Revolutionary Discoveries in Schizophrenia Causes and Treatments

Foreign I'd like to welcome everybody to today's presentation on emerging research in schizophrenia 2025. I know I didn't put 2025 there, but that's what we're talking about. In this presentation we're going to cover genetic and non genetic foundations of schizophrenia. A better understanding of what is what we used to call the dopamine hypothesis. We'll explore neurological findings in people with schizophrenia. We'll discuss the overlap between schizophrenia and autoimmune disorders. And then we're going to start to explore inflammation, stress, trauma, gonadal hormones, the gut microbiome and other things that may contribute to psychotic symptoms. Schizophrenia is a highly heritable psychiatric disorder. 60 to 80% of people who get schizophrenia have someone in their family that has schizophrenia. Schizophrenia. However, that also means 20 to 40% of people who get schizophrenia don't have somebody in their family with the disorder. So it's not just genetics. We can't just say aha, it's this one thing. Non genetic factors. And we're going to really dive into these in depth. But in general, exposure to severe stress, trauma or adverse life events may contribute to neurodev to neuro developmental disruptions that lead to the development of schizophrenia. Environmental exposures may lead to changes in gene expression without altering the underlying genetic code. Disruptions in neurotransmitter symptoms. Systems such as dopamine, acetylcholine, serotonin and glutamate also can cause psychotic symptoms and potentially the development of schizophrenia. Now remember in other videos when we've talked about neurotransmitters, I always say when one neurotransmitter gets out of whack, it usually takes it buddies along with it. It causes changes in all of the other or most of the other neurotransmitter and hormone systems. So what we used to think of as the dopamine hypothesis, it's all dopamine. No, it's not. There are things that are causing dopamine to be in excess. You know, there are underlying pathologies that are causing dopamine to be in excess. Yes, dopamine is a big part of it, but there's also acetylcholine, serotonin, glutamate, and actually histamines. Prenatal stress may increase the risk of schizophrenia. And part of that is because as we've talked about before, when the mother gets stressed, all of those stress hormones, that tsunami of stress hormones is also being experienced by the little peanut. And the little peanut's brain is not nearly as strong and resilient to that kind of insult, especially when it happens a lot. So women who are under a lot of stress end up often having babies whose HPA axis is already dysregulated. They're already experiencing, experiencing sympathetic dominance. And certain infections, particularly during critical developmental periods, may contribute to schizophrenia risk. In terms of neurology, schizophrenia is increasingly recognized as a neurodevelopmental disorder involving excess dopamine. All right, we all, all knew that. 1. Hypoactive NMDA receptors. NMDA receptors are a type of glutamate receptor. Now remember, glutamate is a, well, glutamate and gaba. Glutamate is our main excitatory neurotransmitter. GABA is our main inhibitory neurotransmitter. So when those NMDA receptors are not doing what they're supposed to do, then our GABA and glutamate can get out of whack, Our stress can become out of, out of kilter or excessive, and our ability to relax can become impaired. We also have involvement of histamine receptors and acetylcholine or nicotinic acetylcholine receptors. Your nicotinic receptors regulate dopamine and glutamate release, which if you've worked with people with schizophrenia, you know, a lot of them use nicotine. Whether they're vaping or they're chewing tobacco or they're smoking, a lot of them use nicotine. And part of that is because they're self medicating. Basically their nicotinic receptors in their brain are not as active as they need to be. So by stimulating them with external nicotine, it can actually help them feel better. NMDA receptor hypofunction on GABA neurons may lead to disinhibition of the NMDA receptors on glutamate neurons, leading to increased dopamine activity. So breaking that down, basically your GABA is your relaxation. And when those receptors are the NMDA receptors on the GABA neurons aren't doing their job, then GABA never shows up. And when GABA doesn't show up, then the NMDA receptors on the glutamate neurons can go wild. And that's why we see a lot of people with schizophrenia have high stress levels, high markers of stress. NMDA receptors are a subtype of glutamate receptors that inhibit dopamine release and are crucial for dopamine can start to become excessive. PET imaging reveals region specific abnormalities in people with schizophrenia. 23% of people with schizophrenia now that's just. Or, I'm sorry. 23. Elevated D2 and D3 receptor availability in the associative Str striatum correlates with positive symptoms. So they've got a lot more D2 and D3 receptors than a person without schizophrenia. And there's 18% less D1 receptors in the prefrontal cortex, which is linked to cognitive impairment. A lot of people think schizophrenia is one size fits all. And it's not just like any other mental health issue that we talk about, it's not one size fits all. So some people may have more pronounced impairment in their cognitive functioning and fewer of your positive symptoms like hallucinations and delusions. Other people may have a lot of hallucinations and delusions and less problem with their cognitive functioning, especially when they are in remission or in a prodromal phase. Research interestingly has identified an overlap between 32 genetic markers for schizophrenia and autoimmune disorders. So they've, they're speculating, they've been speculating that there's an inflammatory component in the development of schizophrenia. We know that autoimmune disorders, the key feature of an autoimmune disorder is inflammation. So you've got this group of disorders that their key feature is inflammation, but they also have genetic markers that overlap. So there are people with autoimmune disorders that are at greater risk of schizophrenia. And likewise, people with schizophrenia are at greater risk of autoimmune issues. Individuals with a history of autoimmune diseases had a 29 higher risk of developing schizophrenia. Remember, not everybody has genetic markers for schizophrenia or genetic markers for autoimmune disorders. They can develop from other things. But it is interesting to note that if you have somebody who has an autoimmune disorder, then they may have up to 32 genetic markers in common with someone with schizophrenia. So does that mean that they're more vulnerable to schizophrenia? I would argue probably, but we don't have any direct knowledge of that yet. The other really fascinating thing, again, not one size fits all. We can't say this is the cause. People with celiac disease, type 1 diabetes and lupus, those are all autoimmune related disorders, have been linked to a lower risk of developing schizophrenia. H Now, the articles I looked at did not talk about for people with celiac disease, type 1 diabetes and lupus. How many of those 32 overlapping genetic markers do they have? Didn't talk about that. But it's certainly interesting to note that not all auto, autoimmune conditions are the same. And there May be some, I don't want to say protective factor, because that doesn't sound right. But there's something different about people with celiac type 1 diabetes or lupus versus people with other autoimmune issues. People with schizophrenia have more baseline pro inflammatory cytokines than people without schizophrenia. That means people with schizophrenia have a higher level of ongoing baseline systemic inflammation. All right, that, that's an important point. Inflammation is seen by the body as a sign of disease or injury, which is activated, activates the immune system. So when I can a, an injury, my body sees the injury and it says, oh, we need to send people, we need to send things out to repair that injury. Okay, so then that causes the inflammation because the blood goes to the area and the white blood cells and whatever else is needed to heal the area and that leads to inflammation. So inflammation is a sign of disease or injury, and ongoing inflammation is basically the body saying, I need some more help over here because I can't, you know, heal this situation. Microglia are immune cells in the brain that regulate synaptic pruning, which is, you know, pruning back those synapses, neuron loss, basically neuroplasticity and, and inflammation. In schizophrenia, microglia are chronically over activated, leading to excessive synaptic pruning and neuroinflammation. We've talked before about how unregulated chronic stress or extreme ongoing stress creates what we call a neurotoxic environment. It there's too much glutamate in the, in the brain, there's too much excitatory stuff going on. And if you want to think of it as it's too hot, then you start losing neurons. And when the microglia are over activated, then there's more neuroinflammation. The more neuroinflammation there is, the more glutamate there is, and then the more synaptic pruning we have, inflammation disrupts the blood brain barrier, which allows more toxins to enter the brain and worsens inflammation. So I'm not exactly sure how that particular setup makes sense in the big scheme of survival, but that's what it does. When we have systemic inflammation, it makes our blood brain barrier as well as our gut barrier more permeable. So toxins leak out of the gut a lot easier and leak into the brain a lot easier. So you've got people with schizophrenia who have pretty much an ongoing hyper permeable blood brain barrier and, and gut barrier. Let's talk about, you know, what causes this Inflammation. We recognize that there are a lot of people who have genetic markers for schizophrenia who never develop it. We also recognize there's a lot of people who do. So what's the difference? And the stress hypothesis has held water for quite a while, Is again, not the only thing that happens. But we've recognized that when people are exposed to extreme levels of stress, that it creates a neurotoxic environment and creates changes within the brain. It change creates changes within the dopamine system, the acetylcholine system, the GABA system, all of those systems. And sometimes that can lead toward schizophrenia. Now, we don't know why some people who experience a lot of ACEs develop schizophrenia and others don't, but we do know that it's a risk factor. We do know that the people who are exposed to ACEs who develop schizophrenia, not all of them had the genetic markers. Really important because that tells us that stress itself is pathogenic. Veterans with severe PTSD are 2.5 times more likely to develop schizophrenia or other psychotic disorders. Now, this is interesting too. Think about the brain and the brain's development. Our brain is very malleable and very susceptible to insults, if you will, when it's in its formative period up to about age 24. But the older we get, the more resilient it gets, the more resistant it gets to being harmed by the occasional stressor or ongoing stressor. Children have a very malleable brain. Children who are exposed to adverse childhood experiences feel unsafe, feel disempowered, feel terrified a lot of the time. So they have, and their brain, as their brain is developing, it's developing around this notion of being unsafe and disempowered. It's developing around this dysfunction, and it's saying, okay, well, this is normal for me, so I'm gonna work around it. Veterans a lot of times and, and we're assuming the veteran did not have PTSD prior to going into the military, are much older. When they're going into the military now, 18 to 25, their brain is still developing. It's not fully solidified yet, or whatever you want to call it, fully developed. So it's still somewhat susceptible to stress insults. And those who experience traumas that were significant enough to lead to PTSD are 2.5 times more likely to develop schizophrenia. Chronic physical stress, particularly sleep deprivation, significantly increases the risk of developing schizophrenia or psychotic, like, symptoms. People with major depressive disorder who are not sleeping well, people who have insomnia that are not sleeping well, people who've been up on a three Day cocaine binge who haven't slept are much, much more likely to develop psychotic like symptoms. But physical stress, particularly sleep deprivation in people who are more vulnerable to schizophrenia, can trigger those genes to turn on trauma. And chronic stress activate the hypothalamic pituitary adrenal axis, our stress response system, leading to chronically elevated cortisol levels. Now cortisol levels is, cortisol is one of our main stress hormones. It's also one of our main steroids, it anti inflammatory hormones. Which is interesting because our brain says hey, we don't want to be feeling pain while we're trying to run from the hungry lion. So cortisol levels are high. But when cortisol levels are high and stress is high, it also means glutamate, our main excitatory, our main energy neurotransmitter, is also high. Over time, elevated cortisol and other hormone levels disregulates the HPA axis leading to an increased risk of schizophrenia due to blunted cortisol responses. In other presentations we've talked about glutamate, not, not glutamate, glucocorticoid resistance. And glucocorticoid resistance is when cortisol can't seem to stimulate those receptors to wake up. There's a lot of cortisol in the system, but the receptors just don't seem to pay attention to it. And even when they do get, the receptors do get stimulated by the cortisol, their response is kind of half hearted, increased inflammation. Because cortisol is an anti inflammatory and one of our main anti inflammatories. When cortisol receptors are not doing their job, then we're going to start to have unregulated inflammation. Cortisol is not suppressing it anymore. When we have increased inflammation, we have increased permeability in the gut and the blood brain barrier, we all of this starts causing a neurotoxic environment in the brain which leads to prefrontal cortex thinning. So this area where we do all of our executive functioning, it just starts pruning neurons like nobody's business. So we see a loss of volume in the prefrontal cortex, we see microglia hyperactivity. Remember those are the immune cells in the brain that recognize the toxins that are coming in across the blood brain barrier and they're trying to protect the brain by being active and in the case of schizophrenia, hyperactive. And then we start to see disruptions in the dopamine and glutamate systems. When cortisol's high. When glutamate's high, Dopamine is typically going to be high because our brain is saying, I need to stay motivated to run away from the hungry lion. But just like all of our other receptors, they start to become unreceptive to being activated by that particular chemical. Just like we've talked about with alcohol. When you first start drinking alcohol, you can get a buzz with very little. But if you drink chronically and it takes a whole lot more alcohol to get that same kind of buzz because the receptors have become tolerant. Every kind of receptor we have does the same thing. Insulin. When people have too much insulin, too, too often the insulin receptors become resistant or tolerant to the insulin. And that's our body's regulatory mechanism to prevent overstimulation. So we've talked about stress being something that can create a neurotoxic environment that can lead to potentially the development of schizophrenia. We've talked about the overlap in genetic markers between autoimmune disorders and, And. And schizophrenia. But there are other things they're finding, and this is fascinating to me. Absolutely fascinating. Our gonadal hormones, estrogen, testostero, oxytocin, also may play a role. Estrogen and, and this is in both sexes. Estrogen plays a critical role in brain function, neuroprotection, and dopamine regulation. So if estrogen's too high or too low, then we're not going to be in that sweet spot. Its influence on schizophrenia risk and psychotic symptoms varies based on sex, developmental stage, and hormonal fluctuations. For women, there is an increased schizophrenia onset during low estrogen periods. So during periods where estrogen is low, either during their monthly cycle, postpartum and in menopause, schizophrenia onset is more likely. Estrogen plays a neuroprotective role by enhancing dopamine and glutamate function, which I know I so far I've been talking about, you know, too much glutamate and too much dopamine is bad. Well, yeah, you can have too much estrogen helps modulate how much is coming out. It's enhancing the function. It's not increasing it, it's enhancing their function. Enhancing the function of the dopaminergic and glutaminergic neurons. Estrogen plays a critical role in brain function and dopamine regulation. Low estrogen levels increase oxidative stress. And anybody who's gone through menopause can tell you it's stressful. Low estrogen levels because the estrogen is not there to buffer against some of the stressors and the Toxins, we see an increase in oxidative stress and neuroinflammation, which accelerates brain volume loss. In schizophrenia, low estrogen is linked to memory deficits, poor attention and executive dysfunction, worsening schizophrenia's cognitive symptoms. So remember, we've got the cognitive symptoms and then we've got the positive symptoms of hallucinations and delusions. Well, estrogen is really in that prefrontal cortex area with our executive functioning. Low estrogen reduces dopamine stability, which heightens dopamine sensitivity, which can make hallucinations and delusions worse. So now we're over to the other parts of the brain where estrogen has a slightly different function. There's a higher risk of antipsychotic resistance in people with low estrogen. They're less, less responsive to any of the antipsychotics. So it may be harder to get those symptoms under control. Researchers have found, and this is one of those new findings, that adjunctive estrogen therapy through estrogen patches etc have been shown to enhance antipsychotic effectiveness in women with low estrogen. If they have normal to high estrogen, it ain't gonna do anything. It may make it worse. If they have low estrogen, then bringing that estrogen into the quote normal range is often helpful in improving symptoms. At a lower dose of antipsychotics, men with schizophrenia often have lower baseline testosterone levels. Low T worsens negative symptoms, their apathy, their lack of motivation and their anhedonia due to reduced dopamine. Now we see this even in non psychotic populations. We see that as men with low T have a lot of symptoms of major depressive disorder. Testosterone enhances synaptic plasticity, improving memory and executive functioning. So that's a good thing. We want to have enough, not too much, not too little. Testosterone replacement therapy has been shown to improve cognition in people with schizophrenia. Low testosterone also increases cortisol levels and HPA acts as overactivity, which contributes to stress induced psychosis and worsening paranoia. As testosterone. As testosterone goes down and cortisol goes up, our stress hormone goes up, we start to have more problems. Now let's think about that cortisol for a minute. As cortisol goes up and it's persistently up, it loses its ability to be as effective. So the body keeps pumping out more until it finally hits that level that something's going to get activated. We also know that the higher the cortisol, the lower the melatonin. And people with high cortisol levels have very fragmented sleep, which also contributes to a lot of Cognitive as well as mood issues. Men with low testosterone and schizophrenia experience higher levels of social anxiety and avoidance behaviors, which I thought was really interesting. They didn't really explain why. And low testosterone is associated with greater resistance to dopamine blocking antipsychotics in men, which almost all of them. There may be some out there that don't block dopamine, but all of the ones I can think of block dopamine. So it might be better to say, just like in women where low testosterone makes it harder for the antipsychotics to do their job, in men, low testosterone makes it harder for the antipsychotics to do their job. Women with schizophrenia and low testosterone, and that is low for what it quote should be for a woman. Women with schizophrenia and low testosterone levels exhibit more mood instability, paranoia and auditory hallucinations. Low testosterone may amplify estrogen's effects, worsening psychotic symptoms. Low testosterone in women contributes to deficits in memory, impulse control and emotional regulation. So if testosterone is low and estrogen is also low and you're having the all the problems that come with low estrogen, Low testosterone may actually amplify that. Testosterone supplementation in women with schizophrenia has shown improvements in verbal, memory and executive functioning. So testosterone has a big role, or at least a moderate role in executive functioning in both sexes in of people with schizophrenia. Now let's talk about the other end, high testosterone. High testosterone enhances dopamine and has been linked to greater aggression in people with schizophrenia, Particularly those with paranoid or delusional disorders. Excess testosterone may trigger manic like symptoms including impulsivity, which in this particular study included med non compliance. So whatever. Hyperactivity and increased risk taking behaviors. Higher but not too high testosterone levels in women are associated with better motivation, energy and cognitive function. Again, we'll look at the testosterone levels and we need to recognize that these symptoms are very common. Increased aggression, impulsivity, hyperactivity, risk taking behaviors. We see that in non schizophrenic populations that have excessively high testosterone. So the takeaway is if the person you're working with has schizophrenia and also seems to be particularly aggressive or impulsive or whatever. Let's not assume that it's just the, the schizophrenia or the dopamine. Let's look and see what else is going on. Just like when somebody comes into your office and they've got major depressive disorder. I hope you don't say oh, it must be their serotonin, you know, whatever. But you look and you say let's look at what else might be going on that is also contributing to these symptoms that we can address. Some of this stuff with schizophrenia we still don't fully know how to address. But things that are involved with thyroid hormones, gonadal hormones, we do know how to address those. And if we recognize that some of their symptoms are being caused because their gonadal hormones or their thyroid hormones are too high or too low, that's an easy fix. Women with polycystic ovarian syndrome, which is a condition characterized by high testosterone and androgen levels, have two to three times higher risk of developing psychotic disorders. People with PCOS tend to have very high levels of testosterone for their gender. And it's interesting to note that in another presentation that I did, we discussed chronic stress and people with CPTSD and how there's a high, high correlation between women who've experienced chronic trauma and the development of polycystic ovarian syndrome. And in that video, I explain how all that happens. But suffice it to say, PCOS generally doesn't just pop up out of nowhere. And a lot of times it's due to ongoing chronic stress that disrupts that HPA axis and cortisol's ability to do its job and glutamate starts running wild. And that impacts when our neurotransmitters are out of, out of balance. When our autonomic nervous system, our stress response is out of balance, that also impacts our gonadal hormones and our gut microbiome and our circadian rhythms and everything else. The good thing is we're recognizing this and we're recognizing that, okay, if you've got pcos, getting the hormones in balance is really important in order to not only address symptoms, but also to prevent potential onset of schizophrenia. PCOS is associated with higher levels of testosterone, insulin resistance. Remember, insulin resistance can eventually lead to inflammation and diabetes and chronic low grade inflammation. All of those things contribute to dopamine dysregulation and the increased risk of psychosis. Now, oxytocin, it's our love hormone, it's our bonding hormone. It's also a player in what we're talking about here. Oxytocin is a wonderful anti inflammatory, maybe not as good as cortisol, but it's a good anti inflammatory. Oxytocin regulates the HPA axis, our stress response, and reduces stress induced cortisol release. So the two of them work together. Oxytocin helps with anti inflammatory, but it also reduces how much cortisol is released. When people are feeling more calm, the body doesn't have to Dump as much cortisol. People with schizophrenia have an overactive HPA axis and lower baseline oxytocin. So they have an overactive HPA axis, higher baseline levels of inflammatory markers, higher levels of microglial activation in the brain, and lower baseline oxytocin. Oxytocin dysfunction may worsen stress sensitivity, increasing paranoia, and emotional dysregulation. Well, that makes sense. If oxytocin helps regulate the HPA axis and oxytocin's not doing its job, then it's going to be easier for the sympathetic nervous system, the HPA axis, to go into overdrive. Lower oxytocin levels correlate with increased social withdrawal and paranoia and reduced emotional expression. When we get to that point where the cortisol receptors, the glucocorticoid receptors, are not being receptive, cortisol can't do its job. We have that systemic inflammation and our neurotransmitters start getting out of balance. Then we start to see people having difficulty feeling anything. They feel flat most of the time. When they do have an emotional response to something, it's often an extreme response. So they go from flat to furious or flat to frantic. And part of that may be due to low oxytocin levels. Oxytocin enhances facial emotion recognition, helping people with schizophrenia better interpret social cues. It increases feelings of trust and social bonding and reduces social withdrawal and paranoia. They've shown that intranasal oxytocin can actually help with these things, which is a great find. Oxytocin also may help counteract anhedonia by enhancing reward processing. Oxytocin nasal spray reduces cortisol levels and HPA axis overactivation, which may help people with schizophrenia manage stress and paranoia more effectively to reduce exacerbations. Oh, my gosh. So let's think. If the person in their current state, when they get stressed, they go from flat to furious. Oh, my gosh. That is a really big stressor on the HPA axis. And it's going to keep that HPA axis dysregulated. But if they are able to blunt that response, then the HPA axis is actually given the ability to heal. If the, if it's not being constantly flooded with glutamate and cortisol, then it gives the HPA access time to heal. And that's what we're looking for. We're looking to help people with schizophrenia start balancing their sympathetic, their stress response with their parasympathetic, their rest and digest and repair response. An oxytocin Nasal spray reduces social anhedonia and improves motivation for social interactions. Moving on to the gut microbiome. I know who, who would have thunk that I'd be talking about the microbiome in a presentation on schizophrenia, But I am. The gut microbiome plays a critical role in schizophrenia development and severity through stress induced inflammation. Do you sets a pattern here and gut brain pathways dysbiosis or an imbalance in the gut microbiome where the stress and toxic microbes are flourishing and the good microbes, you know, are kind of hiding in the corner. Dysbiosis leads to neuroinflammation, oxidative stress and neurotransmitter dysfunction, increasing the risk of schizophrenia and worsening symptoms. Chronic stress further exacerbates this process by promoting gut and blood brain barrier permeability, which leads to hyperactivation of the immune system and heightened systemic inflammation. Recognizing Remember the gut communicates with the brain via the vagus nerve. The vagus nerve is one of the main players in our parasympathetic, our rest and digest nervous system. So it would follow that if the parasympathetic nervous system is not doing its job, that the vagus nerve may be too weak to do its job. And that may be leading to increases of the signals being sent to the brain that say hey, we're under attack. There's a stressor here which promotes that stress response. Chronic stress causes tight junction breakdown in the gut, allowing bacterial endotoxins, specifically lipopolysaccharides, to enter the bloodstream. Lipopolysaccharides trigger a systemic inflammatory response, leading to the increase in the gut secretion of pro inflammatory cytokines. Patients with schizophrenia show higher lipopolysaccharide and inflammatory cytokine levels, suggesting that gut permeability contributes to neuro inflammation and symptom severity. Wow. Now we just started. Well, researchers just started accepting this theory of leaky gut about five years ago. It really hasn't been something that has been accepted for that long. Finally it's starting to be accepted. But this is huge if you have a person who has psychotic symptoms or who has full blown schizophrenia helping them adjust their internal body factory to reduce stress, reduce inflammation and reduce leaky gut can help reduce symptoms. Just to throw in some big words. People with schizophrenia have low levels of lactobacillus and bifidobacterium, which leads to lower serotonin and dopamine regulation and worsening mood and motivation. They have higher clostridium and enterobacteria which leads to pro inflammation, pro inflammatory cytokines increasing neuroinflammation. Clostridium has actually been implicated in several issues including autism spectrum disorders. They have lower amounts of fecal bacterium which leads to a lower level of anti inflammatory butyrate production, which increases oxidative stress. When you don't have that particular microbe in your gut, you're not producing as much anti inflammatory stuff as you need. So we start seeing stress, oxidative stress go unchecked and that leads to inflammation. And Akkermansia mucinophilia leads to increased gut permeability, allowing inflammatory endotoxins into circulation. As I've said before, I'll say it again, we can't take a pill and magically reduce one particular killer bacteria in the gut. And even if we did, it wouldn't last because when we're stressed it's not just the bacteria that change, but actually the ph and the environment in which the the bacteria are living. So we need to heal the gut environment so the good bacteria can flourish and populate and the bad bacteria are like eh, you know, I don't want to be around here. Lactobacillus and Phytobacterium supplementation has shown promise in reducing some schizophrenia symptoms. It's not a replacement for antipsychotics, but it has shown good promise. Probiotics which again are like Lactobacillus and Bifidobacterium, reduce systemic inflammation, improving gut barrier integrity and enhancing neurotransmitter production. 90% of your serotonin is made in your gut and actually the mucus that lines the gut is a precursor to serotonin. So knowing that and knowing that you need those probiotics, you need the Lactobacillus and the Bifidobacterium among others to make serotonin, we know that we can supplement. Now again, if we're supplementing and the environment is not hospitable, then it's probably not going to last very long. So people continue to supplement. But if we can supplement for a while as we're healing the gut environment, then eventually it should be able to self sustain. Fecal microbiota Transplantation from healthy donors has improved schizophrenia symptoms in and cognitive function in people with schizophrenia in clinical trials. This is not widespread yet, but it again points to the notion that if we heal the gut system, we can actually heal some of those symptoms. Mediterranean and anti inflammatory diet and vitamin D, which is very anti inflammatory in nature, reduces systemic inflammation and improves metabolic health in people. With schizophrenia, have them go to the doctor, have them get a blood test, have that their testosterone, their estrogen levels tested, their thyroid while you're at it, and have their vitamin D levels and B12 levels tested. It's really easy for them to do and some of these things. And they can even test for inflammatory markers to see where that person is at. And you can use that as a baseline for determining how effective your treatment is. In addition to their overt symptoms, the goal is to reduce their baseline inflammatory markers. Wear. Wearable digital biomarkers represent a really exciting new thing that we're able to do. Using machine learning algorithms that analyze speech, cadence, nocturnal mobility, and other behavioral Metrics detects relapse 14 days earlier than traditional clinical assessments. Well, we're not with them when at night, when they're sleeping, and we're only with them maybe an hour a day. So we don't have that same ability to get all that data. But remote patient monitoring is a really new and exciting field where people can wear, you know, monitors just like a lot of us wear our fitness watches. But those monitors are actually specifically coded to report immediately to the electronic health record on certain parameters. That way the doctor can look at it on a weekly or monthly basis to identify, you know, has there been a positive or negative change in some of these things. Atypical antipsychotics modulate dopamine, serotonin and histamine receptors. Unfortunately, Even with our second generation antipsychotics, our SGAs, there is a high risk of weight gain, diabetes and metabolic syndrome. Weight gain, diabetes, and metabolic syndrome, guess what? They increase inflammation. So we're taking the good with the bad. It's not a panacea. Blocking the serotonin and dopamine receptors in the hypothalamus impairs satiety and increases preference for high fat, high sugar foods. I know there's a lot of us, when we're stressed, we crave high fat, high sugar foods. Well, that's why we're trying to activate those serotonin and dopamine receptors. Histamine receptor antagonism. Shutting down those histamine receptors increases food intake and promotes weight gain. And blocking muscarinic receptors directly impairs insulin release, leading to hyperglycemia and potentially the development of type 2 diabetes. People on first generation or second generation antipsychotics need to be carefully monitored for their A1C levels. Second generation antipsychotics impact to differing degrees, depending on which drug they're taking, impact REM sleep, non REM Sleep and deep sleep, which takes us into sleep. Sleep deprivation is a well established trigger for psychotic symptoms including hallucinations, paranoia and delusions. This is not only in people with schizophrenia, this is in any people. You're deprived of sleep for long enough, you're probably going to start having some of these symptoms. Chronic sleep disruption, which may be due to sleep apnea, it may be due to insomnia, maybe due to schizophrenia, whatever. Chronic sleep disruption increases the risk of schizophrenia onset, particularly in genetically vulnerable individuals. Dopamine overactivity in the mesolimbic system is a key feature of schizophrenia. Sleep deprivation increases dopamine release, mimicking the hyper dopaminergic state seen in schizophrenia. Over time, dopamine receptor sensitivity is altered, increasing susceptibility to psychotic episodes. NMDA receptor hypofunction is a core mechanism of schizophrenia. We talked about that earlier. Remember, NMDA receptors are on glutam, glutamate as well as GABA neurons. So NMDA hypofunction leads to cognitive deficits and psychotic symptoms. Sleep deprivation impairs NMDA receptors functioning, reducing glutamate signaling and impairing executive functioning, impairing people's ability to think clearly. And when we're sleep deprived, we all have that brain fog. Part of that is the adenosine buildup and part of that is, is a reduction in how, how, how sharp the NMDA receptors are. Insomnia is one of the strongest early warning signs of schizophrenia exacerbation. And in older adults who start to have sundowning and in older adults who are having difficulty with sleep for some reason, sleep fragmentation and lack of sufficient quality sleep can lead to the development of psychotic symptoms. We need to figure that out. Is, are the psychotic symptoms due to the Parkinson's disease or is it due to sleep disruption? Circadian rhythm misalignment is strongly linked to worsening cognitive function and negative symptoms. And in most of the assisted living facilities and nursing homes, almost everybody there has circadian rhythm misalignment because the light levels don't change that much, the temperature levels don't change and there's no real schedule. People just kind of hang out. Circadian rhythm alignment can do so much to improve sleep quality as well as improve cognitive symptoms. REM sleep is critical for processing emotions, consolidating memories and regulating mood. This is when we're dreaming. Reduced REM sleep contributes to emotional instability, increased fear based responses, stress reactivity and paranoia, and difficulty distinguishing reality from dreams. So is the person hallucinating or are they having difficulty distinguishing Reality because of their reduced REM sleep, non REM sleep, or your light sleep. When it's fragmented, it impairs sensory processing, making it harder to filter out irrelevant stimuli. So attention deficit and increasing distractibility, intrusive thoughts and cognitive disorganization. And we've talked so many times about how sleep deprivation or lack of good quality sleep makes it harder to control our thoughts. And this is one of the reasons why when we're looking at fragmented light sleep, so if they wake up and every time they go into that light sleep phase, they wake up and they've got to pee, that's fragmenting their sleep. Deep sleep or slow wave sleep is crucial for synaptic plasticity and memory formation, regulating dopamine release and metabolic waste cleanup and neuroinflammation reduction. We really like that. Deep sleep. Deep sleep, if you want to think of it, it's the cleaning crew coming through and clearing up all the debris from the day. It's getting rid of the adenosine, it's getting rid of some of the junk byproducts that developed as a result of living and functioning throughout the day. So we see the longest phases or at the beginning of the sleep night, and we get shorter phases of deep sleep as we go. And we're supposed to do that, but we need enough deep sleep. Reduced deep sleep increases pro inflammatory cytokines because they're not cleaning up the trash, they're leaving all that stuff there, which creates oxidative stress. This leads to microglial overactivation, excessive synaptic pruning and worsening of schizophrenia symptoms. Schizophrenia patients have reduced slow wave sleep or deep sleep duration and weaker delta wave activity. One of the things that we see with the second generation antipsychotics is one of the things they do do very well is increase. A lot of them do a really good job of helping to increase the deep sleep. Now they don't do as good on some of the, on the REM sleep, but people with schizophrenia often have misaligned sleep wake cycles with delayed sleep onset and irregular melatonin secretion. Remember, melatonin is correlated with cortisol. And if their stress response and cortisol is all over the place, then their body's ability to recognize when it's time to sleep and secrete melatonin not going to be there. Circadian misalignment increases negative symptoms, cognitive dysfunction and stress sensitivity. Improving sleep architecture, which means increasing REM and deep sleep and reducing fragmentation can reduce symptom severity. So that's a fancy Way of saying start getting good sleep. Bright light therapy, melatonin supplementation and sleep hygiene interventions often help stabilize the circadian rhythms. Most second generation antipsychotics reduce total REM sleep and, and delay REM sleep onset. This may lead to reduced emotional processing cognitive impairment and increased stress sensitivity. REM deprivation increases cortisol levels and again, most SGAs reduce total REM sleep. So it's again, it's not a panacea. Most SGAs also increase deep sleep and increased deep sleep may be beneficial as most people with schizophrenia naturally have insufficient deep sleep in terms of energy because a lot of people who are on antipsychotics are fatigued and they have very low energy and very low motivation. Well, number one, we're trying to reduce how much dopamine's there. So that's part of the motivation aspect. But also histamine receptors produce, blocking those produces a strong set of sedative effect and increases drowsiness and fatigue. Blocking dopamine reduces wakefulness motivation and causes mental fatigue. Blocking serotonin increases deep sleep but reduces alertness. And blocking your M1, your muscarinic acetylcholine receptors causes cognitive slowing, mental fog and fatigue. Now I've worked with psychiatrists in the past in residential settings who have relatively routinely prescribed second generation antipsychotics for people in treatment to help them sleep, not because they had psychotic features, not because they had schizophrenia. But it was a sleeping pill and now you kind of understand why. And our good old vagus nerve, Vagus nerve stimulation and enhancing vagal tone help modulate the hypothalamic pituitary adrenal axis and reduce systemic inflammation in people in general, not just people with schizophrenia, because remember, they're, they have what we call sympathetic dominance. Their stress response is dominant and their relaxation response can't seem to get a foothold. So by stimulating the vagus nerve and calling it to action, making it work, it becomes stronger, if you will, and it helps balance out the parasympathetic and the sympathetic response. Strengthening the parasympathetic nervous system to reduce sympathetic, not dominance can help reduce inflammation and associated effects triggering that parasympathetic nervous system. Also that involves that vagus nerve that sends those signals to the brain. That also helps improve the environment in the gut microbiome. And finally, last but not least, low intensity focused ultrasound targeting the nucleus accumbens has shown a 50% reduction in auditory hallucinations with effects persisting for up to eight weeks post treatment. For some people, they don't want to be on the level of antipsychotic that they need to be in order to control all of their symptoms. So they're looking for alternatives. Most people with schizophrenia have to be on some level of antipsychotic, second generation antipsychotic, but they're able to take lower doses with some of these alternative treatments to help stimulate the parasympathetic nervous system to reduce inflammation and help the system work more effectively. Low intensity focused ultrasound showed no adverse cognitive effects, making it a promising alternative for non invasive neuromodulation in schizophrenia. Like other issues, schizophrenia does not have a simple cause. However, we're realizing that stress, HPA axis over activation, sympathetic dominance, whatever you want to call it, contributes to systemic inflammation and that greatly contributes to symptoms. And addressing the causes of the stress in each piece of life is essential for recovery. We need to look at what's causing you stress physically. Sleep is one of them. Nutrition, uh, what else is causing you pain, what's causing you stress physically, interpersonally, emotionally, cognitively, environmentally. The more unnecessary stress we can remove, the less that stress response is going to be hyperactivated and it allow the body to start to heal. As we learn more about what triggers the specific neurological changes related to schizophrenia, we will be better able to prevent and address issues in the whole person. Are there any questions? Yes, Rolly Roller girl. There is a nasal spray that is oxytocin and it's probably an oxy. Well, not probably. They've created a, what they call an oxytocin analog, a chemical that responds a lot like oxytocin, that actually lasts a lot longer than actual oxytocin, but it can be administered as a nasal spray in the US I'm not sure where we're at in terms of whether it's easily publicly available or you still have to get it through clinical trials, but it is there and they've been testing it for a long time. They actually, I believe they actually started testing it on people who have autism spectrum disorders, and then they've since branched out to looking at how it impacts anxiety, depression, schizophrenia. One of the things I love about this, and I remember working with a couple of people we had in residential treatment for substance abuse who had a schizophrenia diagnosis. And one of the things that I love about this is there's so much new information we can give people that can help them feel empowered to take control of their symptoms. And that goes a long way when they're not feeling like they are sort of being possessed by something they have no control over. This Helps a lot. And again, being able to reduce the dosage. For a lot of people, being able to reduce the dosage of the antipsychotic helps them have more energy and helps them be able to feel like they're moving toward their prodromal symptoms. Let's see if we can help you reduce the exacerbations, because a lot of people go have periods of remission and exacerbation. And if we can help them reduce their stress and their systemic inflammation, we actually can help them reduce the frequency, intensity, and duration of. Of their exacerbations. It's a great question, Lisa. One of the things I found interesting in this research was the fact that they typically. We thought that the window where most people had age of onset was in early adulthood, but the fact that we, we have seen a lot more of people developing schizophrenia, women developing schizophrenia after menopause. I think it's just fascinating because that's not something, until I did this presentation, that was not something I'd ever heard about. Which again, goes to underscore the point that we can't just assume, you know, people only develop it during this period or that period or for this reason. It's just there's. We don't know enough about the human body. But I thought that was fascinating, the. The connection between estrogen and the development of schizophrenia in women. GABA is your main relaxation chemical. Glutamate is your main excitatory chemical, your main get out of bed and get going chemical. And GABA is your main relaxation. Sometimes I call it our, our own natural internal volume. But you definitely, interestingly enough, GABA is actually made by breaking down glutamate, which, you know, fun fact there. So if glutamate's going wild, then we may not be able to access enough of it to even break it down to make enough gaba.