Why depression isn't what you think | Lisa Monteggia

0:03You're listening to TED Talks Daily, where we bring you new ideas to spark your curiosity every day. I'm your host, Elise Hu. For decades, we've been told that depression stems from a chemical imbalance in the brain, and antidepressants can fix it. It's a tidy explanation. According to neuroscientist Lisa Monteggia, it's also not quite right. Here's the thing. If you look at individuals with depression, many of them don't have decreased serotonin. They have normal levels. And that's a surprise to many people. Lisa has spent more than 15 years studying ketamine, a general anesthetic that many people know as a party drug, but that could quietly upend everything we thought we knew about how antidepressants work.

0:46In this talk, she shares what her research has revealed and why it's changing not just the science of depression, but the story we tell ourselves about what depression actually is. We are not correcting our chemical imbalance. The idea that someone may be broken, as people have talked about with depression, they're broken, they can't make an essential transmitter like serotonin. It's not the case because we're not correcting it. We're not doing anything to it. It's the idea that your brain can adapt, and ketamine is able to tap into that. That's coming up right after a short break.

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3:33Lisa Monteggia: And now our TED Talk of the day. So when people find out that I study antidepressants, they often ask, how do they work? And people are surprised to learn we don't know. And part of that surprise comes from the fact that we've been told that depression is a chemical imbalance, that you don't make enough serotonin. And we know that antidepressants, SSRIs are the most common antidepressant prescribed, increase serotonin. And so they think that what we're doing is we're fixing depression by increasing serotonin. But that's not the whole story. In fact, that may not even be the story. What I'm going to talk to you today about is some of our work with ketamine, a really remarkable drug that has rapid antidepressant effects.

4:22And it doesn't correct a chemical imbalance. It actually causes the brain to change, to adapt. So when we talk about antidepressants, we first have to start with depression. And everyone uses the term depressed. We hear it all the time. I feel depressed. I feel sad. I have melancholy. Creative expression of depression is very common. For centuries, people tried to express the feeling of depressed or melancholy. For example, Picasso went through his blue period and his painting style changed. It really portrayed a sense of sadness, of gloom. We know that writers do this, poets. I mean, you can read a poem and literally be moved to tears by the words.

5:08Musicians, how many sad songs do we hear? Eric Clapton's Tears in Heaven about the loss of his son is heartbreaking. But major depression is more than just sadness. It's a serious medical condition, especially left untreated. Depression is really the dulling of emotion, really losing interest, and sometimes completely withdrawn. The symptoms of depression can vary. Some people, it may impact more appetite, others sleep. It may have effects on concentration, memory, a range of things. So not everyone has the same symptoms. But it's a serious illness, again, left untreated. We know globally it affects over 280 million people worldwide.

6:02So a huge number. Everybody in this room knows someone that's impacted by depression, whether they tell you about it or not. Moreover, depression is the leading cause of disability in the U.S. Disability meaning really loss of productivity, both on the individual and family and on society. Part of the focus that comes from studying depression, though, is really focused on antidepressants. And we all have heard of antidepressants. And how this came about was really completely randomly. It was noticed that certain drugs had antidepressant effects. And as people studied it, they realized that if you increase serotonin, you had an antidepressant effect.

6:49So things like Prozac, Zoloft, common antidepressants, have been studied for decades. And we've seen ads on TV, in doctor's offices. People openly talk about the idea we're increasing serotonin. We're correcting our chemical imbalance. But here's the thing. If you look at individuals with depression, many of them don't have decreased serotonin. They have normal levels. And that's a surprise to many people. This idea that we had a measurable index of depression just because it was less serotonin, many people talked about, but it really wasn't true. So that's been sort of surprising to many people.

7:32But importantly, SSRIs still are incredibly important treatment options. They help many people. They are life-changing and they are life-saving. For many people, they really give them the will to live. The thing about SSRIs is that when you take them, you have this increase in serotonin very quickly, but they take weeks to work. They don't work quickly. And so why do they take weeks to work? And that's the part that we really don't know. But again, they increase serotonin. So if it was simply fixing, it should happen quickly. And so while, again, they're incredibly important treatments, they are life-saving.

8:18And if you're on an SSRI, you should continue to take your SSRI. That's an important message. But that's why some of the research I'm going to talk to you today about ketamine, which my lab and group has been studying now for more than 15 years, has been so remarkable. Ketamine, this is the structure of the drug. What's been noticed is in a clinical study that had nothing to do with depression, it was just an observation, they gave a low dose of ketamine. And some of you may have heard of ketamine. At high levels, it's an anesthetic. At more mid-level doses, it's a party drug. But what they were doing was a study with an incredibly, incredibly low dose.

8:55And for those individuals that were depressed that received ketamine, they had a rapid antidepressant effect. Not within weeks, within hours. We didn't even know it was possible to have an antidepressant effect that rapidly. And so people have been studying why. What is this rapid effect? because it really is remarkable. And it doesn't just work in individuals that could be depressed. It's really been studying in individuals that don't respond to SSRIs, because not everyone responds. And so it sounds pretty remarkable. But it's important to mention up front that ketamine does have risk. And as with any drug, if it's not used correctly or given at very high levels, it can have adverse effects.

9:40So it's really, really important that things are followed in a manner as they should be, not just more is better. That is not the message. So we started studying ketamine, and other groups did as well. And the first thing which we all know is that ketamine doesn't work on serotonin. It doesn't increase serotonin like SSRIs. Instead, it actually focused on a different neurotransmitter system called glutamate. And glutamate is what's important in fast communication in your brain. Now, what's interesting is that ketamine targets glutamate, but it doesn't activate it. It blocks it. So why would blocking fast communication have any beneficial effect?

10:25And what we've been able to show is that ketamine, by blocking this fast communication, what it does is it actually strengthens particular connections in the brain, what we call synaptic plasticity. It's just a change in your brain. your brain is able to adapt and strengthen connections. And we think that's what's driving the antidepressant effect. And so as we've been studying this and trying to understand, okay, what does this mean? How does this work? What we've been able to show is that this is a nerve cell. This is one of the cells that we think actually are strengthening connections. As we're studying this and trying to understand it, it's really providing a lot of different ways of how we're framing what is depression?

11:09So first of all, it's reshaving treatment. This is not a chemical imbalance. We are not correcting our chemical imbalance. The idea that someone may be broken, as people have talked about with depression, they're broken, they can't make an essential transmitter like serotonin. It's not the case because we're not correcting it. We're not doing anything to it. It's the idea that your brain can adapt and ketamine is able to tap into that. So it changes the way that we're thinking about depression. Moreover, it's changing how we're reframing the timing. Instead of an antidepressant requiring weeks to work, you can respond within hours, which is remarkable, especially for individuals that didn't respond to SSRIs that may have been depressed without treatment for decades.

11:57And third, it's reframing hope. The idea that there are treatments, that you're not broken, that this is just a matter of getting your brain to respond, to respond to treatment. And that, I think, is a really important message of how we're thinking about the future. As we continue to study ketamine, there are many different aspects that we're looking at. Ketamine targets a glutamate system. Glutamate is being released and activated. As we're looking at how it's sort of causing this disruption, this blocking of transmission, we're actually thinking, are there other ways to trigger this plasticity?

12:33Some people are looking at when you take ketamine, you have this window of plasticity, do you respond to therapy better during that time? Or what about to other drugs? Perhaps brain stimulation. We also have been looking at it from a context of can we extend ketamine's antidepressant effects? So as we look at this plasticity, what's important to remember is that it's like a painting, an analogy. If you have a blank canvas and you paint, you're adding something new. But then you can dial in the colors. You can make them more brighter or less brighter, however you want. Ketamine is not painting the canvas.

13:14It's not creating new memories. What it's due is it's alleviating that despair. As some people describe with depression, someone noted that they felt before ketamine treatment that because they didn't respond to SSRIs, that they were really living in a dark room with no windows and they couldn't get out. After taking ketamine, it didn't make it a party house. What it did is it made it seem like the light was lifted and there was a door and it provided hope. What ketamine is doing in the painting analogy is it's actually able to dial in to lift this sort of despair, if you will. And that's important.

13:57So as we target this plasticity, we think about how can the brain adapt? How can it change? One of the things we're doing is that this antidepressant effect doesn't last forever, like flowers in a vase. Ketamine treatment lasts a few days, and then it waits. So one of the things we've been able to do is actually initiate studies to look at giving ketamine, triggering this antidepressant effect, and then can we sustain it longer so that you don't have to have another treatment so soon. And we're doing this through targeting this plasticity, this adaptability in the brain. And we think that's quite powerful because again, it's not about having to fix something.

14:40Because again, given all the different symptoms, people have different levels if it were a matter of fixing something. All we're trying to do is to tap in to the brain's ability to change. And so where are we going with this? Well, ketamine, as I've told you, is a really remarkable treatment, but it's not for everyone and it's not without potential harm. If you are currently taking an SSRI, you should continue to take the SSRI. This is the first line of treatment for depression. It's for individuals that don't respond, really, that have been most studied in terms of taking ketamine. If you're interested in it, you should talk to your health care provider.

15:22But we're using ketamine to try to understand, again, how do you generate an antidepressant effect? And the idea that it's not just an imbalance, again, that someone is not broken. Maybe their brain is just sort of stuck and ketamine allows you to adapt, to change. And that, again, is what we think the response is. And so as we continue to study ketamine, we in other labs, we're trying to understand how can we make this better? How can we make this safer? to work for more people, and how can we sustain the effect? And I think those are all really powerful messages of hope because it's not just about seeking treatment today, which is incredibly important, but also for our children and for grandchildren and for others because this is a global issue, and this is something that there's a lot of work going on that's really creating a lot of excitement in the field, and it's also the power of scientific research.

16:20Thank you.

16:26That was Lisa Montasia at TEDxNashville 2025. If you're curious about TED's curation, visit ted.com slash curation guidelines. And that's it for today. TED Talks Daily is a podcast from TED. This episode was fact-checked by the TED Research Team and produced and edited by our team, Martha Estefanos, Oliver Friedman, Lucy Little, Emma Taubner, and Tanzika Sungmarnivong. Additional support from Daniela Ballarezzo, Christopher Faze-Bogan, Valentina Bohanini, Banban Chang, Brian Green, and Lainey Lott. Learn more at podcasts.ted.com. I am Elise Hu. I'll be back tomorrow with a fresh idea for your feet.

17:07Thanks for listening.

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18:04Lisa Monteggia: On the TED Radio Hour, online shopper Aparna Mehta used to get a lot of packages delivered to her door. Oh, per week? 12, 15? Whoa! Sorry, but I didn't think I was doing anything wrong. Look, the store is making it possible for me to order as many as I want and return back what I don't want. Shopping in the state of fashion. That's next time on the TED Radio Hour from NPR. Subscribe or listen to the TED Radio Hour wherever you get your podcasts.