All right. We'll do. Good afternoon. I'm John Lowe, one of the members of the Scientific Program Committee. It's with great pleasure to welcome you to talk on anxiety disorders with Dr. Rapoport, who is the CEO, you can see here, of the Huntsman Mental Health Institute, and the William and Edna Simpson Presidential Endowed Chair, as well as Professor and Chair of Psychiatry at the University of Utah. He's also been past Chair of Cedars-Sinai, as well as Emory. But really, I consider him to be one of the rock stars in our field, but more so, I'm happy to call him both a colleague and a friend. So, Dr. Rapoport, take it away. By the way, his slides will be available on the slide deck in the app. Thank you very much, John, and thank you for the introduction. Good afternoon. Good afternoon. I couldn't hear you. Good afternoon. Good afternoon. Awesome. I could almost hear you. That was great. It's a pleasure to be with you today, and boy, what hearty souls. All of you at the very, very end of the meeting. I am so impressed. I really am. So, I gave this lecture last year in New Orleans, or something like it. It's actually different from the one I gave in New Orleans. So, I got this email, and the email said, well, you've been asked to give this lecture. I didn't respond. The email said, oh, you've been asked to give this lecture. I didn't respond. Ed Pye calls me up and says, Mark, we've been trying to reach you. We want you to give this lecture. And I said, but Ed, I gave it last year. Why would I? Anyone want me to give a lecture again this year on anxiety disorders? And he said, well, we'd like you to do it, but you can change it any way you want. So, I did. And so, one of the things you'll be seeing at the beginning of the lecture is really more about how I treat people when they come to see me in my practice, and how I treat individuals, particularly folks with anxiety disorders. And so, we'll start with that, and then after that, we'll go through and review again what we know in terms of the current state of the art, both in terms of psychotherapies, acute treatment of psychotherapies, and long-term treatment with psychotherapies. We'll talk briefly about what... Oh, you want me to stand taller? No, you want me to speak into the microphone more. I'm so used to a lavalier, and they don't have that. So, I apologize for that. And keep reminding me, because I can tell you, I have a very soft speaking voice. But I have a very loud singing voice. LAUGHTER I'm not kidding. And if you're really bad, I'll do that. Anyway... So, what we'll do is talk about what we know about psychotherapy treatments, acute and long-term. We'll talk a little bit about technology and where we're going there, and what we know and what we don't know. Then what we'll do is talk a little bit again about our current approved treatment choices, potential treatment choices with medications, looking at where we can be going. We'll talk a little bit about using somatic treatments, a little bit about using alternative approaches to treatments, and then some really cool research going on, looking at new ways of conceptualising anxiety disorders in their treatments. So, why don't we rock and roll? Assuming I get the slides to work. Aha, I've got one of these things. So, as you can see, analysis didn't work for me. I'm highly conflicted. All with NIH funds. These are my collaborators. The best work and the best material you see really are the result of these wonderful partnerships, and I really commend these people and their work to you. So, let's rock and roll. As we discussed, we're going to talk about how I care for patients, review the current interventions available, describe some of the potential emerging interventions, and then what we're going to do is talk about why the future is cool and why the future is so bright in our field. But, you know, anxiety disorders are truly a big problem. You know, the pre-pandemic prevalence rate in 12 months was almost 13% of individuals. The lifetime prevalence rate is over 34%. There's a sex difference with women being twice as likely, almost as men, of developing certain forms of anxiety disorders. The lifetime prevalence on pre-pandemic of the common anxiety disorders are listed there. But what's really disconcerting is that these disorders are disorders that have a median onset of age of 11. They affect our children. And once they begin to affect our children, they affect one's ability to get a good education, to have normal sort of engagement with other kids. And they don't just affect that child. They affect the dynamics in the entire family. The parents worry about the child. Once they figure out what's going on, the other siblings are affected by it as well. So it's really important for us to diagnose early. It's important for us to try and prevent the development of these disorders. There's a tremendously high rate of disability with the workplace cost estimated at over $4 billion a year. You know, many years ago, a very famous senator from Illinois said, a billion dollars here, a billion dollars there. Pretty soon, you're talking about real money. And if you think about that, the productivity lost for people with anxiety disorders equates to one week per month. So there's a tremendous loss, both in absenteeism and presenteeism associated with it. One is more likely to develop other medical conditions, and one is more likely to have more complexity and difficulty in treatment if one has an anxiety disorder and other comorbid medical conditions. And, of course, the COVID pandemic did nothing but make this worse. So what I want to do now is spend a few minutes talking to you as a clinician. And, you know, my thoughts are that people suffering from anxiety disorders, you know, our patients, they feel out of control. Just think about when you... Just out of curiosity, don't raise your hand. Keep your hand down if you did not feel, at some point during the pandemic, out of control. I did. So everybody did, right? Most people felt out of control? All right. So you know what our patients are going through. And just think about how those feelings are magnified in our patients. They feel out of control. They have... If they have panic disorder or agoraphobia, frequently they have the fear of the fear. They have the anticipatory anxiety and fear about having the panic attack that's limiting their lives so much. People with social anxiety disorders, of course, have the fear of embarrassment and limit their lives because they're so concerned about the potential of being judged by others. And then people with GAD have this painful sort of fear of uncontrollable, even though they know those life circumstances are normal and controllable. Their worldview is really constrained by these fears, the ruminations, the catastrophizing. And they tend to retreat from the world. Think about your patients. Think about how you've seen that. I certainly have in my practice, how they become circumscribed that way. Many of them feel embarrassed by their illness. They still believe on some level that... Thank God younger people are not quite so much, but many older individuals really feel embarrassed. They feel like, I should be able to tough it out. I should be able to get through this somehow. And, you know, it creates a circumstance where these people really are in a tremendous amount of pain and suffering. And it's not always easy for them to admit it. So what's my approach to engagement, diagnosis and treatment? An ounce of prevention. I always let the patients describe what the problems are and what they're seeking care for. So for example, one time I had a patient who was a really prominent scientist at an institution in the Southern California area. And this person was incredibly bright and talented. And his chief complaint is, I can no longer go into a lecture hall and hear any of my colleagues give a lecture. Because he felt if he got into the lecture hall, he was so constrained, the doors would close and he was going to have a panic attack. But I think hearing our patients and understanding what their chief complaint is, not how we frame it in terms of our diagnoses is so important. I actually ask my patients to identify with me three things that they want to fix. Why they're in therapy, three things they want to fix. And then I ask them to rate them on a one to 10 scale in terms of the severity of the problem for them. And then I ask them, let's monitor them together. I really ask them and we write them out, we score them and then I give them, I'm so old fashioned, I give them a piece of paper. You know, a piece of paper with it on a one to 10 scale, where they are that day and ask them to track it. Now, a lot of them will do that on their phones nowadays. But having our patients begin to get a sense of control over their illness and begin to figure out a way of monitoring it is so important. One of the reasons why it's so important is because frequently, you know, people want to see change, but they don't realize that change really is incremental and two steps forward, one step back. So we'll talk about the fact that, hey, so you've told me right now that, you know, your anticipatory anxiety about going to work in the morning is a nine out of 10. So it's really horrible. So if we're starting a medication intervention, what I'll say to them is, look, we track it daily and what I expect to see after a while is we go from 999 to 98, 98, 98, eight, nine, eight, 87, 87. If we're on the right track, what you'll see over the first few weeks is our subtle changes and one can do it. Now, why is that important? One is it gives people control. Two, it gives people hope. The other reason why it's important, I had a patient I was treating and this person had, in this case, had a depressive disorder. This person was doing really well. The sadness had gone from an eight down to a four and then all of a sudden, the person came in and the sadness score was at an eight. The feeling overwhelmed score had been at a four, went up to a nine and then said, well, and the person came and she said, you know, I'm feeling terrible. I says, okay, I see your scores are bad. What's going on? And he said, well, I got a new car and the first week, my child drove it and wrecked it. But by doing that, we were able to engage in a discussion and figure out what was going on. Respect and reassurance obviously are key, particularly with people with anxiety disorder and giving people the locus of control is so important. I tell patients that they're the captain because it's their lives. I can be the coach, but they're the ones that living their lives. So they need to have that control over taking the medicine or doing the homework, whatever it is, they need to have that sense of control. We'll talk about honesty and there's bad policy and the key is the fit. At the end of my first evaluation with any patient, and we discuss what's going on, I said, look, there has to be a good fit. You have to be comfortable with me and my style and I have to be comfortable with you. And I tell people, I'm okay if you don't wanna work with me, I'll find someone good for you to work with because that fit and that trust is so important. These are lessons I learned the hard way. Identify and track the most important symptoms because that's what people are interested in. Take a trauma history always, ask about their current medications and ask about changes in their medications. Always ask about their current and past medical conditions. Substance use disorders and alcohol use disorders are much more of a problem and many times people will not admit it. Always, always, always ask about natural products and vitamins. To bore you again, I had this patient who worked at the institution I was at at the time and I had known her in other capacities and she was someone who was very much into crystals and into holistic approaches and such. However, she was also a smoker and we had stabilized her panic disorder and we had stabilized some depression she had had with SSRIs, she'd been stable and on those for a year, doing really, really well and she came in to see me and she said, goddammit, Dr. Rappaport, your medicines are making me sick. I said, well, wait, has anything changed? And she said, no, I was trying to get healthier, I've stopped smoking. And I said, well, how'd you do that? And she said, well, I went to the doctor and she said, well, I went to the natural product store and I got these herbs to help me stop smoking. So we looked up the herbs and the dry mouth, the blurred vision, the constipation that all of a sudden she was feeling, of course, were the anti-cholinergic side effects of the herbs she was taking. But it helped me remember to always, always ask about what else they're taking. And of course, when initiating medicines for anxiety disorders, you go low, start low, go slow and frequently end up at higher doses than you do for depressive disorders at times. So let me tell you about a couple of cases. So V.O.B. is a 45-year-old man with situational panic attacks. He was a veteran of Vietnam. When asked about his military history, he said it was okay. He stated he was an occasional drinker but denied substance use disorder. But his symptoms, they didn't respond to antidepressants or benzodiazepines or beta blockers. With further probing, it turns out that V.O.B.'s okay experiences in Vietnam weren't okay. But he had attempted to seal over it. He had been repeatedly sent out on patrol with an inexperienced and cocky platoon leader and many of his friends died. And this kept happening, this sort of wound helplessness and continued trauma kept occurring. When I was able to talk to V.O.B.'s partner, V.O.B.'s occasional drinking meant he drank before going to work every day and drank when he got home. And truly had an alcohol use disorder problem as well. And so we re-diagnosed him as having PTSD and alcohol use disorder. The work circumstances where he said he was having panic attacks when you really probed him hard turned out to be flashbacks. That his supervisor was somebody young, reminded him of the officer that had been sending him out on patrol. So we actually began prolonged exposure therapy with him and treated the alcohol use disorder. It wasn't all wine and roses by any shape of imagination. But he did get better. It was two steps forward and one step back. The second patient is an example of honesty's the best policy. This is a story based on patients that I saw in my internship here when I did a medical internship here. A 50-year-old veteran with COPD, CHF, diabetes, and metabolic syndrome. He was a bilateral amputee. He was on 14 medications, truly. Once a day, twice a day, three times a day, four times a day. I had 25 minutes to examine him, update the history, refill his medications and chart. As you'd expect, as a new physician, I had been a doctor one week at that point. So to be honest, I was a little overwhelmed. So I really asked this gentleman, how do you do this? How do you remember to take these medicines and all these different schedules and stuff? I was just sort of flabbergasted. And he said, well, doc, I don't. I take these four twice a day. I said, well, why do you keep getting all these medicines refilled? He said, well, doc, that other doc was trying to help me so much. I didn't have the heart to tell him. And what I learned from that patient and has been something I've always done with every patient I've ever seen is actually ask them what they're taking and how they're taking it. And help them to understand that the only way I can help them is if I actually know what they're doing. And I just think that that is so important. And with our patients with anxiety disorder, they're frequently frightened of taking medicine. They're already dealing with a lack of sense of control over their life. And the idea of putting something foreign in their body is really scary. And so we have to engage them around that and be cognizant of it. The other thing that happens is, like that patient, they wanna please us. And so we, again, need to know about that. So I always ask people what they're taking and how they're taking it, not what I prescribed. And in fact, that's part of that first session again is saying I'm always gonna do this and I'm always gonna be a pain in the ass and ask you about it. And your job is to tell me what you're really doing because then we can work together. And I did whatever I can and have always done whatever I can, including working with internists and others to simplify the medication regimens. Out of curiosity, so self-disclosure, I have Crohn's disease. So I'm used to taking lots and lots and lots of pills. And the reason I'm bringing that up is because it's a real pain in the ass if you've gotta take some pills once a day, some twice a day, some three times a day. And if you think people, just out of curiosity, if you're taking three or four different medicines and you have to take them on different schedules, please raise your hand if you're gonna be compliant 100% of the time. But we expect our patients to do it, okay, I know you have OCD because we've worked together. But let's try and simplify the timing and frequency of medication. And we really need to facilitate our patients with anxiety disorders, having a sense of control and mastery. One more case, and then we'll get on to more of the review of the data. CT is a 60-year-old senior executive who's almost been a little anxious, but was very, very hard-charging, very successful, a leader in a multibillion-dollar firm. CT reports developing increased anxiety after recovering from a bout of pneumonia. For the first time in her life, she was panicky, commuting across bridges, and actually canceled meetings because of that. That's how CT got to me. CT had an important board meeting the next week, and she really needed to cross bridges. In taking a history, though she had never had any lung problems, her internist had placed her on Tiaflin. And although the levels were therapeutic, this is somebody who didn't have problems with shortness of breath, wasn't having difficulty breathing, could exercise normally. And so we contacted her internist, agreed to tape her off of Tiaflin, gave her a one-time small prescription of a high-potency benzodiazepine, practiced and developed a game plan where others would drive her and she could practice going over the bridge, was able to successfully go to the meeting, and no longer had problems with these attacks of anxiety that were occurring now that she was free of Tiaflin and had had some true exposure approaches. So I've now bored you with how I practice medicine. But hopefully there were some take-homes there that are useful for you. When we treat anxiety, our goals are to reduce anxiety, to improve cognitive distortions, to decrease maladaptive coping behaviors, and enhance functioning. And we're fortunate that we have a host of different modalities to do it. So psychotherapies, pharmacotherapies, somatic therapies are useful in these approaches. What these data look at are the acute, this is meta-analysis of the acute studies looking at CBT for a host of anxiety disorders. And if you look at different symptom complexes, whether they're depression or anxiety or quality of life, what you see is a consistent pattern of improvement acutely with cognitive behavioral therapy for these disorders. If one looks at panic disorder in particular, and this was a network analysis that was performed, what one sees again is that the strongest evidence in terms of psychotherapies are with cognitive behavioral therapy, followed by behavioral therapy, physiological training. And you see the big node for weightless control, because those were the controls used in many of those studies. If we look at third-wave psychotherapies, and as you can see, there are a plethora of them. I'm not going to list them all there, because as you can see, there are about 10 of them there. If we look at what we know in terms of the meta-analyses of results with these third-wave therapies, there have been small studies. Most of them have been against a weightless control condition that show that ACT, MBCT, MBSR, and MCT are all useful acutely in treating GAD. For social anxiety disorder, again, you see ACT, MBCT, and MBSR as being useful. For panic disorder, aside from CBT, the majority of studies haven't been done. The only one that's been done is one with panic-focused psychodynamic psychotherapy. If one looks long-term, and when I was reviewing this, this was actually a little disturbing to me. What one finds from the meta-analyses that have been performed, the good news, is that all of the anxiety disorders seem to improve and continue to have sustained improvement for many individuals for up to 12 months. However, there have been very few studies that actually look at the longitudinal outcomes of people with anxiety disorders going out 2, 3, 4, 5 years. We have some data suggesting that CBT has a small to medium effect size improvement versus control conditions. For GAD and SAD, there may be some positive effect as well, but again, the studies are limited. There's not much, if anything, for GAD. The bottom line is, we need more long-term studies to really understand the value long-term of these therapies. If one looks at some of the newer technology-based approaches, internet-based therapies, virtual reality, computer-assisted psychotherapies and apps, there are fairly compelling data over the years suggesting that computer-assisted therapies for anxiety disorders are useful and can be important. The key is, which computer-based therapy, how one does it, how one engages patients in truly using it, because where one gets into difficulty is, people may start that but not continue with it. In clinical trials, we have coordinators that are checking in on people and are doing work like that. In practice, one really still has to have an engagement with those patients many times to be as successful as it can be. If one looks at virtual reality, virtual reality and virtual reality exposure therapy has short-term efficacy for phobias, agoraphobia, panic disorder and SAD, but not for GAD. Preliminary data suggests that virtual reality CBT and exposure therapy is equivalent to CBT done in a non-virtual setting. In fact, Barbara Rothbaum, who is one of the world's experts in virtual reality and actually was one of the pioneers developing these therapies, gave a series of lectures here at this meeting, again, demonstrating the value of the work she's done. In terms of apps, one of the problems we have is that there are a plethora of apps. There are well over 10,000 apps for mental health, let alone anxiety disorders, available. And unfortunately, we don't have a very good way at this point of really sorting through which apps are useful for people, which apps are not. Some of them certainly are, and some of the data are individual apps, individual studies are compelling. But if there is a good repository of apps available at CyberGuide, and if you see in the bottom of the slide, that's the link to it if you do want to begin to employ adding apps into what you do. But if you do, it's really important for you to actually spend time with that app. See if it's frictionless. By that I mean, see if it's easy for a person to use. Also see if the information that they're receiving through the app are really consonant with best practices and how sessions may be set up with the app. If we look at medications, as you can see on this slide, and I'm sure you can read it all very clearly, you don't have to. You know why you don't have to? Because there ain't nothing new on this slide. What you see here on this slide, or what you would see on this slide, are a list of different classes of medications from the SSRIs and SNRIs to the tricyclics, to the benzodiazepines, to hydroxyzine, to a couple of other agents. And then what you have is whether or not there's actually been an FDA indication for them. And for most of them, there's not. But then what you have are where they're used. And we all know this. The SSRIs and SNRIs as a group we use for treatment of GAD. We can use for panic disorder and social anxiety disorder. They're even better, particularly the SSRIs for OCD. We know that although the tricyclics were never approved for the treatment of anxiety disorders, in fact, the initial work by Don Klein back in 1960, where he reported upon taking imipramine, these people's symptoms of anxiety cleared up. Another Columbia reference, by the way. He was supposed to interact. He's asleep. But we know that before the advent of SSRIs, that both the tricyclics and the MAOIs were very powerful and useful treatments for anxiety disorders. Again, you have to really start at very, very low doses and frequently end up at higher doses. In all candor, if I had a choice with a complicated patient and I only had one time with one medication, I'd probably still use an MAOI. Whether that's somebody with resistant depression or whether that's somebody with resistant anxiety disorder. They're very, very useful agents, and unfortunately they've fallen out of the armamentarium. The benzodiazepines, of course, were approved for anxiety, not for specific disorders, with the exception of alprazolam, with the cross-national study, and clonazepam, both of which were approved for panic disorder. However, what's interesting about those studies is at that time, many of the people that were included in the study didn't just have panic disorder, but actually had social anxiety disorder. Because at that point, it was before Mike Leibowitz and others had really helped define and popularize what social anxiety disorder was. So there was a fair amount of cross-contamination in those studies of people with both panic disorder and social anxiety disorder in those studies. So anyway, these are the older medications. If one looks at the algorithms today, what you see is what you'd expect. The SSRIs and the SNRIs are usually the first-line treatments. Second-line for GAD may include pregabalin and benzodiazepines as a monotherapy or augmenting. The third-line are the tricyclics. And fourth-line frequently has been augmentation with second-generation antipsychotics, which of course can lead to weight gain. For panic disorder, the SSRIs and SNRIs are first-line. Benzodiazepines really are very useful in panic disorder. Being disclosing and being old, I still use benzodiazepines a lot with people with panic disorder. You can get a very rapid, immediate response. You can use them as you slowly taper up the SNRI or SSRI and then discontinue it. If you want to be a hero for somebody who is really suffering from panic disorder, if you initiate a little bit of a high-potency benzodiazepine, it really does work well and makes a huge difference in that anticipatory anxiety and also the sensitivity to panic attacks that they have. MEOIs and tricyclics, again, are frequently used in this population. And for social anxiety disorder, again, it's SSRIs and SNRIs. And then we see vortioxetine and valazodone come in because of some studies that were done there. Augmentation with psychotherapy is always useful, as well as use of high-potency benzodiazepines in low doses when necessary. And then again, you go to MEOIs, pregabalin, and gabapentin. That was a very interesting compound because it actually was—there were a huge series of studies that were done when it was a Park-Davis drug. And those studies were actually positive as a treatment for GAD and for anxiety disorders. The problem with it was that Park-Davis got in trouble, and then it was bought by Pfizer. They got in trouble because they were doing so much off-label marketing to physicians about the drug that the FDA was really reticent, despite some positive studies, to move towards approval there. Part of it was a concern about addiction, which really I don't think is a huge problem with pregabalin. But a lot of it was the fact that Park-Davis had been cavalier in going out and detailing on physicians about the use of gabalin and pregabalin. A little bit of history, I guess, that many of you may not have known. But the challenge is that 50 to 70 percent of our patients still have significant symptoms with either psychotherapy or medication. So what can you do about it? Well, the easy things to do are here. Increase the intensity of CBT or psychotherapy. You switch forms of psychotherapy. You may combine two SSRIs or an SSRI and an SNRI. You may combine an SSRI and a tricyclic, or change and begin to use an MAOI or tricyclic. You may consider adding a neuroleptic. These are all things that you can do. But there's some evolving approaches that you can take. And so we're going to talk now about evolving aspects and evolving things that one may want to consider. I deliberately, by the way, did not include some of the drugs you saw detailed, because I did not think that that was appropriate at the larger convention stuff. So these are all non-FDA approaches to consider. And what you see here are modulation of the serotonin receptors. We've known for years, because of BuSpar, that BuSpar, which was approved for the treatment of anxiety, not any specific disorder, is an effective treatment. The problem with BuSpar is that you really needed to take a TID and you needed to get it to high enough doses. And there were side effects that you had if you escalated the dose of BuSpar too quickly. But we know that modulation of the 5-HT1A receptor is important and can have anxiolytic effects. There also were data with endocitron suggesting that it had anxiolytic effects. In fact, there were a series of studies that were done back in the 80s that suggested the 80s and the early 90s that endocitron could be useful as an anxiolytic agent. Unfortunately, again, the large-scale trials weren't positive for endocitron. As you see there, the 40-oxetine, which is of course approved as antidepressant, may have some role in terms of anxiety. The host of different atypical antipsychotics may have a role as well. We'll talk a little bit more about LSD and psilocybin in a minute. The neuropeptides have really been of interest. They've fallen sort of out of favor, but they actually could be very, very useful. We know that in animal models, CCK antagonists really have anxiolytic effects in animal models of anxiety. We know for a fact that, again, CRF antagonists, if used appropriately, may have anxiolytic effects. There are a host of other tachykinins and neurokinins that have been explored, but unfortunately the work in this area fell off in the early 2000s. If we look at hormone-modifying therapies, oxytocin certainly may have a role in the treatment of social anxiety disorder, PTSD, and alcohol use disorder. Vasopressin 1A agonists may have a role in GAD as well. There's old literature about the use of compounds like ketoconazole in terms of modulating the HPA axis. So these are all approaches that may have a role. In fact, I'm going to talk a little later about some of our work with massage. The way we believe massage works is actually, well, there are two different mechanisms involved, but one involves oxytocin. I'm not going to spend a lot of time, because all of you at this meeting have heard a lot from a lot of different groups, be it MAPS or be it other groups, about the use of psychedelics, and they have far more expertise than I do. The data that exists, the D-cycloserine, is actually really interesting data, because there is a good chance that in the right person it might facilitate psychotherapy, and particularly learning around extinction and extinction behaviors. Again, if you go back and look at the work of Barbara Rothbaum and Kerry Ressler, there were some very, very interesting studies. What happens, and unfortunately happens frequently in our field, is that findings that are done in a very select population get generalized far too rapidly to other populations. And so what happens there when you use a heterogeneous cohort of patients is you will not see a response, because there is a large group of heterogeneous patients where it's not appropriate. So it's a matter of the right patient, the right medication, and I think there may be a role in resurgence with D-cycloserine as a way of enhancing, particularly work that's looking at extinguishing anxiety and anxiety behaviors. There's some work that's gone on with the CB1 antagonists, and again, I'm not going to speak to all the work that I'm sure you've heard from COMPASS and MAPS around the use of hallucinogens as ways to potentiate psychotherapy. Is there value to it? Sure. Do we fully appreciate where? No. Last year I had to, for the state of Utah, review the status of all the work that had been done with various hallucinogens and write a report, a statement for the state of Utah about that. And I think that there's tremendous opportunity for some patients, but I think the challenge we face is if all of a sudden the form of psychotherapy isn't carefully regulated, if the treatment paradigm being used isn't correct, and if it's used in the wrong person, it can have truly deleterious effects. So I think we're going to have a real awakening there, but it has to be done correctly. Otherwise, again, they're going to end up being substances that we're not able to use. So let's switch a little, and let's talk a little bit about other cool approaches. One of course is RTMS. Who in the room has been involved in doing work with RTMS? Raise your hand. Okay. A fair number. RTMS truly is a transformative therapy and truly is something that right now we know for depression is quite useful. There have been some interesting studies that have gone on in PTSD as well. if we look at the studies that exist right now for GAD and panic disorder, there haven't been a lot, but in recent meta-analysis of 13 studies with 667 participants, what they found is that RTMS was useful for GAD, and it didn't matter what they were using in terms of the parameters, it was effective and useful, but it was not helpful either for the anxiety symptoms or panic severity in people with panic disorder. So there may be a role in the future for RTMS and GAD if it's well studied. If you look at TDSC, what you see there is, that's direct concurrent stimulation, is again, there haven't been many studies really done in treatment populations. There was one study contrasting sertraline and TDSC that showed that it was useful in depressive disorders, but that's been really at these studies that I'm showing you here, all research studies, where what they were looking at is whether or not they could augment, in one case, exposure therapy to specific fears with TDSC, and they were able to promote engagement and reduce threat appraisal and distress. In another study where they looked at the left dorsal prefrontal cortex and medial prefrontal cortex, they found reduced fear, avoidance, worries, and improvement in quality of life versus sham control. And then in another study when they were looking at attentional bias, they showed that TDSC was associated with decreased bias for threat-related stimuli. So again, the key message is, there are over 30 devices that any one of your patients can go by and do it. We don't have good control over those devices right now, nor do we know which ones are the best to use or which ones are ineffective. But what we see is that maybe used with psychotherapy, maybe used with other approaches, certain devices may have a positive effect. But we have a lot more work to do there. But the good news is that the future's bright. There is an opportunity that may occur there. Now let's talk a little bit about alternative treatments. What you see here are herbal and food supplements that have been used to treat anxiety disorders. A lot of them, there isn't a lot of data, and that's a real problem. We're going to talk about a couple of them, and the points I want to make are the following. You know, there have been some really nice studies that were done initially in South America and in Europe using KAVA. In fact, there was going to be a huge NIH study that was going to be using KAVA as a treatment for anxiety disorder. Jonathan Davidson, who was at Duke at the time, was going to be the PI of this multi-site study looking at KAVA. Unfortunately, there was one small complication. This. Yeah, you know, there were 78 cases of severe KAVA-related liver toxicity. There were 36 cases of hepatitis and cirrhosis, 11 cases of liver failure requiring transplant and 4 deaths. You know, natural does not necessarily mean safe. If we look at some of the other agents that have been used in studies, and unfortunately there's not enough good data to support the ongoing use of the first three compounds at all. The key fact here is that these substances modulate the cytochrome P450 system, and you need to be aware of that. And that's, again, why it's important for you to know what your patients are taking in terms of natural products. These substances also can influence and modulate glycoprotein P, and also the organic anion transport system, both of which are really important in how we metabolize and get rid of compounds in our body. So it's important to recognize that when we talk about natural compounds, natural does not mean safe. You need to know what you're taking. Now, a disclaimer. I have been funded by NCCIH for over 20 years. I've done work with these compounds. We've done work with St. John's Wort and published some of the papers around St. John's Wort and minor depression. We've been doing work and in fact just received a very big new grant to look at omega-3 fatty acids. And we're convinced that very high dose omega-3 fatty acids may have profound effects on the brain. We've published a series of papers showing the dose-dependent effects of omega-3 in inflammatory depression. And what we can do is actually stimulate at high dose the creation of the naturally occurring compounds that are involved in the resolution of inflammation. And this fits with the data from the cardiovascular literature. But you need to know what you're dealing with. You need to know. When we did our St. John's Wort study, we worked with and looked at over 60 different brands of St. John's Wort. And the majority of them didn't contain St. John's Wort. They contained melamine. They contained amphetamine. But they didn't contain St. John's Wort. And then when they did, you didn't know how much hypericum you were getting, how much hyperforin you were getting. So there were real challenges there. Now St. John's Wort is a second-line treatment in the CanMat treatment algorithms for depression. And there are data to suggest that it may be useful in mild to moderate depression. However, it's also important to remember that St. John's Wort, because it's a 3A4 inducer, there are a number of babies whose middle name is St. John's Wort because it decreases the amount of birth control that occurs. There were case reports in Lancet of a number of patients who were heart transplants who decided to self-medicate with St. John's Wort who began to reject the heart because the induction of 3A4 led to a decrease in the anti-rejection drugs. So natural is not safe. It's important that it's incumbent upon all of us, one, to inform our patients, but two, also for us to inform ourselves because our patients are using these things. And if we don't ask about them and if we don't check up what they're taking, then you have really bad adverse effects that occur. There are some preliminary data that yoga may be effective in decreasing symptoms of anxiety versus a weightless control and relaxation therapy. And there's some data to suggest that there's some beneficial effects in GAD and panic disorder and anxiety symptoms in general of moderate exercise. Now a shameless plug. These are the results of a study we did. What we did was take individuals with GAD and we randomized these individuals to either twice a week massage using a Swedish massage in a manualized way or twice a week touch in a manualized way. And what we did was told people, and we actually measured expectancy, that these were two potentially useful touch therapies. What one saw here was that there was a significant improvement beginning after the sixth session for the group that received Swedish massage versus light touch. And this was published in the journal Clinical Psychiatry. We did follow-up work looking at people six to 18 months afterwards. And what we were able to show is that 40% of these people with a massage intervention remained symptom-free. If you look at the data that we have long-term with other types of interventions, medications or other interventions, you don't get 40% with GAD. GAD is a chronic condition for most individuals. Those that did have a return, in 64% of the cases they were able to identify a significant life stressor that was coincident with return of symptoms. But as you see here, even with return of symptoms, those individuals only had symptoms some of the time, not all of the time. And as you know with GAD, symptoms tend to be pervasive most of the time. Now when we look at their functioning, their quality of life in general, we saw the same thing. We saw significant improvement in both groups and that they were sustained over time. So that looks really cool, right? It's one small study. It needs to be replicated. But what it does suggest is that there may be reasons for continuing this type of research. I'm a skeptic of my own research and I'm a skeptic of everything we do. What was interesting about this study for me was the fact that we did see the effect. And we saw it on both clinician, mass clinician ratings as well as self-report ratings. And we also saw improvement in general in terms of quality of life in these individuals over time, which is unusual for GAD. The hypothesis is that what's going on is what we're doing is taking individuals that are at increased sympathetic tone and modulating and beginning to decrease their sympathetic tone and shifting back into balance of sympathetic-parasympathetic balance. Because individuals with normal parasympathetic tone, one, don't tend to be inflamed. And so they don't tend to have an inflammatory response. And two, are less likely to have subjective feelings of anxiety. The sleep problems that people have, they're less likely to have sort of the irritability and anxiousness, which are associated with sympathetic tone. So anyway, it's kind of fun. It's interesting. We need to replicate it. But it was an interesting thing. Now, I expect all of you have already memorized this, so I'm not going to go over it in detail. But what we have here are some data from the Enigma study. And what the Enigma study is, is an international collaboration of imagers who are working on creating ways of normalizing their data and really looking across many, many sites so that you can look at literally hundreds, if not eventually thousands, of scans and try and discern patterns. And what this particular slide is showing you are the three systems that are involved in, thought to be involved in anxiety disorders. So the green is talking about systems that are involved in perception and how we perceive anxiety disorders. And there's actually a lot of information from this and other sources about that. The red are parts of our brain that are associated with the generation of feeling and how we actually create feelings and from sensory input and such. And then the blue sections are, as you see there, they're mostly the prefrontal and frontal cortex. And these are areas that are involved in modulation of many of our emotions and feelings. And the point behind the slide is merely to point out to you that there's really a tremendous amount of work going on in terms of international consortia that are looking at specific brain regions that are associated with different disorders. In this case, this is the Enigma group working on anxiety disorders. And, you know, if you want to look at it, you can look up under FreeSurfer. It's F-R-E-E and then capital S-U-F-E-R pipeline. And you can see all of these images and many more that are of public access about how we're learning about different circuitry in the brain. So the key there is that we're learning about different circuitry in the brain. Another tool and another approach that may be a very useful intervention, in fact, we at Utah are doing work in this area. I know of a number of other universities that are doing work in this area right now. It's the idea of using MRI guided ultrasound in order to modulate different regions of the brain. And as it turns out, what you can do is attach an ultrasound device to an individual. You can then scan them. And by scanning them, you can begin to locate specific regions that you want to impact. And you can use ultrasound to modulate brain circuits and modulate activities in brain circuits. You can also use focused ultrasound to deliver in a very specific way small molecules to different regions of the brain by creating a circumstance in the vasculature where the vasculature becomes sticky and able to actually facilitate the transport of small molecules in specific regions of the brain. So it's a very exciting technology that will be available to us where their work is going on right now. VNS, as you know, has been approved for treatment-resistant depression. It's very hard to get it funded. But what's exciting is not the traditional VNS which is implantable. What's exciting is the fact that you can use either a portable device that you hold up to your neck for five minutes at a time and can do it at home or an auricular device which, again, you can do and usually it's about 15 minutes or so at a shot. And that these devices really are effective. They're useful not only in experimentally in treating depression but also in treating anxiety disorders. In fact, with my colleague, Doug Bremner, we did an imaging study where we also looked at blood cytokine levels. And what we were able to show is that with using this type of portable VNS, we took individuals that had experienced trauma, put them in the scanner, put them in front of traumatic circumstances, and their level of anxiety was much less if they had VNS versus the sham condition. And their levels of IL-6 lowered with VNS versus the sham condition. And the reason for that is because VNS is thought to, again, increase parasympathetic tone in these individuals. So this is, the point is that these are things that are available in the future. Now, I'd be remiss not to talk about the fact that we also know that not only is there trauma but the impact of racism on our individuals in our society. This is work that came out of the Grady Trauma Project where I had been at Emory. And what this study showed is that individuals that experienced racism, despite there being the same level of trauma, had greater PTSD scores than those that did not experience racism. Those that experienced racism had heightened emotional suppression and inhibition. They were more likely to self-monitor and ruminate. And there was more self-questioning associated with these individuals that had higher scores on these measures of racism. And what one also saw was an 11% decrease in white matter volume, particularly in the prefrontal cortex. I was speaking with, Jodi, are you still in the room? I was speaking earlier in the day with a colleague who was talking about, gosh, you know, it seems like the microbiome is really important. And I wanted to show you, again, some work that came out of Emory University. And what you see here at the top, of course, is serotonin. And then what you see are three different pathways that serotonin can be metabolized in, in the gut, based on the type of microbes that are in the gut. Some of these are associated with normal function, the production of serotonin. Some are associated with actually enhanced immune function. But one pathway in particular leads to the production of endoxyl sulfate. And endoxyl sulfate has been associated with a variety of medical illnesses and problems with kidneys, cardiovascular problems. And in this work by Jodi Dunlap and colleagues, what they showed looking at metabolomics was that endoxyl sulfate was associated with higher scores on the Hamilton's psychic anxiety component and, of course, on the total anxiety component of the Hamilton. And this was based on work that they had done with the Grady Trauma Project. When we talk about psychic anxiety, this is using the Hamilton Anxiety Scale. And these are the first six items on it that tend to deal with psychic versus the somatic aspects of anxiety. One of the other findings of the Grady Trauma Project related to anxiety that's important is this one. There did see, the Grady Trauma Project, and in particular, this particular study that was done, looked at the ratings of anxiety and, you know, the Hispanic individuals, non-Hispanic, white individuals, and black individuals. And there was a difference, particularly in the somatic anxiety pattern that they saw in this population of individuals. These were people all who met criteria for depressive disorder. And there was this difference based on what racial group they were in. And it's work that needs to be followed up, and it hasn't been followed up yet. But the other thing that they were able to show was that there were actual changes, and there was an association between the SCC, the Subculosis Increased Diarrhea Center, and the premotor area. And this was an area of overlap between endoxyl sulfate and Hamilton Anxiety Scores. And so what they were able to show was that there was a modulating effect that occurred between endoxyl sulfate, these changes that were seen in terms of resting state, and the Hamilton score. So this suggests that endoxyl sulfate, which is, again, being generated by these microbiome components may play a role in some people in anxiety disorders. So that's an interesting area of investigation going on now. The other area, of course, is big data. And big data is really going to be very important, and AI, because what it allows us to do with computational science is really analyze systems and processes, and it allows us to make predictions that otherwise we can't make, so that we can better understand the complexity of what's going on with us. And so if you use AI, and this is Nina DeLacy's work in our group, she's able to take hundreds and hundreds of candidate risk factors, and these are risk factors that are involved in dynamic brain processes, brain maturation, human development, and begin to discern patterns and things that are important. She's been particularly interested in the fact that 70% of psychiatric disorders begin between the ages of 10 and 24. Why is that? What is going on during those times? Are there modifiable risk factors? And so what she's done is built these computational models where the intent is to use RDoC-style dimensional approaches in order, in pre-adolescence, to really discern what's going on. And so she partnered with the Child Mind Institute. They had data in over 11,000 youths, 521. They looked at literally thousands of different potential risk factors, including imaging risk factors, with the aim of trying to do, and they did it in both an experimental set and a replication set, to determine 85% accuracy, specificity, and sensitivity. And what Nina found, and this paper is in press right now, is that the factors that predicted the development of anxiety disorders, she's also done this work for ADHD, for SUD, for depression, but the factors that predicted at those levels of 85% sensitivity and specificity for anxiety disorders were adverse life events, as you'd expect, internalizing traits, externalizing traits, increased parental problems and stress, callous and unemotional parenting, and particularly when it came to social cognition, and that these were the factors that predicted young people developing anxiety disorders. So as we are beginning to run out of time, the takeaway with big data is that we're beginning to be able to predict individual cases of mental disorders with very high accuracy, sensitivity, and specificity. Mental disorders are likely complex and multifactorial, and that deep learning with artificial neural nets outperforms other methods, and it really does. So in summary, the FDA-approved pharmacotherapy hasn't changed in decades. Medications combined with evidence-based psychotherapy is really valuable and probably the best approach. Teletherapy and asynchronous therapies are valuable and new approaches. We didn't talk much about asynchronous therapies, but there's some good data showing that sort of, again, AI-assisted and computational-assisted asynchronous psychotherapies can be very useful for certain individuals. Not everybody can tolerate doing it and has the motivation to do it, but John Grist has done some really exciting work in that area. There's evidence for new somatic forms and approaches, and then I think AI and big data will really help us develop preventative interventions. And when they're not preventative, at least they could be preemptive interventions that would help children and family, because if we can keep kids from getting ill in the first place, just think what that's going to do in terms of that child's trajectory, the other children and the family's trajectory, and the parents' life and trajectory is really going to be tremendous. And there's a lot of really exciting new research going on investigating and helping us understand anxiety disorders. So thank you very much for your time and attention today. Hi, I'm Dr. Ron Winchell of the Scientific Program Committee and the Clinical Updates Program. I want to remind you the slides will be posted on the app, as are the slides for most of the presentations in the Clinical Updates Series, and the app will be live for weeks, months actually, and please feel free to go to it. Dr. Rappaport has to be out to get a car at 3 o'clock, so we are going to have to be crisp about it, otherwise apparently it will be turning into a pumpkin, which I think I sort of want to see, so we might barricade the door. We will be alternating questions between the live audience and the questions that have come in from our live stream audience. Please step up to the microphone if you have a question, and if your question is going to start with, I have a patient, please rethink the wording and make it a general question. So let's start with the first gentleman at the microphone. My personal addiction is exercise, and I feel like that's one of the most helpful treatments for anxiety. It's not promoted by pharmaceutical companies, but it's something that gives patients a great sense of control. It can be done individually or in a group. Can you say more about how you incorporate exercise as a first or second line, rather than a fifth line, barely mentioned therapy? Well, you know, I think we've got to do some disclosures, okay? I am an exercise fanatic. I exercise between an hour and 90 minutes every morning before going to work, and if I don't exercise, I feel incredibly dysphoric, and my wife won't speak to me. Actually, I don't think anyone would speak to me, but exercise is useful. The challenge one faces with exercise is if somebody has not had that integrated into their life, then one has to be very careful about how one integrates it into their life. I frequently do that with my patients, but the way I do it is ... Oh, God, okay. Who in here knows anything about baseball? You don't have to know a lot about baseball. I tend to use this as an analogy when it comes to exercise or when it comes to diet. What I say is, look, you know, you're probably the type of person that believes that if you don't get an A on your exam, if you don't hit it 90% of the time or 100% of the time, you're a failure, and boy, does that happen with anxiety-disordered patients. I say to them, but you know, I really would like for you to be more like a baseball player. I want everyone to be more like a baseball player. They look at me and say, what the heck is he talking about? And then I say, you know, we pay baseball players millions of dollars to hit the ball three out of 10 times. They're considered a superstar if they hit the ball three out of 10 times. So if we've agreed that you want to add exercise into your routine to help you, you know, we have to start it a reasonable number of times a week. So okay, let's say we'll start it three times a week. Let's say we're going to, it depends on the person and what they want to do or how they want to do it, but it doesn't matter to me as long as they're doing it at least 20 minutes at a shot. And I'll say, okay, so we're agreeing that we're going to try three times a week now. You need to be a baseball player. I want you to be successful. And that means if you do it one out of three times that first week, you're awesome. You're worth millions of dollars. And by doing that and by talking with people about how difficult it is to change patterns in life, again, you can begin to help them get a sense of control. But also it requires one, them tracking how often they do it, and then two, really following through and praising them and asking them, okay, so you did it. How does it really make you feel? What did you notice? What was good about it? Did the rest of the day go better or not? So it's more than just prescribing exercise, at least when I do it. As you can also tell, when I'm not behind the lectern, I use my hands a lot. And I actually do with my patients too. I do a lot of gesturing because that's who I am. Thank you for the question. Dr. Lowe, a question from the remote audience, please. How long should patients with generalized anxiety disorder and social anxiety disorder stay on SSRIs and SNRIs? Is there evidence that CBT and ACT prevent relapse? I heard the first part. What was the part about the CBT? Does CBT and ACT prevent relapse? Okay. Those are good questions. So I truly believe that both social anxiety disorder and generalized anxiety disorders are chronic conditions. So as we talked about, I've got Crohn's disease. So on a good day, I'm only taking 10 pills a day. I believe that the intent behind medication that we use in the treatment of GAD or social anxiety disorder is to facilitate people having the best quality of life they can have. That's why I take medicine. So I'm symptom-free and I can sit here and pontificate. And so I, particularly with GAD, if somebody's having a good response, I do not want them to go off meds. With social anxiety disorder, particularly if they have had follow-up CBT or ACT, then I think it is reasonable to slowly, slowly taper people off and see how they do. But if they don't do well, it's not a failure. It's just that they need a different combination to enjoy their lives as much as possible. But I very much believe that our medications help people and are useful. And I'm reticent to take people off medicines if they have what I consider to be a chronic condition. And I think both social anxiety disorder and particularly GAD are chronic conditions. Thank you so much for a great talk. Sometimes we see patients who are extremely resistant to any adjustment of medications because of their anxiety, the problem that brought them to treatment in the first place. They wouldn't allow titration of good medication, no matter how small the dose, how gradual it is. They wouldn't allow their prescribing, no matter how gradual and conservative. So I just wonder how would you deal with those, how you deal with those patients. Okay. I think what you were asking me about is the patients that are so anxious about taking medication that they don't allow one to, they don't want to do it at all, right? No, I mean, I'm sorry, I mean, they don't want adjustments. For example, you have them on very low dose of Lamictus, they don't want to get any higher. Oh, yeah. And then you have them on small dose of Klonopin, which does harm, like no matter how gradual it is. Yeah. They just can't. Oh, sure. Well, you know, that goes back to the first thing I always say to patients is, hey, it's your life, you're the captain, I'm the coach. I can tell you the data, I can tell you what I think is best and why I think it's best, but you've got to control your own life and you've got to decide what you want in your life and what richness you want and what you don't. And so are you able to do the things that we talked about initially when you came in that you wanted to do or not? And frequently they'll say, well, I'm better, but I'm not where I want to be. And I said, well, okay, so then let's think about what we can do to get you where you want to be. And sometimes it works, sometimes it doesn't. And, you know, I think we have to allow people that autonomy. I think we give them our knowledge, we give them the best data, we give them approaches, and then after that it's going to be their choice whether they choose to go up or not go up on medication, whether they choose to engage in psychotherapy or others. And that's really been my philosophy with patients. And I think the stronger the relationship over time, you know, sometimes people come back to you and say, okay, there is more I want in my life. So that's sort of how I handle it. Sure. From online, what's your take on hydroxyzine as a standing NPRN for anxiety, especially with kids and adolescents? Well, so disclaimer, I can't really speak about kids because I'm not a child psychiatrist. But there are data suggesting that hydroxyzine alone can be effective as an anxiolytic, and there are studies suggesting that it is useful. And so, yeah, if that's something that an individual is comfortable with and has prescribed, I'm very comfortable with folks doing that because there are data to suggest it is useful. Is there an anticholinergic side effect with hydroxyzine like the other, like antihistamines? Yeah, there is. I've seen elderly patients fall over with post-hypotension from using antihistamines. Absolutely. So I have a concern about the older ones. And of course, their cognitive function is more vulnerable as well. Yeah, that's absolutely true. Yes, please. Thank you for your presentation. For anxiety patients who are responding to an SSRI or an SNRI partially, you get to the top of what's considered the dosing schedule, and they're tolerating it well, but they're not quite where you want them to be or where they want to be. Would you go over in terms of do you sometimes prescribe more than they say, or do you augment, switch? What's your strategy? Thank you. You know, I've, all right, everyone has to do what they're comfortable tolerating. So that's the first thing. Everyone has to be true to themselves when it comes to how we prescribe as a physician. I have many times used much higher doses than what's in the package insert. And part of the reason for that is because I did a lot of those studies. So I did a lot of the studies years and years ago with the SSRIs and the SNRIs. And the way those studies are done, the intent of the study is to get a medication improved and get an indication. That does not mean that they've done studies that look at what doses are best for different individuals. And if somebody is tolerating it well, is partially responsive, I certainly would go up on the dose as long as that person was willing to do so. And I would do that before I add something else to it. And the reason for that is, again, if you can get by with one medicine, why not? You know? So I'm very comfortable doing that. But you all have to do what you're most comfortable with doing. And I also know that the way some of the electronic medical records are today, you get all these warnings and all these other mashugana things. I ignore it. Because my goal is to treat the patient, not the medical record. Is it fair to generalize that, in general, when treating anxiety, one tends to need to go to the higher range as opposed to depression, which often will respond to the lower range? It sounds to me like you listened to my lecture in my fifth slide in. Yeah. I know you said it. But I think it bears repetition. It does. Actually. It's important. And anxiety, if I may say, is trivialized in our society. Everyone knows schizophrenia, bipolar disorder, depression, oh, those are serious illnesses. It costs America and the world a lot of money. But when you talk about anxiety, a lot of people still tend to trivialize it. And speaking as someone who's had panic disorder in the past, as probably 20% of this room has had, it ain't no joke. And chronic generalized anxiety can really screw up a life. And remember, again, that people that commit suicide usually also have high anxiety. Agitated. Risk factor. And it's genderized, which is a problem as well. You all know that in the 1940s and 50s, the gender stereotype for anxiety in this country was the hardworking man bringing the bacon home to the family, and it was considered a badge of courage. And that shifted, if you look at advertisements through the 60s and 70s, until it became feminized. And when it became feminized, as a lot of things, it became dismissed. And it is trivialized in medicine, I think. I agree. Thank you for saying that. I think it's important. Next online question. Could you comment on the dropout rate for CBT and other psychotherapies compared to pharmacological interventions and placebo? That's a very complicated question. One of the reasons why it's complicated is that with the CBT trials, the first question is compared to what? Is it compared to a weightless control? Is it compared to another active treatment? And so if you're doing a therapy trial and you're with a therapist who is prescribing homework for you, is engaged in really listening to you and following up on what you're saying in that therapy, tell me, do you think that person getting that experience would be more or less likely to finish out the protocol? They tend to be more likely. If you're doing a true pharmacotherapy trial where what you're doing is contrasting a medication with in many cases a placebo condition, we worked hard to train our raters not to be overly empathetic, not to be overly therapeutic in those interactions. And so what that tended to mean is that we were lucky if we were getting 70% completion rates in those trials, good ones, 80%, but we were lucky to be able to do that. Because the intent in order to differentiate from placebo is that you try and minimize the therapeutic effect of the interaction. So it does lead to some intrinsic biases and challenges when it comes to contrasting psychotherapy with pharmacotherapy studies. In the work that we've done now, I've done work on massage now for almost 20 years, and in those studies we actually do two things. One is prior to initiating the study, we measure expectancy and credibility that the subjects have for the various interventions we have. We also measure preference. And so we look at all of those as potential factors in the studies themselves. And I think that has been very, very important to do. And in general in studies, it's important to understand what the individual subject's expectancy and thoughts about credibility of the interventions are going to be. We have a special treat for the audience, because unless we let him go in the next 30 seconds, we're about to see a live demonstration of a panic attack. We want to thank Dr. Rappaport for a great presentation. I hear a large squash growing outside. And thank you all. And again, remember, the slides will be on the app.

Dr. Rapoport

psychiatrist

anxiety disorders

personalized care

psychotherapy

medications

technology-assisted therapies

psychedelics

RTMS

VNS

microbiome

exercise