I know this is the last session for the day, so thanks everyone for hanging in there. I think there's going to be quite a crowd in here. I hear that they're going to need an overflow room, so thanks for coming. Let me go ahead and just get started, because of course the introduction is always, we can always go without it, but I'll... My name is Dr. Simon Kung. I'm a psychiatrist over at Mayo Clinic Rochester, and I did my medical school at Mayo Rochester. I did my residency at Mayo Clinic Rochester, and then I stayed on staff there. And my co-presenters, later on I'll have them introduce themselves as well. One disclosure slide I'm going to say is that I did do one of these CME videos for Psychopharm Institute, so that's my only disclosure, and that was on TMS. So the title of this session is, of course, it's part of the resident fellow medical student research track. I have a feeling there's a lot of people here who are kind of past that, but that's the title of this, and I'm glad everybody here wants to learn about this. These educational objectives, it's pretty generic. Basically we want you to be able to know something about TMS, know something about ketamine, and also ECT, and then be able to discuss some comparisons of them. I'm going to just make sure I look at the clock here while I give my talk. Okay. So the rough agenda, 20 minutes for each topic, but we have time saved at the end for a lot of questions, cases, discussions. So we won't be too rigid with the time. We just want to make sure we get you out by 5.15. These slides I'll just briefly cover. So depression, you know it's complicated. It's not just what's the medicine that's going to help it or what's the intervention that's going to help it. So I'll skip over this. Biopsychosocial, that's the biggest thing I tell when I talk to patients and other trainees and my colleagues. I'm always thinking about what's driving this patient's depression. What's going on in the family? How can that be helped, or is it job or other things? So I just put this in here to remind people, biopsychosocial, and there are many different depressions. This is a, and the reason I bring up depression is that's the main indication for these treatments. So TMS, ketamine, ECT, the main reason we use these is to try to help patients with depression. This slide just talks about the proposed brain circuits for depression. By the time a person gets depressed, there are going to be some, usually some brain chemistry changes, let's say. And yes, there's the serotonin hypothesis of depression that we need to increase serotonin. When we're talking about brain stimulation, at least for TMS, there's this idea of there's a brain circuit for depression. And the dorsolateral prefrontal cortex, that's a major player in this. I won't go through a lot of the other details, but just remember, dorsolateral prefrontal cortex, it's one of these brain regions that's involved in lots of different psychopathology. So when a person comes to you with depression, the first thing you do is not to start prescribing medicines, and it's not to tell them to do TMS. Even though the official FDA approval for TMS is if you have failed one antidepressant trial, they'd say TMS is FDA approved. But really, the first steps should be, okay, look at the person, and then the sleep, diet, exercise, what are they doing? Make sure there's no substance use, alcohol, other things going on, providing education, social support. And then the next step really is psychotherapies. So the usual CBT, for example, all the other psychotherapies. And then if those aren't working, then the medications. And then if the medications aren't working, then that's when we think about what else beyond medicine. So that's the interventional psychiatry, which is why you're here, TMS, ketamine, and ECT. So I'll point out, there's this paper by Dr. Mali, which is a really good summary of major depression. And there's a really nice diagram about kind of the circle of medicine try, medicine try, augmentation, augmentation, and then you go to the other interventional steps. I always recommend this to our residents when they're on a service where we've got patients with depression. So as you know, you send a patient to psychotherapy. What's the usual response rate? It, of course, varies depending on what paper you look at. But in general, let's say 50% of patients will get improvement in their depression with psychotherapy, whether it's CBT, DBT, or even ACT. And then if we look at medicines, well, back in the 2000s, the STAR-D study really said 30% remission with one antidepressant. And then after that, if you do up to four trials, then maybe 67% of patients will have remission. Of course, all the numbers vary depending on what study you look at. So there's this term treatment-resistant depression. And years ago, there's always these different definitions. Some definition would be you have to have failed an MAOI, and then you can call it treatment-resistant depression. Or if your disease is ECT, then you say treatment-resistant. It seems like nowadays, things have gotten a lot easier and softer. All you have to do is fail two antidepressants of adequate dose and adequate duration, and that's treatment-resistant depression. So I'll kind of make a little side editorial comment that I think promoting a definition like this really makes it nice for some pharmaceutical companies to then promote their product that, hey, everybody has treatment-resistant depression. Everybody should be eligible or FDA-approved for this new medicine, whatever that medicine might be. Okay. So I'll talk about TMS. So this is a picture of the TMS chair that we have over at Mayo. This is the Neurostar chair. Some terminology. So TMS is really repetitive transcranial magnetic stimulation, because when we use it for psychiatry, it's just more than one click. When neurologists use TMS to study peripheral nerves, it's just one click. So our TMS, so that we can save ourselves from having to say an extra word, we just say TMS. So it uses non-invasive electrical stimulation via magnetic field. So if you think back to physics, which I don't like to very much, but there's this Faraday's law, which is if you have an alternating electrical current on and off, then it sets up a magnetic field, and then that magnetic field sets up another electrical current. So actually, when you get down to the nitty-gritty for TMS, it's not really the magnet that's stimulating the neurons. It's still electrical stimulation of the neurons. But then it does it via magnetic waves, so that's the underlying physics behind it. And then with this magnet, then you can put it anywhere over the brain to target whatever region you think is abnormal or needs some kind of stimulation or modulation. So the thing is, though, that the magnets, they usually, the standard ones, go about three, you know there's an error on this slide, so it's really three centimeters. I must have put inches for middle of the night, but three centimeters beneath the scalp. And then there's a deep TMS that goes up to six centimeters beneath the scalp. And for the FDA-approved indications, this is a timeline. And 2008 is when TMS got first approved for major depressive disorder. And that's about when I started learning TMS from Dr. Charlene Sampson. And every day, we waited for people to come and say, I want TMS, and the people did come and say, I want TMS, but then insurance wouldn't cover it. So we would say, well, it's $10,000 out of pocket, do you want to try this? And it's always, no, no. So it wasn't until 2014 when Medicare started approving TMS that then all the commercial insurance companies said, oh, OK, this is a legitimate thing, we're going to approve it. Then that's when we started getting more patients. So a few other notable things in 2017, neuronavigation was FDA-approved. Neuronavigation is using that brain scan to help figure out where your magnet is in what part of the brain. And then other things, 2018 was the first theta burst stimulation. I'll mention a little about that in a few minutes. And then OCD was also 2018. That started with the deep TMS, the brain's way device. Smoking cessation, which I'm not sure if any insurance company is reimbursing. So I see some shakes of the head. And then anxious depression, which is always interesting to me. It's like some company is looking for another indication, because most of the patients with depression also have anxiety. But anyways, all of these things got approved. The latest thing, which just happened I think one or two months ago, is that TMS got FDA-approved for adolescent depression. So that's a pretty new and interesting thing. I think the age is 15 and above. So all right. I think I've treated maybe one or two patients who are under the age of 18. And that's because over at Mayo, we've got Dr. Paul Corkin, who's a child and adolescent psychiatrist who's a TMS expert. And when he tells me, Simon, it's OK to do that for a 17-year-old or 16, I just say OK. And then, of course, it turns out that the insurance coverage is OK for these patients too. Off-label and investigative uses of TMS would be things like bipolar depression. I've had patients who call me. They're really excited about TMS. And then once you find out their diagnosis is irrefutably bipolar disorder, and there's no wiggle room that you can try to change that, then really you have to say, you can do it. So it's safe, but it's not covered by insurance. So PTSD is something else that it's been investigated for. For major depressive disorder, the treatment protocol is this magnet goes over the left dorsolateral prefrontal cortex. And even with the helmet device, the brain sway, even though it kind of has a bigger, wider area, it still tries to focus in on the left dorsolateral prefrontal cortex. The motor threshold and the intensity, the intensity is set at 120% of motor threshold. So what motor threshold is is the amount of energy that's needed to get the person's fingers or thumb to move. And then for the treatment for depression, then we try to increase the intensity to 120% of that. Treatments are Monday through Friday for six weeks. And then if the patients get better, then there's a six taper session. And each treatment varies anywhere. When TMS first came out, the Neurostar machine was 37 minutes. So that took a while. The Brain Sway machine was 20 minutes, then Neurostar came out with a 20 minute machine. And then now the latest ITBS, Theta Burst Stimulation, is only three and a half minutes. So the results. So this is something when patients come to me and they're all excited about TMS, I do want to tell them, OK, the success rate, what have you heard? And some patients will say, I don't know. I just know I have failed all these medicines and I heard this TMS. So I tell them it's 60%. You'll find some studies recently published, big registry studies of 5,000 people, of which they'll say the response rate is 80% or higher. I tend to be a little skeptical about that. But at least the patient population that I treat, usually about 60% seems pretty reasonable, practical. And then the next thing, which is almost another deal breaker, is I'll tell them the studies show that six months after TMS is done, if you get better, the relapse rate is about 50%. So that surprises many patients and then they start thinking. I'm not entirely a Debbie Downer when I talk to patients about this, though, because what I tell them is when they say, well, why do I even do this then if six months later there's a 50% chance I'm going to be depressed again? So my response to them is, you're in a deep depressive episode now. Wouldn't you like to feel better? And then if you feel better, then other things can be done and then to try to get you on the path to staying well. The only side effect of TMS is it hurts. When TMS first came out, a lot of patients thought, oh, this is a neat treatment. And I was kind of surprised at how much it hurts. Patients are as well. But at least they can usually tolerate it pretty well. There might be some eye or facial twitching during the treatments. The nice thing is there's no anesthesia, there's no memory loss, there's no restrictions on driving. Theta burst stimulation, so this one is they try to mimic the natural brain activity. It was first noticed in rats that are exploring. They noticed this, I guess it must have been the 50 hertz triplet burst. So then they thought, well, for people, is it similar? And then Dr. Bloomberger did a study where he really showed that whether it's theta burst versus the standard 10 hertz, it was about the same effectiveness. So this is FDA approved. So pretty much exclusively we're doing this theta burst stimulation now because it's faster. The only downside is it might hurt a tiny bit more, 0.4 on a 1 to 10 scale. But then overall, you're looking at 40 seconds of pain instead of the 10 hertz stimulation, which takes maybe 20 minutes. And I didn't calculate how many minutes of pain that one is. Dorsolateral prefrontal cortex, I'll just touch upon this briefly. So the way we find it in clinical practice is if you go back to medical school and think about the homunculus where you got the funny looking person and wrapped over the motor strip of the brain and the thumb is all the way down towards the end. So that's what we're trying to find. Thumb or finger movements. But the reason we do that is then that approximately tells us that the dorsolateral prefrontal cortex is about 5 to 6 centimeters forward. So that's the most common clinical way to find dorsolateral prefrontal cortex. There's another method called the beam F3 method. You have to take some measurements of the nasion to inion, tragus to tragus, and then the circumference. You type it into this website that I just Google every time. And I trust that it's got the right numbers. That's another. And this came from MUSC, which is basically Dr. George's lab. So very trustworthy. Neuronavigation is the most precise way to do it. You get the MRI image and then with the magnet you can tell what part of the brain you're over. However, insurance companies don't reimburse for that. The latest thing that people are always asking me about, and probably all of you have heard, is the Stanford protocol, which is the, it's called the Saint protocol. I thought at one point I heard Stanford was trying not to use that term because it sounds religious, too religious. So they say SNT. But it's accelerated TMS. So accelerated TMS means you're doing more than one session per day. So the three hallmark features of the Stanford protocol. One, accelerated. So they don't mess around. It's not two or three. They do 10 treatments a day. And with those 10 treatments, there's 50 minutes between sessions. So the patient pretty much has to go there, stay there, probably 8 a.m. to probably past 5 p.m., yeah. But the nice thing is it's only for five days. And then they increase the number of pulses. That's the second cardinal feature of the Saint protocol, SNT, Stanford protocol, is instead of 600 pulses, it's 1,800. And then they also use a functional MRI to figure out where exactly in each individualized person should the magnet go. So this is the location of the dorsolateral prefrontal cortex, which is anti-correlated with the subgenual anterior cingulate cortex. And I'm glad we don't have enough time for anyone to ask me to explain that further. Okay. So the outcomes of this study, the first study was a very small open-label study. Well, 21 is not, I mean, relatively, it's not too small. But response and remission rate, 90%. When did you last hear of some treatment that gave people 90% response and remission? So of course, everybody is excited about this. After one month, they followed up, and the patient's 70% response, 60% remission, still really good. Then they did a sham-controlled trial, 29 patients, and the numbers are up here. But it's still pretty impressive. Active was 86%, sham about 30%. So this got FDA approved just a year ago. And I know kind of the originator, Dr. Williams, is working on, I mean, he's got a company to commercialize this. But insurance companies are probably going to be pretty skeptical about this initially. Okay. So how do we select patients? Really, you want to make sure the patient has had a few antidepressants that didn't work or intolerance to medicines. Another common thing is if the patient is recommended to have ECT, but they cannot have ECT for whatever reason, then TMS is usually covered. They can't have a history of seizures. But really, the most practical thing is insurance really should cover this. Because I usually tell patients, if insurance doesn't cover it, I don't think I would recommend spending $20,000 or $30,000 on this. If the success rate was 95%, then I would say, sure, take out a second loan or something. But it's not. So I say if insurance covers it, do it. And every insurance company has a slightly different criteria. I'm going to skip over this OCD, except just to point out that Magnet's put in a different place. It's FDA approved for OCD as well. Certain devices are. Response rate 38%, active versus sham of 11%. But remember, for OCD, improvement or response is defined as greater than or equal to 35%. Not for depression as 50%. Other things to consider with TMS is just practical things. So does the patient live close to a TMS center? Because this is 30 treatments. So if they're living two hours away from where you are, are they really going to drive in four hours every day for a treatment? And then do they have the time? Can they take the time off? And then insurance coverage. All right. So that was TMS. We'll hold the questions until the end, because we also have some cases. And let me get the slides set up. I'll have Dr. Singh come up here. My name is Dr. Balinder Singh, I'm a psychiatrist at Mayo Clinic. Here are my disclosures. I received grant support from Mayo Clinic and NDCBD Square, but it's nothing that goes towards me. It goes towards Mayo Clinic and just triggers. It covers the salary, nothing else. So I'll be talking about off-label use of IV ketamine. So before we talk about ketamine, I'd like to talk a little bit about the PCP. Because ketamine, if you are not aware, it is very similar to PCP. So in 1956, Park Davis, they developed this compound, Sernyl. It was used as an anesthetic for surgery, but when people come out after surgery, they'll be delirious. So they realized, we can't use it for humans, but we can use it as a schizophrenia model. So the next thing they did, they tweaked the compound and they created ketamine, which still had some psychosomatic and dissociative properties, but people won't come out delirious after surgery. It got FDA approved in 1970 as a short-acting anesthetic. It can cause visual hallucination, theoretically, and out-of-body experiences. It's a recreational drug worldwide and it can cause ulcerative cystitis in ketamine abuser or people who are using ketamine excessively. So ketamine is FDA approved as a general anesthetic. And for procedural sedation, it's a Schedule III substance. It is not FDA approved for depression. I'm talking about intravenous or racemic ketamine. So the only FDA approved compound related to ketamine is S-ketamine, which is FDA approved in conjunction with an oral antidepressant for treatment-resistant depression. And in 2020, it got second approval for depressive symptoms in major depressive disorder and acute suicidality or acute suicidal ideation, not for suicidal ideation. It's MDD with acute suicidal ideation, but not for suicidal ideation. Yeah, let's do that. No worries. Simon, do you want to take a question? Sorry about that. I can start talking about the next slide while we are waiting. The next slide is about the proposed mechanism of ketamine. That's the only slide where I have information about the mechanism. The most common theory about the mechanism of ketamine is an NMDA antagonist. It sort of blocks those NMDA receptors leading to, then it works on these GABA interneurons and with the main mechanism that leads to surge or creates this hyperglutamatergic state. That's the most common hypothesis about how ketamine works, but that's not the only one. There are studies where they've used naltrexone and ketamine stops working, we don't see much benefit. So there's that opioid receptor pathways that are involved. The other data is that ... You can go up and down. Okay. Go to the next one. Okay. Perfect. Thank you. All right. So the most common, as I was mentioning is, and it seems like the arrow only moves on my screen. Okay. So you can see the number two leads to increase in glutamate and then AMPA activation. There's data that can lead to increase in BDNF or brain-derived neurotrophic factor and ultimately leading to increased protein synthesis and synapse number and function, but as I said, that's not the only mechanism. There are other pathways which are involved. So if you want to know a little bit more about the biomarkers, we have a talk in two days. I think on Monday at 8 a.m. we'll talk more about the biomarkers, but this one I'll just stay focused on the clinical aspect. All right. So this was one of the first ... Well, I think it was the second study, technically. The first study was published in 2000 at Yale. Dr. Berman was the first author. They're developing these models of ... The ketamine was used for schizophrenia, but then this was signaled in patient with depression. So the first study showed ketamine works really quickly. Then the study in 2006 at NIMN, Dr. Zarate, they published ... When Simon was mentioning which other treatment causes 70% or 80% response, ketamine is one, but the problem with ketamine, as you'll see here, and I can move my arrow, but you give the ketamine, 70% of people noticed in that study their depression symptoms went down by 50% or more, but by the end of the week their symptoms came back. So if it works, it works quickly. You don't need to wait for four to six weeks, but if you only give one treatment in a week, they'll be back to where they started. Now there's another controversy with ketamine is, what's the placebo? What's the control? If you use the normal saline, the effect will last for seven days, but when you use midazolam as a control, the effect only lasted for three days. At seven days, it did not differentiate from midazolam. Same with treatment-resistant bipolar depression, quick response, but after three days it was not superior to placebo. So then the next study, well, if effect is only going to last for seven days, what can we do to prolong the effect? So in the next study, what they did is that rather than doing one treatment a week, they did, okay, we do two treatments or three treatments a week, and they realized that if you're doing more treatment, the effect may last longer, and the median time to relapse was almost 18 days. Twice a week or three times a week, it did not differentiate. So in most clinics, you will probably see when the people are going for the acute phase of ketamine, they'll get at least two or three treatments in a week. Going beyond the acute phase, so most of the data I'm presenting here is based on the research, and then I'll have some opinions, which I consider the lowest form of evidence, but most of the data I'm presenting right now is based on this study. It was an open-label trial we did at Mayo, where we had patients who received three treatments in the acute phase, something like a Monday, Wednesday, or Friday, or three treatments within 10 days. If they're remitted, then the next phase they received one treatment a week for four weeks, and that's where the study ended at the end of the continuation phase, and what we saw is that people who responded in the, or sorry, remitted in the acute phase, even if they're getting one treatment a week for four weeks, they are staying in remission during those four weeks, and once we stopped giving the ketamine, their symptoms started to come back, but they still were, they didn't meet the remission criteria, but they're still not at the baseline where they started, so the effect does last longer when you're giving multiple infusion. Now, this is the sort of the model we use at Mayo, where we do a quick screen of patients who had treatment-resistant depression. We start the, we call it acute phase, where you get three to six treatment. Ideally, if you're not seeing any response by treatment number three, it's less likely you will see response later on, but if you're seeing, you know, maybe 20, 30% response in the first two or three treatments, then you can, you know, I think there's some data we can prolong, we can give more treatment. In that continuation phase, once a week for four weeks, and then in what we call the optimization phase, this is where we start to kind of slow down the, reduce the number of infusions, so once every two weeks, three weeks, and it's, now this is the data which is more individualized, you know, we are doing it based on the patient. If you are seeing their symptoms are coming back, that's how we say, okay, maybe this is the maintenance phase and where we do treatment every three weeks or four weeks, okay? And as soon as you're noticing that people are getting better, start engaging them in psychotherapy or, you know, if you have to change the antidepressant, because right now there is no one antidepressant which has shown that it can prolong the effect of ketamine or is better versus worse, so, you know, there's no antidepressant right now. But this is the time once they're coming out of the depressive episode, you know, get them in a partial program, in an intensive outpatient program, do those exercise, walk, all those good healthy things, okay? Now, there are some potential interactions, so the benzodiazepines, so there's data that if you use a high dose of benzodiazepine, it can reduce the efficacy of ketamine. Naltrexone, that's the study I was mentioning earlier, that's the paper published from Stanford where the one group received naltrexone, second group received placebo, the naltrexone group didn't respond to ketamine. There are some theoretical possibilities, at least from a mechanism standpoint, lithium has sort of like synergistic mTOR activation, so we believe, at least from the animal model data, so there's a paper by Price et al. published in Translation Psychiatry where both ketamine and lithium, there's sort of this synergistic mTOR activation, theoretically, if you have to pick one drug which can prolong the effect, I would pick lithium. Lamotrigine, we looked at our data from our clinic, and there's some earlier data as well, that lamotrigine may help reduce the dissociation symptoms of ketamine, so if you have a patient who's responding to ketamine, but they're having intense dissociation, and if you have to use that one drug, I'll probably pick lamotrigine, although some people may consider that controversial with that glutamate modulator hypothesis that maybe lamotrigine will reduce the efficacy from a depression standpoint. We didn't see that in our clinical data, so we don't usually recommend that you don't have to discontinue lamotrigine. If you're using it for whether major depression, bipolar depression, you can continue. And now the S-ketamine, that's the SNN tumor of ketamine, it is FDA approved. It has a higher affinity for NMDA receptors, so that's where that whole receptor theory gets so complicated, that if it was only the NMDA receptor, then S-ketamine should work better. It has a higher affinity four times, it's more potent than NMDA receptor as compared to the resuming ketamine, but its bioavailability is 30 to 50%. There are two contraindications, one is aneurysmal vascular disease, so make sure if you have a patient, you ask them if there's a history, if there's a family history, you want to tease apart those things, and if you need to do an MRI, just to make sure you're not missing those things. Intracerebral hemorrhage, so those are contraindications, in those cases we don't want to use S-ketamine There are some warnings, it can increase blood pressure, cognitive impairment, so usually when you give ketamine or S-ketamine, we usually recommend not to drive the day of the treatment. Embryo-fetal toxicity, there's no data, there are a couple of case reports now, one was recently published in Journal of Clinical Psychopharm, where they had someone in there during pregnancy, they received S-ketamine, but it's an N of 1, so it's not much data out there. FDA approval, first was in 2019, second one is 2020, so there are some restrictions with S-ketamine. First, you have to monitor the patient for at least two hours, second, you cannot send the prescription home, so that means they have to come to your clinic. If you have a clinic, you probably know, but people who don't have a ketamine clinic at their practice, so people have to come to the clinic to receive the drug, it's a simple nasal spray, they can spray it themselves, but there's a two-hour of monitoring. Every patient has to be registered in the REMS program, so there's some paperwork, so if you have some staff member helping, that's great, if not, add some couple of hours for the paperwork. For geriatric depressions, there's only one randomized control trial, where they had patients who are 65 and above, and S-ketamine was not superior to placebo at the end of four weeks, so that's the only RCT I'm aware of, there's no other RCT where they used S-ketamine. They did a secondary analysis where they divided data into 65 years to 74 and 75 and above. In the secondary analysis, the data looked better for the 65 year to 74 years of age group, but the sample size was very low in 75 and above. So if you have a patient who is 65 and above, we tell them the data, it is FDA approved, so FDA has not put a limit that you cannot use it after 65. In our clinic, we don't use IV ketamine for 65 and above, so as long as the patient is interested, we show them the data, and if they're interested, we'll offer S-ketamine as an option. Now the time to relapse, what happens when you give ketamine and it works, and then you stop giving ketamine, or S-ketamine, I should say, sorry. So on the left side, we are looking at, this is the data from the Opal-enabled trial, Sustained. So on the left side, when we are looking at patients who achieve stable remission, on the right side, people who achieved response. Response means in the studies, 50% or more reduction in their depression symptoms. Remission usually has some sort of cutoff, so if they're using MedDRAW scores, it'll be 10 or below some of the studies they used, 12 or below that. So on the left side, what happened is, let's say if you have 100 patients who are getting S-ketamine, and they responded to S-ketamine, they said, okay, one group, we're gonna keep giving S-ketamine along with antidepressants, second group, we'll switch them from S-ketamine to placebo, and the hazard ratio of .49, that means that if they continue to receive S-ketamine, they have a 51% lower likelihood of relapse. So higher the curve, better it is. If they achieved response, then there's a 70% likelihood that they'll, you know, if you continue the treatment, they'll do okay. So what it means is if you have a patient who responds to S-ketamine, they more than likely need maintenance treatment, otherwise they're going to relapse. So having those discussions in the beginning, because a lot of time, you know, you'll get patients in the clinic, and their impression is like, well, it's a miracle drug, you get the ketamine, and everything is hunky-dory. That's not the case. If you're getting ketamine, you have to think about those logistical issues. They can't drive. Someone has to drive them home. You have to get it prior-authorized, and you're looking at maybe five, six months of at least maintenance treatment. Some clinics, they're running into trouble, because once they're in maintenance treatment and you try to wean them off, it's not going well. So then you're looking at patients who are on ketamine for years, two, three, four years. Switching from IV ketamine to intranasal, there's no data from randomized control trial, but there are some case series. This was published in 2021 in Journal of Clinical Psychopharm. We had 10 patients who started with IV ketamine, and once they responded, they switched from IV to intranasal, and nine out of 10 maintained the benefit. So I think a lot of it is, you know, it depends on the financial aspect, because IV ketamine, it's not FDA-approved, so a lot of the time, insurance doesn't cover it, so it becomes out-of-pocket, but it works quicker as compared to intranasal, where we have to do two treatments every week for four weeks in that acute phase. All right, so this paper we just published, so there are two, actually. One is IV ketamine versus intranasal as ketamine, so which one is better? So this is a systematic, sort of a systematic review and meta-analysis published in Journal of Affective Disorder. So on the left side, we are looking at, on the top, remission rates, and the bottom, response rate. The response rate, that sort of black diamond, is touching, just touching the line, and what it means is that, from a statistical standpoint, the response and remission rates are similar, but I think if we have enough samples, that might move to the other side. But for all practical purposes, I'll say the response rate between S ketamine and IV ketamine are similar, but what's different is what's on the right side, the number of treatment required to response and remission, that is quicker with IV. So if you have, so in my mind, when I see a patient who say, well, I don't care if my insurance would cover or not, I am interested and I want to get better soon, then I think IV ketamine has the edge, where you can start with IV ketamine, if they respond, then I say, okay, now we can do the prior auth in the meantime, and if their insurance covers, we can switch to intranasal. Now the next question is the dose. So this data is from randomness control trial. This systematically we just published in Journal of Affective Disorders, so we looked at intranasal S ketamine trials and data from the IV ketamine. So with intranasal S ketamine, the 56 to 84 milligram dose was clearly superior to 28 milligrams. So there was a clear response there that people who are getting this 56 to 84 milligram, they have a higher response, whereas with the IV ketamine, and I think the limitation there was, with IV ketamine we saw there was a similar efficacy at the standard dose, what we use in the clinics, at half a milligram per kg body weight, whereas there are some studies where they use it at 0.2 milligram, there are other studies where they used at 1.0 milligram per kg. The problem is there's only one RCT where they used that 1 milligram per kg body weight, and there is no RCT other than that. So at least on the basis of this systematic review, there's no difference in 0.5 and higher. So in our clinic, we usually just stick with half a milligram. I know there are places where they keep increasing the dose. There are some clinics where they go up to 200 milligram as their cap, our cap is 50 milligram, because we don't necessarily see that if you keep increasing the dose, you will see a higher response. So until we do another RCT with sort of like a dose escalation or dose response, I'll stick with this dose. From a side effect standpoint, the most common one we see is dissociation, nausea, altered taste, that's usually we see more with S-ketamine, not as much with IV ketamine. I think it has more to do with how it's given, more with the intranasal formulation. Dizziness, headaches, somnolence, it can raise blood pressure. Concerns for long-term use, so that's another problem. Ketamine is a drug of abuse, so it can be abused. There's a risk of psychological dependence as well. People coming every week or every two weeks, staying with the nurse with intranasal for two hours, and with IV, 40-minute infusion, and maybe 30 minutes after that, so getting respite. So there's a risk there. So there was a survey where they looked at, sent out the survey, but 11 psychiatrists from US, UK, and Europe replied, and 80% agreed that there should be a minimum duration of six months after they respond, 50% said six to 12 months. So there's no sort of like a consensus, but what we usually try to do when we start someone on ketamine or S-ketamine, we have that discussion. Let's give it a try. If it works for you, let's use it for six months, and in the meantime, let's enhance the psychotherapy piece, let's adjust the medication, but around six-month time, that's when it's okay. Now I think we should start tapering it down and see how you do without it. Now who's a good candidate? Someone who has treatment-resistant depression, who has failed at least two antidepressants in the current episode. Ideally you want to have those antidepressants in different classes. So in my mind, if you're trying four SSRIs, that's not TRD. You are not targeting different neurotransmitter. No active substance use disorder. So we are very conservative at Mayo, so we don't use IV ketamine or intranasal S-ketamine for substance use disorder. I know there's our trials with one infusion, but long-term, you're running a risk there. So no history of psychosis. Again, there are some case series where they used ketamine for people who have depression with psychosis, but theoretical, when we look at the theoretical model, ketamine can itself induce psychosis. It's a little bit risky there. And if personality disorder should not be the primary driver. Practical criteria, if they have tried, most patients when they're receiving ketamine, they have tried at least three, four, five antidepressants. Some have even tried TMS, and we usually use it for 65 and younger for IV and intranasal 65 and above as well. A couple of slides, just kind of showing what's out there. There have been concerns, so in media, I think when the ketamine came out, it was the miracle drug, and then we started having concerns regarding abuse liability, so it's been used for bipolar disorder, OCD, anxiety, irritability, PTSD, alcohol use, you name it, and the number of ketamine clinics have been increasing. There are reported cases where ketamine-induced mania, hypomania, and some unfortunate incidents as well, and there's a case published last year in American Journal of Ketamine Withdrawal for someone who was getting ketamine at a very high dose and in-home delivery of ketamine, so it's a little bit concerning. So ketamine does have abuse potential, so the two studies on the left, they have done an NIMH, again, that's a rat model data, but when they look at that data, it seems like the S-ketamine, so when they look at R versus S in entomer, is the S-ketamine, which has more abuse liability, at least based on the rat model, so it's not replicated in humans yet. On the right side, kind of looking at the trend in the ketamine exposure, so a couple of these papers are published in the last two years where they're seeing the increase in ketamine exposure in bigger cities. These are some of the concerns. Ketamine is being home-delivered, so there are some concerns related to that. FDA has already issued two warnings. One was in 2022. Second was in 2023. So first was for compounded intranasal ketamine, and the second one for the oral compounded treatment. In our discussion, I'll talk quickly about this. Ketamines, antidepressant effect in TRBDs, very minimal data. There are just three RCTs, very small sample size. Then the study came out last year from Canada, where they showed about 30% response rate, 35%, 5% risk of treatment emergent affective switching within just four treatments. So if you're using ketamine for bipolar depression, make sure there's a mood stabilizer on board, so that will help reduce the risk of switching. We just published this case of tachyphylaxis, where a patient was receiving ketamine for long term, and after a while, it stopped working. All right, so discussion. I think we talked about these points. The number of treatment required to achieve response or remission is quicker with IV ketamine. Overall, when we look at the long term data, we haven't published that yet. IV ketamine seems to be a little bit more durable. Patients require a lesser number of treatment as compared to intranasal. Both are tolerated reasonably well, and tachyphylaxis is real. So if you have patients who have initially had a response, and six months down the road, they are noticing it's not working, so it's probably losing its efficacy. But if they responded for first two treatments, and after treatment number four or five, we are not seeing an effect, then probably they had some placebo response in those initial treatment. So for tachyphylaxis, look at at least have some durability. We need a RCT, and I think there's an RCT going on comparing IV versus intranasal as ketamine. And we need to find options to prolong the durability of ketamine. And these are the references and acknowledgment. Thank you. All right. Thank you. And then, why don't George, Dr. Petrides, I'll have you come up. And you want to introduce yourself while we're setting up your slides. I'll go with the first one. Hello, everybody. Thank you for staying for the last talk of the day. So it's nice to be among residents, some of my old residents. It's even better. Just a brief question. How many of you have observed ECT? Oh, we're in a group of experts here. So that's good. So I'm going to be a little bit more boring than the exciting new treatments that we have discussed so far. We're going to talk about an old, boring treatment, which I think we see with new light lately. But just a definition is a form of neuromodulation that entails the administration of a brief electrical stimulus to induce a generalized seizure under well-controlled conditions. So as opposed to TMS, we want to go well above the threshold to make the brain cell membranes discharge and start a cascade of discharge with a seizure. And it started many, many years ago. It's about 80 years ago or almost 100 years ago. We have the effect of different way of thinking of those days. I'm talking about the 1930s. At that time, there was the concept of illnesses that are incompatible. So if you have one, you cannot have the other one. Or by inducing one, you can treat the other one. So that was the first treatment for neurosyphilis. By the way, it was the most common cause for a psychiatric hospitalization at that time was neurosyphilis. It was not anything else that we know. The first treatment for neurosyphilis was malaria. So people found out that if you inject the blood of somebody who has malaria, the spirochetes would cause high fevers. I'm sorry, the malaria would cause high fevers that kill off the spirochetes and treat syphilis. You end up with malaria, which is kind of a more acceptable form of illness, I guess. So the same line of thought was true for epilepsy and schizophrenia, what they used to call dementia precox at that time. So people observed that in post-mortem studies that the brains of epileptic patients were swollen with gliosis, where the schizophrenics were shrunk. And they also noticed that in big asylums that they used to house epileptic patients, there were no treatments for epilepsy at that time. There were not that many crazy people or vice versa. The people who in big asylums were patients with dementia precox didn't have that many epileptic patients. So they started trying to do crazy things. We think of crazy things. Just to induce one illness to treat the other and to induce epilepsy to schizophrenics to treat their schizophrenia. So put people together in the same room so they catch the schizococcus or the epileptococcus. They had transfusions from one to another. Things didn't work that well until in 1934, a doctor in Hungary, his name was Ladislav Meduna, thought of inducing epilepsy with chemical ways. And what he did, he used camphor oil that was known from the ancient Greeks and Romans and the Paracelsus time in the Middle Ages as a substance that can induce seizures. So he injected camphor oil first, found a patient who was catatonic, who was for two years bedridden and tube fed, wouldn't resist anything. So he injected him with camphor oil. And after an hour or so, the patient started seizing. The seizure stopped. And then he repeated that next day for a few days. And all of a sudden, after five or six times, the patient woke up. And that was a miracle. Actually, nobody ever would wake up from this kind of condition. And the patient was discharged. It was another miracle. I mean, no patients were discharged from psychiatric hospital at those times. So the spread of convulsive therapy was very quick, because there were no other medications. The only things available at that time were behavioral therapy, psychodynamic therapy, and chains. So for severe illness, there was nothing really available. So it really was spread quickly. But the chemical induction of seizures was not very reliable. So people were looking for more reliable ways of treatment. So in 1938, in Rome, two psychiatrists, Bini and Cerletti, they were kind of lucky, because they were going to their office or their hospital. They would walk through the markets in Rome. And then they observed that the butchers would kill pigs with electricity, so they don't lose blood that they used for blood sausages. But what they observed is that sometimes the animals would have a seizure instead of dying, and then wake up and run away. So they figured out that electricity can cause a seizure. So they did a few experiments with dogs. Honestly, they didn't know where to put the electrodes. They tried to put it over the chest, because nobody really knew or thought that mental illness is in the brain, right? We're talking about gut feelings, broken hearts. These kind of things were more common at that time. So dogs would die until they put the electrodes on the head, and they would have seizures. And then, again, they found a patient that couldn't resist, who was in catatonic excitement. And they administered an electrical stimulus at that time with a current that comes from the network. And there were maybe 50 or 100 people watching the thing. And the catatonic patient woke up after the first treatment and looked at them and said, what do you guys think you're doing? So it was kind of a good reaction. So again, the news spread quickly. The patients who actually, the idea that you can induce a seizure with electricity was really good news, much more reliable than the chemical induction. A Jewish doctor that was used to work with Binion Satellite in Rome, trying to escape the fascists, got a machine and arrived in New York. He did a few experimental treatments at Bellevue Hospital in Columbia. That's what I found in the New York Times of 1940. It's an announcement for a new hospital in Queens. There was Hillside Hospital that I used to work for 25 years. That was the first place that offered clinical ECT. And if you see the underlying thing, it's the new modern treatment among basket weaving and gardening that is proven to decrease length of stay. So length of stay is a concept that it's been in psychiatry forever. So it's not something new. So since then, ECT was the only available treatment. Actually, that's not exactly correct. There were two other biological treatments available at that time. One was insulin coma. Insulin coma was quite effective. In about 30% or 40% of patients would respond to insulin coma. But it had a little of side effect. It has about 3% to 4% mortality rate. And really, we figured out later on that the people who got better were those people who had a seizure because of hypoglycemia. So it was the seizure. It was not the hypoglycemia itself. And the other one, it was frontal lobotomy, which was available then. And just to show you the difference of mindsets and desperation of the times, frontal lobotomy is the only Nobel Prize that was given to a psychiatrist ever. So that's our pride. 1941. So anyway, but ECT was much easier and much more benign than these other two treatments. It was widespread use. Unfortunately, it was used for everything under the sun, anything that people thought might be a mental illness. That included criminality, conduct disorder in kids, homosexuality, whatever people thought that might be a disorder at that time. So things started changing in the 50s when the first antipsychotics and the first antidepressant medications were introduced. ECT practice started also changing. It was in 1958 that the first ECT treatment was done under general anesthesia. And I have to say here that general anesthesia was not introduced because ECT is painful. There's no pain with ECT. If someone has a seizure, they lose consciousness. They don't feel anything. It was introduced so we can use a muscle paralysis and muscle relaxant so people don't flail and break bones. That was the most common bad side effect of ECT at that time. So the introduction of general anesthesia and muscle relaxation in the late 50s, it really changed the practice at that time. However, in the 60s and the 70s, with the advent of anti-psychiatry movement that was really very strong in Europe with Lacan and Thomas Sass in the United States, ECT was an easy target, as you may imagine. And it went underground. And despite the popular belief that it was used to suppress the masses, it actually was only available in private hospitals and for people who had money to pay for it. So it was available, but not widespread. And education and teaching of ECT went by the side. So at that point in the 70s, because ECT was not taught, was not really properly regulated, so to speak, the APA put together a task force to study ECT and study whether we need to have this treatment or not available for us. The same thing did the British Psychiatric Association. The reports came in 1978 and 1980, respectively. And they both said that ECT is something that we cannot replace in our armamentarium. We need it. And since then, their regular task force from the APA actually, I'm a member of this task force that comes with guidelines this year. So the last one was about 20 years ago. So I guess the task force was in 192,000. In 1984, for the first time, there was a journal dedicated to ECT. It was called Convulsive Therapy at that time. Now it's called Journal of ECT. There was an association created for the first time, the Association of Convulsive Therapy. Now it has changed its name. It's international. It's based in the US. It's called ISEN. Tomorrow they have their meeting. And the use of ECT has increased over time. Estimated about 100,000 patients receive ECT in the US, about a million people worldwide. There are several improvements in technique with changes, with improvements in the different way that we administer the stimulus, right unilateral, bifrontal, the way we calculate the dose, and so forth. And it seems to me, at least, that the stigma has lessened. Even in the lay press, you can see the articles about ECT that may even be positive. Here's a typical ECT patient, as you see. But always the press has to do something. So the APA guidelines for the use of ECT try to stay away from definitions of indications that have to do with diagnosis. So it went instead with the primary and secondary use of ECT. So the primary use is when you need rapid, definitive response because of the severity of the medical or psychiatric condition, including suicide risk. This could include catatonia, could include severe agitation, could include severe psychosis, or suicidality, and so forth. And when the risks of other treatments outweigh the risks of ECT, and that including pregnancy, again, when there is history of poor medication response or history of good response to ECT, and when there is patient preference. There is many times a patient's come to us and said, I had ECT 20 years ago. I did fine for 20 years. I don't want to fuzz around with medications. I want to do ECT. Or my sister had ECT and did well. I want to have ECT. So patient preference is an indication. And then secondary use is treatment resistance or intolerance to other forms of treatments. So and again, if there is continuous deterioration of the patient's condition, and then you need, again, a rapid response. Now, there are many indications that ECT is being used for. As you may see, it will transcend our classification system. It has been major depressions are all good, are unipolar, bipolar, psychotic, non-psychotic. This is a slide from one of our studies from the core group. On that side, that's my left, you see the intent to treat. This is about 500 patients. They intend to treat sample. So if you include the people who didn't get the full course of ECT, it's about 65%. But if you get the patients who really responded, who really completed a course of ECT, the rate goes up 87%. It's remarkable. There's nowhere else. In psychiatry or, I think, in medicine. And if you go with psychotic depression, then their remission rates go up to 95% for ECT. So again, mania, the opposite condition, response to ECT, psychotic or non-psychotic, bipolar, mania or mixed, schizophrenia. Now, in the United States, it's not very common to use ECT for schizophrenia. However, in the rest of the world, it's probably the primary use. It's schizophrenia. And it can be used for acute exacerbation of psychosis, catatonic type of schizophrenia, or when there is history of response to ECT, schizophrenic form disorder, schizoaffective disorder, and psychosis, NOS. This is a diagram from a study that we did in patients with clozapine-resistant schizophrenia. The patients were on clozapine. And then we gave them ECT for up to 20 treatments. And you see a remarkable decrease of psychotic symptoms. These are patients who are already on clozapine, and they still have symptoms. So there is a remarkable synergistic effect there. And this is the CGI for the same study. Other diagnostic indications would be pseudodementia or CD agitation. Actually, now I'm leading a multi-center study funded by NIA to study the treatment of agitation in patients with dementia. And preliminary results are really quite impressive. So we're talking about just patients with agitation and dementia, not schizophrenic or bipolar. Medical disorders like Parkinson's disease, Parkinsonism, and Parkinson's response very well to ECT. We don't use it regularly because you probably have to use it indefinitely. NMS, neuroleptic malignant syndrome, a lot of us think that NMS is nothing else than malignant catatonia. So it really responds very quickly and very. Just to describe the ECT, maybe, again, it's general anesthesia first, then muscle relaxation. The stimulus itself, it's about anywhere between two seconds. That elicits a parasympathetic response first. Then there is a tonic-clonic seizure that elicits a sympathetic response. And then the recovery with mixed hemodynamic response, something that you need to take into consideration. Now let's talk about adverse effects of ECT because it's something that comes up all the time. So there are reported 1.7 deaths per 100,000 treatments. So this is less or similar or less associated with general anesthesia in general. There are no deaths reported anywhere after 2001. And if I give you a comparator, so it's 1.7 deaths per 100,000. For colonoscopy, it's four per 100,000. So it's really a very safe procedure. And it's considered to be safer with deaths associated with medications. Cardiovascular complications, there's something that you need to have in mind. Because of parasympathetic and sympathetic surges, you may have arrhythmias, hypertension, and tachycardia during the treatment or any of those. They're usually benign. You can really manage them during the treatment. Other side effects could be postictal agitation that can be treated with medications at that time. Headaches, muscle aches usually go away. They're usually the first couple of times. Nausea and aspiration pneumonia, it's important and severe risk. That's why patients need always to be with an empty stomach. Because of the parasympathetic response, there is a gastric contraction. So if the patient is with a full stomach, they may aspirate. This is something that you have to take into consideration. And again, the great or the huge burden, it's out there all the time about cognitive effects of ECT. And there are two types. It's retrograde amnesia, and it's anterograde amnesia. Retrograde amnesia means that you forget things from the past. These are real. Never tell your patients that they're not going to have any memory problems. It's like telling a patient who had surgery that they're not going to have any pain in their surgical site. So don't minimize it. But if the patients know about those things, they can make decisions about to go about the ECT or not. So retrograde amnesia, it's about forgetting things that happened in the past. And usually, that happens during the acute course of ECT, and it's cumulative. However, when we stop the acute ECT or spread out the treatments, things from the past come back. So actually, it's not memory loss. It's difficulty to retrieve old memories that happens during the acute course. So anterograde amnesia now, prospective amnesia, it's something that happens during the acute course of ECT and when treatments are close to each other. That means that people forget things that happened during that period of time, especially the day before the treatment or the day of the treatment. It's usually things like what they ate last night or what movie they may have seen or a conversation they had with their relatives. And this can be very worrisome to relatives because I told you yesterday, did you forget that Uncle John called? How could you forget? These are worrisome things, but you can really reassure your patients that this goes away. It's just memories that happen. Memories need time to consolidate, three to four weeks for every one of us. Otherwise, 99.9% of things, we discard them, and some things are consolidated. But this consolidation may not happen during the acute course of ECT. So tell your patient not to make important decisions during a course. Don't get married. Don't sell their house or things like that. Generally, we have 10 minutes left in the hour. OK, I'm done. And we generally see improvement on cognitive status after the course of ECT. I think it's because depression is lifted. It's not because ECT improves memory. Some people may say it could be because we know that there is increased synaptogenesis and neurogenesis. So I'm going to stop here and let time for questions. All right. Thanks, Jerry. So I really skimped on introductions when we started because we were scrambling to get the computers up and running and all that. But let me just mention a few things. So I've been involved with TMS since 2008. And we've got our Ketamine Clinic at Mayo since basically 2018. So we have a good five years experience. Dr. Singh, Dr. Vandervoort, myself are part of the Ketamine Clinic. Dr. Singh and Vandervoort really come up with a lot of the research questions and so on of how to look at our data. Now, I'll mention Dr. Petrides. To me, he just knows anything about ECT. So in the late 1990s and early 2000s, there was a multi-site study in the US called the Consortium on Research in ECT, the core studies. And those are, I think, really influential in our knowledge of ECT and all of the numbers like ECT for psychotic depression up to 95%. That all came from the core study. And Mayo was part of the multi-site study. So that's some context for you. On the slides that I have, I'm not going to bring them up, but I had some summary or synthesis slides. There's one slide that I will say is I thought is pretty nice. I crammed everything I could think of about comparing TMS, ketamine, and ECT, pros and cons, what you have to consider for each one of them. These slides are on the APA website. So if you go to the course, you can download those slides. So instead of me trying to find them, I'll just refer you to them. And then I had some cases, of course, which we won't go over. But let's just open up to questions. We've got until, I guess, we have another six minutes. But I think we're all happy to stay afterwards if anyone wants to individually ask us questions. So go ahead. With what you're saying, you mentioned that MS is decreased the amount of TMS that is applied to some of the studies. That's a good question. I mean, mechanistically, it should. There is no sort of a provider study. We looked at the benzodiazepine data, but we use the same principle. Even when we are considering someone for S-ketamine, we usually recommend them to reduce their benzodiazepine lorazepam equivalent to less than 4 milligram. But there's no sort of data. I don't think, as far as I remember, Jensen has not published any data from a benzodiazepine standpoint. But mechanistically, it's pretty similar. If someone was just taking a electron 10 and a half milligrams per day, do you think that's? That's OK. Yeah, so when we are looking at the paper, when we did the study, we looked at the low dose versus high dose. So the median dose there was 3.43 milligram or so. So in a ketamine clinic, in our SOP, we look at if you're on less than 4 milligram lorazepam equivalent. So in that case, depending on what software you're using, some would say 2 milligram clonazepam equivalent. Some I've seen, they would use 1 milligram. So if your patient is using half a milligram twice a day, it's OK to use that along with that. OK. You know, one thing I'll mention is Dr. Petrides mentioned something about the psychiatrist who got the Nobel Prize. And I was thinking someone else in the audience knew of another psychiatrist who got the Nobel Prize, right? So Dr. Kandel, right? Yes, but not for psychiatric research. It's for memory in the amoeba. Those snails or some kind of snails. But yeah, but anyways, fun fact, I suppose. Question? I'm sorry. My name is Dorothy. I'm looking at the TV. Can you comment on your experience with the electronic machine and the US government? Well, my experience, and I've been using both, there is no difference in terms of efficacy for the treatments. They just follow the same guidelines. One difference that I have to tell you is that in the US, in Canada, the FDA has approved or grandfathered the devices that deliver up to 500 millicoulombs. In the rest of the world, they deliver up to 1,000 millicoulombs. So it differs from. But the machines are the same. Sorry. Go ahead. I'm wondering if you're considering an international fellowship, which actually covers all the modalities that are covered in that. Could you comment on the utility of doing a one-year fellowship, developing columns? I think that would be really good, because these are the latest things that pretty much, I mean, depression is really common. And then people are going to run through medicines, and they're going to ask, well, what do I do next? And one of the nice things about knowing all of those is because you're not just the one practitioner who knows one thing. And that's kind of like that old saying, if you have a hammer, everything looks like a nail. So for me, in my practice, I also do ECT. I'm relatively new to the actual practice of ECT. But when I see a patient, I'm able to discuss with them all the three different modalities of which one is better for you at this time. So I would say, go for it. And there are places I know that now offer interventional psychiatry fellowships. I'll see if Wollender or George have other comments about that. No, I absolutely agree with that. So it's very valuable. I did this by myself for different reasons 100 years ago, because I wanted to change my J visa to a green card. So I had to stay on a fellowship. And that's what I did, although there was no real accredited fellowship at that time. So I think it's a very good experience. I would agree with both. And I think we have a Mood Fellowship at Mayo. We don't call it interventional fellowship, but it covers all these aspects. It's probably one of these, you can make it what you want to be. There's some general stuff. But we'll mix in all of these. So if you haven't figured out where to apply for your interventional fellowship yet, you can consider Mayo Clinic. Yes? I'm actually curious. Can you speak about how you face your continuance for a paper in ECT, or does it make sense? Well, there is a distinction in the literature, which I don't think it's right. They call continuation ECT, whatever it is, past the acute course, meaning weekly or less frequent. And then after six months, you call it maintenance. I don't really understand what continuation means, continuation of what. But that's basically what is in the literature. But nevertheless, for patients who are really with severe form of depression, you may need to continue treatments or have them in maintenance for at least six months. We recommend one year, which is tapered usually once a week for a month, and then once every two weeks for another two months, and then monthly. Yes? I think you had a question earlier. We had 7% of PMS remission. In your center, did you ever see any remission rates there? I don't actually remember calculating the remission rates for us, because it's always discouraging, because they're always lower. So I just remember response rates. For us, it was 60. If I had to guess, probably somewhere around 30% remission rates. I mean, you do have a remission rate. Yeah, I always am a bit skeptical about manufacturer-reported remission rates, so I just look in the literature, as long as the study isn't sponsored by the manufacturer, but yeah. How about in the back, and then over on the side? So that's a great question. The question is, have you seen a difference in response rate between melancholic and non-melancholic? A short answer is no. We are trying to analyze our data into different depression phenotypes, so the only phenotype where we saw a signal so far was if they had more hypersomnia or more sort of that atypical depression. Again, our sample size for that analysis was only 64, but so far there's no sort of consistent data of melancholic versus non-melancholic, so if you have a patient who has treatment-resistant depression, they meet all of those criteria, we'll offer them the treatment. Yeah so the settings aren't changes just every other day so so that way we don't just abruptly stop after 30 treatments so then you know the next week you do three treatments the week after two and then you stop and and and the reason for 36 is that's what usually insurance companies will cover right so that's why so before I take any more questions just to let everyone know it's past 515 thank you all for coming but please whoever wants to ask questions you know you can also come up or just keep asking whoever wants to leave thank you for coming and enjoy the rest of your day but

Transcranial Magnetic Stimulation

TMS

ketamine

Electroconvulsive Therapy

ECT

major depressive disorder

brain stimulation

dorsolateral prefrontal cortex

accelerated TMS protocols

treatment-resistant depression

interventional psychiatry

severe depression