Schizophrenia: Early Signs, Genetics, Treatment, and a Family's Lived Experience with Dr. Consuelo Walss-Bass and Dr. Julio Licinio

In this episode of the Podcast, Dr. David Puder is joined by psychiatric geneticist Dr. Consuelo Walss-Bass and Dr. Julio Licinio for a powerful conversation on the early signs, genetics, and treatment of schizophrenia. Drawing from her lived experience growing up with a mother and sister who both have schizophrenia, Dr. Walss-Bass discusses prodromal symptoms, the 287 risk genes identified by the Psychiatric Genomics Consortium, gene-environment interactions, challenges of early intervention, and why clozapine remains the gold standard for treatment-resistant schizophrenia. Link to blog https://www.psychiatrypodcast.com/psychiatry-psychotherapy-podcast/episode-282-schizophrenia-early-signs-genetics-treatment-and-a-familys-lived-experience-dr-consuelo-walss-bass-and-dr-dr-julio-licinio Link to YouTube video https://youtu.be/HJgPW7QH_jM

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:13David Puder?

  Welcome back to the podcast. Today, we have a rare hour, the lived experience of growing up with a mother and sister who both have schizophrenia and the science of someone who spent 25 years asking why. Our guest is Dr. Cello Wallace Bass. She is a professor and distinguished chair in the Department of Psychiatry and Behavioral Sciences at McGovern Medical School, UT Health, Houston. She directs the psychiatric genetics program and UT Health Houston Brain Collection, which was founded in 2014 with the Harris County

• 0:52David Puder?

  Medical Examiner's Office. It now holds 175 donations, which makes it unusual, not for the number, but each brain is paired with blood, skin, toxology, and psychological autopsy, trauma, substances, the course of the illness. So the same person can be studied after death and through stem cells as living neurons in a dish. She also has more than 100 papers and continuous NIH funding. Her memoir, Why My Sister, was just published this month. Also with me is Dr. Julio Lassino. He is a sunny distinguished professor of psychiatry

• 1:37David Puder?

  in upstate, duly trained in endocrinology and psychiatry. In 1996, he founded molecular psychiatry, and his own work showed that leptin, the hormone made by fat cells, rises and falls in pulses that are the opposite to cortisol. So when cortisol is going up, leptin is going down. When leptin is going up, cortisol is going down and vice versa. And that replacing it in rare leptin deficient adults changed both metabolism and behavior. He also ran some of the first rigorous antidepressant pharmacogenetic trials, and he is here to help me interview Cello. So, welcome to the podcast.

• 2:22Speaker 01

  Thank you for having me.

• 2:24Speaker 02

  Thank you for having me, Julian.

• 2:25David Puder?

  Yeah, it's great having you guys. So, okay, my first question is for Cello. Okay, so talk to me about being raised by your mother with schizophrenia.

• 2:35Speaker 01

  Yeah, so that was hard. I mean, we didn't really know she had schizophrenia. Actually, the word schizophrenia was not mentioned to us, me or my siblings, until I was around probably 17 years old. So before that, I was just really wondering why, why she did the things that she did, some of them violent things, you know, why she talked to herself, why she would or hide herself in her room, or not speak to us for some, you know, many

• 3:17Speaker 01

  different things that were experienced by myself and my siblings. So that was very hard. And I was always wondering why, why was this happening? That was really my main question and what drove me to my research.

• 3:34David Puder?

  And any specific, like now knowing what you know about schizophrenia, what were some of the symptoms that were there that maybe you didn't know what they were like back then, but now you're like, oh, this is what was going on?

• 3:51Speaker 01

  Yes. Well, so the first memories I have of her were she would just start laughing all of a sudden, or she would just seem like she was talking to somebody and what was she talking to? Of course, there was nobody there. But we would say, oh, you're talking to us, you know, me and my siblings are very close. The three of us were three years, one year apart, the oldest ones of five. And anyway, so those are our first memories, just her laughing out loud, talking to someone who wasn't there. That's, and now, of course, I know those are part of the symptoms, the psychosis, the hallucinations, she would see

• 4:35Speaker 01

  things or hear things, hear voices. I have those very strong memories of that.

• 4:41David Puder?

  What about any of the negative symptoms of schizophrenia, any memories of what that was like?

• 4:47Speaker 01

  Yes. So the negative symptoms in her now, I know, understanding are very strong. When she would sometimes see us, but not really see us, like we're not there. Or like she knew who we were, but sometimes it was just no emotion in her at all. Or if we would like cry or something, or fall, or she would be like blank face. Those now I recognize, of course, as negative symptoms, but that was also hard because it would mean like, well, does she doesn't care? Or is she not responding to me? To me, something happening to me? That was hard.

• 5:31David Puder?

  Yeah.

• 5:32Speaker 01

  Not receiving any kind of like care or affection back when something happened.

• 5:40David Puder?

  Yeah.

• 5:41Speaker 01

  Or if he would tell her about something at school, she would just have no emotion whatsoever, no, oh, she'd be, oh, and then that was it. So those things were hard as well.

• 5:52David Puder?

  And any like cognition, kind of memory, frontal lobe types of symptoms that you witnessed?

• 6:02Speaker 01

  Those things, I, you know, I don't have a lot of memories about that because I didn't really understand any of them until I started myself learning about all of this as a postdoctoral fellow. But now that I think of it, yes, she went through periods of time. And the main thing that I think now is I see those, you know, you've seen, I know, as professionals show, sometimes the illness comes and then it goes away and it seems like she's okay. And then it comes back. And there's this pendulum of back and forth. That I recognize it very well in her because there were some periods of time that she was extremely lucid

• 6:42Speaker 01

  and almost like, oh, wow, she's back to the mom that I remember it as a really, really young child. But those, those moments would get shorter and shorter as time went along. And so I think by the time I was in my late teens, early twenties, they were almost non-existent. And so she, when I was really young, she would like prepare amazing meals. She would be a really good mother. I have, I do have those early memories of her. But by the time I was in my late teens, still, you know, living at home, then she would basically

• 7:24Speaker 01

  stay in her room all day and not come out. So those periods, I think her ability to do things, the executive function was really diminishing.

• 7:38David Puder?

  Julia, any kind of follow up thoughts about specifically Cello's mother before we kind of move on to her sister and the story? Yeah.

• 7:48Speaker 02

  Yeah. So Cello, about your mother, one thing that I think is kind of really remarkable is that you, you've told me personally that her family of origin, she's the only one affected. So she has siblings that are doing very well, and they were raised in the same situation, the same circumstances, have the same overall, they're not the same people, but they have overall the same genetic pool from the same parents and grew up in the same, you know, place. And your mother is clearly, you know, affected, has something with her. So it's not that you can just overlook it and say, oh, this is like a small thing and let's look the other way. It's something really, you know, serious that impacts her life very dramatically. And the other ones are fine.

• 8:27Speaker 01

  Yes.

• 8:28Speaker 02

  So can you give us some thoughts? How do you feel about that? Because it's so, you know, so impaired and the other ones so well.

• 8:35Speaker 01

  That is a really good question, Julio. And yes, that is exactly the question that I've had with my siblings and that I know my mother's siblings have. So she's the oldest of six. And all of the other five siblings that I know, and I know them very well, my aunts and uncles say, I've never seen any signs of any kind of psychiatric problem. And they've all have careers and were very successful. They have families. And they have asked me that as well, like, why not when I've started studying this? Why is it that she, she developed these symptoms or this illness and we did not? Honestly, I, I don't know myself yet the answer to that question. That is one of the reasons why I'm studying this. But it

• 9:20Speaker 01

  is, I think of the genetics, genetics of schizophrenia. We know schizophrenia runs in families and there's genes, right, that are inherited. I, the way I have thought about this is that there's a combination of genes that lead to the illness. And, and of course, in conjunction with the environment, the trauma that happens. But those of us who did not have that illness do share some of the genes, but perhaps not all of them. And perhaps some of those genes, I actually think of them as not bad genes in those sense of the word, you know, they may be actually good. There may be some good reason, there's a reason why they survived throughout evolution, throughout, you know, the beginning of time,

• 10:05Speaker 01

  and they're still there, these genes. So there must be something good about them. Perhaps they allow us to think outside the box, to be more creative, some benefit to them. And so I think of that, that perhaps those of us in the same family that did not have the illness benefited.

• 10:24Speaker 01

  From these genes in a certain way, whereas like my sister and my mother, they had the bad combination and the bad environmental exposure that happened at a certain period in time for them. That was different than for us. So during brain development, perhaps the trauma for them was different, even though it was the same trauma.

• 10:46Speaker 01

  The brain was developing at a certain, a level for them that caused this to happen. Does that make sense?

• 10:53David Puder?

  Hmm.

• 10:54Speaker 01

  And of course, those are all theories, but I do think of it, we tend to think of schizophrenia bad and bad genes. But I don't necessarily think they're all bad. And the same thing with depression or with anxiety. There's a reason why we have those things. You know, depression can be good, get help us get out of a situation. Anxiety can help us do something even when we need to do it, you know, it's only the extreme illness itself that's really bad.

• 11:21David Puder?

  I've thought about that specifically for bipolar and hyperthymia. Like a certain percentage of kids of someone with bipolar will end up with hyperthymia, like just high energy all the time. Like Theodore Roosevelt or think Kennedy.

• 11:37Speaker 01

  Yeah, so Vincent Van Gogh, he was very creative, right?

• 11:41David Puder?

  Yeah. So, so even like a little bit of the genes can get someone very active, very creative, very, you know, where they're constantly in this very positive, higher state of activity.

• 11:55Speaker 01

  And that helps them succeed, as you will, in society in advance, perhaps.

• 12:01David Puder?

  Yeah.

• 12:01Speaker 01

  Yes. Yes. You know, in these families, usually we tend to study the illness. The one person who's sick, we don't necessarily pay attention to the other members of the family and what, what about them? So I think it's an important thing that maybe in genetics, we need to start looking at the well siblings also and seeing what combination of genes do they have that

• 12:27Speaker 01

  helped them maybe do something different from the person that was, that did develop the illness.

• 12:35David Puder?

  I, I want you to talk about your sister Patty. Patty was the one with, that ended up with schizophrenia. I want to first maybe talk about the early symptoms, maybe the symptoms before the diagnosis. And then as you share, maybe share like what we know about early symptoms in schizophrenia versus what you witnessed in your sister. And maybe if there's, if there's an overlap or not an overlap there.

• 12:59Speaker 01

  Yes, thank you. That's a really important question and something that I really try to convey to families when they ask me now, what can we do? How can we recognize this illness? I see in her now, I know she was always isolated in a way. She didn't have many friends as a child. She was, she's five years younger than me. I don't remember her really having many friends. I remember one friend that lived down the street from us and she would sometimes go with her, but otherwise, no, she didn't really have a lot of friends and she always struggled in school. But now I don't know necessarily that that is for everybody that develops schizophrenia, but for her,

• 13:44Speaker 01

  she always had a hard time. She, she would struggle from an early age, poor grades. She excelled in art. She was always an amazing drawer. She would draw and she would paint. She was very creative. But everything else she seemed to struggle. So that was early on. And, and now that I think about the isolation itself, I think that was a big sign. But the first symptoms that I would say are really recognizable was that she started to be really paranoid. And she would tell us that we were all plotting against her or that that we were talking about her.

• 14:27Speaker 01

  I remember that various, some reunions, we would all get together usually on Sundays. Dinner, I'll have, you know, the early lunch in Mexico, Sundays. And then she would say things like that. And then we would look at her and be like, no, we're not talking about you. And then she said, yes, you are, and I know it, or those kinds of things that I now recognize were the early, early symptoms of her perhaps hearing those voices telling her something like that.

• 14:58David Puder?

  In, in the, in the book, it seemed like also she would get sometimes angry in public. And kind of make a scene that was, it was shocking to the family.

• 15:08Speaker 01

  That was the first time she did that. That was extremely shocking. And that's,

• 15:15Speaker 01

  I think that was the beginning of the end, I would call it for her, that, that there was one episode, we were at the airport, one time at the airport, we were all going to Orlando. Well, my parents and her and my little brother, Leo was the youngest of us all. And she started making a scene. It was one of those things that she was starting saying that none of us cared about her and that she, we didn't, we ignored her and then something along those lines. And then we said, no, and then she started screaming. But literally screaming loud where everybody around us was, you know, we're at an airport waiting for our flight to board.

• 15:53Speaker 01

  Then she calmed herself down, but then when we got on the plane, that was when it became like she literally started howling where they almost told us that we had to get off, off the plane because she was doing that. So my father had to really, and he never did get violent with us or in any way. But he had to literally shake her and tell her to stop it. And then she did, but that, after that, when we got to Orlando, things got even worse. So it, that I think, yes, that episode was the first of many. Then later she would become more and more irritable, more and more angry for sometimes for no reason. I lived with her

• 16:37Speaker 01

  for a few months. Fortunately, I could not, that was when I realized, no, this, I didn't know at the time she had schizophrenia, but I thought I can't live with her. She became almost violent with me. She never did hit me or anything, but I, but she would stand in front of my face and start yelling at me. And I decided to move out.

• 17:00Speaker 01

  After just a few months, unfortunately, now I realized she needed help, but I didn't help at the time.

• 17:07David Puder?

  And then she got arrested. Do you want to talk about that?

• 17:11Speaker 01

  Yes.

• 17:11David Puder?

  I'm curious like what the arrest was for and.

• 17:15Speaker 01

  Yes. So I don't miss, I don't get into the details in the book. I later knew that, and she never really actually upfront said what happened, but it was for breaking and entering. So what I gathered now, even now, she's, once in a while brings it up. Now she lives with me after she's been living with for 10 years and we have a really good relationship now. So she's brought it up and

• 17:41Speaker 01

  I think what happened, she broke into one of her boyfriends and her, into his house, into his home.

• 17:47David Puder?

  Like a past, like a past boyfriend?

• 17:49Speaker 01

  A past boyfriend.

• 17:50David Puder?

  Okay.

• 17:51Speaker 01

  And I think he's the one that called the police and

• 17:56Speaker 01

  that's why she got arrested.

• 17:57David Puder?

  I think it's important to talk about these things because when we're looking at some of these symptoms before we have the full picture, it could look like something else, you know?

• 18:08Speaker 01

  Absolutely.

• 18:08David Puder?

  Like the differential is pretty broad at this point, you know?

• 18:12Speaker 01

  People think, oh, is she just being an impulsive person or she just has anger issues, but not recognize the actual illness. Yes.

• 18:23David Puder?

  Yeah.

• 18:24Speaker 01

  That's what we all actually thought at the time, that she was just angry or upset or we didn't really know. I guess we should have, even though we could, we had lived with my mom and I think my father did know, but he was really in denial.

• 18:38David Puder?

  Yep.

• 18:38Speaker 01

  But yeah, I think families have a hard time distinguishing what is the illness, but I always say now, take your child to a psychologist or psychiatrist. I think that would have been, if we had done that, if my father had done that, perhaps things would have been different for her.

• 18:56David Puder?

  Yeah.

• 18:58Speaker 01

  Yeah.

• 19:00David Puder?

  And the one thing that comes to my mind for practitioners is so vital to get early collateral. Because you're not going to get the full picture talking to the patient. You're just not going to get it.

• 19:11Speaker 01

  And that is hard, right? Because sometimes they don't, if it's an adult, then they don't, their families, they're not allowed unless there's permission. And so

• 19:21David Puder?

  Yep.

• 19:21Speaker 01

  There's a dis in it.

• 19:23David Puder?

  They can be paranoid about their, their family. They could be all bad on their family.

• 19:27Speaker 01

  So they don't want their family there. And then the doctor does not get the full picture.

• 19:32David Puder?

  Right.

• 19:33Speaker 01

  That happens a lot. Yes.

• 19:34David Puder?

  It's a balancing act because then if you, if, if you want the full picture and you, if you get it, you could thwart the alliance with the client. So you kind of have to like, yeah.

• 19:46David Puder?

  Tow the line of, you know?

• 19:48Speaker 01

  Yes. So I mean, when I first got my sister hospitalized, I was very fortunate. I mean, here in Houston, I was in the system. I knew I had new doctors. I knew I was, you know, here at the hospital as part of my department. So I was fortunate that they did ask me when she was first hospitalized and I, and they, they talked to me and I said, this is what I know.

• 20:16David Puder?

  It seemed like a struggle to get her hospitalized. You, you had to go back to the judge three times. And this is a lot of what families are dealing with nowadays. It's like, they know that their child needs treatment. Their child does not want treatment. And

• 20:30Speaker 01

  And unless they're a threat to themselves or others, but that is like, well, no, but they are going to die if something, if they don't get help now. That is really, I think, what most families do feel. And unfortunately, the law right now is, are they hurting themselves or are they hurting others? That's it. So it's extremely hard, but it does happen. I knew, I think you do have to be persistent and insist and keep going. And I know this is what I have told family now, and then they do succeed. But unfortunately, many families don't have the time or there is, there is no one there to actually go and do that and follow through. So that's another problem.

• 21:11David Puder?

  Yep. Yep.

• 21:15David Puder?

  Yeah. Julia, any kind of, any kind of reflections on the sister's story coming to your mind? Any, any questions, any follow up thoughts?

• 21:25Speaker 02

  You know, when Shiloh was talking, something really came back to my mind, which Cheryl and I discussed when she first came with the book proposal to me, so I'm the editor of the, of the book. And I helped her get it ready for publication. So there is a similar story that was published exactly 28 years ago. And it was another book called Conquering Schizophrenia: A Father, His Son, and a Medical Breakthrough. So it was written by Peter Wyden, who at the time was the journalist in, in the States, who had written the, had the highest number of words published in the, in English, you know, in the United States at the time, the most prolific, you know, writer. And he had two sons, and he discusses this openly in the book. So I'm not saying any, any family is secret or anything, it's published, you can just buy it.

• 22:10Speaker 02

  So it's, um, so he had two sons. Ron, the younger, who is the US Senator for Oregon, very famous Senator. And you see him on TV the whole time, head of committees in the Senate and super, you know, accomplished and successful. And the other one, Jeff, has schizophrenia history, very similar, almost identical to, um, to Cheryl's story with Patty. And the father spent, you know, his whole life trying to help the son, but the father lived in Connecticut, the son was in California. So he was in the public system and the father helped, you know, initially in the private and helped him as much as he could. And then at some point when the father was really elderly, he, he said, I just couldn't help anymore.

• 22:52Speaker 02

  And, um, and so I asked the father to write an editorial for Molecular Psychiatry about, you know, summarizing his, this whole saga that was started in a book. And then unfortunately he had a heart attack as he was writing this, my editorial. So I was his last editor, so to speak, and I was invited to the memorial, the whole thing. But it was essentially the same type of a situation that you have of very accomplished, you know, in the type case was one sibling, but the father too. So you have a very accomplished family and then this one person, for a combination of factors, really falls ill with something that you cannot deny. You know, there is a lot of, you know, people say, oh, depression is not really an illness or anxiety, and there are groups of people that will try to minimize the most psychiatric

• 23:33Speaker 02

  illness, but the, the illness that Cheryl's mother, you know, had and Patty and then Jeff Wyden, you cannot say it's not there, you cannot minimize it, you cannot say it's just like, uh, problems and difficulties in living. It's something, it's a very real, serious illness. And then, and we talk about the bio psycho, bio psycho social model. And what I said before, and what still perplexes me is that the biology, it, it's different individually, but it's not that completely different. The psycho, you know, it's, they were, developed their psyche in the same house. And then the social, they lived in the same society. And then one is so profoundly impaired and the other one is so extraordinarily accomplished.

• 24:16Speaker 02

  And that I think is the, the big question. I, I think the, the, the big problem, um, of trying to identify the symptoms early. And I, I lived for eight years in Australia, there's a big movement there that they call youth mental health. And exactly trying to find people before they fall and like catching them early and then to do interventions. But of the people who had the symptoms that, um, Cheryl described for the sister, maybe one third will eventually become chronically, you know, uh, either schizophrenia or chronic psychotic disorder. And the others may not. So if you begin and identify people too early and start treating them, you may get people committed to medication that may not need them at all.

• 24:58Speaker 02

  And that may really be going through a phase and then it eventually they get out of that. So I think the big challenge for all of us is like, you know, you see a person who is struggling as a teenager. What do you do? You just have to watch closely, but at what point you intervene, you know, do you, if you intervene too early, you can be, you know, over treating people who may not need treatment and be harming them that way. And then if you wait too long, you may, you know, not have treated them early enough and then denied them something that would have helped them. So I think the big question for us is when to do something, when you start to notice that the person, if the person's completely functioning and doing fine, then you know, there's nothing, you, you know, but it's gonna do anything. But if the person is struggling, when do, when is it just struggling? And when is it that something that really requires, you know, more serious treatment?

• 25:44David Puder?

  Yeah. These are really, really good questions. And I think it's, I'm not sure we're gonna be able to completely solve those. But I think that the thing, as you hear, Julia, you have to consider as well, like, he is reading every journal article that's coming through, you know, Molecular Psychiatry and all these great journals for years and years. So you're sitting with all of that knowledge as you ask these questions. And so when, when we talk about how there's no good answers, there, you know, this is, this is currently a struggle. And when we think about the antipsychiatry movement, which I'm very active on X, and I, I, I think because I, I'm annoyed by the antipsychiatry movement, I see, of course, in the algorithm, all the antipsychiatry stuff.

• 26:28David Puder?

  And, um, recently it was like someone who was talking about how they were getting off of antipsychotics. And there's this whole new movement in short form video, like TikTok, Instagram, you know, YouTube, whatever, where they'll talk about getting off of medication. And then you, they're like, I'm gonna get off my medication, follow me in my journey. And, um, sometimes it doesn't go well, right? And sometimes you're like, I don't know if this person was schizophrenic in the first place, but.

• 26:59Speaker 02

  Can I just introduce you something that, um, I was for a few years, uh, the Chair of Psychiatry at the Department of, Department of Psychiatry at University of Miami. And they have their Jackson Memorial Hospital, which is the main teaching hospital, which is the, um, third largest teaching hospital in the country. They have the busiest psychiatric emergency room. So one, it's a separate dedicated emergency room. And one day, I remember we had a census count of 167 visits in one day. So it was the, the, the record there.

• 27:28David Puder?

  Okay, wow.

• 27:29Speaker 02

  Highest in the country.

• 27:29David Puder?

  Very busy.

• 27:30Speaker 02

  It's a very busy setting. And the reason I'm bringing this up is that very, very rarely, it was a completely new person. Almost everybody, I, I, I mean, I didn't work in the emergency room myself, I would go visit and, you know, talk to the people there. Very rarely is a new person, it's usually people who, by themselves even, like, you know, stopped taking medication and stopped going to the clinic and stopped getting care. And then initially they feel okay, because the medications, they take a while to act and then once you stop them, they also take a while for the effect to go. So the day you stop them or the night, that week, you feel fine because you don't have any side effects, you feel a little lighter and you feel more yourself, but, and then you, and then the effect, the clinical effect is still there. But at some point, the clinical effect wears off and then people really fall through the cracks.

• 28:14Speaker 02

  And the vast majority of people who come to psychiatric emergency room and crisis are not new patients, are the patients you were talking about before who stopped the antipsychotics.

• 28:23Speaker 01

  Yeah. I think, uh, you know, speaking about this, uh, people have asked me now, uh, they ask about this, the new diet, uh.

• 28:31David Puder?

  Ketogenic diet.

• 28:32Speaker 02

  Ketogenic.

• 28:33Speaker 01

  Yes.

• 28:33David Puder?

  Yeah.

• 28:34Speaker 01

  And of course, there's a lot of research on that. And we know that, you know, the mitochondria energy, all the metabolism is extremely important. And we are finding a strong link with schizophrenia, with bipolar, in terms of those mechanisms. But I always, you know, people have asked me, families have asked me, because I speak to families all the time and say, well, what about that? What can we do that instead of medication? And I think of it as, you know, if you have diabetes, type one diabetes, where you don't have, you're not processing insulin, right? Having a good diet is extremely important. You need to have diet and take care of what you eat. But you also need to take care of a problem with, with insulin, right?

• 29:18Speaker 01

  You need medications a lot of the times. It depends, of course, on the severity of the illness, if you have type one diabetes, type two. But medications for diabetes are very acknowledged and accepted as you have, you need them, right? In addition to taking care of your diet. So that's the way I think of, people need to think of in schizophrenia, you know? Yes, absolutely. Diet is extremely important. We do that with my sister. We are very, very careful with what she eat and, and it does matter. You know, what you put in your body. But that is not in itself, I think, the cure for many people. And again, it depends on the person, it's all, our people have different symptoms, different severity of the illness, and that needs to be considered.

• 30:01Speaker 01

  But I think it's important to understand medications are extremely important in most severe cases with schizophrenia and diet does help. Yes, it does.

• 30:11David Puder?

  I, I would like to see in the future, like, for the patients that have responded to the ketogenic diet, right? And I don't think it's, um, it's gonna be every patient. It's gonna be a small proportion of patients.

• 30:24Speaker 01

  I don't think so either, I think that we, I agree.

• 30:26David Puder?

  We, we are at a place where there's case studies, right? There is no randomized controlled trials for schizophrenia that I know of at this point. For ketogenic diet, right? So with the patients that do respond, if we have bigger trials where there are certain percentage of patients that do respond. One question is, well, is this a patient that needed an antipsychotic in the first place? Cause we know that a very small percentage, maybe 10%, don't need an antipsychotic long term. Secondly, my question would be.

• 30:59David Puder?

  Is there something unique about their genetics? That makes them specifically positive to respond to the ketogenic diet? And I have, I have a lot of bipolar and schizophrenic patients. I've tried to put them on the ketogenic diet. I have yet to have one of them that could get off their meds. And when I say I try, they all haven't been able to be compliant. Because if you're really sick, it's like-

• 31:25Speaker 01

  It's hard for someone who doesn't have an illness to do that diet, right?

• 31:29David Puder?

  It's, it's very hard. It's very hard. Okay. So more to be revealed on that topic. Julia, do you have any sentiments on this specific question?

• 31:39Speaker 02

  Yes, I do, which is that in one of the early issues of molecular psychiatry, one of the biggest geneticists in the country, Ken Kandler, published a paper that was like, he has a large twin register in Virginia. So he looked at the identical twins, so who are discordant for depression. So some had severe depression, some nothing. And then he looked at the lives and there was nothing specific. That the only thing that he found is that the life stories of the ones with depression were like, you know, more complicated, like the ones without depression. They had gone to school, found someone that they liked, married, and then had a family and everything was okay. And the other ones were going, had gone through a lot in their lives, you know?

• 32:21Speaker 02

  And so the thing with the diet, let's say, can also be like, you know, coincidentally with the phase that the person is in. So you get someone that they change the diet, put on ketogenic diet. Let's say at that point in time, their lives are very stable. They may have a job, they have stable relationships. And then maybe the diet alone can hold them. Then they lose their job or the person they live with leaves or something bad happens. Then they're probably gonna go straight into a severe episode. So maybe the diet can hold people and everything else is okay. And then they may, they might be able to even do without the diet for a while, you know? Without, without anything, but they are like in a kind of a supportive situation. And then when that support goes, they crumble, you know?

• 33:05Speaker 01

  Yeah.

• 33:06David Puder?

  Yeah.

• 33:07Speaker 01

  The environment is extremely important is what we say, right? Everything that happens to us.

• 33:14Speaker 02

  And I think today, I mean, there are, I mean, he had immense twin registry. He ended up looking at 14 pairs. And he only found 14 people out of 1,000, literally, who had like one had this with stable, wonderful, nice, supportive life. And I think in the world today, that's very rare, you know, for you to think that you're gonna go through. And then the next day, you don't lose your job or you don't lose someone you love or you don't get mugged or something like difficult happens to you. And then at that point, if you're only on the diet, that's, that's when I think, you know, you may get into big trouble.

• 33:49David Puder?

  Yeah, more, more research is needed. More research is needed, you know, like if, if, if it comes out 20 years from now, we have a specific genetic profile of a certain type of person that's gonna respond 90 percentile to that diet. I'll be more than happy to run their genetic profile and, you know?

• 34:06Speaker 02

  There is one thing I'd like to add if I could, which is that you have, I know that you have a large audience and maybe people can exert their civil rights and call their representatives. Because as you said at the beginning of the podcast, my initial training was in endocrinology, specifically diabetes. And diabetes, as you all know, especially if you have type one, as Cello mentioned, you have to have this very strict control, which there was a question when I was beginning in the field, do you need that control to be that strict? And are people gonna have complications anyway? So they did this very large NIH funded trials and showed that the strict control was better and led to much better outcomes. And that's how diabetes care evolved. And there are thousands of National Cancer Institute sponsored clinical trials for cancer.

• 34:50Speaker 02

  And in mental health, we don't fund these large clinical trials for schizophrenia, for bipolar, for major depression. And, and I've, you know, tried to get them going, but it's not the priority right now. So I think, you know, it should be a priority and we should try to learn why do some people respond to this treatment combination? And why others respond to that treatment combination? Or to, you know, some people, one antidepressant holds them. Some people need several drugs, an antipsychotic and a mood stabilizer on top of the antidepressant for, just for depression. And so why? And who, who do you treat and in what way and how intensively? And what are the outcomes? So all these questions are unanswered in the psychiatric disorders, but they are very well answered in hypertension.

• 35:33Speaker 02

  The NIH has done very large clinical studies, diabetes type one and type two, all types of cancer. So we need to have that same type of clinical trials and clinical studies for the more kind of severe mental illnesses.

• 35:49David Puder?

  Yeah, absolutely. And we need, the funding needs to be the government because, you know, private, private corporations have, you know, their own sort of like agendas and they're not gonna run really long, very highly organized studies across, you know, tens of thousands of people. Cello, I wanna come back to your sister and clozapine specifically. She was admitted and I think you made the recommendation, clozapine. Put her on and put her on quickly, okay?

• 36:28Speaker 01

  Yes.

• 36:29David Puder?

  Because you only have so many days in the psychiatric hospital. And when I, when I read that, I was like, how do you know this? But so many of my colleagues do not, you know?

• 36:41Speaker 01

  I had been actually doing research on antipsychotics as part of my, at that moment in time, precisely, I was looking at, you know, metabolic syndrome and the consequences of different antipsychotics on the metabolic syndrome, which touches on what we've been talking about, metabolism. But I knew from just researching and looking at accounts that clozapine was the only drug that actually is effective or was extremely effective for psychosis and also for cognition, which is a very unusual combination.

• 37:23Speaker 01

  And I had been following Robert Lightman, who is a big advocate of clozapine. And I had read some of his books and actually knew him personally. And he was, he advocated for that. And, and on top of that, the research, you know, like you say, reading papers, I would, I knew that clozapine works. And I also knew, because, you know, my sister had a husband who unfortunately passed away and he had been taking care of her for the last 10 years. And I had been in touch with him for all that time. And he had told me what she had been on, on all the different medications, back and forth in the hospitals, and then nothing had worked. She had not been on clozapine because nobody wanted to put her on clozapine.

• 38:08Speaker 01

  You know, the doctors would not do that because of these concerns, you know? They would have to take the blood draws and all that. So I knew she had not tried clozapine and she had tried everything else. And that is why I said, I told my, the doctor that was attending her, I said, I know that she's been on everything else and nothing has worked. So please do not waste your time on them. She has not tried clozapine, please do that. And fortunately, he, he did do that immediately and it worked.

• 38:38David Puder?

  And do you know what, how much she was taking? Like how many milligrams roughly?

• 38:43Speaker 01

  So they, they started her low. I think initially, I can't remember now exactly the dose. I think it was perhaps 200, 300 milligrams.

• 38:54David Puder?

  Okay.

• 38:54Speaker 01

  Right now, I can tell her that she is, I can tell you that she is at 600.

• 38:59David Puder?

  600, yeah.

• 39:00Speaker 01

  And I, I, I give her, I put her pills, actually today, I just did that. Every week I do that. We still have to unfortunately take her for blood draws, but she's never had a problem with that. But, so they increased her slowly and got to the point where she is now, which is honestly, she's doing really, really well. She actually now goes to a clubhouse where she, I just dropped her off this morning and she loves it. She interacts with people and she is super excited to go every day. So I do think, I believe in clozapine. I believe it's, I still call it the miracle drug.

• 39:42Speaker 01

  I say in my book, I don't know of any other drug that has that effect right now. Some people respond to other drugs, but a lot of people don't. And I think that's why I said, put her on clozapine right away. Cause I knew she had not responded to it and anything else.

• 39:58David Puder?

  Julia, any thoughts on clozapine? And then maybe I'll ask some specific questions, but just general thoughts, what you're seeing in the research, what you've seen over the years?

• 40:08Speaker 02

  No, I think it's, as you said before, it's not something that's being commercially, you know, exploited. So the industry doesn't have a big interest in pushing clozapine because it's a drug that's been out there for a long time. It's off patent. But like some of these older drugs, it can be extremely effective for some people. So I think that it really needs to be tried. And yes, there are these medical concerns of the blood drawing that which actually have become optional in some, you know, some regions. But it's not as big a problem as people try to make it. And anyway, having a blood drawn and checking labs for someone with, even with a chronic mental illness is a good thing anyway. They should be having regular medical checkups regardless.

• 40:52Speaker 02

  So I think that it's a very important drug that I think then should be a little bit underutilized. And unfortunately, I think lithium is going in the same direction for bipolar. Because there is no big commercial interest and the other drugs are being pushed very strongly. So I think it's in a way, almost like lithium for bipolar, it could be the gold standard of treatment. But people have to take blood levels, they have to monitor and there's no commercial interest behind it. But I really think that if you have a patient with schizophrenia that's not responding to conventional treatment, they should go to clozapine sooner rather than later.

• 41:26David Puder?

  Yeah, and I would say actually, most of the neutropenia issues are in the first like two to three months. And so now, there's even a consider, you know, it's very, very rare, if they've been on it for two years, that they would ever have that issue. You should look at some of that data and reconsider with the doctor how often tests are needed. In my practice, I have some patients that getting a blood draw is like torture. And if they have treatment resistance schizophrenia, sometimes you just have to take a little bit of an educated risk.

• 42:08David Puder?

  You know, talking to the parents, talking to the family about like, okay, this is, you know, if they do get a runny nose, a cold, probably need to go check their blood level in an urgent care. But if they're refusing, clozapine can be life-saving. I think it might be a good paper, Julia, to reconsider, like, under some circumstances, the frequency of use. What do you think?

• 42:36Speaker 01

  Yeah, you know, I think FDA already said that the blood draws, if you had after a year, they shouldn't be necessary. But here in Texas, it's still, we still have to do them once a month. So, and that also brings to the point of where it doesn't do, are there, is there family involved that can help patients go and get the blood draw? Because as it is, that's complicated for anybody, you know, they don't have a car, they have to get themselves to the hospital, to wherever they have to go to get the blood draw. So that's extremely difficult for many patients. And unfortunately, that's a limitation and why many don't do it, or many doctors don't want to do it because there's no family involved. Right?

• 43:19David Puder?

  One specific study I'll show you to kind of like illustrate this is, this study was called Clozapine- induced Agranulocytosis Incidence and Risk Factors in the United States. They looked specifically at data from 11,555 patients who received clozapine. And only 61 had agranulocytosis in the first three months. So this is a pretty low percentage of incidence, right? And very few had it later.

• 43:59David Puder?

  So this, this, this kind of study, I hope, and many others, need to be kind of like on the forefront of clinicians' minds. The real risk and the timing and the consideration, and the REMS program is actually dissolved. So there is, you know, it's not required by the pharmacist any longer to see a lab draw. It's, it's on the physician to know and to kind of have a, an idea on what to do.

• 44:27Speaker 02

  And what's interesting is the state variation. So I looked at New York's requirements. So New York dropped all, you know, blood testing requirement. So essentially, what they dropped, the pharmacy linked to clozapine and blood draw, because in other jurisdictions, I imagine in Texas, the pharmacy cannot dispense until they have the blood draw in their records. So New York broke that. So there is no requirement for blood draw before a prescription can be filled. So it's a clinical recommendation, not like a requirement for dispensing. And the guidelines here in New York are that the patients can get a 90-day supply if they are stable and treated for more than one year, who had no previous low blood counts

• 45:10Speaker 02

  and who lacks safer practical testing access. So the people that Sheila was talking about before, so here in New York, they can get 90-day supply automatically. I don't think that they can in Texas, right?

• 45:21Speaker 01

  No, we still are required to do a monthly blood draw. Yeah.

• 45:28Speaker 02

  Well, you also have to look at the state differences, you know?

• 45:31Speaker 01

  Yeah.

• 45:33David Puder?

  So, okay, from other, if your genetic work, your genetic research, obviously has been highly influenced by your own family's struggles. What kind of epiphanies or what kind of things do you feel like you've come to that have been helpful for you in that journey?

• 45:52Speaker 01

  Yes. So when I started this 25 years ago, we knew nothing. And the genome, the whole was sequenced in 2003. I thought, I started in 2001. So it hadn't happened yet. And that, but the fact that it happened right when I was starting the work, really, for me and my, my own career was instrumental. Because then we have the whole genome sequence and then we could be like, oh, now we can look at the entire genome and see where the genes are. That was huge. And as we've been doing it over 25 years, but now we know, you know, we have 287 genes

• 46:33Speaker 01

  that I do believe are strong candidates for schizophrenia. They have been replicated over three iterations now from the Psychiatric Genomics Consortium, which has been amazing. So people have asked me throughout the years, when they know about my family, I always get this question. They say, well, have you gotten, have you gotten genetic testing? Have you done the genetic testing? Do you know what genes? When they would ask me that, and especially initially, when I was thinking about my children, my children having kids or not, and even when they were little, the people would say, have you tested them? I would say, no. My, I would be very definitely say, no, I know I have a genetic risk for schizophrenia.

• 47:14Speaker 01

  It won't help me right now, at this was maybe 20 years ago. It won't help me at all to see, because I know we have the risk. So help, you know, it wouldn't help. But now I have actually changed my mind. Because, first of all, I have strong confidence in the genes that have popped, that have been discovered. And now we have the tools to study what those genes are doing. Before, we did not. And for me, that was really important because I would say to people, well, even if I knew that there were these genes, what could I do about it? We don't know what they're doing. We don't know how they're influencing the disease. We don't know whether, if we have this particular combination, what treatment can we get?

• 47:56Speaker 01

  But now I think we can with the tools that we are be able to study, you know, brain tissue, virtual brain biopsies of individuals, if we get skin cells or blood cells. So I think that is extremely important because as Julie was mentioning, we know for cancer, we know for diabetes, we know for hypertension, exactly how these things work because we've been able to study the biology. We couldn't do that with schizophrenia. But now we can because we have the tools to do it. So that is where I believe that has helped me a lot and that I could, I think I will have my family's sequence now. And we will know what combination of genes of those 287 we have. Of course, we don't have all of them. Everybody has different, perhaps we'll have 20 of them or so.

• 48:41Speaker 01

  And we will be able to know how strong the contribution of those genes are in our own family. And perhaps then help us identify treatments, prevention. I have my own children. They're, they're still young and I worry about them. They're okay. But they're still in that period of time that is really critical. So I think I will do that now.

• 49:05David Puder?

  Okay.

• 49:06Speaker 01

  Does that answer your question?

• 49:07David Puder?

  Well, let's, let's have you back when you, if you want to, if you want to talk about it, once you get it done.

• 49:14Speaker 02

  I have a question for Sheila, if I can ask, is that okay?

• 49:17David Puder?

  Yeah, go for it.

• 49:18Speaker 02

  Yeah. So one thing that I think is very critical in the book and then in your life, of course, and that's how the book reflects it, is that, you know, your mother had problems and the problems were, you know, becoming worse and worse or bigger and bigger. And then at some point, the words, but nobody had mentioned the word schizophrenia. And then at some point, it was mentioned. So if a family is hearing the word schizophrenia about someone who's not doing so well in that family, but if they are hearing the word schizophrenia for the first time, what do you want them to know today? What does that mean today?

• 49:54Speaker 01

  I think today, they should, they could get genetic testing. They could find out what combination of genes that perhaps their, their family has. And they could, if they have young children, they're, and I've done this with my own children, is Follow them, monitoring, like you said, Yuli, we don't know whether or not they're going to develop the illness or not, but I think taking them regularly to psychologists like we do any other doctor is extremely important. So if they do develop some kind of problem, we'll be able to know whether it is a sign of the illness or whether it's just a sign of struggling for some reason.

• 50:37Speaker 01

  So those two combinations, I would say, know that perhaps you can get your genes tested and see what combination and talk to a genetic specialist, someone who would be able to give you advice on it because it's not a sentence. Having the genes is not a sentence, but then you can control, you try to control as much as you can. And of course, it's not possible to control your environment totally, but as much as you can. Eliminate stress, for example, I'm a bit advocate of that. Sleeping, developing sleep habits, people ignore sleeping, they always think exercise and diet, but I say, sleeping is just as important as those other two things.

• 51:18Speaker 01

  So there are things that can be done, you know, minimizing stress as much as you can. That's my big thing. I've done that with my own children and we talk about it and having a relationship and talking about it, that's extremely important to you. With my own children, since they were 10, I told them, and they knew from seeing their grandmother, for seeing their aunt, and I did not hide it from them. I said, this is schizophrenia and you have a risk and it's in your genes, so you need to know. And we've always talked about it and I don't think they're afraid. I think they understand it and having an understanding of it helps them think about

• 51:59Speaker 01

  their own lives and the choices that they make in their own lives, which we did not have that when we were growing up. I wish I had had that knowledge and understanding of the things that I do matter and the choices that I make matter. So I would say, first of all, it's not a sentence, hearing that word. It is just a risk and a predisposition. And you need to take care of it like a risk for a heart attack or cancer.

• 52:28David Puder?

  Excellent. Kind of like wrapping up our time together, I mean, I'm feeling like we could go another hour, but I know we have limited time here today.

• 52:39Speaker 02

  Can I ask one last question to Cello, which is something that I've, as this podcast is going, it's really stuck in my head here, which is that in the world today, there are some people, and I look people up a lot for what I do, and some people have a lot of information, their whole lives, they're like on Instagram and Facebook and X and it's all out there. Other people are very private and you look them up and you don't find anything. So Cello and her family are more on the private side. And then they come up with this book that really reveals a lot. So what drove you to go from the private, you know, community to the one that's like, you know, puts what's going on out there for others to see?

• 53:17Speaker 01

  Thank you, Julie, for asking that question. And for me personally, when I first started writing the book, it was more about healing for myself and therapy for myself. But it turned out I was, I started writing it during COVID. You know, I was at home and my father was living with me, so he started telling me stories and I had the time. But right around that time, you know, this big anti-science movement started and this people saying things that scientists were just doing things on purpose or things like that. And I told myself, I think it's our own fault. We're very private and we don't talk, we go to conferences, we talk amongst ourselves, but we don't talk to others. We don't talk to the public.

• 54:00Speaker 01

  And I think maybe we need to, we need to do that. And so then I thought as I was, that maybe one day I would publish this, but I didn't do it at all, as you know, because my family was involved. My father, so after I talked to you, I mean, this is when I first talked to you about the book, I went to them and I told them, you know, I'm writing this book and it could get published. I said, should I do this? And they all said, absolutely, yes, do it. I think they understood that people needed to know and that we needed to talk about this more. And they all knew that we never talked about it.

• 54:41Speaker 01

  We are just now talking about it, perhaps part because of the book. So they gave me their blessing and I'm very grateful for them because yes, we are now all exposed and everything's out there.

• 54:54David Puder?

  Yeah.

• 54:55Speaker 01

  But they've been very supportive.

• 54:57David Puder?

  Very brave of you and very important, very important. And it also like, like it makes sense of your story, it makes sense of your passion for genetics and studying genetics. You know, not only are you like an extremely well-published, you know, foundational researcher in this field, but you have lived it yourself, you know, and that's, that's really powerful to share that, to share your journey. I'm so happy for you to come on and, and I hope that it creates some bravery with some of my other listeners, maybe been listening for a long time, maybe you have a story. You know, I think a lot of people haven't put together why they're so passionate about

• 55:41David Puder?

  some field, you know? Like I recently shared that my mother, my mother's mother had postpartum psychosis. I've done a bunch of episodes on postpartum psychosis. And, you know, that definitely impacted my family, my upbringing, my mother. It's one little piece, you know, you've obviously shared a lot more pieces of your life than I have, but I think it's important that we come out and we say, there's a reason why, you know, we believe what we believe.

• 56:08Speaker 01

  Yeah.

• 56:09David Puder?

  You know?

• 56:10Speaker 01

  This is why we do what we do.

• 56:11David Puder?

  Right. Like lithium came out when my mother was 16, 1970, and it definitely helped my grandmother for the rest of her life, you know?

• 56:24Speaker 01

  Ah.

• 56:25David Puder?

  But it wasn't around before that, right? Thorazine came out when my mother was six months old. So there was no antipsychotic before six months old.

• 56:33Speaker 01

  Yeah.

• 56:34David Puder?

  And, and we think about like how the antipsychiatry movement is like forgetting all of this, you know, it's like they have these tropes that they'll say, there's, there's no science, there's no data, there's no biological markers for mental illness. They have these tropes that they repeat over and over again. And I'm just like, no, there's actually like, you know, almost 300 genes for schizophrenia and there's like articles upon articles and, you know?

• 57:01Speaker 02

  Yeah.

• 57:02David Puder?

  It's, it's.

• 57:03Speaker 01

  And we're there, we're at this moment in science that I think it's going to even get, we are going to have, I believe it very, very strongly, like we do for cancer. Now that we can study the tissue, the brain itself, we are going to get a better understanding and better treatments very soon.

• 57:22David Puder?

  Absolutely, absolutely. All right. Well, thank you guys for coming on. Definitely do a follow-up. Each of you have so much to share with my audience.

• 57:32Speaker 01

  Thank you so much. This has been very fun.

• 57:34Speaker 02

  Thank you.

• 57:35Speaker 01

  Thank you.

• 57:36Speaker 02

  Thank you.