Episode Transcript
[00:00:00] Speaker A: Inadequately treated depression shortens life expectancy by 10 years. We don't think about robbing people of 10 years of their life. Why aren't we treating it like cancer?
[00:00:16] Speaker B: John, thank you so much for agreeing to be on the show with me. I'm, I'm so looking forward to this conversation.
[00:00:21] Speaker A: Rand, it's a pleasure to be here.
[00:00:23] Speaker B: John, I'm going to give you a moment to kind of share your background here, but for the audience. John is the chair of the department of psychiatry over at Yale New Haven Hospital. Your professor psychiat at Yale. You also do some really incredible work with the VA on ptsd. John, maybe like just give me a thumbnail sketch of your career and the kind of like milestones along the way.
[00:00:41] Speaker A: So I went to college at the University of Chicago and I came to Yale for medical school and psychiatry residency. Joined the faculty in 1988 and have been on the faculty ever since. And as you point out, I'm now chair of the department of psychiatry here at Yale. My career has been about the neurobiology and treatment of psychiatric disorders and particularly the idea that if we deeply understood the impact of these psychiatric disorders on the brain, that it might lead us to new kinds of treatments. And you know, back in the 90s, that kind of approach led us to identify the rapid antidepressant effects of ketamine, which is now been developed by Johnson and Johnson as bravado.
[00:01:26] Speaker B: Taking behind the scenes there, I think one of your many accolades or things credited to you as being one of the earliest researchers in ketamine for depression. How did you stumble upon that? This is almost 20 years ago, right?
[00:01:37] Speaker A: Yeah, it's older than that, actually. We first reported the finding in 1997, so that's quite a bit older than. And published a paper in 2000, so more than 25 years ago. But the idea was, and I think it's really an important idea broadly as we try to think about what's gonna take us to new and impactful treatments, which is that I started out studying ketamine in relation to schizophrenia, which when I started my work in schizophrenia, people advised me that it was the graveyard of academic careers because research had kind of gotten boxed in in thinking about the biology of schizophrenia and focused on dopamine hyperactivity, which is a part of the biology of schizophrenia, a part that we can actually treat. But the biology of schizophrenia is much more complex. And so when I started my career, you know, in the late 1980s, I thought, well, I, I don't want to follow the same path that everybody else is following, because the field's kind of boxed in. I thought, well, let's take a fresh look at it, focusing on the biology of the cerebral cortex and how the cerebral cortex communicates. And that led me to shift the focus of my early work in schizophrenia from a focus on dopamine to a broader focus that encompassed glutamate, the main information highway of the cerebral cortex that governs our thoughts and actions, and the limbic system that regulates our emotional responses to the world. And the key implication of that was that it led me to try to find ways of studying glutamate biology in people. In 1988, we didn't have PET scans that we could study glutamate or some of these spectroscopy techniques that we now use, or even functional magnetic resonance imaging. So what the idea that we started out with was that we could study the glutamate system in relation to cognitive function and schizophrenia by giving a drug that blocked one of the receptors for glutamate in the brain, called the NMDA glutamate receptor. And the drug that I decided to use in studying that was ketamine, which happens to block the NMDA glutamate receptor. Ketamine had been an anesthetic medication in the 1960s, sometimes used for pain. And we were interested in it because, in studies going back to the late 1950s, ketamine's cousin phencyclidine or angel dust. But phencyclidine had been used given to people who described something like schizophrenia, like symptoms. And so we went back and revisited that work and kind of rigorously identified some parallels between the acute behavioral effects of ketamine and cognitive effects of ketamine to what we see in schizophrenia. And we've pursued that line of research from all the way from, you know, late 80s, early 90s, all the way up to the present, in trying to identify alternatives to dopamine blocking and dopamine receptor blocking antipsychotics, that's, say, 1990. Flash ahead, 1995 or so, my colleague and mentor, Dr. Dennis Charney, who's now the dean of the Icahn School of Medicine in New York, we would get together several times a week at the end of the day and talk science. And. And his work had been on what you might call the monoamine hypothesis of depression. How do chemicals like norepinephrine, serotonin and dopamine, how are they involved in the biology and the treatment of depression? And he had led a series of studies that I was kind of peripherally involved in where you could deplete the norepinephrine system or the serotonin system or both in healthy people. Now, the simple monoamine hypothesis of depression would have predicted that if you depleted all these chemical systems, you would have mimicked the biology of depression. But in fact, healthy people didn't get depressed when those systems were depleted. And that meant for us that maybe depression didn't live in the cells in the, in the brain that release norepinephrine and serotonin. But maybe serotonin and norepinephrine were systems that drugs like Prozac or Zoloft or bupropion, Wellbutrin or others modulated in order to tune and restore function to higher order systems in the brain. In other words, what if depression didn't live in these primitive cells in the brain stem and midbrain, but was a disorder of the cerebral cortex and limbic system, A different disorder than schizophrenia, but represented by some of the same structures in the brain. And we thought, well, how are we going to study that? And we had this kind of epiphany that we could use ketamine to characterize the nature of glutamate, synaptic and abnormalities in depression as we had done in schizophrenia. It just so happened that when we did that, we identified for the first time this rapid antidepressant effect in depressed patients. And it was so striking and unprecedented, at least for us, that we weren't even sure it was real. And our incredulity was mirrored by the reactions that we got when we presented the findings to people in the field. What was remarkable was that we, I think it was maybe May of 1997, we first presented the results. It was kind of shockingly bimodal, the reaction. Some people thought, this is the funniest thing I've seen in a long time. It can't possibly be real. And then other people came up to me at the end of the presentation and said things like, okay, I want to start this in my clinical practice. I said, I think I showed in that first presentation maybe data on seven patients or eight patients. And I said, this is ultra, ultra experimental. Hold your horses. It's not ready for prime time. In fact, if you think about it, we, we presented our data in 1997. Esketamine was approved in 2019. That's 22 years right between when, when we reported the results. Then Johnson and Johnson under really visionary leadership by Hussein Imanji, who is the head of neuroscience at Johnson and Johnson at that Time to see ES ketamine through to FDA approval.
[00:08:50] Speaker B: Take me back to those early days where you were almost in disbelief. Others were in disbelief, like, like, how do you then take the step forward to like, to bring more clarity to the findings?
[00:09:02] Speaker A: So I think that there were two pivotal things that happened. One was that in 2006, Carlo Cerrati, Dennis Charney, Hussein Manji and their collaborators, then at the National Institute of Mental Health intramural research program, replicated the findings in a little bit larger sample, still small, but generated exactly the same profile of clinical response that we had seen.
Whereas our study, we took whoever volunteered for the study, in their study, they explicitly studied people who had failed multiple trials of antidepressant medication. So our study kind of identified the rapid acting part. The replication study identified the efficacy for antidepressant resistant symptoms of depression. And these two studies juxtaposed to each other, I think, had a big, big impact on how people thought about it. The second key turning point for me was a paper from my late colleagues Ron Duman and George Agajanian, friends of mine here at Yale and colleagues. They did a basic animal research study which also turned the field of neuroscience on its head. They were trying to figure out how could a drug like ketamine produce such rapid antidepressant effects. And they used the animal stress models to try to understand that question. And they showed, of course, the rapid antidepressant effect of ketamine. And that had already been demonstrated in animals before then. What was critically important was that they mapped out the biology of what ketamine did in neural circuits to build a story, a plausible hypothesis about a component of the way that ketamine might produce its antidepressant effects. And the story goes something like this. You give ketamine, and the most sensitive cells in the brain are cells that release an inhibitory substance called gaba. These are, we sometimes call them inhibitory interneurons. The main. They're not the main information highway of the brain. Those are the glutamate pyramidal neurons. But these are the neurons that provide the inhibitory tuning that governs the pattern of activity in the brain. So these inhibitory nerve cells were turned off or reduced in their activity by ketamine more so than the excitatory cells. So what happened was that even though ketamine blocks the action of an excitatory neurotransmitter by blocking the actions of an excitatory neurotransmitter on an inhibitory neuron, you then released the microcircuit from inhibition. So you got a little burst of glutamate release. And that glutamate release stimulated glutamate receptors and triggered a response in the next neuron down the chain. That next neuron down the chain had two kinds of reactions that seem to contribute to the antidepressant effect. Academy One is that when you have a lot of stress in order to cope with overstimulation, the glutamate synapse becomes less effective. It gets down regulated. It's sometimes called down regulation or depression of synaptic effectiveness. And then if the stress is extra, extra, more severe, then the synapse is lost altogether because you want to eliminate the synapse to protect the neuron from getting killed by overstimulation, by glutamate. So, so the neuron's trying to protect itself from overstimulation. So it first makes the synapse less effective and then it eliminates it. Well, it turns out from the work of Ron Duman, George Agajanian, and other people like Dr. Connor Liston, who's at Cornell, that within 24 hours, the stressed, down regulated and eliminated synapses grow back within 24 hours of a single dose. ACADEMY and you can see it, you can visualize the regrowth of these synapses. And it turns out that the antidepressant effects of ketamine from a single dose last about as long as these regrown synapses are present. This radical idea, before ketamine, we believed that all antidepressants act through monoamines. All antidepressants take months to work. In the largest antidepressant study ever done, people didn't achieve remission, in other words, get back to themselves fully until about two months of antidepressant treatment with ketamine. We got people back to the same level, the same percentage of people back to the same level. People who had had antidepressant resistance symptoms, people who had not responded before. You can get them better within 24 hours as much as people would normally get after months of treatment. And not only are you not direct acting through serotonin, predominantly what you're doing is restoring the integrity of the structure of the brain and the function of the brain.
And I say structure. It turns out that you can even detect changes on versions of MRI scans of gross changes, restoration of cortical structure with ketamine treatment. That work. That the paper that first laid this out in 2010 by Ron Duman was another pivotal point because now you had a clinical phenomena and you had some understanding, a little bit of understanding at least about why it was happening. And I think that that really was extremely important. Probably the next pivotal moment was the licensing of ketamine and the development of OF S. Ketamine by Johnson and Johnson. They did studies at large scale that showed the effectiveness of ketamine. But it also their studies combined with some academic trials. One trial that I did with a doctor in Taiwan, Dr. Tom Su and his group, another study led by Dr. Maurizio Fava and a consortium of investigators, along with the work done by Johnson and Johnson led helped us to understand that ketamine is. And esketamine are a little bit finicky in terms of the dose. They work in a very narrow dose range. If you reduce the dose by half, it's usually not effective. If you double the dose over the standard dose, you get more side effects, more dissociation, but not necessarily more effectiveness. And that. I think we'll come back to that idea later in our discussion. But that was an important observation. They figured out what doses of esketamine work and then they did two really important large scale studies demonstrating the effectiveness of ketamine, showing that ketamine was not only this rapid acting drug that had remarkable effectiveness in terms of long term effectiveness for treatment resistant symptoms, but they also showed, and I think this is really important for the real world of psychiatry as opposed to the research world of psychiatry, that it was about twice as effective in preventing relapse of depression in people who had had treatment resistant symptoms as standard treatments tend to be. In other words, the patients in their study who were just on antidepressant after having responded to a ketamine plus a new antidepressant, if they stopped taking the ketamine and stayed on their antidepressant, their relapse rate over the year was about almost 60%. Whereas the group that was on ketamine plus their antidepressant, their relapse rate was about 25.
[00:17:32] Speaker B: I've got to ask, you watched this journey kind of play out over 22 years now to the path of Spravato today. What was it like? Kind of like behind the scenes. It sounds like you were doing a bunch of work. A bunch of other, your colleagues and collaborators were doing work. Johnson and Johnson, of course, was doing the work. It must have been a thrilling time.
[00:17:50] Speaker A: It was and it is a thrilling time. You know, one of the things that happened along the way, which was particularly deeply moving was that people who began to get ketamine or esketamine as a treatment began to write to me. Sometimes they would write to me to tell me that they had gotten ketamine, and, you know, they didn't like the way it made them feel or it didn't work for them. But a lot of the times what they wrote to me about was how transformative ketamine was for them and their lives. How after years of depression, multiple different kinds of treatments, nothing really worked. They got on ketamine, they responded to it, and are living a very full and rewarding life now. And that was incredibly. It was and is incredibly moving. The idea that we could be a part of starting something that was giving people their lives back.
[00:18:53] Speaker B: And it sounds like, as you. As you kind of outlined some of the bigger studies, that dosing was kind of finicky, if I could say it that way. But your first kind of, like, study kind of nailed the dosing on the head. How much was that, like, luck? Like, how do you. What do you think about that?
[00:19:06] Speaker A: Oh, gosh. You know, whenever you look back on how these things happen, I'm just shocked that then, like, things worked out as well as they did. But there was a good reason.
So the dose and the route of administration that we used for the antidepressant study was the dose and route of administration that worked the best in our studies of psychosis and cognitive impairment. And it turned out that there probably was a good reason for it. So before we launched our studies, when we were in the pilot phase of the earlier set of studies related to schizophrenia, I was working with different routes and rates of infusion, different doses and things like that. And if we gave too much ketamine, people had very strong reactions. They couldn't answer the questionnaires, they couldn't complete the cognitive test. They couldn't answer the questionnaires that I was giving them. And that was no good to me because I was trying to mimic schizophrenia. And people with schizophrenia are not unable to answer questions, are not so sedated, they can't respond to things.
These are awake, alert, interacting people. So that was not very relevant to me to kind of put people in a kind of quasi stupor. No use. So I had to cut the dose back until we found something where they still had effects of keto, but they were able to respond. It turns out that that juncture between being very absorbed in the dissociation and maybe heading towards anesthesia versus too little effect, no real signal. That middle point where we decided to study in schizophrenia is right at the point where it just turns out to be where ketamine maximally disinhibits the network. If you give higher doses, you shut down the network. If you get lower doses, you don't maximize the release of glutamate. So it turned out that what we were looking for was just about the exact right dose to maximize the antidepressant effect. We didn't know it then, we didn't know it until about 2010 or so, but that kind of practical optimization had a neurobiological basis that optimized it for antidepressant treatment.
[00:21:46] Speaker B: It's remarkable how a pragmatic research kind of requirement for you actually led to, surely not accidentally, but led to kind of like the right dosing that kicked off this entire investigation.
[00:22:00] Speaker A: It's scary because, you know, what if we had chosen a different dose? What if we had. Several companies have tried to develop NMDA receptor antagonists that avoided the dissociative symptoms, and historically, those haven't worked very well. So that, that really, at least for drugs that have the profile at NMDA receptors like ketamine, getting into this dose range seems to be critical. Now, that leads some people to wonder, maybe it's the dissociation. But it can't be the dissociation for a couple of reasons that accounts for the clinical benefit of ketamine. One is we can increase the dissociation symptoms of ketamine by giving a higher dose without getting more clinical response.
The second thing is the dissociation symptoms across individuals aren't that highly associated with the magnitude of the antidepressant effect. And some people get a robust antidepressant effect on ketamine at the therapeutic dose without much in the way of dissociation. So I don't think that dissociate, although I think dissociation is telling us we're sort of in the right ballpark. I don't think it's the dissociation that's mediating the clinical improvement that people have.
[00:23:20] Speaker B: You know, as you kind of describe this, it reminds me a lot of some of the discourse today around this kind of traditional group of psychedelics. The idea of the hallucinogenic or subjective experience versus neuroplasticity. And I know that ketamine and these psychedelics are often conflated and they're entirely different. But I'm curious, like, as you've kind of watched this fueled progress, how do you map your personal experience and kind of research onto that?
[00:23:45] Speaker A: Well, cautiously and humbly, I don't. I, you know, I, what, what I would say is I, at some level, I take on face value what people say about their subjective experiences about psychedelic drugs, which are different, what most than what most people say about their experiences on ketamine. Some people feel that they have a meaningful experience during the ketamine infusion, but that's not that common, really. But a lot of people during the psychedelic administration experience say that that is a very meaningful experience for them. And so if they say it's meaningful to them, then it's meaningful. And one of the things about psychedelic drugs that I think is a possibility is that in a way that ketamine doesn't, that at these psychedelic doses, it's possible that psychedelic drugs activate those circuits in our brain that signal meaningfulness or pretentiousness or importance. Something really important is happening. And I had a number of discussions with a number of people who have personally used psychedelic drugs and have been studying it for a long time. And this feeling of meaningfulness sometimes is greater than the insight that is actually generated. In other words, that even if people can't articulate what it was about the experience that was meaningful, they sometimes still come away with a sense that something really important happened. Even if they There's a drug called 5 Methoxy DMT, which for many people wipes out their ability to think, and they come out of it. And even though they haven't thought anything, they can sometimes say that that experience of mental whiteout was extremely a meaningful experience.
So there's something about these drugs that produce this subjective sense that something really important has happened for people who have no meaning, have lost a sense of purpose and meaning in their lives. It's possible that that experience is important to them in helping them to look at their lives and their future in a more positive way.
[00:26:09] Speaker B: Would it be too reductive to say that? It sounds like the kind of mechanism of action for ketamine is far more kind of like, neurobiological, Whereas for some of these psychedelics, rooted in kind of like more sense of self and perception. Is that too reductive a way to kind of split this apart?
[00:26:26] Speaker A: I think it is, because I think that when people have this experience of meaningfulness and feel that their lives are enriched by it, my suspicion is that's only part of the story about what the psychedelic has done, because I think what has happened is that there is a part of the psychedelic story that converges quite closely to the ketamine story. Ketamine disinhibits network, increasing glutamate release, producing this rapid form of neuroplasticity both functional neuroplasticity in the circuit and structural plasticity in the circuit. Psychedelic drugs stimulate glutamate release and produce many of this exact same, engage some of the exact same signaling mechanisms that restore the plasticity and structural and functional plasticity. So the way that I think about it is that it's possible that this subjective experience, which people find important and meaningful, is layered on top of this part of the psychedelic response, which shares some elements of convergence with the actions of ketamine. It's for that reason that I'm interested, and others are interested in trying to find ways to capture as much as possible of that underlying biologically mediated antidepressant effect plasticity, structural and functional plasticity, and spare people the hallucinatory part of it, because while some people find it as extremely meaningful and fascinating or entertaining, if only entertaining or funny, other people find it terrifying, overwhelming. And one of the things one particular group of people that tend to find it terrifying and overwhelming are people who become flooded with very frightening and overwhelming memories. Many people have told me at the therapeutic dose of psilocybin, which is 25 milligrams, you're not in control of what you're thinking. A lot of people go about their daily lives after surviving terrible, terrible experiences because they learn how to relatively compartmentalize those memories and protect themselves from getting flooded and overwhelmed by them. And what can happen during these, it can happen during ketamine, but it also can happen during the psychedelic. You lose the control and you're just living some horrific version of your worst nightmare. And so for that reason, people have said, well, you can't really separate the psychedelic when you have these kinds of experiences. You can't really separate the psychotherapy from the drug. You really need to prepare people for what could happen. You need to support them during the experience, and then you need to help them pull the pieces back together and make sense of what they've experienced afterwards. Otherwise, some people will find it kind of a traumatic experience in itself. So I'm interested in trying to capture what we can by designing drugs or combinations of drugs that give you the benefit without the risk, which would have an added benefit of not needing an eight hour test day. Less expense, less disruption. And maybe there are ways to capture enough of the benefit to make that worthwhile. A company that I co founded, which is called Freedom Biosciences, is working on just that problem.
[00:30:26] Speaker B: Yeah, I was going to say that the kind of thesis that you just laid out would suggest to me that you would be in support of the theory that you can separate the neuroplastic effect from the subjective experience and still generate similar therapeutic outcomes.
[00:30:44] Speaker A: I would state it more strongly. So our animal data in Freedom Biosciences we have two different drug programs where we can in animals give a combination of drugs that has no produces no increase, one of the drugs being psilocybin. But we combination of drugs that doesn't produce head twitch, which is the animal version of animal signature of a hallucination, but produces an antidepressant effect. And there are other companies that have similar programs using different approaches. The challenge is we can't tell from these animal models whether the antidepressant effect that we see in the animals in these models is that a rapid psilocybin or ketamine like antidepressant effect or is it a slower effect? Is it robust for treatment resistant depression symptoms or is it more like a kind of a standard antidepressant? So these are very early days for these kinds of drugs. But I think they are one of the really exciting areas in depression research right now. Because just because it doesn't have hallucinatory effects, I mean, doesn't mean that it doesn't capture a lot of the other desirable behavioral effects that people associate with psilocybin. And I contrast that with mdma. So we all know that MDMA is like Ritalin plus a strong serotonin releasing component. So it's an amphetamine stimulant drug like other kinds of amphetamines that you're familiar with. It just happens to also release a lot of serotonin. So if it's releasing so much serotonin and it produces a blissful sense of connection and you know, that people find healing, how come it's not hallucinatory? Psychedelic drugs produce hallucinations. Why doesn't MDMA produce hallucinations if it's so serotonergic? And my colleague Al K at Yale has just submitted a paper where he shows where he identifies in a way, one of the reasons that MDMA is not hallucinogenic and he can make MDMA hallucinogenic in animals. My point is that some people say, well, we think MDMA is a great drug and we wish it was out there and we think psychedelics are great drugs and we wish they were out there. But we don't like the idea of non hallucinatory psychedelics. Well, maybe some of these non hallucinatory psychedelics are going to turn out to be like more tolerable non drugs like mdma. But, but without the abuse liability. I mean, MDMA has significant abuse liability. Cause like all stimulant drugs, they have a substantial, has substantial abuse potential. And people think of MDMA as a safe recreational drug. But I personally have treated patients who had both MDMA induced mania and MDMA induced psychosis. And so it is under the right clinical supervision, just like the psychedelic drugs, under the right setting, just like ketamine under the right settings. These drugs in very protected, well thought out, controlled ways. They can be administered very safely and probably used to alleviate suffering that we can't with standard medications.
But each of these drugs can be misused in ways that put people's lives at risk.
[00:34:37] Speaker B: Let's talk about that a little bit. We often hear for some of these psychedelic drugs, the safety kind of risks around induced psychosis, this kind of thing. How should I be thinking about that with respect to ketamine? Who may or may not want to stay away from it?
[00:34:52] Speaker A: That's a great question, and I think it's still a question in evolution. I've probably supervised or given well over a thousand doses of ketamine to people, and I've never had anyone develop a persisting psychosis from ketamine. However, I have visited clinics in China and in Taiwan where heavy ketamine abusers were hospitalized. I think it was in Guangzhou where we visited a unit where everybody on the unit, all the patients, were hospitalized with ketamine induced psychosis. These were people who were using very high doses of ketamine and using it very frequently. So they were using 100 times the therapeutic dose of ketamine every day. That's high tolerant. They were to the drug and they were. And they had what looked a lot like schizophrenia, except that it didn't respond to. Didn't respond to antipsychotic medication. And it spontaneously abated over time, over months, as has been shown by the group at University College, Val Kern's group, that there are residual cognitive impairments from that kind of use that don't really recover that rapidly. And the group in another Chinese city, I'm blocking on the name at the moment, showed, did some FMRI studies showing that there are alterations in circuit function that also resemble schizophrenia. Now, we don't ever see that with clinical, administrative, never seen it. But it does give you pause, for example, in trying to treat depression and schizophrenia. It does give you pause if someone has an evolving psychosis and a strong family history of schizophrenia about giving them the drug.
The second group that seems a little bit vulnerable, I guess I didn't mention it yet is that people who have bipolar disorder, manic depressive illness, who are depressed will get often a very brisk antidepressant response to ketamine. But if they are not on a mood stabilizer, it can sometimes trigger them into mania. It doesn't happen a lot. It's pretty rare. But because it's a real risk, generally speaking, people who have bipolar disorder don't get ketamine as a treatment unless they're already on a stable regimen of mood stabilizing medication like lithium or an anticonvulsant medication.
[00:37:46] Speaker B: My math is probably a little off here, but bipolar depression or bipolar disorder, schizophrenia collectively maybe 1% of like the US population, something like this.
[00:37:56] Speaker A: I've seen population estimates that vary a bit. So I've seen estimates for schizophrenia by itself ranging between about, about, from about a half a percent to about 1% and bipolar disorder about 1% to maybe 2 to 3%. So it's not like major depression where a major depressive episode may be as much, close to 20% of the population at some time in their life will have an episode of depression either with major depressive disorder or some related kind of clinical condition.
[00:38:37] Speaker B: So, so let me, let me be, let me maybe be a little bit difficult here. So we're talking 2, 3% of the population that is probably at risk. Why is this not just the first thing we all try?
[00:38:49] Speaker A: Well, I think there are a couple of reasons why when we think about the, the, the relative benefit of a drug like Ketamine as opposed to a drug like Prozac, which is probably pennies a day for treatment for a big chunk of the people who have major depression, Prozac is a very effective drug, Sertraline a very effective drug, bupropion, a very effective drug, and so on and so on. And so if you happen to be in that group that's responsive, you can be treated reasonably rapidly, extremely effectively, extremely cheaply by, by just starting one of these standard medications, the differential benefit is in the people who don't respond. If we had a test that we could give people a blood test, cognitive test, clinical evaluation, brain scan that could tell us, oh, this person's not going to respond to this class of drugs, then you would be absolutely right. We'd be well within our, well justified in going right to right to a drug like ketamine or someday perhaps a psychedelic or alternative drug like that. It's really only, we can really only demonstrate the differential benefit in the population that tends to be less responsive to ketamine. With one exception. That exception are the people who are urgently ill. So if someone is, has literally stopped eating, is completely immobilized by their depression, is on the edge of killing themselves and you need to get them better within 24 hours to help save their life, then that is an indication. That is an indication, FDA approved indication for esketamine as well. So I think there are those two scenarios, urgently ill where you really need a rapid response and treatment resistant symptoms. Some recent studies have suggested two things about ketamine's effectiveness for treatment resistant symptoms. First, it now appears to be the most effective medication that we have, adjunctive medication that we have for treatment resistant symptoms of depression. The chances of remission on S Ketamine are about twice as high as it is for adjunctive antipsychotic medication, which is the previously most effective class. Second, ketamine seems to be as effective as, as electroconvulsive therapy ECT where you undergo general anesthesia and electrical current is passed through your brain to trigger a therapeutic seizure. So ketamine is much less involved than ect. So the idea that they would have comparable efficacy has in our program tended to move ketamine and esketamine before electroconvulsive therapy in the sequence of our, of our treatments. And then there's one other piece of long term data that was just released in posters and it hasn't come out in print, which at least their preliminary analyses are I think are extremely important. And that is that when we translate what we know about a drug from the very controlled, relatively short term clinical trials to the real world, we also learn a lot at that stage. And there are some things that are very hard to test in clinical trials. And one of them is anti suicide effects. And the reason that they're very hard to study is that you have to provide such intensive anti suicide treatment in those studies that you get what are called floor effects. It's really hard to show improvement over a very intensive psychosocial program. But in the real world, what you see, Johnson and Johnson had some posters where they showed long term data. In other words, an average of 42 months from over 1000 people treated with AS Academy compared to a control data set that they had access to about how people tend to be on standard antidepressant medications. The data still blow me away. And so the first thing they found is that the chances of making a suicide attempt over those 42 months was about tenfold less and for the statisticians out there, a tenfold reduction in the odds ratio over the 42 months, the chances of dying by suicide were about fivefold reduced. And then something called all cause mortality, which is the likelihood of dying of, of heart disease, respiratory disease, cerebrovascular disease, et cetera, et cetera, that was reduced about threefold. And that last, that last finding is really extremely important. Important because it reminds us of a couple things that we need to bear in mind when we think of the impact of depression. First, inadequately treated depression shortens life expectancy by 10 years. Yeah, we don't think about depression and shortened life expectancy. That's the real world of depression. And one of the reasons that it shortens life expectancy is that while the origin of depression may be in your brain, depression is a whole body condition. It affects your immune system and contributes to inflammation in your body. That inflammation can worsen coronary artery disease, it can worsen cerebral vascular disease, it can worsen kidney disease, and so on and so on. And so when you more effectively treat depression, the whole body response of depression gets better and these other diseases can become less lethal. So to me, that's really eye opening because we're talking about, not about ketamine versus placebo. We're talking about treating depression more effectively with ketamine as opposed to less effectively with standard antidepressant treatment.
[00:45:39] Speaker B: Which again brings us back to the I think initial kind of jumping off point of. I understand that the kind of comparative effects in treatment resistant depression are starker than Prozac and traditional SSRIs. But on the basis of this data, I think maybe it might suggest that more broad, like more broad sweeping applications could be warranted. I'm not, I'm not. And Johnson, and Johnson is not paying me to say this. I'm just trying to understand.
[00:46:04] Speaker A: So I come back to. Let's imagine you're a person getting treated for depression. You were treated for three months and you didn't get better at all. And then another medication was added and now you're 40% better. And you're kind of satisfied with the clinical response, but you're also kind of dissatisfied with the clinical response. You know, to me, the data that I was just talking about may make more people who are struggling with residual symptoms of depression more aggressive consumers of these more definitive treatments. By more definitive treatments, I mean things like ketamine as ketamine, electroconvulsive therapy, maybe transcranial magnetic stimulation, et cetera. That if we believe that there's a cost of residual depression, we should be more aggressive about treating it.
And I Think I agree with you that perhaps we have to make sure that people who need access, because we're still dealing in many cases with access issues for all of these treatments. In fact, in this country, we're still dealing with access issues for patients to find a psychiatrist to talk to or a psychologist. And so let alone the possibility of them getting access to something like ketamine. And we do have to treat, we have to stop treating depression like it's less serious than other medical conditions. If depression is robbing people, inadequately treated depression, robbing people of 10 years of their life, why aren't we treating it like cancer, Me treating like heart disease?
[00:47:58] Speaker B: Right, yeah, to use some of the words, you, you've just established like less definitive, I suppose, outcomes that we can kind of point to and have confidence around. John, I want to, I want to bookend this conversation with where we started, which was schizophrenia. A lot of this journey started with schizophrenia. And I can only imagine you've been pursuing the research in parallel. Where are we today and what are you most excited about that you're seeing on, on that front?
[00:48:21] Speaker A: Since we're framing this discussion by my kind of pathway through career. I'll tell you about something that I think is really important from the perspective of my many years in.
And when I started, I was very influenced. I started joining the faculty in 1988. That's when I started doing schizophrenia research. And I was very influenced by a study that was led by the people who inspired me in schizophrenia research in my career, people like Dr. John Kane, Dr. Herb Meltzer and many other people. They did this study where they found people with schizophrenia who had not responded to antipsychotic medication. And then they prospectively treated them with a standard, a robust dose of an antipsychotic medication. So they had a history of non response. And then they prospectively were shown to not respond to medication. And then they randomized them to clozapine, which was a new antipsychotic then versus a standard antipsychotic.
And clozapine clearly emerged in that study as more effective. And so I was starting my career and I looked at Clozapine and I was really impressed by it. And we studied, we were part of the post marketing studies of clozapine. And clozapine has an extraordinary, extraordinarily complex pharmacology. It's the drug of all the drugs I know and have ever heard of. It's the drug that binds to more targets in the brain, I think, than any other drug that I know. And I thought at that point, one of the reasons I got interested in ketamine and wanted to shift out of the monoamines is that I kind of had the reaction to clozapine if clozapine doesn't help it. We have to go outside of the monoamine system to understand more about how to take the treatment of schizophrenia to the next step. The next step, for me, I thought, would come out of ketamine, in other words, because we had. What I was looking for was a kind of biology of psychosis that was not dependent on blocking dopamine D2 receptors. Because, as I said, blocking dopamine D2 receptors is just a part of the biology of schizophrenia. There's a whole other domain of the biology that's not addressed by blocking dopamine D2 receptors. So I thought ketamine would take me to non D2, if you will, antipsychotic medications. And it did lead to some medications that did provide some kind of very intriguing data about antipsychotic efficacy without blocking dopamine D2 receptors. But ketamine was kind of interesting. We couldn't block the ketamine psychosis with a drug that block dopamine D2 receptors, in other words, a standard antipsychotic medication. And we couldn't make the ketamine psychosis worse by giving amphetamine and releasing a lot of dopamine. So we really did think that somehow ketamine would lead us to a non dopaminergic kind of a psychosis. But we didn't succeed in identifying a mechanism that really worked broadly enough to be developed as a treatment in the background.
During this time. In the 2000s, research was being done that would lead to a drug called Kobenfi, which just got approved by the FDA as the first antipsychotic ever that is effective to treat psychosis without blocking dopamine D2 receptors. The history of that story comes out of the same root in a way, which is people at scientists. I think some of the important work was done at Lilly Pharmaceuticals identified that clozapine and one of clozapine's metabolites had activity stimulating a receptor for acetylcholine in the brain called the M4 or M1 receptor. These are two related, very closely related receptors. And then they. They were developing a drug called xanomeline, which they found to be helpful but utterly intolerable for in a pilot study in schizophrenia. That study was led by my friend Anantha Shekhar, who's now the dean of the medical school at the University of Pittsburgh And Anantha showed that this drug, although intolerable, reduced psychosis symptoms and improved cognitive function. And it was intolerable because of all kinds of physical side effects related that you get when you stimulate it. GI side effects, other side effects. And they kind of put it on the shelf. And then Steve Paul and his colleagues created a company called Karuna Therapeutics. And they had the brilliant idea of combining xanomeline with another drug called Trospium. Trospium blocks the peripheral side effects of Xanomaly. And so you took a drug which seemed like it had effectiveness but utter and total intolerability, and you converted through the combination it into a drug that had effectiveness and tolerability. And that drug is very exciting because it looks like it's.
It doesn't cause extrapyramidal side effects, motor side effects that resemble Parkinson's disease and other kinds of problems like standard antipsychotic medications often have the propensity to do. And it's effective for the positive symptoms, psychosis, delusions, hallucinations, and the kind of disengagement, social withdrawal, blunted, you know, emotional kind of dysregulation that you sometimes see in schizophrenia. And it had this other benefit, as we thought it might, which is that when people take standard antipsychotic medications, particularly young people who are early in the course of their illness, they often don't like them because they say they make them feel blunted. I have this problem, yes, I know I need to treat it, but I don't want to feel drugged. This new type of medication doesn't seem to produce that feeling so much of being drugged. And I think that's really could be important, important part of this. These drugs, we don't know whether or not they have any greater efficacy than the older treatments. They look, maybe relative to the older treatments, maybe they're a little more effective for the withdrawal, avoidant blunting kind of thing. Maybe it's just because they don't block dopamine D2 receptors and so don't impair them these symptoms. But if, if people want to take the medications because they feel better as opposed to not wanting to take the medications because they feel drugged, that that in itself would be in advance for the field, and that is pretty exciting.
[00:55:53] Speaker B: Maybe a closing question for you here. We often overestimate what can happen in a year and underestimate what can happen in a decade. What are you most excited to see happen over the next 10 years here?
[00:56:02] Speaker A: So there's so much that I'm excited About this is interview season where the residents are applicing for the, you know, next year's residents. And I tell every group of residents that they are extremely lucky to begin their careers at this moment because this is the most exciting moment in the entire field history of the field of psychiatry. Without a doubt, I think we are on the cusp of, of translating, of first characterizing in a way, the true biology, the true cell and system biology, circuit biology of psychiatric disorders. And as that knowledge really coalesces, we will be able to harness that knowledge to develop many, many more unanticipated kinds of treatments for psychiatric disorders. And I see that ultimately is one of the great, the great next generation of psychiatry. In other words, that the kind of deep, you know, the brain is the most complicated organ, it's the most complicated structure I can think of. And it's taking us a really long time to progressively develop deeper and deeper understanding of brain function. And I would say until now, our level of understanding of brain and brain pathology and psychiatric disorders has really limited our ability to develop new treatments for it. That's why ketamine is the first mechanistically novel treatment for depression in 50 years. That's why Cobenphy is the first non D2 antipsychotic since the early 1960s. And I think we're at a period where deeper and deeper, more fundamental kinds of discoveries will really generate new kinds of treatments that we hadn't imagined. I think we're going to get better at figuring out what treatment you need. In other words, precision medicine in psychiatry. And that's extremely important.
Probably no drug works for everybody. No treatment works for everybody. But if I can give you a much better chance, if I can give you a 90% or 80% chance of responding to a drug that only helps 20% of the patients with depression, that's a huge, still a huge advance. The third thing I think is that we're going to not draw sharp boundaries between the different ways that we have of manipulating neuroplasticity. We can manipulate neuroplasticity with a drug. We can manipulate neuroplasticity with brain stimulation, either transcranial magnetic stimulation, focused ultrasound, deep brain stimulation. We're going to have a growing array of personalized deep brain stimulation treatments in psychiatry that I think are extremely promising. And let's not forget psychotherapies, social therapies, individual therapy, family therapy, couples therapy, group therapy. We're going to be.
We have historically siloed all of these kinds of psychotherapies from full mechanistic integration with our.
Our brain stimulation and our medications. And we know that there are convergent effects on neuroplasticity and the circuits involved in cognition and mood. And I would add to that a whole new area called cognitive remediation, which is sort of like exercising those brain circuits to bring things together. I could go on and on, really, but you can tell that almost everything that I just said is either brand new as a way of approaching the biology and treatment of psychiatric disorders, or kind of only imagined historically. But they are going to be, I believe, the reality of psychiatry to a much greater extent 10 years from now compared to today.
[01:00:13] Speaker B: On this show, I've had the pleasure of interviewing leading academics, industry researchers, clinicians on the front lines, and every single one of them, to a T have said over the next 10 years, this is probably the most exciting time they can imagine clinical practice evolving.
[01:00:27] Speaker A: Yeah, it's going to. Boy, I listen to myself and I think, boy, you are really pushing hard on this. But I'm really hopeful. I am really hopeful.
[01:00:38] Speaker B: I know that the folks who use our platform, the ones who are doing the research online, are equally helpful too. So, John, this has been a riveting conversation. Thank you for meandering with me and chasing some rabbits down some holes along the way.
[01:00:52] Speaker A: Brandon, it's been a real pleasure. Thanks for having me on.
[01:00:54] Speaker B: Yeah, absolutely.
