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I am very excited to introduce this episode today.

It will be called Schizophrenia Treatment, Clozapine, Long-Acting Injectables, Technology and Equity.

John Kane and Lauren Hanna and 2 psychiatry residents, a fourth year Dr.

You may remember from the Clozapine episode I did with Dr.

Cain and his monumental historical work in bringing Clozapine to the US.

Cain was monumental in influencing Another person we're bringing on, Dr.

Hanna, she supervises residents in the early treatment program and on track NY as part of the multidisciplinary specialized team with expertise in treating early episode psychosis.

And we're gonna talk a lot about like early episodes psychosis, how to talk to these patients, long acting injectables.

She is also the associate program director and the director of anti-racism and social justice at the Zucker Hillside Hospital Psychiatry Residency Program.

It is fantastic to meet her today as well.

Also, you're gonna hear from a fourth year psychiatry resident, Dr.

She has conducted some research on mental health, mobile app interventions, social media use, mental health.

And this is cutting edge stuff on how we can potentially have early markers of psychosis from just how people are using their media.

He is also a fourth year psychiatry resident.

He plans to pursue a child fellowship and is a leader in the program.

And he reached out to me after hearing me talk about Dr.

Kane on the Clozapine episode with Cummings and thought, hey, why don't we get a bunch of us together and talk about what happened, the historical event that led to clozapine being approved for treatment-resistant schizophrenia.

So this is a historical moment where we get to, You know, remember the people that changed the face of psychiatry, there is no better treatment for treatment-resistant schizophrenia than clozapine, and it will be great to do another dive into this.

Before we start any episode, we have to give any potential conflicts of interest.

Kane has a number of potential conflicts of interest.

I've looked at them and This is recorded after the episode.

I have thought through what we talked about the episode.

I do not believe these created a conflict of interest.

There are about 20 companies that he is involved in on an advisory board, grant support, shareholder, consultant, and he received some royalties.

I will provide a full list on our website, psychiatrypodcast.com and in the show notes.

And to my understanding, you had to take over a group of Clozapine patients at Hillside Hospital in New York, and you had to wean them off of clozapine.

So as you said, there were some problems with clozapine.

In the mid-1970s, there were a series of deaths in Finland from agranulocytosis, and that was the major adverse effect associated with clozapine.

So there was certainly concern on the part of the FDA in the United States that this was not a drug that could be safely utilized.

So that's a permission from the FDA to use an investigational new drug.

1 of the holders of those INDs was a gentleman named Nathan Klein, who was a pioneer in psychopharmacology, and he had a number of his private patients receiving clozapine, and he was really not keeping up with the paperwork that was necessary to sustain an IND, and ultimately the FDA and the company, Sandos at that time, took away his IND.

That meant that the patients who had been receiving clozapine needed to have someone else to manage their illness, and I was asked to do that because I had expressed interest in clozapine, and although I was quite young at the time, had begun to do research in schizophrenia.

So I was asked to pick up those patients and since the likelihood was that the drug was not going to be available in the US, They asked that whenever possible I try to have these patients taken off clozapine.

or 30 of these patients, and in some cases I thought clozapine could easily be discontinued.

In other cases, some of these patients did not have schizophrenia, but for those who did, we did make some attempt to discontinue the clozapine, but with not very good results.

Some of them were hospitalized at Hillside.

We tried to treat them with other medications, and they failed.

Ultimately, we put them back on clozapine.

I think the responses were quite dramatic so that even the staff on the units, the nursing staff and the mental health aides were quite impressed with the ability of this drug to reduce some signs and symptoms in some very, very ill patients.

And after that, I continue these patients on clozapine.

I joined Sandos in having conversations with the FDA about the potential of this drug.

And the FDA, Paul Lieber at that point was the head of the psychopharmacology division.

And their attitude was, if we are going to consider approving this drug, you really need to do a study to demonstrate that it is superior to conventional medication in the treatment of treatment-resistant schizophrenia.

And there had been some early work, particularly in Germany, that had suggested that this drug would be helpful in treatment-resistant patients.

So we designed a study in conjunction with the FDA and with Sandoz, and I was the principal investigator of that study.

It was published in the Archives of General Psychiatry in

and that's what led to the approval of clozapine in the United States in 1990, but with some very strict requirements for monitoring to determine if patients were developing neutropenia and agranulocytosis.

And in those days, I think the risk of agranulocytosis was both higher and potentially more lethal.

What we've seen over the last 3 decades is the incidence of agonocytosis is lower than it was, and the rate of fatality is extremely low.

So I think clozapine can be given much more safely than what had been anticipated, you know, in the late 1980s, early 1990s.

So since then, I think, sadly, in a way, several factors.

1 is that clozapine is still the only drug approved by the Food and Drug Administration for treatment-resistant schizophrenia many, many years later.

We still don't really know how clozapine works and how it distinguishes itself from other antipsychotic drugs.

It does bind to a variety of neuroreceptors in the central nervous system.

Now we like to say it's a drug with a rich pharmacology.

But the reality is we still don't know how it really works.

And the pharmaceutical industry has tried very hard to replicate clozapine.

In fact, olanzapine is very, very similar to clozapine, but doesn't quite have the same efficacy.

And the third factor is that clozapine is still grossly underutilized, in my opinion.

I mean, We know, for example, that 20% of first episode patients are treatment resistant from the get-go.

They really don't derive adequate benefit from antipsychotic drugs.

Yet the utilization of clozapine in that population is very, very low.

But in the general population of treatment-resistant schizophrenia patients, the utilization of clozapine is much lower than it should be.

So we would estimate that about 30% of patients with schizophrenia would qualify as treatment-resistant.

The utilization rate of clozapine in the US now is still well under 10%.

And I think there are a number of factors that contribute to the underutilization.

It's something that we've been working hard on to try to better understand those obstacles and to work with people to improve their ability to use clozapine.

We could talk about that more in a minute, but I think the sad fact in early phase patients is the extent to which we can get the illness under control in the first couple of years is really critical in terms of prognosis.

And if we have patients with, you know, significant residual positive symptoms, that puts them at risk for many things, also diminishes their opportunity for recovery, etc., etc.

A study that was published in Europe called OPTIMIZE, actually a large-scale study treating early phase patients, after analyzing their data, which included initially being treated with amisulpride, and then those patients who didn't respond were randomly assigned to elanzapine or to continue on amisulpride, and then if that failed they went to clozapine.

Those investigators concluded in their paper that clozapine should be used in early phase patients after only 1 failure, whereas traditionally we expect failure on at least 2 medications.

I personally would be satisfied if people went to Clozapine after 2 failures, and that would be consistent with the regulatory indications, but that doesn't happen.

First episode patients rarely receive Clozapine, and I think that's a challenge for us as clinicians.

And I think, so that's a kind of brief summary of the Clozapine story.

We've seen through many reports that clozapine is associated with a lower rate of rehospitalization than other medications and even a lower rate of long-term mortality.

I mean, that's true of antipsychotic drugs in general.

They reduce rates of mortality in people with schizophrenia.

Long-acting injectable medicines, which we can also talk about, have been associated with a significant reduction in the risk of hospitalization, as well as the risk of long-term mortality.

Because I think that when people are afraid of like, oh, clozapine side effects and risk of mortality, but they don't realize, no, the risk of untreated schizophrenia has high mortality.

Absolutely, no, the risks are significantly higher among people who don't receive medication.

And I guess another debate in the field has been, you know, how long do we need to continue medicine in somebody who's only had 1 episode or 2 episodes?

And the data, particularly from Scandinavia, where they have large registration databases so that every patient with a diagnosis of schizophrenia can be tracked to some extent in the medical records.

You know, they've looked at rates of mortality and rates of hospitalization over periods of many years and shown that it's difficult to identify a point in time where it's safe to discontinue antipsychotic drugs and that suggests, and in fact their data suggests, that the risks may even go up over time rather than down.

So, but we are talking about schizophrenia here.

Sometimes there's confusion in the literature because people publish papers on the outcome of psychosis, and psychosis is not necessarily schizophrenia.

So we do need to be careful that people understand we're specifically talking about schizophrenia, and obviously that's a diagnosis that's not easily made, so 1 should be confident in that diagnosis, and that can take time.

But in those patients, I think the advantages of drugs like clozapine and long-acting formulations are very important, and similar to clozapine, the long-acting formulations are also grossly underutilized, despite the fact that they've been available for many years.

And even the second-generation or atypical antipsychotic drugs, you know, several have been available for many years in long-acting formulations, yet they're still underutilized.

And I guess I would say that the reasons to some extent are similar in that they're both kind of a hassle to use, that it's more work for the clinician.

It's more work in terms of explaining the benefits and also discussing the risks with patients who initially may be reluctant.

But that takes, in my opinion, training and time and practice.

And we've done studies where we've been able to train clinicians on the use of these medications and help them also do a better job in having this shared decision-making conversation with the patient about these medicines.

And often, you know, we as physicians like to think that we're very good at communicating with our patients, but often in talking about these 2 treatments, the communication is not, is far from ideal.

And often clinicians start off with the risks rather than discussing the benefits initially, and then obviously including the risks as well.

And very importantly, to be able to answer frequently asked questions, some of which can be difficult, but we have to be prepared to answer them.

I would love to hear how you have that initial conversation and discussion.

Imagine, I mean, with my audience you're teaching providers, so teach it as if you're teaching a provider like how you would teach them, you know, like what would you say, what questions come up, How do you answer those questions?

Hannah, you as well, probably have been trained in this model, teach residents now on this model, right?

So very early in my career, 1 of my first post-resident, I went to residency at Zuckerhehl site hospital and 1 of my first post-residency jobs was working with Dr.

Kane on like a 4 year grant funded Obamacare project where essentially my role was to travel and evangelize, you know, smaller community-based organizations around New York State on best practices for the use of close opinion LAIs.

So, I still have very fond memories of those many years ago.

But I think in terms of the conversation with patients and families about Clozapine specifically, my strategy is kind of Dropping a little.

Pearl of information like early- in the conversation knowing that it later will be a later conversation.

So I I try to I try to set- patients and families up for success but also.

I also keep in mind that there are some really common, I guess, concerns, questions, things that people will go to.

I think a lot of the things that we try to kind of learn and teach residents at our program is like the evidence-based paths to like not make too many mistakes, like not take too long to make too many mistakes in getting people healthy.

Or 1 of those mistakes would be like maybe not introducing to patients the options of a long-acting injectable early, like waiting, waiting until they've proven that they're not taking their medications.

I want to touch on LAIs a little bit just because, like, we're talking about clozapine, but I really think it's like a really first step before we're talking about clozapine, so I want to talk a little bit about them.

So I think 1 of the really common misconceptions with LAIs, which is patients, families, but also like in the mental health field, is that there's like a stigma related to them, like these are medications that are only for quote unquote bad patients, whatever that means, or quote unquote non-compliant patients, right?

Non-compliant versus not adherent, I think that the terms we use now is more like inconsistent right because how can.

How can a- patient or a person you know be non compliant or not inherent with a medication that they choose to take so.

So it's like for a bad patient or a AOT patient or a inconsistent with medication patients, like this is, or an aggressive patient, all of these kind of loaded terms, these are what LAIs are for.

And really LAI is just a really great treatment option to help you stay well, right?

I think what we know about people who take medications for chronic conditions, and this is like all chronic conditions, right?

We know that it's about 50% of people will take medications as as they're intended and we're not talking about people who have psychosis, who are disorganized, we're talking about like this is even like information from the American Heart Association for people taking chronic heart medications.

These are all people who are humans, right?

And so we just happen for this particular problem to have certain tools that not all other fields have to treat.

And so for LAIs, we counsel our residents to really introduce them early as a treatment option.

You know, hey, you know, are you and your mom, like, getting to arguments about, am I taking medications, am I not?

You know, come in once a month and get a shot.

Hey, are you wanting to go live your life freely, go to college, do whatever?

You don't want people to know you're taking medications, you don't want them to think about it?

Hey, are you having some side effects that are kind of bothering you?

It's more consistent in your bloodstream, so the side effects might be a little bit less.

So we try to offer that as an early option, because if 50% I think LAIs are maybe highly underutilized, maybe like

to 20%, 15% utilized, but if 50 I'm getting head nods from Dr.

So if 50% of people don't take medications as prescribed, 50% of people could benefit from LAIs, only 50% get offered to them or use them.

But then how do you decide which 50% to give your LAI, to offer LAIs to?

You just offer to 100% at the beginning, and then hopefully they're more utilized.

Now say we get to the point of talking about clozapine, right?

So I usually try to highlight the really great things about clozapine.

And when I talk to residents, we speak about kind of like studies and numbers and all kinds of things.

In my experience, I tried that very often with patients and families, and I realized it wasn't super effective.

I think patients and families really want to hear about like, you know, like, oh, positive stories, anecdotes.

I'll tell a story about a young woman, like for example, that I remember from early in treatment.

I'll try and make it very vague because I am very conscious about, you know, like PHI stuff, but you know, who had a Truman Show-like delusion, a very common referential delusion that can happen.

And over a period of, I would say a year and a half after starting Clozapine.

And Clozapine really being kind of really the main agent, she may have had like maybe a benzodiazepine as well or something.

You know, it went from believing that everything going on in the environment was like a reality TV show directed at her, to, and she's really bothered by it, to it's happening less, it's still happening, but I don't think about it, I don't worry about it, to, oh my goodness, I couldn't believe that I was thinking that that was happening.

And it literally took like a year and a half.

So sometimes when I tell that story for patients, it kind of gives them like, oh, okay, this could be me as well.

When I tell that story to teach residents, I tell it to say that, you have to have a little bit of faith in close-uping.

Because I think part of the challenge in part of the challenge that Dr.

Kane mentioned in terms of how it's underutilized is like the rules are a little bit different.

People are afraid to use it and like they use it too late.

And then like if there's sometimes if there's any kind of side effect that scares them, they pull away from it.

So just giving people some confidence that it may take a very, very long time to see good results, even on monotherapy, but the good results can and do come, I think is really reassuring for people to hear.

If I could just add a couple of things to what Lauren said.

So I think, you know, with the long-acting formulations, she really emphasized how common it is for people to have difficulty taking their medicine.

And in fact, if you look at some of the drugs that are used to lower cholesterol, et cetera, people don't even get the prescription filled, not alone take the medicine.

So it really is, as she said, it's really human nature.

And I think we have to de-stigmatize non-adherence.

We have to convey to patients this doesn't mean you're a bad patient or a bad person it's just human nature to have trouble taking your medicine.

1 of the problems is we don't know when somebody's taking their medicine or not.

If they're on oral medicine most of the studies show that doctors are not very good at knowing when their patients are taking medicine because we all like to think that our patients are very compliant.

And in fact, when we've done surveys asking physicians to compare the literature on noncompliance to their own patients.

They always say their patients are more adherent than everyone else's patients, which is just not the case.

So I think the use of long-acting formulations obviously is 1 strategy to address this human nature challenge of taking medicine, but it does have other advantages as well in that we know for sure when someone's getting their medicine.

So if they relapse, it's not a question of, you know, was the person taking their medicine or not.

If they relapse on a long acting, which can happen, it happens less often than on oral medicine, but it can happen.

We know that they've broken through the medicine and we know that we have to, you know, think about other strategies, such as clozapine.

Another factor is, as Lauren mentioned, some doctors sort of say, well, I'll wait until somebody demonstrates non-adherence, resulting in a relapse or a hospitalization, and then I'll introduce the LAI.

The sad reality is they don't usually do it after the first relapse, it's often several.

And data from the University of Toronto, for example, shows that if we let somebody relapse, that their response to medication is not going to be as good as it was in the previous episode.

And this study was done in 130 first episode patients who were treated in the second relapse with the same drug that they received in the first episode, but yet it was less effective.

And so we think that relapse can be sort of part of the trajectory towards treatment resistance, not to mention the fact that in a young person early in the course of illness, a relapse or a hospitalization can have a tremendous impact on their pathway to recovery.

You think about a young person who's been in university and they have to drop out because of a psychotic episode, but they respond well and they go back to school.

What happens if they have another episode?

Or the same thing with employment or with social relationships.

So we really want to try to prevent every relapse possible during the early phase of illness.

And I think The long-acting formulations are just more convenient as well for patients.

Every time you open the pill bottle, you're reminded, I have schizophrenia.

When you go to the clinic once a month, that's not a daily thought necessarily.

And also some young people, they might be at university and have roommates and people don't necessarily want their roommates to know what medicine they're taking and why, etc., etc.

And Lauren mentioned the reduction in family tension that can be a result of using an LAI.

We also, I think, can use lower doses because we know exactly what the patient is getting.

We don't have to worry about them missing a dose or 2.

I also think it can be helpful in patients with comorbid substance abuse.

In our data and some of the national data, between 40 and 50 percent of patients with schizophrenia have a lifetime diagnosis of substance misuse.

So there too, if someone's on a long-acting formulation, we have more confidence that at least they're getting the antipsychotic drug.

They're not going to stop it for the weekend because they want to use a certain kind of drug or what have you.

And then in the case of Clozapine, I think what Lauren said is absolutely true.

And the way I try to present it to patients is, this gets back to the data that she mentioned.

So we know that about half the patients are likely to derive clinically meaningful benefit from clozapine, not everybody, but at least half the patients.

But there's a subgroup of patients, and this gets back to the storytelling that she was referring to, there's a subgroup of patients for whom it's really life-changing, I mean, really life-changing.

We don't have good biomarkers to identify who's gonna benefit from clozapine, to what extent, et cetera, et cetera.

So I think the patient and the family need to know, yes, this is a medication that is the only drug that's approved by the FDA.

There's a good chance it's gonna help you.

There's also a chance it's gonna change your life.

It would be a shame to miss that opportunity.

See all Unknown transcripts on Libsyn

Psychiatry & Psychotherapy Podcast - Schizophrenia Treatment: Clozapine, LAIs, Technology and Equity with John Kane, MD and Lauren Hanna, MD