Dr. John Krystal is Chair of Psychiatry at the Yale School of Medicine. He is best known for leading the discovery of the rapid antidepressant effects of ketamine, which paved the way for the first major new antidepressant drug in decades. Here, Dr. Krystal talks about what we’ve learned in the five years since esketamine nasal spray was approved by the FDA, including efforts to predict treatment response, dosage and frequency, safety, and long-term impact. He also discusses advances in our understanding of alcohol use disorder and weighs in on the search for psychiatric biomarkers.
00:00 Introduction
01:01 Dr. Krystal's Research Journey
03:32 What We’ve Learned Since Esketamine’s FDA Approval
05:59 Avoiding Misuse
08:11 Optimizing Dosage
16:25 Predicting Treatment Outcomes
24:17 Ketamine vs. Psychedelics
25:48 Advances in the Treatment of Alcohol Use Disorder
32:33 Precision Psychiatry and Personalized Treatment Approaches
39:49 Psychiatric Biomarkers
41:03 The Future of Psychiatric Research and Treatment
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
Dr. John Krystal is Chair of Psychiatry at the Yale School of Medicine. He is best known for leading the discovery of the rapid antidepressant effects of ketamine, which paved the way for the first major new antidepressant drug in decades. Here, Dr. Krystal talks about what we’ve learned in the five years since esketamine nasal spray was approved by the FDA, including efforts to predict treatment response, dosage and frequency, safety, and long-term impact. He also discusses advances in our understanding of alcohol use disorder and weighs in on the search for psychiatric biomarkers.
00:00 Introduction
01:01 Dr. Krystal's Research Journey
03:32 What We’ve Learned Since Esketamine’s FDA Approval
05:59 Avoiding Misuse
08:11 Optimizing Dosage
16:25 Predicting Treatment Outcomes
24:17 Ketamine vs. Psychedelics
25:48 Advances in the Treatment of Alcohol Use Disorder
32:33 Precision Psychiatry and Personalized Treatment Approaches
39:49 Psychiatric Biomarkers
41:03 The Future of Psychiatric Research and Treatment
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
NOTE: Transcripts of our episodes are made available as soon as possible and may contain errors. Please check the corresponding audio before quoting in print.
DR. THEA GALLAGHER:
Welcome to NYU Langone Insights on Psychiatry, a clinician's guide to the latest psychiatric research. I'm Dr. Thea Gallagher. Each episode I interview a leading psychiatric researcher about how their work is shaping clinical practice. Today I'm pleased to welcome Dr. John Krystal, chair of the Department of Psychiatry at the Yale School of Medicine. Dr. Krystal is a leading expert in the areas of alcoholism, PTSD, schizophrenia, and depression. He's best known for discovering the rapid antidepressant effects of ketamine, which paved the way for the first major new treatments for depression in decades. In our conversation, Dr. Krystal talks about what we've learned since esketamine was approved in 2019. He also talks about the challenge of predicting patient responses, which speaks to the complex biology of depression. Lastly, he shares advances in our understanding of alcohol use disorder and weighs in on the search for psychiatric biomarkers.
Well, Dr. Krystal, thank you so much for being with us today on the podcast.
DR. JOHN KRYSTAL:
Well, Thea, thank you for having me here.
DR. THEA GALLAGHER:
Can you give us a bit of an overview of your research journey and what drew you to focus on depression, alcoholism, and schizophrenia?
DR. JOHN KRYSTAL:
When I was in high school, the thing I liked to do, most of all, was to play in musical groups, and I continued doing that into college. And I had a number of friends who developed drug problems and that got me interested in the problem of addiction. And so I did that in college, and I had a wonderful biochemistry class in which the teacher brought up interesting facts in biochemistry, and usually something in the news. And one particular week when I was in college, the teacher said, they discovered the enkephalins, the endorphins, the endogenous opiates in the body. And he explained how they had just discovered that there were receptors in the brain for these compounds that were released by the body that were the underpinnings of opiate addiction. And it hit me like a ton of bricks, that these extraordinarily complicated problems had at some level in their foundation, biological changes that were happening in the brain. And that if we really understood what those biological changes were, that addiction and other kinds of problems that people were struggling with could be treated in new ways and we would really have a new kind of psychiatry.
And I was maybe the beginning of my third year in college, and ever since then I've wanted to study the biology and develop new treatments for psychiatric disorders.
DR. THEA GALLAGHER:
That's a great, I feel like origin story, connection to a personal experience at such a young age and feeling inspired to do something and to make changes. I think when we interview a lot of psychiatrists, it's really neat to talk about the research they're doing now, but it's cool to see the human aspect that connects you back to what got you started in the first place.
And you're best known for your work on ketamine, which has led to the first major new antidepressant drug in decades. And so what would you say you've learned in the past five years since the approval of esketamine, and about how to use it effectively?
DR. JOHN KRYSTAL:
Well, I think we've learned, as these things always go, we know a little bit about the drug when it's approved and we continue to learn more about its use in clinical practice. One of the things that I think on the positive side that we've learned about ketamine, and this is or esketamine, and this is based on data that has just come out from Lilly, is about the remarkable long-term impact of esketamine treatment.
They had a poster at the ACNP meeting this year that showed that when people were followed for almost four years on esketamine, and then they compared large scale data to a historical group of people treated with standard kinds of treatments for depression, that the esketamine reduced the incidence of suicide attempts by tenfold. And they found that the chances of dying by suicide were reduced, and the chances of dying of any cause, all-cause mortality was also significantly decreased. Meaning that esketamine not only reduces the chances of dying by suicide, but all those medical problems that we have, which we now know the brain and body are intimately connected, and all of those medical problems, heart disease, lung disease, kidney disease, et cetera, cerebral vascular disease, that are affected by depression, the chances of dying of those conditions is reduced as well.
DR. THEA GALLAGHER:
It's really amazing, the more that we talk on these podcasts about the connection with brain and body and how physical health can be so protected by mental health. And so it sounds like you're definitely seeing that in the data already. That if we can do things to manage the depression, we're going to better manage the physical health concerns as well.
DR. JOHN KRYSTAL:
Yes. And the standard treatments that we have, the antidepressants like SSRIs, Prozac, things like that, they were already helpful for these kinds of issues. The idea that you can see an incremental greater impact with esketamine is really striking.
I'd say the other big thing that we've learned since the FDA approval has been it really is best to keep these medications, at least so far, best to keep these medications in the clinic. Which is that we've had growing reports that when people get large amounts of ketamine to use at home, that there's a risk that they will become a recreational users of ketamine, or misuse the ketamine, or even overdose on ketamine.
And we have had some various sad cases of people who are probably known to this audience. People like Matthew Perry who died. Matthew Perry when he died, had about 10 times the amount of ketamine in his body that we would normally give to someone in treatment. And as far as we can tell, obviously I don't know all the details about this, he drowned because he was anesthetized on ketamine and other substances in his body. And that's just a real tragedy.
DR. THEA GALLAGHER:
I've been listening to his autobiography, and it's just really, it's fascinating in a very sad use of that word. But it's kind of, to go back to your point, it's amazing that if harnessed correctly, we can use these substances to help. Like you said, unfortunately, and we'll talk more about substance use problems when there isn't that maybe internal mechanism of regulating, that's where we see the problems.
But it's still such new, I feel like, new research for our field with ketamine, MDMA, psilocybin to see these drugs that have always been used pretty much recreationally, used medicinally. But it seems like it's really important to have researchers like you behind and informing the dosage and the process. And can you talk a little bit about what do we know about the dosage? About how many times? About how long? About how to keep from becoming recreational or addicting, et cetera?
DR. JOHN KRYSTAL:
One of the things that is not commonly appreciated, but is directly related to your question is that when we use ketamine as a treatment, the goal is to give it as infrequently as possible. So that typically, when we start ketamine treatment, a ketamine or esketamine will be given twice, or at most, three times a week. And then after a month, or a little longer, they try to cut down the frequency from twice a week to maybe once a week. And eventually most people will usually be able to get to a dose every other week. But some people will eventually be able to reduce it to once every three weeks or even less commonly.
And when people misuse ketamine, they tend to take it in binges or they might take it every day. And when they do take it that way, ketamine actually has the opposite effects on the brain. Rather than stimulating brain resilience and growth, it tends to cause neurotoxic effects and shrinkage of the brain and produces depression. So if you speak to recreational ketamine users, compulsive ketamine users, they're more likely to be depressed.
DR. THEA GALLAGHER:
It sounds like the motivation for maybe recreational users or people suffering with addiction, it is maybe to anesthetize the brain and maybe not to get these other benefits. So when we see it used in this more appropriate dose, you said we see a simulating effect. What else do we see that's helpful with depression?
DR. JOHN KRYSTAL:
So what is really striking, and we saw this way back in the mid-90s, when we were doing our first study, and we continue to see it today in our clinics, and I continue to hear from people who've had this experience, is that there's a reasonable probability, with the first dose or at least the very first few doses of ketamine, to have a pretty rapid and pretty pronounced clinical improvement. I remember some of these early patients saying... I say, "Do you feel better?" And they would say, "I feel all better." And it's not a feeling of being drugged. It's not a feeling in any way of intoxication. In fact, the beneficial effects of ketamine tend not to appear until long after the drug itself is worn off, and you don't feel effects in your body. We would give it and then a few hours later people would tend to feel a better. And then sometimes 24 hours, 48 hours after that dose, people tended to have these more pronounced clinical improvements.
And what's interesting is that ketamine itself is a very short-acting drug. So as I say, we tend to give ketamine as a very slow infusion over 40 minutes, and then the effects wear off over the next hour or so. So it's really not any persistence of any kind of euphoria, or stimulating effect of ketamine, or even the antianxiety effects that having low levels of ketamine in your body produce. As far as we can tell, it's the reaction that ketamine triggers in the brain, which has a number of beneficial effects on brain function, that restores normal circuit function, that is associated with the antidepressant effects. And the antidepressant effects in animals, obviously, we haven't yet done this study in people, but the beneficial effects of ketamine tend to persist as long as these positive effects on brain structure and function persist.
And so the short-acting drug, ketamine, generally produces, in the first dose when people are responding, improvement for about three to seven days. And if you don't give another dose, therefore soon after that initial dose, the depression symptoms will gradually come back. Some people, maybe it's about half, are kind of stabilized when esketamine or ketamine are added to their treatment. Some people only need a few months of treatment to kind of return to themselves and to stably be themselves, and then the drug can gradually be tapered away over time. Others are maintained on this kind of intermittent dosing patterns. And I mentioned the long-term data of four years of treatment, or almost four years of treatment, and we know that there are people who have been on these kinds of intermittent dosing schedules for much longer than that.
DR. THEA GALLAGHER:
And it sounds like what you're saying is that even if the measurable effect on the physiology is more acute, there's something that's happening with long-term. I don't know if it's functional or structural changes, but there's something that's happening long-term where this positive impact continues to persist.
DR. JOHN KRYSTAL:
Yes. We know very little about why the duration of the antidepressant effects grows over time. And I would say that there are two or three basic ideas about this.
One comes from the idea that there are synergies between ketamine or esketamine in certain kinds of psychotherapy. So there's a part of the ketamine response which has something to do with learning and neuroplasticity. In other words, how the brain is modified by experience and continues to adapt over time.
And then there's kind of also a growing story that is much newer, which has to do with a study that we did in, it was published in 2020, where we gave a drug called Rapamycin, which has powerful anti-inflammatory effects on the brain, and is sometimes used to treat neurodegenerative disorders. And we gave people a dose of Rapamycin before they got ketamine. And when we did that, it extended the duration of their antidepressant effects, so that at two weeks, instead of having only a few percentage of patients still responding from that ketamine dose, when Rapamycin was given, over 40% of the people were still responding to a single ketamine dose at two weeks. And so we think what Rapamycin is doing is protecting and preserving the beneficial effects that ketamine produces in the brain. And in fact, there's a company called Freedom BioSciences that's developing that combination as a treatment.
So as we learn more about how ketamine produces its beneficial effects on the brain and brain function, we're probably going to get a variety of different kinds of next-generation treatments that will even build on the benefits we're already seeing with ketamine and esketamine.
DR. THEA GALLAGHER:
Which is an exciting frontier for the research.
And speaking of the research, I know I think it's among a lot of clinicians, psychiatrists, the idea is that people who don't respond to the gold standard SRI, or other cognitive behavioral therapy, or treatment refractory patients, that they're going to be put in the ketamine-esketamine camp. Do we have any better ways of predicting who will do well with an esketamine protocol?
DR. JOHN KRYSTAL:
I wish we did. I mean, in fact, there's an idea that we know that depression is an extremely heterogeneous condition. And so if you talk to two people with depression, one person with depression will have no energy. Another person with depression will be anxious, and pacing, and can't relax. One person will be unable to sleep, another person with depression will sleep all the time. Another person will have no appetite. Another person with depression will be eating all the time to try to ease the pain. And so we know that these disorders are heterogeneous. And ideally, someday, there'll be some kind of way to give people questionnaires, or have a blood test, or something that will say, "Oh, you're not going to respond to an SSRI. You should go right to ketamine," or something else. But we do know that there are important differences in the biology depression.
I'll just tell you one study, that pilot study that was done by my colleagues at Yale with ketamine, which was: We use PET scans to measure the number of synaptic connections in the brain. And we previously found that people who have relatively severe types of depression have a reduction in the number of synaptic connections in the brain. And so how does that relate to ketamine?
Well, we did a pilot study led by Irina Esterlis and Sophie Holmes, where we gave people with depression and healthy people a dose ketamine. The healthy people that got a dose of ketamine, it didn't do anything to the number of synaptic connections in the brain. The depressed patients who didn't have any synaptic deficits, they did not have any increase in the number of synapses in their brain when they got ketamine. And yet some of them still showed improvement in mood. The healthy people showed no improvement in mood after ketamine. Depressed patients without synaptic deficits did show some improvement in mood. But the group of more severely depressed patients who had synaptic deficits, they increased the number of synapses, and the extent to which they restored the synaptic connections in the brain was related to the magnitude of their clinical benefit.
So we do think that there are potential markers of people who are more likely to benefit by a drug like ketamine. It's very early days in that work, and we're not ready to use that kind of test to get people on ketamine. But the idea behind this would be, gosh, if we knew who needed the ketamine, we give it to them right away. We wouldn't make them fail another antidepressant treatment in order to get to ketamine, or whatever they would benefit from.
DR. THEA GALLAGHER:
And it seems like we're moving toward maybe a ketamine being one of the gold standard interventions. Maybe not an afterthought, but something that's in the running in the beginning.
DR. JOHN KRYSTAL:
Absolutely. And two studies really make that case that came out in the last couple of years. The first is a study by Reif el al., which appeared in the New England Journal of Medicine. And this study showed that the prior most common strategy for treating antidepressant-resistant symptoms of depression would be to add an antipsychotic medication. But in this study by Reif and colleagues, the odds of responding to esketamine instead of one of these antipsychotic medications was two. Meaning you had about double the chance of responding or remitting on esketamine, compared to what had been the common standard practice.
The other really interesting study was a comparison of ECT Electroconvulsive Therapy to esketamine. And as you know, Electroconvulsive Therapy involves going under anesthesia and then having an electrically induced therapeutic seizure in the brain. And that's been kind of the gold standard for treatment-resistant symptoms for a long time. But in this study, which also appeared in the New England Journal, Amit Anand was the first author, they found that, this was ketamine, was just as good, really, as ECT in producing improvement.
So you're exactly right, which is that this practice of esketamine, which had been kind of marginal, looks like it should be right in the center of treatment planning. And if we want that to happen, then we have to address the challenge of access. In other words, we have to figure out how every town, every city could have a center, a hospital, or clinic where people can get access to one of these new treatments.
DR. THEA GALLAGHER:
That sounds like a job for our population health folks to take on. And I think one of the things that's appealing to so many patients, and clinicians alike, is the safety here of ketamine. Can you talk a little bit to our listeners about that?
DR. JOHN KRYSTAL:
Sure. People are very concerned about the safety and tolerability of ketamine, and rightfully so. We should be thoughtful about how we approach any medication. We've already talked about the addiction risk associated with ketamine or esketamine.
Generally, when people get a therapeutic dose of ketamine or esketamine, they may feel a little sedated. They may feel their blood pressure goes up a little bit. They may feel a little nauseous. And they certainly have altered kinds of sensory perception. People sometimes call it dissociation. Things feel unreal, or some altered sensory changes that persist for about a half hour. But the remarkable thing, in this study that I mentioned, Reif et al., was that more people dropped out of the antipsychotic medication arm due to side effects than that dropped out of the esketamine arm. And maybe it's partly because it's true that there are side effects when you get the ketamine or esketamine, but if you're only taking the drug once a week or once every other week, you're only exposed to those side effects for a very short period of time. Whereas if you take a medication every day, that's drugs in your body all the time, and you are kind of more consistently exposed to the side effects associated with the medication.
Plus when you get esketamine, there are people around you that are supporting you and helping you to manage the side effects, whereas if you're taking a medication every day, you're a little bit more on your own.
DR. THEA GALLAGHER:
And I think that's one of the aspects that sticks out to me so powerfully, that I don't know if we talk about enough, but the idea with ketamine, MDMA, psilocybin, that, like you said, it's the amount of times you actually have to use it or take it. And speaking of access, and just like you said, even just comfort, you're cutting down on that pretty significantly, which from an accessibility and population health standpoint seems like it could have really overarching durable effects in the long term.
DR. JOHN KRYSTAL:
And I think one of the advantages that ketamine has, with respect to MDMA and psilocybin, it's a relatively short treatment. And so if you go in for an MDMA session or a psilocybin session, you're pretty much having an all-day treatment, six to eight hours. Whereas the ketamine sessions or esketamine are about two-hour sessions, but it means that one of the things we have to figure out with these medications once we have an idea that they're helpful, in other words, when the FDA approves psilocybin or MDMA, is how do we use them? How do we take these really interesting opportunities for treatment, and how do we turn them into treatments that people can get access to and use well for their recovery?
DR. THEA GALLAGHER:
And it seems like since ketamine has led the charge with this work, like you said, and also, you have more data to support how helpful it is, and again, how short-term the treatment itself is.
I'm going to turn to your work on Alcohol-Use Disorder, because in addition to leading the first definitive test of the efficacy of Naltrexone for treating AUD, you've also studied the disorder's neuro-biological underpinnings. And so what are the most significant recent advances on that front, and how might they inform therapeutic interventions going forward?
DR. JOHN KRYSTAL:
Alcohol-Use Disorder is another very heterogeneous condition. Some people just binge and have problems with binging, and driving drunk, and trouble controlling their behavior when they're intoxicated. Other people drink every day. So there are different ways that people use alcohol. Some people, it turns out, for example, that men are more likely to drink to get buzzed and high and activated, and women tend to be a little more likely to drink to alleviate anxiety, distress, discomfort. Call that positive reinforcement versus negative reinforcement.
And you can actually see signs of this. We did a study, now a number of years ago, where we had people drink an alcohol drink, an alcohol drink of their choice, and then we looked at how much dopamine was released in the brain. And as you could imagine, given what I just said, that when men drank the alcohol drink, they released a lot of dopamine. And the extent that they were stimulated by the alcohol drink was related to how much dopamine released. Very little dopamine release in the women. And it wasn't really related to some of the subjective responses that they had. Even though relatively speaking, it was the same kind of dose. So men and women are drinking alcohol a little differently. We may someday have different kinds of treatments for alcohol use in men and women.
At the moment, we have three FDA approved treatments. One is Antabuse, and that's the drug that makes you sick. If you are around alcohol or you drink alcohol, you take it. And so the main experience that we have with Antabuse is that if people aren't around reinforcing your Antabuse adherence, a lot of people stop taking it. And that's a real problem. Sometimes it works when the family supervises the Antabuse, but otherwise, for other people it's not so effective.
The second medication, which is probably the most commonly prescribed medication, is Naltrexone and that works by blocking a variety of opiate receptors in the brain. And it seems to, in my personal experience using Naltrexone in research, what I see most prominently is that it tends to reduce the amount that people drink in the laboratory. And what was striking in that study is that they reduce their amount of alcohol consumption in the laboratory, but they still, it didn't reduce how stimulated they were by alcohol, and it didn't reduce their craving for alcohol. So in our hands, it was something about the drinking process, the habit, the expression of that tendency to drink when alcohol is in front of you, that you see in people who drink compulsively in our hands, that Naltrexone seem to work. Other people have reported reductions in craving.
And that contrasts with another medication that we study, which is a drug called Memantine. When we gave Memantine to people and asked them to hold a drink and report how much they wanted to drink that alcohol, Memantine reduced that craving for alcohol. And then we put them in the laboratory and we gave them a tray of their favorite alcohol drinks, and it didn't reduce the amount that they consumed.
And this is really kind of shocking because most people think that you to really want to drink alcohol to drink, in other words, you have to be aware of craving in order to be a drinker. But it turns out that some people drink compulsively or automatically, and may not even be aware of the urge to drink. And those people tend to do a little better on Naltrexone. What we found was that if we added Memantine to Naltrexone, so we were reducing the craving and reducing the tendency to drink, that we could further accentuate the benefit that Naltrexone produced.
DR. THEA GALLAGHER:
It is really interesting. It sounds like you're looking at kind of having a physiological barrier with the Antabuse, and then with the Naltrexone, almost like a harm reduction model. You want less of it or you drink less of it. And then with the Memantine really addressing the craving, which I think going back to your original point really highlights the complexity of the stimulus for drinking and relief, reward, physiology, habits. And so I think something that has maybe been looked at somewhat reductively, you're saying there's a lot of layers to it, and we're trying to address the various layers.
DR. JOHN KRYSTAL:
Absolutely. And I'll just speak for myself. You walk into a room, you don't know anybody there, it makes you feel a little anxious and you think, "Well, a drink might be nice to take the edge off." I mean, who hasn't had that kind of feeling? And so you can understand how problems like alcoholism develop out of that kind of wishing to be comfortable, and to be sociable, and not to feel anxious or whatever. And then the paradox of course is, when you drink heavily and you drink daily, you tend to become more anxious and more depressed. So the process of, even though these substances... It's a little bit like the story we were talking about with ketamine, even though these substances in a single dose can make you feel better, when you drink them too much too consistently, they can have the opposite effect.
DR. THEA GALLAGHER:
And then you're kind of leading to this other piece of chasing the withdrawal feelings as well. So that adds another layer to it.
DR. JOHN KRYSTAL:
Absolutely. The hair of the dog. Winston Churchill. We'd get up every morning and have a Johnny Walker Red, I believe, and he would have his scotch and soda in the bed every morning with his staff around him. People develop the habits too that really, in some ways, work in the short run, but come at a cost in the long run.
DR. THEA GALLAGHER:
We've been talking a lot of the heterogeneity of different conditions, and different people, and motivations, and hard-wiring, et cetera. One of the themes of this podcast that's really come out is this concept of precision psychiatry, and how important that is to so many of psychiatrists doing the research. Can you give us a sense of where you feel like it's advancing and where it might be snagged in your field of experience?
DR. JOHN KRYSTAL:
Sure. I think precision psychiatry, it sounds really complicated, but at its heart, all psychiatry is precision psychiatry. Precision psychiatry has to do with how you use information about that individual patient in front of you to help to choose a treatment that will be best for them? And so for example, when I think about precision psychiatry in clinical practice, I think about, for example, let's say I have a patient in front of me who is a young man who has got a new onset psychosis. Well, he's a young man, so I know he's at risk for certain motor side effects of antipsychotic medications. So I'm probably going to start with a medication that doesn't have so many of those motor side effects. He's a young man, he's probably concerned about putting on some weight. So I might avoid an antipsychotic that has a tendency to put on weight. And that reduces the medications that I would prescribe to just a few medications, and the ones that I would normally use for a young man with a new onset psychosis. And of course, I would want to know from the patient what's important to them, what they're looking for. That's really important part of this selection process as well.
What we'd like to do is have objective tests that we could use that would do what we were talking about before, fill out these questionnaires, take a blood test, maybe an EEG or an FMRI or even a PET scan, and get you right onto the treatment that you need as quickly as possible. And that's really important, because sometimes people have to go a long time to get onto the right treatment combination. We're just talking about treatment-resistant to depression, where it can take a year, sometimes, to get people onto the right combinations. And if we could do it right away, it's good for the patient, it increases the likelihood they're going to stick to treatment, it reduces the disability and distress to them and everyone around them. It helps them to not lose their job or to stay connected at work. It reduces burden at home. All these reasons. It would be great to get people onto effective treatment right away.
The challenge is, that generally speaking, we've done a lot of research that have given us a lot of predictions. But the predictions don't always generalize. And when they do generalize, I think then we make progress. There are certain tests that we can do now that tell us about either drug blood levels or the propensity to metabolize certain medications in certain ways, that can be helpful when people aren't responding to help give us a clue about where to go in terms of dose adjustments or other changes. But we don't yet have, for any disorder other than perhaps Alzheimer's disease now, that kind of biomarker. And there are reasons for that, which is that in Alzheimer's disease, the body accumulates certain proteins in the brain that damage the nerve cells. And we can actually measure those proteins using PET scans, spinal taps, and we can prescribe a medication that way. The first medication that targets one of those proteins. The protein is called amyloid, and there's an antibody to amyloid that helps to clear amyloid out of the body and to slow the progression of Alzheimer's disease.
So a key thing that I just said is, the protein is the cause and the medication targets the cause. And when we have medications that target the actual biological causes of the disease, then having a biomarker is really important and really useful. Because if you don't have the protein, the medication doesn't work.
So most of our medications treat downstream effects of the disease in the brain. So for example, many people know that dopamine is somehow involved in psychosis. You've probably heard of that. And that our antipsychotic medications block dopamine signaling at the dopamine D2 receptors. So the problem is increased dopamine release is not universal in schizophrenia, but increased dopamine release does predict the response to antipsychotic medications. But since we only have one kind of antipsychotic medication, which is medications that block dopamine D2 receptors, there's no point in doing the PET scans because no matter what we do, the only medications we can prescribe will block the dopamine D2 receptors.
We're at a little bit of a tipping point, which is that we have two new antipsychotic medications emerging that more or less converge on a similar mechanism that may give us the first alternative to a dopamine D2 receptor blocking antipsychotic. And those medications stimulate muscarinic cholinergic receptors. And one of them is called KarXT. The other one's called Emraclidine. Neither of them are yet approved. KarXT may be the first. But if all the drugs are the same, then precision medicine doesn't help very much. But if the drugs work through radically different mechanisms, then having precision medicine makes more sense.
Particularly if the mechanisms are related to the progression of the illness itself, then having a biomarker of that process can be very helpful. Many of us are familiar with [HER2], which is a molecule that is expressed by certain breast cancer cells. And if you have that molecule expressed, then, I mean, if the molecule HER2, if the tumor makes that protein, then Herceptin, an anti-cancer medication, works. If it's not there, it doesn't work. And psychiatric disorders may someday have that kind of precision. And when we get there, I think that'll be a real advance for patients.
DR. THEA GALLAGHER:
And it sounds like, from what you're saying and from a paper co-authored last year, that you feel like biomarkers are the best pathway toward that precision psychiatry?
DR. JOHN KRYSTAL:
Well, we're talking about things happening in the brain, and so whatever gets us to the mechanisms in the brain, maybe brain imaging scans or other kinds of techniques, will be critically important. You might say, well, why can't we just ask patients more questions? And the answer is that the brain is so complicated that different biological mechanisms can probably generate the same symptoms, the same experiences. So when we are talking about treatment, we're always talking about the biological mechanisms. So having biomarkers that get us past the conundrum of overlapping symptom profiles, I think will be important to moving this forward.
DR. THEA GALLAGHER:
And for my last question, speaking of what you think is important moving forward, can you speak to an ongoing or future project that you're excited about, or even just something that you're excited to see happen with the research that you're involved in?
DR. JOHN KRYSTAL:
I have to tell you, this is the most exciting moment in the whole history of the whole field of psychiatry. And there's so many things that I find exciting. But for me, I keep going back to what got me excited about this work, go way back in my college days in the '70s, which was the idea that you could go from understanding the complex biology of psychiatric disorders to developing treatments based on that biology. And I think we're right on the cusp of that. I think we're getting there. And it seems you might say, "Well, hasn't psychiatry been developing medication since the 1950s?" But not from a really deep understanding of the molecular pathology of the brain. And the idea that we're finally getting to that point is just incredibly exciting to me.
DR. THEA GALLAGHER:
And it sounds like you're saying the last number of years have really been gathering the data, having the building blocks, and you feel like it's coming to a point where it's really going to bubble up into some really effective solutions for suffering patients.
DR. JOHN KRYSTAL:
Yeah, absolutely.
DR. THEA GALLAGHER:
Wonderful. Well, thank you so much for this amazing conversation.
DR. JOHN KRYSTAL:
Thank you for having me.
DR. THEA GALLAGHER:
Thanks so much for that conversation, Dr. Krystal. If you enjoyed this episode, be sure to rate and subscribe to NYU Langone Insights on Psychiatry on your podcast app. For the Department of Psychiatry at NYU Langone, I'm Dr. Thea Gallagher. See you next time.