Episode 282: Schizophrenia: Early Signs, Genetics, Treatment, and a Family’s Lived Experience with Dr. Consuelo Walss-Bass and Dr. Julio Licinio
This episode is awaiting CME approval
There are no conflicts of interest to report for this episode.
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Schizophrenia Through the Lens of Family and Science (00:00)
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. Consuelo "Chelo" Walss-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 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, toxicology, 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 a hundred papers and continuous NIH funding.
Puder:
Her memoir, Why My Sister? was just published this month. Also with me is Dr. Julio Licinio. He is a distinguished professor of psychiatry at SUNY Upstate Medical University, dually 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's going up, leptin's going down. When leptin's going up, cortisol's 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 Chelo. So welcome to the podcast. Hopefully I got all that bio right.
Walss-Bass:
Thank you for having me.
Licinio:
Thanks for having me too.
Growing Up With a Mother With Schizophrenia (02:11)
Puder:
It's great having you guys. So, okay, my first question and, it's for Chelo. Okay, so talk to me about being raised by your mother with schizophrenia.
Walss-Bass:
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, it was just really wondering why she did the things that she did, some of them violent things, you know, why she talked to herself, or why hide herself in her room, or not speak to us, so many different things that were experienced by myself and my siblings. So that was very hard. And always wondering, “Why? Why was this happening?” That was really my main question and what drove me to my research.
Puder:
Okay. And, any specifics? 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 back then, but now you're like, "Oh, this is what was going on."
Walss-Bass:
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 we were like, "What? Who is she talking to?" But of course, there was nobody there. So we would say, "Oh, you're talking to us?" You know, me and my siblings are very close. The three of us were one year apart. The oldest ones of five. And anyway, those are our first memories, just her laughing out loud, talking to someone who wasn't there. And now, of course, I know those are part of the symptoms, the psychosis, the hallucinations, and she would see things or hear things, hear voices. I have very strong memories of that.
Puder:
What about any of the negative symptoms of schizophrenia? Any memories of what that was like?
Walss-Bass:
Yes. So the negative symptoms in her, now I know. Understanding is 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 cry or something, or fall, or she would be blank-faced. Those now I recognize, of course, as negative symptoms, but that was also hard because it would be like, well, she just doesn't care, or is she not responding to me, or to something happening to me. That was hard.
Puder:
Yeah.
Walss-Bass:
Not receiving any kind of care or affection back, once something happened. Or if we would tell her about something at school, she would just have no emotion whatsoever. None. Oh, she'd be, "Oh," and then that was it. So, those things were hard as well.
Puder:
And any cognition, memory, frontal lobe types of symptoms that you witnessed?
Walss-Bass:
So, those things, I don't have a lot of memories about that because I didn't really understand any of that until I started 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 know now as professional, sometimes the illness comes and then it goes away and it seems like she's okay, and then it comes back, and there's these, like, 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, and almost like, "Oh, wow, she's back to the mom that I remembered as a really, really young child." But those moments would get shorter and shorter as time went along.
Walss-Bass:
And so, I think by the time I was in my late teens, early 20s, they were almost non-existent. And so, she, when I was really young, she would prepare amazing meals. She would be a really good mother. 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 stay in her room all day and not come out. So those periods, I think, her ability to do things, executive function, was really diminishing.
Puder:
Before we move off your mother, Julio, any follow-up questions on that, or any sort of thoughts as we're hearing this?
Puder:
Julio, any kind of follow-up thoughts about specifically, Chelo's mother before we kind of move on to her sister and the story? Yeah.
Licinio:
Yeah, so Chelo, about your mother, one thing that I think is kind of really remarkable is that 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 situations, the same circumstances, have the same overall. They're not the same people, but they have the overall, the same genetic pull from the same parents and grew up in the same place. And your mother is clearly affected, has something with her, so it's not that you can just overlook it and say, "Oh, this is a small thing and let's look the other way." It's something really serious that impacts her life very dramatically. And the other ones are fine. So, can you give us some thoughts?
Licinio:
How do you feel about that? Because so impaired and the other ones are so well.
Schizophrenia Genetics, Environment, and Family Risk (08:04)
Walss-Bass:
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, I've never seen any signs of any kind of psychiatric problem, and they all have careers and were very successful. They have families. And they have asked me that as well, like, "Why not when I started studying this, why is it that she developed these symptoms or this illness, and we did not?" Honestly, I don't know myself yet the answer to that question. That is one of the reasons why I'm studying this. But it is. I think of the genetics of schizophrenia. We know schizophrenia runs in families, and there's genes that are inherited.
Walss-Bass:
The way I have thought about this is that there's a combination of genes that lead to the illness, 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 that sense of the word. You know, they may actually be good. There may be some good reason why they've survived throughout evolution. Throughout, you know, the beginning of time, 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 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.
Walss-Bass:
So during brain development, perhaps, the trauma for them was different, even though it was the same trauma, the brain was developing at a certain level for them that caused this to happen. Does that make sense?
Puder:
Yes.
Walss-Bass:
And of course, those are all theories, but I do think of it. We tend to think of schizophrenia as 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. [It can] help us get out of a situation. Anxiety can help us do something when we need to do it, you know? It's only the extreme illness itself that's really bad.
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.
Walss-Bass:
Yes, or Vincent van Gogh. He was very creative. Right?
Puder:
Yes. So even 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.
Walss-Bass:
And that helps them succeed in society, to advance, perhaps. These families, usually we tend to study the illness, the one person who's sick, and we don't necessarily pay attention to the other members of the family and 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 they have that help them maybe do something different from the person that did develop the illness.
Early Signs of Schizophrenia and the Prodromal Period (11:52)
Puder:
I want you to talk about your sister, Patty. So Patty was the one who 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 what we know about early symptoms in schizophrenia versus what you witnessed in your sister, and maybe if there's an overlap or not an overlap there.
Walss-Bass:
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 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, she always had a hard time. She would struggle from an early age with poor grades. She excelled in art. She was always amazing at drawing.
Walss-Bass:
She would draw and she would paint. She was very creative. But everything else, she seemed to struggle. So that was early on, and now that I think of it, 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 we were talking about her. I remember when [we had] reunions, we would all get together, usually on Sundays, and have dinner. I would have, you know, the early lunch in Mexico on Sundays and 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'd say, "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.
Puder:
In the book, it seemed like she would also sometimes get angry in public and kind of make a scene that was shocking to the family.
Walss-Bass:
Yes. The first time she did that, that was extremely shocking, and that, I think, was the beginning of the end, I would call it for her. There was one episode where we were at the airport. We were all going to Orlando. Well, my parents, and her, and my little brother, Leo, who was the youngest of us all. And she started making a scene. It was one of those things that she started saying that none of us cared about her we ignored her, something along those lines. We said no, and then she started screaming. But literally screaming loud, where everybody around us was. We're in an airport waiting for our flight to board. 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 of the plane because she was doing that.
Walss-Bass:
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 then after that, when we got to Orlando, things got even worse. So, I think, yes, that episode was the first of many. Then later, she would become more and more irritable, more and more angry, sometimes for no reason. I lived with her for a few months. Unfortunately, I could not. That was when I realized 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 she would stand in front of my face and start yelling at me.
Walss-Bass:
And I decided to move out, after just a few months. Unfortunately, now I realized she needed help, but I didn't know at the time.
Puder:
And then she got arrested. Do you want to talk about that? And I'm curious what the arrest was for.
Walss-Bass:
Yes. So I don't mention, I don't get into the details in the book. I later knew that. And she never really actually outright said what happened, but it was for breaking and entering. So what I gathered, now, even now, she once in a while brings it up. Now she lives with me, after she's been living with me for 10 years, and we have a really good relationship now. So she's brought it up, and I think what happened, she broke into one of her boyfriend's, into his house, into his home. And….
Puder:
A past boyfriend?
Walss-Bass:
A past boyfriend. And I think he's the one that called the police and that's why she got arrested.
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? Like, the differential is pretty broad at this point, you know?
Walss-Bass:
People think, "Oh, she's just being an impulsive person, or she just has anger issues, but not recognize the actual illness."
Puder:
Yes. Right.
Walss-Bass:
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 because we had lived with my mom, and I think my father did know, but he was really in denial.
Puder:
Yep.
Walss-Bass:
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 a psychiatrist.” I think that would've been, if we had done that, if my father had done that, perhaps things would've been different for her.
Puder:
Yeah.
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.
Walss-Bass:
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 there's a disconnect there.
Puder:
They could be paranoid about their family.
Walss-Bass:
Yes, they are paranoid. So they don't want their family there. And then, the doctor does not get the full picture. That happens a lot. Yes, I know.
Puder:
It's a balancing act, because then if you want the full picture, if you get it, you could thwart the alliance with the client. So you kind of have to toe the line of, you know….
Walss-Bass:
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 doctors, 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 they talked to me, and I said, "This is what I know."
Puder:
It seemed like a struggle to get her hospitalized. You had to go back to the judge three times.
Walss-Bass:
Yes, it was.
Puder:
And this is a lot of what families are dealing with nowadays. They know that their child needs treatment. Their child does not want treatment. And you come back….
Walss-Bass:
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 think you do have to be persistent and insistent and keep going. And I know this is what I have told families 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 or follow through. So that's another problem.
Puder:
Yes. Julio, any kind of reflections on the sister's story coming to your mind? Any questions, any follow-up thoughts?
Licinio:
I have a very… you know, when Chelo was talking, something really came back to my mind, which Chelo and I discussed, when she first came with the book proposal to me. So I'm the editor of the book, and I helped her get 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 [also known as Peter Weidenreich], who, at the time, was a journalist in the States who had the highest number of words published in English, in the United States. At the time, the most prolific writer. And he had two sons. And he discusses this opening in the book, so I'm not saying any family secret or anything.
Licinio:
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 accomplished and successful. And the other one, Jeff, has schizophrenia, a history very similar, almost identical to Chelo'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 private, and helped him as much as he could. And then at some point when the father was really elderly, he said he just couldn't help anymore. And so I asked the father to write an editorial for Molecular Psychiatry about summarizing this whole saga that was sorted in a book.
Licinio:
And then, unfortunately, he had a heart attack as he was writing this, my editor. So I was his last editor, so to speak, and was invited to the memorial, the whole thing. But it was essentially the same type of a situation that you have a very accomplished, in that 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 are a lot of people who say, "Oh, depression is not really an illness… or anxiety." And there are groups of people out there who try to minimize, you know, psychiatric illness, but the illness that Chelo's mother had, and Patty, and then Jeff Wyden, you cannot say it's not. You cannot minimize it.
Early Intervention and Treatment of Psychosis (23:31)
Licinio:
You cannot say it's just like problems and difficulties in living. It's something, it's a very real, serious illness. And then, we talk about the biopsychosocial model. And what I said before, and what still perplexes me is that the biology, it's different individually, but it's not that completely different. The psycho, you know, they developed a 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. And that, I think, is the big question. I think the big problem of trying to identify the symptoms early. I lived for eight years in Australia. There's a big movement there that they call youth mental health and trying to find people before they fall and catching them early and then to do interventions.
Licinio:
But of the people who had the symptoms that Chelo described for the sister, maybe one third will eventually become chronically either schizophrenic 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 and that may really be going through a phase, and then eventually they get out of that. So I think the big challenge for all of us is, you see a person who's struggling as a teenager, what do you do? You just have to watch closely. But at what point do you intervene? If you intervene too early, you can be overtreating people who may not need treatment and may be harming them that way. And then, if you wait too long, you may not have treated them early enough and then deny them something that would have helped them.
Licinio:
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 there's nothing, nobody's going to do anything. But if the person is struggling, when is it just struggling and when is it something that really requires more serious treatment?
Puder:
Yes. Those are really, really good questions. And I think it's, I'm not sure we're going to be able to completely solve those. Not yet. I think that the thing, as you hear Julio, you have to consider as well, he is reading every journal article that's coming through 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 we talk about how there's no good answers, there is currently a struggle. And when we think about the anti-psychiatry movement, which I'm very active on X, and I think because I'm annoyed by the anti-psychiatry movement, I see, of course, in the algorithm all the anti-psychiatry stuff and recently it was like someone who was talking about how they were getting off of antipsychotics.
Puder:
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 a medication. And then you get, they're like, "I'm going to get off my medication. Follow me in my journey." And 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 there's….
Licinio:
Well, can I just interject something that I was, for a few years, the Chair of Psychiatry at the Department of at University of Miami, and they have there at Jackson Memorial Hospital, which is the main teaching hospital and is the third largest teaching hospital in the country, they have the busiest psychiatric emergency room. So 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 record there. Okay. Highest in the country. Very busy. With 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 mean, I didn't work in the emergency room myself, I would go visit and, you know, talk to the people there.
Licinio:
Very rarely is a new person. It's usually people who, but by themselves, even like, you know, stop taking medication and stop going to the clinic and stop 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 that week, you feel fine because you don't have any side effects, you feel a little lighter and you feel more yourself. And then you, you know, 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. And the vast majority of people who come to a psychiatric emergency room in crisis are not new patients, they are the patients you were talking about before who stopped the antipsychotics.
Metabolism, Ketogenic Diet, and Emerging Schizophrenia Research (27:08)
Walss-Bass:
Yes. I think, speaking about this, people have asked me now, they ask about this ketamine. Sorry, not the ketamine, the new diet. What's that called?
Puder:
Ketogenic diet?
Licinio:
Ketogenic.
Walss-Bass:
Yes. And of course, there's a lot of research on that. And we know that the mitochondria energy and metabolism is extremely important. And we are finding a strong link with schizophrenia, [and] 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, they say, "Well, what about that? What can we do instead of medication?" And while I think of it as, 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 [a good] diet and take care of what you eat. But you also need to take care of a problem with insulin, right? You need medications a lot of the time. And it depends, of course, on the severity of the illness [and whether it is] type one diabetes or type two.
Walss-Bass:
But medications for diabetes are very acknowledged and accepted. You need them, right, in addition to taking care of your diet. So that's the way I think people need to think of schizophrenia, you know? Yes, absolutely, diet is extremely important. We do that with my sister. We are very, very careful with what she eats. 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. People have different symptoms, different severity of the illness, and that needs to be considered. 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.
Puder:
I would like to see in the future for the patients that have responded to the ketogenic diet. And I don't think it's going to be every patient. It's going to be a small proportion of patients.
Walss-Bass:
No, I don't think so either. I think that we agree.
Puder:
We are at a place where there's case studies, right? There are no randomized controlled trials for schizophrenia that I know of at this point. No [RCTs for] ketogenic diet, right? So with the patients that do respond, if we have bigger trials where there are a certain percentage of patients that do respond, one question is, well, is this a patient that needed an antipsychotic in the first place? Because we know that a very small percentage, maybe 10% don't need an antipsychotic long-term. Secondly, my question would be, is there something unique about their genetics that makes them specifically positive to respond to the ketogenic diet? And I have a lot of bipolar and schizophrenic patients [who] I've tried to put them on a ketogenic diet. I have yet to have one of them that could get off their meds.
Puder:
And when I say I try, they all haven't been able to be compliant because if you're really sick, it's hard.
Walss-Bass:
It's like, it's hard for someone who doesn't have an illness to do that diet, right?
Puder:
It's very hard. It's very hard. Yes. Okay. So more to be revealed on that topic. Julio, do you have any sentiments on this specific question?
Licinio:
Yes. I do, which is that in one of the early issues of Molecular Psychiatry, one of the biggest geneticists in the country, Kenneth "Ken" Kendler, published a paper that was, he has a large twin registry in Virginia. So he looked at the identical twins who are discordant for depression. So some had severe depression, some nothing. And then he looked at the lives, and there was nothing specific. The only thing that he found is that the life stories of the ones with depression were, like, you know, more complicated, [than] 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 had gone through a lot in their lives, you know? And so, the thing with the diet, let's say, can also be like, coincidentally with the phase that the person is in.
Licinio:
So you get someone that they change the diet, put on a 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 the job, or the person they live with leaves, or something bad happens. Then they're probably going to go straight into a severe episode. So maybe the diet can hold people when everything else is okay. And then, they might be able to even do without the diet for a while, you know, without anything. But they are in a supportive situation. And then when that support goes, they crumble, you know?
Walss-Bass:
Yes. Yes. The environment is extremely important is what we say, right? Everything that happens to us.
Licinio:
And I think today, I mean, he had an 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 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 going to 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 difficult happens to you. And then, at that point, if you're only on the diet, that's when I think, you know, you may get into big trouble.
Puder:
Yes. I think that more research is needed. More research is needed. You know, if it comes out 20 years from now, we have a specific genetic profile of a certain type of person that's going to respond 90 percentile to that diet, I will be more than happy to run their genetic profile and….
Licinio:
There's 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 as an endocrinologist, specifically diabetes. And diabetes, as you all know, especially if you have type one, as mentioned, you have to have this very strict control. There was a question when I was beginning in the field, do you need that control to be that strict and are people going to have complications anyway? So they did this very large NIH-funded trial 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 institutes sponsored clinical trials for cancer.
Licinio:
And in mental health, we don't fund these large clinical trials for schizophrenia, for bipolar, for major depression. And I've tried to get them going, but it's not the priority right now. So I think it should be a priority, and we should try to learn why some people respond to this treatment combination and why others respond to that treatment combination or to those, you know? Some people, one antidepressant holds them. Some people need several drugs and an antipsychotic and a mood stabilizer on top of the antidepressant, 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. The NIH has done very large clinical studies with diabetes type one and type two, all types of cancer.
Licinio:
So we need to have that same type of clinical trials and clinical studies for the more severe mental illnesses.
Clozapine for Treatment-Resistant Schizophrenia (34:30)
Puder:
Yes. Absolutely. And the funding needs to be [from] the government because private corporations have their own sort agendas and they're not going to run really long, very highly organized studies across tens of thousands of people. Chelo, I want to come back to your sister and clozapine, specifically. She was admitted and I think you made the recommendation for clozapine and put her on quickly. Because you only have so many days in the psychiatric hospital. And when I read that, I was like, "How do you know this?" But so many of my colleagues do not.
Walss-Bass:
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 metabolic syndrome, which touches on what we've been talking about, metabolism. But I knew from just research 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. And I had been following Robert Laitman, who is a big advocate of clozapine, and I had read some of his books and actually knew him personally, and he advocated for that. And, on top of that, the research, like you say, reading papers, I knew that clozapine works. And I also knew, because my sister had a husband who unfortunately passed away, and he had been taking care of her for the last 10 years.
Walss-Bass:
And I had been in touch with him for all the time, and he had told me what she had been 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, you know. The doctors would not do that because of these concerns [that] they 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 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 did do that immediately, and it worked.
Puder:
And do you know how much she was taking? Like how many milligrams, roughly?
Walss-Bass:
So they started her low. I think initially, I can't remember now exactly the dose. I think it was perhaps 200, 300 milligrams. Right now, I can tell you that she is at 600.
Puder:
600.
Walss-Bass
And I give her 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. 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 is, 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. I say it 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.
Walss-Bass:
And I think that's why I said put her on clozapine right away, because I knew she had not responded to anything else.
Puder:
Julio, 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?
Licinio:
No, I think it's, as you said before, it's not something that is being commercially 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 the medical concerns with the blood drawings, which actually have become optional in 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 a chronic mental illness is a good thing anyway, and they should be having regular medical checkups regardless. So I think that it's a very important drug that I think is being a little bit underutilized.
Licinio:
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 could be the gold standard of treatment, but people have to take blood levels, they have to monitor, and then, 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.
Puder:
Yes, and I would say actually, most of the neutropenia issues are in the first two to three months. It’s very, very rare that, if they've been on it for two years that they would ever have that issue. You should look at some of that data.
Walss-Bass:
It is rare.
Puder:
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-resistant schizophrenia, sometimes you just have to take a little bit of an educated risk, you know, talking to the parents, talking to the family about, okay, if they do get a runny nose, a cold, [they] probably need to go check their blood level at an urgent care. But if they're refusing, clozapine can be life-saving. I think it might be a good paper, Julio, to consider, under some circumstances, the frequency of use.
Walss-Bass:
Yes, and I think the FDA already said that the blood draws, if you had, after a year, they shouldn't be necessary. But here in Texas, we still have to do them once a month. So, that also brings to the point of whether family is involved that can help patients go and get the blood draw? Because as it is, that's complicated for anybody. 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 in why many don't do it. Or many doctors don't want to do it because there's no family involved.
Walss-Bass:
Right?
Puder:
One specific study, I'll show you to illustrate. This study was called, “Clozapine-Induced Agranulocytosis—Incidence and Risk Factors in the United States,” and 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 incidents, right? And very few had it later (Alvir et al., 1993). So this kind of study, I hope many others, need to be on the forefront of clinicians' minds. It's the real risk and the timing and the consideration. And the REMS program is actually dissolved [as of June 2025]. So it's not required by the pharmacist any longer to see a lab draw. It's on the physician [or provider] to know and to kind of have an idea what to do.
Licinio:
And what's interesting is the state variation. So I looked at New York's requirements. So New York dropped all blood testing requirements. So you can do it…essentially what it dropped, the pharmacy linked close up in a 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 and who lack safe, practical testing access. So the people that Chelo was talking about before, so here in New York, they can get 90-day supply automatically.
Licinio:
I don't think that they can in Texas, right?
Walss-Bass:
No, we still are required to do a monthly blood draw. Yes.
Licinio:
So you also have to look at the state differences, you know?
Puder:
Yes. So, okay. So from your genetic work…. Your genetic research, obviously, has been highly influenced by your own family 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?
Schizophrenia Genetics and the Future of Personalized Psychiatry (44:11)
Walss-Bass:
Yes, so when I started this 25 years ago, we knew nothing, and the genome, the whole [genome] was sequenced in 2003. I started in 2001, so it hadn't happened yet. But the fact that it happened right when I was starting the work really, for me and my own career, was instrumental because then we have the whole genome sequence, and then we can 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 that over 25 years, but now we know that we have 287 genes that I do believe are strong candidates for schizophrenia. They have been replicated over three iterations now from the Psychiatric Genomics Consortium (PGC), which has been amazing. And so people have asked me throughout the years when they know about my family that I always get this question.
Walss-Bass:
They say, "Well, 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 how children, my children having kids or not, and even when they were little, then people would say, "Have you tested them?" I would say no. I would very definitely say, no. I know I have a genetic risk for schizophrenia. It won't help me right now. This was maybe 20 years ago. It won't help me at all to see, because I know we have the risk. So help, no, 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 been discovered, and now we have the tools to study what those genes are doing.
Walss-Bass:
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?" But now, I think we can with the tools that we are 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 Julio 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.
Walss-Bass:
So that is where I believe that has helped me a lot. I think I would have my family 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, 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 still young and I worry about them. They're okay, but they're still in that period of time that is very critical. So I think I will do that now. Okay. Does that answer your question?
Puder:
Well, let's have you back when you, if you want to and talk about it once you get it done.
Walss-Bass:
Yes.
What Families Should Know About Schizophrenia Risk (47:33)
Licinio:
I have a question for Chelo, if I can ask. Is that okay? 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. Your mother had problems and the problems were becoming worse and worse, or bigger and bigger 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?
Walss-Bass:
I think today, they should, they could get genetic testing. They could find out what combination of genes that perhaps they or their family has. And they could, if they have young children, and I've done this with my own children, is follow them, monitoring. Like you said, Julio, 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. And 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. So those two combinations, I would say, 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.
Walss-Bass:
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 big advocate of that. Sleeping, developing sleep habits. People ignore sleeping. They always think of exercise and diet, but I say sleeping is just as important as those other two things. So there are things that can be done, you know? Minimizing stress as much as you can. That's my big thing. And 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, from seeing their aunt, and I did not hide it from them.
Walss-Bass:
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 they're…. I don't think they're afraid. I think they understand it, and having an understanding of it helps them think about their own lives and the choices that they make in their own lives, which we did not have when we were growing up. I wish I 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 heart attack or cancer.
Puder:
Excellent. Wrapping up our time together, I'm feeling like we could go another hour, but I know we have limited time here today.
Licinio:
Can I ask one last question to which is something that, 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 life is 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 Chelo 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 community to the one that puts what's going on out there for others to see?
Walss-Bass:
Thank you, Julio, 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, as I started writing it during COVID, 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 this big anti-science movement started and people were 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. And I think maybe we need to, we need to do that." And so then I thought that maybe, one day, I would publish this.
Walss-Bass:
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, “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. We are just now talking about it, perhaps, in 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.
Walss-Bass:
They've been very supportive.
Puder:
Yes, but it's very brave. Very brave of you and very important. Very important. And it also makes sense of your story. It makes sense of your passion for genetics and studying genetics. Not only are you an extremely well-published, foundational researcher in this field, but you have lived it yourself, and that's really powerful to share that, to share your journey. I'm so happy for you to come on. And I hope that it creates some bravery with some of my other listeners. Maybe you've 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 some fields, you know? Like, I recently shared that my mother had postpartum psychosis. I've done a bunch of episodes on postpartum psychosis [see episodes 276, 278, 279, 280, and 281].
Puder:
And 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 say there's a reason why we believe what we believe.
Walss-Bass:
This is why we do what we do. Yes.
Puder:
Right. Like, lithium came out when my mother was 16. In 1970. And it definitely helped my grandmother for the rest of her life. 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. Yeah. And we think about how the anti-psychiatry movement is forgetting all of this. It's like they have these tropes that they'll say 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 almost 300 genes for schizophrenia and there are articles upon articles.
Walss-Bass:
And we're there, we're at this moment in science that 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.
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.
Walss-Bass:
Thank you so much. This has been really fun. Thank you. Thank you. Wonderful. Thank you.
References
Alvir, J. M. J., Lieberman, J. A., Safferman, A. Z., Schwimmer, J. L., & Schaaf, J. A. (1993). Clozapine-induced agranulocytosis—Incidence and risk factors in the United States. The New England Journal of Medicine, 329(3), 162–167. https://doi.org/10.1056/NEJM199307153290303