17.1 Clozapine Underutilization with Jose Rubio, MD

[00:00:00] [SPEAKER_02]: The short answer is that we don't really know how Clozapine works.

[00:00:03] [SPEAKER_02]: Clozapine has been around for many decades and it's very unique.

[00:00:09] [SPEAKER_02]: The clinical data, clinical studies show was that it's very effective when other antipsychotics

[00:00:15] [SPEAKER_02]: have failed.

[00:00:17] [SPEAKER_02]: So for people who fail to improve on the medications we would traditionally use, when

[00:00:23] [SPEAKER_02]: Clozapine we have a greater chance of success compared to other drugs.

[00:00:31] [SPEAKER_01]: Somebody get this guy some help.

[00:00:41] [SPEAKER_01]: So today on the podcast I have Jose Rubio, an MD and board certified psychiatrist, researcher,

[00:00:49] [SPEAKER_01]: investigator that specializes in SMI or severe mental illness.

[00:00:55] [SPEAKER_01]: Typically schizophrenia, bipolar one disorder, maybe some traumatic brain injury patients.

[00:01:01] [SPEAKER_01]: He obtained his MD from the University of Valencia in Spain and completed a psychiatric residency

[00:01:10] [SPEAKER_01]: at Zucker Hillside Hospital where he was chief resident for research.

[00:01:15] [SPEAKER_01]: His research has specialized in relapse and treatment resistance in schizophrenia and

[00:01:21] [SPEAKER_01]: he has worked extensively with John Cain, a psychiatrist who was tasked by the FDA to

[00:01:27] [SPEAKER_01]: wean a few dozen patients off of Clozapine in the 1970s due to what I understand as several

[00:01:34] [SPEAKER_01]: Scandinavian deaths from one of its more rare side effects affecting immune system

[00:01:39] [SPEAKER_01]: function.

[00:01:41] [SPEAKER_01]: Dr. Cain found that many of these patients' symptoms reemerged or significantly worsened

[00:01:46] [SPEAKER_01]: coming off of the drug and became a major advocate paving the way for it.

[00:01:52] [SPEAKER_01]: Clozapine's eventual 1989 FDA approval for treatment resistant schizophrenia.

[00:01:58] [SPEAKER_01]: Independently, Dr. Rubio has received several awards including the Excellence in Research

[00:02:04] [SPEAKER_01]: Award from the Feinstein Institutes and a NIH Career Development Award.

[00:02:10] [SPEAKER_01]: Has additionally been recognized by awards from major scientific organizations such as

[00:02:15] [SPEAKER_01]: the APA or American Psychiatric Association, the Schizophrenia International Research Society

[00:02:22] [SPEAKER_01]: and the American College of Neuropsychopharmacology.

[00:02:26] [SPEAKER_01]: He currently works, I believe, as an assistant professor at Zucker School of Medicine at

[00:02:31] [SPEAKER_01]: Hofstra and clinically you see patients at Northwell Health.

[00:02:37] [SPEAKER_01]: Does that summarize?

[00:02:39] [SPEAKER_01]: Does that give introduction?

[00:02:40] [SPEAKER_02]: It summarizes it.

[00:02:40] [SPEAKER_02]: Yes.

[00:02:41] [SPEAKER_02]: Thank you very much for the invitation and yes, that introduction is accurate.

[00:02:45] [SPEAKER_01]: Okay, so yeah, Dr. Rubio, thanks so much for appearing on the podcast.

[00:02:50] [SPEAKER_01]: Here at Renegade Psych, I try to appreciate the nuance involved in complex psychiatric

[00:02:57] [SPEAKER_01]: and medical decisions, educate listeners on the lesser known aspects of the field

[00:03:02] [SPEAKER_01]: and provide an outlet for what is truly evidence-based medicine versus what is more

[00:03:08] [SPEAKER_01]: marketing-based medicine.

[00:03:10] [SPEAKER_01]: It only made sense to have you on to discuss how we treat resistant schizophrenia, how

[00:03:16] [SPEAKER_01]: we should treat it and identify some areas where we're falling short in our efforts.

[00:03:22] [SPEAKER_01]: I'm here to get more of your thoughts about clozapine, the underutilized gold standard

[00:03:28] [SPEAKER_01]: for treatment-resistant schizophrenia as well as your professional thoughts and opinions

[00:03:33] [SPEAKER_01]: on schizophrenia.

[00:03:34] [SPEAKER_01]: Thank you for any, but before we get there, first I want to know a little bit more about

[00:03:39] [SPEAKER_01]: Jose Rubio the person.

[00:03:41] [SPEAKER_01]: So I want to start off with a few kind of rapid fire questions if that's all right.

[00:03:45] [SPEAKER_01]: Of course.

[00:03:46] [SPEAKER_01]: So first, where were you born and raised?

[00:03:49] [SPEAKER_02]: So I was born in Granada which is in Andalucía in Spain.

[00:03:53] [SPEAKER_02]: But I was raised in Valencia also in Spain.

[00:03:56] [SPEAKER_02]: That's a city in the Mediterranean and I trained there as a doctor although I studied

[00:04:03] [SPEAKER_02]: two years abroad.

[00:04:04] [SPEAKER_02]: So I lived in the Czech Republic for another year and I spent another year in Granada again.

[00:04:10] [SPEAKER_02]: And then I came to the US when I was 25 because I wanted to do residency here.

[00:04:16] [SPEAKER_02]: I was attracted by the quality of research.

[00:04:19] [SPEAKER_02]: So I came to New York in 2010 and I worked as a research assistant at Columbia and then

[00:04:28] [SPEAKER_02]: I started residency here and that's where I've remained ever since at Zarcajosa Hospital.

[00:04:35] [SPEAKER_01]: And there is something that brought us together because I've actually been to Granada before

[00:04:41] [SPEAKER_01]: on my one trip out of the country.

[00:04:45] [SPEAKER_01]: My sister-in-law was living in Madrid for two years and we took a trip to Granada

[00:04:52] [SPEAKER_01]: while we were there.

[00:04:54] [SPEAKER_01]: Now is Granada south of Madrid?

[00:04:57] [SPEAKER_01]: Is it in the mountains?

[00:05:00] [SPEAKER_02]: It's south and yes it's in a mountainous area so it has a big ski resort.

[00:05:08] [SPEAKER_02]: And I've been there.

[00:05:10] [SPEAKER_02]: How you speak in the Iberian Peninsula?

[00:05:14] [SPEAKER_01]: Very, just a very quick aside.

[00:05:16] [SPEAKER_01]: The first time I ever went skiing was in Granada and my now wife and her sister-in-law

[00:05:23] [SPEAKER_01]: were they were not advanced but they weren't novices either.

[00:05:29] [SPEAKER_01]: And we went up into the mountains and they said oh yeah just french fry, just pizza

[00:05:35] [SPEAKER_01]: and they didn't give me a very good tutorial on how to ski.

[00:05:41] [SPEAKER_01]: And I wiped out, lost my skis, my poles probably 25 to 30 times that day.

[00:05:50] [SPEAKER_01]: Luckily didn't hurt myself.

[00:05:52] [SPEAKER_01]: I almost did towards the end of the day started getting a little bit of my feet under me and

[00:05:59] [SPEAKER_01]: I almost ran into a five year old girl and her dad speaking Spanish was not very pleased

[00:06:06] [SPEAKER_01]: with me and I didn't know exactly how to apologize.

[00:06:11] [SPEAKER_01]: I was just glad that I didn't actually run into her and wiped out instead but it was

[00:06:17] [SPEAKER_01]: funny I got to the bottom of the mountain last run of the day.

[00:06:20] [SPEAKER_01]: And sometimes you see a group of people and you may think I think they might be talking

[00:06:26] [SPEAKER_01]: about me or maybe I'm just paranoid.

[00:06:29] [SPEAKER_01]: And they're laughing and then at the end one guy came over to me who spoke English and

[00:06:35] [SPEAKER_01]: he said hey I just want to let you know if you if you hang around I would love to

[00:06:38] [SPEAKER_01]: offer you a free training on how to ski.

[00:06:44] [SPEAKER_01]: So they definitely were talking about me but it's interesting that that's that's

[00:06:49] [SPEAKER_01]: around about where you grew up.

[00:06:51] [SPEAKER_01]: So yeah as a as an adolescent as a kid what did you want to be when you grew up?

[00:06:57] [SPEAKER_02]: I didn't know.

[00:06:58] [SPEAKER_02]: I think I was not very I didn't have a very clear idea.

[00:07:05] [SPEAKER_02]: I think it was more I was interested in understanding how we work as humans from

[00:07:12] [SPEAKER_02]: probably a rather concrete perspective of biology.

[00:07:16] [SPEAKER_02]: So I was interested in human biology and then I decided to do medicine because

[00:07:23] [SPEAKER_02]: you know I that was a way of understanding human physiology.

[00:07:30] [SPEAKER_02]: From a very concrete level and then obviously took a different dimension once I was able

[00:07:36] [SPEAKER_02]: to interact with people that were ill and to you know see that you know I could be

[00:07:44] [SPEAKER_02]: very helpful in trying to make their lives better.

[00:07:46] [SPEAKER_02]: So kind of like had those two dimensions that of like helping others which can be

[00:07:52] [SPEAKER_02]: very satisfactory and also to under the intellectual component of trying to

[00:07:59] [SPEAKER_02]: understand better human biology and who we are as entities.

[00:08:06] [SPEAKER_01]: Yeah absolutely I think that you're stating some of the what I would consider

[00:08:11] [SPEAKER_01]: to be the best qualities of a good psychiatrist primarily that a good

[00:08:15] [SPEAKER_01]: psychiatrist is curious because there's a lot of unknowns in medicine but there

[00:08:22] [SPEAKER_01]: are a lot a lot of unknowns in psychiatry and what drives our illnesses and

[00:08:27] [SPEAKER_01]: how best to treat them.

[00:08:30] [SPEAKER_01]: So I was saying you told me a little bit about your kind of professional

[00:08:35] [SPEAKER_01]: journey your path but tell me a little bit about one or two of some of your

[00:08:42] [SPEAKER_01]: greatest professional influences.

[00:08:47] [SPEAKER_02]: Well I mean I could tell you too one of them probably would be my first

[00:08:56] [SPEAKER_02]: the person that was teaching us our first psychiatric courses.

[00:09:02] [SPEAKER_02]: His name is Julio San Juan.

[00:09:03] [SPEAKER_02]: He's retired now but he was a full professor at University of Valencia and

[00:09:12] [SPEAKER_02]: he was really good at making people feel curious about stuff and I was coming

[00:09:20] [SPEAKER_02]: in already very motivated to understand you know to learn about psychology

[00:09:27] [SPEAKER_02]: psychiatry but he really made a great job at feeding that curiosity so he

[00:09:34] [SPEAKER_02]: certainly would be the first person I would highlight you know probably he

[00:09:40] [SPEAKER_02]: had a strong influence on me becoming a psychiatrist and then obviously the

[00:09:45] [SPEAKER_02]: second person would be John Cain.

[00:09:47] [SPEAKER_02]: He's been my mentor and friend for a few years already.

[00:09:52] [SPEAKER_02]: I started working with him when I was a resident and you know I have continued to

[00:09:57] [SPEAKER_02]: work with him ever since.

[00:10:00] [SPEAKER_02]: He's been you know very he's really an example for me in terms of work ethic

[00:10:08] [SPEAKER_02]: and intellectual curiosity and as a whole person not just as a doctor to

[00:10:14] [SPEAKER_02]: me he's an example so those two are I mean if I can if I have to side

[00:10:19] [SPEAKER_02]: to those would be the two I would sign.

[00:10:22] [SPEAKER_01]: Yeah that's an incredible opportunity to be able to work with him and learn from

[00:10:28] [SPEAKER_01]: him as a resident certainly.

[00:10:32] [SPEAKER_01]: So what about when you need to get away from work you need to get out of all

[00:10:37] [SPEAKER_01]: of this and kind of reset mentally emotionally spiritually what do you do?

[00:10:43] [SPEAKER_02]: I babysit.

[00:10:46] [SPEAKER_01]: Now you know my wife says it's not babysitting if it's your own kids.

[00:10:51] [SPEAKER_02]: Okay no I mean well certainly that's a very important part of it but

[00:10:59] [SPEAKER_02]: you know I mean the things that I like and like I enjoy reading I enjoy

[00:11:04] [SPEAKER_02]: traveling and eating new stuff and discovering new things so I think that

[00:11:10] [SPEAKER_02]: that's what I would say but certainly being around my children is really what

[00:11:15] [SPEAKER_02]: takes most time.

[00:11:17] [SPEAKER_01]: Absolutely I can relate to that I got two not quite under two anymore but very close

[00:11:23] [SPEAKER_01]: to it so it takes up a lot of time outside of any work that I do.

[00:11:28] [SPEAKER_01]: Yeah before we go any further I have to ask do you receive any pharmaceutical

[00:11:33] [SPEAKER_01]: funding do you have any other financial disclosures?

[00:11:37] [SPEAKER_02]: Yes yes I do I consult for some companies for different questions related to the

[00:11:46] [SPEAKER_02]: management of schizophrenia so I mean if I have to list what I have done for drug

[00:11:57] [SPEAKER_02]: companies I've done at board for Bristol Myers Squibb I have done

[00:12:08] [SPEAKER_02]: talks on disease management not promotional talks but drugs on disease

[00:12:13] [SPEAKER_02]: management for schizophrenia for Teva and also Janssen also I receive

[00:12:23] [SPEAKER_02]: royalties from up to date because I was one of the authors of the of the treatment

[00:12:29] [SPEAKER_02]: assistant chapter and also I've received I mean I do CME so I get paid for that

[00:12:37] [SPEAKER_02]: so I've done that for a couple companies but not drug companies but CMA companies.

[00:12:43] [SPEAKER_01]: Okay do you feel like any of those associations affect your ability to be

[00:12:50] [SPEAKER_01]: independent in your scientific discourse?

[00:12:55] [SPEAKER_02]: I don't think that they play a strong effect especially when it comes to

[00:13:00] [SPEAKER_02]: clozapine because whatever they do is so unrelated to clozapine that I don't think that there's

[00:13:05] [SPEAKER_02]: any way in which that is influencing me of course you have to trust me and but I really

[00:13:12] [SPEAKER_02]: don't think that there's any effect I mean if anything they should be funding this

[00:13:17] [SPEAKER_02]: this research I wish that I had some conflicts but one of the problems is that no one is funding

[00:13:24] [SPEAKER_02]: this and as a result there's not much development in terms of new drugs for treatment resistance.

[00:13:32] [SPEAKER_01]: And clozapine has been out since the late 1950s so it is certainly generic and probably and

[00:13:39] [SPEAKER_01]: you'd have to back me up on this is not very not very expensive for patients in terms of the

[00:13:45] [SPEAKER_02]: drug itself. No it's I don't think so I mean obviously all of these things depend on how

[00:13:52] [SPEAKER_02]: insurance is negotiated prices but generally speaking no it's not a drug I mean it's generic and

[00:13:57] [SPEAKER_01]: cost is not a major issue yeah generally speaking. Okay and then lastly for the rapid

[00:14:04] [SPEAKER_01]: fire questions an absolutely loaded question how would you describe what schizophrenia is

[00:14:11] [SPEAKER_02]: to an alien who had never heard of it or seen it? I would describe it as a mental disorder that

[00:14:24] [SPEAKER_02]: affects three major spheres in humans if this is talking to an alien. So one would be positive

[00:14:35] [SPEAKER_02]: symptoms which is related to which is essentially psychosis meaning this would be a presence of

[00:14:44] [SPEAKER_02]: perceptions that are not triggered by any stimuli or also some thoughts that are

[00:14:53] [SPEAKER_02]: believe that most people would think are very bizarre but also disorganized speech or behavior

[00:15:01] [SPEAKER_02]: that would also be another dimension of this illness which would be characterized by negative

[00:15:08] [SPEAKER_02]: symptoms things that should be there but are not there things like lack of the ability to express

[00:15:15] [SPEAKER_02]: emotions or the drive to do things motivation and then there would be a third component that

[00:15:23] [SPEAKER_02]: would be characterized by some cognitive symptoms so ability to do abstract reasoning,

[00:15:28] [SPEAKER_02]: ability to recall short-term memories etc so those would be the three dimensions that this

[00:15:36] [SPEAKER_02]: illness is characterized by and obviously downstream there are many complications from this

[00:15:43] [SPEAKER_02]: it typically emerges in in early adolescence or early adulthood so it affects the ability to

[00:15:52] [SPEAKER_02]: develop after that point sometimes there are subtle things that we can see before the

[00:15:57] [SPEAKER_02]: symptoms emerge so certainly it has a developmental component to it which may affect many many

[00:16:07] [SPEAKER_02]: conditions of many aspects of our interaction with the world so it may affect our you know for

[00:16:15] [SPEAKER_02]: the people that suffer this this condition in the fact their ability to develop social

[00:16:20] [SPEAKER_02]: relationships to the ability to work the ability to develop a profession etc which ultimately may

[00:16:29] [SPEAKER_02]: have implications or the financial situation which is going to feedback you know into some of this

[00:16:36] [SPEAKER_02]: other risk factors like living in an environment that is less than optimal which could

[00:16:42] [SPEAKER_02]: can make things even a little bit worse so that's in a nutshell the way I would describe it

[00:16:50] [SPEAKER_01]: yeah and I would just add to that for the listeners that typical progression is negative symptoms in

[00:16:57] [SPEAKER_01]: late adolescence early adulthood typically followed in the next few months probably closer to years

[00:17:06] [SPEAKER_01]: with positive symptoms or the the psychosis that is a lot more obvious and apparent

[00:17:12] [SPEAKER_01]: to somebody in the general public when you know somebody is having under the influence of delusions

[00:17:19] [SPEAKER_01]: or auditory hallucinations I actually practice in an area of the country now our entire country

[00:17:27] [SPEAKER_01]: is under a major drug epidemic right now methamphetamine in particular I see a lot of

[00:17:34] [SPEAKER_01]: misdiagnosis of methamphetamine or chronic meth psychosis as schizophrenia and while they do have the

[00:17:43] [SPEAKER_01]: some of the more typical positive symptoms with persecutory delusion or you know feeling like

[00:17:49] [SPEAKER_01]: they're being followed or monitored there isn't the typical progression of negative symptoms

[00:17:56] [SPEAKER_01]: and it it appears to be a unique condition though I think that there are probably some overlap of

[00:18:05] [SPEAKER_01]: people who either develop the symptoms of psychosis using meth maybe they had a genetic

[00:18:13] [SPEAKER_01]: predisposition to it but still that it's something kind of unique from actual what I

[00:18:20] [SPEAKER_01]: understand to be biologic or genetically based schizophrenia I reached out to you because

[00:18:29] [SPEAKER_01]: I saw you per pushing for more practitioners to utilize clozapine

[00:18:35] [SPEAKER_01]: clozapine is a unique antipsychotic in that it is considered the most effective but it differs

[00:18:41] [SPEAKER_01]: from other antipsychotics pharmacologically with only weak D2 or dopamine receptor antagonism

[00:18:50] [SPEAKER_01]: specific type of dopamine receptor antagonism being blocking effect which is the most often

[00:18:57] [SPEAKER_01]: practice way of managing the positive symptoms of psychosis like as you mentioned delusions or

[00:19:03] [SPEAKER_01]: typically auditory hallucinations in schizophrenia it is considered the gold standard for treatment

[00:19:10] [SPEAKER_01]: resistant schizophrenia and along with with lithium are the only medication treatments that I'm aware of

[00:19:18] [SPEAKER_01]: that have very solid long-term evidence that they reduce the patient's risk of suicide

[00:19:25] [SPEAKER_01]: which is a huge risk factor and cause of death in schizophrenia yet it still remains

[00:19:31] [SPEAKER_01]: widely underutilized in psychiatry can you generally explain how clozapine is

[00:19:37] [SPEAKER_01]: pharmacologically unique compared to other antipsychotics and what it might tell us

[00:19:43] [SPEAKER_01]: being the most effective about the underlying disease of schizophrenia

[00:19:50] [SPEAKER_02]: the I mean the short answer is that we don't really know how clozapine works

[00:19:53] [SPEAKER_02]: clozapine has been around for many decades but and it's very unique the clinical data

[00:20:00] [SPEAKER_02]: clinical studies show us that it's very effective when other antipsychotics have failed

[00:20:07] [SPEAKER_02]: so for people who fail to improve on the medications we would traditionally use when we

[00:20:13] [SPEAKER_02]: use clozapine we have a greater chance of success compared to other drugs so

[00:20:20] [SPEAKER_02]: we see that it clinically is very unique from the perspective of the biology there are some

[00:20:25] [SPEAKER_02]: things that it does that are unusual compared to other antipsychotics as you mentioned the weak

[00:20:31] [SPEAKER_02]: dopaminergic agonism it may also have some muscarinic agonism which is becoming relevant

[00:20:39] [SPEAKER_02]: now that we are understanding that that could also be a very effective mechanism to reduce

[00:20:45] [SPEAKER_02]: positive symptoms but also potentially improve cognition and negative symptoms so certainly

[00:20:51] [SPEAKER_02]: biologically it's a different agent but we don't understand how it works which is part of the

[00:20:57] [SPEAKER_02]: reason why it's and you know it's difficult to develop if you don't understand the mechanism

[00:21:03] [SPEAKER_02]: it's difficult to develop drugs that can address whatever is not working correctly

[00:21:09] [SPEAKER_02]: so that's certainly an area in which I think we need to spend more resources which is to

[00:21:16] [SPEAKER_02]: understand what are these mechanisms of treatment resistance so that we can develop drugs

[00:21:20] [SPEAKER_02]: or strategies doesn't need to be a drug that is more effective than what we currently have to

[00:21:27] [SPEAKER_01]: to address the symptoms yeah and to go with that you know with most antipsychotics whether they be

[00:21:35] [SPEAKER_01]: specifically first generation but also many of the second generation antipsychotics

[00:21:41] [SPEAKER_01]: what we believe as one of the reasons why we're able to mitigate the positive symptom of

[00:21:47] [SPEAKER_01]: psychosis seems to be related to dopamine 2 receptor blockade but that unfortunately does not

[00:21:57] [SPEAKER_01]: just happen in the area of the brain that we want to block dopamine it happens throughout the brain

[00:22:02] [SPEAKER_01]: and likely worsens negative and or cognitive symptoms so a couple of questions about the

[00:22:09] [SPEAKER_01]: pro-cognitive effect which is so important on schizophrenia treatment how robust is that

[00:22:16] [SPEAKER_01]: effect what what is the kind of latest on does it improve cognition does it stabilize cognition

[00:22:22] [SPEAKER_01]: how does clozapine affect negative and cognitive symptoms in ways that other antipsychotics maybe

[00:22:27] [SPEAKER_02]: do not well I would be careful about the con cognition and clozapina if anything I don't

[00:22:35] [SPEAKER_02]: think it's I don't think clozapine is great for management of negative or cognitive symptoms

[00:22:41] [SPEAKER_02]: clozapine is highly anti-collinurgic and because it's so anti-collinurgic it results in if anything

[00:22:48] [SPEAKER_02]: well there are a lot of side effects that come with it that peripherally could present with

[00:22:55] [SPEAKER_02]: it's right well not that try mouth index of clozapine but all could present with

[00:23:01] [SPEAKER_02]: constipation for instance but in the brain it can worsen cognition

[00:23:08] [SPEAKER_02]: because it's so highly anti-collinurgic so I don't think that I would use this drug for people

[00:23:14] [SPEAKER_02]: that are struggling with cognition or with negative symptoms I would I would for sure use it for

[00:23:21] [SPEAKER_02]: people who are presenting with residual psychosis despite two failed trials with an

[00:23:28] [SPEAKER_02]: antipsychotic meaning that they've tried to antipsychotic drugs for sufficient time

[00:23:34] [SPEAKER_02]: meaning at least six weeks if it's in an oral if it's in a lung injectable should be about four

[00:23:39] [SPEAKER_02]: months and for sufficient dose that would be in 600 milligram equivalents of proprosin so

[00:23:46] [SPEAKER_02]: you know if that condition is met and you still have residual symptoms residual psychosis

[00:23:51] [SPEAKER_02]: I think clozapine is a good idea if it's not so much a problem of residual psychosis but

[00:23:56] [SPEAKER_02]: more a problem of negative symptoms or or a coordination I'm not sure I would use clozapine

[00:24:03] [SPEAKER_01]: where does because in my training I was always it always seemed to be a push and pull with a

[00:24:08] [SPEAKER_01]: possible pro cognitive effect do you know where that originally came from research wise or

[00:24:16] [SPEAKER_02]: where that maybe debate originated actually not sure nothing not not so sure about that I'm

[00:24:25] [SPEAKER_01]: not not familiar with that so yeah I don't know do you think that it um affects cognition less than

[00:24:32] [SPEAKER_02]: other first second generation antipsychotics well it it's a complicated picture right because

[00:24:43] [SPEAKER_02]: it's not that cognitive symptoms appear in a vacuum cognitive symptoms appear in the context of

[00:24:49] [SPEAKER_02]: positive symptoms and negative symptoms right so um you know there might be you could theorize

[00:24:56] [SPEAKER_02]: that because it it addresses positive symptoms very well it can help with some indirectly with some

[00:25:03] [SPEAKER_02]: cognitive symptoms that that present whenever you're experiencing uh very severe hallucinations or

[00:25:10] [SPEAKER_02]: thought disorder etc but I think that mechanistically we again I we don't really know how it works

[00:25:17] [SPEAKER_02]: but we know it's highly anti-colonergic and that tends to not help a lot with cognition so

[00:25:23] [SPEAKER_02]: uh you know I think it's probably going to vary from patient to patient but generally speaking

[00:25:30] [SPEAKER_02]: I think it's helpful to categorize symptoms into positive negative and cognitive and then

[00:25:35] [SPEAKER_02]: you know see what's predominant and and then based on that make a decision but if there are no

[00:25:41] [SPEAKER_02]: residual positive symptoms and it's mostly uh negative and cognitive symptoms not sure I would use

[00:25:47] [SPEAKER_02]: flow of another thing that would be the go to drug I would use and that's why we have continued

[00:25:53] [SPEAKER_01]: medical education right correct um what about its anti-suicide effect can you speak to that

[00:26:02] [SPEAKER_02]: right so that literature came in the 90s so there were a couple studies that were conducted

[00:26:09] [SPEAKER_02]: in which flow of being was compared to uh Olanzibing which structurally from a chemical

[00:26:15] [SPEAKER_02]: perspective is a similar drug and has many of the side effects that close been has so

[00:26:22] [SPEAKER_02]: in that study it appeared that people who were treated with close being and these are not

[00:26:28] [SPEAKER_02]: patients that were assigned to close up because they were treatment resistant this were patients

[00:26:33] [SPEAKER_02]: that had suicidality uh not necessarily in the context of treatment resistance clearly in

[00:26:40] [SPEAKER_02]: context of schizophrenia this patients tended to do better in terms of of suicidal ideation and

[00:26:46] [SPEAKER_02]: other outcomes related to suicidality compared with patients that were treated with Olanzibing so

[00:26:52] [SPEAKER_02]: that's why um there was a um that was part of the most robust data that came um regarding its

[00:27:01] [SPEAKER_02]: anti-suicide effects and it's very relevant because the mortality of people that live

[00:27:08] [SPEAKER_02]: with schizophrenia is premature by about 15 years compared to the general population so that is

[00:27:14] [SPEAKER_02]: something that I don't think we pay enough attention to our patients dying much earlier than than those

[00:27:20] [SPEAKER_02]: who don't have an illness and when you look at the drivers it's a very complex situation and

[00:27:26] [SPEAKER_02]: there are many factors that contribute to that excess in premature mortality but certainly suicide

[00:27:31] [SPEAKER_02]: is one of them particularly earlier on in the course of illness that's when patients are most

[00:27:35] [SPEAKER_02]: vulnerable to dying by suicide so so that's it's very you know that's a certainly an outcome that's

[00:27:43] [SPEAKER_02]: very important to prevent and as I said I'm close being has has several pieces of data that are

[00:27:50] [SPEAKER_02]: quite robust in the right direction of anti-suicide or effects yeah I mean I can't agree with you

[00:27:56] [SPEAKER_01]: more that you know suicide is something that if we don't impact early in treatment then

[00:28:01] [SPEAKER_01]: there may not be any treatment to be had after that um I'm a big proponent of lithium treatment

[00:28:08] [SPEAKER_01]: even in low doses as an anti-suicide measure in listening to dr. kane on uh david puter's

[00:28:17] [SPEAKER_01]: psychiatry and psychotherapy podcast I actually started to recognize a lot of similarities between

[00:28:23] [SPEAKER_01]: lithium and clozapine the aforementioned anti-suicide effect but also this fear of its use by patients

[00:28:33] [SPEAKER_01]: and providers due to what I would consider to be a somewhat over exaggerated over exaggerated

[00:28:39] [SPEAKER_01]: side effect profile or maybe better said a lack of respect for the benefit-to-risk ratio

[00:28:48] [SPEAKER_01]: but the way that dr. kane talked about two other aspects of clozapine

[00:28:53] [SPEAKER_01]: one being the idea of clozapine super responders which I've similarly witnessed with lithium first

[00:28:59] [SPEAKER_01]: hand with a robust and sustained response within a couple of weeks but also with how he uh

[00:29:07] [SPEAKER_01]: spoke about talking to patients stating that they need to commit to the medication for three

[00:29:12] [SPEAKER_01]: or four months before dismissing it as ineffective something that I also tell my patients when we're

[00:29:18] [SPEAKER_01]: trying to decide whether or not to start something like lithium he alluded to the effect building

[00:29:25] [SPEAKER_01]: far beyond three or four months similar to um uh evidence that lithium's effects may not max

[00:29:31] [SPEAKER_01]: out until about two years what do you make I got several questions here I can answer them as

[00:29:37] [SPEAKER_01]: you please but what do you make of the similarities between the two do you utilize lithium or even

[00:29:44] [SPEAKER_01]: low dose lithium regularly in your treatment of schizophrenia and do you think that lower doses

[00:29:50] [SPEAKER_01]: of clozapine over longer durations of time can provide similar benefit while minimizing risk

[00:29:58] [SPEAKER_02]: okay so there's a lot of questions I'm not sure I will address all of them but

[00:30:04] [SPEAKER_02]: feel free to follow up with anything I left unanswered so regarding the similarities of

[00:30:09] [SPEAKER_02]: of clozapine and lithium I think that to me one of the first similarities is the fact that

[00:30:16] [SPEAKER_02]: these are highly underutilized treatments so these are treatments that have proven to be

[00:30:21] [SPEAKER_02]: very effective but that are used much less than what you would expect by any by any metric

[00:30:28] [SPEAKER_02]: so I think that this begins with the insufficient training that we have

[00:30:36] [SPEAKER_02]: using the strokes and we know that the way you practice the air ingress and sea

[00:30:41] [SPEAKER_02]: is it's going to be very influential towards the way you practice for the rest of your career

[00:30:46] [SPEAKER_02]: if no one teaches you how to start someone on clozapine if no one teaches you how to start

[00:30:51] [SPEAKER_02]: someone on lithium you're not going to start doing that after your training and and I think

[00:30:57] [SPEAKER_02]: it's a very it's to me it's a big problem and I think it's a missed opportunity that this is not

[00:31:07] [SPEAKER_02]: taken more seriously by some of the organizations that supervise the the medical education but

[00:31:15] [SPEAKER_02]: to me the fact that people graduate without having started the patient in either of these

[00:31:20] [SPEAKER_02]: drugs which happens all the time I think it's very bad and sets a very bad precedent because

[00:31:29] [SPEAKER_02]: you know most of these trainees are not going to start doing this after after their training

[00:31:36] [SPEAKER_02]: you know concludes so so to me that that's that's very very unfortunate and and I wish that

[00:31:44] [SPEAKER_02]: there was a more systematic effort to make sure that when residents graduate they feel comfortable

[00:31:51] [SPEAKER_02]: with using this the treatments because you know there are other drugs or other interventions for which

[00:31:58] [SPEAKER_02]: they're gonna have CME they're gonna you know learn how to use drugs that come

[00:32:03] [SPEAKER_02]: in the pipeline which we need it's not I mean obviously we need those drugs but

[00:32:07] [SPEAKER_02]: you know the drugs that don't have that sponsorship for you know orphan if if that makes any sense so

[00:32:17] [SPEAKER_02]: you know to me that's that's one of the sad similarities also that something that comes

[00:32:23] [SPEAKER_02]: with that is how they are presented to to patients I think that we don't do a very good job

[00:32:29] [SPEAKER_02]: presenting these interventions to patients when you tell someone that I'm going to give

[00:32:35] [SPEAKER_02]: you this drug that may kill you patients are going to say no thank you or when you tell someone

[00:32:40] [SPEAKER_02]: you're not going to give you this drug but you it may kill your kidneys and it is you're going to

[00:32:46] [SPEAKER_02]: have to do regular blood work to make sure that the level is all right they're going to say no

[00:32:52] [SPEAKER_02]: thank you I think that but but that's a very unfair representation of what these drugs are

[00:32:58] [SPEAKER_02]: I don't think that we train people I don't think we evaluate people based on their ability

[00:33:04] [SPEAKER_02]: to provide a and a proper explanation of why we think that this medications is what we should use for

[00:33:12] [SPEAKER_02]: them so um so so to me that those are sad similarities and then more from the clinical perspective

[00:33:21] [SPEAKER_02]: you know the fact that they are both drugs that have shown to gain effectiveness over time

[00:33:30] [SPEAKER_02]: I am not sure I think that I'm not sure why would that be I mean I could hypothesize that if something

[00:33:36] [SPEAKER_02]: works you know over time your life is going to you're going to accumulate some of those benefits

[00:33:43] [SPEAKER_02]: over time right so you know if you're able to have your psychosis under control you may be able to

[00:33:49] [SPEAKER_02]: you know improve some social relationships go back to work etc we're just going to have a positive

[00:33:54] [SPEAKER_02]: effect same same thing might be safe for lithium so you know that could be a reason why

[00:34:01] [SPEAKER_02]: they they seem to work to keep working over time and then regarding the the low dose I don't think

[00:34:10] [SPEAKER_02]: that the the data for augmentation of lithium for instance in treatment resistance you know we

[00:34:17] [SPEAKER_02]: have some people like to use lithium for whenever you're using clover bean and there's a low

[00:34:23] [SPEAKER_02]: white blood cell count that that may help to get those white cells the count of white cells up

[00:34:33] [SPEAKER_02]: but I don't think there are great data suggesting that that increases the effectiveness of lithium

[00:34:39] [SPEAKER_02]: so I that's not something I would encourage generally and and low dose clover bean I think it's

[00:34:47] [SPEAKER_02]: it's not you know I think that you I would recommend using the dose of clover bean that

[00:34:52] [SPEAKER_02]: proves to be effective I wouldn't use a low dose because that may increase the risk of people

[00:34:58] [SPEAKER_02]: developing agronomic doses without getting the full benefit of the drug so I think that that

[00:35:02] [SPEAKER_02]: that's not a way to maximize the risk-benefit ratio so I would recommend the the dose that

[00:35:08] [SPEAKER_02]: that is effective the minimum dose that's an effective addressing symptoms

[00:35:14] [SPEAKER_01]: um is there any pharmacologic overlap that you know of that

[00:35:20] [SPEAKER_01]: that may provide any explanation of the the anti-suicide effect

[00:35:28] [SPEAKER_02]: not not really uh from a more neurobiological perspective I I don't have an insight into

[00:35:36] [SPEAKER_02]: whether there's a shared mechanism um so I don't really know I mean I don't think that we

[00:35:42] [SPEAKER_02]: really understand the mechanism of action of anti-suicidal effects in general so I'm not sure

[00:35:51] [SPEAKER_02]: that it's certainly an area that we need to understand much better yeah and and I maybe take

[00:35:56] [SPEAKER_01]: it a step further in that I fear that there may be a concerted effort against training somebody

[00:36:02] [SPEAKER_01]: like me to use clozapine and lithium because as we've already stated they're so cheap they could

[00:36:09] [SPEAKER_01]: keep people out of the hospital and while that certainly saves the society as a whole

[00:36:15] [SPEAKER_01]: money it does not save the hospital money if they don't fill their beds and they don't have

[00:36:21] [SPEAKER_01]: their regular turnover of admissions I just have some skepticism about that because I really do

[00:36:29] [SPEAKER_01]: think if researchers and scientists drove what was actually effective that we would see a lot

[00:36:37] [SPEAKER_01]: more use of lithium we'd see a lot more use of clozapine but again these are questions that I don't

[00:36:45] [SPEAKER_02]: have the obvious answer to I I disagree a little bit with that because I think it's more the fact

[00:36:54] [SPEAKER_02]: that there are many agendas that and and I don't mean this in a in a bad way but you know like

[00:37:00] [SPEAKER_02]: there are different organizations that want to push for whatever they're working on that thing

[00:37:07] [SPEAKER_02]: does not exist for clozapine or injectables or maybe for injectables a little bit but even there

[00:37:15] [SPEAKER_02]: I mean there's there are many companies that are developing injectables and it's hard

[00:37:20] [SPEAKER_02]: to get people to use them and we know that they work very well and same thing for lithium

[00:37:27] [SPEAKER_02]: right but even when there's an incentive for from companies to have a greater use of these

[00:37:34] [SPEAKER_02]: drugs you see that there's not there's not an over utilization of long acting injectables I mean

[00:37:39] [SPEAKER_02]: LAIs are grossly underutilized same as clozapine so I think it's more that it's it's a very complex

[00:37:49] [SPEAKER_02]: scenario of forces that are pushing and pulling in different directions this requires a major change

[00:37:58] [SPEAKER_02]: in the system because you need to train people differently you need to it's it's not like okay

[00:38:06] [SPEAKER_02]: you need to prescribe more drug a it's it's really you have to practice differently

[00:38:10] [SPEAKER_02]: and that's a huge undertaking I don't think anyone is prioritizing that over other stuff

[00:38:16] [SPEAKER_02]: and as a result you know there's less use of this these different drugs so I think I don't

[00:38:28] [SPEAKER_02]: it would be it requires a lot of work and I don't think anyone is really you know pushing for it

[00:38:34] [SPEAKER_01]: unfortunately yeah and you're absolutely right I mean this this is a multi factorial

[00:38:41] [SPEAKER_01]: issue I mean there is the patient perspective of patients and myself included in that I mean

[00:38:47] [SPEAKER_01]: we want quick fixes we want to go see the doctor we want to take something that makes us feel

[00:38:52] [SPEAKER_01]: different which is why I think it's so important Dr. Cain talking to his patients about look you've

[00:38:59] [SPEAKER_01]: got a suspender disbelief and and commit to the process of taking this medicine for three or four

[00:39:04] [SPEAKER_01]: months and then we will start to evaluate its effects I think there's certainly a major component

[00:39:11] [SPEAKER_01]: of our training and if you do not have people who are training you that

[00:39:20] [SPEAKER_01]: teach you how to utilize certain medications you may never learn how to utilize them then you come

[00:39:25] [SPEAKER_01]: out of training and you're not comfortable with utilizing them but I also think that there is just

[00:39:31] [SPEAKER_01]: you know way too much manipulation of the research system by industry and too much

[00:39:40] [SPEAKER_01]: overlap with the regulatory agencies and the the entities conducting research and how I receive my

[00:39:47] [SPEAKER_01]: medical education and what books and what guidelines I am exposed to but you're absolutely right I mean

[00:39:54] [SPEAKER_01]: there are so many different factors to this and I do want to point out that you know I don't think

[00:40:02] [SPEAKER_01]: that big pharma is this horrible entity I mean they allow for innovation and they fund a lot of

[00:40:11] [SPEAKER_01]: research and there's certainly a lot of good conscientious pharmaceutical companies but there's

[00:40:18] [SPEAKER_01]: certainly evidence of less conscientious and companies that are that are utilizing the system

[00:40:27] [SPEAKER_01]: to their financial benefit so but it's certainly not everybody and you know there's there's a

[00:40:32] [SPEAKER_01]: lot of different factors and entities that that bear a little bit of responsibility there

[00:40:38] [SPEAKER_01]: I could talk about that all all day but not not why I had you on and so tell me what what barriers

[00:40:47] [SPEAKER_01]: are stopping more providers from using clozapine I know we have the REMS program which is

[00:40:54] [SPEAKER_01]: meant to help to mitigate the risk of using drugs that have potentially severe or serious

[00:41:02] [SPEAKER_01]: side effects and clozapine does warrant some fear in terms of you know trainees recognizing that it has

[00:41:11] [SPEAKER_01]: potential fatal cardiac issues like cardiomyopathy enlargement of the heart muscle immune system

[00:41:17] [SPEAKER_01]: side effects a granulocytosis or neutropenia essentially making the patient more susceptible

[00:41:23] [SPEAKER_01]: to opportunistic infections like we may see in HIV progress to AIDS but also nuisance and annoying

[00:41:32] [SPEAKER_01]: side effects like excessive salivation drowsiness sleepiness and constipation which could be annoying

[00:41:40] [SPEAKER_01]: or it could be serious if it progresses to a paralytic ileus or a bowel obstruction

[00:41:46] [SPEAKER_01]: how do you evaluate the benefit to risk ratio of this drug and is the fear about clozapine

[00:41:53] [SPEAKER_01]: warranted or is it maybe over exaggerated well to me the point to start

[00:42:00] [SPEAKER_02]: would be to evaluate this in relative terms not in absolute terms and what I mean by that is that

[00:42:08] [SPEAKER_02]: you have to evaluate what are the risks of bad things happening bad outcomes if I use clozapine

[00:42:17] [SPEAKER_02]: but also what is the risk of those bad outcomes happening or other bad outcomes happening

[00:42:21] [SPEAKER_02]: when if I decide to not use clozapine okay because that's a real choice like do you use

[00:42:26] [SPEAKER_02]: clozapine yes or no we know that people that don't use clozapine and have dream resistance

[00:42:33] [SPEAKER_02]: they tend to do worse as a population okay unfortunately the biomarkers are not developed

[00:42:39] [SPEAKER_02]: to the point that we are able to tell a given person whether they're going to respond or not

[00:42:43] [SPEAKER_02]: or whether they're going to develop a particular side effect or not but from the population level

[00:42:50] [SPEAKER_02]: if you know patients who are not using clozapine tend to live less

[00:42:55] [SPEAKER_02]: and they tend to have more morbidity more medical illness and they tend to have a shorter lifespan

[00:43:04] [SPEAKER_02]: and so then if you use clozapine there's no guarantee it's going to help actually in fact

[00:43:11] [SPEAKER_02]: most patients may not respond okay so we have to be very affront about what are the chances of

[00:43:17] [SPEAKER_02]: of seeing a response with clozapine but certainly the chances of

[00:43:24] [SPEAKER_02]: of response are way way greater than with any other drug and then the potential side effects

[00:43:32] [SPEAKER_02]: could be the annoying but common side effects as you mentioned those are actually quite prevalent

[00:43:38] [SPEAKER_02]: so there's a high chance that some of them are going to be experienced and those are things

[00:43:43] [SPEAKER_02]: as you mentioned like sedation salivation constipation which are generally manageable

[00:43:49] [SPEAKER_02]: I think that the data suggests that that's not a reason why people would stop clozapine

[00:43:54] [SPEAKER_02]: so it means that for those people even when they are experiencing them it's worth because

[00:43:59] [SPEAKER_02]: they are experiencing some improvement in symptoms there are also the the more serious side

[00:44:05] [SPEAKER_02]: effects like agranal cytosis myocarditis these are side effects that we monitor carefully for

[00:44:12] [SPEAKER_02]: and that are very very rare so in general terms I think that again at the population level

[00:44:22] [SPEAKER_02]: there are there's also a lot of risk of bad outcomes if you have three resistance schizophrenia

[00:44:30] [SPEAKER_02]: and are not using clozapine which should be something that should be considered

[00:44:34] [SPEAKER_02]: and the risk of dying from agranal cytosis is like 1 in 3,800 so it's a very very small risk

[00:44:42] [SPEAKER_02]: the chances of experiencing clinical response are about 40 when other treatments have been

[00:44:51] [SPEAKER_02]: used and failed so I think that again in general terms it's obviously a decision that has to

[00:44:57] [SPEAKER_02]: be taken case by case but in general terms I think that the the risky outcomes don't justify to not use

[00:45:05] [SPEAKER_02]: it do not give it a chance if you try it it doesn't work okay then you have to decide what to do next

[00:45:11] [SPEAKER_02]: but to me the first question is should try it hopefully over time we'll be able to develop

[00:45:16] [SPEAKER_02]: biomarkers that tell us whether someone is likely to respond or not and then we'll have to see

[00:45:23] [SPEAKER_02]: what can be done for people who are at low risk of response but we're not there yet I think that

[00:45:27] [SPEAKER_02]: now the only way of knowing is by giving it a try wouldn't it be great if there was a database

[00:45:34] [SPEAKER_01]: available that was maybe monitored by expert mathematician and involved providers and researchers

[00:45:43] [SPEAKER_01]: that could put an actual number on the risk of these things and put an actual number on the

[00:45:50] [SPEAKER_01]: benefit plug all of that into an equation and be able to spit out a essentially a benefit to

[00:45:56] [SPEAKER_01]: risk ratio because like you're saying I mean the the risk of agranulocytosis is very low

[00:46:03] [SPEAKER_01]: and if you compare that with the risk of a positive outcome even after two failed trials

[00:46:09] [SPEAKER_01]: of other antipsychotics then being able to present that to the patient comparatively against

[00:46:16] [SPEAKER_01]: other drugs would probably make it a little bit easier to convince patients to utilize

[00:46:22] [SPEAKER_01]: do you know of anything like that it's like a pipe dream in my in my mind but

[00:46:26] [SPEAKER_02]: we are we're actually getting started in a project an NIH funded project that is doing a little bit

[00:46:32] [SPEAKER_02]: of that so what that is doing is that's using your imaging to calculate the the chances of

[00:46:39] [SPEAKER_02]: treating response to a first line antipsychotic and early phase patients and if you're

[00:46:44] [SPEAKER_02]: predicted to be a non-responder to a first line then the question is are you at risk of

[00:46:51] [SPEAKER_02]: agranulocytosis I'm sorry are you at risk of weight gain so there are some genetic biomarkers

[00:46:57] [SPEAKER_02]: that can be used to that effect and and then if you are at low risk of responding to a first

[00:47:05] [SPEAKER_02]: line and also don't have the generic background that makes you vulnerable to weight gain on

[00:47:12] [SPEAKER_02]: clozapine then we're going to see whether clozapine is a good first choice for you as opposed to a

[00:47:17] [SPEAKER_02]: traditional antipsychotic so we are running that research in which the treatment decisions would be

[00:47:23] [SPEAKER_02]: based on on this biomarkers and you know that's something we're going to start soon so I mean

[00:47:28] [SPEAKER_02]: we are very glad that that will be able to develop that that project in the next few years

[00:47:35] [SPEAKER_01]: yeah absolutely that that sounds uh incredible I wish we had that for all of our treatments

[00:47:41] [SPEAKER_01]: across the board where we could put a factor next to the side effect which agranulocytosis the

[00:47:48] [SPEAKER_01]: factor would be a high number but for something like excessive salivation maybe that factor wouldn't

[00:47:54] [SPEAKER_01]: be nearly as high as the potentially fatal one now you've also done a lot of work on other

[00:48:02] [SPEAKER_01]: key developments in our understanding of effective ways of improving outcomes in schizophrenia which

[00:48:08] [SPEAKER_01]: I really appreciate because you focus on outcomes and regardless of what the theory is behind it

[00:48:17] [SPEAKER_01]: I want to know where I can find good outcomes for my patients I was reading your paper earlier on

[00:48:24] [SPEAKER_01]: the pharmacologic treatment of schizophrenia how far have we come I think from 2022 tell me a

[00:48:32] [SPEAKER_02]: little bit more about that how far have we come well I think that we've I mean if you

[00:48:40] [SPEAKER_02]: look at the history of psychopharmacology of schizophrenia starting with the development

[00:48:44] [SPEAKER_02]: of chloropromasing yes we've we've developed a number of drugs I think that there have been

[00:48:51] [SPEAKER_02]: some highlights that we made on that paper from the perspective of pharmacology I think that we

[00:49:01] [SPEAKER_02]: I mean seems seems very basic but we we are starting to understand that taking meds every day

[00:49:06] [SPEAKER_02]: is not a good way of treating someone that has a chronic illness seems very basic but

[00:49:14] [SPEAKER_01]: you can't say that you can't say we're not supposed to take meds every single day this is America right

[00:49:19] [SPEAKER_01]: we're supposed to take multiple meds every day I'm being sarcastic of course but so right so

[00:49:25] [SPEAKER_02]: I think that we are understanding I mean it's part so the whole thing about long acting

[00:49:29] [SPEAKER_02]: injectables has been very interesting because they were highly or you know they were used

[00:49:34] [SPEAKER_02]: at much at the much higher rate before second-year rations came around then second-year

[00:49:39] [SPEAKER_02]: agent the psychotics came to the market and that and long acting injectables were not being used

[00:49:43] [SPEAKER_02]: anymore and and you know I think that that's unfortunate because it's uh these are also

[00:49:51] [SPEAKER_02]: grossly underutilized interventions that help people stay relapse free and not just that

[00:49:57] [SPEAKER_02]: also help us understand if someone has resistance or pseudo-resistance sometimes

[00:50:02] [SPEAKER_02]: people may be experiencing some symptoms and it's just that they don't have the appropriate plasma

[00:50:06] [SPEAKER_02]: level continuously which is what a long acting injectable delivers so you know I think that

[00:50:11] [SPEAKER_02]: we are understanding that better and we we are underusing long acting injectables but I think

[00:50:18] [SPEAKER_02]: that over time we are I think that that's getting better so so to me that's that's an

[00:50:25] [SPEAKER_02]: improvement I would also say that there are new mechanisms of actions that have that are

[00:50:30] [SPEAKER_02]: being explored that are promising so one of them is a muscarinic agents and full disclosure as I said

[00:50:38] [SPEAKER_02]: before I consult for I consulted a couple times for a company that develops this drugs but I think

[00:50:44] [SPEAKER_02]: that these are very interesting drugs the mechanism mechanism of action is is rather

[00:50:48] [SPEAKER_02]: old I mean it was something that was uh investigated I believe in the decade of the 70s

[00:50:55] [SPEAKER_02]: and and really was not used until recently for various reasons but I think that the data are

[00:51:03] [SPEAKER_02]: very interesting so I think that that's a major development we will see what that looks like in

[00:51:08] [SPEAKER_02]: terms of the treatment that we provide to patients in the next decade but I think that

[00:51:12] [SPEAKER_02]: that that's interesting um I think that other developments is the understanding that it's

[00:51:19] [SPEAKER_02]: not just using one drug that you have to treat a whole ecosystem with each patient right so I think

[00:51:28] [SPEAKER_02]: that to the incorporation of coordinated specialty care into the first line of treatment for early

[00:51:36] [SPEAKER_02]: phase patients also seems very obvious but has only been done in the last few years right so

[00:51:42] [SPEAKER_02]: understanding that yes you have to do evidence based psychopharmacology but also you have to

[00:51:47] [SPEAKER_02]: treat the patient in their context so you have to work with a family you have to work your supported

[00:51:51] [SPEAKER_02]: dedication and employment you have to target not for symptom control but more for recovery so

[00:51:57] [SPEAKER_02]: these are also things that seem obvious but but I think that it's it's only recently that

[00:52:04] [SPEAKER_02]: they are becoming more more basic and more kind of like yeah come on come in that understanding

[00:52:13] [SPEAKER_02]: um yeah so so these are some you know I think that I think that there's been

[00:52:20] [SPEAKER_02]: important progress now I think that with the development of uh biomarkers that's an area in

[00:52:26] [SPEAKER_02]: which I am working I think it's very exciting so that we can bring the beyond the biology to

[00:52:30] [SPEAKER_02]: to change outcomes and to inform specific decisions I hope that that's the next uh

[00:52:36] [SPEAKER_01]: um the next frontier um is one of those drugs in the pipeline uh promoting uh increase acetyl

[00:52:44] [SPEAKER_02]: choline did I see that so the way muscarinic agents work and and there are many of them in

[00:52:53] [SPEAKER_02]: the pipeline uh there are many companies that are investigating different versions of of this

[00:52:59] [SPEAKER_02]: drugs but essentially the way they work is by modulating dopamine not directly on the

[00:53:07] [SPEAKER_02]: detour receptor but upstream and it addresses some of two of the major mechanisms that we and

[00:53:16] [SPEAKER_02]: that we know occur in the pathophysiology is schizophrenia one of them is at a cortical

[00:53:21] [SPEAKER_02]: level uh we know that there is this function of the NMNMDA receptors and that leads to some

[00:53:31] [SPEAKER_02]: what's known as the excitatory inhibitory imbalance in those micro circuits which may lead to

[00:53:38] [SPEAKER_02]: cognitive symptoms so by working by by intervening on cholinergic receptor I'm sorry on muscarinic

[00:53:47] [SPEAKER_02]: receptors the EI the excitatory inhibitory imbalance could be partially addressed so that's one

[00:53:55] [SPEAKER_02]: potential mechanism of action and that might explain the pro cognitive effect of this drugs

[00:54:02] [SPEAKER_02]: but also that restoration of EI imbalance downstream may um may help to reduce the

[00:54:10] [SPEAKER_02]: dopaminergic firing of of neurons into this triadm then some of these other drugs have

[00:54:17] [SPEAKER_02]: other also a calling a muscarinic effect in the in the um in the midbrain which

[00:54:26] [SPEAKER_02]: again reduces the activity of this neurons that that fire from the nigra from the

[00:54:32] [SPEAKER_02]: suspension nigra and the ventral tegmental area into this triadm which may be

[00:54:37] [SPEAKER_02]: driving some of this positive symptom so you know I think that well so these are the two major

[00:54:45] [SPEAKER_01]: hypothesized mechanisms by which this drugs would work yeah and it it's striking to me because

[00:54:52] [SPEAKER_01]: you know I I think if we can be curious about what and why our patients do what they do

[00:54:58] [SPEAKER_01]: we can learn a little bit more about the illness um and the classic example of that is the

[00:55:04] [SPEAKER_01]: high rates of uh tobacco use in schizophrenia um I think it's easy to um ostracize people or demonize

[00:55:15] [SPEAKER_01]: them for their tobacco use which is you know can be kind of taboo but I think it's much more

[00:55:20] [SPEAKER_01]: from a curious perspective to say well why does this population um use nicotine which is uh

[00:55:27] [SPEAKER_01]: you know affects some of those same symptoms and systems that you're talking about

[00:55:36] [SPEAKER_01]: so one other kind of a line of questioning before we wrap up here

[00:55:41] [SPEAKER_01]: so as I was saying earlier I typically find myself somewhere in the middle of most academic

[00:55:47] [SPEAKER_01]: political social issue discussions um for exception for for example I think it should

[00:55:54] [SPEAKER_01]: be the exception to the rule to take a patient's rights away and forced treatment but I also see

[00:56:00] [SPEAKER_01]: the need for it in patients with inosagnosia or complete lack of insight who are influenced by

[00:56:07] [SPEAKER_01]: severe paranoia or psychosis and I've seen people improve in their symptoms and also

[00:56:13] [SPEAKER_01]: be more willing to receive psychological and social services in their medicated state

[00:56:19] [SPEAKER_01]: allowing them to engage in treatment that may not have been possible without the use of

[00:56:23] [SPEAKER_01]: forced treatment obviously with every patient we want to try to meet them where they're at

[00:56:29] [SPEAKER_01]: involve their families their communities and their treatment as much as possible

[00:56:34] [SPEAKER_01]: but sometimes that frankly is just too idealistic and not very realistic

[00:56:40] [SPEAKER_01]: what is your stance on involuntary hospitalization and forced treatment in this population

[00:56:47] [SPEAKER_02]: I mean I think I agree with you in the sense that I mean anyone who has worked as a psychiatrist

[00:56:54] [SPEAKER_02]: a psychiatrist understands that there are always going to be situations in which

[00:57:01] [SPEAKER_02]: there's no alternative I mean there are some situations in which you know people are at risk

[00:57:06] [SPEAKER_02]: of hurting themselves or themselves or others we see this every day at the hospital so

[00:57:14] [SPEAKER_02]: I think that there's really no other way so that they are safe then there's obviously some degree

[00:57:23] [SPEAKER_02]: of interpretation as of you know at what point should you take away the rights of someone

[00:57:29] [SPEAKER_02]: to make a decision I think Jen I mean I'm not sure how it works in other states here in New

[00:57:36] [SPEAKER_02]: York it's either the danger to self others or the inability to care for self there are other

[00:57:43] [SPEAKER_02]: states in which that third component is not included it's a political discussion I mean my

[00:57:49] [SPEAKER_02]: my you know my perspective on this is that based on my experience and what we know from the

[00:57:57] [SPEAKER_02]: research perspectives the perspective for many people their perspective on their illness evolves

[00:58:05] [SPEAKER_02]: over time and especially at the early phases of illness that's when there's greater rates of

[00:58:13] [SPEAKER_02]: through this continuation and to me that's related to the fact that you have to accept

[00:58:18] [SPEAKER_02]: that now you have a chronic illness for which there's a lot of stigma and and and that's very

[00:58:23] [SPEAKER_02]: hard that may really change your life and that's very hard to take that's very hard to understand

[00:58:29] [SPEAKER_02]: and and not everybody has the same degree of support and understanding and

[00:58:37] [SPEAKER_02]: you know I think that that changes over time and over time you may you know realize that

[00:58:44] [SPEAKER_02]: some of this could be beneficial some of the treatments could be beneficial

[00:58:47] [SPEAKER_02]: and some of these drugs which are very nasty I mean I have not heard anyone tell me I love

[00:58:52] [SPEAKER_02]: dysantipsychotic because these drugs are very unpleasant to take so you know at some point

[00:59:00] [SPEAKER_02]: people understand that people are living with in this situation they understand that this drug

[00:59:05] [SPEAKER_02]: sucks but you know there's some positive that comes with it so you know the problem is that

[00:59:15] [SPEAKER_02]: so the problem is that if if you realize of that too late there's maybe not so much that

[00:59:21] [SPEAKER_02]: you can do right so if you have had a number of relapses you've already had problems with

[00:59:27] [SPEAKER_02]: your social network with your ability to stay in a job you know if you realize after damaging all of

[00:59:35] [SPEAKER_02]: that then that's of no good use right so okay um to me that's very unfortunate

[00:59:45] [SPEAKER_02]: so that's why it tend to be I don't know if you want to call it paternalistic but I think

[00:59:51] [SPEAKER_02]: that we should try to help people stay not get to that position so that if they realize and

[00:59:59] [SPEAKER_02]: they change their mind and they start seeing some benefit to treatment they still have some

[01:00:04] [SPEAKER_02]: opportunity to you know to get back on track so so I think that it can be I mean my perspective is that

[01:00:17] [SPEAKER_02]: I are on the side of protecting someone rather than then letting them make a decision if I think

[01:00:25] [SPEAKER_02]: that it's it's going to be um not beneficial or dangerous rather not dangerous and I know that

[01:00:33] [SPEAKER_01]: you've done a lot of work with early intervention services for first episode psychosis um I think it's

[01:00:40] [SPEAKER_01]: pretty generally accepted in psychiatry that the more untreated episodes or the longer the

[01:00:49] [SPEAKER_01]: untreated symptoms the worse the outcomes and the more resistance to pharmacologic treatment exists

[01:00:56] [SPEAKER_01]: um so but I just I ask that because again it it's a situation where I do believe that we should

[01:01:06] [SPEAKER_01]: try to avoid involuntary treatment as much as possible but I think when you've worked in

[01:01:12] [SPEAKER_01]: enough psychiatric units in patients state hospitals that you recognize that some people

[01:01:20] [SPEAKER_01]: really do or can benefit um from some form of uh of forced treatment even though it's not ideal

[01:01:29] [SPEAKER_01]: you know ideally we would have everybody be completely involved in in agreeable to every

[01:01:36] [SPEAKER_01]: treatment but it just doesn't happen in this population all the time and people may be damaging

[01:01:42] [SPEAKER_01]: their brains potentially beyond repair uh without early and in kind of you know I don't want to

[01:01:49] [SPEAKER_01]: say aggressive treatment but um early treatment and kind of getting that started and trying to find

[01:01:55] [SPEAKER_01]: the right pharmacologic aid along with social and psychological services um yeah anything else to add

[01:02:06] [SPEAKER_02]: there no to me to me that's the question I mean to me the ethical dilemma is do you become

[01:02:12] [SPEAKER_02]: more paternalistic when you know that that this can change over time and maybe a few years

[01:02:19] [SPEAKER_02]: from now that person may change their perception on treatment and but but it might be too late for them

[01:02:26] [SPEAKER_02]: to um to you know address some of the problems that emerge with illness like the damage to

[01:02:33] [SPEAKER_02]: social network and employment their ability to stay employed etc so to me that's the ethical

[01:02:39] [SPEAKER_01]: question um well thank you so much for answering these questions educating myself my

[01:02:45] [SPEAKER_01]: listeners on treatment resistance schizophrenia and the importance of using clozapine

[01:02:53] [SPEAKER_01]: is there anything else that you would like to add that you have been working on or are passionate

[01:02:59] [SPEAKER_01]: about um to to throw in here before we wrap up our discussion well I mean if so to your

[01:03:07] [SPEAKER_02]: listeners if if some of them are are living with schizophrenia and have and they think that

[01:03:12] [SPEAKER_02]: they may have treatment resistance I would strongly urge them to not normalize some of this same to

[01:03:20] [SPEAKER_02]: so don't normalize the fact that you're experiencing some delusions some hallucinations

[01:03:26] [SPEAKER_02]: disorganized thought um or behavior I think that's important to make sure that you've

[01:03:33] [SPEAKER_02]: done everything that should be done to confirm that um those symptoms are truly resistant

[01:03:39] [SPEAKER_02]: so you know I would encourage them to talk to the doctors about these of clozapine or

[01:03:44] [SPEAKER_02]: long-acting injectables whenever it's appropriate and to doctors I would tell them that um you know uh

[01:03:53] [SPEAKER_02]: I think that uh patients may really have their lives changed by clozapine we've certainly I mean

[01:04:01] [SPEAKER_02]: we've all seen clozapine super responders not everybody's going to be a clozapine super

[01:04:05] [SPEAKER_02]: responder but certainly for some people it's really a life-changing intervention so I think it's uh

[01:04:11] [SPEAKER_02]: it's important to make sure that we optimize the use of this drug and there are always questions

[01:04:18] [SPEAKER_02]: that come with it if you haven't been using this drug lately or prescribing this drug

[01:04:23] [SPEAKER_02]: but there are many resources I think SMI advisor it's sponsored by the ABA and I think it or

[01:04:29] [SPEAKER_02]: SAMHSA and I think it's a great resource but there's a lot of stuff that you can get as a

[01:04:35] [SPEAKER_02]: that we can all get as a community to to feel more comfortable prescribing this drug is there

[01:04:40] [SPEAKER_01]: anything more um rewarding clinically than to see somebody have a super response to clozapine

[01:04:50] [SPEAKER_02]: I mean I remember the you know I remember the people that I treated when I was in residency

[01:04:55] [SPEAKER_02]: and I remember some of this clozapine miracle so yeah I mean stayed in my mind

[01:04:59] [SPEAKER_02]: you know I've been around for a few years ago but I still remember yeah I had a I had a woman who

[01:05:04] [SPEAKER_01]: I put on lithium 150 milligrams for suicidality didn't even come up in our discussion her husband

[01:05:12] [SPEAKER_01]: had to drive her to her appointment she was afraid of um you know driving off the road or

[01:05:18] [SPEAKER_01]: something on the way there and had active suicidality and uh she came back a month and a

[01:05:26] [SPEAKER_01]: half later and told me that she had had a week every month of her life since the time that she

[01:05:34] [SPEAKER_01]: went through puberty and started having regular menstrual cycles where she would be extremely

[01:05:41] [SPEAKER_01]: suicidal uh she described herself as an emotional wreck lot of crying episodes and she said and I

[01:05:49] [SPEAKER_01]: didn't have that at all um in my last uh uh period and then several months later still

[01:05:57] [SPEAKER_01]: and has not had any uh pms pmdd symptoms and honestly I haven't really seen her a whole lot

[01:06:05] [SPEAKER_01]: lately and that's very rewarding to me uh those super responses are it I haven't seen them with

[01:06:14] [SPEAKER_01]: other drugs typically or if I have they haven't stayed uh over the through the course of time

[01:06:21] [SPEAKER_01]: last thing to add and I should ask this earlier but uh keep me up to date on what is the most

[01:06:28] [SPEAKER_01]: recent kind of um I know there was something going on with the rems program and trying to

[01:06:32] [SPEAKER_01]: take away that requirement for clozapine and and hopefully you know without putting any

[01:06:39] [SPEAKER_01]: patients at risk being able to limit the very tedious lab uh work with a weekly complete blood count

[01:06:51] [SPEAKER_01]: what's the latest on the on the the kind of recommendations with labs and trying to make it

[01:06:56] [SPEAKER_02]: more reasonable for patients to be on clozapine all I know is that the FDA is uh thinking about

[01:07:07] [SPEAKER_02]: how to redo rems I don't I don't know that they are discussing about getting rid of it but

[01:07:16] [SPEAKER_02]: I think that they are reconsidering I think that they're accepting the fact that the current

[01:07:21] [SPEAKER_02]: situation is really unsustainable because it um it doesn't really work so rems is currently not

[01:07:28] [SPEAKER_02]: enforced in part because it's so so difficult to do that it may threaten the um

[01:07:35] [SPEAKER_02]: and some patients may not be able to get their medication because it's so cumbersome to do so

[01:07:42] [SPEAKER_02]: so that's why it's not being enforced but that's not sustainable because then it defeats the purpose

[01:07:46] [SPEAKER_02]: I think that I hope that what the FDA is thinking about is how to implement the model that is able to

[01:07:55] [SPEAKER_02]: to be implemented that can be scaled in a way that's not to cumbersome for prescribers

[01:08:03] [SPEAKER_02]: but at the same time make sure that people are not getting clozapine when they should not be getting it

[01:08:08] [SPEAKER_01]: so that's all I know yeah and that is a very very cumbersome um I think it prevented uh several

[01:08:15] [SPEAKER_01]: patients from having an appropriate clozapine trial when I was in residency simply because

[01:08:21] [SPEAKER_01]: there's a lot of monitoring that had to go on with it and I mean on a very realistic level

[01:08:27] [SPEAKER_01]: you know I do think that some providers will choose the the less restrictive option

[01:08:34] [SPEAKER_01]: at the expense of what may be more beneficial to the treatment again similarly to lithium which

[01:08:40] [SPEAKER_01]: should absolutely be the gold standard in bipolar disorder and I would argue that that goes beyond

[01:08:47] [SPEAKER_01]: just bipolar into uh you know using low doses in schizophrenia and using low doses for

[01:08:53] [SPEAKER_01]: suicidality and unipolar what we now call major depressive disorder but um well hey I've really

[01:09:00] [SPEAKER_01]: enjoyed uh talking to you and um you know I think that uh you definitely have a very uh good head

[01:09:07] [SPEAKER_01]: on your shoulders and and understand things in a definitely about schizophrenia and clozapine at a

[01:09:13] [SPEAKER_01]: at a level up here uh compared to to myself and probably a lot of younger um psychiatrists

[01:09:22] [SPEAKER_01]: who don't have as much experience with it but thank you so much for coming on and um

[01:09:27] [SPEAKER_01]: and yeah if there's ever anything else that that comes down the pipeline or that that you want to

[01:09:32] [SPEAKER_01]: talk about certainly just let me know and we'll bring you back on certainly thank you so much

[01:09:37] [SPEAKER_02]: for the invitation and I hope that this was of interest to the audience absolutely

[01:09:43] [SPEAKER_01]: thanks again for watching and or listening if you're passionate about the subjects that

[01:09:48] [SPEAKER_01]: I discuss on the channel do me a favor and like comment subscribe do whatever you can to make your

[01:09:57] [SPEAKER_01]: voice heard that these are problems that must be addressed in our society if you have any

[01:10:04] [SPEAKER_01]: questions comments or concerns I want to hear them feel free to reach out on social media

[01:10:11] [SPEAKER_01]: or email us at renegadesyke at gmail.com and if you'd like to be a guest of the show

[01:10:18] [SPEAKER_01]: or you have a connection to somebody that you think would be a good guess let us know

[01:10:24] [SPEAKER_01]: thanks again for listening

[01:10:34] [SPEAKER_00]: disclaimer this podcast is for informational purposes only the information provided in

[01:10:37] [SPEAKER_00]: this podcast and related materials are meant only to educate this information is not intended

[01:10:40] [SPEAKER_00]: as a substitute for professional medical advice while I am a medical doctor and many of my guests

[01:10:43] [SPEAKER_00]: have extensive medical training and experience nothing stated in this podcast nor materials

[01:10:46] [SPEAKER_00]: related to this podcast including recommended websites texts graphics images or any other

[01:10:50] [SPEAKER_00]: materials should be treated as a substitute for professional medical or psychological advice

[01:10:53] [SPEAKER_00]: diagnosis or treatment all listeners should consult with a medical professional licensed

[01:10:57] [SPEAKER_00]: mental health provider or other healthcare provider if seeking medical advice diagnosis or