Hello, everybody. My name is John Crystal. I'm the chair of the Department of Psychiatry at Yale University, and I want to welcome you to today's webinar, Rapid Acting Antidepressants, New Treatments, New Hope, and New Insights into the Brain. This is part of the Emerging Topics webinar series of the American Psychiatric Association, and you can stay up to date on important topics through connecting to the APA Emerging Topics webinar series. They're free for all APA members, and they're presented by specialists across the field on a monthly basis, and they cover a range of diverse and pertinent topics, and they provide a chance to interact with peers and subject matter experts. This webinar today offers physician CME credits, so I hope you'll take advantage of those. And we've set aside around a half hour for questions. The questions will come at the end, because all questions are submitted through the question and answer control on the Zoom, so that you can just push that button, go to questions and answers, and submit your questions that way. I won't be able to see the questions until I complete the presentation, so I hope you'll understand that we'll have to save the questions until the end, and then we should have plenty of time to get through most of the questions. Before I begin the scientific part of my presentation, let me acknowledge my financial interests. My principal financial interest is that I'm a co-founder of a company called Freedom Biosciences, which is trying to develop, you might say, next generation versions of ketamine and psychedelic treatments. I consult to a variety of companies, and I have stock in a few, or stock or options. My main other financial interest is that Yale University has a share of patents for intranasal ketamine that were licensed to Janssen Pharmaceuticals and served as the foundation for Spravato. The work that I'm going to be talking about today is really teamwork, and the people who you see here were really critically important contributors and leaders, some of the data that I'm going to share with you today. Going back to the first ketamine study, which I collaborated with Dennis Charney and Rob Berman, and also acknowledging the important collaborations with my late colleague, Ron Duman, who sadly passed away a few years ago, but who in his life did some of the initial groundbreaking work figuring out some of the mechanisms through which ketamine might produce its remarkable therapeutic effects, and also acknowledge a variety of funding sources for the work. Today, I'm going to begin by talking about what are the challenges that we face with the current generation of antidepressants, what led us to test ketamine, and then to talk about ketamine as a treatment. Lastly, I'll talk about what we're learning about the mechanisms through which ketamine produces its antidepressant effects, and how that may shed light on a next generation of treatments. Let's start with the challenge, which is something that I think every psychiatrist who treats patients in day-to-day practice knows, which is antidepressants are less effective for many, many patients than we had hoped for. Some of the most important data in relation to this comes from the NIMH STAR-D study, which suggested that too few patients remit on their initial antidepressant trial. In those who do not remit, and then are treated with other kinds of antidepressants, either being switched to those antidepressants or having other medications from the standard group of medications that we use to treat depression, that the effects of those treatments are too incremental, leaving about a third of patients who haven't remitted at the end of a year of treatments. The effects of antidepressants, if you're lucky enough to remit, are too slow. It can take on average, in the STAR-D trial, two months to achieve remission. In that time, many patients become discouraged and stop taking the medications, and that's a huge problem when we're trying to help people get better. And one of the things that was most frustrating to me in clinical practice, but which is often not appreciated, is that antidepressant response is too unstable, and particularly so in the patients who have treatment-resistant symptoms. In the STAR-D trial, the more treatment-resistant patients, those that were in steps three and four of the study, three-quarters of those patients relapsed within a year of responding to a treatment. And the magnitude of the protective effect of staying on a standard antidepressant is probably less than many of us were taught when we were in training. In a study that we did, a secondary analysis of drug discontinuation studies of duloxetine and fluoxetine, staying on those medications was only 12% better in terms of rate of relapse than placebo. And then there are some of the hidden limitations of these treatments, which might not be evident in clinical practice. My colleague, Relitsa Gorgueva, and I, with Craig Mallincott from Lilly, did a secondary analysis of the duloxetine and fluoxetine clinical trials. And this trajectory of analysis identified one main trajectory for placebo and two trajectories for patients treated with duloxetine and fluoxetine. Three-quarters of the patients who were given randomized, excuse me, to duloxetine and fluoxetine did better than one would predict based on placebo. So here is placebo, here is duloxetine, fluoxetine, and you can see that these patients, three-quarters of them, are better off on drug than they would have been placebo. So the medications really work. On the other hand, about a quarter of the patients in the study treated with duloxetine and fluoxetine were worse off on drug than we would have predicted that they would have been had they gotten placebo. So there are some people who are getting medications and who are non-responders where the medication is really not helping them and maybe impeding their recovery. And that quality has not really had the presence in our clinical discourse that perhaps it should. So how did we get to testing ketamine in depression? Well, the work done at Yale by Dennis Charney, George Henninger, Pedro Delgado, clearly implicated serotonin and norepinephrine signaling in the antidepressant efficacy of these drugs. In other words, if you depleted the body of serotonin and therefore, tryptophan and therefore serotonin, you could produce relapse in patients treated with SSRIs. If you depleted the body of catecholamines using a drug called AMPT, you could produce depressive relapse in patients treated with norepinephrine reuptake inhibitors like duloxetine and bupropion. And if you depleted the body of both serotonin and norepinephrine, then you could produce relapse in patients treated with both of those drugs. So there's really not a debate that serotonin or norepinephrine are relevant to the efficacy of drugs that block those reuptake sites. However, if you take healthy people and you deplete them of monoamines, the data were a little different, at least in our hands. We couldn't produce depressive relapse by combining tryptophan depletion and alpha-methylparatyrosine. And this suggested that perhaps depression wasn't simply monoamine deficits or deficits in ongoing monoamine signaling. And this was a profound challenge to a very simple view of what the monoamine hypotheses of depression might be telling us. And so we began to think a little differently about the biology of depression. We shifted away from a very narrow view about what depression was, which was an illness of the serotonin and norepinephrine neurons, and focused more broadly, having a broader view of the biology and one that would encompass the intrinsic signaling of the cortex and limbic system. Unlike the biology of the monoamine neurons, the main transmitters used for neuronal communication in the cortex and limbic system are glutamate and GABA. And so we decided we would probe the integrity of glutamate synaptic signaling in depressed patients using a drug that I'd been using to study the neurobiology of schizophrenia. This was the dissociative anesthetic medication ketamine, which blocks a particular subtype of glutamate receptor called the NMDA subtype of glutamate receptor or NMDA receptor. And what we found is probably something that by now you're familiar with, which is that ketamine produced expected behavioral effects in depressed patients, a transient mild psychosis, transient state of euphoria, dissociative symptoms with a very similar time course. And these symptoms went away basically completely. But several hours later, after getting ketamine, these patients started to report feeling a little better, a little reduction in the Hamilton depression rating scale. And by 24 hours, some patients reported no symptoms more than mild. And in fact, some of the patients felt like they had returned completely to their usual non-depressed self. This was a shocking finding when we observed it. And it was equally shocking for the audiences that we initially presented these results to way back in 1997. But study after study reported the same thing. And we're now very confident that this sort of trajectory is pretty typical when you study groups of patients with treatment-resistant symptoms of depression. Now, this study was not treatment-resistant depression, but subsequent studies by Carlo Serrati and others clearly demonstrated its efficacy in treatment-resistant symptoms of depression. So rather than me going into a huge detail, I thought it would be useful for you to hear from someone who went through ketamine treatment themselves and what it was like. I've been in treatment pretty consistently since I was in middle school. I had a combination of different styles of therapy as well as different medications. And my functioning was pretty high, but I tended to still really struggle with these feelings of just profound aloneness and despair. And about three years ago, I kind of slipped into what I would consider a very severe depression. I'm receiving intravenous ketamine. And the day after I received my first treatment, I felt like myself. But what was strange, it was immediate. The next day I woke up and I felt I could internalize good things about myself. I could feel positive feelings. I could feel feelings in general. The gratitude I have for this treatment. And so thankful I live in an area where there's such innovation happening. I didn't even know this was possible. Well, I apologize a little bit for the commercial at the end, but I think you get the feeling about how many people who get a rapid acting antidepressant like ketamine can experience the clinical improvement as a kind of transformative event in their lives. The version of ketamine that we used initially is the racemic ketamine, the mixture of the two mirror image molecules, R-ketamine and S-ketamine. And we gave it then and is still most commonly administered as a dose of 0.5 milligrams per kilogram intravenously over 40 minutes. The side effects, as I mentioned, are dissociation, which mostly we manage by preparing people for what they're about to experience, supporting them during the ketamine infusion, and then debriefing at the end of the day. And that's usually good enough, although sometimes if a person is having severe anxiety related to the ketamine administration, you can give a little Ativan to help with that. Increase in blood pressure, ketamine usually increases blood pressure by about 15 millimeters of mercury. And you can manage that if you need to by pre-treating with a propranolol, a beta-adrenergic receptor antagonist. And then nausea and vomiting. Ketamine can cause nausea. It can be a little bit like the spins if you've had too much alcohol to drink. And we can manage that with pre-treatment with Undansetron, a serotonin 3 receptor antagonist. So those are the most common side effects that we see and that we manage in the clinic. S-ketamine, which is the drug Spravato, developed by Janssen Pharmaceuticals. It is administered intranasally. Usually people start at a dose of 56 milligrams, which is one 28 milligram inhaler of ketamine. Insufflator, it's also called. And you put one insufflator per nostril when you are giving 56 milligrams. And the typical effective dose for most people is 84 milligrams, which involves giving three of these insufflations spaced five minutes apart. Overall, the effectiveness of ketamine and S-ketamine seem pretty similar. Now, one of the most important things to understand about giving ketamine as a treatment in the way in which we think about it, and most programs use it, is that it is administered with decreasing frequency over time, which often plateaus at some point. And so what I mean by that is, whether you're getting S-ketamine or you're getting ketamine, we usually start with 12 twice a week treatments for at least the first month. And then if you're doing well, we try spacing the treatments apart by about a weekly. And then if you do well with that for at least a month, then if you're going to continue with ketamine or S-ketamine, we can space it out farther and farther. About three quarters of patients, maybe a little higher, get to every two weeks. The majority of patients in our clinic are maintained about every three weeks. And about 30% of patients who are maintained on a longer term basis on ketamine or S-ketamine are maintained on a frequency of once per month or less. In some ways, this is a little bit reminiscent of maintenance, ECT maintenance treatment, but this is a very tolerated procedure for people on a long-term basis. And also I would add that we do not see evidence of tolerance to the therapeutic effects of ketamine. So by keeping the doses spaced as far apart as possible, it just seems like we're able to prevent the development of tolerance to ketamine. One of the most striking things that emerged from the long-term S-ketamine studies, bravado studies conducted by Janssen, is just how effective S-ketamine is in preventing relapse of depression. So remember when you compare treatment-resistant patients maintained over time from the STAR-D study, that relapse rate was about 75% over a year. Here in the randomized discontinuation study, patients who had responded to the combination of a new antidepressant medication plus S-ketamine were randomized to either stay on that combination or to drop the S-ketamine. The patients who dropped the S-ketamine had a relapse rate at one year of about 57.6%. The patients who maintained the S-ketamine had a relapse rate of 25%. So I told you that the comparison of duloxetine-fluoxetine to placebo was about a 12% difference. Here we're comparing combination therapy to actual antidepressant treatment, not placebo, and still we're doubling the magnitude of the protective effect. This is really a very striking and important observation. Another theme in ketamine research has been the description of its anti-suicide effects, and while the actual studies of changing suicide behavior and ideation in suicidal patients did not show a significant reduction in suicide, that was partly attributed to an extremely intensive psychosocial support offered to all the patients in the study, and a testimony about how useful and effective psychosocial management of suicidal ideation and suicidal risk can be in patients who are getting an otherwise effective antidepressant treatment. But in studies that had a lower intensity of psychosocial supports, this kind of finding emerges over and over again, which is midazolam produces a little bit of a reduction in suicidal ideation, but ketamine produces a longer and sustained reduction in suicidal ideation. In this study by Greenberg et al, Grunebaum, excuse me, et al, when patients were switched from midazolam to ketamine, they did just as well. So being on midazolam did not prevent them from later responding to ketamine. Another question that comes up with long-term ketamine treatment is, is it safe on cognition? Are there risks or toxic effects of ketamine? We know that if you're a recreational user of ketamine or its cousin, fencyclidine, that you can get significant persisting cognitive impairments. But when you space out the doses and use the low doses that we use therapeutically, you do not see detrimental effects. And this is one of the longest and largest, well, it's a small, but one of the longest studies conducted by Sam Wilkinson at Yale, showing that patients followed for a median of 331 days who received ketamine treatment for their depression, there's really no detectable, meaningful effect on cognition. One of the big concerns that we have has to do with the growing recreational use of ketamine. Ketamine is clearly an abused substance. When people have unlimited access to ketamine outside of the clinic setting, they are at risk for misusing ketamine. They tend to use it more frequently than prescribed, and they tend to use doses that are larger than are prescribed. And so among people who have ad libitum access to ketamine for treatment, we have seen, I have seen patients who have developed ketamine use disorders. And in our society, beginning around the time of the collection of the phase three data, we've seen a significant rise in recreational use of ketamine in the United States. Another area of real interest is what the breadth of the application of ketamine might be. So at the moment, it is approved by the FDA for two indications, treatment-resistant depression, as ketamine is approved, for treatment-resistant depression symptoms, and also for depression in the context of elevated suicide risk. There are studies that support its utility in adolescent major depression, bipolar depression, depression with psychotic features. And then there are some intriguing preliminary data in post-traumatic stress disorder, borderline personality disorder, social anxiety disorder. So refractory mood and anxiety disorders may be an area that its application might be considered. This is the largest study of ketamine in post-traumatic stress disorder to date, and I show it as a kind of cautionary note. This is a study of patients who are randomized to a placebo, saline placebo, ketamine 0.2 milligrams per kilogram, a dose that's typically below the level that needed to produce antidepressant activity, and ketamine 0.5 milligrams per kilogram, which is the standard antidepressant dose. They got two treatments for a week, for four weeks, and then they were followed up afterwards. And what you can see here is PTSD symptoms, and overall, the ketamine-by-time interaction was not significant, even though secondary analyses post-hoc suggested that the 0.5 milligrams produced some initial reduction in PTSD symptoms, and the 0.2 milligram dose was, there was a hint of an anti-PTSD effect at the end of the study. In contrast, there was a significant ketamine-by-time interaction in terms of depression severity, and that's attributable to the usual antidepressant effects of ketamine, which were evident both at the beginning and at the end of the study, and overall. So, what I've shown you so far is evidence that ketamine and esketamine are very hopeful treatments. They can produce rapid relief. That's particularly important for acute settings, severe symptoms, and I think this is an important and meaningful advance. It's also very important that they're helpful for patients who have not responded to other treatments, and in our shop, it is moving up the treatment algorithm where we now use it ahead of electroconvulsive therapy. And I've also shown you evidence that when used on a longer-term basis and administered intermittently, it can powerfully protect against relapse. All right, so let's switch now to thinking a little bit about how ketamine might work. When Time Magazine did its article on the antidepressant effects of ketamine, they called it the anti-antidepressant, and I like that because it really makes you think, well, what could be so different about ketamine that enables it to work so rapidly and so effectively? And here, we need to learn some new biology. So let's focus on the glutamate synapse. And what you can see here about the glutamate synapse is that you have a glutamate nerve terminal which has synaptic vesicles that lead to the release of glutamate into the synaptic space. When glutamate is released, it can bind to three different classes of receptors, kinate, AMPA, NMDA, and metabotropic. Of these glutamate receptors, the target for ketamine is the NMDA glutamate receptor. So we've been learning a lot about glutamate abnormalities in depression, and what I'm going to do now is to highlight two particular kinds of abnormalities. And just to set the stage, this is a GABA neuron in red. It's inhibiting the activity of a glutamate axon terminal in blue. In other words, releasing GABA, binding to a GABA receptor. This glutamate neuron has the ability to release glutamate, and that glutamate may bind to various glutamate receptors. Here, I'm focusing on the AMPA subtype of glutamate receptor. And this structure, postsynaptic, is on a dendritic spine, the place on the receiving end where glutamate synapses are made. So what we see in depression is reduced synaptic strength. And this measurement in patients with depression and PTSD echoes what is seen in animal studies of stress effects. And so I'm going to describe to you what I mean by reduced synaptic strength. Normally, when a molecule of glutamate is released, it stimulates metabolic activity in that postsynaptic neuron. We believe, based on animal studies, that when the stressed animals, that some of the AMPA receptors are internalized, which make them less available to be stimulated by glutamate. And so what we measure in depressed patients is that for each molecule of glutamate that's released, we see a smaller metabolic response. And we can make that measurement using a technique called carbon-13 magnetic resonance spectroscopy, which uses a non-radioactive isotopic label to enable us to measure the levels of these various metabolites in nerve cells. We can do this in people in vivo. The other major change that we see in depressed patients is reduced synaptic density. And we have a radio tracer that binds to a protein on these synaptic vesicles, which is called this SV2A protein, or synaptic vesicle 2A protein. And so what we see is reductions in ligand binding, suggestive of reductions in synaptic density. Why do we think these are important changes? Because they affect the way that neural networks in the cortex and limbic system communicate. They make network activity noisy, and they make circuits less plastic. They are also associated with functional impairments. They can impair top-down control, the executive control of emotion, our ability to self-regulate emotion. They change the way in which we process rewards and punishments in our surrounding, and they restrict our behavioral flexibility. So we do think that the reduction in synaptic connectivity and synaptic efficacy are important for mood dysregulation. So how are we going to fix that? So let's talk a little bit about what ketamine is actually doing. In order to understand that, you need to understand something very important about the antidepressant effects of ketamine, which is that at the dose that we tend to study, ketamine tends to be, for most people, both antidepressant and dissociative. If you cut the dose of ketamine by half, it's not very dissociative, but it is not an effective antidepressant. And if you double the dose from 0.5 milligram per kilogram to one milligram, you don't increase the antidepressant efficacy, but you get more dissociation. So antidepressant efficacy is not directly correlated with the degree of dissociation, but rather dissociation is, when it occurs following ketamine, is telling you that you're about in the right ballpark to see antidepressant effects. If you double the dose of ketamine again and take it into the anesthetic range, then interestingly enough, ketamine is not an effective antidepressant. So there's a very narrow window between a dose that's too low, a dose that's about right, a dose that's about right, but associated with a lot more side effects, and a dose that's ineffective. It's a very narrow dose range. So what happens if you give a stressed animal ketamine? What happens in terms of the molecular biology of the brain? What you see is that during the period, and this is the work of superimposing the work of my late colleague, Ron Duman, onto the data that we collected in our clinical trial. So what you see is that at the time points where the acute effects are occurring, but before the antidepressant effects emerge, you see that a lot of the signatures of genes that are induced are of genes that are associated with neuronal activation. However, when the antidepressant effects are emerging, then you see increased expression of genes associated with new synapses. Synapsin 1 and SV2A, this SV2A is the protein that we target in our PET scans, and then other postsynaptic genes. So that pattern of gene expression makes a lot of sense once you understand that ketamine is rapidly regrowing dendritic spines and synapses. Here is a dendrite, a distal dendrite, and you see all the arrows are marking dendritic spines, the places where synapses are made. If you chronically stress the animals, you see that the number of spines has gone down quite a bit and then 24 hours after ketamine, you see that the number of spines has grown quite a bit. What's really interesting is that the onset of, the early onset of antidepressants affects the ketamine in the animal models seem like they happen just before the dendritic spines are regrown, but the persistence of the antidepressant effects produced by ketamine seems to depend almost entirely on the persisting integrity of the regrown synapses, the regrown dendritic spines, and that's a finding from the work of the laboratory of Conor Liston at Cornell. So how does ketamine cause the regrowth of dendritic spines? There are actually several theories. I only have time today to run through one set of hypotheses. If you want to see lots more detail, you can, there's a webinar where I'm interviewed by Tim Ferriss. There's also a paper coming out in the upcoming issue of neuropsychopharmacology reviews that will get into some of the alternative models as well. But basically in the Duman model, ketamine is blocking the activation. In other words, glutamate, NMDA glutamate receptors are activating receptors and ketamine is blocking the activation of GABA neurons. This reduces GABA release and causes or enables increased levels of glutamate to be released. The released glutamate is stimulating AMPA glutamate receptors, and there's some new data to suggest that NMDA glutamate receptors are also stimulated. And the combined activation of AMPA and NMDA glutamate receptors re-potentiates the glutamate synapses by driving AMPA receptors to the synapse, restoring synaptic efficacy. And then elevations in brain-derived neurotrophic factor, a nerve growth factor, stimulating TRACB receptors and activating downstream signaling activates a key intermediary called mTORC1, which drives the growth of dendritic spines. So there is a path from disinhibition, increased glutamate receptor stimulation transiently, and then this regrowth of dendritic spines. So how well does this model derived from animal stress models apply to humans with major depression treated with ketamine? So first, using the carbon-13 magnetic resonance spectroscopy technique that I described earlier, we can directly measure ketamine increases in cortical glutamate levels. Second, using a positron emission tomography, and I should say this study was led by Chadi Abdullah. Second, using a positron emission technique, which indirectly measures glutamate release, we could show that ketamine increases in glutamate release in depressed patients correlated with the magnitude of their antidepressant response. And this is a study led by Irina Estrelis at Yale. What about synaptic regrowth? And here we relied heavily on the PET tracer for the SV2A protein, which gives us an indirect measure of synaptic density. You see that in three groups of patients, there are 12 healthy controls and six patients, I'm sorry, nine healthy controls, and six patients with normal synaptic density or deficits in synaptic density in red. That what you saw was that ketamine across three different regions of the brain did not produce significant increases or decreases, but instead highly variable effects in the healthy subjects or the mildly depressed patients without synaptic deficits. However, in that subgroup of depressed patients who before ketamine had synaptic deficits, we could see signs of synaptic, rapid synaptic regrowth. And what was interesting is that the magnitude of their synaptic regrowth correlated with the magnitude of their clinical improvement. In contrast, in patients who had no, who didn't have any baseline synaptic deficits, the degree of increased synaptic density after ketamine had no relationship to clinical response, if anything, went the other way. And I'm just gonna focus on the right-hand side here, which tells us a little something about the relationship between dissociative symptoms produced by ketamine, that's the Y-axis, and the magnitude of their clinical improvement, that's towards the left. So if you had synaptic deficits and you got dissociated, the higher, more dissociative symptoms you got, the more clinical improvement. So in that group of patients, there was a relationship between getting effective dose and clinical response. However, if you didn't have synaptic deficits, again, the more dissociation you got, if anything, the worse off you were in terms of a milder or lesser antidepressant response. And so once again, dissociation does not equal, efficacy does not appear to contribute to efficacy overall, but if you have synaptic deficits, it may be a sign that you got enough ketamine in your system to trigger the processes that produce synaptic regrowth and improvement in mood. Now, I mentioned that there were two signature deficits. One is the deficit in synaptic density or number, and the other one is the reduction in synaptic function. And here is a study from Carlo Serrati's group at the NIMH Intramural Research Program, showing that one way you could illustrate an increase in synaptic efficacy. What you see is that in healthy subjects, there's no difference between before ketamine in green and after ketamine in blue. This is the magnitude of a sensory evoked response. Essentially the same thing in depressed patients who are non-responders to ketamine, no real change either in the sensory evoked responses on the left or right side. However, if you're a responder to ketamine, you see before ketamine in green, after ketamine in blue, there's a clear enhancement in the amplitude of the evoked response suggestive of enhancement of synaptic efficacy. And there are other ways that you can look at synaptic efficacy. Here's another one from Chady Abdullah, was at Yale now at Baylor College of Medicine. And what Chady showed was that there were reductions in functional connectivity in depressed patients before they were given ketamine and 24 hours after ketamine, these deficits in functional connectivity went away, which may be a signature of enhanced synaptic connectivity as well. Now, one of the questions that comes up a lot is whether there are ways to enhance the efficacy of ketamine by combining it with a behavioral therapy. And I think there are some preliminary data to suggest that there are a couple of different ways that you could think about this question. Now, ketamine blocks NMDA glutamate receptors and NMDA glutamate receptors are key nodes in inducing neuroplasticity in the brain, remodeling circuit function in a more lasting ways. And so this can be harnessed by psychotherapies because if you activate memories that have been established that are maladaptive, such as a trauma memory in a person who has PTSD or a drug-related memory, like a memory of craving for alcohol in someone who has alcohol use disorder, if you activate those memories during ketamine infusion, there are some data to suggest that you can weaken alcohol cravings or weaken the emotional potency of trauma memories in a lasting way. Another strategy though, takes advantage of the fact that 24 hours after ketamine administration, there is a window of enhanced plasticity when synaptic efficacy and synaptic density are enhanced and people may be able to take advantage of that by combining ketamine treatment with a CBT or progressive exposure or other kinds of therapies. And I'm gonna show you one interesting piece of data again from Sam Wilkinson at Yale. And what Sam found is that you could not only increase the magnitude of the antidepressant effect, but increase the duration of the benefits produced by a single exposure to ketamine by combining it with cognitive behavioral therapy. And that's really very interesting. Another strategy to enhance the duration of antidepressant effects may be to combine it with a drug that inhibits a very specific target, mTORC1 in the brain. Now I mentioned that stimulation of mTORC1 at very high levels in the brain can block antidepressant effects of ketamine. But it turns out that if you give a very low dose of mTORC1 inhibition, as you might achieve with a low dose of oral rapamycin, then you see something very interesting. And what I'm showing you here is the result of a 20 patient study within subjects crossover study so that the same patients are given ketamine either by itself in red or in combination with rapamycin, the mTORC inhibitor in blue. And what you see is that there are little hints that maybe there are some benefits initially in terms of higher rates of clinical response and remission, but these are not significant. So really the acute response at 24 hours is not that different if you get ketamine with or without rapamycin. But you may remember that the duration of antidepressant effects is depending on the duration of the dendritic spines. And what you see is that at two weeks following that single injection, by that point, the response rate has fallen off from nearly 80% to 13%. And the remission rate has fallen off from about 50% to about 7%. But in the patients, when they got pretreated with rapamycin, the antidepressant effects of ketamine lasted a lot longer. And so it might be a strategy someday. This is something that a company called Freedom Biosciences is trying to explore to develop a combination therapies that have longer duration of efficacy. So how do we think that psychotherapy or medications might extend the duration of efficacy of the antidepressant effects of ketamine? Now, as you may recall, what I just said, which was that the duration of the antidepressant effects of ketamine is closely tied to the duration of the newly created synapses. And a key regulator of those synaptic densities are the microglia, the immune cells in the brain. When the microglia are activated in a pro-inflammatory way, they engulf and then eliminate synapses in the brain. It's possible that psychotherapies, by engaging experience-dependent neuroplasticity and engaging a potential trophic function of microglia can cause the newly created synapses to be protected rather than engulfed and eliminated. It's also possible that by giving an mTOR inhibitor, we're inactivating the inflammatory activity of microglia and preventing the newly regrown synapses from being engulfed and eliminated. So we can create the spines with ketamine and we might be able to preserve them through activity-dependent neuroplasticity and by pharmacologically inhibiting the microglia. So how does ketamine work? In people without synaptic deficits, there's some evidence that ketamine may interfere with the reconsolidation of maladaptive memories and that it can restore functional connectivity and neuroplasticity and that this capacity may promote the effectiveness of psychotherapies like CBT and reduce symptoms on their own. Additionally, in people with synaptic deficits, ketamine can restore structural connectivity and maintain antidepressant effects. What I've shown you for ketamine may apply to many other classes of medications. For example, ketamine seems to reduce its efficacy in part by inducing a surge in glutamate activity in the brain and a variety of other drugs do that, including the serotonin 2A agonist psychedelic drugs, GABA partial inverse agonist, AMPA kinds, drugs that facilitate the activation of AMPA glutamate receptors and mGluR2 antagonists, which inhibit feedback inhibition of glutamate nerve cells. These and other mechanisms may be explored as alternatives to ketamine or psychedelic drugs for the treatment of depression. But it's very interesting that psychedelic drugs like ketamine produce many converging downstream effects that may be suggesting of some common mechanisms in their antidepressant effects. Psychedelic drugs like psilocybin activate glutamate release and they can do that by binding to thalamocortical terminals and they can bind it by that, by binding to serotonin 2A receptors on the initial dendritic area proximal dendrites of cortical pyramidal neurons with the result of stimulating glutamate release and activating the downstream cascades that I mentioned earlier, including activation of mTOR. And here I'm just illustrating work from David Olson's group showing that you can grow out dendritic spines or neurites in neurons in cell culture. So in summary, what I've shown you is that the having a rapid acting antidepressant creates a variety of new clinical opportunities, particularly for patients with treatment resistant symptoms and that these new treatments, ketamine, S-ketamine, psychedelic drugs, and some other novel agents may be acting through a converging family of mechanisms of actions that shed new light and link in very direct ways to the underlying synaptic pathology associated with depression. And that ketamine and S-ketamine are now established treatments and there are a growing array of treatments that seem likely to follow in its footsteps. So at this point, I'm going to shut down my presentation slides and we can see if I can take some questions. Let me see, I believe it's full screen. All right, so I'm going to switch to the question and answer now. First, a question from one of our participants who said, is there any protocol for intravenous administration of ketamine? Yes, there are a variety of places where you can get the infusion strategy for ketamine. We use zero, as I mentioned, an intravenous infusion of 0.5 milligrams per kilogram, intravenously administered over 40 minutes, which has kind of become a kind of standard. It's not the only way in which that dose of ketamine can be administered. And I can direct you to some papers if you'd like. You can write to me at john.crystal at yale.edu. Have there been any trials of ketamine with sedation? What would people report if they had no recall of the session? Same for psychedelics. That's a great question. One of the things that we've learned is that many of the drugs that produce sedation, such as the benzodiazepines or barbiturates, prevent ketamine from causing, triggering the release of glutamate, even inhaled anesthetic medications do that as well. And those seem to attenuate the antidepressant effectiveness of ketamine. And so, for example, ketamine, when added to ECT, doesn't really seem to synergize, in part because even though people are administering low-dose ketamine, it doesn't seem to have its full antidepressant potency. That, to my knowledge, has not been tried with psychedelic drugs. Any thoughts about ketamine in transitional age use? My understanding is that there may be some questions about using ketamine at a time when the brain is still developing. I think that's a great question. There are concerns about giving ketamine, particularly early in life, like in infancy and in utero. I'm not aware of specific findings related to intermittent ketamine exposure in this way. It's very clear that ketamine used as a recreational drug can produce harmful effects, but you have to understand that some of these recreational uses of ketamine are using 100 times the therapeutic dose of ketamine, sometimes even more. And so the daily administration of 100 times the therapeutic dose of ketamine produces effects in the brain that are diametrically opposite to the effects of sporadic administration of the low dose. There's a randomized trial led by Michael Block and Jenny Dwyer, and those studies suggest that it can be effective for adolescents with major depression, particularly treatment-resistant symptoms. We're all really very concerned about adolescent suicide risk these days, and ketamine may be one path for urgently ill adolescents with treatment-resistant symptoms of depression, so something to consider. Do synaptic deficits measured with PET have any clinical correlates? I think that's a great question. So far, the main clinical correlates are very severe symptoms of depression and treatment resistance, but I wouldn't say that that's a very refined finding because we've only tested a small number of patients with depression using the SV2A tracer, but that's the way it has seemed to fall out so far. What are the clinical differences between S-ketamine and R-ketamine, and what about research is being done with R-ketamine? R-ketamine is the isomer of ketamine. S-ketamine is the S-isomer of ketamine. S-ketamine is the version of ketamine that is approved as spravato. A company called Perception Neuroscience is testing R-ketamine. Unfortunately, so far, the clinical trial with R-ketamine that was reported did not yield efficacy, but that's still, I'd say, early days for R-ketamine research. The next question is, how different is dextromethorphan from ketamine? Dextromethorphan is an NMDA glutamate receptor antagonist like ketamine, so it's a very low-potency NMDA receptor antagonist, and so you would have to give heroic doses of dextromethorphan to get an equivalent degree of NMDA receptor antagonism as one is achieving with the antidepressant dose of ketamine, and I'm not aware of studies that have tested a dose of dextromethorphan that high. For example, the amount of dextromethorphan in Iovelte is not likely to achieve the same degree of NMDA receptor antagonism as the antidepressant dose of ketamine, and that's consistent with the fact that people are not very dissociated on that medication, but there is a complication with dextromethorphan in that there are two groups of people in the population, rapid metabolizers and slow metabolizers. Rapid metabolizers accumulate, if you take very, very, very high doses of dextromethorphan, rapid metabolizers accumulate enough of a metabolite of dextromethorphan called dextrorphan to get some PCP-like effects, in other words, potent long-acting dissociative effects, which can be very distressing, and so it's not likely that dextromethorphan would be used on its own as a full-blown antidepressant. It's possible that the combination of dextromethorphan and quinidine, which protects people who are rapid metabolizers from getting overdosed, that's a possibility, but it's still early days. Where can we access protocols? There are a number of articles about the clinical implementation of ketamine and s-ketamine, and I'm happy to direct people if you want to write to me about it. Is training required to administer ketamine? In many medical centers, in order to be able to administer ketamine, you have to be credentialed in, what do you call it, for light anesthesia. It's good to get training for administering ketamine because then you have the advantage of seeing people reacting to ketamine and getting exposed to sub-anesthetic doses of ketamine. In terms of learning about the procedure of administering ketamine, it's something that anesthesiologists do very frequently, so even if there's not a ketamine clinic around you where you can get exposure to managing the sub-anesthetic ketamine effects, there are often other professionals who can help you to get that exposure. Should psychiatrists administering ketamine have experience with ketamines to optimally support experience with ketamine effects? I think you're asking, should I take ketamine if I'm going to administer it to patients? I'm not sure that that's necessary. I think you can kind of get a good sense of what patients are going through if you have an opportunity to be trained and to observe patients undergoing ketamine effects. Ketamine is best, ketamine administration is best done in a clinic under supervision. People can find the effects very disorienting or upsetting. Sometimes ketamine perceptual changes will be very benign, like watching the walls breathe in and out or having a feeling like your arms are growing longer or shorter. Sometimes the subjective effects, the dissociative or psychotic effects of ketamine can be upsetting. And some of those effects, examples would be somebody who feels like that their body organs are being replaced with machine parts or that they have somehow damaged their brain, that the effects they're experiencing are not due to the drug, but some fundamental change that they've gone through. And it's those people who really need the support of someone with them who knows what's going on, has experience in supporting people through it that can help to manage those symptoms. And if people are prepared for those effects in advance and you can remind them of it during the ketamine infusion, then they usually tolerate those. They understand what's happening and they know that the, and can trust you that the effects will go away once the drug wears off. A local ketamine expert says it is harmful to talk to patients at the end of the infusion. Is that true? Not to my knowledge. What is the most, what are most effective antidepressant drugs to use along with ketamine for the maintenance of its effects? That's a great question. So far, there are only two drugs that have been given along with ketamine to try to extend its effects. One, rapamycin, which I mentioned, and the other one, decycloserine, which really didn't work. There was an effort to give riluzole with ketamine to try to extend antidepressant effects and that didn't really work either. So they really don't have a good answer for that question, but it's a very good question. In terms of the dose of 0.5 milligrams over 40 minutes, what about how often to give it and for how long? So is there any evidence that three times a week is better than two times a week? I've been using it once a week and getting good results. So there was a study led by Jas Singh, which he conducted when he was at Janssen Pharmaceuticals, which compared three times a week ketamine to twice a week ketamine for patients with treatment-resistant depression. And in that study, there was no difference in efficacy in patients, excuse me, who were treated three times a week compared to patients who received ketamine only twice a week. And that was the basis for the clinical practice of not going beyond twice a week for treatment-resistant depression. However, patients vary in the duration of efficacy of their initial dose of ketamine. And so that some people will only get about three days of benefit from a single dose of ketamine. And as you saw from our rapamycin study, somewhere around 20% of patients will get about two weeks worth of efficacy from a single dose of ketamine. So the philosophy of many clinics is to give twice a week rather than once a week at the beginning of treatment in order to make sure that people don't experience a relapse between treatment sessions. So I wouldn't say that once a week is necessary. I mean, once a week is a bad practice. And I wouldn't say that three times a week is a bad practice. Generally speaking, we're giving ketamine enough to prevent people from relapsing in between infusion sessions. There's maybe a little bit of a different story for PTSD. There was a one study of ketamine for PTSD that used three times a week sessions. That was a study conducted by Adriana Fetter at Mount Sinai, Icahn School of Medicine in Mount Sinai. Three times a week was effective in her study. Twice a week ketamine was not effective in our study, but we don't know really whether we used a different, we studied a different group of patients. We studied a different, we had different outcome measures than they used in their study. So we're not entirely sure whether that accounts for the difference in the study. So generally people start at twice a week and that's, how do you choose between ketamine and serago? I'm not, Spravato, okay. You know, this is a really interesting, a really interesting, how do you choose between ketamine and Spravato? For many people, particularly in the United States, Spravato is covered by insurance and ketamine is not. And then the discussion ends right there. If people are paying out of pocket or can get reimbursed for ketamine and have the choice, the luxury of choosing between ketamine and Spravato, then it's in my experience, the most important driver of the choice is what they prefer. Some people would rather have Spravato and administer an intranasal medication and avoid the necessity for an intravenous line and avoiding a needle. In other words, others would prefer the intravenous route of administration because you have a little bit more control over the dosing. In other words, intravenous ketamine is dosed on a milligram by kilogram basis. Intranasal Spravato is dosed either at generally at 54, 56 or 84 milligrams. So there's a little bit less control, precise control of the dose. So in people who don't tolerate Spravato and don't get efficacy, don't tolerate 84 of Spravato and don't get efficacy at 56 milligrams, you can then fall back on intravenous ketamine because you can split the diverts with the intravenous dose. But otherwise, they seem to be very similar in terms of their efficacy. Is there data on combining ketamine or S-ketamine with TMS? I know someone's studying it. I don't think I've seen the data, but it's a really interesting question. In theory, it is something that might be possible that you could deliver TMS a day after ketamine or S-ketamine and get some benefit from that combination. I just don't have any experience with it myself. Can intravenous ketamine be used for bipolar depression? The answer is yes. There has been some concern about very infrequent reports with intravenous ketamine and with S-ketamine about mood cycling. We're not 100% sure that they can be attributed to the ketamine, but there is data to suggest that ketamine is still active when used in combination with commonly used mood stabilizers such as lithium, valproic acid, Depakote, or antipsychotic medications. So I think that the antidepressant effects of ketamine in bipolar depression seem to be very robust. If anything, they seem to have an onset that's even quicker in bipolar depression than in unipolar depression. Question, do we routinely pre-treat with Ondansetron in patients? We usually don't pre-treat at the first dose with Ondansetron because only a minority of patients have problems with the nausea produced by ketamine, but we definitely pre-treat with Ondansetron afterwards if a person has had any problem with that. Or if they say they're very sensitive to nausea and vomiting effects of drug, we have no reason not to pre-treat, but we would generally not want to block a side effect that wasn't present. Is there any data comparing ketamine with TMS? There has been one study, not very robustly designed study suggesting that ketamine was more effective than TMS in the kind of TMS used in that study. We all know that there are many different ways that TMS is being administered now. And so I would not want to conclude anything about whether some form of optimized TMS might be as good at, or maybe even better than ketamine. There is a growing data comparing ketamine and ECT and the studies kind of go back and forth. Some studies, meta-analyses suggest that ECT is more effective than ketamine. Other analyses suggested that ketamine was more effective than TMS. There is some, there's a large PCORI study that's going to come out that will, I think, help to answer this question. And I look forward to seeing those data become available. Oh, yeah, okay. Any data on ketamine and OCD? Yeah, there are two studies, two main studies, a Yale study led by Michael Block and a study by Carolyn Rodriguez now at Stanford. Her data were a little bit positive. Our data were a little bit negative. By negative, I mean that the patients with OCD got persisting antidepressant effects from ketamine, but only a transient reduction in OCD symptoms. The effects were more similar in an initial study by Carolyn Rodriguez, but I'm not sure that she's been able to replicate that finding because I haven't seen this really going forward. Can I talk about the studies in borderline personality disorder? Sure. So borderline personality disorder, which we all know is a cluster of symptoms which is not well-named. It's not people who live on borders. It's people who have emotional and social dysregulation. And borderline personality disorders are a form of a treatment-resistant mood disorder. And so what you see in retrospective studies are some signs of a clinical benefit. A pilot study was just published from our group led by Sarah Feinberg in neuropsychopharmacology. And in this small study, there was a reduction in antidepressant effect. I'm sorry, an anti-suicide effect that just missed significance. There was evidence of improvements in social and occupational function, but there were not significant reductions in a number of core symptoms that we would associate with a borderline personality disorder. So it's kind of a work in progress, particularly when we are... Most patients with borderline personality disorder would be treated with some kind of psychotherapy like DBT and questions about whether ketamine might be optimally combined with these kinds of treatments for synergistic benefits in borderline personality. So I would say that there's evidence of some benefits, but it's still a work in progress. Okay. I think these are all the questions that I see. These are great questions, by the way. Nope. There is a company that sends ketamine by mail. Risky, of course. Any concern that this might lead to bad outcomes that might limit the potential use of ketamine properly? Yeah, exactly. I mean, I think we should all be concerned about ketamine use at home. And I don't wanna judge whatever company it is that you're referring to, but we have a lot of concerns about the safety of ketamine used at home, whether it would be used in the right way, whether people are getting doses that are not adequately supervised. There was a report that people who've been getting take-home ketamine, not from that company, but from their various prescribers have been associated with surprisingly high rates of misuse of the drug. So we have to be very careful about taking the abuse liability of ketamine seriously. And companies that want to develop take-home ketamine treatments, the burden is on them to show that their practice is safe and that people are not misusing the ketamine. Do I have any experience with using the oral troches of ketamine? I do not personally have experience using the troches. Again, from what I was saying before, the critical thing is not whether it's a pill, whether you inject it under the skin, whether you inject it into the muscle, whether you inject it into your vein, whether you inhale it into your lungs or insufflate it into your sinuses. The critical question is whether you're getting the right level of drug in the plasma. And I haven't seen any data yet with the oral doses that suggest that they're achieving the therapeutic blood levels. I'll tell you what is a cause of some concern to me, which is that a typical oral troche size is about 100 milligrams of ketamine. Remember that our typical intravenous doses for a 70 kilogram person would be 35 milligrams. So if patients dissolve the troches, extracted the ketamine and gave themselves an intravenous push of 100 milligrams, that would be sending them into the anesthetic zone. And that would be a very scary thing if there was not adequate medical support around them. So we have to be very careful about how ketamine is treated. And we want to make sure that if a person is getting a version of ketamine to use at home, that there are adequate protections in place. What about the comparison of ketamine with psilocybin and MDMA for the treatment of PTSD, end of life anxiety in cancer patients? So there are different, I'll start with the palliative care population and then I'll work back to the comparison to the drugs. Scott Irwin, who's a psychiatrist now at Cedars-Sinai, when he was at UCSD did some lovely studies opening the discussion about efficacy of ketamine treatments for mood disturbance, end of life anxiety, and particularly pain. So chronic pain, neuropathic pain is a severe problem in palliative care context, often a problem because you can't give enough opiate because people are extremely tolerant. You can't give enough opiate to treat the pain in a population that is suffering quite a bit. Ketamine turns out to have some effects. It's efficacious for treating pain in opiate tolerant patients. It may actually reduce the expression of tolerance to opiates when used intermittently over time. And so from a pain perspective, it's very good to use in palliative care settings. And in addition, it works for, is helpful for mood disturbance and anxiety for some patients in those contexts. I'm not sure that it's working in the same way that psilocybin is working in palliative care settings. The effect of, there is a similar antidepressant effect and anti-anxiety effect of psilocybin in palliative care related depression and anxiety. However, it's important to know that psilocybin produces a very profound cognitive experience which many people have described as extremely meaningful and useful for the kinds of existential crises that people are experiencing as they are in the palliative phase of their care. And that kind of cognitive effect of psilocybin, I'm not sure, is produced in the same way by ketamine. When we think of the treatment now to switch gears from palliative care settings, end of life settings to post-traumatic stress disorder, I showed you data that ketamine is antidepressant in people with a treatment resistant post-traumatic stress disorder. MDMA has been described as being rapidly effective in post-traumatic stress disorder. There's less data in a randomized controlled trials with psilocybin, so you can't really, I can't really speak to that yet. But certainly MDMA in the MAPS phase three trial looked pretty impressive in terms of its efficacy for PTSD. And they have closed their second phase three trial for PTSD. And of the three drugs, psilocybin, MDMA, and ketamine, it seems to be the most likely to be the first drug that the FDA approved for PTSD if all things go as they are. It's not that psilocybin can't work for PTSD. It's just that I don't think we have the data to really be able to draw any conclusions yet. Do you have any upper limit on how long you would keep a patient on regular ketamine maintenance treatments? No, we don't. We've treated patients for five, six years in intermittent ketamine exposures. Most of those patients are patients who tolerated very well and whose treatments are spaced as far apart as we can, you know, three weeks, four weeks. And they also tend to be patients who when we stopped the ketamine had relapses of their depression, that were rescued by reinstating ketamine treatment. So I would say, I don't know about lifetime treatment, but on the order of five years or so, we have enough experience in our institute. Pierre Blier in Montreal has a similar experience that supports that long-term kind of treatment. How often have you seen laryngeal spasm in ketamine patients? I've personally infused about a thousand doses of ketamine. Well, it's probably more than that now. I've never seen it. So I suspect that it can happen somewhere, someone, but I've never seen it. We've never had it in our ketamine clinic. And we're doing about 30 insufflations or infusions let's say on average in a week. And we've been doing it now for a couple of years. So I don't think they've seen any laryngeal spasm either. It may be that it is more of a risk at anesthetic doses than at sub-anesthetic doses, but just haven't seen it. All right. These have been really great questions. And we've used basically our time. So I guess we should start moving to our final announcements, our final announcements. Our final announcements are how to claim credit. So really, thank you all for the wonderful questions. I really appreciated the thoughtful exchange that we've had about ketamine and esketamine. You'll receive a follow-up email within about an hour of this webinar. Click the Access button when you get it, and then you can access your certificate. Click on the My Courses tab in the upper right of the screen, then click on Completed Activities. And lastly, click the Certificate button so that you can get the PDF and your well-deserved CME credit for the course. So thank you so much for coming today. Thank you for your wonderful questions. If you have any additional questions, you can send your email to educme at psych.org. If you want some referrals to papers that describe the clinical practice of ketamine or esketamine, you can send me an email as well. All right, so listen, wonderful to see you all. Thanks so much.

ketamine

esketamine

rapid-acting antidepressants

treatment-resistant depression

intravenous administration

intranasal administration

NMDA glutamate receptors

dendritic spines

bipolar depression

PTSD

safety and tolerability

psychotherapies