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Understanding the Impact of Inflammation on the Br ...
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Presentation and Q&A
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Hello and welcome. I'm Dr. Rob Cotez, Associate Professor at Emory University School of Medicine and Director of the Clinical and Research Program for Psychosis at Grady Health System. I also serve as the SMI Advisor Physician Expert. I'm so pleased that you are joining us for today's SMI Advisor webinar, Understanding the Impact of Inflammation on the Brain, Transdiagnostic Implications. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. Now I'd like to introduce you to the faculty for today's webinar, Dr. David Goldsmith. David Goldsmith is a board-certified psychiatrist who focuses on the treatment of psychotic disorders and studies the role of the immune system in persistent symptoms of schizophrenia. More specifically, he is interested in how inflammation targets the brain, leading to motivational deficits and negative symptoms of schizophrenia. He is the Co-Director of the PSTAR Clinic at Grady Health System, which focuses on the treatment of individuals with psychosis, with a specific emphasis on using clozapine and other pharmacologic and psychosocial interventions for persistent symptoms. In addition to his work in the PSTAR Clinic, Dr. Goldsmith is on the faculty of the Emory Behavioral Immunology Program and is the Associate Program Director for the Emory Psychiatry Residency Research Track. Dr. Goldsmith completed his undergraduate work at the University of Maryland and received two National Institute of Mental Health training awards before receiving his MD from the Emory University School of Medicine. Dr. Goldsmith completed his psychiatry residency training at Emory University School of Medicine, where he was on the residency research track. On a personal note, I've had an opportunity to work closely with Dr. Goldsmith over the past decade, and he is a top-rate educator, clinician, and researcher. Dr. Goldsmith, thank you so much for leading today's webinar, and I'll turn it over to you. Well, thank you so much, Rob. I really appreciate the introduction. I really appreciate the opportunity to come talk to you today and share some of the work that I do and some of the ways that I think about inflammation as it relates to severe mental illness. In terms of disclosures, I have nothing to disclose. I have funding from the National Institutes of Mental Health for my research, but otherwise, nothing else to disclose. In terms of the learning objectives today, I really have three primary objectives, and the talk is really separated into three separate areas. The first thing that we'll really spend a lot of time talking about is how inflammation impacts the brain and how it's associated with certain symptoms of many different psychiatric disorders. That's something that I really hope people walk away from this understanding. We'll then talk a little bit about how inflammation could lead to potential novel approaches to treatment, and we'll talk a bit about some of how the immune system and inflammation may be important for the neurodevelopment and pathophysiology of certain severe mental illnesses like schizophrenia. Finally, the last part of the talk will really focus on a critical appraisal of the current anti-inflammatory literature and really how to best address some of the study design flaws that I think are really challenging and are really keeping us from hopefully one day having more medications and more approaches in our treatment armamentarium for our patients, which ultimately I think is what we all are hoping to eventually get toward. I'm going to start off with actually a poll, and hopefully this works out, and so if we could trigger the poll. The first question is, have you prescribed a medication to target inflammation in a patient with severe mental illness? That's a yes or no response. There we go. All right, so the vast majority of people, hopefully people can see this. Ninety-one percent of our attendees have never prescribed a medication to target inflammation, but about nine percent have, which is very interesting, and so the second question, if we could bring that up, is if you were thinking of starting a medication to target inflammation, or for those of you who have, which would you choose? And we were limited to five choices, so you can choose either silicoxib or aspirin, so NSAIDs, omega-3 fatty acids, minocycline, astatin or metformin, things that target more metabolic disruption, and then lastly, other. So, if we could bring that one up. All right, so it looks like most people would choose an omega-3 fatty acid, followed by statin or metformin, and then NSAIDs, other, and then minocycline comes last. Very interesting. All right, so I think this is good. So, it sounds like we have a wide range of different options that people are thinking about, and I really, you know, I think this is very interesting as we move forward through the talk to get some sense of how we might be thinking about prescribing some of these and why and when we should do so. So, increasingly, you know, the idea of inflammation in medicine has really kind of taken on a really new standing in our approach to medicine. So, back in 2010, science, you know, referred to inflammation as a common mechanism of disease, and this was the insight of the decade, and this has seeped its way into the popular press. You know, I imagine some people on here have had patients come to them asking about this, but we think that, you know, this may be what links many of the different inflammatory types of diseases and disorders that we treat in medicine. You know, this is revolutionized cancer treatment with immunotherapy, and, you know, I think it's really important to think about inflammation because, you know, it has both a good side and a bad side, if you will. So, really, you know, inflammation is the body's natural response to infection or to wounding. So, this is a really important, conserved part of our species, but when prolonged or excessive, it really can do damage to the body and specifically to the brain as well, and we're constantly being surrounded by chronic, non-resolving forms of inflammation that I think are really important for us to think about in relation to our patients with severe mental illness. So, certainly, obesity and metabolic syndrome is a huge issue for us as a society, but if you think about our patients, you know, certainly there is a lot of compelling evidence that individuals, for example, with schizophrenia have metabolic disturbances even before the onset of their symptoms and even before they're prescribed antipsychotics, and then we prescribe many of these medications that have significant effects on weight and weight gain and obesity, which really is a huge problem. Sedentary activity, you know, we're all probably sitting down at our desks right now or on our couch watching this, but certainly this is something that our patients deal with all the time, whether it's negative symptoms, you know, anhedonia and depression, you know, people who are sort of crippled by anxiety. Our patients deal with a lot of time of sedentary activity. Stress is everywhere, and certainly within our patient population, trauma is a risk factor for many neuropsychiatric illnesses, and many of our patients continue to experience traumatic events, which may have really, you know, important roles in inflammation. Aging is obviously something we can't get away from, unfortunately, but this is sort of, you know, a new field of medicine has been born out of this. It's sort of affectionately called inflammation, and that as we get older, our body's immune system and, you know, deals with chronic inflammation that may be involved with some of the chronic illness associated with aging, with the aging process. Dysbiosis refers to the microbiome and leaky gut. This is an active area of interest and investigation for many, many people. Infections, you know, we are in the midst of a major COVID pandemic, and we've seen, you know, chronic inflammation coming from infection with COVID, as well as many other infections, and that have, you know, neuropsychiatric symptoms, and this is something that's quite interesting right now as we learn about psychiatric symptoms as a result of COVID infection. And then finally, other illnesses, cancer, autoimmune disorders, inflammatory disorders, and as well as medical treatments, surgery, chemotherapy, and radiation can all be sources of chronic inflammation that's important for us to think about. Now, this is a bit of a complicated slide, a figure from a really nice review paper, but the thing that I really want to point out here is that, you know, the difference between inflammation in the periphery as opposed to inflammation in the central nervous system. So, you know, there's this question of whether or not the inflammation that we think about when we think about psychiatric illness is this neuroinflammation, which is how we often think about neurological disorders that have inflammatory components. And increasingly, we don't think of this as being a neuroinflammatory issue, that really it may be something related to inflammation and increased inflammation in the periphery within the rest of the body and all those sources of inflammation that we talked about in the previous slide that is able to get to the brain. Now, I won't go into too much detail, but I do want you to walk away with some understanding of how this happens. And so, there are a number of different routes that inflammatory markers may be able to take from the bloodstream or from immune cells to the brain. So, cytokines, which you'll hear me refer to a lot are our body's inflammatory signals. They're small molecules, though they are small. It's long thought that they were probably too big to get through the blood-brain barrier. So, increasingly, there is this humoral route that's been described where cytokines may be able to pass through leaky regions of the blood-brain barrier. And there's a lot of evidence that suggests that in psychiatric illness, the blood-brain barrier may be more porous than in non-psychiatric illnesses, such that cytokines may be able to get through. Cytokines are also able to bind to transport molecules on the blood-brain barrier, which may be another way that they get into the brain via the humoral route. There is this neural route, this neural pathway where peripheral cytokines may bind to afferent nerve fibers, such as the vagus nerve in the periphery, which then sends signals to the central nervous system via those afferent nerves. And finally, more recently, there's a lot of evidence of this cellular pathway, the cellular route, where immune cells are trafficked to the brain. These tend to be activated immune cells, such as monocytes, which get trafficked to the brain and get into the brain vasculature and the parenchyma to induce an inflammatory response within the brain itself. So, I think we've long thought about the brain as being an immune-privileged organ, but increasingly, I think we realize that there is this crosstalk between the periphery and the brain that is really important for how inflammation may impact the brain in psychiatric illness. So, what happens when inflammation gets to the brain? I'll just point out that these are really, I think, beautiful pictures that come from Yoni Kipnis' lab at UVA, who really was the first to describe that the brain actually has its own lymphatic system. This was a recent finding over the last five years or so, which really, again, suggests that the brain probably is not an immune-privileged organ, but actually has its own lymphatic drainage system like the rest of the body. So, a lot of what we know about what happens when inflammation gets to the brain and how it impacts symptoms that may be important for psychiatric disorder and for severe mental illness comes from the treatment of patients with interferon alpha. This is really the work that has come out of Andy Miller's group here at Emory and the Emory Behavioral Immunology Program. And, you know, this came from early observations from our colleagues who were treating patients with hepatitis C and cancers with interferon alpha, which is an antiviral and antiproliferative cytokine. And what they were observing and treating these patients with interferon is that they would get markedly depressed and show symptoms of depressed mood and anhedonia, as well as a number of significant neurovegetative symptoms as well. And I think the original question was, well, you know, could it just be that these patients are depressed because they have cancer or because they have hepatitis? And what was able to be demonstrated was that when you look at depression in the interferon alpha treated group and compare them to this control group, this is a weightless control group. So, these are all patients that still have these cancers and hepatitis, but they're waiting to get their interferon alpha treatment. That depression, as you can see, is significantly higher in these patients who are being treated with interferon alpha, and they have higher scores on anhedonia from the SHAPs. Also, we see these differences in response latency on this psychomotor task. Patients, when you compare them pre-interferon alpha treatment to post-interferon alpha treatment, are significantly slower. So, this really seems to suggest that treatment with this cytokine led to depressed mood, led to anhedonia, led to psychomotor slowing. These symptoms that increasingly we're beginning to think really may be what we should be thinking about when we think about how inflammation impacts the brain. And when you looked at some of these patients who were treated with interferon alpha and did PET scans and looked at what areas of the brain had the most uptake of glucose, you know, in these interferon alpha treated individuals, you really see this significant uptake of glucose in the basal ganglia, which is not something that you see in patients with just run-of-the-mill unipolar major depression. These patients look much more like these individuals with Parkinson's depression, for which we know the basal ganglia is probably impaired. When we go in and look at these patients and put them in an fMRI scanner and have them do a gambling task, where in some conditions you win money, in some conditions you lose money, and you ask the question of what areas of the brain are activated. In the win trials versus the loss trials, which areas are really sensitive to reward, you see this very nice activation of the ventral striatum, which is part of the basal ganglia. And importantly, when you look at how the activation of the ventral striatum was different between the patients with interferon versus those patients who were in the weightless control, you see the significant decrease activation on both sides of the ventral striatum in the interferon alpha treated patients in red compared to the controls in blue. Importantly, this decreased activation in the ventral striatum was in turn correlated with reduced motivation. So again, this idea that this is really important for anhedonia, for amotivation, that we were seeing in these patients who were depressed after receiving interferon. Now, this is not just an interferon story. Other groups have shown this. I appear that this has been shown with endotoxin from the UCLA group and Naomi Eisenberger. UK group has shown this with typhoid vaccine as well. So this really seems to be an inflammatory type process and not necessarily specific to interferon itself. Now, why might this be happening? What is going on? So we know that the basal ganglia is really important for motor activity. It's really important for reward processing. Both of these areas have a lot to do with dopamine. So this is work from Jennifer Felger in our group. This was her doctoral dissertation work where she looked at monkeys, rhesus monkeys, who were treated with interferon alpha. And she placed these microdialysis probes in the caudate, which is a region of the basal ganglia close to the ventral striatum, and was able to measure dopamine and homovalenic acid, the active metabolite of dopamine in the animals treated with interferon and compared them to animals treated with saline. And as you can clearly see here, the interferon alpha treated animals have significantly less dopamine and homovalenic acid concentrations relative to the saline treated monkeys. And what's really cool is with these microdialysis probes, not only can you sample from that brain region, but you can also give different stimuli and then sample and see what happens in response to the stimuli. So what Jennifer was able to do is she would give, you know, at this time point, potassium, which led to a voltage dependent dopamine release. And as you can see, in response to potassium, you see this increase in dopamine concentration in the saline treated animals. But in the interferon alpha treated monkeys, you really see a significantly attenuated response with dopamine release. And then she gave amphetamine, which not only stimulates dopamine release, but also inhibits dopamine reuptake. And you see this huge, you know, peak in dopamine release in the saline treated animals. And again, a much more attenuated dopamine response in the interferon alpha treated monkeys. And what I think is really cool is what Jennifer then was able to do was to actually give and pretreat these animals with levodopa. And when you pretreat with levodopa, the response, the amphetamine, the dopamine response to amphetamine in the interferon alpha animals looked very similar. It sort of reverses the finding. And so this is very, I think, compelling data to support a role for dopamine in the role of inflammation. It may lead to decreased dopamine release. Jennifer has some human data now that she's collected with some L-Dopa imaging studies that is currently being analyzed. And I'm not showing any of it now because it hasn't been finished being analyzed and it's not been published yet. But I would look out for that because I think it'll be really exciting. Now, I think it's important to also point out that, you know, brain regions don't exist in isolation. And so, you know, the basal ganglia is connected functionally and probably, you know, neuroanatomically to other areas of the brain. And so, for example, there is this circuit between the basal ganglia and regions of the prefrontal cortex, specifically the ventral medial prefrontal cortex, which underlies sort of this canonical reward circuit in the brain. And so, what Jennifer did in humans was to ask the question of, could this be potentially sensitive to inflammation? And so, what you see here is some neuroimaging findings where a seed is placed in the ventral striatum, a seed, she also placed a seed in the dorsal striatum, which is thought to more underlie some of the motor issues. And as you can see there, you know, these blue pixels here in the ventral medial prefrontal cortex responds to regions of the brain that are functionally connected. They're activated at the same time and highly correlated with one another that really seem to underlie this reward circuit. But what's most interesting is that it seems to be sensitive to inflammation. And so, CRP or C-reactive protein, which is an acute phase reactant that then sort of goes on to trigger a greater inflammatory response and inflammatory cytokines. We know that there are cutoff points from the American Heart Association and the CDC for CRP, such that individuals with CRP greater than three are thought to have high CRP or thought to be highly inflamed. And those individuals here in blue, as you can see, have less functional connectivity between the ventral striatum and the ventral medial prefrontal cortex. And this seems to be a linear relationship where individuals with low CRP or CRP less than one have greater connectivity. And then people with moderate CRP, with one to three, really seem to be somewhere in the middle between the low and the high as it relates to functional connectivity in this reward circuit. And then what, you know, to take that a step further, the connectivity in the ventral striatum to ventromedial prefrontal cortex circuit was correlated with anhedonia and the dorsal striatum was correlated with motor slowing. So again, we're seeing this relationship between circuitry in the brain, inflammation, and these specific symptoms of anhedonia and psychomotor slowing. And so that's sort of a very broad overview of the story of how inflammation may impact the brain to lead to specific symptoms by targeting specific regions. But, you know, importantly, this is not just a depression story. So cytokines are increased in a subgroup of patients with schizophrenia, depression, and bipolar disorder. But not just these severe mental illnesses, they're increasing multiple psychiatric disorders, multiple neurological disorders, as well as in medical illness. So, you know, cytokines, as we said, are inflammatory signaling molecules that really are important throughout medicine, but may be particularly important for some of our severe mental illnesses. Now, this is data from a meta-analysis that I published a number of years ago. Looking at inflammatory cytokines, and you see the whole group of them here on the y-axis, in a number of a severe mental illnesses relative to healthy controls. So basically, what you see here are effect sizes, and everything to the right of the vertical line here are positive effect sizes, and such that that suggests that these markers are elevated relative to healthy controls, and patients relative to healthy controls. And in green, these are acute patients who are hospitalized for an acute episode of major depressive disorder. In yellow, you see acutely psychotic patients who are in their first episode of psychosis. In red, these are patients who are experiencing an acute episode of psychosis, relapse, and chronic schizophrenia. And in blue, these are individuals hospitalized for bipolar mania. And hopefully, your eye is just drawn to how large these effect sizes are, and how widespread this may be. And there are a number of markers that appear to be important across these different severe mental illnesses. So you see that, you know, for interleukin-1 receptor antagonists, interleukin-6 or IL-6, soluble IL-2 receptor, and tumor necrosis factor, these are elevated significantly in all of these different severe mental illnesses, at least in this acute data. And so it also begs the question of, you know, is this just a phenomena of being acutely, you know, decompensated and in the hospital. And there does seem to be an effect of being acutely ill, because this is the data for the chronic patients. These are all chronic stable outpatients. And again, you see green is major depressive disorder, red is schizophrenia. And then we separated out blue is euthymic bipolar disorder, and yellow is actually bipolar depression. And you can see, though, it's not quite as staggering as an effect as you saw for the acute group. These chronic stable outpatients, for some of the markers, still have significantly elevated inflammatory cytokine concentrations relative to healthy controls. And again, you see interleukin-6 is probably being important across different severe mental illnesses. Tumor necrosis factor seems to be important for all of these as well. And so we think that even in chronic illness, there may be a role for some patients for an effect on these inflammatory markers in their symptomatology. And so sort of getting back to this slide, again, you know, this is important across, you know, this likely is a transdiagnostic phenomena. But really, I think the most important takeaway from this is that cytokines are not about disorders, but really are about symptoms and circuits within disorders in this probable transdiagnostic fashion. So I'm going to sort of transition from this part of the talk, where I hopefully try to sort of, you know, impart to you that there may be some specificity to how inflammation targets the brain. And I want to sort of move on to using schizophrenia as sort of a specific psychiatric diagnosis for which the immune system and inflammation may be particularly important for neurodevelopmental pathophysiology of the disorder. So there's long been some very interesting and compelling epidemiologic evidence that prenatal exposure to different pathogens, infectious pathogens, viral pathogens, put the children born to these moms at increased risk of developing schizophrenia later in life. This is not a huge increased risk, but certainly significant and quite compelling. We're certainly very curious to see if prenatal exposure to COVID may lead to something similar. We're actually actively studying this right now in some basic science models. But that's something that I think remains to be seen. This epidemiologic literature is also supported by a very interesting basic science literature for maternal immune activation models, where laboratory animals, pregnant mice and rats are exposed to different viral bacterial pathogens, cytokines themselves. And what you see in their offspring are increases in inflammatory cytokines, such as interleukin-6. You see increases in autoantibodies. But you see a number of changes in behavior, in brain morphology, in electrophysiologic abnormalities, in neurotransmitter function, in these animals that look very similar to what we see in individuals who have schizophrenia. So this is really this convergence of epidemiologic and basic science literature that really seems to suggest that the immune system may be involved in the underlying neurodevelopment and pathophysiology of a disorder like schizophrenia. This may not be important for everybody, but it may be important for some people. And that still remains to be seen. Moving on, I think it's also important to note that autoimmune disorders and hospitalizations for infection also increase one's risk for schizophrenia, for diagnosis of schizophrenia later in life. This appears to be interactive between autoimmune disorders and infections, and appears to be dose responsive as well. You know, it's very interesting, patients with schizophrenia also appear to have higher rates of autoimmune disorders. They appear to have increased concentrations of circulating autoantibodies, even irrespective of having an autoimmune disorder, which really seems to suggest that something is going on here with the pathophysiology of the disorder. If you look here, this is data from one of the largest genome-wide association studies. This is what's referred to as a Manhattan plot. All of the green lines that sort of come up, once they cross this horizontal red line, which refers to a p-value of 10 to the minus 7th, which reflects genome-wide significance. You know, it sort of looks like the skyline in Manhattan, which is why it's referred to a Manhattan plot. But your eye really should be drawn to this huge peak right here on chromosome six, which encompasses the region that encodes for the major histocompatibility complex, which is involved in, you know, in immune regulation. And importantly, this area also spans a region that encodes for some of the complement proteins. So complement proteins are part of the innate immune system, and are likely involved with things like synaptic pruning. This is data from a paper that was published a few years ago that some of you may be familiar with. It got a significant amount of popular press, including in places like the New York Times and the Washington Post, where individuals with schizophrenia seem to have increased number of risk alleles for the C4A protein, had increased expression of the C4A allele. And importantly, what this complement 4A seems to be important for is for too much synaptic pruning in the brain. So all of us undergo, you know, appropriate neurodevelopmental synaptic pruning as we age, you know, from, you know, infancy onward, in order to really get the brain to a point where circuits are formed, and they are, you know, code for, you know, fast transmission of information. But there's a lot of evidence previously that individuals with schizophrenia have overpruning, which leads to differences in excitation and inhibitory connections between areas of the brain. And, you know, in this work, and I'm not going to go too much into the details, but this really seems to be important around the age of what we think of as the age of onset for schizophrenia, you know, 18 to 25, in some of the animal model work that they do. So this is really compelling work, and now a lot of people are very curious about the complement system. There have been a number of studies looking at complement. There are compounds that target the complement system as well, which is quite interesting too. I want to show a little bit more epidemiologic data. So this is data from Golem Kondiker and Peter Jones's group in the UK, where they use the Avon Longitudinal Study of Parents and Children, the ALSPEC cohort. So this is data from close to 4,500 individuals, where at age nine, they sample blood and get IL-6 and CRP concentrations, and then look at age 18 to see if CRP and IL-6 at age 18 was predictive of either depression or psychosis at age 18. And as you can see here, this is data for the psychotic experiences at age 18. And when you look at the top third of people for IL-6 and CRP, and this is compared to the bottom third of people, there's almost a 75% increase in the odds for psychotic experiences if you were someone who were in the top third of IL-6 concentration. CRP is elevated to the not quite as much, but when you look here at psychotic disorder at age 18, there's more than two times the odds of having a psychotic disorder if you had an elevated IL-6 at age nine. You can see that this appears to also be a dose-dependent relationship as well, where the bottom group had lower percentages of both depression and psychotic experiences at age 18, depending on where you were in your IL-6 at age nine, and that goes up as you go into increasing tertiles of interleukin-6. This work was followed up actually when you looked at CRP at age 15 or 16, and then looked at schizophrenia at age 27. And as you can see here, people who had high CRP, again, this is greater than three based on the American Heart Association CDC guidelines, had much higher rates of schizophrenia and non-affected psychoses relative to individuals with low and medium CRP, medium concentrations of CRP. So very interesting, you know, prospective, you know, longitudinal data. This is actually from over 6,000 participants, which is quite interesting. And this really seems to be important across the spectrum. So, you know, a number of different markers related to the immune system, you know, have been studied, both pre-morbidly and clinical high-risk individuals and individuals with first episode psychosis, acute illness and chronic illness, with really inflammatory cytokines being the most commonly studied across all phases of illness. And this is really, you know, the area that I've done the most work in up until this point. Looking at some of those symptoms that we were talking about earlier. So, you know, from the depression literature that I showed you, individuals, you know, who are exposed to inflammatory cytokines, individuals with depression really appear to have, you know, issues with anhedonia, motivational deficits, psychomotor slowing, all symptoms that we see in patients with schizophrenia, specifically as they relate to negative symptoms. So this is a study that we published a couple years ago, where we looked at individuals who either had deficit or non-deficit schizophrenia. So deficits, you know, schizophrenia or the deficit syndrome refers to, you know, patients with schizophrenia who really have predominant pervasive negative symptoms chronically across the course of illness. And when we measure tumor necrosis factor, TNF, in the deficit patients, they were significantly higher, you know, certainly relative to the healthy controls. But importantly, when we looked at the non-deficit patients, you know, people who were, whose illness was really not marked by predominant negative symptoms, they really looked much more similar to healthy controls. And when we looked at TNF relative to negative symptoms on the positive and negative syndrome scale, or the PANS, there was this very nice linear relationship between tumor necrosis factor and negative symptoms. We followed this up with some work with the North American Prodromal Longitudinal Study, or the NAPLS cohort, in association with Elaine Walker here at Emory. And what we were able to show is that individuals whose negative symptoms got worse over the course of two years, these are all individuals of clinical high risk for psychosis, baseline TNF and IL-6 predicted negative symptoms over time. So this seems to be important, not just for chronic patients, but may be important as part of the underlying disease process, including in individuals at clinical high risk. We've also been able to show, similar to what's been shown in depression, that individuals with schizophrenia have this relationship between inflammatory markers and psychomotor slowing. This is a complicated slide, and I'm not going to go too far into it. But again, we see interleukin-6 TNF as being related to psychomotor slowing as well in patients, but not really in controls. And, you know, this was some preliminary data, unpublished data, that we collected looking again at this idea of functional connectivity between the ventral striatum and the ventromedial prefrontal cortex. We know that patients with schizophrenia have decreased activation of the ventral striatum, have decreased, you know, response to reward that really seems to underlie negative symptoms. But at least in this small group, albeit of five patients, we were able to show that this relationship between inflammation as indexed by C-reactive protein and TNF was negatively associated with connectivity in these regions in the expected direction. We, you know, we now have collected data from 30 patients that we're actually actively analyzing as we speak. I apologize, I'm not able to show it to you today, but hopefully we'll be able to publish on some of that in the near future. But we were very encouraged by this when we first saw it, that this really may be a transdiagnostic phenomena as it relates to depression and schizophrenia. So how does this all impact patients? This is sort of the third part of the talk, and I think probably the most important in thinking about how we may be able to translate some of this to the clinic and how we can really look at the anti-inflammatory literature. You know, certainly as we saw from the polling, a small percentage of people have prescribed anti-inflammatory agents. People have varying different thoughts about what they may choose. But I want to start off with some of the things that we're not using right now, and those are the cytokine inhibitors. These are some of the monoclonal antibodies to cytokines such as TNF, IL-6, and IL-1. These are large molecules that don't cross the blood-brain barrier. And there have been a few published studies in both depression and in schizophrenia that have really targeted these three cytokines. There are some other anti-cytokine therapies that could be used. You know, some of this has been done in other medical illnesses. A lot of these are being used in rheumatoid arthritis and certain dermatologic conditions and inflammatory bowel disease. But, you know, this is one approach that I really think is more, again, is a proof of concept that if we can show that blocking inflammation is important, that gives us a lot of, you know, compelling data to sit alongside the data that we looked at previously, where if you induce inflammation, you can induce these symptoms. You want to be able to show that you can block it and improve symptoms as well. So I'm going to show a little bit of data from this study, again, from Andy Miller's group here at Emory, which randomized 60 patients with treatment-resistant depression to receive three infusions of either infliximab, which is a tumor necrosis factor, antagonist, which is often used in inflammatory bowel disease, or placebo. And so they looked at rates of depression across 12 weeks after receiving three infusions. And as you can see here, after 12 weeks, there was no difference in the change in the Hamilton depression rating scale between patients who received either infliximab or placebo. So this was really a confusing finding and unfortunate, but when they thought about it, they realized that there was this interaction with treatment time and actually CRP, such that those individuals who had a CRP greater than five, who were highly inflamed, actually did show a significant response to infliximab relative to placebo. And those individuals with CRP that was less than five actually responded better to placebo, which really seems to suggest that you need high inflammation to actually respond to an anti-inflammatory. This data really just seems to show that people who showed a 50% reduction in Hamilton, who were deemed responders, when you look at the combined data, there was no difference, but over 60% of patients in the high inflammation group responded to infliximab, whereas only about 30% did to placebo. And obviously in the opposite direction in the low inflammation group. And importantly, when you actually look at what symptoms got better, you saw this real significant effect here for work and activities, which really seems to reflect sort of that anhedonia component. You saw a big effect here for retardation, psychomotor retardation. So again, when we talk about what symptoms may be induced by depression, these are also the same symptoms that are getting better with an anti-inflammatory treatment such as this. There are a number of other anti-inflammatory agents that have been studied. Some of you responded to some of these in the poll. And this literature is quite confusing what to make of it. There are a lot of positive studies, there's a lot of negative studies. And I really wanna offer kind of my view on this and how you can be good purveyors of the literature in order to make good decisions for your patients. One real problem with some of the failures of the anti-inflammatory drug trials really are that many of these anti-inflammatory agents have off-target effects. So I gave some examples here of actually off-target effects that actually have important implications for the immune system. So though cellococci, minocycline, statins may be directly impacting inflammation, there may be doing all of these other things and it's really hard to know what these medications are doing in these individuals in the trials to really say that the findings that you see, whether they are positive or negative, are actually really due to an anti-inflammatory effect. Study design really plagues this anti-inflammatory literature and importantly, not all people who have severe mental illness have evidence of increased inflammation. And so this is data from a large meta-analysis, 37 studies are included in this, over 13,000 patients with depression, over 150,000 controls. And really what it shows is, so these are looking at the proportion of depressed patients showing a high inflammation with a CRP greater than three. And what it's really showing is that only about 27% of patients with depression across these studies have a CRP greater than three, have high inflammation. But even if you look at moderate inflammation, so individuals with a CRP greater than one, just slightly lower than 60% of these patients across studies have even moderately high inflammation. So clearly not everyone with severe mental illness has increased inflammation. And this is really, I think, becoming a major issue in the literature. So for example, this was a big study published a couple of years ago that also got some popular press. This was a trial of tocilizumab, which is a interleukin-6 receptor antibody, a cytokine antagonist for patients with chronic schizophrenia. And ultimately what they showed is that there was really no difference in symptoms when they looked at tocilizumab versus placebo. But when you actually looked at what the baseline CRP was, these are the mean baseline CRPs, it was about two for the placebo group and three for the tocilizumab group. And so they're really not enriching for inflammation. And so similar to what we showed for the infliximab study in depression, if you don't have evidence of high inflammation, you really may not see a difference between placebo and active conditions. And this is a huge problem because these are potentially promising agents and also, again, are proof of concept studies. And if we want to eventually get to a point where we can think about really studying anti-inflammatories for severe mental illness, studies like this are really gonna be problematic in the literature. Now, importantly, most studies have used baseline inflammation and inflammatory markers to predict treatment response only in a post hoc way after the fact. So this is a very recent study that was published a couple of months ago in neuropsychopharmacology. And basically, they were looking at minocycline augmentation to standard of care therapy, treatment for patients with treatment-resistant depression. And what they were able to show is that only the people who received minocycline who had high CRP greater than three were the ones who responded. But that wasn't after, this was an a priori. Excuse me, this was not an a priori finding. This was a post hoc finding that when they looked at this, similar to what was done in the infliximab group, they were able to show that it was people with high CRP. But these minocycline findings are really confusing because this seems really exciting data. And I do think it is exciting data. But when you look at the largest minocycline study in patients with schizophrenia, the Beneman trial, they show no difference for minocycline for negative symptoms, for positive symptoms, for depression, for function, and baseline inflammation, at least as measured by IL-6, really didn't seem to separate the groups out anymore. So it's a little unclear what to make of this. There's some thought that it's possible that it could be because of some of the issues with off-target effects with minocycline. I know we're running short on time, but we're almost done getting through this. There really have been limited studies that really have been rich for increased inflammation. And this really leads to this idea that we really need to design studies in this match-mismatch way. So really no trial to date has stratified patients as a function of baseline inflammation and really determined if increased inflammation are the people that will respond. So we really need to design studies where instead of doing placebo-controlled or doing post-hoc analyses, we really need to look at people with high inflammation versus low inflammation, with the expectation that people with high inflammation are gonna respond. We also need evidence of target engagement. So this is data from a recent study looking at minocycline and cellococcib in bipolar depression. And really they found no difference between these relative to placebo. But importantly, there was no effective cellococcib or minocycline on peripheral measures of inflammation. And so if we're not seeing decreases in inflammation with either of these drugs, why would we expect there to be any difference from placebo? And so without evidence of target engagement, it really doesn't instill, I think, much confidence in our ability to interpret even a negative finding such as this. And lastly, we really need to think about outcomes. So maybe instead of just looking at total symptoms on depression or psychosis, we really need to be thinking about these specific symptom domains like anhedonia or psychomotor slowing. Unfortunately, the FDA won't give an indication for these specific outcomes. They will give an indication for negative symptoms. And I think this is really the holy grail of trying to find compounds that are specific to negative symptoms. But maybe we need to also be looking at things like reward circuitry as well. So where do we go from here? So again, I think it's really important to take away that increased inflammation likely defines a subset of individuals with psychiatric disorders and that it targets specific brain regions and circuits to lead to specific symptom domains such as anhedonia, amotivation, psychomotor slowing. Anti-inflammatory agents really may be useful in our patients with severe mental illness, but the current evidence base is really limited by study design issues. And hopefully you'll walk away with this with some idea of what those issues are and can look at the literature with a keen eye. We may wanna think about downstream effects of inflammation such as the role of dopamine. I didn't talk at all about glutamate, but there is a glutamate story as it relates to inflammation. Perhaps inflammation is not the whole story. There's a huge growing literature and a lot of our work is really shifting towards this idea of this interplay, this interaction between the immune system and metabolic dysfunction, something that we refer to as immunometabolism. And lastly, I think it begs the question of should we be checking CRP and should this become a standard of care where we have a patient come in and we can get a baseline CRP, we can check the CRP in all of our CLIA certified laboratories to see if someone is highly inflamed and that may lead you to say, I may choose something to affect the inflammatory system. And so with that, I'll end there. Feel free to reach out to me with any questions and I will turn it over to Rob for questions. All right, thank you, David, for such a terrific presentation, really thought provoking and I think we're really looking at the future here. So before we shift to Q&A, I wanna just take a moment and let you know that SMI Advisor is now accessible for you from your mobile device. Use the SMI Advisor app to access resources, education and upcoming events, complete mental health rating scales and even submit questions directly to our team of SMI experts. Download the app at smiadvisor.org slash app. Now for the Q&A. There were two questions I wanted to ask you, David. One was, if somebody asked, if someone was struggling with negative symptoms of schizophrenia right now, how do you sort of think about what treatments to give them today and what would you kind of try clinically? Yeah, that's a really great question. I mean, I think it's important first of all, to really make sure you're dealing with primary negative symptoms and not secondary negative symptoms. So positive symptoms that are untreated that look like negative symptoms. So if someone is severely paranoid and not leaving their home, that can appear like they're not motivated to do much as a really maximized treatment in that area. But increasingly, for people with true negative symptoms, I mean, I have been checking a CRP in clinic. And if someone is highly inflamed, I may consider an anti-inflammatory. I may really try to talk to them about things like diet and exercise, which is something that we should be talking to our patients about in general, but may have really important effects on inflammation and on the immune system. So I think we're starting to get to the point where we can start to think about some of these things. I have trialed some of the poll items and they've come to various effect. But increasingly, I think we just need better data on what some of these agents and better designed trials. Maybe it is more dopaminergic agents. Maybe it is more cytokine antagonists. Maybe it is more targeting the metabolic system. I think we're just beginning to get some really compelling data in that area. All right, great. And just one more question. I want you to, if you could, sort of peer into the crystal ball and kind of say a little bit about where you think things are gonna be in 10 years. Yeah, so I mean, I am really hopeful that we may be able to identify which groups of patients may have inflammation as part of their illness. And I think a CRP could be a really nice way to do that. We're doing in depression right now in the Emory Behavioral Immunology Program, a trial where patients are being, with high inflammation are being randomized to more dopaminergic treatment, like Welbutrin, versus a standard serotonergic agent, like I think we're using Lexapro as the comparator, escitalogram, excuse me. And so we'll see what those results show. But I think eventually the goal is to, I think, be able to describe this immunophenotype, if you will, of patients with severe mental illness who we may be able to have new options. Whether those are medications that are used primarily or whether or not they're used adjunctively, I think really remains to be seen. I also think that there's a real, based on the meta-analysis, there may be something about using anti-inflammatory agents in more acute cases of psychiatric illness in order to eventually bridge to more standard treatments like antipsychotics or antidepressants. That's something that I think remains to be seen. All right, thank you so much, Dr. Goldsmith. And unfortunately, we don't have time for any more questions. I thought that went over. All right, great. So if we could, so if anybody does have any follow-up questions about this or any topic related to evidence-based care for people with SMI, our clinical experts are now available for online consultations. Any mental health clinician can submit a question and receive a response from one of our SMI experts. Consultations are free and confidential. So SMI Advisor is just one of the many SAMHSA initiatives that are designed to help clinicians implement evidence-based care. We encourage you to explore the resources available on the Mental Health, Addiction, and Prevention TTCs, as well as the National Center of Excellence for Eating Disorders and the Suicide Prevention Resource Center. These initiatives cover a broad range of topics from school-based mental health through the opioid epidemic. Thank you so much for joining us. And until next time, take care. Thank you for participating in today's free course from SMI Advisor. We know that you may have additional questions on this topic, and SMI Advisor is here to help. Education is only one of the free resources that SMI Advisor offers. Let's briefly review all SMI Advisor has to offer on this topic and many others. We'll start at the SMI Advisor website and show you how you can use our free and evidence-based resources. SMI Advisor's mission is to advance the use of a person-centered approach to care that ensures people who have serious mental illness find the treatment and support they need. We offer several services specifically for clinicians. This includes access to education, consultations, and more. These services help you make evidence-based treatment decisions. Click on consult request and submit questions to our national experts on bipolar disorder, major depression, and schizophrenia. Receive guidance within one business day. It only takes two minutes to submit a question and it is completely confidential and free to use. This service is available to all mental health clinicians, peer specialists, and mental health administrators. Ask us about psychopharmacology, recovery supports, patient and family engagement, comorbidities, and more. You can visit our online knowledge base to find hundreds of evidence-based answers and resources on serious mental illness. All content in our knowledge base is reviewed by our team of national experts from the American Psychiatric Association, Harvard, Emory, NAMI, University of Texas at Austin, and more. Browse by key topics or search for a specific keyword in the search bar. Access our free education catalog to find more than 100 free courses on topics related to serious mental illness. You can search the education catalog by topic, format, or credit type to find courses that fit your needs. SMI Advisor also offers live webinars each month that let you learn about evidence-based practices and participate in live Q&A with faculty. Check out our education catalog often to find new courses and earn continuing education credits. For individuals, families, friends, people who have questions, or people who care for someone with serious mental illness, SMI Advisor offers access to resources and answers from our national network of experts. The individuals and families section of our website contains an array of evidence-based resources on a variety of topics. This is a great place to refer individuals in your care for information about their conditions. They can choose from a list of important questions that individuals who have SMI typically ask. SMI Advisor worked with experts from the National Alliance on Mental Illness to develop these important questions and many of the resources in this section. Watch videos on important topics around SMI, such as what to know about a new diagnosis. They can also find dozens of fact sheets, infographics, and links to other important resources. To access even more evidence-based resources for individuals and families, visit our online knowledge base. All content in our knowledge base is reviewed by our team of national experts from the American Psychiatric Association, Mental Health America, National Alliance on Mental Illness, and more. Browse by key topics and select View All to uncover a list of resources on each topic. SMI Advisor offers a smartphone app that lets you access all of the same features on our website in an easy-to-use, mobile-friendly format. You can download the app for both Apple and Android devices. Submit questions. Browse courses and access clinical rating skills that you can use in your practice with individuals who have SMI. SMI Advisor also created My Mental Health Crisis Plan, a smartphone app that helps individuals in your care to create a crisis plan. The app is available on both Apple and Android devices. It helps people prepare in case of a mental health crisis. They can make their treatment preferences known and specify who should be contacted and who should make decisions on their behalf. The app even guides individuals through the process to turn their crisis plan into a psychiatric advance directive. Thank you for your interest in SMI Advisor. Access our free education, consultations, and more on smiadvisor.org at any time.
Video Summary
SMI Advisor is an APA and SAMHSA initiative that provides resources and support for clinicians working with individuals with serious mental illness. The SMI Advisor webinar discussed the impact of inflammation on the brain and its implications for mental health. The webinar was led by Dr. David Goldsmith, who is a board-certified psychiatrist and researcher in the field of inflammatory markers in mental illness. Dr. Goldsmith discussed the role of inflammation in psychiatric disorders, such as depression and schizophrenia, and how it can affect specific symptoms, such as anhedonia and psychomotor slowing. He also discussed different treatment approaches, including anti-inflammatory agents, and the challenges in studying and treating inflammation in mental illness. Dr. Goldsmith emphasized the need for future research to address study design issues and to identify specific patient subgroups that may benefit from anti-inflammatory treatments. Overall, the webinar provided insights into the potential role of inflammation in mental illness and its implications for clinical practice.
Keywords
SMI Advisor
APA
SAMHSA
clinicians
serious mental illness
inflammation
brain impact
psychiatric disorders
anti-inflammatory agents
clinical practice
Funding for SMI Adviser was made possible by Grant No. SM080818 from SAMHSA of the U.S. Department of Health and Human Services (HHS). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, SAMHSA/HHS or the U.S. Government.
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