In this episode of PsychNews Special Report, we explore the evolving landscape of clozapine therapy, reaffirming its role as the gold standard for treatment-resistant schizophrenia and examining its unique benefits in reducing suicidality. We examine key insights from the Psychiatric News article by Gemma Espejo, M.D., and Farah Khorassani, Pharm.D., which highlights challenges in clozapine utilization—including blood monitoring requirements and clinician hesitancy—alongside updates to monitoring protocols and side effect management.

The episode also touches on augmentation strategies, the potential of pharmacogenomics, and promising innovations in psychiatric treatment.

Read the full article in Psychiatric News here

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PsychNews Special Report is a production of Psychiatric News, a media platform dedicated to serving as the primary and most trusted source of information for APA members, other psychiatrists and physicians, health professionals, and the public about developments in the field of psychiatry and mental health that impact clinical care and professional practice. Learn more at psychiatryonline.org/journal/pn.

Transcript for Audio

[00:12] Adrian Preda: Welcome to the Psychiatric News Special Report podcast, a monthly podcast from Psychiatric News produced for the APA Medical Minds channel. I'm Dr. Adrian Preda, Editor-in-Chief of Psychiatric News and Professor of Clinical Psychiatry and Human 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 key issues at the intersection of mental health, psychiatric clinical care, research and advocacy.

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 remains significantly underutilized. To help us understand why close-up pain is so important, recent updates in its management and why it's not used more often, we are thrilled to be joined by the authors of our May 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 Anatomic Psychiatrist at the University of California Irvine School of Medicine, and Dr. Farah Khorassani, Health Sciences Associate Clinical Professor of Clinical Pharmacy Practice at the UCI School of Pharmacy and Pharmaceutical Sciences. Thank you both for being here.

[01:27] Gemma Espejo: Thanks for having us. Thank you so much for having us. Happy to be here.

[01:30] Adrian Preda: Let's start with the basics. Your article highlights that close-up in is one of the most effective interventions available to psychiatrists. Dr. Espejo, could you elaborate on why close-up in is considered the gold standard, especially for treatment-resistant schizophrenia?

[01:46] Gemma Espejo: Yes, of course. Closapine, you was created much earlier, really didn't become more commonly used until the FDA approved it in 1989 or 1990. Since then, multiple trials have really proven its efficacy in treatment resistance schizophrenia, 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 or BPRS for those who have actually failed at least two adequate duration trials of other antipsychotics, both typicals and atypicals, and those people will have about a 30 to 40 percent chance of responding clinically to close.

[02:34] Adrian Preda: So that efficacy is striking, yet your article notes that it's underutilized. Dr. Kurasani, why do you think that's the case despite this very strong evidence?

[02:45] Farah Khorassani: Yes, it is underutilized and it's unfortunate. I think there's a lot of different variables that play into this. I think ⁓ one major limitation and drawback is the need for blood draws because of the risk of severe neutropenia. And I think patients will report that this is cumbersome. There are studies showing that patients who don't have to do the blood draws and do finger stick 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 another drawback. There are also studies showing that, you know, physicians or psychiatrists or other prescribers are maybe not as comfortable initiating clozapine as they are other antipsychotics. So there's a lot of red tape around it, and I think ⁓ it just leads to a little hesitancy.

[03:37] Adrian Preda: It sounds like there are a few sides to this. So first on the clinician side, this is a medication that requires more complex management, which would make maybe clinicians more reluctant to use it. But that complex management that's required, it could also be somewhat of a disincentive for the patients as well.

[03:53] Farah Khorassani: Absolutely. And something I didn't mention too is on the pharmacy side too, was a, you know, the REMS program 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 be communication between the physicians and the pharmacy. And it led to a lot of discourse.

[04:16] Adrian Preda: 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 recent guidelines, particularly regarding ancestry, that you discuss in your article changing this approach?

[04:31] Gemma Espejo: Absolutely. So for a long time, think people sort of split into two different groups. At least this was my sense. Those who very strictly followed the prescribing information, the package insert, where you 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 break it down by different various ethnicity groups. So they differentiate actually East Asian from of course European and indigenous American people. And what you find is that you actually start at lower doses, titrates smaller, especially for Asian population and a target dose for a therapeutic level actually ends up being lower too. ⁓ 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.

[05:34] Adrian Preda: So what is kind of the typical type titration schedule that's done in the US and how are the titration recommendations different based on this other new data?

[05:45] Gemma Espejo: So if you were to go with one of the lower end ones, they would say that the range may be somewhere 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 of 75, 100 within the first week, rather than starting at 50 and going faster.

[06:15] Adrian Preda: I see. Dr. Khorasan, what about special populations, geriatric patients, pediatric patients, are the titration recommendations different?

[06:23] Farah Khorassani: 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 drugs slower, they excrete drugs slower. 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 side effects. 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 titration and dose-dependent adverse effects.

[07:15] Adrian Preda: How about therapeutic drug monitoring?

[07:17] Farah Khorassani: Yes, definitely. We have many antipsychotics where we can do therapeutic drug monitoring. 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 on clozapine, 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 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 is that 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. And so we'll check that level a little earlier knowing that we might meet that threshold earlier.

[08:12] Adrian Preda: 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 drug monitoring, TDM, we could have more personalized recommendations regarding dosing for different populations, for different patients, which is crucial, right, for optimizing treatment 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 REMS program. Could you maybe give us some perspective what the REMS programs used to be and what it is now and how the requirements have changed?

[08:58] Gemma Espejo: 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 them inpatient, then you would just put the ANCs for your inpatient pharmacy. But once they were discharged, and for outpatient practitioners, the pharmacy had to verify the ANC before they would dispense. And so really for the first six months, it was weekly, then it became every two weeks, and then it was month indefinitely. Now if your numbers drop below a certain threshold, then depending on how far they drop, you would have to ⁓ reinitiate hydration perhaps, but you would also have to change the frequency of lab monitoring at times every day frequently until those numbers went back up. 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 significant delays of accessing ⁓ medications for our patient. Now, it was ruled recently that the FDA did get rid of the REMS process, but it is still recommended, 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 addressed with future recommendations, patients that will be different because that's obviously a big gap that our patients and providers pharmacies are going to have to adjust to, especially ⁓ families that are taking care of their loved ones that are on COVID-19 having concerns about monitoring as well. Dr. Corzoni, I don't know if we have more to add there about the REMS changes and overall eight regular circumstances risks.

[10:52] Farah Khorassani: 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%. ⁓ 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 really have loosened up on the monitoring. ⁓ The risk of agran is much greater in like the first 18 weeks of therapy and really within the first year. But the risk diminishes after that for the literature that we have. And a lot of those countries, their ⁓ blood monitoring guidelines really do mimic that trend. And so my hope is that in the US, we start to move towards what some of the other countries are doing in terms of blood monitoring and loosen up the restrictions to increase access to clozapine.

[11:47] Adrian Preda: So it's important to note that while the centralized reporting went away, monitoring itself ⁓ 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. But with this changing ramps, it seems like, know, what you are alluding to with the difficulties 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 ⁓ your report is myocarditis. Dr. Espejo, how do we approach this risk?

[12:32] Gemma Espejo: Yes, that's a great question because I really think that the management and the approach to 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 than when I was in training myself. And so with myocarditis, of course, there is a fatality risk. 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 or nausea, chest pain. And so, of course, we know that the definitive way is to do a cardiac biopsy, but realistically, 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. And so there's been some work looking at what sort of lab markers and clinical symptoms should 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 and clinical symptoms like, as I mentioned, chest pain, shortness of breath, nausea. If you really look at those for the first four to eight weeks, you are at the highest capture sort of point to find those people and either slow your hydration down or get cardiology.

[14:23] Adrian Preda: And if that happens, what are the recommendations regarding continuing versus discontinuation?

[14:29] Gemma Espejo: So I think it depends on what the labs look like and of course what the patient clinically looks like. And so I think you can have a range where you could say, okay, there's a low suspicion here. 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 the CRP, the turponin and you get those weekly. If you were to...

a suspicion for some symptoms, you may want to get those labs dated. Oftentimes in clinical practice, if those labs ⁓ are concerning, we get cardiology involved and ask for cardiology input. Now, the question of whether you can re-challenge or continue titration is really a patient dependent decision. So I think you can imagine the spectrum of, is this somebody that there is really no other medication we could try other than clozapine?

Or was this somebody who wanted to try clozapine earlier in their course and had maybe a somewhat 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. And I think once you balance those factors, it becomes a very patient-specific decision whether to be challenged as there aren't clear cardiology psychiatric body of literature guidelines of what should be challenged.

[16:00] Adrian Preda: In your report, you discuss the results from a meta-analysis where the success rate is actually not bad, it's 65 to 70 percent, but at the same time, they reported one fatality, 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 going to be, then what?

But it is something that to summarize your recommendations needs to be approached with lots of caution. Consulting with cardiology is recommended. If possible, being very diligent and deliberate in considering the risk factors if re-challenging would be considered is actually the recommendation here. Dr. Kurasan, beyond neutropenia and myocarditis, what are some other common or significant adverse effects of clozapin and how are they typically managed?

[16:44] Gemma Espejo: Yes, I think that's spot on.

[16:55] Farah Khorassani: Yes, and so I kind of group the adverse effects of clozapine into some of the more acute adverse 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 at any dose adverse reactions, or are they dose dependent? So I think when you're first initiating clozapine, usually in an inpatient setting, but it'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 the titration or keeping the dose where it's at ⁓ and checking a level. The other things that kind of come up and these happen acutely but also chronically, I think of bowel issues. So specifically constipation, oposabine has been associated with small bowel obstructions if the constipation is untreated.

Many hospitals have initiated protocols, oftentimes nurse initiated where bowel movements are documented in nursing notes to make sure that we are checking with patients. 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.

[18:26] Adrian Preda: So just a couple of details from your report you are discussing as prophylactic laxatives that could include lactulose, polyethylene glycol, senna, mysoicidyl, but not bulk forming laxatives, right?

[18:40] Farah Khorassani: Correct. And the reason for that is bulk forming laccidates, example, psyllium is what I think of the most, can sometimes, especially if you're not hydrating enough, kind of get stuck in the bowel. And because of that, it can actually worsen impaction or a small bowel obstruction.

[19:00] Adrian Preda: Back to the spejo, what about the weight gain and associated metabolic risk?

[19:06] Gemma Espejo: That's also a long term, as Dr. Forisani mentioned, side of it that we think about with all of our, or most of our anti-psychotics, but especially clozapine. And so I remember when I was training, there was this question of, we be initiating metformin 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 start prophylactic, quote unquote, metformin when you start olanzapine and when you start clozapine. And they actually have a great algorithm in their paper where they break it down versus clozapine 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 and you start clozapine at the same time. Not only are you mitigating the metabolic risk, but you're increasing the likelihood of clozapine adherent. So it's a clear win, I think, to be starting metformin when we're starting clozapine on our patients.

[20:27] Adrian Preda: So it sounds like managing side effects is key to long-term success. What about patients who go ahead?

[20:35] Gemma Espejo: I was just going to say ⁓ absolutely. think we all know as providers, course, advocacy helps the patients want to stay on the medication. But of course, the other hand is that dealing with side effects are probably the number one reason our patients stop taking medications.

[20:51] Adrian Preda: What about patients who don't achieve an adequate response even to close up in? What are the options? Dr. Khorasane?

[20:58] Farah Khorassani: Yeah, so I think when I think of one of my greatest success cases in a clozapine refactoring 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 that extra little push for those patients who are partial responders or not responding to 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 strong literature. Probably the strongest body of literature for specific antipsychotic to augment clozapine is with Abilify. ⁓ 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. If we have to choose, I wouldn't want to choose something like Zyprexa because it's very structurally similar and pharmacologically similar to ⁓ clozapine. So considering doing something like a Risperdal or a Haldol that's structurally different and then again, binds to different receptors. So at least you're not causing more adverse effects and you're kind of targeting different things. I don't know if Dr. Spell, you want to add to that?

[22:26] Gemma Espejo: Yeah, I think one of the things that we think about logistically too, especially as I mentioned 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 a different chronological profile, you get the benefit of that as well. So maybe there is some baseline coverage if they are on a long acting elephant resolve or a long acting or sparedome.

But as Dr. Khorosani said, ECT is the clear winner if you're looking from a data supported perspective. And in large use, antipsychotic augmentation, secondary antipsychotic augmentation of closapine doesn't clearly separate out from placebo. 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 weeks in, reclose a pain, it's very clear from the literature that you want to wait 12 weeks at a therapeutic level. So you want to make sure that you're hitting that 350 therapeutic level and the 12 weeks before you start going down the road of adding another agent that very well may worsen.

[23:59] Adrian Preda: Now, switching gears a bit, so we discuss therapeutic drug monitoring and different recommendations for different ethnicities and maybe different genetics. So you discuss pharmacogenomics in your article. What's the evidence for it? Should we do it? Should we not do it?

[24:17] Farah Khorassani: Yes. So the quick answer to that is there's no evidence that we should be doing it right now for Clozapine. Clozapine is mostly metabolized by CYP1A2 with minor metabolism with 3, 4, and 2D CYP. Currently, there are no recommendations on doing any type of pharmacogenomic testing for people with CYP1A2 polymorphism. And actually, for antipsychotics in general, there's no recommendations, even those that are metabolized by 2D6 and 384. So I think it seems right now that pharmacogenomics is probably not going to become a big player with clozapine treatment unless there's some new discoveries in the next couple of years. I know the ⁓ CPIC, which is a governing body on pharmacogenomics and makes recommendations for testing within the United States, is currently putting together a consensus paper on antipsychotic ⁓ use and pharmacogenomic testing within. So I look forward to seeing that in the future. My guess is there's going to be no recommendations for it, especially with closing.

[25:24] Adrian Preda: Looking ahead, ⁓ your article touches on future directions. ⁓ Dr. Espejo, are there any emerging treatments that might challenge close-up and status or be used alongside it?

[25:36] Gemma Espejo: You asked that we just had a conversation the other day on a unit about, um, so normally in calcium with the new agent that of course is not everybody excited because it has a 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, can we 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 long time for things to trickle down and for medications to become actually accessible. When we of course look at the data, how synomal antipsychotropics has been studied, it's not 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're thinking about augmenting a medication to pick something with a very different pharmacologic profile. So academically, of course, I think a lot of people are excited to see what are we going to 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. So we just don't have that data accessible. I'm hesitant to...

prescribe that or go down that road with patients.

[27:07] Farah Khorassani: And I'll just add that I do think that it, you know, I think the studies are not there yet. Obviously, I think from a mechanism standpoint, it is worth it to study to see, ⁓ you know, right now when we do dual antipsychotics, we are using basically two drugs that are doing the same thing. And this drug has a completely different mechanism of action. And perhaps that could be ⁓ 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.

[27:36] Adrian Preda: What about about neuro modulation as a potential augmentation strategy for close-up in?

[27:43] Gemma Espejo: Think the neuromodulation frontier is one of the most exciting frontiers that we have in psychiatry, 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...

But when we think about Closapine, think most of us are using it for really treatment resistant 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 protocols and our imaging guided personalization of neuromodulation is improving in the future.

[28:38] Adrian Preda: 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 for schizophrenia and schizofractive, but what about suicidal behaviors in other diagnosis?

[29:03] Gemma Espejo: So I think the intercept trial is really the one that got CloserPain the FDA indication for 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, ⁓ CloserPain patients may be doing better because they're checking in more with providers, 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 being checked 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 for suicidal behaviors and bipolar disorder. 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 drug effect and the accessibility of other atypical antipsychotics that are FDA approved to be augmentation for unipolar depression, clozapine falls much further down on the list for those with primary affective disorders.

[30:27] Adrian Preda: It's clear that to our close-up in remains paramount for many, gold standard, right, for the treatment resistant psychosis. The research continues to refine how we use it and explore new options. Thank you so much, Dr. Espejo and Dr. Khorassani for sharing this crucial update.

[30:44] Gemma Espejo: Thank you so much for having us. Thanks.

[30:46] Farah Khorassani: Pleasure to be here.

[30:47] Adrian Preda: This wraps our discussion on Clozapine. We've learned about its critical role as the gold standard for treatment resistant schizophrenia and suicidal behavior, the shift towards personalized ancestry based iteration, the updated monitoring protocols for neutropenia after the REMS program changes, important considerations for side effects like myocarditis, common ones like constipation and weight gain and their management strategies and effective augmentation strategies 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 the gold standard for a more detailed information. Thank you again to our guests, Dr. 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 the podcast. It helps others discover these important conversations. Until then, stay informed, stay compassionate and take care.