Episode Transcript
[00:00:00] Speaker A: I still remember after about the first six or seven people we ran, getting a call from my colleagues saying, who are these people you're bringing in? Their levels are so much lower than anybody we've ever seen before.
[00:00:28] Speaker B: Well, Jerry, thank you so much for taking the time to be on the show. I've been so looking forward to it.
[00:00:31] Speaker A: Oh, great. Thanks, Brandon. I've really been looking forward to it also.
[00:00:35] Speaker B: Yeah. So for the audience, Jerry is a professor of psychiatry at Yale. He's led a lot of fascinating work across some of the earliest research in Academy for Depression, and is currently leading some other interesting work that I'm sure we're going to get into. But before we go there, Jerry, why don't you give us a just a thumbnail sketch of your career and your focus areas.
[00:00:55] Speaker A: Great. Well, been very lucky in my career. I originally started in this field very much on the molecular side.
Really interested in trying to understand how energy metabolism was related to behavior at the very molecular level. My, my PhD is actually in physiology and biophysics. And, and I am in addition to that, from Stony Brook University in New York.
I came to Yale in the late 1990s, actually the mid-1990s, started working with a great group of colleagues who is very interested in at what at the time were new neurotransmitter systems, mainly the amino acid neurotransmitters GABA and glutamate.
I was very interested in trying to understand how to measure these neurotransmitters in the brain using some novel imaging, and also very interested in how it was related to energy metabolism, but also seizure disorder.
And fortuitously we did a simple study where we were looking in epilepsy because there was some evidence to suggest that gaba, one of the amino acid neurotransmitter systems, was very low in people that had poorly controlled seizure disorder.
And we wanted to understand if this was related to the frequent seizures causing the low gaba or was the low GABA more permissive than allowing the seizures to occur. So we had a really simple idea of, let's do an experiment in people that have frequent seizures but don't have epilepsy. And those would be people getting electroconvulsive therapy for the treatment of depression. And we started to run this study. And then I still remember after about the first six or seven people we ran, getting a. A call from my colleagues saying, who, who are these people you're bringing in? Their levels are so much lower than anybody we've ever seen before.
And that really is how it was a hard left to start studying these systems in relation to depression, you know, what these people were being treated for. So we had this evidence of very abnormal levels of GABA and then eventually glutamate in these patients.
I was very lucky that right at the same time, my colleague John Crystal, who's also my mentor at the time, and others were starting to do these early studies with ketamine, a drug that targeted the glutamatergic neurotransmitter system and had incredibly exciting evidence showing that it could produce rapid and robust antidepressant effects.
And then from there, I really just continued to work on how the glutamatergic system, the gaboratory system, could be contributing to the pathophysiology of depression, but also could be targeted for the treatment of depression and eventually follow that into doing proof of concept studies, then larger phase clinical trials.
And after ketamine was eventually received FDA approval in the form of esketamine for the treatment of depression, actually moving into implementation science, like, how do we actually bring these novel treatments to patients in the clinic? And each step along the way gets progressively harder, in my opinion.
[00:04:11] Speaker B: Yeah, and we're gonna get to some of this backstory in just a minute here. But maybe to help us lay the groundwork, can you tell me a little bit more about the glutamate and GABA neurotransmitter systems, the hypotheses for how this works? And then in particular, I understand that there have been some setbacks recently and like, maybe walk me through how our understanding as a result is evolving.
[00:04:32] Speaker A: So most of us, most people that have taken early classes in neurobiology or even in just biology in college, are familiar with neurotransmitters. They usually think of serotonin, norepinephrine, dopamine as some of the major neurotransmitters. But in reality, you know, a relatively small percentage of the cells in the brain, the neurons, actually use that, use any of those three as their primary neurotransmitter. Even a C, the large majority of neurons in the brain use either glutamate or GABA as their major neurotransmitters, glutamate being the major excitatory neurotransmitters. Kind of the gas pedal in the brain. If your neurons are going to fire, the large majority of time, it's going to be through glutamatergic signaling and gaba. Gamma aminobutyric acid, which is the primary inhibitory neurotransmitter in the brain.
So together, depending on the brain region, but they make up about 90% of all the neurotransmission that that's occurring in the brain. The others, all the monoaminergic neurotransmitters, acetylcholine and others, make up a relatively small percent.
So it really has been a long way in developing these treatments. The hard part about developing these treatments is since they're so ubiquitous and present all over the brain, it's hard to manage them. You can get drugs that can act as an anesthetic, or you can generate seizures pretty easily by modulating these systems. But to just have a fine touch on these systems has been a little bit more tricky over the. Over the years. But these drugs have been developed. So the GABAergic system, you may have heard a lot of the drugs like benzodiazepines, drugs like Valium and Xanax, are really targeting this to. To a large extent. A lot of anesthetics target these to some extent or another.
And glutamate, really, the. The sort of the classic treatment targeting it has been ketamine, which targets a specific receptor of the glutamatergic system called the NMDA receptor.
And that, as you are aware of, is primarily was originally developed as an anesthetic drug, really, in the 1960s. Received FDA approval in 1970 as an anesthetic, but only more recently did it progress into use in treatment of mood disorders or other psychiatric disorders.
And I think a lot of that came from the ground, the ground laying work that was done showing that the glutamatergic system was actually involved in the pathophysiology of depression. And a lot of that actually, as we started to understand how depression and neuroplasticity sort of intertwined. And we know that glutamate specifically and GABA are very much involved in the regulation and neuroplasticity.
So the story started to come together, how impacts of these amino acid neurotransmitters on neuroplasticity could be related to some of the pathophysiology we see in depression. And the animal studies seem to show that, in fact, to be the case. And the limited human data that is available also seem to support that.
So it was really a development along those lines that led my colleagues at the time, John Crystal, Dennis Charney, Rob Berman and others, to really try a very simple experiment, if you could use ketamine, which is a drug known to target the NMDA receptor, to have an effect on patients with severe depression. And I Think to their surprise and everybody's surprise, I think Dr. Crystal was on here recently, John was on here talking about it. Really quite shocking how rapidly this response was. And that really set in motion decades of research really trying to understand it further.
[00:08:32] Speaker B: Yeah, absolutely. And as, as we kind of spoke about with, with John, the, the results have been remarkable. Now ketamine has a, a unique kind of property with respect to other NMDA receptor antagonists. I'm curious, like maybe, maybe walk us through why this seems to have worked so well for ketamine and, and maybe not so well for, for others.
[00:08:58] Speaker A: Yeah, well I, I think you're just, you're asking the 10 billion question here.
Absolutely. Why is it that ketamine seems to be so effective and yet we're not seeing it, or at least we're having a more difficult time demonstrating it is probably the best way of saying it. With other drugs that had similar pharmacological pro, you know, properties.
Ketamine, we think of it primarily as an NMDA receptor antagonist, but it does have other properties and it does to varying extents target other receptors in the brain. But even just within the glutamatergic system, even just within the NMDA receptor, it's incredibly rich and complex pharmacology that has several factors. So we now know that ketamine seems to have a dose dependent effect.
So it looks like there is a relatively narrow therapeutic window, especially if you look in rodent models and if you look at changes in, you know, cell function that, you know, it's kind of this Goldilocks phenomena where, you know, a little too little ketamine, you don't seem to get the effect. Then you get this really nice effect, this antidepressant like effect that's accompanied with several cellular changes, this neuroplasticity that we talk about. But if you go beyond that a little bit higher, you tend to lose all those effects.
So it seems to be this dose related.
Then on top of that there's also a time dependent effect where different than other types of medications that we typically think of, where you want that drug to bind to the receptor and stay there as long as possible.
It very much looks at looks like drugs like ketamine and others that, that do have this effect are only there for a short period of time and then gone.
And what it actually does is initiate a cascade of events that actually leads to this antidepressant like effect that don't require this continuous activation and in fact may even be attenuated or inhibited by continuous. So you want something that's there for a while, then gone and then it's the brain's reaction to that that's actually generating the positive effect.
So you got this complication of a dose related response and you have a time related response and you probably also have a region regional effect of which part of the brain.
And the way that actually happens is by targeting specific subtypes of the NMDA receptor, which is related to the different subunits that make it up. So it becomes extremely complex. It, there is the chance that we just got lucky with ketamine, that it has us the right profile at that right dose range to really generate these effects.
And I think that's quite possible. And that might speak to a large part how ketamine is having such a big effect than the other drugs may not be having.
But there definitely are other possibilities that could be contributing. It could be some of the other receptors outside of the nmda, but activation that's contributing to the mechanism of action. Or it could even be some of the psychological effects that ketamine generates that contributes to the large antidepressant response we see.
[00:12:17] Speaker B: And one thing that you've kind of alluded to is the neuroplastic effects that also occur in, you know, understanding that there is a tremendous amount of concurrent research happening in psychedelics. I'm curious, like how much of this do you think might just be the neuroplastic effect? Um, that seems to be an overlapping theme.
[00:12:36] Speaker A: Yeah, it, it, it's a great question and we really don't know.
[00:12:40] Speaker B: I, that's the question.
[00:12:43] Speaker A: Most, if not all of the evidence we really have for neuroplasticity being related to the mechanism of action come from rodent studies. And there I think the data is really pretty clear that ketamine and some of these other psychedelic like drugs can generate rapid changes in measures of neuroplasticity. Probably the clearest evidence is spine density changes. You can really see nude introduct spines being formed pretty rapidly within hours of the treatment.
And in the rodents that's pretty clear. In the humans we have some evidence of that. There's some imaging studies that suggest that is the case, but it's much less definitive.
And then we have the real big question is how directly relevant are those changes to the clinical benefit?
To be honest, it makes a beautiful story and for you draw the cartoons out. It looks incredible, but how directly related it is, we're still working on that. I think in reality it probably does play a large role, but I think there are many other Factors beyond that that contribute to it, and hopefully we get a chance to talk about it later. Even if we do get a chance to mention heal the psychedelic drugs, the real exciting thing, I think, in the field is that there could be a synergy between these two things, between some of these other psychological type effects that these drugs can produce with the neuroplasticity together to actually generate a very large effect.
[00:14:19] Speaker B: Well, let's go there. Let's jump straight to it then.
Tell me a little bit more about this kind of like, compounding effect.
[00:14:27] Speaker A: So I, you know, over the past probably three decades, there's been a real growing, or I should say, an evolution in the way we think of the mechanism of antidepressant treatment. It. It was back in the 1980s, we would commonly say, you know, there was a chemical imbalance that was being corrected.
And I think the field has really evolved over the past three decades to talk much more about changes in neuroplasticity or the way the brain can adapt to changes, sort of rewiring the system to get out of these maladaptive patterns of thinking.
And that really has taken root. And I think there's a lot of evidence for it. And I think that's really sort of the most common belief within the system.
And if we think that these drugs are doing this, even the older, the standard SSRI drugs looks like it has these effects, it just takes much longer for it to induce these changes in plasticity. But they do have these effects, maybe not to the same magnitude. And as I said, it probably slowered, you know, onset of action for that.
But if we think that these drugs, a critical component, is actually changing the way the neurons are communicating with each other, and you start to believe, or you start to expand on that and understanding that much of the circuitry in the brain comes from being reinforced. So as you're forming new connections in the brain, the connections that tend to survive and to be strengthened are the one that is being used.
You really can start to see how there could be synergistic effects between the ability to have plasticity, which.
Which we would.
[00:16:20] Speaker B: Let me stop as always. We'll. We'll cut.
[00:16:23] Speaker A: Um, all right, so let me pick up.
So you really can start to see excitement about the potential synergy where, if these drugs are inducing a level of metaplasticity in the brain, in other words, the ability of the brain to be plastic, and then you can start to have increased levels of hope, optimism, positive behavior, new cognitive schemata that are actually more adaptive and reinforcing you could actually be strengthening or, you know, sort of cementing in more productive or adaptive thought patterns and behavioral patterns. So it really is a great potential to use both of these together to actually have this ability to break out of maladaptive cognitive patterns and behavioral patterns that the drugs may actually induce, but then to also have another layer on top of that that, you know, can allow patients to have this hope and optimism and sort of see a new lease on life. And you can combine those together to really get a large effect in mood disorders specifically.
[00:17:44] Speaker B: You know, one of the questions that often seems to come up when we discuss psychedelics is whether we can isolate the neuroplastic effects from the, from the subjective experience. I'm curious what your take is on this.
[00:17:57] Speaker A: Yeah, well, so this is a great example of where going from preclinical research to clinical research, you know, that there's a, there's always a big black box there. So in the rodent models, it seems to be that these psychedelic type medicines can have very large effects. And in the road models there's even been some evidence if you can block some of the other more psychedelic like features, that you can still get those antidepressant like effects much more complicated and much more complex in humans. And it's very difficult to really understand. If you look at, especially the treatment of depression, we talk about a mechanism of action. What is the mechanism of action? I think that's what you're getting there. Is it the. I'm sorry, you talk about the mechanism of action and we get at what it really is.
Is it neuroplasticity or is it some of these others, other features of it? I think the reality is there are probably multiple mechanisms of action. And if we think about depression in general, if we look at these studies, the actual drug effect is a relatively small amount of the overall benefit we see. So in clinical trials, if you run a clinical trial with depression, the classic way it's done is to have a placebo group and the active group.
In almost every one of these studies, everybody gets better and big benefits. But if you look at the total difference between the active group and the placebo group, you know, in the drugs that work, the active group always does better, but commonly only about 20% better.
So in other words, and people can take this two different ways, say, well, the drugs don't work very well, it's only 20% better than placebo. But the reality is placebo is pretty good in these studies, right? Yeah, there's actually a really big benefit that comes from that, and then the drug has the benefit on top of it.
So if you try to think about what's the critical, and we talk about those as the contextual effects, there's a lot of things that go into that placebo response.
And people.
If you really want to get into the technical side, there's a placebo response and a placebo effect, and they're not the same thing.
The placebo response is made up of several different components. It's made up of things like the natural progression of the disease. So depression is kind of a cyclical illness. So if you wait long enough, people will usually feel a little bit better.
As I said, it's also cyclical. Most people come into a clinical trial when they're feeling their worst.
So even just by chance, they're gonna probably feel a little bit better if you give them four, five, six weeks.
And that would be considered like, regression to the mean.
And then there's even things like the Hawthorne effect just being observed usually has people do better in general.
So not only now they're in a clinical trial, they're doing this, but they're also paying more attention to their other health. So they may try to sleep better, they may try to watch their diet better. So all those other things that contribute to their effect, fats, in addition to the true placebo effect, which is the idea that you're taking a drug and that drug is gonna work, and that has its own set of physiological and neurobiological changes that actually could generate some benefit. So it's really a combination of all these things that is generating the benefit. So unlike the preclinical, the rodent studies, which we don't think all of that is going on, um, where the neuroplasticity seems to really show the main effect in humans, it's probably that neuroplasticity plus all the other stuff.
So I think it. You know, they're. They're all important. Um, yeah, yeah, yeah.
[00:21:53] Speaker B: You. You kind of touched on this, like, idea of there being potentially multiple mechanisms of actions, multiple targets. You know, it's. It's nice to think about the world as very clean.
Um, but you're kind of highlighting that there's all this kind of adjacent effect. I'm curious, like, if you look at the landscape of, like, current hypotheses, there's like, the, like, m. NMDA receptor hypothesis, there's this neuroplastic hypothesis. Maybe. Let me kind of categorize it there. There's also all the stuff that's happening with TMS and neurocircuitry.
Like where are folks leading in terms of unifying these theories? Like certainly this, this stuff acts actually seems to be really promising too.
[00:22:30] Speaker A: And, and I, it's a great way of thinking of it. I think if there is a unification theory in depression treatment. Yeah, I, I think it would at this point be centered around neuroplasticity where I think you can really draw nice lines, whether it is between ketamine, psychedelics, tms.
You know, we really do see this common thread of inducing neuroplasticity, actually more of the metaplasticity, the ability to, the ability to experience neuroplasticity. I think that's one of the main unifying themes.
I think we'd be naive not to also realize that expectations play a large role in that too.
Prior to really the ketamine phenomenon, there really weren't any rapid acting treatments. Maybe a sleep deprivation could generate a day or two of feeling better, but it was just accepted that it was gonna take weeks if not months to really get a good clinical benefit.
And not surprisingly, the placebo response took weeks if not months to see.
Now that we have this expectation of a rapid onset of effect, whether it be from theta burst, tms, psychedelics, ketamine, we also start to see that placebo response get much quicker too.
[00:23:49] Speaker B: Fascinating.
[00:23:49] Speaker A: So, so it really is fascinating. And you know, I think if nothing else, the field has made huge leaps in understanding that, you know, these neurobiological mechanisms are much more complex than a single receptor being activated. And that, you know, it really does involve this level of neuroplasticity. But we also realize that a lot of that neuroplasticity can be generated from inside the cranium that you don't, you know, this can be. Endogenous factors can really have a lot to do with, with modifying the neuroplasticity. And learning how to harness that all together is really the key.
[00:24:26] Speaker B: I think one thing that you just said that really resonates with me or kind of sticks out is this idea that back when we thought the effect would take four weeks, the placebo effect took four weeks. Now that we think the effect is gonna be rapid, the placebo effect is rapid. Is there something here where like the kind of expectation bias is encoded via, like, like the, the metaplasticity, it kind of allows for light expectation to be propagated through.
[00:24:55] Speaker A: I, it's a great question and I, I think it would be hard to imagine so that it's not in some way involved, but exactly How? I. I don't think we have that answer yet.
[00:25:05] Speaker B: Yeah, well, this is. This is. This is one part science, one part sci fi on the.
[00:25:08] Speaker A: Exactly. Exactly.
Hey, I may even say 1.5 for Sci Fi 6.
[00:25:15] Speaker B: Honestly, I think people listen for the sci fi a little bit.
I think one of the most interesting things is getting to talk to experts like yourself and kind of pushing the boundaries a little bit and asking yourself, like what? Like, let's just take some educated guesses here and see where we go with it.
Hey, you know, we had Doug Drysdale from Sibin on the show, and he said that one of his aha. Moments was reading some of the early papers and feeling like some of the results are just way too good to be true.
What. What's your take on that? Is that. Is that the academic perspective too?
[00:25:50] Speaker A: Well, I, I think when the data look incredible, there's the figurative and the literal. Yeah. Definition of incredible. Um, it.
The. The data do look extremely good for them. And there are a lot of factors that I think contributes to that. It. You know, probably there is a real effect of these treatments, and I think that probably. I think there probably is a real effect of these treatments, and I think it's significant.
But I think these expectations are huge and other factors that we don't always think about, but functional and blinding is a real issue. These are treatments that, for the most part, people can guess when they're getting the treatment and when they're getting the blood placebo.
And even. And there's good evidence that even when people know they're getting a placebo, it still can have a positive effect.
But typically, if you have a high expectation that this drug is going to work and be very beneficial, and it's almost an if, then if I have this unique experience, this dramatic effect on cognition and perception, and that's going to make me feel better and I don't have that effect, well, then I'm probably not going to get better.
So there's a real bias for the drug versus the placebo overall. And I think all of these contribute to this, what you may even call incredulous data that it just looks too good. I mean, I think it's real, but I think there are a lot of factors that contribute to why we see these large effect sizes.
[00:27:31] Speaker B: Yeah, I, I want to. I want to go back to your work on ketamine in particular. I understand that you're doing a really interesting study right now comparing ketamine and esketamine. I'm curious if you could, you know, tee that up.
Why are you looking at this and what are you hoping to understand?
[00:27:51] Speaker A: Yeah, so we are very fortunate. We received funding from the Patient Centered Outcome Research Institute to really do a head to head study comparing ketamine, which is really racemic ketamine, which is what we were talking about, that was developed in the 1960s and received FDA approval as an anesthetic in 1970 and has been used for decades, versus intranasal esketamine, which is currently what has an FDA approval was developed by Johnson and Johnson or Janssen Pharmaceuticals as an intranasal treatment. It currently has FDA approval. We're very interested in seeing head to head.
Is there a difference?
Pharmacologically, there's really not much that you would imagine. Racemic ketamine is made up of both the S and R enantama, S and R ketamine in about a 50, 50 ratio.
Esketamine is just purifying out the S enantiomer. So it's just really part half of.
Just really half of what is in the overall racemic mix.
And the reason esketamine was chosen for the development is it has a higher affinity for the NMDA receptor. We talked about that NMDA receptor before. Well, it looks like that's the active site, or at least we think that's the active site. Um, and it's about four times higher affinity than the R ketamine. So it's actually more potent. You could use less of it to get the same effect.
And if you're going to be, you know, insufflating a nasal spray up your nose, you don't want to be spraying, you know, milliliters and milliliters of spray up there. You want to use as little as possible. That was the reason for using the S.
So the difference is though, it doesn't contain the ARC enemy. So it just says yes. And we don't really know what the R is doing. So there may be a real difference there. It may have other effects off target. It may have effects outside of the NMDA receptor that the, that that receptor is specifically targeting.
I mean, that that version is specifically targeting. So we're very interested in understanding how that could play a difference, how that can make a difference.
There's also, from public health perspective, some real important questions here in the community.
There's been a large increase in the use of racemic ketamine, the older version of ketamine, either giving it IV or giving it IM or in some cases compounding it into oral lozenges. Or other things.
Um, and that's become really popular and that's unregulated. Unlike when the FDA approved esketamine in the form of Spravato, it approved it with what's called a rems, or risk Evaluation Mitigation Strategy. So it has to be given on the very control conditions. It has to be given in a healthcare facility under the observation of a healthcare provider for two hours of observation. The pharmacies are strictly regulated. It can't be sent home. It's very strict regulations. You actually have to fill out a form every time you give it. So we can collect all this data using the older version. None of those requirements are there. So it can be given many different ways, all different doses, and we just really don't know. There are papers out suggesting one may be better than the other, but they're really never head to head studies. Um, so this is really an important study saying in a head to head randomized study, is one treatment better than another? We're hoping to have the results in, in a few years.
[00:31:46] Speaker B: Yeah. And this is again in treatment resistant depression.
[00:31:49] Speaker A: This is specifically in treatment resistant depression.
[00:31:53] Speaker B: Yeah.
How. How is J and Jay engaging with you on this? It seems like you could be shaking them to their core, at least on the Spravado program.
[00:32:05] Speaker A: Well, I mean, I have to say I have very good colleagues at JJ and we've worked together a lot, I think, at least within the science community.
And my colleagues at JJ have been very open and interested in trying to know these results.
I'm sure financially it could be a little bit shaking, but, you know, they have been very collegial in their interest and I still collaborate with them on a regular basis. So they've been very understanding of this. I think it's a scientific question we really need to answer. We need to know if that or edamate is really playing major role. We need to know, is there really a big difference between IV and intranasal? And again, you start talking about expectations, does it even make a difference? You know, not even pharmacologically, although there are differences in the actual pharmaco.
Yeah, the pharmacokinetics that occur when you give it IV or intranasally. But even just the idea of giving it IV and intranasal may be different to people.
So these, these are a lot of questions. And, and the cost obviously is very different too. But for public health, it's a real important question. One, is it as effective? And two, is, is it safe?
[00:33:29] Speaker B: Yeah. And, you know, maybe this Is the, the world's dumbest question about this topic, but has anyone studied our ketamine that's been isolated on its own?
[00:33:41] Speaker A: Yeah. No. And, and it's not the world's dumbest question at all. It's actually a great question.
So in fact there have been companies that have tried to develop R Ketamine and it's still working on that.
There are a few studies looking at R Ketamine. It's mainly the one that I'm aware of is out of Brazil.
And I have to say the data for those are really very inconclusive.
Gotcha. It's clearly inconclusive. And again, we talked about before how there's a really important dose response relationship with ketamine and hitting that right dose, now that you're just using R Ketamine may be tricky.
[00:34:21] Speaker B: Yeah.
Now, now you mentioned a public health question. My understanding is that there's a hypothesis here around long term cognitive effects.
I'm curious, like where, like where is that going?
[00:34:34] Speaker A: Yeah. So I think, I'm not sure I would say there's a specific hypothesis about long term coping effects is a fear. I know that really concerned. I mean we know that ketamine can have neurotoxic effects.
We know that these NMDA receptor antagonist drugs clearly can have neurotoxic effects at certain doses. And again, not just the dose, but the duration of the exposure seem to be very important.
It was always one of the main concerns. We know if ketamine has pretty pronounced cognitive effects acutely. So while, you know. Right. While ketamine is in your system and activating it has large effects on perception and cognition. And that. That's very clear.
The question is after that are there any longer term detrimental effects effects and that. That has always been a concern. And we know from individuals that misuse ketamine, ketamine use disorder, the people chronically using high levels of ketamine, there's very good evidence of cognitive impairment in those individuals.
So we know at some level you can get it, you're gonna get toxicity and ketamine is not gonna be good for the brain.
Um, we just don't know where, we don't know where you're gonna run into that, how much is too much. Uh, so that concern has always been there with ketamine.
Now I think there's very good data when used appropriately, meaning under control conditions, usually never more than twice a week for the first month and at relatively controlled doses.
We are not seeing that with ketamine or esketamine.
For that short exposure period, we're not seeing big cognitive deficits like that.
We now have really good data going out up to 6 years with intranasal esketamine because of the REMS people have been following now, not as specifically as some other things, but we're not seeing major reports of cognitive impairment. We have data of up to one year, really intense data using specific cognitive batteries, looking, and we're not seeing any real concern. If anything, there tends to be a little improvement in cognition in those patients. But again, those patients were pre screened to, you know, not be at risk for those type of things to be in generally good health, you know, no unstable medical conditions. And they were only provided the treatment, you know, in a healthcare setting in twice, twice a week for the first month, then once a week after that, and then spacing it out even after that as much as possible.
So under those conditions, I think with Spravato, with intranasal esketomy, we can be pretty confident that for most people that we're not seeing this major, you know, red flag going up.
But as we get further away from that, we know less and less. And, and, and I do remind people all the time, we know at a certain level we will say it, it's where, you know, where you cross that line. We don't know yet.
[00:37:59] Speaker B: Yeah, it's, it's really the, the risk of abuse kind of materializing this.
[00:38:08] Speaker A: I think the risk of abuse, the risk of how the dose, you know, how much and the frequency, all of those, you know, go together.
You know, what we do know is that this intermittent dosing at this relatively controlled dose level in patients that are generally healthy, where we're not seeing anything or we're not seeing, we're not seeing anything, that's really raising red flags.
[00:38:33] Speaker B: Yeah. So while, while we're on the topic of intranasal sprays, I know that you're on the advisory board of VistaGen. We've had Sean on the show as well talking to us about the exciting work that they're leading there. I'm curious, how do you think about this route of administration and when certain compounds should be explored this way?
[00:39:01] Speaker A: So you mean the intranasal insufflation method? Yeah.
[00:39:04] Speaker B: Yes.
[00:39:05] Speaker A: Yeah. It, it's very interesting for, for a few reasons. Um, one is the example with esketamine and I think 99% of the reason driving the use of, you know, intranasal esketamine, intranasal instead of IV is just ease of access, ease of use. Yeah. You know, Especially back then, when this was being developed, going back eight, 10 years ago, the idea that psychiatrists was going to be putting an IV in you seemed pretty far off. Now, I think the world has changed a lot in the last decade, but just ease of use intranasal is a lot easier used than I.V. that's one reason.
The other is the direct.
The privileged route of direct contact to some brain regions that some of the nasal neurons actually have. So you can actually get much more direct access to parts of the brain intranasally than you would get even through IV and so there.
So there is some potential benefit from that intranasal administration as opposed to any other route of administration.
[00:40:19] Speaker B: And I know that Sean was saying that there's this additional benefit of it being non systemic.
[00:40:27] Speaker A: Yeah, so. So one of the quick things when we talk about the sort of the pharmacokinetics, even that, as I said, you're getting some direct access through the, through the brain, but you're also getting through.
You're not having to go through the liver as much as you would if you give iv Getting. Going through the liver and getting all the metabolism that occurs in the liver and the changes that will occur to the drug that way. It's. This is a much more direct route.
So. So there are a lot of advantages as long as you can get that concentration to the brain region that you need to get it to with that mode of delivery.
[00:41:06] Speaker B: Absolutely.
Hey, I'm kind of curious. One of the things that comes up as a theme sometimes is maybe the future of clinical practice, given all the exciting interventional work that's happening. We're. Where do you think this is all going?
[00:41:20] Speaker A: Yeah, I. In psychiatry, I think. I mean, medicine itself is evolving so quickly, but I feel I see the landscape of psychiatry just evolving at a pace that is, you know, sort of breakneck speed at this point, which is very exciting, but also a little confusing to people. What will psychiatric practice look like even 10 years from now? Definitely 20 years. I think if you go back when I was starting in the field 30 years ago, most psychiatric practice was a single psychiatrist in an office who would see patients either at an hour at a time or maybe a few patients, 20 minutes of time to manage medications.
The idea of having any interventions were just really not thought of. Now we have the whole field of interventional psychiatry coming out. You know, places that like ours at Yale, New Haven Hospital, where we use treatments like ketamine S, Ketamine, tms, the old, oldest treatment that was always kind of in this category. Was electroconvulsive therapy, ct.
But it was always kind of a practice onto itself.
Very limited, mainly in hospital setting. We're starting to see these new interventional programs growing so rapidly and really becoming more of referral services.
So I think we're going to, we'll see in 20 years from now what actually does happen. Does psychiatry become this, you know, specialized interventional service, you know, that some people go to, or is it really find a way to go back out into the community where most psychiatrists are using some of these tools, whether they be neurostimulation tools, you know, even deepering stimulation.
Will we see that actually grow or is this really always going to be, you know, an, an area that is really confined to a subgroup of places and you still have your regular psychiatrist in the community that do the bulk of the care and refer. And we'll see what actually happens.
[00:43:37] Speaker B: Yeah, the, the question I think always on my mind is like 10 years from now, does this look like a lot of premium dentist offices?
Right. Or, or is it referred to the major medical centers for the specialty stuff?
[00:43:52] Speaker A: Yeah. And I think we really don't know. And you know, there are so many factors, including financial factors that really are driving this and we're limiting it. Depending on how you think of it, healthcare is a huge part of our gdp.
There isn't much room for it to grow anymore. Right.
[00:44:13] Speaker B: Yeah.
[00:44:14] Speaker A: And mental healthcare is incredibly expensive in large part because much of the benefit that we provide is that actual personal relationship in mental health.
[00:44:25] Speaker B: Right.
[00:44:26] Speaker A: And it's one of the things that worries me is as we do start to develop these novel interventions, do we actually strip away that personal component which I think does offer so much of the benefit to people. And I'm afraid if that isn't compensated correctly, we could really do a disservice for the field if we put all the value on these novel treatments or even these new psychedelic treatments, treatments that require so much, you know, clinician time that there'll be much less clinician time available for the day to day care that, that they typically provide it.
[00:45:06] Speaker B: Yeah. And it, it may be harder to measure the harder to measure the benefits of that kind of interpersonal relationship that's being developed. Certainly no sponsors are measuring it.
[00:45:19] Speaker A: Exactly. I think that really you've hit it on the head. It's so hard to truly measure the benefit and to really, you know, put, to monetize it, to understand what the dollar value of that is. It's so difficult.
You know, much of mental health, the benefit of mental Health is decreasing the cost of the rest of the healthcare system.
It's really hard to understand how do you actually put a dollar value on that?
It's not so easy.
[00:45:51] Speaker B: Yeah. Especially in a payer system where everything is so quantified.
Yeah.
Fascinating.
Jerry, I'm curious, when you look back out on the landscape of innovation, we've covered a handful of topics here. Is there anything we haven't covered that you're really excited about that you're watching closely?
[00:46:14] Speaker A: Yeah, I, I mean I, I am very excited about several lines of novel pharmacologic treatments, you know, that really targeting as we start to understand more about the pathophysiology that, you know, we were stuck for a solid 50 years in targeting the monoaminergic is. Let me, I'm so sorry, I.
Let me see if I can just.
[00:46:39] Speaker B: Oh, that's the kind of thing we can edit, which is nice.
[00:46:41] Speaker A: Yeah, no, but I am going to just close that out so it doesn't happen anymore.
I, I'm, you know, I'm very excited about the ability to target new systems. As we understand more about the neurobiology, we've really opened up completely new vistas that we can start to target. As I said, For 50 years we were really stuck with the monoaminergic system.
You know, how many different SSRIs, SNRIs could you really develop?
But now we're really starting to understand more about the pathophysiology and hopefully we can start to develop some more preventative treatments. You know, if we understand the pathogenesis of these disorders, how you get to that point, what can you do, what preventative measures you can take, whether it be pharmacological or probably even more reasonable, other psychological approaches, other things that can be done to prevent, I think is really important.
And that actually brings me to what I think is incredibly exciting is the ability to capitalize on some of the new technology to use these treatments at much reduced cost and to broader patients. So some of these computer assisted programs, the ability to use cognitive behavioral therapy, which we know is very effective, especially in relapse prevention and prophylactic means, but actually delivering them in a cost efficient manner I think is going to have huge impacts on public health. The ability to monitor mental health passively through either something like a, you know, a wearable or some other type of device that allows us to monitor mental health and the ability to integrate this data. I think there's huge potential benefits at the public health level there.
And you know, together with the, really the advances in the Neuroscience and the advances in the technology, I think there's a lot of room for growth and in a way that is not going to be cost prohibitive.
[00:48:52] Speaker B: And just so I'm clear about the vision you're painting here, we're talking about like preventative mental health via wearable monitoring, passive monitoring, and AI assisted. Like cbt, like.
[00:49:04] Speaker A: Exactly. And computer. Computer assisted. Because getting back to that other point that we talked about is how that interpersonal component seems to be really important. I'm not quite sure in the near future we're going to see a computer treatment that is highly effective.
But these computer assisted treatments where they are linked to actual humans that can provide these treatments, but at a greatly reduced time.
Because really, I mean, sad to say, but if you try to get mental health care in the community right now, you're usually looking at months of a wait, especially by a highly qualified person.
There's just such a shortage of mental healthcare providers. The way of sort of reducing the time burden to the clinicians, I think could be of great benefit from the public health perspective.
[00:50:03] Speaker B: Yeah, fascinating. I mean, it, it seems every day that goes by these computer systems, AI systems are more empathetic than they've.
[00:50:12] Speaker A: They've ever been before.
But we may get to the point sooner than we thought of where it can actually provide that empathy. And I, you know, I'm still a little old school there, I think, I think we're going to need that for a little bit longer, but. Yeah, of course, but even at the point where we are right now, I think they could be very valuable if there's a way of integrating them. Yeah.
[00:50:38] Speaker B: And just scaling the time and effort from the individuals.
Yeah.
Jerry, Jerry, maybe last question for you here.
You know, it's been said many times on this show that we're in the middle of a neuropsych neuroscience renaissance.
And I'm curious, your take, why now?
[00:50:56] Speaker A: Again, I think it's a confluence of many factors.
Why we're at the that point of a renaissance.
For really five decades, the field was dominated by the monoaminergic hypothesis. And there really wasn't great motivation to go beyond it. You know, Big Pharma was making money, there were new drugs coming out, people were generally satisfied. Some of the studies that came out now 20 years ago, things like the star D that you may have heard of, where you start to see things like, well, maybe our treatments aren't all that good. Also coinciding with the fact that most of these other drugs were coming off patent. So now there was a big motivator to. To develop novel treatments that were outside of that, along with, you know, I have to say, ketamine, I think played a major role in this, really showing that you could have this novel treatment that was outside the monoaminergic system that could have these large effect sizes in treatment.
I think that all contributed to the excitement that we're seeing now in multiple new treatments. I think the renaissance, the psychedelic like treatments really has captured the general public.
So I think we're seeing a lot of interest. The big Pharma retreated from CNS in general 25 years ago or so. I think they're coming back in.
They're, you know, they're, they're willing to come back into the market and really invest the resources that are needed.
And I think the general public in general overall is really demanding better mental health care. So I think it's. Many of these factors are all kind of coming together at this point in time.
[00:52:47] Speaker B: It certainly, certainly has been a theme here that it's the most exciting time that we've seen in.
In a few decades.
[00:52:54] Speaker A: I at ludicrous, and I've been here for three decades. I could say by far, for me, the most exciting. Really, the 90s were kind of the trough. We hit a point where, from the basic science side, we were getting huge advances in the 1990s. But on the clinical side, it really was the down period. And since then, I think there's been continuous excitement building.
[00:53:22] Speaker B: Well, certainly I think a lot of this momentum today is downstream of the efforts that you and your colleagues put in, in the 90s and early 2000. So. So thank you for your work.
[00:53:32] Speaker A: Thank you very much, Brian. Yeah.
[00:53:34] Speaker B: Jerry, thank you again for coming on the show. I've so enjoyed this conversation.
[00:53:37] Speaker A: It really was very enjoyable. Thank you.
[00:53:40] Speaker B: Yeah.
