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Clozapine-Related Adverse Events and Managing Inad ...
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Hello, everybody. This is Dr. Jonathan Meyer from the University of California, San Diego, and I'm also a psychopharmacology consultant from the California Department of State Hospitals here to talk once again about Clozapine. I do have some disclosures, and these are available on the SMI Advisor website. Here's our objectives for this lecture, to talk about the rationale for and dosing of prophylactic metformin to manage Clozapine-related weight gain, to identify that seizures are easily managed and should never be a reason to discontinue Clozapine, express the conclusions that, due to the low prevalence of seizures, we really should never be giving people prophylactic anticonvulsants, as these are unnecessary in more than 98% of patients. We'll talk about how to diagnose myocarditis and interstitial nephritis and how to distinguish these from benign fever and benign eosinophilia. We'll talk about how to recognize and evaluate cardiomyopathy and look at a number of other hematologic abnormalities seen in Clozapine-treated patients, which are less common but important to understand. And lastly, we'll look at how to manage inadequate Clozapine response. So first, let's talk about metabolic adverse events. As many of you know, weight gain can be a significant issue in patients on a number of antipsychotics. We think the primary offending pharmacologic mechanism is histamine H1 antagonism at the hypothalamic level. As many of you know, H1 antagonism makes you sleepy, but it also impairs satiety. There's also additional actions seen in some atypicals having to do with antagonism at the serotonin 2C receptor. There may be some individuals with polymorphisms of this receptor and maybe other genes, such as leptin, which are even more sensitive to weight gain. In general, we would give everybody starting on antipsychotics, especially those which are likely to induce weight gain, a prescription for diet and exercise. But as many of you know, this is often inadequate, which is why we'll talk a lot about the use of metformin. Many atypicals, in addition to causing weight gain, can also cause dyslipidemia and hyperglycemia, Clozapine being one of the bigger offenders. The biggest impact on lipids is on serum triglycerides and, to a lesser extent, cholesterol parameters. We think some of this risk is, of course, related to weight gain, but there appears to be a weight-independent phenomenon going on here. As many of you know, elevations in triglycerides often reflect developing insulin resistance, and we think there may be a direct drug effect in this process. The general management, of course, is the use of statins or fibrates. The point of real concern is when triglycerides are over 500 milligrams per deciliter, because we're now getting to the territory where there's a risk of pancreatitis. There's a lot of reasons why people may have just glycemia or impairments in glycemic control. Of course, weight gain, there's personal risk factors, and there may be a direct impact of the drug itself. So again, everyone gets diet and exercise, but even another reason why we want to use metformin, especially in those who have a lot of risk factors for the development of metabolic syndrome or diabetes, particularly family history, ethnicity or race, or a history of gestational diabetes, in addition to being obese. So how do we manage clozapine-induced obesity and metabolic syndrome? Well, a recent review looked at a number of randomized clinical trials of people who have generally gained 10% or more of their body weight. The one which really emerges having the best data and the one which is not going to interfere with the use of other psychotropics besides clozapine is metformin. There were, at that time, three randomized clinical trials which showed robust effects on BMI, weight circumference, and also some effects on lipids and insulin levels. And the benefits seemed to stop when metformin was stopped, and also appeared to be somewhat greater when metformin was started at the beginning of treatment, as opposed to when the patient had gained an enormous amount of weight. There are some studies about adding aripiprazole to clozapine. They do have positive results, but as a reminder, because of aripiprazole's mechanism of action, it tends not to play well with certain other antipsychotics which need high access to the D2 receptor. The partial agonists like aripiprazole, brexpiprazole, and cariprazine all operate between 83 and 100 percent D2 receptor occupancy. If somebody is having their clozapine augmented, for example, with haloperidol or risperidone, the aripiprazole could potentially displace this and destabilize them. So for that reason, I tend not to recommend aripiprazole unless the patient is just on clozapine monotherapy. Whatever clozapine's magic property is in terms of treatment-resistant schizophrenia is not dependent on high levels of D2 blockade. So adding aripiprazole to clozapine, in fact, works out quite well. There's one study of oralistat, which is a lipase inhibitor. It causes a lot of unpleasant GI adverse effects and is generally not used anymore. So metformin is a wonderful molecule because it increases insulin sensitivity, it reduces hepatic glucose production, it improves peripheral glucose uptake and regulation, and also seems to decrease glucose absorption in a dose-dependent manner. What is interesting is that it does not increase insulin secretion, and for this reason is only very rarely associated with hypoglycemia. As I noted previously, we think the greatest impact is in new users of clozapine who are started with metformin concurrently, and again, positive data across all the metabolic parameters, even in established users, but we think the greater effect might be when you start it with clozapine itself. The big concern about metformin was lactic acidosis. You see a rate here of 8.1 per 100,000 person-years, but really it was those who had significant renal dysfunction who were at the highest risk. The original package insert referenced creatinine levels, but in the modern world we do everything by estimated GFR. So now what we say is that there's really no significant increased risk for lactic acidosis for those who have GFRs of 45 and above. As you start to drop below 45, you have to reevaluate the use of metformin, and certainly if the GFR goes below 30, metformin has to be stopped. This rarely becomes an issue in clozapine-treated patients, but certainly as people become older or if they do have renal dysfunction, it's something to be mindful of. The more common adverse effect that people will see is one of GI upset, which is often related to excessive dosing or aggressive titration. So you can see up to 50% might get diarrhea, and for that reason, in adults, we would say keep the starting doses low initially and titrate gradually over the first month. I give you a rough rule of thumb of starting at 500 milligrams QIM the first week, then adding 500 milligrams on a weekly basis to a target dose of 1,500 to 2,000 a day, given in divided doses. If people are sensitive to the GI adverse effects, even with this slow titration, there are extended release forms, and these should be used. I think overall, the benefits of metformin are significant, and if you can manage the GI adverse effects, it's a very well-tolerated medication. So seizures is an important issue because there's a lot of disinformation about this, and part of that has to do with the fact that the package insert seemingly was set in stone in 1989, and many of the elements have not been updated, even though we have a whole new monitoring scheme, which came out a number of years ago. The biggest problem is that the package insert cites a rate overall of 3.5% for seizures, and that was based on a relatively smaller sample size. So I show you here a review paper that was published in the mid-'90s, where we can see as of 1991, we had some of those early numbers which showed that individuals at doses of 600 milligrams a day or higher had a seizure rate of 4.4%. Once we got to much higher sample sizes, you can see by 1994, we have a four times greater sample size of 5,600. Now all of a sudden, the rates are much, much lower, and also what's interesting is that some of that dose dependency seems not to be there anymore, and so the idea that it's always dose-dependent, I think, is a bit of a myth. We can certainly see it at lower doses, but when you look at these numbers from the 1994 study, you can see that there's not a great dose dependency. Even more important in the 1994 study, they reanalyzed the data for those individuals who did not have a prior seizure history. You can see even in the highest dosage group, the rates remain under 2%, and I think that's really the important take-home message is that the majority of patients will never have a seizure. Even if you use the highest number of 1.9% from the total population of the 1994 study, that means more than 98% will never have a seizure, and that's why, as we talk about it, prophylactic anticonvulsants really do not make sense. So the comment about dose relationship is one I just addressed. There was another review, which was published a few years ago in CNS Drugs, which looked at 25 years of data, and they concluded that while some people previously were concerned about this 600 milligrams per day threshold, but the literature very, very clearly notes that there's several cases of seizures occurring at lower doses, there's a lot of controversies and uncertainties, and the idea that serum levels are predictive of seizure threshold is also debatable. So I think the point being, because of the conflicting evidence, clozapine-induced seizures should not solely be based on total dose or serum concentration considerations. When they happen, they tend to be somewhat idiosyncratic, and you need to give people what they need in order to achieve adequate psychiatric response and not be overly concerned about seizure induction. If somebody does get a seizure, these are the early numbers. You can see the majority are generalized or tonic-clonic seizures. We also have some people who get myoclonic seizures as well, and then a few people who actually get atonic seizures, and we'll talk about that. Other types of seizure manifestations, meaning partial, simple, or complex seizures, is really rare and almost not even reported anymore in the literature. So many people are familiar with generalized seizures, but less so with atonic or myoclonic seizures. So myoclonic events are seizure activity that occurs without loss of consciousness, and this may present as jerks or tick-like movements anywhere in the body, but more commonly in the limbs or facial region. At times, if it's in the face, some people might confuse it with tardive dyskinesia, but usually the clinical context will be very helpful, meaning that it occurs, for example, in the closipine titration, and never existed before. Atonic attacks are, again, a type of seizure that occurs without loss of consciousness and result in loss of muscle tone, with the individual falling if it occurs in the lower limbs. So sometimes I've had patients or clinicians say, hey, my patient fell, and they thought it was an episode of orthostasis. I think the most important thing is the patient will often tell you, I didn't feel dizzy, it's just that my legs went out from under me inexplicably. You should be able to diagnose orthostasis just by checking their vital signs, and when orthostasis is not there, and especially when the patient says, I didn't feel dizzy, I just lost the muscle tone in my legs, you have a sense that this is an atonic attack and should be treated very differently, of course, than if it was orthostasis-related fall. Because of the very low rates of seizures, prophylactic divalprox makes no sense. The reason I mention divalprox is that this is the drug of choice for covering both atonic, myoclonic, and generalized seizures, and we'll have a graph and a table to show that information. The reason we're concerned about divalprox is several-fold. For one thing, as many of you know, divalprox itself causes weight gain, and when you add it on to Clozapine, you get additive effects. Divalprox can cause hyperammonemia, which doesn't improve alertness, I'll just say that. It also causes thrombocytopenia, which I think most people are familiar with, but the other big problem which it causes in patients who are at higher serum levels is neutropenia. So I present here a table which looks at, and this is a sample which came from an epilepsy clinic I believe, just looking at people who are on either valproate or phenytoin or dilantin. As you can see, the total white counts are quite comparable, but the people on valproate have significantly lower neutrophil counts. And the problem is you keep people on divalprox, some of whom are going to start to have depressed neutrophil counts, and this may cause problems for maintaining this individual on Clozapine. So really the question is, why would you add a drug which all of these potential adverse effects with more than 98% will never have a seizure? And in many instances, the patients are often being treated in a controlled setting. So here's a couple of seizures. This is scenario one where it occurs after dose adjustment or due to mitigating kinetic factors. And so the idea is you've either just recently bumped the dose, and then a week or two later the patient has a seizure, or somebody added a kinetic inhibitor. For example, the patient was depressed, somebody not understanding that there's a drug-drug interaction with 2D6 inhibitors, added fluoxetine, and over time the level goes up and they have a seizure. So generally what we would say, if somebody has a seizure, you'd like to get a plasma Clozapine level just to see where you're at, hold the Clozapine for 24 hours, and then go back to the prior tolerated dose, if it's after a dose increase, or adjust the dose based on the expected kinetic effect. So for example, the patient was on 400 milligrams at bedtime, they're fine. You bump it up to 500 milligrams at bedtime, a week later they have a seizure. So we would say, okay, hold their dose that day, and then the next day go back to 400 because 400 was tolerated. And then you'll probably need to add something so that you can pursue the higher doses and plasma levels. The other possibility would be, let's say you had somebody on 400, fluoxetine was used because they were depressed, not realizing that you're going to double their plasma levels, and they didn't have a seizure a few weeks later. Now that you understand that fluoxetine likely doubled their plasma levels, and so they're now on the equivalent really of 800 milligrams a day instead of 400, you can make the appropriate adjustments by cutting their dose in half in that circumstance to get them back to a dose that was tolerated and then re-titrate. But I think the idea is if you're holding their dose because it was after a recent dose increase, recheck the plasma Clozapine level at steady state on this new dose, presumably if the person tolerated 400 milligrams by itself before without a seizure and only had a seizure when they went to 500, going back to 400 will also work out. Certainly if you titrate again and the second seizure occurs, then you have to add divalprolex as prophylaxis to allow you to pursue higher plasma levels in search of greater efficacy. Here's another scenario which is sometimes perplexing. The patient has been on a stable dose, dose hasn't changed, nobody's added an inhibitor like fluoxetine, or frighteningly once in a while you'll see somebody have an antibiotic called ciprofloxacin added. Ciprofloxacin inhibits P450 1A2, and this can increase Clozapine levels five to tenfold and can at times be fatal. So here we have no changes, but the patient has a seizure and you're wondering what's going on. Well, generally we would say is go ahead and get the plasma level, ideally it's a 12-hour trough, look to see if there's been any decline in renal or hepatic function. Look at their medication history. Maybe somebody did give them an antibiotic and you weren't aware of it, or they gave some other medication which might interfere with clozapine's metabolism. Again, hold the clozapine for 24 hours and consider reducing the dose. And again, be mindful that large dose reductions can destabilize the patient. And so I would say a range of 25 to 50%. I would try to go towards 25. And then look for other causes. You know, was this person drinking and they stopped drinking? Were they taking benzodiazepines and abruptly stopped them? If the plasma level is really the same as prior stable levels, then add Divalpro-X. It's really uncommon to see somebody on stable levels who all of a sudden has a seizure for no reason. There usually is a reason. And I think that's important to look and see what that reason might be. Once in a while, you will have somebody who either stops smoking cigarettes or switches from cigarettes to vaping. So the thing which induces the enzyme 1A2 when people smoke cigarettes is not the nicotine, it's the burning of the tobacco leaf. And so there's literature out there that when people switch from smoking cigarettes to vaping, that they lose their 1A2 induction, their plasma clozapine levels go up, and one side of that could be a seizure. So certainly if you check the levels in this person, you see the levels have jumped for whatever reason, then of course adjust the clozapine dose and then recheck at steady state. Presumably if the patient tolerated a level, let's say of 650 before, and now it's 850 for whatever reason, you just readjust the dose and they should do fine. Obviously if a seizure reoccurs, then we're gonna add Divel Pro-X. I think the most important thing here is do some detective work and try to figure out what is going on. Did the patient stop smoking? Were they drinking and stopped abruptly? Were they taking benzos and stopped abruptly? Did someone slip them a metabolic inhibitor of 1A2 or 2D6 or 3A4? Try to figure out what it is, because if people are on stable doses and levels, they generally do not have new onset seizures once they've been at steady state for a period of time. If somebody has a seizure, the preferred drug is Divel Pro-X. As I said, it's effective for generalized seizures, myoclonic and atonic seizures. There's literature about some modest kinetic interactions with clozapine, so after you add it, it's always a good idea to recheck the clozapine level at steady state a couple of times to see where it settles out. Divel Pro-X can be orally loaded if necessary at 30 per kilo over 24 hours. It has the greatest number of published case reports, generally pretty well tolerated, but again, the concerns are weight gain, neutropenia risk, and also thrombocytopenia and hyperammonemia. If for some reason the person cannot tolerate Divel Pro-X or it's not an option, Lamotrigine can be used. The downside of Lamotrigine, of course, is the very, very slow titration, but it is effective for generalized seizures and is also used for myoclonic epilepsy. Generally well-tolerated, the nice thing is it doesn't have much in the way of weight gain or kinetic interactions with clozapine. There is unfortunately only one case report of its use with clozapine, which is not a reason to avoid it, but we just don't have the body of information that we have for this particular application. But certainly from what we understand about its mechanism of action and how it works for generalized seizures and myoclonic seizures, it seems an excellent choice. The problem is, of course, you cannot titrate it rapidly, and if the person is on Divel Pro-8 concurrently, you have to definitely adjust the titration so you don't give them Stevens-Johnson syndrome. So the problem is that that timeframe means that while you're waiting for Lamotrigine to become therapeutic, you cannot go up on their clozapine dose and they're sort of stuck where they're at. There are a couple of case reports for both gabapentin and topiramate. They don't have kinetic interactions with clozapine, but neither of these are effective for myoclonic seizures, and they all have their issues. Gabapentin is sometimes sedation really more than anything, and of course, the lack of efficacy for myoclonic seizures. And topiramate, significant cognitive adverse effects, which people often do not tolerate, and there's a risk of metabolic acidosis as noted in the package insert. These are the things which should never be used. We don't use phenytoin or carbamazepine mostly because these are inducers of clozapine's metabolism and will drop your plasma levels by 50%. And so this poses just kinetic problems. And of course, these drugs pose problems for a number of antipsychotics and they're simply just not used. Keppra actually has no kinetic interactions with clozapine and is effective for myoclonic seizures, but the problem is Keppra, which is levotiracetam, has higher rates of neuropsychiatric adverse events than other anticonvulsants. And there's no data on its use with clozapine. It's one in general within the state hospital system we tend to avoid because of these higher rates of neuropsychiatric adverse effects. And then of course, there's clonazepam. Clonazepam is something we tend to avoid in people on clozapine who are often already sedated due to the cognitive effects with the potential for misuse. And most importantly, that it does have benefits for myoclonic epilepsy, but it's generally not so well tolerated. And with all of its side effects, it's something that's just not used generally for this purpose in patients on clozapine. As just a side note, people ask, well, is ECT safe given the fact that clozapine lowers seizure threshold? So a 2015 review looked at data on 208 patients covering 40 total publications. Most were adults with treatment-resistant schizophrenia to whom ECT was added to clozapine for inadequate response. For one thing, the response rates were quite significant. It's really one of the more evidence-based treatments when people have had their clozapine maximized, but still have an inadequate positive symptom response. The side effects noted in this large review were delirium five, tachycardia five, and prolonged seizures four. So the conclusion from the authors was given the large number of cases and the low rates of adverse effects that this combination is considered effective and safe and should be used in those with treatment-resistant schizophrenia for whom clozapine itself has proven inadequate despite optimization of its plasma levels. And then there's a variant out there which we think is a seizure-related phenomenon which is stuttering. Now, the number of cases of this is quite small. There's only 18 in the literature. We think the prevalence, according to the largest case series out of Ireland is certainly under 1%. These people have no generalized seizure activity, but some do report myoclonic jerking in some instances. Generally, these all have emerged during titration or after dose increase, which is a pattern very commonly seen with clozapine-induced seizures. And so we would manage these in the same way, is pull clozapine for a bit, reduce the dose back to the prior tolerated dose, and slow the retitration. If it continues to pose a problem, then you'll probably treat it as a seizure-related issue and use Divel-Pro-X. Okay, these are things which cause people a lot of concern because they're often interrelated, meaning fetal myocarditis and interstitial nephritis. Cardiomyopathy is lumped into here, although it really is a separate issue. It's more of a long-term issue, not an acute issue, but we'll cover that as well. So here's some basic concepts, and this is really important to understand. Fever is not rare. In large case series, 20% will develop some form of fever in the first eight weeks which is benign, meaning there's no evidence of a drug reaction, there's no evidence of interstitial nephritis or myocarditis, and they otherwise have a normal workup. But because that first eight weeks of treatment is the risk period for myocarditis and interstitial nephritis, anyone who develops fever in the first eight weeks gets the workup. So in addition to a standard fever workup, you're also gonna draw troponin levels to look for myocarditis and CRP, as well as getting a BUN and creatinine and a urinalysis to help rule out interstitial nephritis. The most important thing is that this workup can all be done literally within hours. You may have to hold the Clozapine for those few hours while you're getting the workup, but this is not a reason to permanently discontinue Clozapine. And once the workup comes back negative, then you should resume Clozapine where it had been previously stopped. There's a large review looking at myocarditis. The rates tend to be higher in Australia than in other places. The question is whether this is greater recognition and we really don't have the answer. The point being is it's still relatively uncommon. It generally only occurs though in the first six weeks with rare exceptions. And again, when somebody develops fever in that time period, certainly when there's no other cause, and especially when they complain of systemic symptoms like malaise, flu-like symptoms or chest pain, you really should think myocarditis. But again, 20% may not experience fever. So fever is not always the clue to myocarditis and that's why you're looking at other complaints such as malaise, flu-like symptoms or chest pain. Troponin is the diagnostic test for most people for myocarditis. It will be above two times the upper limit of normal in more than 90% of cases. But there's a small fraction under 10% who have normal troponin levels, but they have markedly elevated C-reactive proteins above 100 milligrams per liter. That is why we now suggest don't just order the troponin, but get troponin and CRP when you're suspecting myocarditis. Again, this is gonna be part of the standard fever workup in the first six weeks of treatment. Other lab tests such as eosinophil count and EKGs are less sensitive and less specific and really not helpful in making the diagnosis or ruling it out. Other less common drug-related reactions occurring in these first, we'll call it six to eight weeks, are things like interstitial nephritis, psoriasis, and the DRESS syndrome, and I give you the acronym there. Much less common than myocarditis, but also something to think about during these first eight weeks of treatment, especially when fever occurs without cause or when people report systemic complaints like malaise or flu-like symptoms. And then lastly, cardiomyopathy is a long-term thing, and really it just presents as heart failure as we will discuss. So these are some of the early analyses which came out of Australia. The world's expert in this area is Kathleen Ronaldson. She's a pharmacoepidemiologist, and so she's produced from Australia a lot of the literature that we rely on to understand what to look for with regards to myocarditis. This is her 2010 paper. The reason I like this is that it gives us those clinical features which are both present and absent. So you can see certain things are really indicative of that. Chest pain, not so common, but it certainly can present. And I think most importantly, eosinophil count was really not that helpful one way or the other. The one test would really appear to be very helpful with the troponin level being two times the upper limit of normal. You can see in this case series, all the cases evolve within the first three weeks of treatment, within the first 22 days, but there certainly are cases which go out a little bit longer. So Ronaldson proposed some diagnostic criteria. Essentially, you'll have some evidence of cardiac dysfunction and at least one of the following. And the one we really will rely on for the most part is going to be elevated cardiac enzymes in the form of elevated troponin levels. Other things can be helpful. EKG is suggested, but not diagnostic. Chest x-ray is probably not gonna be the way to diagnosis, but this is what she suggested. Some people might end up getting echoes and that's very helpful if they do end up getting an echocardiogram or an MRI, but among all these, troponin is the easiest to get and it's the one which will come back the fastest. Of course, you're looking at the absence of other plausible etiologies. Every once in a while, somebody gets a viral infection such as Cox-Axley virus and gets heart failure or exposure to other agents, sepsis, other reasons why people might have heart failure. So later reviews look at larger populations, larger case series. These all come from Ronaldson. You can see again, the troponin level beating two times the upper limit of normal or higher really is the test of choice, but there's about 10% in whom this will still be normal. So that's why she sometimes noted that C-reactive protein could be helpful in picking up those other individuals. And then the largest review of the 250 cases, which came out in 2015, gives a larger range of incidents. Again, the highest risk period is still within the first month, but we'll say up to six weeks in particular. Some factors were noted, higher rates when people on concurrent valproate or faster clozapine titration. I think it's not a reason to avoid giving clozapine to somebody on valproate if they need it for seizure control or if they need it to control their bipolar diathesis. On the other hand, if you can switch it for bipolar diathesis patients who are schizoaffective bipolar to lithium, then you don't have to worry about it. Fast titration, there was some association as well. So the monitoring protocol, which we have is suggested by Ronaldson. I would say her suggestion of a baseline echo is really not evidence-based, and she even acknowledges that. We can diagnose myocarditis in somebody who does not have a baseline echo. For that reason, we would say hers are considered suggestions, but they're really not followed anywhere in the world except for Australia. And to be honest, even in Australia, in many places, they don't get that echo right when clozapine is started, and it may not happen for several weeks. She also suggested weekly troponins and CRPs, which can be increased in frequency if there's a reason to do so. Most clinicians follow what I call the reasonable protocol. Maintain a high level of suspicion during that risk period, which is the first six weeks of treatment. If you have any suspicion, order the troponin, order the CRP, and most importantly, if you can't get them at your place, then send the patient to the hospital. If you are at a hospital, let's say a psychiatric hospital, and these come back immediately and are positive, then they're gonna go to an outside hospital for management. If clozapine has to be stopped abruptly, you have to cover the individual for cholinergic rebound. Among non-smokers, 50 to 75 milligrams of clozapine is equivalent to one milligram of benzotropine. So let's say you're early on in the titration, and the individual as a non-smoker is on 150 milligrams of clozapine. If they develop myocarditis, you have to stop the clozapine, and you should be giving them approximately two to three milligrams per day of benzotropine to prevent cholinergic rebound, in addition to giving whatever antipsychotic, which you hope might be effective for their psychosis. Given the fact that many people have no therapeutic alternative to clozapine because they are treatment-resistant, the question is, can I re-challenge somebody who has had myocarditis? As of 2018, there were 17 cases, and 11 were accessible. So around two-thirds. No obvious factor of predictive, successful re-challenge, but I think the idea is you do want to have a cardiologist who's going to help you with this. You'll probably want to do this in an inpatient setting with diligent daily monitoring of temperature, blood pressure, using the world's slowest titration to minimize whatever risk is related to that, and act swiftly if you have any suspicion. That's really all you can do to try to minimize this, but I think the idea is you have all the stakeholders on board, the patient, perhaps caregivers and family, and a cardiologist. So everybody understand what's involved if you do decide to re-challenge this individual. Interstitial nephritis is much less common, but shares some features with myocarditis. It generally occurs early in treatment, generally within the first few weeks, although there are some which are reported as late as 60 days. There's one case report from 2002 by Estebanez, which is up to 90 days, but we think the individual actually had it earlier, it just wasn't recognized. So because of the paucity of cases, this is why I present this table here, most do present with fever, most present with proteinuria, nobody presents with rash. Again, if people are getting fever during that first eight weeks of treatment, I think we would say you need to evaluate them for both myocarditis and interstitial nephritis. What you're looking for is somebody who has what's called a nephritic picture on the urinalysis with proteinuria and red blood cells. And often you will see significant decreases in GFR. I could think of one example we had recently at the state hospital, a relatively young, healthy lady who happened to be on lithium. And the way we picked up the fact that she developed interstitial nephritis was that three weeks into her clozapine titration, she became lithium toxic. And her lithium dose had not changed, but what had happened was her renal function had gone down significantly and she clearly had evidence of interstitial nephritis. And that's how we picked it up. So it's something that often gets overlooked because people are so heavily focused on myocarditis. So you could consider adding a serum creatinine to CBCs if people are getting venipunctures for their CBCs to track this, because it often does get overlooked. So cardiomyopathy we think is generally a late term or longer term problem related to clozapine. It's not entirely clear that these are people who had some form of myocarditis, which was just missed. We really still have that information. You can see the early case series that was published in the New England Journal in 2001 showed a median duration of nine months of exposure with a broad range. Now we would think this person at 14 days probably did have actually myocarditis, but certainly it's something that's not seen for many months or often years. The risk is considered very, very small, but what people present with is generally dilated cardiomyopathy with all the evidence of heart failure associated with cardiomyopathy. And the way you would suspect this is you have somebody, for example, on a stable dose of clozapine for a number of months, all of a sudden who's saying I'm very tired and certainly I'm very short of breath, or they start to have other evidence of heart failure like peripheral edema or basal arousal. If people start to complain at this, you have to send them for an echo and the echo will be completely diagnostic. You'll see what their ejection fraction is. So what do you do about that? Well, stopping clozapine may possibly reverse some of that because this is generally not an emergency. You don't have to stop it abruptly. So you have a little bit of time to decide, well, what am I gonna add in lieu of clozapine and how much bentropine should I use to replace what I'm losing from clozapine? In the meantime, you'd manage congestive heart failure from any other cause, it's not restriction, ACE inhibitors or ARBs, diuretics, beta blockers, et cetera. When you have low ejection fraction, not surprisingly, your mortality is high. This may improve after removal of clozapine, but really the big issue is, is this a patient who really wants to have their clozapine stopped? In those with decision-making capacity, they might say, you know, I was so miserable before I took clozapine. I know that staying on clozapine may shorten my life significantly, but I'd rather have a clear mind to the end than die from heart failure, which I'm probably gonna die from anyhow, and be floribly psychotic. There are three published cases in which people got cardiomyopathy treatment and the patient was re-challenged. The clozapine did not appear to induce further deterioration in the cardiac function, and there was gradual improvement in the injection fraction. And so the idea is maybe clozapine is stopped, but only temporarily while you can optimize the treatment of their cardiomyopathy, and then add back the clozapine to get them back to their point of psychiatric stability. And lastly, there's actually two published cases of successful cardiac transplantation in schizophrenia patients. High-functioning people are great candidates for cardiac transplantation. It's not done very often, but it is certainly something to consider if you have a high-functioning person who develops this problem, and otherwise would meet all the criteria for cardiac transplantation. So, enuresis is one of those embarrassing problems that people don't talk about, which is why you have to ask about it. It can occur up to 40% of patients early in treatment, and about half of those, or 20%, it's gonna be a persistent problem. Because people are embarrassed, they often don't tell you. I certainly know when I was at a state hospital which patients had this problem because the nursing staff would let me know, but when they're outside of the controlled setting, you might not know, and people may not tell you, so ask them. This will be a reason why people say, I don't wanna take this medicine, and they won't say why. So that's why, especially early on, ask people. If at a certain point they're not getting it, then that's fine. But early on, it's one of those things that somebody might not tell you, they're embarrassed, and then they say, I wanna stop closing, and you're not entirely clear why. A couple of risk factors. Number one is a history of childhood bedwetting. Not surprisingly, these are people, for whatever reason, are vulnerable to this, and that doubles your risk. But the one which really increased it a lot was the use of a second antipsychotic. You can see 4% for those without aneurysis in the case control study, 24% for those with. So it increased your risk sixfold. So if people are developing this, it's a reason that if you were cross-tapering closing with the other antipsychotic to try to get rid of that other antipsychotic, and also to let the patient know that it's the combination which may be a big part of the problem, especially if they did not have a prior history of aneurysis as a child. How do you treat it? Well, in some, it gets better, about half. So I think the idea is maybe back off on the titration a little bit. If they were getting all the medicine at bedtime, maybe divide the dose so their brain is not quite as asleep while they are asleep. Certainly, all the usual things, minimize fluids, don't give them diuretics at bedtime, empty their bladder before they go to sleep. Again, if they're on a second antipsychotic, really try to taper it off. There is a case report of the use of pseudoephedrine titrated to 30 milligrams four times a day, which seemed to work out. Of course, you'll have to be mindful of the blood pressure. There are three case reports for desmopressin nasal spray, but you gotta be careful about severe hyponatremia. So really, if you're gonna use that, you have to be monitoring the serum sodium to make sure that they don't develop hyponatremia. Here's a bunch of weird hematologic problems, which we don't see with too many other drugs, except maybe the anemia thing, but you have to be aware of. So once you understand that these are related to clozapine, most people don't do anything about them except just monitor, but sometimes people don't understand that this can be related to clozapine or they think it represents a severe problem and they stop the clozapine, which is not necessary. Leukocytosis, if you use the threshold of 15,500, occurs at a rate of 7.7%. It's usually time limited. As many of you know, lithium increases your neutrophil counts because when you give lithium, it's like giving a colony stimulating factor agonist. Lithium actually increases the production of granulocyte colony stimulating factor. It'll increase your total white count, but what it's really doing is increasing your neutrophil count, which increases the total. Ulysses and people who are not on lithium and they can get neutrophilia, but certainly lithium increases that rate 50%. Again, this is usually time limited. If it's due to the lithium, you'll understand that. If they're not on lithium, you'll say, we're just gonna watch it. It usually runs its course or it stabilizes and no further workup needs to be done. There are occasionally people about 3% or less who either have elevated or lower platelet counts. Now, of course, if the platelet counts low and they're on valproate, we're always gonna bring the valproate and those instances we'll try to switch valproate to something else, but you can see it without people in valproate. Again, these are usually self-limited processes that resolve without need for treatment interruption unless you have local prescribing guidelines and that's usually outside the US, which tell you to do so. Certainly, if people have really low counts, they're at risk for bleeding or if they're really high counts, they're at risk for thrombosis. Only in those circumstances might you consider interrupting clozapine. Otherwise, the rule of thumb is just watch it. It usually runs its course over the first couple of months. And then lastly, eosinophilia. If the older package inserts gave thresholds for eosinophilic counts and told you to do all sorts of things, including stopping clozapine, that language is gone now. What the package insert currently says is, if you have eosinophilia, look to see if it's associated with some type of a systemic problem. Essentially what they're saying is, just look at the patient. Are they having myocarditis, nephritis, DRESS syndrome? Certainly, if it's beyond 60 days, none of those are likely. If it's in the first 60 days, you might wanna take a look. But there's no language about discontinuing or doing anything about eosinophil counts at all. They don't give any thresholds for counts. All they tell you was, look at the patient, be suspicious of this. If you see it and nothing else is going on, don't necessarily be concerned. And then lastly, anemia. So this is an unusual thing, which I noted last year as I was putting together a handbook on clozapine. I had not heard about this. And to be honest, I had not seen it. But there was this long-term case series which showed that over a couple of years, about 25% of people might meet some form of anemia criteria. So again, you should pay attention to what you're getting from the CBC if you're getting a venipuncture CBC and not just a finger stick for A and C. And so if you start to see changes in this, of course, look for other causes. GI losses being a big one, iron deficiency. And occasionally we'll even see that our old friend divalprox causing anemia. And so look for other causes, but when it's not due to another etiology or divalprox, it's not a reason to hold or discontinue clozapine and to monitor. If they look like they have iron deficiency, that's a reason to give them iron. You don't give them iron unless there's iron deficiency. But if there is iron deficiency and the indices support this, you can add iron. But the big concern is iron is very constipating. As many of you know from our other lectures, clozapine-related constipation can at times be very serious and cause ileus. If you're adding iron, you probably will need to add at the same time additional agents, and I'm saying plural, agents to manage clozapine-related constipation so you don't give this patient an ileus. What happens if I'm titrating clozapine and the patient's not getting better? And when I say inadequate response, what I really mean is positive symptom response. That's why we're giving clozapine for the most part is we're trying to reduce the positive symptoms of psychosis. Sometimes we're also doing it for aggression, but the primary target is usually the positive symptoms of psychosis. So here's my general approach. Number one is that are they actually taking the clozapine? Occasionally you will see patients who are non-adherent with their oral medication, especially when they're outside of a controlled setting. And so you have to look at this and levels are the way you're gonna look at this. Are the plasma levels simply sub-therapeutic? Generally we'll use a threshold level of 350 nanograms per ml for clozapine response, but many people will not respond at 350 and they need higher levels. The literature certainly talks about people being pushed to levels as high as 1,000 in search of efficacy, assuming that they tolerate this. But to conclude that clozapine is a failure because somebody did not respond with a level of 400 nanograms per ml is an accurate way of looking at it. What you have to say is 400 was not enough for this brain and maybe they need higher. Let's go ahead and march along. The most important thing is address any tolerability issues that might limit titration. For example, the patient had a seizure before. Well, guess what? Why don't we add Dival products so we can push up their clozapine levels so maybe we can get response. What are the adjunctive options? We can give adjunctive antipsychotics. The effect sizes are small. The ones mostly studied are risperidone, haloperidol or aripiprazole. I gave you a couple of caveats. If you're adding aripiprazole on another antipsychotic besides clozapine, but if you're only adding it to clozapine, it's not an issue. Certainly worth a try. You might squeeze out a little more symptom reduction. ECT really has emerged as one of the more evidence-based strategies, generally well-tolerated. There's very small incidences of delirium and prolonged seizures. Post-treatment hypertension can occur. And some people may complain transiently of some CNS adverse effects, but it's usually not persistent. Non-antipsychotic options really have limited efficacy data. Minocycline, which is an antibiotic, memantine, topiramate, high-dose famotidine, even lamotrigine. They can be tried if you're really running out of options and either ECT hasn't worked or wasn't sufficiently effective and the patient's already on clozapine plus a stronger D2 antagonist. I think you consider these, but again, you want to do no harm and try to find those agents which are gonna be the most benign and not gonna render the patient with significant adverse effects. For example, like topiramate, which really causes a lot of cognitive impairment. And then the other thing is, when people have had trouble tolerating clozapine, you need to adjust the titration accordingly. In many institutions, both clinics and hospitals, there's a standard template and everybody uses it, but really that's inappropriate. You really have to adjust it depending on who you're treating, how old are they? Are they smoking or not? How vigorous are they? If I have a 69-year-old non-smoker who I'm starting on clozapine, that titration is gonna be very, very different than an agitated 24-year-old on a forensic psychiatric unit. I think the most important aspect is dosing it all at bedtime is the standard in North America. Do not split it up unless you're forced to for tolerability reasons. And really managing the titration early on may allow your patient to stay on clozapine because they won't develop side effects so quickly that you can't get on top of them. And the things people don't like are sedation, orthostasis, and sciarrhea early on. Most are pretty good at managing constipation, but these are other ones that can prove tricky. Again, if you titrate too quickly and the patient has the right to refuse clozapine, you really are stuck in a situation where you have nothing else to offer them. And so get really good at managing these, get good at adjusting your titration, and really talking with the patient. Say, look, if you start to develop these problems, let me know so we can back off, so we can treat these issues, allow you to develop some tolerance, and then we can kind of move on from there. Certainly, slowing the titration for orthostasis and sedation is really, really kind of the way to manage these for the most part. There are some people who may need adjunctive medicines to manage their orthostasis, but for sedation, it's really, let's go slow, let's let you get tolerant, and if we have to stretch out the titration over months, we'll do so, if that's what allows us to get you on clozapine. Ciarrhea, of course, requires a very specific kind of treatment. So overall conclusions, there's ways to manage some of these things, but you have to understand the way to approach these different problems. The metabolic issues, especially weight gain, is not unique to clozapine, but most will advocate the early use of metformin right off the bat as an evidence-based option, again, titrating slowly to minimize the risk of GI adverse effects, using an extended release preparation if needed. Seizures really occur in under 2% of people do not ever give somebody prophylactic divalpro-X. If you need to use an anticonvulsant, that is the drug of choice, bearing in mind the risks associated with divalpro-X. The risk period for myocarditis and intraditional nephritis is the first six to eight weeks. We confirm these by labs, which includes troponin and CRP for myocarditis, GFR and UA for nephritis. The eosinophil count is not relevant and is really not the way to diagnose or rule out either of these syndromes. There is a small number of hematologic abnormalities, which people should be aware of, most of which are usually time-limited, although the anemia may be more persistent, may require some more extensive workup. And then lastly, a lot of people don't respond to Clozapine simply because they're undertreated, either due to non-adherence or underdosing. Maximize the levels, push it to the point where either the patient cannot take any more or you get to the level of 1,000. And if that's the case and there's still an inadequate responder, there's some evidence-based options, with EGT really rising to the fore as being perhaps the most evidence-based and most effective option, despite the absence of double-blind randomized studies. So thank you all again for attending this lecture and I hope you find this useful in your practice and in your use of Clozapine. Thank you very much.
Video Summary
In this video, Dr. Jonathan Meyer from the University of California, San Diego discusses various aspects of Clozapine, an antipsychotic medication. He starts by addressing the issue of weight gain associated with Clozapine and explains that the primary mechanism behind it is histamine H1 antagonism at the hypothalamic level. He suggests that in addition to diet and exercise, prophylactic use of metformin can help manage weight gain caused by Clozapine. Dr. Meyer also discusses metabolic adverse events associated with Clozapine, such as dyslipidemia and hyperglycemia. He mentions that statins or fibrates are commonly used for managing dyslipidemia, especially when triglyceride levels are high. According to Dr. Meyer, seizures are easily managed and should not be a reason to discontinue Clozapine in most cases. He emphasizes that prophylactic anticonvulsants are unnecessary for over 98% of patients. Dr. Meyer also talks about diagnosing and managing myocarditis and interstitial nephritis in Clozapine-treated patients. He explains that fever in the first eight weeks of treatment should be investigated for these conditions. He mentions using troponin levels and C-reactive protein to diagnose myocarditis, and urges clinicians to be vigilant in looking out for symptoms such as malaise, flu-like symptoms, or chest pain. Dr. Meyer further discusses various hematologic abnormalities seen in Clozapine-treated patients, including leukocytosis, thrombocytopenia, eosinophilia, and anemia. He advises monitoring these abnormalities and distinguishing them from other potential causes. Lastly, Dr. Meyer addresses the management of inadequate response to Clozapine, suggesting options such as adjunctive antipsychotics, electroconvulsive therapy, or other non-antipsychotic augmentation strategies. He reminds healthcare professionals to adjust the titration rate based on individual patient characteristics and to manage side effects effectively to ensure patients can benefit from Clozapine therapy.
Keywords
Clozapine
antipsychotic medication
weight gain
metformin
dyslipidemia
hyperglycemia
seizures
myocarditis
interstitial nephritis
Funding for SMI Adviser was made possible by Grant No. SM080818 from SAMHSA of the U.S. Department of Health and Human Services (HHS). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, SAMHSA/HHS or the U.S. Government.
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