Good morning, everybody. I think I'll wait. We have a couple of minutes, right? Maybe. Just wait for people to come in. The volume is low. I probably need to come closer to the mic. Can you hear me now? Okay, yeah. We'll wait. Some issues, I was told that if you ask any questions, you probably will be best to come towards the mic. And maybe you can come forward because we don't have a lot of audience, so maybe there can be some good question and answer session and some interaction. I appreciate that. And basically, the questions need to be because nothing is recorded if you are not close to the mic. So that is the reason why I was requested to do that. Anything else? Okay, so I think I can begin now. Let me first declare that I don't have any disclosures relevant to this presentation. And let me introduce my presenters for today. So Dr. Vimal Agha is an Adjunct Assistant Professor in Neurology and Geriatric Psychiatrist, and he is NIA-funded Leighton Aging and Alzheimer's Research Center, Department of Neurology at Oregon Health Sciences University, Portland, Oregon. And he is a Senior Geriatric Psychiatrist and Hospitalist at the Oregon State Hospital where I used to work with him a few years back. He received his medical schooling from India and completed a psychiatry and geriatric psychiatry fellowship from the University of Wisconsin in medicine. He has extensive experience in working for the dementia patients, and he conducts some West Coast Geriatric Fellows' most difficult case conferences. He has been a presenter in several general sessions and other presentations at APA and otherwise, and he has written several papers and book chapters as well. So Dr. Agha will be talking about very interesting cases which are relevant to this presentation in terms of the innovative psychopharmacological, but from a diagnostic perspective more importantly. And then this is me. I'm not going to talk a lot about myself. I am an adjunct professor at UNLV, which is the University of Nevada, Las Vegas. And I also am affiliated with the Toro University, Nevada. And I have to tell you this. We just recently got a new psychiatry residency program in Las Vegas, and I'm the PD for that. So I was so excited to have that because I've always been interested in teaching. So let me move on. And Dr. Suarez is actually a very well-known psychiatrist, and he is from Houston. He's a professor and chair the Department of Psychiatry and Behavioral Sciences and is also at Rutherford Chair in Psychiatry at the McGovern Medical School. And I used to work with him a few years back as well. And we have this Pittsburgh connection, you know, because we were together at Western Psychiatric Institute and Clinic. So I know him very well. Executive Director of the UT Health Harris County Psychiatric Center, and the list keeps on going on. And you can see that he has a Center of Excellence for Mood Disorders, and he's the director of that. He's the Vice President for Behavioral Sciences at UT Health Houston. He received his MD degree from University of Sao Paulo, School of Medicine, Brazil, and did his PhD as well from Federal University in Brazil. And he has a fellowship in brain imaging from the Yale University School of Medicine, Department of Psychiatry. And he has published over 350 papers and book chapters. And we're really, really honored and excited to have him as our discussion today. And Dr. Anwar Mezi, because of family reason, could not come, but I just wanted to introduce him. He's from Southern Illinois University. He is an associate professor, and he's a fellowship director over there, and he also published several papers. So let's begin the presentation. So I'm going to introduce what this presentation is all about, and I'm going to follow this discussion with some cases, so that I can make a justification for what is innovative psychopharmacology, and what do I mean by that, and what is problem-based learning, and how it can actually motivate residents and the trainees to take interest in psychopharmacological training, which is, I think, a need for these times, as there are so many explosive discoveries and novel treatments in various psychiatric indications. These are very exciting times. So the objectives are that we are going to learn historical, medical, legal, and ethical aspects of innovative and collaborative learning in psychopharmacology, and we are going to differentiate between evidence-based and innovative psychopharmacology. So this is a topic very close to my heart, and I have been actually kind of a little bit, you know, evidence-based medicine, we are all told is the gold standard, and it is. You know, I don't disagree with that, but the reason why I want to discuss about innovative psychopharmacology is that there is a lot of this increasing number of treatment-reflectory patients, and they are on polypharmacies, and sometimes we just conduct error and trial, you know, kind of use the error and trials method, and the patients are suffering side effects of their uninformed polypharmacy, which results in drug interactions and undesirable effects, and sometimes lethal outcomes, right? So evidence-based medicine, you know, the question is that what is the quality of the evidence? Sometimes, you know, there are really great studies, good research designs, and by any means, use that in population which are relatively easier to treat, and you don't come across any problems, clinical challenges, right? But I think in the treatment-reflectory population, there is lack of evidence in that population, and you have to be really innovative and logical. You can call it innovative psychopharmacology, you can call it positive psychopharmacology, based on belief, justice, idea, or you can call it, you can give it any name, you know, logical psychopharmacology, rational psychopharmacology, doesn't matter. What I'm trying to say here is that you really need to know your psychopharmacology and apply it based on the mechanistic and neurobiological understandings of the, not only the psychopathology of the psychiatric disorders, but also the molecular targets for the agent you are using in combination or as a monotherapy. So that's the whole gist of what I'm trying to say here. And then we are going to have, we are going to learn some hypothesis-driven neurobiological justification for innovative use of psychotropic medications, and then we will discuss a little bit about the clinical application of evidence-based and mechanism-based psychopharmacology, which will be exemplified by some cases which I will present today. And then, hopefully, we'll have a very interactive case-based discussion with you guys, and please feel free to ask us the questions. And I want this session to be quite interactive because that is one of the goal of this, major goal of this presentation. Now, innovative teaching. First, I'm going to talk about innovative teaching. What do I mean by innovative teaching in psychopharmacology? And what do I mean by problem-based learning? I'm sure all of you must have heard about problem-based learning, right? I think if you are an American graduate, you know, a lot of universities, actually, a large number of universities during the medical school used problem-based learning. You might remember those binders of cases, and your instructor or your supervisor gives you one page at one time, and you begin to learn more about the patient, and then they ask questions, what could be this, what is the differential, what does this lab value mean, and where are we going, right? So that has been a very, very kind of, in my opinion, very useful way of teaching medicine. I have been involved with the American Society of Clinical Psychopharmacology for a long, long time, and Dr. Ira Glick, who was the director of developing the psychopharmacological curriculum, for the residents, medical students, and psychiatrists, actually asked me that, Dr. Shah, you know, you should actually work on, I'll create a committee for you, and you should work on developing some interesting learning tools in which you can motivate the trainees and other people so that they are interested in learning psychopharmacology, because it is becoming so complicated, and it is becoming difficult, despite the explosive increase in our knowledge in the mechanism-based psychopharmacology, which we are, you know, you went to the exhibition hall, you know, you should be excited. The things which are happening, I've never seen those before, yeah. So I think exciting things are happening, but the communication to the trainees, and the gap is widening between the increase in psychopharmacological knowledge and the training of our residents and other people, right? So basically, these are very exciting times, as I just mentioned, and I'm not going to go beyond that, because you have already, I'm sure you have been to the booths, and exciting things are on the road and on the way, and there are a lot of novel agents which are already approved, and some of them I will discuss. So what is problem-based learning? I already told you what it is, because you are given a binder, and you know, gradually, increased information is released to you, page by page, and, you know, increasing multiple layers of medical information, lab, investigation, and then you are asked questions, what could be this, what could be this, and you provide further information, and then you are able to, you know, finally kind of come to what you can establish a diagnosis, and the management for it is also discussed. But in psychopharmacological teaching, what I have done is, I've used the same paradigm, but with a little bit of modification, because, you know, we are in the very initial stages of this. Although our problem-based learning cases have been published, are at the website, at ASCP, you know, we are going to, we are going to, you know, make it better, based on the feedback and presentations to the residents, which actually, we already did the first time, but we want to modify it further. So basically, what we do is, very briefly, that we actually present slides, rather than doing a binder, and in the slides, we gradually release the information to the residents, and then the note section is used, instruction for the discussant, or the supervisor, or the faculty, so that what kind of questions they can ask about at that point of the presentation, and there are, obviously, some instructions on how to answer, because, you know, none of us knows everything about everything, so we have to provide that guidance. So that's how, basically, that's how we did this. And, you know, one of the biggest reasons why I selected problem-based learning is because it provides collaborative learning, it provides flexible knowledge, and you can discuss all of that. Effective problem-solving skills are developed in the trainees, and there is motivation, because they become interested when they are asked about, you know, when they are provided information, and there is a group kind of effect. I may not call it contagion effect, but there is interest, and these are relatively small groups, you know, and sometimes, actually, we do a kind of team-based learning, which is kind of a modification of PBL, where you actually create different teams, four or five or six on a table, and then you have many tables, and then you, in kind of a competition, who comes up with the answers, and so there is further motivation, and so we can use that model as well. So I'm going to skip this, because I've already discussed about this a little bit. So let me tell you how we did this. So the session basically starts with a brief introduction of the residents and their interest and career plans, and then the materials, reading materials are assigned for each session before we start the session, so there is a sort of a home or take-home kind of materials, which they can read before that. We provide a very friendly interactive atmosphere without any kind of non-judgmental interactions, and this completely non-judgmental, and we tell them no question is stupid. Please, you know, ask anything, and you are free to ask. Please, there are no restrictions. Nobody is going to pass any judgments. So this actually promotes patients, I'm sorry, the residence conference in case presentation, and they can agree with each other, they can disagree with each other, and then you can, with your expertise and with the feedback provided in the slides, you can actually tell them what could be a better solution to the problem, and what could be the diagnosis and management, and you discuss the facts, you generate hypotheses, and the learning objectives of the case are presented in the beginning and at the end, and then we got a paper published in academic psychiatry based on the survey which I conducted. I actually know a few program directors in America, and we actually involved some program directors to present those problem-based learning cases in their programs and get the resident feedback, and so we actually evaluated their responses, and we published that paper in academic psychiatry, and we actually got really good numbers ranging from 90 to 100 percent satisfactory rate after the presentation of the case, the pro-PBL cases. So this was, but this was, we can expand on this because, you know, I didn't do a pre-presentation survey, which I'm going to do next time, because it was just decided to do like this at the spur of the moment. So this is the paper which was published, and I just told you that the green-shaded questions, the first question was, was psychopharm, PBL in psychopharmacology was helpful, and the second question was whether they like to have PBL in their psychopharmacology edit their curriculum, and the responses, and there was a third question which asked if they had any feedback to improve this, and so the responses on the two questions were really, really very nice and motivated us further to continue this. Now let's go to the next topic of this presentation after we have discussed what I have done with the problem-based learning. So now the question is, what is evidence-based medicine, and what versus innovative psychopharmacology, which I introduced to you a little bit, a few minutes back, right? So let's see. So there are some limitations of evidence-based medicine psychopharmacology, as I discussed earlier, and again, let me repeat, evidence-based medicine is the gold standard whenever it is available, but at the same time, you know, if you are having patients who are treatment refractory, and you have tried every evidence-based treatment, and it's not working, what are you going to do? You know, it is a major problem, and the only way you can resolve this is to know your psychopharmacology well. You need to have a sort of, it's difficult to teach, because we relatively, there is a lack of translational neuroscience perspectives in teaching psychopharmacology, and so it's become difficult, but I think if we train our residents based on that, and we create a future force who can use this kind of model of very neurobiologically based psychopharmacology, then the things can improve. Because otherwise this gap between training and increasing knowledge will keep on widening. So that is one thing which is very important for me. So there is a growing population of treatment-reflective patients, I've already told you, and we need to do something about that. What if the evidence-based treatments are not effective, if no FDA-approved treatments are available? I just told you that, so let's go to the next point. Some treatments may be approved for a specific indication, despite clear evidence for efficacy. You must have thought about this, right, fluoxamine, which is an SSRI, didn't get approved for major depressive disorder, why? It's not rocket science, right? Most people who are knowledgeable about this know that the study design was very faulty, and there was a very high placebo response, and that is why fluoxamine did not separate from the placebo, and so it didn't get approved for major depressive disorder. Do you really believe that fluoxamine is not effective for depression? I've used it so many times, and it has some edge, some kind of advantage over some of the other SSRIs. I have found in some patients who are not responding with OCD, that is approved for OCD, but I'm just trying to make a point, major depressive disorder with obsessive-compulsive feature, that's what I'm talking about, it can be really effective. I think the most important thing which I like about this medicine is that it is the least frequency of sexual dysfunctions, for some reasons. So if there's a young guy, and they are really concerned about their sexual function, this can be one of the top choices in the list of SSRIs. So this is actually an excellent example of what I'm trying to say here, that evidence-based medicine is sometimes limited. Atomoxetine. Atomoxetine is a drug which is approved for the treatment, is a non-stimulant, approved for the treatment of ADHD. So if you are thinking mechanism-based kind of approach to psychopharmacology, you would know that bupropion also has some chance of working in it, there's no evidence for it, but theoretically, neurobiologically, it makes a lot of sense that valbutrin or bupropion is also a norepinephrine reuptake pump blocker, just like atomoxetine. So you can argue that if for some reason atomoxetine cannot be used, you can go to bupropion, and for that matter, you can also go to dizipramine and nortriptyline. These are the secondary amine tricyclic antidepressants, which actually are all relatively selective for blocking the norepinephrine reuptake pump, and can make a difference. So for example, if a patient comes to you and they have depression, and they have some cognitive deficits in attention and concentration, and you hypothesize that the patient might be having some remnants or some subclinical symptoms of ADHD, having lack of concentration or attention, you can always think about these other strategies and kill two birds with one stone. So this is what is innovative psychopharmacology, where you look at the mechanism, other drugs are not working, you have choices, and so that's a real psychopharmacological, this art of psychopharmacology, that I would like to label it sometimes, the art of psychopharmacology is very important. Why VANS? Is FDA approved for binge eating disorder? Do you think other stimulants will not work? They might, yeah, because why VANS is a stimulant. It increases dopaminergic activity, right? And if that is the mechanism you're looking at to reduce binge eating, then why not? Why VANS may not be available, may be expensive, maybe you could think about some generic options, right? So this is how I teach my residents, and the people I train, is that this way of thinking, you know, in addition to the evidence-based medicine. Again, I will repeat that. There are a couple of new medications, one of them Brexinolone has been approved as a treatment for postpartum depression, and this is the first treatment ever approved for kind of close to a psychiatric emergency. It's a really serious condition, right? All of us know that. And so this is really exciting, this is actually one of the most exciting news we have after ketamine, that a GABA mechanism drug can actually work for postpartum depression. And so we never used to think about glutamate and GABA, but ketamine and this discovery has completely changed that paradigm. Now we have moved beyond monoamines, and I've written some reviews about that as well. And these are very exciting times. And sometimes when you sit and you think about how many years we have not thought about these two major neurotransmitter systems in the brain, which are the most abundant in the brain. One is excitatory and one is inhibitory. And we just kept on focusing on monoamines, but it's never too late. I think exciting things are happening now. So Brexinolone is approved, but Zuranolone, which is under FDA, the FDA is almost kind of going to make a decision about it. Somebody told me the date, I forgot, it's very recent. So they are going to approve it or not approve it, but I have looked at the data and it looks very exciting. And the major advantage of Zuranolone over Brexinolone is that Zuranolone can be given orally and it is not that expensive because Brexinolone is a 60-hour infusion, which costs about $60,000, if I remember, and Zuranolone is not only orally administered, but also can be used, what I've looked at the data, can be used as a monotherapy. It's not an augmentation agent. So maybe even better than the ketamine because it's only used as an augmentation agent. Now we're getting these exciting mechanisms as a monotherapy and also non-treatment refractory depression, very important point to remember. And then onset of efficacy is also not as quick as ketamine, but it's pretty decent. And so all these things are coming and they are applied for both indications, postpartum depression as well as depression. So exciting things are happening. So this is what I was talking about that why there is so much exciting things happening in our field. And dexmethadromidine, it's difficult for me to say, but I don't know whether I'm pronouncing it correctly, but this is a drug which is recently approved for the treatment of agitation in older patients. And so it is an alpha-2 agonist. So when you look at the mechanism, you say, oh, why should I use such an expensive trade name? Why not go to a genetic drug which is also alpha-2 agonist and guanfacin and clonidine and viloxazine is not a generic, it's relatively recent, but approved for the treatment of a similar treatment. So I think this is what I'm trying to communicate, that you look at the mechanism, evidence may not be there, but based on the mechanism of action, if you have no other tools, evidence-based treatments have not worked, what are you going to do, right? You have to do something. And believe me, I've used clonidine many times and it has been helpful in some patients. This is a little busy table, but I just wanted to bring you, highlight the differences between evidence-based psychopharmacology and innovative psychopharmacology. So I was thinking about this and I came out with this idea that evidence-based psychopharmacology is missing the trees for the forest. Why do I say that? Because you are looking at a population response, right? You are not looking at individual patient. So you might be missing the trees for the forest. But what about the innovative psychopharmacology? You may be missing the forest for the trees. Which one is better? We are moving toward personalized medicine. So I'm not going to argue in favor of either one of them, but you know what I'm saying, right? Evidence-based psychopharmacology, trials done in close to perfect population, patient population. You know these clinical trials required by the FDA are conducted in patients who have almost no comorbidities, substance use disorders, psychiatric comorbidities, medical comorbidities. What is your real population? Completely unlike that, right? And the comorbidities, especially after COVID, are on the rise. So that is why sometimes the treatments which might be effective in the clinical trials may not have that kind of robust response in general population. And that's why we do effectiveness trials, such as STARD, KT, Cutlass, STEP-BD, which is a bipolar disorder effectiveness trial, right? What are the results? Not good. So this is something which evidence-based psychopharmacology has one of the limitations. Innovative psychopharmacology, in contrast, in real world population, applying a personalized approach. And that personalized approach can have anything. It can have pharmacogenetics. It can have pharmacogenomics. They are not ready for prime time, but in treatment refractory population, they may be helpful if there's nothing to lose, right? They may be 2D6 genetic polymorphisms. They may be 2C19 genetic polymorphisms, and you can find them. And I have, in the patients I've had, I've actually made some significant differences in their response and tolerability by knowing these two enzymes, which are most relevant. And I'm not making a kind of a hyperstatement here, because FDA has approved CYP2C19 and 2D6 analysis. So this is approved. I'm not talking about anything which is not approved here. And then you have the quality of evidence. I also already talked about that. The failure of fluvoxamine does not mean that it is not effective in the treatment of major depressive disorder. And then the innovative psychopharmacology, actually there is lack of evidence, except maybe you find some cases or case reports or case series, but there may be some evidence out there, as I'll show you, which supports innovative psychopharmacology in difficult patients. And then significant gaps in formal evidence with innovative psychopharmacology, you have understanding of the pharmacokinetic, pharmacodynamic understanding of psychotropics to match with the neuropathology of the symptoms the patient has. That's a very important point, which is going to make, increase your chances of being successful. And then, you know, our treatments, our disorders, which we treat with evidence-based psychopharmacology is based on DSM diagnoses. All of you know the limitations of DSM. It is a theoretical book, you know, just based on people's observations and surveys and talking to the expert. It has almost no neurobiological support. I was hoping that this year we might have some addition of neurobiological and some of the biomarkers for some illnesses, which we can add. I was hoping that we will do that, but that still is not there. So when you use psychopharmacological evidence, evidence-based psychopharmacology for diagnosis, which may not be reflective of what is really happening with the patient, you know, the results may not be optimal, right? Whereas in innovative psychopharmacology, you actually look at each symptom domain. You look at each symptom domain that can be targeted separately, and then you can combine medications in a rational polypharmacy. I already talked about lack of neurobiologically informed treatments, whereas innovative is absolutely neurobiological-based. There are multiple negative studies with evidence-based psychopharmacology where the clinical trials, the preclinical trials conducted to get the drug approved, several negative studies. I think very few people might know this since I've been in research for a long, long time and I participated in industry, the phase three clinical trials from the industry. You know how many studies were negative with Prozac? Nine. And there were only two positive studies. And the FDA rule is that you need only two positive studies to get the drug approved. And then you have placebo effects. If you ask me, one of the biggest problems in getting reasonable response and separation from the placebo of a drug you're investigating, placebo response is the biggest problem. And people have tried. Some people have developed sequential alternate treatment approach. Maurizio Fava from Massachusetts, I'm sorry, Harvard, he actually developed with the sequential design. But even there, you know, you have to create two groups of patients, one based on response from the medication and one based on the placebo response. And then placebo response is taken out from the whole cycle and you only work with those who actually responded to the active treatment. But that does not, that has limitations too. Because then you cannot apply that information to the general population, right? Any modification you make in a design of a clinical trial is going to be problematic. So there's no real answer at this time for placebo response, how to control that. And in my opinion, placebo response has killed so many potential molecules which could have been really, really effective. And that's a huge problem. And then you have ethical and legally kind of aspects of these two treatments. Evidence-based psychopharmacological approach complete, you know, much more legal and ethical protection than the innovative psychopharmacology obviously, right? But if you document well, if you say that we have tried this, this, and this, and nothing is working, and you document your rationale for using an innovative approach, I don't think, you know, you can be in trouble. Because documentation, documentation, documentation, right? So that's what we are told in the first year of residency when we start. So the bench-to-bedside, that is another aspect of my presentation. So basically, you know, bench-to-bedside, I've already touched on some of the aspects of this, that there is a lack of bench-to-bedside transfer of knowledge. And I'm not going to spend a lot of time because, you know, we have limited time. But just wanted to tell you that some of the problems which I'm really passionate about and I'm really kind of irritated by this is that the high drug acquisition costs. You know, the patient who deserves the innovative strategies are the treatment refractory, homeless, patients with very low socioeconomic status and cannot afford in no way the exciting developments in psychopharmacological treatment. And so we cannot do anything about that. You know, for example, you have heard about this new antipsychotic medication Lumetipurone, right? And Lumetipurone, and I'm not a speaker for any one of these, so I don't have any conflict of interest, but I just look at the mechanism and I find that Lumetipurone, if it was available for some of the treatment refractory population out there, you know, in this city, have you seen the homelessness in this city? Most of them are psychiatrically ill. It's actually brought down the city to get, you know, we have all noticed that, the change, right? If we can get those treatments to the patients who are most deserving, it can really make a difference. But unfortunately, the high costs are. And I'm not blaming the pharma, because pharma spends billions of dollars in developing a molecule. So I don't know what is the answer, but there's got to be some government support for this. Mandatory monitoring requirements? Well, the whole population is out then, because they are non-compliant. They are non-adherents. How they are going to follow the REMS regulations, which are associated with a lot of these innovative approaches? Insurance coverage, of course. And the COVID-19 has actually made a major difference in our health care systems, and the gap which is increasing. Now, this is the last part of my presentation. So I'm going to just give you a few examples very quickly, so we can invite our next speaker. These are some of the hypothesis-driven justification for innovative psychopharmacology. And we are going to present to you some adult geriatric and addiction cases. Addiction is not, I'm sorry about that, because the speaker who could not make it was going to present addiction. So what is the hypothesis one? Any drug that displaces high-potency, long-acting injectables will help to relieve adverse effects due to excessive long-term D2 receptor blockade. I'm talking about long-acting injectables, high-potency, haloperidol, flufenazine, even risperdal is a potent D2 blocker and cause major problems. So this is my hypothesis that a drug which has a high-potency, long-acting injectable will help any drug that displaces that drug from their binding site to the D2 receptor is going to help with the long-term side effects of a long-acting injectable. Because you know why I'm saying that? You are stuck with a long-acting injectable. What are you going to do, right? So that's the hypothesis. Let's look at some of the case report-based evidence. Rational, I just told you, that medications like haloperidol, decanoate, or flufenazine, decanoate, they bind. It also depends upon the dose. I have seen high dosages, especially in the state hospital populations where I used to treat patients. Like 200 is pretty common a month. And what is that going to do? And 200 milligrams of haloperidol decanoate will translate functionally into a 20 milligram dose. Simple math. Almost, right? May vary from patient to patient, but on average, right? So 20 milligram, more than 80% D2 receptor blockade. What are you going to get? Hyperpolactinemia, extrapyramidal symptoms, cognitive blunting, iatrogenic negative symptoms look like deficit syndrome, anhedonia. Negative symptoms will be potentiated. Amotivation, evolution, all the whole spectrum, you are going to impact. Reward, motivation, enjoyment in life, enjoying something in their life which they already have nothing left, these are the real issues. So what are you going to do? So what we did is we used a partial agonist, like eripiprazole. And we have published those cases. And now other people have done this too. But I think my cases were probably one of the first ones. And what we did is we just added a low-dose eripiprazole to the long-acting injectable. And some of the prolactin levels come down significantly. Why? Some people will say, why, Dr. Shah? Because eripiprazole is considered to be a weak antipsychotic, right? A lot of people is wrong, but some people think it was a partial agonist, right? But very few people know that despite its mechanism of action at the D2 receptor, which is partial agonism, it has much more potency to bind to the D2 receptors. So it displaces haloperidol. So the displacement of haloperidol from the binding site is the result why APS decrease, prolactin levels come down. This is what I'm talking about, innovative psychopharmacology, where you can deal with. Because in a lot of patients, anticholinergic may not be effective. Some people would say, Dr. Shah, why not anticholinergic? Well, I'm sorry about my sentence. Are we that stupid? So first we induce the side effects, and then we induce those side effects with another medication, which cause further side effects? It's a moment to think about. OK, so that's basically what we did. So three cases. I'm not going to go into detail. Just wanted to tell you about them. They are published. And this was a retrospective case series, and we used eripiprazole in three patients. And all of them benefited from eripiprazole. And you can find them on the website and Google. I'm sorry, PubMed. Yeah, so I'm going to skip those. Now the second hypothesis. The second hypothesis is mild glutamate receptor blockade is effective in managing psychosis-related agitation in geriatric patients. Just remember the mild NMDA receptor blockade. We don't want to have a potent NMDA receptor blockade. Why? Because potent NMDA receptor blockade can cause psychosis, like fencyclidine does, like high dose of ketamine does. So what is the rationale? Elderly patients are frequently reported to have psychosis-related agitation. And many patients with psychosis-related agitation do respond to low dose antipsychotic medications. However, there are a few patients who either are intolerant or non-responders to antipsychotic medications. And that's what happened with our patients. So where is the evidence-based medicine there? We have to go outside that, right, to do something here. Glutamate hyperactivity actually has been identified in research as playing an important role in mediating that agitation. What are the rationale continues? However, potent, I already told you, PCP can cause psychosis. But a milder blockade might be achieved with the memantine or ketamine. And now with the dextromethorphan, all of us know the story, right? Very exciting story with dextromethorphan. And we'll talk a little bit more about that. So if dextromethorphan is given with a CYP2D6 inhibitor, cunidine, which is a very potent 2D6 inhibitor, it increases the levels of dextromethorphan quite significantly. And that increased level is required to have any meaningful NMDA receptor blockade. So a company came out with a drug which is called Nudextra. And that Nudextra is a combination of dextromethorphan and cunidine. And it was approved for the treatment of pseudopulpar palsy, not for psychosis or anything else. But I was struggling with three geriatric patients when I was working with my co-presenter, Dr. Agha, at Oregon State Hospital. And I thought, why not try a glutamatergic mechanism and see whether we can control their agitation, psychosis-related agitation? And so what we did is we were actually lucky to get non-formulary approval, because it's very difficult to do that. You have to go through a long process at a state hospital. But we were lucky to get that approval. And we were able to start Nudextra. And there were four cases. Out of four cases, three cases were successfully treated with Nudextra and the combination of dextromethorphan and cunidine. One patient, we could not make any difference. And the reason could be that I'll show you a table in the next slide. So these three patients. And the most important thing was that in these three patients, we were able to only reduce agitation, but we did not reduce psychosis. Very important point. And look at the table. Actually, it shows you that the patient number four, who did not respond, had serious traumatic brain injuries in the past. And he had multiple medical comorbidities. So that could be the reason. But we really don't know. So there may be a subset of geriatric agitated patient due to psychosis, which can be out-of-the-box thinking. You can think about this. And so that was the moral of the story. And I'm going to skip that. But dextromethorphan and bupropion story is also worth mentioning. This is the art of psychopharmacology, what we are doing. So we knew that dextromethorphan is an MD receptor blocker. So instead of using it with cunidine, we are using it with bupropion, which is also 2d6 inhibitor. And we got this drug approved to manage depression. And the most beautiful thing is that, unlike intranasal ascetamine, now you have a drug which you can use in non-treatment refractory population, you can use as a monotherapy, and you can give it orally. How beautiful is that, right? Now you have a ketamine-like drug, which does not have REMS registration. Can you imagine that drug? You're now getting all these. Once we know the mechanism of action, a novel ketamine-induced improvement in depression, we can build on that, just like we are doing now. This is cutting-edge psychopharmacology. So how much time do I have? So I'll finish it, because there is a third hypothesis. I've taken a lot of time. So I would like to invite Dr. Agha, who is going to talk about some really interesting issues, including frontotemporal dementia. And this will be a treat, because he is really, really very knowledgeable about this topic. Thank you. Thank you. All right, good morning. Can you all hear me OK? All right, so I'm going to talk about something a little different from Dr. Shad, who is a very hard act to follow, because he is so good. I'm going to talk about cases where not only don't you have a treatment, but you don't even have a diagnosis. And when you do come up with a diagnosis, you find that the diagnostic criteria are changing. None of this the patients know anything about, because patients present without reading the textbook. And so now you're left with cases where you really don't know what to do, except practice innovative psychopharmacology. And we will see how we did that in these cases. So my family and I don't have any disclosures that are relevant to this presentation. And I'm going to jump right into the cases. And I'm actually going to read the cases, because these are really important. What I want you to do while I'm reading these three cases is think about when in the history you think that this is an atypical case. This is somebody who is not a usual patient that you would see in your practice. And that you need to think about this patient differently, maybe do some brain imaging or other kinds of labs or investigations that you would not do in your usual case. So this is the first patient, the hyper-religious pilot, 55-year-old right-handed white male. Oh, they're not coming? Why are they not coming? Hmm? Yeah? Oh, yeah, you have to do this. Oh. All right, sorry about that. Okay, so the first case is a 55-year-old right-handed white male with no prior psychiatric history. He was a successful steam fitter, had a pilot's license, owned a ranch and a farm, previously successfully treated for depression. So pretty successful guy at baseline. Until age 54 when there was a marked change in his behavior. He assaulted a peer, he was shouting, cussing in public, he was driving his truck on a municipal airport runway. So they used to live out in the country, he had access to a municipal airport. And he damaged the runway while doing that. He was trapping and torturing a baby deer. Started to become over-familiar with children at church, attempted to strangle, by then this was his ex-wife, dragging her by her hair, resulting in a restraining order against the ex-wife and their three children. And then he violates the restraining order leading to civil commitment and hospitalization, initially at a community psychiatric hospital. During the civil commitment hearing, the man was masturbating in public. He was transferred to a state-run psychiatric facility, which is when we saw him. He already had a diagnosis of schizophrenia, by that time. In the hospital, we noticed other symptoms, such as an increase in religiosity. He would end every interview with, God bless you. Delusions of grandeur, he felt like he was personal friends with Donald Trump, who was not the president at that time. He was perseverating on the same statements, regardless of the questions asked, such as, I will give you $10,000 if you let me out of the hospital. And then, of course, God bless you. There were repetitive hand behaviors that mimicked what he was seeing on television programming. No insight into his illness. He thought he only had a mild depression. In terms of previous history, there was a history of alcohol and cannabis use, and urine tox was positive for cannabis during his initial community hospitalization. Medical and family history were unremarkable. So, that's the first case. Again, think about when in this history you think, okay, this patient is not my usual patient. I have to think out of the box, perhaps start with brain imaging. The reason I'm presenting three cases is also to show how different these patients are in terms of presentation, in terms of symptoms, in terms of age, and yet they turn out to have the same etiology which we will talk about. All right, so case number two is the disengaged science teacher. This is a 77-year-old white male, so substantially older than our first case. A retired high school science teacher, long history of depression with intermittent antidepressant treatment. Began to experience problems with short-term memory about five years before I saw him in my clinic this time. This was not an inpatient hospitalization. And this was, the wife became worried about him when she noticed that he was unable to help his granddaughter with her elementary school science project. So remember, this is a high school science teacher, and now he cannot help his granddaughter with her elementary school science project. There was marked worsening of cognition noticed in the 18 months prior to his clinic visit. Visual spatial impairment, including misplacing items and getting lost in the small Oregon town where he and his wife had lived for many, many years. Difficulty tracking while reading, increasing apathy. His wife said that he was completely disengaged. He started using inappropriate language and swearing in public, completely unlike his baseline behaviors, and had some trouble identifying faces of acquaintances, although this was not a prominent symptom, as told by his wife. So in the previous year, he had about six months of paranoia, resolved spontaneously, but there was an increase in superstitious thinking. Relevant medical history included hypertension, hyperlipidemia, overactive bladder, obstructive sleep apnea, and a history of a TIA. A long history of alcohol use. The PCP had told him to cut down and stop drinking. About two years before I saw him, he did cut down on his drinking, but he didn't stop completely. There was a family history of stroke in his mother and maternal great aunt, and a completed suicide in his father at age 90. Think about that. Completed suicide at age 90, but we thought that this was related to the fact that his father was diabetic and he was about to have his leg amputated for gangrene the next day, so he ended up killing himself the previous night. The dad used to live alone. He was a widower. This patient was diagnosed with Alzheimer's dementia before I saw him. He was started on Aricept, Donipazil. And before his first visit, he was started on TMS. And he had completed 36 treatments for TMS for treatment-resistant depression with minimal improvement. And then the last case, so 80-year-old white female. So this is an even older patient than our first two patient. High school graduate, some college credits, successfully ran a trucking company with her husband until they ended up selling it. Alcohol use in the past. She was diagnosed with bipolar disorder at age 65 when she began to display erratic behaviors, including heavy gambling, combativeness, lying. She was started on Abilify. Don't ask me why. I didn't do it. And she was actually on Abilify for eight years with some improvement in her symptoms. And then she stopped taking it. Unclear why. She said she just did not want to take it. And then she began to engage in more hostile behaviors, frequent outbursts. Her husband had a cabbage in 2018. And he came home after cabbage. And she threw away and hid all his medications. So ended up getting a restraining order. And she was arrested for violating the restraining order, ended up in jail, where now she had more disorganized behaviors, attempting to kiss, hug, grab, and hit jail staff, and using feces to decorate her jail cell. Again, Donald Trump figures in this story as well, because she thought that Donald Trump was going to come pick her up in his private jet. But then he was already president. She was found to lack capacity to stand trial. She was released. She was sent back home, where she had more mental health contacts, would even be hospitalized briefly, and then would be allowed to leave the hospital against medical advice. Eventually, she had a construction worker sweep her with her vehicle, fled the scene. Also, her husband fell at home. She refused to call 911, leaving him on the floor in his underwear covered in urine for approximately eight hours. So she was arrested again eventually, transported back to county jail, psychiatrically hospitalized for another competency to stand trial evaluation. When I had done these slides in April, the evaluation was still pending. But subsequently, she was found never able and has been discharged to a community facility, this time not back to home. In the hospital, we noticed that she was requesting and eating bananas 10 to 12 a day, which was a new behavior for the family. Exit seeking every day, insisting on going downstairs. That's why this case is about the woman who wanted to go downstairs, because she wanted to go downstairs 100 times a day, even after she'd been told we were on the first floor of the hospital and there was no downstairs. She also wanted to go meet her husband downstairs, who was in no condition to drive by then. He was already in the facility. The medical history was remarkable for hypertension and hyperlipidemia. And she was an only child with an unremarkable family history. So if there's one thing that stands out in all three cases, does anybody want to shout it out? We have a small audience here. So what stands out? If I were to ask you one thing, that's really unusual. I'm sorry, can you speak? The late onset, correct. The late onset of symptoms is the most unusual feature in all three cases. So we ended up doing neuropsych testing in the first two cases, cases one and two. I'm not going to go into all the details of what the testing found. But there were two things that you need to notice in this slide. One is that there was almost complete discordance between the neuropsychological symptoms in case one and case two. The only concordance in the symptoms was, I have marked that in red, that was delayed recall. That was impaired in case one and case two. And then facial recognition was not even tested in case two. So this happens when you don't tell the neuropsychologist what you're suspecting, because often testing for facial recognition is not the usual thing that they do in the neuropsychological battery. And if you don't provide them information about what you think the clinical diagnosis might be or the differential diagnosis might be, they will probably not test for facial recognition. And that's what we saw in the second case. And I will tell you in just a bit why that's important. Case number three, all we could do was a slumps, because she was very uncooperative and, of course, wanted to go downstairs all the time. So even during the testing, she wanted to go downstairs and meet her husband. We were eventually able to do a slumps. She got a 13 out of 30, which is well within the dementia range, losing four out of five points for delayed recall. So the third case also had issues with delayed recall and also four out of eight points for the story recall on the slumps. So what do these cases have in common? Why am I presenting all these three cases together? And this is what they have in common. So for those of you who are familiar with how to read a brain scan, I'm going to show you three scans. They're going to be in radiological convention. So left is right and right is left. The first one, this is an FDG PET scan of the brain. The significant finding on this brain scan is marked with a red arrow. And I'm going to ask one of you what this is. I'm not going to tell you what the finding is. So the first one is an axial view. The second one is a coronal view. This is an MRI scan of the brain, not an FDG PET scan of the brain. And again, the significant finding is marked with a red arrow. Below the second scan, there are results from the volumetric analysis. I'm sorry, that's really, really small. So most of you can't read it. But what it says is that the hippocampi was at the first percentile for age. And the inferior lateral ventricles were at the 99th percentile for age. So the reason I put this in is because this shows you one of the drawbacks of doing volumetric analysis, which we often all end up doing in dementia patients, which is that volumetric analysis will do an average of both sides. So what this tells you is that the hippocampi are at the first percentile, but it says nothing about the asymmetry in the atrophy of the hippocampi, which is so evident on the screen. And this is a CT scan in the last patient. This is, again, a coronal view. And again, the most significant finding is shown by the red arrow. Can anybody tell me what the significant finding is in all three cases? So it's right-sided asymmetric, right-sided medial temporal atrophy. That's what the finding is in all three cases who presented at different ages with completely different or almost completely different clinical presentations and different cognitive domains that were involved. And we published this first case. So what is right temporal variant FTD? Because that was the diagnosis in these cases. So this is a simplified way to approach brain scans in the FTLD, the frontotemporal low body degeneration spectrum disorders. For those of you who are not familiar with this, so if you have disinhibitions, compulsions, loss of empathy, and hyperorality, you might want to think about behavior variant FTD. And there's atrophy in the right frontal cortex. If you have agrammatism, apraxia of speech, you might want to think non-fluent variant, primary progressive aphasia. And there is atrophy in the left frontal cortex. And this is very, very general. It's much more complicated than that, but just for the purpose of having a general discussion about this. Confrontation naming problems and single word comprehension problems, you have semantic variant PPA, primary progressive aphasia, where there is left medial temporal atrophy, and then, of course, right temporal variant FTD, where, as the name indicates, there's right medial temporal atrophy. And these are what the atrophy patterns look like individually. So behavioral variant FTD, or BVFTD, there is right frontal. In non-fluent variant PPA, there is left frontal. In patients with semantic variant PPA, there is left temporal. And patients with right temporal variant FTD, there is right temporal. So what is this right temporal variant FTD? So until the diagnosis of right temporal variant FTD was identified as a separate kind of dementia, people used to think that semantic variant FTD or semantic variant PPA is of two kinds, left and right-sided. Most of it is left-sided. They present with language dysfunction, but about 30% is right-sided. And these present with impairment of non-verbal semantics. Word finding and single word comprehension is less common in these patients. While there is loss of person-specific semantic knowledge. And what that is, I'll tell you in just a bit. Right temporal variant cases have more difficulty accessing semantic knowledge through visual rather than verbal modalities. These cases may resemble BVFTD and semantic variant PPA. And the behavioral changes are more pronounced and occur earlier in these right temporal variant cases. So what is impaired person-specific semantic knowledge? So let's start with what is prosopagnosia, which I think we all know. That's the inability to recognize faces, including one's own, despite intact vision. So that's very important. There is no reduction in visual acuity. These patients can identify parts of a face. They can identify. They have the concept of a face in their minds. They can even identify persons by cues and other sensory modalities. So if a person shows up and they start speaking, they know it's their husband. But they look at the face and they can't identify that it's their husband. Person-specific semantic knowledge loss, on the other hand, you have loss of knowledge about known people using stimuli in all modalities. So when the person comes up and speaks with them, they do not know that this is their husband because they have lost that knowledge in all modalities. So they cannot identify familiar people from their name, from their face, from their voice, from their biographical information, or even when given information about their relationship to the person. So like I said, behavioral symptoms in right temporal variant FTD are very common. And some of the most common symptoms from the systematic review that looked at 41 studies, some of the most common behavioral symptoms are disinhibition, apathy, obsessive behaviors, altered eating habits, depression, aggression, loss of empathy, and hyper-orality. So think about how many of these symptoms were present in our three cases. So in 2020, a diagnostic tree was proposed to diagnose RTV-FTD, right temporal variant FTD. There were three core clinical features out of which two had to be present, process of prognosia, memory deficit, or behavioral changes. There were, and the behavioral changes had to be two of four, disinhibition, apathy, loss of empathy, or compulsiveness. There were one of three supportive clinical features that had to be present out of word finding difficulties, naming difficulties, and depression. And then the neuroimaging, you had to see right temporal atrophy or poor uptake of the tracer on a PET scan, or poor blood flow on a SPECT scan. So there had to be radiological evidence of right temporal atrophy. And if you did the first three steps, the core clinical features, the supportive features, and the neuroimaging features, the sensitivity and specificity of your diagnosis would be about 70% and 99% respectively. I'm not going to the fourth step, which is the amyloid status, because that is not something we typically do in clinical practice. That is only available to us in research. But then, like I said, we are talking about diagnostic criteria that are in a state of flux. So another group came out with this paper in 2022. And now they're calling right temporal variant FTD as semantic behavioral variant frontotemporal dementia. And their diagnostic criteria are a little different. So now they have early core symptoms, which are loss of empathy and person-specific semantic knowledge loss, not prosopagnosia. And then complex compulsions and rigid thinking. And then later symptoms include loss of verbal semantic knowledge, and eventually apathy and disinhibition. So let's look and compare these two criteria, the 2020 criteria and the 2022 criteria, and then look at our cases. So again, I'm not going to go through all of these because they are going to be available in your handout. And by the way, I updated my handout. So the one that is on the APA app is not the latest handout. So please send me an email if you want the updated handout, and I'll be happy to send it to you. So the few things I want you to see in this is one spared visual spatial function was in the 2022 criteria, not in the 2020 criteria. It was present in all three of our cases. The other thing I want you to see is that difficulties with object naming was present in the 2022 criteria, not in the 2020 criteria. It was absent in all our cases. And then episodic memory deficits were present in the 2020 criteria, not in the 2022 criteria, and they were present in all three cases. So again, there is not a one-to-one correlation between the criteria, and none of our cases met all the criteria for either the 2020 diagnostic criteria or the 2022 criteria. So this brings us to the innovative psychopharm section of my talk, which is what do you do when the diagnostic criteria are in flux? There is no evidence-based study for the treatment of right temporal variant FTD, which is such a new condition. It's been newly renamed. Absolutely, there's no evidence-based studies. There are no randomized control trials. So when you get a patient, you just send them home and say that, oh, we don't have any RCTs in your case, so please go home and hope for the best. You don't do that. What you do is you try and look at a known syndrome with partially overlapping features. The overlapping features might be clinical, they might be radiological, they might be pathological. You try and see if there is a known treatment for that syndrome. So in our case, the overlapping features were with semantic variant PPA and behavioral variant FTD. Unfortunately, there are no good treatments for those conditions as well. And then if syndromic treatment fails, you provide symptomatic treatment for the most distressing symptoms, what Dr. Shad was talking about, which is innovative psychopharmacology. You target the most difficult distressing symptoms, and you make rational decisions, maybe based on case reports or case series, about what would be the best drug to try in those cases. So talking about pathology, so these are the most common primary pathologies in the common dementias. This is a busy slide, and I am not going to discuss all of it. I'm just going to discuss TDP-43 and tau, which are the common pathologies underlying frontotemporal dementia. And if you see on the right side of your screen, semantic variant PPA is at the top, which is mostly TDP-43. And agrammatic or non-fluent variant PPA is at the bottom, which is mostly tau pathology. And then the other two in the middle are sort of balanced between a tau and TDP-43. So you're trying to look now at a syndrome where there is either tau or TDP-43 underlying pathology, because that's where your syndrome falls. It's either tau or TDP-43. In fact, now we've shown that in semantic behavior variant FTD, it's mostly TDP-43 cases. So in BVFTD, there has been a lot of small studies that have been done. And this was an overview of drug treatment studies in FTD, not in RTVFTD, but in BVFTD. And what they found is that grade one recommendation was for only two drugs in all of these case series. And that was Celexa, Citalopram, and Trazodone. So I want to discuss just a little bit about Trazodone, because there's very interesting data about Trazodone from one small randomized control trial, and then some case series, and an open label extension of the randomized control trial. If you see on your screen, the N for all of these studies was really small. The randomized control trial was only 26. The open label extension of the randomized control trial was only 16. Also, all of these were done by the same group. So you want replication by another group. Why does that not happen with Trazodone? Because Trazodone is not under patent. It's available as a generic. It's a very cheap medication. And nobody gains to benefit, unfortunately, except the patient, from a large randomized control trial of Trazodone in any kind of frontotemporal dementia. So those studies are not being done. But note that even in the randomized control trial, about 50% of patients had treatment emergent side effects, including fatigue, dizziness, hypertension, and cold extremities. And in a much more recent study that came out in 2018, this was a study done in a nursing home setting. What they found that even low-dose Trazodone, and it was defined as a dose under 150 milligram a day, the median dose in the study was 50 milligram a day, it was no safer with respect to falls and fall-related injuries than starting a new benzodiazepine. So that is the problem with Trazodone. So you have to be very careful about using it in older adults. So here's my approach to cases within the FTLD spectrum. You have to decide whether they might have FTLD pathology or AD pathology, and that depends on what the clinical presentation is, whether it's mostly behavior or memory. If you think that it's mostly FTLD pathology, whether it's TDP-43 or Tau, you start with a selective SSRI, such as Celexa or escitalopram. If there's response, you continue. If there's no response, you try Trazodone. For reasons I just explained, again, if there's response, you continue. If there's no response, then you move to innovative psychopharmacology, and you start targeting individual symptoms. This is based on case series and individual case reports. So for apathy, methylphenidate. For disinhibition, valproate or carbamazepine. For compulsive behaviors, maybe fluvoxamine or another SSRI. For hyperiorality, binge eating, topiramate, and now maybe Vyvanse. For disruptive behavior, psychosis, quetiapine or Abilify. And for Pseudobulbar effect, like Dr. Shad was saying, new dexter, and then if you think that AD pathology is more likely because of the clinical presentation, then you might want to start with the cholinesterase inhibitor like rivastigmine. No response, you switch to the other side of the algorithm, and if there's response, of course, you continue. So what happened in our cases? So case one, failed trial of sertraline, bupropion, citalopram, quetiapine, and olanzapine. Eventually got stabilized in trazodone and acetalopram, didn't do all that well until we added new dexter, and we were able to discharge the patient on that combination. Case two, refusing treatment. We have not been able to encourage this gentleman to get treatment so far. He's an outpatient, and so we keep encouraging him to take treatment, and then the last patient, failed trials of trazodone, haloperidol, lorazepam, and has improved on the low dose of quetiapine. We were able to discharge her to the community, and with that, I'm going to stop and see if there are any questions. Thank you. So, you know, I'm going to invite, without wasting any further time, our discussant, Dr. Suarez. Okay, well, good morning, everyone. Thanks, Dr. Shah, Dr. Aga, for the really excellent presentations. So, I would just, you know, make a few brief remarks and then save some time for us to have questions at the end. I really like the, you know, the discussion on, I guess, evidence-based approach versus perhaps being more innovative as a recognition of, you know, how challenging our field is and how much the outcomes aren't really great, you know, for most things we treat. This is really an illustration of, I guess, how challenging, how complex the field that we embraced in psychiatry is in neuropsychiatry, definitely. The part that makes me a little bit envious, you know, when I compare ourselves in psychiatry, our colleagues in neurology, behavioral neurology, neuropsychiatry, so you guys have some conditions, and that's one illustration here where, you know, the pathophysiology may be a little more clear. At least, there are specific tests that will show us changes that are actually diagnostic, you know. That's, I think that's a great start. It does not necessarily lead us to better treatments, at least not for now. And again, I mean, we know how complex the brain is. We know that with the tools we have, the brain can heal a little bit, but not all the way back. So in psychiatry, the conditions that Dr. Arshad focused on, you know, mostly severe, complex, psychotic disorders, you know, those are conditions where we end up talking a lot about psychopharmacology and not as much about psychosocial interventions. But there are other areas, like, for example, I'm mostly a mood and anxiety doctor. I mean, we're treating patients with treatment-resistant depression or more complex case of bipolar disorders, severe anxiety disorders. We see, you know, how important different types of psychotherapy approaches and modalities are alongside with the psychopharmacology. You know, for certain patient populations, if we just focus on trying to find the best medication regimen, we're not going to be, you know, addressing much of the dysfunctional patterns and ways in which someone is managing their relationships and stressors in life that tend to perpetuate, you know, many of the mood disorders. So when I think about evidence-based versus innovative psychopharmacology, you know, there is always a slippery slope there. I mean, obviously, if I'm going to be extremely innovative and disregard, you know, evidence, that's not going to be good for our patients. Or if I pick things where there is no evidence, you know, that they help or perhaps the safety isn't even that well-established, being innovative in that way, I mean, puts me at an extreme that's, in all likelihood, it's not going to be beneficial to our patients. So there's always a trade-off there. So personally, I like the approach where, I mean, obviously, we start being evidence-based, like Dr. Shad pointed out, but for many of our more complex patients, well, first, you know, our diagnoses aren't that great. I mean, we do the best job that we can to recognize certain clusters of symptoms and some seem to be more consistent than others. So it starts, you know, with the fact that our diagnostic systems, you know, aren't that great. They're the best we've got and we make the best use of them. And in that process, I mean, we help many patients. That's also a recognition, you know, a reflection of the fact that, you know, unlike a disease like frontotemporal dementia, the psychiatric conditions that we treat, I mean, even though there is a lot of evidence there for us to truly understand and acknowledge, accept them as brain diseases. We call them disorders because we don't know the specific mechanisms and pathophysiology. So those, they tend to be more subtle. I, you know, I tell people, I tell my patients and others, I say, look, in psychiatry, these disorders, they don't seem to be much about the hardware. They are mostly about the software. So any changes we find with imaging, they tend to be more discrete and non-specific and not diagnostic. So these tools aren't really at a point that, you know, that they will help us best diagnose and manage our patients, you know, unlike what, you know, our neurologist, a colleague has shown us here today. I do believe that for that, it is a matter of the sensitivity of the tools that as, you know, sensitivity improves, perhaps we will find certain patterns and abnormalities that will, you know, help us diagnose. I mean, I was just so envious when I saw 99% specificity for a diagnostic test in neurology based on imaging. You know, that's as good as it gets. Well, anyway, I love the approach where, you know, unlike the times, I mean, we, when I say we, me, you know, we aren't getting any younger and when we learned psychopharmacology in medical school, it was mostly based on lectures and, again, we did the best job we could. So now, you know, the students that we teach, that Dr. Shad and others and many others here teach, I mean, we learned that, I think, making it more problem-based and, you know, assembling groups where people will be engaging, that tends to lead to more sustainable learning. So that's, you know, I believe there is a lot of evidence for that. That's the reason why most medical schools and residency programs have moved that way, you know, so that is important, not much discussion there. So my, I guess my final thing, I mean, we are forced to be innovative because we don't know much about what causes these disorders or the mechanisms involved. We have no tests to help diagnose. We have treatments that help, but the outcomes for many patients aren't great. But it is a slippery slope. I mean, I would not want to be the most innovative person in the room where I'm taking stuff for which there is no evidence and running with them. Worse yet, you know, if I do that repentantly, which is what we normally do, you know, we practice innovative psychopharmacology in the context of very complex cases and we do that repentantly, conservatively, compared to, you know, if I become very proud of that and, you know, find a way to justify, which is not hard, by the way, and run with the stuff that, you know, I don't know if it works, as if that was the greatest treatment that's going to work for all. You know, we've all seen that and essentially stretching little evidence, sometimes actually for, you know, financial gain. So that does not give us the reputation that we want as a profession and, you know, it may actually help us, you know, lose the respect that we've gotten from our colleagues, you know, by years of hard work, by being more, you know, thoughtful and, you know, if we become too innovative and there is no evidence to corroborate that, there is not much that separates us from the, I guess, the person who sells the snake oil, you know, for conditions where, you know, patients are kind of desperate because the treatments aren't great, where they are just, you know, more willing to want to embrace whatever little hope we can offer them. So, I mean, so that's the extreme that we, you know, have to watch out for. We do use a lot of, I guess, non-approved uses of off-label is the word that I was looking for, you know. Off-label is kind of like the name of the game for the ones of us who end up dealing with more complex cases, you know, patients that have gone through different colleagues where first, second line of treatments have been tried. At that point, things that are safe, meaning, I mean, they are already approved for some other indication, even if not truly safe, I mean, we kind of know what the risks are because they've been given to a good number of patients. As long as, you know, we are counseling our patients properly so they, in essence, they understand that that's sort of like, you know, unusual, it's not an approved use, and we, from personal experience or maybe limited literature that we know in that area, we believe that might work, may be a reasonable thing to try, and become more innovative that way, you know, that is kind of like the way forward. So I definitely sympathize with what Dr. Shad presented on that. Thank you. So I think we should have a very short time. If there are any questions, please. And I did not fulfill my promise. I said I was going to speak for a few minutes. It's all right, please. Dr. Shad gave me the microphone. Thank you. Thank you, Dr. Agha, Dr. Shad. I had the good fortune of working with both of them in Oregon State Hospital, and thank you, Dr. Saras. Come closer to the mic. Can you hear me now? Yeah. Okay. I've yet to come across a case which reads like an article. The description of the symptoms, the presentation would come across exactly like a research article that I read. That may be my inexperience. I'm five years out of training. Maybe after 20 years, I might come across a case that matches exactly what I read. In that sense, what Dr. Shad was saying earlier about the studies being with patients who are completely clean, you know, particular disorder, no comorbid substance use, no psycholegal issues. I mean, you can't clean the patient anymore before you use the particular medicine to treat a disorder. But in real life, we don't get that. So in that front, I agree with the art of using this medication based on what you have in front of you, as opposed to boxing ourself into treating disorders with certain medications if it's FDA approved only. So I agree with you on that. This is my question. I frequently see people chasing symptoms. Patient comes in with psychosis. Unspecified psychotic disorder is the main diagnosis that I see. There's not much diagnostic sort of exploration. Like, you know, DSM is conceptual, but still there is some math to why we give certain diagnosis. There is a reason why we would give schizoaffective versus bipolar disorder. There's a reason for that. But what I see is people give diagnosis such as unspecified psychotic disorder and then start an antipsychotic halfway through an antipsychotic. For whatever reason, you end up going to another antipsychotic. You don't have evidence to use two antipsychotics at suboptimal doses, right? I see that too. I don't want to label that as the art of using medications as much as chasing symptoms. What is the remedy for that? I mean, I see this often enough, and it's a pet peeve of mine, if I see someone doing it as to why don't you optimize one medication, take it to its logical end, and then think about others. Could you shed some light on it? Yeah, I would comment on it, and if Dr. Agha and Dr. Suarez want to talk about that, that's good. But that is a major problem, and that's why, you know, my first topic was how can we optimize training in psychopharmacology? Because I think if I remember correctly, you said subtherapeutic dosages, and patient is labeled a treatment refractory, and then moved on from medicine to medicine, and it's trial and error method without adequate duration and dose to be given to the patient, and then we go into this vicious cycle, and patient keeps on becoming more treatment refractory, because the longer the duration of effectively treated psychosis is, the more treatment refractory the patient will become. So this becomes a really vicious cycle. So I think the basic answer to that is to improve our training. Unfortunately, residence training is not focusing a lot on kind of the psychopharmacology I was talking about, but you are actually taking a step back and even saying that there are problems in people identifying the right dosages, the adequate dosages and adequate duration. One of the thing is that, remember, that adequate dosages and adequate duration can still be there in a different scenario, but then if you're not talking about like 2d6, is a very polymorphic enzyme, right? And if somebody is ultra rapid metabolizer, and you give even if adequate dosages, they can actually respond as subtherapeutic dosages. So this is the tip of the iceberg, you know. The only way we can address these things is to optimize training, to tell them, educate them about, look, if you have a point of view that genetic testing is not at all worth, you know, does not have any evidence, should not be used. No, there are some places where in treatment refractory population you can do and improve the patient's outcomes, right? So nothing, there are pros and cons of everything. Nothing is useless, nothing is completely effective, right? So we have to, but the basic art of psychopharmacology is to know all this and train people about this. Sorry, I took a long time, but yeah. Well, I totally agree that by the way in which we do the clinical trials, we're throwing the baby with the bathwater, where we look for average effects, for something that may work for subgroups, but not for others. So ways to make it more precise would be very important, you know, going forward. I see a colleague on the back with a question, please. Thank you for the excellent presentations. I mean, I really like when we get into the deep weeds on specific cases. I think we learn a lot from that, both in general and specifically how to approach patients going forward. Can you come closer to the mic, please? Oh, sorry about that. I wanted to ask specifically about the aripiprazole for kind of EPS or extra symptoms with a long-acting injectable. Just the thing that struck me was, what's kind of the benefits of that versus decreasing the dose of the LEI? Like, are you using that temporarily, like for periods of time, or is it just that you can't quite get it between the doses? Yeah, the apparent half-life of a long-acting injectable is months, if not weeks, and so the patient is stuck with it. You've got to do something. You just cannot... Oh, got it. So if it pops up in a patient, you increase the dose. So long-acting injectables, that's why I was talking about long-acting injectables. I did not talk about other orally administered or other route of administration antipsychotics. I was talking about long-acting injectables, which actually the patient is stuck with. It's like a Titanic. The maneuverability is not there, so that you can do anything to address the side effects. Okay, that makes sense. So it's a bridge until you can get to that lower dose. Okay, perfect. Okay, I think we are out of time. Thank you so much for very few diehard, you know, interested in this topic, but your presence was much appreciated. Thank you so much for coming, and if you have any questions, we can discuss, you know, down the stage.

psychiatry

neuropsychiatry

evidence-based medicine

innovative psychopharmacology

treatment-refractory

pharmacokinetics

neurobiology

off-label uses

frontotemporal dementia

personalized patient care

clinical trials

patient-centered approach

scientific insights