It's my great privilege to introduce Dr. Charles Nimroff. Just a few bookkeeping aspects. This is the second year for our popular clinical updates track. There are 18 practical and pragmatic sessions by renowned leaders presenting on practical domains clinicians deal with every day. Presenters combine their expertise with tangible learning points that provide you with a clear what and why, which can be applied directly into your practice right away. As we move on with this presentation, at the end, there will be a Q&A session. And as this is both being live streamed and also in person, as it gets time to the Q&A, we'll alternate between the live audience and the virtual audience, giving a chance for everyone to participate. It's my great honor to present Dr. Charles Nimroff, who is the professor and chair of the Department of Psychiatry and Behavioral Sciences at the Dell Medical School, University of Texas at Austin. He also directs the Institute for Early Life Adversity Research within the Department of Psychiatry as part of the Mulva Clinic for the Neurosciences. He received his medical degree and doctorate degree in neurology from the University of North Carolina School of Medicine. So here to discuss his work on neurobiology and treatment of PTSD is Dr. Charles Nimroff. Thank you. I see there are even a few people in the audience that were here for my 8 AM presentation. So you are gluttons for punishment, honestly. And I told a joke then, so I'm going to modify it for, I hope you forgive me for repeating this joke, but I thought we'd start off with a little bit of a joke, and then we could talk about this very serious topic. So first and foremost, PTSD is a really difficult disorder to treat, one of the most difficult disorders to treat in psychiatry. And so there's a psychiatrist walking along the beach in Malibu, and about 6 in the morning, taking a stroll, and this bottle washes ashore. And he picks up the bottle, and he rubs the bottle to see what's inside. And a genie comes out and says, I'm going to give you one wish. I've been trapped in the damn bottle for a millennium, and whatever wish you want, you could have. And so he says, you know, my wife and I love to drive, and what I want you to do is build a bridge between the United States and Europe so we can drive back and forth, and it would be such a windfall for everybody. So the genie says, that's a really big ask. Is there something else you could ask for? And he says, well, you know, I'd like to have a treatment, a single treatment, that brings all of my patients with PTSD into remission. And the genie looks at him and says, you want two lanes or four? OK? So we're going to talk today about post-traumatic stress disorder. We're going to talk about the clinical presentation of post-traumatic stress disorder. I can't help but talk a little bit about the biology of what we've learned about post-traumatic stress disorder. And then we're going to talk about what the treatments are that are available and some up and coming treatments for PTSD. So these are my financial disclosures. All of my research is supported by the NIH, and it is largely in the area of PTSD, childhood trauma, and its impact on children and adolescents and adults. And then I consult to a number of companies that are listed here and serve on a number of scientific advisory boards. I'm the president of the Anxiety and Depression Association of America as well. So I want to start off and have you understand where I'm coming from in conceptualizing major psychiatric disorders. And it's depicted on this slide, just like the weakest pointer known to mankind. So I could hardly see it, so you probably can't either. But fundamentally, this is a diagram that I published in the journal Nature Reviews Cardiology. It was an article about depression and heart disease. But the point I'm trying to make here is that there's the life cycle from birth to death. And the y-axis is this odd conceptualization that I came up with called organ integrity. And the notion is that as you go through life, you have one or another vulnerability to disease. Some of you are vulnerable to diabetes, others to heart disease, others to PTSD, others to depression. And the problem with Western medicine is on the right-hand side of the slide, you can see that we see patients when they're symptomatic. So they come to us, they're depressed, they're suicidal, they're anxious, they're having problems with their memory, they're psychotic. But the problem is that by the time we see people in that clinical state, their brain often has changed. So if they have alcohol use disorder, you know their brain has changed. And maybe they have peripheral signs of alcohol abuse. If they have psychosis, we know that the 10th episode of psychosis or five years after an initial psychotic episode, the brain looks different than the first. We know in depression that never treated depressed patients from our own studies respond best to antidepressant psychotherapy, but that if you go treatment-resistant over time, you're going to end up with brain changes that you could see on brain imaging. And that's what I mean by impairment in organ integrity. And what I'm going to suggest to you is that patients with PTSD bring their own disease vulnerability to the table and also have consequences over time that change their brain. Where the future of psychiatry is is right here, which is can we identify who's at risk? Who's at risk for these disorders? Oh, we have a new panelist. That's great. Yeah. Great. I did, and I said that this morning. We have two other seats here. You're welcome to come on down. Yeah. It's sort of like the price is right, you know? OK, so wouldn't it be great if we could identify patients who are at risk for PTSD, major depression, bipolar disorder, schizophrenia, and maybe develop interventions that would intercede before their first episodes? And if we understood the underlying biology, neurobiology, then we could do so. And that'll probably involve genetics, and I'm going to talk a little bit about that today, and maybe brain imaging as well. But that's where the future is. We don't have enough mental health professionals to deal with the epidemic we have right now in suicide, depression, anxiety disorders, et cetera. So we're going to talk about PTSD today, and I like this slide because it's a picture from Fenway Park in Boston, and you can see what's happening here. These folks are sitting there in the audience, right? They're watching a Red Sox game, and a broken bat goes flying into the crowd. And look at what's going on here. They are showing a fear response, right? You can be sure their adrenal glands have just squeezed, and they're pumping out cortisol. Their heart rate has gone up. This is a classic hardwired stress response, and that happens to all of us when we're exposed to a traumatic event. What happens with PTSD is it doesn't extinguish. It doesn't go away. It stays with you, okay? And we're going to talk a lot about that. We've learned a lot about PTSD from 9-11. Everybody in this room knows where they were on 9-11, and we learned a great deal about trauma and its sequelae after 9-11. And unfortunately, there's enough tragedy in the world that there's a tremendous amount of trauma that we see in our patients and all around us. So let's talk about the diagnosis. So frankly, PTSD is the only diagnostic entity in DSM-5 that requires an environmental event, right? The criteria A trauma. And you can read along with me, you know, what it says here about what the criteria are. And fundamentally, it's either experiencing a out-of-usual experience that is life-threatening or witnessing it as far as someone else is concerned. You cannot fulfill the criteria for PTSD unless you've had a criteria A traumatic event, okay? So we're doing a study in Texas called the Texas Child Trauma Research Network, and we've collected 1,700 children in the immediate aftermath of trauma. And one of the things we've learned and have broadened the criteria has to do with two types of trauma that are generally not talked about in the PTSD realm. One of them is medical trauma. And why am I bringing this up? Because if you ended up infected with COVID and were hospitalized in the ICU for two weeks and had a near-death experience, that is a sufficient traumatic event to provoke PTSD. And we've learned, as it turns out, that having a burst appendix, having a cardiac arrest, all of these life-threatening medical events which generally are not thought about as being an A criterion for PTSD, they are. And you need to think about that for all your patients. The second category that has been unrecognized and unincluded in DSM is bullying and cyberbullying. And you better be sure to know that adolescents who are cyberbullied, many, some of whom end up committing suicide, right, that that is indeed a criteria A event. And so I want you to sort of broaden your conceptualization. And then there are these other criteria, which all of you are really familiar with, so I don't have to go over it in detail, but it includes intrusion symptoms, right? It includes arousal symptoms like hypervigilance, and it includes cognitive and mood symptoms. And then there are the usual caveats in DSM-5 that I'm not gonna bore you with, because you all know them. So if you don't remember anything I say today, remember this. This is the PCL-5, the post-traumatic stress disorder checklist for DSM-5, which you should have in your office, on a table, tablet, or printed out to hand your patients before you see them. It's a wonderful screening tool for PTSD. Patients will put things on this that they might not tell you during their first visit because of issues related to shame, related to not trusting you when you first see them, all the issues that relate to individuals who've been through trauma. And the great thing about the PCL-5 is it's 20 questions. They're rated from zero, which is nothing, to four, which is extreme. So the maximum score is 80. And the diagnostic cutoff that has been shown to be reliable for the diagnosis of PTSD is 33. So this takes not any time for you. It could be done prior to seeing you in your office. And this is what it looks like. And the great thing about the PCL-5 is that the symptoms for each cluster are together. So there's the criteria B cluster, the C cluster, and you can see the kinds of questions you're seeing here. Are you having intrusive thoughts about the traumatic event, right? Do you have a strong physical reaction, right? Are you having nightmares? So I would strongly implore you to utilize the PCL-5 as a screening tool. And you can also have patients complete it serially over time and watch as they get better, their scores fall, right? So you wouldn't measure someone's blood pressure by looking how florid their complexion is. And this gives you a quantitative measure of their PTSD symptom severity. Now, the problem with PTSD to begin with is that unfortunately, lifetime trauma is extraordinarily common worldwide. Common in some areas more than others. But this is an old study that was done by Ron Kessler, who's the leading psychiatric epidemiologist at Harvard. And you can see that a quarter of men and women reported a criteria A trauma in their lifetime, but more than that reported multiple criteria A trauma. So this is a very common phenomenon. There are certain groups that are unusually susceptible to trauma. And I really as another one of those, I'd like you to take home this message, which is individuals who are in minority groups, either racial minority groups, ethnic minority groups, or sexual orientation minority groups are at much higher risk for trauma. So you all know me well enough to know that I'm all about the data. I want you to see the data. So let's look at prevalence of PTSD. So in the heterosexual men and heterosexual women, let's start with the fact that women are more susceptible to PTSD than men. We'll talk about a couple of reasons why that may be the case. There's no doubt in every study that's ever been done, exposure to trauma, women twice as likely to develop PTSD than men. Now, one of the factors that I've studied for the last, you know, 30 years is the fact that childhood trauma increases the risk of developing PTSD after adult trauma, which is the second pearl of wisdom I'm gonna try to impart to you. Get the childhood trauma questionnaire, you can get it online, have your patients fill that out. And then in the first visit, you know A, whether they have PTSD or whether they have childhood trauma or both. Because if they have both, they're gonna be harder to treat. Because patients with childhood trauma respond more poorly to treatment for PTSD and for treatment with depression. So if you look at childhood trauma, what do you notice? You'll notice that sexual choice minority groups, minorities in the sense that gay and bisexual men and women have higher rates of PTSD and they have higher rates of childhood maltreatment, which of course corresponds into higher rates of syndromal major depression and PTSD. Look at the interpersonal violence levels here. And you can see again, gay men and lesbian women have inordinately high rates of interpersonal violence, which is of course an A criterion for PTSD, right? And then look at these others, I don't wanna belabor the point, but unwanted sex. Heterosexual men have very low rates of unwanted sex. Look at these other groups. It's extremely high. Being attacked or beaten, being a domestic violence victim, or having witnessed someone else being injured or killed. So when you see someone who is in one of these minority groups, you should be thinking about PTSD as a potential diagnosis. Now this is sort of the classic textbook view of PTSD, or I should say the evolution of PTSD after trauma. And what you see here is that at the time of trauma, everybody is in a emotionally rot state. Think of the times you've been traumatized in your life and think about what it was like when something really tragic happened to you, loss of a loved one, any traumatic event that you suffered. Everybody, 100% of people have difficulty sleeping, can't stop thinking about the traumatic event, but look what happens over time. This is sort of the textbook view is that even in the face of the worst trauma, war trauma, combat, terrorism, 9-11, that if you are a year out of the trauma, only about 30% of people develop PTSD and the rest do not. Doesn't mean all the rest are completely asymptomatic, but I'm talking about syndromal PTSD. The holy grail that I've spent the last decade trying to figure out is why do some people develop PTSD and some people don't? And it's an important question that I think we can answer. This is a more sophisticated view of the trajectory that I just wanna talk with you about. So the bottom dotted line are people who simply are born with tremendous resilience. These are people who are constitutionally unable to develop PTSD in the face of the most extraordinary trauma. Accounts of individuals who were in the Holocaust or in concentration camps, they got sad, they were upset, but they never developed PTSD. Those are the kind of people you hope are flying your plane back to wherever you're going, right? Then there are the people who, as I mentioned, develop PTSD. We've talked about that. And you see the recovery, so over time. And one of the least studies aspects of PTSD is the so-called delayed profile. This is relatively rare. I was just talking to somebody about this a few minutes ago. I was talking to Maria about this. And that can occur when you've had a traumatic event or more, but you've had an incredible social support system around you, family, friends, et cetera, and then you lose that, and then PTSD can emerge. So you can see it, it's relatively rare. What I will say is what's extraordinarily unusual is for someone to be exposed to a criteria, a trauma, and have no PTSD symptoms at all, and without any change in their ecology, they end up suddenly developing PTSD out of the blue. And that's pretty uncommon. So what are the risk factors for developing PTSD? So women, two to two and a half times more likely to develop PTSD than men. I'll show you some biology data that might help explain it, but we don't totally understand this anymore than we understand why women are twice as likely to develop a major depression, twice as likely to develop GAD and other anxiety disorders, but are not more likely to develop bipolar disorder. We really don't understand why. I've already mentioned childhood maltreatment as a risk factor. Having a family or personal history of a previous mood or anxiety disorder is an increased risk factor. Poor social support before and after the event, for sure. A history of stressful life events clearly is a precipitating factor. And then there are people who believe that the more severe your reaction is at the time of the trauma, then the more likely that you will develop PTSD. I'm not exactly convinced yet by that data, but there's some sense of it. So let's look at some data. This is from my friend Charlie Marmer, who's the chair of psychiatry at NYU. Almost 300,000 veterans in the United States returning from Iraq and Afghanistan. And I want you to take a look at this. So I just figured out that I'm looking at the pointer and it's not on the screen. And I've been thinking I've been pointing this out to you the whole time. Geez, you notice that? I mean, there's the pointer there, right? Geez. OK. So what you're looking at here are the solid line is when they were shipped out to combat, either to Afghanistan or Iraq. So the data before then is their baseline rates of PTSD in red, drug use disorder in green, depression in blue. And as you can see, those numbers are pretty much what you see in the general population, right? Relatively low rates of those disorders with depression being the most prevalent. And now let's look at what happens in the three years that follow their combat experience. In red, at the very top, is the prevalence rate of PTSD. And you can see that it gets pretty high. It's up to about 19%. So from less than 2% to 19% ever exposure to combat, obviously, a criteria trauma. Look at blue is depression. You can see that's now way up there to 14%. It's extremely high point prevalence rate. And you see alcohol use disorder down here, which has also gone up. The biggest problem I have in my research is that when I write grant applications about PTSD, the reviewers say that I have to study pure PTSD without depression. Where am I going to find those people, right? They don't exist. And so my PTSD patients have PTSD. They have depressive symptoms. And they also have various levels of alcohol abuse. And they all have cannabis use disorder, right? That's the real world. We'll talk about this in relationship to treatment. Now, people with PTSD have cognitive symptoms, dysfunction, in addition to the other symptoms we talked about. And this is an example of a study done in Vietnam veterans showing a clear deficit in verbal memory. And so the question is, why do patients with PTSD have these cognitive deficits? And it turns out that patients with PTSD have a smaller hippocampus. By structural brain imaging, that's what you're seeing on the right, compared to the normal hippocampus. And it's believed in that top diagram that what severe stress does is it changes hippocampal neurons. And the hippocampus is a major waystation for learning and memory. The idea is that you're knocking off either the neurons themselves or dendrites or axons associated with those neurons. And that's responsible. And if you measure the size of the hippocampus in people with PTSD, as you can see, there is a reduction in hippocampal size, which is small in magnitude, but highly statistically significant. How clinically meaningful this is, I'm not sure. But there is a correlation between their performance on these cognitive functions, verbal memory deficits, and the size of the hippocampus. So the people with the smallest hippocampus had the largest deficits in verbal memory. So there seems to be some connection. I'm going to get back with that in a minute. And it's not just combat that does this. This is a group of women that were unfortunately exposed to severe sexual abuse. And now using a different measure of PTSD severity, the CAPS instead of the PCL-5, another validated measure, you see this very highly significant correlation. So when I was at Emory and working with Barbara Rothbaum, we did a study with Clint Kiltz in which we had these women who were victims of sexual assault, who had PTSD, and they were both suffering with high PTSD severity scores, as you see here, 77, and major depression, a HAMD of 24. So both syndromally of PTSD and depression. And then we asked them to write a script of their trauma. And then we asked them to read it while they were undergoing PET imaging. And the reason is that in this case, radioactive water is a measure of the activity of different brain areas. So I wanted you to take a minute and see this script so you get a feeling for what I'm talking about. So it's 11.30 at night. I just got back from McDonald's. I pull into the driveway and listen to the news update on the Peachtree Fire. Suddenly, as I get out of the car, I'm grabbed around my neck from behind and pulled into the woods. My heart is absolutely racing with fear, and I'm scared to death. He keeps calling me bitch and whore, telling me that I know I want it. I'm fighting to get away from him, but he's beating me, beating my head into the tree and tearing at my clothes. Oh my god, I can't believe this is happening to me. Now he's got me laying on the ground. His foot is on my chest. He's telling me I better do what he wants me to do, or I won't ever do anything again. I could smell the alcohol and cologne all over him as he forces me to perform oral sex, and it sickens me. The sweat is pouring off my body. I'm trembling for my life. Now he's trying to get out of his pants, and suddenly he stumbles and falls backward. Quickly, I roll over, and now I'm running just as fast as I can to the house, and he's chasing behind me. He's yelling, get here, bitch, get back here, bitch, and I'm out of my mind with fear. That is a horrible, horrible experience. And so we took this group of women, and we asked them to rate at baseline before they were treated with an evidence-based psychotherapy how anxious are you on a one to 10 scale, how ashamed, how afraid, how angry, how vivid is the memory? And you can see it's all just about maxed out. On all those symptoms, and how relaxed are you? Not at all. And then we treated them with standard prolonged exposure therapy, a la Edna Foa. This is an evidence-based treatment for PTSD. And here they are six weeks later, and you can see that they're better. They're not totally well, but you see they're less anxious, less ashamed, less afraid, still angry, but not as angry. But look at the memory. Look how vivid. It's still vivid in their memory, although they're able to relax. And when we look at their fMRI scans, what we discover is that they have a decrease in amygdala activity after the psychotherapy. So beforehand, they have wild elevations in amygdala activity and some changes in the cortex. And then after the therapy, with the improvement, there are brain changes. As an aside, if you haven't figured this out, that means psychotherapy is a biological treatment, right? Change the brain. You have to believe that. So one of the real questions about PTSD is there are really two theories. We've written about this in a paper in Neuron recently. There are two fundamental theories about PTSD. One of them is it's a failure to extinguish, right? Most of us have experiences. We incorporate a memory into our hippocampus, and then over time, we don't retrieve it, and we lose it. You know what it's like to drive it in the car, and a song comes on, and you say to yourself, I used to know who did that song, right? I don't remember it anymore. Okay, that's the normal extinguishment of memories. But for people with PTSD, one theory, and I believe this to be true, is they're unable to extinguish the memory of the trauma. The second has to do with what's called trauma generalization. It's not just that they are now symptomatic in relationship to that memory. They've now generalized that trauma to a host of other circumstances. So you know what? I can't go out of my house at all, because when I went out of my house, something bad happened, and I'm never gonna go out of my house again. And this was a study, a remarkable study. You'll remember the Paris terrorist attacks in 2015. They took a group of patients with PTSD, and they taught them, they gave them a relatively innocuous memory. They exposed them to a sort of story, and they took a group of controls that were in Paris, but were not exposed to the attacks. And it turned out that these patients with PTSD, they couldn't extinguish the story even, an innocuous stimulus. It changed the dynamics of their memory system. So what's the matter with people with PTSD? Why do only 30 to 40% develop PTSD, even in the midst of the most remarkable and severe trauma? Why do other people simply don't develop it? And so the systems that we've looked at, and others have looked at, largely have been the stress systems. So what are the systems in the body that mediate stress? You all know what they are. The hypothalamic pituitary adrenal axis, and the sympathetic nervous system, right? You all learned this in medical school or graduate school. And so there's the pituitary adrenal axis, and it's all driven by corticotropin-releasing hormone, the brain's orchestra of the stress response, right? It drives cortisol secretion to stress through the pituitary. It also drives the autonomic, the behavioral and the immune responses to stress. So we did a study and we showed that in PTSD patients, there's an elevation of corticotropin-releasing hormone in cerebrospinal fluid in depressed patients compared to controls. We did a second study in which we collected cerebrospinal fluid over the course of five hours in a group of veterans, shown at the top, and a group of matched controls at the bottom. And again, we showed this elevation. So clearly, the pituitary adrenal axis led by CRH is involved. And as we talked about, we know that early life trauma results in a increase in risk. Am I drinking your water? Okay. I don't wanna drink someone else's water. Okay. There's a whole case of water down here. Okay. So I wanted to determine with my colleagues whether early life stress sort of programmed you to be more susceptible to depression and PTSD in adulthood. So we did a study in Atlanta at Grady Memorial Hospital of 500 African Americans, 99% of the sample, who were sitting in an internal medicine clinic waiting room, waiting to be seen. They weren't psychiatric patients. And we interviewed them, provided informed consent, a highly indigent group of patients, as you can see here. And we measured their BDI, we measured their childhood trauma questionnaire, we measured their post-traumatic stress disorder symptoms. And the first thing you're looking at in the upper left-hand corner is, this won't surprise you, the more criteria A trauma you suffer, the higher your PTSD severity scores. So you could see from no trauma to four or more trauma, you see that measure of PTSD severity going up. Then at the bottom left-hand corner, it's a question of no child abuse, one type of child abuse, like physical abuse, or two or more types of child abuse, like physical and sexual abuse. Again, look at the DUS response curve in terms of PTSD severity. And then on the right-hand side of the slide, it's all additive. So early life trauma, childhood maltreatment, coupled with adult trauma, makes everything worse, makes symptom severity worse, make disease vulnerability worse. Okay, we're gonna talk a little bit about biology, and then we're gonna talk about treatment. But I can't help but not talk about biology. You just have to bear with me. So you all know that 22,000 genes in the human genome, and you know that they come, many of those genes occur in different forms, that there are mutations that result in what are called single nucleotide polymorphisms, SNPs. And that's why, guess what, we don't all look alike. We don't all act alike. You know, we have, everybody in this room, 99% the same genome. What's different about us is that we have these genetic variations that are responsible for all the differences that we celebrate in humankind. And so there are two ways to fundamentally affect gene expression. One of them is to have a mutation, and that that mutation actually affect the gene product. There are 22,000 genes. The other is what's called epigenetics, which is the process whereby gene expression is turned on and off, that doesn't involve structural alterations, but involves environmental effects. And we'll talk about both of them. So there's a gene called FKBP5, and in the upper right-hand corner, you can see all of those lines are genetic variations that occur in this gene, happens to be on chromosome six. And on the left, what you can see is this gene, which codes for a protein that regulates the action of cortisol all over the body, but in the brain too, that those variations, those four variations right here, at the top right there, interact with child abuse and neglect to determine whether or not you develop PTSD when you're exposed to an adult trauma. And we picked this gene because we knew it had something to do with the stress system and the actions of glucocorticoids, cortisol. So just show you what the data looks like. Here are, these are two important points to make. One, in the absence of child abuse and neglect, doesn't matter what your gene variant is. You have the same rate of PTSD. But if you're abused as a child, look what happens. There's one variant that high risk for PTSD, and one that's sort of resilient variant. And here's another variant, again, that will confer risk to develop PTSD after trauma. Well, how does this work? I mean, this is pretty wild that a single gene variant would interact with child abuse and neglect. We were really puzzled about this. But I have students that are much smarter than I am. And so they said, you know what it must be would be that there's an epigenetic effect of child abuse and neglect that interacts with this vulnerability variant of the gene that ends up regulating whether or not you develop PTSD or not. And so we published this paper in Nature. And here's what it looks like. So there's the childhood trauma questionnaire. The more trauma you have, you notice that the measure of epigenetics, the methylation only is associated with that particular gene variant. So that's how childhood maltreatment interacts with this gene variant. So I gave this talk in LA. I was trying to raise money for the Child Abuse Center, hard thing to raise money for. And this woman came up to me and she said, I didn't understand a thing you said, Dr. Nemeroff, but I'm a film producer. And I could produce a film that would make this understandable to real people. I said, well, hell, have at it. ♪ Damage done, history haunts me ♪ ♪ Didn't get what I needed, I was so young ♪ ♪ The fear from my past, I carried with me ♪ ♪ Can I ever be covered from what you've done? ♪ ♪ Cause you marred expression of my tears ♪ ♪ While I was developing ♪ ♪ While I was developing ♪ ♪ Messed up my circuitry, you ruined me ♪ ♪ Later when the stress comes on ♪ ♪ My HP is not that strong ♪ ♪ I cry when there's nothing wrong ♪ ♪ You ruined me, nothing wrong with ATGC ♪ ♪ Just a broken MBG, it's killing me, you ruined me ♪ ♪ Marred expression of my tears ♪ ♪ While I was developing ♪ ♪ Messed up my circuitry, you ruined me ♪ ♪ Later when the stress comes on ♪ ♪ My HP is not that strong ♪ ♪ I cry when there's nothing wrong ♪ ♪ You ruined me, nothing wrong with ATGC ♪ So the notion is that early life trauma sensitizes and changes the stress system. So when exposed to subsequent stress, it's simply not able to have the normal response. And I think we have lots of evidence for this. A couple of other quick things about biology. One is this is an entire different stress system. And I just wanted to point out to you that my students, but I'm not an author of this, showed that a gene variant in this system would appear to be responsible for the vulnerability of women to develop PTSD in the face of a history of childhood maltreatment, not men. And they did an elegant study here. And as you can see, the gene structural variant only comes up in women. And they did this twice with a replication sample, as you can see here, and the findings were pretty profound. So what we've discovered is there are a number of gene variants that have an effect on whether you develop PTSD. And if you're really unlucky, you have four or five or six of these gene variants, and then the diacidic cast that you're going to end up developing PTSD. So for the sake of time, I'm going to move on to talk about treatment. So the best treatments for PTSD are psychotherapeutic treatments right now. So the best treatments, the evidence supporting the treatment of post-traumatic stress disorder, the biggest effects are with cognitive processing therapy and a form of cognitive behavior therapy, often called prolonged exposure therapy, in children it's called trauma-focused CBT. And there are two medications that are approved by the FDA for the treatment of PTSD. One is sertraline, the other is paroxetine, and as I'll show you, there's very good evidence that venlafaxine is also effective in the treatment of PTSD. But none of these treatments bring people into remission, and that's going to be one of the take-home messages that I have, and the hope for the future. And don't worry, I'm going to talk about the psychedelic data that's now been published that I can talk about as one of the potential game-changers in the field. So this is the goal, and I'll just point out to you just straight up that there's not anybody in this room that couldn't tell me a definition of response or remission in depression. You've all heard those talks a dozen times, you know what they are. There's nobody in this room could tell me what the agreed-upon definition of response is for PTSD, or what the agreed-upon remission definition is for PTSD, because we don't have one. And the criteria that have been used in pharmaceutical trials is a very low bar, right? So saying that someone no longer fulfills criteria is not a great outcome. If you go from a 55 on the PCL-5 to a 32, you still have a lot of symptoms, even though you may not fulfill criteria anymore. So you're in your office, and you see these patients, right? And there you are, and you're on the antidepressant highway, and you're trying to figure out what to do, right? And what is the database for the treatment of post-traumatic stress disorder? So there is some evidence that psychoeducation about PTSD in the form of very brief four to five sessions of psychotherapy in the immediate aftermath of trauma can be helpful. Certainly social support and a great deal of education about what to expect can be helpful as well. Unfortunately, what we learned after 9-11 was that every well-meaning therapist in the United States descended on 9-11, and they were determined that they were going to treat every single victim of that attack. And what they did was they demonstrated to us that if you rip off the defenses of people that would normally be resilient and recover, you can make them have PTSD, okay? These were really well-meaning people, right? Who forced children and adults at the 9-11 experience, people who lost family members, people who were actually there, firefighters, policemen. They were inundated with people who were extremely well-meaning, who wanted them to continue to relive the traumatic event. And that's guaranteed to generate PTSD in people that would have already otherwise recovered. So we learned from that experience. What do we know doesn't work? Well, as we talked about, a lot of controversy about parazysm. Parazysm doesn't work. Parapsychotics don't work. This idea about propranolol, which I thought was one of the silliest things I've ever heard. Oh, let's give people a drug that causes amnesia. That was the idea. Propranolol will prevent them from incorporating the traumatic memory, right? No. That's really silly. That didn't work. We'll talk about antidepressants as well as we move along. And what you don't want to do is marinate people with benzodiazepines, because it turns out that they're not effective in treating PTSD at all. So prolonged exposure therapy developed by Edna Fowern and her colleagues at Penn has, as you know, it's a manualized therapy for treating PTSD. It has a number of manualized steps. It can be done with imaginal exposure. It can be done with virtual reality exposure. You can create an imaginary battlefield. You could have the patient actually design the battlefield related to their own traumatic memory. And the data is just really good in terms of compared to a weightless control or psychoeducation, prolonged exposure therapy works. The problem with prolonged exposure therapy is that it's painful. It's hard. And some patients can't tolerate it, right? And so that led to something called cognitive processing therapy developed by Patti Rezek, who's at Duke. And this is an example of a study that I wanted to impart to you, because this was asked a great question. Instead of seeing one patient at a time, why don't we just put 10 people in a group and we'll do cognitive processing therapy, and it will be sort of economic for the patient. And economic, and there could be a group process. Seemed like a great idea. It was funded by the VA. So these were 8 to 10 participants per group, 90 minutes per group versus 60 minutes of individual sessions. And what you're looking at here are the results. So the PCL-5 is on the right-hand side of the slide, a different scale on the left. And what you see is a really decent response in the individual therapy and almost nothing in the group therapy. Group therapy using cognitive processing, it just doesn't work, okay? Most importantly, I want you to see the scores. The mean PCL-5 score here is 55. These are really sick people, right? And here they're at the end of treatment. And where are they at the end of treatment? They're at a 42, at best. And then after the follow-up, they creep up a little bit. 55 to 42, that's the best we could do with psychotherapy and treating PTSD. And it's great. I'm going to skip this for time because I want to be able to answer questions too. So just bear with me. This is one of my favorite studies. So this will, an astute observer when I last gave this talk told me, hey, you said group therapy doesn't work. I said, well, that was in a combat situation. This is one of my favorite papers in the New England Journal of Medicine. So this was a study of cognitive processing therapy in Congolese survivors, all women, of sexual violence. This is the kind of study you read and you say, I wish I thought of that. What a great study. So what they did was they trained individuals to deliver cognitive processing therapy and they divided the villages into being assigned to cognitive processing therapy or just individual support, otherwise known as rent-a-friend, right? And then they just followed them over time to see the development of depression or anxiety. And they had 65% of the participants in the therapy group completed all three assessments, half in the individual support group. So what did they find? Look at the measurements of depression and anxiety in the top graph and then PTSD in the bottom. So group CPT in this population worked tremendously well, tremendously well in these victims of sexual violence. So now we're going to talk about pharmacological neuromodulation and psychedelic treatment of PTSD. I'm going to show you the data that the FDA used to approve Sertraline. And what I want you to see here is that a response rate was defined as a CAHPS improvement of 30%. Now, in depression studies, we define a response rate as 50% or better. 30% is pitiful, right, but the FDA accepted that as a measure of response. And you see the difference between Sertraline and placebo in these two pivotal trials. And the Sertraline-treated patients clearly had an improvement in measures of quality of life, as you can see here. An additional pearl of wisdom I want to try to get out to all of you is unlike depression, PTSD takes much longer to respond to medication. And if you stop too early, after four weeks or six weeks or eight weeks or ten weeks, the patients aren't going to reap the benefit. Look at the HAMD scores here at baseline, at three months, and at nine months. And look at the, this is a different trauma scale, the Davidson trauma scale, look again at baseline, three months from 73 to 42, and at nine months down to 24. So you can see it really takes time. There are two studies that have looked at whether combining cognitive behavior therapy with an antidepressant is additive in improvement. One study showed no benefit whatsoever. The other, this is the Sertraline study, showed a very small benefit with the combination. I of course intuitively believe that the combination treatment is better, but the actual evidence is pretty meager. Here's the paroxetine data. This is the immediate risk form of paroxetine. None of us prescribe paroxetine anymore because of, A, it makes people fat, B, there's a problem with abrupt discontinuation, withdrawal. And so we tend to not use it very much, but it is effective in the treatment of PTSD, as you can see here, change in the CAHPS scores. And again, using the same sort of meager CGI definition of response, you can see that both doses were clearly better than paroxetine. What about other SSRIs? One study with fluoxetine showed a nice effect, again, a meager definition of remission. And I meant to say that like Sertraline, paroxetine shows an improvement in quality of life measures as well. One study with mirtazapine, a little confounded by the fact that it improves sleep. So you're going to get a score, right, a reduction, just because mirtazapine will make you fall asleep, right? It'll also make you fat. You know what I use mirtazapine for? I'm a geriatric psychiatrist. Little frail patients in the nursing home, it's a gangbuster. You could put beef on them and turn them into the Michelin tire boy, okay? And they sleep, right? So I love mirtazapine, not for anybody else. So how cool is this? If you treat people for a year with paroxetine, and you know that there are reports that antidepressants increase neurogenesis in the hip campus, PTSD study, as you can see here, we saw an increase in their memory as they got better with paroxetine. But even better, look what happened to their hippocampus. It grew back, suggesting that maybe there is a relationship between hippocampal size and PTSD. My favorite antidepressant currently is venlafaxine for treating PTSD. Here's a nice big study, 180 patients per group, showing venlafaxine to be as effective or more effective than sertraline. And if you look at quality of life measures, symptom-free days, venlafaxine did better. The only reason it's not approved by the FDA is the company that owned it got eaten by Pfizer who already had sertraline, and they didn't want to have a competition among their own drugs. But it is a good drug. And here's a meta-analysis of all of the SSRI data showing that they all do improve symptoms in patients with PTSD. This one very long-term venlafaxine study, which I wanted to show you, which is quite impressive, a six-month randomized controlled clinical trial showing a continued improvement over time with venlafaxine. I tend to use high doses of venlafaxine in this population. When I say high, I mean 300 to 450 milligrams. If you go slowly with the dose, the patients can tolerate it. And you can see here, much higher rates of remission, even if you're using a sort of liberal definition. Okay, now we're going to go into the more recent treatments very quickly. Xanax, no. No, this is a substance-abusing, alcohol-abusing population, okay? Some of them use opiates. A lot of them drink alcohol. Oh, you're wearing a UNC shirt. Yeah, go Tar Heels. Okay. Sorry, my alma mater, okay. What about ketamine? Two studies of intravenous ketamine done both at Mount Sinai in New York. This was the standard dose of ketamine. It was a small study, 41 patients. Many of you know I'm not a big ketamine fan. I worry about the rebound. But here's the data. This compared ketamine and midazolam. So instead of using saline, they used midazolam. You can see that ketamine looked pretty good at day one, a sort of rebound at day two and day three. It didn't look that different than midazolam. A second study has now been published in the American Journal of Psychiatry by the same group indicating that if you give repeated ketamine over the course of a few months that you can keep people feeling better. I still have concerns about it. So the most exciting development in the field of PTSD has been the use of MDMA, which is a so-called antactogen, one of the classes of psychedelics in the treatment of PTSD. And I think tomorrow I'm giving a lecture, PTSD, in association with MAPS, which is the group that is sponsoring these MDMA trials. A few caveats about this work. Of all the psychedelic trials, the only group that is actually doing a manualized, validated psychotherapy after the treatment with a psychedelic is MAPS in this program. And so this was a randomized, double-blind trial. Does all of us agree that you can't do a blinded trial with psychedelics? Because if the walls start breathing and the colors start moving and the music sounds really weird, you sort of know, hey, I didn't get placebo, right? No, seriously, that's a problem. Because you know how important randomized controlled trials are. Be that as it may, this is a remarkable paper that was published in Nature Medicine, and I'm not going to go over all of it, other than to say if you read this, you'll be able to see they were carefully prescreened. They were educated about what the experience was going to be like. They received MDMA on two separate occasions. MDMA is really different than LSD psilocybin. You know, it's colloquially known as ecstasy. It's called an ataxogen because it allows people to be more in touch with their feelings. And then, as you can see here in green, are these psychotherapy sessions that follow. When you look at the data, this is the largest magnitude effect of any psychedelic that's been studied for any psychiatric indication. And they have just completed their final pivotal trial, and they are currently getting ready and are in conversations with the FDA to ask for approval for MDMA for the treatment of PTSD. And if you look at this data, I think you would agree with me, if you look at the CAHPS data in the upper left-hand corner, that is as big a separation as I've ever seen in a PTSD trial. It's a bigger effect than we see with sertraline or venlafaxine. So I feel we have to really listen to this, and I think that we have to determine who will this be good for, how often could it be prescribed, what are the economic issues associated with it. There is some ongoing studies, but one published study of transcranial magnetic stimulation for PTSD, that is something you can do a sham treatment on. Obviously, you can apply the magnet but not turn it on. And so in this study, there was a small study, but there was efficacy. Thirdly, we did a study in the VA looking at ECT, which has not been studied very much in PTSD. And so we looked at patients who had comorbid PTSD and MDD, and what we discovered was something really fascinating. What we found was that ECT had a remarkable and robust improvement in both PTSD and MDD symptoms in patients who had comorbid disease, was better than antidepressant alone, which was largely sertraline in this population. What was really remarkable was that ECT treatment actually reduced the death rate in these patients, and the death rate was reduced not just to what you would think, which was suicide, but also cardiovascular mortality. So ECT is something you should at least think about. So where are we going in the field? Well, this is from a website in Austin. This is an all-service spa. You can come here and you can get ketamine, and you can get a needle put in your neck so that you could block your sympathetic nervous system with an injection of Novocaine in the stellate ganglion. Here's what it looks like. And you can get both treatments. You could pay $1,000 for the stellate ganglion block, and you could pay another $1,000 for the ketamine. Right? Because, you know, we're Americans. We can get anything we want. And so the idea is that stellate ganglion blockade reduces the sympathetic hyperactivity in PTSD. And those of you who remember your first semester of psychology will remember that there were theories that were debated about whether the physiological consequences of anxiety was what really caused it. Right? It was the increase in the heart rate. And if you didn't have the increase in the heart rate, you know, maybe you would be asymptomatic. So here we go. Published in JAMA Psychiatry, right, there's the first and only randomized clinical trial. There is currently a multi-site trial being funded by the VA, led by Paul Holzheimer at Dartmouth. But fundamentally what they did is they administered stellate ganglion blockade at baseline and then two weeks later, and the patients either received a sham injection or they received the blockade. And this was in a group of veterans. And they used the PCL-5 and used a cutoff of 32 for the diagnosis. And they decided that they were going to just make their own definition of response. So they decided that the 10-point reduction in the caps would be the definition of response. And they screened almost 200 subjects. And they ended up recruiting 100 men and 13 women who they entered into the study. And what they found was a statistically significant reduction in the PCL-5 scores with stellate ganglion blockade versus the controls. But I want to show you the data because you know me well enough to show you the data. So here on the left is the baseline. And you can see what their CAHPS score is actually. They used the PCL-5 for entry, but so their mean CAHPS score is about 35. It's not terribly symptomatic. It's not super severe. And then you can see the reduction in the patients with stellate ganglion blockade versus the sham. And that's not a very robust difference between those groups. Statistically significant, clinically, in my mind, meaningless. But we'll see what happens in the controlled study. So the last thing I want to mention is sleep, because one of the biggest problems in patients with PTSD is sleep, right? Nightmares, intrusive nightmares, disrupted sleep. They have a lot of comorbid disease. So Murray Raskin at the University of Washington did a study with Parazysin published in the American Journal of Psychiatry. Said it was the greatest thing since sliced bread. Said the Pittsburgh Sleep Index improved. Nightmares diminished. This was fabulous. And that led to a multi-center VA study at 13 academic VA medical centers. Very well-powered study to look at the effects of Parazysin in PTSD. 300 patients randomized equally to Parazysin or placebo. 10 weeks trial, and there was absolutely no difference in any sleep measure. So as you can see here, there's the CAPS recurring distressing dreams item. No effect whatsoever. The Pittsburgh Sleep Index quality right here, nothing. And it just wasn't anything there. After this talk, 10 of you are going to come up to me and say, I use Parazysin all the time. It's a great drug for my patients. And my response will be, well, maybe it is. Maybe you're such a wonderful doctor that it's a placebo response, but it doesn't matter if they're better, right? But we have to go with the data. So I wanted to leave time for questions, which I have. And I just want to thank all of you spending the afternoon with me. Thank you. And keeping in mind that there is both questions here from the virtual audience, the guidance I've received is that make sure that you attempt to state your question in 30 seconds or less so that there is something specific to be answered. And we'll start with you. Hey, Charlie. That was a wonderful synthesis of decades of data. I wanted to ask about the psychedelics because it's the new frontier. I think I wasn't around for the 60s, but those of you who were, the sense I get from the psychedelic experience is that everybody talks about oneness, togetherness. And I'm curious if you've thought about mechanism, probably thinking in the more of the black box zone than the true neurobiological zone, but thinking about if it's something about a restoration of trust and safety that might be driving that much bigger effect size than we see with more of the commonly used therapies. So for true transparency, Alyssa is one of my academic children. This was not a planted question. So psychedelics is a really big, big, big topic these days. And so I could spend a long time, and I won't, talking with you about the unanswered questions. I'll just say a few things about them. Timothy Leary talked about set and setting, the set being your mindset and the setting being where you are. And I think safety is a really important part of this. But the problem with psychedelics is that the experience is incredibly individualized. And so if you look at the data from the Davis paper in JAMA Psychiatry, the side effects listed in table eight of the supplement, hidden, are pretty terrifying. That the psilocybin experience was pretty damn scary. A third of the patients thought they were going to die. Half the patients thought about suicide. I mean, it's a scary experience. If we could just think for a minute about what psychedelics do, in my mind, what psychedelics do is they tear down your natural defenses. And so all of us have things we worry about every day. We worry about the world. We worry about our children. We worry about our grandchildren. We worry. But we go on because we have defenses. Under the influence of psychedelics, they're ripped away. And there are certain people that you know, and patients that you have, that I would imagine you'd agree probably wouldn't do well with that. That have very little, what we used to call, ego glue. Right? Also people that have extremely rigid personalities that are sort of control freaks, generally don't do well with psychedelics. So there's a lot we need to know. I'm fascinated with the idea that micro dosing of psychedelics may have therapeutic benefits without the psychedelic experience. And that's an answerable question. Can you have a therapeutic response in the absence of a psychedelic experience? And I think we'll eventually know the answer to that. But the issue of safety being so preeminent in the mind of people with PTSD. Right? And so what I'm really worried about in the Oregon experience is that all of you know that unfortunately, there are individuals in the mental health arena who have taken advantage of patients. So what Oregon has agreed to do, and they just opened their first dispensary yesterday for mushrooms, is that you can now go to the mushroom store, you can buy your psilocybin mushrooms, and then you're going to go to a therapist who's been trained online. And you're going to pay the therapist $1,000. And they're going to be with you for the eight hours while you're under the influence of the psychedelic. And it's totally demedicalized. And I worry about patients being taken advantage of under the influence. They're not being, as we do in our center, always have a man and a woman with the patient during the randomized trial. So a really good question. She was a fabulous MD-PhD student. Online question. Does psychedelic psychotherapy help patients with PTSD? What's that? No, let me read it. Does psychedelic psychotherapy help patients with PTSD? So I have an editorial. The question is about psychedelic psychotherapy. So I have an editorial coming out in the American Journal of Psychiatry, which fundamentally asks, what is psychedelic-assisted therapy? Because it implies that what psychedelics do is it assists therapy to work. With the exception of the data I showed you with MDMA, the other therapies that have been attributed to use in the clinical trials for psilocybin are not evidence-based therapies. They're not CBT. They're not interpersonal psychotherapy. They're actually more psychodynamically-based therapies. And so what is it like? You all remember, those of you who are trained psychodynamically, that they're very open-ended. And so after the session, no therapy happens when you're hallucinating, because that's just not possible. But after the session, the following days, you meet with the therapist. And the therapist finally say, what was it like? And the patient says, I've been thinking about that I'm not as good a parent as I should be. And the therapist says, oh, because that's what non-directional open-ended therapists say, right? So there's never been a study that has compared a psychedelic versus psychedelics plus psychotherapy of any kind. So I personally think whatever is driving this is the drug, not the therapy. But we don't have any data. So. My question is, you mentioned bullying and cyberbullying as criterion A. I'm wondering if you can expand on that. Is that for adults and children? And does the patient have to believe their life is endangered by the bullying? Yeah. So the question is about cyberbullying. So this is the Nemerov edition. This is my interpretation. I've just seen too many adolescents and young adults who have been victims of cyberbullying who have developed PTSD, right? These are individuals who fundamentally, the classic case is a 16-year-old who ends up with a sex text that then gets sent around to everybody in high school, right? And the patient is absolutely mortified, humiliated. And it gets being shown to not only the classmates, but to their other friends, their parents, et cetera. I consider that a pretty brutal trauma. And so I believe it fulfills the criteria. It's not, you know how it's life-threatening? It's life-threatening because some of these kids commit suicide. So I think we need to consider it. Next question is about, would you comment on EMDR for treatment of trauma? Somebody always tortures me with this question. OK. So EMDR is sort of like a cottage industry. And you all know about what EMDR is, right? Eye movement desensitization response. So fundamentally, the idea is that if you focus on something else other than the trauma, then it will help you extinguish the response. And so the effect size is mild to moderate in people with relatively mild PTSD and not so much in people with severe PTSD. So Cochran's analysis would say there's some mild evidence of efficacy. My favorite study that was done compared a Tetris video game with EMDR and found that it was just as effective in reducing PTSD symptom severity. In the back. Thank you. Very timely. Just a tiny bit of extra torture. On the EMDR issue, I've looked so hard to see if there's any increase in the effect size from the add-on of the eye movement to the cognitive component and haven't really found anything. Do you think it adds anything to the cognitive therapy part to it? So are you talking about what the cognitive effects are of EMDR? No, no, no. I'm just wondering if there are any additional benefits, if the eye movement itself increases the effect size of the cognitive therapy. There's this very cool company that I've been consulting with named Sensai that happens to be in Austin. And they have a, no kidding, as you know, the eye is connected to the brain, right? And it turns out that they came up with this really cool idea using an AI platform that you could expose patients with an iPhone to a stressful image and determine whether people with PTSD would actually have an abnormal ocular response. Not just pupillary size, but saccades, gaze, eye movement. And they've come up through this AI platform, which as you know, with machine learning, trains itself. They've been able to distinguish between, in a pilot study, between patients with PTSD and normal controls. And they're trying to develop it as a diagnostic tool, as an augmenting agent for us in diagnosing PTSD. So it's sort of a cool idea. Next online question, could you comment on topiramate use and treatment of PTSD? Topiramate. Topiramate. Well, topiramate, the issue with topiramate, which trade name is Topamax, and the patients call it Dopamax, OK? Because if you get above 200 milligrams, it has decided cognitive dysfunction. And so the PTSD trials with topiramate have not been successful. But what topiramate has been helpful for is alcohol use disorder, which often is comorbid with PTSD. And secondly, it can help with weight loss in patients who are taking medications that are increasing their weight. My question is around the diagnosis of it. And you had mentioned the delayed onset is pretty rare compared to acute onset. And I was just curious, like, your distinction or if you could expand on that. I tend to treat a lot of first responders. And so they tend to not have like a one hit event. It's like a series of things. And so when we get into things, it's not just one. It's a whole list. So we have a program with the Austin Police Department so that we could see first responders sort of in the immediate aftermath of trauma and try to provide those three, four, five sessions of cognitive behavior therapy to help them to overcome that. So first responders are an interesting group for many reasons. First, they're going to have repeat trauma, right? And so the ones who get in the most trouble in my mind are people who have a history of childhood maltreatment. And then they take a job as an EMT or fireman or whatever. And they see terrible things. They see dead babies. They see victims, gunshot wounds, et cetera, et cetera. So it's not a good job for a long period of time, OK? No matter how resilient you are, it'll eventually wear you down. If you're not vulnerable to PTSD, you're going to get depressed, right? And so it's always hard seeing those folks. I don't have any easy answers. Question from online. There was a study that was positive regarding methylphenidate in PTSD. Can you comment on the use of that, especially with patients with traumatic brain injury? I love it when people say there was a study of something, and I don't know the study. So in general, you worry about the use of psychostimulants, right? On the one hand, I will say that MDMA is related to ANFED. And so one might think about whether stimulants may have role. I'm not familiar with that study. I don't know if it was blinded. I don't know how you could be blinded with ANFEDamine any more than you could with psychedelics. I don't know what tools were used. In general, I worry about substance abuse in the PTSD population. But I'm agnostic. I'd love to see it. In the back. I realize there have been entire lectures around cannabis with PTSD. I do wonder if you could just give a brief, if that's possible, sort of opinion on that. I'm at one of the VAs in Chicago, and it's sort of an ongoing. So I don't want to give my own answer. If that would be wonderful. Thank you. So I'm not an expert in the cannabis field. We published a review in the American Journal last year on cannabis. And there are extremely few studies. I can't think of any that have actually done a randomized controlled trial with appropriate dosing of cannabis in treatment of PTSD or MDD or comorbid PTSD and MDD. One of the problems we have with clinical trials in psychiatry right now is if you eliminate people that have a positive urine drug screen for cannabis, you're never going to recruit anybody into the trials. Because half of damn America is taking cannabis. And so it's confound. I was not a big fan of how cannabis was legalized across the country, because I see the aftermath of it in three ways. So you asked me the question, so I'm going to get on the horse here. The first is, there's no doubt that if you're genetically vulnerable to schizophrenia and you're exposed to cannabis as an adolescent, your risk goes from 1% to 4%. That's a fourfold rise in risk for a really serious mental illness. Number two, a lot of individuals I see who are very treatment refractory with depression and anxiety disorders have marinated themselves in cannabis for many years. And they don't seem to respond well to conventional treatments. So that worries me. But the third really has to do with the fact that I'm a dog lover. And there's an epidemic of dog overdoses of edible cannabis in Colorado. And that's just not right. So we don't have enough data to speak to the question you asked. Dr. Nemerov, also, any thoughts on the use of quetiapine for use in anxiety, sleep issues, and PTSD? So the issue with quetiapine is, quetiapine is a, at low doses, it's a histamine antagonist. So if you want to use quetiapine, you can at 25 or 50 milligrams. Or you could just prescribe 25 milligrams of Benadryl, and you'll get the same effect. If you want to use quetiapine because you want its antidepressant effects, you're going to have to increase the dose. And as you increase the dose, you're going to end up with an increase in triglycerides, cholesterol, weight gain, insulin resistance. So I generally use tracitone before I use quetiapine. Dr. Winchell? A piece of information regarding the question of separating out the benefits of psilocybin from the therapeutic add-on. In the current issue of the American Journal, there's a report by Roger McIntyre's group of a single patient in their trial. I reviewed the paper. Ah, OK. I'd be glad to mention it. So thank you for bringing it up. So Roger McIntyre had a patient in a psilocybin trial for depression who received the 25 milligrams of psilocybin. And he had no psychedelic response whatsoever. But he had a therapeutic response in terms of his depression improving. And after the trial, he went to Dr. McIntyre and said, I lied. I'm on 300 milligrams of tracitone. And so tracitone is a 5-HT2 antagonist. It clearly blocks the effects of 5-HT2 agonists. So that is the single N of 1 that would suggest that you could get a therapeutic effect with a psychedelic without a therapeutic effect for the depression without having a psychedelic experience. If I may make a comment about that. I don't know why we're calling it medication-assisted psychotherapy. We might as well be calling it therapy-assisted medication. There's no evidence that shows that the therapy is necessarily necessary or even inherently therapeutic or superior to it. But there is an industry already developing around this. Many therapists are already taking courses in how to provide this therapy. There are businesses doing ketamine and are clearly set up to be ready to provide. When we see an economic interest developing two or three years before the drug is going to be available, this is going to seriously distort the use of this medication. So I couldn't agree with you more. And we've seen it with the ketamine clinics, right? So once there was a huge economic windfall for primary care doctors and anesthesiologists who figured out that they could deliver IV ketamine and a bottle of IV ketamine, which gives you five to 10 doses, costs $40. And you're charging $500 to $1,000 per injection. And all the charges for that therapy. Yeah. So that was my comment about my concern about Oregon and the demedicalization of psychedelics. And I'm sure all of you know this, but MDMA is an amphetamine derivative. You get a whopping increase in blood pressure when you administer it. It's not long-lived. But still, wouldn't you want to check someone's blood pressure and make sure it's not 200 over 120 before you give them the MDMA? I mean, that's what I'm worried about. In the worst scenario, what's going to happen is psychedelics are going to become broadly available, and there are going to be several disasters, medically or otherwise. And then the federal government's going to come in and say, we're going to go back to 1970. So, yeah. We're out of time, so I just wanted to thank Dr. Nimroff for his wonderful talk. Thank you.

PTSD

Dr. Charles Nimroff

psychiatry

diagnosis

treatment

neurobiology

stress systems

genetic variances

risk factors

psychotherapies

SSRIs

MDMA-assisted psychotherapy

psychedelic drugs