Hello, I'm Dr. Richard Shelton from the University of Alabama at Birmingham, and I'm going to be presenting today on ketamine for depression. I suspect that virtually everybody hearing this conference has heard about ketamine treatment for depression over the last decade. This has been building for a long time, and of course, the intranasal form of ketamine called S-ketamine has been approved over the last couple of years for treatment-resistant depression and for depression with suicidal ideation. The question I'm posing today is a hype holding up, and I want to talk about mechanism, so give you an introduction into why ketamine, what ketamine is doing, and why we would expect ketamine to be helpful, and then talk about the evidence, including some of the controversies about the treatment. I first want to express my appreciation to the APA and to the program committee for inviting me. It's always an honor for me to present at the APA, and I also want to express my appreciation to you who are participating in this conference. Let me first put up my disclosures. As you can see, we've had grants from the NIH and other federal agencies. We have also worked with a number of companies over the years, and I've underlined companies that I think might have some relevance to the presentation I'm going to have today. Of course, Janssen Pharmaceuticals is the most significant of them because they are the manufacturers of S-ketamine intranasal. I'm also going to be discussing some off-label use of drugs. This includes IV ketamine for treatment-resistant depression, TRD, bipolar disorder, and PTSD. Of course, IV ketamine is not approved by the FDA for those indications. I'll very briefly at the end talk about some medications currently in clinical trials for depression, particularly treatment-resistant depression, but of course are not approved yet by the FDA. These are our learning objectives, and it can be broken down into a few basic statements here. We're going to be talking about mechanisms. I'm going to be talking about the evidence supporting the effect of both ketamine and S-ketamine. I'm going to talk about the risks associated with the treatment, the position, that is where I think it belongs in a treatment algorithm, and some limitations and controversies about the treatment. Let me give a very brief background on ketamine development. It was first synthesized by Calvin Stevens, working with Park Davis Labs back in 1956, and it was finally approved by the FDA as an anesthetic in 1970. The first reports of non-medical use, that is abuse of ketamine, came out in the early 70s, but ketamine really came forward as a party drug, so to speak, in the 1990s and beyond. The first paper that I could find on an antidepressant-like effect of ketamine was actually 1975, but the intensive work on ketamine and related compounds, drugs that target a specific receptor called the NMDA receptor, really started in the early 1990s, and I would point to the work of Dr. Phil Skolnick, who at that time was at the NIMH, that really kind of pioneered that work. We then see the first in human studies, for depression anyway, the study by Dr. Robert Berman at Yale in 2000, and Carlos Zarate in 2006. Carlos is at the NIMH, and again, I'll talk about the specifics of those studies as we go along. And then we see the emergence of the Janssen intranasal S-ketamine development program, which went from 2012 to 2020, and that culminated, of course, in the approval of S-ketamine intranasal for treatment-resistant depression in 2019, and major depressive disorder with suicidal ideation in 2020. I'll be reviewing the data and kind of showing you those relevant studies and some pros and cons about those studies as we go forward. So first, let's talk about mechanisms and talk about, really, how does the brain regulate itself, or specifically, how does the brain regulate emotion? And one of the concepts that's emerged over the last 20 years or so is the notion of functional connectivity, and what that means is one brain region can regulate the activity of another brain region, and it does so through connections. And that could be, for example, from the ventromedial prefrontal cortex that we know regulates the function of the amygdala, where some of the symptoms of distress were thought to arise. The connection there is probably in part through the anterior cingulate cortex. So the connection of one brain region to another can help us to control or regulate our mood state. And by the way, I think that that's a broad concept there, and I'll come back to that when we're talking about other applications of ketamine toward the end of the talk today. But we can also think about connectivity in a different way. So we can think about how individual neurons connect with other neurons. So you have a pyramidal cell showing you up at the top. The pyramidal cell has an axon. We have axon terminals that innervate dendrites and, of course, form synapses, and transmitters can be released from the presynaptic neuron to that postsynaptic neuron and regulate the activity of that neuron. There's also a second set of connections that are important for today's discussion, and that can be through what are referred to as interneurons. Interneurons are not like the typical pyramidal cells or other principal cells or neurons that we're accustomed to. These are really predominantly regulatory in their function, and the ones that we're most interested in today actually act through the brain transmitter, GABA, immunobutyric acid or GABA. And so interneurons will form innervations with other neurons and regulate their activity through that inhibitory transmitter, GABA. And so interneurons function as an important part of the network in how the brain regulates itself. But fundamentally, the number and density of synapses that are formed between various neurons is kind of what's critical in terms of the ability of the brain to regulate itself and, in particular, to regulate the emotional state. It's how we regulate our emotions. Now on those dendrites, there are what are referred to as spines, which form synapses. And so we'll see in a few minutes that dendrites will grow spines and will form synapses, and that's where those synaptic connections come from. This is a very dynamic process. It can happen really quickly, as I'll show you in just a couple of minutes. Now what we know about the brain under conditions of stress is that the brain loses those spines and synapses. And so you can see in this data that came originally out of the late Ron Dumond's lab that in the normal condition on the left, you'd see this has 18 spines and synapses. I know because I counted them one day. And then under a stress condition, those synapses are significantly reduced. What that means is stressful experiences, in this particular case for rats, but also probably for people as well, cause a reduction or retraction of those spines and synapses, and the brain is less able to control or regulate the emotional state. And we all know that this is true, right? When we're under conditions of stress, we all feel bad, right? We all have negative mood states. But that also appears to be associated with depression, certainly depression-like behavior in animal models, and we think also probably depression in people. So again, the regulation of spines and synapses are really critical in terms of the regulation of the emotional state, and those are lost under conditions of stress. Not that every depressive episode occurs after an episode of stress, but we know that stress is an important factor in precipitating depression for people. Now, I'm going to be moving into a discussion of the actions of ketamine and how ketamine can regulate this system, but I want to stop for a moment and just remind us about some specific terminology. Now, I've already mentioned GABA at the top, the GABA-R, in the subsequent diagrams, that's the receptor for GABA. We also have glutamate, which I'm sure everybody's familiar with, the most abundant excitatory transmitter in the central nervous system. There are two receptors, AMPA and NMDA. The AMPA and NMDA receptors, which are receptors for glutamate, that will be critical in the subsequent discussion. There is also this protein complex referred to as the mammalian, also known as molecular, also known as mechanistic, target of rapamycin complex 1, and again, this is a complex of proteins. It refers to rapamycin, which is an immunosuppressant because it is the target of that drug, but it has broader effects in the cell, as we're going to be talking about in a few minutes. I'm sure everybody's familiar with BDNF, brain-derived neurotrophic factor, but a very important neurotrophin and a critical aspect of the model system that I'm going to discuss. And then finally, there's the receptor for BDNF, which is called TRKB, tyrosine or tropamycin receptor kinase B. So TRKB is the receptor for BDNF and controls the downstream function of BDNF. And this is how this works. So BDNF is released into a synapse, it binds to its receptor, TRKB, it activates a set of downstream mechanisms that ultimately activate that complex, that mTOR complex that I mentioned to you earlier. That then stimulates protein synthesis, and that's critical for the formation of those spines and synapses. Glutamate is involved in this process because glutamate activates AMPA receptors, and it's just a receptor for glutamate, which then activates voltage-gated calcium channels and the influx of calcium causes a quick release or rapid release of BDNF. So activation of AMPA is critical for the release of BDNF, which is required for the neurotrophic factors that we've talked about, the formation of those spines and synapses. And by the way, not just the formation, but also the maintenance of those spines and synapses. And then we're going to be talking about the fact that glutamate can either act directly, excuse me, ketamine can act directly on glutamate, causes the release of glutamate from presynaptic neurons, but it can also be metabolized to norketamine, which is a direct-acting AMPA agonist, so it directly activates AMPA receptors. And those two mechanisms are thought to underlie the effects of ketamine in depression. Now, this slide is intended to illustrate a couple of things. So first of all, this just is looking at how standard antidepressant medications work. I'm just illustrating here an SSRI, and you can see ultimately by acting through a pretty complicated set of mechanisms, it ultimately affects the expression of BDNF, and that then can be released, binding to its receptor, and activating that downstream system that I've talked about before. But the other thing that this slide shows is how complicated this system is. I mean, going all the way back to the patient has to pick up the medication at the pharmacy, right? You have to pick it up, the patient has to take the medicine, it has to be absorbed and distributed through the system and get to the brain, and then you have all these other mechanisms like the formation of serotonin and the storage and release and binding to serotonin receptors, and then downstream effects on gene expression. You can see BDNF is formed as a precursor, preproBDNF, which is then metabolized eventually to the mature form of BDNF, which then has to be released. And the reality is that this is a system that has the potential for lots of error. So there are many places in which the system can break down. And at best, this system is slow and relatively weak. So this is the effect that tends to accumulate over an extended period of time. But the research done in many labs, including Dr. Duman's lab that I mentioned to you earlier, has shown that the downstream target of standard antidepressant drugs is still that same BDNF to TRKB to mTORC mechanism. And if you block those mechanisms, you prevent the actions of antidepressants, at least in animal models. But this is a complicated system and it's slow. Now, one key thing to understand about this is the role of GABA. And by the way, this is still that same system activating AMPA release of BDNF and downstream effect on spines and synapses. But GABA is inhibitory to that process. And so GABA becomes an important regulatory transmitter. Now, we talked about its broader function as a regulator, sort of the emotional state earlier. But in terms of the actions of ketamine and what it's doing with ketamine, this is an important piece of it. So there is an inhibition or presynaptic release of glutamate by GABA acting through the GABA receptor. And the NMDA receptor actually stimulates the GABA neuron and causes GABA to be released. And so activation by glutamate of the NMDA receptor functions as sort of a blocker. A break or a stop in the system so that it causes the release of GABA and inhibition of the glutamate neuron via that mechanism. Now, when we bind ketamine, when we block ketamine, excuse me, when we block the NMDA receptor with ketamine, that then produces a release of glutamate and binding of glutamate to the AMPA receptor. And then again, that same mechanism going downstream. However, ketamine acts through a second mechanism, and that is through its metabolism to norketamine. And norketamine functions as a direct acting agonist, meaning it activates the AMPA receptor directly. And I would point to the work of, again, the lab of Dr. Carlos Zarate at the NIMH, really one of the first investigators to highlight this function. So we see that ketamine is acting in at least two ways. Number one is it blocks presynaptic NMDA receptors on GABA-containing neurons. But it also then is metabolized to norketamine, which directly activates the system. There's also at least some evidence that ketamine can act in that post-receptor neuron that we see on the right-hand side. It can have an inhibitory effect toward that mTOR complex that we talked about. And blocking the NMDA receptor on that side can also enhance this process. The net effect of all this, however, is a pretty rapid and dramatic effect. So you get this immediate release of glutamate, activation of AMPA, downstream effects on BDNF. So instead of having to wait for a long time for the effect to sort of trickle along, we can see that this can produce downstream effects very quickly. And as far as formation of those spine and synaptic proteins and other related proteins, we can see here work again in Dr. Duman's lab that indicates that with ketamine administration, the production of those proteins happens very, very quickly. You can see at one hour, two hours, six hours, 24 hours, 72 hours, we see an increase in the formation of some of those critical spine and synaptic proteins. So what happens, we can begin on the left-hand side, and this is just looking at, again, those dendrites that we talked about before. You can see the control condition. This is really without being stressed. We have a normal amount of the spines and synapses. The proximal and distal tuft just basically refers to the location of these dendrites. You can see the stressed condition in the middle with a reduction in the number of spines and synapses, and then stress plus ketamine. When you add ketamine to the system, you produce a rapid return, rapid restoration of those spines and synapses. So we see an effect within 24 hours. And you can see that graphically on the right-hand side, the control condition, the stress condition in the middle, but then how ketamine reverses that stress condition and normalizes the number of spines and synapses within the system. And so what that means is ketamine has the ability to restore that regulatory control to the brain and helps to theoretically normalize mood. Now, what I want to do now at this point is to transition into a discussion of human data, and then we'll talk about the clinical trials as we go forward. The first study that was done along these lines was a study by Robert Berman, then at Yale. He did a very small study, but this was a double-blind crossover study. People were started on either ketamine or placebo, treated, observed for a period of time, and then crossed over to the other condition. And the ketamine was given at 0.5 milligrams per kilogram, which has become the standard dose. This was based on estimates, based on earlier research, some of which was done by Dr. Bita Moghadam. And that dose has continued to be kind of the standard dose for IV ketamine for depression. There was a larger study that happened later. This is the study done in the lab of Dr. Carlos Arati that I mentioned to you earlier. This, again, is a double-blind crossover design, so 18 patients. Everybody eventually got ketamine in this study, and patients got either ketamine or placebo at the beginning and then crossed over. And as you can see in the open circles, ketamine produced a very rapid and pretty robust effect. And these are patients with very severe resistant depression. So they were selected specifically because of treatment resistance. So those open circles indicate to us that there's a beneficial effect that begins within a couple of hours, and it maximizes out at about a day. Now, the good news is ketamine really seemed to work in these highly treatment-resistant patients. But the bad news was that, of course, the depression started coming back within that first week. And so after this, there was sort of a proliferation, many single-dose studies, but relatively little data on whether repeated administration of ketamine could preserve the effect going forward. And that's until this study. This is a study that was supported by Janssen Pharmaceuticals. We participated in this trial. The first author of the paper in the American Journal is by Jas Singh, who directed this project at Janssen. And this was published in 2016. This was a comparison of twice a week versus three times a week administration of IV ketamine. And as you can see from the graphic, there was a pretty significant, pretty robust response. The study only lasted for a couple of weeks. So people either got the ketamine four times or six times. And as you can see, twice a week worked about as well as three times a week. That's pretty critical because of some toxicity issues of frequent use of ketamine. And so the twice a week appears to be reasonably safe. But I'll show you the data specifically as we go forward. So the next study I'm going to present to you is the first study of intranasal S-ketamine for treatment-resistant depression. And this study I will highlight was supported by Janssen Pharmaceuticals again. I was, again, one of the investigators in this study. And what this shows is the result of treatment with either placebo or S-ketamine 28, 56, or 84 milligrams. And as you can see, all three doses seem to work reasonably well. But as I've highlighted here on this graphic, the 84 milligrams, those seem to produce the most robust effect. And because this effect happened robustly and quickly, intranasal S-ketamine was awarded breakthrough therapy designation by the FDA, which means that it would be fast-tracked through the system. That's going to be important as we go forward looking at the clinical trials that supported the effectiveness of S-ketamine and the data that were used to support the approval for the indication. This is, by the way, the extension of that study. I showed you the first week data on the previous graphic. But people continue to get intranasal S-ketamine for the first, as you can see, 74 days, twice a week for a month, once a week for a month, and then every other week. And as you see, the effect was fairly well-preserved during that follow-up period. The treatment was then discontinued, and people were followed for another eight weeks. And the effect seemed to be preserved for most people through that period of time. Now, I want to be careful to say I'm going to show you data later with continuation treatment that's going to indicate that some people will relapse after discontinuation, but also even with continued treatment with S-ketamine. So it's not the perfect treatment for everyone. But at least for many people, it seems to maintain that effect. The next is the first registration trial. This is the so-called TRANSFORM-1 trial. And this was a fixed dose of either 56 or 84 milligrams compared to placebo. There's sort of a unique twist to this trial, though, that I think it's important to highlight. And that is the FDA required that both the active treatment, the S-ketamine groups and the placebo group be started on a new antidepressant medication. And so that created a pretty high bar for S-ketamine treatment in this regard. And as you can see in the control condition, I don't want to call it just a placebo condition because there was an active antidepressant medication change at that point, you can see that there was a moderate response in the placebo group. Now, the primary outcome in this study was for the 84 milligram dose. And the reality is it did not reach statistical significance. It's a relatively modestly sized study that was non-significant. However, I mean, it was close. The P was about 0.08, but it did not achieve significance. So the secondary analyses, for example, of the 56 milligrams per day dose really couldn't be really couldn't be accepted as legitimate data. But I will say in this study, the 56 milligrams per day dose was, in fact, effective. It was statistically significantly better than placebo, but pretty modest effect overall. Or excuse me, modest difference overall for this particular treatment. I do want to highlight, however, the amount of benefit that we see that we saw at day two. This is 24 hours, which is about nine points in the isketamine treatment conditions and about 18 points at the end of day 28. It'll be important as we go forward. And so the first study was a negative trial. It was not considered supportive of the indication. Then we move on to the TRANSFORM-2 trial. And this was a flexibly dosed study of either 56 or 84 milligrams. About a third of patients by the end of the study were on 56 and about two thirds on 84 milligrams. and this was a positive study. Again, the design, it's the same. The new antidepressant medication was started at the beginning. There was a moderate level of placebo effect, but a stronger effect and overall more robust effect in the esketamine treatment condition. Again, pointing out, in this particular case, about eight points of change at day 2, 24 hours after the first treatment, and about 20 points of change by day 28. So pretty robust effects both acutely and over time, and more so than the placebo condition or control condition, which of course, included a new antidepressant medication. Now, that was the first so-called registration trial, the first trial that was submitted to the FDA to support the indication. This is the second trial. This is the so-called sustain one trial, and this is a maintenance treatment study. It took esketamine responders from previous trials, so people who had done well with esketamine previously, and randomly assigned patients to either continuation of the active esketamine or continuation of placebo. The relapse criteria are shown to you in the upper right, two weeks of elevated Madras scores, the Montgomery-Gillisburg Depression Rating Scale scores, or hospitalization for worsening of depression or serious suicidal ideation or attempt. And across the way, you can see here in the responders, there was a better effect of continuation treatment than discontinuation after the initial optimization phase. Now, I will say that we're showing a moderate level of relapse even in the continuation phase here, but that doesn't necessarily mean that people continued with depression. Many of these people continued to receive esketamine and in fact, improved after that. These are in the esketamine remitters, which is peculiar. These are the folks who got completely well or close to well as we typically get with esketamine treatment. And as you can see, the remitters didn't do quite as well, and particularly after that first six months. The reason for that actually is probably because the number of people who stayed in the study after the first six months was relatively small and diminished over time. Those hash marks that you see across the lines at the top are people who dropped out of the study because that happens in longitudinal studies all the time. And also a lot of people dropped out. And once you get to relatively small numbers, the data can get kind of wonky and it's kind of hard to interpret that. So I've looked primarily at the first six months or so of data and the two graphs actually look fairly similar to each other in that regard. But still overall, it appears that continuation of esketamine would be effective. Now, in terms of what I discussed earlier, many people who relapsed would then respond again, would actually get better with continuation treatment with esketamine. I think it's illustrated in this study. This is the so-called SUSTAIN-2 trial. Again, this is a study where people rolled over from previous trials and continued into the continuation phase. And overall, you can see that the antidepressant benefit of people who had previously responded reasonably well to esketamine was preserved. So people were maintained reasonably well in an ongoing way. As you will see occasional relapses in patients, and we do this clinically, we have an esketamine treatment clinic. We treat patients long-term, some of them long-term with esketamine, some will relapse but then recover that effect with continuation of treatment. But some concerns about long-term treatment come out of the literature with regard to toxic effects of drugs that block the NMDA receptor, and that would be primarily fencyclidine or PCP and ketamine. And the two issues, first of all, are either interstitial or ulcerative cystitis. And so there was some concern about even twice a week or once a week, would that cause an increased frequency of cystitis? There were five cases or 0.6% of patients who developed cystitis in the trial. We actually had one at my side at UAB in Alabama. So there were a few patients, but as you can see, the rate is pretty low. We also used a scale called the Bladder Pain Interstitial Cystitis Symptom Score. I never heard of that scale before we did the study, but the BPIC-SS was evaluated at two thresholds, a score of greater than 18 or a score of greater than 30. So that's moderate or severe or more severe symptoms. And as you can see, the rate of bladder symptoms was really quite low. And again, probably what we would expect to see in the general population. But some patients did develop bladder discomfort. It's not really pain, it's really more discomfort measured by that scale. The second issue relates to Olney's lesions. And Olney's lesions, the technical term for it is NMDA receptor antagonist neurotoxicity. This is a kind of brain toxicity that was first observed by John Olney in animals that were given relatively high doses in relatively frequent doses of NMDA receptor antagonists. So that would include fencyclidine or ketamine. Now, and so one of the concerns, and by the way, that was also subsequently seen in people who are regular abusers of either fencyclidine or ketamine. So people were using ketamine, for example, daily or almost every day. So there was some concern about whether there would be some adverse cognitive effects in patients. The bottom line with it is the esketamine treated patients showed improvement in cognitive functioning and stable cognition in all domains. And you can see the three areas that were measured below reaction time, verbal learning and memory and executive function with one caveat, and that is patients over age 65 actually had a very mild decrease in reaction time while they were being treated with active ketamine. And it didn't seem to be associated with other adverse effects, but that was something that was observed in the study. What I'm showing you here is the effects on working memory for the Cogstate computerized test battery. Down is improvement on this particular scale. So you can see that with a blue arrow on the right. And as you can see, as would be expected with improvement of depression, there was also improvement of cognitive function. So depressed patients often have some degree of cognitive impairment in areas like reaction time and working memory. And if you can see the working memory function as an example, improved and really normalized in those patients. So there was not evidence of significant cognitive impairment in patients treated very long-term in these trials. Now let me transition at this point and talk about ketamine and S-ketamine effects in suicidal major depression or major depression with suicidal ideation. And I would refer you first to a paper published by Sam Wilkinson at Yale that is a meta-analysis using individual patient level data. This is a meta-analysis of 10 studies and it evaluated two scale items that were rated in those studies, either the Madras item 10, this is the suicide item on the Madras scale or the item three on the Hamilton rating scale for depression or HAMD, that's also the suicide item. And as you can see, combining all the data, there seemed to be a significant and fairly robust effect of ketamine, certainly greater than either a placebo control, a saline control in the ketamine studies or midazolam treatment. We'll talk briefly about midazolam treatment. So midazolam was used as a comparator in a study in this particular meta-analysis. And as you can see, ketamine produced a greater effect on suicidal ideation as measured by those two items. And there were 10 studies that were reviewed there and those kinds of studies supported the push for the indication for esketamine for major depression with suicidal ideation. And this is a paper by Carla Canuso who was the medical director of this particular project. Carla works for Janssen. And in this particular study, this particular study that we participated in as a trial site included patients with major depression with imminent risk for suicide. These are folks who were going to be hospitalized for depression and they were randomly assigned to either intranasal placebo or intranasal esketamine. And their antidepressant treatment was changed at the same time. So the placebo treated patients weren't treated only with placebo, just like in the previous studies that we talked about. Patients were started on a new antidepressant or augmentation strategy. They were followed for about a month and then we had some follow-up after that, but the esketamine was stopped in that regard. It's interesting here that the primary focus in this trial, even though these are depressed patients with suicidal ideation, was on the depression, not simply on the suicidal ideation. And the reason for that is just the presumption that depressed people who are suicidal who come into the hospital and immediately have their treatment changed actually show pretty rapid improvement as a rule in their suicidal ideation. So investigators in the study didn't necessarily expect that there was gonna be a significant difference in suicidal ideation per se, but that there might be a significant benefit of esketamine treatment on depressive symptoms. So the focus here was primarily on depression. This shows you the outcome of that study. The top just shows you the first couple of days. Day one is just four hours post-dose and day two is 24 hours after the dose. As you can see, there's a significantly greater effect of esketamine treatment in that first 24 hours in the active treatment condition compared to the control condition. And again, it's not technically a classic placebo control because an antidepressant medication was started at that time. You can see the overall data, the one month data and the bottom graphic, which shows that there's a pretty robust effect of esketamine initially, but there's also benefit in the control condition. Those patients got better and continue to get better and the lines sort of gradually approximated with each other, which is sort of what we would expect. Really what we're seeing here is sort of an acceleration of the antidepressant response with esketamine relative to what we would eventually achieve with an antidepressant medication alone. Now, obviously that has potential benefit with depressed patients who are hospitalized for suicidal ideation, because theoretically they can get out of hospital quicker. And I'll talk about the kind of pros and cons and some of the problems that exist with that as we go forward. Keep in mind also that this was not a treatment-resistant sample. And so the effect was really quite robust. As you can see, about 20 points of change within the first three days or so. So there was a pretty big change with the Montgomery-Ausberg scale. So about 18 points at day two and 25 points by the end of the study. So pretty significant change in that regard. The second study is the ASPIRE-1 study on the left. As you can see, the data look pretty similar to the previous one, a little bit more of a placebo effect. And this was a significant study against supporting the benefit. And then we have the ASPIRE-2 study on the right-hand side. This was a non-significant trial, but you can see that the difference here is primarily the effect of placebo. So placebo has a little bit more robust of a response in that regard. But the drug effect is about the same. As you can see, about 15 points by day two with each of these and overall effect across the course of the study of about 25 points. So this is gonna be significant as we go forward and talk about some of the controversies about this. As you can see, the drug effect with intranasal ascetamine is relatively similar depending on the population. Less of an effect, a little bit less of an effect initially in the TRD sample, more robust effect in patients with MDD with suicidal ideation. Now, I wanna go next to the data from the Carla Canusto study on suicidal ideation per se. This looked at the Modris Item 10. And what I'm illustrating for you is the Modris Item 10 score of four to six. This would be moderate to severe suicidal ideation. So the question is when you start people who are significantly suicidal, what happens to them over time or what happens to their suicidal ideation over time? Part of the good news here, as you can see in the control condition is the fact that control patients are going from severe to mild or no suicidal ideation fairly quickly. As you can see, 42% of patients at day one, which is after the dosing of ascetamine were already better and 58% by day two, which indicates that going into hospital and having a change in treatment does benefit these patients. You see 10% by day 25. Ascetamine produced a greater effect at day one. So that's that four hours post-dose. So a greater immediate effect but there were no significant differences after that. So day two, even though it was a pretty substantial reduction in the ascetamine patients, this was not statistically significant. And by day 25, you can see that the lines are very close to each other. So some evidence of benefit, a greater benefit of ascetamine treatment relative to the control condition by day one, which was reduced in subsequent follow-up visits. Now that led to this sort of unusual language here. So the treatment resistant depression language is pretty straightforward in the FDA approval but the FDA approval for a depression with suicidal ideation reads depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. So again, there's not a claim in the indication that there's a greater effect, a significantly greater effect on SI although there was in that first day of treatment. The indication here is specifically for depression. We saw at least some evidence for an acceleration of that effect. Let me talk briefly about side effects and really focus on dissociation as a side effect. You may know that ketamine is a dissociative anesthetic which means people experience dissociation reactions which can, for some people can be pretty unpleasant although most people tolerate it pretty well. As you can see both 56 and 84 milligrams dose produce significant dissociation. Other side effects include nausea, vertigo, vomiting, occasional elevation in blood pressure. There were some patients that were treated with antihypertensive medications along the way. We did not have any patients that require treatment in our experience in the clinical trials or in our clinical experience but we do keep metoprolol in our clinic in case a patient does have elevations in blood pressure. Dissociation is described by patients in various ways. Really the most common thing that we see is a sensation of floating. So people feel sort of disconnected from the chair underneath them but they can feel disconnected in other ways from body parts or from their body. They can feel like they're floating outside of their body or from body parts like arms and legs or from the environment around them. Their vision can be distorted. There can be altered colors or sounds and altered time perception. There can be a lot of things that are associated with what is referred to as dissociation. Occasionally people can be kind of dysphoric with this but we prep patients pretty well and we find that patients tolerate this actually reasonably well. I will talk more about the dissociation events in just a moment. I do want to mention serious adverse events that occurred in all the clinical trials that I've talked about before and others that were done. There were three suicides that occurred either four, 12 or 20 days after the last esketamine dose. And all of those were in esketamine treated patients. What appears to be the case, all of those patients had improved with esketamine. And the concern here is of course that their depression started coming back after stopping esketamine and they committed suicide in that situation. Well, we're dealing with pretty highly suicidal patients. Excuse me. There was one motorcycle accident 26 hours after the last esketamine dose, one sudden death five days after the last dose and one MI six days after the last dose. All of those occurred in esketamine treated patients but all of those occurred in situations where the esketamine would have already cleared completely from the system. So it doesn't appear to be the case that esketamine was necessarily the causal factor. It's just odd and sort of peculiar and maybe a bit concerning that all of these deaths occurred in patients that had previously been treated with esketamine. There are other serious adverse events are listed below from three of the trials that were done in the development program. As you can see, there were relatively few significant adverse events in that regard. Now, as far as dissociation and this comes from that SUSTAIN-2 trial that I mentioned earlier, you can see that the standard measure, the CADS scale here, which is a measure of dissociation was modestly high, moderately high in the beginning and declined with repeated doses. So you can expect that dissociation is gonna gradually improve with continued treatment. And it's what our patients described to us is that they have really minimal dissociative symptoms after about the first month or so of active treatment. This is how esketamine is typically used. Of course, this is the brand name is Spravato. It's given in 28 milligram spray bottles. As you can see, the patient's head is reclined at 45 degrees and they spray it, one spray in each nostril. The 56 milligrams dose is two of these spray devices and the 84 milligram dose is three of the devices. The induction phase is typically twice a week for the first month. Now, we take a pause at that point and see if patients are responding reasonably well. If patients are not responding, we typically stop the treatment after the first month of the induction phase. Then there is once a week for four weeks, that's the maintenance phase. And then in the continuation phase, which is nine weeks and after, we can go to every other week and we try to taper patients down. And we find that some patients can taper off and other patients don't seem to be able to do that. And so we have found really the majority of our patients that we've had in our esketamine clinic have required ongoing treatment with some frequency going forward. And we're continuing to taper those off. And so in some sense, conceptually, this is similar to what we would see with ECT. You give a course of ECT until people respond and then you reduce the frequency of treatments and then continue to try to reduce that to take patients off. But the folks that we're seeing typically are very highly treatment resistant. And so we're not surprised that we're not able to step people completely off of the treatment altogether. Now let's talk about concerns that were raised. So first of all, I will point out this website. This is Kaiser Health News. It's from the Kaiser Health System and perfectly reasonable, legitimate site. And they ran an article which we think was the first in this sequence that was entitled FDA Overlook Red Flags in Drugmakers Testing of New Depression Medicine. And then of course, in the internet echo chamber that was immediately picked up by lots of other sites and just basically reproduced verbatim or almost verbatim. And so if your patients go on the internet and read about Spravato or esketamine, they're probably gonna see some of these websites because it was reproduced in several different places. Now, if you read this title, it reads like the FDA, at least it reads to me, like the FDA overlooked something in their approval of esketamine as a treatment. Meaning to me that the FDA was sort of negligent in their review. So let's look at those red flags briefly and kind of talk about each one of them. So one of the things that was highlighted as a red flag was that esketamine failed to achieve a rapid response. So one of the indications under the breakthrough status. Then we see IV ketamine on the right, excuse me, on the left. And as you can see, the Montgomery-Osborn Depression Rating Scale score 10.5 points initially, this is by day four, as of the second infusion. Again, this is the data from the paper by Jas Singh and a total of 18 points by the end of the two weeks. I compare that against erpiprazole on the right, which only had three points of change the first week, 6.5 points of change by the second week. And a total of nine points of change by the end of the study. So pretty clearly, IV ketamine produced a much more robust effect and a much more rapid effect than in this particular case, erpiprazole. I then will show you the intranasal esketamine data. And as you can see, eight points of change at day two, this is 24 hours. By day eight, about the same eight points. And by the end of the study, a total of about 20 points of change. Now, again, remember, this doesn't show as big an effect relative to placebo as the IV ketamine, but this is not a true placebo condition, right? This is a saline treatment plus an antidepressant medication change. So in fact, I would suggest that this does show a pretty rapid response relative to other augmentation strategies. And by the end of the study or into treatment, there was a very large overall effect. I don't think I agree that there is no rapid response. Now, there isn't a huge amount of separation from the control condition, but for the reasons that we talked about before. And this, by the way, just highlights the similar kinds of results that we see with brexiprazole in the augmentation trials in treatment-resistant depression. So again, about three points of change in the first week about eight points or so change over the six-week treatment period. So again, I would suggest it probably does represent a rapid response. The second red flag was that the treatment-resistant depression was a bit different for this trial than for previous augmentation trials in the past. So usually in the past, it was two antidepressants of different classes. So people have had to have been exposed to two antidepressants. In this particular study, it was two antidepressant medications of any kind. So it could be the same class or it could be different classes of medications. So that was different. And this was a somewhat legitimate concern. However, the concern in that regard is that this might have selected out a less treatment-resistant sample, right? So that's what was expressed by one of the red flags, so to speak. However, I would argue that that probably would lend more toward a type 2 error than a type 1 error. And it's more of a type 2 error that is accepting the null hypothesis, because we would expect that the placebo effect might be greater in less treatment-resistant patients. More treatment-resistant patients do tend to have less of a placebo response. And in fact, we did see a moderately robust placebo effect, as I've already shown in the presentation to this point. But again, that made it more difficult for esketamine, not less difficult for esketamine, to separate from placebo, which is what was critical in that regard. Next, were the trials included in the approval by the FDA? Recall that I remember that we would usually be accustomed to two acute treatment trials to support approval of a medication. And in this particular case, because of the breakthrough status or breakthrough indication, this was one acute treatment study and one maintenance study that were used to support the approval of the medication. However, I would point out a couple of different things. First of all, I don't really have any serious question at this point that IV ketamine itself is pretty effective. But I also would point out that there were a number of studies that were done in the development of esketamine along the way, which include both the studies for treatment-resistant depression and for major depressive disorder with suicidal ideation. And the majority of them were positive trials. There were some negative trials, but that was not because of the overall effect. I would suggest that's not because of the overall effectiveness of the medication. The magnitude of the effect appeared to be very similar across studies, either within the TRD sample or in the MDDSI sample. But the placebo effect did vary somewhat between studies, and that probably accounts for the difference here. The next concern was no safety trials beyond 60 weeks. Honestly, I don't know any medication that came to market with safety trials beyond 60 weeks. There is a concern here about the possibility of adverse effects in very long-term treatment. Now, I just heard Dr. Carla Canuso present data on the very long-term follow-up study up to four years last week, and there don't seem to be any surprises in that study. We participated in that study as well. So that's the good news. However, there hadn't been a huge number of people in those studies, and I'll come back to that in just a couple of minutes. There were three suicides in the trial, all in the active condition, which is, of course, concerning, except for the fact, of course, that these were all suicides that occurred after patients had completed the study and probably when depression was getting worse. And then the possibility of withdrawal reactions, which is legitimate. There were no withdrawal data that were presented in the FDA application that I'm aware of. There was a withdrawal study, the one I mentioned to you earlier. The SUSTAIN-2 trial. And you can see that there are some significant side effects or significant effects that did occur. However, I'll point out a couple of things about them. So in the red, I highlight significant or frequent, relatively frequent adverse effects that either increased over the follow-up period after discontinuation of esketamine or were stable, and only one, fatigue, lethargy, lack of energy that seemed to go down over that time. And the ones that I've highlighted here, including that dysphoric mood depression, really suggest that what we're observing here is a return of depressive symptoms across this follow-up period, not a classic withdrawal symptom. And that'll be important in terms of another aspect of the critique of ketamine that we'll see going forward. There was another paper that was published around the same time. This is a paper by Eric Turner, who was on the FDA panel reviewing the data. This was an editorial in Lancet Psychiatry that he published. And this presents seven concerns that he had about efficacy and FDA approval of esketamine. The first two here that I've listed for you, we've already talked about definition of TRD and the rapid response. And this is really more that there was not a huge effect between active treatment and placebo within the first week or so. The third was a concern that the randomized withdrawal trial was restricted to patients who had previously responded to esketamine. It seems like an unusual concern on his part that the placebo patients were not put into the randomized withdrawal trial, because I don't know of any randomized withdrawal trials that included placebo patients, but that was a concern of his. It would have been interesting data, curious data, but I think was not necessary. He suggested that the results of the randomized withdrawal trial were not robust. And this was an observation that the studies could be affected by the removal of one or more sites from the data. This is specifically pointing to a site in Poland, which recruited a lot of participants apparently, in which all the patients in the placebo condition or the control condition relapsed in the continuation period. And that was a concern. The FDA evaluated the site and audited the site and did not raise any red flags on their part in terms of the quality of the data from that study. And if you think about it, whenever you do a study across many centers, which the study was done, that's the SUSTAIN-1 trial, you study across multiple centers, you're going to have some centers that are going to have a lower rate of relapse on a placebo and some centers with a higher rate of relapse on the placebo. And if you take the ones with higher rates out, you take more of those out, you will in fact diminish the effect. By definition, you're going to do that. But the reality is this is sort of a distribution across sites. And it's kind of a reverse cherry picking. For example, you could take out sites that had lower rates of relapse, take that out, and it would increase the relative effect, which we would refer to as cherry picking. But this complaint or concern is more like reverse cherry picking, and that is coming in after the fact and taking data out of the study. The next item, I think, is a significant one. It's one of the non-significant trials involved older patients, and it raises concerns about esketamines' effectiveness in the older population. And I think that's a legitimate concern, and I'll mention that again as we go forward. And I'll just highlight these last two. The mean drug-placebo difference in the positive short-term trial was only four points, and the drug-placebo difference was equal to or less than olanzapine, fluoxetine, erpiprazole, and quetiapine. And as we can see, the overall effect of the esketamine was quite robust in there, but the drug-placebo or drug-control conditions were relatively similar. I mean, they were close. There was a separation between them, but there was a pretty significant control response. But again, remember that this was a control condition in which patients had an active medication added to their treatment regimen. The next issue that I'd like to raise is one that was identified by Nolan Williams, who works in Allen Schatzberg, who did the study in Allen Schatzberg's group at Stanford. And this is an observation of the attenuation of antidepressant effects of ketamine by blocking opioid receptors. And this is giving naltrexone along with ketamine at the same time. And I'll show you the data supporting that in a moment. This relates to the fact that ketamine, in fact, does bind to opioid receptors. As you can see, it has very strong binding to the NMDA receptor, but the two splice variants of the opioid receptor, the muopioid receptor 1 and 2, there's a fairly significant binding, particularly to the muopioid receptor type 2. It's still about 50-fold less potent than the NMDA receptor, but that's not a trivial amount of binding to that particular receptor. And so the question that they raised, which is perfectly legitimate, is whether the binding to the muopioid receptor could account for the beneficial effects seen with ketamine. Now, I show you the delta opioid receptor and the capoid opioid receptor data here as well. And by the way, remember that for binding studies, lower numbers are more potent. This is 0.25 nanomolar for the NMDA receptor. This was a very small trial. This was, again, another crossover trial in a double-blind fashion. So people were treated with either ketamine alone at the bottom or ketamine plus naltrexone at the top, and they were crossed over to the other condition and then evaluated. As you can see from this graphic, if you look at the instances in which patients were treated with ketamine alone, as opposed to ketamine plus naltrexone, which, of course, antagonizes or blocks the muopioid receptor, the naltrexone appears to diminish the overall effect. You see the total sample on the left, and only the responders, those who responded to ketamine, on the right-hand side. And again, those were the ones who responded in the ketamine plus placebo condition. So it does appear to be the case that if patients are taking naltrexone and blocking the muopioid receptor, that that diminishes the effect. The question is, is the binding of ketamine to the muopioid receptor, which we know that it does to some degree, is that what's producing the antidepressant benefit? The first thing I will point out is the fact that the half-life for ketamine is relatively short at three hours. The half-life of norketamine is about 12 hours. Now, the data online range anywhere from one hour to 12 hours, but the fact is we know that norketamine is a muopioid receptor antagonist. That is, it blocks the muopioid receptor completely. Or not completely, but it blocks the muopioid receptor. So it would not be contributing to this effect in any way. And the reality is, because of the short half-life of ketamine, the fact that we continue to see a beneficial effect between doses is different than what we would see with a muopioid receptor agonist treatment. So heroin, for example, or oxycodone. So although people feel better when they're using heroin or oxycodone and may feel less depressed, that effect goes away when the heroin or oxycodone is metabolized away. So there are no sustained or between-dose antidepressant benefits from typical mu agonists. The second is that we haven't really seen any evidence, either in the clinical trials or practice yet, of drug-seeking or craving in patients. Theoretically possible that people have had these experiences and haven't told us, but we certainly have not seen this clinically or in clinical trials. There does not appear to be significant drug withdrawal effects. Remember that table that I showed you earlier? These are not typical drug withdrawal effects in the way that you would expect with a muopioid agonist. The next issue is an interesting one from a physiological standpoint, and that is that while ketamine does bind to the muopioid receptor, it does not act like an agonist. That is, it does not down-regulate the sensitivity of the muopioid receptor. If anything, it enhances the sensitivity of the receptor. So it makes the receptor more sensitive or more responsive. And this is, again, from basic laboratory data. And that indicates that it's acting as an allosteric modulator of the muopioid receptor, not as a pure agonist or antagonist. But that's important in terms of what's going on here. I mean, why does naltrexone block the effect? Why does ketamine need to bind to the NMDA receptor to produce the effect? Or why does binding to the muopioid receptor enhance the blockade of the NMDA receptor? And the answer to that, as best as I can tell, and we went back through the literature and tried to study this as much as possible to understand this, and that is that there is at least some evidence of an interaction between the muopioid receptor and the NMDA receptor, such that the effects of ketamine on the muopioid receptor appears to sort of potentiate or enhance the effect at the NMDA receptor. The data on this are pretty limited, but there does appear to be some interaction between mu and NMDA that could explain this effect. What doesn't appear to be happening, however, as I mentioned earlier, is that ketamine is producing activation of the muopioid receptor, and by doing that, it's producing its antidepressant benefit. I think the story is more complicated than that. Let me talk about what I consider to be substantive concerns at this point. Number one, in the clinical trials, people were included that had no more than five adequate antidepressant trials previously. That's important because we know that there are people that are going into ketamine treatment that have had more than five prior treatment failures. Now, does that mean it's not going to be effective in those patients? The answer to that is no, I don't think we know that. But I think what that does mean is that we'll just have to accumulate experience with that, and we really do need to have data that kind of speaks to the effectiveness of esketamine in more advanced resistant depression. Secondly, the number of patients included in the reported long-term studies is relatively small. Now, as I mentioned, there is another long-term study or another set of data coming out on very long-term treatment, but that has not been published at this point. But even with that, the number of people who've been exposed to esketamine over months or years at a time is still relatively low, at least in the clinical trials data. And so there could be some surprises that could come out of long-term treatment with esketamine. I doubt that that's going to be the case, but it's always possible that that will be the case. There's an issue with unblinding that I'm going to talk about with this. It's very difficult, it's really impossible to blind participants to whether or not they've received esketamine. And then there's some practical issues that I want to close with in just a couple of minutes. So let's talk about unblinding. So basically unblinding means that patients who get the active treatment experience some side effects, and for that reason, they know they're getting the active treatment. And that was addressed, I think, pretty effectively by this study by James Murrow and colleagues published a while back. And this is a comparison of ketamine with midazolam, so IV midazolam, which of course is a benzodiazepine, which produces a side effect profile that in some ways is similar to ketamine. And as you can see in this particular graphic, the overall effect of IV ketamine acutely was greater than midazolam, and that effect was maintained over seven days even after a single infusion. So it appears to be the case if you kind of deal with that functional unblinding issue, that ketamine still seems to be better than the control conditions or more robust in control. Now, there are practical issues. So for example, there's the FDA-mandated risk evaluation and mitigation strategy, and this requires the clinic and the provider, the physician or nurse practitioner, and the patient, all to be registered in the RIMS program, and there are requirements for doing that, which is a bit cumbersome. This treatment requires nurse or CMA monitoring, so you have to have medical personnel observing the patient. We have also – which, by the way, to back up for a second, many psychiatrists don't necessarily have a nurse or CMA working in their office, and so they would have to hire someone to do that. There are substantial prior authorization hurdles, and particularly in our state in Alabama, it's very hard to get this treatment authorized for patients, although we are treating patients at this point. There are significant issues with reimbursement, and that is the average reimbursement to physicians providing the treatment is still relatively low. There are ways of getting around that, and I'm happy to talk about that in the question-and-answer period, but reimbursement for this is not robust, so there's not a strong, at least financial incentive, for clinics to start providing the treatment. There are issues with drug handling and accountability. This is a controlled substance and obviously has to be handled correctly and documented, and everything has to be done in a proper way. There's also the issue of bundled payments for the MDDSI indication. Hospitals are typically paid a set rate for the treatment of patients with MDDSI, and there isn't, at least in our state and nowhere that I know of in the country – there may be some places, but we haven't heard of any – where additional payment would be given by the managed care company for Spravato treatment while patients are in the hospital. But in terms of the MDDSI indication, there's a more serious issue, which is the post-discharge treatment. Once the patient comes out of hospital, who is going to actually provide the Spravato treatment for those patients? Our clinic is full all the time. Right now, I have 30 patients waiting for esketamine treatment. We certainly do not have space to absorb patients being discharged from hospital. It might not be the case all over the country, but I think it probably would be the case in most places, that there may not be a place for patients to receive their post-discharge follow-up treatment. Remember, the treatment is twice a week for a month in suicidal patients. I want to very briefly talk about the fact that there are new GABA glutamate-targeting compounds, particularly compounds that are targeting the NMDA receptor. That includes the R enantiomer of ketamine and a selective NMDA receptor subunit antagonist, one in particular, the MIJ-A21 compound that Novartis is developing currently. There are other compounds going down the line. D-cycloserine is being used in a trial in bipolar depression, which interacts with a glycine site on the NMDA receptor. Dextromethorphan is being tested with both quinidine and bupropion, which elevate dextromethorphan levels, ostensibly causing dextromethorphan to bind to NMDA receptors. There is the mTORC1 activator compound. There are also compounds that target other glutamate receptors that interact with this same system. There's a lot of action, so to speak, in this space, a lot of treatments in development. However, there have already been a number of pretty spectacular failures of NMDA receptor-targeting medications. I encourage these trials to go forward, and I think this is a very exciting time. But we may not find other compounds other than ketamine that, simply by blocking the NMDA receptor or interacting with the NMDA receptor in some other way, may be effective. It may or may not be the case. We'll just have to wait and see. But as we've already discussed, ketamine does have some special properties. It's metabolized to norketamine, again, an ampa agonist. It also interacts with the muopioid receptor, which may enhance the effect of NMDA receptor blockade. I think we have to just stay tuned to see if these medications make it forward. Now, to move forward to the indications that are not FDA-approved, there is a study from Carlo Zarate's lab that indicates that ketamine does seem to work in bipolar depression. As you can see, a pretty robust effect on the Montgomery-Osborn Depression Rating Scale score, but actually a very large effect, about 20 points. And so ketamine does seem to work in bipolar depression, but there are really not enough trials, and there are no longer-term follow-up studies with repeated dosing, at least that I know of, that supports the use of ketamine in bipolar depression. There's also a recent paper by Dr. Fetter and colleagues published just this year in PTSD patients. This is, again, a relatively small study, six ketamine or midazolam infusions. Ketamine is in the orange color, midazolam is in green. And as you can see in the CAHPS-5, it's a measure of PTSD symptoms. The CAHPS-5 total score, significantly greater effect of ketamine. And the subscale scores indicating a broad effect of ketamine in PTSD symptoms. Now, again, this is not FDA-approved. We definitely need more data, but it's certainly very promising and pretty exciting as a potential treatment for PTSD. Now, the next issue is, where do we put this ketamine? Obviously, this would be a treatment that would come along after typical trials of SSRIs, SNRIs, perhaps other antidepressant medications, combination therapies with atypical antipsychotics or bupropion. But we put this in line ahead of RT-MS and ECT, and it's sort of asterisk beside the MAOI treatment here. The reason in our state that we do this, and I think this is true in other parts of the country, is that managed care will not pay for esketamine treatment in patients who have previously had RT-MS or ECT and have failed those treatments, those treatments were not effective for those patients. So for practical reasons, we put esketamine in this place in our treatment algorithm. It is perfectly reasonable and legitimate to think of putting it after RT-MS or ECT or even VNS if you want to, but it really depends on kind of the local environment and whether managed care companies will be willing to pay for the treatment under those circumstances. Now, MAOIs are pretty effective in treatment-resistant depressed patients. We actually continue the treatment moving along with esketamine patients and have had some really good successes in patients with partial response to esketamine put on MAOIs. So using esketamine doesn't prevent you from using an MAOI, and I use MAOIs actually quite frequently. So in conclusion, ketamine is effective for TRD and MDDSI, seems to be reasonably effective. Intranasal esketamine has been approved in both indications, although the trials data are mixed and somewhat controversial. Our own experience with both IV and intranasal esketamine has been positive overall, but the clinical use is pretty challenging, and so far we think most of our patients are going to require longer-term treatment. There are reimbursement challenges for esketamine, for TRD, and I don't know of a good reimbursement path yet for MDDSI. Thank you all very much.

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