I'm going to try to do something a little different this morning than I normally would, and most of you who know me know that I usually show a tremendous amount of data and sort of blitz you with science and data. But I decided instead to take a somewhat different approach today, in that I'm going to show you much fewer slides, probably less data, and want to involve the audience. I want to leave maybe 30 minutes of time that we could have some interaction and questions. I'm looking out in the audience, there's some experts out in the audience who have come to join me today. David Sheehan is sitting out there in the back, and he is as smart or smarter than I am, and I might even call upon David during the question period to help me address some of your questions. So those of you who know me also know that I'm an eternal optimist, and so I really believe that the glass is half full, not half empty, but I thought since it's early and you all braved less sleep in order to come here, I'd start off and tell you a joke, a modification of a joke I told yesterday at another presentation, and it's relevant to this topic. It has to do with a psychiatrist, elderly psychiatrist is walking along the beach at Big Sur, and a bottle rolls up, and he picks it up, and it's sort of a little dusky, and he wipes it off, and a genie comes out of the bottle and says, you know, thank you so much for letting me out. I've been in that bottle for a millennium. You know, I'm going to grant you a wish. Whatever wish you want, I'm going to grant you. And so the psychiatrist thinks about it, and he says, you know, I'd like you to build a bridge between the United States and Europe so that I could drive to Europe. My wife and I love driving, and it would be really terrific. And so the genie says, mm, that's a really big ask. I mean, a bridge between the United States and Europe? Is there another wish that you might have that I could do that would be easier? That psychiatrist thinks for a minute, he goes, I need an antidepressant that will work for all of my patients. And the genie looks at him and says, do you want two lanes or four on the highway, right? And sort of what we're dealing with, right? So what we're going to talk about today is sort of the state of the art of treating major depression with the focus of where we are and then where we're going. And so let me just start off, and here are my financial disclosures. All of my research is supported by the NIH. I serve as an advisor to several startup companies, and I'm president of the Anxiety and Depression Association of America. I serve on the board of the Brain and Behavioral Research Foundation and Scientific Council. I'm involved with Gratitude America, which is a veteran's PTSD group. So let's get some nomenclature out of the way. Our goal in treating depression is the same goal as oncologists. We want to return patients to their premorbid level of functioning. We want patients to say to us, I feel the way I did before I was ever depressed. We have arbitrarily defined remission as a number on a rating scale. So if you're using the Montgomery Asperg Depression Rating Scale in a clinical trial, the generally acknowledged definition of remission is 10 or less. For the Hamilton, it's 7 or less. But I also want you to think about the fact that if you have a mattress score of 9, you're not totally well. What are the symptoms that you have if you have a mattress score of 9? Are you having a sleep disturbance? Are you having difficulty concentrating? Are you having fleeting suicidal thoughts? And so I believe that those metrics are not as rigid as they ought to be. We really want to return patients to their premorbid level of functioning. It's harder in disorders like bipolar disorder. Kreplin of course believed that in between episodes, patients were completely euthymic and normal. And those of you who treat bipolar disorder know that's hardly the case. That in between episodes, patients still have some level of morbidity. So I'd like to think that we can get patients to a HAMD below 3, a Madras below 4 or 5. But from a conceptual point of view, when we're talking about treatment response in depression, the numbers that are thrown around, and we'll talk about that, are remission numbers and response numbers. So what does a response mean? A response is defined as a 50% improvement in symptom severity. Now think about that. If you see a patient who comes in with a Hamilton score of 24, and you treat them and they know a Hamilton score of 11, they're not well. So they're responders, but they're not remitters, right? And if you translate this into other branches of medicine, cardiology, oncology, are you satisfied if you go to the cardiologist and you have atrial fib and he or she say to you, I think I can cut down 50% of the episodes. No, of course you're not. And even worse is in oncology, those of you in the back, there are seats up here, feel free to come in and let the other folks let you into the aisle. There are lots of seats here in the front. No one likes to sit in the front. I'm not going to call on you, I promise. And frankly, if you need it, you know, we have a bunch of chairs up here. For those who are enterprising, you can move the chairs down there if you want. Seriously. Feel free to come and get these chairs up. I'm not in the furniture moving business, but feel free to grab a chair. So I want you to truly think about the fact that if you're unfortunately diagnosed with cancer, you want somebody who's going to try to eliminate it and get you into remission, not somebody who's going to cut the tumor load by 40%, right? So when I'm going to show you data about response and remission, you have to understand that a large percentage of the patients we treat are not in remission. And this is doubly true for patients who have seen a primary care. Now primary care doctors have a tremendous burden. They see two-thirds of the depressed patients that are out there in the United States and probably in other worldwide settings as well, right? And they have, on average, about 14 minutes to see a patient. Most of them know how to prescribe SSRIs. So they'll prescribe 50 milligrams of sertraline, and then the patients will tell them that they're better, but it doesn't mean that they're well. And most primary care doctors stop at that. Fewer side effects, the patient's better, they're not complaining. So this is the gold standard, the holy grail of treating depression is remission, okay? And that's what our goal is. Well, why is it so important? It's important because the consequences are dour. Incidentally, there's still empty seats here for those of you in the back, unless you like have a bad back and you don't want to sit down, but I'm looking at some empty seats here. Don't be shy. Yeah, let those people in. So the consequences of failing to get into remission are dour, and I've listed them here. First, the longer you're depressed, even if you get better, there's a greater likelihood that you are going to relapse. And the fact of the matter is, if you're a responder, if you're 50% better, but not a remitter, then there's an even greater chance that you're going to relapse with subsequent episodes. And the longer you're sick, the harder it is for you to respond to treatment. And I'll talk about that a little later. Our patients have all sorts of factors that impact on their ability to become remitters. You know, if you're living in abject poverty, if you're under tremendous stress, if you're worried about your children, if you're in the face of tremendous air pollution, if you're concerned about having enough food to put on the plate for your family, those are factors that contribute to the treatment of depression. So you need to think about the context of the patients that you're seeing as you're evaluating the depressive syndrome. Clearly, depression is associated with a reduction in both social and occupational functioning, lost work days. This has an economic consequence, obviously, for society, and it's one of the arguments for increased parity. Depressed patients utilize health care facilities at a greater rate than patients who are not depressed. They go to the emergency room more often. They see their internist more often. They have a lot of somatic symptoms, including chest pain, GI disturbance, et cetera. All of that leads to increased cost of treatment. Of course, what we worry about the most is the risk of suicide in depressed patients. And we've seen a, there was, interestingly, a small drop in the United States in the suicide rate during COVID. It has rebounded with a vengeance, with a vengeance, particularly in adolescents and young adults. So top 10 cause of death in the United States, the only one that's increasing in number. All the others are decreasing, heart disease, stroke, diabetes, cancer. Part of that is because it turns out if you throw money at a problem, you can actually make inroads, right? The National Cancer Institute budget is more than three times the size of the National Institute of Mental Health budget, right? And of course, the problem of comorbid substance and alcohol abuse, which confounds the treatment of depression. And I'm going to talk a little bit about a complicated phenotype of depression that we all see for which we have no data on how to treat these patients. And then an area that's been very dear to my heart, no pun intended, is the increase in vulnerability and poor outcomes of depressed patients who have comorbid medical disorders, particularly heart disease and cancer, but also diabetes. So very briefly, what you should know is if you're depressed, you're more likely to develop coronary artery disease, and you're more likely to die after a myocardial infarction, as well as after a CABG surgery. If you have congestive heart failure, if you have any number, mitral valve surgery, any cardiac condition in the context of depression associated with a poor outcome, and an increase of vulnerability to develop those diseases. Same is true of many cancers, particularly breast cancer. Women who are depressed have a higher likelihood of developing breast cancer than women who are not depressed. So depression is a serious risk factor for morbidity. So we learned a great deal from this NIMH funded study, one of the last studies the NIMH ever funded, clinical studies. They're not in the business of funding large-scale clinical trials anymore. So this was a study in which everybody, like 2,400 patients, all were treated with citalopram, up to 40 milligrams. And the shocking finding, the patients knew what they were getting, the doctors prescribing them knew what they were getting, a reasonable dose of citalopram. Our expectation, I was not involved in the study, was that the remission rate would be very high, 50% maybe, maybe higher. And the remission rate using the HAMD was 28%, 28%. This was a sobering moment in American psychiatry, because it fundamentally told us that what we believed, that SSRIs were great treatments for depression, and this was an effectiveness study. It took all comers. It took patients that had comorbid medical disorders. It took patients that had comorbid substance use disorders. It took patients that had comorbid anxiety disorders. All the patients you see every day. And the remission rate was 28%. Whoa. We're not really as good as we thought we were at treating depression. And then those who failed went on to a number of other treatments. You've all seen these data, I'm not going to repeat it, but they're two take-home messages. So you could be switched to bupropion or cognitive behavior therapy, or sertraline or venlafaxine. You could have a bupropion or buspirone or cognitive therapy added to the citalopram. You could, if you fail that strategy, you could go on and be augmented with T3 or lithium. You could even receive an MAOI. Or you could look at the combination of venlafaxine and mirtazapine. The take-home message here is the more you try to get people who are resistant better, some percentage of them got better. They absolutely got better. But it took a really long time. And those who took the longest to get better relapsed the fastest. And of course, there was a big side effect burden as you added medications. And the part of the study that was the most disappointing was that atypical antipsychotics were not included in the treatment algorithm. So that we wouldn't know where they stood in the treatment algorithm. I've got four chairs up here that any of you in the back are welcome to come and take. Can I sell a chair? $25. The charity. David Sheehan knows that I was going to include this slide because it's one of my favorite research areas. But if you're beginning to think, and we're going to get to this, about how do you feel when you're seeing a patient in your office and you've made the diagnosis of major depression, and you've eliminated, you're a great doctor. You've eliminated medical causes of depression. You've eliminated that. You've looked at thyroid. You've measured testosterone in men. You've done all the right things. And you have this depressed patient in front of you. What should you treat them with? And why are they depressed? And you're asking about family history. This is one of the reasons. Is that childhood maltreatment is associated with two important findings. The first is an unfavorable course of illness. Of course, the first is vulnerability to depression. Every study that's ever looked at this, our studies, other studies have shown that a history of childhood maltreatment is associated with increased risk of depression and other things. And that the course of the illness is worse. So if you look at the data, the course of the illness is worse in terms of earlier age of onset, more suicide attempts, more inpatient hospitalizations. But the response to treatment is poorer in people with a history of child abuse and neglect. Namely, both in psychotherapy, in pharmacotherapy, and in the combination. So here's this solid line. It's like the worst pointer I've ever seen. Oh, there it is. Okay. So that solid line would be no effect of childhood maltreatment. Everything to the right are studies that have shown a poorer response in individuals with child abuse and neglect histories to pharmacotherapy, psychotherapy, and the combination. Now, there has never been a study done of this population. So Dr. Sheen and I have sat on many pharmaceutical company advisory boards, and I've said, hey, you need to worry about this when you do studies. You need to measure child abuse and neglect with the childhood trauma questionnaire so that you know whether your drug is effective in patients who have this history. And you know what their response usually is? We'll just eliminate those patients from the trial, because that's a confound. Well, that's not helping you or me, because we see a lot of these patients, and childhood maltreatment is common. And we still don't know how to treat those patients, but they don't do as well. So let's get to the treatment of depression. Here we are. We're in your office with you. You have a patient who's come to you either because they're referred for so-called treatment-resistant depression, or you have treated them. We'll just make this up. You started them on escitalopram. You started at 10 milligrams. You went to 20. You went to 30. And now they're on 40 milligrams of escitalopram. And the first thing you wanna know, are they better at all, okay? Do they have a 25% or better improvement on the SSRI? Assuming you've treated them for, let's say four to six weeks, are they better? If they're not better at all, the answer is not to leave them on that medication, okay? But you have to make a decision. If they're better, what can you do to make that effect more robust by doing something else? Now, I will say to be, as a small side note, when you're sitting there with that patient, you've done the evaluation, you've made the diagnosis, you're all thinking to yourself, I know the best treatment for this patient. And you're saying to yourself, I have a lot of years of experience. I know that this is a venlafaxin responder. I feel it in my bones. I feel that way when I see these patients. Or you say, you know, this is gonna be an escitalopram response or this patient ought to get cognitive behavior therapy before they get a medication. Now, I know you're gonna present the possibilities to the patient, but I'm talking about how you're feeling. And you're feeling like, you know, even this may be an MAOI patient. I got it, I know that, okay? And we all have these beliefs, but the truth is there's no data to support this at all. Zero, okay? And I think I'm a pretty good clinical psychiatrist, but I have to laugh at myself because just because I prescribed sertraline and the patient got better didn't mean they wouldn't respond to something else. So you have to dispel the notion that you actually have any idea about what the best treatment is for a patient. And I'm not gonna talk about it today, but I just want to give you a summary of a meta-analysis that we're about to send to the American Journal of Psychiatry where we have now revisited the pharmacogenomics platforms for predicting antidepressant response. And the short summary is, no, don't do it. Don't prescribe it. You're throwing your patients and their insurance company's money in the garbage. Now, there is a future, there will be a future in finding biomarkers to predict antidepressant response, but the commercially available platforms are not the answer. We have reviewed every single study that's ever been published, and I have finished this very large monograph that we're probably submitting in the next days to the American Journal of Psychiatry. I'm sure you're gonna see it. But the fact is, those studies that have been reported are terribly flawed, and there's just no evidence that you can predict antidepressant response by pharmacogenomics. So, and they're dangerous. So, you know, patients come to me, this happened recently, a patient came to me, a 42-year-old woman who I treated for depression, and she was on a combination of Venlafax and Mirtazapine. Her Hamilton score, when I last saw her, was about four. She had done great. And she came to me, she had a relapse. I hadn't seen her in a while. She lives in Florida. I saw her by Zoom. I said, you know, what kind of stressors are going on in your life? She said, well, I saw my primary care doctor. He ran this test, and the drugs you prescribed were the red sign, the stop sign, and oh my God, Dr. Nemeroff, how could have you prescribed this drug for me? So he told me to stop taking them. So I did. Well, how are you feeling? Well, I can't sleep. I've had suicidal thoughts. My husband says I'm really irritable. And I said, well, could have you called me? Could have we had this conversation? And you know, some small percentage of patients who have responded to a treatment, when they stop taking the medicine and you re-challenge them, they don't have a great response. So you really need to be cautious about this. But let's get back to the meat of the story here. So you're sitting with the patient in your office. What are you gonna do with this patient who's 25% better, right? So you're gonna have to decide in terms of S-italopram. You can't decide that you're gonna switch to something else. Maybe an SNRI. We did a meta-analysis some years ago showing that Benlofexin was slightly more effective than SSRIs. Most of those studies were with Prozac, with fluoxetine. So just take that with a grain of salt. But in my clinical practice, can be at higher doses more effective. And speaking of dose, I want to remind you that the PDR is a guide to what the companies did in their clinical trials. It's not a guide for you. You don't have to adhere to the dosing schedule in the PDR. So I have patients, try to believe this, I have some patients on between 450 and 600 milligrams of Benlofexin. They didn't respond to anything below that. Why did I do that? Well, they didn't have any side effects and they were starting to have a clinical response. So when I say this to audiences, people say to me, oh my God, the upper end of the Benlofexin XR dosing in the PDR is 225. I said, yes, but the IR was actually higher. It was 350. And the truth of the matter is, you don't have to be guided by that. You know, what you will do is you'll get an email from the pharmacy, of course, who knows more than you do, right? And he's going to tell you that, oh, look, what have you done, Dr. Nimrod? Okay. So you can switch and there are drug classes you could switch to. This part of my presentation is all about what we currently have. And then I'm going to move on and talk to you about the newer agents that are in the pipeline and are coming out. Or you could add a second agent to augment the effect of the antidepressant. And there's a lot to choose from. The great thing about treating depression, even now, is it's not like treating schizophrenia. You know, the textbook on treatment-resistant schizophrenia has one page. It's called close-up, right? There's nothing else that's ever been shown to be effective in treatment-resistant schizophrenia. But we have a medley of choices that are evidence-based and we'll talk about that. Instead of augmentation, which is technically adding a substance that in and of itself is not an antidepressant, to an antidepressant to achieve a better response, the other is to combine antidepressants of different classes. Bupropion and SSRIs, or tazopine plus of enlofaxin, et cetera. Or you could now think about neuromodulation. And we'll talk about neuromodulation. We'll talk about TMS. We'll talk about accelerated theta burst TMS. We'll talk about ECT. I'll just remind you that no pharmaceutical or other device company has ever had the courage, with one exception, to do a head-to-head comparison with ECT. So ECT is the gold standard, most effective treatment for depression. It doesn't mean it doesn't have side effects, but it's the most effective treatment. There's been one head-to-head study ever done which was with ketamine, and ketamine failed against ECT. So ECT is the gold standard. No other company has ever been willing to take that challenge. So if you're going the augmentation route, you have a lot to choose from from an evidence-based point of view, right? The two oldest augmentation therapies are thyroid hormone, T3. So it's a little confusing for people. So just to be clear, if you have normal thyroid access, your TSH is normal, and you want to use thyroid hormone as an augmenting treatment, you can use 25 micrograms or 50 micrograms of T3. That's Cytomel. No one markets it. Most of my residents don't know anything about it. It has no side effects. Do not send these patients to endocrinologists because the endocrinologist will say, oh, it's going to affect bone density. No, 25 micrograms of T3 is not going to affect bone density. It's an easy thing to do. And in the STAR-D trial, it had a better response rate in the non-responders than did lithium. So it's sort of interesting. And then there's lithium, originally studied by Pierre Blier in Canada, at the time in Montreal, added to tricyclics. It can be added to SSRIs, SNRIs. You all know about lithium. You know it has to be monitored. A certain percentage of patients will convert from non-responders and non-remitters to responders if you add lithium. Not very often utilized because, again, lithium isn't marketed. As an aside, I see patients all the time in our comprehensive evaluation program with bipolar disorder who've never even been treated with lithium. The gold standard, okay? There's nothing better for treating bipolar disorder than lithium. And I end up seeing patients marinated on antipsychotics with bipolar disorder who've never received lithium, who've been hospitalized multiple times. I mean, it's a tragedy. I'm going to mention Pramopexol. It's a D2, D3 agonist later, not approved by the FDA, but we'll talk about that. We'll talk about atypical antipsychotics in a moment. Mood stabilizers, other than lithium, there is no data, none, that any mood stabilizer is an effective augmenting agent in unipolar depression. Now, half the patients with unipolar major depression who are treatment resistant that I see are on lamotrigine because practitioners like lamotrigine. It's a great drug for bipolar depression, but it has failed in every trial for the treatment of unipolar depression. But all these patients that I see are on lamotrigine, so go figure. Buspirone. My friend, Jerry Rosenbaum at Mass General had the famous quote about buspirone many years ago. He said it had everything you ever wanted in a drug except for efficacy. Okay? And so the truth is there was one study done by Don Robinson. David will remember that. 90 milligrams of buspirone was actually an effective antidepressant, but the company never went on to study it. So you can use buspirone. You could start at five milligrams TID, go to 10 milligrams TID, go to 20 milligrams TID, and see if you get an effect on comorbid anxiety and depression. The Pindolol story has not panned out. This is a beta blocker, largely studied in Spain as an augmenting agent, but unfortunately has not shown efficacy. So I want to use this as an object lesson, which is the aripiprazole data. I'm not picking on aripiprazole. I just want to show you the data. So these are the two pivotal trials that led to the approval of aripiprazole as an augmenting agent in depression, in treatment-resistant depression. So I just want you to look at, these are two well-powered studies, 180 patients approximately per group. All of the patients were on an SSRI, and then they were randomized to aripiprazole or placebo. And you can see in the orange line that aripiprazole was better than placebo in both studies. And you can see the absolute difference between them. And perhaps during the discussion period, Dr. Sheehan and I might comment about whether a three-point difference on the Madras is statistically significant or clinically meaningful. I want you to think about that. What's interesting about this study is we did the first study with aripiprazole as an augmenting agent in depressed patients, an open study. And what we didn't realize at the time was that patients on SSRIs are extremely susceptible to akathisia when you add aripiprazole. So like an idiot, I started the trial at 15 milligrams of aripiprazole, right? And so I've got these patients on, you know, 40 milligrams of citalopram. I add 15 milligrams of aripiprazole, and they did not do well. We later learned that you need to start at 2 milligrams of aripiprazole, then go maybe to 5 milligrams. At any rate, let me show you the proof of the pudding here of the remission rates in this study that led to FDA approval. So everybody's on an SSRI. These are the two studies I just showed you. You see in orange is the remission rate when you add placebo. So placebo gives you about a 15, 16% remission rate. Why is that? Well, partly placebo, but remember, you're adding six weeks more of an antidepressant treatment to these people who were on an SSRI, and some people respond slower than others. But look at the aripiprazole remission rate. It's not great, 25%, 26%. That's not wonderful. And the brexpiprazole data, spite of the fact that I was watching the Heat Game the other day, and brexpiprazole was being advertised at every break, right, I don't know whether they think people who are sports fans have more depression, I don't know. I think the Celtics fans have a lot of depression. I'm a Heat fan, so I'm having a good time. This isn't good. Think about the fact that aripiprazole and brexpiprazole are very good drugs for schizophrenia, for bipolar disorder, but for the point of treating depression, that's not fabulous. We're not as good as we thought we were. One of my favorite people, one of my heroes in our field was Jan Fawcett, who unfortunately passed away this year, and he published this case series in the American Journal of Psychiatry, and for quite some time, I have argued that the pathognomonic symptom of depression is anhedonia. Right, think about your depressed patients. If you have a patient who's depressed, but does not have either relative or absolute anhedonia, you ought to rethink the diagnosis, right? And so, what's the neurotransmitter system that probably has the most valence in reward? It's dopamine, right? Think about sex, drugs, and rock and roll, right? It's dopamine. We hardly ever touch dopamine when we treat depression. We touch it with very high doses of sertraline. When you get to 150 of sertraline, it starts to block the dopamine transporter in addition to the serotonin transporter. So at 200, at 250, you're getting an increase in dopamine availability. MAOIs clearly affect dopamine. Other than that, we're not messing with dopamine. Seems a little weird that antidepressant treatment where anhedonia is a central feature and we're not addressing dopamine. So Jan picked this drug approved for restless leg syndrome and Parkinson's disease, a D2, D3 agonist of the receptor, and he treated patients with both bipolar and unipolar depression, and he ended up with very good outcomes. And I use Pramopexil all the time in my clinical practice. The key with Pramopexil is to start at a low dose. It comes in very weird doses, 0.025, 0.037, 0.05. Most of my patients are between one and three milligrams a day, and it really works really quite well. Not FDA approved, but I would want you to think about it. What about the combination of evidence-based psychotherapy and pharmacotherapy? So a nice study done in Japan of patients who were treated with treatment as usual, meaning their SSRI plus CBT. And you can see this remarkable improvement in their, this is in the Hamilton, a remarkable improvement with the addition of psychotherapy. Now, not all of our patients can avail themselves of CBT. Another problem is who in your community is actually practicing real evidence-based CBT? This is not what I call rent-a-friend psychotherapy, right? This is you actually were taught by the Beck Institute or something similar to deliver manualized CBT. Well, how do you know? Because I say to my patients, oh, you're in therapy. What kind of therapy are you getting? And the patients say, oh, we talk, OK? And I say, do you get assignments? If you're not getting assignments, you're not getting CBT, right? And CBT is not meant to be interminable, right? It's not like psychoanalysis, right? So you need to find out, identify a good psychotherapist in your community and work with them. OK. What about newer developments? So you all know the story that a very small pilot study was done at Yale many years ago with IV ketamine, a dissociative anesthetic. And it was found to have some antidepressant properties. And up has sprung across the United States 250 ketamine clinics, only one third of which are run by psychiatrists. The rest are run by pain doctors, family doctors, nurse practitioners. And the truth is that if you have between $500 and $1,000, you can get IV ketamine regardless of what ails you. Because if you look at their websites, it says it's like better than sliced bread. I mean, it treats chronic pain, PTSD, migraines, irritable bowel syndrome, depression, the Celtics losing streak. And then one of the pharmaceutical companies, Johnson & Johnson, developed the S form of ketamine in a nasal spray for the treatment of depression. And I've been extremely critical of this data. I'm going to show you why. There were three pivotal studies that were submitted to the FDA. One was a geriatric depression study that was a complete failure. S ketamine did not separate from placebo. There was a relapse prevention study. And then there was this study that I'm going to show you. This was their outpatient study. And published in the American Journal of Psychiatry. And this was the results. So the patients were treated by their practitioners with regular treatment. Any of you could have been part of this study. You're all good psychopharmacologists. You treated the patients as, you know, with the best treatment available. So you used venlafaxine, you used duloxetine. And then half of them had S ketamine added twice a week. And these are the results. So look at the yellow line. My conclusion to that is, you know what? Good treatment works. That's used prescribing. That's all of you. So guess what? Really good diagnosis and treatment works. You guys ought to let the people on the outside of the room get in here. You guys can come in. Don't be shy. I don't want you to stand out in the hall. We got plenty of wall space. We got a seat right here. Seat right here in the front. Come on and grab it. Yeah. And again, I'll still invite any of you to sit up here with me. And then look at that. Well, look what S ketamine did. So it's better. But again, I would say, is it that much better? Is that a clinically meaningful effect, this change in the depression rating scale score? And let me show you a breakdown of the data. This is the kind of thing that Dr. Sheehan has taught me, is to do a deep dive in the data. So now you're looking at subgroups of patients and which of the subgroup favors placebo and which subgroup favors the drug and where is there no effect. And I want you to see a few things. Here are the men in the study. There was no effect of S ketamine in the men at all. It was no different than placebo. Look, right there in the middle. Well, what else can you glean from this? Well, if you were 18 to 44 years of age, you didn't have any effect of S ketamine either. That's pretty interesting. If you had less than three prior episodes, you didn't get better on S ketamine compared to placebo. That's pretty interesting. So I'm not impressed. An author named Turner published a paper in Lancet Psychiatry saying seven reasons why the FDA should not have approved S ketamine. And it turned out that in one of the pivotal studies, there was a single site in Poland that had a 0% placebo response rate and 100% S ketamine response rate. And guess what? With that study, a population was taken out. There was no difference between drug and placebo. And you know how much this drug costs? It costs $5,260 for a two-week treatment. Yeah, so I'm not a big fan. There have been other ketamine studies done. R ketamine is the other isomer. It now has had a failed trial in the treatment of depression. And I should say one other thing about ketamine that you should know. What's the mechanism of action of ketamine? It is said to be an NMDA receptor antagonist. So why is it that Alan Shatsberg and Nolan Williams at Stanford did a study in which they took depressed patients, very depressed patients, gave them IV ketamine with or without pretreatment with 50 milligrams of naltrexone? What is naltrexone? It is a mu-opiate antagonist, right? It's one of the purest drugs in all of pharmacology. The only thing naltrexone does is it blocks the mu-opiate receptor. So what did naltrexone pretreatment do to the ketamine antidepressant response? It completely abolished it, both the antidepressant response and the anti-suicide response. What does that tell you? Well, it must tell you that ketamine's acting on the opiate system. And if you didn't notice, we sort of have an opiate problem in the United States, right? And ketamine is, after all, a drug of abuse, right? That's why it's called Special K. Think about it, okay? All right, let me move on. This is brexanilone. It is a positive allosteric modulator of the GABA-A receptor. There's been a lot of talk about GABA-A over the years. And this study showed that it is highly effective if infused for 60 hours in the hospital in the treatment of postpartum depression. The company that manufactures it, Sage, received FDA approval for this treatment. But it's pricey. It's pricey. In inpatient hospitalization, the drug itself is expensive. There are the treatments that one could use for treating postpartum depression. And then they developed an oral form of it called xeranilone. And this paper was published in the New England Journal of Medicine. And what's interesting about this drug is it's only administered for two weeks. So it's administered every day for two weeks. And then about half the patients do well for a persistent period of time. And about half the patients end up needing to be retreated. It is now before the FDA. The FDA is considering the approval of xeranilone for the treatment of major depressive disorder as well as the treatment of postpartum depression. My assessment of the data, looking at it from 50,000 feet, is this drug is particularly effective in patients who have depression with prominent anxiety. And that's the role it's going to have. I've noticed several of you taking pictures of my slides. You just need to send me an email and I'd be glad to send you my slides. So you don't need to burn out your iPhone here. Let me show you the data. So this is the New England Journal paper. So two weeks of treatment. And you can see a very clear improvement on the HAMD with a big 15-point change compared to about nine points with placebo. In antidepressant trials, that's a big effect. Subsequent trials, maybe not as big an effect. But I believe this drug will be approved and it will find its way into your armamentarium. A couple of red herrings that are out there that have not been followed up very well. Really interesting paper that came out of Sao Paulo looking at nitrous oxide. You know nitrous oxide? You know what you get when you go to the dentist? At least if you're lucky, you get nitrous oxide. You sort of listen to rock and roll music while they're torturing you. A randomized double-blind small study showed that nitrous oxide was effective. I was sort of a little skeptical about this. And then science translational medicine, a second study was published, but this from Washington University in St. Louis by two very well-known clinical and basic investigators, Chuck Conway and Chuck Zeromski. Again, seeing a very clear antidepressant response. So interesting. I don't know that there are any companies particularly working on getting this approved. I don't know where you can send your patients to the dentist and tell them to, you know, have a NO experience, but I felt I would at least tell you about it. This is a completely different mechanism. This is called isogabine. It's a drug that acts on channels, potassium channels in particular. This sort of came out of the blue. Again, a very well-respected group. Jim Murrow is a professor at Mount Sinai in New York, was the lead investigator in this trial, and the results were quite interesting. If you look here at the effects that you can see in the madras on the left and the quids on the right, you can see quite a significant antidepressant response. So isogabine may have some life, and you might be seeing this coming up in the future. So this is sort of an interesting and somewhat sad story, which has to do with the drug called S-methadone being developed by a company called Realmada. So this study, again, by a group of very well-known psychopharmacologists, Marisa Ofava, who's the chair of psychiatry at Mass General, did a study, and this was published in the American Journal of Psychiatry, showing that it was quite effective. There have been two subsequent large-scale phase-II trials that did not separate from placebo because the placebo response rate was too high. There's a third study going on. I wrote an editorial about this, and fundamentally, in the editorial about this paper, what I said was, number one, I want to make sure that this drug really has no drug abuse liability. It's an enantiomer of methadone, and what they claimed was that R-methadone was the drug that's used to treat opiate addiction, but S-methadone has very little in the way of abuse liability. I think we still need to know that. We'll see if this third trial is effective. If they get a lower placebo response rate. If so, I think it has a reasonable chance of getting approved. Now let's talk about psychedelics. I was at Woodstock. You know, only the old people laughed. You know, the young people were thinking, what's that? So, yeah, I remember sitting there, and Jimi Hendrix was playing, and there was an announcement that came over the loudspeaker that said, the brown acid is poison. And somebody next to me said, oh, my God. Okay. So, I really do want to spend a little time on this. So, you cannot be involved in anything on the Internet without hearing about the use of psychedelics. So, traditionally, psychedelics have been classified into three classes. Ketamine was originally classified as a psychedelic. It's really a dissociative anesthetic. I would not consider it a psychedelic. There are two other groups of psychedelics. One are psilocybin, DMT, 5-MeO-DMT, ayahuasca, LSD. They have a shared property of being serotonin, a 2A agonist, okay, pharmacologically. They may do other things, but that's what they do. And then there is a drug called MDMA, which is not a 5HC 2A agonist. It is classified as something called an intactogen, and it has largely been studied in PTSD. And I'll talk, excuse me, I'll talk about that later today when I give my PTSD presentation. So, I'm going to limit my comments here to the traditional psychedelics, which largely has been psilocybin. So, this is the first randomized trial, and let me just, as a praise see, say that when people come and talk to me about psychedelics, and we've established a Center for Psychedelic Research and Therapy at the University of Texas at Austin, because we need to provide scientific rigor to this incredibly confusing field, and patients will ask you about psychedelics. And the first thing I tell people is that the discussion of whether psychedelics are an effective treatment for a psychiatric illness is a different conversation than if you do not have a psychiatric illness, and you're interested in exploring your inner self and want to use psychedelics for personal growth. That's a different topic. We're not going to talk about that today. What we're going to talk about is whether there's any evidence that psychedelics may be able to help all these people that I've already talked to you about who are treatment-resistant. And, you know, I didn't mention this earlier, but in the study we did of never-treated depressed patients, virgin patients, 350 never-treated depressed patients, we were with S-cytallopram, duloxetine, and CBT, three arms, to get about 50% of those patients into remission. So the sooner you treat patients, the better. They're going to respond better, and over time, depression changes their brain and they become less responsive. So important to be aggressive. So what about psychedelics? This is the first study done at Johns Hopkins. It was a small study of 27 patients. There had previously been some studies done in end-of-life, people with stage four carcinoma, showing that it improved mood and anxiety in those patients, but I'm limiting myself to a conversation about depression. This is a small study, two doses. This is a pretty, pretty high dose. These are high doses. So 20 milligrams is a substantial dose, 30 milligrams is a higher dose than I would use in clinical trials. I think the current trials we're doing used 25 milligrams. Only 15 patients were in the study, so very small. Why was that? These are really hard studies to do because of all the regulations from the feds and the FDA about how to get this done. I can't tell you what we've gone through to try to do clinical trials. I had to buy a safe that Houdini couldn't break. I mean, it costs like $18,000 and it weighs 8,000 pounds. Yeah, who's gonna move it, right? Okay, so this was the study that was done, and it also included a great deal of prep time, getting the patients ready for the study, telling them what to expect. And these were the results. So they compared the patients who received psilocybin to the patients who were in the second cohort that waited, and what you can see is a pretty clear antidepressant response. No one would disagree with that. So that seemed exciting, but there were two important findings. One, the second dose didn't seem to make any difference. It didn't add to the effect of the first dose. But understand that none of these trials are blinded. You know how important it is to do double-blind, randomized controlled trials. Well, you know, if you take a pill and the walls start breathing, you know you didn't get placebo, right? It's important. But what I want to show you here, and I apologize for how hard it is to read this, but I want you to see what the experience was like for the patients. So what annoyed me is that this was buried in supplement table eight of the JAMA psychiatry paper. So let me just try to — I'll shout loud enough that you can hear me. 92% of the patients said they felt like crying. 80% had sadness, emotional and physical suffering. Three-quarters of the patients felt like heart was beating. And then feelings of grief, 60% despair, the same anxiety, the same fear. More than half of the patients had felt isolated from everything and everyone. 45% panic, 20% I thought something terrible would happen, 33% I thought this state would last forever. A third of the patients, I experienced my own death. A third of the patients. This is not a pleasant experience, right? I felt like I was dying, 25%. So when we're recommending psychedelics as a potential treatment for patients, we need to understand that these are incredibly powerful medications, and there are patients who don't do well. So when Dr. Sheehan and I were youngsters and we were in the emergency department, people would come in on bad trips, and they were terrified. And we gave them like 200 milligrams of Thorazine, right? Because they wanted it to stop. So let's not pretend that these are benign agents. They may have a role, but let's be clear about what we have here. So this is the second study. Did I get this right? Let me see. Yeah. So this is a second study published in the New England Journal of Medicine, which compared escitalopram, which is an only head-to-head study, escitalopram versus psilocybin. And what you see there are the results, and there's no statistically significant difference between escitalopram and psilocybin in this study. It looks numerically like psilocybin was a little bit better, it was not statistically significant. And then the latest study. So, you know, we're a site for the COMPASS Pathways final pivotal study, and this came out of their phase 2 study and it was just published recently in the New England Journal of Medicine. And I want to show you the data. So there it is. To their credit, they studied three doses of psilocybin, one, 10, and 25 milligrams. One milligram fundamentally has no effect. Ten milligrams is meant to sort of tickle you a little bit, but it's not a full psychedelic dose. And then 25 milligrams is the real deal. And there are the data, there's the results. And what you see is no effect at 10 milligrams, and for 25 milligrams, you see this effect. But the response and remission rates were not great. They were okay, but they were no better than atypical antipsychotic augmentation in terms of response and remission rates. Now, there were a lot of confounds with these studies that we could talk about. So I want to talk a little bit now about where the field is going. And then I'm going to finish with a conversation about advances in TMS and then we'll have a lively discussion. So this worries the hell out of me, okay? So 25 states are now considering various bills to allow the dispensing of psychedelics in one form or another. Most of them relate to either MDMA for the treatment of PTSD or psilocybin. The state that has led the field is Oregon. Oregon has now legalized the availability of psilocybin and it can be purchased in mushroom stores that are approved by the state. So your patients can go to Oregon and they could go up to the mushroom store and they could order, you know, I want 100 grams of mushrooms. And they'll get the mushrooms. And, you know, obviously there's an underground for this as well. So many of us have had patients do this. And then the idea in Oregon is this is completely demedicalized. There's no requirement for any medical screening of any kind, none. So I want you to think about the idea that if you had a patient who was depressed who had a loaded history of bipolar disorder, family history, or schizophrenia, do you think that psychedelics are a good idea for that patient? And I published a paper in the American Journal of Psychiatry in December of a patient of mine who took psilocybin on two consecutive days and ended up having a psychotic manic episode. Ended up being hospitalized, misdiagnosed with schizophrenia. $400,000 later that exhausted her entire bank account. She went from being psychotically manic to horribly depressed. And we ended up treating her. She turned out to respond to Pramapaxil. But it was a horrible experience for her. So understand if you're in Oregon, you can now go to the mushroom store. You could buy mushrooms. You could then get online and find a therapist who has taken the internet training course. OK, what are their qualifications? They do not have to be a PhD in psychology. You just have to take the course. And you could hang out your shingle. And you are a psychedelic therapist. And then the patient brings the mushrooms to you where they're going to weigh out the dose. Now keep in mind that different mushrooms have different concentrations of psilocybin. So as one of my patients said, well, I like to take one gram every day. It's sort of microdosing. I know it's helping me. But if I really want to have an experience, I take three to five grams. Well, how do you do that? Well, I weigh it and then I cut it. And so you go to the therapist. And the therapist collects their $1,000 for spending the next six to eight hours with you. And then you may have subsequent sessions. One of the areas in psychedelic medicine that is unanswered is this misnomer called psychedelic assisted therapy. So I just have a paper coming out in the American Journal of Psychiatry, a commentary on why this is a ridiculous term. Because what it implies is that what the psychedelics really do is assisting therapy. So that begs the question, what's the therapy? So let's describe. I'm putting the MAPS program aside because that is a real form of therapy. It's manualized. It's been validated. But that's for PTSD. I'm talking about the clinical trials and the clinical use of psilocybin for depression. So typically, the patients come in. They are evaluated by a health care professional. And they are told what the experience is going to be like. And then what to expect is what you might experience during this eight-hour experience. They pick out a playlist. I personally recommend Vivaldi. Some people pick The Grateful Dead or Led Zeppelin. I don't particularly recommend it. And then they are brought into a room where they have eye shades and headphones. And then, ideally, two individuals in the room, a man and a woman, to make sure that aren't any shenanigans that are going to go on. Because unfortunately, if you go on the internet, unfortunately, have now been episodes of individuals who have taken psychedelics that have then been sexually exploited by the, quote, therapist. So that ought to worry you. At any rate, the experience takes six to eight hours. And then there are a number of what are called integration sessions. Well, what are integration sessions? What they really are is what us old people were trained to do in psychodynamic psychotherapy, which is totally open-ended. What was your experience like? Well, I thought about how I could be a better partner. What have you learned from that? I thought about I need to spend more time with my children. Oh, seems like a good idea. This is not therapy that you and I understand to be real evidence-based therapy. So the idea that psychedelics assist therapy is just downright silly. There's never been a study done comparing a psychedelic versus a psychedelic plus therapy. I suspect where the therapeutic here is with the drug, not with that treatment. So what are the other unanswered questions? Well, what about microdosing? If you Google psilocybin or LSD microdosing, you'll get 100,000 hits. Michael Pollan's book about microdosing, it's changed their life. And I have an endless number of very good-hearted Navy SEALs and Army Rangers who come to me, horrendous life stories of miserable war experiences, came back with severe PTSD, who fundamentally say, I microdose a psychedelic. Or I went to a yurt in Costa Rica, and I had a eye-opening experience. And since then, I'm microdosing, and it's changed my life. I've stopped drinking. I've been nicer to my family. It's a game changer. And you know, that's wonderful, but the plural of anecdote is not data. There's never been a randomized controlled trial that has any kind of scientific weight about microdosing. It begs the issue as to whether you have to have a psychedelic experience in order to have a therapeutic effect, right? There's a case of one that's published in the American Journal, a really interesting case of a patient of Roger McIntyre's in Canada, who was in a psilocybin trial, who didn't have any psychedelic experience, but had a therapeutic response. And after the trial, the patient said, I lied. I was taking Trazodone. OK, 300 milligrams. Well, Trazodone is a 5H2A antagonist, and so it blocked the psychedelic effects, but he still had a good therapeutic response. So maybe you don't need a psychedelic experience, right? So a lot of unanswered questions about psychedelics. Maybe they will have a role. And I think the PTSD data with MDMA is probably the biggest effect I've seen with psychedelics, certainly bigger than the depression effects. And then it gets back to the age old question, who will it be best for, right? What kind of patient? Are there going to be biomarkers to predict response? I think it's an exciting part of the field, but we shouldn't get ahead of our skis, and I don't want everybody to have availability. I need to, I'm running out of time, and I want to have a question. So let me talk to you about the most exciting development currently in the treatment of depression, and that has to do with the Stanford Neuromodulation Therapy, also called SAINT, on the editorial board of the American Journal of Psychiatry. The first paper, this is the second paper. The first paper used the SAINT abbreviation for Stanford Accelerated Interventional Theta Burst. And then one of the reviewers said that they were offended by the use of the word SAINT. Get a life. Really? So they had to change it to Stanford Neuromodulation Therapy. So you all know about TMS. It's approved by the FDA. There are about four or five companies that sell TMS units. You all know that it's a six week FDA approved treatment, 45 minutes a day, five days a week for six weeks. It was originally approved for treating resistant depression, and then changed for just depression. And it's an effective treatment. Those studies were compared to sham. So Nolan Williams, who's a brilliant young psychiatrist at Stanford, fundamentally said, I think we can improve this in two ways. Number one, we can use functional magnetic resonance imaging to identify where precisely in the left dorsolateral prefrontal cortex we should target the TMS so that we won't have any people getting the treatment, but not at the appropriate target. Because people's brains are of different sizes and shapes. And then secondly, he said, why don't we deliver a huge amount of magnetic energy in one week instead of six weeks? What we'll do is we'll do it for five minutes an hour, 10 hours in a row. And that way, patients can get the full treatment in one week. It was a pretty bold experiment. The biggest concern was, with this much energy, could it be associated with an increase in seizure risk? And the answer is, it's not. So they did an open study published in Brain, a second small pilot study published in the American Journal. And this is their more recent study. And this is the comparison. These are really treatment-resistant patients. These are people who failed at least four previous evidence-based treatments, who also, many of whom failed ketamine or ECT. So this is a really extremely treatment-resistant population. You're looking at the top. These are the Madras scores and the Ham-D scores. So at the top, the top line is the sham treatment. So they're getting the exact same treatment. The patients could not discern whether they were getting the active stimulation or the sham. I'll tell you a funny anecdote about that in a minute. And then look at the active treatment and look at the six-week period. These are people who failed everything that have responded in one week in a remarkable way. So this is going to be a game changer. Now, I'll tell you a funny anecdote. So we were doing some of this TMS work when I was in Atlanta. And we were having a meeting trying to figure out how to do the sham without the patient knowing it was a sham. And so we took a break, went out to use the men's room. And I come back, and there's a guy polishing the floor with one of those electric waxers. And he said to me, hey, doc, I was listening to your conversation in there. And I just wondered, why don't you just take the magnet and turn it on its side so that it's still there, but it's not providing any stimulation? And I said, that's a great idea. I went back in. I said, hey, I have an idea. OK. This is my last slide. And I want to take my hat off to Andy Crystal, who is a vice chair of psychiatry at UCSF here in San Francisco. He was one of my residents when I was at Duke. And if you want to really look at some science fiction, you ought to pull this paper out. So they had this patient with the worst depression known to mankind. It failed everything. And they fundamentally said to the patient, if you're willing, we're willing to work with a neurosurgeon to go into your brain and under the dura to put a gauze with multiple electrodes in it in order to see if we can find a stimulation site that would eliminate your depression. And of course, the great thing about the brain is it doesn't experience pain. So this can all be done with the patients awake. And in this remarkable paper, N of 1, but published in Nature Medicine, so you ought to think it's important, they found a stimulation site which removed the patient's depression, unique to that patient. So the idea that deep brain stimulation may have a role, I think, is fundamentally worth following up. I think there are a couple of things I haven't mentioned that I'd like to. There are some companies that are exploring pharmacological treatments of symptoms. It's not an approach that I particularly have felt good about in the past. It's gotten psychiatry in trouble. You don't give stimulants to people because they don't have enough energy, and you don't give them barbiturates. But there's a company working on a drug to target anhedonia. And anhedonia is such a pervasive part of depression. I think that's something worth thinking about. I recently met with a group that is working on a way to implant in patients a very small, in the scalp, a small electrode that then have allowed TMS to be delivered at home that you would control from your office. And that would prevent patients from having to come in. And it would also allow you to absolutely have the right site. So I think the future is really bright. I'm looking forward to an interesting conversation with you. And I'm grateful for you to spend your morning with me. Thank you. Dr. Sheehan, would you like to make some comments? Dr. Sheehan is as much of a scholar in this area as I am, and so I would be remiss if I didn't ask him to make a few comments. David? Well, Charlie, that was masterful. I think everyone would agree, right? So, Charlie and I are on the same page, and I echo everything that he said. Maybe one tiny detail to amplify on a point that he made is, if you're using Pramipexole, which I also think is underutilized and not enough information known about, what I would recommend is use the extended release formulation of it. Because one of the things with dopamine agonists is they tend to have a very short duration of therapeutic action, and if you use the sustained release formulation, you extend that out. So that seems to work best, and in fact, the studies that looked to me among those that have been published that had the better data were the ones that were using the extended release formulation. But other than that, really, it was fantastic. So thank you, Charlie. Great talk, Charlie. Thanks for being here. It's good to see you again. I recently had a primary care doc that I do in collaborative care with ask me, had I seen any data about GLP-1 agonists, the Ozempics and Oigovis, having an antidepressant effect? She had discovered a review paper which she sent to me, which I'd never seen, but it was all essentially animal data with depressive behaviors as the variable of interest, except for one uncontrolled small trial that suggested that Ozempic, Oigovis, all those may have an antidepressant effect. She was worried about insurance companies stopping those agents for people and the backlash if it did have an antidepressant effect. I had never heard any of that. Wondering if you have. You're talking about Lemostre gene, right? No, Ozempic, the weight loss agent. And the diabetes agents, the GLP-1s, yeah. Semiglutamide? Yeah. Yes, yes. Yeah. So, you know, all of my patients want me to prescribe it, you know, and, and one of the problems is, you know, I feel guilty about all the weight they've gained from the drugs I've prescribed to them. So I have a particularly brittle patient with bipolar disorder who's had a fabulous response to Borrexpiprazole augmentation, but has gained 40 pounds. And so I just broke down and prescribed the weight loss drug. I've had about five patients who've had the drug prescribed to them by their primary care doctors and thus far the side effects have been brutal in terms of diarrhea, constipation, abdominal pain. So I don't know enough about it to know where it's going to fit in the psychiatric armamentarium. Obviously, obesity is associated with type 2 diabetes. That in and of itself is a risk factor for depression. None of the other weight loss drugs we have are worth a damn. And these drugs really do work. So I think we'll have to wait and see. But yeah, it's important. Yes, sir. Oh, wait a minute. Let's go to the back. Yes, sir. Thank you for a wonderful presentation. And I just wanted to run a few things by you. I don't know if you have any experience with a vagal nerve stimulator. I have an N-of-1. Patient did lose about 30 pounds and was doing much better. much better, the anhedonia disappeared. So I missed, is it vagal nerve stimulation? Correct, sir. Oh, great, thank you. He had a seizure. The sound's terrible in the room, so it's hard for me to make it out. So, vagus nerve stimulation was approved by the FDA many years ago, but remarkably, and in a form of stigma, CMS, the Center for Medical Services, that regulates Medicare approval, approved it for formicoresistant epilepsy, but not for depression, in spite of the fact that the data was just as good in formicoresistant depression as it was in epilepsy. There is a new company called Levonova that has negotiated with the FDA, and they're doing a year-long study of vagus nerve stimulation, and the FDA has agreed, if the study's positive, it will approve it, and CMS has agreed that it will then support its efficacy, which means, in terms of third-party payers. The remarkable thing about VNS is that it takes a really long time to respond, but it works. So if you look at the long-term data, some people don't respond for six or even eight months, but by nine to 12 months, they show a clear response. So I think it should be part of your armamentarium. Understood. Then, talking about the dopamine receptor, I had a patient on 20 milligrams of fluoxetine, who wasn't doing so well. Added on some Welbutrin, and remarkable improvement. Took it up to 300 milligrams, and she had a seizure. So I had to withdraw the Welbutrin. 40 milligrams of? 300 milligrams of bupropion, Welbutrin. She never had any seizures before. She was sleep-deprived for two days, traveling to Central America, so I don't know if that. So, you know, I understand that idiopathic seizures are very common in the general population, and so when you see something like that, you never know whether it's drug-related or not. And was she evaluated by a neurologist or epileptologist? No, she did go to the emergency room, but we withdrew the Welbutrin, and she's doing well since then, but feeling very depressed. So I started on duloxetine, but I'm wondering if paramipraxol, if that hits on the dopamine receptor, and what your thoughts are on the stimulant regarding dopamine. Yeah, I'm not aware of any data in that regard. That's the I don't know answer. Okay. Yes, sir. So yes, sir, very interesting. You make fun of psychotherapy assisted cytosol therapy. I think it is said and setting has a lot to do with the response of the patient. In other words, if the patient is very agitated, it's very likely that the patient have a very bad response. So the psychotherapy really deal with the set and setting. And besides, in other fields of psychiatry, for instance, when we prescribe MAOI, we do provide literature for the patient, we warn the patient, or we use clozapine. So you make fun of it, but I guess this is really some area that it deserves to look at it more carefully into that. Yeah, so, you know, you're probably all surprised that he didn't mention MAOIs in the presentation. I prescribe more MAOIs than any person in Texas. So I love MAOIs. They make me a hero every day. Because the thing about MAOIs is nobody else prescribes them. And a huge number of patients respond to them really well. The issue about psychedelics and preparing the patients for the effect. So what do psychedelics really do? And what they do is they tear away your defenses. And so all of us in this room are high-functioning individuals, and there are a number of things that we could spend a lot of time worrying about, right? We could worry about the war in the Ukraine. We could worry about, you know, our parents. We can worry about our children. We can worry about all sorts of things. We don't, to a great extent, because we have defenses. And so, yeah, I don't like to think about the fact that maybe I only have 20 years left of being able to go fly fishing, right? I still think of myself as, you know, like 30, which I'm not. What psychedelics do is they tear away those defenses, okay? And that can be really scary for people. And one of the things we didn't talk about is are there characteristics of the patient that would, in your mind, improve your level of comfort in recommending them for a psychedelic experience or the opposite? So this is what Timothy Leary meant when he talked about set and setting. And set was the patient's mindset, right? All of you have worked with people who are incredibly rigid and controlling. That's not the personality characteristics, I think, of a patient who's gonna do well with psychedelics, right? If you're not flexible, if you're not able to sort of let things in, I think it's gonna be difficult. So you're absolutely right about the preparation for the patients. One of the tough parts of the field is some of the trials have been contaminated by patients who've had prior psychedelic experience. And that's a confound because of expectation, right? And we have to be rigorous about these trials, but good points. Sir. Dr. Nemiroff, can you speak to the efficacy of clozapine in treatment-resistant depression? Of clozapine? Yeah. I love clozapine. So the issue with clozapine obviously has to do, number one, with the blood monitoring. And it has to still be done every two weeks for the first six months, and then thereafter at a reduced rate. So it's inconvenient. There's never been a randomized controlled trial of clozapine in treatment-resistant depression. It's obviously off-label. I mean, you know, it's off-patent. I love clozapine for rapid cycling, bipolar disorder, intractable mania. You know, the best drugs we have are the dirtiest. Clozapine is the dirtiest of all of the antipsychotics, sort of like the clomipramine of the antipsychotic world. And frankly, for treatment-resistant depression, I use clomipramine because it's such a remarkably effective drug. So would I use clozapine? Yeah, absolutely. You remind me to say something about a patient population that I see all the time that I wanted to just share with you. So we have this very high-end, comprehensive referral service, and patients come to us from all over the world. It's pricey. And these patients come to see me and my team. And the history is something like this. Wealthy families, spoiled kids, started using marijuana at age 13, started using cocaine at age 15, started using heroin at age 18, used methamphetamine after that, fundamentally had a 10-year period of being marinated in every drug known to mankind. Now they come to see you, and they have either of two presentations. One is what I would call the defect state, that they're completely anhedonic. They don't have the cardinal, vegetative signs of depression. They sleep well. They eat well. But they can't concentrate. They have no motivation. They're anhedonic. And they technically fulfill criteria for depression. The other group have intractable auditory hallucinations with no history of schizophrenia or bipolar disorder in the family. And I'm just having a hell of a time treating these people. I don't know. There's never been a study done of this population, a randomized controlled clinical trial. They never get in a clinical trial, right? And I don't know what to do with them. They have failed psychotherapy. They've been hospitalized multiple times. I suspect that the chronic drug abuse has fundamentally changed their brains in ways that they're not responsive. But very, you know, I'd be curious if any of you have any ideas about that population. But thank you. Thanks. Hi, Charlie. David Hellerstein from Columbia. Great talk. I'm just struck by the fact that all of the research on psychedelics, which I've been part of as well, has been done by industry, sorry, small startups and foundations. There's really no NIMH support. And secondly, with all these novel treatments that are being prescribed willy-nilly, different locations, different settings, I don't know if you have much exposure to mail-away ketamine mills that also send people ketamine. So one is, do you think NIMH should start supporting clinical trials and other kinds of investigations of psychedelics? Secondly, will we ever see a STAR-D2? To sort of round up a lot of these new treatments compared to conventional SSRIs and so on and figure out what actually is best for whom. So you want to ask, you asked me the most politically charged and difficult question in a public forum. Why not? So, well, number one, the current NIMH leadership has been very clear about the fact that they will not fund any STAR-D2 or any large scale clinical trials like CADI or STAR-D or STEP-BD. And they have chosen a road that I publicly have disagreed with, which is they believe that the only clinical trial work they will do has to do with what's called target engagement. That you must identify a target and that there are two phases to the study if it's approved. The first two years of the study is the proof of concept to show that the target is correct. So I submitted a grant some years ago looking at a measure of immune function, of inflammation as the target. And they came back to me and said, well, you didn't pick a single target. You picked a number of inflammatory markers and you have to pick a single one. And I said, well, I don't know which one to pick. And number one, and number two, I have a more important question. If our treatment works, but it doesn't engage the target, can we do the next three years of the study? And they said, no, we wouldn't fund that. I said, well, let me understand this. You just told me that if I found a novel treatment for depression and it worked, but it didn't engage the target, you wouldn't fund it. They said, no, we would not. So that was disheartening. Secondly, on the positive side, there was a meeting a year ago of all the NIH institutes and the decision was made that they will go forward and fund some psychedelic trials. And so we're currently about to send a grant to NIAAA, the Alcohol Institute, and we've been in conversations with them and they're very receptive to the idea. What I wanna do is look at patients with alcohol use disorder who have been refractory to treatment, who have co-morbid mood or anxiety disorders, because they all do, and they're excited about that. So I think the rest of it is all foundation funded and company funded. Right, so that's sort of the nitty gritty aspects of it, but I think sort of policy-wise or vision-wise, it seems like a question that has validity to it. Why can't the field actually study these things in a way that would be relevant to actual patients who are in treatment right now? Well, there's a huge underground, right? People who wanna get treatment can get treatment right now. I don't recommend it, but people who want to can do that. You know, the people who are driving this field, and there are gonna be changes made, the FDA, it's just so hard to do this work. I can't even begin to tell you what we've been through with the FDA to do a trial in which we're combining accelerated theradiverse TMS with psilocybin in extremely refractory depressed patients. But for me to get the FDA to get this approved has taken me two years, and I've had the funding from a foundation to do it. You know what, guys? They need this room. Thank you very much. They need this room. We're gonna have to stop. So, great to see you. Thanks for being with me. Thank you.

interactive session

audience participation

depression treatment

remission

residual symptoms

SSRIs

SNRIs

neuromodulation

TMS

psychedelics

socioeconomic factors

resource allocation

ethical management