Genetic and Environmental Influences of Schizophrenia

In this episode, Dr. Puder is joined by Dr. Liam Browning and Dr. Nicholas Fabiano to explore the complex genetic and environmental factors that contribute to schizophrenia. They unpack how heritability is measured, what twin and genome-wide association studies reveal, and why the "missing heritability" problem matters for our understanding of mental illness. The discussion also covers how prenatal factors, childhood trauma, cannabis use, and social adversity increase risk and how modern neuroscience reframes schizophrenia as a disorder of brain connectivity rather than a single genetic disease.

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

• 0:13David Puder?

  All right, welcome back to the podcast. I am joined today with Liam Browning and Nicholas Fabiano. They have both been on the podcast before. See, before, we talked about creatine, and Liam was on for microdosing, a whole series on adverse childhood experiences, and many more. So yeah, welcome back to the podcast. Today, we are doing an episode on the heritability and environmental influencers of schizophrenia. And we have an amazing handout. As always, go to psychiatrypodcast.com to get the full handout. It is vastly more detailed, maybe,

• 0:55David Puder?

  than we're gonna hit. But I think the important part of this is to kind of bring the mental health sphere up to date with where the data is. And I think the data's changed. So we have to kind of bring it all together for you guys, so you guys can understand how genetic, how environmental schizophrenia is, what are the genes, what are the mechanisms for schizophrenia sort of relayed. And so, yeah, Liam, where do you want to start out?

• 1:30Speaker 01

  Yeah, thanks for having me back on, as always. I think it'd be useful to start with the history of the schizophrenia diagnosis, just because I think schizophrenia is somewhat of a poster child in psychiatry for like severe mental illness and the biological psychiatry model. So I just want to touch on where that initial conceptualization comes from.

• 1:54Speaker 01

  So it really goes back to the early 20th century with Emile Kreplin when he delineated dementia precocks from manic depressive insanity, as many people are familiar with. But at the time Kreplin and the field of psychiatry was really focused on symptoms at the time, like they had terms for symptoms like mania, melancholy, insanity, but there was not a clear diagnostic classification system that they had. So Kreplin, through his observations of thousands of patients, wanted to like add to this, this field by having some classifications of symptom clusters. And so what he found was through his observations, he saw that there are some patients with insanity

• 2:37Speaker 01

  who had a chronic deteriorating course that started in early adolescence or adulthood. And they went on to develop personality disillusionment, cognitive decline, and then inevitably would end up with dementia or various, very illness. And he noticed that there are other psychotic patients who had more of a shorter term course, a more fluctuating course, and a preservation in their cognition and personality. So with this, with this line of thinking, he, he believed that there were neuroanatomical reasons for why people were presenting with these different symptoms. Um, at, you know, at the time, there, there wasn't really a clear explanation, uh, but he believed that there would be explanations behind the neurobiology of these different

• 3:22Speaker 01

  disorders.

• 3:23David Puder?

  I think some of the early, or one of the early people found syphilis in the brain. And so they kind of had, oh, look, there's something physically in the brain causing the psychosis, right?

• 3:36Speaker 01

  Right. Even before Kreplin came onto the scene, there was, they had the syndrome recognized, but they didn't know exactly that there, there was a bacteria causing the syndrome. So that was like one of the first syndromes that people had tied to a brain pathology, or they thought this automatic, this presents with these certain sets of symptoms.

• 3:57David Puder?

  Yeah, so Kreplin mostly came up with the categorization, and I think it's a helpful in general splitting between, okay, this person has episodic manic episodes, some depressive, and this person is chronically psychotic, paranoia, delusions, hallucinations. Right? Someone with bipolar can have those things, but they can be episodic in nature. They can have, like, one patient who's bipolar, they could be normal for a year and then have a severe episode, start ramping up over weeks, get manic. Okay, so keep going with this history lesson here.

• 4:43Speaker 01

  So after Kreplin, the next sort of major thinker in this topic was Eugene Boyler. He renamed the condition of dementia pre-cocks to schizophrenia in 1911, and he believed that it was more so a group of schizophrenias. He noticed that there is heterogeneity in terms of how people presented. So after Boyler, there was sort of a dying off of this type of, this line of thinking with the rise of psychoanalysis in the mid 20th century. And then after this wave of psychoanalysis in the 60s and 70s, there was this growing movement to want to legitimize psychiatry within the medical field. And so people were

• 5:27Speaker 01

  turning towards biological mechanisms to try to understand the symptoms and the diagnoses that we're seeing. So that ultimately led to the DSM III, as again, we're trying to legitimize psychiatry. And ever since then, we've had a biological oriented field where we're trying to look at diseases through the understanding the mechanisms.

• 5:54David Puder?

  Yeah, and there's, um, I think you were gonna talk about how the Nazis utilized some of this early stuff, weren't you gonna talk about that?

• 6:04Speaker 01

  Yeah.

• 6:05David Puder?

  Is that the?

• 6:05Speaker 01

  Yeah, so, yeah, the first genetic evidence actually comes from one of Kreplin's successors, his name is Ernst Rudin, and he conducted like the first large-scale family sodium psychiatry. Prior to him, there was an understanding that insanity ran in families, like sometimes the parent would have peculiar behaviors and so would the children, but it wasn't always guaranteed, not all the children would develop that, some would have resilience. But Rudin identified that after Kreplin recognized dementia pre-cocks, Rudin was trying to look into whether there was a Mendelian pattern of inheritance behind schizophrenia.

• 6:47Speaker 01

  So he conducted the first large-scale study of 2,700 siblings of 800 people with schizophrenia. And essentially was looking at the rate of schizophrenia in the siblings. And he found that there is about a 5.4 to 7.7% increased risk of schizophrenia in the siblings of people with schizophrenia. And this is actually remarkably close to some of the modern-day estimates of schizophrenia that are produced by looking at these family studies. It's a little bit on the higher end of what modern people, what the modern estimates would be, but I still think it's pretty interesting to note that he found a very similar number to what we see now.

• 7:30Speaker 01

  But again, you can't really talk about Rudin without mentioning his role in the forced sterilization movement and the genetics movement that ultimately led to the Holocaust. And, yeah, I just thought it was interesting how psychiatry and behavioral genetics is rooted in this dark history of Rudin, and there's always going to be some people who are echoing some of these thoughts. So I think it's important to have that historical background of where things have gone.

• 8:06Speaker 01

  And I think even the name of the schizophrenia is interesting that we've retained it because you mentioned it alludes to split psyche or split mind and we know that's not the case, yet we still use the term. So there's even been recent literature and experts in the field saying maybe we should rename it to positive and negative symptom disorder. But with all this historical contact, we still retain the name schizophrenia, which has stigma behind it. It has, even the nomenclature isn't entirely correct. So I think from the genetic background and even the nomenclature perspective, it's interesting that how accurate some of these measurements were, but also how the nomenclature has persisted.

• 8:43David Puder?

  Yeah, the names are sometimes archaic, but necessary for us to continue to talk about the same thing, right? But I think there's other worse, worse words. But I think, okay, it's, it's obviously awful that Rudin's work became sort of weaponized to create this master race by eliminating people with mental illness. And I think one of the interesting statistics is like, most people with schizophrenia do not have family relatives. Can you talk about that?

• 9:19Speaker 01

  Yeah, most, most people with schizophrenia don't have a relative with it. Up to 60 to 90% of people with schizophrenia don't have the relative. And, and most people will use that as an argument to say, well, actually, all of schizophrenia is sporadic. It's not inherited then if it doesn't run in families. But in reality, that's not what heritability in epidemiology would, would indicate. So you can still have a disorder that's heritable and influenced by genetics without having it run in families. So that leads us to discussion of what, what actually is heritability. A lot of people will hear that schizophrenia is 80% heritable, and that means that 80% of cases of schizophrenia are due to genetics,

• 10:04Speaker 01

  or if my dad had schizophrenia, I have an 80% chance of getting it because it's 80% heritable. When in reality, eighty percent heritability, in the context of heritability, means that eighty percent of the variance in liability for schizophrenia in a population is associated with genetic variation. So again, and genetics, heritability is a measure that describes the population, the phenotype that differs across the population due to differences in genetics within that population. So it doesn't apply to individuals, it doesn't say anything about an individual's risk or what percent chance that they develop schizophrenia.

• 10:45David Puder?

  That's confusing to a lot of people, I think. It seems, eighty percent seems very high, and it seems to say that this is almost genetically determined eighty percent of the time. And that is not what you're saying.

• 11:02Speaker 01

  No, no, it's, it's the how much the phenotype can thought to be attributed to genetic differences across a population. It's not an intuitive concept because it's two different ratios of, of change. And I think to put it into context, it makes it a little bit easier to understand that heritability also depends on the environment. So when environmental conditions are the same within a population, then heritability actually plays a larger role. That means because the genetics are being able to exert more difference if the environment is exactly the same for the entire population.

• 11:44Speaker 01

  And the inverse is true too, where if there's environmental disparities, so for example, looking at how countries differ in malnutrition, if one country is highly malnourished, then they're going to be small, they're going to be shorter on average, even though height is a highly heritable condition in most circumstances. So for example, with China, they lifted one billion people out of poverty from the 1980s to today, and they actually increased their height by three point one inch, three point one inches, the average male. So that tells us it's not, their, their height didn't change due to genetics, it changed due to the environment. So in this example, when China was malnourished, they had more of their phenotype of height

• 12:27Speaker 01

  influenced by the environment than the genetics. So the heritability in that population was actually less than eighty percent.

• 12:35David Puder?

  Nicholas, do you have another way to put this to make?

• 12:37Speaker 02

  Yeah, I think Liam did a good way explaining it. I think it's looking at it almost like two different variables. Where you have, if you're controlling one, and Liam explained maybe height in this example, if you're controlling, say, a population level of food intake and resources and sunlight exposure, if all of that's the same for a population and you're looking at a variable like height, for instance, and nutrition and all that different things. Then the genetic influence becomes so much more important because that other variable is not really moving. Everyone else is receiving the same thing. So that genetic part is really the only significant differences, which is why we see heritability differences when we hold one thing constant. You can kind of look at it through the lens of how we conduct RCTs even. When you're holding that one variable constant, if you're changing something else, that being the genetics,

• 13:22Speaker 02

  that becomes so much more important when everything else is the same. So it's a very confusing way when we describe it in 80% heritability, because I think like we alluded to in the beginning, you think that means I have an 80% chance of developing schizophrenia, but it's so much more complicated than that. And yeah, it just shows how much, and we'll get into it more, how much your genes and environment interact to produce the phenotype of schizophrenia, or whatever that may be.

• 13:49David Puder?

  So if you're confused at this point, consider yourself to be ready for the rest of this episode. We have to start with, we have to start with some degree of confusion, right? What does this 80% mean? I think height is such an interesting one because height is so genetic. But yeah, you're right. There if, if you have a culture with a lot of poverty, a lot of malnutrition, with a lot of stress, in general, the whole population is gonna, you know, not be as tall. Interestingly, I was looking at all the variables for height because I want my kids to be tall. Because they play basketball. And sleep is one of those variables. So because when you sleep, well, you produce human growth hormone.

• 14:35David Puder?

  So we're like 8:20, let's go to bed.

• 14:38Speaker 02

  Get those hours in. Well, one thing that's interesting to with the conversation of schizophrenia from a heritability perspective and even evolutionary, I think, is the concept of selecting and non-selecting for different genes. And you would imagine something like schizophrenia, which societally sometimes for these people, it's hard for them to live, hard to get a job, all these different things would select for not passing on those genes. Yeah, what we see in the population is either stability or even increases in some areas. It's very interesting to see and it shows how much more complex it is than the eye can see because you can imagine other traits in the past that were negatively selected for that's natural selection, stuff goes away. But with schizophrenia, even though it's detrimental to our societal functioning

• 15:21Speaker 02

  for that person with schizophrenia, it stays, which is, I think it's a very interesting phenomenon that we're seeing where it doesn't intuitively make sense. And then it just adds more layers to this question of heritability and why stuff is selected for and why things are expressed. So not to add more confusion, but I always thought that was an interesting point to to think about from an evolutionary psychiatry perspective as well.

• 15:43David Puder?

  Right, right. Yeah, a lot of schizophrenic patients that I treat have a more difficult time being in a relationship, right? They have a more difficult time, like a lot of them are very isolated, very, you know, in their own sort of room, locked up, you know, not, not really getting out much, not very, not doing a lot. The common sort of pathway of, in my mind, towards schizophrenia and severe mental illness is isolation. So yeah, it's interesting to think like, okay, why is the population, it's about 1% of the population, right? Like, why is that the case? Okay, let's get into the twin studies. Liam, what did the twin studies say?

• 16:30Speaker 01

  Right, so the twin studies, we're kind of talking about holding one variable constant, like keeping the environment constant, and that allows for genetic effects to be observed the most. And twins are the best example of that, where you hold the genetics constant, and you can pretty much assume that the environment is constant too, because they're growing up in the same household, same parenting dynamics, same nutrition, same schooling system, same peer system, pretty much. So you can look at the differences in phenotypes from identical twins and fraternal twins. And essentially, the difference between the two phenotypes, you can almost entirely attribute to genetics, if you assume that they are under the same environmental influences.

• 17:11Speaker 01

  So that's where that 80% figure comes from, is looking at the rate of schizophrenia between the identical twins and the fraternal twins, and seeing that difference.

• 17:21David Puder?

  Yeah, so if a monozygotic twin, which shares 100% of the genes, has schizophrenia, what percentage of the time does the other monozygotic twin have schizophrenia?

• 17:35Speaker 01

  Earlier estimates were suggesting around 50 to 60%, but some of the modern day estimates are actually around 15 to 30 to 35%, around that range. So it's not an 80% type of deal, just because heritability is 80% doesn't mean like the genetics are automatically going to determine that they're gonna have, if they have the same genetics, they have an 80% chance of developing, it's actually far less than that.

• 18:01Speaker 02

  And to me, that's really interesting too, because beyond genetics of monozygotic twins, you can imagine being reared together, all these different factors as well too. Their environment is very similar as well too, so it's very interesting to see that these figures aren't closer to even 100% when you have exactly the same genetics, and a lot of the exposures are likely the same as well too. So it's very interesting to see these estimates.

• 18:26David Puder?

  And when we, when we hear like, okay, so let's, let's say it is 50%. We could say, oh, it's 50% because of the exact copy of the genes that they both share. But we also have to consider, they were in the womb at the same time. And they were subjected to very similar, like if the mother got ill, if the mother had an infection, they both were, experienced that, right? So, so there are these kind of environmental factors which monozygotic twins experience. But you could say like, okay, but don't dizygotic twins experience the same sort of things, right?

• 19:09David Puder?

  So that, what is the, if, if one dizygotic twin has schizophrenia, what percentage risk does the other one have schizophrenia? It's about 10%, right? We don't, we don't want to overlay you with too many statistics. Seven to 17%, but about 10%. So we're looking at about 50% for monozygotic, 10% for dizygotic. But I think you have the important point, Liam, that monozygotic might experience life differently than dizygotic twins. How, how would you say that's true?

• 19:44Speaker 01

  And that's like the, the crux of what's called the equal environments assumption that, because the way you calculate the heritability is assuming that the environment's exactly the same between the two. So you kind of simplify things. Some, some of the modern studies will try to account for these effects, but I think it's easier said than done because there's just so much complexity that goes into someone's life course. But monozygotic twins, you can imagine they're, they're treated very similarly by their peers, by their parents, because they look the same, they, they act more similar. For almost every trait that we've looked at in genetics, monozygotic twins are more similar on them than anything else, than any other siblings.

• 20:24Speaker 01

  Even if they're reaper part, they tend to develop the same preferences for jobs, partners, like eating habits, like fitness, all these different variables in someone's life, they're far more likely to end up on that same path. So. The assumption that the environment is the same between them is kind of violated by the fact that they are going to act similarly and interact with the environment the same way, where you wouldn't expect dizygotic twins to have that same interaction with their environment. Dizygotic twins are going to do their own thing, and that environment is going to exert itself differently on the dizygotic twins compared to the monozygotic twins. Because they're going to put themselves in more different situations. So imagine like

• 21:06Speaker 01

  for monozygotic twins, if they have a increased risk for substance use, then, and they interact with an environment that has a lot of substances around it, then they're far more likely to develop substance use versus dizygotic twins. Maybe one doesn't have as much of a genetic proclivity for it, or they're not in that same environment because they act differently than the monozygotic twins. So, the equal environments assumption that goes into producing these heritability estimates, I think it makes it so that the heritability estimates from twin studies are a little bit inflated.

• 21:42David Puder?

  Like the placenta. I think, tell me about how often monozygotic versus dizygotic twins share a placenta?

• 21:51Speaker 01

  Yeah, monozygotic twins almost always share the same placenta. And, and there's also other factors that go into that, too. Like, sometimes there can be twin-twin transfusion syndromes. One twin will get more nutrients than the other, but for the most part, sharing the same placenta exposes you to more similar, like, blood flow environments and like toxins exposures, compared to having two different, two different placentas, at least presumably.

• 22:18David Puder?

  Yeah, you know, it depends on when the zygote splits, do they share the placenta or not? But dizygotic twins never share a placenta. So yeah, maybe that has, that has an impact as well, in kind of the difference. So there's these, these small differences that we kind of, maybe don't think of when we think of that 10 versus 50%. Okay, let's talk about the Molecular Genetics and Human Genome Project, and how it gave rise to candidate, this candidate gene era.

• 22:53Speaker 01

  Right, so at this time, in the 1990s and early 2000s, we had the dopamine hypothesis as the forefront to explain what's going wrong with schizophrenia. And around the same time, we also have the development of human genome sequencing and the first, the sequencing of the first human genome. So there's a lot of excitement in the field to find genes that are responsible for schizophrenia. As we saw with Huntington disease, it's a single gene that's disrupted. There is cystic fibrosis, sicko cell anemia, all these single gene disorders with a complex phenotype. So we're hopeful that maybe mental health disorders can also

• 23:36Speaker 01

  have, be traced back to faulty genetics. So in the 90s and early 2000s, we looked into certain subsets of genes because it wasn't as cheap to sequence the entire genome, so we just looked at a handful of genes, maybe a couple hundred genes that might be important. So again, we looked at some of the dopamine regulating genes. We looked at genes important for neurodevelopment. And we essentially found that there are dozens of genes that were associated with an increased risk of schizophrenia. And we found genes that had gene environment interactions, such as cannabis, early adversity, being exposed to, you name it. There's a thousand, there's hundreds of candidate gene studies. But the problem is that none of them are really replicated.

• 24:19Speaker 01

  And they're pretty much all chalked up to false positives because the way that you account for multiple comparisons in a study. So if you're testing hundreds of genes and only reporting on the one that's statistically significant at a p-value threshold of 0.05, you have a 5% chance that that was just a fluke if you tested 100 genes. So when these candidate gene studies were coming out, there wasn't any correction for multiple different genes that they're looking at. A lot of times, they're just reporting this one gene. And when they looked at a shotgun approach of hundreds of genes. So that led to a lot of false positives and low replicability.

• 24:59David Puder?

  Nicholas, how hard is it going to be to get your paper published if you show only negative findings?

• 25:05Speaker 02

  It's gonna be pretty hard. I think that's the problem with treatments or genomic findings. When there's anything negative, it it'll probably end up in pre-print land forever. And and journals aren't very interested. There there's always this narrative of, you know, publisher negative findings is great, and I agree with that. But the reality of it is, you know, journals oftentimes you end up in this cycle of, submit, reject, submit, reject, because the the how it works is people like the flashy results. They like the things that go in the news headline. This is what gets you another grant. This is what gets the journal citations. So a lot of these findings that Liam's describing that were were negative, there's probably a whole larger literature source out there that hasn't even been published. And the problem with that is then we re-explore these things over and over and over.

• 25:47Speaker 02

  And it's not cheap, too. We're spending millions and billions of dollars probably searching for different biomarkers and genes. And I think one of the biggest issues is we we do this across psychiatry, even in depression. We're we're very obsessed with a genetic cause or a biomarker for a specific condition. And we base it off of oftentimes, like Liam mentioned, the prevailing theory of the dopamine hypothesis. And then the other thing is we have to realize we make these diagnoses. We we put together, this is schizophrenia based on these symptom clusters. But we know that even things like psychosis, they're transdiagnostic. They go across bipolar disorder, depression. And then we try to say, does this one gene cause this syndrome that we have made up essentially?

• 26:28Speaker 02

  And then we're surprised when we can't find a gene that caused this thing that we put together artificially. So I think it's gonna be this kind of, and and we've seen it happening in front of our eyes, where we're constantly searching for these genes. And there's never a one candidate marker that explains all of schizophrenia, because the problem is schizophrenia is so broad. And and we've seen it clinically with so many different patients that present so uniquely across the spectrum. And Liam alluded to at the beginning of cognitive deficits versus very prominent negative symptoms versus very prominent positive symptoms. And yet we're in this cycle of just chasing what is the one cause? And I don't think we'll ever find it, because how we've defined it, there isn't one cause. But the research will continue. And as as we discussed at the beginning,

• 27:12Speaker 02

  people will not publish their negative findings, and it leads to this whole cycle.

• 27:16David Puder?

  So what you're saying, because there's no one cause, there's no one gene, this thing doesn't exist. Is that what you're saying?

• 27:22Speaker 02

  Not that schizophrenia doesn't exist, but I think in our.

• 27:26David Puder?

  Well, I say that a little tongue in cheek because I was thinking about.

• 27:31Speaker 01

  People say that.

• 27:32David Puder?

  I was thinking about hypertension.

• 27:34Speaker 02

  Yeah.

• 27:34David Puder?

  And it's like, you don't get anyone on X or Twitter, you know, social media saying hypertension does not exist, you know? Now, you may get some people who say you shouldn't treat hypertension. That's another thing. But how many genes relate to hypertension? And these studies show it's over like a thousand genes can impact it. Does hypertension exist? Like, well, your blood pressure is high. It's, it's so much more simplistic and no one's really arguing against hypertension. Right? Or the necessity of, you know, measuring it, treating it long term to prevent strokes, to prevent other issues, to make it easier for your heart to push blood around your body, you know?

• 28:18David Puder?

  So, you know, but with, with schizophrenia and with mental illness stuff, like, of course there's going to be hundreds of genes that relate and new mutations, right? And new contributors and, you know? But I think early on, and I think this is what Liam is saying, is we were really hoping for like the dopamine receptor genes, the dopamine metabolism genes to be the big issue.

• 28:48David Puder?

  And they weren't, right? So you could have a disillusionment to it, or you could say like, well, of course, right? There's so many things going on. And so where does this lead us with these, the GWAS studies? And explain that, Liam.

• 29:05Speaker 01

  Yeah. I, I think first, before I get into the GWAS studies, I think it's the most dangerous aspect of this line of thinking where you have a single causal mechanism is in how that's a still a pervasive idea throughout psychiatry that it is a dopamine problem. So let's just treat them with an antipsychotic and that's going to be the treatment. Don't need to look into this person's life. Think about what things keep them socially isolated, what things keep them going back to substances, like, and addressing their cognitive functioning. Like, there's no, there's no attempt at doing that in, in many institutes. So I, I think as we move forward in the field of psychiatry, we need to pay attention to, it's not just a single problem. So the treatment cannot be just one single thing, right?

• 29:51Speaker 02

  And I think that applies to even even depression, right? We took the same approach with in a simplistic lens serotonin being the sole cause or a low serotonin. And then our approach being treated with esterides, but we know that it's so much more complicated as well. So we're seeing resurgence and interest in other interventions, looking into the social aspects of people's lives, even exercise and creatine and things like this where before, again, it's, as you said, very harmful to look at it through this lens of schizophrenia is high dopamine. That's it. We need to get that down. Same thing with depression of depression is low serotonin. We need to get that up sort of thing. It's a very simplistic way of looking at it. It's helpful to conceptualize things, but it it doesn't treat the person in front of you as a person.

• 30:34Speaker 02

  It treats them as a level, which again, going to the hypertension example, it's great to say, yes, your blood pressure is this, let's get it down to here. But I don't think we can necessarily apply that directly across psychiatry.

• 30:47David Puder?

  Right. I I'm also reminded of the episode me and Liam did on sauna. And this, you know, the nice Finnish sauna, you know, where you pour the water over the rocks, which I enjoy every morning, by the way, now. And the studies, the study showed it reduced psychotic events in this cohort that they followed, like 67% or something like that, something crazy. It was crazy how it reduced it that. Okay. But but like, why did it reduce it so much? You know, was it reducing future episodes of delirium? Probably. Uh, did it help?

• 31:26Speaker 02

  Is it the person like in just engaging socially because Finnish saunas, they are a communal activity like it's not your, uh, your Huberman bro type of type of deal where it's just the guy sitting in the sauna by himself, working out. It's everyone is communally in the sauna together with their family every night.

• 31:44David Puder?

  Yeah. And maybe that's and and we talked about maybe that's the, uh, that that factor they didn't really control in their long term cohort finding. They just found like it did reduce risk of dementia. It did reduce risk of stroke like 60%. So, so, yeah, I think, I think if we can like open up our minds to a degree of openness with something like schizophrenia, like, okay, maybe there are multiple. Things going on, maybe psychotherapy is going to be very important. I had Michael Garrett did an amazing episode on psychodynamic and CBT treatment for schizophrenia.

• 32:24David Puder?

  But what I'm also reminded of as we talk about this is it's it's going to take a lot of providers across, you know, the world to get excited about doing psychotherapy for schizophrenia, because it can have its unique challenges and it's not necessarily as intuitive as like depression, anxiety.

• 32:48Speaker 02

  Hmm. And I can speak to you. Right now, I'm on my inpatient schizophrenia rotation and not directly to the structured psychotherapy approach, but a lot of our patients with schizophrenia have a very treatment resistant course. That's why they're on the inpatient unit right now. And there's only so much utility sometimes our medications have. So from a therapy or even just cognitive restructuring of having these psychotic experiences and being able to ground themselves and not allow that lead to behavioral changes or different things of that sort, I think is so important. And I don't think we place enough emphasis on that on either the inpatient or outpatient setting. And we're so focused again on dopamine is too high, let's get that down sort of thing. Which, again, I think we need to really look at it from a full person centric approach.

• 33:32David Puder?

  And I would say the anosonomia or the the lack of knowledge that they have an illness that needs treatment is is very difficult to treat without a very frequent relationship that you have with them. With the patients I see and I spend the time to get to know them, you know, once a week, it allows me the context that they will take the medication. But I've had a lot of patients refer to me in the last decade where in the in the normal system, they're refusing to take meds, they're still isolated in their room, they're still having psychotic symptoms. The family is like, I don't know what to do. And

• 34:17David Puder?

  It takes, it takes a relationship. It really does take a relationship. Okay. Let's keep getting into the weeds of the statistics. I know everyone's wanting us to do that.

• 34:27David Puder?

  So tell us about the GWAS scores and the small nucleotide polymorphisms. So these are the genome-wide association studies that we can now do. And by the way, I'm really excited for AI, the next level of AI looking into these things as well. I think we're going to have an even more clear picture and an individual picture as we do whole genome studies on individual patients. And, um, okay, but tell us about this.

• 34:59Speaker 01

  Right. So essentially GWAS studies are looking at the single nucleotide polymorphisms or SNPs, which are just one nucleotide differences that are common within the population. Common meaning greater than 1% of people have this polymorphism and this change. And so what we can do is we can total up all these different SNPs and look at which ones are associated with schizophrenia, which ones are associated with depression, bipolar, and so on. So the largest GWAS study to date was using 76,000 people with schizophrenia and they compared them to 240,000 people without schizophrenia. And they estimated by summing up all of the SNPs across the entire genome

• 35:44Speaker 01

  that there is a 24% heritability using this, this sort of summation of all the SNPs. So 24% is far less than the 80% that we saw from the twin studies. But again, this method of measuring heritability is looking at just associations of these small nucleotide polymorphisms between people and across the population. It's, it's, you get a little bit less.

• 36:11Speaker 01

  Like genetic, as you have more of a genetic similarity between two people, there's more of a nonlinear relationship. So to go from looking at twins to go and then to go to looking at individuals across the population, I don't think you can expect to get that 80% heritability because you can't really account for the genetics as well. So this method essentially just looks at what are some of the single SNPs that are associated with schizophrenia and then trying to total that up. And so what we found is that that's for looking at the entire genome and looking at specific SNPs. But when you look at the SNPs that reach that p-value threshold, when you correct for

• 36:56Speaker 01

  multiple comparisons, like when you're looking at millions of genes, you have to drop that p-value from .05. So when you do that, you actually find that there are only 287 SNPs that cross that threshold that are so significant enough to where we can actually say, yep, these are important for schizophrenia. And the heritability from these 287 SNPs is only 2.3%.

• 37:24David Puder?

  That's not, the p-value for this group was less than 5 times 10 to the negative 8? That's a very low p-value for those 287 SNPs. Why did they need a p-value that was so low? This is not the .05%.

• 37:46Speaker 01

  Because you'd have so many false positives if you were using that threshold because you're detecting millions of genes. So you have to drop it down to actually say which ones are repeatedly seen across the population. And we can reliably say that these 287 SNPs have been associated with schizophrenia.

• 38:06David Puder?

  Why do you think the heritability is so low? I mean, this 2.3% is very low, right? And then why is it so high in the monozygotic versus iizygotic studies?

• 38:21Speaker 01

  Yeah, kind of what I was trying to allude to where I think as you increase genetic relatedness, imagine it like on the X axis, genetic relatedness on the X axis and then phenotypic relatedness on the Y axis, you'd expect like a linear curve, but in reality as twins, they share all of their genes, they share all the gene environment interactions, those gene to gene interactions, it's a nonlinear curve, like it's an exponential change in the phenotype as the genotype increases. So as you get that similarity, then you're going to see more of a, an effect of the genes and introducing that phenotype because you're going to have all the same gene interactions and the same gene environment

• 39:05Speaker 01

  interactions. Whereas if you're looking at a population level study, it's very hard to summate those genetic heritable effects because they're, you're looking at so many different people with so many different lives and to find a signal behind the genetics is extremely, extremely hard to do.

• 39:24David Puder?

  I think, I think because schizophrenia involves thousands to tens of thousands of risk variants, right, in the genes, there's only like, what, what this is saying is there's probably a ton more genes that are so rarely seen that you're not going to pick them up even in this like genome wide study, right? So it's not necessarily a failure of genetics, it's a feature of the complexity of traits. Okay. And like there, because you know, there are rare variants that one family will have, like I've, I've read these, these studies

• 40:04David Puder?

  of like one family has a very high degree of multiple relatives with schizophrenia and there's one specific gene, but that gene is super, super rare and almost unheard of in all the other schizophrenia patients, right? Outside of that family. And so there are these, you know, kind of very slight whispers that would lead to like a family having a high heritability, but then don't get picked up in a huge study like this.

• 40:41Speaker 01

  Right, and those are called the rare variants or copy number variants, which are essentially deletions or duplications of large portions of the DNA. So you can imagine, these are not things that are going to be passed along through natural selection very easily, because they're going to be selected against, especially if they're encoding for, if the genes that are knocked out are encoding for vital things like neural functioning and whatnot. So one of the most common examples of this is the 22q11.2 deletion syndrome, or DeGeorg syndrome. And this was a deletion of a segment of chromosome 22

• 41:23Speaker 01

  that contains 40 to 60 genes, including catecholamine methyltransferase, which is a dopamine metabolizing enzyme, and then also other genes important for dopaminergic signaling and neurodevelopment. And then also the development of thyroids too, and the cranioforengial pouches. If you're in medical school, you remember that. But essentially, this knockout of these 40 to 60 genes on chromosome 22, that leads to an increased risk for schizophrenia. But it is also, leads to an increased risk for other aspects. Like, it's a syndrome that you see.

• 42:03Speaker 01

  So that's like the most common variant, or the common, the most common copy number variant that's seen. And there's other variants that are associated with rare coding variants. So thinking about very rare mutations in genes that code for proteins that are important for brain development, or transcriptional regulation within the brain, or different ion transporting proteins. So these examples are incredibly rare, less than 0.1% of the population will have it.

• 42:39Speaker 01

  But the the effects can be very damaging and and expressing the phenotype. And these are these genes aren't picked up in in the SNP analyses. But it's also important to note that these genes are also present in people without schizophrenia as well. They just might be a little bit more prevalent in people with schizophrenia.

• 42:56Speaker 02

  Hmm. Yeah, you read my mind. I was gonna bring up the DeGeorg syndrome as well to where to add some more statistics to it. I think 25% of people with that syndrome end up going to develop schizophrenia. Whereas if you look at people that have schizophrenia, I forget the exact number, but I think it's 0.25 or something around that that actually have DeGeorg syndrome. So it's just it's very interesting to see because you you see how there's these high-risk populations, but when you actually look at the the broad population schizophrenia, you don't see it as commonly there sort of thing. So I'm just highlighting kind of some of the points you you made there.

• 43:31David Puder?

  Yeah, so GWAS chips are not going to pick up, so in summary, everything, right? They're not going to pick up rare variants. They're not going to pick up copy number variants like deletions and duplications. They're not going to pick up gene-gene interactions, right? Where you'll have A times B does not equal B plus A plus B. So it's not additive. So it's not picking up the additive components, right? Where certain genes may interact with other genes in a very sort of complex way. And it's not going to pick up gene environmental factors like cannabis. Like being in a very urban environment or trauma

• 44:14David Puder?

  is going to interact with genes. It's not going to necessarily be picked up in this GWAS studies, though, that you're going to be able to capture how an environmental thing and a gene interacts in a very additive way, right? So that those are my thoughts. Any other thoughts on this before we move on?

• 44:35Speaker 01

  No, I think we can talk about the polygenic risk scores. This has picked up a lot of hype by people because it's like, okay, well, why don't we just use this to select embryos? Like if we can see what genes are associated with schizophrenia, then look at all the genetics of the embryos for in vitro fertilization and then try to pick the ones that have the lowest risk of schizophrenia. So there are companies that are starting to do this. But essentially what this figure comes from is it comes from these GWAS studies, looking at all the SNPs that have a measurable effect size, meaning they reach a p-value threshold that's like 0.01 or somewhere around there.

• 45:17Speaker 01

  And when you summate all of those genes together, you get a heritability estimate of 7.3% for schizophrenia. So that's just the identification of the SNPs that have an actual effect that you can measure. But that's still, for schizophrenia, that's less than the SNP heritability estimate, which is all of the entire genome SNPs, not just the ones that have an effect size. And I think it's interesting how in height, when you look at the polygenic risk score or the polygenic score for height, you can summate all of the genes that have an effect. There's actually more identified genes related to height compared to schizophrenia.

• 45:59Speaker 01

  And there's less of a gap between that polygenic risk score and the SNP, the genome-wide heritability estimate based on all of the SNPs. And that tells us for schizophrenia, the polygenic risk score is at 7.3% now. But if we keep adding more and more studies and larger sample sizes, then we can increase that number closer to the 24%, which is kind of like the maximal amount that we could ever get to with polygenic risk scores.

• 46:28Speaker 01

  But polygenic risk scores in and of themselves, I don't think that they have much clinical use at this point, but from the study that did calculate it, they looked at the highest percentile polygenic risk score of the people in the study and compared them to the lowest percentile polygenic risk score. And they saw that the the odds of having schizophrenia was 40 fold higher in the people with a higher polygenic risk score compared to the lowest first percentile. That tells you that it does actually have an effect at the individual level. Like you can have some level of predictive capabilities when you use the polygenic risk score and apply it to someone, which isn't necessarily true of looking at heritability

• 47:13Speaker 01

  per se. But if you look at all the genes that this person has and try to correlate that to certain phenotypes like schizophrenia, bipolar, depression, then maybe there could be a signal there.

• 47:28David Puder?

  I'm against this kind of idea of trying to design our babies, having designer babies. Something about that doesn't feel right to me. That's my gut instinct. It sounds like a different form of eugenics almost, you know? It sounds like we're going back to.

• 47:46David Puder?

  And yeah, I've seen these companies advertising for this height IQ, stuff like that.

• 47:53David Puder?

  Right, yeah, I'm concerned about this.

• 47:56David Puder?

  So maybe we'll have to do a deeper dive on the ethics of it.

• 48:03Speaker 01

  And I think another point that's important to to talk about is that other disorders also are heritable in psychiatry. We see that bipolar is on the similar level of heritability to schizophrenia, where the heritability from twin studies are like 0.7 to 0.8. And then the SNP based studies, the SNP based heritability. So again, looking at the entire genome, which SNPs can you measure? The SNP based heritability is 17 to 24% depending on the study. So right on par with schizophrenia. Meanwhile, depression is about 9%. And what's notable is actually that the polygenic risk score for schizophrenia has a high overlap with bipolar.

• 48:47Speaker 01

  It's about a point seven correlation. So again, this kind of goes back to our point of there is a transdiagnostic effect of these genes and increasing risk for psychosis or psychotic-like illnesses.

• 49:03Speaker 02

  Hmm, because you see it clinically too, right? Like, a lot of people with mania, fifty percent even, present with mania with psychotic features, which arguably transdiagnostically, these diagnoses, they overlap so much, and even the treatments for them overlap. If you look at first-line measures for bipolar, sort of sure there's lithium, and sometimes we do use that even in schizophrenia, not very often, but we use antipsychotics like quetiabine, we use things like alanzapine, and a lot of these treatments are used across disorders, which I think is also telling, because through the lens that we've formed these hypotheses of dopamine, et cetera, et cetera, if we flip that over and say, but these treatments are working to treat almost everything too, I think it really shows how much overlap that is, and then when you see it in the face of what you mentioned about

• 49:48Speaker 02

  the genetics, I think it really ties together the picture very nicely.

• 49:53David Puder?

  Yeah. I think it's one thing that sort of has come to me is that, okay, we can't really predict the vast majority of people with schizophrenia from genetics yet, right, from these SNPs. So when we say, oh, but look, there's a seventy percent overlap from the ones we can predict, right? It's not like we're predicting the majority of them to start with, right? So it's like not a huge statement to say seventy percent in this case, because the vast majority of the different, unique genetic aspects or the genetic environment aspects are unpredictable.

• 50:39Speaker 01

  Okay, does that make sense?

• 50:41Speaker 02

  Hmm. And I think that goes to something we'll probably get on later is where our clinical target should be right now is, as Liam alluded to, a lot of these things don't yet have a lot of utility to the patient in front of us to change management. But as you mentioned, some of these risk factors that we don't interact with the risk of schizophrenia at different time points in adolescence and all of these things like cannabis use or low SES, all these different factors that can contribute to the development of schizophrenia. I think we have much more utility intervening at that level where we're at, rather than trying to intervene at the gene level to prevent the onset of psychosis. At the more clinical level, there's more potential and we have more evidence to say that as well, too.

• 51:25Speaker 01

  Yeah, I think what we are trying to look for with these GWAS studies is to be able to find where can we intervene? Like, are there a certain subset of genes that are intervenable upon? And I think the conclusion, like you mentioned, it's not something that's going to be actionable. The conclusion is that the genes associated with schizophrenia, related to the ion transportation, neuronal migration, transcription, these things are isolated to neurons. So that does tell us that the genes related to schizophrenia are within neurons. So it is within the brain. It's not like in the liver or in the kidney or something. So it tells us that there are potential biological pathways that are intervenable upon in the future.

• 52:10Speaker 01

  But it's not, so to speak, like you can't just do like genetic therapy for someone with schizophrenia at this point. Maybe for some of these rare copy number variants or for some of these rare coding variants where they're present in less than 0.5% of the population and it is very damaging to this person because without that gene, then they probably wouldn't have developed schizophrenia. So maybe you can have some sort of drug targeting that, but that's few and far between in terms of moving the needle on treating schizophrenia. But I think what you conclude is that, yes, genes related to schizophrenia are within neurons.

• 52:50David Puder?

  And there's a multiplicity of them. And they may have additive effects. They may have the unique environmental things may uniquely trigger a certain mutation to be to activate in a way that we did. We would not desire like cannabis could activate certain types of people with certain mutations. But we are not fully aware of all of this. And maybe in the future, we'll be there. And I think actually with with people getting fully sequenced, with databases increasing, with fully sequenced people. That's beyond GWAS studies, right? And with, you know, these governments that have these databases,

• 53:35David Puder?

  as they also collect environmental things that are unique. We probably will get a much more personalized medicine 10 or 20 years from now than we've ever thought possible. AI, I think, will be able to find links and and solutions potentially that we didn't think possible. I had one patient in particular. This is kind of a happy story. I've treated this guy for about 10 years. Severe autism, aggression would attack his parents. The only thing that really got the aggression under control was with was clozapine.

• 54:18David Puder?

  And I mean, behavioral interventions, tons of those, right? Didn't really control it. So clozapine decreases aggression. But then we did genetic testing years later, right? And it comes back with an issue of processing medium chain fatty acids. So counterintuitive to myself. Eliminate all omega threes. Eliminate fat from the diet, right? Anything with medium chain fats. Eliminate him being in a fasting state. So this is like the opposite of ketosis, right?

• 55:01David Puder?

  And we're going down on the clozapine and he's fine. We're about half the dose right now. We're going down slowly. Obviously, it's a big risk, you know, immediately removing a medicine because he's.

• 55:14David Puder?

  Because he's a, his aggression is, was so bad. And it's like, when is he the worst? After he does some sports, he's, he's, he's actually an athlete despite being almost completely nonverbal. He, he, he's very athletic.

• 55:30David Puder?

  After he gets back, it's, he's, he's more dysregulated. And so I'm like, of course he is because exercise has thrown him into a fasting state. He's producing more medium chain fatty acids. Those are toxic to his brain, right? So I, I hope that the future of psychiatry has a more individualized plan for each person, right? We are not there yet. And so we have big guns that are broad, that do multiple mechanisms like clozapine that are still very valuable. But, and it, but they don't always work either, right? So we have to get creative.

• 56:12David Puder?

  And hopefully someone's listening to this who's young, who's gonna do their PhD and they can take this information and run with it. And that's what we need. We need to inspire more researchers like Nicholas, you're doing, you're gonna do PhD, maybe you said?

• 56:29Speaker 02

  Yeah.

• 56:31David Puder?

  I mean, you're already publishing more than most PhD students, I imagine.

• 56:37Speaker 02

  But no, I agree with the point you made of, of, that's a very interesting story too, where you wouldn't even think of that as a, as a, as a causative factor until you saw some of that. But I think it applies to so many different people across disorders where we're so fixed. And that's why our treatments, when you look at them in meta analysis for antipsychotics, for antidepressants, is pretty much across the board. They're all pretty much the same, apart from, like you said, our big guns like clozapine, which hits every receptor, it causes a mess of things. But by doing that, you're probably targeting the receptor that needs to be targeted in that specific person. And that's probably why it has that higher effect. But it, it shows that if we have more of an individual approach, maybe instead of making that big mess and causing side effects and all these different things, we can say, oh, this is what's wrong.

• 57:21Speaker 02

  This is the treatment that would benefit you because of this. Not, you know, try this first line, switch to second line, hope that works, switch to third line. And, and if we could skip those steps, I think it would be amazing from a treatment perspective, but also just quality of life for the patients that we treat.

• 57:38David Puder?

  And I think some of it may be tragic, right? Some of it may be like, okay, you have an issue with neuronal migration and growth. That happened when you were an infant. It's happened. There's, there's nothing that we can do about the poor neuronal migration that's happened. But we can try to treat the symptoms. Right? So I think that there, there will be cases where it's like, there's no good solution. Right? Maybe, yet, right? Yet, yet being the key word here.

• 58:19David Puder?

  Put a, put a, put a brain chip in them and maybe it counters the, uh,

• 58:27David Puder?

  the neuronal migration issue. I don't know. Okay.

• 58:31David Puder?

  Let's talk about environment. Should we jump to environmental factors? Because some of these are really interesting to me. Some of these are like, like the whole idea of, well, we'll, we'll get there. Let's go, let's go through it progressively. But paternal factors, more than maternal. Tell me about that, Liam.

• 58:51Speaker 01

  Yeah, so I think the interesting aspect about this is that men, they produce sperm continuously throughout their lives. So there is a greater chance of de novo mutations due to like radiation or errors in DNA replication. Because DNA replication is happening throughout their entire life. Usually for women, the eggs are all formed at the same time and they just sit stagnating. And they can accumulate mutations as well. But I think with, with, with men, because the sperm are continuously being produced, if there's one mutation that happens early on, then that can be carried through, through the rest of the sperm. So when these cells accumulate some mutations, they, they've been associated with like autism,

• 59:31Speaker 01

  achondroplasia, Marfan syndrome, and then potentially schizophrenia as well with increasing paternal age as these mutations increase.

• 59:41Speaker 01

  So there, there is one Swedish national patient registry that looked at advanced paternal age, meaning age greater than 50 years old, and noted that it was associated with schizophrenia compared to younger fathers of 20 to 29 year olds. There's about a threefold increased risk. And then another study actually showed of almost a sixfold increased risk. But then you also have to think of other things that will count for late paternal age such as maybe less like more so- social isolation and the younger years and then also maybe some more impulsivity in later years and whatnot. So a lot of these studies don't always control for those factors, but I think it is an interesting

• 1:00:25Speaker 01

  thing that people have picked up on over the years.

• 1:00:30David Puder?

  I, I, this got me thinking like, should, should men, you know, put ice on their genitals when they go in the sauna as a way of preventing this, and I don't think that's the case, unfortunately, like that's probably not going to be what reduces the risk. But yeah, so advanced, advanced paternal age impacts this is the summary.

• 1:00:58Speaker 01

  Right.

• 1:00:59David Puder?

  Yeah, okay. The, another environmental impactor that increases risk of schizophrenia is what is going on in the mother when the baby's in the womb. I think some of the interesting prenatal exposures that increase the rate of schizophrenia. One in particular was the Dutch Hunger Winter Famine in 1944 to 1945. This was Dutch individuals who were going through Nazi occupation. They were currently pregnant during that time and they, in certain regions, they were limited, limited to a thousand calories per day during these months of pregnancy. And so

• 1:01:43David Puder?

  in this group of people, they had twice the risk of developing schizophrenia later on. Like that to me is very significant and it shows how the environment can increase the future progression of a disease that happens in people in their twenties, you know, because of the, because of the, the, the impact on the brain, the environment, the stress on that baby, the baby maybe not having the nutrition to develop their brain in a normal way in the womb. Liam and Nicholas, I'm curious if you guys have any thoughts on this?

• 1:02:24Speaker 02

  Yeah, I think it it just really shows how important any early stressor, even before you're born, can really affect your risk of schizophrenia. And then that continues after because a lot of these stressors that occurred, these people maybe were exposed to that throughout life, even after. And we know that a lot of these different stressors do increase your risk of schizophrenia, whether it be ACEs or adverse childhood experiences, all these different things, infections, lack of access to food, whether it be in utero or even when you're born as a kid growing up, really influence your risk of schizophrenia. So it's how they interact with the genes, which is a good example of what we've been talking about. We've been mostly speaking about specific variants,

• 1:03:07Speaker 02

  but it's this is now we're talking about at a phenotypic level, at a person-to-person level, how these genetic risks are interacting with one another and producing something like schizophrenia or worsening the course of schizophrenia.

• 1:03:20Speaker 01

  Yeah, and I think what's really interesting about this study too is that it wasn't just increased risk of schizophrenia. There is also congenital neurodevelopmental defects like autism and other learning disorders, even like spina bifida, things like anencephaly. So anything that really affects CNS, the development of the brain to a profound scale probably can increase the risk for schizophrenia if we assume that schizophrenia is associated with a developmental problem.

• 1:03:52David Puder?

  I think it's worth talking about the adverse childhood experiences. We've talked about this before, Liam. This was a study in 2012 where they looked at 75,000 participants. The odds ratio for developing psychotic symptoms if they had higher ACE scores was 2.78. That's significant.

• 1:04:15Speaker 01

  It is incredibly significant and this study controlled for different factors related to socioeconomic status, IQ, educational attainment, drug use, and genetic liability even. So that we have to conceptualize schizophrenia as not only a genetic disorder, it's not going to cause, the genetics is not always going to cause the disease. I'm sure that there are certain cases of people with schizophrenia that if not for their genetics, they would not have developed schizophrenia. And I think there are other cases too that, and for ways and reasons we don't understand yet, if they're exposed to some adverse prenatal environment, or and/or adverse childhood experiences, stress

• 1:05:00Speaker 01

  growing up, leading to social isolation, maybe some cognitive dysfunction, and how that can increase the risk for developing schizophrenia or their psychiatric diseases over time.

• 1:05:13David Puder?

  Another big impactor is poverty, socioeconomic status, right? And in this one study, where they looked at 2.1 million individuals born in Sweden, they looked at social adversity by five factors, living in rented versus owned homes, low parental socioeconomic status, single parent household, parental unemployment, households receiving social welfare benefits. And what they found was that the hazard ratio, the risk of developing future schizophrenia

• 1:05:53David Puder?

  increased as the number of adverse social variables increased, all the way to 2.7.

• 1:06:04Speaker 01

  And I think when we see numbers like this too, we have to put on our almost public health hat and say, at a large scale, if we can have interventions to mitigate some of these disparities in populations, you can have very broad impacts and reduce, if we're looking at just schizophrenia, for instance, obviously this will affect health outcomes and everything beyond that. But just through the lens of schizophrenia, if we wear that public health hat and we advocate for different housing, or safe use of substances, all these different things.

• 1:06:33Speaker 02

  You're going to have a very big impact on reducing, based on this data, the people that maybe go on and develop schizophrenia. So we're not talking at a one-to-one basis. That's important, talking about the person in front of you and trying to mitigate these risks. But from a population health lens, if this is something you're advocated for in Canada, the US, for a whole population, that that number, that risk ratio of two on a large scale is lots and lots of people. So that's why it's so important, I think, right now where we're at, although the genetic information is so important and it's going to progress over the years. I think to really have impact from a public health lens, these are some of the interventions where, beyond just that one-to-one interaction, we can actually prevent, hopefully, the onset of schizophrenia for people, uh, which is why it's so important and what we've highlighted so far.

• 1:07:19David Puder?

  Yeah, and I think, I think this is where we who are kind of looking at these studies can kind of step back and say, okay, what are the, what are the impactors that we can potentially change as a society that are the biggest? And the ones that are going to make the biggest impact. And I, in my recent episode I did, I don't know if you heard it, guys, on um, intergenerational trauma, how a mother with a history of trauma, who has lower reflective function, has a higher rate of disorganized attachment in the child. So it's like, okay, how can we, as a society, come alongside and then,

• 1:08:04David Puder?

  you know, give resources to mothers that are at risk? How can we help?

• 1:08:10David Puder?

  People during these, these very vulnerable periods of time? And um, support, you know, two-family households, support some degree of stability for people that are struggling with mental illness.

• 1:08:26David Puder?

  So yeah, these are, these are kind of the, the questions, the higher level questions. Or how do we reduce cannabis use in people with high risk of developing psychosis, right? This is another factor. Nicholas, go ahead and tell us about this one.

• 1:08:44Speaker 02

  Yeah, I know you guys did a whole episode on this, but I'll, I'll give an overall mini view of it. And, and we recently put a paper out on with regards to this too. But yeah, it's another example of a population level intervention through education, through informing people of risks. You can really have a big difference because at least in Canada, we know the THC content, which is the psychoactive component of cannabis, has increased by over five times over the last two decades. So a lot of the argument for cannabis being this, this safe substance that people can use, people have in their mind what cannabis was in 1990 or even before that. And now we have these very synthetic strains that are very powerful. And we know that higher THC content, regular use, previous history of mental health disorders,

• 1:09:27Speaker 02

  being younger, male, these are all risk factors for developing psychosis. And eventually even going on to develop a schizophrenia spectrum disorder. And we've, our group has also done a study looking at this topic where we took 9.2 million people in Ontario and we looked at people that presented to the emergency department for cannabis use or cannabis induced psychosis and then saw who did, who developed schizophrenia after three years. And we see that people that had a cannabis induced psychosis had a 242 fold risk of developing schizophrenia within three years. Again, there's a lot of confounders there because this is an observational study. But I think it really shows that. And I know we're talking about cannabis, but we also did a recent study with psychedelics because it's a very hot topic now, or I should be more specific and say hallucinogens, which is a more umbrella term.

• 1:10:13Speaker 02

  And we did the same sort of study looking at people going to ED for psychedelic use or hallucinogen use. And we saw that those people that presented and had a hallucinogen induced psychosis, right, I believe a 15 fold higher risk of developing schizophrenia in three years too. So these substances that we perceive them to be so benign.

• 1:10:31Speaker 01

  They have inherent risk to them. And I think, again, with that public health hat, it's important that we are informing the public. It's important that through the government, too, that we're making sure that people are educated, that younger people aren't getting access to these substances. Because with these with these numbers, they're quite staggering. And if we're able to intervene, we can really make a big difference. And beyond treatment, which we're so focused on in psychiatry, we can actually have an emphasis on prevention. So these people hopefully never go on to have that stressor and develop a schizophrenia spectrum disorder.

• 1:11:04David Puder?

  Excellent. Yeah, that odds ratio is wild. Like, when we think of odds ratio, we usually think of like, oh, this is a this is an odds ratio of two. But this is like, this is an odds ratio of like, 200, right? And that's that's ginormous. Okay.

• 1:11:24David Puder?

  So that's one thought that I have is like, wow, that's a big odds ratio. Anything more on environmental things, Liam, or anything on the THC?

• 1:11:35Speaker 01

  Regarding the cannabis, I think that that odds ratio is incredible, because I think about how many people try cannabis and don't end up in the emergency department. So what does it take for someone to actually end up in the emergency department? It's probably some underlying risk factor for psychosis. So I think there is like the genetic risk component to it that we talked about in the last episode. But and I think one of the one of the more interesting findings of cannabis and how it might increase risk for psychosis is the we talked about a study in the podcast on this. But following teenagers from like the age of 15 onward, seeing the ones that started using cannabis regularly versus

• 1:12:20Speaker 01

  the ones who don't, they had a faster rate of cortical thinning. And schizophrenia, we know actually that prior to the onset of psychosis with, on average, when a subset of people is with schizophrenia who develop first episode psychosis, they will also have increased cortical thinning in the years prior to their psychosis. So that also lends more support for the idea that cannabis can influence brain development and then maybe increase risk for psychosis.

• 1:12:52David Puder?

  When we have patients in our practice that get psychotic from cannabis, at that point, having a clear conversation, like your, your, your brain, for whatever reason, is allergic to cannabis and you will likely continue to get psychotic the more cannabis you use. There is a degree of denial, a degree of, you know, not wanting to hear that, thinking that you're part of the system, and a sonoma, like not, not, not having insight into the, the gravity of it, that is very common, but we need to have that conversation.

• 1:13:33David Puder?

  So, gosh, we could, I feel like this is probably a good episode in and of itself right here. I know we were going to get to the neurobiology of schizophrenia, but what do you think about like having a part two rather than overloading people? I think the people are probably saturated by this point.

• 1:13:51Speaker 02

  Yeah, I think that makes sense because I think neurobiology in itself, there's so many things to, to talk about, so I'm totally okay with that, too.

• 1:13:58Speaker 01

  That sounds good to me, too.

• 1:14:00David Puder?

  Okay. Summary statements. Liam, what's your summary of the episode?

• 1:14:06Speaker 01

  Again, I think in psychiatric genetics research, we were excited about the idea of having one or two genes associated with schizophrenia. It's not turned out to be the case, but we do know that there are hundreds to thousands of genes that increase risk for schizophrenia that are present across the entire genome. And the genes that do seem to be related to schizophrenia are within neurons and it's, they regulate neuronal function through NMDA receptors, through transcription factors, and maybe there are other genes out there that were left to be discovered. But in my mind, I think we need to focus more on intervening at the individual level,

• 1:14:49Speaker 01

  trying to meet people where they're at and try to understand what are some of the things that increase their symptoms, addressing their cognition, addressing their social life. And the solution is not just antipsychotics, it's, it's far more than that. And also the trends diagnostic effects.

• 1:15:07Speaker 01

  These genes aren't specific to schizophrenia. They overlap with bipolar treatment resistant depression. So that also kind of raises some questions about the validity of the schizophrenia diagnosis and whether we should start to think more through dimensional aspects like looking at positive symptoms, negative symptoms, and cognition. So that's where I'm at, at least with schizophrenia.

• 1:15:28Speaker 02

  Yeah, that's a great summary. I'll have a slightly more brief one just to add to that of, I think, I agree with everything that you said. And I think the biggest thing is that genes interact with the environment to produce schizophrenia. It's not just this genetic sort of disorder. There are higher risk individuals. And like you said, at the individual level, I think we can really have more effect. So changing that environment, whether that be for the person in front of you, whether that be on a population level advocating for change with regards to cannabis, or housing availability, or food avail, all these different things, go a long way in, you know, the overall health of people, but also just reducing that likelihood of developing schizophrenia. And I think that's where we're

• 1:16:10Speaker 02

  at now. I think we'll see developments through that genetic side of things where we see more specific genes that are contributing that are causative for schizophrenia. And maybe eventually one day we'll have, similar to Huntington's disease, where they had that recent, you know, trial come out that was able to intervene at the gene level and actually have an effect. But I think we're still a ways away from that. But it's an interesting time. And I think, again, emphasizing that in interacting at that individual or environmental level will be the most hopeful right now.

• 1:16:41David Puder?

  Nice. And I would, I would just emphasize that if you're listening to this, and if you have a kid, a relative that suffers from schizophrenia, and you're here because you're curious, like, what caused this? And I think a lot of parents will feel a lot of, like, guilt, and like, gosh, did I do something wrong? You know, I would hope that you could leave with a level of, there's a level of complexity to this, and randomness, that there's, there's no way of really predicting or preventing some people developing schizophrenia. It's been 1% across the population in most countries.

• 1:17:25David Puder?

  And we can advocate for the future generations. But hindsight is 2020. And if this, if this has given you any sense of like guilt, I would want to counsel you to consider that there are things that you could focus on, but the guilt itself is probably mostly hindsight bias. The things you can focus on are finding a prescriber that will meet weekly. If, if, if your kid has not overcome having someone who's like a good friend or feels like a good friend to your kid with schizophrenia.

• 1:18:09David Puder?

  Takes a while to develop that sort of friendship with someone. But I think that that has helped. The patients that I've been able to help get unstuck is developing that close relationship over time where there's trust, where they will take the medication. So, okay, those are my thoughts. So, all right, guys. Thank you so much for coming on and we'll stop here. Thank you for having us. Yep, thanks for having us.