Doctorx Unscripted Bold Conversations about Patient-Driven Science - Bristol Myers Squibb

Tania [00:01] Welcome to Doctors Unscripted. I'm Dr. Tania Small, and I'm here to bring you into a different kind of conversation with some of the brightest minds in medicine and research. It starts with a missed appointment, a wrong turn on a familiar road, and a name you just can't quite remember. But what if memory loss is only the tip of the iceberg? Today, over 7 million Americans are living with Alzheimer's, and that number can nearly double in the next decade. In this episode of Doctors Unscripted, I sit down with world renowned geriatric psychiatrist, Dr. George Grossberg, a trailblazer, an educator, and one of the world's foremost experts in Alzheimer's care for over 40 years. In part one, we've explored the subtle signs, the biomarker revolution, and the inequities shaping who gets diagnosed and when. This isn't just about identifying Alzheimer's disease, it's about recognizing the window to act earlier, smarter, bolder. So, join us as we shatter outdated paradigms because the future of Alzheimer's care is being rewritten. Now, let's get started. Welcome Dr. Grossberg. 

Dr. Grossberg [01:30] Thank you.

Tania [01:30] I'm excited to talk about a topic that affects millions and millions of people and families

Dr. Grossberg [01:36] To me that's been actually misunderstood, misdiagnosed sometimes, and so happy to have you bring clarity to it.

Dr. Grossberg [01:44] What topic is that?

Tania [01:45] And that is Alzheimer's and Alzheimer's psychosis.

Dr. Grossberg [01:48] I've never heard of that disease. Just kidding. That's kidding. No, that's a very, very important. In fact, it's been just a couple of weeks ago that the US Alzheimer's Association has recalculated the numbers

Speaker 3 [02:01] And

Dr. Grossberg [02:01] Now they feel that we have over 7 million Americans that are affected in families with Alzheimer's disease and related disorders. So it's a huge issue. Huge problem.

Tania [02:13] So before we even go into the details of Alzheimer's, I want the listeners to get to know you on a personal level. So my first question, let's take a step back. What made you decide to go into geriatric psychiatry?

Dr. Grossberg [02:29] I was doing my residency at a non-for-profit Catholic hospital in St. Louis County, and they ran a clinic in St. Louis County and a very impoverished section of St. Louis County for a free clinic for indigent adults. And the clinic was basically run by the internal medicine residents. And one afternoon I arrived a little before one o'clock and the nurse was head of the clinic, welcomed me, hi Dr. Grossberg, and she had all these charts. This is before the era of electronic records, all these charts piled up and she said, oh, a lot of your patients are already here. And they were sitting in little booths where I would go from one to the other. And she said, oh, in booth one we have the lady with congestive heart failure and booth two, we've got the guy with poorly controlled diabetes, and booth three, we have somebody with some other. Every patient became a disease. And, I had all these patients to see in a limited amount of time. And I said, wow, is this where medicine is moving? I started thinking about assembly line medicine where you have to see so many patients in a limited period of time, and I would never get to know any of them. And I said to myself, as fun as it was to figure out these medical diseases and how to manage them, what I was really interested in addition was what I called the person behind the disease. And if I have 12 minutes per patient, I'm never going to get to know them. So literally the next day I called over to St. Louis University where I had done my medical training to talk to the residency training director in psychiatry. So I told them I would do better in psychiatry. They interviewed me and they actually accepted me into the residency. But then of course, recognizing that I liked the medical things and I like of course to get to know my patients and their families and the psychiatric things I liked, the brain and neurologic things. That really moved me into geriatric psychiatry, the discipline that brings all of those together in the typical 85-year-old or his family. So that's how it kind of happened.

Tania [04:48] So Alzheimer's, what I want to do is really even start with the basics. What is Alzheimer's and how is it different than other types of dementia?

Dr. Grossberg [05:03] So what we know is it is not part of normal aging. It is a specific brain disease. We now think we understand most of the causes, not all, most of the contributors to why cells die in Alzheimer's disease and that it's very, very common and it's different than other brain diseases, other dementias like Lewy body dementia, vascular stroke related, Parkinson's, dementia, frontotemporal, so on and so forth, that it's by far and away the most common cause of not only memory but cognitive loss in later life. And we're learning more and more about how to treat it and how to try to slow it down. It's very exciting and risk factors for it. Then identifying it early.

Tania [05:51] So if we start with the pathology of Alzheimer's, what do we know now?

Dr. Grossberg [05:56] So we haven't learned a lot about the pathology. That's different than when Professor Eloise Alzheimer described it in the early 19 hundreds. He described over a hundred years ago, plaques, neurotic or amyloid plaques and neurofibrillary tangles that he saw at autopsy in the first patient that he diagnosed. So the plaques and tangles are still the primary findings that we see in Alzheimer's disease. And the plaque more recently have been a focus for therapy for Alzheimer's disease to try to slow down the deposition of plaque. The evolution of these neurofibrillary tangles, which basically are in the neurons in the cells that cause the cells to kind of become dystrophic or dysfunctional. So those are the key neuropathologic changes, and those have not changed.

Tania [06:55] What is the clinical manifestations of Alzheimer's in the different stages?

Dr. Grossberg [06:59] So there are different schemes to staging Alzheimer's disease, but I think what's really important is to try to pick it up early and to diagnose it early and look for the early signs and early symptoms. And they do vary from person to person, but there are some things that are much more common. One of the things that's extremely common early on and what brings people in is that not necessarily the person themselves, the older adults herself or himself, but someone in the family has noticed that mom or dad or grandma grandpa is starting to become more forgetful and not just forgetful, but forgetful to the point where it may be affecting their day-to-day functions. So I'll give you an example of it. So a patient that I saw recently was a woman in her eighties came with her husband and also with a daughter. It's very common, actually came with a couple daughters. The reason that they came was was that they were concerned because they were getting calls from different stores about their mom leaving her purse in the store. Now, if that had only happened one time, people could say, well, it's possible she forgot her purse. But this was happening almost weekly at different places. And they were calling and saying, Hey, your mom left her purse here and her wallet's in it, and so on and so forth. So that was the earliest kind of manifestation. So there can be problems with short-term memory and recall problems with orientation, problems with higher brain functions like managing a checkbook or being able to drive responsibly. It's a spectrum of cognitive or brain related changes that makes us concerned that something like Alzheimer's disease might be going on.

Tania [08:48] So at what point is the patient aware that he or she's losing his memory or developing something different? And I ask this because my grandfather was diagnosed with Alzheimer's, again, not officially diagnosed, but clinically, and I remember there was a point where he was embarrassed that he wasn't remembering certain things and was not talking about it. And then he got to a point where he just didn't even know that he didn't know anymore.

Dr. Grossberg [09:16] Yeah, that's a good point. So it really varies from person to person. Most of the patients that I see are brought by the family. They’re not self-referred. So they may not be as aware of the changes that have occurred and the impact of those changes. But the family is very, very much aware. So I had a patient, a very sweet lady in her late eighties was sitting in my office, her husband's next to her and we're doing an initial evaluation, and I'm asking her, by the way, how's your memory been? And she said, oh, my memory's great. In fact, it's probably better than most of my friends who are my age. And the husband who's sitting next to her is shaking his head, no, this is not true. But she wasn't aware. So often the patient doesn't have the insight and the awareness, but sometimes they do. And when they do, it can be very frustrating. It can be particularly difficult because they may not understand exactly what's going on, but they realize that on some level that they're just not able to function as well as they did before. And that can be very disturbing, can be frightening. It's something that's not a positive kind of feeling state.

Tania [10:31] If you can go a little bit more into the different stages explaining how they manifest.

Dr. Grossberg [10:39] Yeah, we could talk about the stages. So most people talk about three stages in Alzheimer's disease. I've actually added a fourth stage. So generally speaking, in the early stages, patients are very functional. So their basic activities of daily living are preserved. Things like being able to eat on their own, dressing, bathing, grooming, hygiene, their continent, for example, early stages. Those things are all preserved as you move into language is generally well preserved. As you move into the middle stages, each of those basic areas starts to begin to suffer. So for example, the person may begin to wear the same clothes over and over again if they were able to drive in the very early stages, now they're getting lost and they're maybe not able to safely drive anymore. Individuals may begin in the middle stages to have a little more difficulty with continence, particularly urinary kind of issues, which can be a problem when they move into the more advanced stages. One of the hallmarks of that is that they no longer have control of bladder and maybe even bowel functions and language deteriorates. So in the middle stages, families might report that the individual may be searching for words or has difficulty with fluidity of speech. In the more advanced stages, that becomes really a big problem. They may only say a few words here and there. They tend to be much more quiet, much more subdued, lack of spontaneity. So we see different hallmarks. There's a fourth stage, which is what I've called the terminal stage, unfortunately, of Alzheimer's disease. At which point patients often become hospice eligible. They may in fact no longer be able to ambulate. Their balance is not good. They're at risk for falls. They're often in wheelchairs, sometimes even curled in bed, in a fetal position in bed in the nursing home. They may not recognize their loved ones. They're not able to produce any recognizable kind of speech. That's the terminal stage. The broadest stage is that broad middle stage. And our goal with treatments and with lifestyle and so on, even in people that have Alzheimer's disease, is to keep them in that early to middle stage for as long as possible. So what I tell my patients and my families is that we don't yet have a cure for this disease, but our goal is to keep mom as functional as possible for as long as possible.

Tania [13:18] When it comes to diagnosing Alzheimer's, at one point, I remember a while ago, they said, well, basically you diagnose it on autopsy if it's true of Alzheimer's. Now I know there's a lot of different diagnostic methodologies that we are using. How are we now diagnosing Alzheimer's and what is the best method?

Dr. Grossberg [13:42] Going back a few years, like you pointed out, that's what we used to say was that the only way to be definitive as far as diagnosing Alzheimer's disease is that brain autopsy. And as families would ask us, do you think this is Alzheimer's disease? We'd say, well, the clinical symptoms, they all point to Alzheimer's disease, but we're not sure. The only way that we can be a hundred percent sure is to look at a piece of mom's brain at autopsy, and hopefully

Tania [14:08] That's what they said to me about my grandfather.

Dr. Grossberg [14:09] Hopefully that won't happen for many years to come. We want her to live a long life, whatever. So that's what we used to say. But that was before the era of what we call biomarkers. So in talking about biomarkers, we're looking at a whole range of different things. Probably the earliest biomarker that we had was spinal fluid biomarkers and looking for evidence of the brain disease and the spinal fluid. Now, people in the US are not very eager to have a spinal tap. They don't stand in line to get one. It's not like a blood test. But nonetheless, those that did get spinal taps, we could see evidence of the brain disease in the spinal fluid. So that was probably the earliest biomarker.

Tania [14:52] Are you looking for what

Dr. Grossberg [14:54] Amyloid is actually decreased in the spinal fluid, the A beta 42, Then you have increase in the Tau, which is part of the neurofibrillary tangles. But looking at that ratio could be very useful in telling us in the spinal fluid, what's going on up in the brain. Right after that, or almost at the same time, neuroimaging biomarkers started to be developed, particularly PET scanning and looking at amyloid PET. There's also tau pet, but amyloid PET where we could visualize the plaque in the brain and we can quantify the amount of plaque in the brain, much more benign, less invasive than a spinal tap, but very, very expensive, very costly, and often not reimbursed by insurance. And many facilities all over the country don't have PET scanners, much less the ability to do amyloid pet rural areas, for example, and so on. But that's another viable biomarker. What people call the holy grail of biomarkers is a blood-based biomarker. Because, again, having a simple test, a blood test that's going to have a high level of sensitivity and specificity for Alzheimer's disease is where we are now. We are really in that era, in that time where we have blood tests specific and sensitive blood tests that rival spinal taps and the amyloid PET scan.

Tania [16:22] And I'm assuming that's the p-Tau.

Dr. Grossberg [16:25] p-Tau217 is the one that looks most promising and it's relatively affordable, at least compared to a six to $8,000 PET scan and a little bit more tolerable than a spinal tap, just a simple blood test. Hopefully that could be maybe the first round of testing after the clinical scenario indicates that this might be Alzheimer's disease.

Tania [16:48] When I looked at the data, I think it's about 90% accurate.

Dr. Grossberg [16:52] That's correct. Maybe a little over 90%. That's exactly right. Exactly. Which is very similar to the other tests that we have. Yeah.

Tania [16:58] So in the future, do you see just looking at plasma or do you see doing both plasma and pet, where do you see the field going?

Dr. Grossberg [17:05] Well, because of the expense of the PET scanning, I can see that the blood-based biomarkers may replace the more expensive and not as comfortable to administer testing like spinal fluid testing. So that's the direction that we're moving. The really big question related to what you're asking is will these blood-based biomarkers replace clinical symptomatology Or the clinical diagnosis? And there's a big argument in the field about whether we should go strictly with the biomarkers or it should be a combination approach. I like the combination approach. I think it's very important to diagnose patients based on clinical symptoms and to get a good, detailed history, develop a relationship with the patient and with the family and say, well, we're not sure what the exact diagnosis is, but we need to do some tests. First of all, we need to do some blood work to rule out contributors to memory and cognitive change. Could it be a thyroid problem? Could there be some bad medications on board? We need to review your medicines to make sure there isn't something that can impair memory or cognition. So I think the clinical aspect and differential diagnostic aspect, could the person be depressed and have a so-called dementia syndrome of depression that I think is really, really important. But there's no doubt that blood-based biomarker that's going to become part of the diagnostic process, especially in the areas where you don't have access to the more sophisticated technology. But in general.

Tania [18:44] So then who should be tested? And I ask this because, so we have patients that show clinical symptoms of Alzheimer's, but then what about those that have a family history of Alzheimer's and yet not show any kind of clinical symptoms?

Dr. Grossberg [18:58] So that's also a very good question. So we're not sure. So the current thinking is that we want to test people who maybe have clinical symptoms that are suggestive of Alzheimer's disease, and let's say for example, that we do a PET scan, an amyloid PET scan, or we do a blood-based biomarker that's looking also at amyloid and other changes that accompany Alzheimer's disease. If you have a negative amyloid PET scan or you have a negative blood-based biomarker, that's where it's the most useful because it tells you that whatever's going on here, this disease process at this point in time, it's not Alzheimer's disease. If you have a positive biomarker, let's say a blood-based biomarker, it doesn't tell you definitively that that person has clinical Alzheimer's disease. It's not a hundred percent, and it doesn't tell you what stage things are in. Maybe we're in the preclinical stage, but we don't have evidence yet that looking at risk individuals who are totally asymptomatic. But it's a good idea to use any of the biomarkers, whether imaging or spinal fluid or blood-based biomarkers that they're not predictive of who's going to have Alzheimer's disease. But that's a direction that we're moving in.

Tania [20:22] Going back to the biomarkers, from what I understood, I think an article that came out about a month ago or two where it showed the p-Tau217

They noticed that while it's 90% accurate for the general population, for some reason, I don't know if it was, I think it was in African Americans, it was about 70% accurate.

Dr. Grossberg [20:42] So you're bringing up another very important point. So most of the norms and the findings that we have are not in the ethnic minority population, so we have to be very, very cautious in how we interpret the data. It may not be as sensitive. You mentioned African-American populations or other kind of ethnic minority populations, whether it's Hispanic populations, Asian populations, and so on. So that data is still emerging. We don't have enough numbers of the minority patients to be as confident as far as the sensitivity and specificity.

Tania [21:18] And I'm curious to know why would there be a discrepancy? Is it just levels of p-Tau in the blood?

Dr. Grossberg [21:28] Yeah, there could be many mean, we'd have to speculate. I mean, I don't know for certain what the reason would be, but again, how people manufacture the plaque or the amyloid plaque and the developmental stages of the plaque may differ in different racial and ethnic groups, the rapidity of synthesis, how it's deposited, to what extent it might be visible on a scan, but that's a tough question to answer. And there can be, of course, genetic loading and genetic vulnerability, which is different in different populations as well.

Tania [22:04] And I'm also curious, there are maybe different ethnic populations. Are they over-diagnose them with Alzheimer's?

Dr. Grossberg [22:11] So we know that one of the major risk factors for Alzheimer's disease are things that are bad for the heart, cardiovascular disorders. So in any racial or ethnic group where there may be a higher prevalence, particularly of poorly controlled or not as optimally controlled diabetes or hypertension or heart disease, you're going to see more Alzheimer's disease. And that's true for African-Americans in particular.

Tania [22:38] So then some recent, I don't even want to call it recent, maybe over the last five years I read that particularly Latinos and African-Americans are diagnosed about two to three years later than their white counterparts as well.

Dr. Grossberg [22:50] Yeah. So that's another issue. And there are racial disparities. There's no doubt. Part of the reason might be, and I can use kind of our clinic as an example. So we are located in the city of St. Louis, the middle of the city. The city of St. Louis is about 50% African-American. If you look at our memory clinics, our geriatric psychiatry clinics, our neurology clinics and so on, you would think that a 50% or pretty close to that of our patients would be African-American patients. But the reality is it's more like 10%. So often racial minority patients feel more uncomfortable going to the ivory tower, The big medical center than the usual kind of white patients. They feel more comfortable in their own neighborhood, maybe going to the neighborhood doctor or physician who may not be a specialist. They're a generalist and their suspicion level and their index of suspicion for things like Alzheimer's disease may not be as high as if they come to a specialty clinic. So one of the things that we've been trying to do, and this is especially the case for clinical trials where we're developing new treatments, is to reach out to, in our case, to the African-American community, to go to them rather than expecting them to come to us to set up a memory clinic in North St. Louis, which is one of the centers for the African-American population in collaboration with the primary care doctors, that they have a comfort level going to rather than expecting them to come to us because just not happening. And this is not just St. Louis, this is all over the country. That's everywhere. It's a big issue. And at least until recently, one of the things that the NIH and the FDA have always emphasized is that we need to recruit more racial and ethnic minority patients into our clinical trials to develop new treatments because they may not respond as well, or they may be more sensitive to side effects to new treatments than the usual population that's included in clinical trials. So it's a big challenge and also an opportunity. It's an opportunity for us to do outreach.

Tania [25:15] There are a few medications that you see a difference in terms of efficacy, in terms of, to your point, side effects and

Dr. Grossberg [25:23] Dosing and

Tania [25:24] Dosing. And I think the diversity action plan that FDA initially required, I think that was huge

Dr. Grossberg [25:31 ] And related to what you mentioned before. So the data relative to biomarkers is no different. So the data relative to biomarkers needs more racial and ethnic minority recruits and participants so that we can actually say that this is a blood-based biomarker that's going to be sensitive and specific, not just in white populations, but also in racial and ethnic minority populations.

Tania [25:58] That's exactly what I was thinking. At least that will widen the net of them being able to pick up patients that potentially have Alzheimer's more than they are doing now.

Dr. Grossberg [26:08] So we do know that we mentioned African-Americans that they do have a higher rate of Alzheimer's disease, and it may be because of undiagnosed and untreated risk factors, particularly the cardiovascular risk factors. But in all patients, there are just a whole range of different risk factors for Alzheimer's disease that are a modifiable. So we need to do a much better job educating middle-aged individuals that are moving into their later years to basically try to avoid or to manage and treat these risk factors so that we can decrease the rate of Alzheimer's disease later on, or delay the onset of Alzheimer's disease. I mean, all kinds of things. Everything from smoking to obesity to high lipids, cholesterol. I mean, there are many different modifiable risk factors, and the earlier we get them under control, the better one's going to be as far as their risk of Alzheimer's disease. Later. I was a teenager. I was in high school, and one afternoon I came home. My mother was in the apartment and on the couch of our apartment was this little old lady with gray hair. It was stranger. She thought, come on over. Let me introduce you. This is Mrs. Krazner, and she's going to be living with us. I said, oh, that's interesting. A couple weeks later, this little old lady had multiplied. There were two ladies with gray hair sitting on the couch. Make a long story short, my mom figured out that with her nursing background, she could do a lot better taking care of older people than working on an assembly line for $25 a week. And I grew up with all of these surrogate grandparents. One day, the chair of our department came to the resident group and said, we have a really exciting opportunity. We can go and provide consults in a nursing home. Well, I'll tell you, every resident in that room except for me, moved to the back of the room. They didn't have anything to do with these old people in nursing homes. Whereas I stayed in front and I said, Hey, that's great. I'll go. I had this comfort level and I just felt good about it. That's something that was threatening to me.

Tania [00:01] Welcome to Doctors Unscripted. I'm Dr. Tania Small, and I'm here to bring you into a different kind of conversation with some of the brightest minds in medicine and research. In part two, I sit down with world renowned geriatric psychiatrist, Dr. George Grossberg. We delve into the exciting world of emerging targets, the hidden crisis of Alzheimer's psychosis, and the science that's shifting this disease from something we manage to something we delay and eventually prevent. So join us as we shatter outdated paradigms because the future of Alzheimer's care is being rewritten. Now, let's get started. Can you take me through when someone is diagnosed with Alzheimer's, what are the different spectrum of mood disorders that can be associated with it?

Dr. Grossberg [00:58] Yeah, so there's a spectrum of mood disorders and a spectrum of behavioral disorders. Everything from major or clinically significant depression early on and later on as well, as well as more of a situational or reactive depression, which may actually respond very well to interactive psychotherapy, but also very common throughout the disease. I had a patient recently who heard and saw and very much believed that there was a family with small children living in her basement, and she tried to convince her adult children that this family's here, they're living in my basement and they're not supposed to be there. And of course, every time they would go down to the basement, they didn't see the family, and then she would say, well, they must have snuck out because they knew you guys were coming, and so on. So psychotic symptoms are also not rare. So there's a spectrum of what we call neuropsychiatric symptoms that can accompany Alzheimer's disease from the earliest stages to the middle or moderate stage, and then also in the more advanced or severe dementia stage.

Tania [02:01] Is there an early sign that these patients may develop these types of psychosis or any kind of mood disorder?

Dr. Grossberg [02:09] That’s a really good question. So I'm not sure that we can predict that, But what we do know is that people who early on develop these neuropsychiatric symptoms, whether it's agitation or psychosis or depression, the spectrum of behavioral symptomatology, they don't tend to do as well as people who don't have them. They tend to progress more rapidly. They may end up institutionalized more earlier or more frequently than those that don't have them, but we don't really have a good way to predict who's going to have them. Now, of course, if someone has, you mentioned depression before, if they have a history of recurrent depression and now they're diagnosed with Alzheimer's disease, they're going to be at greater risk of developing depression down the road. But as far as the other neuropsychiatric symptoms, they're very hard to predict.

Tania [03:01] How do we recognize psychosis in Alzheimer's and how is it different than other different mood disorders?

Dr. Grossberg [03:08] Yeah, those are important issues. So when we treat patients with Alzheimer's disease, we're not just looking at the cognitive aspects, although the newer medications for Alzheimer's disease have been developed with that kind of focus, including the disease modifying kind of therapies that are now becoming available, we're also thinking about the associated, what I call neuropsychiatric symptoms of Alzheimer's disease. And there are several, the most common actually, but not necessarily the most disabling, is apathy or a lack of motivation being kind of a serious couch potato, serious couch potatoes. They don't cause a lot of trouble. So often it's not paid attention to, people are apathetic about apathy, but the ones that you can't be apathetic about, the ones that are really, really impactful are agitation, even overtly aggressive behaviors and psychosis. So psychosis in Alzheimer's disease is very common. To your question, maybe 50% of patients have psychotic symptoms sometime during the course of the disease. Most often it's going to be delusions kind of firm, false beliefs that a patient has that don't jive with our sense of reality. They could be, for example, accusatory or paranoid a patient recently in the long-term care environment who started believing that the nurses were out to get her and that her food and medicine was actually poisoned. So if she refused to eat, she refused to take her medication. I had another patient recently that had visual hallucinations that were very frightening. There were these frightening creatures coming through the window and people would see her shaking and she would try to describe what she was seeing, but it was very hard to kind of follow her in the more advanced stages of dementia. Patients can't tell you what's going on, but they can't have psychotic symptoms. They can have visual hallucinations, and an evidence of that might be that they're picking at things that nobody else sees. I had a patient recently also in the assisted living memory care environment with Alzheimer's disease where the nurse's assistant was walking into her room to clean the room or clean her sheets, whatever, and the patient was facing the corner of the room and carrying on an animated conversation with someone that wasn't there. So you can assume that she may be hearing voices and maybe having auditory hallucinations, maybe even visual as well as a manifestation of psychosis. So psychosis, agitation, they can often come together, can be very, very disabling as can depression. So depression is very common throughout Alzheimer's disease, and if we don't recognize it and don't treat it, it can accelerate disease progression. We know that all of these neuropsychiatric symptoms when they occur in Alzheimer's disease, especially early on, are a bad sign because even if we treat them appropriately, there can be more rapid disease progression. And of course, if we don't treat them appropriately and they remain uncontrolled, the family can no longer take care of that kind of individual, and they often end up having to place them in a nursing home or in a long-term care environment. So these are ancillary symptoms beyond the cognitive disturbances that we see in Alzheimer's disease that are just as impactful, if not more so for patients and family than the cognitive disarray that they see with the disease. But in all patients, there are just a whole range of different risk factors for Alzheimer's disease that are modifiable. So we need to do a much better job educating middle, middle-aged individuals that are moving into their later years to basically try to avoid or to manage and treat these risk factors so that we can decrease the rate of Alzheimer's disease later on or delay the onset of Alzheimer's disease, everything from smoking to obesity to high lipids, cholesterol. I mean, there are many different modifiable risk factors, and the earlier we get them under control, the better one's going to be as far as their risk of Alzheimer's disease later.

Tania [07:45] So our audience that listens, they're mostly HCPs, and so I would love you to take us through what should we be doing to manage these symptoms or different diseases to delay?

Dr. Grossberg [07:59] So that's a very important topic. I talk about lifestyle modification.

Tania [08:03] Yes,

Dr. Grossberg [08:04] And I always start with the cardiovascular because there's this saying that what's good for the heart is good for the brain. So anything that's going to be decreasing, the risk of heart disease, heart attacks and so on. Things like high blood pressure, hypertension, diabetes, hyperlipidemia, obesity, lack of exercise and so on, and the better those are controlled, the better it's going to be not just for your heart, your cardiovascular system, but also for your brain. Then we talk about habits, things like smoking, things like alcohol, especially in excess, which may be problematic. That leads us to dietary alterations and changes. We now recommend very, very highly what's called the MIND diet, which is a combination of the Mediterranean diet with low sodium or low salt, which is the dash diet for hypertension.

Tania [08:59] Even though the Mediterranean does come with wine

Dr. Grossberg [09:02] Mediterranean very limited amounts of wine. That's true. We are learning now that alcohol is a kind of a two-edged sword, that there may be some benefits of very modest drinking, but there may be other liabilities even of modest drinking. So alcohol is very controversial right now, but what we do know is in my older patients who are having cognitive issues, the best amount of alcohol to take is zero. Once you start to have memory problems, we talk about activity, the importance of activity, and I talk about activity in four spheres, all important talk about physical activity, 150 minutes a week or more of walking or some kind of exercise, more is better. Mental activity, challenge your brain, keep your brain active. Social activity, don't be a hermit or a couch potato spiritual activity, whether it's religious activity or things like meditation, mindfulness, yoga, all four are very, very important, and we want to make sure that you're doing those on a regular or day-to-day basis. There can be other things that we want to keep people active in, so people considering retirement, sometimes we'll ask 'em if they have hobbies or other activities to get into. If they don't, maybe you should reconsider retirement. Obviously, depression, if it's recognized, needs to be kind of treated promptly. There are many different risk factors. Hearing vision, if you have hearing loss, get hearing aids, if you have visual issues, get that fixed. All of those are risk factors for Alzheimer's disease if they're not recognized and not addressed. So there are many different risk factors that are modifiable and the more of those that we kind of work on and employ the microbiome. So we do recommend either fermented foods like cultured yogurts and things like that, or a probiotic to introduce good bacteria into the system. That's part of lifestyle modification. If it's not part of your lifestyle, you need to make it part of that together with the mind diet. But the bottom line is the more of these things that we do, the better the likelihood of either delaying or decreasing the risk, even if you have genetic loading, that's very recent data showing that you can even overcome the genetic loading by doing more and more of these lifestyle modification approaches utilizing more of these approaches.

Tania [11:38] So what do we say to the non-believers? Because we've, there's a lot of discussions talking about the brain, gut connection, health and access, and there's still a lot of non-believers and a lot of physicians still don't believe in it. Can you share a little bit more of the data and how do we convince them? 

Dr. Grossberg [11:54] It's interesting because I'm actually working with one of our super bright fourth year medical students. We're putting together a presentation on the relationship between dysbiosis, bad bacteria in the gut and how they may actually get into the bloodstream and cross the blood brain barrier and maybe contribute to cell death or inflammation of neurons, which is part of Alzheimer's disease and other brain diseases. But there's really quite a bit of evidence that what happens that bacteria in the gut may actually have systemic effects or benefits or may have deleterious effects on brain functioning. One of the areas that to me also has been always very fascinating is the relationship between gum disease. As people get older, they often have inflammatory changes of their gums. They may lose teeth because of that. So gum disease is caused by a specific bacteria that actually has been found at autopsy in close proximity to the plaques and tangles in all Alzheimer's disease, and we think may contribute to inflammation and cell death. And there is, in fact, one of the risk factors for Alzheimer's disease is periodontal disease, especially if it's not properly and effectively treated. So that's one evidence or one area of evidence. We also know that there are diseases that are caused by certain bacteria that affect the gastrointestinal system, where if you can introduce healthy bacteria into the GI tract, it pretty much wipes out the pathology. H pylori is the example of that. So there are many little pieces of evidence that kind of show us or are beginning to show us that what happens relative to bacteria in the GI tract may have systemic effects and specific effects on the central nervous system. And we think introducing good bacteria addressing this dysbiosis is what's called maybe beneficial, and it's so easy to do.

Tania [14:11] Let's talk about microbiomes

Dr. Grossberg [14:13] The microbiome. Another hot topic.

Tania [14:15] Yes.

Dr. Grossberg [14:16] So we do recommend either taking a probiotic capsule or eating fermented foods like the cultured Greek yogurts. Things like kimchi and sauerkraut and kombucha and things of that nature can introduce good bacteria into the system and may have benefits. Yeah,

Tania [14:36] There's data, and this is separate in oncology that shows your point that bacteria can increase resistance to certain medications, and so there's a lot of studies happening out there.

Dr. Grossberg [14:47] Yeah, no, that's a really exciting area and kind of an emerging area. A lot of people don't know much about it. Some of the earliest data actually was in some posters at the international Alzheimer's meetings where some scientists from Asia actually examined bacteria in stool and patients who had Alzheimer's disease versus non Alzheimer's age match sex, match whatever controls and found a lot more of the bad bacteria with Alzheimer's patients versus the good bacteria in those that didn't have it. So that began this inquiry into the importance of the gut bacteria, a microbiota,

Tania [15:38] So biologically what is happening when it comes to different types of psychosis.

Dr. Grossberg [15:42] So we think that there are similar phenomena to what we see with psychosis and other neuropsychiatric diseases, maybe related to dopamine, maybe related to the nicotinic system and nicotinic receptors as well that trigger the symptoms of psychosis. And we do know that the current generation of anti-psychotic medications can be helpful for psychosis in Alzheimer's disease. The problem is, and they all work very similarly in that they basically block excessive amounts of dopamine And older patients, whether with or without Alzheimer's disease, are much more sensitive to the common side effects. They develop the Parkinsonian side effects more readily. We worry about the metabolic side effects, effects on blood sugar and so on. Lipids, high lipids, they already have problems with that. Some of them are too sedating, some of them drop blood pressure, which can increase the risk of falls, which is huge in this patient population. But in many other areas of medicine, we're starting to learn that what we learned at medical school isn't what we now know at the present time. So what I learned in medical school was that psychosis was basically too much dopamine be manufactured and you block the dopamine with one of the older or newer kind of antipsychotics, and you're going to help with the positive symptoms of psychosis in any disease that has those kind of manifestations. It's only been more recently that we realize that there may be other very important players that precede the excessive amounts of dopamine being secreted, and that would relate to the nicotinic receptors, particularly the M1 M four receptors. You're preceding the excessive synthesis, and these drugs work in the regions of the brain that are most affected not just by psychotic symptoms, but also cognitive symptoms. The M1 receptors can be more involved in the cognitive arena and the M four decreasing the excitatory changes that are triggered by glutamate in the glutamatergic system, and we're looking at parts of the brain like the hippocampus, for example, which are the seed of memory and cognition. So that's a new understanding and I think potentially a big breakthrough.

Tania [18:18] We spoke about the psychosis piece. I can only imagine the toll that it also takes on a family. I mentioned that my grandfather was diagnosed with Alzheimer's, and I spoke to you about certain behaviors he had, such as thinking someone stole his money and which

Dr. Grossberg [18:44] Is very common,

Tania [18:46] And you look at patients who were sometimes head of households and head of families now with Alzheimer's disease plus the added psychosis to it, how do you counsel families, because you spoke about earlier also it's the community, it's the family. How do you manage, help them manage

Dr. Grossberg [19:09] Through? Those are great questions, and I think it's particularly important because a lot of families are even embarrassed and reluctant to talk about these neuropsychiatric symptoms, whether it's accusatory behaviors or agitation. They don't understand that these are common important parts of the disease. So unless we as healthcare providers ask about, so one of the things I've been advocating is that if you're a primary healthcare provider that's taking care of an older patient, working with them in the family that maybe has a dementia like Alzheimer's disease at every visit, at every visit, you should ask them and ask the family, has there been any behavior change? Has there been any personality change? Is there something going on other than just the memory and cognitive arenas that we need to be aware of? Recognizing that it's these behavior or neuropsychiatric symptom type changes, whether it's agitation, psychosis, depression and so on, that really are most stressful to families. They're the number one reason within Alzheimer's disease where families finally just give up, throw in the towel and say, I just can't take care of mom or dad anymore. And they think about institutionalization right now in the US the number one reason for ending up in an institutional setting like a nursing home is false. Number one is false. So when the family can no longer guarantee safety of their loved one, they start thinking about long-term care. But number two, running neck and neck, right behind that are the neuropsychiatric symptoms like psychosis, agitation against a background of a dementia like Alzheimer's disease. Those are the most distressing, much more so than forgetfulness or some of the cognitive changes. So it's very important to recognize them, to diagnose them and to obviously offer treatment and to educate the family that whenever you go see your doctor or your healthcare provider, make sure you tell them about these kinds of changes. Very common and they're very impactful.

Tania [21:17] So there's something along that line that we call patient driven science. We talk about it all the time on this show, and it's really making sure that we're developing the medicines for patients. So it's not a product-centered drug development process. It's a patient-centered and really following the needs of those patients. With that in mind, because there's a lot of new studies coming forward when it comes to Alzheimer's, yet it's so many have failed, what do you recommend when we're thinking about designing the right medicines, the right studies for patients? And I'm going to start with clinical endpoints. What is most relevant to families, to patients when we're designing these studies?

Dr. Grossberg [21:59] So we always have to think about patient and family as being one entity, and then of course, they together with us are part of the therapeutic alliance. There's no doubt about that. But we also want to keep in mind that we want to focus on clinically relevant and impactful symptoms. I like the word impact, and we're not just talking about impact on the patient, but also impact on the care partner.

Tania [22:31] What, in your opinion, are truly impactful clinical endpoints that we should be looking at? Yeah.

Dr. Grossberg [22:36] Well, behaviors are clinically impactful. There's no doubt that our focus has been primarily on two areas. Cognition and activities of daily living and of the two activities of daily living to me are much more impactful than just memory or cognitive functions. So knowing about how independent or dependent a patient might be, those need to be increasing areas of focus. And we talk about activities of daily living, two different groups, basic and more instrumental activities of daily living, the basic activities of daily living, and we ask about those is how independent is the person in things like dressing and bathing and grooming and feeding themselves and hygiene and so on. Those are not lost until the more advanced stages of Alzheimer's disease. But there's also what are called the instrumental activities of daily living. Those would be things like being able to go to a grocery store and pick up some items that you need, being able to drive, maybe being able to balance a checkbook or being able to participate in healthcare decisions or financial decisions to even decide what you want to order at a restaurant on a menu rather than depending on someone else to kind of order for you. Those are important and points that often are not paid as much attention to because we're focused on memory and cognitive arenas. And then the other area is what we've been talking about. Another important endpoint is what impact can we have on behaviors that are going to be very distressing to the family, to the care partners, whether it's psychosis, whether it's agitation, whether it's depression, anxiety, irritability, and so on. So those can be built into clinical trials as well and move higher up the totem pole than just looking at what evidence we have that this new treatment might stabilize memory or maybe slow down some of the cognitive changes. Those have been generally considered secondary endpoints, but it would be nice to move them further up the totem pole.

Tania [24:46] So let's talk about what's new, what's next in this world of Alzheimer's disease as well as Alzheimer's and psychosis?

Dr. Grossberg [24:53] Yeah, it's very, very exciting, I think, and you talk about it in two arenas. We're talking about the disease itself and then the neuropsychiatric symptoms, and we focused on a couple of the neuropsychiatric symptoms, psychosis, which is very common and very impactful, impacting quality of life of both the patient as well as the family, the care partners. But let's talk about the disease itself. So up until two years ago, we've been treating Alzheimer's disease once it's diagnosed, and we mentioned we're making a lot of headway and biomarkers and more accurately diagnosing Alzheimer's disease, but we've had what are called the symptomatic therapies. Those have been beneficial and may still be useful, but we haven't been able to really make an impact on disease progression up until almost two years ago when the first of the NOW two disease modifying therapies became FDA approved, and a lot of us are combining the symptomatic approach with the disease modifying therapies in a similar way that you and I were talking about the field of oncology. Oncology, yes, often combines drugs of different mechanisms to better control various neoplastic kind of disorders. So we're using that as a model in Alzheimer's disease. The other exciting, I think, futuristic model for Alzheimer's disease, and these are being tested now, is to see if the disease modifying therapies, which we are giving to people very, very early in Alzheimer's disease, what if we give them to at risk individuals? Can they over time decrease the risk of developing Alzheimer's disease or maybe delay it together with the very, very important disease, very, very important lifestyle modification approaches to Alzheimer's disease. And as you and I were talking, I personally believe that lifestyle modification is as robust a treatment as any medications. And when you combine lifestyle modification with some of the new and up and coming promising medications, that may have a major impact on the prevalence of the disease as far as onset and maybe even potentially delaying it in individuals who are genetically vulnerable. Similarly, in looking at the neuropsychiatric symptoms now, we talked a lot about how our old thinking about psychosis is now very different. We now have for the first time an FDA approved treatment for agitation specifically in Alzheimer's disease, but we didn't have before. So I think the future looks very bright both as far as potentially prevention and or delay. We're already at a much better diagnostic kind of sensitivity arena than we were before. And the future looks very bright as far as being able to treat the neuropsychiatric symptoms in a tolerable fashion, specifically psychosis and conditions like agitation,

Tania [28:01] Especially, I mean, you talk about the combination piece and obviously in oncology that is what we do. We do double. It's triplets sometimes quads,

Dr. Grossberg [28:08] Exactly. We're also worried about drug drug interactions, and we want a medication that's relatively clean in that regard, recognizing that our older patients, they're often on several different medicines that are needed to control their blood pressure or control their diabetes. Now, you had brought up earlier this other exciting future area of the GLP one agonists. They seem to have anti-inflammatory effects in the central nervous system.

Tania [28:35] So you talked a little bit about prevention. I want to kind of poke at that because I mean, imagine if we could get to the point where we can prevent, not just slow down, but prevent someone from converting to true Alzheimer's disease. Do you think that's in the future?

Dr. Grossberg [28:50] I hope so. A number of years ago, someone asked me about how long I thought it was going to be before we had a cure. I don't know what that means, but a cure for Alzheimer's disease. And I went out on a limb and I said, well, maybe in the next couple of decades. That was, I think a couple decades ago, we haven't had a cure yet, but we're moving in the direction of prevention. If a combination of different things together may be able to either delay significantly, delay onset, or perhaps decrease the risk even in individuals who are genetically vulnerable. A recent study, which we haven't talked about was in genetically vulnerable individuals, those that had a first degree relative that was diagnosed, specifically diagnosed with Alzheimer's disease, and now we're looking at the progeny. So it's an adult son or daughter with a mom or dad diagnosed with Alzheimer's disease. Strict lifestyle modification approaches have been shown to be beneficial even in those individuals as well as those that already have the early stage of Alzheimer's disease to maybe significantly slow it down. So one of the areas that I like to emphasize is the power of lifestyle modification in addition to the new pharmacotherapies that are being developed, which are pretty amazing.

Tania [30:11] Yeah. So what advice do you have for healthcare providers in this field?

Dr. Grossberg [30:16] One of the pieces of advice that I have for treating healthcare providers, whether it's physicians or PAs or advanced practice nurses who are on the front lines, is the importance of always involving the family is the importance that anytime you see an older patient in your office and there's a concern on the part of a family member about that person having issues with memory or cognitive change, that that needs to be taken seriously and should be promptly, thoroughly evaluated. So we can remedy reversible factors and identify individuals that can benefit from the new treatment approaches to Alzheimer's disease.

Tania [30:59] Thanks for all the work you're doing and all the work you've done to move this field forward. Sometimes it's hard to see within our generation the big changes that have been made, but from the time you've started until now, you've seen the growth in the field and a lot of it has to do with you and the work you've done. So thank you much.

Dr. Grossberg [31:17] I won't take the credit, but thank you,

Tania [31:24] Dr. Grossberg. Now, let's go back in time. What would you tell your 1980’s self if you could?

Dr. Grossberg [31:31] I would pretty much tell myself to do what I've done, which is pursue what you really, really have a passion for doing. And for me, the passion wasn't just in taking care of patients and families, but in also educating the next generation, because that can be as meaningful as all the hopefully good help that we're providing to our patients and their families.

Tania [31:53] In other words, you wouldn't change a thing?

Dr. Grossberg [31:56] Well, no. I really like it the way it was, and I hope to influence young doctors in training to do what I do and have a passion for what they do, and particularly a passion for working with older adults and their families who are so needy and can really benefit from our health.

It is a forward-looking conversation that equips you with new cutting-edge insights for the future. 

About Dr. George Grossberg

George Grossberg, MD, is a trailblazer, educator, and a clinical psychiatrist who provides comprehensive psychiatric services for patients ages 65 and older.  Dr. Grossberg is the Henry & Amelia Nasrallah Professor in the Division of Geriatric Psychiatry in the Department of Psychiatry and Behavioral Neuroscience at Saint Louis University School of Medicine, Missouri. He's also the past president of the American Association for Geriatric Psychiatry and of the International Psychogeriatric Association.

Dr. Grossberg is a paid consultant for BMS.

00:00:01:13 - 00:01:32:14 [Tania] Welcome to Doctors Unscripted. I'm Dr. Tania Small, and I'm here to bring you into a different kind of conversation with some of the brightest minds in medicine and research. 

How do we respond when a person diagnosed with schizophrenia commits a crime during a psychotic break? Do we see a criminal or a human being worthy of treatment, dignity, and a second chance at life?

Our guest today, Dr. Ilan Melnick, is challenging every assumption we’ve held about severe mental illness, justice, and rehabilitation, with a 90% reintegration success rate and 0% recidivism. Today, we'll explore psychosis on trial, rehabilitation and evidence-based care, rights reclaimed, and compassion on locks. We'll step inside Passageways, the largest forensic reintegration facility in the US, a pioneering model built not on confinement but on trust, empathy, and comprehensive care.

And here's the remarkable part. There are no locks on the doors. That's right. No locks. Dr. Melnick will show us why these individuals don't just need care; they deserve to be seen, treated, and unlocked. Now let's get started.

Thank you so much for joining us here at Doctors Unscripted.

00:01:32:14 - 00:01:35:12 [Dr. Melnick] Thank you so much for inviting me. I really appreciate it.

00:01:35:14 - 00:01:51:07 [Tania] So I have a lot that I want to get from you. 

00:01:51:09 - 00:03:00:18 [Dr. Melnick] Talk to me. 

The first question is when you were in med school…actually, let me take a step back. When did you know you wanted to be a psychiatrist?

Great question. So, my path really didn't start with psychiatry. When I was in medical school, I loved working with my hands, I thought it was just really cool to be in a controlled environment, and really thought surgery. Actually went and started a residency in surgery and ophthalmology at Harvard, at Mass Eye & Ear.

And, after about 2 months, realized that it was something I really hated doing. At the end, I was stuck doing refraction a lot and not something I really enjoyed. One of my mom's friends was head of Jackson Memorial Hospital Crisis, and he invited me to come and see what he did. And day one, I walk in and we’re, like, tackling people to give Haldol and Ativan to people.

And I thought this was so much cooler. Really loved it. Loved every moment of it. And realized quickly that this is - this was a better fit. Quit my residency in surgery and ended up starting at the University of Miami.

00:03:00:20 - 00:03:04:19 [Tania] Usually in med school, we can typically predict what people are going to be.

00:03:04:19 - 00:03:05:21 [Dr. Melnick] Yes.

00:03:05:23 - 00:03:08:11 [Tania] What did people assume you are going to be?

00:03:08:13 - 00:04:14:08 [Dr. Melnick] Gosh. A dropout, I think, was what they were…No, in med school, I was, you know, growing up with dyslexia was always very difficult for me to kind of imagine myself doing anything that had to do with reading a lot and managing those kind of patients. So I think surgery was where people really thought I was going to do well.

It is something that really that I learned early on when doing psychiatry that my ability to recognize patterns really was helpful in being able to become a better psychiatrist. Being able to recognize how people think and realizing that neurotransmitters do play a role in that, and being able to figure out what neurotransmitters were either too high or too low, and being able to manage it was something I thought was so cool.

And so, although, yes, surgery was something that I really thought I loved a lot, I realized that this is really my true calling.

00:04:14:10 - 00:04:21:14 [Tania] So talk about a little bit what kind of psychiatrist are you. I know you — I learned a little bit about forensic psychiatry. Can you tell us a little bit about that?

00:04:21:14 - 00:05:04:04 [Dr. Melnick] Yeah, sure. So, I'm one of these — I have a lot of different types of practices. So although I do work in forensics, and forensic psychiatry is not what you see on TV. A lot of it has to do with testifying. A lot of it has to do with recognition of patients that maybe are found either incompetent to proceed or are not guilty by reason of insanity.

But the other half of my practice is working with celebrities, models, and athletes in a concierge psychiatric practice. So I get the balance of working with the, you know, the very sick who don't think they're sick and the not so sick who think they're desperately ill and pretty much everywhere in between.

00:05:04:06 - 00:05:11:16 [Tania] What led you there in terms of forensic psychiatry? And then, what exactly does that mean, and how does that translate to the patients that you see?

00:05:11:16 - 00:05:53:19 [Dr. Melnick] So I came into forensic psychiatry kind of by accident. I was doing a lot of, a lot of testifying in court. I was, talking to different types of patients. And I realized that this was a very difficult-to-treat population, but gave me a lot of challenge. And I was asked to cover for a forensic psychiatrist at a program and I thought that was kind of cool. And, when I had the opportunity, they asked me if I would join in, and, as the chief medical officer. And at the time we only had, like, 25 patients. And then we managed to escalate it now. I've been there since 2008, and now we have about 130 patients there.

00:05:53:19 - 00:05:59:16 [Tania] So take me through the process. You're in court, so a patient is found.

00:05:59:18 - 00:06:03:02 [Dr. Melnick] Well, let's put it this way: A patient goes and they commit a crime.

00:06:03:06 - 00:06:04:12 [Tania] Okay. Start there.

00:06:04:14 - 00:06:11:14 [Dr. Melnick] So they commit a crime. At that point, either they're competent to proceed to trial or incompetent to proceed to trial.

00:06:11:20 - 00:06:12:02 [Tania] Okay.

00:06:12:06 - 00:06:36:20 [Dr. Melnick] If they're competent, then they go through the normal court system. If they're incompetent, they have to restore competency within a forensic psychiatric facility, where they give them classes to understand the criminal justice system. And some of those patients are restorable and where they're able to become competent, and some are considered nonrestorable, where they're not able to regain competency.

00:06:36:20 - 00:06:39:21 [Tania] And how do you determine if a patient is nonrestorable?

00:06:39:22 - 00:06:49:11 [Dr. Melnick] So it's usually about 5 years. So if a patient after 5 years is not able to become restorable, they kind of drop all their charges.

00:06:49:12 - 00:06:50:03 [Tania] Interesting.

00:06:50:04 - 00:06:51:01 [Dr. Melnick] Yeah.

00:06:51:03 - 00:07:04:02 [Tania] And you said at one point, which I found fascinating, you can tell whether someone is, I guess, faking versus truly, truly not guilty due to reasons of insanity. How can you tell?

00:07:04:04 - 00:07:48:08 [Dr. Melnick] Yeah, it all has to do with the patterns. Patients who are illogical are consistently illogical. So, usually when patients start changing from becoming illogical to logical within conversations, we normally think very linearly, where we think in a straight line. And what happens is that, as, you know, patients who have psychosis and they're having delusional thoughts, they may become circumstantial and sometimes even tangential. With a, you know, when you're dealing with patients and, and asking them questions, I usually will start asking things very quickly to try to get them off beat, to see whether or not the illogical becomes logical within their, their thought process.

00:07:48:09 - 00:07:49:20 [Tania] Give me an example.

00:07:49:22 - 00:08:47:11 [Dr. Melnick] I will say things like, you know, ask questions in rapid successions. You know, what's your name? Where are you from? You know, where did you go to high school? And then start going into more theoretical questions and start changing topics. And people who are illogical will continue in the illogical thought. People who are logical will start thinking, why is he asking me all these questions in different orders?

And, and oftentimes that shows me that the patient is, you know, not able, it is not really telling the full truth of things. We also look at body reactions, body tone. If they are very comfortable in the way that they're talking, even though they're talking about some illogical things, compared to people that, let's say, are trying to come up with ideas, what you'll see is that they'll start stuttering things won't make sense. You know, things they say at the beginning differ from things that they say at the end. The story isn't fully developed.

00:08:47:12 - 00:08:56:04 [Tania] Let's talk about the illogical. First, it starts illogical or not straight. And then what is your end game, is it to get them to… 

00:08:56:05 - 00:10:40:19 [Dr. Melnick] Basically the, the laws in the United States say that you cannot try somebody or someone who doesn't understand what they're being tried for, or whether the court system, that they understand the court system at all. Reasons why we can't, you know, people with severe mental retardation, you can't bring them to court for certain, you know, crimes that they commit.

Once they were able regain competency, then all of that changes; they are able to come out with, they're able to then understand what the court system is all about, you know, why they're there, what the seriousness of their charges are, what are the consequences of the, of the charges that they had. In that way, we’re able to restore competency.

So once you restore competency, then they go to trial. And either they're found guilty or they're found not guilty. Now, if they're guilty, then they go to jail, whatever it might be for whatever crime they committed. If they're considered not guilty, then you have either they're not guilty because they get let go or they're not guilty because at the time of their crime, they didn't understand what was right and wrong, they didn't understand what was happening within that, that moment because of their mental illness. So patients with schizophrenia who hear voices that say, the people on the bus are, you know, aliens, and it's my job as a citizen to kill all the aliens on the bus, and so that may happen. It didn't mean that they were killing them with the idea of, of just killing people for, you know, fun; it was really because of the delusional thought process that they were having. Once they get better in their delusional thought process, these people would probably not have killed those people on the bus.

00:10:40:21 - 00:11:07:01 [Tania] So then let me ask you this question because, how do you reconcile, I guess, the ethical dilemma between knowing that this patient did not know what they were doing and really couldn't control their actions, versus to the actual crime being committed? Like, like, do you ever walk into this ethical dilemma when it comes to that? Because you're seeing families who may have lost a loved one versus a patient?

00:11:07:03 - 00:12:13:06 [Dr. Melnick] So oftentimes in our forensic facility, it's usually directed at family members themselves. So it's, usually it's their parents, it could be their children, it could be, you know, spouses. The idea is, is that usually the ones that do it because of insanity, do it because not, there's no secondary gain or any, any secondary gain to, to do the crime.

I'll give you an example of an arson. We have a patient that was cold one winter, and he lit a, a little can on fire, just to kind of heat himself up. And it caught a dumpster on fire, which then caught a building on fire. And it wasn't, you know, he was a person with chronic paranoid schizophrenia, and he ended up having to go to prison because of that.

But, you know, when he was then found, you know, when he went out and was found not guilty by reason of insanity, he became a part of our program. And we've now been able to rehabilitate him to the point where, it's not like he was trying to hurt somebody, it was just accidental that this happened.

00:12:13:08 - 00:12:17:16 [Tania] And did he understand what he had done over time?

00:12:17:17 - 00:12:35:05 [Dr. Melnick] Yeah. So at the moment, he was just trying to get warm. It had no bearing on, you know, what was going on. And if it wasn't for his mental illness, not being able to cognitively come up with good ideas or, or really rationalize the consequences of what was going on, then he probably would have never done, lit the original can on fire.

00:12:37:11 - 00:12:57:10 [Tania] So these patients that you, I guess, come across, is it, do you come across them once they get into the court system, or do you have patients that haven't been to court and yet they're still part of your facility?

00:12:57:12 - 00:13:16:03 [Dr. Melnick] Yeah, so, to come to our facility, these people are usually found not guilty by reason of insanity. And they are then committed to a forensic psychiatric facility, usually about 3 to 4 years, while they stabilize. And after they stabilize them, then at that point they can apply to come into our program.

00:13:16:03 - 00:13:34:17 [Tania] At your facility, I saw those paintings, and again, just fascinating taking us through, I guess, the process of this patient's mind, you know, that you were able to see visually. Can you just tell us a little bit about the step process that it took to get her there?

00:13:34:23 - 00:14:10:01 [Dr. Melnick] Yeah. When she first came to us, she was very psychotic. And you start seeing the disorganization of thought. And she heard voices at the time. And then, you start seeing that when she's finally comes into our facility, she starts learning coping skills, life skills, she's able to kind of manage herself a little better. And once her brain starts getting more organized and the paranoia starts going away, the focus of the art changes to something much more organized, about people, about caring, versus the disorganization and the paranoia that you saw in the previous paintings.

00:14:10:03 - 00:14:24:17 [Tania] Now, how frequently can you get a patient going from that level of, of disorganization to, to actually have an empathy, to have an insight? Because from what I understood, that is the hardest piece to get to.

00:14:24:18 - 00:15:12:13 [Dr. Melnick] Yeah. So in our facility we're, we're close to 90%. I mean, part of what we do in our psychoeducational groups is to understand the seriousness of the crimes and how their actions impacted others and why, maybe they aren't, you know, they, they don't call every week to see how they're doing. Despite the fact that, in their minds, a lot of them didn't know that what they did was wrong. So what we're seeing here is we're seeing that change, and we're starting to incorporate empathy, and how they respond to others is a big component of their wellness. So as they move through the levels, that's one of the things that we look into is how they're able to, how they're able to empathize with the seriousness of the crime, despite the fact that they were considered not guilty due to it.

00:15:12:14 - 00:15:27:14 [Tania] You said a lot of the way this works was based on trust. You say, sometimes they, they leave your facility and become outpatients. How do they continue on their medication? How do they continue on the regimen when they're now outpatient, not being watched?

00:15:27:18 - 00:15:33:19 [Dr. Melnick] So the first level, when they're in the outreach, in their second phase of our program, they actually come in to take their medicines every day.

00:15:33:19 - 00:15:35:00 [Tania] Okay, okay.

00:15:35:00 - 00:16:01:03 [Dr. Melnick] And then as they kind of go and show that they're able to do things, we take away their morning, they can take their night doses at home, but they have to call in every single day to tell the staff that they took their medicines. And usually those patients are in there with somebody who's much more seasoned. And that person also monitors their pills. So there's a 360-degree view of what happens with the individual patients.

00:16:01:05 - 00:16:25:10 [Tania] So when, you know, again, maybe you can educate me and whoever's listening, from what I understood, a lot of the medications that are out there do not, do not really treat cognition; they treat, to your point earlier, they treat mostly positive symptoms. But yet, what you're telling me, these patients are becoming, the cognition starts to improve, insight starts to improve. Is that the medication? Is that the, the, like, what, like, like what do you think is allowing that to happen?

00:16:33:23 - 00:17:20:11 [Dr. Melnick] There's a certain part, you know, when the psychosis is gone, patients are able to think a lot clearer. But also the psychoeducational groups that we go through actually help improve cognition. Everything we do has a purpose. And so they'll, they'll do puzzles and they will do, as part of their psychoeducation they'll do word finding, they’ll, you know, and, depending on what level they're at, in terms of their functioning, we're able to kind of go and find ways to challenge them mentally. So we have them come up with ideas, we have them work in groups, we have them, you know, do things together to try to find if, you know, ways that they can think in a group. And that way we’re able to kind of get them a little bit more of a cognitive recharge.

00:17:20:14 - 00:17:21:06 [Tania] Yes.

00:17:21:08 - 00:17:24:03 [Dr. Melnick] More than it is just the medicine itself.

00:17:24:05 - 00:17:29:10 [Tania] You know, what I hear is also group thinking is also, it’s very interesting. So they do it in a group, not just individually.

00:17:29:10 - 00:17:33:05 [Dr. Melnick] Correct. Yeah. They do projects together.

00:17:33:07 - 00:17:42:05 [Tania] Now I'm very curious about a prison system. And how many patients do you believe are actually misdiagnosed that are in the prison system?

00:17:42:05 - 00:18:17:05 [Dr. Melnick] Vast majority. You know, it's, the Twin Towers in Los Angeles is the largest psychiatric facility in the United States. Here in Miami Dade County, same thing; it's one of the largest psychiatric facilities in the United States. The prisons have become the new forensic psychiatric facilities. And it's really sad because these patients, when they're in the prison system, don't get the services that they really need or the help that they need, as the money is usually funneled into taking care of the guards and the people that are staffing the prison versus the patients that really need the help.

00:18:17:07 - 00:18:22:14 [Tania] How do we get into the system and get these patients better diagnosed?

00:18:22:16 - 00:18:46:20 [Dr. Melnick] Yeah, it's unfortunate, but that happens quite a bit. I wish, better training, I guess would be the first. You know, the, the reality is, is there's not enough space. Psychiatric facilities have been closing down, not opening up. When they open up new ones, they're fractionally the size of what they were, the hospitals that they replaced. And unfortunately, the money just isn't coming in to the people who need it.

00:18:46:22 - 00:18:53:09 [Tania] What you do needs to be replicated, and we need to figure out how to support such type of program to really expand it.

00:18:53:15 - 00:18:54:14 [Dr. Melnick] Yeah.

00:18:54:15 - 00:19:08:23 [Tania] We talk about rehabilitation and that's exactly what you have done. So again, going back to the question asked about the end goal, what does success look like for you? And then I will have to then talk about how do, how do you get there.

00:19:09:03 - 00:19:47:08 [Dr. Melnick] Yeah. So success for me is really trying to do what I can to help as many patients as possible. You know, I've always, you know, I went into medicine to really be a patient advocate. Not only finding the right medicine for the patient and doing it in a successful way, but the other piece here is keeping them out of hospitals, keeping their brains healthy, keeping their physical, you know, well-being intact, and being able to teach them those life skills and coping skills so that they can go out in the community to be members of society rather than just the outcast that we've all trained them to be.

00:19:47:10 - 00:20:04:22 [Tania] You and I spoke about clinical trials, and a lot of it being done in academia. But then you have the hands-on experience, and each patient, I think, as we spoke about before, gets more of a personalized approach. How do you do that? Like how do you know what's the optimal treatment for each patient?

00:20:05:00 - 00:21:19:09 [Dr. Melnick] Yeah, I mean, I got to tell you, it's, it has a lot to do with understanding the pattern of behavior and what they're doing and how they think and how early they are into the disease state. The earlier into the disease state, the better outcomes we're going to look at, right? So when you're looking at medicines, and you're trying to get a patient stable, you know, we're trained to use some of the older medicines which tend to hit a lot of off-target receptors.

And what we see now with some of the newer medicines is that they're very guided, very, you know, they're, they're, they're very much targeted, exactly, to this, to these receptors. And by doing so, doesn't hit the off-target receptors, which can give us some effects that maybe we weren't counting on. And so hopefully that way we're able to not only get them better, but keep them well on the medicine for a longer period of time.

And we've been able to successfully manage our patients in a way that's not only good for their mental health, but by keeping them out of the hospital, preventing relapses, our patients actually do better in a healthier way long-term. Medicines that have less side effects, in that are newer; the way I describe it is a laser beam versus a shotgun approach to medicines.

00:21:19:11 - 00:21:35:18 [Tania] You know, it’s funny, I think about it as I think through chemotherapy versus targeted therapy, same thing in oncology where I usually tell people chemo is like putting a blindfold on and just shooting, right. You're just knocking down everything versus getting very specific to get on-target effect and less get off target.

00:21:35:18 - 00:21:36:12 [Dr. Melnick] Exactly.

00:21:36:18 - 00:22:00:02 [Tania] So let's talk about relapses. I watched a program that you spoke on, and you explained that every time a patient relapse, you know, it gets worse and worse and worse. So my assumption is to go then to, I guess to your point, get the ideal treatment early, prevent the relapse, and therefore you can actually keep their brain as healthy as possible. Like what is, what is the, I guess, the method to this. 

00:22:00:04 - 00:22:48:22 [Dr. Melnick] Yeah, it's exactly what you said. I mean, the earlier the intervention, the longer that they've been on medicines that help them stay stable and out of the hospital and prevent relapses, the more intact they are not just cognitively but functionally. And there are multiple studies that have shown how we're able to kind of manage those patients successfully and keep them out of the hospital, but also give them the cognitive reserve that they deserve as time goes on. We know that patients that have early psychotic symptoms have worse prognosis. We know that people that break later on have, have better prognosis. But what if we were able to get those patients stable and not have any more episodes? Well, then at that point, we're able to keep their cognitive reserve intact and be able to get them to become more functional members of society.

00:22:49:00 - 00:23:01:12 [Tania] You took us through the patients that you treat, which were really, I guess I'm, I guess we assume are pretty severe to get to that point. How do we get ahead of it? How do we get, how do we prevent that from happening?

00:23:01:14 - 00:23:53:19 [Dr. Melnick] Great question. Early recognition is vital. You know, we tend to, we tend to use medicines that are, that, that really don't allow our patients to really show their wellness over time. We know that some of the typical antipsychotics, which are still being used quite a bit, especially in psychiatric facilities, are neurotoxic, as per Dr. Henry Nasrallah.

And, you know, we're seeing how the newer generation of medicines are not only able to get our patients stable today and to treating their positive symptoms, but also, long-term, minimize the chances of having some of the movement disorders, cardiovascular issues, diabetes, and waking. And as we're able to get these patients better, we're able to keep them better for long-term.

00:23:53:21 - 00:24:04:15 [Tania] You've seen the change in medicine over the last 10 years. Where do you see it going over the next 10 years when it comes to treating patients with severe mental illness?

00:24:04:16 - 00:24:28:20 [Dr. Melnick] Yeah, I mean, there needs to be an approach that's done beyond just giving somebody medicine and sending them home. There needs to be a, you know, biopsychosocial formulation to every patient that walks through your door. This is not a cookie-cutter disease, unfortunately.

00:24:28:22 - 00:24:53:06 [Tania] In terms of stigma, even when people have family members diagnosed with this, people get afraid, and they’re embarrassed and they're ashamed. How do we unwind that and, and get people to understand that this is a disease that, that deserves a chance, it deserves people, it deserves empathy, deserves care. How do we, how do we, change that around?

00:24:53:06 - 00:25:58:20 [Dr. Melnick] For many years, people with schizophrenia were just thrown into hospitals. You know, they were mistreated, they were locked in dungeons, they were put on insulin. They were, you know, frozen, given seizures. I mean, so many different ways that they were mistreated. We finally have resources, and we need to start changing our way of thinking. The stigma is our creation, not theirs.

And we need to start doing what we can to bring these patients out into the community, which is what we've done at Passageways: being able to give patients their lives back even though they've had mental illness, even though they've committed serious crimes. The fact that we're able to get them into community and be able to become functional members of society is something that needs to be taught and educated about. That these people are not people we just throw away into a hospital or into a hole like we used to do, but actually are able to be rehabilitated. Maybe not all, but the ones that can and the ones that want to, we got to give them that opportunity.

00:25:58:22 - 00:26:57:13 [Tania] So I'm going to switch gears a bit because, you know, most of our listeners will be practitioners. And as we spoke about before, what you have done, to me, is remarkable. And, I mean, for those who don't know, when I first heard you speak, I had a whole list of questions I wanted to ask, which got thrown away because I was so fascinated by what you did. I mean, coming into medicine, you're, our, our goal is to make a difference in patients’ lives. Our goal is, is, is to turn things around. And, and when you hear about patients who have committed such crimes being rehabilitated in a way that most people think is impossible, I mean, it was, I'm fascinated, I'm touched. It is the way, to me, medicine should be practiced.

What advice, what knowledge can you impart on people seeing patients that want to rehabilitate, that want to get them better and just don't know how to do it.

00:26:57:15 - 00:27:29:18 [Dr. Melnick] I mean, first is, I tell my residents, don't ever follow the same rut that everybody has laid down. You know, everybody tries to follow the same path. And what we need to start doing is creating new paths. You know, and when you come up against a wall, don't just stand there and expect the wall to move down. Go around the wall; figure out new ways.

We need to start thinking outside the box, and we need to start changing our mindset and putting our patients first, which we really haven't been doing for many years.

00:27:29:20 - 00:27:35:21 [Tania] So then, with that, what is your proudest moment?

00:27:35:23 - 00:28:38:13 [Dr. Melnick] My proudest moment professionally is, is really seeing patients get out of from underneath a hole, underneath a rock, be able to kind of come out and be able to see the light at the end of that tunnel by rejoining society, being able to move into their own apartment, being able to keep it clean, being able to, you know, start dating.

We have patients that have started to date, we've had 2 that have gotten married. The idea is, is that where before our limits were just the fact that, well, they have schizophrenia, we're going to have to take care of them. But we've been able to show that that's not the way this works. We're able to get some of those patients back into society and be able to become functional.

And my proudest moment are the days that these patients graduate high school, they learn how to read and write, which before they were not able to do so, are able to get jobs, are able to go out and really start making something more than just a patient with schizophrenia.

00:28:38:15 - 00:28:51:02 [Tania] Yeah. And last question. What advice do you have to give to all of us, whether we're in pharma or treating practitioners? Any advice?

00:28:51:04 - 00:29:37:09 [Dr. Melnick] Yeah. Again, follow your own drum. You know, don't allow others to tell you what has to happen. If you feel a medicine is the one that's right for your patient, fight for them. Be a patient advocate. We all went into psychiatry to be patient advocates. We didn't do it for the money. So it's important for us to find ways to be able to go out and be able to manage those patients appropriately so that they can be successful patients in society.

And my advice is don't allow people to tell you no, don't allow people to say you have to do this, this, and this. Follow your heart, follow your brain, follow your own path to be able to get to what you feel is important for your patients.

00:29:37:11 - 00:29:44:01 [Tania] I've learned a lot from you. You've given me optimism on what we can do, what you've done. Imagine if this can be replicated.

00:29:44:03 - 00:29:45:01 [Dr. Melnick] I hope it will be.

00:29:45:04 - 00:29:59:01 [Tania] And thank you now for taking the time to go through this experience with us. Thank you for taking us through your center. Thank you for sitting with us. This has been quite, I would say, an inspiring discussion.

00:29:59:01 - 00:31:06:21 [Dr. Melnick]  Thank you.

Some of our patients really respond to art pretty well. What we start learning from them is that when they're more psychotic that they are, you start seeing some of those things come through the art. This is one of our patients. This is a woman who ended up killing her husband. And while killing her husband, you see in the top, you see a machete going through a heart. You see the x’s through the heart, and you see her underneath it, holding the heart up. But what you also see within the heart are the different faces that she was. You see the white face at the bottom of the heart. But you also see at the upper right hand side a teal face as well. This was in ‘89, right after she committed her crime.

You see here in 2008, 2009, much more organized in her thought process. You start seeing that there's organization within the paintings and much less of the paranoia that comes out, less psychosis. So same person painting in different ways. Showing the wellness of her after we ended up treating her in 2009. Part of what our program does is teaching empathy, teaching the remorse.

Dr. Melnick directs a dignity-first program that blends comprehensive psychiatric treatment, cognitive-restoration therapy, trauma-informed support, and structured community re-entry. The outcomes are extraordinary: 0 percent recidivism and 90 percent sustained reintegration — results that upend long-held assumptions about severe mental illness, justice, and what true healing can look like.

Together, Drs. Small and Melnick unpack how this model works, why it succeeds, and how clinicians can begin adapting its principles today. This conversation reveals what becomes possible when we treat the person behind the psychosis — with dignity, rigorous care, and a roadmap for real-world impact.

About Dr. Ilan Melnick

Ilan Melnick, MD, is the primary psychiatrist in two outpatient clinics in the Miami, Florida area, as well as a staff psychiatrist and chief medical officer at Passageway Residences of Miami-Dade County. In addition, Dr. Melnick is a staff psychiatrist and medical director for Jewish Community Services and performs independent medical and psychiatric evaluations for Miami-Dade County police, fire, transit and aviation departments.

Dr. Melnick received his medical degree in Bayamon, Puerto Rico and went on to do his residency in psychiatry and fellowship in geriatric psychiatry at the University of Miami/Jackson Memorial Hospital. He continues to be involved in education as an assistant professor at Florida International University School of Medicine and through his role giving grand rounds at major universities and hospitals around the world.

Dr. Melnick is a paid consultant for BMS.

00:00:04:07 - 00:01:11:08 [Tania]  Welcome to doctors Unscripted. I'm Doctor Tania Small, and I'm here to bring you into a different kind of conversation with some of the brightest minds in medicine and research.

Today I'm joined by Doctor John Kane, an internationally acclaimed psychiatrist renowned for his pioneering research in early psychosis and patient centered innovation, and with over 900 peer reviewed publications. Doctor Kane is redefining mental health care. We'll explore what drew him to psychiatry, unravel the biology of schizophrenia, decode the triad of symptoms, examine breakthroughs challenging the dopamine dogma, and discover how patient driven science and partnerships are shaping the future.

Now let's get started.

Doctor Kane, thank you so much for joining us in downtown New York City for our first episode of Doctors Unscripted.

00:01:11:09 - 00:01:14:01 [Dr. Kane] Thank you. My pleasure. Thanks for the opportunity.

00:01:14:03 - 00:01:49:02  [Tania] I have a few questions for you today. But I'm starting off with the hardest one, and that is, do you remember when you were med school and you were trying to figure out what you wanted to do? Most of us were trying to figure out at least what we wanted to do, what fields we wanted to practice in.

And a lot of times, most of our colleagues could guess what fields we were going to. For example, my colleagues figured I was either going to go into ob/gyn or onc, and I ended up going into onc. What did your colleagues believe you were going to go into, and what inspired you to go in to psych?

00:01:49:02 - 00:02:32:13  [Dr. Kane] So they didn't have to guess because I told them. I knew when I went to medical school that I wanted to go into psychiatry, and it had been something that I was interested in ever since high school. And rather than just studying psychology, I wanted the medical degree to be able to really have a, you know, a medical perspective on mental illness.

But I think as a teenager, I was reading novels and got very interested in trying to understand, why did people act a certain way and what determined their behavior, and why were people so different? And I became fascinated with, sort of the human mind and behavior and, and then trying to understand mental illness.

00:02:32:15 - 00:02:33:23 [Tania] Since high school.

00:02:34:01 - 00:02:35:11 [Dr. Kane] It was high school.

00:02:35:13 - 00:02:41:12 [Tania] Was there anything that really stuck with you while you were in med school or even in residency that really changed your [perspective]?

00:02:41:13 -  00:03:18:14 [Dr. Kane] Well, I remember the first time in medical school that I actually interviewed a young man with schizophrenia, and he was pretty much my age and had his first episode of schizophrenia, in the recent past. And I saw him at Bellevue Hospital and, it was a pretty powerful experience because I think I was trying to understand the way he was thinking, and he was quite delusional.

And I was asking myself, is it is it possible that he really believes these things?

00:03:18:16 - 00:03:19:18 [Tania] Yeah.

00:03:19:20 - 00:03:47:02 [Dr. Kane] And then I also met with his parents and I saw the anxiety and the devastation that they were feeling at that time. And it was for me, it would be it would be great if we could figure this out and understand why. Why does this happen? You know, this is a young person with a lot of a lot of promise that becomes psychotic and develops an illness that's really can be quite disabling.

00:03:47:04 -00:04:48:19 [Tania] I remember, when I was learning a lot more about schizophrenia, when I started working in pharma, I learned a lot more about schizophrenia and someone explained it to me this way because, as a pediatric hematologist oncologist, a lot of times you just have so much hope for these kids, and your goal is to get them through it so that they can really fulfill the life that they're meant to live.

And someone told me you could imagine a newly diagnosed person with schizophrenia, and sometimes immediately it can look like lights out, and their goal is to turn on that light. And I guess my question is like, I know one of the things that you focus on is really early psychosis. And, how did the families actually, feel about it?

How did the patients get through it in the beginning?

00:04:48:21 - 00:05:48:04  [Dr. Kane] It's very hard., We had a grant application for the RAISE Project, but, I had never used a quote from a poem in a grant application. A lot of my colleagues thought that that was not such a good idea. But the quote was, tread softly because you tread on my dreams.

That's a quote from Yeats. And I thought that really kind of summed up what we're trying to do here is that, you've got a young person, you've got a family, lots of hope, lots of potential. Parents are always worried. But, you know, you see something like this develop unexpectedly and, it turns out to be a pretty serious illness, and it's devastating, you know?

So this led us also to understanding the importance of early intervention. And, you know, can we diagnose this condition early, can we intervene rapidly and try to get it under control?

00:05:48:06 - 00:05:52:07 [Tania] Yeah. About what age are people with schizophrenia diagnosed?

00:05:52:10 - 00:06:19:20 [Dr. Kane] So the median is in the early 20s. It's usually late teens, early 20s. And, you know, it's occurring at a time, which is really critical in people's development, whether it's educational or psychosocial. And so it has a tremendous influence, tremendous impact on what people can do subsequently.

00:06:19:22 - 00:06:31:11 [Tania] And let's talk about that and talk about the biology, because I know a lot of times, again, people hear schizophrenia. They think it's just a homogeneous disease and can't put their finger on it. What do we know about the biology so far?

00:06:31:11 - 00:08:18:07  [Dr. Kane] So it is very heterogeneous. I mean there's a very strong hereditary factor, but we don't understand the genetic the dynamics of the genetic influence. There have been many, many genes that have been implicated, but all with very small effect size. So we don't we don't have a major gene or genes that we can point to and say, this is the reason I think I would say that schizophrenia is probably not one illness that right now, we approach it with this sort of diagnosis, but I think it probably includes what we will one day learn are multiple different phenomena with different etiologies and different pathophysiology, so that we're trying to do research and understand this illness. We don't have great tools yet to really stratify people into different categories. But there is hope with genetics and brain imaging etc. that will come to understand it better. I mean, up until now, we've sort of had the dopamine hypothesis of schizophrenia, the idea that there's too much dopamine being produced in certain brain areas.

And so we tried to block that with medication and to some extent it's been effective. And we can treat the acute signs and symptoms of schizophrenia with medication. And it often works pretty well. And then the other problem we get into is people need to take medication on an ongoing basis to prevent a recurrence or a relapse. And I think nonadherence is a challenge in any chronic illness, whether it's hypertension and diabetes or epilepsy or asthma.

But in mental illness it's perhaps even more of a challenge with and people with schizophrenia also have cognitive dysfunction. And, that that can make it even more difficult.

00:08:18:08 - 00:08:31:08 [Tania] You spoke about the different pathways. You spoke about dopamine and blocking dopamine. Is that where we landed now or do we know a lot more about schizophrenia?

00:08:31:11 - 00:09:19:23 [Dr. Kane] Yeah, I think we've learned a lot more. For example, the notion has been that, it's excessive dopamine release, presynapticly, and the way we've been treating it up until now is to block the postsynaptic receptor. So, you know, I think there has been a better understanding of some of the pathways and new approaches to treating the illness.

But I think we were left with, as we said before, a very, very, heterogeneous phenomenon. And there may be people who have different mechanism of action. It may be we see the interaction between genetics and environmental factors. And we need to better understand in which category people fall into.

00:09:20:01 - 00:09:24:02 [Tania] Are there any biomarkers on the horizon so that we can understand this better?

00:09:24:08 -  00:10:25:00 [Dr. Kane] There's certainly excitement about genetics and about neuroimaging and even electroencephalography. But we don't at this point have biomarkers that are useful at the clinic level, to help better understand which treatment to use or which treatment might work or to predict the prognosis of that person. So we're really trying the best we can to take advantage of different treatment modalities.

We know that medication can be very helpful. We also know that psychosocial interventions are very important. And ideally we want to combine the two. Even though we consider this a biological illness or a brain disease, we know that psychosocial interventions, therapy, family therapy, family psychoeducation can also be very important in helping people achieve better outcomes.

00:10:25:02 - 00:10:35:07 [Tania] Doctor Kane, I want to ask you a little bit about the different symptoms. Can you explain the difference between positive, negative and cognition and how do we manage those symptoms?

00:10:35:08 - 00:13:10:19 [Dr. Kane]  Well, positive symptoms are things like delusions, which are fixed false beliefs, hallucinations, hearing a voice when no one is speaking, having difficulty communicating in a logical fashion. Negative symptoms involve no motivation, diminished affect, diminished expression, lack of involvement with day-to-day activities. Seeing friends, hobbies, socialization, sometimes poor self-care, and then cognitive dysfunction, which really is a core feature of schizophrenia and affects probably 80% of patients, involves things like, difficulty with attention, with verbal memory.

So remembering things like, if I give you a phone number, will you remember it long enough for you to actually dial the number? Attention obviously is very important. And then social cognition, which is how do we understand social interactions? Can I read someone's facial expression in a way that's meaningful? Do I understand my own emotions?

So these are all problems that people with schizophrenia have to deal with. And our understanding is that the cognitive dysfunction actually begins long before the other signs and symptoms. And so it really is a core phenomena. The negative symptoms also, which affect at least 50% of patients, also often begin before the positive symptoms. But once when someone gets to a point where the diagnosis of schizophrenia is actually made, we'll often see all three of those things.

One of the challenges is that the medications we have had up until now work mostly for the positive symptoms. They don't really help the negative symptoms as much as we'd like, and they don't help the cognitive dysfunction as much as we'd like. So we're very eager for new treatments to be available that can help patients in those particular domains and even positive symptoms.

Although medications can often be quite effective, they're not 100% effective. And then in terms of preventing subsequent episodes, medicine is very important, prophylactically. So even when someone improves from their acute episode, they're at risk for having another episode. Could be six months later, could be a year later. It could be two years later. The medicine is very, very effective in reducing the risk of a subsequent relapse.

But many people have trouble taking the medicines.

00:13:10:21 - 00:13:16:23 [Tania] And why is that? Is it because of the disease itself? Is it because of the side effect profile of the medication?

00:13:17:04 - 00:13:18:00 [Dr. Kane] It’s all of the above. Okay.

So the disease itself, I mean, sometimes people don't fully appreciate what's wrong and they can't really kind of wrap their heads around it. Sometimes people feel better once the medicine has worked for the acute symptoms, they feel better or they're out of the hospital. They're not having those delusions anymore or not hearing voices. So they feel, well, maybe I don't really need to take medicine anymore.

Nobody wants to take medicine on a long-term basis. Side effects. I mean, all of these things. And then I think it's human nature to have difficulty taking medicines too long. Whether you have diabetes or hypertension or epilepsy or asthma, it's a challenge. So the cognitive dysfunction maybe adds to that as well. Because I'm not as well organized as I could be. And remembering to do something. So yeah, it's many, many factors. But it's a huge problem. And you know half of our patients have difficulty with adherence. There was one study that was done in Finland, where they followed 2500 patients who were hospitalized for the first time with schizophrenia.

And within 60 days of leaving the hospital, they weren't getting their medicine. So it's a big challenge.

00:14:31:09 - 00:14:43:01 [Tania]  And I want to go into two pieces that you said you spoke about. The first symptom tends to be cognitive dysfunction. Is there a way or is there anything that allows us to diagnose it at that time?

00:14:43:03 - 00:15:12:17 [Dr. Kane]  It's hard. It's hard because when someone has cognitive dysfunction, unless it's really, really severe, you don't necessarily recognize it because you don't know where they should have been or where they sorted out if there's been a decrement. I think we are getting better at that. And now there's a lot of research going on in what's called the clinical, high risk, population, where we do see that cognitive dysfunction may be a predictor of somebody actually developing schizophrenia.

So there's a lot of research going on in these domains looking for early signs so that we can intervene earlier.

00:15:25:05 - 00:15:38:05 [Tania] You spoke about the research as well. You said that even getting patients on clinical trials sometimes can be challenging. Why is that and what can we do to improve that to get those answers?

00:15:38:08 - 00:16:07:19 [Dr. Kane]  Well it's interesting. You came from an oncology background. And I think if you look at, the clinical trials that go on in oncology, it's like many people participate in that because that's something that's brought to their attention very early in their treatment history and psychiatry. That doesn't happen. And I think it would be great if we could develop, you know, more clinical trial and clinical trial networks so that when people come into a hospital, they're offered opportunities to participate in some kind of research.

We could do research about anything. It could be access, how did you how did you get here? Who referred you? How long did it take you to realize that something was wrong? How did your parents react? Or it could be a treatment trial. It could be a registry, a long-term study.

There's so many things that we could learn from, but the average patient is not participating in research in psychiatry. And I think we need to do a better job of making research available to people explaining to them why it's important. A lot of people think, oh, I don't want to be a guinea pig.

You know, that's really not what it's all about. This is how medicine progresses, right? We have to learn from each other.

00:16:47:19 - 00:17:06:08 [Tania] I want to learn more about that because, when practitioners are treating patients, they see patients day in and day out. And there's a lot of research that's there. But how do you manage your time to learn all the new information, continue to see your patients and then apply it? Is that a challenge?

Is it too much information that needs to be distilled? What do you think is the real challenge, when it comes to that education?

00:17:13:00 - 00:17:32:05 [Dr. Kane]  I think that's a big part of it. I think there is so much - people are just deluged with information. You know, where attention is a challenge, right? What do I pay attention to? So I think we have to help clinicians. We have to synthesize data and present it to them in a way that's meaningful to them.

They often react to studies and say, but does that apply to my patient? So we have to do research that's really generalizable, that's real world to help clinicians understand, how does that apply to my patient. That means sometimes being more inclusive in our clinical trials so that we understand the impact of treatment in general.

I think we are getting better at these things, but we still have a ways to go.

00:18:01:08 - 00:18:23:22 [Tania] So you opened another door because I want to walk through and that is inclusivity. When it comes to clinical trials and even just beyond clinical trials, we know that there's still disparities when it comes to health care, particularly in this patient population. Where are we with that? And then I want to go into how do we make our trials more inclusive.

00:18:24:00 - 00:18:47:12 [Dr. Kane]  So I think we've made progress. We still have a ways to go, obviously. The US is very diverse. I think people struggle with, who can I trust? And I think we need to make sure that we have people working with us who who can talk in a meaningful way to anyone who's afflicted by a mental illness.

I think peer counselors can be very helpful. The idea of having someone else with the same lived experience, but who speaks your language, who comes from your culture, who understands what you're going through on a personal level. I think I think that can be very powerful. I don't think we use that often enough.

But we're making progress in that direction, too. I think more people are being trained as peer counselors. I think we're we recognize how important that is. I think there's been more emphasis on including people with lived experience when we design our clinical trials, when we execute our clinical trials to make sure that we're really hearing the patient perspective. Patient reported outcomes are very important.

But again, the diversity issue, we need to make sure that all of these things are available to everyone.

00:19:41:05 - 00:20:05:05 [Tania] You know, I was speaking to a colleague of mine, and one of the things, again, that he put in perspective for me was, when someone is diagnosed, for example, with cancer, what do we do? We go in and we say, how are you dealing with things? Are you okay? And all of a sudden you have this empathy, more sympathy, at least towards them.

And then one of the things he told me, though, is what happens when you meet someone who was diagnosed with schizophrenia instead of leaning in, you tend to lean out because of all that is associated with that. So I just wonder, as a health care community, how do we get more people to lean in? Is it a lack of understanding?

Is it a is it a fear factor? But what can we do?

00:20:28:23 - 00:20:51:16 [Dr. Kane] I think it's all of the above, in a sense. There is a fear factor. I think people tend to be afraid of what they don't understand. But we have to recognize that mental illness is an illness like any other illness. We have to treat it the same way, with the same kind of understanding, appreciation and consideration.

I think in schizophrenia. We also need to do research and we need people to participate in research and benefit from the research also to make sure that we get the support that we need. I don't think enough funding goes into research on mental illness, for example. I mean, everyone is sympathetic to oncology or to heart disease.

But the reality is mental illnesses account for a tremendous amount of disability, not to mention personal suffering and family burden and even shortened lifespan.

00:21:25:20 - 00:21:50:15 [Tania] There's something that I like to call patient-driven science. And that is where we develop our drugs for patients. So we move from a product-centered drug development to a patient-centered drug development. And in pharma we create the technology. As a physician, you have the expertise and patients, they understand - they're living their disease.

How do we come together to really develop the best drugs for patients?

00:21:55:09 - 00:22:22:11 [Dr. Kane] So we need to really have ongoing communication between the federal agencies in the US, whether it's NIH or the FDA and industry and academia and clinicians in the field and patients and families all working together for a common goal. Everyone has their role to play in that process. But it's really a collaborative process.

00:22:22:13 - 00:22:40:13 [Tania] And I'll say this, one of the things I tell my team all at the time is even though you may not be touching a patient at this time, you are still a part of this treatment team. And the outcome of that patient is still our responsibility collectively, as part of the health care community.

00:22:40:13 - 00:23:01:14 [Dr. Kane]  And it's really true. I mean, everybody, when we're doing, a clinical trial or we're doing research, the study coordinator or the person working on recruiting has to understand the critical role they play. Everybody plays a critical role. I mean, I think that's true across the board that we need to understand that everybody's important and they need to they need to recognize that.

00:23:02:11 - 00:23:19:19 [Tania] But that's so important because I think we forget that. And so how do we all hold hands and make sure that we all feel that responsibility for that human that we are treating?

What are you most excited about when it comes to innovation for patients living with schizophrenia?

00:23:27:01 - 00:23:48:03 [Dr. Kane] Well, I am excited about what we were discussing earlier, which is the evolution of new thinking about how we might manage the dopamine dysfunction that exists in schizophrenia. The development of muscarinic agonists I think is very exciting. There are half a dozen companies now that are involved in developing such drugs. So I think that's very welcome.

I think other innovations we're seeing more and more, in brain imaging; trying to understand neural networks and problems in connectivity in various brain regions. It's great to see the innovation that's going on now there. You know, there's been a lot of interest now in a in a new way of looking at the control of dopamine in the brain.

00:24:11:18 - 00:24:19:15 [Tania] You spoke about muscarinic receptors. And that's a new mechanism that I know there's been a lot of discussions about. Can you tell us a little bit more about it?

00:24:19:17 - 00:24:39:20 [Dr. Kane]  There's been interest in muscarinic receptors for years and years, but I think now we're getting a lot closer to fruition. And a sense of what we've seen is that by influencing some of the muscarinic systems, if you will, we can have an influence on that presynaptic release of dopamine.

And importantly in the brain areas that are critical to the development of schizophrenia.

00:24:45:13 - 00:24:53:21 [Tania] What advice do you have for us in order to improve the patient experience together for those living with schizophrenia?

00:24:53:23 - 00:25:22:06 [Dr. Kane] People have to understand what mental illness is, how common it is, how it affects people, how it affects individuals, families. And then, as we were talking earlier, the right collaboration between all the stakeholders. And that means the patients, the families, the pharmaceutical industry, academia, federal agencies, etc., to really go after this problem in a major way and it is getting more attention.

I think there's more awareness of mental illness. I think during the pandemic and after the pandemic, there seemed to be kind of an emergence of a better appreciation of mental illness. But, we still have a long way to go.

00:25:35:23 - 00:25:47:01 [Tania] Well, I think all of us are ready to lean in to this together. And I just want to thank you for your time. Thank you for your expertise. Looking forward again to continue to move this field forward.

00:25:47:02 - 00:26:00:04 [Dr. Kane] My pleasure. Thank you so much for this opportunity.

00:26:00:06 - 00:26:04:18 [Tania] What was that novel that you read initially?

00:26:04:20 - 00:26:16:05 [Dr. Kane]  Well, probably just the Crime and Punishment novels are not necessarily all fiction, right? I mean, a lot of it is actually based on lived experience that people have had. It took me a while to realize.

It’s a forward-looking conversation that equips you with fresh insights — and a new lens on what’s possible in psychiatry.

Abour Dr. Jane Kane

Dr. Kane is an internationally recognized expert in the treatment and study of schizophrenia, with over four decades of leadership in academic psychiatry and clinical research. He serves as Senior Vice President for Behavioral Health Services at Northwell Health and Chairman of Psychiatry at the Zucker Hillside Hospital. He is also Professor and Chair of Psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. Dr. Kane has authored more than 900 peer-reviewed papers and led numerous landmark studies focused on early intervention, treatment adherence, and relapse prevention in schizophrenia. His work has helped redefine how we understand the illness and how we care for those living with it.

Dr. Kane is a paid consultant for BMS.