So unfortunately, Dr. Fu couldn't join us today, but we still want to be doing a podcast. So today we're going to be trying to make clozapine a little bit more buzzworthy by making it a top 10 list. So we're going to be doing the top 10 things you need to know to be prescribing clozapine. And we have someone new today. And what is your name?
My name is Roxanne. accent you told me i could be whoever i wanted today you don't have to do the psycho farm podcast that's not what you said he actually just picked me up up off the street today and asked me to answer these questions i basically have no
credentials or background oh no you have some credentials actually uh A lot of people who work for Carlat are married to NPs or social workers. A friend was joking with me that he tells his students to stay away from those Carlat fellas. All right. So today we're talking about clozapine. And relatively recently, the FDA got rid of the REMS requirement. I'm sure you were celebrating greatly.
Huge party. I'm still very hungover. Yeah.
So it's actually, it is a pretty big deal. So the REMS requirement made it so that you had to input the neutrophil count, the ANC count. It was a little burdensome. It wasn't too terrible. But the thing was that that was annoying is if you didn't put it in, then the patients had a really tough time getting their medications. So it was a pain in the butt and the FDA removed the requirements.
Now, of course, that doesn't mean... that people don't still get severe neutropenia. So we still have to do ANC monitoring, but you no longer have to report it to a central registry. So I imagine your life is much better because of that.
Well, my life hasn't really changed much because I don't prescribe much clozabine, to be honest. But I will say I used to work in an emergency room and we had... very frequent patients that would come in not able to get their dose because their prescriber forgot to put their ANC into REMS. And so they'd end up in the emergency room just for that reason. So maybe it'll help with that.
And at the same time, it was a little concerning that maybe people would stop the necessary blood work, but hopefully people will still do what they need to do.
I really hope that people don't stop monitoring because there's a lot of providers who don't do the appropriate monitoring. Before we get to the top 10 lists, let's first discuss the mechanism of clozapine. The mechanism is a little bit special. So we know that for basically all the first and second-gen antipsychotics, it's dopamine antagonism that's kind of the big dog that's driving the antipsychotic mechanism. But clozapine is a little bit different.
And we know that because whereas all the other antipsychotics block at least 60% of the D2 receptor in order to work, clozapine still works when it's only blocking like 30% to 40%. So we know that something else is involved with regards to as to why it works as an antipsychotic. There's a bunch of different theories as to what it could be. Some say it has to do with the glutamate modulation.
Some say it might have to do with muscarinic agonism. Others say it has to do with TAR1, which I haven't read about since med school. But it might be all these different things kind of combined. But the antipsychotic part is doing some little special magic thing that we don't really know what it is that separates it from the other antipsychotics. Now, it does hit other receptors. Do you know about the ham receptors?
Just from your videos, they do.
Yeah, I guess it's not actually a thing. It's more of a thing that I made up. So I call it ham receptors. So histamine H, alpha-1A, and muscarinic M. So the ham receptors... And a lot of the second-gen antipsychotics block these receptors. And they're pesky receptors. So I like to call them the pesky ham receptors. That's because it causes a lot of sedation from the epistamine. It causes a lot of orthostatic hypotension from the alpha-1.
And then the muscarinic antagonism causes you to dry up all over the place. And there's a particularly bad thing it does with clozapine. Do you know what I'm going to say with regards to the muscarinic antagonism?
I have some guesses, but I'm not sure.
So it's constipation. And while we get into that, it's one of the things that we'll be talking about. But those are the other receptors that are those pesky ham receptors. All right. So now are we ready for our top 10 things you need to know before prescribing clozapine?
Top 10 things. Let's get into it.
So the number one thing is its effectiveness in treatment-resistant schizophrenia. So when nothing else works in schizophrenia, for reasons that only God knows why, clozapine works. So now do you know the definition of treatment-resistant schizophrenia? I apologize. I keep pimping you on here.
I think I'm supposed to be asking you questions. Isn't that what I signed up for here?
I know. I'm sorry. I'm sorry.
All right. I'm just going to guess. Two failed treatments.
So you nailed it. It's two failed antipsychotic treatments for an adequate time, and typically that's about six weeks. And then the antipsychotic needs to be at an adequate dose. And there we're talking about 600 thorazine equivalents. That's the chlorpromazine. So the exact definition has changed over time. So sometimes it used to be considered one of those trials had to include Haldol. So it had to include a first-gen antipsychotic.
But for now, the definition is basically someone who's failed two previous antipsychotics at an adequate dose, and they took the medication for an adequate amount of time.
Okay. That's a big chunk of people.
So one thing that's super important that I feel like a lot of people kind of pass up on. So when we're talking about treatment resistant schizophrenia, it doesn't count as a trial if someone just doesn't take the medication. So I would see this all the time in the hospital. We would call it, someone would call it treatment resistant schizophrenia because the patient kept coming back to the hospital and then they like quote unquote failed an antipsychotic.
But the truth is the antipsychotic worked. The patient just stopped taking it. So that shouldn't be included in the patients that were considering treatment resistant. Right.
That makes sense.
And the reason why you don't want to include them in treatment-resistant schizophrenia is because clozapine has a lot of side effects. So it does, even though it's a great antipsychotic, it does cause a lot of problems. So it's an awesome drug that's magical with regards to schizophrenia, but there are a lot of problems that comes with it.
And maybe we're going to be getting to this, but I guess is the main problem the severe neutropenia risk? Is that the reason why you have to fail two other antipsychotics, which obviously all have their own problems?
So that's only just like one aspect of it. And that's what the REMS monitoring really was for, was for the neutropenia risk. But there's a bunch of other problems that are just as bad as severe neutropenia. So more patients actually die each year from the constipation issues than they do from the severe neutropenia.
Yeah, I was wondering about the cardiac risk too because I know that's a major implication here.
So that's going to be one of our top 10 things.
All right, I couldn't help myself. I haven't been able to sleep wondering about the cardiac risk here.
All right, so how good is clozapine? So when we're talking about treatment-resistant schizophrenia, it works about 60% of the time. And that's even more impressive when you consider how ineffective other antipsychotics are at that point. So other drugs work about 5% of the time. Even olanzapine, which is like our second best antipsychotic, it only works about 7% of the time. So it's not like we're comparing it to some other crummy drugs, like we're comparing it to the next best antipsychotics.
In addition to its effectiveness in that population, it also reduces suicide attempts more effectively. It lowers hospitalization rates, and there's less need for antidepressants compared to if you were to use olanzapine. So even if we're comparing it to the second best drug, it's really crushing it compared to all those important metrics. So that's the number one thing in terms of the top 10 things you need to know is how effective it is in treatment-resistant schizophrenia and how useful it is.
But make sure you save it for treatment-resistant schizophrenia because you don't want to get too loosey-goosey. And we're going to be talking about the reasons why that is. Now, there are a bunch of guidelines that say you should be prescribing it earlier than after two failed trials, but you do need to be wary of the problems that the clozapine costs.
Okay, thanks.
All right, are we ready for number two?
Number two.
So number two is the unique benefits for clozapine. So clozapine has a bunch of other things that make it a special drug. So first is its suicide reduction in schizophrenia. So it's one of the few meds that we know that reduces suicide. And that's for the schizophrenic population. Do you know the other med that famously reduces suicide risk?
Lithium.
You got it. So that's... Lithium reduces suicide risk in bipolar. And I also think it just reduces suicide risk generally. Clozapine is the only med that gets the FDA nod for suicidal reduction in schizophrenia. It also has... a little special benefit in violence reduction. So it reduced violence in randomized trials of violent schizophrenic patients, including those with comorbid cocaine use. And then this isn't an FDA thing, but it also reduces criminal behavior.
It's also got a special nod for psychogenic polydipsia.
Interesting.
It's a fun little one. So schizophrenia with persistent aggression, which is related to the fact that it helps with violence, it's independent of its antipsychotic defect. So it's not just that you're treating the psychosis and then the aggression goes away. One of those little magical things that it does, you know, maybe the glutamate, tar, or muscarinic agonist weird mechanisms is responsible for that. It also works in treatment-resistant mixed bipolar states.
So the other thing it does really well with regards to schizophrenia is it's helpful for negative and cognitive symptoms. So most of the other antipsychotics cause problems with regards to the fact they worsen negative symptoms, something that we call neurolepsis. So clozapine actually helps in that regard. So it's one of the few antipsychotics, maybe the only antipsychotics. I feel like some of the new partial agonists are claiming that they help with negative symptoms.
But I still really consider clozapine in a class of its own with regards to the negative and the cognitive symptoms and schizophrenia.
Yeah, and that's like really huge for quality of life.
Yeah, and that's the thing is we think of schizophrenia as only the positive symptoms and that we just treat the psychosis. But we forget that schizophrenia is a syndrome that comes with positive symptoms, negative symptoms, and cognitive symptoms. So when you're treating schizophrenic patients, you're not just stopping hallucinations and then saying your job's done. You're treating the illness with clozapine.
It's always really shocking to me how the people that do get on clozapine tend to stay on it and how adherent they basically are with their treatment. They go for the blood work, they go to all these appointments, they go to groups, and not everybody, but there's a large population that does this. And so for lack of a better word, they're kind of great patients.
Yeah, and there's studies showing that patients subjectively really like clozapine. And we think of it as this messy drug with all these problems, but patients are reporting that they really like it. And I remember in residency, when I got my caseload, I had a bunch of clozapine patients, and I was worried going in, just thinking I was going to have these super sick patients. And they were by far my favorite patients.
I loved my clozapine patients.
Yeah, and I guess they're sort of selected for by means of like needing to be able to do all this stuff. At the same time, I wonder if the cognitive dulling impact could also help, you know, just like doing some of those basic things that people need to do.
Absolutely. And you mentioned like it can be helpful to get out of your house and go to those appointments. So I do very much so miss my clozapine patients. Hopefully we can go into some of those fun stories of clozapine patients. Are we ready for our next number three, I think, for our top 10?
Number three, let's do it.
So number three is neutropenia monitoring. So we know that clozapine can cause agranulocytosis, and it's some weird autoimmune process related to the neutrophils. And so what the REMS was monitoring for was severe neutropenia, which is the same thing as agranulocytosis. So the risk of getting it really, the earlier you're taking the medication, the higher the risk. So it peaks within the first six months, especially the first 18 weeks.
And then after one year, the risk is very, very low. So I think the risk after one year drops to less than 1%. And after two years, it's like six per 10,000 or something super duper low. So now it's probably even more important to remember the monitoring because we don't have the REMS to help us out and tell us every single time since we're not inputting it.
I have a very simple way that I remember it. So the first half of the year, you do it weekly. Then the second half of the year, you do it every two weeks. And then after one year, you do it monthly. So to say that again, first half of the year weekly, second half of the year biweekly, then at the end of one year, you do it monthly.
And what you're really getting there is, so you're getting the CBC, that's the blood test that you're ordering, and you're checking the absolute neutrophil count, the ANC. Now, in regards to the numbers that you're looking for, you're trying to make sure that it's greater than 1,500 per microliter. Sometimes the number it spits it out, you actually have to multiply it by 1,000 because I remember my lab would just spit out like
5, so it would be like 3,500.
Yeah, you type it into REMS and they tell you you've got a big problem and then you...
Yeah, exactly. Like everyone, when you're first a resident, your first time, you're like, oh, 5. And it's like, that's an emergency.
Like, uh-oh.
So yeah, if you have a number that's super duper tiny, take a look at what the lab should say. Chances are you're supposed to multiply it by 1,000 or you should probably stop the closet beam.
Actually, before we move on, I was just kind of remembering something similar to Lamictal. There's like a period of time where if people miss their dose for a few days or a week or whatever, then you have to kind of start everything over. You have to start monitoring back at the beginning and a low dose and all that. What was the deal with that?
Oh, yeah, that's actually a really important safety detail. So if a patient misses more than 48 hours of clozapine, you have to restart the titration from the beginning. And technically, it's a little different for each medication because the risks for re-titrating medication are different depending on the med. So for clozapine, you're worried about the early risks of starting the medication. So there you think about orthostatic hypotension.
So if you went from like zero to... a fully titrated dose, the patient has a super high risk of orthostatic hypotension. And then the other early risks like seizures and myocarditis, which can jump back if you jump back to a high dose. The ANC monitoring schedule doesn't reset. It continues based on how long they've been on the drug. But the dose titration does reset. So the rule of thumb, if they go back, if they miss two days of medications, you go back to
5 milligrams and you titrate them out. You could probably go a lot more quicker than you did the first time because you know they can tolerate it. But yeah, you need to restart after 48 hours.
Okay. So totally different than like with Lomecdell where you're worried about Steven Johnson's. This is actually for orthostatic hypotension.
Yeah, and it's a relatively short period of time, like two days.
Yeah, it's a really short time.
Yeah. So let's jump back to the ANC in regards to what you're supposed to do with the actual numbers. So when you're looking at the absolute neutrophil count, it's based on how severe the neutropenia is. So it's considered mild if the count is 1,000 to 1,500. It's moderate if it's 500 to 1,000. And then severe is less than 500. So just to repeat that, it's less than 500 severe, 500,000.
to 1,000 moderate, 1,000 to 1,500 mild. So if it's 1,000 to 1,500, you want to monitor the ANC three times per week until it's greater than 1,500. And then you can just return to whatever your previous monitoring schedule was. Wow. If it's moderate, so 500 to 1,000, then you stop the clozapine and you monitor the ANC daily until it's greater than 1,000, at which point you can restart the clozapine.
And then you do the monitoring three times weekly until it's greater than 1,500. And then you do it weekly for four weeks. And then you can return to the previous monitoring. I know that's a little confusing. But essentially, if you're there, you should be looking it up. If it's severe, you stop the clozapine and you discontinue it until the ANC is greater than 1,000. And then you check it three times per week until it's greater than 1,500.
At that point, you should probably be getting a heme consult and really start to be worrying about the patient and consider bringing them to the hospital.
Yeah. Yeah, I remember there's like certain populations out there that can get by with a lower level of neutrophils.
Exactly. So it has something to do with some sort of blood protective thing for malaria. And then there's a way that I remember it. I don't I'm not sure if it's racist.
Oh, God, if you have to ask, let's not do it.
I don't think it's – it has to do with Uncle Ben's rice. And I know that Aunt Jemima got canceled. But I don't – did Uncle Ben get canceled?
Oh, what about him?
Well, Uncle Ben, benign ethnic neutropenia, helps me to remember that it's found in African, Middle Eastern, and South Asian populations. It's a mnemonic technique. I think it's passable. 25% to 50% of those patients have African descent. So the rice helps me remember the benign ethnic neutropenia population. I think it's a reasonable technique. I don't know.
Okay. I would think that the word ethnic in the actual term would suffice. But if you need it, you need it.
Well, you know, that is a broad term. We all have different ways of remembering things. So the gist of benign ethnic neutropenia, essentially their ANC is going to be lower and still be functional. So it's not a problem as much for them. So the cutoff kind of bumps down. into the by 500 total so the the cutoff is not until the thousand so the thousand to 1500 that which would be mild in the normal group that we don't really worry about them in the benign ethnic neutropenia group So whenever you have a patient that's African, Middle Eastern or South Asian, you can consider using different monitoring schedules.
There is a particular test you can do to see if they have benign ethnic neutropenia. But some doctors think that if you just kind of have proof that they have a naturally low ANC and they're in that ethnic population that you can just assume on clinical grounds that they have it.
So you don't actually have to do the testing?
That's what some doctors think is that like if you see consistently low ANCs and they're in that population, then you can just kind of assume.
A baseline before they start the medication, they have a low ANC and that sort of suffices in their opinion.
Yeah, if they're one of the appropriate ethnicities. All right. Are we ready for number four?
We're ready for number four. Let's do it.
All right, so number four is constipation risk and management. Very hot topic. Now, I feel like in med school, I would memorize things that were like totally independent facts. And then once you're actually practicing, it sort of clicks that they're connected things. So the constipation... the ileus, the small bowel risk, those are all the same thing, just kind of progression of the worsening constipation and having sequelae.
So you don't have to memorize them as a bunch of different things. You just have to think of like, if someone gets constipated, they're going to be at risk of perforating or they're at risk of a small bowel obstruction that causes you problems there. So the gist is the medication is so constipating that people... Don't go to the bathroom and they get ileus. And then that keeps backing up and it causes an obstruction.
And the cause, the reason why it's so constipating is because it's anti-muscarinic. So it's super common for clozapine patients to be constipated. That by itself isn't terribly scary because it's like 60% of patients get pretty bad constipation. Ileus, which is a medical emergency, is less common, but it's still pretty common. So there we're talking about like 1% to 3%. So clozapine slows colonic transit. Do you know what a colonic transit time is?
Is that similar to Pacific Standard Time?
It's a little different than Pacific Standard Time. It's the amount of time that when you eat food and then it comes out the other end. So a normal time for a person is 24 hours. You could feel free to run the experiments yourself. but if you take clozapine it slows things down to 110 hours which is pretty significant so your patient's going to get constipated and you should have a protocol ready for the patient so whenever you start someone on clozapine you should be giving them a bowel regimen now the medication that is recommended to start is docusate typically 250 250 milligrams po daily or bid now i don't do you ever remember did you ever put docusate in into like submit it into the hospital
Yeah, I remember we would get an alert.
Yeah, that alert. It would always say like, do not prescribe docusate. The hospital's frowns upon it. So there's some weird thing that medical doctors think you should never be getting it. And for some reason with clozapine, it's recommended first line. So docusate should pretty much be started on every single patient that you start clozapine. Some guidelines suggest starting with an osmotic laxative like polyethylene glycol, which is Miralax.
and then adding a stimulant laxative if needed. But in practice, you see a lot of people still give docusate by default with clozapine. Now, just because they get it, they might still be constipated. It's not a guarantee it'll work. So if they're still constipated with the docusate, then you need to add an osmotic laxative. So there we're thinking the polyethylene glycol, Miralax. If they're still constipated and you've maxed both of those things out, you add a stimulant laxative.
So there you're thinking like senna or bisacodyl. And if they're still constipated, then you can use some of the newer agents. So lubopristone, which apparently works pretty well. But the gist is that constipation is a real thing with clozapine. So you really need to ask all your patients about their bowel movements.
Thank you for bringing this up because back when I was a nurse, I really vividly remember like before I even knew anything about psych medications or decided to go into psych, I was just kind of brand new on a psych unit. They told me to ask every clozapine patient, when was their last bowel movement? And every time they were discharged, I just wondered, who's going to ask this person about their bowel movements every day?
Who's going to be at home with them? How are they going to get by without someone asking them when their last bowel movement was?
Yeah, there's not going to be that person asking them every single day. But the point is, it's super important. So, you know, it makes me very happy to hear that the nurses were checking. Yeah. I hope all of our doctors here are checking. So in terms of why this is important, as I mentioned, there's deaths from bowel obstructions. And there's more deaths in the bowel obstruction than there is from neutropenia.
So the whole REM infrastructure was built out to protect patients from neutropenia. But the bowel obstruction is a real thing. So... Ask your patients about their bowel movements because Roxanne can't do it for you.
Roxanne's off duty. I'm sorry.
And start them on a bowel regimen and follow the necessary steps to make sure they're moving.
All right, number four was kind of shitty. Can we just move on to number five?
Oh, that's a good one. All right, so number five. Yeah, it's fine. Number five, we're going to be talking about the cardiac risks, the ones that you were mentioning earlier. So again, it sounds like it's a ton of different things, all the different cardiac risks, but there's only a few different ones, and it's all a similar thing. So there's the acute myocarditis. And then there's potential long-term cardiomyopathy.
And then there's also tachycardia. Maybe it is a little bit more confusing for non-medical people. But it's the myocarditis and the tachycardia that actually leads the cardiomyopathy. So that's the long-term thing. Is that a little confusing? It's very confusing. Okay, maybe it'd be helpful to go through the different words and to help make sense of it. Acute myocarditis. So myo is muscle. Itis is inflammation. So acutely someone can get inflammation of their heart.
Cardiomyopathy. Again, myo is muscle. Pathy is there's problems with the musculature. So... I think it's dilated cardiomyopathy. So basically it just becomes like very floppy. And that's a result of the fact that the person's heart is racing and overworking for a prolonged period of time that the heart muscle itself becomes problematic. So cardiomyopathy is a long-term thing. And then the acute myocarditis is a short-term thing that's just an acute inflammation of the heart muscle.
Okay, so what are some of the warning signs? I'm just trying to think back to my nursing days of the stuff that we would like be checking out for.
The two big things you're looking for are the flu-like symptoms and cardiac symptoms. So if you see any sort of fever, fever is often the first sign, also along with like things like fatigue, muscle ache, and then they also have cardiac symptoms. So tachycardia, chest pain, shortness of breath. Now, one thing to make things a little bit more confusing, there is tachycardia that's not the result of myocarditis, but we'll get there in a second.
So for the acute myocarditis, it's a pretty significant risk. It's like 1% to 3%. It usually occurs within the first six weeks, so 90% of the time it occurs in the first month. So long term, you're not too worried about these patients. But when you first start the medication, you really want to keep a close eye and be asking specifically for any sort of fever or chest symptoms.
As I mentioned, the big signs that you're worrying about are fever, cardiac symptoms, signs of like evolving CHF. If at any point you suspect there's myocarditis, you should be checking troponin and CRP. And there's actually something called the Ronaldson protocol. So you should be getting a troponin, a CRP. Those are the main things. And then EKG. So if a troponin is greater than two times the upper limit or the CRP is greater than 100, those are big red flags.
If the troponin is abnormal, that's a sign of myocardial injury. And you really need to stop the clozapine. And at that point, you really need to be sending them to the emergency room. Now, as I was mentioning, the acute myocarditis is a short-term risk. If it persists, it can lead to the dilated cardiomyopathy. On top of that, and separate from these two things, is that the tachycardia, so elevated heart rate, is fairly common with clozapine.
It occurs 20% of the time. And that tachycardia increases the long-term risk of dilated cardiomyopathy as well. So if you're able to, it's much nicer to have the PCP help you manage it. And you can talk to your PCP if you suspect that clozapine is causing tachycardia. It's not unreasonable to treat tachycardia. So there you would just be using beta blockers, like the one that they use the most is atenolol.
I think it's because it doesn't cross the blood brain barrier. So it doesn't cause any sort of psychological mental slowing. There it's pretty common to use atenolol 5 milligrams. And your goal is just to get the heart rate to less than 100. All right.
That was a lot.
Yeah, that was a fun one. Are we ready for the next one?
I think so.
All right. Hopefully the next one's a little bit more straightforward. The next one, not quite sure. I think we're at number six is seizures. So with clozapine, there's an increased seizure risk because it lowers the seizure threshold. And the risk is higher than for the other antipsychotics. And the biggest risk factor is how quickly you titrate the clozapine. So the faster you titrate it, the higher the risk there is of dropping the seizure threshold.
The risk is dose-dependent, so less than 300 milligrams. It's a pretty tiny risk, like 1%. 300 to 600 milligrams, 7%. Greater than 600 milligrams, 4%. So it's very clearly dose-related. Now, you would never get like a routine EEG or something like that for someone on clozapine. Clozapine itself actually causes EEG abnormalities. So you wouldn't just grab an EEG just because you're just suspecting randomly that it's going to occur.
But there is one thing. Myoclonic jerks are a warning sign before they get a seizure. So... Another thing is you don't necessarily have to stop the clozapine just because the patient gets a seizure. So typically Depakote is what's going to be used to treat it. But again, you wouldn't use Depakote before confirming they have a seizure because the two medications actually don't play that well together.
Okay, so we're not really getting routine EEGs and we're not starting Depakote prophylactically. We're really just waiting until something happens essentially. Okay.
Exactly. All right, moving on to our number seven. Number seven is weight gain and metabolic risks. So clozapine and olanzapine are probably the two worst drugs we have in regards to metabolic risk in terms of weight gain. It's more significant in non-white patients. It's very reasonable to start metformin from day one. So if you do start metformin, just a little bit of advice, because a lot of psychiatric providers aren't commonly prescribing these things, Don't titrate the metformin too fast.
So it does cause a lot of DGI distress. So start low. Typically the dose is the same as if they had diabetes. The metformin is really just helping to mitigate the metabolic side effects. Pretty soon be reading more about using GLP-1s and hopefully they become more part of psychiatric purview is using those medications.
I think it's going to change a lot about how we practice.
Absolutely. Now, one thing that's worth knowing is not everyone gains a lot of weight on these medications. Actually, like the vast majority of my clozapine panel were these like rail thin, super thin guys.
Really?
Yeah. So it's not like just absolutely everyone gains weight. It's important to be aware of it. It's important to monitor it. But for some reason, it seems like there's just different patients that some subsection of patients that don't have the weight gain.
Did you have any patients that discontinued it because of the weight gain?
Fortunately, I didn't. Like I said, I just got lucky and a lot of them were super thin dudes.
That's interesting. So I feel like with the olanzapine, you see that all the time.
Yeah, definitely. I have seen patients that gain a ton of weight, especially on olanzapine or other antipsychotics. The thing is with clozapine, when you're at the point that you're using clozapine, you're a little bit less worried about those other risks because of the benefit and necessity that clozapine kind of offers. Yeah. Whereas I've seen olanzapine used much higher up. I've seen people use olanzapine first as a medication.
Yeah, and I guess this, again, kind of speaks to the idea that a lot of times, and not everyone, of course, this is a generalization, but a lot of times people like their clozapine and they want to stay on it.
Yeah, I really got to pull up that study that said like, I think clozapine had like the highest subjective rating of the antipsychotics. Yeah.
All right, let's go to number eight.
All right, so number eight is orthostasis. So orthostasis, there I'm just referring to orthostatic hypotension. So essentially when you stand up, you have super low blood pressure and you get dizzy. I think I have a video on YouTube that kind of reviews how that works.
Yes, I remember the tourniquet visual.
Yeah, I think I turned a water bottle that I dyed red.
Oh, yeah.
The orthostatic hypotension is due to the alpha-1 blockade. Super common, 20% incidence. And that's why we have to titrate slowly because you don't want to zonk the patient so that when they stand up, they're just going to completely pass out. In terms of management, it's pretty simple. You encourage hydration. You increase sodium intake if it's possible. If it's possible, you should avoid other alpha-1 blockers, avoid benzos.
There are medications you can use to treat it. Fluidocortisone can treat the orthostasis, but I feel like that's kind of getting in the realm that you should be talking to a PCP and have them help you out if you get to that point. All right, so we're on number nine. So the number nine thing you need to know about clozapine is the cialurea, which is drooling. So it's believed to be due to the norclozapine, which is one of the metabolites of clozapine.
As I mentioned, it's super confusing because clozapine is a muscarinic antagonist. And it has a metabolite that's a muscarinic agonist properties. So it's believed that the drooling... Well, we know muscarinic antagonists dry you out. So you would expect a very dry mouth. So it's like the hot as a hair, dry as a bone, whatever that mnemonic we had to learn in med school is when you block muscarinic antagonism.
So you wouldn't expect drooling. But it's believed that the metabolite nor clozapine has muscarinic agonist properties. And that's possibly what leads to the clozapine drooling. So it's super common, 30% to 80% incidence. The reason why we want to treat it is because it's not only socially annoying, but it can increase aspiration pneumonia risk because the patient can aspirate the saliva and that can cause problems. So the first-line treatment...
that you hear people use is glycopyrrolate. Do not use glycopyrrolate first line. So you do not want to increase the muscarinic burden of these patients. So glycopyrrolate, which is a systemic anti-muscarinic medication, well, the clozapine, like we've talked about the ham receptors, is already very anti-muscarinic. So you want to use local muscarinic antagonism.
That explains the eye drops. I remember patients putting eye drops in their mouth.
Yeah, the eye drops in the mouth, exactly. So the first line thing should be used is atropine.
Yeah, it's an ophthalmic solution that they, you know, like the pharmacist writes a little special sticker on it and it says, put it in your eyes, which is very confusing for everyone involved.
Yes, that's correct. So one to three drops, you swish and swallow. Do not put it in your eyes. So you just drop it into your mouth. The second line is Ipertropium, which is a nasal spray. And same thing as we're saying, you put it in your mouth and you swish and swallow. I actually have a funny story from residency. I remember one of my co-residents was presenting and they said, my patient has really bad drooling from clozapine.
Like, what should I use? And another one of my co-residents started speaking up and she was like, do not use atropine. She's like, I had to use literally 30 bottles worth for one month. And everyone's like sitting there and being like, 30 bottles? And she's like, yeah, just for the one month they had to use 30 bottles. Okay. Fortunately, our attending, we're all like scratching our heads.
And our attending was pretty smart. And they were like, were they swishing and swallowing? And the co-resident was like, what do you mean? And it's like, are you just having the patients drink the atropine? So this poor soul was just chugging atropine until... it stopped the drooling so that's not using it locally uh so yeah don't be like that co-resident don't don't have your patients chug the atropine because i'm
drinking it going like this is the worst shot i've ever had yeah just doing shots
of atropine so first line treatment is swishing and swallowing your atropine then ipotropium second line treatment is botox interestingly uh So we know Botox works on muscarinic receptors, something snare protein, muscarinic neurons, but it basically just stops the muscarinic neurons. So the Botox injections, the salivary glands are pretty helpful. It's not a perfect fix, but it can be helpful when the atropine and ipratropium aren't doing what you want them to.
As I was saying, some people will use the glycopyrolate. It's best to avoid it. There's already such a big muscarinic burden with clozapine. So if possible, try to avoid it. On the topic of muscarinic burden, if you have a patient on any other anti-muscarinic medications, really try to minimize them. So 100 milligrams of clozapine is actually equal to 2 milligrams of benstromine. And this can be helpful to know because if you ever need to stop the clozapine suddenly, you can actually use benchtripine to help you so the patient doesn't get hit with a really bad muscarinic rebound.
Okay, so any medications that come to mind that we should probably avoid if patients are on clozapine?
The medications you should be worried about and that you should consider tapering off. So a lot of the TCAs have a lot of anti-muscarinic activity. Paroxetine is very anticholinergic. The anti-Parkinsonian medications, the meds that treat overactive bladder and that are bladder relaxants. Benadryl is a big one. A lot of the antihistamines also have a lot of anti-muscarinic activities. So these are the medications that, if possible, you'll really want to minimize if you're using in a patient with clozapine just because they're already getting blasted with anti-muscarinic receptor activity.
Actually, it reminds me, I think I talked about this on another podcast. I took over a patient that... In their note, it said they were on a high-dose TCA for clozapine-induced sexual dysfunction. And he reported that it helped. It didn't make any sense to me. I tapered him off the TCA because I didn't have any clue as to how that makes any sense. It's counterintuitive. He didn't report any decrease or increase of sexual problems after tapering it off.
So who knows?
You probably took away the poor guy's atropine shots too. You had nothing to do at night.
I know. We're really just not a fun prescriber. All right. So number 10 is just... The number 10 thing you need to know is the metabolism and drug interactions and the plasma monitoring. So in regards to plasma monitoring, you can get a clozapine level. So you can check plasma levels. Remember, you should be getting a trough. So that means... You have to wait five days after dose change before the levels are appropriate in their blood.
The typical target plasma range is 350 to 600. You can go above 600, but there's really diminishing returns above 1,000. So it's worth getting levels. especially since you're doing the blood monitoring, you should be checking their blood for the ANC. You can also just make sure that they're adherent to the medication. If it's below 350, you can consider getting them on a more appropriate dose. So as I mentioned, 600 is a point that you can still consider going higher, but you really want to make sure that they're tolerating it okay.
So if they're tolerating the medications and they're still symptomatic, you can go up to 1,000. 1,000, you're kind of, yeah, diminishing returns.
Okay, so you're probably just checking, I guess, in the beginning when you're titrating and then maybe if you're concerned about adherence, but not so regularly.
Yeah, you can also check it whenever you add new medications to sort of make sure there's not interactions. And there's things you wouldn't expect, like if a patient's drinking orange juice and they switch to grapefruit juice, that can impact their levels a lot. So it's kind of just helpful whenever there's sort of big life changes. If the lab's already covering it, you just tack it on to the other blood work they're getting.
In regards to drug interactions and metabolism, so the two key enzymes involved, CYP1A2 is doing the majority of metabolism. The second one, which is a less significant pathway but still impacts levels, is CYP2D6. So for CYP1A2, the strong inducers, which lowers levels like 50%, the big one is smoking, so cigarettes. So it's not the nicotine. It has to do with the actual burning of the leaf, the polyhydromatic carbons or whatever you have to answer correct on the boards.
Yeah, that's one of those pop quiz questions, I think. I guess I'm just thinking about the smoking too. When you have patients on the inpatient unit and they're smoking for a period, sorry, they're not smoking for a period of time when they're on the unit, they get discharged, they immediately start smoking again, their symptoms get worse and no one really knows why.
Yeah, and like it would always be nice if you could have the patients continue to smoke if they were like, I don't know, like smoking rooms in the hospital. So you can get an actual accurate assessment of what their appropriate dose is. One thing I found funny is there's a prominent psychiatrist when he talks about clozapine. He's like, it's not the nicotine or the smoking, it's the burning leaf.
I don't know, just like this very like buttoned up guy in a bow tie talking about burning leaf, man.
That's what it's all about, bro.
Aside from smoking, other inducers, most of them you don't really see much. I'm thinking like carbamazepine, you might see that a little bit. But phenytoin, rifampin, the one you might see is omeprazole. So if a patient has GERD, you're going to want them on a different medication. So strong inhibitors, they can increase levels like 5 to 10 times. they're the big medications we worry about so cipro the antibiotic so there's a real interaction there that can raise levels significantly luvox fluvoxamine so fluvoxamine has a little bit of 1a2 inhibition um yeah that's that's uh that's all i got i think that's i think that's our top 10 list that was a lot to think about All right, so I guess I'll just kind of review the top 10 things you need to know.
So number one is its effectiveness in treatment-resistant schizophrenia. Number two is the unique benefits. There I'm thinking about the help with suicide, the help with violence reduction, the reduction in criminal behavior, the reduction in aggression. Number three is keep doing that neutropenia monitoring even if REMS doesn't care about it. Number four is the constipation risk and make sure you're managing it and starting your patients on a bowel regimen.
Number five is cardiac. So we're thinking about the myocarditis in the short term, the cardiomyopathy in the long term, and the tachycardia, which isn't necessarily dangerous, but is super common. Number six is the risk of seizures. Number seven is the weight gain and the metabolic risks. Number eight is the orthostatic hypotension and how to manage it. Number nine is the drooling and the atropine shots. And then number 10 is the metabolism and the drug interactions.
All right.
All right. Well, thank you for joining us, Roxanne.
No problem. Oh, actually, one thing I always thought was interesting about clozapine, I should have done this a while ago, but I don't remember reading it anywhere, but I've heard it anecdotally a lot that clozapine can actually worsen OCD symptoms. Have you seen that?
I personally haven't seen it, but it is well documented that clozapine can cause worsening OCD symptoms. So you can get it, I think, with the other second-gen antipsychotics. I think Zyprexa, I think also, olanzapine also causes it. So thank you for bringing that up.
Yeah, it's good to know about the interactions we talked about given that comorbidity.
Yeah, thank you for bringing that up and thank you for joining our podcast, Roxanne. So now we just need Dr. Fu to return so that Roxanne doesn't ever have to do this again.
Yeah, please, please, Dr. Fu.
Thank you.