December 11, 2024 • 25 mins
Major Depressive Disorder. Serious Depression. PTSD. Alto Neuroscience CEO, Dr. Amit Etkin talks about developing new and innovative drugs tied directly to each patient’s underlying biology. For every drug, there is a test...
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Dr. Moira Gunn (00:18):
Major depressive disorder, serious depression,
PTSD, challenging medicalconditions for which successful
treatment is usually a matter oftrial and error, of seeking,
waiting, and hoping for success.It's not surprising to find
biopharmaceutical companiesworking on new efforts in this
(00:39):
field. But what is surprising isone company's approach. Doctor
Amit Etkin is the founder andCEO of Alto Neuroscience, a
neuroscientist and psychiatrist.He's a member of the faculty at
Stanford University.
In both his university researchand at Alto Neuroscience, it is
(01:00):
not just the compliment of drugsbeing developed, which are
innovative. What is key is eachpatient's underlying biology.
And now, doctor Etkin. Well,doctor Etkin, welcome to the
program.
Dr. Amit Etkin (01:13):
It's a pleasure to be here. Looking forward to
our discussion.
Dr. Moira Gunn (01:16):
Well, from the outset of this interview, I want
listeners to know that we havesome first here. What we're
talking about is not justanother shot on goal, but a very
different approach to majordepressive disorder, which you
might know as clinicaldepression, serious depression,
as well as PTSD. So what you'rehearing will be some significant
(01:41):
firsts, that you have not heardbefore. So let's start with
major depressive disorder andPTSD. You're studying them
together.
From the experience of theperson who suffers, what's the
difference and where are theythe same?
Dr. Amit Etkin (01:57):
So with depression, which people just in
their day to day lives may havea general sense of, with
depression, we think aboutthings like not only low mood,
lack of motivation, but alsochanges in appetite, changes in
attention, in sleep, a lot ofthings moving together.
(02:18):
Sometimes those come out of theblue. Sometimes a person has had
depression before and gottenbetter and then relapses, and
sometimes that's related totrauma they experienced. And
that's where things start toshade into this commonality
between depression and posttraumatic stress disorder or
PTSD. Often, I think in popularculture, people associate PTSD
(02:40):
with veterans in combat.
But actually, having a severetrauma, life threatening event
can lead to feelings of ofdetachment and fear and
depression and and kind of thisarousal where you just have to
watch your environment the wholetime, and quite often comes with
(03:01):
all of those things that weassociate with clinical
depression itself, except inPTSD, it's the trauma that
clearly caused this. Indepression, a portion of
depression is caused by trauma.In fact, people after a trauma,
if they develop a psychiatriccondition, pretty much equally
go on to develop depression orPTSD. So so you can think of
(03:23):
these things as from a symptomand experience perspective, a
spectrum of illness. What wewanted to do in trying to
understand these conditions, andeven though our primary focus is
on depression, is to understandwhat is the range of people who
are out there and seeking help?
How does the biology that we areleveraging give us insight on
(03:46):
that whole spectrum rather thanvery narrowly defining the
population we're trying tounderstand.
Dr. Moira Gunn (03:52):
Typically, people who suffer from these
symptoms go to their doctors andfrom these external symptoms or
personally perceived symptoms,they're prescribed
antidepressants. Sometimes theyhave to keep switching medicines
until they find one that works.And as a Stanford University
(04:13):
professor and researcher, andnow as founder and CEO of Alto
Neuroscience, You think thatcould be different. How?
Dr. Amit Etkin (04:22):
That's a great question. And I think we have to
start by understanding how bigthis problem is. So depression
is the most disabling conditionacross all of medicine across
the world. You'll see it onaverage in around 6 or 7 percent
of people as a whole, and thepandemic has only made that
worse. So when you look at howbig the problem is and now you
(04:46):
look at the tools we have toleverage, there's a few really
critical things in there.
So we do have a lot of drugs,but a lot of the drugs are very
similar. And exactly as yousaid, it's a lot of guesswork
because we don't know what willwork for each person. What we
don't have any of is any teststhat tell us about any aspect of
the biology of the patient thatcould be used to guide what it
(05:09):
is that's really driving theirdepression or for that matter
any psychiatric disorder. Andhow do I use that information to
prescribe a drug that willactually work for them, will
work faster, and will workbetter? And that's the
frustration that patientsexperience as a psychiatrist and
a clinician.
I experience in trying to treatthe, patients is that it's just
(05:32):
guesswork. And the worst partabout that guesswork is that it
takes months to find out if thedrug worked for them. And if it
didn't, you start all over againwith a brand new drug, and that
has consequences. You know, youhave a high rate of suicide with
depression. There's all theimpact on the person, on their
(05:53):
family, on their work, onsociety.
The cost of mental illness ingeneral is really, really high.
It's the biggest driver of costfor insurance in the United
States, for example. And so it'sa bit shocking when you look at
where the state of medicine isin, you know, now, 2022, 2023,
(06:16):
where we should be sosophisticated, and yet we're
still treating our patients muchlike we did in the 19 eighties.
Dr. Moira Gunn (06:24):
Now how do we measure depression? I mean,
we're looking for measures, buthow do you measure it? We don't
have a depression, organ that wecan just, you know, take a blood
test and see how it's operating.
Dr. Amit Etkin (06:38):
Exactly right. But we do know a few things. So
we know that that subjectiveexperience of depression is
important. We never want todiminish that. That's critical
to how a person experiencesthemselves and what drives their
dysfunction as they try to livetheir lives.
But we also know that the brainin generating these feelings and
(07:01):
driving psychiatric disease hasattributes that you can measure
that link to our concept of whatdepression is. For example, when
you talk about motivation, whenyou talk about appetite, when
you talk about sleep, all ofthese things can be grounded in
measures. So we use behavioraltests, for example, of of
(07:24):
cognition, of attention, anddecision making, and memory. We
use other tests of emotional,biases and how you deal with a
reward and how much motivationthat gives you in driving your
activity. We measure your sleepand your circadian rhythms using
a wearable device like tens or100 of millions of people have
(07:47):
just as they walk around everyday, it's generating
information.
And we also measure how theirbrain functions directly. We do
that with a tool called EEG orelectroencephalography, which is
known as brainwave recordingsmore commonly, and that tells us
about how active orinterconnected different parts
of the brain are. So we can useall of the neuroscience that
(08:11):
we've been doing a lot ofresearch on when I was a
professor at Stanford, had a biglab doing this, and the field as
a whole doing this for years,and leverage that information
about how people's brains workin different parts and different
functions in those brainsagainst what it what it is in a
(08:31):
clinical syndrome and how it'sexperienced by the patient.
Dr. Moira Gunn (08:35):
You put all that data together and you start to
see the person. You're not justsaying, well, try this drug.
People must break down intovarious subgroups. It's not a
fishing expedition anymore.
Dr. Amit Etkin (08:51):
There turns out to be a lot that we know, and
actually that's something wecapitalize on. There's a lot
that we know that we can measurethat's reliable. So if you take
the test now, it'll yield thesame result as if you take it 3
months from now. So it'smeaningful, it's reliable, that
can characterize people. And andit's important in all of this to
(09:11):
understand that a lot of thesethings we talked, for example,
about about attention and andcognition and about appetite and
and sleep and these sorts ofthings, it turns out people
can't introspect and give youaccurate information on.
I mean, trivially, let's thinkabout, could you tell me what
your sleep stages were like andwhat different parts of your
(09:34):
sleep architecture was if you'reasleep? Well, obviously, that's
going to be hard to report on.But even something like
cognition, you you the way youdeploy your attention and you
can we can turn things on andturn things off and avoid
distraction, remember things,you know, deploying memory,
understanding how to makedecisions in a better, more
(09:57):
balanced way. It seems like youought to be able to report on
these things. But it turns outwhen you actually test these
things using objective measures,computerized tests, EEGs, and
the like, that you getinformation that the person
simply can't tell you, becausethat information is just not
really accessible to them.
(10:19):
It's by putting that togetherwith the drugs that we're
developing, that I think thereally exciting steps are taken.
To be clear, our history inpsychiatry is developing drug
after drug with no idea of whowe're giving it to, and
literally throwing spaghettiagainst the wall and hoping
something sticks. And the vastmajority of the time, 94% of the
(10:41):
time, it fails. On the otherhand, we have all these tests,
but a test by itself, well, itcan tell you something, but it
tell it doesn't tell you whatyou're going to need to do about
that. So as a physician, that'sreally not all that useful to
me.
It's by combining a drug with atest. With a test is for whether
(11:02):
you'll respond to the drug. Thatis how I think we're making
progress in understanding thedisease and even more
importantly in treating thedisease.
Dr. Moira Gunn (11:13):
I have to say that frequently when I speak
with people who are developingdrugs, they'll say, we have a
test, which is great, which isgreat. You don't just have a
test. I'm looking at this data,such disparate data. You know,
sleeping and cognition and andeverything else. It's like you
(11:36):
got a lot of data here.
How do you possibly put thattogether for an individual and
how do you possibly put thattogether looking at all the data
you have for everyone which isbound to tell you something else
in addition.
Dr. Amit Etkin (11:51):
That's right. So it's not just, of course, a
little bit of data that yougather on a person, it's how
that comes into the context of alot of data that we gathered on
a lot of people and understandthings like, what does that mean
for how they respond to anexisting treatment? What does
that mean for the diagnosis ofone diagnosis versus another or
(12:12):
the risk of developing somethingover time. It's in that context
that we learn a lot and whatwe've learned, and this gets
reinforced in how we develop ourdrugs, is that there's certain
areas that you can quantifyreadily. So cognition is a is a
really good one, or sleep andand circadian rhythms is
another, and and emotionalprocessing, things that are
(12:35):
negative and sort of in relatedto a state of high anxiety or
things that ought to bemotivating but aren't
sufficiently that are related tolack of pleasure and hedonia.
All of these things can definedimensions of function and
dysfunction in people's brainsthat characterize smaller groups
of people within this really bigbroad diagnosis of depression
(12:59):
that tells us somethingmeaningful about them. What is
going on in their brain that iscompletely 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 thesesmall groups to then find which
drugs best speak to that area ofdysfunction, and then develop
(13:23):
those drugs in those smallergroups. To be clear, our goal is
not to develop a drug for all ofdepression. We think that there
are many different depressions,and that relates to different
biology.
That biology can be measured andscaled so we can do this in a
clinically feasible large scaleway, and that biology should
(13:48):
line up with a treatment thataddresses what's going on in a
much more effective manner.
Dr. Moira Gunn (13:53):
Now Alto has 11 drugs in the pipeline. We can't
possibly get to them all. I dowanna talk about your most
advanced drug known as Alto 100because you've got data, phase
2a data, your first phase 2study for people suffering from
major depressive disorder and orPTSD, first, tell us about the
(14:16):
study and tell us what youfound.
Dr. Amit Etkin (14:19):
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 thebrain to be flexible and take in
new information, works betterfor those people where we
thought plasticity was low. Andthat is people with poor
cognition and low mood. And sowe set up a study with several
(14:44):
100 people where we couldanalyze the data as we go, where
everybody's getting the drug.And so the question is, does it
work better for people withworse cognition relative to
better cognition? And can wefind that in such a way that
gives us a lot of confidence?
We can replicate that over andover so that we know now when we
(15:05):
go to test the drug againstplacebo, that we have an idea of
the people for whom it's goodfor, that that's a very
different approach to the usualapproach when you're testing
drugs, which is just give it toeverybody. And to be frank, hope
that it works without any realidea of why it would work and
for whom it might work beforeyou ever do this test.
Dr. Moira Gunn (15:29):
You could get this positive response and say,
good enough. We're gonna throwit into the mix with all the
others, and they can try this oneverybody as well. It's like,
no. That's not what you're doinghere, which is another first.
Dr. Amit Etkin (15:42):
Exactly. So the the use, of an objective test we
talked about the lack ofobjective tests in psychiatry.
The use of an objective test totell you who responds better and
who doesn't, that's reallysomething that's been missing in
the field of psychiatry and isthe centerpiece for our
approach. There is no drug inour mind that doesn't have a
(16:04):
test. And likewise, there is notest without a drug.
These two things have to gotogether. And this is really the
first study finding that kind ofan objective test. One that
could be scaled to millions ofpeople relatively easily,
actually, to identify who it is.And it turns out in a way that
(16:24):
you can't just ask them, hey.How's your cognition?
You have to do that test.
Dr. Moira Gunn (16:30):
Now you did mention placebo. I just wanna go
down the science just a littlemore. You've determined that
with low cognition peoplesuffering from depression that
they responded much better. Mynotes here say 80% response.
And, you know, we're talkingabout we know the measures
you're taking.
(16:50):
Let's stick with the sciencehere. On this particular drug,
alto 100, and this drug alone,what do you study next now that
you see that?
Dr. Amit Etkin (17:02):
There's a couple of interesting directions that
this is going to go. So thefirst one that's happening now
is a randomized trial wherewe're giving the drug to people
or placebo and trying to see ifin fact there is a bigger
response in poor cognition, andwe're including both people with
and without poor cognition. Andso that way we can really
compare and contrast them. Butthe other opportunity that this
(17:26):
drug and the the test give youis something that has not
happened in psychiatry before,which is now you have the
biology of the person that youcan measure, you have the action
of the drug, and it's not justin depression that we see poor
cognition, we see it across theboard. And a lot of other
disorders including those thatmight be completely separate.
I mean, schizophrenia you maynot think of as overlapping with
(17:50):
depression, but the level ofcognitive impairment in those
poor cognition depressedpatients is actually similar to
what we see in schizophrenia,where we think cognitive
impairment is actually a bigpart of the clinical picture.
And so having a test with a drugand that leading to a better
response starts to open up theaperture on what's possible in
(18:12):
psychiatry and allows us to go alot faster in developing and
deploying drugs than you couldif you just randomly threw it
against different populations.
Dr. Moira Gunn (18:22):
Now I'm just gonna even though you have 11
drugs, I'm gonna just ask youquickly about another one that
you have, a different drug, Alto300, and it's currently in a
study. And we'll see someresults in the late spring,
early summer. And this is aphase 2 study. How is that study
(18:42):
different? How is that drugdifferent?
Dr. Amit Etkin (18:45):
So the study as a whole is similar in that we're
studying depression, and we'retrying to understand for whom is
that the right drug. But thedrug works in a different way.
It works on circadian rhythmsand works on sleep. And so the
expectation is that the signal,the test, that will predict who
best responds to that drug isdifferent from ALTA 100. And you
(19:06):
can then imagine, well, ifthat's the case, there's an even
more exciting outcome at the endof this.
Because if you can now advance 2drugs roughly the same time that
work in new and distinct waysfor different populations, each
with their own tests that maybedoesn't overlap at all or only
partially overlaps, you can nowmuch more effectively address a
(19:28):
much larger segment of thedepressed population by giving
them a test with a aligned drugand having multiple options,
multiple tests, multiple drugsthat all should work better.
That's a pretty exciting future.I mean, for me as a as a
psychiatrist and as aneuroscientist, it's really the
coming together of these twoaspects of my own experience and
(19:52):
training to really see clinicalchange by understanding the
brain and and finally collectconnecting these dots in terms
of how understanding the brainleads to actually better
treatments in the near term.
Dr. Moira Gunn (20:06):
Now I do wanna say, you know, we're we're
extremely grateful for all theantidepressants out there today.
In fact, we may be able todevelop tests for them in the
future to see where where dothey work, take the guesswork
out of them. I guess I guess thethe mantra here is, it's a
(20:26):
question of matching the rightperson with the right drug and
not just for depression.
Dr. Amit Etkin (20:32):
That's right. So, you know, we've talked about
it from the lens of psychiatrywhere this is a first. But
there's other areas of medicinethat actually teach us that this
is the right path to go downbecause they've been going down
this path for years. So oneexample for that is, a drug
called Keytruda, which is a drugto treat cancer and and actually
(20:55):
many different kinds of cancer.And that drug was about to be
shelved in much the way that alot of psychiatric drugs are
shelved, which is they triedthey tried it on a very broad
population, and it really didn'twork.
And so they said, well, you knowwhat? I don't think this really
has a future. But then throughadditional research, people
(21:16):
realized, actually, you canidentify a small group of
patients for whom it worksextraordinarily well. You know,
we talked about the 80% responsein that, subgroup within the
ALTA 100 study, similar concept.And it turns out when you grab
on to that test and thatinsight, you can now start
deploying the drug, in thatcase, KEYTRUDA, but we've seen
(21:38):
it in other drugs as well, muchmore effectively across a
variety of different tumors,just like we think of a variety
of different psychiatricdisorders as benefiting from a
drug that gets at a mechanismthat you could test for.
So that really bright futurethat's already being realized in
cancer therapeutics, that'swhere we wanna go soon in
(22:01):
psychiatry by doing itdifferently and and really
taking a page out of areas likeoncology.
Dr. Moira Gunn (22:07):
I understand that many people with
depression, they don't wannatalk about it. They don't even
wanna talk about the fact thatmaybe taking antidepressants.
There are also other people whodon't wanna talk about it so
much they're not gonna seektreatment. There's almost a
stigma to it today.
Dr. Amit Etkin (22:26):
There's a stigma in a couple of different and
really important ways inpsychiatry. So it turns out that
half of depressed patientsaren't even in care. So we
talked about 6 or 7% of peoplehave depression at any given
time. Only half of them areactually getting treatment,
which means the other half aresuffering, and and that can lead
to a range of problems andobviously suicide is a really
(22:48):
big one. As a public healthissue, it's critical that we
find a way to bring those otherpeople into treatment as well as
treat them more effectively.
One of the things that I thinkis holding back psychiatry is
what we started to talk about atthe beginning that it feels like
you're just throwing randomthings at a patient. You don't
really know what works and thatgets everybody frustrated and
(23:10):
and actually oftentimes even thepeople who seek treatment might
drop out of treatment. I thinkthat there's a an interesting
potential here for this approachof pairing a test with a drug,
and that we can talk about thatbiology in objective terms that
takes away stigma from havingdepression or any psychiatric
(23:31):
disorder. It's not just quoteunquote in your head, it's
something we can measure. And bymeasuring it, we can treat treat
you better so that the abilityto actually deliver on a relief
of suffering becomes better.
And the 2 of these thingsinterplay. Mental illness is in
a really unique place in termsof medicine and and in terms of
(23:52):
our experience as people. Mostpeople with diabetes don't talk
about coming off their insulin.When they think about their
diabetes, they think about it asa biological state that can be
diagnosed and for which there isa treatment. And yet a lot of
people, and this is part of thestigma in depression, wanna come
(24:13):
off their medication becausethat understanding is not really
there.
So bringing a test to tell us,to tell the patient, to tell the
provider, here's what's going onand here's what you could do
about it in a new and moreeffective way, that has to
decrease stigma. That has tobring more people into
treatment. And I think if we canbend the curve in terms of
(24:35):
suicide rates, in terms of thesocietal impact of depression,
we'd have done a lot of good.
Dr. Moira Gunn (24:42):
Well, needless to say, while your your drugs
are on their way to beingapproved at some point, you're
gonna get it right somehow. Ifyou get a drug from Alto
Neuroscience, you gotta take atest.
Dr. Amit Etkin (24:54):
That's right. There is no escaping it. We've
just simply gotta know whatwe're doing to do it better.
Dr. Moira Gunn (24:59):
Well, doctor Etkin, thank you so much for
joining us. I hope you come backto see us again.
Dr. Amit Etkin (25:04):
It was my pleasure.
Dr. Moira Gunn (25:06):
Doctor Amit Etkin is the founder and CEO of
Alto Neuroscience. Moreinformation is available on the
web at altoneuroscience.com. ForTechnation, I'm Moira Gunn.
Major depressive disorder, serious depression,
PTSD, challenging medicalconditions for which successful
treatment is usually a matter oftrial and error, of seeking,
waiting, and hoping for success.It's not surprising to find
biopharmaceutical companiesworking on new efforts in this
(00:39):
field. But what is surprising isone company's approach. Doctor
Amit Etkin is the founder andCEO of Alto Neuroscience, a
neuroscientist and psychiatrist.He's a member of the faculty at
Stanford University.
In both his university researchand at Alto Neuroscience, it is
(01:00):
not just the compliment of drugsbeing developed, which are
innovative. What is key is eachpatient's underlying biology.
And now, doctor Etkin. Well,doctor Etkin, welcome to the
program.
Dr. Amit Etkin (01:13):
It's a pleasure to be here. Looking forward to
our discussion.
Dr. Moira Gunn (01:16):
Well, from the outset of this interview, I want
listeners to know that we havesome first here. What we're
talking about is not justanother shot on goal, but a very
different approach to majordepressive disorder, which you
might know as clinicaldepression, serious depression,
as well as PTSD. So what you'rehearing will be some significant
(01:41):
firsts, that you have not heardbefore. So let's start with
major depressive disorder andPTSD. You're studying them
together.
From the experience of theperson who suffers, what's the
difference and where are theythe same?
Dr. Amit Etkin (01:57):
So with depression, which people just in
their day to day lives may havea general sense of, with
depression, we think aboutthings like not only low mood,
lack of motivation, but alsochanges in appetite, changes in
attention, in sleep, a lot ofthings moving together.
(02:18):
Sometimes those come out of theblue. Sometimes a person has had
depression before and gottenbetter and then relapses, and
sometimes that's related totrauma they experienced. And
that's where things start toshade into this commonality
between depression and posttraumatic stress disorder or
PTSD. Often, I think in popularculture, people associate PTSD
(02:40):
with veterans in combat.
But actually, having a severetrauma, life threatening event
can lead to feelings of ofdetachment and fear and
depression and and kind of thisarousal where you just have to
watch your environment the wholetime, and quite often comes with
(03:01):
all of those things that weassociate with clinical
depression itself, except inPTSD, it's the trauma that
clearly caused this. Indepression, a portion of
depression is caused by trauma.In fact, people after a trauma,
if they develop a psychiatriccondition, pretty much equally
go on to develop depression orPTSD. So so you can think of
(03:23):
these things as from a symptomand experience perspective, a
spectrum of illness. What wewanted to do in trying to
understand these conditions, andeven though our primary focus is
on depression, is to understandwhat is the range of people who
are out there and seeking help?
How does the biology that we areleveraging give us insight on
(03:46):
that whole spectrum rather thanvery narrowly defining the
population we're trying tounderstand.
Dr. Moira Gunn (03:52):
Typically, people who suffer from these
symptoms go to their doctors andfrom these external symptoms or
personally perceived symptoms,they're prescribed
antidepressants. Sometimes theyhave to keep switching medicines
until they find one that works.And as a Stanford University
(04:13):
professor and researcher, andnow as founder and CEO of Alto
Neuroscience, You think thatcould be different. How?
Dr. Amit Etkin (04:22):
That's a great question. And I think we have to
start by understanding how bigthis problem is. So depression
is the most disabling conditionacross all of medicine across
the world. You'll see it onaverage in around 6 or 7 percent
of people as a whole, and thepandemic has only made that
worse. So when you look at howbig the problem is and now you
(04:46):
look at the tools we have toleverage, there's a few really
critical things in there.
So we do have a lot of drugs,but a lot of the drugs are very
similar. And exactly as yousaid, it's a lot of guesswork
because we don't know what willwork for each person. What we
don't have any of is any teststhat tell us about any aspect of
the biology of the patient thatcould be used to guide what it
(05:09):
is that's really driving theirdepression or for that matter
any psychiatric disorder. Andhow do I use that information to
prescribe a drug that willactually work for them, will
work faster, and will workbetter? And that's the
frustration that patientsexperience as a psychiatrist and
a clinician.
I experience in trying to treatthe, patients is that it's just
(05:32):
guesswork. And the worst partabout that guesswork is that it
takes months to find out if thedrug worked for them. And if it
didn't, you start all over againwith a brand new drug, and that
has consequences. You know, youhave a high rate of suicide with
depression. There's all theimpact on the person, on their
(05:53):
family, on their work, onsociety.
The cost of mental illness ingeneral is really, really high.
It's the biggest driver of costfor insurance in the United
States, for example. And so it'sa bit shocking when you look at
where the state of medicine isin, you know, now, 2022, 2023,
(06:16):
where we should be sosophisticated, and yet we're
still treating our patients muchlike we did in the 19 eighties.
Dr. Moira Gunn (06:24):
Now how do we measure depression? I mean,
we're looking for measures, buthow do you measure it? We don't
have a depression, organ that wecan just, you know, take a blood
test and see how it's operating.
Dr. Amit Etkin (06:38):
Exactly right. But we do know a few things. So
we know that that subjectiveexperience of depression is
important. We never want todiminish that. That's critical
to how a person experiencesthemselves and what drives their
dysfunction as they try to livetheir lives.
But we also know that the brainin generating these feelings and
(07:01):
driving psychiatric disease hasattributes that you can measure
that link to our concept of whatdepression is. For example, when
you talk about motivation, whenyou talk about appetite, when
you talk about sleep, all ofthese things can be grounded in
measures. So we use behavioraltests, for example, of of
(07:24):
cognition, of attention, anddecision making, and memory. We
use other tests of emotional,biases and how you deal with a
reward and how much motivationthat gives you in driving your
activity. We measure your sleepand your circadian rhythms using
a wearable device like tens or100 of millions of people have
(07:47):
just as they walk around everyday, it's generating
information.
And we also measure how theirbrain functions directly. We do
that with a tool called EEG orelectroencephalography, which is
known as brainwave recordingsmore commonly, and that tells us
about how active orinterconnected different parts
of the brain are. So we can useall of the neuroscience that
(08:11):
we've been doing a lot ofresearch on when I was a
professor at Stanford, had a biglab doing this, and the field as
a whole doing this for years,and leverage that information
about how people's brains workin different parts and different
functions in those brainsagainst what it what it is in a
(08:31):
clinical syndrome and how it'sexperienced by the patient.
Dr. Moira Gunn (08:35):
You put all that data together and you start to
see the person. You're not justsaying, well, try this drug.
People must break down intovarious subgroups. It's not a
fishing expedition anymore.
Dr. Amit Etkin (08:51):
There turns out to be a lot that we know, and
actually that's something wecapitalize on. There's a lot
that we know that we can measurethat's reliable. So if you take
the test now, it'll yield thesame result as if you take it 3
months from now. So it'smeaningful, it's reliable, that
can characterize people. And andit's important in all of this to
(09:11):
understand that a lot of thesethings we talked, for example,
about about attention and andcognition and about appetite and
and sleep and these sorts ofthings, it turns out people
can't introspect and give youaccurate information on.
I mean, trivially, let's thinkabout, could you tell me what
your sleep stages were like andwhat different parts of your
(09:34):
sleep architecture was if you'reasleep? Well, obviously, that's
going to be hard to report on.But even something like
cognition, you you the way youdeploy your attention and you
can we can turn things on andturn things off and avoid
distraction, remember things,you know, deploying memory,
understanding how to makedecisions in a better, more
(09:57):
balanced way. It seems like youought to be able to report on
these things. But it turns outwhen you actually test these
things using objective measures,computerized tests, EEGs, and
the like, that you getinformation that the person
simply can't tell you, becausethat information is just not
really accessible to them.
(10:19):
It's by putting that togetherwith the drugs that we're
developing, that I think thereally exciting steps are taken.
To be clear, our history inpsychiatry is developing drug
after drug with no idea of whowe're giving it to, and
literally throwing spaghettiagainst the wall and hoping
something sticks. And the vastmajority of the time, 94% of the
(10:41):
time, it fails. On the otherhand, we have all these tests,
but a test by itself, well, itcan tell you something, but it
tell it doesn't tell you whatyou're going to need to do about
that. So as a physician, that'sreally not all that useful to
me.
It's by combining a drug with atest. With a test is for whether
(11:02):
you'll respond to the drug. Thatis how I think we're making
progress in understanding thedisease and even more
importantly in treating thedisease.
Dr. Moira Gunn (11:13):
I have to say that frequently when I speak
with people who are developingdrugs, they'll say, we have a
test, which is great, which isgreat. You don't just have a
test. I'm looking at this data,such disparate data. You know,
sleeping and cognition and andeverything else. It's like you
(11:36):
got a lot of data here.
How do you possibly put thattogether for an individual and
how do you possibly put thattogether looking at all the data
you have for everyone which isbound to tell you something else
in addition.
Dr. Amit Etkin (11:51):
That's right. So it's not just, of course, a
little bit of data that yougather on a person, it's how
that comes into the context of alot of data that we gathered on
a lot of people and understandthings like, what does that mean
for how they respond to anexisting treatment? What does
that mean for the diagnosis ofone diagnosis versus another or
(12:12):
the risk of developing somethingover time. It's in that context
that we learn a lot and whatwe've learned, and this gets
reinforced in how we develop ourdrugs, is that there's certain
areas that you can quantifyreadily. So cognition is a is a
really good one, or sleep andand circadian rhythms is
another, and and emotionalprocessing, things that are
(12:35):
negative and sort of in relatedto a state of high anxiety or
things that ought to bemotivating but aren't
sufficiently that are related tolack of pleasure and hedonia.
All of these things can definedimensions of function and
dysfunction in people's brainsthat characterize smaller groups
of people within this really bigbroad diagnosis of depression
(12:59):
that tells us somethingmeaningful about them. What is
going on in their brain that iscompletely 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 thesesmall groups to then find which
drugs best speak to that area ofdysfunction, and then develop
(13:23):
those drugs in those smallergroups. To be clear, our goal is
not to develop a drug for all ofdepression. We think that there
are many different depressions,and that relates to different
biology.
That biology can be measured andscaled so we can do this in a
clinically feasible large scaleway, and that biology should
(13:48):
line up with a treatment thataddresses what's going on in a
much more effective manner.
Dr. Moira Gunn (13:53):
Now Alto has 11 drugs in the pipeline. We can't
possibly get to them all. I dowanna talk about your most
advanced drug known as Alto 100because you've got data, phase
2a data, your first phase 2study for people suffering from
major depressive disorder and orPTSD, first, tell us about the
(14:16):
study and tell us what youfound.
Dr. Amit Etkin (14:19):
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 thebrain to be flexible and take in
new information, works betterfor those people where we
thought plasticity was low. Andthat is people with poor
cognition and low mood. And sowe set up a study with several
(14:44):
100 people where we couldanalyze the data as we go, where
everybody's getting the drug.And so the question is, does it
work better for people withworse cognition relative to
better cognition? And can wefind that in such a way that
gives us a lot of confidence?
We can replicate that over andover so that we know now when we
(15:05):
go to test the drug againstplacebo, that we have an idea of
the people for whom it's goodfor, that that's a very
different approach to the usualapproach when you're testing
drugs, which is just give it toeverybody. And to be frank, hope
that it works without any realidea of why it would work and
for whom it might work beforeyou ever do this test.
Dr. Moira Gunn (15:29):
You could get this positive response and say,
good enough. We're gonna throwit into the mix with all the
others, and they can try this oneverybody as well. It's like,
no. That's not what you're doinghere, which is another first.
Dr. Amit Etkin (15:42):
Exactly. So the the use, of an objective test we
talked about the lack ofobjective tests in psychiatry.
The use of an objective test totell you who responds better and
who doesn't, that's reallysomething that's been missing in
the field of psychiatry and isthe centerpiece for our
approach. There is no drug inour mind that doesn't have a
(16:04):
test. And likewise, there is notest without a drug.
These two things have to gotogether. And this is really the
first study finding that kind ofan objective test. One that
could be scaled to millions ofpeople relatively easily,
actually, to identify who it is.And it turns out in a way that
(16:24):
you can't just ask them, hey.How's your cognition?
You have to do that test.
Dr. Moira Gunn (16:30):
Now you did mention placebo. I just wanna go
down the science just a littlemore. You've determined that
with low cognition peoplesuffering from depression that
they responded much better. Mynotes here say 80% response.
And, you know, we're talkingabout we know the measures
you're taking.
(16:50):
Let's stick with the sciencehere. On this particular drug,
alto 100, and this drug alone,what do you study next now that
you see that?
Dr. Amit Etkin (17:02):
There's a couple of interesting directions that
this is going to go. So thefirst one that's happening now
is a randomized trial wherewe're giving the drug to people
or placebo and trying to see ifin fact there is a bigger
response in poor cognition, andwe're including both people with
and without poor cognition. Andso that way we can really
compare and contrast them. Butthe other opportunity that this
(17:26):
drug and the the test give youis something that has not
happened in psychiatry before,which is now you have the
biology of the person that youcan measure, you have the action
of the drug, and it's not justin depression that we see poor
cognition, we see it across theboard. And a lot of other
disorders including those thatmight be completely separate.
I mean, schizophrenia you maynot think of as overlapping with
(17:50):
depression, but the level ofcognitive impairment in those
poor cognition depressedpatients is actually similar to
what we see in schizophrenia,where we think cognitive
impairment is actually a bigpart of the clinical picture.
And so having a test with a drugand that leading to a better
response starts to open up theaperture on what's possible in
(18:12):
psychiatry and allows us to go alot faster in developing and
deploying drugs than you couldif you just randomly threw it
against different populations.
Dr. Moira Gunn (18:22):
Now I'm just gonna even though you have 11
drugs, I'm gonna just ask youquickly about another one that
you have, a different drug, Alto300, and it's currently in a
study. And we'll see someresults in the late spring,
early summer. And this is aphase 2 study. How is that study
(18:42):
different? How is that drugdifferent?
Dr. Amit Etkin (18:45):
So the study as a whole is similar in that we're
studying depression, and we'retrying to understand for whom is
that the right drug. But thedrug works in a different way.
It works on circadian rhythmsand works on sleep. And so the
expectation is that the signal,the test, that will predict who
best responds to that drug isdifferent from ALTA 100. And you
(19:06):
can then imagine, well, ifthat's the case, there's an even
more exciting outcome at the endof this.
Because if you can now advance 2drugs roughly the same time that
work in new and distinct waysfor different populations, each
with their own tests that maybedoesn't overlap at all or only
partially overlaps, you can nowmuch more effectively address a
(19:28):
much larger segment of thedepressed population by giving
them a test with a aligned drugand having multiple options,
multiple tests, multiple drugsthat all should work better.
That's a pretty exciting future.I mean, for me as a as a
psychiatrist and as aneuroscientist, it's really the
coming together of these twoaspects of my own experience and
(19:52):
training to really see clinicalchange by understanding the
brain and and finally collectconnecting these dots in terms
of how understanding the brainleads to actually better
treatments in the near term.
Dr. Moira Gunn (20:06):
Now I do wanna say, you know, we're we're
extremely grateful for all theantidepressants out there today.
In fact, we may be able todevelop tests for them in the
future to see where where dothey work, take the guesswork
out of them. I guess I guess thethe mantra here is, it's a
(20:26):
question of matching the rightperson with the right drug and
not just for depression.
Dr. Amit Etkin (20:32):
That's right. So, you know, we've talked about
it from the lens of psychiatrywhere this is a first. But
there's other areas of medicinethat actually teach us that this
is the right path to go downbecause they've been going down
this path for years. So oneexample for that is, a drug
called Keytruda, which is a drugto treat cancer and and actually
(20:55):
many different kinds of cancer.And that drug was about to be
shelved in much the way that alot of psychiatric drugs are
shelved, which is they triedthey tried it on a very broad
population, and it really didn'twork.
And so they said, well, you knowwhat? I don't think this really
has a future. But then throughadditional research, people
(21:16):
realized, actually, you canidentify a small group of
patients for whom it worksextraordinarily well. You know,
we talked about the 80% responsein that, subgroup within the
ALTA 100 study, similar concept.And it turns out when you grab
on to that test and thatinsight, you can now start
deploying the drug, in thatcase, KEYTRUDA, but we've seen
(21:38):
it in other drugs as well, muchmore effectively across a
variety of different tumors,just like we think of a variety
of different psychiatricdisorders as benefiting from a
drug that gets at a mechanismthat you could test for.
So that really bright futurethat's already being realized in
cancer therapeutics, that'swhere we wanna go soon in
(22:01):
psychiatry by doing itdifferently and and really
taking a page out of areas likeoncology.
Dr. Moira Gunn (22:07):
I understand that many people with
depression, they don't wannatalk about it. They don't even
wanna talk about the fact thatmaybe taking antidepressants.
There are also other people whodon't wanna talk about it so
much they're not gonna seektreatment. There's almost a
stigma to it today.
Dr. Amit Etkin (22:26):
There's a stigma in a couple of different and
really important ways inpsychiatry. So it turns out that
half of depressed patientsaren't even in care. So we
talked about 6 or 7% of peoplehave depression at any given
time. Only half of them areactually getting treatment,
which means the other half aresuffering, and and that can lead
to a range of problems andobviously suicide is a really
(22:48):
big one. As a public healthissue, it's critical that we
find a way to bring those otherpeople into treatment as well as
treat them more effectively.
One of the things that I thinkis holding back psychiatry is
what we started to talk about atthe beginning that it feels like
you're just throwing randomthings at a patient. You don't
really know what works and thatgets everybody frustrated and
(23:10):
and actually oftentimes even thepeople who seek treatment might
drop out of treatment. I thinkthat there's a an interesting
potential here for this approachof pairing a test with a drug,
and that we can talk about thatbiology in objective terms that
takes away stigma from havingdepression or any psychiatric
(23:31):
disorder. It's not just quoteunquote in your head, it's
something we can measure. And bymeasuring it, we can treat treat
you better so that the abilityto actually deliver on a relief
of suffering becomes better.
And the 2 of these thingsinterplay. Mental illness is in
a really unique place in termsof medicine and and in terms of
(23:52):
our experience as people. Mostpeople with diabetes don't talk
about coming off their insulin.When they think about their
diabetes, they think about it asa biological state that can be
diagnosed and for which there isa treatment. And yet a lot of
people, and this is part of thestigma in depression, wanna come
(24:13):
off their medication becausethat understanding is not really
there.
So bringing a test to tell us,to tell the patient, to tell the
provider, here's what's going onand here's what you could do
about it in a new and moreeffective way, that has to
decrease stigma. That has tobring more people into
treatment. And I think if we canbend the curve in terms of
(24:35):
suicide rates, in terms of thesocietal impact of depression,
we'd have done a lot of good.
Dr. Moira Gunn (24:42):
Well, needless to say, while your your drugs
are on their way to beingapproved at some point, you're
gonna get it right somehow. Ifyou get a drug from Alto
Neuroscience, you gotta take atest.
Dr. Amit Etkin (24:54):
That's right. There is no escaping it. We've
just simply gotta know whatwe're doing to do it better.
Dr. Moira Gunn (24:59):
Well, doctor Etkin, thank you so much for
joining us. I hope you come backto see us again.
Dr. Amit Etkin (25:04):
It was my pleasure.
Dr. Moira Gunn (25:06):
Doctor Amit Etkin is the founder and CEO of
Alto Neuroscience. Moreinformation is available on the
web at altoneuroscience.com. ForTechnation, I'm Moira Gunn.
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