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Clozapine in the Elderly and Those with Medical Co ...
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Welcome, everybody, to this week's edition of the Closed Pete Educational Series. I'm Dr. Jonathan Meyer, psychopharmacology consultant at the California Department of State Hospitals and also clinical professor of psychiatry at University of California, San Diego. This week, we're going to talk about the use of Clozapine in the elderly and those with medical comorbidity. And we'll talk about strategies to maximize both the acceptance of Clozapine and its continuation across care transitions. So this is who I am, and my disclosures have been previously posted on the website. Here's the learning objectives for today. We're going to talk about the fact that elderly patients with treatment-resistant schizophrenia can be safely started on Clozapine. We'll talk about how to treat those who are at higher risk for adverse events, such as both older patients and those with medical comorbidities, with Clozapine, employing some common principles, such as adjustment of titrations, minimizing pharmacokinetic and pharmacodynamic drug interactions. We'll talk about how to use Clozapine safely in those with metabolic or seizure disorders. We'll look at when to re-challenge and the risks involved, and also how to develop methods for communicating and managing unique Clozapine-related treatment issues to increase acceptance and also to increase the success as patients transition across care settings. So first, let's talk about the use of Clozapine in elderly patients. We, of course, do have concerns about using Clozapine in this setting, partly because patients often will have some age-related issues which are common and which must be acknowledged, one of which includes the fact that older people have reduced serum albumin levels, so often have more unbound drug. They also have more lipophilic tissue, and this often results in partitioning of drug and extension of the drug half-life. There are age-related declines in cytochrome P450 1A2 activity, and as we'll discuss in the section on kinetic interactions, 1A2 is a P450 enzyme responsible for most of Clozapine's metabolism. Older individuals often are much more sensitive to alpha-1 adrenergic antagonism and result in problems with orthostasis. And then lastly, Clozapine is strongly anticholinergic, which can cause not only peripheral issues such as constipation or urinary retention in males, but also CNS adverse effects such as confusion, and that can be additive with the antihistaminic effects which cause sedation. One good thing, and there is a good thing, is that the early concerns that the risk of severe neutropenia was higher in older individuals have not been replicated. No elderly person with treatment-resistant schizophrenia should be deprived of a Clozapine trial on that basis. We do not have prospective randomized studies in this population, and so what we have to do is look at the retrospective literature to comment on both the tolerability and efficacy of Clozapine. So the best case series is this one which comes out of Israel, where they started a group of people, 43 individuals of mean age, almost 70 on Clozapine. And you should note that these people have been ill on average for 39 years, which I think speaks to the idea that sometimes patients are deprived unnecessarily of Clozapine simply because of age. And as we'll see, even though they are older and have been ill for a long period of time, these patients responded and had improvements in their psychiatric outcome as reflected in lower rates of re-hospitalization. Most importantly, Clozapine was well-tolerated, and none of the 43 patients had to stop their treatment due to adverse effects. They did not provide plasma levels in this paper, but the mean Clozapine dose was relatively low, 264 milligrams on average. And as we discussed, part of this may be the fact that as people get older, there are some age-related declines in P450-1A2 metabolism. Over the next five years, the psychiatric hospitalization rates were significantly lower than for the five years prior to Clozapine therapy. You can see they went down quite significantly. And during the follow-up, the mortality rate for the Clozapine-related cohort was equal to that for other older individuals with schizophrenia treated in the same clinic with non-Clozapine antipsychotics. With respect to drug metabolism and drug dosages, this is perhaps the largest case series or retrospective data that we have. These individuals called the UK Therapeutic Drug Monitoring Service for the years 1996 to 2010 to find all of the data available on plasma levels for individuals age 65 and older. So they had a sample of 778 patients, and from that, they had almost 2,000 laboratory results to examine. A couple of things we can see. The dotted line shows you the mean dose for each age group. And you can see that overall, the mean doses were quite low, 200 to 300 milligrams. Now even if we accept the fact that many of these may not be smokers, this is still quite low. And as you see in the second bullet, the ratio of Clozapine to nor-Clozapine was 1.8, which is higher than what would be expected in a non-smoker. Usually we expect levels around 1.32 for that ratio. So this also, again, reinforces the concept that lower doses may get you higher plasma levels just due to age-related issues in drug metabolism. If we look at the actual plasma level data, you can see for the group 65 to 69, the mean plasma Clozapine level is roughly above 500. So certainly, your target for treatment in that population will be above the response threshold of 350 nanograms per mL. As you can see, when patients get older and older, eventually you may be able to maintain them with levels even below 400 nanograms per mL. But I think this data speaks to the idea that the initial target for this population, in terms of efficacy, should still be 350 nanograms per mL for a Clozapine level, assuming that they haven't responded to lowered levels. So how do we manage the titration in this age population? For one thing, we have to really account for any kinetic or pharmacodynamic drug-drug interactions and really do everything you can to minimize both. Really, the most important concept is slow titrations. We really want to minimize the risks of sedation and or for stasis. Low starting doses for the first few days are strongly suggested, and the titration should be as slow as you can possibly make it. The idea is that if you give somebody orthostasis, certainly if they fall, that may be the end of their Clozapine trial, and we really don't want that to be an outcome. And we also don't want the patient to complain literally of dizziness, sedation, or other adverse effects, which may limit their, you know, desire to continue with Clozapine treatment. As I noted before in the prior article, lower Clozapine levels may result in clinical benefit. And so again, the slower titration may allow you to see those people who might respond at plasma Clozapine levels under 350 nanograms per mL. If you inherit an established patient on Clozapine who's over the age of 65, and they are both responding to and tolerating that plasma level, nothing needs to be done immediately. But as you follow that person over the ensuing years and decades, what the data show is that they may do just as well over time with slightly lower doses and plasma levels. And then lastly, aggressively manage constipation. Many of you may be aware that in late January, the FDA strengthened the warnings regarding ileus and severe constipation in Clozapine-treated patients. Although we worry very much about the consequences of neutropenia, this is not really the primary reason patients end up experiencing mortality from medical causes. It is related to poorly treated ileus. And we'll talk a bit more about that in the next section. So you have somebody who is older, maybe not elderly, they're on a bunch of other medications or they have medical comorbidity. What do you do about it? Well, the first thing and the easiest part about it is accounting for drug-drug kinetic interactions. So this is just a basic table about how Clozapine is metabolized, its bioavailability. I think most importantly, it does go through the P450 enzyme 1A2 preferentially, it does go through other P450 enzymes as well. And as we will see, there can be drug-drug interactions from both 1A2 inhibitors as well as 2D6 and 3A4 inhibitors. And opposite, there may be effects of inducers. And generally, we try to remove inducers before people start Clozapine treatment simply because their presence may make it very difficult to get a therapeutic level. This is a brief table giving you, I think, the more common strong and moderate inhibitors of P450 1A2, 2D6, and 3A4, as well as the inducers of 1A2 and 3A4. 2D6 does not appear to be an inducible cytochrome enzyme. Among the things to be mindful of is that smoking, of course, is a 1A2 inducer, but so is the PPI omeprazole. Omeprazole is commonly used for people with reflux or other gastrointestinal complaints. It is an inducer. There are another of other PPI, such as lansoprazole or pantoprazole, which can be used in lieu of an omeprazole. There's nothing special about an omeprazole. So this is something you will try to change. And among the inducers, we would like to get rid of all of these before starting Clozapine because, as I mentioned before, this may cause problems in reaching a therapeutic plasma Clozapine level. So how do we begin to approach this? So let's go through the different inhibitors. Non-inhibitors, such as fluvoxamine, can increase plasma levels as much as five to tenfold. Generally, we would say these must be discontinued prior to starting Clozapine. Again, there are some expert-level commentary out there about using drugs like fluvoxamine to boost Clozapine levels, but this should only be done in consultation with somebody who has done this before. Generally, this will be done at the beginning of treatment and fluvoxamine not added to existing treatment because, literally, you could increase their levels fivefold and this might be a fatal outcome. If you have people who are on strong 2D6 or 3A4 inhibitors, for example, they're on the antidepressant paroxetine or fluoxetine, you can keep those in place, but we would reduce the titration by 50%. And the idea is, again, the effect is not as large as it is for fluvoxamine and much more manageable simply by decreasing everything by 50%. As I mentioned before, if you have people on carbamazepine or phenytoin, really, they need to be switched to something else. This is going to cause problems and, of course, carbamazepine has its own package insert warnings about leukopenia. Rifampin is typically not a long-term treatment, so if somebody is getting rifampin as an antibiotic, one could certainly wait until that has been discontinued to begin the clozapine titration. The one most people overlook is omeprazole and, again, we have numerous alternatives to omeprazole for proton pump inhibitors, so just switch them to something else. This is the binding profile for clozapine and its metabolite. Norclozapine, again, small values mean high affinity. As most of you know, some of the highest affinities for clozapine relate to things that we don't want, like histamine H1 and muscarinic receptors. What is interesting about norclozapine is it may be an agonist in some of these muscarinic receptors, and this is probably one of the reasons why we get sciarrhea. So what do we do with some of this information? So you have to acknowledge that we get a lot of H1 antagonism from clozapine and also norclozapine, and this contributes to sedation, as well as the weight gain related to impaired satiety. Unsurprisingly, the large degree of alpha-1 blockade increases the risk for orthostasis, and this could be a big problem. We have muscarinic antagonism, which is responsible for the high rates of constipation and sadly ileus, and we have agonism at muscarinic receptors, which also gives us sciarrhea. So this is likely the only drug that's available, which is both anticholinergic in the gut, but maybe procholinergic at the salivary glands. Okay, let's talk about the big one, which is ileus. As I said before, very rarely will anyone succumb to severe neutropenia with our extensive monitoring, especially in a first world country like the US, where severe neutropenia is picked up immediately and people get treated immediately. On the other hand, sadly, there continue to be deaths from ileus, and this is really a preventable problem. Number one, you have to know what are the anticholinergic drugs out there and do something about them. So this is a list, which I use commonly in doing some data analyses within the state hospital. The big offenders are chlorpromazine, olanzapine, especially in higher doses, quetiapine at higher doses, and tricyclics among the psychotropics, obviously the anticholinergic antiporkinsonians people are familiar with. Some people are not familiar with some of the non-psychiatric medications used for overactive bladders, such as oxybutynin and the others. These are all designed to be strongly anticholinergic. And then last on this list, we have glycopyrrolate. The unique value of glycopyrrolate might be for individuals with sialorrhea, which is not controlled by local medicine, such as atropine drops in the mouth or ipatropium spray in the mouth. Sometimes we have to use glycopyrrolate when the locally applied medicines don't work, and where there is no access to botulinum toxin injections into the salivary glands for sialorrhea. But if you ever use glycopyrrolate, you really have to be aggressive in managing the problem with ileus, because you've now added a second constipating medication on top of clozapine. The other constipating medicines to be aware of, of course, are iron and opiates. So what does one do? Most importantly, if you inherit somebody or you have a patient where you want to start on clozapine, who, for example, is on chlorpromazine or high-dose olanzapine, generally what we would say is these will be cross-tapered as clozapine is added, with the eventual goal of complete discontinuation of the other anticholinergic medication. If at the end of the cross titration, you have trouble, for example, getting rid of that last 10 milligrams of olanzapine, because seemingly they benefit from some of that dopamine blockade, generally we would say, find another antipsychotic which can provide that D2 blockade without the anticholinergic burden. The easiest agents to get rid of during the cross titration are the anti-Parkinsonians. For example, you have somebody who is on 15 milligrams a day of haloperidol and one milligram BID of benztropine. What does one do? So assuming that you can't taper these off before starting clozapine, during the cross titration, we would substitute these in the ratio of 50 milligrams clozapine equals one milligram progentin for nonsmokers. If these are smokers, then the ratio is 100 of clozapine is one of benztropine. But the idea is clozapine is strongly anticholinergic and will provide all of that property that you were getting from benztropine. You should never have a patient on benztropine or clozapine chronically, only during a period of cross titration. And then the non-psychiatric medications are important. Most internists are simply not familiar with the pharmacology of clozapine and you really have to discuss with them that clozapine is strongly anticholinergic and we simply cannot combine clozapine with medicines such as oxybutynin, darufenicin, and the like. If there is an issue of overactive bladder prior to starting clozapine, then a consultation with a urologist might be helpful to see if there are alternative solutions. Again, the idea is if somebody is on one of these anticholinergic medicines, then they should be tapered off as clozapine is added. If you combine clozapine with another anticholinergic, you double the risk of ileus, and this is simply unacceptable. If you have somebody who is on iron, we generally would say it's okay to stop the iron for a period of time when they're starting clozapine. For most patients, stopping iron for six or eight weeks is not going to be a significant medical problem. You're going to be getting routine CBCs and the main instance is if you're getting a finger stick, you could also just get a venipuncture CBC for the indices and looking at iron stores as well. Once the patient is established on clozapine and their constipation is well controlled, then you could add the iron back and then, of course, make the appropriate adjustments in their constipation regimen to keep them going. The same will be true for that rare individual who also might be on opiates. There also is a very specific medication for opioid-induced constipation, and this should be employed. I, in fact, have actually never seen anybody on chronic opiates and clozapine, but I suppose there must be one human being out there. Perhaps the most important concept on this whole slide is that medicines which are commonly used for constipation, like psyllium, cannot be used in clozapine-treated patients. Psyllium is appropriate, and these are agents like metamucil, for people who have garden-variety constipation, which means their transit time is around 50 hours, which is about twice normal. People on clozapine who are constipated have colonic transit times which may exceed 100 hours. If you add psyllium in this context, it sits around for such a long time in the colon, it actually dries out and forms a gel. This will exacerbate the problem. And so we would say as a rule of thumb, psyllium should never be used to manage clozapine-related constipation. Again, this is a concept that many internists or those trained in internal medicine or primary care will be unfamiliar with because psyllium is so commonly used for the type of constipation they see, but this is a whole different level of constipation, and psyllium should not be used. Okay, ornithostasis and sedation, of course, are often modifiable by adjustment of the cross-titration. I think, again, one has to be mindful of which agents, especially among the psychotropics, might be contributing to this problem, as well as other medications like the older ones which are used for BPH, prazosin or tirazosin, and, of course, antihypertensives. So here's some basic approach. Those older medicines like prazosin really are not the standard of care for people with prostatic hypertrophy, and most prefer tamazolosin just due to the lower incidence of orthostasis. Of course, you'll adjust your titration of clozapine. If you start to run into problems with orthostasis and the patient is on antihypertensives, discuss with the provider prescribing these about adjustment of the doses of those blood pressure medications. And then, lastly, of course, you'll cross-taper the offending antipsychotics as clozapine is added. There are concerns about additive sedation when people are on benzodiazepines, especially if they've been added very recently and the patient's not tolerant to the sedating effects. So the general approach is to taper down benzodiazepines as much as possible prior to starting clozapine. But if you do have people who are on stable doses, so you have a patient who's been on one milligram of clonazepam for over a year, they're tolerant to this, they show no evidence of sedation, you don't have to stop this prior to starting clozapine, but I think the idea is that this should be gradually tapered off during the first month of treatment. Some patients may have a lot of risk factors, but you would like to re-challenge them simply because you have no other alternatives. So what is it that you want to do? Let's look first at the case of Ilias. So the case for re-challenging somebody with Ilias, even with bowel restriction, is strengthened particularly when their prior treatment, we would say, is suboptimal. So for example, we had a patient at the state hospital who previously, in prior years, developed Ilias, had to go to surgery, but sadly this person was never given one of these new intestinal secretogogues which are quite effective. And unfortunately, they were also given cilium. So particularly when you see these instances where there was suboptimal practice, the patient was on multiple anticholinergics along with clozapine and got Ilias, or there was use of cilium, or for whatever reason, none of these newer agents were used to manage their constipation, I think you can say, you know, there were prior management issues which resulted in the Ilias problem, but we think we can do better. And also, we have nothing else to offer this patient in terms of their psychiatric response. So let's go ahead and give it a try. How do we do this? Generally we would say, for one, don't make the mistakes that the other provider made, you know, make sure there's no anticholinergics on board, make sure there's no cilium on board, and also start the secretogogue prior to or concurrent with starting clozapine along with docusate. Most of you know that when you start clozapine, we'll give everybody docusate, but the idea these people who are at such high risk, we would like to start something much more effective. And so we have a list here of four agents which have been approved over the years, would be Prostome, which is ametiza, linaclotide, which is Linzess, and then the two newer ones, plicanotide and bucalopride. Among these four, personally, I have less experience with the latter two, plicanotide and bucalopride. Among the first two, I think we're getting a sense that maybe linaclotide might be a bit more effective, and I would just endorse on the basis of no systematic data, but just anecdotal experience that between these two agents, which are equally inexpensive to some extent, a few hundred dollars a month, I would tend to vote for lenacletide. If that is not enough, then you add other agents as needed with the goal that this patient will never need PRN medications, will never complain of straining or constipation. Other patients may have had problems which resulted in clozapine discontinuation. So let's talk about these. Number one is seizures. Seizures these days are really almost never a reason to stop clozapine, but perhaps in the past, it was stopped for a variety of reasons. I think we would say that these are people who absolutely should be re-challenged. Most people, even if they have a seizure disorder, could be maintained successfully on clozapine, and this should not be a reason that they should not be re-challenged. Some people in the past, especially those with really poorly bandaged diabetes or unrecognized diabetes, developed ketoacidosis or hyperosmolar hyperglycemic states. If this happens, again, we would treat the acute medical problem. Once the person has stabilized, there's no reason, again, not to resume clozapine, but this time with much tighter glycemic control and monitoring. So one of the big concerns, of course, is myocarditis. As many of you know, untreated myocarditis or unrecognized would be fatal. When people develop myocarditis, this was often a very sad event because the concern was whether we could actually re-challenge these people. And again, if they need clozapine, we really have almost no viable options for their treatment-resistant schizophrenia. So as of 2018, there were seven reported cases of re-challenge, and 11 were successful, so about 2 3rds. There was no one factor that predicted successful re-challenge, but I think the recommendation, if you're considering this, is that you wanna have a cardiologist on board. You'll have diligent monitoring of both their vital signs, temperature and blood pressure, and also very frequent monitoring of the troponin and C-reactive protein to track whether you start to see a trend up in the latter two particularly. We would always suggest the world's slowest titration in these circumstances, because if it does reoccur, it may be very quickly, and we will like this perhaps to be a slower event so we can get on top of it and stop clozapine. If people have had other, what we'd call immune-related problems in the past, such as interstitial nephritis or the DRESS syndrome, as of now, we would consider these not to be candidates for re-challenge. Cardiomyopathy presents sort of a different set of issues. This tends to be a later occurrence in clozapine treatment. Often, the patients really have no alternatives, and it becomes an ethical question of whether stopping clozapine will get much improvement in their ejection fraction, and whether the patient really wants to tolerate that. There will be instances in which you have patients who really do have decision-making ability who will say, I would rather not be deprived of clozapine. I'd rather stay on it, even though I know my lifespan will be relatively short. At least I'll have mental clarity and stability. There are pre-published cases in which patients were aggressively treated for their cardiomyopathy, and then clozapine was reinstituted, and their ejection fraction remained stable. And so this becomes, again, one option for certain patients. We say, how about if we take away your clozapine? Let's see how much better we can make you with the full medical options for the management of cardiomyopathy. And then we will add back clozapine. At least we have three cases. It's a small sample size of which this seemed to work out, and the ejection fraction did not worsen. Priapism and venous thromboembolism are also two very concerning events. So there are some cases where people have tried to re-challenge, but some people may experience recurrence. Again, the concern with priapism is that this person may in fact become permanently impotent. But there are three cases of successful re-challenge. And so this also will involve a lot of discussion with the patient and other stakeholders regarding whether in fact the patient understands the consequences of the re-challenge. Really, we're talking about permanent impotence for the most part. And whether they might be willing to consider options which could diminish priapism recurrence rates, such as surgical shunting within the penis or the use of antiandrogen agents. So there's a lot here to talk about. And again, it's important to have everyone on board with this to decide what options should be taken, whether re-challenge should be even considered, does the patient understand the consequences? Do they have the capacity to consider some of these options to maybe diminish the recurrence rate? Again, some patients may be intelligent enough to say, you know, I don't really mind being impotent because I was so miserable when I was off of Clozapine. I would rather choose that. But if there's something that can be done, perhaps with the use of an antiandrogen or surgical shunting, maybe I'd be willing to consider that. So venous thromboembolism literature is very interesting. For one thing, although Clozapine is sometimes wrongly identified as an agent of much higher risk, when you review the literature, it's not entirely clear that this is the case. That being said, if somebody develops a venous thromboembolism, the first time it's treated and will continue to Clozapine, typically they will be on anticoagulant medication for a period of time. If they have a second one, then they usually get more workup for a primary hypercoagulable state if that did not already happen. At that point, the considerations include, you know, maybe switching from Clozapine to an agent which theoretically may have lower risk. When I say theoretically, the literature very clearly indicates that we have a group of people with schizophrenia on antipsychotics who appear to have some innate risk and the differences between agents are not particularly large. So the idea that somehow by switching from Clozapine to Olanzapine, you're gonna be free of risk of this problem really is not an evidence-based decision. Also, the fact that this patient will now have probably a problem with their psychosis, it has to be taken into account. One of the other options for somebody who's had now a second episode of a venous thromboembolism is of course a lifetime anticoagulant therapy. There's sort of burdens of monitoring for some of the older agents such as Warfarin. We have newer direct anticoagulants, but for them, the risk is one of bleeding. And then lastly, does the patient have decision-making capacity? What are their wishes in this area? What can they be safely treated with? What seems reasonable? Is this somebody who could be treated with a direct anticoagulant? Maybe Warfarin is no longer necessary if we have somebody who understands the risk of bleeding and what to do about it. So there's a few things to consider, but I think again, the first one, that switching from Clozapine to another antipsychotic somehow markedly decreases the risk of this problem, I think is really not an evidence-based decision. And then every once in a while, we'll run into people who are deprived of Clozapine simply because of lab abnormalities. So we certainly see, not uncommonly, that there are some people who can have early increases in liver function tests. So the AST and ALT exceed three times the upper limit of normal. So early on, sometimes there was concern that there's systemic illness, but in the absence of severe problems in the past, we would say that these are individuals who could be successfully resumed on Clozapine, maybe with more careful monitoring and also perhaps with a slower titration. We're not sure why some of these people have these transient bumps in their transaminases, but again, in the absence of other viable options for managing their treatment-resistant schizophrenia, we would say, if the only problem in the past that caused discontinuation was simply the isolated liver function test abnormalities, there was no evidence of systemic reactions, we would say, go ahead and we challenge this patient, perhaps simply do a slower titration. And of course, as part of their weekly labs, it would make sense to throw in now the liver function tests just to track how they do. In other instances, you'll have patients who develop elevations of their transaminases as a more insidious process. They've been on Clozapine for a number of months or maybe years, and their LFTs go up. People wonder what to do. In those cases, the idea that this is somehow a Clozapine-related drug reaction seems unlikely. And often what we have found is that there are other things to be considered. The biggest one, for example, is that either another medication has been added in the interim, such as Diprox, which itself can cause elevations of liver function tests, or the more common one is the patient has gained weight, they become somewhat insulin-resistant, and now they have non-alcoholic fatty liver disease. So NAFLD, non-alcoholic fatty liver disease, is quite common when people gain weight. There often is associated changes in serum lipids, especially elevated triglycerides, which indicate the problem with insulin resistance, and often there's an elevated fasting glucose as well. If they're not overtly diabetic, many are pre-diabetic or meet criteria for metabolic syndrome. The first thing we always consider when the patient has been on Clozapine and gained weight is really fatty liver. And for these people, the initial workup is a right upper quadrant ultrasound, which typically will confirm the increased echogenicity of the liver, and in those instances, we will take measures to try to minimize the impact of insulin resistance through both exercise, if we can get the patients to do it, dietary modification, and the use of metformin. Lastly, eosinophilia is an interesting topic because prior package inserts often presented thresholds for eosinophil counts for stopping Clozapine, and you may, in fact, run across somebody who had their Clozapine stopped for no other reason than their eosinophil count went beyond a certain threshold. This is no longer a reason to hold Clozapine in the US, and particularly when there was no evidence of systemic involvement, myocarditis, nephritis, DRESS syndrome. All of these patients should be re-challenged. Again, when there was no evidence of systemic involvement, we do not consider eosinophil count now to be a reason to do anything different except to examine the patient and make sure there's no evidence of systemic disease. As was talked about in a prior lecture, the period of risk for things like myocarditis, nephritis, or DRESS syndrome are usually within the first 60 days. So certainly when the patient had an eosinophil count elevation beyond that, this is simply an idiosyncratic reaction to Clozapine itself, doesn't portend anything bad, should not have been a reason to hold it in the past, but certainly is not a reason to hold it now and is not a reason to avoid re-challenging that individual. So severe utopaine, of course, is the big one where people will ruminate a lot about what we should do. In the past, these people were deemed un-re-challengeable and in fact, in most countries throughout the world, that language still exists. Thou shalt not re-challenge those patients. Now, with the revised package insert, we have some language which says, look, you may be willing to reconsider this. There may be other things which happened during that time, which may mitigate your decision-making. For example, I consulted on a patient who was starting on Clozapine and for some reason at the same time, it was decided to treat their hepatitis C with some of the older drugs, which caused neutropenia. So that interferon-ribavirin combination was started about six weeks into the Clozapine therapy, completely bottomed out the initial fill count. Of course, they had to stop the Clozapine. But we said, we think there was a circumstance there which was unwitting to Clozapine. Let's re-challenge that individual with very frequent CBC monitoring. We actually suggested three times a week for the first couple of weeks and then tapering down to the usual weekly schedule by the end of the first month. The comment in the package insert, I think should be respected though. In general, we're not gonna re-challenge patients who have had severe neutropenia on Clozapine. But of course, as I noted in the book, there is a literature of about 30 cases as of 2017 where people with a history of various types of neutropenia were re-challenged with Clozapine, including some with severe neutropenia. Many of these people were able to continue Clozapine. But I think if you are considering doing this as somebody who has had severe neutropenia, you wanna have a lot of documentation, a lot of case conferences among all the stakeholders, which is patients, caregivers, anyone else involved in their care. You have to have expert guidance, not only from a hematologist, but also from somebody who has done this previously and feels comfortable with using what will be needed, which is filgrastim at times to support their neutrophil counts. This is something not to be taken lightly. On the other hand, because we often have no other alternatives for these individuals, it's something that on a case-by-case basis should be considered. So you finally talk to patients that take in Clozapine or they're worried about it. What can we do to improve their acceptance? And once they're on it, how can we maximize the chances of success once they transition out of our setting, especially from an inpatient to an outpatient setting? So among the evidence-based methods to increase acceptance include really talking with them about the fact that the response rates for Clozapine and treatment-resistant schizophrenia on average are around 50%. And for everything else, it's virtually zero. The concept that they'll try another drug, which just came out, really does not make a lot of sense. Sadly, what has often happened in the past is that you had other providers who spent a lot of time talking about Clozapine's adverse effects and not the fact that trying a new drug is really a waste of the patient's time and has almost zero chance of managing their treatment-resistant schizophrenia. I also talk about decreased rates of psychiatric hospitalization, lower rates of suicide, and lower rates of all-cause mortality. So I'm gonna talk about the fact that this person has suffered, that the statistics show that no new drug out there is likely to have any benefit whatsoever, and that also we're much better at managing the adverse effects, and that what they were told previously may simply have been wrong or a gross distortion of the risks related to Clozapine treatment. One of the great inventions now in the last couple of years is this point-of-care device for neutrophil counts. And so I would say, look into this seriously. It gives people a lot more flexibility about when and where they get the neutrophil counts. You get the results back within minutes. And most importantly, it is much less uncomfortable than a venipuncture. If people really have to get venipunctures because the point-of-care device is not available, use topical lidocaine, use vapor coolant spray to numb the site, whatever you can to make that a less painful procedure. And then, of course, as you're starting Clozapine, don't take one of the other drugs until Clozapine is effective. Now, sometimes we will have to cross-taper strongly anticholinergic antipsychotic, such as high-dose olanzapine or chlorpromazine. But routinely, if I have people on high-potency agents or non-sedating or non-anticholinergic antipsychotics, I see no reason not to leave those on board as Clozapine is added. They're not gonna cause additive adverse effects if the other antipsychotic doesn't cause sedation or orthostasis or is not anticholinergic. And then once Clozapine becomes effective, I can taper those off. But I think sometimes people are still concerned, for example, about the overlap between olanzapine and Clozapine and the risk for ileus. They take away that olanzapine too quickly before Clozapine is even close to being therapeutic. While the threshold of 350 nanograms per ml is a good starting place, again, many people may need much higher levels for response. So don't assume, based upon levels that were obtained at earlier doses, that, oh, the patient should be at a level of 350, I can take away the other antipsychotic. Whether they will do well or not is really something we often cannot predict for a given level. If someone will respond to 350 or not, you will only know you take away the other antipsychotic. But I would say, take away the other drug quite slowly so that if you realize the Clozapine is not yet effective, despite having a level, for example, of 400, you can backtrack a bit, get them stable, and then continue with the Clozapine titration. And then lastly, people, of course, often get started on Clozapine on inpatient units. Sometimes barriers to going to lower levels of care include the fact that people are really concerned about whether they will take the Clozapine or even in an outpatient area, going from a more structured to a less structured setting has to do with, can they even maintain themselves? Are these people who just need very, very high levels of case management, which may not be available locally? Is this somebody who always lapses into substance use once they're outside of a controlled setting? And these are always realistic considerations which have to be handled on a case-to-case basis. If you are the provider who has started somebody on Clozapine on a more controlled setting, like an inpatient unit, it's really critical that you document the plasma Clozapine level at which the patient responded and whether the patient is a smoker or not. If they are a non-smoker, many of these patients, as soon as they get to a place where they can smoke, will resume their smoking activity. If the patient is expected to resume smoking, one must educate the new providers that the Clozapine levels will be driven down by about 50%, and they must start tapering up the dose of Clozapine to get their plasma level back to where it was when it was therapeutic as a non-smoker. Some providers understand this, but they don't understand how quickly they need to act once the person resumes smoking. Once I start smoking, I can fully induce my cytochrome P450 enzyme within a week and drop my levels over two weeks. So this is something which has to be acted on fairly quickly, and again, if you know the person's gonna smoke, it's not a big deal. You simply say, look, when they were a non-smoker, they responded to a dose of 400 milligrams at bedtime, and on that dose, their Clozapine level was 450. We would expect them, once they start smoking, that their level's gonna go down 50%, and so we're gonna have to bump their dose by about 50%, and they will likely need a dose now of 600 milligrams at bedtime. If they're gonna start smoking on day one, as soon as they leave the inpatient unit, you might as well have a planned titration over the next couple of weeks to get them up to that dose of 600, and then recheck their dose at steady state after about a week on that dose to get the new level. Because people often on Clozapine require a number of adjunctive medications to manage things like salaria, they're really bad constipation, where every once in a while, we'll have to use adjunctive lithium to boost the neutrophil count for somebody who keeps dipping below that threshold, which now requires more intensive monitoring. You must communicate the reason why. Otherwise, somebody will say, well, this patient has schizophrenia. They're not schizoaffective bipolar. Why do you want lithium? The patient has no idea. They stop the lithium. Then the neutrophil count goes from 1,600 to 1,400, and of course, now the patient has to get stuck more often, and it becomes a whole big fiasco. Lastly, the important medical issues, as I alluded to before, have to be communicated, why they're on certain medicines, why certain medicines should be avoided. Again, in the outpatient world, not everybody understands, for example, that you should not be using psyllium to manage constipation, that there are these new secretogons available, which are very effective, and so you often have to do a bit of education in your discharge summary to indicate this is what should be done. The idea is you wanna provide as much information to somebody who may not be quite as expert as you to make this transition as successful as possible. So in conclusion, people should not be deprived of clozapine simply on the basis of age. We had that wonderful case series of Israel, 43 people, almost age 70, all of whom were successfully started on clozapine with reduction in psychiatric hospitalization. Of course, when you have older people or individuals with medical comorbidity, you have to account for both drug-drug interactions of the kinetic variety, as well as the pharmacodynamic interactions. Minimize these as best you can or account for these during the cross titration to minimize the dynamic interactions or adjust the titration doses if people are on inhibitors, which will increase clozapine exposure. If you're considering re-challenge, these should be done on a case-by-case basis, and really depends on the reason for prior discontinuation. For things such as seizures, we would say these people are always re-challenged. It was for ileus, and especially with a treatment previously with some optimal, we would say these people should be re-challenged. Other conditions require a lot of discussion among the patient and stakeholders about how to do this and how to do this safely. And then as people transition between settings, communicate as best you can with the person who's going to be inheriting the patient. It's often best if you can actually do this over the phone. You can talk to them, explain the issues, go through the treatment plan, why they're on certain adjunctive medications, what their target level is, if there's gonna be a change in smoking status. And of course, communication is the best way as you get people started on clozapine or to get them started on clozapine to get them and their caregivers to accept clozapine treatment. And do whatever you can to minimize the burdens of the weekly neutrophil counts by either getting a point-of-care device or simply using topical anesthetic agents to minimize the pain of venipuncture. Thank you very much.
Video Summary
In the video, Dr. Jonathan Meyer discusses the use of Clozapine in elderly patients and those with medical comorbidity. He emphasizes that elderly patients with treatment-resistant schizophrenia can be safely started on Clozapine, and outlines strategies for treating those at higher risk for adverse events. He also discusses the use of Clozapine in those with metabolic or seizure disorders, and the risks and benefits of re-challenging patients who have previously discontinued Clozapine. Dr. Meyer emphasizes the importance of thorough communication and management of unique Clozapine-related treatment issues to increase acceptance and success as patients transition across care settings. He also discusses the use of point-of-care devices for monitoring neutrophil counts and offers recommendations for managing side effects such as constipation and orthostasis. Overall, the video provides insights and recommendations for safely and effectively using Clozapine in elderly patients and those with medical comorbidity.
Keywords
Clozapine
elderly patients
medical comorbidity
treatment-resistant schizophrenia
adverse events
metabolic disorders
seizure disorders
communication
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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