Anti-depressants don’t work for everyone. Psychiatrist Conor Liston, MD, PhD, describes four effective treatments that restore the brain’s lost connections and repair the cellular changes that cause depression. Magnetic stimulation, deep brain stimulation, electroconvulsive therapy, and low-dose ketamine (“Special K”) have all been shown to relieve the symptoms of clinical depression and correct the functional impairments that can be so crippling to patients.
Dr. Stieg: I'm pleased to welcome Dr. Connor Liston today to talk with us about some exciting advances in diagnosing and treating depression. Dr. Liston is an associate professor of neuroscience and psychiatry at Weill Cornell Medicine where he is also conducting research to advance our understanding of the neurobiology of depression and treating psychiatric disorders. Today we're going to focus on older treatments, improved and innovative things that you're working on in the laboratory and hopefully taking to the patient. One of the things that I know you are particularly interested in that's new and innovative is transcranial magnetic stimulation. Can you explain to us how that works and what it's doing to the brain?
Dr. Liston: Transcranial magnetic stimulation or just TMS is a new treatment for depression. The actual technology has been around for a while. It works by applying a magnetic field to the brain. Kind of like, again, kind of like you get an MRI, magnetic resonance imaging brain scan, but it's focused just on one part of the brain and by pointing the magnetic field at that part of the brain and kind of turning it on and off rapidly, it can activate brain cells and —
Dr. Stieg: Can it go deep into the brain. Or is it just work on the surface?
Dr. Liston: So in the future we hope that it might be able to go deeper into the brain, but right now it's really just on the surface and that is a limitation.
Dr. Stieg: And when you were starting with this, were you just kind of marching around the brain and finding where it worked and a person's depressive symptoms improved?
Dr. Liston: Yeah, we really benefited from research that came before that showed that a particular brain region, kind of on the left side near the front, we call it the dorsal lateral prefrontal cortex. The name is not so important, but this particular brain region, when you stimulate it and you do it repeatedly for a couple of weeks, people's depressive symptoms tend to improve. And that was just kind of a serendipitous discovery that was made some years ago.
Dr. Stieg: Okay, so explain what goes on. This isn't a probe that goes into somebody's head. It's a device that you put on the surface of the skull. So it's outside. Describe the process.
Dr. Liston: That's right. It's a noninvasive process. It's painless. Patients come in to my office and they leave the same day. They're there for about an hour. It's an office-based treatment as opposed to a surgical one. That's important for people to understand, and what a patient would experience — they'd sit down in a chair, in an office, kind of like the one we're in now, and this device would be kind of pointed at their head at a particular location on their head, on the left side. And when we turn it on, they hear a loud kind of clicking noise and they can kind of feel sometimes like a scratching sensation on the scalp, but no pain. And that's really the extent of what the patient experiences.
Dr. Stieg: So you're sitting in a room, a doctor comes in or a technician comes in and puts the probe on the surface of your head. And how long is it on there?
Dr. Liston: Usually there are different kinds of treatments, but the most common one is about 30 minutes.
Dr. Stieg: It's 30 minutes. So you just have to lay still. Can you put the TV on so somebody who's entertained or do they have to be…
Dr. Liston: You can put the TV on. Sometimes patients like to bring their favorite music in. They can really do whatever they want as long as they're kind of sitting still during the treatments.
Dr. Stieg: So it's really a pleasant experience. Have you seen cases where a patient comes in that they're significantly depressed, really sad, they get the therapy and you know they start cracking jokes by the and or is it, does it, does it work quickly or does it take a little time?
Dr. Liston: It can work quickly, but the most common kind of pattern is it takes a few weeks before patients really start to feel a lot better. But you do notice that they come in, you can kind of see it on their face, they look kind of glum, not a big range of kind of emotional expressions on their face and after a few weeks they start to look different, more expressive, smiling spontaneously more. Sometimes they'll crack a joke, something they haven't done in weeks or months. And that's really rewarding to see.
Dr. Stieg: Is there, of the four subtypes of depression, is there one particular subtype that's most responsive to this TMS?
Dr. Liston: We found that when we scan people's brains and identify these kinds of brain scan based subtypes which are diagnosed by looking at how different brain regions are connected to one another, we found that those subtypes are related to your likelihood of responding to TMS. That one of them you're quite likely to respond well and that's two of the other subtypes you're, you're not as likely to respond. And kind of the, the fourth one's kind of intermediate.
Dr. Stieg: So like the clinical subtypes that we talked about, there are also four physiologic or functional MRI imaging categories for depression. And one of those four is particularly responsive to this TMS. That's exactly right. Can you describe for us what that means? Is that fibers that go from the middle part of the frontal lobe to a particular part of the brain or what is it about that functional MRI that says, “Hey, you know, that's that that person's going to respond to TMS.”
Dr. Liston: That's, that's a question we're investigating in the lab and trying to understand better, but what we know so far is that this particular subtype, patients often come with elevated levels of anxiety compared to other people with depression. Sometimes they have trouble sleeping and those symptoms are associated with changes in connections with this region of the brain, the amygdala, which is associated with fear processing and with anxiety. And we think that TMS might be acting partly to kind of fix those, those altered connections.
Dr. Stieg: So in that subtype, if you, you have this sleep problem and an anxiety disorder, what percentage of those patients do respond to this TMS?
Dr. Liston: In our hands, about 80% of people who are really treatment resistant, meaning that they've tried a number of drugs and they didn't work for them. And so those people don't tend to get better spontaneously — in our hands, about 80% of those people show at least a partial improvement and about half of them get completely better in response to this kind of TMS.
Dr. Stieg: You're really using this on people that are because of their depression, they're not leading functional lives.
Dr. Liston: That's right. They have, they have some kind of functional impairments in their life. Oftentimes you wouldn't necessarily, if you didn't know them well, know that they're depressed. It's not like they can't work or can't have family relationships. They're not hospitalized, but they wouldn't be there if they didn't have some kind of functional impairment in their life.
Dr. Stieg: So you're, you're one of those fortunate 80% that gets better one time or do you have to come back for repeated therapies,
Dr. Liston: You have to come back for one kind of course of treatments, which lasts four to five weeks and then many of those people, like we said, about 80% of them get better and many of them will stay better and that's kind of the nature of depression. Some of them will get depressed again at some point in their life and will need some other treatments. But some of them will stay better.
Dr. Stieg: With only one therapy.
Dr. Liston: With only one course of treatment, meaning five weeks.
Dr. Stieg: So five, does that mean once a week they come in or they come in usually once daily.
Dr. Stieg: Oh really? That often –
Dr. Liston: Monday through Friday for five weeks.
Dr. Stieg: But that’s still fantastic because we're talking about patients that are resistant to normal pharmacology.
Dr. Liston: That's right. These aren't the, you know, this wouldn't be the first treatment you'd try. Most of these people have tried multiple medications and they didn't work for them.
Dr. Stieg: Right. And I'm also curious about the fundamental problem of healthcare insurance just doesn't pay for psychiatric care. Depression is a common problem. How are we going to solve it for the person that doesn't have enough money to go to a psychiatrist five days a week for five weeks to get their TMS?
Dr. Liston: Uh, it's a big problem. I should emphasize that TMS is now actually covered by many insurance panels. You can't get it right away. You know, we need to make sure that TMS is the right treatment for you, that you've tried other medications and they haven't worked. But that being said, you bring up kind of a bigger problem in mental healthcare in our country, which is just that mental health care generally isn't covered as well as other medical conditions are. And that's kind of a policy level question that I think needs to be fixed.
Dr. Stieg: It's above your in my head. But unfortunately it's such a common problem. I mean I remember hearing at one lecture I was at that suicide is probably the number one cause of death in America. You know, not heart disease and lung disease, but it's just not talked about.
Dr. Liston: That's right. There's an epidemic of suicide right now related to probably many different factors. Depression's one of them. People need to know there are options out there for them and they should seek help.
Dr. Stieg: And what's also interesting is as part of your research that you've been doing with these functional MRI scans, you're really, you're not only able to look at the connections or the neural networks in the brain, but you're also able to look at some of the basic cellular anatomy, meaning the, you know, the cell body of the, the, of the nerve cell. And, and that leads me into that something old, the ketamine or as you, I guess like to refer to it as special K. Ketamine is a drug that's been around since what the 1960s, it's one of the old, uh, psychedelic kinds of drugs. And now your finding that it has potential in treating again, pharmacologically resistant depression.
Dr. Liston: That's right. Ketamine is a drug that's been around for a long time. It's also, it has a medical use as you know, especially in kids who need surgery. Ketamine is an, is a go to choice as an anesthetic agents when you're going into surgery. But more recently psychiatrists have discovered that ketamine at a much lower dose than you'd use in an operating room can also have antidepressant properties. And one of the most exciting parts of it is that it's rapid. Um, unlike most of our other treatments, we're just talking about TMS takes five weeks, people get better right away with ketamine on the next day.
Dr. Stieg: And what's really interesting is what you're finding in the laboratory about how it changes the cells.
Dr. Liston: We've found that depression and chronic stress, which can trigger depressive episodes in some people, that that changes cells in your brain. It causes some of them to lose connections. These connections are vital for communicating between nerve cells and in depression. We think that some of those connections are lost and ketamine, it turns out restores those lost connections.
Dr. Stieg: And it restores it permanently. You said that the onset is almost immediate. How durable is it?
Dr. Liston: That's another important point for, for most people, the benefits of ketamine aren't durable beyond a week or two. So what that means is we can get someone better rapidly, but we need to do other things to help them stay better. And that might mean some other medications. It might mean psychotherapy, it might mean other interventions as simple as exercise or better sleep. There are many things we can do to help people kind of maintain their mood.
Dr. Stieg: And I find it interesting there was a recent article that came out from studies, I think it was in Australia or in New Zealand about the impact of stress. I think it's important for our listeners to know that stress as you've demonstrated a key component in the onset of depression.
Dr. Liston: That's right. And I think again, it kind of makes sense intuitively to us. Depressive episodes don't usually just come out of the blue out of nowhere. They do sometimes, but usually people can tell you, something stressful happened in my life. I lost my job. Or a breakup in a significant relationship or some other kind of personally stressful experience.
Dr. Stieg: You with your studies are now showing that with stress, there's cellular changes in the brain that account for it and you know, they're just sick. It's like having a bad heart, bad kidney, a broken leg, you know? And there are ways that we can go about fixing the brain now.
Dr. Liston: There's a lot of stigma associated with depression for many people. And, and I think that's just because not everyone understands that depression, like any other medical condition, it's a problem with a biological cause and it's one that we can fix.
Dr. Stieg: A more invasive way to take care of depression obviously is this deep brain stimulation where a neurosurgeon puts an electrode down deep into the center of your brain? Is that coming back into the field or is that just something that's been there and not really a prominent subject now?
Dr. Liston: Deep brain stimulation I would say is an area of increasing interest really in the field. In depression, you know, not everyone is going to be a candidate for deep brain stimulation as a treatment. It's not the first thing we would consider of course, but for some people like those same people who are getting TMS, who've tried many medications and they're just not working deep brain stimulation, I think in the future could be a very good option. The trick is kind of figuring out, we don't understand how the brain is altered in depression. If we could understand that a little better, we could probably design the deep brain stimulation interventions to be more effective.
Dr. Stieg: It brings up the interesting question for me is, you know, when all you have is a hammer, everything has to be a nail, you know, and if you're a psychiatrist, you're going to go through what you know. What's the advantage of being in a major medical center or affiliated or somehow with a major medical center to know that you, I don't know when it's appropriate to be thinking about DBS versus TMS versus routine drugs versus just some psychotherapy.
Dr. Liston: That's a great point. It's one of the things I take advantage of every day here at Weill Cornell Medicine. I can't an expert in everything, but I'm surrounded by people who have relevant expertise in almost any question I might have. And so just being exposed to my colleagues and neighbors here and what they're doing can be really beneficial for my patients. What I know, as you said, isn't working. I can refer them to somebody else. Kind of having your finger on the pulse of what are the options for treating depression is really critical.
Dr. Stieg: So I guess what I'm saying is that patients need to recognize that when they're not responding to a certain form of therapy and that's all the tools that a doctor has with them, they should look around. They shouldn't feel badly about looking, right.
Dr. Liston: No doctor would ever be offended about getting a second opinion and looking for other options. It's good advice.
Dr. Stieg: Let's go back to something a little less invasive but certainly old, tried and true electroconvulsive therapy.
Dr. Liston: Yes. Electroconvulsive therapy or ECT has also been around for many years. Dating back to the forties probably and it's still actually the most effective treatment that we have for depression. I also always like to emphasize to my patients and hopefully to your listeners that ECT, I think, has a bad image in the media and it's not like what people see in movies. ECT, you go in to get this procedure, you get a mild anesthetic agent like you would if you were going into surgery. You basically just sleep for a little bit and wake up after the procedure and, and it's, it's very well tolerated by, by most people.
Dr. Stieg: It’s done as an outpatient —
Dr. Liston: It's often done as an outpatient. It depends how sick the person is, you know, whether they're safe from their — a depression point of view to be outside and at home. But it can be done as an outpatient. And again, this is reserved for patients that have gone through all of the psychotherapy, drug treatments, maybe now even TMS and that's all failed.
Dr. Liston: That's right. It's not the first or second or usually even the third thing we would try, but it is super effective. So, for people who didn't respond well to those other medications or TMS, ECT is a great option.
Dr. Stieg: Is it particularly useful for one of the subtypes of depression that you were referring to? Both symptomatically, meaning the atypical melancholy or the biological subtypes that you're characterizing with functional MRI?
Dr. Liston: So we haven't looked at the biological subtypes, but for the clinical subtypes, like the seasonal depression, the melancholic depression, ECT seems to be effective for all of them. Really does. It really does work for most people, frankly.
Dr. Stieg: Yeah. How bout for the person that's really deeply depressed and has expressed suicidal ideation? Is ECT a good therapy?
Dr. Liston: It is a good treatment. So, ECT will improve all of their depressive symptoms, including thoughts about suicide.
Dr. Stieg: How about for a patient who's pregnant? Can you use ECT?
Dr. Liston: ECT can be used for patients who are pregnant under the right circumstances. It's again, like depression in pregnancy, it's its own special thing that requires a lot of special considerations like any other medical condition in pregnancy, but it's an option.
Dr. Stieg: And what about for old patients are getting older. Okay, so you're 75 I consider that middle age nowadays. You're 75 years old. Are you a candidate for ECT?
Dr. Liston: You're a candidate for ECT even if you're older, absolutely.
Dr. Stieg: You described the a very passive process where a patient comes in, they're put under mild sedation, they get treated and they wake up and can be done as an outpatient. Can you describe what actually happens to the patient while they're asleep?
Dr. Liston: Sure. Um, so a patient comes in, we give them an anesthetic agent in an operating room. It puts them to sleep. And then the actual ECT procedure electrodes, basically little paddles are placed on the scalp and an electric current is run through those paddles and that causes the person to have a seizure. Again, we don't fully understand why, but causing these seizures especially, repeatedly, tends to relieve depressive symptoms for many people.
Dr. Stieg: And like TMS, is ECT something that you, you have to do several days in a row or several weeks in a row or you just come in once and you're, you're good for a while and you come back later?
Dr. Liston: There's two kinds of ECT. So the second thing you just described, we'd call maintenance ECT where you're already better, but we want to keep you better. And oftentimes that can mean just coming in occasionally, but when someone's really sick, that kind of ECT usually requires, like TMS, it requires daily treatments typically or maybe three times a week for a couple of weeks. And people tend to get better after 10 or 15 sessions of ECT.
Dr. Stieg: Oh, I just like to touch on these topics that are a little bit out there and the suggestions that new tropics or nutraceuticals over the counter additives can be beneficial in the treatment of depression. What are your thoughts?
Dr. Liston: Yeah. Many of my patients come in asking me about that. It's a thing that a lot of people are interested in. Personally. My approach to treating my patients with depression is to focus on interventions like those that we've discussed today that have a really strong evidence base that we know that they work and many of these like nutraceutical interventions, they just haven't been very well studied. So my advice would be for any patient considering those, to really discuss them with your psychiatrist and come to a decision that's best for you based on that conversation with an expert. I think another thing, this doesn't apply to all nootropics, but it's received a lot of attention in the media. They aren't regulated in the same way that drugs are, that medications are, and so you don't always know what you're getting when you go to a store and pick one of these bottles up. So it's another reason to talk with your psychiatrist and, and make sure that you know what you're actually putting in your body.
Dr. Stieg: Connor, thank you so much for giving us hope about how we can approach depression when it strikes. It's, it's clearly a common problem in America and throughout the world, and it's good to know that clinicians and scientists like you are hopefully inventing new and easier ways to treat this common melody.
Dr. Liston: Well, thanks for having me here.