For the estimated 2.8 million Americans suffering from treatment-resistant depression (TRD), the arrival of esketamine nasal spray in 2019 couldn’t come soon enough. The FDA’s decision to approve the drug, the first ketamine-based antidepressant, was the latest chapter in ketamine’s journey from anesthetic to club drug to antidepressant. It was also the result of two decades of research, including by Dennis S. Charney, MD,* Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai, and James Murrough, MD, PhD, Associate Professor of Psychiatry and Neuroscience and Director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai. On Road to Resilience, Dr. Murrough explains about how ketamine differs from existing antidepressants and shares actionable insights into the neurobiology of depression.
From the Mount Sinai Health System in New York City, this is Road to Resilience, a podcast about facing adversity. I'm Jon Earle. The drug ketamine was developed as an anesthetic in the 1960s, today it's being used to treat patients with treatment-resistant depression or TRD. Ketamine tends to work much faster than traditional antidepressants, like Prozac, sometimes within hours instead of weeks. And while it's not a cure, it can be a godsend for patients suffering from severe depression and suicidal thoughts. In 2019, the FDA approved intranasal esketamine, a form of ketamine. It was the first truly new kind of depression drug to hit the market since Prozac did 30 years ago. The arrival of an esketamine nasal spray was the culmination of two decades of research, including by the dean of our medical school, Dr. Dennis Charney and my guest today, Dr. James Murrough. Dr. Murrough is an Associate Professor of Psychiatry and Neuroscience and Director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine. In our conversation, Dr. Murrough explains why ketamine works and what it teaches us about the neurobiology of resilience. But before we get into it, full disclosure, Dr. Dennis Charney, who I mentioned before, is a named co-inventor on several issued and pending patents filed by Mount Sinai related to ketamine. Patents have been licensed by Mount Sinai to Janssen Pharmaceuticals, manufacturer of Spravato, the esketamine nasal spray, and the medical school and Dr. Charney has received and will receive future payments from Janssen. Dr. Murrough, my guest, has no financial interests related to ketamine. Okay that's that. Here's Dr. Murrough. Enjoy.
Dr. Murrough, welcome to Road to Resilience.
Dr. James Murrough: 01:42
Thanks for having me.
I don't want to assume that anybody listening to this knows anything about ketamine. So can you give us a brief, what is ketamine?
Dr. James Murrough: 01:51
Absolutely. So ketamine is a drug that's been available in the United States for a long time, more than 50 years, I think. It was approved as an anesthetic, so it's used in anesthesia often in combination with other drugs for surgical procedures, things like that. It's also analgesic, which means it reduces pain. So that's what it is. It's actually unusual even as an anesthetic just in the way it works, in its pharmacology, it's considered the only medicine of that type that affects the way people think and feel.
Would you consider it a psychedelic?
Dr. James Murrough: 02:22
It's a little bit of a gray area. I think most people would consider it not to be a classic psychedelic. When people talk about classic psychedelics, often they're talking about LSD or psilocybin, and those have a primary mechanism in terms of their chemistry of interacting with serotonin. And ketamine doesn't do that. Ketamine does cause an altered state of consciousness, but the way it does it chemically and the qualitative effect of that seems to be somewhat different from what we might call classic psychedelics. And we certainly didn't consider it a psychedelic when we started researching its effects for depression.
There's a whole story to ketamine as there is for all of these drugs. It went from being a pure analgesic to a club drug and now, in new forms, as a medicine. Take us through that story.
Dr. James Murrough: 03:13
Well, you mentioned club drugs, that was in parallel and long before I think any ideas around it might be helpful to treat depression. In terms of depression, there was a small study—I think it was published in the year 2000 with less than 10 patients—they reported patients with depression in a hospital, giving them an injection of ketamine, and then reported that in the following days, at least some of those patients reported their depression got better. There were a few things that were unusual about that. One is that all drugs that we came to understand could treat depression worked on basically the same systems in the brain. Ketamine didn't work anything like that. Also, antidepressants tend to take, you have to take a pill every day for a couple of weeks before it starts to have any benefit typically. But the idea of giving one treatment and then the depression gets better didn't fit the mold in terms of how we think antidepressants work.
I want to give people a sense also of the problem that we're attacking and the urgency. We're talking about a population of—I found somewhere between three and five million Americans have treatment-resistant depression. And suicide is the second leading cause of death for Americans age 10 to 34.
Dr. James Murrough: 04:23
So there is a big group of people who need something new. Can you speak to that urgency?
Dr. James Murrough: 04:30
Yeah, I mean, depression is common, it's chronic, and it can be lethal. Many patients fortunately do well with available treatments—standard or conventional antidepressants, psychotherapy—but there is a group that's larger than we would like, estimated to be about a third of all patients that suffer from depression, have some form of what we might call treatment-resistant depression. They really don't do well with standard treatments, which is exactly the backdrop of studies and the observations around ketamine to say, wow, could this be a different way to treat depression? Because all of our antidepressant medicines kind of work the same way in the brain and have the same type of chemistry, which is broadly speaking the case before ketamine.
Yeah. And there are lots of different antidepressants, Prozac, Zoloft, Lexapro, you name it, but you're saying they all function in pretty much the same way. And ketamine's very different.
Dr. James Murrough: 05:20
Was there a moment for you—you've been working on ketamine for how long now?
Dr. James Murrough: 05:25
More than a decade, I think. I started at Mount Sinai actually as a trainee, a resident in psychiatry in 2005. I think I started working on the first ketamine study here in 2006 or 2007. So it's been a while.
I'm wondering for you, when was the moment when you went, "Oh, my God. This is really powerful stuff. This could be a game-changer for a lot of people."
Dr. James Murrough: 05:46
I don't know if there was one moment, but a series of moments. We were aware of the first paper that was done that I mentioned in a very small number of individuals showing this rapid effect. But it wasn't until I think we started doing the studies here at Sinai that you could actually see the patients and how—you know, it's not a panacea and it didn't work for everybody, but many of the patients that we would treat had had many treatments and they had been depressed often for years and years. And I remember one patient in particular who, in those days the studies we were doing was just giving a single dose and then we would measure their depression one day after the treatment and see how it compared to basically the day before the treatment. And I remember one patient came in for that follow-up, you know, she looked like a different person. Her face was expressive, she was wearing makeup, and she said she didn't feel depressed, and it was the first time in more than 10 years. And you saw that, again, not every time but enough to say, "There's something here."
You mentioned very importantly that we're talking about a treatment and not a cure. Can you give us a sense of the percentage of people who come through the studies who respond to ketamine?
Dr. James Murrough: 06:59
So in these studies we're describing, what would consider the classic studies—single-dose, intravenous ketamine—across the studies we were seeing response rates of about 60 percent.
I want to compare ketamine now to some of the other drugs, like psilocybin, like MDMA, these other drugs that have gone through that journey we described as being experimented with many years ago, being illicit, and then having a resurgence in medicine. Let's just compare it for example to MDMA-assisted psychotherapy. How is that aimed at a different target and applied in a different way than ketamine?
Dr. James Murrough: 07:38
In terms of MDMA, the approach there really was very different from the way we were thinking about ketamine. With ketamine our research group and others tended to come at it from a very what I would say medical model, meaning we basically knew that ketamine affected glutamate and the NMDA receptor. And then a lot of research was focused on understanding how that could be related to stress and depression, and the field settled on a biological model accounting for why ketamine could rapidly reverse negative effects of stress and basically be antidepressant based on the way it affects brain cells. Going back to MDMA, that treatment, for example, in PTSD, where it's the farthest along, the anchor there was psychotherapy. PTSD and depression they tend to be comorbid, but they are quite different. And, of course, the nature of PTSD, post-traumatic stress disorder, of suffering a trauma, there's something critical about processing the traumatic material, like a psychological-based approach. And the idea with something like MDMA is it can in some unique and profound way facilitate the ability of that psychological work to happen or to stick. Whereas if you look at the history of the development of ketamine for depression, it's not been linked at all to psychotherapy. Although I will hasten to add that in the emergence of what looks to be very promising data about combining psychedelics with psychotherapy, many people are wondering, well what about combining psychotherapy with ketamine?
They're on very different tracks, but it seems like if I'm understanding you correctly, there could be a merging of that track in the future.
Dr. James Murrough: 09:25
I think that's right.
I guess this is a two-part question. First, why does ketamine work? And secondly, what have we learned about depression from studying ketamine?
Dr. James Murrough: 09:37
So one of the things ketamine taught us without knowing anything about what it was doing in the brain is that someone can experience a lifting of their depression within a few hours or a day, or two days, which broke the mold of what we thought we knew. And, by the way, we never did fully understand and still don't why if you're depressed now and you start taking a conventional antidepressant like we've been talking about—these are the selective serotonin reuptake inhibitors, SSRIs, the Prozacs, etc. As the doctor prescribing it, what we usually tell patients is, okay, you take it every day, don't miss a dose, and my goal would be to start to see a lifting of your symptoms, a lifting of the depressed mood, negative thinking, starting to feel better, enjoy things, hopefully as soon as about two weeks. Often it takes more like four to six weeks and studies suggest people might be responding even up to 12 weeks and later. So that's three months of taking the medicine every day before they start feeling better.
Which is too slow for somebody who may be suicidal.
Dr. James Murrough: 10:46
That's right. And we don't fully know why the delay is. Because the levels of serotonin in the brain increase within hours of the first dose, so we know it's not that. There's probably some downstream effects on—broadly we talk about neuroplasticity, basically the ability of brain cells to change and to adapt to different forms of stress. The theory is that over time change happens in the brain and that's what's ultimately the mechanism of someone coming out of depression. So we think that somehow ketamine is actually—it might be doing something similar to a standard anti-depression but much faster.
This whole idea of neuroplasticity and new neural connections is so exciting. I mean, it's exciting, first of all, to realize that even deep depressions can be lifted. That it's even possible is exciting. And then secondly, the idea that a brain can grow and change and adapt to new habits is exciting. Ten years ago, you co-authored a paper about the neurobiology of resilience. Of course this is a podcast about resilience, and I'm wondering if there's been any movement in the last 10 years that's really exciting, that has a lot of potential, that you could share with us.
Dr. James Murrough: 12:01
It's not unrelated to our discussions about neuroplasticity. In the last 10 years I think the field has learned a lot about what happens in the brain under stress, which is giving clues on how that could be blocked, buffered, or reversed. One area of research that we've been very excited about and following up on is a very specific change in the brain that we think we could actually harness to think about a new type of treatment, a medication treatment, actually. We know a lot about boosting stress resilience in terms of behavioral, psychological things, even basic things like exercise is so important for resilience to stress, more and more studies show that. But what about medicines that could take advantage of what we know about how stress affects the brain or how the brain is resilient to stress? So I'll just give you one example of that. One of the early observations was—you might think if you have mice that show depression after stress and then some that don't, you might think that if you looked at the changes in the brain, you can look at gene expression or these measures of basically how cells are responding. Cells are always responding to their environment by increasing proteins or genes and other things. And you could just count up, well, how many genes, how many cells are activated? It's actually the resilient mice that have more changes in their brain, which you might think—
Yeah, [we] think of resilience as firm and tough. [We] don't think of resilience as flexible.
Dr. James Murrough: 13:29
We're talking in the plane of neuroscience, of chemicals in the brain, but I'm wondering what your work has taught you about human resilience. And when you go out and live your life in the world, has it affected how you think about resilience on that plane?
Dr. James Murrough: 13:45
You know a lot of the things that we study or try to understand about how is the brain responding to stress—short of, again, I gave you an example of maybe in the future engineering specific medicines that could treat people that have disorders that result from some type of lack of resilience, or that develop a depression. And it's important because sometimes there's a connotation that if someone develops depression or PTSD, you say they're not resilient, as if there's something wrong with them. So I'm always quick to say resilience is just, again, from a scientific perspective, it's—look, everyone has different brains, different bodies, different minds, some respond more adaptively than others to stress. We don't know why, and it's nobody's fault if they don't, right? But what can we learn about the brains that do really well under stress to help the people whose brains don't. But outside of the world of brain chemistry and things like that, there's more and more studies that just tell us that the most basic things are really important for coping with stress and being resilient to stress. I mentioned exercise. One of the ones, in addition, that comes up over and over is social support, social networks. And there's all kinds of studies, you can count the size of people's social networks now, of course. And so you can link these things. And then with COVID and the pandemic, when there's this huge overlay of stress like a blanket over the whole world, over the population—it affects everyone differently, but stress across the board was increased, and then researchers, epidemiologists, were trying to figure out, well, who's coping better? What can we learn from this? People with richer social networks tend to do better. So if I'm sitting there and it's Friday at six o'clock and I just feel like turning on the TV, I think, "Maybe I should call my friend that I haven't talked to in a while." Because you put in that effort. Sociality is like plants—you have to water them, but then they give back. So little things like that. And I try to tell my patients, too, particularly when you're depressed and you don't feel like it, that's when you have to put in the extra effort, because you're going to need those people, and we're social creatures. So I think reminding us of the importance of social relationships, tending them, putting in the energy because it is energy, and exercise and eating right and all that if you can, but easier said than done.
Would you say that because of the pandemic there's more urgency behind your work or behind the work of treating people with depression?
Dr. James Murrough: 16:21
I would say, yes. I mean, again, before the pandemic, we knew that depression was one of the biggest causes of disability of any medical illness worldwide. 800,000 suicides worldwide a year. So it was a major problem before, and I think with the experience of COVID in the last year, it's just brought that point home as well. So there's definitely a sense of urgency in our lab. The research staff, everyone that makes all this happen, coordinates with referring doctors, reaches out to patients, trying to get the research done, to find new treatments, and also to get people that need care before, during, or after a research study, or having nothing to do with research, into treatment. And whether that's with conventional antidepressants, psychotherapy, often we suggest a combination depending on how severe. And then for more severe treatment-refractory cases, some of these other things like ketamine or some additional treatments, we're seeing demand up across the board for all those things.
Flexibility is another thread I want to pull on. We were talking about neuroplasticity a bit earlier and I wonder if there are also ways to encourage one's own flexibility or neuroplasticity outside of a laboratory setting.
Dr. James Murrough: 17:47
This is a very active area of research and interest. There's a lot of work being done on how we stave off age-related cognitive problems, Alzheimer's, things like that. There's many apps now available and there's data that by engaging in certain activities we can improve some of our functions. And the basic stuff we've all learned for a long time, like, you know, read. Try to read more than you're watching TV. Keep the mind active. That all still holds true. I don't think we have enough data to say whether there are specific interventions that are better than others, but I think the common things that, again, we're probably all aware of are about keeping active, doing your crossword puzzles in the newspaper, things like that. I think that's based on something. Flexibility is interesting. There's a whole domain of what we would call cognitive functioning and you can break it into memory, language, things like executive function. But what does flexibility mean? There's lots of different definitions, but it seems to be really, really important for mental health. And I don't think there are that many active studies or areas of investigation that are really trying to figure out what treatments can actually just increase flexibility in thinking. There are definitely some, and like I said, there are some apps, but it's a form of cognitive functioning that more and more seems like it's very important. Interestingly, going back to the psychedelics, I saw someone giving a talk who said that what's the psychedelic drug doing that's allowing the therapy to work? And the suggestion was it's increasing psychological flexibility. And so I think there's really something to that. And we're learning more and more about how that works in the brain. You can measure brain states by looking at small changes in blood flow. And there's some indication that in some of these stress-related problems we're talking about like depression, the brain less easily transitions between different states. And if you talk to patients with depression, they'll talk about feeling stuck. They'll also talk about things like rumination or repetitive negative thinking. "Stuck" keeps coming up when you talk to people, and so I think part of what I'm going to be trying to think about more and I think many others are, too, is whether it's a medication or a psychotherapy approach, how do we get people to practice increasing flexibility? Is it trying to get them to think about different things in a sequence more quickly? So I think there's a lot to that and I think that's an exciting area of research in the future.
There's a lot left to be learned.
Dr. James Murrough: 20:30
Yes. That's most certainly true.
You're going to be busy for a long time.
Dr. James Murrough: 20:34
That's right. No shortage of work to do.
As we come to a close, I was wondering if you could speak to somebody who maybe themself is experiencing severe depression or knows somebody who is, and maybe give them some idea of where they might be able to go with that.
Dr. James Murrough: 20:51
The first thing I would say is if you're experiencing depression, help is available, get help. It may sound simple, but talk to your doctor. There are things online. And sometimes if someone hasn't had depression before or they just don't know about it, they may not know that's what they're experiencing, but they feel like something is wrong, they're just not feeling themselves. I mean, everyone has an off day, but if it's day after day, week after week, then see your doctor, because most forms of depression can be successfully treated. And I always hasten to add that because we tend to study and try to understand and try to develop treatments for the individuals that have a more difficult, chronic, what we would call treatment-resistant course, but most people can respond well to psychotherapy or the available treatment. So if you're depressed, don't be afraid to bring it up with your doctor, tell your family if you need help. Because for the vast majority of people help is out there and it makes a big difference.
Thank you, Dr. Murrough.
Dr. James Murrough: 21:55
You're welcome. Thank you.
Dr. James Murrough is the Associate Professor of Psychiatry and Neuroscience and Director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai. To view transcripts, photos, and links to all of our episodes, check out our website, mountsinai.org/podcasts. Road to Resilience is a production of the Mount Sinai Health System in New York City. It's made by me, Jon Earle, Nicci Cheatham and our Executive Producer, Lucia Lee. From all of us here, thanks for listening and we'll see you next time.