Hello and welcome. I'm Dr. Donna Roland, Director of the Psychiatric Mental Health Nurse Practitioner Program at UT Austin School of Nursing, and also the nursing expert for SMI Advisor. I'm pleased that you're joining us for today's SMI Advisor webinar, Leveraging Knowledge of Clozapine's Pharmacodynamics and Pharmacokinetics to Improve Outcomes. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. Today's webinar has been designated for 1.0 AMA PRA Category 1 Credit for Physicians and one Nursing Continuing Professional Development Psychopharmacology Contact Hour. Information for participating in today's webinar will be available until August 15th, 2021. Slides from the presentation today are available in the handouts area, found in the lower portion of your control panel. Select the link to download the PDF. Please feel free to submit your questions throughout the presentation by typing them into the question area found in the lower portion of your control panel. We'll reserve 10 to 15 minutes at the end of the presentation for Q&A. Now I'd like to introduce you to the faculty for today's webinar, Dr. Robert Cotes. Robert Cotes is an Associate Professor at Emory University School of Medicine in the Department of Psychiatry and Behavioral Sciences. He serves as the Co-Director of the PSTAR Clinic, Persistent Symptoms Treatment Assessment and Recovery. Also as Director of Project AERO, Achieving Recovery Through Resilience, Optimism and Wellness and Co-Director of Open Dialogue Atlanta at Grady's Outpatient Behavioral Health Clinic. He's an investigator for multiple research studies focused on treatment options for psychosis. His research focuses on clozapine, mitigating cardiometabolic side effects of antipsychotic medications and first episode psychosis. Dr. Cotes, thank you for leading today's webinar. Donna, thank you so much for that introduction. It's great to be here. Donna is also very knowledgeable about clozapine and can give this talk just as well as I can. So it's great to have her as a moderator. And thanks again to everybody for tuning in. So here are some disclosures. I've received research funding from Otsuka, Lundbeck, Roche, and Alkermes. And I'm a consultant to Saladex Biomedical that makes an assay for clozapine levels and the American Psychiatric Association. So today's talk is really about fine-tuning your clozapine practice. And there are four learning objectives here. And at the completion of this activity, what I hope you'll be able to get from it is that you can list three common drug-drug interactions with clozapine and if they increase or decrease clozapine levels. Then list three scenarios when obtaining therapeutic drug monitoring for clozapine per the ASCP-AGMP guideline would be valuable. Then we'll calculate clozapine's metabolic ratio and use this information to guide clinical decision-making. And then we'll also talk a little bit about how clozapine may work and two hypotheses about its unique efficacy in treatment-resistant schizophrenia. So the outline for today's talk is we're going to give an overview of persistent symptoms of psychosis. Then we're going to talk about pharmacokinetics, and that's what the body does to the drug. Then we're going to talk about pharmacodynamics, and that essentially is what the drug does to the body. And then a combination of those things are sort of involved in clozapine side effects, which we'll talk about. And I think this is important because clozapine has a narrow therapeutic index. So knowledge of both its kinetics and its pharmacodynamic properties are useful for clinical care. So we're not going to spend too much time on the overview, but I think in sort of working in a clozapine clinic over the last decade, the whole term of treatment-resistant schizophrenia is probably misnamed. And I think that it does, just the name instills a bit of a hopelessness. And people who have treatment-resistant schizophrenia actually can respond quite well to clozapine. So I like to say persistent symptoms of psychosis, and we will talk a little bit more about those. So TRS we know is costly to the system. Individuals have high rates of suicidal ideation, high rates of smoking, and substance abuse. And estimates are sort of difficult to get a great handle on this, but about 20 to 30% of people with schizophrenia have some degree of treatment resistance. And in a prospective study, looking at 392 never treated people with schizophrenia, you can see a little bit about the remission rates at three years during follow-up treatment. And you can see that the remission rate for symptoms was 60%, for functioning it was 45%, for well-being it was 57%, but then 14% never fulfilled any remission criteria. And I think that what is important to take away here is that schizophrenia has a heterogeneous course. Some people will have a chronic course, some people will have more of a relapsing-remitting course. So I think the heterogeneity, both from the clinical perspective and from the biological perspective is important here. So we didn't used to have a consensus definition for what TRS actually was, but in 2017, the TRIP guidelines were published that specify exactly what the criteria are for treatment-resistant schizophrenia. And the key thing to take away from this is that it involves two or more antipsychotic medication trials that have not been successful. And this is in contrast to the clinical belief that, you know, clozapine is a last resort option for individuals with treatment-resistant, you know, for people with schizophrenia. Really, after people have failed two antipsychotics, we should be thinking about clozapine, not nine antipsychotics or seven antipsychotics. So the FDA has only one medication that's approved for treatment-resistant schizophrenia, and that's clozapine. We know that although 20 to 30% of people with schizophrenia have treatment resistance, only about 5% of individuals with schizophrenia are actually prescribed clozapine in the U.S. And I think that there's a number of reasons why that's the case, but sometimes it's our own hesitancy or our own lack of knowledge that may sometimes get in the way of clozapine prescribing. So the APA Schizophrenia Guidelines that were published last year talk about three main reasons for when to use clozapine. The first is sort of in line with the FDA indication we just talked about, minimal or no response to two trials of antipsychotics. The second is also an FDA indication. People with schizophrenia are treated with clozapine if the risk of suicide attempts or suicide remains substantial despite other treatments. And then the third is about the risk of aggressive behavior remains substantial despite other treatments. A little bit more about clozapine and suicide. People with schizophrenia are at increased risk for suicide attempts and completed suicide. And one meta-analysis suggested that a lifetime rate was about 5%. And we know from the Intercept Study that clozapine was associated with less suicidal behavior and suicide attempts than olanzapine. And this is also true in more naturalistic data in the Swedish and Finnish registry studies where clozapine tends to have an advantage in mortality. Next, we also know that clozapine has unique effectiveness for violence. And in this set of studies, individuals who were prescribed clozapine had superior results in comparison to those who received olanzapine or haloperidol in reducing assaults for inpatient hospitalized folks. And the difference was even more profound if individuals had a diagnosis of conduct disorder before the age of 18. So I think by the, you know, when you're thinking about TRS, Jim Rohrig had some helpful framework to think about this using the five C's. The first thing is to make sure you have the correct diagnosis. You know, maybe the person has depression with psychotic features and they're not getting better because the depression is not being treated, comorbidities including substance use disorders, PTSD, anxiety disorders, compliance, better known as adherence or medication consistency is an issue. And then concentration of antipsychotics, we'll talk about using plasma antipsychotic levels. And finally, continuous psychosocial stressors and just sort of how responsive can things be to medication. In taking a systematic approach is extremely important, especially when you're working with folks who are on clozapine. So using brief rating scales for positive symptoms, trying to figure out what it is you're targeting is really important. And one example of this is the CRD-PSS, which is the clinician rated dimensions of psychosis symptoms severity, or then that's found in the back of the DSM-5. Okay, on to pharmacokinetics. So clozapine is rapidly absorbed to the GI tract, it reaches peak plasma concentration within two hours. It's not affected by food, and it usually takes about five days to reach steady state concentration. Clozapine exhibits linear pharmacokinetics, which means that the concentration during the therapeutic ranges really only depends on the dose and the half-life will remain constant. So it's different than something that has nonlinear pharmacokinetics in which there's saturation of a major metabolic pathway or absorption pathway. It's bound to protein. It undergoes significant first path hepatic metabolism, mostly by the SIP system. It's also a substrate for the PGP-E-flux transporter. You can see here that clozapine has a number of metabolites. The two major metabolites that clozapine has is endosmethyl clozapine or norclozapine, and then clozapine anoxide. And the half-life for clozapine is about 10.5 hours, 19.2 hours for norclozapine, and then clozapine anoxide is an inactive metabolite that actually sometimes gets converted back to clozapine, and that has a shorter half-life. These half-lives are actually important when you're thinking about the metabolic ratio for clozapine and you're looking at clozapine versus norclozapine ratios. So a little bit about clozapine levels in general. Clozapine levels should be drawn 12 hours after the last dose or right before the AM dose if you're doing BID dosing. Clozapine levels can help you to make sure that you're in the ballpark of where you should be from an efficacy and tolerability standpoint. And the AGMP guidelines recommend the clozapine level between 350 to 600. The risk of adverse drug reactions increase at levels greater than 1,000. So I like to show this normogram over here because it shows the variability in clozapine can often be sort of understood based on people's sex, age, and smoking status. And you can see that to get to a level of 350, a male smoker would need to have 525 milligrams of clozapine, whereas a female non-smoker would have to have 265 milligrams of clozapine. So that half as much. So a big range. A big question I had for this talk is how do you make a pharmacology talk fun? And one way you can do it is by having a wheel of drug-drug interactions. Okay, so clozapine is broken down by multiple CYP isoenzymes. The most important one is CYP1A2, especially at low doses of clozapine. And we will talk about CYP1A2. So highlighting CYP1A2 for a moment, the inducers of CYP1A2 decrease clozapine levels. And that includes aerohydrocarbons, broccoli, insulin, modafinil, and omeprazole. But the big one here really to think about is our aerohydrocarbons and omeprazole. Inhibitors increase clozapine levels. And the two main ones to think about are ciprofloxacin and fluvoxamine. So this can happen if you see someone in the emergency room and they receive CIPRO for some sort of infection, and then you can see just an extremely high clozapine level because of that. I usually tell my patients, if you get prescribed an antibiotic, let me know and we'll talk about it and make sure there's not an important drug-drug interaction. So let's talk a quick, let's give a quick case example here. This is a guy that I was working with earlier this year, 22-year-old male, stable on 800 milligrams of clozapine, doing well, he's in school. He met with us in early March to pick up medication and to get labs. This is sort of what his clozapine levels have looked like over time. X-axis we have the date and Y-axis we have clozapine level in nanograms per mil. And you can see that the clozapine level was sort of running between, kind of running all over the place a little bit, but mostly around 500, 600, some 800 readings. And then when we saw him, there was a big spike in a clozapine level and his clozapine level was 1600. And that was, you know, a bit unexpected. And we were wondering what was that about? And we looked and scoured the electronic medical record and it turned out that he had a seizure in an outside hospital in early March that you kind of had to take a deep look to find. So what some approaches to, you know, thinking about unexpectedly high levels, you have to do a little bit of detective work. So you have to look for increases in side effects. So this particular person was, you know, tolerating the medicine fine at the moment that we saw him. There was no evidence of the toxidrome. We definitely did consider a laboratory error, but because he had the seizure, we were, you know, definitely more concerned about that. And that was several days before we saw him. He didn't tell us about it, which was interesting. Then you know, if somebody has a high level, you have to consider kinetic issues, adding an inhibitor or the removal of an inducer. And then if people are actually demonstrating features of the toxidrome, you want to reduce the dose to get to a level of less than a thousand. So for this young man, basically he went from smoking a pack a day to stopping completely and vaping instead. And this is something that you need to know about from your patient. So the interaction here is that the aryl hydrocarbons bind to the aromatic hydrocarbon receptor. That protein then binds to the CYP1A2 promoter region, which it causes an increased expression of mRNA. And this causes an induction of CYP1A2, and it can happen with up to seven to 12 cigarettes per day, and it can almost double clozapine levels. So after he stopped smoking, he started vaping, his clozapine level shot up, and then he had a seizure. So when we met with him, we reduced the clozapine dose. Okay, next, a little bit about CYP2D6. And this is important because many mental health medications that are prescribed are often inhibitors of CYP2D6, including many commonly used antidepressants. So I have them up here, fluoxetine, paroxetine, proprion. There are inducers of CYP2D6 as well, including dexamethasone, rifamicein, and haloperidol. So those are some more to keep in mind. Next, we have CYP3A4. And CYP3A4 may have even a greater importance at higher clozapine concentrations. And the classic inducers include phenytoin, carbamazepine, and rifampin. And then the inducers will increase the level, and you can see some of the inducers here. So we've been talking a little bit about therapeutic drug monitoring. And the recent AGMP guidelines on therapeutic drug monitoring strongly recommend therapeutic drug monitoring for some antipsychotics, which are listed here, clozapine being one of them. And then there are five others, which include flufenazine, haloperidol, lanzapine, parazine, and profenazine. And they suggest that TDM may be helpful in the following situations. If you're uncertain about adherence, if there's a lack of response within established dose ranges, maybe there's a kinetic issue, or maybe somebody's an ultra-hypermetabolizer. For symptom recurrence during maintenance treatment, high or low body weight, certain populations, pregnancy, elderly, children, people with intellectual disability, acute or chronic inflammatory conditions, postoperative care for restrictive GI resections, switching between oral and LAI agents. And the reality is, if you don't check the level, you're not going to know what the... There's really not a good way to guess what the level is going to be. And in this study, they actually found that only 33% of individuals who were on clozapine had a level between 350 to 600 nanograms per mil. I want to talk a little bit about the metabolic ratio. And the other way that you can look at this is the CD ratio or the concentration dose ratio. We're going to talk about the MR ratio here, clozapine versus norclozapine, and it can help you to look at things over time and understand if there's an inhibitor or inducer present. The expected metabolic ratio for a non-smoking male is 1.32, and that doesn't change during poor adherence unless clozapine is taken just prior to the level. So this table will help you to interpret the metabolic ratio, and what you would expect is 1.3. But if there's an inhibitor around, or if the person's a 1A2 or CYP2D6PM or poor metabolizer, then you're going to have a MR ratio of greater than 1.7. If there is a strong inhibitor present, like it's like ciprofloxacin or fluvoxamine, you may see an MR ratio of greater than 3, or somebody may have an ongoing viral or bacterial infection. It's thought that with infection, it releases inflammation, and increase in inflammation may have an effect on CYP1A2, somewhat shutting it down and can increase levels and then subsequently increase the MR ratio. Now on the other hand, if you see someone who has a MR ratio of less than 1, they may be an inducer or they may be CYP1A2 ultra-rapid metabolizer. So this is a bit of guidance, but you still have to do some detective work about how to use the MR ratio and how to sort of think about it over time. So I just did in the clinic that I work in called PSTAR, just some practical information about when do you actually get a clozapine level. And for us, we have a pretty low threshold to do this. We recently switched to an in-house clozapine assay that gets our level completed with the regular blood work and the regular analyzers, and it comes back in the same day, which has been incredibly helpful. Before that, we had about five or six days to wait before the clozapine level came back, and then we had to sort of piece it together. So obtaining more rapid clozapine levels have been really helpful. Now, if you're in a practice setting where, for example, you may work on an ACT team and everybody is only getting point of care ANCs, and it's more difficult to obtain a level, then that's understandable. I think it's important to just sort of monitor the person carefully, but if you have access to getting levels, they can really be quite helpful. We also get levels early in the titration, at least at a dose of 100 milligrams. We get it with any substantial dose increase, when there's a suspicion for non-adherence, and when there are new adverse effects or a lack of response. And the non-adherence is important because if somebody has a, you know, if you're talking to somebody and their clozapine is not working and you're considering going from 300 to 400 milligrams, you get a clozapine, the person's having symptoms, you get a clozapine level back and it's zero, you know, you don't want to just go ahead and give them 400 milligrams. You want to probably re-titrate clozapine at that time or figure out how long they've been off. So the stakes are high for people with TRS, and it's not like there's an easy move to go back to a different antipsychotic. Usually people are on clozapine for an important reason. So even if somebody has a clozapine level of 350, you know, you might want to consider going higher. You might want to consider going higher than 600. Few people respond at levels greater than 1,000, but we certainly have some people in our clinic who have, and it's just important to kind of monitor those folks for side effects. All right, now on to pharmacodynamics. You're going to hear me say this a lot, but there's a lot about the pharmacodynamics of clozapine that we just do not completely understand, and it likely has the most complex receptor binding profile of any antipsychotic. By and large, clozapine acts as an antagonist at multiple receptors, including V2H1, alpha-1, M1M3. It's an inverse agonist at 5-HT2A and a partial agonist at 5-HT1A. And the way that you measure the potency of inhibitors through the inhibitory constant, or the KI, and the KI specifically means a concentration which 50% of the receptor is occupied, and a lower KI means a higher affinity. And if you really want to take a look at this, the best resource to take a look at the KI is the PDSP database that UNC has put together, and there's all sorts of results about KI and various receptor binding profiles for clozapine on this website. There's a really interesting image that I'm sharing here with you all that uses data from the PDSP that compares antipsychotics to each other and the receptor binding affinity profile, so it's very difficult to see here, but it's something that you can take a look at. And in this, it's interesting because the KI is in a logarithmic scale, so it's going to be reverse of what it normally is, and if something has a pKi of 9, that means it has a higher affinity for that particular receptor rather than the other way around. So just if you look at this, understand that that is flipped. So the question about why clozapine is unique from an efficacy standpoint, I think hearing about this for the first time is what got me into using clozapine and being an advocate for clozapine in the first place. In comparison to other commonly used antipsychotics like haloperidol, risperidone, olanzapine, and quetiapine, you can see here the KI for D2 serotonin 2A, then I also have here for you the ratio of D2 to 5-HT2A and also D4. So clozapine is unique because it has a relatively weak affinity for the dopamine D2 receptor. But not as weak as something like quetiapine. 5-HT2A and clozapine, it has a fairly strong affinity for the 5-HT2A receptor. Olanzapine has slightly higher, and then also risperidone as well. Haloperidol has KI of around 61 at 5-HT2A. Clozapine, the D2 5-HT2A ratio for clozapine is 81, and you can see that that's higher than some of the other antipsychotics, which may be something that might make it a bit unique. And then clozapine also has some moderate binding affinity for the dopamine D4 receptor. So another reason clozapine is unique is because at therapeutic levels, clozapine generally binds about 60% of the dopamine D2 receptors. In contrast, risperidone, olanzapine, and haloperidol occupy about 80% of D2 receptors at therapeutic levels. Additionally, clozapine is a fast-off antipsychotic, meaning that it kind of sticks onto the D2 receptor for 15 seconds and then comes off versus haloperidol and risperidone would stick around a little bit longer. And this may explain in part why you can dose clozapine once a day instead of two or three times a day. Despite its half-life only being about 12 hours, it's not all about just blocking out the D2 receptor. So our colleague Fred Nusifora wrote a nice paper about some reasons why clozapine has a unique mechanism of action and evidence for and evidence against. As we talked about, clozapine has a low D2 receptor occupancy and rapidly dissociates from dopamine D2, but there's also quetiapine, which has a low D2 receptor, and quetiapine is not clozapine from an efficacy standpoint. D4-wise, pi D4 receptor affinity, pi D4 D2 receptor affinity ratio, but there's other antipsychotics that affect the D4 receptor, including olanzapine, zeprazidone, and centipene. And then pure D4 receptor antagonists are not effective for the treatment of schizophrenia. What about the 5-HT2A story? And clozapine has a unique, I think, a unique 5-HT2A D2 receptor affinity ratio, but also many others, and pure 5-HT2A receptor antagonists are ineffective. Now I'd like to go a little bit into the side effects of clozapine and talk a little bit about how they may occur, what we understand about that at least, and what we can kind of do about them. So, of course, the place to start is severe neutropedia. The mechanism is unclear, but we think that it's likely immune-mediated rather than direct bone marrow toxicity. For those reasons, we have to monitor the absolute neutrophil count for the first six months on a weekly basis, and then every other week from month 6 to 12, and then monthly at 12 months. And during the pandemic, if people were on monthly monitoring, there was a consensus statement that said that maybe you could increase the frequency of monitoring to every three months if people had no other way of getting to the lab and if people had had no history of neutropenia in the past. So the incidence of neutropenia is important, and this meta-analysis shows that there was a 3.8% risk of neutropenia due to clozapine, a 0.9% risk of severe neutropenia or a granulocytosis, but death was rare due to a granulocytosis or severe neutropenia. Those terms are used interchangeably, 1 in 7,700. It makes sense that the peak incidence is around one month after initiation of clozapine, and most of the cases of severe neutropenia occur at one year. You also have to make sure that your patient is not inappropriately being excluded from opportunity on clozapine because they have benign ethnic neutropenia. And these are folks whose ANC hovers around 1,500, and confirmatory testing can be made by looking at red blood cell antigen testing, and people are usually Duffy antigen A and B negative. But confirmatory testing is not needed to make a diagnosis of BEN, nor is the hematology consult. Okay, myocarditis is next. Myocarditis has gotten a lot of attention, especially lately, and myocarditis is interesting. The mechanism is unclear. It's possibly an IgE hypersensitivity reaction. It causes increased cytokine release. The incidence varies, and it's difficult to really pinpoint because there's been sort of difficulties detecting it, but the largest meta-analysis suggests that the rate is about 0.7% of individuals on clozapine. It happens early during the clozapine titration with a mean time of onset 17 days. 82% happen within the first two to three weeks, so that's a key time to be on the lookout for this. Known associations include concurrent sodium falproate use, age, and rapid clozapine titrations, and that means clozapine titrations greater than 300 milligrams at two weeks. Myocarditis comes with a number of nonspecific symptoms, including fever, fatigue, flu-like symptoms, chest pain, tachycardia, palpitations, and some of this stuff just looks like a regular clozapine titration, so you have to be vigilant. A number of people get clozapine-induced fever, and it's probably not myocarditis. One thing that is, I think, that is done increasingly in clinical practice is using a screening protocol during clozapine initiation where you use weekly CRP and troponins for the first four to six weeks. In the United States, most people do not obtain an echocardiogram before clozapine use, but that's one thing that you can consider. If somebody does develop myocarditis, immediately you probably want to stop the clozapine. You want to make sure that the person doesn't have sort of a cholinergic rebound and consider treating them with an anticholinergic if you have to stop it all of a sudden, especially if they're at higher doses of clozapine and the titration is fast. And then the best test to get diagnostic specificity is cardiac biopsy, but in clinical practice, cardiac MRI is used. And there have been examples of successful re-challenges after myocarditis. Next, we have seizures. So the mechanism of seizures in clozapine is unclear but possibly has to do with selective binding at the dopamine B2 mesolimbic receptors. The incidence of seizures is three and a half percent in phase two and three clinical trials. And in comparison to other antipsychotics, the hazard ratio is about three. If somebody has a seizure on clozapine, it's important to do some detective work and try and figure out what else may be going on. It often happens during dose increase or if the CYP1A2 inhibitor gets added, that might jack up the clozapine level. There's some debate whether or not if it's dose dependent or not, but I think that most would agree that levels greater than a thousand may be a risk factor, kind of like what happened with the case I was telling you about earlier. Regarding the management of seizures, it can usually be controlled with a dose reduction or adding an AED like valprite. But of course, with sodium valprite, there is a potential kinetic interaction with clozapine and it can also contribute to greater risks of neutropenia and sort of a cardiometabolic double whammy as well. So consider obtaining levels if you use sodium valprite and monitoring metabolically carefully. Okay, so just sort of circling back to the pharmacodynamic properties of clozapine, you know, if you understand the way that clozapine works and the receptors that it may affect, then you can kind of predict how these side effects are going to play out for people. We're going to talk a little bit about sedation, tachycardia, orthostatic hypotension, constipation, hyperphagia, weight gain, and scialleria. So sedation, this sort of table that we're going to look at here with alpha-1, H1, and M2, we're going to be revisiting several times. And you can see that with sedation, the clozapine really has a very high affinity for the H1 receptor. It has a high affinity for M2, and it's thought that a contribution of H1 and M2 are responsible for its sedative properties. And just to sort of review what these do, you know, the alpha-1 receptor antagonists have to do with hypotension, priapism, low libido. H1 antagonists increase appetite, sedation, cognitive dysfunction, may contribute to weight gain. M2 is more like cognitive dysfunction, urinary retention, and constipation, which we'll talk about. So what do you do for sedation? Some people develop a little bit of a tolerance to the sedation over time. It often helps to move the clozapine dose fully to bedtime if you can, because it can be quite sedating if you use the BID divided dosing, like if you use a third of clozapine in the morning and then two-thirds at bedtime, it's very difficult to get up and function that way. Some people can tolerate that okay, but if people are having significant AM drowsiness, you might want to shift things to bedtime. Morning drowsiness can be helped by caffeine, but keep in mind that caffeine can cause clozapine levels to increase, especially with a lot of use. It's a substrate for CYP22. So I encourage people to, you know, use caffeine, but let me know how much they're using and use it in moderation and then also being active. Small amount of literature for erythrofibrosal augmentation to help with sedation as well. Tachycardia, a very common side effect of clozapine. Tachycardia is mostly related to clozapine's M2 antagonism. It, you know, if M2 is blocked, it results in muscarinic receptors leading to vagal inhibition and also probably presynaptic alpha tumors, adenoreceptors cause increased sympathetic activity. And you do tend to see some tachycardia with clozapine pretty early on. 25% of people may experience tachycardia. If somebody does experience tachycardia, you want to make sure you do a work up for this and get an EKG. And then you want to make sure, especially early on, that somebody's not having myocarditis. But there's also other things that contribute to this, you know, things like glycopyrrolate use. So medications can certainly contribute, smoking can contribute, caffeine use, et cetera. In my practice, I tend to, if it's clearly clozapine-induced tachycardia, I tend to treat the tachycardia because if you just walk around with a fast heart rate, it likely increases risk of cardiomyopathy and other cardiovascular conditions, stroke, et cetera. So I like to try and get my patients to a resting heart rate of between 80 to 100. And then, you know, you give people sort of lifestyle advice how to do this, but sometimes it really takes using a beta blocker. And you could use things like atenolol, metoprolol. Atenolol is nice because it's a non-selective beta 1 adrenergic antagonist. It doesn't have a lot of CNS penetration. It's renally metabolized, so you're not going to get drug-drug interactions with the SIP system. If you use atenolol, you can start it at 12.5 milligrams daily in the morning, and then you can increase by 12.5 milligrams every seven days. Also in your note, if you're using atenolol, you probably want to be very clear that it's because of clozapine-induced tachycardia. I don't know how many times, you know, somebody goes to another medical provider or something, and they see this beta blocker, and they're like, why in the world is this person on beta block? Why are they doing this? And I think if you're just very clear that it's related to the clozapine-induced tachycardia, you'll be okay. Okay, orthostatic hypotension. So, yeah, I mean, clozapine is a non-selective antagonist in alpha-1a and alpha-1b, and can lead to a subsequent reduction in vascular tone. So it's really the 1a properties that have to do with orthostatic hypotension. The risk is really earliest in the clozapine titration and can occur with rapid dose increases. If somebody, back into the tachycardia slide, if somebody has tachycardia, you want to make sure they're not orthostatic, and you probably want to do a test. There's some things that you can do for orthostatic hypotension. Some of them include dividing the dose during the day, and some of them include slow dose titration, and then flutocortisone has also been used as well. Constipation. Very serious side effect from clozapine. Definitely needs a lot of attention and monitoring. It's likely related to its H1 and M2 antagonism. Clozapine is also a weak antagonist at 5-HT3, which may have something to do with it. So mostly M2, to a lesser extent, probably H1. This is really, so I just want to go back to the constipation. People who are on clozapine have an extremely long colonic transit time, often greater than 100 hours. So it really tends to slow it down, and it's very, very important to prevent constipation and also educate the patient. So in the prevention category, you want to reduce or eliminate opioids if they're not needed. Iron, especially if it's not needed, is quite constipating. And then, of course, anticholinergics like glycopyrrole that's often used for cialorrhea can be constipating. Hydration, avoiding bulk laxatives like psyllium are important, and you have to sort of ask people if they're taking psyllium supplements sometimes. And then, you know, I like to go through the Bristol stool chart with people, talk to them about constipation. You have to ask very specifically. And then if people are having frequency changes in their bowel movements, you want them to be able to tell you that. This is a, sorry, a little bit of a technical issue. But just to talk a little bit about the sort of management protocol for using for constipation, really the first step is to use probably prophylactic docusate. And then after that, it may be helpful to use something like polyethylene glycol. And then after that, you can consider a senoside. And then after that, you may consider one of the secretogogues like lubiprostone or lenactotide, which are quite effective for clozapine-induced constipation. Next is a little bit about the cardiometabolic side effects of clozapine. These are very well documented. We know that for people on clozapine, it's one of the most significant offenders of weight gain, hyperphagia. It has to do likely with its H1 antagonism. The weight gain probably plateaus around year four, but by then a lot of damage is done. And for my patients who are on clozapine, you want to, I typically exceed the monitoring guidelines by the APA, ADA. So at least every six months, hemoglobin A1c and lipid monitoring. It may be more associated with more clozapine levels, interestingly. And then as far as the management goes, tapering or discontinuing other contributors of weight gain, valproate is one, but then you can also use augmentation strategies like metformin, which has been the best studied in a meta-analysis, suggested that there was about a three and a half kilogram weight difference in comparison to placebo for those who receive metformin. You probably want to get the dose to a thousand BID if people can tolerate it. Consider long-acting forms. There's other things that have been tried, orlistat, topiramate, bupropion, aripiprazole, liraglutide, exanatide. Those can, especially liraglutide and exanatide, there's some interesting data that has been published about them and can really help people. Sometimes it's difficult to get a hold of those. Okay, I want to talk a little bit about sialaria, and, you know, with sialaria, you sort of have to throw the old chart out because it mostly has to do with noreclosapine, and we were talking a lot about clozapine's muscarinic antagonistic properties, and you would think, well, somebody had dry mouth then related to clozapine. But, in fact, because of noreclosapine's unique properties, that might be what causes sialaria that's quite bothersome for people. So we know that clozapine is an agonist at M4. It's an alpha-2 antagonist, but noreclosapine has potent M1 agonism, which, you know, the salivary glands express M1, and that can definitely contribute to the sialaria. Also, interestingly, if you use a straight-up M1 antagonist that's not available in the U.S., that actually can be a treatment for sialaria. So we know that sialaria is common and often bothersome for people who take clozapine. It can lead to a lot of, you know, people lowering of self-esteem, especially people who are in public and they have daytime sedation. There's an interesting association now with sialaria and possibly related to an increased risk of pneumonia, especially aspiration pneumonia for individuals on clozapine, although I think there needs to be some more research in that area. Most of the time, people develop sialaria at bedtime, but it can happen during the day, too. I typically will ask people how much is the sialaria bothering them and if they want me to, if they want us to sort of do something about it, but I think that given this increased potential risk of aspiration pneumonia with untreated sialaria, I'm more likely to try and treat it if people are agreeable to that. And some strategies that you can use, you know, there are some of these things like sleeping with a towel on the pillow or chewing sugarless gum, but really a lot of times you need to move towards some of the other pharmacologic treatments. Ophthalmic atropine is one place that you can start, and this is used sublingually, obviously not in the eye, and you want to make sure that people are using the drops on the salivary glands and they have it there, they're sort of there, and they're swishing and swallowing after it absorbs for a little while with, you know, about five mils of water or something, you know, you want to make sure you're not diluting the atropine. Also, peritropium may be helpful. Glycopyrrolate has been studied and can be helpful, but the problem is that it can contribute to tachycardia and constipation, so be careful of that, especially higher doses of glycopyrrolate. And then there's some nice literature that's been evolving about Botox in the submandibular glands, so in some of the salivary glands, and that tends to really work very well if you can get that. Okay, so in conclusion, a couple of things. So treatment-resistant schizophrenia is a major public health issue, and clozapine is the treatment of that. And if you can get people on to clozapine, it needs to be initiated after two antipsychotic trials. Clozapine has a narrow therapeutic index and a complex and incompletely understood mechanism of action, but if you have a sense of what is known about the mechanism of action and its pharmacokinetics, you can help really to improve outcomes for your patients and you can feel more confident using it. And I think that, you know, people can stay on it without it having to be earlier, you know, this sort of early discontinuation. Okay, great, and that's the end of my prepared remarks. Thank you for such an interesting presentation, Dr. Kotez. Before we shift into Q&A, I want to take a moment and let you know that the SMI Advisor, SMI Advisor is accessible from your mobile device. Use the SMI Advisor app to access resources, education, and upcoming events, complete mental health reading skills, and even submit questions directly to our team of SMI experts. Download the app now at smiadvisor.org. And now we'll shift into some Q&A questions. We've had several come in. The first one, well, there's, it's a two, one is related. I'm going to ask them both together. Any thoughts on concurrent use of the oral contraceptive pill with Clozapine and its effect on Clozapine serum level? And then somewhat related, what about Clozapine in pregnancy? Oh, okay, thank you, Donna. Let me just unmute myself here. So, it's a great question about Clozapine and OCPs. It kind of depends on which oral contraceptive is being used, but generally it's thought that the estrogen component of oral contraceptives may inhibit CYP1A2, and progesterone may have, may be an inhibitor of CYP3A4. So, you know, I think what that, what that will lead to is that oral contraceptives can increase Clozapine levels. So, if people are taking oral contraceptives, you probably need to, you know, be thinking about levels, which I think is a nice segue to the next question about, well, what if someone becomes pregnant when they're taking Clozapine? And, you know, generally, yeah, Clozapine in pregnancy is interesting. Like, it's, prior to the FDA's change in labeling, it was a Category B medication, and now the FDA doesn't use that same sort of nomenclature system, but, you know, Clozapine, I think that the short answer here is that Clozapine in pregnancy, you're often left with not a lot of other options, and if someone's on a different antipsychotic, it can considerably worsen their symptoms, because they probably got to Clozapine for an important reason. So, but there are a couple of things to watch out for. I mean, I think in one study, there was a two, there was about a two and a half fold risk of increased, of digestational diabetes for pregnant moms who were taking Clozapine, and there also has been a, some information about neonatal seizures and floppy infant syndrome, but I think that's much more rare. So, sometimes people will reduce the Clozapine dose prior to delivery, usually greater than 50%, but I think that oftentimes, it's, of course, an individual decision. The risks are likely to outweigh the benefits for people who are taking Clozapine in pregnancy. Now, lactation is a different story, and lactation, Clozapine, probably not recommended. Clozapine can pass into the breast milk, and there have been case reports of infants developing severe neutropenia, even from small amounts of Clozapine. Great. Thank you, Rob. I've grouped a couple more questions together. Can you explain in more detail about the caffeine interaction with Clozapine, and what do you consider moderate caffeine use to help with sedation? In general, how much of a change in someone's caffeine use will result in a significant change in Clozapine level? Yeah, so, caffeine is a substrate for CYP1A2. It's not an inhibitor or an inducer, so I think that what happens is it will compete for Clozapine for the CYP1A2 receptor, so that's one thing to sort of make clear, but the functional effect is that caffeine use can increase Clozapine levels. The effect, my understanding, is not as profound as cigarette smoking, where you can get, you know, 1.5x or 2x change in levels. I typically will say, you know, like, drink a cup of coffee, or, like, if you do use caffeine, like, maybe have a cup of coffee in the morning, but, you know, I would be a little bit more concerned with heavier caffeine use, you know, especially the energy drinks and things like that, but the best way to do it is to have people tell you how much caffeine they're drinking, and then monitor that, and then get Clozapine levels, if you can, to help figure out if there's going to be a relevant interaction there. Wonderful. Thank you. Our next question, does ECT affect Clozapine in levels or efficacy? My understanding is that Clozapine does, ECT does not affect Clozapine levels. This is an important issue, because if someone has persistent symptoms on Clozapine, one of the best studied augmentation treatments is ECT, and we know that there is some really well-done studies that sort of look at ECT augmentation, and the number needed to treat for response for positive symptoms was about three, and this has also been sort of shown in other studies and in meta-analyses, so ECT is really one of the better evidenced treatments, like when you add, you know, if somebody's having persistent positive symptoms despite being on a therapeutic dose of Clozapine. I think there was even a study that looked at Clozapine levels for ECT and found there was no difference in Clozapine levels for those who received ECT. Thanks, Ram. Okay, our next question, can you advise on how much more Clozapine contributes to hypotension than Olanzapine? This participant has a palliative care patient in ICU intubated on vasopressors and Clozapine. I'm not sure of a level, but considering whether it might be wise to change to Olanzapine rather than Clozapine. Okay, I think in this situation, you know, you have to sort of consider, first of all, what you may lose by switching to Olanzapine if the person is on Clozapine, and just particularly how severe the hypotension is. You know, Clozapine itself has a much greater binding affinity for Alpha-1 than Olanzapine. You know, Olanzapine, it's about 44 and Clozapine, it's about 7. So I think that it can be a pretty significant offender for hypotension. There, you know, there could be some things to be done. I mean, one consideration could be, you know, working with medicine and considering flutocortisone. There may be other reasons why the patient has hypotension as well, if they're in the ICU. So I would try and get a sense of that. Thank you. Is Clozapine-induced myocarditis reversible, or does the myocarditis inevitably lead to heart failure? Yeah, it's generally reversible. I would say unless it, I think, especially with early detection, Clozapine-induced myocarditis is reversible. Now, Clozapine-induced myocarditis is different than Clozapine-induced cardiomyopathy, which is a sort of an adverse event that can happen later during the Clozapine titration, where people tend to develop heart failure after being on Clozapine for many years. And in those sorts of situations, you know, like it's not going to help you to screen for troponin and CRPs. Thanks, Rob. A question about Atropine for sialorrhea. How long after administrating the Atropine should the patient rinse with water? I usually tell people to have the Atropine hang out there for about a minute. The problem with Atropine is people don't like the taste of it. And, you know, you probably don't want, you can, I think it's debatable about how much Atropine can be used, but, you know, sort of three drops of Atropine is, some people would say, would be the higher dose of Atropine that can be used. Okay, our next question is about BEN. Does benign ethnic neutropenia put patients at greater infection risk if they're using Clozapine? Well, there's some literature that suggests that people with BEN actually do not develop a granulocytosis, that there may be a protective effect for people with BEN. Thanks, Rob. Have you ever had problems using certain or different generic brands of Clozapine? Yeah, you know, I think, in my experience, people sometimes have said that, you know, it feels different, shifting to a different generic for them, and in that situation, I think that's a pretty good reason to get a level to see if, to see if there's any change there. So, anecdotally, this has happened a bit, and I don't, I don't know, I don't really know how big of a, how much to make of it, but, but I think that if people are noticing it, you know, just sort of check a level and see, and then sort of make, make adjustments. And let's do one last question. How does weighing the quality of life with the risk and benefits of starting a patient on Clozapine, and then having to give them additional medications to address potential or experience side effects, how do you work that out? Yeah, I think that's a great question. You know, there are studies, you know, like the FIN11 and the FIN20 study, which show that people who are prescribed Clozapine who have schizophrenia have a reduction, potentially, in mortality than other causes, then, then maybe even those who take other antipsychotics. So, there is some benefit, which may, may be part of, you know, people just having improvements in symptoms, or it may be sort of an anti-suicide effect, but I think that for many people, the benefits of the prospect of having improved symptoms, improved functioning, returning to work, often outweigh the risks. But, you know, that's, I think that that's a discussion that we have to have with our patient, and people may have very different priorities about that. So, I really tend to approach Clozapine use in a very shared decision-making framework, where people, you know, I'm happy to provide the information about Clozapine to them, and then really have them make the best decision for themselves, because it is a big investment, you know, to get labs once a week, and, you know, there are potential side effects, but they can be managed, I think, with, with vigilance, and with sort of knowledge about how they present, and how they look, and I think that if you can communicate to your patient that if people do develop side effects, you, you know, you feel confident knowing what to do, and you have, you can help them get through that. Wonderful, and I said that was the last question, but I have one follow-up question to that. How often is it recommended to check Clozapine plasma levels once a patient is stabilized? Yeah, I think that's a really important question. I mean, the, the APA Schizophrenia Guidelines do not make a recommendation about, like, when you have to check a plasma Clozapine level, so there's not a specific guideline about when you would want to do this. Like, if somebody is doing well, they're on Clozapine, they're, you know, they're doing their thing, and they're, you know, not having symptoms, or sort of, and they're not having tolerability issues, you know, I mean, you could definitely wonder, like, well, what, why really do, then do a Clozapine level? So, I usually do not get Clozapine levels, just, I, I, unless I'm sort of suspicious that there's an adherence issue, there's a kinetic issue, or making changes, people are still symptomatic, and, you know, you can also, you, you may argue that, that sort of obtaining Clozapine levels periodically will help you to, to sort of establish a baseline, but I think people, people utilize Clozapine levels in different ways. Wonderful. Well, thank you again, Dr. Cortes, and we'll wrap up with a few more brief slides. If you have a follow-up question, or questions about this, or any topic related to evidence-based care for serious mental illness, our clinical experts are available for online consultations. Any mental health clinician can submit a question, or receive a response from one of our SMI experts. Consultations are free and confidential. SMI Advisor is just one of the many SAMHSA initiatives that are designed to help clinicians implement evidence-based care. We'd encourage you to explore the resources available on the Mental Health, Addiction, and Prevention Technology Transfer Centers, as well as the National Center of Excellence for Eating Disorders, and the Suicide Prevention Resource Center. These initiatives cover a broad range of topics from school-based mental health, through the opioid epidemic. To claim credit for participating in today's webinar, you'll need to have met the requisite attendance threshold for your profession, verification of attendance may take up to five minutes. You'll then be able to select next, to advance, and complete the program evaluation before claiming your credit. Please join us next week on July 23rd as Dr. Javier Ballester-Gonzalez, with the University of Utah, presents Bipolar and Alcohol Use Disorder, Break the Magnetic Force. Again, this free webinar will be July 23rd at 12 p.m. Eastern Time. Thank you for joining us. Until next time, take care.

clozapine

pharmacodynamics

pharmacokinetics

treatment-resistant schizophrenia

receptor binding profile

drug-drug interactions

side effects

sedation

weight gain

shared decision-making