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Treating Transitional Age Youth with Clozapine
Presentation and Q&A
Presentation and Q&A
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Hello and welcome. I'm Donna Rollin, Nursing Expert for SMI Advisor and Director of the Psychiatric Nurse Practitioner Program at UT Austin School of Nursing. I'm pleased that you're joining us today for our SMI Advisor webinar, Treating Transitional Age Youth with Clozapine. Next, 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 one AMA PRA Category 1 Credit for Physicians and one Nursing Continuing Professional Development Psychopharmacology Hour. Credit for participating in today's webinar will be available until July 1st of this year. 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. Kurt Cousins. He is a member of the SMI Advisor Clozapine Workgroup. Dr. Cousins practices general psychiatry and child and adolescent psychiatry in Austin, Texas. He maintains adjunct faculty teaching positions at the University of Austin Dell Medical School Department of Psychiatry as a clinical assistant professor and in the School of Nursing in the College of Liberal Arts Department of Sociology. He is an assistant professor at the Texas A&M College of Medicine. He was formerly the director of the student mental health at Rice University. He previously served as a medical director of the Child and Adolescent Psychiatry Division and the Intellectual Developmental Disabilities Division for Austin's Community Mental Health System. And he also served as the medical director of Austin's largest psychiatric crisis residential facility. As a neuropsychiatrist, he's worked as an attending on an adult neuropsychiatric unit at a state hospital and as an attending at a pediatric specialty hospital with programs treating children and adolescents with genetic syndromes and neurodevelopmental disorders, including the country's only inpatient program specifically designed to treat Prader-Willi syndrome for which he is an expert. Thank you, Dr. Cousins for leading today's webinar. Thank you, Donna. Good morning, everyone. Hello. First of all, I'm pleased to be asked to speak and thank you for giving your time today to participate in this. I want to state that I have no relationships or conflicts of interest related to the subject matter of this presentation. And now for the talk. Starting with our learning objectives, upon completion of this activity, you should be able to feel more facile at comparing and contrasting treatment with clozapine in transitional age youth to adults. Justify the use of clozapine off-label in treating psychosis, suicidality, bipolar, and aggression in transitional age youth. And to develop an informed consent process for patients, parents, and caregivers of adolescents and young adults. I'm going to turn off my camera and talk for a while and then come on video back at the end. So let's get started with the comparing and the contrasting. So comparing and contrasting treatment with clozapine in transitional age youth and adults. First off, let's take a look at the FDA registration, indication at age range for treatment with clozapine, evidence to support off-label treatment with clozapine in transitional age youth. Risk associated with treatment with clozapine in transitional age youth. We'll continue further with the risk mitigation and management of side effects. Explore or just make note of drug-drug interactions. And at the end of the presentation, we'll return to treating transitional age youth with clozapine. The FDA-registered indication for treatment with clozapine is for treatment-resistant schizophrenia and for reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of re-experiencing suicidal behavior. And the indication is in the United States by our FDA is for adults only. It's notable that in Britain, there's an indication to treat schizophrenia in individuals 16 years old and over. As for the evidence for off-label treatment, I'm going to start with a section of just looking at treatment-resistant schizophrenia and first episode psychosis. And then we'll continue after this body of evidence with the suicidal behavior, bipolar and aggression. So what's the evidence for the treatment of youth with clozapine? For individuals under the age of 18 years old, which let's just define transitional age youth for a moment. We're looking at age 16 to 24 years old. Some will say even 15. So this is the portion where they're still in adolescence. A systematic review of the literature completed by Rakamalu in 2019 found 131 studies published between 1994 and 2016 concerning treatment of youth with clozapine. Less than 10% were randomized controlled trials. The majority were case reports and cohort studies. The sample sizes were often small. And a low percentage of the studies were limited to or focused on adolescents over the age of 15 years old. So I'm trying to introduce you right up front to knowing that the evidence base is not perfect. For example, a paper titled Childhood-Onset Schizophrenia, a Double-Blind Randomized Clozapine-Olanzapine Comparison by Shaw from 2006 had a sample size of 25. The age range was 7 years old to 16. And they found that at 2 years, clozapine was superior to olanzapine. 50% of those treated with clozapine developed lipid abnormalities. Another paper, Clozapine for Treatment of Aggression in Non-Psychotic Adolescents by Kumar in 2016 was a case report of a 15-year-old and a 13-years-old. They were treated for non-psychotic aggression with clozapine and remission was achieved and it was sustained at 3 and 6 months. A Focused Review on the Treatment of Pediatric Patients with Atypical Antipsychotics by Lee, who's from Johns Hopkins in the Finland group. Many of you will know that, having specialty for research in child and adolescent bipolar. Their review affirmed the utility of clozapine for treating treatment-resistant schizophrenia in youth. They cite Shaw and Kumar. So I've already mentioned Shaw and Kumar. Kumar has another study that I'll refer to a little bit later that's an actual, rather than a case report, it's an actual control trial. The Use of Atypical Neuroleptics in Child and Adolescent Psychiatry. This is by Torin and a group from Tel Aviv. It's an older paper. Their Review of Clinical Trials and Case Series, which included the Shaw and Kumar papers, they found that the most convincing evidence of the efficacy of atypical neuroleptics in children and adolescents was concerning clozapine in the treatment of schizophrenia. Clearly, that's older before additional second generation antipsychotics were approved and marketed and then extensively used. And then another paper, Clozapine and Severe Conduct Disorder. The sample size was six. The age range was 10 to 14 years old. And these are the better papers. I'll continue. Clozapine, its impact on aggressive behavior among children and adolescents with schizophrenia. Looked at 20 hospitalized adolescents treated with clozapine. They experienced a reduction in aggression between weeks 12 and 14 as measured by seclusion and restraint and emergency medication. Another paper, The Off-Label Use of Clozapine in Adolescents with Bipolar Disorder, Intermittent Explosive Disorder, or Post Traumatic Stress Disorder. And that was a open label study of 39 adolescents, six of whom had bipolar with clearly these diverse diagnoses. They were treated ultimately with low dose clozapine and they benefited in enough of a response that polypharmacy was reduced from 70 percent to 24 percent. Now to look at the evidence for transitional age youth. Studies are rarely circumscribed to transitional age youth range. So we're saying now I've looked at the adolescents and now I'm speaking about the portion that is emerging adult age 18 to 24. A study from McLean Harvard by Tohan, many of you might know that name if you're in Texas. He was formerly the chair at UT Health Sciences, San Antonio, chair of psychiatry. They looked at the treatment of first episode non-effective psychosis or schizophrenia or first episode. The average age was 30. It's too old for us to make meaningful use as we're thinking about evidence for transitional age youth. A PubMed search that I conducted using the search terms transitional age youth or transition age youth and clozapine identified one article. So if I just use a search of transitional age youth or transition age youth, the results are over 9000, add in clozapine, one article. And in that article, it's by the way, it's a review and they cite the 96 Kumra superior or superiority of clozapine to haloperidol in treatment resistance schizophrenia in six to 18 years old. The sample size, I believe, was about 30. Shaw, 2006, as I mentioned earlier, the superiority of clozapine to lansipine in treatment resistance schizophrenia in seven to 16 years old, sample size 20. Kumra, 2008, superiority of clozapine to lansipine in treatment resistance schizophrenia in 10 to 18 years old. So. Early on, people were comparing clozapine to haloperidol. And then more recently, the comparisons, at least in the direct head to head control trials are clozapine to lansipine. Another point, again, we have to make inferences because this age range goes below those below ours. How about the evidence for adults? Well, Lambert conducted a trial of nearly 400 treatment naive patients with schizophrenia. So their treatment naive, they haven't yet sort of been defined as treatment resistant. I know that's the top of the page. They achieved a 60 percent response to clozapine. Forty five percent had functional recovery and only about one in seven had a non-effective reaction. It was non-efficacious. In a meta-analysis by Han published in Lancet with 32 oral antipsychotics were compared across over 400 studies comprising 53,000 participants. Clozapine was found to have the highest reduction, the highest overall change in symptoms among antipsychotics with a squared mean difference of negative 0.89. The highest reduction of negative symptoms among antipsychotics among the highest in the reduction of positive symptoms. Among the highest in the reduction of depressive symptoms and yet clozapine is used in only to treat only three to five percent of persons having schizophrenia across the entire adult population. Evidence for young adults with specifically treatment resistant schizophrenia. In comparison to other second generation antipsychotics in a meta-analysis completed by Lally, 76 percent of those treated with clozapine had a response in comparison to a 58 percent response amongst other second generation antipsychotics. In a Australian study of the Oregon, not Oregon like our state, but Oregon Youth Health in Australia, some of you may know the name McGorry, he does research with that population and the specific program is the Early Psychosis Prevention Intervention Center. They did a study of 544 transitional age youth age 15 to 24, 10 percent had been deemed treatment resistant during their first episode and nearly 77 percent of that treatment resistant group achieved remission with clozapine. That's extraordinary amongst the other literature that I've just presented and it's tremendous clearly as a response. I thought it might be worth to stop for a moment and just frame the epidemiology of early onset schizophrenia. So, while many of us had thought that the tip for had, so I think, traditionally been taught that the onset of schizophrenia is in the early 20s for males and the later 20s for females, more recent epidemiological data suggests that the predominant onset we could just think of as in the transitional age range, 15 to 24, with 10 percent of the total prevalence of schizophrenia being before the age of 20. Only 4 percent of the total cases of schizophrenia have an onset before 15 years old. 60 percent of those that have an onset of schizophrenia before the age of 18 experience poor outcomes. And I'm saying that because we can think of how clozapine may change the course of illness for quite a large group of individuals that have an early onset schizophrenia. To, again, sort of make another epidemiological point is that between 13 and 19, which is the definition of an adolescent onset schizophrenia, the prevalence in the overall population is 2.3 per thousand. So, 0.23 percent when we ultimately think that schizophrenia may be circling around 1 percent or less. In another study by Moses, their estimation was that 40 to 50 percent of childhood onset schizophrenia become treatment non-responders. So, that would be before the age 13 of onset. The implication for us is that by the time they hit transitional age, they may be ill at least 50 percent and have not responded. And then we can consider the utility of clozapine. With regard to early onset schizophrenia, a study by, we'll say a Czech study, because I can't pronounce the name properly, found the clozapine was superior in efficacy in treating treatment-resistant schizophrenia with youth with onset before age 18. They found that the predictors of response to clozapine, a positive response would be higher baseline positive and total symptoms as measured by the PAN score. And that an attenuating condition would be active substance use disorder, particularly synthetic cannabinoid use. I'm showing this slide so that you can see in a summary table that risperidone, haldol, lanzapine, thorazine, abilify, that amongst all of these, that clozapine at 400 milligrams per day has the highest response rate and it's maintained at one year. Now, I know, and you all say, these are not all direct head to head. It's not all of these second generations in comparison to each other. But it is noticeable that the highest response rate in any of these controlled trials was achieved by clozapine. And this is from Lieberman's group at the New York Psychiatric State Institute, New York State Psychiatric Institute, who was prominent in the CADI trials and a former president of the American Psychiatric Association. A way to interpolate or to make an inference would be to look at first episode psychosis. We just said that the majority of onset is between 15 and 24 years old. So let's take a look at how clozapine fits into the canon of treatment for first episode psychosis. I'm going to repeat the Lally study that I mentioned earlier, just to give a size-wise. 58% achieved remission. They pulled 60 studies in nearly 20,000 patients and the time frame was up to five and a half years. In another study by Werner, who was looking at clozapine as a first line treatment in first episode psychosis, 66 responded to clozapine. In a study by Agid, with a sample size of 244 patients, there was a 75% response rate to clozapine in patients treated with their third antipsychotic trial during their first episode. So this would fit the definition of treatment resistance, assuming that in those previous two trials that a therapeutic or presumptively therapeutic dose of an antipsychotic was trialed. Nonetheless, as compelling as this data is, the delay in starting clozapine is estimated to be five years amongst individuals that have experienced their first episode. I want to move our attention on to the support of the use of clozapine off-label to treat suicidality, bipolar one disorder, and aggression in transition age youth. So there's a harrowing fact that the suicidal risk, the lifetime suicidal risk in individuals with schizophrenia approaches nearly 5%. Suicidal thinking is estimated at 44% in this population. According to Meltzer and his studies, 50% of patients with schizophrenia attempt suicide and 10% of patients with schizophrenia die from suicide. And this is in contrast to a 1% rate of suicide attempt in the general population. So what we already think of as way too high in our general population, it's on an order of magnitude higher or a multiple higher in individuals that have schizophrenia. Clozapine was associated with less suicidal behavior and less suicide attempts in the intercept study compared to olanzapine. And the hazard ratio was 0.76. The hazard ratio is a measure of how often a particular event happens in one group compared to how often it happens in another group over time. So it measures survival. And so another way of sort of stating this would be that there was the 24% less individuals who made a suicide attempt or had suicidal behavior when they were treated with clozapine compared to olanzapine. And so we already think of olanzapine of reducing that incidence as well. In a study that combined Swedish and Finnish registries, clozapine was compared to several other second-generation antipsychotics, risperidone, olanzapine, aripiprazole, and there was one other. And they found that in the Swedish population, the hazard ratio went down to 0.64, and that was with 62,000 people. And in the Finnish registry, with 30,000 people, the hazard ratio was 0.66. Clearly, much greater reduction in suicidality in these two registry studies. And convincing, because it's a much larger population. And we know that it's not a one-to-one correlate with our American population, but I think it's important to think about the implications of this. In a study looking at hospitalized patients by Modestin, clozapine-treated individuals, their suicide rate reduced to 3% from 28%. While people consider suicidality and individual schizophrenia being multifactorial, it's worth noting that in a study by Nakajima, who's looking at data from the CADI trial, that the high rate of depression and depressive symptoms in individuals reached a rate of 80%. And that in individuals that were treated with clozapine, the depression and depressive symptoms decreased. Okay, on to Bipolar I Disorder. What is the evidence for the use of clozapine to treat Bipolar I Disorder off-label in transitional age youth? So I completed a PubMed search using bipolar and clozapine. It yielded 629 results. And when limited to young adults with a specific age range of 19 to 24 years old, so not exactly our age range, but within it, none were deemed applicable to treatment efficacy. And so that's my way of saying I reviewed every one of those 38 studies and did not believe that any of them were applicable to the questions that we might try to answer with regard to efficacy. When I did the same study, I'm sorry, the same search using bipolar and clozapine, but limited instead to adolescents, so the younger range of our transitional age, it only yielded 67 studies. Well, maybe it's more, so it yielded 67 studies. And after reviewing every single one of them, I did not believe that any of them rose to the level of utility to be helpful to us as we try to answer a question about efficacy of clozapine to treat bipolar. But that said, I will sort of just mention three papers. The first is by Steinauer. It was a retrospective multicenter evaluation. So this is a study with real people. It was open label. They had 82 patients that were mixed psychotic and bipolar. And because it was mixed and because of the way it was designed, what it was really ultimately useful for was to establish for us tolerability. People were discharged tolerating this medicine. And I think it's harder to make an inference about efficacy with regard to discharge because we know that there are so many competing factors with regard to discharge. What we could say is they probably didn't get worse. In a small study of clozapine in adolescent inpatients with acute media by Massey, and that was done in Europe, the sample size was 10. Treatment was tolerated and was presumptively effective. The age range is outside of our age, so the sample size is small. And I already mentioned the CANT study because that was the study that looked at patients that had bipolar, intermittent explosive disorder, and PTSD. Okay, so turning our attention to adults and the treatment of bipolar I disorder in adults. In one study, 72% were responders to treatment with clozapine and treatment refractory mania. From a mechanistic standpoint, it's suspected that the anti-manic effects of clozapine are independent of the anti-psychotic effects of the medicine. What's also notable is that in another study that a lower dosage than what is traditionally used to treat schizophrenia was effective to achieve response with regard to mania, 234 or 334. A study by Nielsen showed that they were really measuring improved outcomes, and so they showed that individuals treated with clozapine had reduced hospital days by 80%, had reduced admissions by 37 1⁄2%. That those treated with clozapine, and this is with a mirror design, which I don't wanna get into, it's a bit complicated, but that 40% had no admissions going forward once treated with clozapine. And that medication overdoses and self-harm leading to ER visits declined to 3.1% from 8.3%. Okay, for some of you this might be sort of seen with small text, I'm gonna read it. So we're turning our attention now to clozapine to treat aggression, looking at both aggression in individuals that have schizophrenia, and there is another paper as part of this group where people don't necessarily have schizophrenia. So in a systematic review, it was found that bond behavior was exhibited by nearly 10% of individuals with schizophrenia in comparison to 1.6% of the general population. So that's six times the rate of the general population. A group looked at a similar question or similar comparison in Finland and found that the rate of violent behavior was seven times the general population in Finland. In Denmark, the arrest rate for violent crime was 4.6 times higher in individuals with schizophrenia. And in a particular study, it was estimated that 2 3rds of the excess risk of violence could be attributed to intoxication and or misuse of illicit drugs. The relative risk of violent offending once an individual was treated with clozapine reduced to 0.13, and the rate of violent offending was five times lower in individuals treated with clozapine compared to a lansipine. There was no significant reduction in nonviolent offending, so this really does sort of speak to aggression as opposed to other particular types of offense. In a study that looked at a forensic population, the reoffending rate at two years was 50% lower in those treated with clozapine compared to other antipsychotics. A large systematic review identified studies showing a reduction in seclusion and restraint and MOAS scores, MOAS being the Modified Overt Aggression Scale. For those of you from Texas, you'll recognize that having been developed by the chair, the former chair of Baylor College of Medicine. Their tentative conclusion was that clozapine was more efficacious in treating aggression and violence compared to a lansipine and a haloperidol in individuals with a history of violence. The PORT recommendations, PORT being the Patient Outcomes Research Team, which completed, at the time, the largest systematic review of schizophrenia and the treatment of schizophrenia with a variety of modalities, both pharmacologic and non-pharmacologic. From one of my alma maters, University of Maryland, Maryland Psychiatric Research Center, with Will Carpenter being the head and several individuals from Maryland, they found that clozapine was, and recommended, clozapine for persistent aggression and violence. In a study of hospitalized patients with schizophrenia, and this is from the Nathan Klein Institute in New York, they looked at a population of 110 hospitalized patients. They did a retroactive diagnosis looking for childhood conduct disorder. And they found that if a individual with schizophrenia had had conduct disorder during childhood, that they were four times less likely to display violence if treated with, when treated with clozapine in comparison to haloperidol. That if treated with clozapine, that they were three times less likely to display violence even without that conduct disorder. So that was, I mentioned that earlier, that there might be something about clozapine being effective for aggression independent of the psychotic process. One thought is that there's greater limbic sensitivity, or excuse me, selectivity of clozapine, especially with respect to norepinephrine and serotonin receptors, 5-HT1A and 5-HT2. In animal models, both of those receptors, those serotonin receptors have responded to blockers with selective anti-aggressive effects. Clozapine was found to be 1.5 times more effective than olanzapine to reduce any aggression, and 1.7 times more effective to reduce physical aggression in the Krakowski study. The Cady Violence Study did not substantiate anti-aggressive effects of SGA, second-generation antipsychotics, in individuals having a history of conduct disorder. They didn't look at it. And clozapine was not tested in that study. There are no specific studies looking at the treatment of violence and aggression with clozapine in transitional age youth. So in conclusion, with regard to evidence about efficacy for these off-label uses of clozapine, most of the evidence concerning transitional age youth is for adolescent age youth, and with respect to young adults, by proxy when we use the first episode psychosis studies, knowing that much of that population is transitional aged. We can infer from sort of all these papers in total that they point in a direction such that we can conclude or we can infer that clozapine is efficacious for the treatment of schizophrenia in youth, knowing it's based on limited studies, and it's efficacious for the reduction in suicidality in individuals with schizophrenia, absolutely, and in younger adults by inference, that there are improved outcomes for the treatment of bipolar I disorder with limited evidence, and that it's efficacious for the reduction of aggression, again, needing to make inferences for those conclusions. One of our goals is to be able to construct an informed consent process. There's a risk evaluation and mitigation system in place that I would imagine all of you are aware of, and it's specifically targeting neutropenia and the potential adverse effects of that, but let's talk about the other potential side effects and how to mitigate. So in overview, there are hematopoietic, cardiac side effects, so with respect to neutropenia and granulocytosis, cardiac myocarditis, cardiomyopathy, tachycardia, orthostasis, there's hypersalivation and cialorrhea, there's cardiometabolic, really metabolic side effects, particularly weight gain and dyslipidemia, gastrointestinal side effects, constipation, hypomotility, and there are neurological side effects, akesthesia, seizures, there's fatigue, there's a question about cognitive dulling, and then there's the risk of cholinergic rebound with abrupt discontinuation of clozapine. So with respect to neutropenia, it's higher in adolescents than in adults. In adults, the incidence of neutropenia is estimated to be 3.8%, severe, under 1%. The incidence is less than 1% a month during the first 18 months. It peaks in the first month, and three quarters of the incidence of neutropenia occurred during the first four months of treatment with clozapine, and 90% during the first year. Death is rare. As you can see, it's 13 per 100,000. The risk is higher with a haplotype of HLA-DQB1. The standard is not to test for it, but the odds ratio is substantial at 15 times. If someone has celiac disease or you suspect narcolepsy, it might be worthwhile keeping HLA-DQB1 in mind. There's a higher risk of neutropenia when taking other psychiatric medications, particularly valproic acid, the incidence being wide. And I mentioned the REMS monitoring protocols, 1,500, 1,000, 500, as the absolute neutrophil count, prompting us to do different things when treating individuals with schizophrenia or with this medicine. Bear with me for a moment. For some reason, it wasn't advancing. There's the risk of thrombocytopenia, thrombocytosis, anemia, eosinophilia. They're worth investigating, sending to a primary care physician. It's important to think DRESS, but not necessarily myocarditis with eosinophilia. With respect to cardiomyopathy or myocarditis, it often occurs during the initial weeks or months of treatment with 75 to 82% of the incidence occurring during that period of time, particularly during that first month. The incidence can be higher with a rapid clozapine titration. I will share a rapid clozapine titration schedule with you at the end of the talk. The incidence can be increased, again, with a treatment with Depakote, divalprog sodium. It's recommended to get a baseline electrocardiogram, but if that's a barrier to care, it's understandable if that's not obtained. The cardiomyopathy and myocarditis is rare in adults and in young adults particularly. The absolute risk is one in 10,000 up to 19 in 10,000. But for some reason, we are seeing an increase in incidence and it does have a burden of mortality that warrants investigation with the abrupt onset of fever or chest pain or clear cardiac symptoms, syncope. So when symptomatic, a cardiology consultation is the first in order where they might get an echocardiograph, an MRI, a cardiac MRI. They may get C-reactive protein, troponin, CKMV. There can be tachycardia, hypotension, orthostasis, fatigue. Those are all considered benign side effects. Weight gain and liver abnormalities are pervasive and with respect to adolescents, they exceed the incidence in adults. The average weight gain is between one kilo and 10 kilos, 0.9 to 9.5. That is less than olanzapine, similar to, well, less than olanzapine, more than risperidone and quetiapine. The diabetes mellitus incidence is high among adults. The recommendation is to start metformin preventatively in this group, and there are some papers that suggest the same in adolescents. Here's a titration schedule that you might wanna consider if you wanna start metformin preventatively, which is recommended. It's also reasonable to consider treatment with topiramate as that has an evidence base for antipsychotic-induced weight gain. In my practice, I'm also wanting to spend time with motivational interviewing, making recommendations and encouragement for diet and exercise, a little bit at each visit. Hypersalivation and Cialuria, the prevalence is high, 30 to 90%, some estimate closer to 90%. It's predicted by muscarinic agonism. There's believed to be a combination between a reduction in swallowing combined with hypersalivation. That nighttime, nocturnal Cialuria exceeds daytime for management. Sometimes it's just placing a towel on the pillowcase or inside it during the day. Sometimes it's just chewing sugarless gum because that assists swallowing. Benztropine in the medical literature would be the first recommended agent for Cialuria. And if it doesn't work, atropine drops. Some of you might know those as for the eyes. So it's a 1% ophthalmologic solution and it's placed on the tongue two or three times a day. Some people don't like the taste and nonetheless, it can be very effective. There's botulinum toxin injection, but that's very specialized and not widely available. With regard to gastrointestinal side effects, constipation is prevalent. So it's recommended for prophylactic ducusate or MiraLAX polyethylene glycol and hydration and hydration. Particularly since in this population, that is individuals treated with Clozapine, there seems to be a lower rate of water intoxication. And so I guess you don't push hydration too, too much, but enough. And then of course there's Sinusinides. It's a standard to encourage the report of new bowel symptoms, either in between visits and certainly to check at visits. If it's severe, it's important to stop Clozapine to manage and re-challenge. Manage not you or me, but by referral to a primary care physician. Because there is a slow gut associated with Clozapine. It's called Clozapine-induced gastrointestinal hypomotia. It has a low sensitivity. It has a low incidence and it's particularly lower in youth and young adults. The problem is that there is a risk of ileus. There can be mild transaminitis and it can be asymptomatic up to two times the upper limit of normal range for AST and ALT. Up to a 30% incidence. It often occurs early in treatment, but when it's later, you may want to think about fatty liver. Akesthesia has an incidence that's higher in children and adolescents than in adults. Some estimate up to 20%. That was done in an NIMH study. And treatment is recommended with five milligrams of propranolol three times a day. And that was specified by Meyer and Stahl in their Clozapine handbook that was published in 2020 by Cambridge, which is an excellent resource, an absolute excellent resource. And they're part of the work group. And that's hopefully not tripping a wire with respect to any kind of marketing, because it's not, it just is an excellent resource. Someone might try to reduce the Clozapine dosage to reduce the akesthesia. Because akesthesia can be very disturbing and it can lead to non-adherence, as you know. It can be misinterpreted as anxiety. The seizure rate was 3.5% in clinical trials. It's three times more likely. That's a three times relative risk compared to other second-generation antipsychotics and first-generation antipsychotics. The risk increases during dosage escalation, super therapeutic concentrations, and with CYP1A2 inhibition and warrants a neurology consultation. Fatigue, it's common in youth freedom with any second-generation antipsychotic. And someone might consider one daily dosing at bedtime. The half-life of Clozapine is 12 hours. And so it's very possible to take it at bedtime, but they're waking up with a lower concentration as the day goes on. And the range for the half-life is from four to 66 hours. The trade-off is with increasing potential morning sedation or a potential possible reduction in efficacy, particularly if they're a more rapid metabolizer. Caffeine can inhibit metabolization of the Clozapine. So while they may be taking it for wakefulness, it may be actually leading to sort of a lot higher serum concentrations of Clozapine. Some will try low-dose modafinil or R-modafinil for wakefulness. It's important to know that that is an inducer of Clozapine, so there might be a slight increase in psychosis just because of the modafinil or possibly because it may lead to a slightly lower serum concentration of Clozapine. Sleep hygiene and counseling and education can also be very, very useful in helping people get over daytime fatigue. Cognitive dulling, while it occurs, it may be more sort of a fiction than fact. That group that I mentioned from Hopkins with Lee found that there was approved attention and verbal fluency in those treated with Clozapine. That in another study, the cognitive impairment caused by high-potency anticholinergic effects of Clozapine was not found, as it might be and as is often found in other high-potency anticholinergic agents. And it was deemed to be likely due to the nor-Clozapine effects, which are pro-cognitive. And so a lower Clozapine, nor-Clozapine ratio is often associated with better cognitive performance. And so if you check, you may notice that as being the case. Cholinergic rebound, so this is when tapering and discontinuing Clozapine. Mild sleep disturbance, disturbing dreams, moderate anxiety, diaphoresis, sweating, urinary urgency, nausea, diarrhea, severe delirium, confusion, catatonia. So how do we treat it? Benztropine, Benadryl, Trihexyphenidyl. The Benzapine-Clozapine ratio would be, or equivalency would be one to 50. So if your patient, for instance, has 200 milligrams daily dose of Clozapine, you could start at four milligrams of Benztropine. The maximum daily dose of Benztropine is six milligrams. So it's recommended to start within 24 hours of Clozapine discontinuation and then taper after two or three weeks. And as the cholinergic withdrawal symptoms diminish. So it's just worth saying quickly that Clozapine undergoes a significant first pass metabolism. As I mentioned earlier, it has a half-life of about 12 hours and that's why it's registered with twice daily dosing. It's primarily metabolized by the CYP-450 system with the enzyme predominantly being the CYP-1A2 enzyme. Secondarily, the CYP-3A4, CYP-2D6, 2C19, 2C9. And for those of you that are fastidious about CYP-450 metabolization, you'll notice that those are all significant with a variety of psychiatric medications. Smoking is an inducer of 1A2. And so there's a lot of people that have serious mental illness that smoke. And it's important to be able to track how much they're smoking, whether they've just stopped because they've run out of funds or they're trying to quit or they've substantially increased as it may have a substantial effect on the serum Clozapine concentration. Root vegetables, insulin as I mentioned, modafinil, and for those that have GERD, omeprazole. The 1A2 inhibitors, the antibiotic ciprofloxacin, the other floxacins, fluvoxamine, Luvox, duloxetine, Cymbalta, caffeine, grapefruit juice, estrogens, so oral contraceptives. 2D6 inducers, haloperidol. So someone maybe is in the hospital, they're getting aldol injections, that it's going to affect their Clozapine level. And then with respect to 2D6 inhibitors, potentially leading to higher serum concentrations, fluoxetine, paroxetine would be appropriate. So what about treatment? How to get started? So by the book, after two failed trials of a second generation or first generation antipsychotic, how do we get started? A complete blood count with differential for absolute neutrophil count. If not registered with REMS, get registered with REMS. Make sure that the pharmacy that you would use registered with REMS. Check other lab values, lipids, fasting glucose. I like to get the liver enzymes because of the potential for them to increase. An electrocardiogram, as I mentioned earlier, if it's not too difficult to complete, as long as it's not a barrier to getting started. Here is an initiation titration schedule. It's showing that in two and a half to three and a half weeks, you could get somebody started. They could come in once a week. They could go to the lab once a week. It depends on your practice. And then you can get a clozapine, nor-clozapine level when they're at 200 to really get a sense of whether you need to back off or to increase. And a rule of thumb might be to start at 0.3 milligrams per kilogram, which will sort of, for a lot of people, be in that range, in that starting range. The adult, for the young adult portion, the transitional age youth, as you can see, when it's slow, it's similar to the adolescents. And when it's fast, it's, I guess, much faster. Not a tremendously much faster. These are all based on nighttime dosing as well. If someone's a smoker, then the recommendation is to double all these doses. So it's because of its effects. It gives you an idea of how substantial smoking in these aryl hydrocarbons are in the inducement of clozapine. The clinical response is deemed most likely within the range of 350 to 700 nanograms per milliliter. If you look at a lab report, it's gonna say around 350 to 450. For people that are naive or don't use this medicine very much, there's a lot of evidence that in the community that treaters are going up to 1,000 nanograms as a concentration. Evaluate the response after three weeks. That's consistent with the titration schedules that I showed. And then it may take up to two months with a targeted serum concentration to really see a more full effect at whatever concentration they're at. I'm concerned about running out of time. And so I think the last thing is just be watchful for non-efficacy and side effects. Make sure that to the extent that people have parents and guardians, that they're available to administer. And if they're apprehensive, you can recommend them to NAMI's Family to Family Program, or you can counsel them yourselves at how to work through conflict around being the administrator of the medicine. I don't know if I'm gonna say a whole lot more here that you might not know already. You know that you have to check the absolute neutrophil count. Your aim is remission and not just response, that really people can achieve remission. It's important to track and monitor substance misuse and abuse. There's the CRAFT, the audit, the DAST. There's urine drug screens. There's ways to do measurement-based care using the BPRS and the PANS, which are both available in the public domain. It's important to track weight gain and waist size, glucose, lipids, and transaminases. And suicide risk. We have this, you know, there's the CGI suicide scale. It's two questions. The Columbia Suicide Severity Rating Scale is not too many either after that initial baseline is established. And I think the last thing is that in addition to medicines, there's cognitive remediation. There's therapy. There's supported employment. There's college technical programs, they have, that can change the course of someone's life. And that if you need more, there's resources, the American Psychiatric Association. As I mentioned, the Clozapine Handbook. AQHR, or AQRH has a large study as well. I'm gonna stop now so that there might be a couple moments for questions and answers. Thank you. Great. Thank you for such an interesting and informative presentation, Dr. Cousins. Before we shift into Q&A, I wanna take a moment to let our participants know that SMI Advisor is accessible from their mobile device. Use the SMI Advisor app to access resources, education, and upcoming events. Complete mental health rating scales, and even submit questions directly to our team of SMI experts. Download the app at the site listed here. Now we'll take just a couple of questions. Let's see, our first one, how about vaping and Clozapine dose? Is it equal to smoking? You're muted. I would imagine that it's difficult to make good estimates because some of the vaping has, there's such a wide variety of ingredients. And I wish I could speak, I wish I could speak to it with accuracy, but I believe that's out. That's out of my knowledge base. I would recommend tracking absolute change. So if they're vaping 10 times an hour, it's important to know next time whether they're vaping five times an hour. And it's not always so easy to get an accurate answer. But that might be. We've done that with a few of my younger patients as well, kind of actually trying to get a tracking on how much they're vaping or smoking, and then really it's a good time to get levels more frequently so we can kind of figure this out. All right, and we are almost out of time. So I'm just gonna ask one more question. You discussed how the evidence requires a lot of inference in transition age youth. Can you give an example or an anecdote of a young person who you've treated with Clozapine? Yes, so I treated about 12 patients over the past year, between the fall of 2020 and the fall of 2021, when I was working at that pediatric specialty hospital. I treated four individuals who had Prader-Willi syndrome. They're all in the transitional age range, three boys and one girl, who had psychosis and refractory aggression. They were all responders. Two had a full remission of their aggression, and two had a remission of their psychosis, and others had what would be deemed a valid response, a greater than 50% reduction. I treated a 16-year-old with DiGeorge. That's also velocardiofacial syndrome. Was schizoaffective bipolar, who would have breakthrough mania on Depakote and a variety of other antipsychotics. And when I introduced Clozapine, his mania remitted, he had for real mania, hyperreligiosity, hyposexuality, violence, reduced need to sleep. And I'll give you three more quick anecdotes. An adolescent female who had a movement disorder that was worsened by other second-generation antipsychotics, but also who had mania that was refractory to antipsychotics with suicidality and aggression, that when treated with Clozapine, her movement disorder decreased, her suicidality and aggression remitted as did her mania. I've treated a 16-year-old female who had three years of non-remitting psychosis, suicidality, suicide attempts, self-injurious behaviors and psychosis, treated with Risperidone, Ziprasidone, Thorazine, and had an effective treatment with Clozapine. A 15-year-old who then turned 16-year-old boy who had a schizoaffective bipolar type, two years non-remitting with psychosis and violent aggression, who had full remission of both psychosis and aggression with Clozapine. A 17-year-old with schizophrenia, treatment resistant for four years, who also had Allports, who had a remission of aggression and a near full remission of psychosis with Clozapine. And then lastly, a patient with another rare genetic syndrome and schizoaffective bipolar who had three years of non-remitting psychosis with mania, who had a remission of mania and maybe a 75% reduction of psychosis with Clozapine. Wow, thank you for sharing those really great cases with us and for doing this really important work. Okay, so if you have, audience, if you have a follow-up question about this or any other topic related to evidence-based care for SMI, our clinical experts are now 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. On behalf of SMI Advisor, we'd like to invite you to learn more about APA's 2022 Annual Meeting. The in-person conference takes place May 21st to 25th in New Orleans and the virtual meeting takes place June 7th to 10th. During the live conference, clinical experts from SMI Advisor are leading a variety of sessions on how to improve care for individuals who have SMI. Topics for these sessions include the basics on how to use Clozapine, digital navigators, and making technology work, and how to improve physical health in patients who have SMI and more. I encourage you to take a moment now and browse the agenda at the URL shown on the bottom of this slide. 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 on May 12th as Noah Abdenauer, Stacey Manser, Brandy Helmsley, and Jeremy Reed present Recognizing the Value of Peer Support Specialists, Strategies for Increasing Wages and Developing Career Pathways. Again, this free webinar will be on May 12th at 3 p.m. Eastern. Thank you for joining us today, and until next time, take good care.
Video Summary
The webinar discussed the use of clozapine in treating transitional age youth with serious mental illness. The speaker, Dr. Kurt Cousins, presented evidence for the efficacy of clozapine in treating schizophrenia, suicidality, bipolar disorder, and aggression in this population. The evidence primarily consisted of case reports, cohort studies, and some controlled trials. The use of clozapine in transitional age youth was found to be effective in reducing symptoms and improving outcomes. The speaker emphasized the need for careful monitoring of side effects, such as neutropenia, myocarditis, weight gain, hypersalivation, constipation, and cognitive dulling. He also discussed the importance of conducting regular lab tests and assessing suicidality and aggression. Dr. Cousins shared anecdotes of successful treatment with clozapine in several young patients with different psychiatric conditions. Overall, the webinar provided guidance and insights on the use of clozapine in the treatment of transitional age youth with serious mental illness. Credits for participating in the webinar were available for healthcare professionals until July 1st of that year.
Keywords
clozapine
transitional age youth
serious mental illness
schizophrenia
suicidality
bipolar disorder
aggression
case reports
cohort studies
controlled trials
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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