Hello and welcome. I'm Dr. John Torres, the Director of Digital Psychiatry at Beth Israel Deaconess Medical Center and a member of the SMI Advisor Clinical Expert Team. I'm very pleased that you're joining us for today's SMI Advisor webinar, Ketamine-S-Ketamine in the Treatment of Serious and Persistent Depression, Practical Considerations. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. Now I'd like to introduce the faculty for today's webinar, Dr. Jerry Santacora. Dr. Santacora is a George D. Gross and Esther S. Gross Professor of Psychiatry at Yale University School of Medicine, the Director of the Yale Depression Research Program, and Co-Director of the Yale New Haven Hospital Interventional Psychiatry Service. Dr. Santacora's career has focused largely on elucidating the pathophysiology mechanisms associated with mood and other neuropsychiatric disorders and using this information to inform the development of novel treatment strategies. He has led a series of studies examining the mechanisms of action and efficacy of rapidly acting antidepressant treatment, and he has helped to provide direction for the rational use and development of these novel treatments in clinical settings. Among his many awards, he has received the Stiftung International Award for Investigation of Biological Substrate and Functional Disturbances of Depression and a Joel Eskes Research Award for Outstanding Contributions to Psychopharmacology from the American College of Neuropsychopharmacology or ACMP. He's also a fellow to ACMP. So Dr. Santacora, thank you so much for joining us and leading today's webinar. Without further ado, I'm going to hand it over to you. Thank you, John, and thank you all very much for inviting me for this presentation. I think it is actually a very timely and important topic of coverage as this is really starting to emerge as one of the novel treatments that are available to people, but there's growing difficulty and growing concerns about how to actually understand how to use this most appropriately to help patients, especially patients with severe and persistent depression. I do want to provide my disclosures. I consult and work with many different companies, including Janssen or Johnson and Johnson, who is the maker of S-ketamine, which I will be presenting some data on here. And I also do hold some equity in another company called Biohaven Pharmaceuticals. And the other important thing to mention here is that I will be talking about off-label medication. In fact, when I talk about the use of ketamine for anything but the use as an anesthetic agent, basically, we'll be talking about ketamine, racemic ketamine hydrochloride being used off-label. As of right now, only the S-ketamine intranasal formulation has received FDA indication for the treatment of treatment-resistant depression. So I broke this down basically to three components to talk. The first part is really just to give a brief history of how we got to the idea of using ketamine and where this actually came from. The second and really the most important thing is to outline what are the critical questions that still remain. I'll start with giving some of the questions and how we answered some of them over time, but it still leaves us with several questions that we have to resolve. And then the bulk of this talk will really be going through the studies that at least helps us address what these questions are. And in some cases, I think we have satisfactory answers. In other cases, I think we still have a lot more to learn. And then hopefully, we'll have time to talk about that and question and answer after. Okay. So the first part is the main question is, all right, we already have well over two dozen approved treatments for depression. And that's just pharmacologic. We have somatic therapies. We have talk therapies. Do we really need another antidepressant treatment? And I think, I hope I'm preaching to the choir a little bit here saying that despite our current armamentarium of treatments, depression still is a major problem for us in treating depression. It is recognized as one of the major causes of disability throughout the world in terms of disability adjusted life years from the World Health Organization. Unfortunately, over the past decade, we have actually seen the rates of suicide increasing in the US, not all of, but much of the suicides associated with depression. And also the fact that we have several large real-world studies that have been completed over the past 10 to 15 years, really showing us the benefits, but also the limitations of our standard oral antidepressant treatments and including cognitive therapy. And also adding the fact that even when we are able to get people to have a response, it takes on average about six weeks for 50% of people to feel 50% better. So not only do we have a substantial proportion of people that aren't really benefiting from our standard treatments, but even when they are, it can take weeks to obtain that benefit. And I always include this just because I think it's very telling of where we are in the field, that it was just 20 years ago that it was just accepted that all antidepressants take several weeks to work. And it was always kind of held out as the Holy grail that it would be really nice to have something that could work rapidly. That would be one of the characteristics of an ideal antidepressant. But then if you see the last line here, however, no drug appears to work more rapidly than any other. And the time course is generally prolonged. I think if nothing else, what the research with ketamine has shown is that that doesn't necessarily need to be the case, that we can get a more rapid onset of antidepressant effect. And I hope I can show you some of the data supporting that. So why ketamine? Of all the treatments, where did this idea come up of using an anesthetic agent? Ketamine was developed in 1960s really, received FDA approval as an anesthetic agent in 1970, or it was commonly used in field hospitals as an anesthetic agent. Now it's much more commonly used in pediatric anesthesia or in emergency room settings. But where did the idea come to use this as an antidepressant? Well, there were several lines of evidence that pointed in this direction. The first line was evidence suggesting that the monoaminergic system, while possibly contributing to the antidepressant effects of our medicines, and possibly having some role in the pathophysiology of depression, clearly wasn't explaining why people were depressed. It clearly wasn't just a shortage of serotonin. So we started to realize that back in the 1980s. So there was increasing evidence suggesting that the amino acid neurotransmitter systems, meaning GABA and glutamate, were significantly involved in the pathophysiology of depression, both from animal model studies and from actual studies in postmortem samples from depressed patients. But I think most importantly was the evidence suggesting that when we look for pathophysiology, when we look for abnormalities in patients with severe depression, we saw more cortical systems and actually sort of cortical limbic pathophysiology, not really deficits in the raphe nuclei or in the nuclei much more closely associated with the monoaminergic system. And it was really this idea that if there were primary deficits, it probably is much more related to cortical limbic pathophysiology. And the fact that there was increasing evidence suggesting the amino acid neurotransmitters, such as glutamate and GABA, seemed to be disrupted. The idea came that, well, if we could target these systems, we may have ability to at least probe what the pathophysiology of depression is, if not develop a treatment. So this is actually a quote from John Crystal and Dennis Charney, who were two of the main authors on that first paper, really presenting their view of what inspired them to that first treatment. And most of you at this point have seen the results of that first study that was done in the late 1990s, published in 2000. This was a randomized placebo-controlled crossover study, counterbalanced, where one week these depressed patients, and if you notice, it was only eight people in this study, so a really small study. This was done at the West Haven VA Hospital. But patients, one week would come in and get an infusion of saline. That's the placebo treatment. The other week, they would come in and get an infusion of ketamine at 0.5 milligrams per kilogram, given over 40 minutes. And the reason that dose was chosen was because previous work done by Dr. Crystal and others show that that was a dose that could create significant effects in cognition and perception, but allow the patient to stay awake enough to report them. That was really how that dose came about. There was no specific hypothesis that that was the perfect dose for depression in any way. So when you look at the results of that study, it really is quite striking. So you can see the week in blue that the patients received placebo saline, really no effect at all. But when they received the ketamine, within three hours, there was a very clear antidepressant effect. And by a day out, a very, very strong antidepressant effect that seemed to last for about three days. And if we follow this curve out, they did tend to go back up over the preceding days, over the following days. But this magnitude of antidepressant effect over this short period of time was really something that hadn't been seen before. And most of us in the academic community became extremely interested in it, but most of us all set out to try to understand the mechanism. How could this be? What's leading to this rapid onset of antidepressant effect? It's amazing that it took six years. Oh, I should just mention that this finding really was surprising to everybody, including the authors of that first paper. Again, this is a quote from John Crystal, basically saying to the amazement of everybody, including them, that this had such a rapid onset of antidepressant effect. But the other amazing thing is it actually took six years for a replication study to be done. So this was done at the NIMH, Carlo Serrati, again, Dennis Charney down there, where if I would have showed the same thing, just the change in depression severity using the Hamilton Depression Rating Scale, it would look almost identical to that first study by Berman. But here I'm actually showing in the percent responders over time. And you could see over 70% of people had a response within one day, meaning 50% improvement in the Hamilton score. And about a third of them actually would have reached the level that had minimal symptoms, what would have been considered remission. And if you look over to the right, it's pretty remarkable because this is about the level of response that we would expect to see with the standard SSRIs or SNRI or bupropion after eight weeks of treatment. So within one day, we were seeing the magnitude of an antidepressant response that's typically only seen after eight weeks with a more standard oral antidepressant. So really pretty phenomenal finding. Since that study was done, there was a flurry of other small, relatively small, usually with ends of less than 20, clinical trials that were done that seemed to replicate this finding. And you can see this is a report that came out of the APA Council on Research Task Force, showing that the odds ratio of having a response to ketamine as compared to placebo is about tenfold. This is much, much higher than we see with any other standard oral antidepressant. And even if you looked a week out after a single dose, you still have over a fivefold chance of having the response to ketamine than oral antidepressant, even with just a single dose. So this is really unique in many ways. One, it's a very rapid onset of effect. And it's an effect that seems to last well beyond the drug being in the system. Ketamine is relatively rapidly metabolized. So within a few hours, it is gone from your system. There may be some metabolites that last a little bit longer, but nothing really at the level that could explain this prolonged antidepressant response that can go on for days after a single dose. So this data that really was coming out, by this point, it was around, you know, coming out around 2010, mostly studies, this was done in 2015, this short meta-analysis, really stimulated a huge amount of interest, and largely from the lay media. You can see media reports were very, very favorable, suggesting that ketamine may be this new treatment for depression that could offer hope to people that did not respond to standard oral antidepressant drugs and could actually possibly make people feel better within hours, as opposed to waiting weeks or months. So it really gained a huge amount of attention and an increased need was perceived. So this was a survey that we did now going back about three, four years ago, three years ago, where we started to look at the increasing numbers of people that were offering ketamine or centers that were offering ketamine as a possible treatment for depression. You can see this very rapid increase, and this was only really up to the year 2016. If we were to carry this out for an additional three years to where we are now, that curve, I think, would continue at the same trajectory that we see here, with large numbers of people starting to offer the treatment, despite the fact that up until this point, almost all of the studies were very small in scope and sample size, and many of them only were analyzing a single treatment, not even looking at the effects of repeated treatment. So it really became a big, both medical and ethical issue about how do we move forward with this treatment? We have this treatment that seems to offer real hope and potentially really benefit maybe even lifesaving properties to people with severe treatment-resistant depression, but yet we had so little data to really encourage us in what was, in fact, the real case at the time. That prompted the APA to ask several of us to put together a consensus statement. In fact, we were originally asked to put together some guidelines on how to use this treatment, and I think after looking at the data when we went through it as carefully as we could, I think we all agreed that, well, it's really not possible to give guidelines because there's just not enough information available to make guidelines, and we decided that we could at least issue a consensus statement where we really set out to highlight what are the major issues that need to be considered and kind of set the framework or the groundwork for what questions need to be answered, and if you are using this treatment clinically, what you really should be aware of and what you should make available to the patients in terms of informed consent. So that was really the point, and this was just three years ago. We're talking about the state of the art three years ago. Since then, there's been major changes, and that's what I really want to show you where we are now, but at the time of that paper, the big questions that were left, and as I said, some of these I think we've been able to resolve, but many of them still are questions, is first, what is the optimal dosing frequency in terms of the route, the actual dose, the frequency? As I mentioned, that initial dose of 0.5 milligrams IV given over 40 minutes was chosen based on previous work looking at the psychotomimetic effects of ketamine, not at all done to optimize the antidepressant effect. And as I mentioned before, almost all those initial studies were done after a single dose of ketamine. Some of them went out to two weeks of dosing, twice a week or three times a week, but really no data at all suggesting that this treatment had long-term effectiveness and definitely no data available for long-term safety at that point. And then we were left with several other really important questions that were unanswered, such as what are the moderators of the response? And by that, I mean, are there specific people that are more likely to show benefit or to show adverse effects? Are there specific subtypes of these mood disorders or other psychiatric disorders? Are there genetics? Is there any endophenotypic differences that may help predict either a positive or a negative effect of the drug? And then also very important, we knew very, very, very, very little about the drug-drug interactions. So we didn't fully understand the mechanism of action. It was really difficult to know what the drug-drug interactions would be. So we had a lot to learn about how to use this drug. And that's really the more important clinical relevance, more immediate. But then even in the long-term, we had so many other questions about how this actually worked. What was the mechanism of action? Both proximal, and we talk about that from pharmacology, it's what the drug is actually doing most immediately, but then the downstream effects. And I'll get a chance to talk about that because I think ketamine is extremely interesting in that it seems to set off a cascade of events that generates the antidepressant response. But the actual presence of the ketamine may not be necessary for the whole response to occur. And we'll talk a little bit about that. And then the idea of that is if we could really understand the mechanisms, we may be able to develop new treatments similar to ketamine, but that may not carry some of the same unwanted baggage as ketamine does. All right. So the first step is, well, what is the optimal dosing and dosing strategy? That's a really important thing if you're going to be treating people with the medication. And I promise the next two slides are the only two slides that I'm going to present rodent data, animal data, but I think it's really important for everybody to just get a sense of how we're thinking about this. So some of you may have heard about a paper that was published in 2010 by Ron Duman's lab. It became a very, very well-known paper in science where they were able to show that ketamine can produce these very rapid antidepressant effects. And if you look at FST as the forced swim test, it's an animal test for antidepressant activity. And they could show that after giving ketamine 24 hours after that, they can show this very strong antidepressant-like effect in their rats, but only if it's given at a sub-anesthetic dose. 10 milligrams per kilogram given into peritoneal in a rat is a sub-anesthetic dose, and it generated this very strong antidepressant-like effect. But when you gave 80 mg per kg, which is right in the anesthetic range, for an animal IP, you no longer saw this effect. So very interesting that the lower dose seemed to have an effect, but higher dose didn't. The next slide actually shows the phosphorylation of certain proteins that's involved in the mTORC-C1 pathway. Again, don't worry so much about it, but it's a pathway that seems to control local protein synthesis and actually probably has a lot to do with local neuroplasticity. So again, interesting dose response curve that there seems to be an increase in the ability to modify the cellular function up to a certain point, but going beyond that point, you actually lose that effect again. We were able to replicate this using another technique. And again, don't get so caught up in the methodology here. The idea was this is a technique that could actually measure glutamate-glutamine cycling, so we can measure how much glutamate is being released. And we can see that, again, there's increases through the sub-anesthetic dose ranges. But when you get to these higher doses, that 80 mg per kg, which is, again, anesthetic, you no longer see this effect. So you no longer see this rapid release of glutamate after giving the treatment. And again, we were able to replicate the behavioral side that 24 hours after this, we could see this effect with the sub-anesthetic doses, the higher levels of the sub-anesthetic dose, especially having bigger effects, but losing it when you go too high. So it gives you this idea that you have what's called an inverted U-shaped curve, that you can get benefit by increasing the dose to a certain point, but beyond that point, you actually lose benefit by increasing further. And that actually matches very nicely with older data. This data is over 20 years old, using microdialysis to show the release of glutamate. And again, that through the sub-anesthetic dose ranges from 10 to 30, you see this increase, but going out beyond that, you actually see the opposite effect. And the other important thing that we're able to tell by our C13 imaging studies in the rodents is that this effect seems to be pretty short-lived. So after giving the ketamine, within the first eight minutes, we start to see increases in the turnover of glutamate and glutamine. And you can see it lasts for about a half hour, up to an hour, and it's back to normal. Interestingly, when you look 24 hours out, when we do the behavioral studies, when we see that antidepressant like effect in the rodents, it's back to normal, if anything, a slight trend towards a decrease, which is probably not meaningful at all. But it does show us that you don't need the acute effects of the ketamine to be continued, at least in terms of the glutamate release and glutamate cycling. So it's very interesting that this looks like the effects of the ketamine is something that happens acutely, but then the actual antidepressant effect is just initiated, and it sort of has a life of its own after that point. So it goes with the idea that you don't need to continuously give this medicine to get that effect. All right. What about in the clinic? Is there a real dose response curve in the clinic? So this was a study that we participated in, sponsored by the NIMH. This was a rapid study sponsored by the NIMH, where five academic sites got together and tried to do a dose response curve with IV ketamine given over 40 minutes. And if you look at the curve here, you look at these lines, this is looking at the response both one day and out. And looking at the HamD6, you can see that there's different doses using here. The purple was the control. When this was an active control, it was midazolam, a versit, a short-acting benzodiazepine to do our best job of blinding what the actual drug was. And then there were different doses of ketamine, 0.1 mg per kg, 0.2 mg per kg, 0.5 mg per kg, which is the standard dose that had been used primarily up to that point, and then doubling that dose to 1 mg per kg. And if you look at the colors here, so all of the doses of ketamine outperformed the antidepressant effect of midazolam, numerically at least, they all outperformed that. But if you look at the one that actually seemed to have the biggest effect, it was the 0.5 mg per kg, the dose that had been used previously. There's some interest in the fact that the 0.1 mg and the 0.2 were flipped of what you would think if you were thinking of a regular dose response curve. I think that this is probably just much more that these weren't very large samples. There were about 20 people in each one of these groups. So I think if you average these together, they're probably both somewhere in the middle. But I think one of the other really important findings is that the 1 mg per kg, the dose that's twice the dose of the 0.5 mg, the typical dose, didn't show any added benefit at these time points at all, despite the fact that the patients were much, much more dissociated. So this idea that the more dissociation you get, the more of an antidepressant effect you get, did not hold true in this study at all. The 0.5 mg dose had at least as good, if not superior efficacy to the 1 mg dose in these measures, but clearly had significantly less dissociation. So what is the optimal dosing frequency? So we talked about what's the dose, but how frequently do you need to give it? I showed you evidence to suggest that you don't really need the ketamine to stay on board. There's very, very little evidence that. In fact, I think most people would think it would be crazy to keep ketamine on board all the time. It's an NMDA receptor antagonist that impairs cognitive function, impairs perception. It's just not something you want around all the time. But how frequently do you need to give it if it's going to be given in a pulsatile manner? And it's really amazing how little data there is looking at this. But this is probably the best study to date. This was done, we did this in collaboration with Johnson & Johnson, Janssen. This is using regular racemic ketamine, given IV over the standard time, 0.5 mg per kg. But the way the study was designed, patients were randomized either to receive twice a week dosing or three times a week dosing for two weeks. And then within that group, they were randomized to receive either active, which was the ketamine, 0.5 mg per kg over 40 minutes, as I said, or saline placebo. And if you can look, the people that received twice a week dosing did just as well, if not numerically, possibly even a little bit better than the people getting three times a week dosing. They both clearly separated from placebo nicely. But this was the evidence to suggest that, well, there was no reason to dose three times a week. It looks like we're getting just as good an effect as twice a week. And this is really sort of the groundwork that was used for the large phase two and phase three studies moving forward with S-ketamine. So, the question still remains, could you give it once a week? What if you gave it every two and a half days? We haven't answered all those questions, but here's at least good evidence that twice a week was just as good as three times a week. Interestingly, that survey that I mentioned before, we asked the clinicians that were giving this. So, we asked the clinicians how they were giving it, these sites that were using it around the country and in Canada. And we asked them just how many times a week are you typically And this is before there was much data out, but it seemed that the consensus in the field, this is just a frequency diagram. People were typically giving it two or three times a week anyway. That's what it was coming out to, which is interesting to see how the clinical field is moving in the absence of actual having really strong data for it. The next question is, does delivery really matter? Here, it comes down to the fact of practicality in some ways. I know most psychiatry sites are not really prepared to be giving IV medications on a regular basis. I know that was a real struggle for a lot of sites, especially in the beginning. And there was hope that maybe ketamine could be delivered by other routes. Orally, it can be given, it's just very poorly distributed. But the idea is, could you give it intranasally? And would that be an easier route of delivery? The problem again is bioavailability. How do you get a reliable dose? I showed you before that it really does look like dose matters. And it looks like there may be somewhat of a narrow therapeutic window, meaning, you know, if you're going to give it intranasally, you're going to have to give it a little bit more. And so, the idea came out that, well, if we could really concentrate the ketamine, if you can get the ketamine concentrated and give a smaller dose, because if you had to give it intranasally with a large dose, that actually is a pretty large volume, and how would you actually keep it all up there and make sure it's getting absorbed? The idea is, well, if we made a more potent version of it, that you could deliver a smaller volume but still have the same effect. And this was the idea when you look at ketamine, racemic ketamine, everything I spoke about to this point, is really a mixture of an S and an R enantiomer, just mirror images of the molecule, and that makes up the racemic mixture. But if you just look at S ketamine, which is really just the S enantiomer, it has a much higher potency for the NMDA receptor. So, if we go back to this original idea that ketamine has its antidepressant effects by targeting the glutamatergic NMDA receptor, you'd be able to deliver reduced volumes and still have the same or even higher potency or effect on the NMDA receptor. So, it's this idea that if you could use S ketamine, and this was the Janssen and Janssen's approach, if you could use S ketamine to more selectively target the NMDA receptor, you might be able to use lower doses and have an easier intranasal formulation. And in fact, they showed with IV that intranasal, I'm sorry, that S ketamine used IV even at doses at 0.2. Now, half of what was typically used for racemic ketamine had a very nice antidepressant response, seemed identical to a dose of 0.4, which actually would be higher than the 0.5 racemic ketamine. So, they felt pretty comfortable at this point that this was a sufficient dose that would be able to attain the plasma levels and ultimately brain levels that's needed for the antidepressant-like effect. Then there was a small study done just looking at dose response with S ketamine, the S ketamine enantiomer delivered intranasally. And again, you can see that same general trend that the lower doses at 28 milligrams, just not quite reaching the same level as the 56 or 84 milligrams. In these small sample sizes, it's really hard to separate statistically, but very consistent trend that moving up at least within this dose range, you get an increase. And especially if you look at the duration of the effect. And if you look on the bottom in terms of the response and remissions, again, pretty consistent findings that there was some increase as you moved up within this dose range. But really little benefit above the 56 and 84. And this was the studies that were used to move ahead and look at the large phase three trials that were done by Janssen with S ketamine intranasally or Spravato. And here's where I want to spend the last few minutes really going through, because I think this is some really important data. So, this is looking at all these large phase three trials. This is an incredible amount of work. So, I mentioned before, most of those studies had ends of less than 20. Some of them ends up to 60 in those studies. Now, you're just seeing ends of over almost 350 and 220 in their randomized placebo-controlled arms. And in the geriatric study, almost 140 people. And in the long-term studies, almost 800 people in these studies. So, now you're looking, and in this last study, 3004, receiving it for over a year, or up to a year in this study, and then continued in a later study. So, now you have huge amounts of data, and we're starting to really understand a lot more about the safety and efficacy over time, at least of S ketamine. Again, I just want to highlight the uniqueness of these studies. So, these studies that were done with S ketamine, these are the phase three trials that were used for the FDA approval. They required people to have documented non-response to at least two treatments. So, these had to be real people that were not responding to antidepressants, at least two antidepressants, in order to enter into the study. Now, here's the real unique part of these studies in general. Unlike almost any other study in clinical trial in antidepressants, all of these patients would then, after meeting inclusion criteria, would then all start it on a brand new oral antidepressant. So, they either got a new SSRI or a new SNRI, and then on top of that, they were randomized either to receive S ketamine nasal spray or the placebo. So, again, the difference is everybody gets a new antidepressant. So, there's really nobody here just getting a placebo. Everybody gets a new antidepressant, and then on top of that, they either get the esketamine nasal spray or they get the placebo. And then you're looking at responses. And then there's the follow-up phases. We'll talk briefly on the longer term. But here's the data for this, which I think is really important. And I wanna, you all have access to these slides so you can go through all the details more carefully. I just wanna hit the highlights for purposes of time. This was the first study. This is fixed dose, either 56 or 84 milligrams, given over a month, twice a week for a month. And you can see the separation from placebo. Very clear, both doses in almost every study like that look very similar, just like they did in the phase two. And separating from the placebo numerically, but interestingly, the way the statistical design was set up on this, it did not statistically meet the criteria that was set up a priori on this. So you may hear people say, well, the clinical trial is only one of the three randomized placebo control trials met significance. This is one that did not meet, but you can see pretty consistent findings, but due to the way the design was set up, not meeting the primary endpoint. If you go and look at the response and remission rates, you can see that nearly a 50% response, above 50% response for both doses of esketamine over that period of time, compared to about 39, almost 40% for the standard oral antidepressant. And those people continued to come in, they were getting the IV, I mean, the intranasal treatment. So they were coming to the settings twice a week getting treated. So these were really intense studies with a lot of patient contact. And if you look at remission rates, again, average about 37 for the two arms of esketamine compared to about 30. This was the second study. This is a flexible dosing, meaning they could either use 56 or 84 milligrams, depending on how the patients were doing compared to placebo. So you can adjust the dose as a clinician. And again, the important thing to realize is this is almost identical to that initial fixed dose study if you look at the difference here, it did meet statistical significance. So there was an effect, which is the positive study that people will talk about. But as you can see, if I just flip back quickly, almost identical in terms of the two graphs. And again, if you look at the response and remission rates, here, almost 70% response in the patients treated with the oral antidepressant plus esketamine compared to about a 50% response with just the new oral antidepressant and placebo. And if you look at remission rates, over 50%, which is pretty high for almost any study we looked at with the combination of the oral antidepressant plus esketamine where about 30% for just the new oral antidepressant with placebo. So really interesting findings. And again, very replicable between these two studies. I mean, you're seeing really pretty consistent data. The next part is, do we see longer term effects? And this is, there are some concerns for safety. So ketamine is known to have some neurotoxic effects. It's also meant to have some effects on the urinary bladder. So this can't be given without some concern. Here, I just have an example of two animal studies suggesting that repeated dosing of ketamine may have some toxicity. And we know from patients that misuse ketamine or abuse ketamine, that it is associated with some cognitive changes. It's also associated with some neurologic changes, especially when it's used at more frequent dosing frequencies or higher dosing frequencies. Interestingly, patients that seem to infrequently abuse ketamine don't seem to show those same changes. At least the data that were collected originally, and this is some of our data and also data out of the UK and out of Minnesota, we didn't see any evidence after at least two weeks of treatment of any cognitive impairment associated with repeated ketamine. If anything, there's trends for numerical increases, but really no evidence to suggest any impairment in cognition. At the Yale Interventional Psychiatry Service, we have been treating people off-label with ketamine probably for about seven years now, outside of clinical trials even. Really, we started treating people clinically when we felt the real need ethically to offer this to some people that had been in clinical trials and had a response, but then didn't have access to it. So we followed some of these people now for many years. And you can see from the data up in the upper left corner, these are really severely depressed patients. Many of them had failed ECT. Most of them had been hospitalized and had previous suicides. So these are, in the large part, either people that had tried and had failed ECT or were not able to tolerate ECT for one reason or another. And again, we're not really seeing any consistent findings. Some of these people now have been getting treatment for six, seven years with space dosing, not really seeing any clear evidence of cognitive difficulties, which is good. It's not enough to say there aren't any problems, but at least we're not seeing any bright red flares out there that's causing major concern for us. Back to S-ketamine, what I was showing from Yale was actually the racemic ketamine. Back to S-ketamine, if we look at the long-term safety studies, we can see that this is the study that went out for up to a year of treatment. And you can see the number of people here. The study was stopped once there was a sufficient number of people reaching the one year and six month time points. So it doesn't mean that people are dropping out of the study. It just means that people are at different points along when the study was stopped. But you can see pretty remarkable that antidepressant response that is achieved tends to be maintained over time with repeated dosing. Now, these people, about one third of them were receiving treatment once a week, about another third were receiving treatment about once every other week, and about one third of them were switching back and forth between once a week and every other week. Now, don't be misled to believe that you get a response and people just stay well. This is when it's averaged over hundreds of people. There's fair amount of variability for each individual. They have good days, they have bad days, they bounce around. But when you average it out, it's a pretty consistent response that can be maintained. And we also learned a lot about what are the adverse events. And now if you look at what percentage of people at any point during the time of treatment will experience adverse events, it's pretty much what we expected. We see a lot of dizziness, nausea, dissociation that occurs during the treatments. There's some level of vomiting, but these are all generally very time limited, very transient, lasting only during the first hour, 90 minutes at most of treatment. And in terms of the nausea and vomiting, very amenable to treatment with Andantetran or Zofran doing quite well. If you do look, the other real concerns that we had were that the interstitial cystitis of the bladder, we really didn't see any cases of interstitial cystitis of the bladder in these trials, now treating hundreds of people. What we do see and what would be predicted is that you do see some increases in blood pressure and heart rate that for some people could actually be concerning. So we had about 4% of people that had a systolic above 180 or fast talk about 110. Now for most of us, we can handle that for 40 minutes, an hour or whatever, we'd be getting it during this time. But for people that are at risk, this could be a real problem. It's one of the main reasons to do a thorough evaluation ahead of time. As I said, there clearly are dissociative effects and some minor problems with the nasal tolerability. It really wasn't pleasant and people didn't like it. It had a terrible taste and sort of stung in the nose a little bit, but beyond that was pretty well tolerated. The interesting thing is what happens when you stop? So this was a study that was designed to look at randomized withdrawal. So these were people that had a response to the esketamine and then had it maintained for several months. And then at some point were randomized to either continue with the active treatment or to start receiving saline placebo. And you can see the way this was designed is they wanted to look at the people that were real remitters, meaning they had minimal effects. And if you look at those, you see continue on the medication, the majority of people remain well, and you see these numbers get small. So it's hard, the actual numbers get small. So these numbers out here are a little bit less meaningful than the numbers up here. But you see people say pretty well, but there is some relapse. But if you stop the treatment, you get a little bit more. So by the end of about six months, you're getting close to 50% relapsing if you stop the medicine. But importantly, if people are responders, meaning they're at least 50% better, but not really remitters, not really doing great. In those patients, if you continue the medicine, you can keep the majority of people doing well going out. But if you stop the medicine, you tend to get a more abrupt relapse of symptoms. So we're starting to learn, how long do you need to keep this? And it's probably going to be individualized for individual patients. Interestingly, during that survey, when we asked people for IV ketamine, about how frequently were they treating people, they came out to about once every three weeks, once every two weeks, people will respond, came back for a boosted dose. And that is in general what we're finding with S-ketamine too. This is just a quick slide to say that we're very interested. And one of my colleagues, Sam Wilkinson, is working very hard to see if there's a way of combining non-pharmacologic treatments, in this case, specifically cognitive behavioral therapy, intensive cognitive behavioral therapy with the ketamine and S-ketamine to see if we can maintain that response. All right, and just lastly, doing some rapid fire, because I want to leave time for questions. Who's appropriate, this is when we talk about the moderators, who's appropriate for ketamine treatment? You know, the big question is, well, does gender or sex matter? Pre-clinically in the road models, there is some evidence that female mice may have a differential response compared to male mice and possibly a better response. When we did the rapid study, we did a sub-analysis, Marlon Freeman was directing that. We really didn't see a big difference between men or women, or even between the phases of the estrous cycle, or whether they were pre or post-menopausal. So we didn't see it, but again, this is a sample of about 110 people, so it's really hard to know how much of an effect you're seeing. We also didn't see that anxiety made a big difference, but again, very small sample. This would have to be replicated before there's much to be said about it. If we look at all the data for the two adult phase two trials with S-ketamine, you can see that there may be some hint that maybe females are doing a little bit better than the males. This is up here where it looks at gender, but important to note that there were fewer males, so there's a much greater error bar. So I wouldn't be too confident that this is all that meaningful. And in fact, in another study that was just done, this doesn't seem to be holding up. So something to consider, but I think still very questionable. If you do look at the data, again, there's some evidence that people with the more, the larger number of treatment failures may do a little bit better. And if you look at people that are more, more functionally impaired may do better than the people that were less functionally impaired. So this may be a treatment, and I would suggest a treatment that's probably more appropriate for the more severely ill, more treatment-resistant depressed patients. All right, does age matter? This is the last real highlight slide. So this is the last of the randomized placebo-controlled trials with S-ketamine. And the results are really interesting and actually quite confusing. So you can see that it actually had a pretty good effect. And right by the end, just missing statistical significance at the end point, but clearly not what we were expecting to see in terms of the timeline of antidepressant response and the timeline separation from placebo. Now, there are several reasons that this may happen, but the important thing to know is overall, the response rate and the remission rates were much lower in these patients over 65 compared to the general adult population under 65. If you look at remission rates, remember before we were showing you remission rates with the drug were up over 50%. Here, it's 17% and over. But if you look at the placebo, just the new oral antidepressant plus placebo, incredibly low remission rates and response rates. So it's difficult to interpret what this means. Is it just that older brains take longer to respond to these medicines or respond less well, but they tend to respond less well to everything? Or was it in some ways confounded by the fact that the clinicians really followed the adage, start low and go slow. And in this study, they were able to use the 28 milligram dose. And many, especially in the early phases of the study, many of the clinicians were very hesitant to increase the dose up to 56 or 84 milligrams in these older patients. And then the last thing is in terms of anti-suicidal effects. This was a group, this was a meta-analysis that we did. Sam Wilkinson led this with Kate Ballard from the NIMH, Sam from Yale and Elizabeth Ballard from the NIMH put this together where they got all the individual data from all the single dose trials with racemic ketamine and separated just the effect on the single measure of suicidal ideation and showed a very large effect very early on within a day with ketamine compared to the control. And you can see that even more than 50% of the people said they no longer had any suicidal thinking within a day of getting ketamine. The followup studies done with S-ketamine intranasally were designed specifically in people with major depressive disorder and an imminent risk for suicide on several things, but basically they had to present to an emergency room and it was determined by the physician in the emergency room that the patients had to go inpatient. And it was at that point, they were randomized to either receive the best treatment they can get plus placebo or the best treatment they can get plus S-ketamine. And you can see the results here. The green is with the S-ketamine compared to the red, which is just the best standard treatment we can give. Interesting finding, it hit the primary endpoint, which was the response in this case at four hours. That led to two other large phase three trials with the same inclusion criteria. And you can see very similar looking responses. And again, I just wanna make the point, as a scientist, but as a clinician, I like to see replicable data. I like to see something that I can see over and over again. And that's what we are seeing with this response. So you start to really know what you're gonna get. You do see this increased response early on, and this is looking at total depression scores. You see it over on, and it seems like it's maintained about the same level of response over time. It doesn't seem like the addition of the S-ketamine continues to grow. You really see that big benefit early on, and then it stays. And if you look at, again, remission and response rates over time, this is looking at remission rates. Compared to placebo, you see that the group that received the S-ketamine plus placebo always does a little bit better. Now, we can talk about whether this is clinically meaningful differences or not, and I hope that's something that will show up. The important thing also to remember is that the secondary measure in these studies were actually trying to measure suicidal ideation. And there wasn't a consistent finding there, and that's probably due to several different factors. And lastly, I just want to wrap up by giving you some take-home messages that you can look at. I realize time got away from me here, so I do want to make sure there's time for questions. I think the main point here is that there is good clinical response. We've shown that you can do it for, sustain that ability, and do it safely as long as it's with the right precautions, at least with S-ketamine, we now have enough data for that. But we clearly need more data to refine the use of this, whether it can be useful as a monotherapy, whether it could be effective in other treatments besides treatment-resistant depression, and whether it could be used at all for people with comorbid substances. I just want to thank everybody there and see if there are any questions.

ketamine

depression

antidepressant

S-ketamine

intranasal spray

treatment

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dosing frequency

cognitive effects