Why Depression Isn't What You Think | Lisa Monteggia  🔗 **Source:** [Why Depression Isn't What You Think | Lisa Monteggia](https://share.snipd.com/episode/7224f698-9280-4aa8-9b04-5d5468c398ef) ## Highlights - **Depression Is Not Simply A Serotonin Deficit** - Depression is not reliably a serotonin deficiency because many people with depression have normal serotonin levels. - SSRIs raise serotonin quickly but take weeks to relieve symptoms, suggesting the therapeutic mechanism is downstream adaptation, not simple chemical replacement. Transcript: Lisa Monteggia 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. And 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. Musicians, 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 Depression is really the dulling of emotion, really losing interest, and sometimes completely withdrawn.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. So 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 US. Disability meaning really loss of productivity, both on the individual, on 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. So 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. But 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. ([Time 0:01:57](https://share.snipd.com/snip/3e2b77b8-5b7b-467e-bac1-4213b08b5f29)) - **Ketamine Can Lift Depression Within Hours** - Ketamine produces antidepressant effects within hours rather than weeks, revealing a faster biological route to symptom relief. - The discovery came from an incidental low-dose observation where depressed patients unexpectedly improved during a study not aimed at depression. Transcript: Lisa Monteggia 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. And 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. Musicians, 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. So 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 US. Disability meaning really loss of productivity, both on the individual, on 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. So 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. But 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. And 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. And 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. ([Time 0:02:07](https://share.snipd.com/snip/e8a3ba55-8d69-4e7d-bdbc-be42670af0c1)) - **Keep SSRIs Unless Your Doctor Says Otherwise** - If you are on an SSRI, continue it; SSRIs remain first-line and life-saving for many people. - Consider ketamine only for SSRI nonresponders and discuss risks and suitability with your health care provider before pursuing treatment. Transcript: Lisa Monteggia And 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. And 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. So 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? And 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. So first of all, it's reshaving treatment. This is not a chemical imbalance. We are not correcting a 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. And 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? Some 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 vibrant, more brighter, or less brighter, however you want. Cetamine is not painting the canvas. It'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, they 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. So 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. Because, again, given all the different symptoms, people had 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, catamines, 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 ([Time 0:06:10](https://share.snipd.com/snip/89c1b175-6352-46ef-90a5-0ff572c9e27d)) - **Blocking Glutamate Sparks Synaptic Strengthening** - Ketamine acts on the glutamate system rather than serotonin, and it blocks fast glutamate transmission instead of activating it. - Paradoxically, this blockade triggers synaptic plasticity and strengthens specific neural connections thought to underlie the antidepressant response. Transcript: Lisa Monteggia 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? And 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. ([Time 0:07:47](https://share.snipd.com/snip/57eb23a4-abba-44d9-8088-4a40716066d0)) - **Reframing Depression As A Problem Of Brain Plasticity** - The therapeutic model shifts from 'fixing a broken chemical' to enabling brain adaptability; ketamine taps into plasticity rather than replacing missing transmitters. - This reframing changes treatment expectations and offers rapid hope for people who didn't respond to SSRIs. Transcript: Lisa Monteggia So first of all, it's reshaving treatment. This is not a chemical imbalance. We are not correcting a 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. And 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. ([Time 0:09:02](https://share.snipd.com/snip/d2bddf6b-ba1e-44bc-95d5-c85f9842d61d)) - **Use Ketamine's Plasticity Window To Improve Outcomes** - Ketamine opens a temporary 'window of plasticity' that could make psychotherapy or other interventions more effective during that period. - Researchers are exploring combining ketamine with therapy, stimulation, or other drugs to extend and sustain antidepressant effects. Transcript: Lisa Monteggia Some 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 vibrant, more brighter, or less brighter, however you want. Cetamine is not painting the canvas. It'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, they 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. So 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. ([Time 0:10:25](https://share.snipd.com/snip/130173d1-53b6-4223-8114-2e28e81e853b)) - **Patient Image Of Emerging From A Dark Room** - A patient described living in a dark room with no windows before ketamine and then seeing a door after treatment, illustrating the change in perspective. - Ketamine didn't create joy but lifted despair enough to reveal hope and possibilities for change. Transcript: Lisa Monteggia 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, they 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. ([Time 0:11:08](https://share.snipd.com/snip/c3340047-5999-4009-a979-44842fe4eebe)) - **Sustaining Ketamine Benefits Is The Next Challenge** - Ketamine's antidepressant benefit typically lasts days, not forever, so research focuses on sustaining effects rather than repeating high-risk dosing. - Strategies under study include leveraging plasticity to consolidate change and developing safer, longer-lasting drugs or combination approaches. Transcript: Lisa Monteggia 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. Because, again, given all the different symptoms, people had 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, catamines, 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. But 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? ([Time 0:11:54](https://share.snipd.com/snip/4776cc82-2ec4-4446-8fc6-08a03b4fcf7f))