first starting the medication and bringing it up. And over time, they reduce down to being negligible after a couple years. But because this system was in place, patients who could really benefit from this medication just weren't getting it. Another curious thing that was happening around this time, as clozapine was being studied more and was being proven in, for example, one of the most famous antipsychotic trials in history, the Katie trial, and phase two of that trial, patients were switched to clozapine from other second-generation antipsychotics, and they stayed on clozepine longer, and they were less likely to uh quit clozapine because it was ineffective than any of the other medications that they were on, which included olanzepine, raspiridone, and cityapine. But as patients began to stay on clozapine longer, we noticed other side effects that maybe we were kind of ignoring before because we were so scared of the agranulocytosis. So these side effects include metabolic syndromes. You're going to gain a lot of weight, you're going to have uh high blood fats, you may develop high blood sugar or even diabetes, and then other annoying side effects such as cyallurrhea, where you drool a lot, and probably the most overlooked and most dangerous side effect of clozapine, which is this gastrointestinal hypomotility syndrome that can result in something called an ileus, where your bowels just quit moving things forward. Stuff stacks up, builds up inside your belly, and you can have a perforated bowel and die. The incidence of the hypomotility and chronic constipation is very high. Probably about a third of patients who take clozepine have a lot of difficulty with constipation, which can result over time in an ileus which can kill them. So that is potentially, over the lifespan of the medication, far more of an issue than agranulocytosis or cardiomyopathies. But I don't remember learning about that at all in medical school. And it was just one of our prescribers when I was in residency who wanted to make that point a lot. Of course, a lot of people didn't have experience giving clozepine. Now, clozepine is recommended by some societies as being the third choice. If you fail one uh antipsychotic, especially a second-generation antipsychotic, you try another one. If you fail that one, you start clozapine. There are also practitioners out there that say, well, if you fail one second generation antipsychotic, the chance of you actually doing well on another one is very low, so you should just go straight to clozapine. These are reasonable things to do. But you need to know what you're doing when you go to clozepine and what some of the problems can be. There are some generally accepted consensus guidelines for how to initiate clozapine. So for the first one to 18 weeks, you need to monitor people's absolute neutrophil counts because this is the highest risk period. You may also be drawing troponins to see if the heart is struggling at all. After week 19, you can reduce from drawing weekly labs to drawing monthly labs, and do this until about year two. And after year two, you only really have to draw labs if someone is symptomatic or as part of just regular annual screening. Currently, what is considered a low absolute neutrophil count is anything less than a thousand cells per microliter, and this is where you might consider stopping clozapine in the general population of people being treated. If you're going up on it and the absolute neutrophil counts drop below 1,000 cells, it's time to stop. But if you have a condition called benign ethnic neutropenia, and I've seen this in some patients, and it's common in individuals with African, Middle Eastern, and West Indian descent, they just have lower baseline absolute neutrophil counts than other people. And sometimes they'll drop below one just naturally. One, I mean a thousand cells per microliter just naturally. So the recommended threshold for them is less than 500 cells per micro. And this is intended to prevent unnecessary discontinuation of a medication that is likely to be the most effective medication this person has ever taken. So for absolute neutrophil counts at baseline, you need to know what it is before you start the medication. So you draw it. They may have benign ethnic neutropenia. If that's the case, you know not to freak out until it gets below 500 cells. If they don't, you're looking at 1,000 cells. Also, before you start clozapine, you need to get a full metabolic panel. This means you need to know their baseline weight and their body mass index. You need to know their baseline blood pressures, their glucose level, which would be an uh HBA1C, and their baseline lipids, because clozapine is going to affect all of those things. When you get that, after you start clozapine, you do regular monitoring. And the exact frequency of this might change. If anyone who's taking clozepine is complaining of being lightheaded or a little bit dizzy, you also want to get postural blood pressures. So you want to get it when they're laying down, and then when they're sitting up, and then when they're standing up, to see if their body is able to quickly adapt, or if they're going to have orthostatic hypotension because of being on clozepine. Because clozapine can have so many metabolic side effects, and so can other second-generation antipsychotics like olanzpine and catiapine, which were developed to be like clozepine without agranulocytosis, but they were never quite as effective. But they were just as bad as causing all of these metabolic problems. You may consider starting metformin after starting clozapine, very soon after starting clozapine, in order to help prevent some of these metabolic issues, reduce the amount of weight that they gain, lower their average blood sugars and lipids over time. Now, another way to do this would be to initiate uh GLP1 receptor agonists, and this should be strongly considered as a primary preventative, especially in someone who has high risk of metabolic issues. For example, at baseline, they already have some metabolic issues, and then you're going to be starting a medication that's going to definitely worsen those. So consider GLP1 receptor agonists. I am going to mention a few other things. One is that you definitely need to know their smoking status because smoking can induce the cytochrome P4501A2 enzymes. So the CIP1A2 enzyme is a primary pathway for clozepine metabolism. So the more they smoke, the more that enzyme is induced, the lower their average clozapine levels are going to be in their blood. So if they're going to reduce their smoking, you need to know this because you may need to reduce their clozapine levels as they're reducing their smoking. Also, caffeine. It's a competitive inhibitor of CYP1A2, and so it can do the opposite of what smoking does. It might increase levels of clozepine in the blood. So if someone is taking clozepine and you know that they are drinking significant amounts of caffeine, for example, more than 400 milligrams a day, which is easy to get with these energy drinks. I mean, if you're drinking something like a Celsius, it has 200 milligrams of caffeine in just one drink. So screen for caffeine use and know that it might increase clozepine levels in the blood. This is true for any other medication that you might be giving. For example, fluvoxamine or luvox can also inhibit CYP182. So it could drastically increase the levels of clozepine in the blood by five to even ten times. So you need to know this. And if you are using these strategies because you have to, like they really need this other medication, it's going to interact with CYP182, then you could draw levels of clozapine and try to figure out exactly what's happening to them. It might require a significant dose decrease to avoid worsening of side effects. Now let me go into more specifics about what clozapine is probably going to do to your patient that you don't necessarily want. So some of the side effects, especially when you're first starting the medication, and many of these can persist. For example, like constipation, in at least probably a third of patients, they're going to have significant constipation when they're on this medication. And it might even be as high as two-thirds. So definitely look for constipation. And when you're treating constipation in these patients, the one thing you definitely want to avoid giving them is any stool bulking agent like fiber. The problem with them is that they are not transiting stool quickly through their intestines, and it's just building up. So there's this hypomobility syndrome that is induced by clozpine and at its worst can become an ileus, like I said before, and you can have bowel perforations, and this can kill your patient. I was just reviewing the chart of a patient who is supposed to come to me for an initial visit and noticed that they have been in the emergency room twice in the last six months for belly pain. They got x-rays that showed severe constipation, and they are on clozapine. Another annoying side effect is cyallurea or hypersalivation. And this happens especially at night, so it can it can be difficult for them to sleep, and it occurs in like most patients. Some studies have reported like 90% of patients are going to have this problem. And it is definitely a quality of life issue and can be a risk factor for aspiration pneumonia. So if it may be that they're not able to lay on their back at night anymore when they're sleeping, they might have to sit up or they might be sensitive about going into public now because they're drooling all over themselves and they have to carry around a rag. Another thing that is very common in clozapine is sedation and fatigue. So they just feel tired or they easily fatigue. And this is often worse when they're starting treatment or if you increase the dose. And it's probably a consequence of clozepine's really potent antagonism of the histamine receptors. So it is an antihistamine, a strong one, and also a strong alpha-1 adrenergic antagonist, which means that it's probably lowering your blood pressure, which can make your heart have to beat faster in order to keep up, which can make you tire out quicker. So tachycardia is one of the things that is found, especially when first starting the medication, where the vast majority of patients have significant increases in their baseline heart rate. And this might be due to compensation for the medication's direct effects on your blood pressure. Now, for my psychiatrists in the audience, I want to get a little bit more into depth on some of this gut hypomotility and exactly why clozapene causes that. The first and most obvious thing is that it's highly anti-cholinergic. So this we know slows down transit in the gut because it is an antagonist of peripheral muscarinic M3 receptors that are located in the gut wall. Blocking these receptors inhibits peristalsis and leads to, in severe form, an ileus or paralysis of your gut. Clozepine itself is metabolized into norclozepine. And norclozepine is a potent agonist at the delta-opioid receptors in the gut. So it, similarly to how opioids cause constipation, will itself cause constipation. So clozepine hits the gut like over and over and over again with anticholinergic activity, and then one of its metabolites will have opioid receptor activity in the gut. So all those things contributing to constipation is what makes clozapine such a huge problem for people who take it. So because this is such a huge issue, and most patients, maybe two-thirds or even more patients on clozapine are going to experience something like this, even if it's in a milder form, it's reasonable to just go ahead and start something like docucate, which is the stool softener, as soon as you start clozapine, and this could help the weaker peristalsis to actually push things forward. Another thing that might start is just regular use of an osmotic laxative like PEG, polyethylene glycol. Peg is going to increase the amount of water that remains in the colon and soften the stool that way. But you also might give stimulant laxatives like Sena at bedtime, along with a stool softener. So you wouldn't want to give a stimulant laxative if they have a very hard stool that's not going anywhere in there. That could just cause them lots of discomfort. But if they have been on a stool softener and it's not enough, you can add on a stimulant laxative. The one thing you should never do, and I've mentioned this already earlier, but I want to mention it again just so that you avoid this. Don't take bulk-forming laxatives. So don't take cillium, metamusil. All that's going to do is add more stuff to the stuff that's already there. It's not going to cause the gut to push things out faster. And this will increase the risk of further obstruction, fecal impaction, and death of your colon. So just don't do it. Don't give bulk forming agents to people on clozapine. Another thing you can do is just minimize all the extra things. I mean, clozapine's already hitting the gut three different ways, so you could potentially not hit the gut even more. Like, don't give things like anticholinergic medications. So benstropine, don't give benstropine. It's common to give when people are getting other antipsychotics, despite the fact that the evidence for it is not that great, but that can worsen all of that. So when you're giving clozepine, don't give benstropine, or benidryl, or like ciproheptidine, or hydroxazine, or promethazine, just to avoid all of these antihistamines, especially the first generation antihistamines. Also, you want to avoid using tricyclic antidepressants if you're trying to augment for, say, depressive symptoms or anxiety. So don't give things like ametryptyline, immipromine, or clomipramine. A lot of people who have psychotic illnesses also have OCD-like symptoms, so avoid giving those medications. And if they have OCD-like symptoms, don't give luvox. Don't give anything that inhibits CYP1A2 because you're increasing the anticholinergic burden. You probably also want to avoid things like bladder antispasmodics. So if they're having some urinary incontinence for some reason, look for other ways to treat it besides giving like oxybutanin or trospium. You also want to avoid giving certain other antipsychotics as PRN medications, so as needed medications for if, say, they get a little bit more agitated while they're on clozepine. Things like chlorpromazine or olanzepine, especially at higher doses, or even cotyapine. So avoid those. And any gastrointestinal anti-spasmodics, don't give a modium AD, don't give dicyclamine. Anything that's going to make the gut less modal is going to make this worse. I'm going to wrap things up today. I really tried in this episode to go over some of the things that I see as a big problem and reinforce them over and over again because I did not learn about these things very extensively in my training. And I'm hoping that I can augment other people's training by focusing not on the things you're probably going to learn about Clause Bean already, but on the things that you're not going to learn about Clause Bean and you really need to know. The RIMS program is now gone. So providers get to decide what to do. And there are some recommendations out there that you can follow. I also behoove you to go back and read them yourselves. Some of the various groups, international recommendations versus recommendations from American groups, maybe a little bit different. Just know what you're doing and why. Adopt a kind of evidence-based system for yourself and your clinic. In the end, everything you do is going to need to be personalized based on your patient. What was their baseline status before they even started clozapine? What is it that they can do? Why are you giving the clozapine? Are they able to manage things for themselves? Is it reasonable to expect them to increase their level of activity? Who do I need to talk to about this? Do I need to talk to their caregivers or are they competent themselves in order to do this? And if they are, how can we maximize their chances of success and their chances of being adherent to the medication? So, really, there needs to be a very personalized and holistic approach to the patient. You need to know about their life, you need to know about what it is that they can and can't do, you need to know about all of their social supports in order to be successful when giving a medication like clozepine. Because if you're giving clozepine, you're probably giving it because they are either psychotic, they might be catatonic, or they might be very aggressive, or chronically suicidal. So these are big things. You need to learn as much about your patient as you can before starting the clozapine so that you can have the greatest chance of being successful. Thank you for letting me get up on my soapbox today. I'm Dr. O'Leary, and this has been an episode of Psidactic.