Full episode transcript (beware of typos!) below:
Nick Jikomes
Lisa Monteggia, thank you for joining me.
Lisa Monteggia 2:06
Thank you for having me, Nick. I like to start out by just having people describe what they work on and who they are. So can you tell everyone what your background is? So my name is Lisa Monteggia. As you mentioned, I am currently the director of the Vanderbilt Brain Institute at Vanderbilt University. I've been here in Nashville for three years.
I started my career, actually working in a pharmaceutical company and then sort of made the jump into academics, and was in Texas for quite a while before I was recruited here. But our research throughout my whole independent career has really focused on how antidepressants work. And we've had a second side project focused on a gene called MEK P two, which is a gene that's linked to Rett syndrome, which is a neurodevelopmental disorder. And part of that came from the fact that I trained as a postdoctoral fellow in a lab, Dr. Eric Nasser's lab, who is a leader in the field of addiction. And when I started my own lab, I really wanted to do something different, moving to a different field. And so I was really fascinated by the question of how antidepressants work. So we initiated projects in the lab, but since as an assistant professor, you really never know what's going to pan out. I started a second project on MEK P two, because it had been identified, but its role in the brain was really unknown. And I've been very fortunate to continue both lines of research throughout my career.
So you actually went from the pharmaceutical industry into academia, which is fairly uncommon, right? Uh huh. Yeah. Yeah. What what prompted that and and your interest in antidepressants?
So, I think, you know, I will say a lot of times when people make jumps, it's because they were unhappy, or they were looking for something else. I was actually quite happy in industry. I found it really fascinating. I worked with some incredible scientist. I like to have the fast paced action of moving around on different projects. But I really wanted to focus in at least spend part of my career focused more in on a project. And so I took a leave of absence was initially a leave and then I ended up giving up my position to do a postdoctoral fellowship with Eric nesler. And it was in the area of addiction. It allowed me to really have a wonderful, very interdisciplinary component in academics, of really trying to answer translational type questions. And I like that approach of really trying to think about basic questions that could have clinical relevance. And I have read, I really had no experience in the field of depression, but I had read a number of papers, and I just found it was really fascinating. The idea that everybody knows someone that's depressed or that takes an antidepressant. They're widely prescribed, relatively safe drugs. But we don't really know how they work. And from a very broad standpoint, I think one of the things that I found was particularly intriguing was that if you think about diseases of the brain, you broadly classify them into neurological or psychiatric. And often with neurological you think of Parkinson's, Alzheimer's, Huntington's types disorders. And those will have a component of neuro degeneration cells are dying in some way. And you're trying to think about slowing that cell death, or, you know, how can you maybe prevent it. But with psychiatric illnesses, you don't have this neuro degeneration. In fact, when you look post mortem, there's really no huge anatomical structural changes, but yet you can have these devastating disorders. So you have these two very differences in what we know about the pathology. what's intriguing is there really are no great treatments for Neuro lot most neurological diseases. But yet there are for psychiatric diseases, even though we know so little about them. So I just thought it was an interesting idea of how you can know so little about what causes it. And yet, we've stumbled upon some treatments. So how can we advance that?
Yeah, there's a lot there that I want to unpack. So you've made this distinction between neurological disorders of the brain and psychiatric disorders of the brain. They're, of course, all neurological disorders in the sense that they're affecting brain cells. But I think what you've told us is, when you have a neurological disorder, by your definition, something like Parkinson's cells are obviously dying in the brain, there's a clear cut physical abnormality, and it causes motor, let's just say motor problems, some sort of motor problem. And it may or may not cause say, a problem in mood or cognition. Or as these neuro psychiatric disorders like major depression, when you look at the brains of people that have it, there's not this gross and a top anatomical abnormality, like you would see in someone with a tumor or a lesion. And yet, it has this debilitating effect. Is that a fair summary? Yeah, I mean, again, this is very, very broad strokes of what a neurological and psychiatric disease are, there's different examples of neurological diseases. But when you ask a, you know, an individual of what a neurological diseases they typically would say Alzheimer's, Parkinson's, you know, along those lines, because there's a huge focus. And as it rightly should be, but again, it's different when you think about psychiatric illnesses. And the fact that there's no gross, you know, cell death or anatomical structural changes suggests that it has to be functional. I mean, how can you have a brain that looks so normal, and that you could have such a debilitating disorder, such as schizophrenia, or major depressive disorder that, you know, without treatment could result in suicide?
Nick Jikomes 7:54
Yeah, no, I want to end up talking about the difference between the traditional medications for things like depression and other psychiatric conditions, like SSRIs, as well as a lot of the research that that you and others have been doing recently, on ketamine and, and the sort of next generation of potential treatments. Before we get there, let's unpack a little bit more. What psychiatric diseases like major depression actually are, and what we know about what's going on in the brain. So can you sort of define for everyone in broad strokes, what major depression is, and how big that this burden actually is on society.
Lisa Monteggia 8:32
So major depressive disorder, is characterized by a range of symptoms. And there's actually a clear definition of a number of different criteria, but you only have to hit a certain number of them. And so what this means is that people can present very differently. Some people may have weight gain and sleep and not feel great. Other people may have very different symptoms, but they're still depression, it's very heterogeneous, the term, not all the patients look the same. And so that can make it very challenging, if you will, you have a disease very heterogeneous. But if you think about it even broader, we know that there's different types of depression. You know, there's postpartum depression, which we hear about shortly after birth mothers that can be affected by it. Those can be a very different type of patient than say someone that suffers from, you know, major depressive disorder, or bipolar disorder. So these mood disorders can look slightly differently and how they manifest and again, they're, in the end often just referred to as depression.
Nick Jikomes 9:41
And so, you've told us so far that if you were to just sort of step back and take a bird's eye view of the brain of a normal individual and someone with one of these depressive disorders, they would pretty much look the same. You wouldn't notice anything super obvious. What what is actually going on under the hood initially terms of how depression arises? And could you maybe discuss that from the perspective of the, what I would call the sort of standard cartoon idea of depression that a lot of people have, which is, it's a chemical imbalance and you don't have enough serotonin. Yeah.
Lisa Monteggia 10:15
So we really don't know what causes depression, we know there's a genetic component, but there's not one gene. It's not as if you have one gene or one mutation, you have depression, it appears that it's probably a complex interplay of many genetic factors as well as potentially environmental factors. So that's made it difficult, therefore, you can't just go and get a blood test. And say you have a gene. And now you're, you know, you have a clear diagnosis of depression. It's so that really highlights the complexity of it. It's, you know, going back to your previous comment, you know, depression is characterized by the World Health Organization as the number one cause of really lost productivity in the world. And it affects many, many people, everybody knows someone that's depressed or you know, takes an antidepressant. And people are surprised to hear how little we know about it. Especially because there are drug treatments like antidepressants. Depression, though, we really, we don't know what causes it per se, ik and we know there's genetic components, we know there can be environmental influences, but how all those work together is unclear. And the fact that people as we talked about can show different symptoms, really highlights the fact that there's probably many different brain regions that can be involved that can trigger depression. And that's why some people may present with certain symptoms, depending on you know, the type of depression versus others. So it is quite complex. So sort of coming back to what people have seen, there were these ads on TV, and they would show your brain and they would have two cells, and one of them would be producing a neurotransmitter called serotonin. And the other cell, you know, would be sort of the receiver, if you will. And what it would show was that this is your brain. And then when you're depressed, there's less serotonin. And when you take a typical antidepressant, there's more serotonin, it corrects it, if you will. And while that's true, in essence, in terms of antidepressants, increasing serotonin, that's clear, as well as other monitoring means things like Prozac, which, for example, everyone has heard of, or, you know, Wellbutrin, typical, more typical antidepressants, typically increase monoaminergic transmission, very quickly, that these drugs still take several weeks to work. So even though you increase serotonin quickly, that's not sufficient to alleviate the depression. And it's really been unclear why that is. But to go back to the cause of depression, while again, these drugs increase serotonin, the evidence that there that depression is caused by loss of serotonin really is not at all. Something that's concrete in the field. You know, if you clearly deplete all neurotransmitters, yes, you're gonna have many issues, and maybe with serotonin, as well. But it's not just a simple you can measure Oh, you have less serotonin, therefore, you're depressed. It doesn't work like that. Again, it's much more of a complex interplay.
Nick Jikomes 13:36
Yeah, that that makes sense. And there is this interesting observation that when you take an SSRI, it basically works with respect to increasing serotonin levels right away. And yet, when it does work in people with depression, it takes many weeks before you start to see that improvement. So what's going on in those several weeks? What's what's sort of happening in between elevated serotonin levels and symptom change? What what, what in the brain at the cellular level might be happening?
Lisa Monteggia 14:02
So that's a great question. And it's something that really is not clear. We know that there's this increase in serotonin, as Sue mentioned, but yeah, it takes several weeks to work. So people have postulated before this work with ketamine and sort of the rapid antidepressant effects, which we're going to get into. But typical antidepressants, people had argued that you increase these mono mini mono amines. And that it takes a while because there's different types of changes that have to occur in the brain, including neural rewiring, and that's what an antidepressant effect really becomes. actionable, if you will, but there's all these steps that we don't know we have to understand to get to this point. In my lab, one of the first papers we published was, we were interested in how antidepressants work. This was a new field of research as I mentioned. So your new epi You're moving into a field, what are you going to focus on? And so what I did is I read a lot of papers really quickly trying to figure out what was no loser concrete genes, maybe that may be involved in how an antidepressant work. And there was one gene where there was a lot of sort of anecdotal evidence, and that was a gene called brain derived neurotrophic factor or BDNF. And it's a Neurotrophic, it's factor. So it's involved as sort of a growth factor in the brain. It plays important roles in development. But there were numerous studies that showed that antidepressants increase this growth factor. And then maybe it's important. And since it's involved in growth, maybe it's triggering things like growth in the brain in some way. But it was really unclear. What we did is we deleted this gene in the brain. And when we did, we found out that antidepressants didn't work. And this was, of course, an all in preclinical models. And when we published the paper, we did a lot of work on this showing that typical conventional antidepressants could not produce antidepressant action, it received a lot of attention, because it was the first gene really suggested to be involved in an antidepressant response was required. And people went on and replicated that, which was great, you always want things replicated. What's interesting is that there is a polymorphism in the BDNF gene in humans. So what that means is, humans have this BDNF gene, but there's a change of one amino acid in the protein. And if you have this change BDNF, and how it's released, is dampened, if you will. And so what was shown is that patients that have this polymorphism, so they don't release as much BDNF, if you will actually appear to have an attenuated response to conventional antidepressants, the antidepressants don't work as well. So it's not an all or nothing effect. And there's probably many different factors. But it really suggested that this gene was identified preclinically, that they could have some involvement. And so we showed this and we continue to follow up to show that it was this growth factor in a part of the brain called the hippocampus that was required. But how do you go from increasing serotonin to requiring this growth factor has been something that we've continued to study, but we don't have a clear linear progression of how you get there.
Nick Jikomes 17:26
So even if some of those details aren't filled in, Can you unpack for people the relationship between neurotransmission and neuromodulation, and plasticity with genes going in between I think, when the average person probably is hearing someone, like you're talking about the brain, and then all of a sudden you're talking about genes, you know, someone might naively say what a genes have to do with the brain function. So what actually happens to take you from neurons talking to each other, to some sort of gene expression change that results in rewiring.
Lisa Monteggia 18:00
So genes are expressed genes are in every cell in your body, and including in your brain. And when they're expressed, they can be made into proteins. And those proteins are actually what function if you will, and they can be put to different parts of a nerve cell. A neuron is what a nerve cell as they can put input in different parts. And they really can regulate how this nerve cell functions. But a nerve cell doesn't function in isolation. They work with each other, they communicate. And so for example, there have been some ads on TV for different drugs where it will show like a neuron and it comes in and it releases the neurotransmitter and then it acts on the other neuron that's communicating downstream. The point of that interaction is called a synapse. And that's really, really important because of how neurons this is where they communicate. So again, a neuron isn't going to work in isolation. So what happens is when a neurotransmitter is released from one nerve cell, and it can act, um, there's many different examples of neurotransmitters, things like glutamate, GABA, those have much more fast acting effects. were things like neuromodulators, which serotonin, which we've talked about have Effexor, they typically more slower acting in a way because of how they act. So there's different types of neurotransmission in the brain, it's not all or nothing. In the sense of, you know, there, it's one clear thing it's there's different types of neurotransmission. And neurotransmission, can produce a number of different changes, again, how neurons communicate, it can trigger motor movements, it can trigger, you know, all sorts of cognitive processes. It really is an essence, you know, every component of who we are and what we're doing. In terms of plasticity, plus, this is a very generic term that's used often in neuroscience, but it has very specific meaning Because just like there's different types of neuron transmission in terms of what's released, and how adapting, there's different types of plasticity. So plasticity is kind of come in a very psychiatric type later really just mean changes, there's some sort of in there usually postulated to be good, right, sort of good changes, that happens. But there's different types of plasticity. And we'll talk about this a little bit when we get into the ketamine story. But again, the brain, it's so complex, there is billions and billions of synapses, there's all these cells, it's really an unknown frontier. If you have a heart attack, and you get to the hospital, there's very good treatments, because we know a tremendous amount about the heart, the type of cells, how they communicate, what can go wrong. And you know, the power of science has developed really amazing treatments. With the brain, it's so much more complex, there's different types, even though there are neurons in the brain, there's other types of cells as well. And then even among neurons, there's different types of neurons. So you have different types of neurons, different types of neurotransmitters, there's neuro modulators, which again, are just different types of neurotransmitters, if you wish, they could also be different types of neural peptides as well. So you're starting to see these layer upon layer, which is why we know so little about the brain. And it's why, you know, it's been hard to really make, I think, huge discoveries and some of these very deep debilitating illnesses, because, again, the complexity that we see, you know, some people sort of joke, the brain is really the unknown frontier in the body.
Nick Jikomes 21:40
So if we had to summarize this, in very basic terms, when we say that plasticity happens in the brain, we more or less mean that the brain has physically changed somehow that perhaps it's made, or broken some connections between certain neurons. And when that happens, if we imagine a single neuron, it's sort of talking to a bunch of other neurons. And when that pattern of neurotransmission onto that neuron changes, the plasticity is actually caused by inside that cell, it's actually changed which genes are turned up or turned down, so that it's maybe making more proteins to build a new synapse or something like that. Yeah,
Lisa Monteggia 22:17
I mean, I think that that's fine. In terms of this working audience. You know, again, there is more complexity with it. But again, that's a general idea. We're talking again, about changes. And, you know, again, you can turn on genes, or perhaps you're just turning on proteins, which work in a slightly different way. But again, it just highlights again, the complexity, I think, though, before we go too far down on the complexity, I think the important thing, really to mention here is that this techniques, as well, as approaches, especially over the last two decades, have really, really advanced our understanding of what happens in the brain. And there's still so much work to do. But where are we we're where we are now, we've made tremendous progress. And we're continuing to build on this. So it's a really exciting and dynamic time to be thinking about brain science.
Nick Jikomes 23:11
Before getting into some of these antidepressant drugs. A couple more things I want to unpack on depression. How? So we've we've sort of talked about how big of an issue depressive disorders are, we've talked about them at one level, the other level I want to talk about them on is? Oh, so we've mentioned that SSRIs can take several weeks to work, but we haven't mentioned yet is approximately what proportion of people do they actually work for and not work for? And what do we know about sort of the effect the overall effectiveness and some of the side effects of traditional SSRIs.
Lisa Monteggia 23:47
So depending on the clinical study, you look at typical antidepressants work in probably 50%, maybe two thirds of individuals, but there's at least a third to maybe even a half of patients that do not fully respond to antidepressants, some do not respond at all. There can be side effects on the newer SSRIs have a lot less of side effect profiles as some of the earlier antidepressant drugs. But the question really has been, you know, why do they work in some patients and not in others? And it's really unclear. And as we discussed, you can't just go in and get a simple blood test to know if you have depression. There's not any clear one marker that tells you you have it. It's really going in talking with your psychiatrist and really getting a diagnosis. And once that happens, you know, you think, Okay, I'm diagnosed with depression, give me an antidepressant. Well, again, they don't work in every patient, you're talking at least a third of all, probably at least a third if not more of our patients don't work. What happens though is you don't know if that antidepressant is going to work or not, and you're not going to know for a couple of weeks. So you Gonna take the drug, hopefully it's gonna work in a couple, you know, typically a couple of weeks, you're gonna start to feel better. But if you don't, after this few weeks, then they're going to try you on a different antidepressant. And hopefully you will respond to that. If though you don't respond after two to three different drugs, then you can be termed treatment resistant, and that you haven't responded to typical antidepressants. And after that, then, you know, people will talk about electroconvulsive therapy, perhaps, but really, there is an unmet need of what do you do, if you don't respond? So the hope is that patients will respond quickly, the ones that don't respond, though, with time, those are the individuals that are most at risk for suicide.
Nick Jikomes 25:53
In when we're talking about the effectiveness of these drugs, and how many people take them and don't respond to them, by default? Are we talking about people that are given SSRIs? In conjunction with psychotherapy? Or are we talking about everyone, including people that are just given SSRIs and sent home?
Lisa Monteggia 26:08
Pretty much everyone. So some people are just given SSRI, some do it in conjunction, it really just depends. But in general, most of it has been looked at just very broadly, like, you know, different types of clinical analysis, meta analysis to look through that. So a lot of times, it's just really more put together as a broader paper.
Nick Jikomes 26:31
I see. So, in principle, it must be possible, then that some portion of people that are not responding to SSRIs, or similar drugs, even if they're treatment resistant, they've tried two or three, it could simply be that they have tried those drugs in isolation that they have not been doing psychotherapy as well. Oh, it's possible.
Lisa Monteggia 26:49
It's possible, you know, it's up to the patient. It's up to the psychiatrist. It's also about resources that are available.
Nick Jikomes 26:57
And so even when they do work, we've touched on the fact that there's this several week period that it usually takes for the effects to kick in some of the work that you've been doing recently is is on what people have called fast acting, antidepressants. And so these are presumably drugs that are acting right away, or at least faster than SSRIs. And so can you start to unpack for people what we're talking about with fat, fast acting antidepressants and how long this research has been going on?
Lisa Monteggia 27:28
Yes, so we, we, as I mentioned, we have been working on typical antidepressants since I started my lab. And the field really has been focused in trying to understand are there ways to make better antidepressants that work potentially faster? And this has been a question that's been ongoing. And what happened was a clinical study that came out a little more than 10 years ago now more than 10 years ago, and it was in an inpatient units, patients that were in an inpatient psychiatric hospital, and they were given the low dose of a drug called ketamine. And most people have heard of ketamine, and very high doses. Ketamine is an anesthetic, and more mid level doses, it can be an adverse drug and classic sort of a high. What they did is they infused an extremely, extremely low dose of ketamine into patients over 30 minutes. And they watched these patients, and rather surprisingly, they had a rapid antidepressant effect. This wasn't what they were looking for. It's just what they observed. And, you know, these were patients that were well known by the doctors, by the nurses that were taking care of them. And it really seemed to be an antidepressant effect. It wasn't that they were so high for days, they had no idea what was going on. It seemed to be this rapid antidepressant effect, and it was published. And it was a small number of individuals. And I think there was a little bit of, you know, confusion in the field of like, what does this mean, and it's ketamine because ketamine doesn't its primary target is not serotonin. It's glutamate. That's one of these fast acting antidepressants, it actually blocks a receptor that glutamate binds to. So it's a totally different madness. And this finding then was replicated clinically. And shown that ketamine appears is very low dose infusion triggers this rapid antidepressant effect, rapid meaning that some patients are starting to see antidepressant effects within 30 minutes. I mean, typically, by two hours, they have an antidepressant effect if they're going to have one. And what's remarkable is that the single infusion in some patients can produce an antidepressant effect that lasts out for days to even maybe weeks. So it's rather remarkable.
Nick Jikomes 29:49
So they're getting an infusion of this drug. Within hours, they're feeling less depressed, meaning that if you just ask them, How are you feeling to say, actually, I feel much better?
Lisa Monteggia 29:57
Yeah, yeah. I mean, it It's really remarkable. And so you know why we became interested in studying ketamine are really kind of highlighted by what I've just told you, we were interested for two reasons. Because for the first time, it was demonstrated that pharmacologically with a drug, it was possible to trigger a rapid antidepressant effect, up to the work of ketamine. All with all the drugs that are out there, we always talked about how there have to be changes, and it takes weeks. Now we know it's possible that you actually can trigger a rapid effect. And secondly, as I mentioned, ketamine is a drug that's been around for a long time, it's well studied. And it's known to block NMDA receptors, which are glutamate receptors. And so, for us, the question is, okay, we know that it can block these types of receptors, can we for the first time really tried to lead in sort of a sequential order? What is an antidepressant effect? If you can start to really dissect out what it is, then you can really start to ask questions, how do you generate an antidepressant effect? Can you perhaps intervene in different parts of the pathway for new treatments? How do you get the long term effects? If you can understand that, then could you prolong? And that antidepressant effect even longer ways to sort of potentially eat it longer? And even further out, you could ask, okay, we don't understand how typical antidepressants work. But is there a point of convergence? Rapid effects work one way, slower, slow, but is there some point where they actually meet? Well, I think it provided a lot of different ways to really think about what an antidepressant effect is, and really what it could tell us in the field.
Nick Jikomes 31:49
So one interesting observation that you mentioned, was that ketamine is acting through a very different mechanism than SSRIs. It's binding to this glutamate receptor called the NMDA receptor. And that's super interesting in itself. But the other thing that I think it's interesting, because we're talking about, you know, the implied discussion is almost always about plasticity here, because in some sense, you're going to need some plasticity to happen somewhere to help someone with a disorder like this. Can you talk to people about what's interesting about NMDA receptors in terms of what we know that they do for neuronal plasticity?
Lisa Monteggia 32:27
Yes, um, so, NMDA receptors. So first of all, we talked about glutamate, just very briefly, glutamate has very rapid effects. In the nervous system. excitatory effects work on different receptors, and one of those is the NMDA receptor. So glutamate binds to it, it activates it. And it can trigger downstream processes that can produce effects on plasticity in the brain in the hippocampus, or brain region, which we think is important for how antidepressants work. I can then trigger effects that are similar to what's been postulated as sort of a cellular model of learning and memory, you can actually trigger this sort of type of plasticity in the hippocampus. And when you activate NMDA receptors, you can actually strengthen connections. And you see this sort of response. And that's, again been postulated to be sort of a, it's called long term potentiation, or LTP has been considered, and cellular form of learning and memory. So there's been a lot of work that's been done on NMDA receptors in that sense, which makes it exciting. Now, the caveat, though, is that ketamine doesn't activate those receptors, it blocks them. And that became sort of the challenge that we faced, we could show that those NMDA receptors were involved, but it wasn't through activating them, it blocks them. Is that
Nick Jikomes 33:57
is that sort of the opposite of what you might naively expect?
Lisa Monteggia 34:01
Yes, exactly. Because originally, people were thinking like, well, if you have plasticity and everything, the NMDA receptors are good candidate. We know that it can cause plasticity. This is great until you really sit back and say, but it blocks NMDA receptors, it doesn't activate that. And that became part of the puzzle of trying to tease apart, how do you block those receptors and trigger downstream effects and get to possibly a plasticity mechanism, which is what our work is, has done. But I can tell you, it was not very direct, it was a lot of work, and it's been years in the making to get to that point.
Nick Jikomes 34:39
So so what else have we have we learned at that time? So it's blocking NMDA receptors, what have you guys or other groups discovered in terms of what's actually linking that mechanism mechanism to the antidepressant effects?
Lisa Monteggia 34:55
So what our work is done, and this has been over the last decade, in practice been publishing on this. What we've shown is those NMDA receptors are crucial for the antidepressant effect. So ketamine by blocking it, normally what happens is with glutamate, you activate those receptors. And what happens is a molecule called calcium comes in, and it activates downstream processes that can produce long term potentiation. And this type of plasticity. What happens is ketamine by blocking a certain type of NMDA receptor, that calcium doesn't come in, and it triggers a cascade of effects that are very specific. And so you trigger this cascade that involves this particular protein called EF two kinase, which rapidly up regulates protein synthesis. So suddenly, you're not going through transcription mechanisms, you're just rapidly increasing protein at the synapse, including our friend, BDNF, which is required, if you delete BDNF ketamine doesn't produce an antidepressant effect. And so it's increasing that. And it actually then engages processes to produce a novel form of plasticity. So you can actually get plasticity, not only by activating these receptors, which is known for learning and memory, but as ketamine does by blocking them, but it's a different form of plasticity. And what we can show is sequentially as we go through this path to get to this plasticity. If we block any stage in this pathway, then we don't see an antidepressant effect. But we also lose this plasticity, if you will, this novel form of plasticity. And we went on to test this. I mean, it's like great, we have an idea. This is all interesting, but how do you test it? So one way that we've tested it is that we've worked closely with clinicians and really trying to move with the field to really have questions that we're asking that are relevant. So clinically, when ketamine was shown to have these rapid antidepressant effects, people were excited, but it's ketamine. And again, at higher doses, you can have these potential side effects. What happens I mean, even if you give a patient ketamine, they have a rapid antidepressant effect. Maybe it lasts for days a week, maybe longer, but you're gonna have to give ketamine again at some point. So are you going to have potentially abuse liability? What's going to be the long term effect because you're probably going to have to be on this drug for a long time because it's not as if it's curing everything. So with that, ketamine, as I mentioned, blocks, these NMDA receptors, well, there's another drug that blocks NMDA receptors called mantiene. And then mantiene, you may have heard of, because it's been FDA approved in the US for Alzheimer's disease. It's not, you know, a wonder drug of working for everyone, but it has been approved and it doesn't have this potential risk factors of psychosomatic effects and stuff that ketamine can have. So they both BlockLess NMDA receptor. So there were numerous clinical studies that have been done to examine whether amantii can trigger rapid antidepressant effects. And it doesn't even studies that have went out for weeks don't.
And so it was posited in the literature. How can two drugs the both block this receptor? One triggers the antidepressant effect, and one does it? Are we sure this is the target? Perhaps there's another target. So we looked at this and we said, well, you know, we understand the argument. However, what's important to remember is that these NMDA receptors are so important. They're important for learning and memory. They're important for so many cellular processes, not just you know, ketamine is antidepressant effect, that they're modulating in different ways. It's not just every single one, every single drug that blocks the receptor works exactly the same way. There's subtleties that have happened. So what we did is we compared ketamine to mantiene. If you look in preclinical animal models, ketamine triggers this behavioral action of an antidepressant act like action, but mantiene does, which is somewhere to what sane and patients, if we look in the hippocampus, we don't see this change, if you will, in terms of if we actually do recordings and cells, we look at the NMDA receptors and how they function. Ketamine amanti work slightly differently. And in the way that they work differently, the effects downstream are different. So while ketamine blocks particular types of NMDA receptors to inhibit this EF to kinase, up regulate protein synthesis and trigger this novel form of potentially ation. mantiene, doesn't have the same functional effects. So it doesn't engage this kinase. It doesn't trigger any sort of rapid change in proteins that we don't see this plus just So it provides sort of, if you will, a sort of a correlate of trying to explain what an antidepressant action is. And that's important, because you can't just go in and give any NMDA receptor antagonist and see an antidepressant effect, there has to be specificity. And that's what our work is trying to understand what does that specificity because if you can understand it, then you can start to look at really requirements, if you will, what's necessary for that antidepressant effect if you wanted to design better drugs, different drugs?
Nick Jikomes 40:33
Yeah, this is a theme that's come up in several podcasts I've done, where you have this functional selectivity where you can have two drugs that activate the same receptor, or in this case, two drugs that block the same receptor, but they do not have the same effects. Because what they're triggering inside the cell can be different, even though they're both sort of doing the same thing to the receptor. Yeah. And, and so is it fair to say that it's, you know, when you're thinking about what drugs do, you know, it's useful to understand if they block or activate a receptor, but it's almost never going to be sufficient to tell you what's going to happen downstream, you really need to know what's going on inside the cell after they bind to a receptor.
Lisa Monteggia 41:14
Right. So I think the key is, I think what I would argue is a lot of times what we know about a receptor, and how a drug acts is binding, like you just said, doesn't bind. So we know how we can this is important information to you bind to your target. But what's important, I think, in this example, is the function. How do you change the function of that receptor. And the way that we showed that you change the function was to do electrophysiology to actually look at the functional component of that receptor. And when you look at the function of that, which is different than binding, when you look at the function, you see difference in function, which therefore can trigger differing downstream effects. And so I think the power of really using electrophysiology, which I think has been some of the power of our work, to really ask very mechanistic questions to really move from one stage to the next is important. A lot of the literature whenever mantiene failed, but you know, and cure, ketamine has antidepressant effects, was talking about the binding. But it's like, well, the binding, though, doesn't tell you the functional effects. And so those experiments are, you know, pretty time consuming, very technically demanding. So they're not, you know, the first thing that everyone's going to want to do, but I think they're really important to answer the question.
Nick Jikomes 42:38
So we've talked a little bit about the time course, so ketamine has this rapid antidepressant effect, this happens at quite a low dose, if I'm understanding correctly, and it can last for days or weeks, but it certainly doesn't last forever. Correct. So how do we think about how do we think about the clinical administration of this? Are people focusing on using ketamine to assist psychotherapy so that the effects persist longer? Or, or what are we doing there?
Lisa Monteggia 43:09
So in terms of this intravenous administration, it's being used is primarily being used for patients that are treatment resistant. And there's, this is an active area of investigation, there are a number of laboratories that are looking at it, and trying to really look at the dosing. You know, if you give a dose once a week, how can you maintain it or maybe twice a week without having the side effects? And so this is, again, this is an active area of investigation going forward. I will mention Johnson and Johnson has an in 2019 received FDA approval for a ketamine derivative, if you will, that is through oral administration, or I'm sorry, not world, it's an oral through nasal administration. And so, you know, that is moving forward as well. But a lot of patients, you know, that contact us are looking for, you know, a referral or, you know, a place to get the ketamine IV administration, and then to be followed up along the lines of, you know, really maintaining that effect as long as they can.
Nick Jikomes 44:21
So this this nasal spray, I've heard about this, it's probably looks like a nasal spray that you would get for allergies or something, maybe from your doctor, you take it home with you and you can just self administer, you know, one or two sprays of that as needed, is that the basic idea?
Lisa Monteggia 44:36
So um, I'm not a psychiatrist. So I'm not going to go into the specifics of the j&j drug. We have not worked on the nasal administration of it. So I really I can't comment. I'm going to leave that to other experts that you speak to on that front. We've focused more on the administration that's been done in the clinical settings in terms of the intravenous administration.
Nick Jikomes 45:08
And I've heard about s ketamine. So what is S ketamine? What are these different versions of ketamine that people may have heard of?
Lisa Monteggia 45:15
So ketamine is a drug that when it's synthesized, you have sort of two parts, like it's not, it's two separate drugs. It's sort of an S version and an AR version. They're just two mirror images, if you will. And it's a pretty easy synthesis. And so this ketamine administration is intravenous administration has both r and s ketamine in it. It's, that's what's been used clinically. It's been around for a long time, no one's going to have a patent on ketamine. Because, again, it's been around. So what j&j did is they patented one and antemer s ketamine, which is in the nasal spray, there's a patent that's, you know, been issued for our ketamine as well. And there's clinical work going on with that. The idea is, is one, either, if you separate out RNs, the idea is, does one of them produce a better antidepressant effect, maybe a safer antidepressant effect without side effects. And so, the real way this is going to be answered is going to be really clinical studies, look, comparing ketamine versus r versus S, to see really an a side by side comparison.
Nick Jikomes 46:29
I see. So in principle, it's possible for two different enantiomers, like a left and a right handed version of a drug to have different effects. But it sounds like what's happened here is that companies have patented, you know, pure formulations with one version and not the other simply so that they had something to patent but we don't actually know yet, if they're superior in terms of their side effect profile or their effect.
Lisa Monteggia 46:52
You know, there's work going on on this, on this on this question of our versus us. And there's some literature out there on our vs asked, but I think it really depends on the group that's publishing it and what's happening with it. So we'll have to see, the thing with the S version is its patented is for treatment resistant. And again, it's a different route of administration. It's nasal administration. So you know, one active area of research, which people are looking to see, as you know, as we understand the mechanism, are there different ways to maybe trigger a rapid antidepressant effect? It would be great to give something orally, you know, but ketamine, if you just take it orally, just how it's metabolized and stuff. It's not a great drug to take in that manner. So routes of administration matter.
Nick Jikomes 47:43
Yeah, yeah. And so it has these rapid antidepressant effects, you're taking it or it's being given to achieve this at a relatively low dose. So it's sub anesthetic, people aren't gonna fall asleep as they would on a very high dose of ketamine. Are there any what is the side effect and the risk profile look like at those low doses?
Lisa Monteggia 48:03
So again, I'm not a psychiatrist on it really low doses, some patients, you know, I've seen some, I've seen patients receive it, I've talked to clinicians doing it. Some patients will say while the infusion is going on, they may feel odd, other patients who don't, but it seems to be a true antidepressant response. It's not as if you know, patients are so hallucinating that, you know, they feel better from that since then. It No, it seems to be an antidepressant. And it seems quite to be quite well tolerated.
Nick Jikomes 48:36
I see. I want to move now to how someone like you actually studies, depression and drugs like ketamine, or SSRIs. In animal models. So starting in a relatively high level, when you're studying depression or anxiety, say, in a mouse or in a rat, how exactly did neuroscientists typically do that? What does it mean for a mouse or rat to be depressed, quote, unquote? And how? How much should we read into that when we're thinking about depression in humans?
Lisa Monteggia 49:10
So, as we mentioned at the beginning, depression is a very human condition. You know, it's a psychiatric illness. And there are a number of different symptoms that you could have, and you don't have to have all of them. It's just a certain number, that fitness category. And so it really, it again, it highlights the complexity, we talked about it being heterogeneous, and all depression looks the same, but ultimately, it's a human condition. So you're never going to make a mouse that's fully depressed, like how do you talk to a to even know if it's depressed, right? That's how we diagnose depression. It's not a blood test. It's, you know, having an actual conversation to make the diagnosis. So what people have done is that we know that there is a comorbidity between stress and depression. So not everybody that is stressed is depressed. And not everybody that suffers from depression has went through stress. But often there can be a comorbidity. So what people have done is they often use stress dressing animals, so that you see changes in hormones. Now, maybe they're not sleeping normally, they may have rapid loss in weight, I mean, different changes that happen that can mimic aspects of depression. And then trying to understand what brain regions may be implicated what may, what changes may be happening in the brain, and going from there. The caveat of this is that I think that all sounds great. And this really is what the field does. But different stress paradigms can produce different effects, both behavioral effects, as well as changes in the brain, which isn't surprising. I mean, different types of stress, do different things. So again, it highlights the complexity of really trying to study this in an animal model.
Nick Jikomes 51:03
And so can you talk a little bit about so when you're studying mice or rats in the lab, and you are putting them through these behavioral paradigms, where you're measuring behavioral outcomes that you think are akin to depression or anxiety? What sorts of things do the mice do behaviorally that are signatures of having some sort of abnormality like this? And do mice respond in the same way, broadly speaking, that humans do something like an SSRI.
Lisa Monteggia 51:32
So there's various paradigms that people will use. And we know that while there's a range of features in humans, you know, a range of symptoms that you may have, one of the most consistent is called anhedonia, the sort of lack of pleasure. And so often what you'll do is people will stress animals, and then the look to see well, the animal drinks sucrose, because normally they like sucrose, so as sucrose as pleasurable as it was before, there's a range of sort of tests that you're trying to look at, to see, you know, are there also the physiological chronic cortisol, the sort of stress hormone that people have heard about? So look at corticosteroids, is that increased? Right? So you're looking, you can look at drummers are they sleeping, let's say as much or little. So you're just looking at sort of crude changes, if you will. And I don't mean crude, they're really just behavioral changes, or sometimes neural chemistry type changes, that can be seen in patients with depression. But again, you're only going to be able to model some of that you will don't get a full representation. But the idea has been if you can focus in on part of that, maybe the neural circuitry that elicits that behavior, then can does that tell you something about depression.
Nick Jikomes 52:58
And so, for the classical SSRIs, if you administer them to rodents, do they get better, broadly speaking, similar to what you see in humans.
Lisa Monteggia 53:10
So the idea was been done behaviorally is that you have an animal and you always have your sort of control animal where nothing's really happened to it, it's all happy as you can be as an animal, and then you stress it, and you'll often see a change, like you drink less sucrose, for example. And if you give the antidepressant, then you are back to drinking sucrose normally. And so it's sort of trying to normalize the behavioral deficits has been the idea. It's interesting, because with SSRIs, the majority of the tests that are used, we know that SSRIs in humans take weeks to work. In these paradigms, though, even though they sort of are used as predictive of antidepressant effects, because it can reverse behavior. In these animal models, most of the classical antidepressants work much quicker than they do in humans.
Nick Jikomes 54:10
I see. And we've, we've talked about it a little bit, but presumably, in rodents, you're also seeing this very rapid antidepressant effect, even though the SSRIs are apparently working relatively quickly compared to what they do in humans. And we've talked a little bit about some brain regions that have been potentially important for depression. Can you talk a little bit more about what we're seeing in animal bottles about the specific areas of the brain or types of changes and circuits that some of these SSRIs or ketamine are actually inducing?
Lisa Monteggia 54:42
So um, okay, so I think this is a really good point because people have looked like, again, a lot of it is using various stress models and looking at different you know, behaviors and again, would be antidepressant reverse that behavior Looking at the brain, people have done electrophysiology, and they'll see particular changes. And then they'll look to see if the antidepressant can maybe fix that, if you will. There's a whole range of changes that people have looked at, because we don't know what particular circuitry causes depression. My guess is, it's probably many, because you can have a whole range of symptoms, it's difficult to imagine at least, you know, very, very general standpoint of looking at things I used to try to look at them first rules, sort of a simple perspective, you can have people that present so differently, are they all just having the exact same neural circuitry affected that they all can have such different symptomology? No, there's probably many different neural circuits that are engaged in various ways. And so people, like I said, have focused really on this idea that if you stress and then an antidepressant must be reversing those changes. And if you sort of Fast forward to ketamine, what's interesting is that in these animal models, if you give ketamine, you can generate a rapid antidepressant response, within 30 minutes, that sort of mimics much more what's seen clinically, that you do have this rapid effect. But here's the thing, we've really focused on this idea with studying depression with typical antidepressants, so we must be fixing something right neurocircuitry is have to be rewired by typical antidepressants, it takes time for plasticity to be invoked. And you know, we don't really know how but that's been the idea. We even as we talked about the cartoons that show your brain, right, less serotonin, and now with an antidepressant, you've normalized it right? Even though there's not a lot of evidence to really show that decreased serotonin is what causes depression, that's not the case. You know, from the literature. So now we go to ketamine. So you give it to drug, and within 30 minutes clinically, not just in animals, but clinical, you're starting to see antidepressant effects, you start to see them within a couple hours. So Is that really possible to cause this massive rewiring the circuits in that timeframe? It's so fast. And so I think the other component of this is that how we're thinking about this, which is different is that if you start with typical antidepressants, they take several weeks to work. And say you and I are both diagnosed with depression. And you take typical antidepressants for the next 10 years, and you do quite well. But then you decide you're going to go off with them, and say I take them for three months, I have a response, and then I decide to go on. We've chained them very different lengths of time. But when we go off of them, have you really fixed your brain? Are you really going to go through like much much of a longer time before you become depressed again, relative to me? No. So I think the question is, have we really fixed the underlying pathophysiology of the disorder. And if you think about ketamine, it has a such rapid effect. What is fixing, we love the idea that we're fixing something. But our work has really suggested something maybe different. Maybe we're not fixing it, maybe what we're doing is we're inducing a novel form of plasticity, that can sort of mask if you will, the symptomology to make you feel better.
Nick Jikomes 58:39
I mean, in essence, you could just be improving their mood in a way that they're not used to. And it does literally mask what's going on. But that's why then maybe fades away. Yeah,
Lisa Monteggia 58:49
but maybe it's not fixing it. I mean, a different way to think about it is that we talk about antidepressants, as we're doing here, we're talking about them in the context of depression. But antidepressants are used and prescribed for a whole range of illnesses, a whole range of you know, mental disorders, thinking about all the different circuitry that's probably involved ways we don't know what some of these other disorders, but yet these drugs work. You know, you have PTSD and antidepressants can be so are they really in all these various disorders fixing the underlying pathophysiology, which is probably different? Or are they triggering maybe changes in the brain that are doing something different? And this is a very different idea? Yeah, yeah. People have really focused on this idea that we have to fix something that again, whatever stress does, we have to fix it? But while there may be changes that we see that are different with an antidepressant versus what stress does, is that causative for the in this case, antidepressant effect, or perhaps, based on like I said, in the example of ketamine, you're doing something different. We're not fixing it, but That's okay, that's still clinical improvement. Yeah.
Nick Jikomes 1:00:03
And on this theme of, you know, fixing it, or simply, you know, addressing a symptom or masking something temporarily. You know, one of the things that I think has come up in several of my podcast discussions is, you know, I talked to a patient who participated in a clinical trial using psilocybin assisted therapy for his addiction, I talked to someone from Maps about MDMA assisted psychotherapy, for PTSD. And in these trials, you've seen these remarkable results. But the general idea seems to be that it's not the MDMA. It's not the psilocybin not the drug that's fixing it, it's the drug that is probably causing changes in the brain that enable plasticity to happen. But that's not good enough, you need to direct that plasticity. And that's what the psychotherapy does. Can you talk a little bit more about any thoughts that you have about the interaction between the drugs that we're giving people in conjunction with psychotherapy?
Lisa Monteggia 1:01:00
I, I really can't, because this isn't an area that I work on, per se. I mean, we know that psychotherapy has enormous benefits for many, many people. And, you know, some people choose that instead of taking a drug in the beginning, perhaps, you know, some people do this hand in hand, some people may only take, you know, the antidepressant. So part of that is I think, personal choice. And again, also, do you have a good, you know, psychotherapist, nearby, somebody that you can get to, I mean, in many places, many rural places in the country, you may be more limited. So, I think there's a lot of different things that factor into this. But I can't relate because we haven't studied that. I can't really say it. I will say what's interesting is that people, I was at a couple of talks after we published our first paper, which is a very high profile paper on ketamine, we showed this novel form of plasticity. And I walked into a seminar, and they were up on the screen was our plasticity, ketamine induced plus this and again, it's blocking NMDA receptors, it's not activation. It's not LTP. This learning and memory cellular correlates, it's not before was up on screen was this plus to Sansum. C, ketamine produces plus to state, this is in the hippocampus, it's probably learning in memory, so psychotherapy will boost it. And I was like, Wait, that's our data. But we haven't done anything with psychotherapy. It's not learning in memory, it's a different for, does it have a you know, I don't know how that would relate. But it was funny to see, you know, my own data sort of used in that way. But we don't we don't have data on it. It's an interesting question of this interplay. Because, again, it's patients if they respond differently to so many things, we haven't done anything with psychotherapy. So I can't comment on that. But I think the idea of plus just to be what we're suggesting is it's not any type of plasticity, that's being gauged a specific type of plasticity. That's, you know, I think it's interesting.
Nick Jikomes 1:03:10
Yeah. And I think this is worth dwelling on for people, because plasticity is this sort of catch all term that gets thrown a lot around in both technical and non technical contexts. And plasticity isn't one discrete thing that's either up or down, or good or bad, there's many different forms of plasticity, they can go up, they can go down. And, you know, if someone simply says, as a blanket statement, you know, plasticity is good, or this will induce plasticity, that's really not the statement like that just really don't have the level of specificity, you need to really know what's going on.
Lisa Monteggia 1:03:47
Right? You have to have the specificity. And you have to the right amount of plasticity, right, you can't have a parent plasticity. I mean, again, it's the brain, things have to be finely tuned. So what we're suggesting is that, and again, this is a different way of thinking. But however you get depression, whether it's through, you know, genetic component through stress, whatever there is, there's many different ways that you can get it. That's why there's all these different symptoms. But ketamine works, by working through a specific pathway, and triggering this plasticity. And perhaps for patients that don't respond to ketamine. It's because maybe they have a polymorphism, or a change in the gene that's involved, those genes that are involved in making those proteins along the pathway. I mean, just as a possibility.
Nick Jikomes 1:04:43
One of the things that we've touched on in different ways is that depression is also a term that's it's a pretty broad term, and there's probably multiple forms of depression that might present in similar ways, but they are effectively different things with different causes. I don't think this is your area of research. But can you comment on any work that's out there being done today around creating a more rigorous taxonomy for things like depression? Like, is there any work trying to figure out in animal models or in humans, how you would actually discern the specific subtype of depression, someone had said that if you had 10 people come into a clinic, you'd want to get to a place where you could say, okay, these four people have subtype a, these were of subtype B, these two have subtype C, and each one requires a different treatment. How are people thinking about that?
Lisa Monteggia 1:05:30
So, um, you know, this is I know, in the clinical world is something that is clearly important. Because if you can start to maybe stratify symptomology, then maybe you can start to get better treatments for those who's going to respond to those. So that is, I know, a topic clearly going on clinically. I think in the preclinical world, though, it's very difficult. Because again, how much are we going to model this type of behavioral changes in preclinical models? You know, people right now, I think there is this idea, again, that depression, if we understand what depression is preclinically, then you know, will that tell us what happens clinically, and I think it's really hard, there's probably many different ways that you can get the same symptomology. But does that really tell you what you need to fix per se? Um, people have been focused more recently on an hedonic depression. Were anhedonia, those sort of lack of pleasure, that maybe he's trying to study and hedonic depression in animals. But again, that's just one symptom. Yes, it is a common symptom. But is that going to inform us on how an anti how you generate an antidepressant effect? I'm not sure. A different way of thinking about this kind of moving it back a little bit, is someone asked me once, and I thought about this off and on, I think this is an interesting perspective is how important isn't going to be to have personalized care for depression, meaning not for your own self, it would be great to know what you would respond to absolutely everybody, I think agrees with that. But the idea of as we're trying to talk about targeting this molecule, this molecule, this molecule, and someone said, and this was a cancer survivor that told me this, you know, if you think about it, the body is really amazing. And some of the best chemo agents out there are rather broad, because when you start to get very specific and nearly becomes like whack a mole, the body induces mutations, and all sorts of things happen. And so is the best you can do for depression, maybe antidepressants that do 50, to, you know, 60% of patients, and then work on other treatments for those other ones and start to really make a ranking of treatment options instead of focusing in on a particular gene that may be linked to depression, because ultimately, how many patients is going to affect you have genetic components? And again, all the complexities that come with it, sometimes broad approaches aren't bad? And I thought that was an interesting idea.
Nick Jikomes 1:08:25
Yeah, I do think that's an interesting idea. Because there is this long history, I would say, in academia and in the clinical world of not not wanting a quote unquote, dirty drug of wanting something that affects one receptor in one way, like in a very, very specific manner. And I think what you're saying is that the potentially our mindsets are shifting a bit. And there's a place at least for certain in certain contexts, where you might want these sort of broad spectrum drugs for lack of a better term.
Lisa Monteggia 1:08:56
Yeah, I mean, in the sense of conventional antidepressants, they are pretty broad. We don't know how they work. But there are life saving to many people. And so when we talk about the only work in you know, maybe 50% of individuals, maybe two thirds of individuals, that's a
Nick Jikomes 1:09:12
lot. Yeah.
Lisa Monteggia 1:09:13
Oh, yeah. And again, they're life saving treatments. So unfortunately, they don't work with everyone, but are we going to get a treatment that's going to work for everyone on such a heterogeneous disorder? And so, you know, do we need to think about really focusing on trying to understand other treatment routes? I mean, one eye idea that we're pursuing is that we've shown that ketamine blocks this NMDA receptor, triggers this pathway to get rapid protein synthesis that triggers this novel form of plasticity. This plasticity if we do anything to interfere with this plasticity, we lose ketamine is antidepressant action. So are there different ways that you could target it? Can you get it pass blocking the NMDA receptor If you can get it a different way, could that have rapid antidepressant effects as well, and maybe be able to target other patients that don't respond Academy. So I think it just starts, I think there's a lot of ideas and ways that the field could move, because it's such an exciting time. But I think simply just focusing on you know, depression is loss of spines, of on neurons or depression is, you know, a one particular circuit, because we have no idea really what circuit is, or one particular brain region. And that's what we need to focus on to generate an antidepressant effect may not necessarily lead us forward for treatment. Our work suggest, and others have also contributed but in terms of ketamine, as well as to plan to the presence or work has really suggested that the hippocampus is one brain region is important for the initiation of antidepressant responses. And we think from there, it then moves to the prefrontal cortex and then on to other brain regions. And there's been a lot of work in terms of human imaging, suggesting the hippocampus may be involved in antidepressant action. There's also some work that, you know, depression may involve the hippocampus, the reality is depression probably involves many different brain regions. I'm not suggesting just because ketamine, which we think from our data, you know, looks like it's initiated in the hippocampus, that that means that that's a sign of depression. There could be many other brain regions involved, we're just looking at how antidepressants are trying to work and try to understand them. Is there a flow of information of how antidepressants work? Is there some specificity again, instead of just these global effects are occurring all over the place?
Nick Jikomes 1:11:51
So there might there might actually be a there might not only be multiple circuits and brain regions involved in a psychiatric disease like this, but there might actually be a time course, or a kind of order of operations for how the brain needs to deal with getting better. Is that sort of what you're saying?
Lisa Monteggia 1:12:06
Yeah, I mean, that our data is really suggesting that, yeah, it's not just these global effects everywhere, but again, that there may be an actual commonality of what how you generate this effect, but especially if you're not fixing it, especially if it's sort of, you know, triggering a plasticy maybe masking in some way, which still can provide treatment relief.
Nick Jikomes 1:12:29
What do you make of these ketamine clinics that seem to be popping up? I think I even have one in my neighborhood now. And I'm not 100% sure how they're intended to work. But it seems like it's a clinic of some kind where you go in and you tell them what's going on in your life, and it looks relatively lacks, and then you pay what looks like a fairly high sum of money to get IV ketamine is this becoming more common? Is that something that people should be skeptical of what what's going on with these ketamine clinics?
Lisa Monteggia 1:13:04
So there are a number of ketamine clinics that have been popping up over the last few years. And I've seen some advertisements for this in some very prestigious newspapers, which when you look and you're like, Okay, if you're really advertising your ketamine clinic, you've come pretty mainstream. They often are not necessarily being run by a psychiatrist. It's more of going in, you're not going to have the psychiatric evaluation per se and going through the whole thing and the follow up in terms of psychiatric care. Typically, what this is, is somebody that is desperate, that pretty much is probably treatment resistant, has heard about ketamine can go in can get infusion will wait a certain amount of time just to make sure they're okay. And then they'll leave and hopefully they'll have an antidepressant effect. And then they'll come back at whatever, you know, the dosing regimen is to hopefully continue to maintain it. They're not covered by insurance, and they typically are quite expensive. But patients you know, can be very desperate. I mean, major depression is, is incredibly debilitating. People that can't get out of bed, they can't work. They you know, nothing is pleasurable, their quality of life is incredibly poor. And you know, they can become suicidal. So they are desperate for having a response and, you know, they want to perhaps they haven't been able to find a academic clinical setting to get into a trial or maybe there's not one around them, that these ketamine clinics are showing up all over the place.
Nick Jikomes 1:14:51
So you have these clinics today and then you have the historical use of ketamine as an anesthetic so it has some well defined uses in the clinic. Where does ketamine Insert in our drug scheduling scheme and what kind of changes might be on the horizon given the the research on antidepressant effects?
Lisa Monteggia 1:15:11
So ketamine used as an antidepressant as just an incredibly low dose, but it is a scheduled drug. So in terms of FDA and those aspects, I really I don't know where that stands, I don't know where that stands. Um, it is a scheduled drug, you know, even to use it preclinically, we obviously go through drug authorization. Ketamine is a fairly well known drug in the sense that it's been around clinically for a long time, people know quite a bit about it. It's a pretty inexpensive drug per se, relative to many other drugs. So, you know, there's a fair amount of familiarity with it. But again, while people, you only have to Google it, you can see pages upon pages of what's known about ketamine. It's interesting from the antidepressant effects. what's intriguing is that when you get to higher doses, Academy, higher is not better in terms of antidepressant effects, you lose, you sort of start to lose the antidepressant effects. So it's only in this low dose range, that you see the effects. So it's not as if you know, any doses equal. And dosing really matters. And that's, I think, a really important component of this, that it's, again, this low dose, you can't go up to like anesthetic doses, and you know, or near that and think, Well, now I'm going to have a better antidepressant effect, it doesn't work like that.
Nick Jikomes 1:16:42
And it's not common with drugs, where you have this what some people call the inverted U relationship between dose and response.
Lisa Monteggia 1:16:48
So often there is with drugs, it depends on the drug of where that is. What's interesting with ketamine is that it has these very different effects that are well characterized, you know, in high levels is anesthetic effects, mid level doses, you know, this abused range, which people talk about, and rather surprisingly, you know, this very, very low dose, it has this antidepressant effect. So it's such an intriguing
Nick Jikomes 1:17:13
drug. So sorry, you saying that, you know, it has different effects at different doses, as many other drugs do. But the differences for ketamine at these different dose levels are very different.
Lisa Monteggia 1:17:24
They're different in the fact that, you know, at this low dose, you have this therapeutic effect and high doses, ketamine used to be used as an anesthetic. Now, not so often because of potential side effects. But again, just how the struggle has been around for such a long time, and studied in different ways. It's amazing, there still is how much we're still learning about it.
Nick Jikomes 1:17:43
And one thing I didn't touch on before when we were talking about its ability to antagonize NMDA receptors, was that I'm curious if it does anything else that we know about, is it binding to any other receptor systems and are people looking into that?
Lisa Monteggia 1:17:58
So ketamine, especially when you get to higher doses, can start to have many other effects. The NMDA receptor is not the only target is the probably the most well characterized because it's, you know, blocks the NMDA receptor, people postulated that it could have a range of effects on what the antidepressant effect is. However, I'm not aware of any literature that has linked a particular another receptor in some sort of systematic way to really put forth a hypothesis, it's really testable past some people have proposed, you know, various targets, but then, in general, they haven't really held up. And if you're going to have iPods, it's really the idea of testing it. How do you go from what hypothesis that we have in regards to the dose is that ketamine by blocking these NMDA receptors, this really low dose of ketamine triggers the antidepressant effect. Our thought is, is that that blocks the NMDA receptor specific types of NMDA receptors to trigger this cascade, and we get a little higher doses sort of this cycle mimetic this sort of abuse potential, you start to be blocked just blocking NMDA receptors very broadly, and that maybe it was triggering this sort of cycle, mimetic or abuse potential. When you get to really high doses with anesthetic, you're probably starting to hit many other targets past NMDA receptors. So we've been kind of looking at that in different ways. But you know, that's one hypothesis of how there may be some specificity for the NMDA receptor because again, at this low dose, were in higher doses, you're starting to see various effects of the drug because you're hitting different systems.
Nick Jikomes 1:19:38
So what are the what are some of the questions that your lab is pursuing now or that the field broadly speaking, is trying to answer next for ketamine?
Lisa Monteggia 1:19:47
So we just had a paper come out here at about a month ago that I think is important, and it really looks at the long term effects of ketamine. So we've been looking at this rapid effect. The idea is what does it take to trigger a rapid effect? and others have been looking at this as well. What we proposed again in terms of this blocking NMDA receptors in this pathway, and this plus this has been replicated by others. We sort of said though, okay, this makes sense. If you interfere with this plasticity, you interfere with antidepressant effects, this pathway is important for both the plasticity and the behavioral effects. But how do you explain long term that you have this antidepressant effect? I mean, this plasticity doesn't last forever. And in fact, if we look at the hippocampus, we give ketamine, you know, we see this plasticity very quickly, and it's stable for quite a while. But if you look a week out, you can still detect antidepressant effects, but that plasticity is gone. So it's like, Well, if that plasticity is important, how do you solve the behavioral effect? We think it's because ketamine initiates this antidepressant effect and triggers this plasticity in the hippocampus. And then as information is transferred to other brain regions, like the prefrontal cortex, and then moves out, this plasticity isn't staying in the hippocampus, it's moving out, and you're triggering these effects. But what are these effects? And so what we've been able to do is we've been able to work through part of a signaling pathway that's downstream, that seems to be important for the long term antidepressant action. And what's interesting is that there are molecular targets that you could potentially think about, as you know, potentially interfering with or activating maybe to, hopefully sustain the antidepressant effects of ketamine. what's intriguing is that, clinically, it's been shown that when you give a ketamine to patients, they have, you know, an antidepressant effect. And when you give it again, it's not as if they lose it. It's not as if you have to get more of the drug. If anything, they talk about the drug having cumulative effects, it nearly seems like the drug is better. And why would that be? It's kind of a strange idea, right? Like, okay, you have this cumulative effect in patients. And so what we found is that we have this downstream pathway that's involved for long term effects. And I think one of the things, you know, and we show that this plasticity is important for this long term effect, right, if you interfere with the pluses, you don't get the long term effect, even though that plasticity leaves the hippocampus and moves on, is still was important for sort of initiating. When we give another dose of ketamine, though, we give ketamine we wait a week, and then we give another dose of ketamine. What we see is if we look back at in the hippocampus at this plasticity, so you have this plasticity if you give a single dose of ketamine, but when you give a second dose, that spaced apart, we get an increase in plasticity, sort of a meta plasticity, a plasticity of plasticity is even better. And so what we're wondering is, is ketamine sort of priming the system such that then when you give the next dose of ketamine that spaced apart like a week of partner experiments, that you actually then are able to reengage it even better, if you will. And that may explain why patients have this sort of cumulative effect, your reengaging in the hippocampus, but now you're sort of stronger and able to move through the pathway a little better.
Nick Jikomes 1:23:21
I see. So you guys only done the two dose experiment.
Lisa Monteggia 1:23:25
So we've only at this point, looked at the repeated ketamine down for like a couple. Yeah, like a couple weeks, that's that we haven't taken it out for weeks or months yet. But the idea is that does it start to explain the clinical idea of this cumulative effect, we weren't expecting to see this, we were just looking do we reengage the same mechanism. And if anything, again, you have this hyper plasticity. So I think the importance of it is that plus to see mechanism important for the antidepressant effect. And they may be actually even further engage for repeated antidepressant effects. That explained some of the clinical observations.
Nick Jikomes 1:24:00
I see. So at least in principle, that sounds encouraging because it means it's at least possible that you might use something like ketamine repeatedly, but not have to use it forever, so that you can get benefit that maybe last if you take it a few times, but it's not necessarily going to be something hopefully that you'd have to keep taking. Yeah,
Lisa Monteggia 1:24:19
or perhaps if you can understand this mechanism better, then you could give ketamine and then if you could give some other perhaps drug or something to engage this plus to stay longer, you wouldn't have to continue to give ketamine and have the potential side effects or long term concerns with ketamine.
Nick Jikomes 1:24:36
I see. So if it's if it's engaged in this sort of priming meta plasticity mechanism, yes, allowing a subsequent drug to have an effect that would perhaps have
Lisa Monteggia 1:24:45
perhaps, we're postulating that's one of the things we're looking at. You know, could you engage it downstream to prolong the antidepressant effect even longer?
Nick Jikomes 1:24:54
Are people trying or thinking about at all using ketamine and SSRI in tandem, where you get the rapid effect with ketamine, and then you sort of can come off the ketamine and a few weeks have gone by such that the SSRI is now taking over, so to speak.
Lisa Monteggia 1:25:10
So clinically, people have been talking about this, this has been an active area. So, because ketamine can have potential abuse liabilities in the clinic, ketamine primarily is being used for patients that are treatment resistant, so they failed, at least to antidepressants. So, we do know that ketamine not works, from clinical studies works in patients that are treatment resistant, not all of them, but probably at least 60% or so based on the numbers that are out there. There has been at least one study where it was looked at patients that were just depressed, that were not treatment resistant, and ketamine worked in those as well. So it's an interesting idea, because people have talked about this, could you give ketamine and sort of engage plasticity mechanisms, and then give an SSRI to try and extend it, it takes a while. And I don't know of any literature out there that supports that idea. I think it's a really interesting idea. A different way, that's also possible, though, is, perhaps, maybe it won't work. Maybe what happens is, is because ketamine is being used in patients that are treatment resistant, so they've already failed an SSRI. So perhaps you failed the SSRI because you have some polymorphism, or something along the way of how the SSRI works, that's why you fail. But you give ketamine, it works in a different manner. And that's why you can trigger a rapid antidepressant effect in a number of those patients, because it works through a different mechanism. And for those individuals that don't respond to either SSRIs or Academy, perhaps it's because at some point, there's a point of convergence between rapid and typical antidepressants. And if you have some sort of polymorphism there or change there, then you just can't engage the mechanism. And perhaps then, you know, you may not with either met with either way, if that's the case, then ketamine can engage the mechanisms. But if you didn't respond to SSRIs, you still may not if the idea is that it works to polymorphisms. So it's an interesting idea of kind of going back and forth. We don't know yet. We don't know. But I don't I this is something people have been talking about for quite a while. And I have not seen data on this.
Nick Jikomes 1:27:34
I see. Well, at least I want to be respectful of your time so that you can get back to whatever grant you're inevitably working on right now. Are there any final thoughts you'd like to leave people with on this general area of ketamine and antidepressants?
Lisa Monteggia 1:27:48
So I think it's a really exciting time in neuroscience, being able to really probe these questions. And the findings with ketamine are some of the most exciting in the field. I mean, up until the finding with ketamine again, we thought typical antidepressants took several weeks to work. That's what we know they took several weeks to work, we thought an antidepressant response required several weeks. So when now we know that it's possible to have a rapid effect. And so being able to translate that is important. And so I guess what I leave your listeners with is really the power of preclinical research, because you can argue, well, we have ketamine in the clinic, we have typical antidepressants, you know, why do we need this preclinical work. And the power of this is really, I think, in terms of future drug development, and really advancing the field. And the examples I was give to individuals are if we take sort of a step back, and if you look at in the 80s, AIDS, when people talked about AIDS, it was terrifying. No one knew what AIDS was, they didn't know what caused it, how you could get it. I mean, individuals that had AIDS, I mean, often might not see be seen by a doctor or a dentist, small children may not be able to even go to school. And what happened is very, very quickly, it was identified that as was caused by HIV, and there was a lot of work that had been done on these types of viruses. And by the end of a decade, based on the knowledge that was done being able to really put efforts forward, we were able to develop therapeutics for individuals that were HIV positive to have normal qualities of life. Now, it's not unusual to meet someone that is HIV positive, they can have a very, very good quality of life. It's no longer a death sentence. If we look in the past year, of what happened with COVID-19 in the pandemic, the idea year later that we would have a vaccine is phenomenal. But it didn't just happen in this past year. It was really built on this preclinical research that's been going on for decades and And it just so happened that, you know, this virus that came in was Coronavirus, that came in, you know, was with some research that lined up and we were able to move forward. We weren't starting at ground zero. So the brain is so complex, but I think there's tremendous amount of hope. And I think to really have clinical impact, it requires preclinical information and preclinical work, we don't want to just suddenly, you know, be trying any drug and patients, we want to have a very focused approach, trying to explain why ketamine works, my mantiene starts to focus in on making drugs that work on trying to look at pathways, yes, it may take a while. But hopefully, we're going to get there to have better treatments, more efficacious treatments that are going to impact more people. And so I think the most important message I can leave you with is the hope to the future of what I think is going to happen as we move forward and understanding the brain and understanding these diseases as well as their treatments.
Nick Jikomes 1:31:04
Yeah, that's, that's really great. It reminds me of that saying that I hear some times, it takes years and years of practice to become an overnight success. Exactly. And I love your I love your bit about COVID as well, because it does seem to many people like, wow, we innovated these vaccines from scratch in less than a year. And in some sense, yeah, there was a lot of innovation that happened rapidly, but it was built on top of this corpus of research that had gone on for decades. And sometimes I think people get frustrated with with research and preclinical research because it might seem for years or even decades, like nothing is happening. But building up that corpus of knowledge can allow something to then happen very quickly.
Lisa Monteggia 1:31:46
Absolutely. And that's what's important because again, we never know when the next you know, let's hope not, but pandemic. I mean, that was a word we never thought we'd hear in our lifetime, but that we're prepared and you never know where that's going to happen. The brain is complex. But ketamine, the work on ketamine came up, they were not studying ketamine and depression. This was just a serendipitous finding, but being able to build on that and continue to expand that, I think really has huge therapeutic potential. And again, we don't know what the future holds, but I really do feel it's much brighter with a lot of treatment advance ahead.
Nick Jikomes 1:32:28
Well, I think that's a great place to end. Thank you for your time.
Lisa Monteggia 1:32:30
Well, thank you
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