Episode Transcript
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Welcome to the Psychiatric News Special Report podcast, a monthly podcast from PsychiatricNews produced for the APA Medical Minds channel.
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I'm Dr.
Adrian Preda, Editor-in-Chief of Psychiatric News and Professor of Clinical Psychiatry andHuman Behavior at University of California Irvine School of Medicine.
Each month, we sit down with the author or authors of our special report to discuss keyissues at the intersection of mental health, psychiatric clinical care, research and
advocacy.
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Today we are taking a deep dive into a critical topic in psychiatric care, close-up pain.
It's often called the gold standard for treatment resistant schizophrenia, yet it remainssignificantly underutilized.
To help us understand why close-up pain is so important, recent updates in its managementand why it's not used more often, we are thrilled to be joined by the authors of our May
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special report, Close-up Pain Revisited, Updates to the Gold Standard.
Please welcome Dr.
Gemma Espejo
Health Sciences Assistant Professor of Psychiatry and Human Behavior and AnatomicPsychiatrist at the University of California Irvine School of Medicine and Dr.
Farah Khorassani Health Sciences Associate Clinical Professor of Clinical PharmacyPractice at the UCI School of Pharmacy and Pharmaceutical Sciences.
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Thank you both for being here.
Thanks for having us.
Thank you so much for having us.
Happy to be here.
Let's start with the basics.
Your article highlights that close-up in is one of the most effective interventionsavailable to psychiatrists.
Dr.
Espejo, could you elaborate on why close-up in is considered the gold standard, especiallyfor treatment-resistant schizophrenia?
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Yes, of course.
Closapine, you was created much earlier, really didn't become more commonly used until theFDA approved it in 1989 or 1990.
Since then, multiple trials have really proven its efficacy in treatment resistanceschizophrenia, specifically K2.
There are very well-structured studies that look at different measures of efficacy,whether it's discontinuation rates or efficacy response in PAM.
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or BPRS for those who have actually failed at least two adequate duration trials of otherantipsychotics, both typicals and atypicals, and those people will have about a 30 to 40
percent chance of responding clinically to close.
So that efficacy is striking, yet your article notes that it's underutilized.
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Dr.
Kurasani, why do you think that's the case despite this very strong evidence?
Yes, it is underutilized and it's unfortunate.
I think there's a lot of different variables that play into this.
I think um one major limitation and drawback is the need for blood draws because of therisk of severe neutropenia.
And I think patients will report that this is cumbersome.
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There are studies showing that patients who don't have to do the blood draws and do fingerstick draws actually prefer and are more adherent to being on clozapine.
So the blood draws are a big major drawback.
Clinician comfort with monitoring patients and initiating clozapine is also anotherdrawback.
There are also studies showing that, you know, physicians or psychiatrists or otherprescribers are maybe not as comfortable initiating clozapine as they are other
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antipsychotics.
So there's a lot of red tape around it, and I think um it just leads to a littlehesitancy.
it sounds like there are a few sides to this.
So first on the clinician side, this is a medication that requires more complexmanagement, which would make maybe clinicians more reluctant to use it.
But that complex management that's required, it could also be somewhat of a disincentivefor the patients as well.
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Absolutely.
And something I didn't mention too is on the pharmacy side too, was a, you know, the REMSprogram was just removed by the FDA, but that was a significant drawback up until recently
from the pharmacy side.
You know, we would have to get authorization codes and then there would have to becommunication between the physicians and the pharmacy.
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And it led to a lot of discourse.
Yeah, that makes sense.
So let's delve into the management.
Dr.
Espejo, can you walk us through the typical close-up intitulation process and how recentguidelines, particularly regarding ancestry, that you discuss in your article changing
this approach?
Absolutely.
So for a long time, think people sort of split into two different groups.
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At least this was my sense.
Those who very strictly followed the prescribing information, the package insert, whereyou start at 12 and a half or 25 milligrams.
And those who did more aggressive titrations, where you started at 50 milligrams or more.
Now, recently, in the past few years, there's been these ethnicity guidelines that breakit down by
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different various ethnicity groups.
So they differentiate actually East Asian from of course European and indigenous Americanpeople.
And what you find is that you actually start at lower doses, titrates smaller, especiallyfor Asian population and a target dose for a therapeutic level actually ends up being
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lower too.
um Dr.
De Leon and his colleagues wrote a very long paper with supplementary data.
the tables type you hear each hydration for a different ethnicity group.
So what is kind of the typical type titration schedule that's done in the US and how arethe titration recommendations different based on this other new data?
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So if you were to go with one of the lower end ones, they would say that the range may besomewhere starting at 150, or a lot of people previously were thinking a therapeutic dose
could be 300 milligrams, 250 milligrams or more.
And so the titration really becomes starting at 12 and a half with maybe a whole dose of75, 100 within the first week, rather than starting at 50 and going faster.
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I see.
Dr.
Khorasan, what about special populations, geriatric patients, pediatric patients, are thetitration recommendations different?
That's a great question.
There's no published guidelines like what Dr.
Espenga was talking about, but in general with geriatric patients, they metabolize drugsslower, they excrete drugs slower.
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So, proclosapine, it is renally excreted and the half-life is variable.
It can vary and age would definitely impact that.
for a young adult in their 20s, you expect about a day half-life.
For a geriatric patient, it could be up to three days.
that could impact the titration.
Because if the drug is sticking around longer, it's not excreted, that leads to more sideeffects.
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So more risk of orthostasis, more risk of sedation.
And so you kind of have to watch the patient because there are no specific guidelines.
But you would expect to have to go a little bit slower to avoid some of those titrationand dose-dependent adverse effects.
How about therapeutic drug monitoring?
Yes, definitely.
We have many antipsychotics where we can do therapeutic drug monitoring.
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Obviously, clozapine has the best data for it.
We aim for a level of greater than 350.
There's some good data showing that patients above that 350 threshold will do better onclozapine, especially if you leave them on that dose at that level for 12 weeks or so.
And so it is recommended.
In general, you're checking a level after a steady dose of like five days.
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to see if that patient is above the 350 threshold.
For patients of particularly Asian descent, what I've noticed in some of our inpatients isthat we'll check a level at lower doses and we'll see that they'll still be therapeutic.
So maybe an Asian woman might be therapeutic with a level of 450 on a dose of 100 to 150.
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And so we'll check that level a little earlier knowing that we might meet that thresholdearlier.
So it sounds like the one dose fits all approach is probably not recommended, right?
In fact, not only based on dosing requirements, but on the TRM, the therapeutic drugmonitoring, TDM, we could have more personalized recommendations regarding dosing for
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different populations, for different patients, which is crucial, right, for optimizingtreatment and durability.
So discussing about monitoring, the risk of severe neutropenia,
has been historically a major concern with Clozapin.
Dr.
Espejo, there are the changes that you're discussing in our article about the REMSprogram.
Could you maybe give us some perspective what the REMS programs used to be and what it isnow and how the requirements have changed?
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So many of us are familiar with the Closing Pink Roms program.
We had to enter the patient into the registry, put in the ANC, and if we started theminpatient, then you would just put the ANCs for your inpatient pharmacy.
But once they were discharged, and for outpatient practitioners, the pharmacy had toverify the ANC before they would dispense.
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And so really for the first six months, it was weekly, then it became every two weeks, andthen it was month
indefinitely.
Now if your numbers drop below a certain threshold, then depending on how far they drop,you would have to uh reinitiate hydration perhaps, but you would also have to change the
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frequency of lab monitoring at times every day frequently until those numbers went backup.
And as Dr.
Khorassani mentioned, the delay of communication between ordering the CBC for the patient,the patient getting the CBC, and then the
going back to the doctor and then going back to the pharmacy really led to significantdelays of accessing uh medications for our patient.
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Now, it was ruled recently that the FDA did get rid of the REMS process, but it is stillrecommended, however, that prescribers still follow the recommended guidelines as per the
package insert.
Now, of course, there's a lot of talk in the community that this will likely be addressedwith future recommendations.
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patients that will be different because that's obviously a big gap that our patients andproviders pharmacies are going to have to adjust to, especially uh families that are
taking care of their loved ones that are on COVID-19 having concerns about monitoring aswell.
Dr.
Corzoni, I don't know if we have more to add there about the REMS changes and overalleight regular circumstances risks.
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Yeah, I agree with everything that you said.
I mean, again, the risk is, is what I think the FDA agrees with is a bit overblown.
You know, if you look at the actual incidence rates for the literature, like less than 1%.
uh And so it's a lot of other countries that use close-up in much more than us in the US,like Australia and New Zealand and some countries in Scandinavia.
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really have loosened up on the monitoring.
uh The risk of agran is much greater in like the first 18 weeks of therapy and reallywithin the first year.
But the risk diminishes after that for the literature that we have.
And a lot of those countries, their oh blood monitoring guidelines really do mimic thattrend.
And so my hope is that in the US, we start to move towards what some of the othercountries are doing in terms of blood monitoring and loosen up the restrictions to
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increase access to cozipine.
So it's important to note that while the centralized reporting went away, monitoringitself uh is still recommended with the weekly CBCs for the first six months.
And if no issues arise, then scaling back to bi-weekly and then monthly.
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But with this changing ramps, it seems like, know, what you are alluding to with thedifficulties that we discussed before, this change allows for more clinical flexibility,
trust the provider's judgment, which in turn, hopefully,
The goal here is to improve access and utilization.
Is that a fair summary?
Another significant problem is that you are noting in uh your report is myocarditis.
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Dr.
Espejo, how do we approach this risk?
Yes, that's a great question because I really think that the management and the approachto it and monitoring has really changed in the past 10 years or so.
I would definitely say our approach to it here on the unit with trainees is different thanwhen I was in training myself.
And so with myocarditis, of course, there is a fatality risk.
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So it is one of the big, quote, scarier things that we are worried about and think about,especially in the initiation.
And we find out that those while we're
in the initiation phase are the highest risk for myocarditis.
Now, myocarditis, the tricky thing is it can present in a variety of different ways.
You can have lab afteralities, but you can also have symptoms like shortness of breath ornausea, chest pain.
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And so, of course, we know that the definitive way is to do a cardiac biopsy, butrealistically, we are not doing that with our patients on an inpatient unit.
And a lot of studies
will do like a cardiac MRI.
Again, also not something super accessible to most inpatient providers and patients.
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And so there's been some work looking at what sort of lab markers and clinical symptomsshould we look out for and what's the period that we should monitor.
And so there are protocols that suggest following things like CRP, terponin, EKG.
and making sure that you're of course monitoring vital signs for things like feeders andclinical symptoms like, as I mentioned, chest pain, shortness of breath, nausea.
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If you really look at those for the first four to eight weeks, you are at the highestcapture sort of point to find those people and either slow your hydration down or get
cardiology.
And if that happens, what are the recommendations regarding continuing versusdiscontinuation?
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So I think it depends on what the labs look like and of course what the patient clinicallylooks like.
And so I think you can have a range where you could say, okay, there's a low suspicionhere.
So maybe we should slow our hydration down and continue monitoring labs more frequently.
So the protocol that we write about and that we mostly use are the ones where you get theCRP, the turponin and you get those weekly.
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If you were to...
a suspicion for some symptoms, you may want to get those labs dated.
Oftentimes in clinical practice, if those labs uh are concerning, we get cardiologyinvolved and ask for cardiology input.
Now, the question of whether you can re-challenge or continue titration is really apatient dependent decision.
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So I think you can imagine the spectrum of, is this somebody that there is really no othermedication we could try other than clozapine?
or was this somebody who wanted to try clozapine earlier in their course and had maybe asomewhat decent response to another medication?
So I think you have to think about the strength of your suspicion for myocarditis,paradiology's input, and the symptomatic burden of the psychotic symptoms for the patient.
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And I think once you balance those factors, it becomes a very patient-specific decisionwhether to be challenged as there aren't clear cardiology.
psychiatric body of literature guidelines of what should be challenged.
In your report, you discuss the results from a meta-analysis where the success rate isactually not bad, it's 65 to 70 percent, but at the same time, they reported one fatality,
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which is really scary and concerning, right?
So it's a difficult decision to make.
Clozapin has clear benefits and it is a last resort many times.
So when that doesn't work because the patient develops myocarditis, the question is goingto be, then what?
But it is something that to summarize your recommendations needs to be approached withlots of caution.
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Consulting with cardiology is recommended.
If possible, being very diligent and deliberate in considering the risk factors ifre-challenging would be considered is actually the recommendation here.
Dr.
Kurasan, beyond neutropenia and myocarditis, what are some other common or significantadverse effects of clozapin and how are they typically managed?
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Yes, and so I kind of group the adverse effects of clozapine into some of the more acuteadverse effects that you see that when you're titrating the medication versus kind of the
more chronic effects.
And also thinking about are these idiosyncratic, we call them, or kind of just random atany dose adverse reactions, or are they dose dependent?
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So I think when you're first initiating clozapine, usually in an inpatient setting, butit's happening more and more in an outpatient setting,
The things that I'm looking for are going to be sedation or the stasis, right?
Those are the dose effects.
They're also oftentimes dose dependent and can be managed simply by just slowing thetitration or keeping the dose where it's at um and checking a level.
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The other things that kind of come up and these happen acutely but also chronically, Ithink of bowel issues.
So specifically constipation, oposabine has been associated with small bowel obstructionsif the constipation is untreated.
Many hospitals have initiated protocols, oftentimes nurse initiated where bowel movementsare documented in nursing notes to make sure that we are checking with patients.
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And so those are kind of the main ones that I think of.
Of course you have other long-term products.
You have other cardiac effects long-term as well.
Risk of cardiomyopathy.
We think of myocarditis in the short term, cardiomyopathies in the long term.
So there's a lot to consider.
when putting patients on close attention.
And of course the metabolic risk that you see with all antisyc, atypical antisyc.
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So just a couple of details from your report you are discussing as prophylactic laxativesthat could include lactulose, polyethylene glycol, senna, mysoicidyl, but not bulk forming
laxatives, right?
Correct.
And the reason for that is bulk forming laccidates, example, psyllium is what I think ofthe most, can sometimes, especially if you're not hydrating enough, kind of get stuck in
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the bowel.
And because of that, it can actually worsen impaction or a small bowel obstruction.
Back to the spejo, what about the weight gain and associated metabolic risk?
That's also a long term, as Dr.
Forisani mentioned, side of it that we think about with all of our, or most of ouranti-psychotics, but especially clozapine.
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And so I remember when I was training, there was this question of, we be initiatingmetformin when we start clozapine?
And we just didn't have that data to support that.
But now there have been recent papers, Dr.
Carolyn is the first author.
where they did large studies in the United States, they did a study where you startprophylactic, quote unquote, metformin when you start olanzapine and when you start
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clozapine.
And they actually have a great algorithm in their paper where they break it down versusclozapine and olanzapine, the high risk antipsychotic and the medium risk, lower risk, and
also think about things like EMI.
So Dr.
Alkowal, who also worked on that paper, and he does a lot
psychosis work in Canada also was talking about looking at when you start metformin andyou start clozapine at the same time.
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Not only are you mitigating the metabolic risk, but you're increasing the likelihood ofclozapine adherent.
So it's a clear win, I think, to be starting metformin when we're starting clozapine onour patients.
So it sounds like managing side effects is key to long-term success.
What about patients who go ahead?
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I was just going to say uh absolutely.
think we all know as providers, course, advocacy helps the patients want to stay on themedication.
But of course, the other hand is that dealing with side effects are probably the numberone reason our patients stop taking medications.
What about patients who don't achieve an adequate response even to close up in?
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What are the options?
Dr.
Khorasane?
Yeah, so I think when I think of one of my greatest success cases in a clozapinerefactoring patient, which is also a literature supported treatment modality is ECT.
We have good data, small studies, but good data showing ECT really, really can be thatextra little push for those patients who are partial responders or not responding to
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clozapine.
So ECT is kind of the first recommended treatment modality.
Of course, not everyone is able to access ECT as it's invasive, expensive, all of that.
And so we have some literature on antipsychotic augmentation, albeit not strongliterature.
Probably the strongest body of literature for specific antipsychotic to augment clozapineis with Abilify.
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uh We have data with Abilify Maintana augmenting clozapine.
But the way I view it is if we have to augment, we can't do ECT or ECT didn't work.
Ideally, we pick something that's different from a pharmacologic standpoint.
than clozapine.
And so I wouldn't want to obviously take out the literature part of it.
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If we have to choose, I wouldn't want to choose something like Zyprexa because it's verystructurally similar and pharmacologically similar to uh clozapine.
So considering doing something like a Risperdal or a Haldol that's structurally differentand then again, binds to different receptors.
So at least you're not causing more adverse effects and you're kind of targeting differentthings.
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I don't know if Dr.
Spell, you want to add to that?
Yeah, I think one of the things that we think about logistically too, especially as Imentioned before with RAS, but also realistically enhances an issue for our patients that
are taking close to me.
And so if you choose a medication that has a long acting injectable option with adifferent chronological profile, you get the benefit of that as well.
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So maybe there is some baseline coverage if they are on a long acting elephant resolve ora long acting or sparedome.
But as Dr.
Khorosani said, ECT is the clear winner if you're looking from a data supportedperspective.
And in large use, antipsychotic augmentation, secondary antipsychotic augmentation ofclosapine doesn't clearly separate out from placebo.
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If you break it down agent for agent, you do see perhaps a signal with an erythrozole.
But to zoom out a little bit, if I may.
I think the key thing that we...
is to not give up on it, so to speak.
So with our other anti-psychotics, you maybe look for a response, you know, a few weeksin, reclose a pain, it's very clear from the literature that you want to wait 12 weeks at
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a therapeutic level.
So you want to make sure that you're hitting that 350 therapeutic level and the 12 weeksbefore you start going down the road of adding another agent that very well may worsen
Now, switching gears a bit, so we discuss therapeutic drug monitoring and differentrecommendations for different ethnicities and maybe different genetics.
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So you discuss pharmacogenomics in your article.
What's the evidence for it?
Should we do it?
Should we not do it?
Yes.
So the quick answer to that is there's no evidence that we should be doing it right nowfor Clozapine.
Clozapine is mostly metabolized by CYP1A2 with minor metabolism with 3, 4, and 2D CYP.
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Currently, there are no recommendations on doing any type of pharmacogenomic testing forpeople with CYP1A2 polymorphism.
And actually,
For antipsychotics in general, there's no recommendations, even those that are metabolizedby 2D6 and 384.
So I think it seems right now that pharmacogenomics is probably not going to become a bigplayer with clozapine treatment unless there's some new discoveries in the next couple of
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years.
I know the um CPIC, which is a governing body on pharmacogenomics and makesrecommendations for testing within the United States, is currently putting together a
consensus paper.
on antipsychotic uh use and pharmacogenomic testing within.
So I look forward to seeing that in the future.
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My guess is there's going to be no recommendations for it, especially with closing.
Looking ahead, uh your article touches on future directions.
ah Dr.
Espejo, are there any emerging treatments that might challenge close-up and status or beused alongside it?
you asked that we just had a conversation the other day on a unit about, um, so normallyin calcium with the new agent that of course is not everybody excited because it has a
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unique mechanism that doesn't deal with dopamine at all.
And I think we have a lot of patients already asking about it.
In fact, I have a patient who's is on closer team right now and the family is asking, canwe try COVID?
We've seen the ads and we're hearing about
And as we're all familiar with, takes some, for a lot of medications, sometimes a longtime for things to trickle down and for medications to become actually accessible.
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When we of course look at the data, how synomal antipsychotropics has been studied, it'snot in treatment resistance schizophrenia, and it's not in closer pain augmentation, of
course.
But as Dr.
Khorasadi said, when you're thinking about, it makes sense logistically, when you'rethinking about augmenting a medication.
to pick something with a very different pharmacologic profile.
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So academically, of course, I think a lot of people are excited to see what are we goingto start seeing, ACE reports or larger studies looking at xenomalutroxine augmenting
clozapine or being seen in treatment resistance schizophrenia.
But of course, it just came out.
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So we just don't have that data accessible.
I'm hesitant to...
prescribe that or go down that road with patients.
And I'll just add that I do think that it, you know, I think the studies are not thereyet.
Obviously, I think from a mechanism standpoint, it is worth it to study to see, uh youknow, right now when we do dual antipsychotics, we are using basically two drugs that are
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doing the same thing.
And this drug has a completely different mechanism of action.
And perhaps that could be uh helpful to augment.
And I do believe that they will be doing those augmentation studies in the future.
So I look forward to seeing them.
What about about neuro modulation as a potential augmentation strategy for close-up in?
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think the neuromodulation frontier is one of the most exciting frontiers that we have inpsychiatry, especially with TMS and how much personalization we can do with transcranial
magnetic stimulation.
know, ECT, black clozaphen, been around for a long time, proven efficacy.
I think, you know, there are people who are looking at TMS for like cognitive...
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But when we think about Closapine, think most of us are using it for really treatmentresistant positive symptoms.
And I think with neuromodulation, again, as of the course on it was mentioning for, know,xenobalintoxin, we're really waiting for larger studies that really indicate.
But of course, I think the potential is there again, as we're coming up with new protocolsand our imaging guided personalization of neuromodulation is improving in the future.
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Yeah, that is exciting.
So we focused our discussion on the treatment of treatment resistant schizophrenia.
Clozapine has another known indication for suicidality.
Any new data regarding its potential use for suicidality, as of now it's approved forschizophrenia and schizofractive, but what about suicidal behaviors in other diagnosis?
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So I think the intercept trial is really the one that got CloserPain the FDA indicationfor suicidal, for addressing suicidal ideation, suicidal behaviors in those with
schizophrenia, schizoaffective disorder.
And really that was an important trial because I think a lot of people were thinking, oh,CloserPain patients may be doing better because they're checking in more with providers,
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checking in more with healthcare teams just because they are getting less.
and intercepts a really good job of making sure that the Alanzapine cohort was also beingchecked in with the same frequency to match the same frequency.
I think as far as new large data, you know, I don't have that.
I think you can find some smaller studies or case reports about clozapine being used forsuicidal behaviors and bipolar disorder.
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And I've even seen a case report of it being used in mortal.
personality disorder.
But again, think because of the cold, red tape around clozapine and the adverse drugeffect and the accessibility of other atypical antipsychotics that are FDA approved to be
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augmentation for unipolar depression, clozapine falls much further down on the list forthose with primary affective disorders.
It's clear that to our close-up in remains paramount for many, gold standard, right, forthe treatment resistant psychosis.
The research continues to refine how we use it and explore new options.
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Thank you so much, Dr.
Espejo and Dr.
Khorassani for sharing this crucial update.
Thank you so much for having us.
Thanks.
pleasure to be here.
This wraps our discussion on Clozapin.
We've learned about its critical role as the gold standard for treatment resistantschizophrenia and suicidal behavior, the shift towards personalized ancestry based
iteration, the updated monitoring protocols for neutropenia after the REMS programchanges, important considerations for side effects like myocarditis, common ones like
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constipation and weight gain and their management strategies and effective augmentationstrategies like KCT.
It's a complex but vital medication in psychiatry.
We encourage our listeners to review the full article, close up in revisited update to thegold standard for a more detailed information.
Thank you again to our guests, Dr.
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Gemma Espejo and Dr.
Faraz Khorassani.
And thank you all for listening to the Psychiatric News Special Report podcast.
You can read the full May Psychiatric News Special Report at psychnews.org.
We posted a link to the article in the episode description.
If you enjoyed today's episode, please take a moment to subscribe, rate and review thepodcast.
It helps others discover these important conversations.
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Until then, stay informed, stay compassionate and take care.
you