Six Decades of Schizophrenia Care with Nina Schooler, PhD

Journal of Clinical Psychiatry

Publisher of peer-reviewed research discussed in this episode.

Dr. Nina Schooler – LinkedIn

https://www.linkedin.com/in/nina-schooler-11022870/

NIMH – Recovery After an Initial Schizophrenia Episode (RAISE)

https://www.nimh.nih.gov/research/research-funded-by-nimh/research-initiatives/recovery-after-an-initial-schizophrenia-episode-raise

NIMH overview of the RAISE initiative and coordinated specialty care model discussed at length in this episode.

SAMHSA – Early Serious Mental Illness Treatment Locator

https://www.samhsa.gov/find-help/locators/esmi 

Locator for coordinated specialty care programs, funded through the SAMHSA block grants described in this episode.

Dr. Nina Schooler is a social psychologist whose career in psychiatric research spans more than six decades. She began her work at the National Institute of Mental Health’s Psychopharmacology Service Center in the early 1960s, contributing to the first NIMH collaborative antipsychotic trials. Over her career she has conducted pivotal research on antipsychotic maintenance treatment, adherence, long-acting injectables, tardive dyskinesia, and negative symptoms, including the landmark Hogarty studies and the RAISE early-intervention initiative for first-episode psychosis.

Ben Everett, PhD, is the creator and host of The JCP Podcast, a series that brings together leading voices in psychiatry to explore the latest research and its clinical implications. Everett earned his PhD in Biochemistry with an emphasis in Neuroscience from the University of Tennessee Health Science Center. Over a two-decade career spanning academia, publishing, and the pharmaceutical industry, he has helped launch more than a dozen new treatments across psychiatry, neurology, and cardiometabolic medicine. His current work focuses on translating complex scientific advances into accessible, evidence-based insights that inform clinical practice and foster meaningful dialogue among mental health professionals.

This transcript has been auto-generated and may contain errors. Please refer to the original audio recording for full accuracy.

0:00 – Introduction: Six Decades of Schizophrenia Research

Dr. Ben Everett: Hello, and welcome to the “JCP Podcast.” I’m your host, Dr. Ben Everett. On the podcast, we sit down with leading clinicians, researchers, and educators to explore the science shaping mental health care today with a focus on the insights that matter most in clinical practice. Every once in a while, you have a conversation that feels like much more than an interview. It feels like a tour through the history of a field. That’s what happened in our conversation today. My guest today is Dr. Nina Schooler, a social psychologist by training, whose career in psychiatric research spans more than six decades. She began her work at the National Institute of Mental Health Psychopharmacology Service Center in the early 1960s, as antipsychotic medications were beginning to fundamentally change the treatment of schizophrenia. And because she came to psychiatry as a social psychologist rather than as a practicing clinician, her perspective was somewhat different from that of many of the researchers around her. She worked directly with patients in research settings, but her career was fundamentally focused on research, understanding what happened when these new treatments were introduced into the lives of people with serious mental illness and what happened beyond symptom improvement. She had a front-row seat to an extraordinary period of psychiatric research. Over the course of her career, Dr. Schooler was involved in pivotal work on antipsychotic treatment, maintenance therapy, adherence, long-acting injectables, tardive dyskinesia, negative symptoms, cognition, psychosocial treatment, and ultimately coordinated specialty care for first-episode psychosis. Her work stretches from the early NIMH phenothiazine trials and the landmark Hogarty drug and sociotherapy studies to RAISE decades later. Our conversation ended up being quite different from what I originally expected. Rather than focusing on one particular intervention or one chapter of her career, we found ourselves talking about the evolution of treatment for schizophrenia and other serious mental illnesses, what the field believed when antipsychotics first arrived, and what the early research taught us, what we got right and what we needed to tweak, and how those discoveries shaped the way we think about the treatment of these disorders today. It is in many ways a conversation about the history of modern psychiatry through the eyes of someone who was there for much of it.

Dr. Ben Everett: With that Dr. Schooler, welcome to the JCP podcast.

Dr. Nina Schooler: Thank you so much. Appreciate the extended introduction.

2:30 – Joining NIMH’s Psychopharmacology Service Center in the 1960s

Dr. Ben Everett: Yeah. I think humility is is something that’s important to both of us. We talked about that a little bit when we were getting ready for this episode. But look, let, let’s get right into it. Let’s start at the beginning, and I don’t want to talk just at, at, at the beginning of your career, but specifically of this field itself. So you joined National Institute of Mental Health, Psychopharmacology Service Center in the early 1960s, and this was really in the timeframe which chlorpromazine had arrived in the US. What was the intellectual atmosphere like in that time?

Dr. Nina Schooler: Well it was a very heady period to say the least. I was joining as the most junior member of a team that was essentially inventing the field of clinical psychopharmacology. We were led by Jonathan Cole, who was in many ways an extraordinarily charismatic leader. The National Institute of Mental Health had been charged by Congress with developing a program in psychopharmacology.

And they hired Dr. Cole, who was then a very young psychiatrist actually probably just a couple of years out of residency, to head the program. And his first job was to try to figure out what grants the National Institute of Mental Health was giving that actually were in clinical psychopharmacology, namely the use of these newly developed psychoactive drugs, and this goes back to, of course, chlorpromazine in the treatment of patients.

And essentially, he scoured the grants to try to find what he could that seemed to be addressing these problems because he had money to spend and had to show that it had been spent. Essentially, he found very, very little. And therefore, because Dr. Cole was perhaps among the most creative people in our field that we’ve ever had, we were lucky to have him at the beginning.

What he did was he decided that he needed to do a study, and that would be a study that compared three of the phenothiazines, chlorpromazine and two others, to a placebo. And the question that was really sort of concerning to the field at the time was, was it really that these drugs made a difference, or did they only make a difference if treatment was kind of not so terrific?

And therefore, what he did was he recruited nine hospitals around the country. There were several that were state hospitals what are now called psychiatric centers, but in those days were state hospitals for long-term treatment of patients. Several places that were acute admission facilities where patients came in off the street, and then several sites, hospitals that were what were called silk stocking hospitals. These were places like Payne Whitney Clinic in New York the Institute of Living in Connecticut. And these were places which had very, very high staffing, where patients stayed for a long time and indeed actually received psychoanalytic therapy, which was at the time sort of the gold standard.

And these hospitals then conducted a six-week trial. When Dr. Cole and the group published the results, they’re actually indexed under Anonymous as opposed to under Cole’s name because the author line was the Psychopharmacology Service Center Collaborative Study Group. I came in in the middle of the project to the coordinating center, and we didn’t even have the word coordinating center at the time into the group that was conducting the study.

And perhaps my contribution to the article was actually drawing the graphs that are published in the paper. I was at the time, what’s known in the PhD trade as ABD, which is All But Dissertation. And to the credit of the Psychopharmacology Service Center they were the group that supported me in the conduct of the research that I subsequently did to obtain my degree.

But I should mention, and that’s probably useful at this point, that my degree actually is in social psychology and my training in clinical psychopharmacology which is how I currently identify myself was all on-the-job training. I’m not actually a person who treats patients directly, but I certainly do interact with patients in terms of connecting with them.

And I certainly consider myself to have some understanding of the treatments particularly with antipsychotics that they receive. That’s kind of long-winded, but perhaps it’s a start.

Dr. Ben Everett: I think it was great. And I tell you, there’s a couple of things there that, that I caught up on that, that I want to follow up on. So first of all, as a, as a recipient of a PhD myself, I, I appreciate the the ABD or all but dissertation reference. They, they’ve cleaned it up a little bit now, and now they say that you’re a PhD candidate once you’ve passed all your qualifiers.

But there’s still a lot, it’s m- a lot more than just writing a research a, a dissertation, right? It’s a couple years of research usually, and, and then you gotta write everything up. We’re really gonna get into this pretty heavy today. But I’m curious, so when you first arrived and these antipsychotics were, were really just brand new, was there, might be too strong a word, but was there a conviction or a shared conviction among people, you know, studying these that these were really gonna make a difference in patients’ lives?

Or was it we’re just gonna have to figure out where the research takes us?

9:00 – Shifting Terminology and the Boundaries of a Schizophrenia Diagnosis

Dr. Nina Schooler: No, I think one of the things that was most interesting and someone I met a couple of years later was Heinz Lehmann, who was a a European psychiatrist, I believe, I’m not– I believe Austrian, who came to Canada, and he was one of the first people to actually do a study of chlorpromazine in North America. And what he said was, he said, “I knew it worked.” There was no question that this was different and, and indeed different from the other treatments that he had worked with because he was– he had always believed that there was a biological basis to this i- to this illness of schizophrenia.

And therefore, he had, you know, studied things like, um, you know, cold packs, hot packs uh, electroshock therapy, insulin therapy, all of insulin coma therapy. All of these things had been studied with no effect whatsoever. And with chlorpromazine, people saw a difference. I think one of the things that you have to remember is the terminology that we used at the time.

By the time we were doing that first collaborative study, the nine-hospital study the term being used was neuroleptic, seize the neuron. But the more general term that was used was major tranquilizer, which spoke to the fact that these were not drugs like Librium, which were some of these early treatments that kind of preceded the benzodiazepines.

But these were treatments, they were major in that they attacked major mental illnesses such as schizophrenia. And we could get into a whole discussion of what was considered schizophrenia at the time because the definitions were indeed very different in Europe and the United States. And the definition in the United States was quite broad and probably included patients who today we would qu-classify as bipolar disorder or, depression or, or psychotic depression.

In other words, any features of psychosis could clap you into the diagnosis of schizophrenia, but that’s a topic for another day.

11:30 – A Social Psychologist’s Lens on Early Treatment Outcomes

Dr. Ben Everett: Yeah. Well, maybe we’ll have to co- get you back on and we’ll, we’ll do that later. So as a social psychologist in a world that was rapidly becoming really pharmacocentric then how did that shape your research orientation? You’re, you’re getting into this at the beginning of your career, halfway through. How, how do you think that shaped your, your research interest moving forward?

Dr. Nina Schooler: In two ways. One of the ways was that I was interested in what, uh, what seemed to me to be possibly non-pharmacologic aspects of treatment. So the first paper that I was involved– that I wrote as a, as first author was called One Year After Discharge. And what it did was to look at the patients who’d been in this nine-hospital study one year later, and to try to understand how they had, how their, what their outcome was a year after the formal intervention had ended.

Because once the intervention ended they were eligible for discharge from the hospital. And what was interesting to me was that indeed, we saw differences in the groups that seemed to be related to the treatment, but in peculiar kinds of ways. So one of the things that we saw was that the patients who’d been treated with placebo seemed in some ways to be doing better than the patients who had been treated with drug.

And at the time, and this is nineteen sixty, this was nineteen sixty-eight, I think, sixty-seven perhaps I speculated that the reason was that when the blind was broken and they discovered that patient had been treated with placebo, they became, they were more attentive to them, and they got even better care because indeed they were eligible to receive medication.

So that was kind of the orientation of a social psychologist at the time. I, I have to say, I’ve rethought that since. And one of the other things that as a psychologist I brought was an interest in methodology, and that’s something that I’ve sustained to this day. So it turns out that one of the flaws in that truly innovative study that Dr.

Cole did was that we did what was called replacement of subjects who dropped out. So if participants dropped out of the study before they’d completed the six-week trial, they were replaced And one of the things that I observed, because we were actually packaging the drugs at the Psychopharmacology Service Center, was that when they– when a site would call in for a new canister of medication, they were often calling in for a canister to replace a placebo-assigned patient, so that we were distributing more placebo than we were drug.

What that meant was that the patients who could not survive six weeks of placebo treatment were not included in the trial formally because we only analyzed the data from the six-week completers. And therefore, the one year after discharge paper only included people who were both six-week completers, and indeed those were placebo patients who could survive six weeks on placebo, plus patients who were discharged, which was also a hurdle that needed to be met.

So there could be an addendum to that paper if anyone cares to read it today.

Dr. Ben Everett: Yeah, that’s fascinating because y- the way we do clinical research now is obviously very different, but it’s built on, you know, as Isaac Newton said, you know, “If I’ve seen further, it’s only because I, you know, stood on the shoulders of, of giants,” and, and somebody has to do the first studies. And yeah, I’m just thinking now like, well, yeah, this is why we do intent to treat analyses and, you know, when people drop

Dr. Nina Schooler: Exactly. And

16:00 – Open Questions on Lifelong Treatment and Parallel VA Research

Dr. Ben Everett: You don’t just add more patients in. Like you’ve got your power calculation, and that’s what you’re gonna do. So well,

Dr. Nina Schooler: Well

Dr. Ben Everett: Ask you one more thing about

Dr. Nina Schooler: Sure.

Dr. Ben Everett: This paper. All right, so when– a-and I’ve got it at ’67 when this paper on community adjustment after discharge came out,

Dr. Nina Schooler: Right

Dr. Ben Everett: Was, what was the real question you were trying to get to then? It’s like, okay, we’ve got patients who seem to be responding to drug or not. Wa-was there an idea that this is a lifelong medication, or was it, you know, working on the psychosocial skills and, and psychosocial, you know, issues to, to try and get to it?

Dr. Nina Schooler: I,

Dr. Ben Everett: Too far ahead of myself?

Dr. Nina Schooler: Yeah. Well, it, it’s kind of tricky. The, the question was, did the treatment effects persist? And I think one of the que- the, the question that that short-term study left open, and, and I think this was a very real question, was whether people need… Was exactly the point you made. Do, is this a lifetime treatment?

Do people need long-term treatments? And shortly, we’ll talk about the studies that Hogarty, Goldberg, and I did in terms of long-term treatment, because that question was still pretty open. And the, the, the other, the other issue is there’s another stream of research related to the work that was being done at NIMH, which was at the Veterans Administration hospitals.

One of the things that was kind of interesting at the time was that many of the VA hospitals were essentially stocked packed with men who had been in World War II and who had either suffered psychotic breaks while in the army or im- or after discharge. And so the VA was also conducting studies of the then neuroleptics, and they had a a central unit that was coordinating these studies, and there was some intense collaboration.

There was some collaboration between the two. We did studies at the NIMH, and they did studies, what were called collaborative studies through the VA. And those studies that y- that, that, that entity, by the way, at the VA still exists. They’re now called cooperative studies, and they’re again centrally coordinated.

18:30 – The Hogarty-Goldberg Studies and the Two-by-Two Trial Design

Dr. Ben Everett: You mentioned the, the Hogarty-Goldberg studies in the 1970s.

Those are now just considered foundational. You were a co-author, as you mentioned. What did the results of those studies, you know, tell the field? And maybe you ought to set up the studies a little bit before we really get to the result.

Dr. Nina Schooler: Sure

Dr. Ben Everett: And, then I’ll ask some follow-ups.

Dr. Nina Schooler: So building, essentially building on the foundation of that first study one of the things that I think we learned from that study was there was no question that there was a difference between phenothiazine drugs, and all the drugs that were studied were phenothiazines and placebo.

And having already mentioned the fact that the study design was flawed in that only patients who could survive six weeks on placebo were included, um, we still saw a massive difference between drug and placebo. But we were absolutely unable to find any differences among the three phenothiazines. In other words– Oh, I, e-excuse me, except in terms of side effects.

In other words, if you look at the drugs, there were side effect differences, but there were no differences in efficacy that, that could be determined at the time. And so the, the question then seemed to be that placebo was not necessarily the right treatment in the short term, but the question that still remained was how long did patients need to be on medication in order in order for it to work.

In other words, once people improved, did they need to continue medication treatment? And I, I should mention that the three of, the three people who were most intimately involved in the Hogarty, Goldberg and my s- the study that I w- I was the third author. So if you’re, when you’re doing citations, you do still get included if you were to look at the three of us, none of us were physicians.

Gerard Hogarty had a master’s degree in social work. Solomon Goldberg was also a social psychologist by training and became a clinical psychopharmacologist of some renown. And then there was me. So the issue w- that was of interest was what was the role of an additional therapy, a sort of psychosocial treatment for these patients?

What would that do? And so the design of the study was one that was very common in a field like social psychology, namely a two-by-two design in which there were two factors being considered. The first factor was drug treatment, and that was indeed chlorpromazine versus a placebo. And the second factor was a psychosocial treatment that Hogarty developed, and it was called major role therapy.

And what major role therapy was designed to do was to combine two treatments that were already available within the social work field. One was occupational therapy, which was designed to get people jobs train them to be homemakers, and so forth. And the second was social casework. But the reason it was deemed major role therapy was the idea was to get patients up and out and participating in social activities in the way that they needed to.

It was a very prescriptive therapy. The social workers who led it, because it was a social worker-delivered therapy with the support of occupational therapists, were very much of the model of, well, you’ve got to get up in the morning set an alarm, do what you’re supposed to do. It was not patient-centered in any kind of way that we would think of today.

And it was a two-year trial. And what we looked at were, of course, symptomatic outcomes, and most importantly among the symptomatic outcomes was relapse.

And as I remember, because I actually wrote this sentence in the discussion, one of our issues was, did these patients really relapse? In other words, at some level, the relapse was d- the, was a decision made by the clinical team at the site. This was a, this was actually a three-site studies, three state hospitals in Maryland, so that we were able to provide much closer supervision of the sites than in the nine-hospital study, which was across the United States.

At any rate, what was interesting about this was that what I– the, my claim about proof that it really was relapse was that ninety percent of the patients who we declared as relapse had to be re-hospitalized. And that was, in a sense, a point of design pride on our part. In other words, that it was a very tight definition.

Today, when we do relapse prevention studies, we are extraordinarily, extraordinarily interested in not seeing patients return to hospital, but having symptomatic criteria that we can use to declare a relapse so that we do not impose another hospitalization on patients. Again, a difference between the 1970s and the post-1990s.

But at any rate, what we found in this study was, first of all, a massive demonstration of the value of medication fully 80% of patients in treatment, regardless of whether they received the sociotherapy or not, relapsed. 20% of patients did not relapse at the end of two years. And we struggled mightily to identify the 20%.

In other words, who were these people who could survive for two years on placebo? And certainly with the tools available to us at the time, namely all sorts of social psychological variables and of course symptomatic variables, we were unable to do so. So the conclusion from that was that medic– this, this study was perhaps the best demonstration of the long-term value of phenothiazines.

We did find something curious about the psychosocial treatment, and that’s been a something that we’ve been chasing, I think, in some ways ever since. And that was that if patients did manage to get to the two-year point in treatment, who– and if those patients were receiving the major role therapy, there were virtually no further relapses among those who received major role therapy in the second year.

But that was a post hoc observation, and it was it’s visible if you look at a survival curve. It i- it is, as they say in the modern parlance, it appears to be numerically different, but it certainly would not meet a statistical test. But it was an extraordinarily interesting finding which has had ramifications subsequently.

27:30 – Expressed Emotion and the Camberwell Family Interview

Dr. Ben Everett: I’ll tell you another kind of nuanced finding of the study that I thought was interesting was the two-year relapse data showed that there was a group, it was kind of a small group, and I don’t know if you found it or if one of your collaborators found it, that showed that sociotherapy alone, and this is in the patients that did not receive medication, was not only not protective, but in some cases may have even, you know, been harmful in terms of an odds ratio if patients returned to an environment that was high in expressed emotion, so a highly EE environment.

Dr. Nina Schooler: Great.

Dr. Ben Everett: I’m curious who found that because it’s a very nuanced finding, but I think it’s an important one.

Dr. Nina Schooler: Yeah, it’s interesting. And indeed that was a whole– That was do- I can’t remember who it was, but that was done by somebody else looking at this is other data. So the– what’s interesting about it… Meanwhile one of the things about the United States and all of us have a sort of solipsistic view of the universe.

And then I invented the wheel, and after I invented the wheel, I went on to discover fire, something like that. But at any rate, on the other side of the Atlantic, there was a whole stream of work that was going forward at the Maudsley Institute, and it was focused on something called on a very intensive scale that was able to identify characteristics of family members And one of the things that was identified in this was family members who expressed what they called high expressed emotion, and that came to be known as, “Oh, these are high EE families.”

High expressed emotion was a complicated measure which came out of something called the Camberwell Family Interview, which took two hours to administer and could only be– you could only learn to administer it by going to the Maudsley, which was located in South London in Camberwell, which is how it came to be called the Camberwell Family Interview.

And it c- and was complicated because it could be two things. It could be, one, an over-involved family member who sort of couldn’t let go of the patient and was hovering. I guess we would now call that, in modern parlance, it would be the helicopter parent. And the other was a distant and withdrawn family member who was rejecting.

And the third element was that the family member was somebody who expressed ambivalence about the patient, and that would be something like saying “Well, I certainly hope you’re gonna be able to come to dinner tonight, but I know you probably won’t because you’re busy.” And then the question is, if my mother says invites me to dinner that way, does she expect me to come, or doesn’t she expect me to come?

And all of these were lumped together as high expressed emotion. And the idea was that patients who returned home to families that were high in expressed emotion were like, more likely to relapse that was, that became a very interesting concept, and it was actually a concept that propelled Hogarty to his, to his next study.

And he may be the only person in the history of psychosocial treatments for schizophrenia and psychosis who actually invented three different and distinct treatments for schizophrenia, each one of which built on the results of a study that showed that a treatment didn’t work. So when major role therapy failed, Hogarty went on to study a treatment that he developed that was designed to treat high expressed emotion in patients and their families, so that it was a treatment that included families formally, which major role therapy had not.

That was focused on patients alone. But, but that’s a whole… That’s a different story. I can get back to the story of expressed emotion when we talk about the treatment strategies in schizophrenia study, which specifically, addressed expressed emotion by not addressing it, if that’s not an odd way to put it.

32:30 – Controlled Trials Versus Real-World Adherence

Dr. Ben Everett: Oh, yeah. All right, so let’s move on a little bit from this period. When you look at the schizophrenia research, there’s, I think, a central tension, it seems to me, has always been that, all right, you’ve got a controlled environment, and there’s what you can do in a controlled environment with all of the issues with enrollment.

Even these days, you know, there might be a new treatment, but I’ll maybe go talk to someone in education. They’ll be like, “Yeah, but they didn’t study the really sick patients,” right? Those patients were all excluded, so we don’t know if it works in this patient population or that one. There’s always these different tensions, right? So there’s what a medication can do in a controlled trial, and then what happens when it gets to the real world, right? Where

Dr. Nina Schooler: Right

Dr. Ben Everett: Don’t have c- study coordinators and research nurses and all of the additional attention on the patient. Adherence in the real world, we know, is much worse. And, and adherence leads to relapses, right?

You spent a, a good bit of your career working on just this issue. So specifically I’ll set up this 1991 Schizophrenia Bulletin paper you had. It, found that dose reduction strategies in maintenance treatment were, were highly influential. So the question, I guess, is what was driving the field’s interest in getting doses lower at that point in time, right? ‘Cause it’s like, hey, patients are well controlled, but hey, can we lower the dose? Can we lower the dose? And what do you think were the, were the casualties?

Patients relapse. Did the pendulum go too far the other way? Kinda what, what

Dr. Nina Schooler: That’s

Dr. Ben Everett: Issue in the early ’90s?

34:00 – Tardive Dyskinesia and the Push to Lower Antipsychotic Doses

Dr. Nina Schooler: Right. So the issue at that point was essentially tardive dyskinesia what had happened was remarkably tardive dyskinesia emerged as a major, major concern. And it was a concern not only because it affected patients, but because the, the the best treatment we had for it were actu- was actually increasing if it, maintaining a dosage of medication, if not increasing it.

Because essentially what it appeared to be was that the medication masked the symptoms of tardive dyskinesia, and that you essentially saw them when you reduced dose or discontinued medication. And what had happened was that this had become an issue for litigation. And lawyers always, always attract issue interest.

So there was enormous, enormous interest in it from that perspective. In addition, there have always been people in the field who believed that the side effects of antipsychotic medications were more pernicious for patients than were the treatments we were giving them. There’s, there’s always been a kind of movement within the field and also external to the field of people who believe that medications have deleterious effects, and which they do.

I mean, there’s absolutely no question about that. The question for most of us is, well, what’s the balance? In any event at that point, there were actually I would say by that point, there was no question that anyone would consider an actual placebo treatment as an efficacious treatment for patients.

What was considered plausible was whether we could have patients who were medication-free, but at the same time, by careful observation, we could determine when they were developing a new episode. In other words, we could identify early signs of relapse and therefore intervene early enough so that we could prevent the full relapse.

36:30 – Designing the Treatment Strategies in Schizophrenia Study

In other words, avoiding what I considered the gold standard in the Hogarty trials, namely they went back to the hospital. So could we avoid a relapse by early intervention? Then the other strategy that was seen as of interest Could we use what would be seen as a sort of sub-threshold low dose of medication so that again, we would avoid the deleterious side effects?

Perhaps if tardive dyskinesia was, as some believed, related to cumulative dosage, we could reduce the dosage burden that people received to a low level. And then the third, of course, was, well, we’d maintain the standard dose. And that was what, that was the design of the treatment strategies in schizophrenia study.

In other words, three dosage conditions, what we called early intervention, which was indeed a placebo, low dose, and standard dose. And the one thing that we did to ensure that we actually obtained those three dosage conditions was to use injectable medication. And by using a long-acting injection, we were able to ensure that people received either a placebo injection, an injection that had a low dose of the medication, or the standard dose.

And of course, what that meant, unfortunately at the time, was that the medication we used was fluphenazine decanoate, which was the only approved medication that we could use in the study. But We also believed we were quite taken with the expressed emotion literature at the time. And so we also thought that what we needed to do was to include a psychosocial treatment which would provide an intervention for patients with schizophrenia, a family-focused intervention.

Because as we understood it, the expressed emotion literature relates to families, and patients return to their families in the community. So we scoured the world for a family-focused intervention that we could use in a multi-site clinical trial. And the person we landed on for the family-focused intervention was a psychiatrist named Ian Falloon, who had developed what he called had developed a family intervention, Intensive Family Management, it was called.

And he had the ability to train people to do intensive family management. And, but of course, we needed a control treatment for that. And so our control treatment was a family-focused multifamily groups where families would get together periodically. And so we now had three medication interventions, two family-focused interventions, which gave us a two-by-three or six-cell clinical trial design.

And we did that at five centers in the United States. And that was a absolutely marvelous, marvelous experience. The sites were wonderful. The collaborators were absolutely fabulous, and we did a great study.

40:30 – Results: Medication’s Value and a Young, Family-Involved Cohort

Results. We found– First of all, what we found was something that, for some of us, was a known phenomenon, namely, darn it, or not darn it, medications work.

And what we found was that despite the efforts at early intervention, and maybe I should describe how we were able to do early intervention at the time . Early intervention at that time meant filling out an early, a early signs questionnaire every week. We were able to see people weekly, and the early signs questionnaire included what are standard early signs of relapse, namely changes in sleep, changes in mood preoccupation with certain things.

But we also felt– we also created what we called the i- idiosyncratic early signs, which were early signs that related to a particular patient, so that these were recorded at the beginning of the uh, study and then asked about every week It turns out that if you’re trying to achieve early intervention, weekly is not probably good enough.

That wasn’t good enough for us to be able to rescue people with either of the two lower lowered medication conditions. What we did see, though, was that in the lower dose, not in the no dose condition, but in the lower dose condition, we were able to avert hospitalization. In other words, a lower dose, when augmented at the time that a relapse was essentially either observed or predicted in the community you could save a person from hospitalization.

Again, that’s an observation. The two clinic– the two family-focused treatments did not distinguish one from the other, either in relapse prevention or in symptom exacerbation. Those are the data published by the study, the study team. However, those data, this is in the modern era now, are now in the public domain, and others have found nuanced results that relate to those data in the community.

What’s instructive, though, by that, that I should mention, which was initially your question, was how did this relate to expressed emotion? And the way it related was that we decided that regardless of whether families demonstrated high expressed emotion, they deserved family treatment. The other thing that’s important about this study, and it leads to an area where I’ve been working much more actively more recently is that, well, actually starting in the ’90s, is that in order to have families, we didn’t rely on what’s considered a standard definition of an informant, namely someone who’s had four weeks of contact with a patient in the past week.

We wanted people who were either living with their families or had very active involvement with families. And as a result, this study had a very young population. The mean age of the patients was in their mid– I believe the mean age was 28, which in terms of modern clinical trials for schizophrenia is about 15 to 20 years younger than what we will see in pharmacologic clinical trials today.

So it was a young patient population, and it was very influential for me in stimulating interest in early and first episode.

45:00 – Long-Acting Injectables: Adherence Myths and the PROactive Study

Dr. Ben Everett: That’s fascinating. I mentioned in the introduction that we recently did this consensus panel on psychosocial interventions in, in schizophrenia. And, you know, several of these things are still very currently talked about. It’s something we wrote about in the consensus panel. We talked about a good bit, and I think it gets to several things.

But one, you know, the idea of adherence is still a big problem. I, I think community samples now, it’s still forty to sixty percent of patients with schizophrenia still struggle with adherence. And also long-acting injectables are still very, very underutilized. If you just look at prescription databases, you know, they’re used in inpatient, and they tend to be used in like region eight type of facilities, those type of facilities.

But in the community, they’re really not widely utilized. All right, so you actually looked at this at studying long-acting injectables. You, you mentioned fluphenazine trials in the 1970s. You were still working on that issue in 2012 with the PROactive study. So has anything fundamentally changed? I would hope so. Things have fundamentally changed in our understanding of who benefits from LAIs and, you know, why are they still so underappreciated by practitioners?

Dr. Nina Schooler: Well, I think one of the let me start with the basic question was “Hi there. How’d you like an injection?”

Dr. Ben Everett: Yeah.

Dr. Nina Schooler: And one of the things about long-acting injectables is that they are indeed injectables. And there is a general assumption about injections that they’re, they’re not good things, and that if we can possibly avoid them, that is good.

The other thing that I think has been relevant for clinicians is the idea that, injections are good for patients who’ve con- have been, have demonstrated their non-adherence. In other words, if I know for sure that you’re non-adherent, then I’m gonna… then there’s really no other choice, and we’re gonna have to go with this.

And I’m gonna offer, I’m gonna, I don’t know if the word is offer then an injection is a really good idea. But if you haven’t demonstrated non-adherence I’m gonna, well, for one, I’m gonna take you at your word that you’re taking the medicine, which actually is a terrible idea because people’s word for taking medication is…

Well, anybody’s word for taking medication is to be doubted. One of the things that that I’m very good at it, but that’s partly because I work in this area. So I’ve developed all kinds of strategies to convin- to make sure that I take medication when I need to. Medications are positioned in the right place.

The things I take with breakfast are positioned so that they will be there when I start breakfast. If there’s a medication I need to take before breakfast, it’s positioned somewhere else altogether so that I’m sure to do it, and so forth. But many people will find that if they’re o- admit, offered a 10-day supply of an antibiotic that needs to be taken three times a day, and they just rely on opening the bottle and taking the medicine out when they need it, when they come to the tenth day, they will surely find at least three capsules, pills sitting in the bottom of the bottle.

So why should we expect people with psychosis and schizophrenia to do any better? One of the challenges in studying long-acting injectables, and this is a challenge that goes back to the very first study that I did with them back in the 19, published in the late 1970s, was you need a control condition.

And that’s the point that you raised in s-setting up this question, the difference between the controlled condition and actual reality. At the time that we did the, our first prospective study comparing long-acting injectable, and in that day it was still fluphenazine decanoate, to oral medication The studies that we had that made us think these might be useful were clinical studies that were mirror image studies.

So someone would compare patients who’d received an oral medication previously to prospective after medication or injectable, and they found that relapse rates went down substantially. When we did a controlled trial, and indeed we were doing a very fussy kind of trial in that it was what’s called a a double-blinded trial in that patients received both injections and pills.

So either you got a fluphenazine injection or a placebo injection, and you were given a supply of pills to take home for the two weeks between the injection. And either you got placebo pills or actual pills. And we showed absolutely no difference. And what that told us was that if people came in and collected a supply of medication and received an injection, they were likely to be people who were indeed adherent to treatment.

And in fact, if you didn’t come in to get your injection, we’d call you up. We’d send a taxi. All of the sort of efforts that we put into clinical trials, and in that context, we showed no difference between drug and placebo.

51:30 – Research Diagnostic Criteria for Tardive Dyskinesia and the AIMS Scale

Dr. Ben Everett: Yeah, I like it. When you look at the literature, and actually I didn’t know that study, that’s really, really fascinating where patients will get an LAI and then be discharged with actual medication or placebo. This, pretty genius design. With that in mind, when we talk about long-acting injectables, the, the literature is, is full of survey data and whatnot. And I know Joe Goldberg had a poster on this at ASCP two years ago, two ASCPs ago in ’25. That, you know, in, in, in Joe’s poster, they literally, they just interviewed patients and, and said to patients, “Hey, what has your provider offered you in terms of medications?”

And then they asked the patients, “Had– have you ever been offered a long-acting injectable?” And they explain everything about the LAI. The patients are like, “No.” And the patients were actually upset with a lot of their providers that like, “This seems like it’d be a really good option for me.” And then I know another thing is just, you know, the way the intervention is brought up, right?

It’s when you go through all of the pros and cons of the different things again, there’s data in the literature that indicate that many patients, most patients, in fact, will say, “You know what? I’ll try the LAI.” So I just think in ter-in, in terms of shared decision-making, it’s always very important just to make sure that, you know, we offer our patients what there is access to.

Okay. So you mentioned tardive dyskinesia. That remains one of the biggest problems with antipsychotics, maybe a little bit improved with some of the atypicals, but it is still a really big problem. You and John Kane published the research diagnostic criteria for TD back in 1982, and really that has shaped how the field has measured and monitored the condition for decades. W-what do you think about TD in terms of a, a distinct functional driver for impairment? And looking back, do you think the field managed the TD risk responsibly during this first, you know, when really all we had were these strong D2 blockers?

Do you think it was managed appropriately or, you know, just doing the best you could at the time.

Dr. Nina Schooler: I think it’s what’s so remarkable about it is now that we have medications that actually treat tardive dyskinesia and can manage it it’s really fascinating to watch the difference in the way the field responds to it. One of the things that happened was there was a huge push toward monitoring, and as I may have mentioned earlier that was one of the pushes toward lowering dose and toward this whole notion of intermittent or targeted treatment, the idea that you could perhaps have an impact on tardive dyskinesia that way.

And I think that the what was so interesting about it, it was as though it was an epidemic which sort of rose, peaked, and died down kind of in the way that epidemics do in other areas you know, when it’s an infectious agent. And maybe the infectious agent in this point at this point was information about it.

One of the things is that the whole idea of the, the research diagnoses for tardive dyskinesia were essentially designed as a research tool. If you– We had offered it as an article to the, to what was then Archives of General Psychiatry, and it actually ended up being published as a letter to the editor.

They weren’t interested in all of the details, but just wanted to get the information out there. And it became, it did become kind of a what’s the word I want? Sort of a standard. And the, the standard is actually a little challenging because the actual standard for diagnosis in the RDTD requires a period of time off medication to see whether the movements persist, um, after medication has been withdrawn.

And the period that we s- that we identified in that paper, in that, uh, in that piece was actually three months. And I don’t think they’re applied, I don’t think they’re actually applied that way. The other thing that happened at the time was that many organizations, including the VA, instituted a requirement for periodic evaluation using a, some move, some scale for abnormal movements, and the Abnormal Involuntary Movement Scale the AIMS, is the one that’s most frequently used.

And, um, I have a very long story about how that was, how that scale was developed and never formally validated?

Dr. Ben Everett: That’s interesting. And, and I know now that the, uh, you know, the, the guidelines do say that every patient should be screened at every encounter. And just remind our listeners, that doesn’t mean you have to be a prescriber or anything else. You could be a nurse in the clinic or, or anyone else can, can do the screening.

56:30 – Negative Symptoms, Cognition, and the Risperidone Question

So all right, so let’s move on to negative symptoms and cognition. The- these are frequently called out as the most difficult to treat. We don’t really have any medications to get to negative symptoms, cognition. Hopefully some coming. I know there’s been a lot of drug development in this area, but nothing has worked out to date.

The consensus panel called these out as the largest driver of functional impairment. I know you’ve been thinking about this for a long time, and in fact, in, in nineteen ninety-four, you had a JCP paper on risperidone and negative symptoms.

Uh, and it was published at a moment when these second generation antipsychotics were being positioned in part as a, as a way to, to get to negative symptoms. They were gonna do better with negative symptoms. How do you assess that claim or what they were trying to do?

Dr. Nina Schooler: So one of the things that’s so interesting about this is that notion that negative symptoms respond to medication goes all the way back to that very first collaborative study. Uh, well, I’m sorry, not to… Yes, to that very first collaborative study, where we also did see improvement in negative symptoms in that six-week trial with the medications.

And indeed, the same thing was the case with risperidone. And I think what the issue is, is the– and this is what my question is about every class of drug that has come along, a-along the way. Remember, of course that very first collaborative study was acutely ill patients being treated with antipsychotics in hospital.

The risperidone trial was also acutely ill patients being treated in hospital with risperidone, and that’s been the case absolutely going through. One of the issues that it, what it turns out to be, in my understanding, is that acutely, yes, there is a significant reduction in negative symptoms in patients who also experience psychotic symptoms.

And I can explain that with an example. And this is a case example of one patient, but I think it really says it all. It was a patient that explained to me why it was that he couldn’t speak to me In other words, he was limited in what he could say, so his answers were very limited, very narrow, as monosyllabic as possible.

He would give me yes and no. After he was treated, he explained that the problem was that there were dogs who were outside of the hospital and who had the ability to tear through the barred windows of our state hospital, come in, and were threatening to tear out his throat because he was speaking to us.

Well, I wouldn’t be very communicative either. So that these are the psychotic symptoms. Delusions and hallucinations can drive what we see as social withdrawal or, um, anhedonia. These people don’t seem to enjoy anything, or lack of communication, um, or flat affect. They’re non-expressive. All of the things that we consider classic neg-negative symptoms can be driven by the positive symptoms.

When you improve the positive symptoms, as we did with risperidone, as we had done with chlorpromazine, and as I believe we’ve done with every drug we’ve had since then, all of these drugs improve psychotic symptoms. What they then do is expose underlying negative symptoms which we may not have seen before that are not the sort of secondary ones that are related to psychotic symptoms.

So if you’re studying acute treatment, if what you have is a short-term trial, you will see improvement in negative symptoms, and you will extol your drug for the fact that it improves negative symptoms. If you then go into longer-term treatment, it will turn out that the drug is not as effective. And so we get early promises of effectiveness in negative symptoms.

Dr. Ben Everett: Yeah, I think that’s really interesting. I, I think also one of the things that I know you’ve done some work on a-and, and, and as well as just kind of understanding the field and the literature, it’s been a big problem methodologically just to try and identify, assess and, and track negative symptoms in a, in a rigorous controlled trial.

And the regulatory authorities may or may not agree with what comes up with. So you’re still sort of at the behest of, of what the FDA, in the case of United States, would consider an approvable objective, you know, marker or something like that. And, and, and FDA had a, uh, a, a– Yeah, FDA had a workshop, couldn’t remember what they called it, but if it was a white paper or what.

And FDA actually had a workshop looking at this as recently as August of twenty twenty-four.

1:02:30 – The FDA Workshop and Consent Challenges in the CONSIST Study

Dr. Nina Schooler: Well, that was a very interesting workshop. I was a participant, and so I saw it up close and personal. What was really fa- what’s fascinating to me as a methodologist and, um, uh, let me give you a, again, a c- a case example. So this is the example of having tried to conduct a trial in, done a large trial in negative symptoms.

This was the CONSIST study, which was a multicenter study. I was one of the one of the site investigators on this and participated in the design of the study. But since we were a site, I also had responsibility for consenting patients to the trial. What was challenging about it was that the patients that we most wanted in the study, the patients with profound persisting medic- negative symptoms, wouldn’t consent to participate in the trial because being in a clinical trial requires something called effort.

In other words, this was a trial which required you to come in for weekly appointments and take medi- an additional medication every day. That’s a challenge, and when you would ask people whether they were willing to do this, they might have a family member who was very enthusiastic, but the patient who indeed had the capacity to consent would refuse.

And so the problem we’ve had in many clinical trials looking at negative symptoms is that the patients we most want to include will not be included in the trial because participating in a clinical trial requires effort, and that’s something, extra effort, and that’s something that is absolutely not suitable for somebody who feels that the best situation is just to sit at home quietly and do absolutely nothing.

To me, that’s an almost insurmountable challenge given the kinds of criteria that are required. The other piece is I’m not rushing to say, let’s not– let’s just abolish consent because one of the things about the trial that, the Consist trial that I’m describing is that actually I was often, in many cases, able to get consent.

In other words, I could convince the patient to actually sign the piece of paper. However, these patients would then not validate their consent by actual participation. So in other words, there are multiple hurdles because even if somebody will agree to participate, then when it comes, when push comes to shove, they don’t.

So either they drop out early, or they are clearly not adherent to– you learn that they have not been adherent to medication, and there are all kinds of problems. So their data end up contributing less to the clinical trial than one would like.

1:06:00 – Digital Interventions, EMA, and Smartphone-Based Treatment

Dr. Ben Everett: What does it tell you a-as a researcher that we’re still having this conversation, you know, many decades later?

Dr. Nina Schooler: I think they’re very promising, and that, that gets back to the to something we discussed earlier. In other words, all the things that you can’t do with paper and pencil tools, and with meetings with patients that are difficult to schedule more than once weekly and get to adherence to, to sort of trial practices rather than adherence to treatment.

And I think that, um, um, what, what are now called– what’s now called ecological momentary assessment, EMA, and I think that of… in, in terms of abilities to assess and also to provide treatment may be useful, may be very, very useful kinds of interventions. And one of the things that we’ve seen change over the years is that patients now, almost invariably, including schizophrenia patients, will have access to smartphones.

They may not be the most advanced smartphones, in other words, with cameras with five lenses, but they’re gonna be smartphones. And as long as these apps can be made available to any phone, in other words, tailored to your phone rather than this app works on this and this app works on that they can be very helpful.

The real question is that w- in many cases, what we see is that app adherence maintains a trajectory where, for many people, it declines after some certain number of weeks of use. So if you’re thinking about for example, the CT intervention that you described, what you’re hoping is that it serves a training function and not that it works like an antipsychotic medication, which means that once you stop it, the effects go away.

So you want it to be something That’s a learning experience so that once a person has learned the particular skill or thing that they’re supposed to learn, that they maintain it without continued use of the app.

Dr. Ben Everett: Yeah. Another interesting finding. So yeah, so it’s really interesting. So you can convince a patient , to give consent, but when, you know, left to the natural course of their illness, they’re just not going to be adherent.

I’m curious though, because there are now a number of digital interventions that are you know, moving through clinical research. I believe there’s one called CT. I’m gonna forget what it is. I believe it’s, uh, Boehringer Ingelheim is, is co-developing this one. Yeah, CT one fif- one fifty-five, it actually met its, its primary endpoint in phase three.

And maybe that’s a potential solution around this because it’s digital, it’s just an app on their phone. What do you think about, uh, these digital interventions and, and the role they may play in, you know, helping to improve cognition, negative symptoms or, or adherence, anything?

1:09:30 – Designing RAISE: A Cluster-Randomized Approach to First-Episode Care

Dr. Nina Schooler: Sure. Um, So the study that I was part of was actually led by John Kane, Delbert Robinson, and I were sort of the central members of a huge coordinating team. It was a multi-investigator, multi-site study in the United States. It was in response to a request for a contract from the National Institute of Mental Health, and their request was to design an early intervention trial.

First episode psychosis was the target. S- First episode non-affective psychosis was the target, and the idea was that it was a treatment that could be delivered in the community. In other words, this was not supposed to be a treatment that was delivered outside of the community, but was delivered in the community and addressed and used interventions that were known to be already effective What’s important about– what’s most important about the intervention part of the RAISE study was that having said it wanted evidence-based treatments what that meant was that we were looking for treatments that had some evidence base that they worked in schizophrenia, possibly in first episode, but certainly in some aspect of schizophrenia.

And there were two groups that were actually funded to do this. And what was interesting was that both groups actually used very similar multidimensional, multicomponent treatments to deliver. And those treatments included medication, antipsychotic medication. The treatment included some form of early of individual treatment.

Ours was called individual resiliency training, something that looked at families, and ours was a sort of family-focused psychoeducation, and then a form of supported employment. So this is a multifaceted treatment program. And what I want to talk about, which is more important in terms of our trial, because this was similar to the other group, which was based out of Columbia and led by Jeffrey Lieberman and Lisa Dixon.

What was more important about our trial was the design of the study. And so we designed the study to be at community mental health centers around the country. In other words, not academic sites, although some might have an academic affiliation, and also not clinical trialist sites. And what we were concerned about was the problem of teaching a complex multicomponent intervention to clinicians and then saying to those clinicians, “Now what we’d like you to do is offer this treatment to half of your patients, because we’re going to do a random assignment clinical trial,” because a random assignment clinical trial is the gold standard What we realized, and I think this was actually John Kane’s genius, that what we needed to do was a cluster randomized trial in which some of the sites were randomly assigned to deliver the multi-component treatment, and other sites were randomly assigned to deliver the treatment they would usually do to patients who arrived with first episode psychosis.

And that was what we did. And what that meant was we only had to gain consent from the sites to do the treatment, and then only train the treat– the sites that were assigned to do the multi-component treatment, which we called Navigate, to provide that treatment. And the other sites we trained to do the assessment protocol only.

Everyone was trained to do the assessments, but only the intervention sites were trained to do the intervention. And what that meant was we needed to exclude any site that already had a first episode treatment program in place, so that we were only including sites that were de novo to early intervention and that were willing to be randomly assigned to either treatment And we recruited 37 sites.

As I remember it, there were two sites that were eager to provide treatment but weren’t willing to agree to randomization to the two conditions, and there was one site that already had an early intervention program going. The result of this was that indeed we did show numerous kinds of advantages for the early intervention treatment during a two-year, uh, during the initially specified treatment, which was a two-year treatment program.

1:15:30 – RAISE Results and the Challenge of Personalized, Team-Based Care

And that was very, very gratifying. What I have to add about the results of the study is one thing that we did not show a difference in between the two treatments was time to rehospitalization. First of all, rehospitalization rates were very low in both treatment groups, and they did not differ. So but we did show a difference for the treatment.

The problem with the difference that we showed is twofold. One, these were four, I mentioned four treatment components. All of these treatment components were offered to the patients and their families who were participating in the study Not all patients accepted all of the treatments, and patients had very– participants had various degrees of participation in the treatment.

So what we can’t say is, was it the medicine that made a difference? Oh, no, it was the individual resiliency training, because this was a treatment that was designed to be time-limited and built on patients’ strengths and personal goals. Oh, no, no, no, maybe it was the family involvement that made the difference.

Or was it the supported employment? So when you look at, for example, as I know your panel on psychosocial treatment t-d-did, the effectiveness of individual treatments, that’s one story. The real question is, and the panel did, uh, agree to this that the issue was that these had to be personalized. But the personalization, one of the things that we’re unclear about is, does the patient always make the right decisions?

In other words, I certainly, uh, concur with the notion of shared decision-making, that the patient needs to be a participant in what we’re going to do. But the fact of the matter is, we often have patients, and we had this in the RAISE study, who would say at the beginning, “No, you can’t involve my family.

My mother actually tried to poison me. Why would I want her to be part of this?” And then later, as he got better, agreed that it might be useful to bring his family in. We were unable to address the family of a, a patient older than eighteen years of age if the patient didn’t consent.

So that’s a hurdle, which is a, an insurmountable one in clinical care. So one of the– that’s one of the issues. Psychosocial treatment researchers who have done complex interventions like the Navigate intervention that we provided in RAISE will often talk about what those set the stage for are what they refer to as dismantling studies, where you do a study in which instead of doing all four components, you randomly assign patients to three of the components.

In point of fact, those studies are rarely, if ever, done So the challenge I think for the psychosocial treatment field is that I don’t absolutely believe that individual interventions in themselves work. My sense of schizophrenia as a treatment target is that it’s a team sport, and that it requires a team of people to engage with patients offering a range of treatments for which I see medication as the absolutely essential platform on which other things, can indeed build.

But what the structure looks like is going to be different for different patients, and that of course remains the challenge uh, for the future. And I guess I will say is that despite having worked in this area for as many years as I have, I’m still interested willing to be engaged, and very optimistic for the future.

1:21:00 – From RAISE to SAMHSA: Scaling Coordinated Specialty Care

Dr. Ben Everett: Yeah, I think that’s the, the whole goal of any psychosocial intervention, and that’s– these definitely fall under that more psychosocial or psycho functional intervention type of, uh, of, of intervention. All right, so let’s move on. Really one more major topic and then we’ll, we’ll, we’ll close it up. But I want to spend a few minutes talking about the, the idea of, of early intervention and how important that is.

So the RAISE early treatment program may be what you’re most known for, at least in me- in recent years. It brings together really everything that we’ve discussed today: medication, psychosocial treatment, systems of care, and the question of what early intervention can actually accomplish. So can you, uh, set up the RAISE trial for us and, and tell us about the results and, and, you know, where we are with the RAISE trial today?

Dr. Nina Schooler: So yes, it made a difference, but not just because of the study. One of the things that happened was, um, Robert Heinssen, who was the major NIMH collaborator in the RAISE study, after the initial initiative which was spearheaded by a psychiatrist named John Shao. Robert Heinssen liaised with SAMHSA to create the SAMHSA programs which provide block grants for early intervention treatment to the states, and those were based on the RAISE initiative.

So the way Heinssen framed it was that our study showed the, would show the efficacy of an early intervention, what he called, CSC, coordinated specialized care is the term that Heinssen has used to cover both the Navigate program and the On-Track program, which was provided by the Lieberman-Dixon study. And they actually never did a controlled trial. They sort of delivered the treatment. And Heinssen dubbed the combined– both treatments coordinated specialty care and persuaded SAMHSA to do these block grants.

And what that has done is that both the Navigate group and the group that did the and the Lieberman-Dixon group went on to develop training programs that can be disseminated to sites across the United States that are delivering coordinated specialty care. So it’s it had to be a two-arm sort of approach.

Namely, one approach that demonstrated efficacy which provides the scientific background for that. And there have, of course, been early intervention studies across the globe earlier on in, um, Australia, all across Europe that support this. And then of course, a financial mechanism that makes it possible for sites to actually deliver this kind of treatment, because this kind of treatment is more intensive than the normal block grants that SAMHSA provides to sites to provide mental health treatment.

That’s the challenge. And I would also say that whether sites that have received Navigate training from the Navigate provider training group which exists, whether those sites provided with fidelity to the original treatment model, I wouldn’t even begin to speculate. But there are early intervention programs around the country, and they have multiplied.

It’s still the case that most people who experience a first episode of non-affective psychosis are not within driving range of a a CSC program. But m- probably 40 to 50% of the country is currently covered by such SAMHSA programs.

1:25:30 – Has RAISE Changed Community Practice?

Dr. Ben Everett: Well, that’s wonderful. Let me ask about the RAISE study. Do you think it was one of these things that just stayed in the literature and was an interesting academic finding, or do you think it’s actually made it into the community and made a difference in the way schizophrenia is being treated in the community?

Dr. Nina Schooler: Well, I have to say that when I– It’s a great question, and I feel like a unicorn in the field. And I think the reason is that increasingly, when I talk to young people who are interested in a career that might not mirror my own, but is derived from the kinds of interests that I have in methods of clinical trial patient outcomes treatment, particularly pharmacologic treatments, I encourage them that what they need is degrees in psychiatry and probably a PhD in some other field.

And, um, actually, a good specialization in genetics might not be, might not hurt. I honestly feel that the, the future is going to be, not only controlled, but the questions that need to be asked going forward are probably not the questions, um, that my training background would enable me would enable me to answer.

These are much more nuanced questions. They’re more subtle questions. Um, another, another area that I would comment on was early on, I felt fully competent to be the person who was doing the analysis of the data that we had gathered using the methods that I had learned in graduate school. Nowadays I would argue that the services of a, a clinical trial-trained biostatistician is absolutely critical in the conduct of any trial.

I think what’s happened is that we’re increasingly specialized, and I’m happy to participate as I can these days. But increasingly, um, I see that many of the questions that are being asked are questions that I, I can’t even, I can’t even follow the question, much less critique whether the an- answers are being appropriately derived.

1:28:00 – Toward Meaningful Functional Recovery: What Must Change Next

Dr. Ben Everett: Very interesting.

Well, it’s certainly better than, than where it was historically, but it shows that we still have some, some way to go. All right, so last question. Um, we’ve, we’ve referenced our consensus panel discussion a couple of times. It– The paper itself calls for a, and this is a quote, “A paradigm of meaningful functional recovery,” end quote, moving beyond symptom control as the primary endpoint. So given everything you’ve seen in your, you know, over six dec-decades of a career in this area looking at schizophrenia, what would have to change in research and clinical culture and health systems for that paradigm shift to actually happen?

Dr. Nina Schooler: Yeah I mean, it’s a, it is a laudable, laudable goal. The question for me is whether the underlying parameters of schizophrenia make that goal actually possible. One of the things that we’ve said over the decades is, if we could only intervene earlier, and I think that’s been a really interesting shift in the field.

Um, and it’s interesting to me that consensus panel didn’t address the sta- the various stages of illness. We’ve moved from treatments which were targeted to patients who’d been ill for decades to treating first episode psychosis, and there’s now a robust field in the f- in the area of high risk, which is the notion that prevention is actually what needs to be done.

And this is not primary prevention in the sense of putting fluoride into water. This is actually secondary prevention in terms of treating people at clinical high risk in a v- with a variety of strategies in order to prevent the development of the, quote, “actual illness of schizophrenia,” or people experiencing a formal first episode of psychosis.

And my guess is that’s where the field will move increasingly. And this is n- very– I mean, it’s something we’ve absolutely seen very dramatically in the Alzheimer’s field where that move has absolutely taken place. And I think we will see that, uh, going forward here as well. And there I think the idea will be, now what are the treatments that need to be applied during this period that will make a difference?

Dr. Ben Everett: That’s fascinating. And I think it’s, it’s really a credit to the field and all of the work that numerous researchers and patients have put into this that at least we can envision a goal as, as lofty and laudable as, you know, full functional recovery for, for these patients suffering from, uh, schizophrenia.

But Dr. Schooler, this has been a, a blast. It’s really been a living history of this field, looking at psychopharmacology from a research lens and really a, a clarifying lens on where we still need to go. I wanna thank you for your time today, your candor for, for your career, uh, and for all this work that has made such a measurable difference in so many different patients’ lives and, and their families too. With that, this has been the JCP podcast. Insightful, evidence-based, human-centered