Good morning, good morning, and welcome to this newly established track. We call that clinical update at the 2022 APA annual meeting. So the purpose for this one is that by the end of the session, we want to leave clinicians with practical evidence-based tools you can take home and use right away in your practice. So under the, quote-unquote, anxiety track domain, including three renowned speakers. So yesterday, we heard from Dr. Charlie Nemiroff about PTSD, and this morning, we heard from Dr. Blair Simpson about OCD. And our third outstanding distinguished presenter is Dr. Mark Rappaport, who will speak about anxiety, disorders, treatment, current status, and the future promise. So my name is Edmund Pai. I'm the moderator for this session. I want to thank you again for your patience, for your attention, for your cooperation, and finding all the empty seats. So now it's fully booked. No more waiting lists. Everybody has to be outside to watch the big screen. So I am Professor Emeritus of Clinical Psychiatry and Behavioral Science at University of Southern California, as well as Clinical Professor of Biobehavioral Sciences at University of California, Los Angeles. So you can see on the slides, and Dr. Mark Rappaport is a distinguished life fellow of the APA, the founding co-editor of current editor of the APPI, AP Journal, so-called FOCUS. And he's the inaugural CEO of the Huntsman Mental Health Institute at University of Utah. The William H. and Edna D. Stimson Presidential Endowed Chair and the Professor and Chair of the Psychiatry at the University of Utah School of Medicine. Previously, Dr. Rappaport was the Chair of the Department of Psychiatry and Behavioral Sciences, Chief Psychiatric Officer for Emory Health Care, and Co-Director of Emory Brain Health Center. So with that, please join me to welcome our speaker, Dr. Rappaport. Thank you. Thank you very much. This will be participatory, at least at the beginning, and then again at the end. So the first thing we're going to do is say good morning again, because I couldn't hear you. Good morning. Good morning. I could almost hear you. That was good. Ed, thank you for the wonderful introduction. I have had the great pleasure of knowing Ed Pye from the time when I had dark hair. Now, Ed has always had dark hair. He's lucky, genetics. Me, not so lucky. Anyway, so what we're going to do today is the following. We're going to talk very briefly, and the first bit will be participatory, about DSM-5TR. It will be a one-question participatory thing. As you may know, I also moderate the Focus Live sessions that will occur on Tuesday, and so we'll have a couple of teasers about that. But unlike Focus Live, where we actually use the ARS system, we're going to use the ancient ARS system for this one, where people are going to raise their hands and tell me what they know. Let me see if I can move these forward. Yeah. And I moved them forward faster than I wanted to. So these are my conflicts of interest. I've had the good pleasure of being the founding co-editor-in-chief and the editor of Focus for what will be 20 years in January of this coming year. And I currently have funding from the National Cancer Institute and the National Institute of Mental Health, and NCCIH, the National Center for Complementary and Alternative Medicine. These are my collaborators, and a lot of the really cool work you're going to see and the best ideas come from these individuals. What we're going to do today is talk briefly about DSM-5TR, then what we're going to do is talk briefly about the impact of racism on the biology of individuals. After that, what we'll do is review the current state of treatment, looking briefly at our psychotherapies and then our existing FDA-approved pharmacotherapies. Then we'll talk about where we're going in the future, or where we hope to go in the future, first by looking at medications, looking a little bit at natural products and some of the concerns that these natural products may raise. Talking briefly then about what Dr. Brzezinski is going to be talking about on Tuesday, which are non-new approaches, new somatic approaches to treatment of anxiety disorders, and also how imaging may really help us with those future treatments. Then after that, what we'll do is talk a little bit about primary prevention and two really interesting initiatives. One is some work that's being done by the Rural Mental Health Institute in Montana with young children, and then the other is work by Dr. DeLacy, who's an expert in child psychiatry, but also, as it turns out, is really one of the foremost experts in big data and AI. She's been doing some really exciting work about predisposing factors that may help us develop new treatments, and also using AI as a way of reconceptualizing how we look at diagnosis. That's what I hope we'll accomplish today. Back to where you're going to raise your hand, okay? An intent in developing DSM-5-TR was, one, to greatly modify the diagnoses in DSM-5. B, to add a variety of new diagnoses. C, to add information about social determinants of mental health and cultural humility to our nosology. Or D, to make the life of the average clinician more complicated. All right, we're going to go reverse order. Who says D? How about C? How about B? No one. How about A? How come, guys, so many of you wimped out? The majority of people didn't raise their hand at all. You know that? Heck. The correct answer is C, to add information about social determinants of mental health and cultural humility to our nosology. That really was the intent of it. What I want to do now is really talk a little bit about how valuable this is and why this is valuable at this time. What I'm going to be doing is talking very briefly, just three or four slides, about some of the wonderful work that Nagar Fanny is doing at Emory University. Nagar has been looking at racial discrimination, verbal microaggressions, nonverbal social exclusion, and the fact that it's uncontrollable, unpredictable, and yet an ongoing phenomenon. Over 70% of black Americans have reported this as a real ongoing issue in their lives. What one sees here is, first, one of the measures used to look at racial discrimination. Have you ever experienced discrimination, been prevented from doing something, or been hassled or made to feel inferior in any of the situations because of your race, ethnicity, or color? And then there are a host of situations there. And in the work that was done by Yara and colleagues, what they demonstrated is the severity of symptoms of PTSD, independent of the other trauma going on, increased dramatically with the larger number of these experiences of discrimination. If one looks here, what one sees with Masten's work is that the right interior cingulate lit up, and lit up in a way of increased activity based on, again, the number of discriminatory events that an individual had had in one's life. And what one also has been seeing is that discrimination and racism leads to heightened self-regulation, emotional suppression and inhibition, increased self-monitoring, rumination, and questioning of self. Racial discrimination is also associated with a decrease in both gray and white matter volume And because this isn't going to be the thrust of my talk, I'm only showing you the white matter volume data. But it's important to understand that it is associated with losses of white matter in the corpus callosum, and particularly in the frontal cortex regions of the brain. What we see with racism and discrimination are these cognitive challenges, hypervigilance, heightened self-regulation. And if you think about our discriminated underrepresented minority communities, if you think about what's gone on in the LGBTQ plus communities, there is an increase, particularly in the underrepresented minority communities, increase in cardiovascular disease, metabolic disease, neurodegenerative disease, and stroke. There also are increases across both in anxiety, depression, PTSD, and substance use disorders. So what we have in DSM-5TR is really important information that's getting at really critical issues that we as clinicians, all of us as clinicians, need to begin to understand and embrace. You know, back in the dark ages, again, when I had dark hair, but when I was a medical student I had a patient in psychotherapy, and she was a black woman. And she looked at me at the end of the second session and said to me, you know, you're just like all the other ones. Me talking to you is like talking about blue to a blind man. You don't get me. And she was right. She was absolutely right. I didn't appreciate all that she had gone through. And I think by us learning and understanding cultures differently and really respecting people from where they're coming from and understanding that better, it will facilitate all of us being better clinicians. And I think particularly today, this is very important. All right. Enough preaching. Now we do learning again. The goals of treating anxiety disorder really are to reduce anxiety, improve cognitive distortions, decrease maladaptive coping, and enhance functioning and quality of life. Now we are fortunate in that we have a variety of approaches to do so, including psychotherapies and certain types of pharmacotherapies that are currently approved. Looking good, of course. This is a meta-analysis that was recently published by Carpenter and colleagues. And what they did was take the CBT trials that had been done, did a very careful job going through them. And what these data are looking at are studies where there was either a placebo or some other type of control group. And what one sees, if you look at social anxiety disorder, PTSD, panic disorder, OCD, GAD, and acute stress disorder, is that these psychotherapies, these evidence-based CBT approaches have actually pretty profound effect sizes. The largest are with OCD, which Blair, I'm sure, talked about, and with GAD. If one really looks at the size of them, what one sees is that, with the exception of OCD and GAD, most of them are in the moderate range. However, we still have work that we need to do in terms of refining our treatments for social anxiety disorder and panic disorder in particular. If one breaks down the components looking at its effect in anxiety, what you see, again, is that there is a small to moderate effect size difference that we see on anxiety symptoms associated with panic disorder, social anxiety disorder, and PTSD. One sees a similar sort of picture when you look at depression. But what, to me, is really striking, and suggests that we've got to do better, is if you look at the quality of life and the improvement there in quality of life. What this suggests is, although these psychotherapies are really quite good in terms of treatment, one of the things that they don't do is adequately address, how do we get people to appreciate their lives again? How do we get people to fully be able to engage in the activities that create richness in people's lives? This is a study from Dr. Hogue, and she's been doing a lot of work with MBSR. This is one of the first studies that she did, and what this showed was that MBSR versus stress management did improve the back anxiety inventory and CGIS. It did improve the HAM-A, but not to a significant degree. There are more studies that have been done with mindfulness-based psychotherapies, and they are effective in treating anxiety disorders, though the body of evidence is still quite limited. If one looks at a network analysis of the panic disorder psychotherapy data, what one sees is that cognitive behavioral therapy is the size of the ball indicates how strong the data are in favor of a specific therapy. The connection between them, the thickness of that, is the strength in relationship between that and other approaches. What one sees is CBT is the, again, the most successful therapy that we have there, followed by behavior therapy, but what's always disconcerting is when you look at things like the weightless control, because what you see there is the weightless control, again. For many people in these studies of panic disorder, it was effective in decreasing signs and symptoms of panic disorder. What that suggests, again, is that we have good treatments, we need better treatments when it comes to psychotherapies. There's a third wave of therapies that's developing, and I'm not going to go into it in extensive detail, but they include internet-based therapies, virtual reality, and virtual reality really is quite effective. I'm sure Dr. Nemeroff talked with you about it in PTSD. There's outstanding work by Barbara Rothbaum and others using VR in PTSD with tremendous success. In fact, Dr. Rothbaum's invented a two-week intervention, a PHP for treating PTSD, and her couple-year data now demonstrate the effectiveness of that is greater than what we see with conventional approaches and treatment, and VR is a major component of that treatment. VR is also quite effective in treating different forms of social phobias and such, and really it's an exciting and interesting area of work. The computer-assisted psychotherapies are quite effective, and I'll show you some data about that in a minute, and there's a burgeoning area in apps. In fact, there was a report recently that over $1.4 billion of VC money has been pouring into mental health, and a significant portion of that VC money is going towards apps and other types of development. In fact, two of the undergraduates I mentored while at Emory, they were Georgia Tech undergraduates. They developed a series of apps, one for substance use disorder, another one for mood disorders, and their company is now valued at $200 million. So it's a burgeoning area. The problem we have with the apps and with some of the things that's going on in telehealth right now is that there isn't good quality assurance, and there in many cases is not good data to demonstrate that what's being promulgated is actually useful for our patients. There's so much of it going on right now. I think all of you have seen those ads now for psychotherapists on the TV where they'll hook you up with a psychotherapist. Unfortunately, more times than not, those companies have no quality control about whom they're having a patient see, nor are they necessarily individuals that have the expertise to treat that disorder. So it's a really rampant area where we need to do better, and we need to figure this out. So this is some of the work that my friend John Grist shared with us, and what it looks at is the effect sizes associated with computer-assisted treatment, or in computerized treatment for anxiety disorders. And what you see is that there's actually good data suggesting that computer therapy for anxiety disorders is useful as long as one is using a reputable therapy. John has been doing this work for many, many years. I just had a curiosity. Has anyone heard of that little company, Epic? Well, John and Jeff Jefferson, along with their nurse, and their nurse actually is the owner and CEO of Epic now. But they began doing work in this area back in the late 60s, and he's been a real proponent for this. And the data are better than one thinks, as long as one has the right app to use. So if we look at the evidence-based recommendations for pharmacotherapy, we're going to focus on GAD, panic disorder, and social anxiety disorder, because my boss, Dr. Pai, told me to. So this slide, and I apologize because I know it's difficult to read, but this slide summarizes where we are right now with FDA approval for medications for the treatment of anxiety disorders. And if you look at this slide carefully, which of course you in the back of the room can do very easily, what you see is that the group of medications that have specific approvals and tend to be the SSRIs and the SNRIs. But if you look actually at what's been approved by the FDA for treatment, where the trials were actually done, the majority of them were in either panic disorder or GAD. One with approval for social anxiety disorder. If you look further down that list, what you see is a whole bunch of medications approved for anxiety. And what you're seeing there are medications that were approved many, many years ago. The benzodiazepines, hydroxazine, and buspirone were not approved for any specific disorder. At that time, the FDA approved drugs for a global treatment of anxiety. And so what you see there again is that the benzodiazepines, except for alprazolam and clonazepam, were all approved just for anxiety alone. What you see in the next category is the fact that the off-label use of these medications, and what you see is that, as we all know, the SSRIs and the SNRIs are very commonly used to treat many anxiety disorders, even though in certain cases, they have no FDA approval for it. And that's absolutely fine. I think we've done that for years. What you'll also see is that the tricyclics and the MAOIs, again, used for years, back in what I call the salt-and-pepper age, when I had a little gray hair but more dark hair. Back then, when I started my practice, those were the drugs that we used. Those and the benzodiazepines were the drugs we used to treat anxiety disorders. And today, unfortunately, those are still, this group of drugs here, the SSRIs, SNRIs, the tricyclics, the MAOIs, the benzodiazepines, and hydroxycine and BuSpar are really still what we have available right now as approved treatments for anxiety disorders. If one looks at an approach based on, ah, I'm supposed to use this. I'm terrible with these, by the way. If you look at an approach for the treatment of generalized anxiety disorder, and this is work that came out of Mass General, and also what they did was summarize CANMAP and summarize existing literature, and it was recently published in Focus. Eric Boye was the guest editor of that edition of Focus. What you'll see is, as you'd expect, the SSRIs are the first-line treatment for generalized anxiety disorders. Two of them have been approved for treatment of generalized anxiety disorder. The SNRIs are suggested. If somebody has a chronic pain or fibromyalgia as a first line, you again go to the SSRIs, and then there's the suggestion, although it's not approved for this, to go to pregabalin. Pregabalin's an interesting drug, and it's an interesting story. Pregabalin used to be owned, it was initially developed by Park Davis, and what had happened was that Park Davis at that time was also had gabapentin, and it was doing a lot of marketing of gabapentin for the treatment of anxiety disorders. Park Davis got in trouble with the FDA because of that, and partially tarnished because of that the GAD studies that were done, and they were actually pretty good studies because I was called in as a consultant to look at the data. The GAD studies that were done with pregabalin were actually pretty good, particularly at the higher doses. It's said one should use it between 150 and 600 for GAD, and in the doses of 450 to 600, the data were actually pretty good, but pregabalin never got approved by the FDA because of concerns about potential side effects and problems with addiction that really didn't pan out. The benzodiazepines, both as a monotherapy and as an augmentation therapy, are suggested as a second-line treatment for GAD, with the third-line treatment being the tricyclics, and then the fourth line, the augmentation with the atypicals. Olga Braun-Mintzer did some very interesting early work looking at augmentation in GAD, and some of that was actually quite positive. If one looks at panic disorders, the SSRIs and SNRIs are the first-line treatment. Benzodiazepines are the second-line treatment. For years, benzodiazepines were the first-line treatment, partially because of the tremendous work that was done by Bruce Liddiard and Jim Ballinger and David Sheehan and others, who actually did more work describing the disorder of panic disorder than anyone, and through those studies, they led to the approval of Alprazolam as a treatment for panic disorder. There was the Cross-National Panic Consortium that those guys were involved in leading. Clonazepam, again, is approved for the treatment of panic disorder, and a lot of that work came out of Jerry Rosenbaum and the group at Mass General at the time. There have been studies, by the way, with both Clonazepam and with Alprazolam where they've been used in combination early on. Andy Goddard did some of the earliest work in this area, and then we actually published a paper in 2006 in this area where we used the combination of a benzodiazepine during the first six weeks of initiation of the SSRI, and with that approach, we were able to ameliorate symptoms of anxiety in these people very, very rapidly, and then we tapered at, during the end of the six weeks, we were tapering people off of the benzodiazepine. They got off the benzodiazepine, continued to do well with the SSRI in place. Monoamine oxidase inhibitors are a fourth-line treatment with tricyclics and mirtazapine, which, again, does not have an indication as a third-line treatment, and then, again, valproic acid and the antipsychotics. One looks at social anxiety disorder, you see the same picture. Now, I should point out to you that there have been extensive studies that were done with both vortioxetine and velazodone. Unfortunately, neither of them will get necessarily approved by the FDA for the treatment of GAD. The vortioxetine trials, even the meta-analyses, really tended to be negative. The velazodone meta-analyses, and there have been a number of them, some are positive and some are negative, and so it really is a mixed bag, but when you consider the heterogeneity of the patient populations and the limited sizes of the studies, that may also make sense, but it's important to know that. With social anxiety disorder, but I'd contend with any of these, having good psychotherapy is really, really important and useful. Then we have the MAOIs, gabapentin and pregabalin. If we're looking at using gabapentin, we're really looking at a higher dose of 3,000 to 4,000 milligrams a day, and you need to give it in divided doses, of course, and some people can tolerate it and some people can't. The pregabalin doses, as we talked about with the GAD, would be about the same, 150 to 600. It's important to recognize that pregabalin is approved, at least by the EMA in Europe, for the treatment of GAD, and then we have mirtazapine and olanzapine as fifth line for social anxiety disorders. So what do we do next? Because at best, 50 to 70 percent of individuals have symptomatic relief from CBT and or medication. Well, what do you do? You can increase the intensity of CBT, and there's some data suggesting that that is valuable. You can combine two SSRIs, or an SSRI and an SNRI. One can use a combination of an SSRI and a tricyclic. Now, what you get, and this goes back to the work, initially in OCD of Larry Curran, when you combine fluvoxamine with clomipramine, what you do is massively increase your levels of clomipramine because fluvoxamine is a very potent inhibitor of 2D6 and several of the other 450 system enzymes. Higher doses of SSRIs and SNRIs, and in combination with the neuroleptics, particularly for obsessive and psychotic symptoms, which do present with these anxiety disorders. You know, it's interesting that it's there, that says it there, because we recently were treating a young woman. She was in high school, and she was admitted to our inpatient unit, and she came in, and she'd been treated by someone else in the community, and she came in on very high doses of an SSRI. She was on high doses of vilify, and she was clearly apathetic. She was clearly agitated. She was reporting that what she was hearing were thoughts. She called them voices within her head at night, but they truly were thoughts, that, you know, if she's going to feel this bad and she's scared that she should kill herself. We markedly decreased the SSRI. We got her off of the antipsychotic, and this young woman had GAD with a depression mixed in, and as you know, most anxiety disorders frequently also have depression, but it's important that we be careful when we look at adding the neuroleptic to these medications, because it really can exacerbate, and so we have to carefully monitor what we're looking for in terms of response and what we're looking for in terms of side effects, because, you know, this poor young woman, you know, five months of her life were taken away from her. What goes beyond CBT and SSRIs, the art of psychotherapy, the art of pharmacotherapy, we'll talk about some small trials, uncontrolled trials and case reports, and as we know, you need to start low and go slow, particularly when you're treating anxiety disorders. I learned that the hard way, by the way. Back in the dark ages again, I was treating a woman with panic disorder, and I made the mistake of starting her on 50 milligrams of mepramine, and her panic disorder got much, much worse. I started getting calls from her, from her husband, and they hated me. I should have started it lower. I should have started her at most 25 milligrams and built up slowly, and that really is the case with anxiety disorders. We've got to be thoughtful and understand that. I know it's tough. I know it's tough also because, you know, you've got managed care, you've got people telling you, oh, you can only see this person, you know, so frequently, but these patients need for us to start low, go slow. The other thing I tend to do is I will make five-minute check-in appointments with people, particularly when I'm starting a new medication for the first couple weeks, just five minutes check-in at the end of the day, and that's it, and it helps so much in terms of mitigating some of their concerns and anxiety and allowing me to help them through phases when they may feel anxious and out of control. Okay, so what may the future be or not? You could have laughed at that, but I blew the line, sorry. We'll talk a little bit about medication options, natural products, somatic therapies, internet-based screening interventions, and big data and AI. So these are non-FDA-approved potential pharmacological interventions, unlike what I just showed you, most of which was non-FDA-approved, as we talked about earlier. There are a host of compounds that could be available and could be useful in treating anxiety disorders. Unfortunately, most of these compounds are not actually being investigated. A good friend of Ed's was actually a partner of mine on Dancetron studies. Yours, Ira, Ira and I were involved in doing the Andancetron studies. Those were back in the 90s. There was an attempt to use Andancetron as a treatment for anxiety disorders by Glaxo. The 5-HT1D antagonists, again, have an unfortunate past. Buspirone, we've talked about, and the fact that filazidone has that as part of its mechanism of action. Unfortunately, the vorteoxidine data just have not been that strong. It would be interesting to use carprezine, but it hasn't been done. The data using the psychedelics are really premature. There are the studies, particularly impressive studies, using psychedelics to treat anxiety associated with individuals that have malignant cancer. However, it's important to recognize that what makes that work is the psychotherapy. This is not something that is in itself useful. It's useful within the context of the psychotherapy. The psychotherapy being done is long, and when they give these people these medications, they're with them for eight hours. There are usually two therapists with them. Now, just out of curiosity, how many of you think that that would be great in your practice? Eight hours, one patient, two therapists. Wouldn't you make a fortune? Nope. So it's an interesting area, but we really have to figure it out. There have been a lot of work with neuropeptides in the past, and I get to gladly tell you that I've been involved with a whole bunch of those negative studies. The one neuropeptide right now that is moving ahead in an interesting way is the NPY stuff, and that's coming out of Mount Sinai. They have some really exciting translational work going with NPY right now. They've been using it in GAD and PTSD, and so it's really exciting, and there may be something there in the future. You know, if we look at the GABAergic compounds, we've talked about gabapentin, we've talked about pregabalin. I'm not a big proponent of using the opioids, either the agonist or the partial agonist for treatment of anxiety disorders. Do some people do that? Yes. The addition of that for some individuals, does it make a difference? Yes. I had one patient who came to me on that combination, but his anxiety broke through, and we had a devil of a time getting him off of the opioid agonist. And then the benzodiazepines we've talked about. So this is a really cool area. There may be a lot that's gonna go on in terms of hormonal modifiers. In particular, there's really exciting work that's going on in this area. The PH94B, which is an intranasal use of a synthetic neurosteroid for social anxiety disorder, is gone through phase three. There may be potential there. And where it would be used is not as a continuous treatment. Where it'd be used is prior to certain circumstances where one can anticipate there'd be problems that would develop with somebody who has social anxiety disorder. So it's not a continuous treatment, but it's much more of a specific treatment that'd be used on a PRN basis. There's also some other developments, particularly using intranasal approaches, that may be exciting. The issue that we're gonna face there is acceptance. A number of years ago, Pfizer tried to introduce an oral insulin. And all one needed to do was use an inhaler for insulin. And they were not able to get the patients to accept it. They were not able to get the patients to tolerate using it. So it's an interesting area. The work with oxytocin is very interesting. Larry Young at Emory has done some really outstanding work in that area. And I think there's real potential for that, as well as the VP1 agonist in GAD. So this'll be an interesting area. Now, natural products. I've been funded by NCCIH for almost 20 years. We've done a lot of work both in natural products and in something else I'm about to show you. The issue you face with natural products is that natural does not mean safe. Natural products in general, as is the case with what we were talking about with some of the psychedelics, the problem is that there are many, many active ingredients in these compounds. And there's no good manufacturing standards that are really enforced, although there are some companies that are really good and quite reputable. If we look at kava, for example, it was purported to be an anxiolytic and anti-convulsant and muscle relaxant. There were 12 positive trials throughout the world. It had similar efficacy in trials to venlafaxine and buspirone. It was effective in treating mild anxiety, you know, like you'd see in GAD, early GAD, but not panic attacks. And there was even some thought it might have an antidepressant effect. Now, what happened with kava, though, is that there were 78 cases of severe kava-related liver toxicity, 36 cases of hepatitis and cirrhosis, 11 cases of liver failure requiring transplant, and four deaths. So the key there is that natural does not necessarily mean safe. That doesn't mean that they aren't useful. I'm funded by NCCIH. I've been funded to do work with high-dose omega-3 fatty acids. And the reason why we are interested in high-dose omega-3 fatty acids is that, anyone here have inflammation before? Yeah? And you know how inflammation in psychiatry is kind of a cool thing now? Well, as it turns out, most of the ways people have approached treating inflammation, whether it's in psychiatry or in cardiovascular literature or other areas, has been to use biologics that are designed to inhibit the pro-inflammatory side of the cascade. But, well, think about it. Just out of curiosity, any in this room ever have a cold or a flu or that disease, what would we call it, COVID? Anyone? Yeah, I have. So when you have any of those circumstances, as you'd expect, what you have is an inflammatory response, right? So are you taking a biologic to decrease that inflammatory response? No. What people don't talk about is there's an entire second phase to the inflammatory cycle, which is the resolution of inflammation. And as it turns out, the compounds that are involved in the resolution of inflammation all have omega-3 fatty acids as their backbone. And so we've been doing work with colleagues at Mass General, and we have a wonderful grant in right now with Dilip Justy in San Diego, as well as folks at Emory and Mass General, looking at high-dose omega-3s, with the idea being that if you can use that to enhance the resolution of inflammation, one may not need to use these biologics, which put people at risk for severe infection, and in certain cases, neoplasms. But anyway, what you need to be is very careful, because what you see here, again, is something that people don't talk about, which are the effects of herbs on drug-metabolizing enzymes in transporters. And what you see with goldenseal, with green tea, with milk thistle, is significant decreases in cytochrome P450 systems, and also in terms of milk thistle, and you're looking at changes in some of the other systems involved. The P-glycoprotein system, which is involved in clearance of medications. If you look at St. John's wort, do you know that there are some babies whose middle name is St. John's wort? And that's because St. John's wort, in contradistinction to most medicines that we use, is actually an inducer of 3A4. And so St. John's wort causes a decrease in both birth control pills, but also a really frightening decrease that can occur in individuals that are on HIV medication. And it also can cause people to reject organs, because the medicines used to keep people from rejecting organs are all metabolized through 3A4. There were actually a series of documented cases in Europe of heart rejection associated with the addition of St. John's wort to medication. So it's important to understand that these compounds, although I think they're going to be incredibly useful over time, need to be studied carefully. These are medicines that are thought to improve psychotherapy. The de-cycloserine literature is really mixed. The initial studies, which were done by really good psychotherapists, were positive. Then some other studies, many of them again done by good psychotherapists, couldn't replicate the findings. There was a recent Cochrane analysis that suggested that they could not find a positive effect for de-cycloserine versus placebo in enhancing the psychotherapy response. However, there was another analysis that was done that suggested that if someone had a really profound response to de-cycloserine in the first session and had really profound extinction, for example in PTSD, that those individuals tended to do better with de-cycloserine than placebo. But again, in general, the data there are quite mixed. We've talked briefly about the use of hallucinogens. I'm actually chairing for the state of Utah a task force on this issue right now. It's very disconcerting to know the number of true believers versus the individuals that are doing science. Right now, there is very good science that's being done by eosoma. There's very good science that's being done by COMPASS. There may be something there, but we need to be very careful. Again, there are going to be huge issues about dosage. There's going to be issues around the amount of time that people have to be monitored. And there's going to be issues around when is it effective and when is it not. And we really don't know that at this time. These are some of the other things that have been used, minocycline. There's animal work with fecal transplant, and there's also been some work in pandas. Hyperbaric oxygen. There's been some interesting work by Saeed Khalsa and others at the Laureate Institute using flotation and looking at interoceptive and flotation. It's really quite interesting. Neurofeedback, of course, has been used. And now you guys are stuck. You know why you're stuck? Because I'm a massage researcher. And so I'm going to show you one of our NCAM studies. What we did was a six-week study where we contrasted massage versus a touch control condition in the treatment of individuals with GAD. And what we were able to demonstrate versus light touch, they were touched the same amount of time that was highly scripted, was that massage was very effective beginning at session six, halfway through the treatment, in decreasing anxiety on the Hamilton anxiety scale versus an active control condition. We also found that massage was very significant in decreasing symptoms of depression in these individuals. When we looked long-term, we did a six- to 18-month follow-up with these individuals. And what we saw was that 40% of individuals remained symptom-free, which is actually remarkable. If you look at the medication data and if you stop medication for GAD, most people have recurrence of GAD. If you look at the psychotherapy data long-term, you may get response rates that are a little higher than this, but not a lot. Of those that had recurrence of symptoms, 64% had a life event that triggered that recurrence of symptoms. And what one sees is that the recurrence of symptoms were only in the sometimes range rather than in the always or often range or extreme range. And when you look at quality of life, by the way, this paper is in press right now, what one saw was that these individuals had really good physical well-being, overall quality of life, ability to deal with stress, and work productivity. So it's an interesting area. We've just been funded to do an imaging study in GAD. So we'll be comparing, contrasting people with GAD prior to the massage intervention and after the massage intervention. And then from another source, we're going to be also looking at controls and getting the same imaging data. No one's ever done this before. So as you can see, we know how the brain works. So these are experimental non-medication interventions that can be used. Brain surgery, radiosurgery, DBS, VNS, RTMS, CES, TDS, and magnetic stimulation, and near infrared. Now, unfortunately, there isn't a lot of work in most of those. There has been some work in transcranial direct current stimulation. There are over 30 of these devices that are in existence. There's a low incidence of side effects. But there really is an absence of well-controlled studies, be it in depression, or there have been two studies in anxiety disorders. They were both very, very small. One was positive and one was negative in GAD. I think all of us know about RTMS. The only point I want to make about RTMS, aside from the fact that Sasha Bistritsky is going to give a great lecture on Tuesday from 4 to 5.30 on all of these non-invasive therapies, is the fact that RTMS has really advanced tremendously over the last few years. What we've been able to do by changing the types of coil and coil design is really get much deeper than we could initially with the initial studies that Mark George and others did with TMS. And we're at a point now where we can actually use TMS to look at and impact deeper structures than we've ever been able to before. As of the meta-analyses that was done recently, there had been 17 RCTs with RTMS. Of those 17 RCTs, the majority of them were in PTSD. There were four in GAD. There were two in panic disorder and two in SAD. The data for panic disorder and SAD were mixed at best. The data for GAD were actually pretty strong, though there were only four small trials at that time. And the rest of the studies were in PTSD where, again, there was a fair amount of positive data. And it looked like there were moderate effect sizes within the context of the four studies that were done in GAD and the studies that were done in PTSD. But one of the things that's really exciting is there are two things exciting here. One is some of you may have attended the great lecture that was done yesterday by Amit Etkin where he talked about neurocircuits. What's happened is that with the advent of MRI and where it's going in terms of the new sequences being used and other approaches, and with the development of 7T, we're really beginning to appreciate neurocircuits and the importance of these circuits and how we might be able to impact the circuits themselves. And that's one of the thoughts with RTMS, is that you can focus it and actually impact some of the underlying circuits. And that's also the thought with MRI-guided ultrasound. And so this briefly just shows you an individual who's going through MRI-guided ultrasound. And what it really allows one to do is have a much better sense of deeper structures in the brain and also a sense of what stimulating those structures may do in terms of alleviating symptoms and resolution, at least temporarily, of a disorder. I think focused ultrasound is really exciting, and I think there's a tremendous opportunity there. You know what focused ultrasound can do, which is really remarkable, is discreetly open up the blood-brain barrier. And so what that allows you to do is potentially, over time, to discreetly have nanoparticles that will go to very well-described areas of the brain. And I think that may be one of the ways it's used in the future. The other thing you can do with focused ultrasound, as we were talking about with RTMS, is you can use it to actually impact brain circuits in a much more precise way. So these are exciting opportunities that are going to get developed in the future. And at least I'm optimistic about it. But then my wife says I'm optimistic about almost anything. Vagus nerve stimulation. Sounds old, right? We all know of the original studies with vagus nerve stimulation where you were doing a surgery and all that. Well, what's really cool now is that there's auricular vagus nerve stimulation, and there's also a device, a handheld device, that you can hold up to your neck and do vagus nerve stimulation. So you can attach an electrode to the ear and do vagus nerve stimulation, or with a handheld device, hold it up to the neck. And what's neat is that the preliminary work in this area, a lot of it was actually funded by DARPA. What's really cool about this work is that, unlike what we did with the invasive vagus nerve stimulation, where you had the stimulator pulsing on and off every five minutes or so, and it was there until the battery ran out, unlike that, this is something that can be done for a discrete period of time, and it isn't something that you have to do continuously or all the time. There's some really exciting preliminary work going on in this area. Doug Bremner at Emory, who is a colleague of mine and was generous enough to include me in some of this work, Doug's been doing work looking at individuals that have been exposed to trauma, and by using the VNS, the handheld device, they were able to actually show both a decrease in response to fearful faces and also changes in terms of MRI function that was suggestive that they were not having the same type of anxiety response they had during the periods of time when the sham was used rather than the active device. What also Doug was able to show was that one of the things that stimulation of the vagus nerve does, as you obviously think, is that it increases parasympathetic tone. One of the reasons why I'm very interested in increasing parasympathetic tone is because if you do so, you decrease inflammation. It's one of the ways our bodies decrease inflammation is when parasympathetic tone is increased. Parasympathetic tone tends to be more pro-inflammatory in nature. There's really exciting work in non-invasive VNS that will be, I think, very useful for our patients in the future. I want to talk briefly about early identification. This is work done by Julie Anderson and Janet Lindau at the Rural Behavioral Health Institute. Janet Lindau is an interesting person in that she has a PhD in molecular biology from MIT, but then went on and did a fellowship in implementation science. She was an associate professor at Yale and was involved in doing implementation work in Brazil. Her group was one of the first groups to describe the Zika findings and the problems with the brain malformations associated with mothers being pregnant with Zika. Janet then had an epiphany. She moved to Montana and got interested in psychiatry and mental health. What she's done is taken her skills in implementation science, because one of the major problems we have is how do you effectively bring our treatments to market? How do you do it in a way that people get to use it? What she did was the following. Partnering with school systems there. The reason for partnering with the school systems is Montana, like Utah, has one of the highest rates of suicide in school children in the country. Partnered, used a web-based approach. It took five to eight minutes. Results were then given to the school. Within one minute, these were the screening tools used, the CSSR, depression ratings, anxiety ratings, and the WSAS. There are other measures that are possible. What she did was link universal school-based screening that any youth had with treatment, same-day mental health treatment. What they were able to do by using this approach was really phenomenal. In this pilot work, they screened 874 students. 8% had recent suicidality. 19% had a lifetime history of suicidality. 11% had depressive symptoms, and 11% had anxiety symptoms. This screening is really critical, and really is one of the things that we need to do, and one of the ways we need to go. I think we all know, and there was a lecture, I think, competing with this, talking about the second pandemic, the prevalence of anxiety and depressive disorders and suicide that's occurring in young children today. I'm firmly convinced that we need to go to models like this. I won't do it during the talk, because I want to have time for questions, but we've initiated at the Huntsman Mental Health Institute a project in rural, suburban, and urban schools as an attempt to intervene at this level. I want to talk briefly about big data and artificial intelligence, and how it may offer both preventative and preemptive interventions for us. This is work of Nina DeLacy, whom I mentioned earlier. Nina is a young faculty member at the University of Utah, who previously was at the University of Washington, and she's doing really innovative work in this area. We know this about psychiatry. It's the world's leading cause of disability. It's the costliest health condition, and the only one in the US that continues to be increasing in disease burden. It's the second leading cause of mortality for people 10 to 44 in this country. That's the way we used to treat disorders. What's really important is this. This slide is really critical. What you see here is that 70% of mental disorders have onset, usually between about the ages of 10 and 25. It's one of the reasons why the number of disability-adjusted life years for psychiatric disorders outpaces cancer, and outpaces heart disease, and any other disease in the world. Where I think we need to go, one of the places we need to go is with computational science. That's really at the interface of applied math and numeric methods, computer science, and our discipline of science. The intent there is to build models as scientific tools, and analyze systems and processes, to make predictions about future illness, about the mechanisms behind illness, and new ways of intervening. You can test things in silicone. If you were to build a computational model of mental illness, how do you do it? You need to take a variety of things into account. One is, in Nina's work, what we've been focusing on are the peri-adolescent sensitive periods. The intent is to predict individual cases of mental illness using a dimensional approach, and discover the factors that are causing these illnesses. It's a real attempt to do precision medicine, is what we're talking about here. The risk factors include socioeconomic, demographic, cognitive, neural, and genetic. As you can see with those risk factors, it's real simple, right? Snap. No. Look at those risk factors. Look how complex they are. It's actually one of the reasons why, at the Huntsman Mental Health Institute, what we do when we're tackling these problems nowadays is, we have experts in public policy, in law, in business, in AI, in big data, in translational science, working with the clinical science, and translational and basic science. In order to tackle these big problems that we face, we've got to take a comprehensive approach, but in doing so, you really need experts from a variety of different fields. The risk factors are huge. The intent is to use dimensional, in Nina's work, to use dimensional measures. What she does, which is really unique, is we talk about GAD. We talk about social anxiety disorder. We talk about panic disorder. We talk about depression. But if you look at the signs and symptoms of these disorders, if you look at the comorbidities we see in our nosology today, what it suggests is that, although this nosology is useful for us and functional in certain ways and allows us to communicate with our patients and our healthcare systems, what it is not is anything more than an approximation of what's going on. So by using these types of measures with AI, what one will do eventually is develop a new nosology and a new approach that's much more personalized when it comes to the treatment of individuals. And that's the whole intent of this work, is to individualize treatment approaches, to understand better the mechanisms behind it, and have a much better understanding of prognosis than we do today. The rationale for using AI, as we just talked about, it's very simple. We looked at the other slide. We looked at what? Economic factors. We looked at sociocultural factors. We looked at biological factors. We looked at changes in brain imaging. Yeah, it's simple, right? No. We have hundreds of candidate factors, and it's likely a multifactorial process. The mechanisms are currently poorly defined or undefined, and the brain's dynamic. As it's, you know, you have both human development and maturation of the brain going on simultaneously, and we also have the impact of the environment on the body and the brain. So if we look at AI itself, it's a system's ability to correctly interpret external data to learn from such data, and that's the key point, to learn from the data, and to use the learnings to achieve specific goals and tasks through flexibility adaption. So there's general AI, which is a system can cope with any task to ask of it, like being a person. And then there's narrow AI. Narrow AI, you guys, anyone have a cell phone here? Welcome to narrow AI. Siri. Narrow AI. Let alone all those messages you get because all of a sudden they've seen that you've been looking for something online. It's narrow AI. So this is some of Nina's work. She collaborated with the Child Mind Institute. They had over 1,100 young people, five to 21. It was enriched for psychopathology with 2 1⁄3 of the individuals having a DSM diagnosis. But they had a really rich phenotyping, which we'll talk about in a minute. And they had fMRI. We're only going to look at the anxiety disorders data because, again, there's far too much. But what they did with this sample from the Child Mind Institute is look at demographic, socioeconomic, cognitive, developmental, and neurodata. They took all of that data, they trimmed it appropriately, and then put it in the computing systems for AI. They used a model where there was both a test, they had a test sample that was withheld, and they used the first as the experimental sample. And the intent was to develop a series of predictive factors that were both sensitive and specific. And the intent there is a parsimony. You don't want to have a huge number of factors. But they looked at, in order for them to be successful, they had to be at greater than or equal to 85% accuracy, specificity, and sensitivity. They actually ended up at 95% accuracy, 94% specificity, and 95% sensitivity with this work. And the factors that predicted, that prior to onset of illness, predicted that individuals would get ill were not imaging findings, they were not biomarkers, they were adverse life events, having high levels of internalizing traits and externalizing traits. If the parents were under a lot of stress, if the parents' coping style and style was a callous and unemotional style with their children, and the type of work that Ned Kalin was talking about earlier about social cognition and the anxiety that certain kids have, they were able to successfully use that to predict who would get ill. So the intent here is to suggest that in the future, what we may end up doing is use measures that look at adverse life events, the SDQ, which looks at internal and externalizing traits, hyperactivity, and then look at parental measures. And by doing so, again, I didn't share the data because we're running out of time, but what you would see is they were able to discern predisposing factors for trauma, anxiety, depression, disruptive behavior, and ADHD using this model. So the key is that AI may be a very useful tool for us. As you can see in Nina's work, it was accurate, it was sensitive, it was specific. It can allow us to develop this new nosology based on what the actual findings are rather than what we've had to do, which is sort of intuitive nosology. And then, yes, we validated beginning with DSM-3, but it's still an intuitive nosology, and we're really describing large syndromes rather than specific disorders. By using this type of approach, we'll have a much more robust classification of mental illness, we'll have better understanding of the mechanisms involved, and new ways of treating individuals. So big data, we can predict individual cases of mental illness with high accuracy, sensitivity, specificity. Mental illness is likely complex and multifactorial. Deep learning in AI with neural networks will be the way of the future. And we know that certain screening instruments in the clinic really are quite valuable. So in summary, the FDA-approved pharmacotherapy has not changed in decades. Medication in combination with evidence-based psychotherapy is valuable and works for most people. Teletherapy, asynchronous therapies, and a variety of other new approaches are going to be valuable in helping us with our patients. There's emerging evidence for new somatic approaches, and I think within the next decade, we'll see a lot more approval for RTMS and other disorders. And AI may help us in terms of identifying risk factors and really intervening prior to somebody getting ill. That's the intent there. The intent is to intervene prior to illness, or to intervene early enough that we can preempt. I'm a parent, I'm a grandparent, and I know that I'm disrupted if my kids are in trouble. I'm disrupted if my grandchild is in trouble. If we can keep kids from getting ill in the first place, or if they do get ill, if we can intervene appropriately and early enough, that will save the family, that'll save that child, and allow that child to progress normally. And I think that's really critical. Thank you for letting me preach for a long time. Thank you very much. Thank you very much. Thank you very much. Thank you very much. It was so wonderful. Take a sip of water, so prepare for the Q&A session. Anybody has any questions, please use the microphone. Or if you have an answer, please use the microphone. Yeah, we'll wait until some of our participants leave the room, yeah. Hi. Good. Hi, so I have a question about one of the slides that you had earlier about combining two SSRIs and one SSRI and an SNRI. So if you could talk a little bit more about that, because that wasn't something that was particularly encouraged in our training, or, you know. Yeah, you know, you're right. And so what's important to understand is that the SSRIs are not identical either in terms of their pharmacodynamics, or, you know, at all. And so sometimes combining two actually does lead to a better response. There have not been good studies doing that. And the reason for doing it, it would be based on looking at the differences in pharmacodynamic profiles of the agents, and seeing if by doing so, you might be able to enhance response in certain individuals. It's part of the art of psychopharmacology. It's not something I would do commonly, but it is certainly something that can be considered, as is combining an SSRI with an SNRI, or combining, oh boy, I'll get in trouble. You can also, of course, combine an MAOI with these other compounds, but you have to do it right, and have to be very, very careful if you do anything like that. But sometimes that's what's necessary in order to get someone well. Please. I was wondering your opinion on mood stabilizers for anxiety. It looks like there was some mention of Depakote, and maybe some SGAs on the side, but even like Lamictal, or even lithium, either in straight anxiety, or if there's a comorbid mood issue, it doesn't quite meet criteria for bipolar I or II. Yeah, again, I think that it is mostly dependent on one's practice and one's patience, but it certainly is reasonable to, particularly if one has a patient who's not able to fully benefit from the conventional treatments, to look at using, whether it's Lamotrigine, or using valproic acid as an adjuvant. But in order to do so, I think what's critical to me, and I'm old, I'm gray, a long time ago I learned that my patients know a hell of a lot more than I do. They really do. They know what symptoms they have. They know how a disease is affecting them. So what I do, and I do this with every patient anyway, but I would certainly do it in cases like we're talking about where people are treatment resistant, is I ask them what's bugging them the most, and I actually ask them to partner with me and chart, not the DSM symptoms, but what in their lives is bothering them the most, and what would be success for them. And by doing that, then when I've done things like add anticonvulsants to treatment, I know whether it really is helping them or not. And that's been very, very useful. But yeah, you certainly can consider using other anticonvulsants as well. Thank you. Sure, please. Hi, is there any recommendation for a patient with a recent arrhythmia, like to change fluoxetine? I mean, this patient is a very younger, like 25, and she has the diagnosis of general anxieties like three years ago, and she started with palpitations, and cardiologist says she has an arrhythmia. So do you think that she must change the fluoxetine, or there's any other option for that? Well, I guess it would depend a little on the arrhythmia, but the association between fluoxetine and arrhythmias is not nearly similar to what you see with citalopram, for example, and arrhythmias. So I would work in concert with the cardiologist, but I would probably end up, if she's responding well to the fluoxetine, I'd keep her on the fluoxetine, unless there was another medicine that the cardiologist was trying to use in conjunction with it. Yeah, because we give her like 20 milligrams, and then we increase it, because the symptoms were getting worse of the arrhythmia. So apparently with the fluoxetine, the palpitations started getting worse, and so we decided to reduce the doses. But... So was it the palpitations that were getting worse, or was it an arrhythmia getting worse? No, apparently it was both. So she started having more anxiety, and that would make us go to the cardiologist to see if there's something else. I see. So it was like a finding. Yeah, but I would actually consider some of the other approaches, aside from an SSRI and someone like that, because the other thing that may be going on, there's some patients that are exquisitely sensitive to SSRIs, and I've also seen individuals, particularly individuals that were poor metabolizers, really end up on much higher levels with a low dose. So I'd consider another approach. Okay, thank you. Sure. Hi, I'm Dr. Galante, I'm a psychiatrist from New York. Right now, I have a fear of public speaking. So right now, my heart is racing, I've got a little bit of tremulous in my voice, I'm a little tremulous also. And this is my question. In the old days, a long, long time ago, somewhere I read about the use of propranolol, beta blockers. Yep. What is it? Why aren't we using those things? Why aren't we doing anything about the feedback from, I guess, adrenaline and fight and flight syndrome? Yeah, I've used, particularly with individuals that have specific phobia, I've used propranolol a lot with good success. And so, yeah, I've used it with people that have fear of flying, I've used it a lot with people with public speaking phobia, with a fair amount of success. And so, yeah, I think it's very reasonable to use in a PRN basis. Thank you. Hello, my name is Lawrence. Question here is treatment for long term. After six months to about a year or more, these patients on these medications have different side effects, especially weight gain that is burdensome to the psychiatrist treating them. And most of them want to get off these medications. So how do you deal with them? Because most of these medication pros, I just name it, weight gain is severe after a long time. So what do you do? I think that there are several things to do. One is to acknowledge that it is a challenge for some people. Second thing one does is talk with them about whether the disorder itself is worse than the weight gain or is the weight gain worse for them. And if they want to try tapering off, years ago, so one of the first things I tell a patient when I work with them, I tell them two things. One is that there has to be a fit. There has to be a fit between who I am and who they are. And they have to be comfortable with me. The other thing I tell patients is that they're the captain. I can coach, but they're the captain. They're the ones on the field. They're the ones living their lives. So the first thing I tell them about that is, look, I may be prescribing you something, but what I really need to know is what you're taking. Not what I'm prescribing, but what you're taking. As I digress more, I learned that from, I did a year of internal medicine, and my very first outpatient clinic, there was a guy with four VA charts, four big VA charts. I'm a new doctor. I've been a doctor for a whole week. And my first clinic patient was a gentleman who was a bilateral amputee who had COPD he had heart disease, he had hypertension, he had diabetes, he was on 14 different medicines, Q-Day, BID, TID, and QID. And being a great new doctor of one week, I looked at him and I said, sir, how do you do this? How do you take all these medicines? And he looked at me and he said, well, doc, I don't. I take these three twice a day. I said, but you've been filling these medicines for years. He said, well, doc, that other doc was trying so hard to help me. I didn't have the heart to stop. But what it taught me was one, to always ask what people are actually taking, not what I'm prescribing. And two, the other thing it helped me understand was how important it was to hear my patients and hear the Alliance. And we'll do things, I'll work with people. I'll say, okay, well, let's increase your exercise. Let's work together to see if we can mitigate some of the stuff you're seeing with weight gain by increasing your exercise. Or tell me about your diet. Tell me what's going on. And more times than not, and then we'll talk about, well, you remember when you were tracking your symptoms, and right now your symptoms are all zeros. They were up at eights and nines. We can try tapering the medicine, but if your symptoms, as we're tracking the medicine, start coming back, we're gonna have to look at that medicine or something else to help you. I'm sorry I don't have more wisdom. Thank you very much. Thank you for the presentation. My name's Dr. Michelle Morgan from Phoenix. My question is about benzodiazepines. I have a number of, and I'm sure many of us have inherited patients who've been on a benzodiazepine for 30 years. They've been taking this dose. Their history is that they've been tried on this, this, that, and the other. This is the only thing that works. They're stable. They're not overtaking or abusing the medication. There's tremendous pressure right now because of this possible correlation with dementia that's controversial. To get these patients off of benzodiazepines, my inclination has been always just to leave them alone as long as I don't have evidence that they're doing anything other than taking them the way they're prescribed. But again, there is this pressure. I just wonder, could you speak to your thoughts about that? Sure, and get me kicked out of the APA. I agree with you. There are certain patients, these are not patients that are abusing benzodiazepines. These are patients that have gotten a really good response, have been stable on them for years, and what happens is that sometimes we get, whether it's peer pressure or whether it is the pharmacy that's trying to do it, my goal is always to take the best care I can of the patient. I'll talk with them about what the data may show, but if it's working, and if their quality of their life is good, and if they're not symptomatic, you know, there was a very, very wise psychopharmacologist named Louis B. Mayer of Metro-Government Mayer. He was a filmmaker, not a pharmacologist. And I was about to give you the wrong quote. Damn, let me do it this way. There was a great baseball player, and Yogi Berra said, if it ain't broke, don't fix it. And I truly believe that. So I would tend to, you know, explain the risks and benefits, and if the person, you know, it's their life. If they're stable, if they're comfortable, if they understand where we're coming from, I'm fine keeping them on benzodiazepine. I've had people on benzodiazepines for years, because that's what worked. Thank you. Sure. Last question. Hi. My name is Sarah Cash, and I work in outpatient psychiatry, and my question is about, you know, the clients. We use our resources pretty well in our clinic, and, you know, what do you do with those patients that are very motivated to get better? They do everything that you recommend. They get some relief from medication. They have some relief from inpatient treatment, TMS, partial hospitalization, frequent therapy, but they still don't have the satisfaction that they want. They're still having really severe anxiety. You know, what's the next step? Well, you know, that's a... Thanks for asking the million-dollar question. Well, I didn't know if you had, like, more accessible... Obviously, working in a university, you have more accessible resources. Well, I do believe that... The first thing I always do when I get a new patient, particularly somebody who's treatment-resistant, is really try and understand that person. And you may know these people well, but I would not. Yeah. And so one of the things that I've seen persist so many times is that there's hidden trauma. And the role of trauma in these individuals is really profound. Another thing that happens frequently, particularly with people with anxiety disorder that's non-responsive, is that there may be more use of alcohol and other substances than people realize. And it happens more often than one thinks, because people, in general, minimize the amount of drinking that they do. A third issue to look at, there was some work years ago by Hogope Kiskel. And Hogope was very interested in looking at variants of bipolar disorder. And one of the things that Hogope talked about was how the use of antidepressants in people on the bipolar spectrum disorder actually caused anxiety and massively increased anxiety in these individuals. So it would, again, behoove one to just be very careful and look at the family history of bipolar disorder, look at, within that individual, whether or not there was any hyperthymic sort of picture to that person, and consider then another type of therapy. And then going back to our colleague who talked a minute ago about benzodiazepines, as I get myself kicked out of the APA again, I use benzos. I think that they can be very useful. I think they have to be carefully monitored. But they are good drugs. And for many people with resistant anxiety, they may be the only thing that ends up working. Okay, thank you. Sure. Thank you, guys. Thank you, a round of applause for our speaker. Enjoy your meeting. So that was okay. That was great. Hi.

anxiety disorders

evidence-based approaches

clinicians

PTSD

cognitive behavioral therapy

internet-based treatments

virtual reality treatments

high-dose omega-3 fatty acids

hallucinogens

neurofeedback

massage

AI

tapering off benzodiazepines