Good afternoon. My name is Edmund Pai. I'm the moderator for this session, and I'm Professor Emeritus of Clinical Psychiatry and Behavioral Science at University of Southern California, as well as a clinical professor at UCLA, Department of Psychiatry and Biosciences. And it's my great privilege to moderate this session, and then before I do that, I would like to share this wonderful news with the colleagues here, and APA decided to establish this new track called the Clinical Update Track at the 2022 Annual Meeting. That's why you are here, APA Annual Meeting. So by the end of session, the sessions, and we want to leave clinician with a practical and evidence-based tools you can take home and use right away in your practice. That's what the clinical update is. And there will be, for the anxiety track, we call it Anxiety Domain, three renowned speakers will present on the topics that clinicians deal with every day. So today, we have Professor Charlie B. Nemeroff with us, but tomorrow, early in the morning at 8 a.m., we have Dr. Blair Simpson to talk about OCD, and then after that, it will be 10 o'clock, and followed by Dr. Mark Rappaport to talk about anxiety disorders. So these are the three presentations for the anxiety track. Again, I say that it's my great privilege and honor to moderate this session and introduce our speaker. Dr. Charles Nemeroff, MD, PhD, is a chair and professor with the Department of Psychiatry and Behavioral Sciences. He also directs the Institute for Early Life Adversity Research within the Department of Psychiatry and Behavioral Sciences as part of the Mova Clinic for Neurosciences at the Dale Medical School, University of Texas at Austin. So he has served as a president of American College of Psychiatrists, as well as the American College of Neuropsychopharmacology, and sits on the Scientific Advisory Board and Board of Directors of American Foundation for Suicide Prevention and the Anxiety and Depression Association of America. He has received a number of research and education award, so I won't be, we won't have time to mention that, otherwise we would deprive Professor Nemeroff to present on this topic today. And he was elected to National Academy of Medicine in 2002. He's a member of the APA Council on Research and chair both the APA Research Colloquium for Young Investigators and the APA Workgroup on Biomarkers and Novel Treatment. And speaking of his publications, that he has published more than 1,000 research reports and reviews, and his research is currently supported by a grant from National Institute of Health. And his research is focused on pathophysiology of mood and anxiety disorders, with a focus on the role of child abuse and neglect as a major risk factor. He has also served on the Mental Health Advisory Council of National Institute of Mental Health and the Biomedical Research Council for NASA. He is co-editor-in-chief of the textbook of psychopharmacology published by the APA Press and now in its fifth edition. So please join me to welcome Professor and Dr. Nemeroff to talk about neurobiology and treatment of post-traumatic stress disorder. Well, I think I have a captive audience because there's a torrential downpour outside, and none of you want to go out in that, so I'm really looking forward to being with you. Okay. What a great audience, like all the – you have nothing better to do than hang out with me today? I'm going to talk for about an hour, and then I'm going to open it up for a free, willing conversation I'd like to have about post-traumatic stress disorder. As you know, Dr. Pai allowed me to get a little outside the box because PTSD is no longer considered an anxiety disorder. It's in a different category in DSM. But because a lot of my clinical work and research focuses on PTSD, and all those patients have a great deal of anxiety, I wanted to go ahead and talk about this with you today. So all of my research is supported by the National Institutes of Health. I've consulted with a number of companies in the last year that are listed here. I own stock. I hope all of you do. I owned less than I did a few weeks ago, so talk about stress. I serve on a number of scientific advisory boards, and I'm president of the Anxiety and Depression Association of America. So I want to start off and talk to you a little bit conceptually about psychiatric disorders in general, and then focus on PTSD. So this is a cartoon that I published in, of all places, Nature Reviews Cardiology, when I was writing a paper about depression and heart disease. And what you see here is... I'm just seeing that the pointer doesn't work. Okay. Yeah, it does. Okay, there it goes. It's fine. Okay, great. So here's the X-axis is the lifetime from birth to death, and the Y-axis is this odd axis that I labeled organ integrity. And what do I mean by that? Let's go over here, where we are all sitting and seeing patients that come to see us. And they come to us with various clinical manifestations. They're depressed. They're anxious. They're having nightmares. They're having problems with their memory. They're using substances. And we do our best to provide evidence-based treatments for them. The problem with this approach, which is largely the Western medicine approach, is by this time, many of our patients have an impairment in organ integrity. You could appreciate that in someone who has marinated themselves in alcohol. You could appreciate that with somebody who has plaques and tangles due to Alzheimer's disease. But we also know that every episode of depression changes the brain, and that the 10th episode results in patients less likely to respond than that very first episode. The same is true of schizophrenia and bipolar disorder. So conceptually, what I would like to suggest to you is our entire field needs to move back here to these two areas. One is an area of being able to identify people who are at risk for psychiatric disorders. If we could identify them, the truth is we cannot screen the entire general population, because there aren't enough mental health professionals. We don't have enough accurate screening tools to identify vulnerability. But if we could identify who is at risk, we could be proactive. We could intercede, and I'm going to talk to you about that today. And then maybe if that's not good enough, could we intervene right at the tipping point, before the first manic episode, before the psychotic episode? And if we knew who is at risk, could we intercede before the development of, in this case, post-traumatic stress disorder? Now, all mammalian organisms are hardwired in terms of the stress response. And this is a photograph at Fenway Park in Boston, and you see what's happened. A broken bat is heading their way, and there is a great stress response, right? You're protecting yourself. If we were able to sample these patients, their adrenal glands just contracted, a huge amount of cortisol just entered their bloodstream, their heart rate went up, the sympathetic nervous system. Indeed, stress responses are adaptive and hardwired, and they're two major parts of the mammalian stress system, the pituitary adrenal axis on the one hand, and the sympathetic nervous system on the other. Unfortunately, in the world we live in, untoward life events in the form of extreme trauma are increasingly more commonplace. Whether you're living in the Ukraine, or whether you're living in Buffalo, or whether you're living at Sandy Hook, or whether you were at the World Trade Center on 9-11, very unexpected traumatic events occur that are outside the normal repertoire of human behavior. We're not talking about being upset about minor events. I'm talking about life-threatening events that you either experience yourself that are witnessed. We've learned a lot, unfortunately, naturalistically, from 9-11. We have this criteria for what we've come to know as post-traumatic stress disorder. One of the points I want to make, which is almost never talked about, is distinguishing acute stress disorder, ASD, from post-traumatic stress disorder. The fact of the matter is, there's almost no one in this room exposed to an event like I just showed you at 9-11 that wouldn't suffer from acute stress disorder. The key here is that most people that have that acute stress disorder response fundamentally extinguish it and end up returning to the baseline level of functioning. It's the people who do not, that develop post-traumatic stress disorder, is the subject of what we're talking about. Let's start with the only diagnosis in DSM that is dependent on an environmental event, and that is post-traumatic stress disorder. You must have the criteria A stressor fulfilled, and I want you to broaden your concept of what that is. What it says here is an event involving actual or threatened death, serious injury, or sexual violence, or being exposed to it, such as witnessing someone get run over by a car while you're at the bus station or in the subway, learning about something that's happened to a family member of yours, and having it repeated to you multiple times. Now I want to just be very clear that there's ironclad data, not in DSM yet, that medical trauma fulfills the criteria A stressor. It's really important for those of you who work in a consultation liaison capacity, general psychiatrists, if you have a sudden myocardial infarction, if you suddenly run a high fever and are septicemic, if your appendix explodes, if you have a stroke, if you have a life-threatening medical emergency, like being in the ICU with COVID and being intubated, that is sufficient stressor to precipitate post-traumatic stress disorder, and it's not generally appreciated by psychiatrists, but not at all appreciated by non-physicians, and it's something that we all need to educate our colleagues about, and this is true about children as well as adults. The other criteria listed here, you're all familiar with them. I'm not going to go through it, but the intrusive thoughts criterion, which are memories of the trauma, nightmares, dissociative reactions. Those who have dissociative reactions at the time of the trauma are more likely to develop PTSD than those who do not. And then part of the intrusion is avoiding traumatic reminders. And then the avoidance criteria is I had a student at NYU who was a patient of mine. She couldn't return to the dorm room because she saw the planes from her window flying into the tower, and so she literally could not go back there. So avoiding trauma-related thoughts, they don't want to talk about it, they don't want to talk about it with their families. And then this sort of grab-bag criteria D, which is cognitive and mood symptoms, particularly related to shame, related to guilt about the event, some role that the patient might have had, as well as some symptoms that overlap with depression, like loss of interest in significant activities and some constricted affect. And then arousal. So this is the hypervigilance criteria, people that are scanning all the time, that are worried about never going out again because they were assaulted and it might happen again. Exaggerated startle, what you never do with a patient with presumptive PTSD is walk in behind them in your office and you never clap your hands. If you do, they lift off the chair about three feet. You don't want to do that. And part of the arousal is the sleep disturbance, which is one of the cardinal features of PTSD and one of the hardest actually to treat. And then the symptoms have to last for at least a month or longer. And then the usual caveats, exclusions, which are silly because a lot of these patients are already on medication, using substances, and it's really hard to determine whether they had any role in the syndromal diagnosis or not. So if you don't remember anything I say tonight, remember this. The PCL-5, which is the post-traumatic stress disorder checklist for DSM-5, is your friend. It takes a few minutes for the patients to fill out in your office. It's available on the website. It doesn't cost anything. And it not only gives you a measure of symptom severity, but it also helps you make the diagnosis because cut off of some people say 31, other people say 33, is consistent with the diagnosis of post-traumatic stress disorder. So I want to show it to you because it's your friend. It has 20 items, and they're scored from 0 to 4. So the highest score you can get is 80. That is if you pick extreme for every single symptom. And what's nice about it is that the questions are clustered according to the different clusters in the diagnostic criterion. So here you see the cluster B, which is the intrusive thoughts cluster. You see cluster C is the avoidance questions. Cluster D, as you can see here, is the cognitive and mood symptoms. And finally, the hypervigilance criteria. So if you use this, most patients who have PTSD will come in, and they'll have a score of 50, 55, maybe 60, and you're going to try to get them down to below 30, right, to at least no longer fulfill criteria. And you're going to give this to them every time they come to your office, and you'll be able to follow their progress, and it works like a charm. Well, how common is trauma exposure? This was an old study done before 9-11, and it turns out in the United States, trauma is pretty common. So this is the question of, have you been exposed to a criteria A traumatic event? And as you can see, about a quarter of the population in the United States said yes to one, and a third to another quarter said multiple traumatic events. Now, unfortunately, individuals in underrepresented sexual identity have much higher rates of both PTSD but experiences traumatic events. So that means that when I was talking about at-risk populations, individuals who are gay, bisexual, in the LGBTQ plus community are by definition an at-risk population for PTSD. If you look at the prevalence rates for men and women, ranging from heterosexual to the other remaining so-called sexual minorities, and that includes individuals that identify as heterosexual but have same-sex sexual partners, you can see this is almost as clear-cut as you can imagine. First, heterosexual women have more than twice the rate of PTSD than men, very clearly. But you see these sexual minority groups have inordinately high rates of PTSD. Now, one of the themes that I'm going to try to convince you of is that one of the major risk factors for PTSD is a history of childhood maltreatment, abuse and neglect. And you can see here, not surprisingly, that these groups also have much higher rates of childhood maltreatment. They have higher rates of interpersonal violence overall, and these are staggering numbers. The lesbian population, 60% have been exposed to interpersonal violence. Unwanted sex, I mean, it's just unfathomable. And then being attacked or beaten or being a victim of domestic violence or witnessing someone else being injured or killed. So please remember this when you're seeing patients, thinking about who's at risk. So this is sort of the classic textbook view of PTSD, which is of 100% of people exposed to a trauma, you know, a criteria trauma, you'll see a week after the trauma, everybody has acute stress disorder. The only difference between PTSD and acute stress disorder is the timeline. And you see what happens that even in the worst of traumatic events, the majority of patients get healed, they get better, they do well. Only about, I would say, a third of patients develop PTSD, two-thirds do not. So that's really important because we want to understand what is the trajectory. This is a more elaborate view of the course, and I just want to make, I'll put it here because I want to make a comment about it. So the bottom line here is that this is sort of standard PTSD. So here's the event in blue, and then you see this is the sort of standard recovery. People get better over time, depending on what the timeline might be here. There are people who have acute stress disorder and they just have PTSD, and they have chronic PTSD, and those are largely many of the people you see. This is a line that I think is neuromythology. You can't think of patients that I've seen over the years who had an acute trauma, had no symptoms after the trauma, and then a year later develop PTSD. We can argue about this during the discussion period. You can try to convince me that you've seen a lot of patients like this. I've probably seen 1,000 patients with PTSD. I can think of maybe two or three that actually showed this delayed pattern of developing this PTSD after six months, a year, a year and a half, without any intervening additional traumatic events. So who's vulnerable for PTSD? Well, let's start with women. Women are, like major depression, two to two and a half times more likely to develop PTSD after trauma. Those who have a history of child and adolescent trauma, particularly sexual abuse, physical abuse, and neglect, much more likely to develop PTSD after adult trauma. If you have a previous history of a mood or anxiety disorder, or if you have a family history for a mood and anxiety disorder and you're exposed to a criteria A trauma, you're likely to develop PTSD. If you have poor social support, either before or after the event, lower IQ and lower educational attainment, if you've already suffered with stressful events in the past year, or following the trauma. And then if you have this dissociative or severe panic at the time of the event, you're also more likely to go on to develop chronic PTSD. So let's look at some data about the development of PTSD after trauma. This is almost 300 U.S. veterans returning from Iraq and Afghanistan that we're seeing at the VA. Charlie Marmer, the chair of psychiatry at NYU, did this study, and I think it's really quite informative. What you're looking at here is, here's the beginning of the war, as you can see, and you see the rates at baseline of depression, alcohol use disorder, and drug use disorder, and PTSD. PTSD in the red squares, depression in blue, alcohol use disorder in orange, and substance use disorder in green. And so this is not an unusual point prevalence rate for these disorders. And then look what happens after the combat begins. So here's depression. We know that stress will precipitate depression in vulnerable individuals. So from 2003 to 2006, a three-year period, you see the prevalence rate of depression now is almost 14%. You can see alcohol use disorder going up to about 6%, substance use disorder to about 3%. But look at PTSD. Virtually no one had PTSD who's entering combat. And now look at this remarkable increase to a prevalence rate of 18%. It's not uncommon data relative to other studies have been done. Now, what characterizes PTSD in combat veterans? Well, they clearly do show deficits in learning and memory. And this is a study that was done, 26 Vietnam combat veterans, 15 controls, showing a very clear deficit in the Wechsler memory scale, both immediate and delayed recall, relatively simple memory tests. That began to raise questions about the hippocampus, which is of course the part of the brain for which memory is encoded. And a number of studies began to look at the size of the hippocampus in normal volunteers and in PTSD subjects. And as you can see from this diagram, it looks like the PTSD subjects have a smaller volume of their hippocampus. And the notion here was that the cells didn't degenerate, but they ended up with having pruning of their dendrites and their axons. So the dendritic tree, if you will, lost a lot of its arborizations. That was the hypothesis. So a study was done at Yale at the time looking at the volume of the hippocampus and combat-related PTSD in those same subjects I showed you. And you can see this reduction in hippocampal size. It's not huge, a couple of percent, but it was definitely measurable. And there was a relationship between the size of the right hippocampus and their performance on the Wechsler memory test. So that seemed consistent with the hypothesis. This is also true in individuals who are victims of domestic violence. There's a study of women who were, unfortunately, victims of sexual abuse. And you can see the relationship between the measure of PTSD severity, the CAPS, which is relatively equivalent to the PCL-5 that we talked about, and the more severe their PTSD symptoms, the poorer their performance in terms of their memory test. So we did a study of women who were victims of sexual assault who had PTSD and comorbid major depression. Their CAPS score was 77. That's about a 60 on the PCL-5. And they were also depressed. Their Hamilton score was 24. And what we did was ask them to, we studied them before treatment and after treatment, and we asked them to write an autobiographical script of their trauma that they read in the scanner at baseline. We could see how their brain reacts to this autobiographical script. And then we treated them with evidence-based prolonged exposure therapy, form of trauma-focused CBT, and then re-scanned them. This is one of the scripts I'm going to read to you from one of our subjects in Atlanta. It's 11.30 at night, and 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 my car, I'm grabbed around my neck from behind and pulled into the woods. My heart is absolutely racing with fear. 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 that I better do what he wants me to do or I won't ever do anything again. I can't believe this is happening. I can smell the alcohol and cologne all over him as he forces me to perform oral sex and it sickens me. Sweat is pouring off my body. I'm trembling for my life. Now he's trying to get out of his pants and he stumbles and falls backwards. Quickly I roll over and now I'm running just as fast as I can to the house. As he's chasing behind me, he's yelling, get back here, bitch, and I'm out of my mind with fear. Horrible, horrible traumatic event. That was one of the subjects in our study. We asked our subjects to rate the severity of these categories on a Likert scale from zero to 10. How anxious are you? How ashamed? How afraid? How angry? How vivid and how relaxed? Not at all. You could see the severity of the subject's symptoms. Here they are six weeks later after undergoing trauma-focused CBT and you can see they're clearly better. They're less anxious. They're less ashamed. They're less afraid. They're still angry, but not as much, but the memory is still very vivid. It hardly has been reduced at all. They're more relaxed, certainly, but they're certainly not totally relaxed. Then we looked at their brains and what we found was a change in limbic activity and I want to show you what it looked like. Fundamentally, they had increased limbic activity, particularly in the amygdala while they were reading the script, but after the six weeks of trauma-focused CBT, their amygdala calmed down and they didn't have as much of a response, indicating that the trauma-focused psychotherapy helped them extinguish the intensity of that trauma. Now, one of the biggest questions in the field has been whether patients with PTSD are capable of suppressing memories. This is an interesting study that was published in Science, which is the top-ranked scientific journal, in which they took individuals who had been involved in the 2015 Paris terrorist attacks and they asked the question, are individuals who are exposed to trauma with PTSD or without PTSD able to suppress a memory? So they taught them a new memory in the lab and then they went ahead and asked the question, who could suppress the memory? The trauma-exposed individuals without PTSD suppressed the memory without any difficulty. The PTSD patients couldn't do it. Even though it was a memory that was unrelated to their trauma, they have a defect fundamentally in memory suppression. Before we get to talk about treatment, which will be the bulk of my presentation, I do want to talk to you about the neurobiology of PTSD and some of the strides we've made in understanding this disease. Clearly, part of what PTSD is, is a stress response that's gone awry. Think about the way you feel when you're in the horror house on Halloween and you have that startle response when the scary monsters come out. Think about having that all the time. Your heart pounds at the slightest provocation. We look at this as a chronic overactivity of the mammalian stress system. That means focusing on the hypothalamic pituitary adrenal axis, which is the major mammalian stress system. It turns out this neurotransmitter called corticotropin releasing hormone is the orchestra leader of the stress response. It mobilizes and integrates the endocrine, the autoimmune, sorry, the endocrine, the immune, the autonomic, and the behavioral response to stress. We did some studies in which we showed that patients with PTSD have a hyperactivity of this stress system in the brain, showing elevations in cerebrospinal fluid of this brain's representative of the stress axis, these PTSD patients. We confirmed that in a second study, which we actually captured cerebrospinal fluid over a five-hour period using an implanted lumbar catheter. You can see compared to normal controls, there's a hypersecretion of this anxiogenic-depressogenic stress neurotransmitter in the central nervous system. We also know that early life experience predisposes to development of PTSD in response to adult trauma, and we've been able to show this both in humans and in animal studies, that early life stress sensitizes the stress system for subsequent stressors, and early life stress permanently changes the brain and the body, and setting it up for being pathologically involved in PTSD. So we did this study in Atlanta. We recruited about 500 African-American patients who were sitting in the emergency room, sorry, in the general internal medicine clinic at Grady Hospital, waiting to see a general internist. They were not psychiatric patients. They were a highly indigent group. You could see their income was terrible, and two-thirds of them were unemployed, and we administered a variety of tests to them, including measures of post-traumatic stress. In some studies, the post-traumatic symptom checklist I told you, and others, the post-traumatic symptom score, it's another measure. We learned a few things in this population. First, we learned that the more adult trauma you have, the higher your post-traumatic stress disorder symptoms are. So that shouldn't surprise you, in an almost dose-response relationship. Secondly, the more childhood trauma you have, the more severe your PTSD symptoms. And then, no surprise to any of you, child and adult trauma are additive, and you can see that the patients who had the most adult trauma and the most child trauma had the most severe PTSD symptom scores. So now, I'm going to give you a three-minute precis on genomics and epigenetics. Everybody in this room has a genome that you inherited from your parents. It is immutable. It cannot be changed. It's yours for a lifetime. Every cell in your body has the same genome, and we all together have about a 99% homology of our genome. But the 1% that's different is because some genes occur in different forms, and those are largely called single nucleotide polymorphisms, or SNPs. And these are just mutations that have occurred, and there are about millions of them in the human genome, and it's what makes us all unique and all different, because some of these variants in the genes change gene expression and result in changes that are very simple, like height and weight and artistic talent and IQ and temperament. So that's one way to show genetic differences. And you can see the nucleotide base pairs here, and this is just an example of a mutation of this one gene that switched the nucleotide sequence. Remember, there are only four letters in the genome that make up the triplet code that codes for amino acids and make proteins. And here's what the DNA looks like, as you know. And so there is a gene, you don't have to remember the name of it, called FKBP5. It regulates the effects of cortisol, the major mammalian stress hormone. So we asked the question, of all the variants in that gene, which I'm pointing to here, do any of them interact with child abuse and neglect to increase or decrease one's vulnerability to develop PTSD after trauma? And we found these four variants of this gene that modifies the action of cortisol actually determines whether or not you're going to develop PTSD after you're exposed to trauma, if you're a victim of child abuse and neglect. And here's what the data looked like. Here are two of those genetic variants. You can see in the absence of child abuse, there's no increase in risk for PTSD as a function of which gene variant you have in either of these two SNPs. But in the presence of child abuse, look at the difference. One appears to be a protective element, and then these two are very serious vulnerability genes. And these are the genetic variants themselves, because those are the nucleotides. So we were very curious about this, and we wondered how is it that a gene variant can interact with child abuse and neglect in order to change your vulnerability to PTSD? And so the way most gene expression is altered is not by those sequences I talked to you about. It's by a process called epigenetics. And epigenetics is a really critical process in the body for reasons you'll understand when I tell you this. So every cell in the body has the same genome, and we know there are about 23,000 genes. But every cell doesn't express every gene. You don't want your brain cells expressing liver genes, right? And you don't want your liver genes expressing brain cell genes. So there has to be a process to regulate what genes are being expressed in individual cells. And there are proteins called histones that circle the DNA in each cell, and they can cover up the gene sequence so it can't be expressed, or they can open it up. And that's controlled by a process called methylation and demethylation. So we thought that's probably the mechanism. So we looked at this polymorphism, this SNP in the FKBP5 gene, and we looked at its methylation as a function of child abuse. And lo and behold, we published this paper in Nature Neuroscience. We found that the severity of child abuse, as measured by the Childhood Trauma Questionnaire, was related to the amount of regulation of gene expression, namely the methylation, only of this vulnerability gene, this FKBP5 risk allele. That's the mechanism by which this gene variant controls your vulnerability to develop PTSD if you're a victim of child abuse. So I gave this talk to a group of donors, because I'm always trying to raise money for child abuse and neglect research. And this woman said to me, I don't understand a word you said. I mean, I just don't have any clue. Could I make a movie for you explaining? The fear from my past, I carry it with me. Can I ever recover from what you've done? Cause you marred expression of my tears, while I was demyeloping. Mist of mountain circuitry, you ruined me. Later when the stress comes on, my HPA is not that strong. I cry when there is nothing wrong. You ruined me. Nothing wrong with ATGC. Just a broken MEG. It's killing me. You marred expression of my tears, while I was demyeloping. Mist of mountain circuitry, you ruined me. Later when the stress comes on, my HPA is not that strong. I cry when there is nothing wrong. You ruined me. Okay, so I'm going to tell you about one last gene, and I'm going to switch to treatment. We're going to talk about treatment the rest of this time. There's one other gene called the PAC-1 receptor, which is a gene for this neurotransmitter. And the only reason I mention it to you is because in our studies, this is not me, but my students, it looks like for women, variants in this PAC-1 receptor gene actually are a major contributor to developing PTSD in individuals with a history of child abuse and neglect. That's the data. It had no effect in men, but a huge effect in women. And this was done in two separate samples, an original sample and a female replication sample. So that's getting to the issue of who's at risk and can we identify at-risk populations. And now we're going to talk about treatment. And PTSD is a tough disorder to treat. And there are psychotherapies that are evidence-based. I'm going to talk about them. And then there are pharmacological treatments. And then there are some newer treatments that I'm going to at least mention to you. The goals of treatment are obvious to you. And there are two theoretical frameworks that have been somewhat oppositional in recent years about the understanding, the psychology of PTSD. One has to do with the school of thought that fundamentally says PTSD is a disorder of extinction, that most of us who suffer a traumatic event, we subsequently venture forth, and over time we learn that the world isn't quite as dangerous a place as we thought it was in the immediate aftermath of trauma. We extinguish what we learned in this traumatic event. The other school of thought has more to do with generalization of anxiety, so that patients not only become anxious about potential traumatic events, they develop generalized anxiety, and they develop anticipatory anxiety. And that's different, more of what you see in generalized anxiety disorder. So what to do when the patient is sitting in your office? You're on the antidepressant highway or the psychotherapy highway, and you're trying to decide what are you going to do, right? So Barbara Rothbaum and her colleagues at Emory have provided pretty good evidence that in terms of early intervention, very brief CBT, just four to five sessions, is beneficial. Obviously social support and psychoeducation. Remember, this is acute stress disorder. It's not PTSD. These are people in the immediate aftermath of trauma. What might be helpful might be groups. Spiritual support may well be helpful. But there are things that are not helpful. One of the things that we learned during 9-11, where every well-meaning mental health professional on the East Coast fled to 9-11 to take care of all the victims. Remember that 65% of the victims were never going to develop PTSD. But those that were forced by these well-meaning mental health professionals, they were forced to relive the trauma over and over and over again, ended up developing PTSD at a higher rate that didn't have any intervention. So you need a dose psychotherapy the way you would dose medication. It's not benign, right? You need to think about it. The things that definitely do not work are I'm going to talk to you about prazosin, which many of you probably prescribe. I'll show you the data. Antipsychotics, propranolol, tricyclics. We'll talk about antidepressants. I'll show you the data. The best data is for trauma-focused CBT, also called prolonged exposure. This was invented by Ed Nafoa, now at the University of Pennsylvania, along with Barbara Rothbaum at Emory. This is also known as trauma-focused cognitive behavior therapy. Multiple studies have shown it to be effective. There's no question about it. It can involve imaginal exposure. It could be done using virtual reality exposure. There's no question that the various components, including education, relaxation, and cognitive therapy together are effective. Many years ago, 20 years ago, all the studies were reviewed. All 12 were positive. 8 of the 12 got an A rating. There's no question that this works. But it needs to be provided by somebody who knows how to do it. Going for a weekend course isn't sufficient. You need to find a psychologist or a psychiatrist in your area who is really well-trained in developing either CBT or the second evidence-based treatment called cognitive processing therapy, developed by Patty Resick, now at Duke. The fact of the matter, it's effective. It's a little less difficult than trauma-focused CBT or prolonged exposure because it's a little less hard on the patient. But it's also very effective. This was a study that was done. Asked the question, could you deliver it in groups or does it have to be done individually? Interesting question in terms of health services delivery. This was a VA-funded study of 268 active-duty service members, and the bottom line was group didn't work. Delivering CBT in a group setting was not anywhere near as effective as individual CBT. My guess is it's all about your relationship with the patient. All of you know that that immeasurable relationship that you have with the patient and the patient knowing that you care about them and that you're partners and trying to help them get better, you don't get that in the group setting. So the answer is no. You can see the PCL-5 scores. I just want to point out to you in this study the patients came in at a 55. Okay, all of them. There's the group result. They get down to about 47. And here's the individual. They get down to about 43. But remember, here's the diagnostic cutoff. These patients aren't well. They're better, but they're not well. I'm going to skip this for lack of time. It's just another psychotherapy study. So bear with me. This is one of my favorite studies. Published in the New England Journal of Medicine. It's a study of evidence-based psychotherapy delivered in the Congo. So these were 16 villages in the Congo in which cognitive processing therapy was going to be delivered compared to just support to women who were victims of sexual violence. And they had very high levels of PTSD symptoms and depression. And so 157 women received the active treatment, and 8 villages, 248 women, received the, quote, support. And so 65% of the women completed the therapy group, 52% the individual support group. And the bottom line is a picture is worth a thousand words. So the results were extraordinary. So here's the depression and anxiety scores. You could see that the women, after six months, had a marked reduction in anxiety and depression. And here's the PTSD symptoms as well compared to simply individual support, which I always call a rent-a-friend, right? Rent-a-friend. Now let's talk about medication. There are two FDA-approved medications for the treatment of PTSD, sertraline and paroxetine. Here's the original submitted data to the FDA for sertraline compared to placebo. This is using a relatively liberal criteria for response, a 30% improvement in that CAP scale I mentioned. So clearly the sertraline patients did better in both pivotal studies than placebo. And in terms of quality of life, the standard scale, the QLESQ, a big, big effect of sertraline in all of these subscales of quality of life. Now one of the minor pearls that I'm dispensing to you today, PTSD takes much longer to respond to medication than depression. You've got to stick with the patients. Here's a nine-month study that Jonathan Davidson did looking at sertraline. And look at the HAMD scores, and this is another, this is a Davidson trauma scale, a PTSD scale, at baseline three months and nine months. Look at the difference between nine months and three months. It's very palpable. So clearly it takes a longer time for these medications to work, and look at the measure of quality of life. So you have to stick with it for quite some time. It's not like the eight weeks that we see in treating simple major depression. One study reported that if you combine prolonged exposure therapy with sertraline, you get an even better response compared to sertraline alone. There wasn't a prolonged exposure arm alone in this study to compare it with. Then there's paroxetine, also approved by the FDA. Here are the CAP scores, placebo, and then 20 or 40 milligrams of paroxetine, clearly effective, no doubt about it. And if you look at response using the CGI, again, much better response with the two doses of the SSRI compared to placebo. And remission, which is defined a little liberally here, the CAP score under 20, probably could have been under 10, in studies of paroxetine, and then surprisingly, the only Prozac study ever done showed a decent effect as well. It's never been followed up on. If you look at the, again, quality of life scales using the Sheehan Disability Scale, paroxetine has a profound effect on the overall scale, but in the work, social life, and family life as well. One study with mirtazapine, I will say it does help people sleep, but it does, of course, cause weight gain, showed a significant effect. It's the only study ever done in PTSD with mirtazapine. Well, the paroxetine manufacturers were kind enough to include in a subset of their patients an MRI study of the hippocampus in the patients that were treated with paroxetine with PTSD. And remember me showing you the reduction in hippocampal size in patients with PTSD. After one year of treatment, look at this increase in hippocampal volume. This is an increase in their memory performance, right? So you remember their memory performance was decreased. After a year of treatment with paroxetine, their memory performance improved, and damned if their hippocampal size didn't improve as well. So that was associated with the improvement, a clinical improvement. The other antidepressant that has received a lot of attention but is not FDA approved is venlafaxin. I would say it's my drug of choice for treating PTSD. I like it because it has a wide dose range, and I can go from 75 to 150 milligrams at the low end to 450 and even 600 milligrams at the high end. And I've had some amazing successes with this antidepressant, and in this study it actually beat sertraline in terms of efficacy. And the number of symptom-free days that patients had was increased with venlafaxin compared to sertraline and placebo. This is the scorecard of SSRIs in the treatment of PTSD, and this favors the SSRI. This favors placebo. You can see the overwhelming evidence is that SSRIs are effective in reducing PTSD symptom severity. And then the venlafaxin folks did a larger study. I'll just show you the data. It was a six-month study, and again you see this very nice reduction in CAP scores. So they went from about 70 down to about 20, which is a pretty remarkable effect. And this is the remission rates, which, as you can see, were higher than what we saw with the sertraline or paroxetine data. Don't. Don't use Xanax. Don't. It's the worst choice for PTSD that you can imagine. This is a population at risk for substance abuse. It has a short half-life. There's a lot of rebound anxiety. If you're going to use a benzo, I don't particularly recommend it, but some of my patients are on clonazepam, which is a long-acting benzodiazepine, but don't. Okay, what about ketamine? Many of you know that I'm not a big fan of ketamine. I've been extremely critical of the depression work, and I've been extremely critical of the S-ketamine approval by the FDA. I think I have real issues with the data that was presented, but I feel compelled to say there were two studies of intravenous ketamine in chronic PTSD. This was the first study, the standard dose of a half milligram per kilo compared to midazolam, and they found a greater reduction of PTSD symptoms with ketamine than with midazolam, and a reduction in cobarbid depressive symptoms. But again, I just want to show you the magnitude of the effect. Here's midazolam. All of you know that for when you've had a colonoscopy, unless you're a propofol fan, you know. And here's the ketamine effect. It's definitely effective on day one. By day two, you're losing some of its effectiveness. And here's by day seven. In my experience, by day 14, the patient's pretty much back to baseline. This is the second study that was published very recently by the same group, and it showed similar results. Now, what are we looking at towards the future? This is the most exciting finding in the PTSD world, and that is the MDMA-assisted therapy. You know MDMA is classified as a psychedelic, also known as an intactogen. It's not like psilocybin. It's a drug that's typically called ecstasy. It was a drug that was used to presumably improve empathy. And the MAPS group conducted a placebo-controlled phase three trial. It's the largest study ever done with PTSD, where patients were randomized to receive manualized therapy with MDMA or with placebo. It was really a very well-done study, and the magnitude of the effect was quite large. And so they're going to be moving forward asking for a FDA approval of MDMA in the treatment of PTSD. Lots of questions remain, but we have to go with the data. It's an impressive data. And this was the protocol in which it's a little hard for all of you in the back to see, so I'm not going to go over it with detail. You can read the article, but fundamentally there were three treatment sessions, lots of psychoeducation beforehand. But here's the results, looking at the BDI, Beck Depression Inventory Scores, the CAP Scores, the She and Disability Scores. And I don't think you have to be a statistician to figure out the red line looks a lot better than the blue line. It's a very clear and highly significant effect. I believe there will be a role for MDMA in the treatment of PTSD. There may also be a role for TMS. There's never been a study of accelerated data burst TMS, but this study was conducted, a small study, 20 subjects, but it was a sham-controlled study, and it found evidence for efficacy, which then, after a full course of six weeks of treatment, started losing its effectiveness two months later. This is a study we did showing that ECT in patients with comorbid PTSD and depression was more effective than medication antidepressant treatment. This was a large retrospective study of several thousands of patients in the VA, but what impressed me the most about this study was remarkably reduced mortality, from suicide but also from cardiac mortality after treatment with ECT. So I think ECT in patients with comorbid depression and PTSD is something you should think about. Well, you know, the surgeons had to get involved, or at least the anesthesiologists, so this notion has been introduced that you could block sympathetic nervous system activity by injections into the stellate ganglion in the neck in order to block the sympathetic nervous system. I know all of you would like to set this up in your office, and you would have a procedure, right? This could be cool, right? So there's one study that's been done. It was published in JAMA Psychiatry, and I'll just describe it to you. It was a multi-center blinded sham procedure in which, in a two-to-one ratio, patients received stellate ganglion blockade or sham injection performed by an anesthesiologist, but the nurses and the patients were blind to which intervention they were getting. They used the PCL-5, and their cutoff to admit the patients was the 32 or more, which is not unreasonable. So they decided to pick an outcome of 10 points or more on the CAHPS as their improvement, and I could argue with those results as to whether I would think that's a reasonable definition of response or not, but the bottom line was they did find efficacy, but I want to show you the data. So here's the CAHPS-5 scores, and so they used the PCL-5 for the entry, but the CAHPS for efficacy. So this is the baseline measures. They're at about 40, and then here are the patients at week 8 after getting two of these injections in their neck, and this is the difference between sham and stellate ganglion block. So you go from about a 40, 38 to about a 28, so it's about a 10-point drop in the CAHPS. It's not the most robust effect I've ever seen, but it's better than the sham treatment, but remember the sham treatment dropped about 5 points. So it's interesting. If stellate ganglia blockade works, then why doesn't other drugs that block the sympathetic nervous system work, like propranolol and other beta blockers? So in the last couple of minutes, I just want to talk about what to do, what to do. So sleep problems is a problem, and this is a group that has a high rate of substance use disorder comorbidity, and so you're sort of stuck. I tend to use trazodone. I tend to use mirtazapine in folks that weight gain won't be a problem. I don't use gabapentin at all, and then, of course, there's the parazepine, and, of course, I try to make sure that our patients don't have obstructive sleep apnea. So this is a study, the follow-up study to the famous Raskin study in the American Journal of Psychiatry that said that parazepine was the answer in terms of reducing nightmares, improving sleep quality. This was a wonderful study of 13 VA medical centers that randomized patients to parazepine or placebo, 20 milligrams. they could increase the dose to 20 milligrams in men, 12 milligrams in women, which are pretty heroic doses. 304 patients, randomized half to paralysis and half to placebo. At 10 weeks, there was no difference at all in the CAHPS score, so it didn't improve PTSD at all, which you worry about because of the sleep disturbance part of the PTSD symptom severities, but there was also no difference in any of the sleep measures. So this is really disturbing, right? So here's the distressing dreams item, no difference at all after 26 weeks. The Pittsburgh Sleep Quality Index, no change at all between placebo and parazysin. And their CGI score, no difference. So the conclusion was that parazysin was ineffective. So I don't use parazysin anymore. Now there may be a placebo effect. So what do you do when you're confronted with the patient with treatment-resistant PTSD? So there is data that some patients, even with chronic PTSD, will spontaneously recover. There's no doubt that either a cognitive processing therapy or trauma-focused CBT should be a component of the treatment. EMDR is of mild to some would say moderate efficacy, I would say, there's evidence for mild efficacy in some patients. It was a study done that compared EMDR with giving patients the Tetris Game Boy to play, and it did just as well as EMDR. And I think EMDR is distracting patients, which may be a good thing. Please continue your pharmacological trials way out beyond what you normally would. Address comorbidity, get urine drug screens, and try to use CBT-I for patients for which insomnia is a big deal, right? There is, I don't have time to talk about the subtype of complex PTSD, but patients with a history of child abuse and neglect and chronic PTSD are unusually treatment-resistant. And then there are all these silly little randomized trials on the left showing some efficacy for, I mentioned metazapine, some antipsychotics, pregabalin, tapiramate. And then on the right, all of the negative trials with some of the same agents. So not very helpful to you. And then everybody has seen these open label studies where everything works, right? Cannabis is probably not a good choice. So I think until we really understand the underlying neurobiology of PTSD, we're stuck with a situation in which most of our patients get better, but they don't get well. So don't use Alprazolam. Use clonazepam if you have to. Be careful about forcing patients in the immediate aftermath of trauma. You should use an SSRI or SNRI. Unclear about atypical antipsychotics. Curious about lorazodone and lumatepirone because of their unusual qualities. And let's think about TMS and ECT. So I'm going to stop there. Thank you very much. Thank you. Thank you so much. This is certainly cutting edge and the most current information we're getting in terms of neurobiology and treatment and diagnosis. So now we're going to open up for questions. And please, if you have any questions, use the microphone. Hi. I'm Linda Hotchkiss from Detroit, Michigan. Large medical group. Two questions. One is, do you see any difference in the age of women, usually women, who have been abused, do you see any difference in terms of their response to treatment based on their age? Younger versus older. And then... Let me answer that first because I'm never going to remember it again. Okay. I'm beyond the point of remembering two questions. So first, age is a critical determinant. And just to start off, understand that women who are abused before puberty likely develop depression and symptoms of PTSD, whereas women who are traumatized after puberty tend to develop primarily PTSD. Secondly, there has never been a study, a randomized clinical trial in either psychotherapy or pharmacotherapy where comorbid depression and PTSD were studied. Because the FDA insists on indications for a single entity, companies are forced to recruit patients with PTSD only or depression only. And the issue of childhood maltreatment is a particularly difficult one because in and of itself portends for poor treatment response. And companies, it's been somewhat of a comical dialogue I've had with companies in which I've pointed this out and said, you know, if you don't take into account a history of childhood maltreatment, you're going to confound your study because it's possible that the different groups would have different rates of early life trauma. And their response has been, well, if they have a poor response, we should just eliminate them from the studies. Oh, well, that's really helpful. So there's never been a study done of women, or men for that matter, with a history of childhood maltreatment who have current PTSD or depression. And because they have a different biology, we just don't know how to treat them. Second question has to do with resiliency. What's your theory about people who have gone through tremendous trauma and it's been so great you would expect them to have PTSD but they don't? I think my answer is sort of like, reminds me of my Uncle Willie, who smoked, you know, four to five packs of cigarettes a day and never had lung cancer or any lung disease. I think sometimes you've just got to be lucky. And I think those people are not genetically able to be depressed or develop PTSD. I'm not sure they don't develop other things. Resilience is a really hard thing to study because it's the absence of pathology. And so it's very hard to find those subjects because they don't come for help, right? I have seen patients who've told me about horrendous life stories who never got depressed, who were coming to me for some other reason, people who went through the Holocaust, for example. And they were angry, they were irritable, they were sad, but they never developed syndromal depression or PTSD. So it's probably genetic, probably has to do with temperament. In the back. Yeah, so I'm an addiction psychiatrist. And in treatment of women who get sober, I mean, it just has blown me away, the percentage of women who have childhood sexual or other kind of abuse. I've always thought of them as having chronic PTSD. Although I was really interested in the way you were presenting the data. You were presenting it more as women, well, anybody as an adult who has PTSD is more likely to have worse PTSD if they have a history of child abuse. So I'm not sure if it's just a matter of nomenclature or if I have to adjust my thinking about whether what I was looking at was chronic PTSD versus character disturbance based on the early experience, et cetera. From what you just said, I don't think you're going to have any data for this, but I'd like to hear your thinking about it. So I just saw a patient last week who was a 23-year-old woman who was brought up in a middle-class to upper-class family in North Carolina who had an extremely abusive mother, and eventually Child Protective Services removed her from the home. And her parents were divorced for some time when she was given to her father. And she comes to me, and she's in an abusive relationship. She's being sexually trafficked by her boyfriend. She takes whatever drug he gives her and has taken as much as 20 milligrams of Xanax in a day, has used opiates, and fundamentally fulfills criteria for PTSD, major depression, dependent personality disorder. And she said something as an aside that no patient had ever said to me. She had a lot of tattoos, and I commented on them. She said, I don't really like them, but I like the pain that I get when I get them, and it's better than cutting myself, which I thought was sort of an interesting clinical, like educating me, right? So the way I think about this is I think that those patients you're talking about have a totally different brain and body than the patients who have PTSD or depression without a history of child abuse. And I can tell you their brains look different. They have high inflammatory markers, and we have no data to know how to treat them. My dynamic training would suggest to me that these are the kind of people that would probably benefit in addition to pharmacotherapy with a more psychodynamic approach if they had the ego strength to tolerate it, because fundamentally this woman has no ego, and I think it's a consequence of the trauma and then the adult trauma. Yeah. Parenthetically, some of them do very well in 12-step recovery, so it kind of fits what you're saying. Yeah, but the problem is their relationships, right? And they end up engaging in risky sexual behaviors, and the drugs are just, you know, you can't get better if you're using opiates. Thanks. Thank you. Thanks. Mike Cooper, a psychiatrist from Victoria, B.C. I recently worked a couple of years in a treatment facility focusing on military veterans and first responders. Our main treatment modality was group cognitive processing therapy, so I was a bit concerned when I heard your comment about that, especially given the numbers of people, individuals, who will need something like CPT and group would be perhaps, you know, make a bit of a dent in that. Also, I noted that the study, the COGGO study, was group-based. I wonder if you might have any further comments on group CPT. So you're an astute observer. You get the gold star today. We also got good response. That's the other thing. It was really a great working situation because after 12 weeks we were able to document good results. We didn't publish anything, but we should have. So the short version of the story is the group cognitive processing therapy study showed that individual was superior to group. It wasn't that group was worthless. It was certainly better than the waiting list controls, but individual was better. The COGGO study was really interesting because the severity was higher than most other PTSD studies, and secondly, the therapists were bachelor's level lay therapists that were trained by the investigators to deliver therapy. They were not psychologists or psychiatrists, so a very different population. So, you know, Patty Resick is sort of the CPT god. She's the one who developed it. The CPT and the CBT people don't much like each other, and I just sit back and watch the wrestling match. But, you know, I would say CPT group therapy is better than no therapy, and it's a numbers game, right? I mean, how many people can you treat at a time? So, good point. In the front, please. Yes. Oh, okay. So I actually also had two questions. The first one is I saw you mention that – sorry, I'm Esther Kelly-Cook. I'm from Houston. Hi. But you mentioned using venlafaxine up to 600 milligrams, and I was wondering if you have any kind of, like, clinical tips on when you choose to use a dose that high, if there's any special things you document or monitor other than blood pressure. So, you know, the point is that the PDR is based on the studies that were submitted by the FDA to the agency, and so the recommended doses relate to those measures that were reported. In the original venlafaxine studies, dosing was actually as high as 375 milligrams in the IR studies, right? But when the company conducted the XR studies, they didn't go any higher than 225. And so that's what the label says. I've just seen a tremendous dose-response relationship if you're willing to go slowly, right? And so I think at best you could document in the chart that you're going above recommended doses, that the patient has no side effects, that their blood pressure in particular is unaffected. But I have, I'd say, three or four patients that are getting 600 milligrams right now. These are the kind of people that at 225 I say, like, are you having any side effects? And they go, I don't feel like I'm taking anything. They're probably rapid metabolizers. Okay, fair. The second question was, and I wrote this down so that I could try to phrase it in a way that makes any coherent sense. So lately I've been reading the book that everybody tells me I needed to read called The Body Keeps the Score. And one of the things that he talked about in there, which was kind of like an interesting theoretical idea, was when he was talking about PTSD, he mentioned, you know, something we all see clinically, which is like people are very emotionally numbed and have a lot of anhedonia. And so he mentions in this book, if we have a bunch of people who are emotionally numb and have a lot of anhedonia, if we use a prolonged exposure therapy to then desensitize them and decrease that amygdala response, is that a good thing and does it help that symptom? Or is there something else we need to be doing in addition to that to also help that symptom? And that's about as coherent as I can make that question. It's a politically contentious discussion. So, you know, Bessel has made contributions to the field, and I think books like that are very helpful for patients and for practitioners to understand PTSD. But he's not a scientist. He doesn't conduct studies. He doesn't conduct trials. He's sort of a theoretician. And so that's an open-ended question that you raised. Yeah, and mostly I want to know what are your ideas on this theory? So, you know, there's a concept that patients bring to me that I'm sure they brought to you called muscle memory, and patients will talk about this, and I don't know what to make of it, right? I think there are a number of somatic symptoms that patients have who have suffered with trauma, right? And the comorbidity with medical disorders, 60% of women who have IBS have a history of childhood maltreatment, right? There's this link between irritable bowel syndrome and other functional GI disorders. That's not true with ulcerative colitis. It's not true with Crohn's disease. It's true with irritable bowel syndrome. I believe it's probably related to the lingering inflammation that child abuse and neglect has, and I think every time you have a traumatic event, you end up with an inflammatory response, and that inflammatory response affects your body, right? There's a reason why PTSD patients and depressed patients are at risk for heart disease, stroke, diabetes, and a whole bunch of different cancers, right? So it's not just a brain disease. It is a body disease, and that way he's right. So how to treat it? There's never been a study of any inflammatories of any kind of PTSD. People are just beginning to even measure inflammatory markers. Yeah, so the question wasn't actually about inflammatory markers but about anhedonia and desensitization of, like, enjoyable activities and things like that, and when you mentioned the other study, it didn't list that as things that had necessarily improved. I didn't see it on the diagram. So the question was do you treat that with something else? So, again, the field is in the midst of a controversy about whether anhedonia is fundamentally the same across diagnostic categories. So I want you to think about melancholic patients or PTSD patients, on the one hand, who have anhedonia and schizophrenic patients of anhedonia. Is that the same, and could it be targeted the same way? You know, most of us would say that drugs that increase dopaminergic availability are the best for treating anhedonia. Pramopexol is probably the drug of choice, high doses of sertraline, and maybe monoamine oxidase inhibitors, but that's an unexplored area. Thank you so much. Hi. So psychiatry is kind of a new field as a specialty for me, so this may be elementary, but I'm baffled. I am seeing, on an outpatient basis, adolescents, and one in particular with a known history of trauma as an infant, taken from the home, in now a safe environment, 13, but presenting with anxiety, depression, hypomania, OCD symptoms. I'm having trouble prioritizing. I would like your thoughts on how to prioritize when you have a huge ball of wax with trauma kind of at the center. Thank you. So you're starting off with, like, a really easy patient. So the symptom that you mentioned that's the first, in my mind, that has to be dealt with is the hypomania, because it's going to determine whether you think this person is bipolar or not, and that's the most important branch point decision you are at this moment, because treating them with an antidepressant compared to lithium or a mood stabilizer is going to be a game changer for them. So the critical question there is, and it's a singular question, is have you ever had a period of time in your life when you had a decreased need for sleep? Not that you couldn't sleep, and it had to be in a period when you were not using substances. If the answer is yes, that I slept three or four hours and I woke up totally refreshed and I was ready for the day, then you have a diagnosis of hypomania and probably bipolar 2 disorder if they fulfill the other criteria. If the patient says no, it's never happened, then they don't have bipolar disorder. So once you make that cut, then you're left with the trauma, you're left with the anxiety, you're left with the depression. And remember, adolescence is a time of turmoil anyway, right? And remember, that person's brain is not going to mature until age 24. So you've got to be thinking, how am I going to deal with this in a systematic way? They're going to need therapy of some kind, for sure, and a therapeutic alliance with you and perhaps someone else. Most likely, if you're sure they're not bipolar, you're going to start with an SSRI or another antidepressant. Our time is up, so I'm sorry that we need to adjourn the meeting. I'll stick around. And then maybe you can pass the number off. Thank you.

PTSD

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DSM

PCL-5

symptoms

risk factors

cognitive behavioral therapy

pharmacological treatments

medications

well-trained therapist

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