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Welcome to BIOTECH NATION !!! With understandable interviews requiring no background in science, BTN attracts a wide global audience. From everyday people looking for hope in treatments in development, to bioentrepreneurs interested in the experience of their fellow travelers, to venture capitalists looking for possibilities in cutting-edge breakthroughs, to scientists simply interested in the work of others, BioTech Nation is the voice of human endeavor, driving science to new realities for everyone. These interviews are drawn directly from the public radio program, "Tech Nation", which also can be heard in numerous global radio and podcasting venues.
Major depressive disorder, serious depression, PTSD, challenging medical conditions for which successful treatment is usually a matter of trial and error, of seeking, waiting, and hoping for success. It's not surprising to find biopharmaceutical companies working on new efforts in this field. But what is surprising is one company's approach. Doctor Amit Etkin is the founder and CEO of Alto Neuroscience, a neuroscientist and psychiatrist. He's a member of the faculty at Stanford University.
Dr. Moira Gunn:In both his university research and at Alto Neuroscience, it is not just the compliment of drugs being developed, which are innovative. What is key is each patient's underlying biology. And now, doctor Etkin. Well, doctor Etkin, welcome to the program.
Dr. Amit Etkin:It's a pleasure to be here. Looking forward to our discussion.
Dr. Moira Gunn:Well, from the outset of this interview, I want listeners to know that we have some first here. What we're talking about is not just another shot on goal, but a very different approach to major depressive disorder, which you might know as clinical depression, serious depression, as well as PTSD. So what you're hearing will be some significant firsts, that you have not heard before. So let's start with major depressive disorder and PTSD. You're studying them together.
Dr. Moira Gunn:From the experience of the person who suffers, what's the difference and where are they the same?
Dr. Amit Etkin:So with depression, which people just in their day to day lives may have a general sense of, with depression, we think about things like not only low mood, lack of motivation, but also changes in appetite, changes in attention, in sleep, a lot of things moving together. Sometimes those come out of the blue. Sometimes a person has had depression before and gotten better and then relapses, and sometimes that's related to trauma they experienced. And that's where things start to shade into this commonality between depression and post traumatic stress disorder or PTSD. Often, I think in popular culture, people associate PTSD with veterans in combat.
Dr. Amit Etkin:But actually, having a severe trauma, life threatening event can lead to feelings of of detachment and fear and depression and and kind of this arousal where you just have to watch your environment the whole time, and quite often comes with all of those things that we associate with clinical depression itself, except in PTSD, it's the trauma that clearly caused this. In depression, a portion of depression is caused by trauma. In fact, people after a trauma, if they develop a psychiatric condition, pretty much equally go on to develop depression or PTSD. So so you can think of these things as from a symptom and experience perspective, a spectrum of illness. What we wanted to do in trying to understand these conditions, and even though our primary focus is on depression, is to understand what is the range of people who are out there and seeking help?
Dr. Amit Etkin:How does the biology that we are leveraging give us insight on that whole spectrum rather than very narrowly defining the population we're trying to understand.
Dr. Moira Gunn:Typically, people who suffer from these symptoms go to their doctors and from these external symptoms or personally perceived symptoms, they're prescribed antidepressants. Sometimes they have to keep switching medicines until they find one that works. And as a Stanford University professor and researcher, and now as founder and CEO of Alto Neuroscience, You think that could be different. How?
Dr. Amit Etkin:That's a great question. And I think we have to start by understanding how big this problem is. So depression is the most disabling condition across all of medicine across the world. You'll see it on average in around 6 or 7 percent of people as a whole, and the pandemic has only made that worse. So when you look at how big the problem is and now you look at the tools we have to leverage, there's a few really critical things in there.
Dr. Amit Etkin:So we do have a lot of drugs, but a lot of the drugs are very similar. And exactly as you said, it's a lot of guesswork because we don't know what will work for each person. What we don't have any of is any tests that tell us about any aspect of the biology of the patient that could be used to guide what it is that's really driving their depression or for that matter any psychiatric disorder. And how do I use that information to prescribe a drug that will actually work for them, will work faster, and will work better? And that's the frustration that patients experience as a psychiatrist and a clinician.
Dr. Amit Etkin:I experience in trying to treat the, patients is that it's just guesswork. And the worst part about that guesswork is that it takes months to find out if the drug worked for them. And if it didn't, you start all over again with a brand new drug, and that has consequences. You know, you have a high rate of suicide with depression. There's all the impact on the person, on their family, on their work, on society.
Dr. Amit Etkin:The cost of mental illness in general is really, really high. It's the biggest driver of cost for insurance in the United States, for example. And so it's a bit shocking when you look at where the state of medicine is in, you know, now, 2022, 2023, where we should be so sophisticated, and yet we're still treating our patients much like we did in the 19 eighties.
Dr. Moira Gunn:Now how do we measure depression? I mean, we're looking for measures, but how do you measure it? We don't have a depression, organ that we can just, you know, take a blood test and see how it's operating.
Dr. Amit Etkin:Exactly right. But we do know a few things. So we know that that subjective experience of depression is important. We never want to diminish that. That's critical to how a person experiences themselves and what drives their dysfunction as they try to live their lives.
Dr. Amit Etkin:But we also know that the brain in generating these feelings and driving psychiatric disease has attributes that you can measure that link to our concept of what depression is. For example, when you talk about motivation, when you talk about appetite, when you talk about sleep, all of these things can be grounded in measures. So we use behavioral tests, for example, of of cognition, of attention, and decision making, and memory. We use other tests of emotional, biases and how you deal with a reward and how much motivation that gives you in driving your activity. We measure your sleep and your circadian rhythms using a wearable device like tens or 100 of millions of people have just as they walk around every day, it's generating information.
Dr. Amit Etkin:And we also measure how their brain functions directly. We do that with a tool called EEG or electroencephalography, which is known as brainwave recordings more commonly, and that tells us about how active or interconnected different parts of the brain are. So we can use all of the neuroscience that we've been doing a lot of research on when I was a professor at Stanford, had a big lab doing this, and the field as a whole doing this for years, and leverage that information about how people's brains work in different parts and different functions in those brains against what it what it is in a clinical syndrome and how it's experienced by the patient.
Dr. Moira Gunn:You put all that data together and you start to see the person. You're not just saying, well, try this drug. People must break down into various subgroups. It's not a fishing expedition anymore.
Dr. Amit Etkin:There turns out to be a lot that we know, and actually that's something we capitalize on. There's a lot that we know that we can measure that's reliable. So if you take the test now, it'll yield the same result as if you take it 3 months from now. So it's meaningful, it's reliable, that can characterize people. And and it's important in all of this to understand that a lot of these things we talked, for example, about about attention and and cognition and about appetite and and sleep and these sorts of things, it turns out people can't introspect and give you accurate information on.
Dr. Amit Etkin:I mean, trivially, let's think about, could you tell me what your sleep stages were like and what different parts of your sleep architecture was if you're asleep? Well, obviously, that's going to be hard to report on. But even something like cognition, you you the way you deploy your attention and you can we can turn things on and turn things off and avoid distraction, remember things, you know, deploying memory, understanding how to make decisions in a better, more balanced way. It seems like you ought to be able to report on these things. But it turns out when you actually test these things using objective measures, computerized tests, EEGs, and the like, that you get information that the person simply can't tell you, because that information is just not really accessible to them.
Dr. Amit Etkin:It's by putting that together with the drugs that we're developing, that I think the really exciting steps are taken. To be clear, our history in psychiatry is developing drug after drug with no idea of who we're giving it to, and literally throwing spaghetti against the wall and hoping something sticks. And the vast majority of the time, 94% of the time, it fails. On the other hand, we have all these tests, but a test by itself, well, it can tell you something, but it tell it doesn't tell you what you're going to need to do about that. So as a physician, that's really not all that useful to me.
Dr. Amit Etkin:It's by combining a drug with a test. With a test is for whether you'll respond to the drug. That is how I think we're making progress in understanding the disease and even more importantly in treating the disease.
Dr. Moira Gunn:I have to say that frequently when I speak with people who are developing drugs, they'll say, we have a test, which is great, which is great. You don't just have a test. I'm looking at this data, such disparate data. You know, sleeping and cognition and and everything else. It's like you got a lot of data here.
Dr. Moira Gunn:How do you possibly put that together for an individual and how do you possibly put that together looking at all the data you have for everyone which is bound to tell you something else in addition.
Dr. Amit Etkin:That's right. So it's not just, of course, a little bit of data that you gather on a person, it's how that comes into the context of a lot of data that we gathered on a lot of people and understand things like, what does that mean for how they respond to an existing treatment? What does that mean for the diagnosis of one diagnosis versus another or the risk of developing something over time. It's in that context that we learn a lot and what we've learned, and this gets reinforced in how we develop our drugs, is that there's certain areas that you can quantify readily. So cognition is a is a really good one, or sleep and and circadian rhythms is another, and and emotional processing, things that are negative and sort of in related to a state of high anxiety or things that ought to be motivating but aren't sufficiently that are related to lack of pleasure and hedonia.
Dr. Amit Etkin:All of these things can define dimensions of function and dysfunction in people's brains that characterize smaller groups of people within this really big broad diagnosis of depression that tells us something meaningful about them. What is going on in their brain that is completely different from somebody with the same symptoms, but a different brain or behavioral or or sleep profile. And we use that information about how to characterize these small groups to then find which drugs best speak to that area of dysfunction, and then develop those drugs in those smaller groups. To be clear, our goal is not to develop a drug for all of depression. We think that there are many different depressions, and that relates to different biology.
Dr. Amit Etkin:That biology can be measured and scaled so we can do this in a clinically feasible large scale way, and that biology should line up with a treatment that addresses what's going on in a much more effective manner.
Dr. Moira Gunn:Now Alto has 11 drugs in the pipeline. We can't possibly get to them all. I do wanna talk about your most advanced drug known as Alto 100 because you've got data, phase 2a data, your first phase 2 study for people suffering from major depressive disorder and or PTSD, first, tell us about the study and tell us what you found.
Dr. Amit Etkin:So when we set up this study, it was to try to understand whether this drug, ALTA 100, which increases brain plasticity, the ability of the brain to be flexible and take in new information, works better for those people where we thought plasticity was low. And that is people with poor cognition and low mood. And so we set up a study with several 100 people where we could analyze the data as we go, where everybody's getting the drug. And so the question is, does it work better for people with worse cognition relative to better cognition? And can we find that in such a way that gives us a lot of confidence?
Dr. Amit Etkin:We can replicate that over and over so that we know now when we go to test the drug against placebo, that we have an idea of the people for whom it's good for, that that's a very different approach to the usual approach when you're testing drugs, which is just give it to everybody. And to be frank, hope that it works without any real idea of why it would work and for whom it might work before you ever do this test.
Dr. Moira Gunn:You could get this positive response and say, good enough. We're gonna throw it into the mix with all the others, and they can try this on everybody as well. It's like, no. That's not what you're doing here, which is another first.
Dr. Amit Etkin:Exactly. So the the use, of an objective test we talked about the lack of objective tests in psychiatry. The use of an objective test to tell you who responds better and who doesn't, that's really something that's been missing in the field of psychiatry and is the centerpiece for our approach. There is no drug in our mind that doesn't have a test. And likewise, there is no test without a drug.
Dr. Amit Etkin:These two things have to go together. And this is really the first study finding that kind of an objective test. One that could be scaled to millions of people relatively easily, actually, to identify who it is. And it turns out in a way that you can't just ask them, hey. How's your cognition?
Dr. Amit Etkin:You have to do that test.
Dr. Moira Gunn:Now you did mention placebo. I just wanna go down the science just a little more. You've determined that with low cognition people suffering from depression that they responded much better. My notes here say 80% response. And, you know, we're talking about we know the measures you're taking.
Dr. Moira Gunn:Let's stick with the science here. On this particular drug, alto 100, and this drug alone, what do you study next now that you see that?
Dr. Amit Etkin:There's a couple of interesting directions that this is going to go. So the first one that's happening now is a randomized trial where we're giving the drug to people or placebo and trying to see if in fact there is a bigger response in poor cognition, and we're including both people with and without poor cognition. And so that way we can really compare and contrast them. But the other opportunity that this drug and the the test give you is something that has not happened in psychiatry before, which is now you have the biology of the person that you can measure, you have the action of the drug, and it's not just in depression that we see poor cognition, we see it across the board. And a lot of other disorders including those that might be completely separate.
Dr. Amit Etkin:I mean, schizophrenia you may not think of as overlapping with depression, but the level of cognitive impairment in those poor cognition depressed patients is actually similar to what we see in schizophrenia, where we think cognitive impairment is actually a big part of the clinical picture. And so having a test with a drug and that leading to a better response starts to open up the aperture on what's possible in psychiatry and allows us to go a lot faster in developing and deploying drugs than you could if you just randomly threw it against different populations.
Dr. Moira Gunn:Now I'm just gonna even though you have 11 drugs, I'm gonna just ask you quickly about another one that you have, a different drug, Alto 300, and it's currently in a study. And we'll see some results in the late spring, early summer. And this is a phase 2 study. How is that study different? How is that drug different?
Dr. Amit Etkin:So the study as a whole is similar in that we're studying depression, and we're trying to understand for whom is that the right drug. But the drug works in a different way. It works on circadian rhythms and works on sleep. And so the expectation is that the signal, the test, that will predict who best responds to that drug is different from ALTA 100. And you can then imagine, well, if that's the case, there's an even more exciting outcome at the end of this.
Dr. Amit Etkin:Because if you can now advance 2 drugs roughly the same time that work in new and distinct ways for different populations, each with their own tests that maybe doesn't overlap at all or only partially overlaps, you can now much more effectively address a much larger segment of the depressed population by giving them a test with a aligned drug and having multiple options, multiple tests, multiple drugs that all should work better. That's a pretty exciting future. I mean, for me as a as a psychiatrist and as a neuroscientist, it's really the coming together of these two aspects of my own experience and training to really see clinical change by understanding the brain and and finally collect connecting these dots in terms of how understanding the brain leads to actually better treatments in the near term.
Dr. Moira Gunn:Now I do wanna say, you know, we're we're extremely grateful for all the antidepressants out there today. In fact, we may be able to develop tests for them in the future to see where where do they work, take the guesswork out of them. I guess I guess the the mantra here is, it's a question of matching the right person with the right drug and not just for depression.
Dr. Amit Etkin:That's right. So, you know, we've talked about it from the lens of psychiatry where this is a first. But there's other areas of medicine that actually teach us that this is the right path to go down because they've been going down this path for years. So one example for that is, a drug called Keytruda, which is a drug to treat cancer and and actually many different kinds of cancer. And that drug was about to be shelved in much the way that a lot of psychiatric drugs are shelved, which is they tried they tried it on a very broad population, and it really didn't work.
Dr. Amit Etkin:And so they said, well, you know what? I don't think this really has a future. But then through additional research, people realized, actually, you can identify a small group of patients for whom it works extraordinarily well. You know, we talked about the 80% response in that, subgroup within the ALTA 100 study, similar concept. And it turns out when you grab on to that test and that insight, you can now start deploying the drug, in that case, KEYTRUDA, but we've seen it in other drugs as well, much more effectively across a variety of different tumors, just like we think of a variety of different psychiatric disorders as benefiting from a drug that gets at a mechanism that you could test for.
Dr. Amit Etkin:So that really bright future that's already being realized in cancer therapeutics, that's where we wanna go soon in psychiatry by doing it differently and and really taking a page out of areas like oncology.
Dr. Moira Gunn:I understand that many people with depression, they don't wanna talk about it. They don't even wanna talk about the fact that maybe taking antidepressants. There are also other people who don't wanna talk about it so much they're not gonna seek treatment. There's almost a stigma to it today.
Dr. Amit Etkin:There's a stigma in a couple of different and really important ways in psychiatry. So it turns out that half of depressed patients aren't even in care. So we talked about 6 or 7% of people have depression at any given time. Only half of them are actually getting treatment, which means the other half are suffering, and and that can lead to a range of problems and obviously suicide is a really big one. As a public health issue, it's critical that we find a way to bring those other people into treatment as well as treat them more effectively.
Dr. Amit Etkin:One of the things that I think is holding back psychiatry is what we started to talk about at the beginning that it feels like you're just throwing random things at a patient. You don't really know what works and that gets everybody frustrated and and actually oftentimes even the people who seek treatment might drop out of treatment. I think that there's a an interesting potential here for this approach of pairing a test with a drug, and that we can talk about that biology in objective terms that takes away stigma from having depression or any psychiatric disorder. It's not just quote unquote in your head, it's something we can measure. And by measuring it, we can treat treat you better so that the ability to actually deliver on a relief of suffering becomes better.
Dr. Amit Etkin:And the 2 of these things interplay. Mental illness is in a really unique place in terms of medicine and and in terms of our experience as people. Most people with diabetes don't talk about coming off their insulin. When they think about their diabetes, they think about it as a biological state that can be diagnosed and for which there is a treatment. And yet a lot of people, and this is part of the stigma in depression, wanna come off their medication because that understanding is not really there.
Dr. Amit Etkin:So bringing a test to tell us, to tell the patient, to tell the provider, here's what's going on and here's what you could do about it in a new and more effective way, that has to decrease stigma. That has to bring more people into treatment. And I think if we can bend the curve in terms of suicide rates, in terms of the societal impact of depression, we'd have done a lot of good.
Dr. Moira Gunn:Well, needless to say, while your your drugs are on their way to being approved at some point, you're gonna get it right somehow. If you get a drug from Alto Neuroscience, you gotta take a test.
Dr. Amit Etkin:That's right. There is no escaping it. We've just simply gotta know what we're doing to do it better.
Dr. Moira Gunn:Well, doctor Etkin, thank you so much for joining us. I hope you come back to see us again.
Dr. Amit Etkin:It was my pleasure.
Dr. Moira Gunn:Doctor Amit Etkin is the founder and CEO of Alto Neuroscience. More information is available on the web at altoneuroscience.com. For Technation, I'm Moira Gunn.