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Melanie Cole (Host): Welcome to Back To Health, your source for the latest in heath, wellness and medical care; Keeping you informed so you can make informed healthcare choices for yourself and your whole family. Back to Health features conversations about trending health topics, and medical breakthroughs from our team of world-renowned physicians at Weill Cornell Medicine. I am Melanie Cole

If you’ve heard of ketamine, it’s probably for its history as a club drug. But it could also be one of the biggest breakthroughs in treating severe depression in years, our topic today is the exciting announcement of a study indicating the effects of ketamine on the brain of the severely depressed. My guest is Dr. Conor Liston. He’s an Associate Professor of Neuroscience and Psychiatry in the Feil Family Brain and Mind Institute at Weill Cornell Medicine. Dr. Liston I’m so glad to have you with us today. tell us a little bit about the prevalence and the general impact of depression in this country.

Conor Liston, MD, PhD (Guest): Well thanks for having me. Yeah, depression is a major problem and a growing one. In fact, by one estimate, it is now the leading cause of disability in the United States and many other developed countries. It’s enormously costly. Estimates vary, but on the order of hundreds of billions of dollars a year are spent on treating depression and due to lost productivity at work for depressed people. And of course, it’s also a tremendous burden for the patients who are actually depressed.

Part of why those statistics are so grim has to do with the prevalence of depression. By some estimates, about 15% and maybe up to 20% of people will get depressed at one point in their life. And for a subset of those people, they will go through repeated depressions, recurrent episodes of depression over the course of their life and finding the right treatments and getting it to work quickly is a major obstacle and challenge in treating people with depression.

Host: Wow, that’s quite an impact both on patients, the country and on providers to treat Dr. Liston. What are the current and past standards of care as far as medicational interventions?

Dr. Liston: Right. There are a variety of medications for depression and many of them are quite effective, that’s the good news. Patients have many different options for treatment. But finding the right treatments for the right individual has always been a challenge. The kind of mainstay of treatment are drugs like Prozac. We call them selective serotonin reuptake inhibitors or SSRIs. These are the first line treatments for depression.

They work for many people, but they don’t work for everyone. And they usually take like weeks or up to a couple of months for us to discover whether a particular antidepressant was effective in this particular individual and if it wasn’t, then we need to kind of go back to the drawing board and try another one. And that’s one of the reasons ketamine is so exciting that it seems to act much more rapidly than most of our conventional antidepressants do.

Host: And we’re going to talk about ketamine in a minute here, but why would someone not see results from standard antidepressants? Tell us a little bit about treatment resistant depression.

Dr. Liston: Right. A substantial proportion of people who get depressed will try one antidepressant and find that it didn’t work and then they’ll try another antidepressant and find that that one didn’t work either and we usually classify people as treatment resistant if they’ve tried at least two or sometimes three antidepressants at an adequate dose and for an adequate duration of time which usually means like six to eight weeks and unfortunately, a substantial proportion of people who get depressed will fall into that category where they won’t get better with many of the conventional antidepressants.

Host: Then what is ketamine? What’s the history of it? How has it been used in the past?

Dr. Liston: Yeah so, ketamine actually – it’s been FDA approved for other purposes for a long time, mainly as an anesthetic agent. I broke my arm when I was a kid. I had to have surgery when I was a kid as many kids do and kids who have surgery, the anesthetic of choice if often ketamine for various reasons. But at much lower doses, it turns out that ketamine is also useful as an antidepressant. That was discovered by groups at Yale and the Nation Institute of Mental Health going on, it must be close to 15 years now where they first started working on that.

Initial studies showed a lot of promise where people got an IV infusion of the subanesthetic dose of ketamine so a dose that wouldn’t be sufficient to produce anesthesia to put someone to sleep. But when delivered IV, it kind of went through their system and within a few hours of the treatments; these people were suddenly feeling relief from their depressive symptoms.

That was really remarkable because a lot of these people did fall into that treatment resistant category where they tried multiple antidepressants in the past and found that they didn’t work for them even after weeks and months whereas ketamine seemed to be achieving these really wonderful results quite rapidly.

Host: Isn’t that interesting? And now I really want to hear about your groundbreaking study regarding ketamine and depression. Why is this such a big deal and why did you see the need to do this?

Dr. Liston: Right. So, ketamine is a really exciting new development in psychiatry. It’s really one of the first kind of fundamentally new antidepressants that we’ve had in a long time. Many of the existing antidepressants are closely related to one another. Ketamine seems to work by a very different mechanism and so there’s a lot of excitement in the field about whether ketamine and maybe drugs like ketamine could be useful for treating depression going forward.

But there’s also some limitations with ketamine. So, the way that it’s mainly used right now is to achieve acute really rapid relief of depressive symptoms in people who are really sick and might be at risk of suicide. And so, you can give them an infusion of ketamine and they can feel rapid relief of their symptoms. But those benefits don’t always last, unfortunately.

So, one of the big challenges with ketamine treatment is figuring out what else we can do in addition to a single dose of ketamine to kind of prolong the antidepressant effects. What the studies have shown us is that many people will feel almost immediately better within hours after getting an infusion of ketamine but absent some other intervention; if you check back in a week; many of those people will have a recurrence of their depressive symptoms. And if you check back in two or three weeks and you haven’t done anything else for them during that time; most of those people will be depressed again.

So, it’s a really potent effect and it’s rapid, but it’s not necessarily long lasting. So, one of the things we wanted to understand in this study was what are the mechanisms by which ketamine induces this antidepressant effect acutely and which mechanisms are involved in sustaining the antidepressant effect over time.

Host: Well that segues nicely into my next question. What is the biological reason for why ketamine works like this? What are some of the things that you found out?

Dr. Liston: So, right. In this study and I should emphasize this study was in animal models not in patients and so it’s an open question to what extent similar processes are happening in the human brain. We have a lot of reason to think that something similar is going on. But basically, what we found is that the formation of new synapses, new connections between brain cells in a region of the brain called the prefrontal cortex seems to be quite important for mediating ketamine’s antidepressant effect but not in the way that we initially thought.

So, previous studies had pointed to the fact that the formation of these new connections was probably important, but it wasn’t clear exactly what role they played. And what we found by collaborating with a team at the University of Tokyo led by Drs. Haruo Kasai and Haruhiko Bito. They had developed a new technology that allowed us to basically optically delete newly formed connections in the brain in a really precise way and ask by deleting those new connections whether they were required for ketamine’s antidepressant effects.

And what we found contrary to our initial expectations, was that they weren’t actually required for inducing the effect acutely. So, in fact, the mice in our study had antidepressant benefits, behavior effects of ketamine very rapidly after the treatment within just a few hours but these new connections didn’t start to form until 12-24 hours. So, they came after and so that logic just tells us they can’t be required for inducing the effect acutely.

But what we did find was that they were required in a different way, not necessarily what we expected initially. It turns out that they are important for maintaining the antidepressant effect over time. So, if you delete those new synapses after they formed; the mice exhibit these antidepressant behavioral effects initially, but they don’t last. They antidepressant effects wear off after a time.

And we think that’s really interesting and potentially important because it suggests that the formation of these new synapses, these new connections might be important in maintaining, sustaining the durability of ketamine’s antidepressant behavioral effects and if that’s the case, then new interventions that could be new drugs or it could be brain stimulation interventions, or it could be something as simple as exercise which we know can promote synapse formation.

Interventions like this might be helpful for enhancing the durability of ketamine’s antidepressant effects over time and perhaps augmenting this treatment.

Host: That’s so cool Dr. Liston. What a fascinating study that could have such implications. What about the concerning side effects of ketamine. Is this a controversial study, do you feel? Is there a fear of dependency and if the side effects are concerning; then how is it administered? What are some things to watch out for as you are doing this study?

Dr. Liston: Right. Well again, we are doing the study in mice in a very controlled environment. So, there’s no concerns about adverse side effects of ketamine in our experiments. But I think your question is also getting at the bigger picture that matters to patients and doctors more of does ketamine have concerning side effects when administered to people. And yes, it can. So, you mentioned at the beginning of our conversation that a lot of people know about ketamine because it’s a club drug like historically people have used ketamine to get high and it does have this potential for abuse and perhaps addictive properties.

And so, I don’t think anyone is contemplating giving ketamine to people in an uncontrolled setting. That would probably not be a good idea. And another big question is the safety of giving ketamine repeatedly. I think that’s a question that no one really knows the answer to yet. I think different investigators are working on that and hopefully we will know soon. But what we know now is that ketamine is very safe when administered properly in a controlled clinic setting once.

But more work is needed to understand whether ketamine can be safely administered to people repeatedly and to avoid any concerns about abuse or addiction.

Host: That was a great explanation Dr. Liston. So, where do you see this research going in the future?

Dr. Liston: Well one thing we’re really excited about is kind of what I alluded to a moment ago which is whether other interventions that might enhance the formation of new connections in the brain after ketamine treatments, augment the ketamine in other words. Or interventions aimed at sustaining those synapses so I didn’t go into detail on this, but as it turns out, what happens when you get treated with ketamine is a bunch of new synapses form and those new synapses, some of them will persist, but some of them will disappear over time and our data suggests that interventions that kind of enhance the proportion of synapses that survive, that persist for days or weeks, that those kinds of interventions might be really useful for augmenting ketamine as a treatment and there’s a lot of ways you might imagine testing interventions to accomplish that goal and that’s one of the things that we’re excited about doing here in the lab.

Host: It is exciting. This whole research is exciting. Tell us about your mission at your laboratory and your team.

Dr. Liston: Right, so, I’m a psychiatrist and a neuroscientist and my lab operates at the interface between these two really exciting fields. One of the things that gets me excited about coming to work every day and I think a lot of people in my field share this feeling is that neuroscience is being transformed by these new technologies that are enabling us to ask questions that would have seemed like science fiction just a few years ago.

And I think the potential for the field to generate really groundbreaking discoveries that are going to transform our understanding of how the brain works and how the brain is dysfunctional in psychiatric illness; that these discoveries are just around the corner. In my lab, we are particularly focused on understanding how brain circuits support learning and memory and motivation and how those processes are disrupted by factors like stress, sleep, and antidepressant factors that are so important in influencing people’s mental health. So, that’s kind of the focus of a lot of our work and a third component is looking at whether we can develop new brain imaging technologies to rethink the way we go about diagnosing mental illnesses and depression in particular and hopefully identify diagnostic subtypes with a stronger correspondence to biology that might in turn be useful for informing treatment selection decisions.

So, these are some of the things that we’re really excited about studying here in my lab.

Host: Well they certainly are such important aspects to be looking at. Dr. Liston as we wrap up, what an interesting topic we’re discussing today. Tell other providers and any patients listening what you would like them to know and take from the studies that you are doing on mice, on the effects of ketamine and severe depression. What do you want them to take away from this and what should they be looking forward to, to read from you in the future?

Dr. Liston: Yeah, I mean I think the bigger picture with ketamine is just many physicians may not – many physicians will be familiar with ketamine as an anesthetic agent but may not be aware that ketamine is now being used as an antidepressant and so I think I hope that one of the take away messages can just be kind of increased awareness of this option as a treatment for depression and also that it’s probably best administered by experts in a clinical specialist setting, but that it is an option that’s out there. And so, for people who are acutely suicidal, who are in danger of harming themselves in the near term; ketamine offers this great new option that can achieve really rapid relief of their symptoms in just a few hours. And that’s very exciting.

That being said, there’s a lot of work to be done in figuring out what we can do to prolong ketamine’s antidepressant behavioral effects and that’s some of the work that we are so excited about doing here in my lab.

Host: Well, it certainly is exciting, and I can’t wait to hear more results from you Dr. Liston. Thank you again for joining us. concludes today’s episode of Back To Heath. We’d like to thank our listeners and invite our audience to download, subscribe, rate and review Back To Health on Apple Podcast, Spotify, and Google Play Music. For more health tips go to weillcornell.org and search podcasts. Parents – don’t forget to check out Kids Health Cast!