Ashley: Hey there, Ashley here. I'm currently off gallivanting
in Denver at Podcast Movement, so I'm re-releasing this very popular
episode that dropped back in 2021. Chances are, you've never heard it before,
but even if you have, it's worth hearing again, not just because the stuff that Dr. Sanacora has to say is only getting
more important, but also because it's fully remastered with fancy
AI audio tools — thanks Descript! — so it's a much better listen. Seriously, if you're curious,
check ou
t the original in the feed and then listen to this one. The difference is pretty dramatic. And if you're watching on YouTube, hi! I didn't record video for this back in
the day, so you're gonna get an audiogram. I made it as fancy as I could for you. Hope you like it. I'll be back at the end to see you off. For now on with the show. I used to think that
depression was easy to spot. I mean, I knew that people with
depression were sad and they'd start to skip their favorite
activities to stay in b
ed all day. They'd basically just
shut off from the world. But it turns out that depression is
so much more complicated than that. Like, depression can make
it hard to concentrate. You can be going to work every day like
you always do, but you just start to forget things and make silly mistakes. Some people, particularly older people,
they might even fall more frequently because they're not paying attention. Depression can make you angry. If you feel hopeless on the
inside, you might lay the bla
me with others and that can make you
lash out at friends and family. And depression can hurt. Studies have shown that
people with depression have a decreased tolerance for pain. Your head, your joints, and your whole
body might just feel worse overall. And just like there are a lot of different
symptoms of depression, there are also a lot of different causes, causes that
scientists haven't fully untangled. In fact, depression is
still a pretty big mystery. We can't fully explain why it happens,
what's going on in the brain when it does happen, or how exactly
therapies and medications help. But one thing we do know is that
they do help and that our treatments for depression are getting better
all the time, despite the fact that those treatments can come
from some pretty strange places. Today we're gonna talk about what we
do and don't know about depression, why not knowing is actually
okay, and why hallucinogens are making their way into the clinic. I'm Ashley Hamer, and
this is Taboo S
cience. The podcast that answers the
questions you're not allowed to ask. Depression is incredibly common. Scarily common. Like more than 260 million people
worldwide are affected by depression. So you'd think this would
be an easy thing to answer. What is depression? Gerard Sanacora: That is
actually a very good question. Ashley: That's Dr. Gerard Sanacora. He's the director of the Yale Depression
Research Program and co-director of the Yale Interventional Psychiatry Service. And to him, the qu
estion isn't so much
what depression is as what it isn't. Gerard Sanacora: Depression is an
interesting thing that is actually what we call a diagnosis of exclusion. So in medicine that means that
you have a set of symptoms, signs, and we can't find an explanation. So for depression, it's typically a set
of nine core symptoms related to sleep, appetite, mood, concentration, zest for
life, willingness to to live related to those general categories that affect your
cognition, perception, emotions,
and we can't find another explanation for it. So in other words, we can't find
an endocrinological problem such as hypothyroidism, or we don't find
another neurologic disorder such as Parkinsonism, that could be related. Ashley: According to the latest edition
of the Diagnostic and Statistical Manual of Mental Disorders, or the DSM
V, these are the things the symptoms can't be caused by in order for it
to be categorized as depression: They can't be caused by a
medication or drug abuse. They can
't be caused by another
medical condition, and they can't be linked with manic episodes or
better explained by other psychotic disorders like schizophrenia. Up until 2013, they also couldn't
be explained by bereavement after the loss of a loved one. But the DSM V removed
that as an exclusion. That's because grief doesn't
exactly protect you from depression, and it can sometimes lead to it. Do we know what does cause it, then? Gerard Sanacora: I think the
big question is, is it an it? Which you s
aid did what causes it. It's probably many different
pathophysiological pathways to get to what we call depression. There's probably many different
pathophysiologies, actually, physical changes in brain structure
function that we call depression. So it's very unlikely that it's a
single illness or a single disease. It's, it's a disorder that probably
is what we call heterogeneous, meaning there's many different
ways you can get that diagnosis. Ashley: Yeah, that, that strikes me as
strange becau
se you did just say that if it's something that we know isn't
endocrine and it isn't like it isn't these other things, but it sounds like
it could be a lot of different things. Gerard Sanacora: Exactly. So we can tell you — that's what
a diagnosis of exclusion is — we can tell you what it isn't, but
we can't tell you what it's, Ashley: There are a few risk factors
we know can lead to depression, though. Stress at home or at work, a
traumatic event, isolation, and other stressors can all have an
effect. Chronic pain and other ongoing medical
symptoms can lead to depression. And then of course, there
are the biological factors. Your brain chemistry, your genetics,
and even your personality can all influence your risk of depression. So if depression can be caused by lots
of different things, both in your life and in your brain, how do we fix it? Gerard Sanacora: For the past
five or six decades, the primary types of treatment has been either
talk therapy or antidepressant therapies, for
the most part. There are neuromodulatory therapies
and other types of the that's used there too, but those are the
predominant, especially as a first step in the treatment of depression. Ashley: Right. And there are a lot of different types
of antidepressants, I understand. Gerard Sanacora: So, yes and no. There are a lot of different
antidepressant or, you know, we're talking about oral antidepressant medications. So there are a lot of
individual different ones. There are well over two dozen
ap
proved antidepressants, but they do generally tend to fall
in one of a few small categories. The monoaminergic medicines are the
ones that go back the furthest, uh, of the ones that we currently use. The monoamine oxidase inhibiting drugs. Or the tricyclic antidepressant drugs. Those really target primarily
norepinephrine, serotonin. Ashley: That was a lot of big words. So let's back up. Monoaminergic medicines target monoamines,
which is just an umbrella term for dopamine, serotonin, and norepi
nephrine. Those are the brain chemicals
that are thought to be involved in depression, specifically when
you've got low levels of them. It's the job of these chemicals to
help brain cells communicate with one another, and when there isn't enough of
them, those signals can't get through. So then monoamine oxidase inhibitor
drugs block an enzyme called monoamine oxidase, which is responsible for
coming in and cleaning up any leftover monoamines once they've done their job. By blocking the enzyme,
the drug
is believed to keep levels of those feel-good chemicals high. Tricyclic antidepressants do something
similar just in a different way. They keep some of these chemicals,
mostly norepinephrine, from being reabsorbed into nerve cells. Like Dr. Sanacora said, these are the
drugs that go back the farthest. They've also got a lot of side effects. So these days, they're not
the first choice for someone who's new to antidepressants. We've got more options these days. Gerard Sanacora: And then t
he SSRIs
that many people heard of that were developed later, the Prozacs and
others in that class, uh, are the selective serotonin reuptake inhibitors. Ashley: Selective serotonin
re-uptake inhibitors or SSRIs inhibit the re-uptake of serotonin. Or to put it another way, they keep nerve
cells from reabsorbing serotonin in order to maintain high levels in the brain. This sounds a little bit like
those tricyclic antidepressants, but these are different. For one thing, tricyclics mostly
work on no
repinephrine and SSRIs mostly work on serotonin. And SSRIs are a lot more precise
than tricyclic antidepressants. They're better at targeting the receptors
that are important rather than just hitting receptors all over the body
and causing unpleasant side effects. Prozac is one kind of SSRI. Gerard Sanacora: So most of those drugs
and even many of the versions that have followed after that really are drugs that
either target norepinephrine or serotonin. Uh, and that is the large majority
of the
medications out there. There are a few other smaller
classes that are beginning to develop that actually are targeting
different neurotransmitter systems and different mechanisms of action. Ashley: So do these drugs work? Gerard Sanacora: This is a a little
bit of a loaded question 'cause in fact they are quite effective. The medicines do tend to work very well. The struggle is that placebo
also works fairly well too in the treatment of depression. And it works fairly well in the
treatment of a
lot of different disorders, even outside of psychiatry. So I personally don't
like the term placebo. Because I think at this point it
is laden with a connotation of sort of, it shouldn't have an effect. It, it's sort of a trick or
something we're, you know, giving that shouldn't have, have benefit. I think the term that is
more appropriately used is a non-specific effect. So we know that, for example, a diet,
if you start somebody on a diet besides the diet, they start to pay a lot
more attentio
n to what they're eating. They start to increase exercise,
they start to do a lot of other things that is in addition. It's non-specific to the
type of diet that you give. It's very much like that with
medications or, or any treatment. Once you start to get involved in
the treatment, it's not just the pill you're taking and, and even the pill
itself has years of conditioning. So we learn that if we take a
pill, our headache goes away. So the next time we have a headache, even
just the simple act
of seeking anything, we're conditioned to have that belief
that our headache is gonna go away. So you become conditioned to
certain things are gonna work. So that's part of a placebo response,
but there are many other parts of that placebo response that have big effects. Like you start to pay more
attention to your emotions. You start to think about things
differently, and you start to see a therapist or a doctor, so somebody
else that is now you can share your concerns and thoughts with. So it
's a lot more involved than
taking a medicine or or any form of medical treatment than the simple,
specific effect of the drug or the surgery or whatever you're getting it. So it's all those non-specific effects
and they're incredibly powerful. The medicines work quite well if you would
just look at people that took medicine and people that didn't take medicine, but. It's called a wait list type approach
where you look at people that started on treatment, people that don't. Where it becomes more
difficult to
reliably show a difference is when you have a treatment used against the placebo. Because the non-specific effects are
so large, you need large sample sizes to really show how much benefit the
drug has over the non-specific effects. The danger is, I, I really do try
to make clear, is that you don't get the non-specific effects unless
you take the drug in many cases, or unless you take the treatment. Whether it's a drug, whether it's a
talk therapy, whether it's whatever. You can't
really extract one from the
other so clearly, and that, that's where things get very complicated. Ashley: Got it. So when someone just sees the
headline that, antidepressants work about the same as placebo,
there's a lot more going on there. It's much more complicated than
you just think like, oh, that just means it doesn't work. Like that's not what it means. Gerard Sanacora: Exactly. And that's where the, there's
a miscommunication or, or it could be misleading. And it, it's very important and
,
and I don't think too many people spend nearly as much time as I do
and others looking at this issue. So if you just hear that, I think it's
a natural response to say, oh, well if it doesn't work much better than
placebo, then it doesn't work very well. But that's not really what it means. Ashley: But it does seem like with some
drugs, I don't know, for heart conditions, it's like you give the drug and most
people have about the same reaction. Maybe. Maybe I'm oversimplifying, but —
Gerard San
acora: I think
you're oversimplifying much more than you think you are. Ashley: Really. Well, yeah. I mean, I guess that's
like the perception, right? Gerard Sanacora: Yeah. And, and I think that's
a, a misperception. There are relatively high placebo
response rates for antihypertensives. There, there are relatively high
sham response rates to surgeries like, uh, orthopedic surgeries. The non-specific effects go well beyond
what we typically think of in depression. Even things like Parkinson's d
isease,
which you wouldn't imagine would have big non-specific effects is notorious
for very large placebo effects. Ashley: Dr. Sanacora says that even the
experience some people have with antidepressants where they need
to try many different kinds before they find one that works for them. That's pretty similar to
hypertension medications. People usually start on say, a diuretic,
and if that doesn't work, they'll try a beta blocker and on and on. Gerard Sanacora: It's very common,
especially in
the treatment of hypertension is a good example of that. So the treatment of depression
isn't so unique in that way. Ashley: But antidepressants like these
aren't the only options out there. Recently, research has demonstrated real
promise for some drugs that I, for one, was told to stay away from in DARE class. You study a bunch of different
therapies for depression, and one of those is ketamine. Like when I first heard that people were
using ketamine to treat depression, I was like, how could
that possibly work? Like, that's like a street drug, right? How does that work? Gerard Sanacora: So ketamine was
originally an anesthetic agent. It was, uh, a major breakthrough
in the field of anesthesia. It was actually FDA approved in
1970, for, as the use of anesthetic. It really gained a lot of prominence
'cause it's a relatively safe anesthetic that could be used in
situations where you weren't able to monitor patients as closely. So in field hospitals, it became
very popular in third worl
d countries, it's still a critical
drug as the use of an anesthetic. And it's, even in the US, it's used
commonly in pediatric anesthesia or emergency rooms where you need
a quick, uh, use of an anesthetic. If you're wondering why someone
would use an anesthetic illegally, well, it's because ketamine works by
putting people in a dissociative state that detaches them from any pain. You can see how that might be desirable
outside of the operating room. And that's before you get to
its hallucinogen
ic effects. Again, the lay person may look at
this as kind of a street drug, but it has a 50 year history of being
considered a critical drug to the world by the World Health Organization. So this is a long medical history,
but it still is a pretty unique story that this anesthetic drug
would have antidepressant effects. Ashley: Yeah. And so how, why does it
have antidepressant effects? Gerard Sanacora: So, I, I wish
I could tell you exactly why. I can tell you what we,
why we think it does. And
I can tell you why
it was initially tested. There was increasing evidence
really towards the end of the last millennium, in the 1990s or so, that
the neurobiology of depression was much more involved than that idea of
a chemical imbalance, or that there was low serotonin, low norepinephrine
levels, which is really where the thinking was in the 1980s, 1990s. And we started to realize that the
brain was much more complex and there was many other neurotransmitter systems
that were involved and als
o that the plasticity of the brain, the way the
brain connects to change and adapt to different environments and different,
uh, events in life was very important. And there became increasing evidence
that parts of the brain that were predominantly using glutamate, which is
the major neurotransmitter in the brain. So about 80% of all your neurons,
the cells in your brain use glutamate as its primary communication, you
know, its primary neurotransmitter. So it became increasing that glutamate
and
GABA, which is the major inhibitor of neurotransmitters, that those
two neurotransmitters probably have lot to do with the pathophysiology
of depression, as we said, whatever depression is that broader sense of,
and the ability to modulate plasticity. Ashley: One thing we've learned is
that stress and trauma can actually change the structure of the brain. Animal studies have found that chronic
stress can degrade neurons and parts of the brain responsible for learning,
memory, and executive funct
ion. Those areas are also smaller with fewer
connections in patients with depression. Some of that is probably because
of problems with the neurons that deal with glutamate and GABA. Gerard Sanacora: So it was at that
time some of my colleagues had, the idea, uh, like, uh, John Krystal and
John — Rob Berman and others had the idea that ketamine being a drug that
specifically targets the glutamate system and what's called the NMDA
receptor, which binds to glutamate, the fact that they knew that t
here
was this drug out there that had been used safely for decades had a dramatic
effect on this neurotransmitter system. They really followed a pretty simple
hypothesis that this may have an effect on people with depression. And that was original study done in
the late 1990s, published in 2000, that showed this very rapid onset of effect,
which really was a surprise to everybody. I mean, everybody was interested in
it, but I don't think anybody, and in fact, I am sure none of those primary
auth
ors 'cause they, they make it very clear, thought that they would
see this rapid improvement within hours that would be sustained for
at least days following a treatment. Ashley: Wow. But because it's an anesthetic,
does it, I mean, does it make it so you have, you can't do everyday
activities when you're using it. Gerard Sanacora: So that, that's the
other extremely interesting and important point to make with ketamine, especially
the early studies with ketamine. So it's not given at the level
that
you would use for anesthesia, but it is still given at a level that would
dramatically impair your cognition. So you, you at the dose that is
being used in those original studies, yes, you do need to be monitored
closely and you're not gonna be going about your normal daily activities. But unlike most other antidepressants
where you have to take it all the time, this was something that you
take, and typically an infusion originally was lasting for about
40 minutes and then you stop it. Keta
mine is metabolites very quickly
in your body, so it disappears out of your system pretty rapidly, but then
the antidepressant effect actually builds over time after you stop it. So the majority, the large majority
of that time, you're not on the drug, that you actually get the benefit. Which is again, a novel approach
and really a completely new finding within the field. Ashley: So is this
becoming more widespread? Are, are, are more people using
this in just like therapy settings? Gerard Sana
cora: So it is growing
dramatically and in 2019, the FDA has approved a version of ketamine, which
is actually esketamine, which is really just half of the natural substance that
occurs in what we call racemic ketamine. It's, uh, just half of what we would
normally find in, in regular ketamine. It was approved for the treatment
of patients with treatment-resistant depression, and then more recently,
uh, in 2020, was actually approved for patients with depression who
also have suicidal ideations.
Ashley: Even though it wasn't FDA approved
until 2019, clinics had been using ketamine to treat depression since 2012. And that wasn't illegal. Instead, it was just yet another
benefit of a drug that had been used for something else for decades. See, these clinics just used ketamine
off-label the way doctors commonly prescribe an anti-seizure medication for
bipolar disorder or how some musicians I know get beta blockers, a type of blood
pressure medication, for stage fright. It's a thing. Using
drugs off-label is legal. It just carries some extra risks since
the FDA hasn't determined that the drug is safe and effective for that off-label use. But that was then. Gerard Sanacora: So it is now an
FDA approved, indicated medicine for depression, but it's not a
medicine for everybody, definitely. And it is still a medicine that requires
relatively close monitoring, especially in the way that it is being given. You know, as of today, and according
to the FDA regulations and guidance. We tal
ked a lot about ketamine as a
game changer, which I really think it was because we were locked into about
50 years of thinking very specifically about how to treat depression, and
either with talk therapies or with oral antidepressant medications that primarily
targeted serotonin, norepinephrine. I mean, there was always the treatments
like ECT that actually predate, electroconvulsive therapy, that
predate even the, the oral medications. Um, but since that time of ketamine,
there's really been a
n explosion of alternative treatments besides
the regular oral antidepressants and, uh, chalk therapies. There's neuro stimulatory therapies like
transcranial magnetic stimulation that has really, uh, become quite popular. There's, uh, vagal nerve simulation. There's even studies with deep brain
stimulation that, that are going on. But then in terms of other pharmacologic
treatments, there are several new lines of interest, but the one that
I think recently has gained a lot of attention and is e
xtremely interesting
to many people is the idea of using drugs, uh, such as psilocybin. Drugs that fall into this general
psychedelic category of drugs. Ashley: Yep. Ketamine isn't the only
dark horse in this race. There's also psilocybin, the
active ingredient in what some call magic mushrooms. Yeah. How does psilocybin help with depression? Do we know that? Gerard Sanacora: So, first of all, we,
I don't think we can say we know that it does help with depression, yet. We're still doing those st
udies. So there are early reports that look very
promising, but I always do emphasize these are early reports and you know, we, we
really still have to demonstrate that this is an effective treatment in depression,
and that really is the first step. And, and that I think many of us
are working, um, very hard to, to determine, uh, what the actual efficacy
and obviously the safety of this treatment would be for depression. In terms of if it does work, how it works,
there are many different hypothe
ses. Uh, I, I think sort of the mainstream
line of thinking about it is that it may work very similar to ketamine. So we think what ketamine would do,
and quite possibly these psychedelic medications I mentioned before, this
idea of neuroplasticity actually altering the way the brain cells
communicate with each other, uh, and actually even structurally altering
the way that brain cells communicate with each other and how they adapt to
novel environments and novel events. And it looks like, just
as ketamine
can have these rapid effects on the neurons' ability to communicate with
each other, it looks like some of these psychedelic type medicines like
psilocybin may have very similar effects. Now, obviously, these are still
hypotheses that need to be tested, and there are other hypotheses. These may have more, more effects that
go well beyond the simple brain chemistry or even the neuroplasticity, uh, in
terms of some of the spiritual side of, uh, these drugs and the other effects
they ma
y have in social relatedness. So there, there are many
different hypotheses. So we really don't know how
any of them work for sure. But we are starting to learn quite a bit. Ashley: Yeah. One thing I've heard is that an idea
might be that it gives you more of a sense of oneness with the world
and takes you out of your own, like focusing in on your own self. And because depression is,
there's a lot of like looking inward that it helps that way. Gerard Sanacora: So that is definitely one
of the hy
potheses that have been proposed. And there's a fair amount of
research looking into that. I don't think any of these
mechanisms are necessarily exclusive. I think the likelihood is that there's
some component of all of these in generating the benefits that are seen. But I do say, yeah, the first part
is we'd have to demonstrate to a high degree of certainty that these
are effective and safe treatments. We're still at that stage, so. Ashley: Here's what I didn't
realize about depression. Just be
cause we don't fully
understand how it works in the brain doesn't mean we can't find
better ways to give people relief. You don't have to know how something
works to know that it does work. Millions of people suffer from depression. And researchers like Dr. Sanacora are constantly making
progress toward more effective treatments, and maybe someday
we'll know how they work so well. Thanks for listening. I'm back in 2023 to read the credits. Thanks a ton to Gerard Kora
for talking to me back in 20
21. He's since done a lot more work on
Ketamine's role in treating depression, and I'll include links to some of that
work in the citations on the website. And if you'd like to hear a really
excellent podcast episode all about ketamine, which also features Dr. Sanacora, definitely check out
the science versus episode about it from April of this year. All include a link in the show notes. Taboo Science is written and
produced by me, Ashley Hamer. The theme was by Danny
Lopatka of D L C Music. Epi
sode music is from Epidemic Sound. If you need music for a project,
just use my referral link in the show notes and it'll help out the show. We've got some really fascinating new
topics coming in the next couple months. I, for one, am really excited. So hit that subscribe button to
make sure you don't miss an episode. And tune in next time. I won't tell anyone.
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