Psychiatry & Psychotherapy Podcast - Clozapine for Treatment Resistant Schizophrenia

Episode Date: June 20, 2019

What is clozapine? Not only is clozapine the gold standard medication for treatment-resistant schizophrenia, it is also one of the most unique drugs used in psychiatry. It was synthesized 1958, only eight years after chlorpromazine, the first antipsychotic drug, was created. At that time, researchers tested for antipsychotic properties by taking various compounds and testing to see if lab mice developed dystonia and catalepsy. When researchers tested clozapine, they found that it did not cause dystonia, but instead made the mice sleepy. Because of this, clozapine was almost missed entirely as an antipsychotic medication. Eventually, however, clozapine was found to be more successful than other antipsychotic drugs. By the 1970s, Austria, Germany, and Finland had produced positive data on clozapine proving its efficacy. However, clozapine was also found to have caused severe neutropenia in sixteen patients in Finland, and even caused the death of eight of those patients. For this reason, clozapine did not enter the United States until it was approved by the FDA in 1989. By listening to this episode, you can earn 1 Psychiatry CME Credits. Link to blog. Link to YouTube video. Instagram:dr.davidpuder Twitter:@DavidPuder Facebook: DrDavidPuder Youtube channel

Hello and welcome to the psychiatry and psychotherapy podcast with over 32,000 mental health professionals listening every episode. Why? Because we need to stick together to survive the mental off field. I'm here to talk about getting rid of burnout, increasing job satisfaction, and feeling like an expert in what you do. All right, welcome back to the podcast. I'm here with Dr. Michael Cummings. He's been on several episodes, an episode on psychopathy, schizophrenia. We did a series on psychopharmacology, the basics. And today we're going to do a deep dive into clausoryl, clausopine. It is antipsychotic drug for treatment-resistant schizophrenia.

This is going to be an episode more for the practitioner and for the serious, curious, listener, but we're really going to go into a lot of the details. We're going to talk like psychopharmacologists, and yeah, so Dr. Cummings. Hi, I am indeed happy to be back and also happy to talk a bit about chlozapine, one of the most unique drugs currently in use in psychiatry. It actually was almost missed as a psychiatric drug. It was synthesized in 1958 only eight years after chloropomazine, the first antipsychotic. At the time, they were testing for antipsychotic compounds by, taking a candidate compound and seeing if mice essentially developed dystonia and developed catalepsy.

Closopine does not cause stiff mice. Instead, mice only gets sleepy. And consequently, it was almost missed. If it had not been for the fact that two other analin group antipsychotics, perlopene and loxapine, had been successful, odds are it would not have gotten further testing done. As it turned out, though, eventually it was discovered to be more effective than other antipsychotics. So cataplexy and cats, I love it. So, yeah, it is sedating. So tell me, tell me where it went from there. So they found it.

They tested it. They found it in the early and early and mid-1960s, it produced positive data first. in Austria and then in Germany and was approved, first in Austria, then in Germany, and then in Finland between 1972 and 1975. It was clearly more effective than other antipsychotics, and had it not caused severe neutropenia in a group of 16 patients in Finland, odds are it would have taken over the antipsychotic market in Europe, half of those patients, however, died, which led to clozapine being withdrawn from the world market. It did not make it into the U.S. Pharmacopoeia until it was approved by the Food and Drug Administration in 1989,

largely as the result of continued work in New York by John Kane and his group looking at Clozapine's efficacy compared to other antipsychotics. Wow. And what did they find that in their initial studies, what do they find? Essentially what they found was that if you strictly define treatment resistance, that is the person has failed to, other antipsychotics that were given for at least six weeks, and a minimum of 600 to 1,000 chlorpromising equivalents,

and the person then also failed a prospective trial of haloperidol, 15 milligrams a day. The odds that they would respond to chlozapine ranged from about 50% to 60% while the probability of an antipsychotic response to other drugs was between 0% and 5% with an average right around 2%, meaning other drugs in a truly treatment resistant schizophrenic population had essentially a 98% failure rate. Wow. And that's really hopeful, actually, because two antipsychotics in, you're starting to. wonder, okay, is this person going to get stuck in this? Psychosis. And it is truly miserable to get stuck in psychosis.

Indeed, those numbers have largely held up in truly treatment-resistant populations. There's a group, Howes et al, who in 2017 published criteria for treatment resistance, which largely followed Kane's original criteria. except that they don't include a prospective trial of haloperidol, largely because most people clinically are not, of course, doing a research trial. But essentially, it's very similar. If the person has truly failed to adequate trials of antipsychotics, given adequate dose, adequate duration,

with measurement of plasma levels to assure adherence, then the odds that they will respond to anything other than clozapine is basically 7% or less, while the response rate to clozapine remains in the 40% to 60% range. There have been meta-analyses published in recent years suggesting that closopine was not more effective than other antipsychotics. A criticism of those studies, was that they included data from studies that didn't use any definition for treatment resistance. And consequently, it was very likely they were including schizophrenic individuals who were not treatment resistant.

And indeed, in that context, clozapine is not more effective as an antipsychotic than other drugs if the person's not in that treatment-resistant category. What do you think in terms of the studies like Cochrane, the meta-analysis that Cochran have done, do you think that those are making the same mistakes about the treatment resistance? They have tended to, largely because, as you know, Cochran analyses typically look at studies that have been published, an area that they did not pay adequate attention to in selecting which studies they would analyze was did the study do a good job of defining treatment resistance. Closopine does have benefits other than treating psychosis that are unique to it.

However, as an antipsychotic, if the person is not treatment resistant, then response rates are about the same as for other antipsychotic medications. given at adequate therapeutic doses. Other unique effects of chlozapine include suicide reduction that's independent of its antipsychotic effect, reduction in violence that's independent of its antipsychotic effect, reduction in criminal behavior, and an ability to treat some rather unique conditions

like psychogenic polydipsia, and also refractory mixed bipolar states. So it's clear that clozapine is different than other antipsychotics, both in terms of treatment resistance and in terms of the overall range of things that it is capable of treating. Talk to this about the mechanism of Closopin and why it has different effects. Okay. From the mechanistic perspective. All of the first generation antipsychotics are dopamine antagonists.

That was their mechanism of antipsychotic efficacy. The R squared or the variance, D2 blockade accounted for 92 to 93% of the variants of all of those antipsychotics. And frankly, when anything in science, when you get to the point where something accounts for greater than 90% of the variant, You sort of pack up and go home because there's nothing else major to discover. The second generation antipsychotics are still, by and large, dopamine antagonists, but with the ability to actually assist dopamine signal transduction in the frontal lobes, as opposed to impairing it everywhere, by virtue of their ability to antagonize 5HT2A serotonous.

receptors. The partial agonists are, of course, just what their name says. They partially agonize dopamine receptors, but they're still modulating dopamine as their primary antipsychotic mechanism. Closopine is different from all of them in that it likely provides little or none of its antipsychotic efficacy by altering dopamine signaling. Even at Robben's, busts plasma concentration, Clozapine's occupancy of D2 and D3 dopamine receptors is only about 30 to 40 percent. Below those levels that are typically known to have an antipsychotic effect, those are more like 60 to 80 percent.

Instead, it appears very likely that Clozapine exerts its antipsychotic efficacy by modulating glutamate signal transduction, particularly in the frontal and temporal lobes. Essentially, glutamate is the brain's primary stimulatory or on neurotransmitter. And one of the major characteristics of schizophrenia spectrum disorders is hypoactivity in neural circuits in the frontal and temporal lobes. Improving glutamate signaling appears to be associated with a reduction in positive psychotic symptoms as well as improvements in negative and cognitive symptoms, something else that distinguishes it from the first generation drugs in particular, which may actually

worsen negative and cognitive symptoms. Yeah, that is so amazing. And so the frontal lobe seems to be lower in activity. And that's, I'm wondering also if that has to do with the prodrome of schizophrenia. Often years leading up to schizophrenia, there's more social isolation. a little bit more socially aloof. As we've touched on before when we talked about schizophrenia, essentially the data would suggest that Kruppelin was right when he characterized it as dementia precox. It really is a developmental dementia

in which there is not only abnormal neuron migration, but then there is an ongoing excessive. loss of neurons and loss of synaptic connections that results essentially in a brain in which dopamine activity is excessive in the temporal lobes, which likely results in the positive symptoms of psychosis. But the frontal lobes are hypoactive, leading to cognitive deficits and negative symptoms. Closopine is relatively unique in its its ability to essentially get the frontal lobes to awaken and to then do their job in terms of modulating the activity of the temporal lobes.

Yeah, that's, and I've seen that in clinical practice, whereas some of the other heavy D2 blockers can actually make people a little bit more blunted. Closopine doesn't have that effect. No, it doesn't. And in fact, as we mentioned, one of the chief effects of clozapine is to reduce violence, which is something of interest in forensic hospitals like Patton. It appears to do that, a study by Kuroski et al, essentially found that when they've randomized, not treatment resistant, but just violent schizophrenic patients to either olanzapine, haloperidol, or rindol, or.

Clozapine, the decrease in pan scores, the psychosis scores, was about the same across all three groups, but the level of violence dropped dramatically more in the Closepine group. And what that correlated with in terms of psychological testing was the Closepine group had a significant increase in executive functions, which are, of course, mediated via the frontal lobe. These people could think, they could consider, they could weigh consequences, and if someone's brain is more able to do those things,

it is less likely they'll resort to violent behavior. There's something about that that doesn't make sense to me because of how anticholonegic clozapine is. And I'm wondering how you make sense of that, because normally when we put someone on like a Benadryl or something, it's not like their full mind there. They're not thinking as critically. sensorium goes down. Yeah, you would think that, especially given how antich colergic

chlozapine is, for those who want a comparison, 100 milligrams of chlozapine exerts about the same anticholinergic effects at muscarinic receptors as 2 milligrams of benzthropine. So say if you have somebody on 500 milligrams of chlozapine, that's the same as putting them on 10 milesopine. milligrams of binstrapine. For most people, that would be an intolerable impairment in terms of memory and cognitive functioning. It appears with chlizapine, however, that the positive effect on glutamate is so robust that it just overrides the anticholinergic effect of the drug in terms of cognition and executive

functioning. Yeah. So do you think also people get used to that anticholinergic burden? I had one patient in particular that I could not elevate the dose to a significant level because the sedation was so high and he just wanted to sleep all the time. And he felt he felt really groggy. He didn't feel himself. He felt like he was in fog.

Indeed, you know, Clozapine's major side effects in terms of day-to-day side effects are mediated by its being an antihistamine. It's actually an inverse agonist at histamine 1 receptors and is potently anticholinergic. Both of those have sedating effects. Usually there is some adaptation

to those effects as people take the drug. For some individuals, however, the adaptation is incomplete. And certainly those are particularly at higher plasma concentrations, those often become the limiting side effects of chlozapine. It's also a very robust alpha and adrenergic antagonist,

which is why we have to titrate it slowly. If people got a very large dose of chlozapine initially, they would be hypotensive and likely would faint. One thing I was listening to Dr. Myers talk about this, and he talked about reducing the anticholinergic burden that's already there. And with this particular patient, he was also on an afronil for OCD, which is a heavily anticholinergic. Do you think that might have been one of the big issues

for why he couldn't tolerate clausoryl on top of that? Yeah, certainly it could be. Anaphrinil is among the most anticholinergic of the tricyclic antidepressants, although it's used mostly to treat OCD. It also is an antihistamine, so you get additive effects in both those areas. One of the reasons we worry so much about overall anticholinergic burden with chlozapine is actually, you know, when people think about serious adverse effects, they most often think about severe neutropenia.

However, with current monitoring the mortality rate from severe neutropenia in the U.S. per 10,000, so it's relatively low. The far more dangerous long-term risk with calizapine is constipation and bowel obstruction. That's actually resulted in a much larger number of deaths than the drug's ability to suppress neutrophil production. And for that reason, we usually advise people to try to avoid or minimize other drugs with anticholinergic effects as much as possible in Closopine-treated patients. Yeah, I was reading it's like 60% of people on Closepine will get constipation or somewhere

around there. The package insert says 14%, but that's likely an underestimate because they only, in the package insert, they only recorded those cases where people complained spontaneously. They didn't ask them. and indeed if you ask people, even for those people who are sort of doing okay, they'll tell you, yeah, they don't go to the bathroom as often, and it's not as easy as it used to be.

I once helped a hospitalized patient have a bowel movement through various, you know, several drugs that we had to give her to have a bowel movement, and she was the happiest person who ever met the morning after, She had the bowel movement. Yeah, indeed, one of the things we've recently done as a group, the PRN group that I belong to, one of the things we've done for the Department of State Hospitals, is actually write a protocol for Closopine-treated patients recommending how to approach bowel management.

Essentially, everybody who gets put on Closepine at the very least gets a stool softener like Docusate-250 B-I-D. The majority of people get on top of that an osmotic laxative, most often polyethylene glycol. If those two things don't work, then they have added to that an irritant laxative, like Biscadil. If those three things don't work, then usually the irritant laxative gets replaced with a secretory laxative like Lubyprostone. are Placonicide, or linoctide. I've heard more fiber does not help. It can actually make it worse.

No, indeed. One of the chief recommendations with treating or managing somebody's tendency toward constipation who's on clozapine is to avoid the bulk laxatives. On average, you know, the typical average bowel transit time is right around 24 hours in most people.

If you take a person who normally has a bowel transit time of around one day, put them on clozapine at therapeutic doses, the average increases to about 110 hours. And, of course, that means the stool sits in the colon and dries out, becomes hard. Well, if you add something like cillium to that, it's a great recipe for making what is essentially concrete. Oh, dear. Okay, let's go through some of the other side effects and treatment. So I have a lot of patients complain of drooling, and that can be nauseous, even more for the spouse or the loved one.

So any thoughts on first line? Yes, there's several ways to manage that. First, caveat is try to avoid use of systemic anticholinergics to decrease salivation, because, of course, that's going to increase. the constipation risk. It's essentially the, primarily the metabolite of chlozapine, desmethal-closopine, also known as nor-closepine that's responsible for the scyalluria. It, unlike chlozapine, is actually an agonist at all five muscarinic receptors, and basically it causes the prodig glands to produce excessive saliva.

first approach is in most patients you can dose clozapine all at night so you can reduce daytime salivation that way next step is to use topical anticholinergic medications either epitroprium nasal spray 0.3% or 0.6% applied subalingually not in the nose under the tongue,

with a swish and spit after a few seconds, that often will serve to dry up the prerotic glands. An alternative to that is 1% atropine drops, two or three drops under the tongue, again with a swish and spit, either of those can be given up to two to three times per day and more severe cases, something that psychiatry is beginning to borrow

from neurology. In this regard, though, is injection of the prodig glands with botulinum atoxin. For primary neurologic scyalleria, neurologists have been using botulinum toxin now for a number of years to decrease excessive salivation. As it turns out, it works for chlopine-induced scyalluria as well. This is a injection with a very tiny needle, a 32-gauge needle, small volume, into each prerotic gland. The effect lasts for about three to four months. And indeed, it was one of the researchers who established its use for Closopin-inducale areia.

It is currently on faculty over at Lomelinda University. Oh, wow. Who's that? Actually, I don't remember his name, unfortunately. It's okay. But I can send you, in context of the podcast, I can send you copies of the articles to post along with the presentation. Yeah, as always, we'll put all the articles that he's talking about in the resource library.

So you can, and the notes will be on my website as well. So, okay, let's go into seizures. So there's an increased risk of seizures with clozapine more than other antipsychotics. Yes. And I've heard the depicode is the treatment of choice for the seizures. Would you add anything to that? Both of those are accurate. Closopin lowers the seizure threshold more effectively than other antipsychotics.

All of them lower seizure threshold. It's just better at doing so. Primary risk factors are the rate of titration. If you titrate too quickly, you're more likely to induce a seizure. And this is an area where the package insert is pretty good, starting at 12.5 milligrams and then 12.5 milligrams BID, titrating slowly so that at the end of the first week, you're up to about 100 milligrams, and then week two, another 100 milligrams, so that by the end of week two, the patient's taking 200 milligrams of close-zo.

And then after that, being sure that no single dose increase is bigger than 50 milligrams until you get up to your target dose will help mitigate against risk of seizures. Also, as people get to higher concentrations, usually greater than 700 nanograms per milliliter, there is an increasing risk of seizure induction. often with the heralding sign of myoclonic jerks. If the patient begins to exhibit myoclonic jerks, it's a good warning that they may be on their way to either a myoclonic or tonic-clonic seizure.

Having a seizure, however, is not a reason to discontinue closopine. It is a reason to introduce treatment with an anti-epileptic. And as you pointed out, The first choice usually is valproic acid, very effective, very broad spectrum. If there are reasons not to give valproic acid, often the second choice is leviter acetam or capra. And let's go back to sedation. I want to hear your thoughts on treatment of sedation. We already talked about trying not to give more anticholinergic than necessary.

I'm wondering what your thoughts are on like concerta or modafinil? People have used concerted successfully. Or if not concerted, even for those who have just a hard time waking up, the immediate release, methylfinidate. Unfortunately, modafinil and noonafinil have both been tested. And at least in control studies, they don't do any better. than placebo in terms of reversing clozapine-induced sedation. So that at least in terms of groups, modafinil and new daffinil, don't appear to be effective

treatments. Having said that, I have seen individual patients who responded to those two drugs in terms of chlospine-induced sedation. So it may be worth a try, but with the caveat, that it's not effective often enough to produce good controlled data. The other thing people can do and that sometimes people don't realize is that once the titration of clozapine is finished, and the person's alpha receptors and acetylcholine receptors

and histamine receptors have accommodated to the drug, in the vast majority of people it can be consolidated to bedtime, permitting the person to have a lower plasma concentration during the waking hours that does not appear to affect the drug's efficacy, but can help the person be a little more awake in the daytime. Okay. Yeah, that's what I usually move it to nighttime. And I have one patient also on Concerta

and the person that's been able to get through school and do really well, function at a high level going to a graduate school. And really, really has been helpful for him. The good news is, is since indeed, Clozapine exerts its benefits for psychosis, not via dopamine blockade, increasing dopaminergic input to the frontal lobes,

is not, in essence, getting into a tug of war with Clozapine. Okay, what about agranulocytosis? Okay, agranulocytosis. In the case of Clozapine, unlike chemotherapy drugs, it's an autoimmune process. Its highest risk is right around one month of treatment. It reaches a little over 1% risk, and then it begins to decline so that by the time people are out to a year of treatment, that risk is down to, you know, right around 0.38%.

By the time they're done with two years of treatment, the risk of clozapine-induced severe neutropenia or agranulocytosis is down to about 6 per 10,000 cases. So the risk does decline over time. Currently, the FDA defines severe neutropenia for colozapine as an ANC count of less than 500 cells per cubic millimeter. If that occurs, then chlozapine needs to be stopped.

An important caveat in stopping chlozapine is to give the person a tapering dose of benz-tropine or other antichinstropine is the most common, usually starting at 2 milligrams BID and then gradually decreasing by around half a half. milligram of the daily dose per week. That's to prevent colonergic rebound from the loss of chlospine's anticholinergic effects. Such rebound can cause a fairly severe delirium along with nausea vomiting diarrhea. So not a very pleasant syndrome. This is some good nuance here. It's important to, the other important and probably the most important element of treating clozapine-induced severe neutropenia is to give the person philgristim, the synthetic analog of colony stimulating factor, a 480 microgram dose subcutaneously as soon as it is available.

That's the maneuver that's actually going to save the person's life. Daily philgristim is needed initially. The average length of time to response is about 12 days. So the bone marrow is going to, there's going to be a delay before the bone marrow responds, which is why it's important to put the person in a situation where they have reverse isolation and also very careful monitoring for any evidence of infection. infection or temperature above 100.4 degrees Fahrenheit increases the mortality rate from 1 and 10,000 to between 5 and 10%. Something that used to not be allowed after somebody had severe neutropenia was rechallenged, because this is indeed autoimmune.

There is an immune memory, and it's very likely that. re-exposure to chlozapine will ramp up antibodies against the neutrophil progenitor cells, causing the whole thing to happen again. The FDA now does allow re-challenge if chlopine is really the only viable treatment option. There have been two studies published looking at can you do that, provided you give the person careful monitoring and ongoing. philgristim support 300 micrograms a week to twice a week. And the answer is 70% of the time, yes, you can get away with rechallenging the person with

chlizapine, which is an important new development for those people for whom literally nothing else is a viable option. So you would rechallenge, how long would you wait to rechallenge again? You want the bone marrow to recover, that is you want the bone marrow to recover, that is you want the absolute neutrophil count to be above 1,500 cells per cubic millimeter. Usually this is going to be a good four to six weeks after the person became neutropenic. And at that point, you can indeed reinitiate chlozapine, but reinitiate it with ongoing philbrostem treatment. Currently, at DSA-Patin, we have...

three patients who require ongoing philgristam oh like every day every week every week and because they they had the neutropenia once and then you reach out and then you put them back on yes indeed because these are people for whom frankly the other antipsychotics are a waste of time no effect on their psychosis you know these and these are also very ill people who are at great risk of harming themselves and harming other people if their psychosis is not adequately treated. And indeed, that's another important issue with chlozapine, as we've discovered in recent years, I think, 2016 or 17, Yamashura et al in Japan published a study in which they looked at, well, do the effects of chlopine begin to fade if the person is true?

treatment resistant long enough. And indeed, they found that Clozapine's efficacy begins to decline after about 2.8 years of meeting the criteria for being treatment resistant.

Which is an argument that and those people who don't respond to other antipsychotics, we really should be thinking about chlozapine sooner rather than later. Yeah. Yeah. And I imagine that's

because just being chronically psychotic is damaging to the brain? Yes, there have been a number of studies looking at that, that ongoing uncontrolled psychosis causes further deterioration of the brain. You know, the loss is highest early in the illness after onset of overt psychosis, loss of 2% of brain mass per year for the first five years, or 10% of the person's brain. Fortunately, it slows down after that, but it doesn't drop to zero.

And there's a positive correlation between the number of acute psychotic episodes and the degree of loss of brain mass. And does Clozapine decrease that or does it continue? It decreases that and indeed, because Clozapine is more effective than other antipsychotics, it appears to slow progress

of schizophrenia more than the other antipsychotics do. Although, to be fair, all of the antipsychotics as a group have had an effect on schizophrenia that has been substantial. If you go back and read Emil Krippelin's original papers, most of his patients reached a relatively vegetative state by the time they were in their 40s. people sometimes still reach that state, but now it's in their sixth or seventh or eighth decade. So we've slowed down the illness. We're still a long way from being able to reverse the pathophysiology.

But among the agents we have, clozapine is probably the best and is one of the most neurotrophic of the antipsychotics. Yeah, this is where I get passionate about lifestyle, strength training, cardio, and healthy diet with this population because those are the main things that prevent dementia from progressing. Exercise, cardio, strength training, that's where I think the best science is for dementia prevention. And there are some evidence supporting

that cardiovascular exercise in particular may also be beneficial for schizophrenic patients, a very difficult population to motivate at one of the major health risks for people with schizophrenia as they tend toward a sedentary lifestyle. And on average, people with schizophrenia live about 20 years less than the general population. One of the findings with Chlozapine,

actually at the Maudsley group in London, was that Chlozapine, despite all of its health risks, actually tends to prolong life in schizophrenia. At first they thought that, well, maybe that's just because these people are getting monitored more often. But they controlled for that statistically and indeed found that, no, it was the chlozapine itself that was producing greater longevity, likely because, well, being actively psychotic is a dangerous condition to have for your overall health. Yeah. And I would say this also brings up the topic to me about the importance of the therapeutic alliance and having a long-term psychiatrist can be so important for this population because

they really will get easily paranoid and exile family members and people and friends if they're psychotic. And so having a trusted doctor they can go to, although it can be very difficult to build that trust, I think it's so important because then they actually take the medications or they're more likely to take the medications if they have a strong therapeutic alliance and then they're more likely to continue in treatment, which is a big issue with this population. Yes, indeed it is. In fact, non-adherence is probably the major factor in terms of treatment failure for the schizophrenic population at large. Invariably, when they've done careful studies of adherence, and even giving people a bit of fudge room, saying, well, if you take

80% of the doses, we'll count that as adherent, the adherence rates for oral antipsychotics is consistently less than 40%. That can be partially addressed with the long-acting injectable antipsychotics. Of course, because of its health risks, chlozapine is not available as a long-acting. acting injectable. It does, however, come in a variety of dose forms. It's available as tablets, wafers that dissolve in the mouth as well as in liquid form. Yeah. And this is where, like, as an outpatient psychiatrist, what I do is I look at how often they

need refills. And if they're not requesting refills, then they're not using the pills as prescribed. And it gives me an idea. I also utilize family members a lot in this population to really kind of monitor whether the people are taking the medications or... Yeah, both of those are very important. The other item to promote

is use of plasma concentration measurement. Yes, yes. For two reasons. One, adherents, obviously, if the person is taking the drug consistently, they should have fairly consistent plasma concentrations. And secondly, just to be sure that you're actually dosing plosopine or any other antipsychotic optimally, people vary tremendously with respect to things like absorption, rate of metabolism.

So that, you know, what's listed in the package inserts as the dose range for any of these drugs is an estimate based on average. groups. It's not necessarily true of each individual. In fact, for some of the drugs, the variation across the entire population can range as much as 30-fold in terms of rate of metabolism, which is why measuring the drug to be sure you're actually giving it at the optimal dose is an important issue. And this is something that I've really started doing since working with Dr. Cummings here, or collaborating being mentored by him. And I would say, you know, at first I thought genetic testing would be helpful, but there's so many factors leading to blood levels that are not measurable by genetic testing.

And, you know, genetic testing is not predictive of what the blood levels are for these drugs. And so getting a level, one, when they're not doing well to see if you can continue to go up. And number two, when they are doing well, to see what blood levels are, blood level of something like Chlosapine actually gives you the effective dose because then when they're not doing well in the future, you can say, okay, I'm gonna recheck their blood level and lo and behold, look, it's so much lower

because they started smoking more cigarettes, that lowers the blood level of chalosapine or so on and so forth. I don't know if you have anything to add to that. Yeah, no, that's right, because there are a number of factors that can alter hepatic metabolism of drugs, either exposure to other drugs, smoking induces hepatic enzymes, or in some cases it may be the absence of something.

I had a patient who loved grapefruit, and grapefruit indeed inhibits 1A2, which is the primary enzyme responsible for catabolizing chlozapine. Well, he decided to switch to oranges in the morning. and his clozapine level plummeted because he was no longer inhibiting the enzyme that catabolizes the drug. Yeah, so this is where there's so much complexity that goes into it. Having a little bit of idea on P450s and what's going on can be helpful, but really checking the blood levels can help you catch things that otherwise you wouldn't catch

and know how to monitor these things. Indeed, the genetic testing can tell you whether somebody's an extensive, or a slow metabolizer with respect to a particular P-450 cytochrome enzyme, but it can't give you the end result in terms of a particular drug concentration with the precision that's simply measuring the drug itself does. Talk to me about blood levels for clozapine. What are the ranges that you try to get someone in? For treatment of psychosis,

you're aiming for a minimum level of 350 nanograms per milliliter, and likely an initial target range of 350 to 600 nanograms per milliliter. If the person doesn't respond adequately within that range, meaning they still have symptoms, but they are tolerating the clozapine adequately, you can then gradually titrate upward because more treatment-resistant patients may require blood level somewhere between 600 and 1,000 nanograms per milliliter. After 1,000 nanograms per melloliter, there's a diminishing return on further increases

and essentially much greater increase in adverse effects without a lot more. benefit for most patients. Now having said that, there are rare patients who require chlizpine plasma concentrations that are above the norm. We have two patients at DSH Patton who require plasma concentrations of right around 1,400 nanograms per milliliter, which is a truly heroic plasma concentration. Now, if the drugs being used for other purposes, such as treatment of criminality or violence in a non-psychotic person, they often respond to much lower plasma concentrations. At the Broadmoor in England, they did a study in seven psychopathic patients and got a dramatic

reduction in violence in all of them with an average plasma concentration of 171 nanograms per milliliter so depending on it's like everything else the amount required may vary by illness yeah let's jump into clozapine-induced cardiomyopathy myocarditis what is it both myocarditis and cardiomyopathy? They are separate, but one can lead to the other. Acute myocarditis is estimated to occur in 2 to 3% of people who take closapine. It's characterized by fever, chest pain, or shortness of breath, and essentially the signs of the signs of,

and symptoms of evolving congestive heart failure, edema. All of the cases reported worldwide have thus far occurred in the first six weeks of treatment, with 90% occurring in the first four weeks. So this is a very early risk of clozapine. When it does occur, the first step, when it is suspected, is to measure both troponin and C-reactive protein. Troponin that is twice the upper limit of normal reflects myocardial injury. And there are rare cases where the troponin does not increase,

but C-reactive protein does, which is why the secondary measurement for inflammation is tested. If those things are positive, then indeed the person needs to be taken off of clozapine and they need an echocardiogram. And in the majority of cases, if the closopine is stopped, the myocarditis resolves. This is a myocarditis that's mediated by increased eocinophils. Unfortunately, measuring the eosinophils by itself is not useful because about half of clozapine-treated patients show an eocinophilia.

Most of those are benign, however. They're essentially not active eosinophils, so they don't mean anything. The inflammatory measures and then the echocardiogram are the important measurements in that context. If it is prolonged, the myocarditis, can lead to a dilated cardiomyopathy. The other route to cardiomyopathy with chlozapine is about 20% of people who take chlozapine develop a persisting tachycardia. They don't have myocarditis, but they're tachycardic with a heart rate above 110

at rest. On an ongoing basis, that's a long-term risk for developing dilated carcaditis. in such patients, it's fairly easy to treat. It can be treated with a beta blocker. The drug of choice often is a tenolol because it does not cross the blood-brain barrier and it's cheap and has once a day dosing. And usually starting at low doses, 12 and a half milligrams within titration as needed to get the person's heart rate under 100. That's good. What do you think about treatment of the myocarditis? The myocarditis, the main element of treatment is the discontinuation of the clozapine.

There have been some groups who've looked at then giving also the person intravenous steroids to interrupt or suppress the inflammatory response. the jury is still out on whether that changes the overall course of the acute myocarditis or not hopefully in the next year or two we should get some studies that will shed some light on that one of the problems of course in studying any sporadic adverse event is it's hard to put together a prospective study of something that happens here there and everywhere and only rarely. Yeah.

Is there anything else you would really like us to understand about Closapine? I think probably the chief take-home message I would give people is if you have somebody who's suffering from schizophrenia or schizoaffective disorder and they are not responding to what are clearly adequate trials

of other antipsychotics pursue chlozapine with that person sooner it is truly presently our gold standard for treatment well that is

that is really a deep dive into chlopine hope that's been helpful to people who have been listening to finish up I did want to give a plug

Jonathan Meyer who is one of the physicians I work with in the PRN consultation group has just written a Clozapine handbook. It's one of Stalls, one

in the series of Stalls handbooks. It has just been published by Cambridge Press and can be ordered from Cambridge Press. Presently, as of May 31st, it will become available through Amazon.

Have you read that? I know you. I have, and indeed I helped edit parts of it. It is an excellent book. It deals with both the benefits and how to manage all of the various issues that can arise with clozapine. It's about 300 pages and is available. I think the retail price is just under $50.

Yeah, so I'm going to put a link to all these things in the show notes and on the website, and I will put the resources that Dr. Cummings talked about, and I talked about including good blood levels for the different antipsychotics in the resource library. And as always, I hope that you guys find this helpful. This one's a little bit more cycle farm than usual. But I think it's important especially because in treatment resistant schizophrenia, this is the go-to treatment that I use and other psychiatrists use. And we should all become experts in it for those treatment-resistant patients.

So Dr. Cummings, thank you so. so much for coming on. Thank you for having me.