Show Notes & Links

Dr. John Krystal, Robert L. McNeil, Jr. Professor of Translational Research and Professor of Psychiatry, of Neuroscience, and of Psychology

Yale Department of Psychiatry

Yale Center for Clinical Investigation

Center for the Translational Neuroscience of Alcohol

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Episode Transcript

Tanimu Deleon
On behalf of the Academy members, welcome to Learning and Living STEM in Connecticut, the podcast of the Connecticut Academy of Science and Engineering. My name is Tanimu Deleon. I’m an elected member of the Academy and serve as an officer on its council. I invite you to learn more about the Academy by visiting our website at ctcase.org. Today, we will talk about the reconceptualization of the biology of depression and the discovery of ketamine as first exemplar of a rapid-acting antidepressant. I am joined today by Dr. John Krystal, the Robert L. McNeil Jr. Professor of Translational Research and Professor and Chair of the Department of Psychiatry, Professor of Neuroscience, and Professor of Psychology at Yale University.

John is the recipient of the 2026 Connecticut Medal of Technology for the discovery of rapid antidepressant actions of ketamine. Welcome, John, and congratulations are in order, and thank you for being part of this podcast. Before we start, will you share a bit about your background?

John Krystal
Sure. You know, I spent my entire career since medical school at Yale. Arrived, it scares me to say this, in 1980, and I had a wonderful experience in medical school. And then I trained in a very special place in residency at Yale called the Abraham Ribicoff Research Facilities, which was a collaborative and still is, 60 years into the collaboration, a joint initiative of the Connecticut Department of Mental Health and Addiction Services and the Yale School of Medicine.

And there I learned about translational neuroscience, the biology of the brain, while becoming– getting my psychiatry training. And I also worked in another collaboration, you might say, between Yale and the VA. For a long stretch of my career, I worked at the VA Connecticut Health Care system, and actually did the discovery of ketamine at the VA hospital in West Haven, Connecticut.

I really have benefited from a community that has come together to try to support depression research, Yale, the state of Connecticut, and the Department of Veterans Affairs.

Tanimu Deleon
No, that’s fantastic. I mean, it’s nice when, you know, everything soup to nuts is in one place, and you’ve provided so much to so many in a place that you like, you call home, and you know, work and reside. So that, that’s fantastic. So we– I think Connecticut owes you a debt of gratitude for, uh, everything that you’ve done thus far in your career.

John Krystal
I feel the same way about Connecticut. I don’t know that I could’ve had this career anywhere else, and I feel very proud to have spent the last almost 50 years here in Connecticut.

Tanimu Deleon
Nah, that, that’s absolutely fantastic. So let’s, uh, let’s jump into this discussion because this is a really interesting one for everyone. You know, first off the bat, you know, what is depression? And is it a form of mental illness, or is it something else? Lack of– or lack or abundance of, you know, some kind of neurotransmitter? I mean, can you break it down for our listeners, please?

John Krystal
Sure. You know, first off, we have to acknowledge that many people who don’t have the diagnosis of depression have the experience of depression at one time or another. And by the experience of depression, I’m talking about feeling sad, feeling down, not having energy, being very distracted, and not being able to focus.

And, you know, it, it’s a normal part of life because life can be very discouraging. But the difference between depression and feeling depressed is that most people bounce back from that very down experience, but people with depression don’t bounce back from it and can spend years that way if they don’t get adequate treatment. Another part of depression is that we now know that it’s a whole-body illness.

In other words, when you feel depressed in your emotions, in your thoughts, and in your behavior, it stimulates certain changes in your body that are really not good for it. And so, for example, one process which can promote the, uh, onset of depression besides stress is something called inflammation.

So people have aches and pains, they may be overweight, they may have heart problems or other things, and this creates inflammation in the body. And inflammation in the body can create inflammation in the brain, and inflammation in the brain can cause depression. And depression in the brain worsens the inflammation in the body.

It’s a vicious circle that goes round and round. And for that reason, people who have inadequately treated depression have worse outcomes of their heart disease, of their respiratory disease, of their kidney disease, of their cerebral vascular disease, and they die, believe it or not, up to 10 years earlier as a result of the depression.

So we really do… When we talk about depression, even though the symptom of depression is a very common thing, this kind of depression that, that goes on and on and on and doesn’t get better is a really serious medical problem that we need, need to take seriously. The other obvious bad consequence of depression, and we hear too many stories too frequently these days, is the way that depression increases the risk for self-harm and suicide.

And so we lose people through medical complications, and we lose people through suicide from depression. And it– And there, there are effective treatments out there. So the most important thing is that depression is an illness that people need to take seriously and get help for because that can really improve their lives.

Tanimu Deleon
Yeah. Thank you for really hitting home there because I mean, it, it is an insidious illness. You know, people don’t really– They don’t see the harm. They don’t see like a laceration on your hand, so it… There’s nothing wrong. You know, thank you for really, you know, making that very clear and and just showing how abundantly important it is to take this very seriously. So can you describe the shift in the neurobiology of depression that helped, that you helped initiate?

John Krystal
Yeah. You know, this was, this was really grown out of a longstanding conversation between me and a psychiatrist named Dennis Charney. His office was on the ninth floor, my office on the eighth floor, and at the end of the day, we would, you know, go up and just talk science, you know, touch base, talk about what was on our mind.

And, uh, Dr. Charney had been studying depression for about a decade or more before we, uh, started working together at the VA. And he had been studying the systems that most people have heard about in relation to the biology of depression. One chemical system called serotonin, which is targeted by medications like Prozac and Zoloft, and all these SSRI medications that people have heard so much about.

He studied another system called the norepinephrine system, and there are medications like Wellbutrin and desipramine that target it. And so people had come to believe, because the antidepressants worked on the serotonin and norepinephrine system, that depression itself was an illness of serotonin and norepinephrine.

And, um, and a study that or a series of studies that Dr. Charney had led really raised some serious questions about that idea, which were that they depleted the body of serotonin and norepinephrine, and people didn’t get depressed. So whatever it was about serotonin and norepinephrine that the antidepressants were doing, perhaps these medications are more recruiting resilience systems in the brain, more or less successfully, than they are reversing the actual biology of depression.

And so that made us wonder, if depression doesn’t live in the serotonin norepinephrine system, perhaps depression lives, if you will, in the higher centers of the brain controlling emotion and cognition that are targeted by these serotonin systems in order to drive recovery. And those systems, the cerebral cortex and the limbic system, turn out to use different chemical messengers than serotonin and norepinephrine for their main communication.

In fact, the main communication highway of the brain, something like 70% of the synapses, maybe more, uses a chemical called glutamate to drive excitatory neurotransmission. In other words, to, to the, to be the electricity of the circuits of the brain. And so we thought, well, gee, uh, this– You have to understand this is before brain imaging, a lot of the current brain imaging technologies.

We thought, “Gee, it would be great if we could probe the glutamate system to see if it’s signaling, uh, abnormally in depression.” And it just so happened that was the area that I was working in, glutamate signaling. And we could use a drug that had been around since the 1960s to probe the integrity of the glutamate circuits.

And we could do that by giving a low dose of the drug, just enough to block some of the r-glutamate receptors, and see how reactive behavior, cognition, and other things were. When we did that in depressed patients, we could document the effects of ketamine, the NMDA glutamate receptor blocker anesthetic.

We could document the effects of ketamine on mood and, you know, cognition, and those effects wore off when the drug wore off, so within about two hours. But we noted that about four hours later, people started to feel a little bit better, and by the next morning, some of the people in the study were completely better, back to themselves.

And we thought, “Gee this never happens. Could this really, you know, be real?” But, uh, we saw it a number of times, and what we were watching really for the first time was this rapid antidepressant effect of ketamine, which had not really been characterized before in a placebo-controlled trial. And then over the years, different groups replicated that finding over and over.

That’s how science progresses, through discovery and replication, and it was shown that ketamine was very effective for treatment-resistant symptoms of depression. Um, then Johnson & Johnson took up the cause and developed S-ketamine. Ketamine is a molecule that has two mirror images, you know, like your hands.

They don’t overlap. They’re mirror images. And the S image or S version or S isomer of ketamine was the version that Johnson & Johnson developed under the leadership of Dr. Husseini Manji. And, in two thousand nineteen, about twenty years after we discovered the antidepressant effects of ketamine, it was approved by the FDA for treatment-resistant symptoms of depression.

And it’s proven to be about twice as effective as the next approach, next most effective approach for, uh, the, uh, managing these treatment-resistant symptoms of depression. It’s proven to be the most rapidly effective treatment for depression currently approved by the FDA. It’s about twice as good at preventing relapse to depression in long-term treatment as standard antidepressant treatment.

And in long-term studies, there is some preliminary data to suggest that it can, uh, reduce suicide attempts, death by suicide, and it can even reduce all-cause mortality, which is this worsening of other medical problems by depression and the downstream consequences of that. So it has really been a kind of revolution in terms of, uh, the treatment of depression.

And it took a little time for people to get access to it because it needs to be administered in the clinic. So there are now 6,000 clinics around the United States that are delivering ketamine or esketamine as a treatment. It’s reimbursed by Medicaid, Medicare, and private insurance. So if there’s a program around them, m- uh, most people can find a place to get access to, uh, ketamine or esketamine as a treatment.

And it’s making a difference in people’s lives, which is just really wonderful to see.

Tanimu Deleon
That’s that is quite the discovery that you made. So you did mention that ketamine and esketamine are mirror images of each other. So is there a difference in which one you administer compared to like standard antidepressant treatment or does it not make a difference?

John Krystal
So the R isomer is somewhere between two and five times less potent at its brain target, the NMDA glutamate receptor. And so far, the company that was developing it didn’t use high enough doses to show that it was effective because you have to compensate for the fact that it’s lower potency, and so you have to give, you know, probably have to give a much higher dose of the R ketamine than you give a dose of the esketamine.

So at the moment, we can give racemic ketamine (R and S together), or we can give the S isomer by itself. Those are the two FDA-approved versions of ketamine.

Tanimu Deleon
And you did mention that it’s administered in a clinic. So is this over like what’s the duration of this procedure? Is it, you know, a couple of hours or is it over a course of several days or what– how would it work for someone?

John Krystal
Yeah, it’s– So it’s generally a two-hour session, and people usually come into the clinic twice a week at the beginning. And that makes sure that you don’t have breakthrough symptoms of depression between your treatment days. And then gradually over time, the frequency of treatment can be reduced.

Most people get to at least every week or every other week, dosing some people less frequently over time. And so that it has some advantages because, uh, the drug is only in your body for a very short time, so you don’t have a drug effect from the ketamine in your daily life when you’re in treatment, uh, with ketamine.

And sometimes other treatments that people take have side effects that they don’t like and that are with them all day, every day, and you don’t really get that with, with, uh, with ketamine. When people get ketamine as a treatment, and the ketamine is in their body, they may feel nauseous or even vomit, and if they have that, then another medication can be given with the ketamine.

Um, they may have an increase in blood pressure. Again, another medication could be given with the ketamine to manage that so that it can be very safe and very well-tolerated in the clinic. But you can tell by the way that I’m talking that I’m talking about monitoring, and I’m talking about giving other medications, and so that, uh, this is one of the main reasons that ketamine is only given as an inside-clinic treatment.

The other is the abuse liability of ketamine. So some people may know of ketamine by its street name, which is called Special K. And you know, and, uh, and so what happens if people get a lot of ketamine at home to use for their self-treatment of depression is that they– there’s a big tendency to misuse the ketamine, to take more than they need it, more frequently than they need it.

One person that I talked to, instead of taking it every day, was taking a dose every two weeks; he was taking it six to eight times every day. He had a bottle with a nose dropper, and he would, uh, when he was feeling stressed, he would just take a little ketamine. That’s not the way that ketamine works as a treatment, and it creates addiction problems that are their own problem.

And so we don’t want we don’t want ketamine to become a drug of abuse, so that’s why we keep– that’s part of the reason we keep it in the clinic.

Tanimu Deleon
Okay. And you said he, with a nose like an eyelet dropper, was taken?

John Krystal
Yeah, so you get a bottle of ketamine, and a lot of people have gotten this from compounding pharmacies or things like that.

Tanimu Deleon
I see.

John Krystal
You know, they get a bottle of ketamine, and then when they, they just put some nose drops in. And, it turns out that ketamine is not very well absorbed orally, so we gave it intravenously so we could control the blood level very carefully.

And the Johnson & Johnson developed an intranasal version, not nose drops, but a high, a fine spray that’s shot into the sinus and absorbed through the sinus where the levels can be consistent the absorbed levels can be consistent. When you let ketamine run down your throat, it’s inconsistently absorbed

Tanimu Deleon
Yeah. I mean, similar to other medications and, you know, so that, that, yeah, ’cause that when you, when you had mentioned like, controlling the dosage is critical, I was like, “Oh, eye drop?” I was like, “That’s, that’s pretty interesting.”

John Krystal
I would say the control is not so great with the eye drop.

Tanimu Deleon
It doesn’t sound like it, no. No. So you did mention that it blocked the NMDA receptor. Is that how ketamine affects the feeling of euphoria or the antidepressant effects? Is that where it comes in, or is there a cascade from that blocked receptor that allows ketamine to produce that extraordinary response?

John Krystal
Yeah. So this is really an important point, which is that the euphoric effects go away before the antidepressant effects emerge. And w- the way that ketamine produces recovery is a complex and evolving story, and I don’t, I don’t think we still have all the answers. But there are a couple of really interesting things that ketamine does in the brain.

One of these things is to trigger the release of a nerve growth factor in the brain called brain-derived neurotrophic factor. It’s also known affectionately as BDNF. And so BDNF is a really powerful nerve growth factor that helps the brain cope with stress. And one of the things that BDNF does that’s very powerful is that stress causes the brain to lose some of its synaptic connections, the way that nerve cells communicate to each other.

And, um, when BDNF release is triggered, it promotes the regrowth of synaptic connections. It does this in a more subtle way by shifting the balance away from synaptic elimination and toward synaptic growth. So, it’s not exactly a one-to-one process, but clearly the key synapses need to regrow because the antidepressant effects of ketamine only last as long as the synapses that have regrown.

When they start to fade away, the beneficial effect goes away. And so that’s why we have to dose it twice a week when we start out. So in a way, what ketamine does more effectively than standard antidepressants is to recruit the brain’s own resilience mechanisms, which I think is a kind of cool idea

Tanimu Deleon
So does that play into plasticity, or is that something different?

John Krystal
Yeah. So by restoring connectivity in the brain, another thing that happens when you give ketamine is it triggers the brain to move some other glutamate receptors into the synapses. So one of the ways the brain adapts to stress is by depotentiating synaptic connections. So it doesn’t necessarily just remove them; it can make them less effective.

And it does that by removing glutamate receptors from the synapse. And so ketamine also triggers the glutamate receptors to go back into the synapse. So it’s restoring the effectiveness of communication of the existing synapses, and it’s regrowing synapses at the same time

Tanimu Deleon
Wow. Okay. That, that’s really interesting. It’s almost like I don’t know. It seems like it’s one of those answers for everything almost.

John Krystal
It, you know, I’m not sure that it is an answer for everything, but it is a really profoundly different way of thinking about the treatment of depression. And it may help in combination with certain kinds of psychotherapy for post-traumatic stress disorder. It’s being studied for some other conditions as well. But most robustly so far are the effects that we’ve seen in depression.

Tanimu Deleon
So what– So yeah, you mentioned PTSD. So what kind of patient would benefit from the ketamine treatment then? It just doesn’t strike me that it would just be someone that i-is, I mean, has depression but not maybe severely depressed or does that not make a difference?

John Krystal
I think at the moment the two indications approved by the FDA are right on target. So the first are people who have been in treatment, maybe they tried one or two, three, four different antidepressants alone or in combination with other medications, but they’re still dragging at work. They can’t quite get over the hump.

They’re still can’t experience pleasure in their life. They still feel negative, have negative thoughts throughout the day, are unable to focus, and are not really engaging with other people. These people with treatment-resistant symptoms are very good candidates for something like ketamine or esketamine.

The other group, exactly as you suggested, are the ones who are extremely ill. They’re not eating, they’re not responding, they’re in very bad shape, or they’re on the– they’re very high risk for suicide. Both of these groups of urgently ill patients are also good candidates for ketamine or esketamine.

And if you’re urgently ill like that, you don’t need to try two or three different medications. You can go right to ketamine or esketamine. Esketamine is the FDA-approved treatment for depression

Tanimu Deleon
Okay. So you did mention you could get, uh, you could go down to a– there’s clinics, you have like over 6,000 clinics, so from an access perspective,

John Krystal
I don’t have 6,000…

Tanimu Deleon
No, I know. Yeah. I didn’t mean to put words, I didn’t mean to put words in your mouth, no. But the, writ large,

John Krystal
Yeah. The country. Yeah, absolutely.

Tanimu Deleon
So is there… So I guess h-how, so that patient that you just described, how would they get access? Is it they go to their psy- psychiatrist and then like what’s the process for some… Cause some of these people might be listening to this podcast, so…

John Krystal
You know, my advice for people who are thinking about it who are already in treatment is to talk about it with their doctor or their nurse practitioner and have a chance to think through the, the option. And if together they think it’s a good idea to get referred to one of the clinics in their area who can work in collaboration with their ongoing treatment to make sure that there aren’t gaps in the treatment, you know, that there aren’t discontinuities where, uh, the person’s being discharged but the out- the treater doesn’t know it.

Their current treater and the ketamine clinic treater should be working hand in glove to ensure a seamless, coherent treatment process. But sometimes it– you can call the clinic directly if you’re– particularly if you’re in this kind of severe depression state and you’re worried about your safety.

You know, if you’re, if you feel like you’re suicidal or you might harm yourself, the first most important thing is to get to a safe space, and for many people, that’s an emergency room. And then they can contact, help you get connected to a ketamine clinic. So there are many different ways.

Most academic medical centers these days have a program that delivers ketamine as a treatment. We have a very large and active program called the Interventional Psychiatry Program at Yale, and I can give you the number that we can provide to the people on this podcast.

And it’s really important to pay attention if you’re feeling an urge to harm yourself, because there’s no need to harm yourself. We can help you feel better and manage the situation you’re in.

Tanimu Deleon
Yeah. We’ll definitely want to include that in the show notes so people can access that information if needed. So, can you just give us a quick summary? We mentioned it’s two hours for the treatment, and you’re doing it, I believe, twice a week, just to make sure there are no effects that aren’t caused by the ketamine.

I guess if someone were to talk to their primary care or their psychiatrist, and they start on this treatment, what would it look like for them, I guess, long term?

John Krystal
Yeah. So it’s quite variable. So some people, uh, do something like one or two months of treatment, feel like they got everything they need out of it, and are fine in their life, and then the frequency can be tapered down or discontinued. Other people find that they c- really can’t sustain their mood improvement without ongoing treatment.

So there are data like the ones that I referred to where patients were treated on average for 42 months in ongoing treatment there. In other words they hadn’t stopped it at that point. They were continuing. And, um, and the outcomes were extremely good. And so for many people, the– what happens when they get into treatment is they start on the more frequent dosing, and then they try to space the dosing farther and farther apart gradually over time.

And there are data to show that if you have a breakthrough of your depression symptoms because you spaced your treatments too far, then, then if you make the treatments more frequent again then those symptoms will go away. And and so it, it- it’s, you know, a partnership really with the patient and the treater to figure out what’s the what the right pattern of treatment is for them.

Tanimu Deleon
Okay. And FDA approved, so it would be covered by insurance?

John Krystal
Yes. The esketamine is generally covered by insurance. The R-Esketamine is an FDA-approved anesthetic, but it’s not approved for the treatment of depression. And it’s more common… You know, there are some places like at Yale New Haven Hospital where there are some insurance plans that will cover the R-Esketamine, the intravenous version as well.

But generally, around the country, that’s not very common.

Tanimu Deleon
Okay. Okay. So with the fact that you know, you found the antidepressant effects of ketamine, where you found these around like the year 2000 has there been any progress in developing better versions? I know you mentioned two of them with the mirror effect, but are there any others beyond that or

John Krystal
Yeah. So there are different versions of ketamine being studied by several groups. The NMDA receptors are a family of receptors, and some drugs are being developed to target specific subtypes of these receptors. We’ll see how those perform.

And a company that I’m involved with, called Freedom Biosciences, is developing a combination of ketamine with another drug, which is an immune modulator, and that combination looks like it has longer effects for each dose. And so instead of taking it twice a week, maybe people would only take it once every two weeks.

Now, this drug is at a very early stage of development, and we’ll see whether it whether these early findings hold. But it is an example of what might be developed to try to take ketamine treatment or S-ketamine treatment to the next level.

Tanimu Deleon
And you mentioned an immune modulator. Can you expound upon what that means with this new drug that you’re coming up with?

John Krystal
Yeah. So one of the gatekeepers for ketamine’s antidepressant effects turns out to be immune cells of the brain called microglia. And, uh, one of the really interesting things about microglia, um, y- as I mentioned, because they’re involved in the immune or inflammation response, they’re hyperactive in the brain of people with depression.

And my colleague Matthew Girgenti led a major study showing that these cells are hyperactive in postmortem brain tissue from people with depression. And what they do, what the microglia do when they’re hyperactive, is they surround and gobble up the synaptic connections in the brain. They do other things.

They can actually hurt the white matter that insulates the nerve fibers, and they can affect the support cells of the brain called glia. So when microglia are, are bad, they’re very bad for the brain. And, and, um, and, uh, and so what this immune modulator does is help ketamine or S-ketamine to repolarize the microglia from a state where they’re promoting the depression to a state where they’re releasing BDNF, this resilience mechanism, and protecting the brain.

But you can turn the microglia into cells that are promoting recovery from depression by combining, ketamine and this immune modulating drug. At least it looks that way. And and I think that’s really exciting because one of the things that happens when science advances is intellectual barriers between fields just crumble, right? And here, h- here we have, a, uh, a crossing of the boundary of, of, uh, immunology and neuroscience, and it turns out to be critical for something like the antidepressant effects. In animals, they’ve done studies where they have, where they have killed the microglia in the brain. And when you do that, it blocks the antidepressant effects academy.

And a Yale recent, uh, a graduate of Yale Dr. Wohleb in Cincinnati just did a fascinating study where he showed that, that if you block the BDNF gene in– selectively in the microglia, you also block the antidepressant effects academy. Meaning that s- a key source of the BDNF that regrows the synaptic connection of the brain is actually coming from these immune cells, not from neuron cells, which is a completely wild idea that, that we would have never anticipated until we started going down this road of breaking down the boundary of neuroscience and immunology

Tanimu Deleon
Wow. It’s, it, yeah, it’s, it really is a balance, right? Like it’s, you can’t have one thing without having the other thing. So a- as it’s a bad cell, I guess, when it proliferates, but when you have just enough of them, it actually turns out to be a good thing. So yeah. Wow.

John Krystal
Incredible!

Tanimu Deleon
Mar- yeah, marvelous. That’s it, really marvelous.

Is there any- anything else you’d like to add to the conversation here?

John Krystal
You know, just, you know, just to say that the science environment in Connecticut has just been wonderful, and the opportunity to have my career here has been just something I’m extremely grateful for. And I just want to thank my colleagues in the Connecticut Academy of Science and Engineering for recognizing me with the Medal of Technology.

It’s a very meaningful honor, and I’m very grateful to receive it.

Tanimu Deleon
Yeah, we are very fortunate to have you in our state, and you know, we salute you for all your hard work, and you know, congratulations once again for everything you’ve done for the state of Connecticut. So thank you so much.

On behalf of CASE, I want to thank our guest, Dr. John Krystal, for joining us today to share insights into his work in neurobiology and psychiatry.

Listeners, I encourage you to subscribe to this podcast on Apple Podcasts, Spotify, Amazon Music, or YouTube. Visit the academy’s website at ctkcase.org to learn more about our guests. Access those show notes, ’cause there’s gonna be some good information in there from this discussion, with additional resources.

Please read the episode transcripts, or sign up for the CASE bulletin.

Thanks again to our guest. It’s been an absolute pleasure to talk with you today, and I think a- almost every single person knows someone who has suffered or has had some issue with depression, you know, this is a very meaningful conversation today.

So thank you for that.