 So let's talk about evolution and schizophrenia. Now, schizophrenia is a particularly fascinating topic in the realm of evolution because it really makes no sense. You know, we have this very harmful condition with this genetic component and it's surprisingly common in our modern population. So we're going to look at this paradox, some ideas on why this might be, and then some clinical implications we can derive from some of these ideas. But first of all, what is schizophrenia? And you know, from the outside looking in we get a lot of our ideas about this concept of schizophrenia through the media. And a lot of these stories sent around themes of homelessness and violence. And you know, not all patients are homeless, but because there is, you know, this increased rate of homelessness in this population, we do see an increased vulnerability for other problems such as being a victim of violence. And those are important to remember. But what else do we know about schizophrenia? And so a lot of you are probably familiar with these positive symptoms of hallucinations and delusions. But how abnormal is this and how different are we? So it seems that disorders of psychosis probably exist on some kind of spectrum. And there's some interesting studies showing that psychotic-like experiences are actually fairly common in the general population. And these experiences aren't necessarily associated with an increased risk for psychosis, but are thought to be more experiences within the normal range. Now when we discuss schizophrenia specifically, schizophrenia is commonly said to have a worldwide prevalence of 1%. When we look at a little more careful analysis of this data, the estimates are probably better to be around 400 to 700 people per 100,000 in the U.S. population. Now even if we take this lowest estimate at 400, this is still a lot more common than you would expect from a Mendelian disorder or a single gene disorder, and much more common than some of our other psychiatric conditions such as autism. It's especially common given that it has an increased mortality rate of 2.6 times the general population, and a significantly reduced fertility rate compared to the general population. Now there's definitely a genetic component here, and as we'll see will be important when we discuss some of these theories later, there's this paternal age effect where with an increased age of the father, there's an increased risk for the child to develop schizophrenia. Now if all of these things are true, why does schizophrenia still exist? Why do we have this harmful condition? Well, some of the earliest theories around schizophrenia and evolution centered around our uniqueness as a human species, with characteristics such as intelligence, language, social relationships, and creativity. One of the very earliest theories focused on this language aspect, and one of the main proponents of this theory, Crow, has this saying that schizophrenia represents language at the end of its tether, and this provides some interesting mental imagery on a condition where the distinction is blurred between internal speech or thought and external speech, as in the words that are spoken to you and that you speak to others. So with schizophrenia, we have schizophrenia and language both persisting in populations that have been separated for thousands of years. So Crow suggests that whatever genetic component is behind these, must have occurred before these populations separated or at the time of species transition. He suggests that the change that happened at this time was cerebral lateralization, and basically what that means is it's the ability to focus a particular task in one area of the brain so that a particular area of the brain becomes specialized in, for example, language. Now, something else that's associated with this cerebral lateralization or specialization in one area is handedness, and there are studies showing that those with schizophrenia were more likely to be ambidextrous as a child. Other studies associate language in schizophrenia in that those with schizophrenia and their children have increased reading impairments, and we also see that those with reading impairments have an increased prevalence for psychotic symptoms. Now, this is very interesting because recently studies have proposed that we have this overlap between the reading impairments we see in schizophrenia and dyslexia, and that maybe we can take the reading assessments that we do with children in school, combine that with their family history, and use this as a predictor of risk, and that if we can use these assessments and identify which children are at greater risk for later developing schizophrenia, we can then place them in programs that we use for children with dyslexia, and hopefully that would be beneficial for them. Now, there are some problems with this model, and one of them is that language evolution is thought to be more gradual rather than this sudden leap that is proposed for this model. And also, although schizophrenia has this disordered language, there are also problems with social behavior and executive function, so we need a way to explain some of those aspects of the disorder. So what about humans as a social species? Now, primates do have some social behaviors, but as humans we have an increased ability to understand the world around us and to act on and affect change in that world around us. And in this theory, it's suggested that we need continued exposure to a healthy social environment in order to develop. And because we're dependent on that exposure, it also makes us more vulnerable to harmful social environments. And in this case, schizophrenia is seen as a disconnect with the social world. So this idea has some support from studies showing difficulties in theory of mind or difficulties relating to other people's perspectives and difficulties in understanding emotions and reflecting emotions of others. As far as creativity, there are studies showing that those non-affected relatives of people with schizophrenia are more likely to hold positions in academic or artistic professions, which makes sense because we see greater cognitive flexibility and increases in divergent thinking in this population. One of the theories that's related to creativity includes this neuronal membrane phospholipid theory. And in this theory, it suggests that we evolved near water with good access to essential fatty acids, and this allowed for enhanced cognition and memory and creativity, but it also kind of paved the way for problems such as dyslexia, schizophrenia, and manic depressive disorder. Now, in the past, our traditional diets may have counteracted some of these harmful effects in phospholipid metabolism mutations, but as we move away from those traditional scenarios, we may be creating a more harmful form of disorder. Now, when we step back and look at some of the main categories in place evolutionary theories under, we have ancestral neutrality, balancing selection, and polygenic mutation selection balance. This first theory of ancestral neutrality is the idea that you have these ancestral alleles, which aren't necessarily beneficial, but they're not really detrimental, they're just there. And when we take those ancestral alleles and we take them to our modern environment and start interacting with our modern environment, there's a mismatch between those ancestral alleles and our current context, and this creates a problem. Now, was schizophrenia neutral in the past? While we can't say for sure that schizophrenia was detrimental in the past, we can infer from its current harmful effects that there is a good likelihood it did have some fitness reducing effects in the past. Now, one argument that's been made for ancestral neutrality is variable prevalence across locations with the higher rates being seen in urban locations. Now, this fails to explain the overall low prevalence of schizophrenia that we see today, because if this disorder was truly neutral, we should see much more variation in this disorder and its prevalence. We would also have to have this disorder be neutral across different cultures and places in past times. And one of the biggest problems here is this problem of genetic drift. And genetic drift is the concept that you have this random sampling error over time, and so if these alleles are truly neutral, there's no push for them to either remain or to be removed, and they can be lost over time. Now, there was an interesting example given in one particular review where the authors proposed this scenario and they say that, you know, if schizophrenia was due to a single recessive allele, you know, that's neutral, and given its current prevalence rate at 1%, then in 1600, 42% of the population would have had to have schizophrenia, which seems highly unlikely. So what else can we use to explain schizophrenia? Well, we have this concept of balancing selection, and this includes the models of antagonistic playtropy as well as heterozygote advantage. And probably an example you're most familiar with here is the example of sickle cell anemia with its heterozygote advantage in protection against malaria. Now, protection against various infectious agents has also been proposed as a benefit in schizophrenia, but this hasn't seen a lot of support, and this heterozygote advantage as seen in sickle cell anemia is very rare in nature. Some other benefits that have been suggested for schizophrenia include this group splitting hypothesis, where you have a charismatic leader who can kind of create a following and then take these new tribes to explore new territories and prevent that main group from getting too big. It's also been proposed that enhanced territorial instincts and inventiveness could be other benefits. However, this is a very, very harmful condition, and if there were some benefit to offset that detriment, it should be very obvious, and we really don't see any obvious benefits here. Even in non-affected relatives of those with schizophrenia, we see reproductive rates that are comparable to the general population. And probably the biggest argument against this balancing selection idea for schizophrenia is that paternal age effect that I mentioned earlier. So with increased age of the father, there's an increased risk for the child to develop schizophrenia, and why this is important is that it indicates an association with an increased number of mutations, and this would be more in line with a model such as the polygenic mutation selection balance theory. And so we know that fitness as a trait itself relies on many complex processes and on many genes, and our brain function also relies on many complex processes and on many different genes. You know, mutations in a large number of genes are going to have an effect on brain function. So this can help explain why in schizophrenia we see some variation in the presentation of symptoms from patient to patient. We can have many different underlying processes affected, and while these mutations may be selected against, each individual mutation on its own is only mildly harmful, and so can be kind of selected against and taken out at a very slow rate. Now this model also fits in with our current prevalence rates, and it's congruent with the difficulties we've had in finding good risk alleles for schizophrenia, and you know, the difficulties we've had in being able to reproduce the results of those studies. And then the very small effects of those risk alleles. Now one argument that's been made against this model is the uniformity of brain changes that we see from patient to patient. But with this, you know, it can also be seen as this is the end result of an accumulation of mutations, just like we can have many different tiny processes interfering with a particular function to lead to something such as impaired glucose utilization. Now we can appreciate that there's definitely a genetic component, and there's different ways we can help explain or try and understand this, but we have to remember that there's an environmental component involved in the manifestation of the disorder by taking this genetic risk and bringing someone from this genetic risk to the actual symptoms of schizophrenia. And so I won't go through all these here, but I'll give one example in the form of toxoplasma infection because I like microbes and I have to talk about some kind of infection. And so with toxoplasma, it's kind of an interesting evolutionary story all of its own. So you can have this mouse get infected with toxoplasma, somehow lose its kind of natural fear of its predator, the cat. And then once the mouse is inside the cat, the parasite is able to complete its life cycle inside the cat's intestines. Now we can become infected with toxoplasma through things such as poor hand hygiene, exposure to pet cats, undercooked meat, and several other factors. But in a healthy human, our immune system should be able to suppress that infection and lead to the formation of what are called dormant cysts. Now in someone with schizophrenia or with a propensity for schizophrenia, you know, with possible genetic ties to immune function, the immune system isn't able to do this. And we have problems, you know, in many ways. But for example, toxoplasma can increase dopamine. So dopamine increases on infection. Dopamine allows toxoplasma to replicate. Toxoplasma has an affinity for dopamine-rich areas of the brain. And strangely enough, toxoplasma is also able to create its own serotonin and dopamine precursors. So this is quite a smart little bug. And, you know, there's a lot more to the story, but hopefully you can appreciate that there are many interrelated factors at play here. Now recognizing the role of environment is really important because this is where we can step in and have some hope of creating a therapeutic difference. We're all familiar with this story of, you know, agricultural revolutions, industrial revolutions, traditional diets being shoved aside, and various adverse health consequences. And the story is really not that different in the case of schizophrenia. Now we do see with, you know, where we have these traditional societies with low grain consumption, and then we have the introduction of Western grain products. We see that the rates of schizophrenia dramatically increase. In one place I read that they went from 1 in 30,000 to 1 in 100. So that's quite a substantial increase. And then when we look at some interesting analyses of World War II food shortages, we see that in countries where there was shortages that led to decreased wheat consumption, such as some of the Scandinavian countries, there's a dramatic decrease in the rate of hospitalizations for schizophrenia. And in the United States where wheat consumption increased during that same period of time, we see that rates of hospitalization for schizophrenia increased. Now there's a significant relationship between schizophrenia and GI inflammation. With rates as high as 50% in the stomach, 88% in the small intestine, and 92% in the large intestine. And we have this relationship between celiac disease and schizophrenia where having celiac disease increases your risk for later developing schizophrenia and having schizophrenia increases your risk for celiac disease. There was an interesting case of this one woman who had celiac disease and was on a gluten-free diet, but they gave her, I think it was 30 grams, an experimental dose of gluten, and she experienced an acute psychotic episode. And what was especially interesting in this case was that her symptoms subsided in a few days, but she had a brother with schizophrenia. And this highlights the interplay of genetics and environment. Now patients with schizophrenia can also be sensitive to gluten through other mechanisms. So if we go back to toxo for a minute, we can see that when you have an infection with toxoplasma, antibodies to gluten increase. Now there are several trials that show removing gluten from the diet can lead to a significant improvement in symptoms, but this is probably beneficial for a subgroup of patients. So not necessarily everyone. Now another diet that's been looked at is the ketogenic diet. And not a lot of attention has been paid to this diet in the case of schizophrenia, but there was an interesting trial in 1965 where they took 10 patients, placed them on a ketogenic and saw a significant improvement in symptoms. The authors here started this trial based on their observations that patients seem to crave carbohydrates before they experienced a worsening of symptoms. And they had this hypothesis that perhaps these patients have trouble using carbohydrates. Now more recently we've seen animal studies of schizophrenia and ketogenic diets showing that ketogenic diets may be beneficial for their effects on disruptive glucose metabolism and on their ability to normalize glutamate and GABA levels. So when we have this very daunting condition such as schizophrenia, it can be difficult to believe that something as simple as diet can have such a dramatic effect. But for many of you, if not all of you, you've probably seen that dietary changes have made a beneficial effect in your own life. And so I'm going to introduce you to a few cases where a change in diet made all the difference in the world. So this first patient is a 33-year-old female. She has a diagnosis of schizophrenia, but she presented to the hospital for non-psychiatric symptoms. Now they did all these labs and imaging on her, and they found that she had decreased blood flow to part of her brain, which was very interesting. They diagnosed her with celiac disease and placed her on a gluten-free diet, and her symptoms, both physical and psychiatric, resolved in a matter of days. And she remained asymptomatic a year later. But what was really interesting was that at six months out, they repeated that imagery, imaging, and they saw that those blood flow abnormalities had actually corrected themselves. So that was pretty amazing. Now, this patient is a 70-year-old female, very treatment-resistant. She had a longer list of medications that couldn't control her symptoms, and she had had multiple hospitalizations for extreme self-harm behavior, multiple suicide attempts, hallucinations, and other psychotic symptoms. Now, in this case, it decided to try a ketogenic diet. And this was pretty amazing because you have to consider that she had been dealing with this for 53 years of her life. And she'd been hearing these voices and seeing skeletons, and they placed her on this ketogenic diet, and she experienced a resolution of symptoms in eight days. So that was pretty remarkable. So these are important interventions to kind of consider. But what about the patients for whom diet isn't quite enough? What else can we do? And before I get into supplementation, I want to mention this curious finding in patients with schizophrenia that when these patients experience a high fever, they have a reduction in symptoms. But when that fever abates, their symptoms return. So, you know, Corbin makes this connection between fever and phospholipid metabolism, suggesting that if a fever can enact that dramatic of a change, maybe we only have a minor biochemical glitch, and maybe we only need a minor kind of intervention. So what might such a minor change look like? Well, in this case of this 31-year-old male, the minor change was 2 grams of icosapentanoic acid per day. And this was kind of a cool case because they actually had imaging from the year prior to starting this treatment. And in the year prior to starting treatment, the imaging had shown that the ventricles in his brain were getting bigger, as you would expect with schizophrenia. And at follow-up imaging, six months after beginning this 2 grams of EPA per day, they show that the ventricles were actually decreasing in size and kind of going back to normal. And not only that, but he experienced a dramatic improvement of symptoms only two months from the beginning of this treatment. And at six months, his positive symptoms scores had dropped from a 46 to a 4, and his negative symptoms scores from a 16 to a 3. Now, the most impressive part of this particular case was what this meant for the patient in his day-to-day life. And what this meant was that he was able to go back to university and work on that degree he'd had to abandon when these symptoms first presented. There was a few different imaging types used between these case studies. I don't remember exactly which was which. Now, what might be happening in these cases well, in fever, we're thinking that the fever provides kind of a sink for excess arachidonic acid. And by supplementing with EPA, we're changing the EPA to arachidonic acid ratio and we're providing the same kind of end result without having to use a fever to reduce symptoms. Now, omega-3 supplementation has been, you know, fairly promising in trials, but it's suggested that omega-3 supplementation may be best for those at a high risk for psychosis or those experiencing a first episode of psychosis. Now, there are also studies showing that omega-3 supplementation reduces the dose needed for antipsychotics and reduces the negative side effects of those antipsychotics. And newer studies are starting to look at combinations of omega-3s and antioxidants. Now, I also want to mention vitamin D briefly because vitamin D is kind of the darling of mental health supplements and there is an association in schizophrenia between low vitamin D levels and schizophrenia. And what we also see that's particularly interesting is that in rat models of vitamin D deficiency, we see brain changes that are similar to that seen in schizophrenia. So it can be very tempting to want to jump in and be like, okay, let's try supplementing vitamin D. But there's a few reasons to hesitate here. And for example, there's also a relationship between high neonatal vitamin D levels and the later development of schizophrenia. The trials that we have so far are very few. There's only a couple and they're not super promising. And then, going back to talk so just for fun, we see that in animal models of toxoplasma infection, the addition of vitamin D actually increased animal mortality. So there's a few reasons to kind of hesitate on this. Now, this doesn't exclude the possibility that vitamin D supplementation may be helpful in a subset of patients. But we need more research to kind of clarify who exactly this would be helpful for and if there are cases in which it would be detrimental. Now, going on to some lifestyle considerations, you know, there's definitely... it's definitely important to consider infection and immune regulation. There are many case reports of, for example, urinary tract infections or certain antibiotics causing an acute psychotic episode or being associated with an acute psychotic episode. So in the cases of acute psychosis, it's important to assess all these factors. And then, going back to our uniqueness as a human species and this aspect of play, it's important to consider some of these alternative therapies. For example, if we think about creativity and language, well, what can we do with art therapy and music therapy? And art therapy is very popular in many countries in their guidelines for treating schizophrenia. And it's been shown, although it doesn't have a ton of effect on positive or negative symptoms, it does improve self-confidence, self-esteem, it increases emotional well-being and emotional expression, and decreases isolation. And music therapy, as well as animal assisted therapy, have shown improvements in social functioning. Now, animal assisted therapy is particularly valuable because it's often done outside bringing in the therapeutic values or influences of sunshine and nature, especially for institutionalized patients. And there's very good compliance for this therapy. Patients often form good bonds with the therapy animals, which are usually dogs or horses. Movement therapies, such as dance movement therapy or body psychotherapy, have shown really exciting improvements in negative symptoms. And this is important because negative symptoms are particularly difficult to treat. And these studies show a 20% reduction in negative symptoms, which is higher than what we've been able to achieve with pharmacological agents. So these are important to keep in mind when addressing the whole person in the case of schizophrenia. So, as we've seen here, there's definitely room to have an impact through modification of some of these factors. So, although we have this condition of schizophrenia, which is very harmful, you know, it has this genetic component and is yet very common in our modern population, we can look at schizophrenia through some of these different theories and we can approach it from some different angles and gain some insights on what treatments might be useful in the future and hopefully give a little more hopeful prognosis on these patients. So that is that. And if you have any questions... What a wonderful presentation. I'm sure we have many questions and we can start lining up to ask Tiffany some questions. From a pharmacist perspective, integrated pharmacists, it was interesting to me that many of our antipsychotics have anti-toxoplasmic activity, right? And the antibodies against toxo, they completely co-relate as the drugs work. They lower and go down in the body. So it's believed partly schizophrenia, maybe even autoimmune, just as we see for anglo-losing spondylitis or Hashimoto's. There's a viral component or bacterial component or fungal component. And it's so fascinating what we're seeing between the microbiology, immunology, and then our mental health. Thank you so much. Any other questions? Yes. Thank you so much. That was fascinating. I come from a family of very divergent thinkers, one of whom has a schizophrenia diagnosis, another of whom has had multiple psychotic episodes throughout her life, and another one who is my child, who is on the autism spectrum. So I had two questions. One was about the autoimmune connection, but my second question, and perhaps if I was to stick to one, would be is there anything that you have seen in the literature that connects the autism spectrum by COSIS and schizophrenia? I've always throughout my life expected that there was some connection between the creativity, the divergent thinking, and these various manifestations of what could be considered mental health issues in my family. Yes, so I haven't looked too much into that connection specifically, but there is an association between, you know, the autism spectrum and then these disorders like schizophrenia. And part of that, you know, there's this difficulty with theory of mind we see in schizophrenia, which we also see in autism. So that's an interesting length there. There's some interesting stuff on priming and, you know, the maternal priming and the paternal priming and conflicting goals, you know, so the maternal aspect of that would be, you know, we want to conserve energy and the paternal aspect would be we want to spend energy and, you know, make this healthy child. And autism and schizophrenia, in that case, were suspected to be, you know, the opposite. You know, one is more paternal, one's more maternal. So one's taking a lot of resources and one's not really getting a lot of resources, but I haven't looked, you know, too much further into that connection. Hi. Great talk. I work as a clinical dietician in the inpatient setting in a hospital and one of the units I'm on is actually an inpatient psych ward. So I see a lot of schizophrenic patients. If I go to the doctors and, you know, be like, you know, trying out the gluten-free, kinogenic diet and all these additional supplementations, they're probably going to look at me like I'm crazy. But if I could try to implement one thing in my unit, what do you think would have the best results? That's a very difficult question to answer, partly because schizophrenia is thought to have many different ideologies. You know, there's even a recent news article suggesting that we get rid of this concept of schizophrenia altogether because there are so many different factors at play and there are so many different causes. And because, you know, there are so many different ones, what works for one person is not necessarily going to work for the other. So it's really difficult to say. There are studies where they, you know, they take this set of institutionalized patients and they implement a gluten-free diet and they don't see a change. Well, maybe you just missed the population that would, you know, that would help. So it's very difficult to say, you know, one particular thing over the other. So my question was sort of related. It's kind of a little outside of strictly diet and movement in these things, but excuse me, you brought up in sort of that last piece, the lifestyle and art therapy in these things and I've gotten to work with teachings of mindfulness and other sort of modalities to individuals in an inpatient setting. And I was curious, my throat is terrible right now. If you had looked into some of the other aspects of community and some of the community things that are being done for individuals with schizophrenia and what's being done for them to try to incorporate them back into society because with a lot of things in mental health there's huge stigma. And I was curious if that was something that you had looked into or had seen because on one end you think, why would I put up on just schizophrenics in the same room? That sounds like a terrible idea, but actually having that sort of community environment being something that's very positive. Yeah, so I didn't look at that community aspect specifically as community but within these therapies such as art therapy, music therapy, the animal assisted therapy those are done in group settings and so you have that community experience and that did improve social functioning and especially what was interesting with the animal therapies was that the patients learned how to take care of the animal they taught them how to groom the animal, take care of the animal and understand what another living being needed and so that also correlated with some improvements in the patient's ability to take care of themselves and then improve social functioning with their peers so as far as that these therapies kind of incorporated some of those community aspects. Still trying to formulate my question here but in terms of like an ancestral functionality or a usefulness of what we call schizophrenia I'm kind of curious if there's any research around that I saw the one thing on the group splitting as maybe that was the idea there but beyond maybe some idea of charisma is there anything else that you've come across? You know as far as group splitting there was one interesting mention that I read of these charismatic leaders that are also really detrimental for example during World War II Hitler was a very charismatic detrimental leader and so they this particular paper was saying there's these examples where these people that are very they're very kind of divergent thinkers they're creating this new kind of movement, this new group and that maybe our modern society isn't as accepting of those behaviors and so those people are seen as having this disorder because in ancestral times that might have been okay but in our modern context that's unacceptable so that was kind of an interesting finding there I keep talking if nobody else has a question I'm interested in the ego and how the ego is it maybe a little bit more glaring in modern life and maybe then was when it had an indigenous home and the ego is more of a sign of mismatch at some level and so I guess I'm really thinking like is schizophrenia purely pathological or did it have functionality and I think maybe that's a longer conversation but I'm intrigued by this idea of like okay is it language pathology kind of taken to an extreme or did it have some relationship in a more simpler integrated human society that you know it's maybe hard to see because that's not what our reality is right now and some of those things including the those religious aspects have been suggested you know maybe these were beneficial maybe they had some role in the past it's just that with the current harmful effects the current genetic component we can't necessarily use that to explain why it still persists today although you know maybe it wasn't quite as harmful in the past you know those models don't provide a very thorough explanation for our current situation thank you