Dr John Krystal: Why ketamine can solve a mental health epidemic

Welcome back to Brave New World, the evening standards podcast where we explore the cutting edge of science, medicine and the future of humankind. I'm your host Yvgeny Lebedev and in this season we're pushing the boundaries even further and packing the latest breakthroughs in neuroscience, longevity, artificial intelligence with Deepak Chopra, Peter Atiyah, Jordan Peterson and many many more. In today's episode of Brave New World I'm honored to welcome Professor John Crystal, a renowned world expert in psychiatry and neuroscience whose work has transformed the understanding and treatment of mental health disorders. As known for leading the discovery of rapid antidepressant effects of ketamine in depressed patients, Professor Crystal's pioneering research has opened up new possibilities for those with treatment-resistant conditions. As professor of psychiatry in neuroscience and psychology at Yale University, he brings decades of expertise to our conversation, exploring the groundbreaking science of ketamine, its impact on neuroplasticity and its ability to restore balance in the brain. Join me for an enlightening discussion with one of the most influential figures in modern psychiatry. I'm really fascinated to talk to John because we're speaking about ketamine today and it's a very, very interested, if little known subject because it's got quite a bad reputation, what's mostly known about it is that it's a horse tranquilizer and that Matthew Perry died from it. I think those are the things that most people know. Beyond that, people know it's very, very dangerous and whilst it has that, of course, ability to be dangerous, if abused, just like anything else, it's got some very, very interesting and exciting properties that potentially could be a paradigm shift in psychiatry. So welcome, John. Could you please tell us a little bit about yourself and about what you do and then we could jump straight into talking about ketamine? I have getting great to be with you here today. I'm a psychiatrist and I study the neurobiology and treatment of psychiatric disorders. I've been in this business for a long time and one of the reasons that we're here today is that I've been studying ketamine since around 1990, which is now getting to be a long time. Trying to both understand what we can learn from it in terms of the system of the brain that it works on, which turns out to be very important for higher cognitive function and emotion, as well as the neurobiology and treatment of psychiatric disorders as it turned out. So this issue of ketamine, what is it good for, what is it risk, is something I've been thinking about for a long time. What's his ketamine and why does it have such a bad reputation? Well, I think the reason that it has a complicated history is because of both the narrow way that it was developed and its abuse liability. But let's start at the beginning. When we think about the biology of the brain, most of us think about chemicals that we've heard about like neuropronephrine and serotonin and dopamine. You might associate serotonin and neuropronephrine with depression or stress. You might associate dopamine with reward or psychosis. It turns out that collectively serotonin, neuropronephrine, dopamine, they constitute just a few percentage of the synaptic connections in the brain. And that the single most important system in terms of the main information highway of the brain, in terms of excitatory communication in the brain, involves the neurotransmitter glutamate. Glutamate is responsible for when you have a thought and one nerve cell activates another nerve cell activates another nerve cell. Most of that involves glutamate. Now glutamate has several different kinds of receptors for it through which glutamate activates brain activity. One of that type of glutamate receptor is called the NMDA class of glutamate receptor. And what ketamine does, what fancik leading does, what dextromethorophane cough syrup does, what alcohol to a certain extent does, and what some other inhaled anesthetics do is to block this NMDA glutamate receptor. And the glutamate system, because it's so finely tuned in the brain, it has some interesting properties that are reflected in the subjective effects of ketamine. So if you have just a little bit of ketamine in your body, it feels like you've had a glass of wine. And that's partly because both ketamine and alcohol share this ability to reduce the function of that glutamate receptor. If you have a lot more ketamine in your body, then you get the dissociative effects of ketamine. Cognitive function gets altered. Perception gets altered. This happens at a dose that experienced heavy drinkers describe as the equivalent of about six to 12 drinks of alcohol. In that dose range, and just really in that dose range, ketamine turns out to have antidepressant properties. So if you go from a glass of wine, which is like a 0.1 milligram per kilogram of ketamine, the antidepressant dose where you get these cognitive perceptual dissociative changes at 0.5. If you double it, you still get antidepressant effects, but much more in the way of side effects. And if you double the dose, again, it's an anesthetic medication. So ketamine has this range of effects that are all related to the same action. Euphoria at really low doses, dissociation at the middle doses, and anesthesia. So you can do surgical anesthesia at higher doses that are not that much more than the therapeutic doses, maybe four times the therapeutic dose. And so ketamine was developed as an anesthetic first. So what's the history of ketamine? When was it developed first? So ketamine is a derivative of fancycillidine, a range of dust. And fancycillidine was first developed in the late 1950s, and it was too powerful, too long lasting. And its effects on behavior were too disruptive. And so what ketamine is is a weaker, insurer-acting version of a fancycillidine-like drug. And they found that worked really well as a battlefield anesthetic. And as an emergency room anesthetic. Was it used quite a lot in Vietnam War? It was. And there are a couple of reasons for that. When you're out in the battlefield, it's hard to manage a person's blood pressure while they have a wound or something like that. And unlike most anesthetics, ketamine does not drop your blood pressure a lot. The second thing is that most anesthetics suppress breathing. And so on the battlefield, if you are trying to do surgery on someone right there close to the front of the battlefield. You need to manage their blood pressure. You need to intubate them and breathe for them. That's a lot of infrastructure. And you often don't need that with ketamine. The third thing that makes ketamine really useful on the battlefield or a popular still as an anesthetic is that it's good at controlling pain. Because of ketamine's effects on a process that I know we're going to get to, which is called neuroplasticity. Not only helps to control the pain while it's in your body, but it helps to protect your body from getting neuropathic pain reactions to nerve damage in the context of surgery or in a context of a wound. So ketamine was a very good and continues to be a popular anesthetic because of these unique effects on blood pressure, on breathing, and on neuroplasticity. Okay, John, that's a great introduction to what ketamine is. I'd like to unpack a little bit of your previous introduction to how ketamine works on depression or treatment resistant depression. I know it's a very complex process and we still don't know exactly how it works, but it would be good to explain how these neurotransmitters work. But the flip side of these neurotransmitters is that they control on the positive aspect of their presence. It's for serotonin, it's mood. As far as I understand, it's mostly mood regulation, right? Serotonin's function. Yeah. So all of these systems are extraordinarily interconnected. The way that I think about it is more love. like an engineer. I think that these systems in the brain interact in complex ways to affect our mood, our thinking, our behavior. And I think of Norpeneff and Serotonin endopamin as tuning mechanisms. In other words, the main information highway of the brain is the glutamate system that's excitation balanced by GABA. But the functions, when we have a thought, when we are trying to remember something, when we are having an emotion or a feeling, the glutamate system is tuned by these other chemical systems. And so I think it was natural in a way, once in the '50s and into the '60s, when these neurotransmitters were first discovered-- believe it or not-- our knowledge of the brain is very recent. It's quite extraordinary. Yes. And so I think that's one of the reasons that we're beginning to see now, 50, 60 years later, finally, the breakthroughs of the '50s and '60s are starting to be realized now. It's taken a long time to figure out how these chemical systems interact. And people have wondered whether maybe these problems are just too complicated for psychiatry to really understand in neuroscience. And they were. They were too complicated for us to be able to really understand given the neuroscience of the '60s and '70s and '80s. But we're starting to get real traction now. And that has helped us to understand that while the neuropronephrine and serotonin and dopamine systems can be important to engage in order to treat depression. In other words, the medications that we use to treat depression like prozac or fluoxetine, that's targeting the serotonin system, buproprion or well-butrin, that's targeting the neuropronephrine and dopamine system, catapene targeting serotonin and dopamine, all of the standard medications that we had to treat depression, sort of built on this idea that depression might be a disorder that lived in the primitive neurons that contain neuropronephrine, serotonin, dopamine. These nerve cells live in the midbrain in the brain stem and are evolutionarily extremely old. And yet they play this important function of tuning glutamate in GABA, the inhibitory transmitter in the brain. And what happened in the 1980s, particularly from work led by my mentor and colleague, Dennis Cherny, was that it turned out that if you depleted the body of serotonin and neuropronephrine, that although you could reverse the antidepressant effects of drugs like fluoxetine or prozac, transiently, you couldn't make healthy people depressed. And the important idea there that we had to grapple with, this was probably 1990, 1991, '92, was what if depression didn't live in these serotonin and neuropronephrine neurons? But rather, we just took advantage of the ability to tune brain function using these drugs, but that the disease itself lived in the higher centers of the brain, the cerebral cortex, the limbic system, the parts of the brain involved in generating emotion and governing our emotional life. So that's what brought us to ketamine in the first place, which was that we thought, well, perhaps we could learn something really important about the biology of depression. If we could understand what was happening in the glutamate synapses, the connections between nerve cells and the brain. And because I had been studying ketamine, I had in my toolbox an approach to studying this glutamate signaling mechanism, the NMDA glutamate receptor. By blocking it, we could then evaluate its effect on depression. So we gave depressed patients this low dose of ketamine that just put it up into subjective effects in the dissociative range. And what we observed really, too much to our surprise, was that some people had a dramatic effect, starting to improve within a few hours of administration, and in some cases being in remission. In other words, no meaningful symptoms of depression by the next morning. And some of these people had had been depressed for quite a long time. And so it was as surprising for them as it was for us to see that they were having this dramatic response. And we weren't even sure that it was real when we first saw it. And so over time, when various groups began replicating the effect that gave us a lot more confidence in the initial observation. So as far as I understand, this was a complete surprise to discovery and to your discovery. In a way, it's a complete surprise. And in a way, we were aware it was a possibility. So a friend and colleague of mine, Phil Skolnik, a few years before we had done archedemene study, had done some studies in rodents and rats that suggested that these drugs might have beneficial effects on animals and stress models that are sometimes used to provide clues into antidepressant activity. However, one of the problems with these models is that they're not terribly predictive of what a drug will be like in depressed patients. And the other part was that it couldn't really predict that these models aren't designed to tell you whether a drug you have to administer it for many weeks or whether a single dose will work or things like that. And so we were aware of the possibility that in some way, NMDA receptor blocking drugs like ketamine might have some antidepressant effects. But we couldn't predict. And we were very surprised by the rapidity and the robustness of these antidepressant effects. And you have to remember that what we were seeing within 24 hours of a single dose was in many cases more robust than what you would see with several months of treatment with standard antidepressant medications. So we were absolutely not prepared to see such traumatic results. And I believe those quite a lot of disbelief to begin with in the community. That is an understatement. I think the first time I presented the results was in 1997. And I would say shock, disbelief, amusement, those were the modal responses to the presentation. And I can understand it because even when we were seeing it, even when we were talking to these folks, it was a bit of a surprise to us. Well, since we're talking about this groundbreaking discovery and what it potentially means for psychiatry, let's talk about the highlights. Let's talk about what are the highlights of ketamine. So ketamine is dramatically different than any other medication treatment that we had before. So let's level set here, which is that no medication is a magic bullet. No medication works for everybody. Some people don't have a good clinical response to it. Some people find the side effects intolerable, et cetera. But when it works, people can start to feel better within two or three hours of administration of the first dose. They can be sometimes, many times, back to themselves within 24 hours of their first dose. Even people who have failed to respond to many prior treatments. And that improvement can generally be sustained by repeating the dose. So the general practices for people to get two doses a week for the first month and then gradually to taper down the frequency of dosing over time. And then just on that, John, while we're there. So the protocol that you've been working on is that the therapeutic dose is 0.5 milligrams per kilogram. Right? That's the dose for ketamine, which is the drug that we studied. The drug that was developed by Janssen Pharmaceuticals, Johnson and Johnson, is the S version of ketamine. The version we studied is two mirror images, molecules that are mirror images of each other, are ketamine and S-ketamine. The S-ketamine, which is the more potent version of the drug, was developed by Johnson and Johnson and developed as S-ketamine. And that was approved in 2019. It's been marketed in America and around many parts of the world as spravato because it's administered as a nasal spray. And that-- drug is dose that doses typically of 56 to 84 milligrams. And is ketamine approved by the FDA for depression in the states as well? Yes. So ketamine was approved for treatment, resistance symptoms of depression in 2019. And a year or so later, it was approved by the FDA for treating depression in the context of increased suicide risk. And that was studied because of one of the things that was found in some of the early studies was that it was effective for reducing suicide ideation. That proved difficult to demonstrate in the clinical trials, the randomized clinical trials, but long-term observational data and supporting the idea that it reduces suicide risk. So the onset of effectiveness is the most rapid of any treatment we have for depression. It's very robustly effective, even for patients, many patients who have not responded to other treatments. When people are on the protocol, stick to the dose and stick to the protocol where it's been shown to be effective, it is more effective in protecting against relapse, a two-depression over long-term treatment. You know, one of the things that a psychiatrist like myself becomes very aware of when you work with patients is that there's some people that you try a variety of different treatments. It can take six months or a year to get somebody better. And then within a month or so, they may have a relapse of their depression. And that's because when you are treating people with the standard antidepressant medications and they have treatment-resistant symptoms, the chances of them relapsing are pretty high over the subsequent year. But, as Academy looks like it about halves that relapse rate that you usually see over long-term treatment. I was at Virginia Woolf committed suicide, not because of depression, but because of the feeling that she was going back. That's right. She wrote a very heart-rending suicide note before she killed herself, which is, I think, reflexive experiences that many people who have very severe depression wrestle with, which is she felt it coming back and she couldn't bear the idea of putting herself and her loved ones through all that she went through with her earlier experience with depression. And that's apparently why she killed herself, loaded her jacket with stones and waited out into the water. That's very sad. And, John, what's the effectiveness rate? It's about double the effectiveness of adding a medication like catapene, which is one of the most common strategies for treating antidepressant-resistant symptoms of depression in long-term, in what are sometimes called naturalistic study, where they just compare the long-term follow-up of their data to what general treatment looks like in the population. In other words, not a randomized controlled trial, but just observational. Johnson and Johnson followed over a thousand people treated almost four years on average with S. Catamy and compared it to historical data set. And they found a tenfold reduction in the odds ratio of attempting suicide over those four years compared to standard treatment, about a fivefold reduction of the chances of dying by suicide, and about a threefold reduction in the odds ratio for all cause mortality. Yeah, that's what we explain, please, how that's calculated, because that's an incredible statistic. Yeah, so what all cause mortality is really brings us back to a really fundamental idea that I think people who experience depression intuitively understand, which is, of course, depression is a brain disease, but it's also a whole body disease. When you're depressed, basically almost every medical condition gets worse, heart disease, respiratory disease, kidney disease, arthritis. And that's partly because some processes in the body that contribute to depression, including one called inflammation, also contribute to worsening these other diseases. And by exacerbating these kinds of disease processes, people die at a younger age. What people often don't appreciate about inadequately-tapreded depression is that it shortens your life by exacerbating these other medical conditions, and it can shorten it by up to 10 years. So when you have a more effective treatment for depression like Catamy, compared to the standard treatments, you reduce all cause mortality. In other words, the chances of dying from these other medical problems. Yeah, well, these are really, really extraordinary highlights. And I wanted specifically you to bring these up, and I'm very pleased you did, because it shows a very different picture from the one I painted when I opened this conversation that it's a host tranquilizer and then killed a famous Hollywood actor. It could potentially be completely transformative. I do think it's a transformative treatment. Catamy and as Catamy seem to be as effective as electroconvulsive therapy, where you put someone under anesthesia, where you interpret and breathe for them, and where you produce an electrical seizure through their brain. And the idea that this brief medication treatment can do all that is really extraordinarily important. And I think that while it has taken America a while to build the infrastructure to make Catamy and the Catamy accessible to patients, I think it's having a huge impact. What we struggle with is that Catamy is also a host tranquilizer is also an abused substance and also played a critical role in the death of Matthew Perry. And we have to deal with that dichotomy, respecting and protecting people as much as we can from the risks of Catamy. At the same time, trying to make this important treatment accessible to people. I started studying Catamy not to understand depression, but to try to understand the extraordinarily complex biology of schizophrenia. The problems that we have with our earlier limited understanding of depression were paralleled by a very oversimplistic ideas that we had about the biology of schizophrenia. We were convinced by the early 90s, by the late 80s that schizophrenia was a disorder of the cerebral cortex. And yet we had very few tools to study the signaling of the cerebral cortex. And that's what got me to study Catamy in the first place. And so because I was interested in studying and modeling the subjective experience of schizophrenia and the cognitive impairments associated with schizophrenia, I had to experiment with various doses where I could get the dose high enough to produce those cognitive impairments, but not so high that people couldn't do the tests that I was giving them. So it turned out that by experimenting with that dose range and optimizing it for the kind of testing I was trying to do, I just happened to stumble upon the dose range where Catamy has a profoundly paradoxical effect on the brain. And that is that when you think of an anesthetic medication, you basically think of a drug that turns the brain off. And if you give Catamy an anesthetic doses, that's basically what it does. It reduces the activity of the glutamate system of the brain to the point where people are not responsive anymore. But if you back it down to the dose range that I was studying in this narrow window where you get high enough to produce the effects, but not so high, then it turns out that it hits the internarons. It reduces the activation of the inhibition system, dis-inhibiting brain circuits, activating brain circuits. And so even though the drug, all the drug does is block activation itself, because it has differential sensitivity to hit different cell types and thereby dis-inhibits brain activity, it triggers a downstream cascative events that produces the antidepressant effects. So the actual drug effect in the brain isn't probably what produces the antidepressant effects, but it's the overall impact on brain circuits, activating brain circuits, triggering therapeutic neuroplasticity in the brain and having some surprising effects that we've learned about, which we can talk about if you want. Okay, well, why don't we talk about that very thing? Why don't we talk about how ketamine works on the brain as it's administered and how it works in its aftermath. Like most of our brain, there's still questions to be answered. But I think let's start with talking about the glutamate receptors and GABA and how they interact and what ketamine does when it's administered. Whenever you talk about the brain, the final word is it's complicated. And so what I'm going to present are some ideas that we've been studying and other groups have been studying now for about the last 15 years or so, which builds on work that we and others did earlier to just try to understand the biology of ketamine effects in the brain generally. But let's take a step back and take a slightly different opinion about the biology of depression, because that sets the stage for understanding why the effects of ketamine might work to treat depression. So we started out talking about depression as a chemical imbalance, particularly in serotonin, or prenephrine dopamine. And then we shifted to the idea that maybe it's a chemical imbalance, but that imbalance is taking place in the higher centers like like in the cerebral cortex and in the limbic system, the motion centers of the brain. And to a certain extent, all of that's true. But there's another piece that we just began to talk about, which has to do with inflammation, stress, and the biology of the brain. So in the body, if you have a lot of inflammation, you get atherosclerotic heart disease, you get those plaques blocking your coronary artery. The equivalent of that cumulative stress depression effect in the brain is that you get inflammation in the brain. And the brain starts, it initially tries to adapt to that stress. And then that stress starts to take its toll on the brain. And one of the things that happens is that the immune cells in the brain get activated in a detrimental way. Those immune cells are called microglia. And they start gobbling up those synaptic connections. And what that means is that while when you have a bad day and you feel depressed and you have a bad mood, that's kind of neurochemical imbalance. But when you have chronic severe depression, particularly the kind of depression that hasn't responded to antidepressant treatment, that is a neuro degenerative condition. You're losing synaptic connections. There's some evidence of reductions in volume on MRI scans and other kinds of changes. And so you do see with long term treatment, you know, with prozac and other kinds of antidepressants, some regrowth of the volume of the brain. And so these drugs that are antidepressant do over time produce some regrowth. What's incredible is that with 24 hours after a single dose in animals, stressed animals, you see the synaptic connections regrow. And 24 hours after a single dose of ketamine and depressed patients who have these synaptic deficits, you can see an increase in synaptic density in the brain using a PET scan. And that increase seems like it might be related to the extent to which people improve in their depression. And that, of course, is an extraordinary thing because we've been quite recently, I believe thought that the brain is not a plastic organ and it doesn't change. It doesn't grow. And the fact that synaptic connections can be regrown and that ketamine stimulates that regrowth is yet again an extraordinary quality for this drug. And is the effect of neuroplasticity related to the regrowth of synaptic connections? Yes, I think so. They're not exactly the same thing. So it looks like ketamine may enhance synaptic plasticity a little bit earlier than it does regrow the synapses. Like that early antidepressant effect within a few hours, that probably doesn't depend on the regrowth of the synaptic connections. But one of the things that ketamine does that in parallel with increasing the structural plasticity of the brain, in other words, regrowing it, is it makes glutamate synapses more effective. And so you can see this in a variety of ways. One of the simplest tests that has been done is to just have people listen to a sound or experience a sensory stimulation of some kind. And that evokes electrical response in the brain. And in people who respond to ketamine, they increase the magnitude of that evoked sensory response. In other words, their synaptic connections have become more effective within 24 hours of a dose. So how would that relate into one's life? For example, if someone with depression or anxiety, and we should talk about anxiety as well, doesn't look at the sky or doesn't look at the flower, or rather looks, but doesn't respond in a way that a joyful person would respond. What you're talking about will change that response. Yes, that's right. One of the things about mental illness is that the way in which we talk about depression is reflected in the way in the brain itself. For example, the Greeks used the term melancholia, black bile. This idea that there was something that was just so awful and terrible, that wasn't sad. It was different than being sad to understand depression. And a lot of other people used the term blue. Because when they're feeling depressed, colors don't seem so bright. The connections with other people aren't so vivid. And people do describe that within 24 hours of their first dose of ketamine, feeling light, feeling engaged ability to experience pleasure, ability to react in the ways that they normally do. And that is probably a reflection in part about this restoration of synaptic connection, both structural and the functional connections that people have. And what's interesting to a neuroscientist type, like me, is that the duration of the antidepressant effects of a single dose in animals looks like it lasts about as long as the synaptic connections that are regrown last. In other words, I wish ketamine was a cure for depression. In other words, that we give you a single dose, you feel better and that's it. We're done. But it doesn't work that way. Gradually, for reasons that we don't entirely understand, gradually, those synaptic connections that are regrown by ketamine go away and you have to get another dose of ketamine to sustain the clinical benefit. Presumably, there's also something to be said about how those synaptic connections, and perhaps there is no science about this, but it seems common sense that if the person who's been given these new synaptic connections goes out and makes certain changes in their external environment because of these synaptic connections that they've been given, maybe these synaptic connections will last that little bit longer. I think you're absolutely right. And we don't have a lot of research that concretely validates that. But one of the pieces of data that's very interesting is that if you combine ketamine with cognitive behavioral therapy, the antidepressant effects of a single dose of ketamine seem to last longer, seem to be maybe even a little bit more robust. So I do believe that when you get a dose of ketamine, and you have the state of heightened neuroplasticity, there are things you can do in that window, which probably include many things that we haven't yet studied well, like psychotherapy, like exercise, like going to an art museum, like listening to music, or things that are ways that we draw on to be emotionally resilient, that I think probably do synergize with ketamine. Ketamine has one paradoxical effect, though, that might be surprising. And to understand that paradoxical fact, we have to go back to the idea that I said at the outset that what ketamine does, even though the therapeutic effects are paradoxical at its heart, what ketamine does is block the NMDA glutamate receptor. And one of the interesting things about the NMDA glutamate receptor is that that is a pro neuroplasticity receptor. So ketamine has paradoxical effects that promote neuroplasticity 24 hours after a dose. But while the ketamine is in your body, it's reducing plasticity. That's why it protects against developing neuropathic pain after surgery, why it is a good battlefield anesthetic. So how does it I find it quite difficult to get my head round that I have now, I think, having spoken to you and listened to your other conversations that, whilst it blocks the receptor in the time, the receptor, which is actually responsible from your plasticity, the after effect is the creation of your plasticity. That's right. And so it creates this paradoxical opportunity to interfere with the strength of a male adaptive memory. So there is a group at University College London, the first author on the paper was Ravi Das, where they had people deal with male adaptive alcohol-related memories. And they had people hold a glass of alcohol and sniff it, activating the circuits in the brain associated with those alcohol and memories. And then they gave ketamine. And because ketamine reduces neuroplasticity, it reduced the strength of these memories through a process we call reconciledation. It interfered with the reconciledation of those memories. Every time you activate a memory, you make the neural representation of that memory plastic. And so if you tell people things when you activate that memory, you can create false memories. You can alter the memory. That's kind of what psychotherapy is in a way. So this is where ketamine works with PTSD. Exactly. So if you have a trauma memory, my colleague here at Yale, Elon Harpaz wrote him, led a team of people that showed that not only can you weaken the physiological reactivity to those emotional trauma memories, but you also reduce the activation for a long time when people are re-exposed to those trauma memories. When you're treating PTSD with ketamine, you can have one effective ketamine that's just the antidepressant effect of ketamine, which people with PTSD also show. But then you can layer on top of the ketamine, this memory manipulation, which can help to manage the trauma memory part of PTSD. So drugs like ketamine have kind of distinctive effects that come from taking advantage of all that we understand about its effects on neuroplasticity in the brain. To help us understand the default mode network and its role in mental health, I asked John to take a moment to break it down. John explains how this intricate system works, what happens when someone suffers from depression and how ketamine can restore balance. Maybe I can just put this idea of default mode network into a little context. We can think of many levels at which the brain is organized. So the brain is organized at this one synapse between two nerve cells. And then the next level of organization is a group of a few nerve cells are organized in a small circuit. And then you have a few neurons that are organized around the brain, the frontal cortex and the parietal cortex. And as you get to higher and higher levels of organization of the brain that are representing some of the emergent properties of behavior, what you discover is that the brain is organized in these kind of mega networks. And one mega network helps us to manage and control and be flexible in our behavior. That is called the executive control network and the king of the executive or queen of the executive control network is the prefrontal cortex. And the executive control network, I mean, the brain turns out to be a little bit like game of thrones because it operates through antagonism in a way. It tunes itself through opposition. And so you have the executive control network which is trying to get us, keep us engaged in activity, planning our next behavior in a very rapid state of engagement and response to the environment. But we can't always just live in the moment. We have to take a step back. We have to reflect. We have to respond emotionally to other people. We have to respond in order to do that, you have to tune down the executive control network and allow other networks in your system to be activated. The default mode network, as you can gather from the name, is the network that is activated in opposition to the executive control network through which we daydream reflect, think what happens in conditions like depression where we're locked into our own heads is that the default mode network is running the show. It's running all the time. The frontal cortex can't turn it off. And so when you give a drug like ketamine, you tend to restore the balance of the executive control in the default mode network. And that is both an observation from brain imaging research and a metaphor. And when I say metaphor, what I mean is that we have to appreciate that when we get to these higher and higher order organizational properties of the brain, our knowledge of them at a mechanistic level becomes less and less. Now, there's a lot more room for error in these extraordinarily complex network functions. In terms of what we understand it. But the reality is we've talked about so much about neuroplasticity, about network organization. And all of this is relatively new. The fault mode network is early 2000s. So we're talking about science, which is relatively new that is still in some ways getting worked out. But is shedding some really profound and interesting new perspectives on both the biology, the experience of depression as well as its treatment? My right is saying there's about 80 billion neurons that a human brain has. So it's quite my boggling, the stuff we're discussing. It's, you know, I would my very rational mind try and put it together in some kind of, but rational, but yet simplistic understanding of neuroscience, try and get my head around that excuse the pun. But as you say, it's also new and so, so much is to be discovered still. Absolutely. But you know, ketamine is an example. And there are some other examples that have followed it where as we revisit some of these old drugs, ketamine, as we were saying, dates back to the 60s, as we revisit some of these old drugs with new neuroscience perspectives. We're beginning to see new opportunities for treatment. So as you know, there's a lot of research with psychedelic drugs, which you also go back to the 60s. LSD was synthesized earlier than that, but didn't really enter psychoparmacology research in a meaningful way until the 60s. And MDMA, an old drug, which is being studied for PTSD in parallel in schizophrenia, another old drug, which goes back to the 1990s, just got approved for the FDA to treat schizophrenia without blocking dopamine D2 receptors. So there's a sense that our neuroscience has moved forward another kind of generation and is starting to have new kinds of traction and understanding problems that people have and suggesting new treatments. Yes, absolutely. It seems like there's a real paradigm shift happening if it hasn't yet happened in psychiatry and neuropharmacology in the last 25 years. And I would be remiss if I don't ask you about anxiety because anxiety seems to me different side of the same coin with depression. And I believe there is, it correct me if I'm wrong yet again, I'm sort of, I tread on thin ice venturing back into a neurology, but the dying off of synapses is also a symptom of generalized anxiety disorder. And I've heard a metaphor of if we look at a healthy brain, it's like a tree in the summer. If you look at either a generalized anxiety disorder brain or treatment resistant depression brain, it's like a tree in the winter in terms of synapses. Well, you know, one of the things that you're getting at is that the boundaries of our psychiatric disorders are not perfect. In other words, orthopedic surgery is lucky because if you break your leg, you know that you didn't break your arm, but in psychiatry, if you're depressed, you can also be anxious. You can also have other problems. And the boundaries are not so rigid. And within a category, the symptoms and experiences that people can have are quite heterogeneous. Some people with depression will have severe anxiety as part of their depression. Other people won't. And when you look at the genetics of depression and anxiety, the disorder are tend to be pretty closely genetically related. So about 40% of the risk of developing depression is genetic. About 40% of the risk of developing the anxiety disorders is genetic. And there's a lot of overlap in terms of the genes that are implicated in depression in anxiety. And the overlap in twin studies between generalized anxiety is so great that the people who are studying it led by Ken Kendler concluded that generalized anxiety disorder and major depression are the same disorder separated by distinct environmental exposures. So when we talk about anxiety problems and depression problems, there's a lot of overlap in what we'll say. When it comes to ketamine though, there's a critical difference, which is ketamine can treat generalized anxiety disorder. There's some evidence of that. Maybe treat post-traumatic stress disorder, which has an anxiety component. And it does so at the antidepressant doses so that even when the ketamine is not in your system, if you get an antidepressant dose of ketamine, your generalized anxiety symptoms may be reduced for a long period of time. But, and this is a really important issue for people to understand. If you get a low dose of ketamine, then ketamine acts more like a benzodiazepine like valine. In other words, if you have the dose of ketamine and you give someone like 1.1.2 milligrams per kilogram of ketamine, people get an anxiolytic effect that lasts while the ketamine is in their body, which means several hours. But it's not so clear that it produces any kind of lasting effect like you get the lasting effect from an antidepressant dose of ketamine. And so, this has led to some confusion. I think confusion on the part of psychiatrists as well as patients, where doctors are willing to prescribe people ketamine to take home, to treat anxiety symptoms with ketamine through, you know, it drops through. So, maybe in effect, micro dosing. In effect, micro dosing ketamine. And what happens is they manage their anxiety that way, but they don't treat their depression. I mean, some people can manage this, okay, I'm sure. But some people start to use more and more ketamine when they're feeling more and more stress. And so, maybe they use a couple of drops on an average day. It takes the edge off. They do what they need to do. Then they have a big presentation or they have something very stressful coming up in their life. Then they take more ketamine. And then they have something else coming out that stressful. And they take more and more and more. And so, what can happen, particularly because their depression is never effectively treated at these doses. And so, they have this persisting malaise along with their anxiety is that they are set up in a way to develop a maladaptive pattern of ketamine use. And so, we have not, and the FDA has not approved in the United States, take home ketamine for management of anxiety or depression. And firstly, speaking, the, I understand there is some interesting research on anxiety from Australia. I believe. Right. Right. Is it a more than a therapeutic dose that was used for treatment of depression that is used there for anxiety? I think they're looking at a broader range of doses than we have looked at. But they started out more with the therapeutic dose. I think they're trying to explore some a little bit lower doses now, but their work, I think, helps to make the case that at the therapeutic doses, it has this anti-anxiety effect, which you also see in the depression trials. And how does it actually work? How does the treatment actually work? What happens? Say someone in the United States wants to go to ketamine clinic to try and treat their treatment resistant depression. Please explain what happens. So what tends to happen in the United States now, because ketamine is limited to patients who have treatment resistant forms of depression or urgently severe depression, is that people have already been seen by a mental health practitioner or doctor of some kind. And they've been evaluated and they've generally failed at least one, generally two kinds of medication trials. So it's very, very commonly happens in the United States. Is people go to their family doctor or their family nurse practitioner? They say they're depressed. The doctor or their nurse practitioner says, "Okay, we'll start you on an antirepressant. Let's see how you do." And they say, "After a month or two, they come back and they're not better." And then they try adding another medication or they refer to a psychiatrist at that point. And then they get the second trial, which is very often either adding another antirepressant to ketamine or adding a medication like a tie-apene or a pepperazole, these, what are sometimes called second generation antipsychotic medications, which have a big therapeutic effect for many patients. And if they fail to get better or adequately better at that point, then they're often referred to a ketamine clinic for the administration of ketamine or esketamine. And what's kind of interesting is that first, some routine psychiatric practices have started to adapt to being able to prescribe esketamine in their clinic. In other words, they dose people in their office, they have them stay in a waiting room or another room where they check on them periodically and then discharge them. The second thing is that we have seen, as you describe, the growth of ketamine clinic, which is our practices specifically devoted to ketamine, which may be psychiatrists or non-psychiatrists, often pain doctors or anesthesiologists, that focus on ketamine and administer ketamine for all the different indications for which ketamine is approved. In other words, they might give it for chronic pain, they may give it for depression, maybe they give it for other kinds of conditions. In those clinics, it's really critical that the mental health practitioners who referred the patients to the ketamine clinics follow the patients and are engaged with the clinic because ketamine is a procedure, but the treatment process is bigger. And even when people get better with ketamine, it doesn't mean their life is now solved for many people. For many people, that's the point where for the first time in a long time, they're in a position to start dealing with the other issues that have been building up in their lives, like the fact that they have trouble getting along with people at work or they aren't happy with their career or whatever. And paradoxically, one of the things that can happen is that people who get referred to ketamine sometimes have been depressed for five years or on and depressed on and off for a long period of time. And their whole world has adapted to them being depressed, not suggesting things, not wanting to do things, just going along with the flow, accepting what everyone around them has been telling them to do. And when they get better, all of a sudden, they're things they want now. They don't want to go along with the flow. They want to do things that they haven't been able to do. And sometimes that causes some issues in their lives. And so getting better with ketamine is not just for many people, not just getting the drug in your system and recovering from depression, but also coming to terms with what it means to really recover from that depression. And that's really important. And of course, presumably, ketamine assisted therapy or therapy around the treatments is a really important factor. Well, we talked earlier about how the therapy around the ketamine treatment may help the ketamine to work better. And we talked about how recovery is more complicated than just alleviation of symptoms. And the third part is that you can have good days and bad days. And someone really needs to be watching out and available as a resource and a support. If you have really severe depression and you're getting better with ketamine, but you have relapse of your depression or going through a bad patch of trouble in your life, things like that, somebody needs to be watching out to make sure that maybe you need an extra dose, maybe you need more supportive therapy, you know, looking out for your overall well-being. And sometimes that's the ketamine clinic, but very often the people who are taking the big picture view of treatment and putting all the pieces together may be the therapist or the psychiatrist in the community. ketamine has been a game changer in treating depression and anxiety, but like any powerful treatment, it comes with side effects that patients and providers need to consider. Dr. John Crystal explains the side effects to watch out for during catamin administration and how careful preparation and monitoring can make all the difference. So the side effects during the catamin administration that we look out for are nausea and vomiting. That's the part that patients, if it happens, are most uncomfortable to them. If they have that as a side effect, there are medications that can be given as a pre-treatment to prevent that from developing or to minimize that. Catamin transiently increases your blood pressure about the same amount as walking up a flight of stairs. That's fine for most people that that's not an issue, but if people have high blood pressure already, then they need to get that blood pressure under control before they do their catamin treatment. The dissociative symptoms we've talked a little bit about, mostly we deal with that by helping people to understand what's going to happen to them, being very present during the catamin infusion if they need support in dealing with those dissociative symptoms. But the real risk is really this abuse liability. It's not really a problem so much when people are only getting catamin in a clinic, the abuse liability issues really happen when people are getting at home and using it in ways that are not optimal for treatment. And long term, do we know about long term side effects? Yeah. As far as we can tell, with catamin treatment, when I say catametriamin, I mean treatment the way that I think of catametriamin, which is you get it twice a week, then over time you go to once a week. About 75% of people can get to every other week over the first several months of treatment. And some people can get to a point where they are using it sort of in a maintenance way, just every three weeks, every month or something like that. When you use it like that, as far as I can tell, in terms of long term cognitive data, for example, there are no ill effects that have been described so far. If you give massive doses of catamene, if you give anesthesia like doses of catamene frequently every day, there are very detrimental effects on the brain. And I studied people in China and in Taiwan who are heavy catamene users who are using 100 times the therapeutic dose of catamene frequently. And they have very detrimental effects, as you might expect. In fact, when you use catamene in a abuse like pattern, everyday high doses, binges, lots of binges, things like that, what you see is that catamene has negative physical effects, it damages or irritates the lining of the urinary bladder so that one of the pathomonic symptoms of catamene misuse is needing to go to the bathroom a lot. I read you saying somewhere, it was about 42 months, was the longest clinical follow-up, yeah. Yes. And that didn't have any long term side effects. Okay. Evolutionarily, why does the human brain have this ability to get depressed? The question of why do people get depressed? And part of it, I think, is that we have this genetic vulnerability. You know, 40% of the vulnerability is this genetic vulnerability. So you might wonder why isn't it selected against? And my guess about that is that the genes that make us more vulnerable to get depressed have other positive evolutionary attributes. So for example, one of the things that makes us vulnerable to depression is empathy. So I would trade empathy for depression any day because empathy is what pulls us together and empathy is what makes our relationships meaningful. But we know that when we get close to people that invariably there's some pain connected to that. So it wouldn't surprise me if some traits like empathy which bond us together socially and make us in some ways resilient as a group come at the cost of personal or individual vulnerability. But I did want to say one thing which about vulnerability and resilience that I find so interesting about ketamine, which is it's not an accident that ketamine produces these antidepressant effects because the signaling mechanisms that ketamine engages, it just happens to engage very effectively are mechanisms that are in our brain all the time. In other words, it raises the level of a chemical, a nerve growth factor, a brain resilience mechanism. That's there all the time and engaged by exercise and other kinds of pro resilience activity. It's just that ketamine gives us a royal road, if you will, to these resilience mechanisms and helps us to engage them. This is brain derived the tropic factor. That's right. That's one of the key ones. And is that what then leads to neuroplasticity? It is an important step in triggering the structural neuroplasticity and probably contributes to the restoring the synaptic effectiveness as well. It's a very important player. And am I understanding this correctly? I read one of the studies that ketamine could potentially also mimic BDNF. Yes. Now we're at the controversy level. So there's a really great neuroscientist, Aero-Castrin, who in his group that made this observation that ketamine and psychedelics and maybe even some antidepressants might be able to bind directly to the target for brain derived neurotrophic factor or BDNF. That receptor is called the track B receptor, TRKB. It would be interesting. One of the things that I suspect about ketamine given its incredible effectiveness is that it probably acts through multiple complementary signaling mechanisms. And it wouldn't shock me if ketamine had the effect that we had focused on another group at Vanderbilt, Dr. Lisa Monteggio and Ege Cavalloli, have focused on another set of mechanisms. The Castrin's group is focused on this other mechanism. The story is perhaps more complicated than I tried to present a little bit more simplified way. But what's interesting is how they converge on this theme about ketamine enabling the brain to harness its own intrinsic resilience mechanisms and in a relatively direct way to trigger this recovery. And I guess the last thing I wanted to ask you is, why do you think there is such an epidemic of mental illness, anxiety, depression? Clearly we, evolutionarily, we're not prepared for the conditions we live on. I've been interested to hear your opinion and particularly how you see this developing. I suppose everybody always feels that they're living in an extraordinary time. I was about to talk about how stressful life is now, how isolated people are. And the phrase from the philosopher Thomas Hobbes that life in the state of nature is nasty and brutish and short popped into my mind. But there are some things that are qualities of our life now that I think set us up for anxiety and depression. One is high demand. We're extremely stimulated. We're extremely connected to all the stress and pain and challenges of our world through news, through social media, through our connections, our virtual connections. The world is a scary place. And then that is matched by levels of personal isolation that we probably have never had before. We're connected virtually but not in person in ways that we had. And social connection, real meaningful social connection is one of the most important sources of resilience that we have. My guess is that other forms of resilience like regular exercise and finding time for relaxation and meditation, we also probably don't take advantage of it as much. And so we certainly, particularly during COVID, saw increases in the rates of depression and anxiety problems, extraordinary increases in those rates. And what was interesting to me as we followed our own medical community here at Yale, but parallels the general society data is that the levels never came down after the pandemic. And it may be because the problems that emerged during the pandemic have reverberated, continued to reverberate in people's love. And we know that those stresses and burdens were not equally distributed in society, but that under-resourced or marginalized groups tended to be have the greatest burden from the pandemic and have the greatest continuing climb back to typical rates of depression anxiety. Yeah, absolutely, John. And of course, as we were saying earlier, this mind-body connection is quite a new understanding by science, particularly the understanding of other disciplines has been there for a while, but scientific understanding is quite recent and it is just as important as diet, exercise and sleep, emotional health is super important and the lack of emotional health then leads to mental unhealth. You rightly say there is no silver bullets out there when it comes to psychopharmacology, but ketamine seems like it's pretty damn close to one. Well, it's certainly a step forward. And I think a lot of times when you have new treatments, they have small overall impact. In other words, you have one antidepressant. You have a drug that is a little better tolerated, it's a little can be taken. Sometimes the impact of those treatments are not palpable in the way that ketamine is. And partly because ketamine is the first of what could be a new generation kind of treatments of ketamine, psychedelics, MDMA drugs that have these really big effects on brain function, rapid clinical response and have to be treated with the respect that they deserve. And the other part is that ketamine is the first mechanistically novel antidepressants. So you can think of treatments being a filter. So people had maybe 50 different kinds of antidepressant effects, drugs that they could have been treated with. And they're all converging on just a few mechanisms of antidepressant treatment. And so the people that were left, the half of people who get treated with depression who often don't get an adequate antidepressant response, they needed something different. And in some ways, ketamine was the first drug that was really profoundly different mechanistically from the older medications. And I think that's another reason why it has such a big therapeutic impact. It's a really exciting stuff, John. And thank you for such a fascinating introduction to ketamine that I believe so little is still known about by the public out there. Professor John Crystal, thank you very much for coming to Brave New World. And this from what you're talking about is really a Brave New World. Well thank you and it's been a pleasure to chat. Thanks for listening to today's episode. If you enjoyed what you heard, please consider subscribing to Brave New World on your favorite platform. And don't forget to leave us a rating and review. Your feedback helps us reach more listeners like you. Also be sure to share this episode with friends and family who might benefit from the discussion. Until next time, take care.