Episode Transcript
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Speaker 1 (00:00):
Hi, I'm Haley. I'm twenty four, and this is my
story with's so looft so. Growing up, I was the
kid who was scared of everything. In sects, people in costumes, heights,
you name it. But beneath all that fear, we're intrusive
thoughts that no one else could see. For instance, my
mom's allergip bees. I was constantly worried that I, rather
rest would get stung and we would die. I tried
(00:22):
to relieve these thoughts through avoidance, skin picking, and checking,
with very minimal relief. I attempted to explain my fears
to pediatricians and school counselors, but I was never given
any real concrete answers. I began to believe this was
just who I was. College is when things began to worsen.
When the pandemic hit in spring of twenty twenty, my
anxiety exploded. I remember obsessively locking my windows and shutting
(00:47):
the blinds, convinced that someone'd break in or try to
bring the virus inside. I was diagnosed with an adjustment
disorder and was even taken off my birth control because
that was believed to beet the issue. Eventually, in the
fall of twenty twenty, I was able to get an
appointment with our head college doctor. She truly listened and said,
I think this might be an anxiety disorder, and she
started me on fifty milligrams as Soloft, and for the
(01:09):
first time, I felt like I could breathe. I had
very minimal side effects, only some sleepiness and some GI
upset for the first two weeks. The next fall, I
began wondering if it might be OCD. I began tracking
my thoughts, looking into patterns, but unfortunately, in the spring
of twenty twenty two, my depression took over. My depression
manifested into intrusive thoughts, telling me to hurt myself, even
(01:31):
though I really didn't want to. I knew something was
really wrong, and so I went back to my head
college doctor. She increased my soul off to one hundred
milligrams and that definitely helped. Still, none of my doctors
felt qualified to diagnose OCD. My pediatrician later admitted she
had suspected it for years. In twenty twenty four, one
(01:51):
year out of college, I finally got my OCD diagnosis
for my current therapist. My new primary caper provider was
really thrilled to hear this and one defy me a
regimen that worked. So typically for OCD, you give the
patient a top dose of their preferred SSRI, but for me,
she kept me on my one hundred milligrams of zolof
(02:12):
and added a dose abuse bar and that worked for me.
In my thoughts got quieter and I was able to
finally start making progress again in my OCD therapy. SSRIs
have truly changed my life. I used to spend every
day fighting my own mind, and now I'm able to
achieve goals that I had set for years, such as
applying to medical school. I'm really lucky to have had
(02:35):
very few side effects and not have to go through
many different medications. I really cannot imagine going back to
a life where I was not on SSRIs. They don't
just help me function, they have given me back my future.
Speaker 2 (02:50):
My name is Sarah, and I started using SSRIs during
my master's degree over ten years ago now. So, while
I was sudying for my masters, I started to experience
really profound anxiety and a lot of obsessive thinking. I
became convinced that I had plagiarized all the work I'd
(03:11):
ever done and that ireparably harmed every person I'd ever encountered,
and I spent all day a lot of days, checking
my work and seeking reassurance or reaching out to apologize
to people for things I imagined i'd done. I was
diagnosed with obsessive compulsive disorder and originally tried to manage
(03:34):
it with just cognitive behavioral therapy, which helped a bit,
but it reached the point where I was very unmanaged
and was having suicidal ideation and thinking I had to
drop out of school. So I began to use an SSRI,
and after the first few weeks when it started to
(03:55):
take effect, I had this amazing experience of that used
to be thoughts that I would obsess over and would
ruin my week because I would spend all of my
time in service of those obsessions. Now, as the SSRIs
kicked in, my brain would just sort of slide off
of those thoughts and I could go on to do
(04:17):
other things that day, and it was really wonderful. So
with that under control, I was able to complete my
master's degree and publish some work from that, and after
several years of being under good control, I've been able
to start studying for my PhD. So I'm very fortunate
that for me, SSRIs have not had substantial negative side
(04:40):
effects and that they've been effective and helpful. And because
of that, I've been able to really enjoy my work
and do research that I think is significant and impactful
for the world, while actually getting joy from that instead
of just anxiety.
Speaker 3 (05:44):
Thank you so much for sharing your first hand account
that it really means. It means the world to us.
It's so important to have that that personal experience to
learn from and to get an insight into how SSRIs
work or don't work, or just the impact that they've had.
Speaker 4 (06:02):
Yeah, it's not something that we can convey by ourselves,
So thank you for sharing with us. And thank you
to everybody who wrote in. I know a lot of
you did, and we really really appreciate everyone's willingness to
just share your story with us. That's not an easy
thing to do and it means so much.
Speaker 3 (06:20):
So it really does.
Speaker 2 (06:21):
Hi.
Speaker 4 (06:22):
I'm Aaron Welsh and I'm Erin aman Updike.
Speaker 3 (06:25):
And this is this podcast will Kill You.
Speaker 4 (06:27):
We're back as promised, we are with part two of SSRIs.
Speaker 3 (06:34):
How do they work? What are they? What is serotonin
besides something that does everything.
Speaker 4 (06:43):
I mean, you told us a lot about that, Aaron,
Let's be honest, but.
Speaker 3 (06:47):
Like I was just like, and it does these things? Yeah?
How does it do those things? Oh?
Speaker 4 (06:51):
I'm not going to get into that, Aaron. Watch this
not be at all what you wanted to learn in
this episode. But that's okay. We're going to have fun regardless.
Speaker 3 (07:00):
I'm a blank slate. I'm happy to learn anything.
Speaker 4 (07:03):
If you we do. If you missed last week's episode,
do check it out. Aaron welshwak just through the history
of serotonin. How did we even figure out it was
a thing? Wow? And how we came up with ssriyes,
and how pharmaceuticals have advertised them.
Speaker 3 (07:22):
Yeah.
Speaker 4 (07:24):
Yeah, And then today we're gonna we're gonna take it
from there.
Speaker 3 (07:27):
Love it short and sweet. But first we are drinking
the same thing that we did last week for our
quarantiny really Placey Brita time the serotonin sprits, serotonin sprints,
apple cider and pineapple juice and soda water and it's
(07:48):
simple and freshing.
Speaker 4 (07:51):
Enjoy it's online.
Speaker 3 (07:53):
Check it out. Check it out. I feel like I've
been forcing you to do the website just by being like,
what do we do now? So I'll do the website.
Speaker 4 (08:02):
Okay, great.
Speaker 3 (08:04):
You can find lots of things on our website This
podcast will kill You dot com. You can find things
related to our sources for each and every one of
our episodes. We've got links to bookshop dot org, affiliate account,
our Goodreads list, links to merch links to Patreon, links
to music by bloodmobile transcripts, a contact us form, and
more things.
Speaker 4 (08:24):
I loved it and I also love when you go
into your like semi.
Speaker 3 (08:28):
Newscasters caster voice. Yeah, I know. My secret dream is
to be like just a voice on the on the TV,
on the documentary and look of a voice actor blah
blah blah. Yeah, wouldn't it be nice?
Speaker 2 (08:40):
Yeah?
Speaker 3 (08:40):
I have a training for that.
Speaker 4 (08:42):
Anyone anyone hiring?
Speaker 3 (08:43):
Yeah, please let me know. Reach out this podcast will
Kill You dot com on the contact us form on
our website.
Speaker 4 (08:52):
If you haven't already rated, reviewed, and subscribed on your
favorite podcast here, are you listening on iHeart Podcasts? Are
you listening on Apple podcasts? Are you listening on Spotify?
Check the subscribe button and make sure that you clicked
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or a review. If you like us. If you don't,
you don't have to do that part. You can unsubscribe.
Speaker 3 (09:13):
In fact, the visuals, just so you know, are very
good for what Erin is currently doing, and so if
you are so inclined, you can see them on YouTube.
If you want to watch the video for these podcast episode.
Speaker 4 (09:27):
You can follow the exactly Right network channel on YouTube.
Speaker 3 (09:30):
Yep, the end.
Speaker 4 (09:32):
Shall we start now?
Speaker 3 (09:33):
I believe that we shall. Okay, take a quick break
and get started.
Speaker 4 (09:37):
Okay, So Erin, Erin, you walked us through last week,
(09:59):
so beautiful about what we know about, like how serotonin,
like where it came from, how long it's been with us,
how we came to find SSRIs intentionally, which is so interesting,
and some of the issues with how we have marketed
them and how we think about in like the popular
media sense, how we think about how they work, which
(10:22):
I think has led to a lot of the controversies
that come with SSRIs today, though there's a lot of
other reasons for that, which I'll get into. So I
want to start by just setting the stage for what
I am actually going to cover today, because it's a
lot of things and not a lot of things at
the same time, huh. I'm tempering expectations. That's what I'm doing.
(10:46):
I will not just end with we don't know how
these work, Okay, Okay, though I will probably still say
that a lot of times as usual. But this is
not an episode where I dive deep into the neurobiology
of depression or anxiety, because those are topics that deserve
their own episodes, definitely, and we'll have them at some point.
(11:08):
I Am not going to get super nitty gritty on
the five HT one A autoreceptor blah blah blah. Like
we're talking. There are so many serotonin receptors and I'm
not gonna I'm not gonna get us, you know, up
to our eyeballs in it. Okay, okay, But my goal
is to give us all a real sense of how
(11:30):
we actually use SSRIs today, Like how are they used
in kind of clinical practice? How are they thought of?
Not in social media circles or political circles or popular
media circles, but how are they thought of by the
medical and scientific communities that use them and that research them.
What do we think that we know about how they
(11:52):
are treating the disorders that we use them for? Are
they effective? And what does that mean.
Speaker 3 (12:00):
What does that mean? Okay?
Speaker 4 (12:02):
Yeah, and then hopefully do a little bit of like
myth busting and a little bit of like grounding of
big picture. How do these conversations that we're having about
SSRIs tell us about the way that we think about
mental health conditions as a society. Oh, small feet ready? Yeah,
So SSRIs, selective serotonin re uptake inhibitors are considered one
(12:26):
of the possible first line therapies for both depressive disorders,
which there are a lot of depressive disorders. There's major
depressive disorder or MDD, but there's others. There's persistent depressive disorder,
there's design yet like there are a lot, Okay, and
also first line one of the possible first line therapies
(12:47):
for anxiety disorders, of which there are many, Generalized anxiety disorder,
Social anxiety disorder PTSD, OCD and more. If anyone listening
needs convince sing as to the importance of these mental
health disorders, the Global Burden of Diseases study from twenty
twenty two, which importantly includes data only up till twenty
(13:11):
nineteen and does not include the massive increase in mental
health disorders worldwide that we saw due to COVID, But
in twenty nineteen, depression and anxiety were top ten causes
of disability adjusted life years in adolescence and adults worldwide.
Self harm behaviors, which often coincide with depression, was the
(13:34):
third leading cause of disability adjusted life years in adolescence
age ten to twenty four. Yeah, gosh, And there's no
evidence that these disorders are decreasing over time. If anything,
they are on the rise. Anxiety disorders and depressive disorders
are estimated to affect three hundred million people each worldwide,
(13:57):
with an estimated lifetime prevalence of depression of close to
twenty percent like lifetime risk.
Speaker 3 (14:04):
Okay.
Speaker 4 (14:06):
In the US in twenty twenty, nearly one in ten
Americans experienced a depressive episode in the last year alone,
and nearly twenty percent of adolescents and young adults experienced one.
But in this study, which looked at like I think
a five year period helps, seeking behavior has not been increasing,
(14:26):
right And in a lot of studies, less than half
of people with depression reported having spoken to any healthcare
professional about their depression or receiving any treatment for their depression.
In Europe, according to the European Psychological Association, Nearly one
in five people is diagnosed with depression at some point
in their lives, so that's pretty much that twenty percent
(14:48):
lifetime prevalence, and they estimate twelve month prevalences of depression
around six percent, and anxiety in the UK is estimated
at around four percent, with worldwide estimates that vary from
like one percent to about six percent. And like I
mentioned last week, depression and anxiety often co occur, and
when they do, it can be more refractory to treatment,
(15:09):
especially when it comes to depression that like overlaps with anxiety.
Speaker 3 (15:13):
When they co occur, it's more challenging to treat. Just
a quick question, can you and maybe you're about to
do this, but define clinical definitions of anxiety depression?
Speaker 4 (15:24):
Yeah, It's it's hard because there are so many specific,
you know, specific disorders that you can define within that, right.
Speaker 3 (15:33):
So maybe what about a depressive episode?
Speaker 4 (15:35):
Yeah, so a major depressive disorder is like would count
as like one depressive episode, right, Okay, and that is
usually at least two weeks of at least all of
a whole bunch of different symptoms. So there's like these
different checklists basically that you go through. So there has
to be disruptions in sleep, which could be sleeping too
little or too much. There's disruptions in your interest or
(15:59):
like what call anhedonia, so not finding interest or pleasure
in things that you used to like to do. There's
energy issues, so you don't have as much energy as
you used to. There's issues with concentration. There's actually feeling depressed,
like having a low mood or maybe crying more easily
than you used to. There's appetite issues, which could be
(16:20):
eating more or eating less than you usually would. Sometimes
we see psychomotor issues, so walking or moving very slowly
or like more rapidly than you used to in the
case of like anxiety for example, okay, and then there
of course can be thoughts of suicide or suicidal ideation
when it comes to anxiety kind of one of the
(16:41):
biggest ones is generalized anxiety disorder, and there's separate criteria there,
but a lot of it comes down to are you
worrying about things like unnecessarily? Are you not able to
sleep or you know, do the things that you need
to because you're up all night worrying, so you're having insomnia?
Are you And what's really important and that's not an
(17:02):
exhaustive list, but there's a bunch of different questionnaires basically
that you go through and you have to score certain
scores in order to meet criteria. But the thing that's
important about all of these, almost all of our mental
health disorders, is that one of the criteria in order
to diagnose them is they have to cause some kind
(17:22):
of functional impairment, which means that the last question on
any of these questionnaires, whether it's an anxiety questionnaire depression questionnaire,
is how much is this How difficult is it making
your life? How difficult is it making you to be
able to do your work, to be able to do
your home life, to be able to do the things
that you need to do right? And that is the
(17:43):
kind of like final criterion. So that's like a very
brief overview of how it's not perfect with us, how
we define a lot of those things. And I've got
papers you could read more. Okay, okay, So full disclosure.
Also because we use SSI eyes for anxiety disorders as
well as depressive disorders, yea. But a lot of the
(18:07):
data on them and a lot of the like mechanistic
looking into how do they work relates to how we
use SSRIs and think about them for depression. So that
is most of what I'm going to talk about, but
I will also mention their use in anxiety, and know
that a lot of the data in terms of like
is it effective or not, how much of a placebo
(18:28):
is there or not, it's also true in anxiety the
numbers might be slightly different, but I'm mostly focusing on
SSRI I use in depression. They're also really important for anxiety.
Speaker 3 (18:38):
Okay, yeah, yeah it is, And I think that's just
probably a historical artifact to some degree. Is that what's
most of the studies have been focused on. And I'm
sure that there's increasing like attention totally other Yeah.
Speaker 4 (18:53):
Well, and yeah, all of them that are kind of
like approved for indications for anxiety, they had to have
those studies in order to be approved for that indication.
So again, the data exists, The data is there, and
I have a bunch of papers that people can read
to do more on it, but I had to be
selective because we only have so.
Speaker 3 (19:10):
Much time.
Speaker 4 (19:12):
And so Aerin last week, you walked us through how
we came up with the idea of using serotonin as
a target, right in large part because we figured out
I never knew it had to do with tuberculosis, but
through the effects of these older what are now often
called first generation antidepressants, the MAOIs and the TCAs, that
(19:35):
that is how we've picked serotonin as a target. The
beneficial effects of those types of antidepressants pointed to this
monoamine hypothesis of depression. And like you told us last week, Aarin,
this is not the cause of depression. Serotonin decreases in
serotonin is not the cause of depression. But it has
(19:57):
led us down the road of understanding a lot more
more about depression than we used to. And because all
of the different antidepressants that we use, including the kind
of what are called atypical antidepressants that are not SSRIs
or SNRIs, all of these, even the new fancy ones
(20:18):
that people are very excited about, like ketamine and like zilocybin,
all of these, to some extent or another, do in
fact modulate some of our monoamine neurotransmitters serotonin, yes, also
nor epinephrine and dopamine. Okay, So clearly there is something
(20:40):
to the fact that these monoamines are involved in depression
and anxiety and modulating these to one degree or another
can help reduce the symptoms of depression and anxiety, even
if we don't quite understand why or how. So to
do a quick recap on what serotonin is so that
(21:00):
you know how it's working in our bodies, I'm gonna
actually take a quick step back and just talk about
the idea of a neurotransmitter because I want to be
able to explain what they're doing in our brains. Yeah, okay,
And we've talked a lot about neurotransmitters on this podcast,
like I've said the word a lot. But let me
recap what these really are. These are compounds. These are
(21:22):
chemicals that we make in a bunch of different parts
of our brain and throughout our body. Serotonin, like ninety
percent of our serotonin we actually produce in our gut,
in neuroendocrine cells in our GI tract.
Speaker 3 (21:32):
What the heck amazing, I know, right.
Speaker 4 (21:35):
But so, neurotransmitters broadly are these chemicals that help to
translate electrical signals in our brain and our peripheral nervous
system into chemical signals that then cross what is called
the sinnaps either between two neurons because there's a gap
at the end of a neuron before it touches another neuron.
(21:57):
There's a gap called a synapse or between a neuron
and say a muscle, right where it's going to have
an effect, and signals are passed in our neurons and
in our brain with electricity essentially, And when these signals
get to the end of a neuron, in order to
cross that gap, that synapse and send the message onwards,
(22:20):
these electric signals have to be transmitted via chemicals. Chemicals
are released, they cross that gap, bind to receptors on
the other side, and whatever neurotransmitter is released and whatever
receptor it binds to sends whatever message it is that
we're trying to send. Is that right? Generalized enough?
Speaker 3 (22:38):
But you gotta have somebody throwing the baseball and someone
catching it.
Speaker 4 (22:43):
Exactly aarin, whay did you go with the baseball? Metaphors
hitting it out of the park, Let them go on. So,
serotonin happens to be a neurotransmitter that is involved in
so many parts of our brain.
Speaker 3 (23:00):
Yeah, and our whole body, our whole bodies.
Speaker 4 (23:03):
But in our brain specifically, it helps to regulate things
like mood, like sleep like, sexual activity, appetite, cognitive function, okay,
And in our peripheral nervous system, it does so many
other things that regulates our gut motility, our visceral sensitivity.
It is part of this gut brain axis that someday
(23:24):
we will have to do. It's also taken up by
our platelets, which is why I got so excited when
you said they saw this clotty stuff. Yeah, serotonin is
involved in our clotting cascade. What so, serotonin is truly everywhere.
Selective serotonin reuptake inhibitors or SSRIs are drugs that bind
(23:46):
to a transporter protein on the presynaptic side. That is
where we are releasing serotonin from on our nerve cells
on our neuron, and this transporter's job is usually to
collect the serotonin after it's been released. The catcher, the catcher, exactly. Wow,
(24:11):
we're gonna keep going the baseball analogy.
Speaker 3 (24:13):
We really don't have to.
Speaker 4 (24:15):
No, I like it.
Speaker 3 (24:15):
The goalie like.
Speaker 4 (24:16):
What, I don't catcher.
Speaker 3 (24:18):
You can only think of sports related things right now
for some reason.
Speaker 4 (24:22):
And the catcher is taking all of these serotonin balls
and putting them back. Maybe it's really like the ball boy. Honestly, Okay, okakay,
that's a catcher, slash ball boy, whatever, yeah, yeah, and
putting them back into our neurons so that the serotonin
can either be recycled broken down by monoamine oxidase, or
(24:43):
it can be recycled like reused again. Okay, I get
a pitching machine exactly. Okay, we'll stop there. I think
that might be the end of it. So what these
(25:11):
drugs do is they bind to these transporters and block
them so we cannot re uptake, repackage this serotonin back
into the presynaptic part of our neurons. What that means
is there is an increase in serotonin in this synaptic space,
this extracellular space. Okay, that is how they work mechanistically,
(25:38):
all right. So the thought was, okay, we're increasing serotonin
in the extracellular space, and that is improving depression. But
like you mentioned aarin, that happens pretty quickly after the
introduction of SSRIs. But the effects that we see in
terms of its improvement these drugs improve on depressive and
(26:01):
anxiety symptoms takes some time, and so that tells us
that it is not just increasing this extracellular amount of serotonin.
There's actually a lot more complicated mechanisms that happen because, surprise, surprise,
our brain is a complex creature. What I know, right,
(26:21):
So what ends up happening is that the parts of
our neuron that usually release serotonin m hm, the picture,
I guess. I know this is really getting out of
control here.
Speaker 3 (26:34):
The pitching machine, the pitching machine, because if it's multiple
little serotonin.
Speaker 4 (26:38):
Balls, okay, it's a pitching machine, our serotonin pitching machine,
it stops doing its job because it's like, hey, there's
plenty of balls out here, right right, So we see
a compensatory down regulation in the serotonin release from these, okay,
And then what we actually see later on is a
(27:00):
post synaptic receptors, the ones who are being flushed with
all of this serotonin. Because there is an increase in
the synaptic serotonin, they also kind of modulate their sensitivity
to that serotonin where they're like, I'm not gonna swing
at every ball. That's a really bad analogy. But the
receptors aren't going to bind to every molecule of serotonin
(27:22):
because there's so much out there. Because there's more out there, okay,
and because our brain is trying to keep things to
some degree homeostatic, it recognizes, Hey, there's been a shift
in something, and we don't want that to get out
of control.
Speaker 3 (27:36):
Okay, Okay, So what happens with SSRIs is that there's
a ton of serotonin just flooded into that intersynaptic space,
and then which go ahead.
Speaker 4 (27:48):
Well, and it's not that it's like a ton. There
is an increase in serotonin, but it's because the serotonin
that's there already lingers for longer and can't be scooped
back up.
Speaker 3 (27:59):
Okay.
Speaker 4 (28:00):
And then because of that, you would think that, oh,
the pitching machine just keeps throwing out more serotonin. Then
you have a huge increase, but we don't actually see
that stops.
Speaker 3 (28:07):
It just kind of compensates, flows down increase exactly. And
then the catcher or whoever's hitting or whatever is like,
I'm not going to swing at every ball.
Speaker 4 (28:17):
Now, right exactly, I'm not going to Okay.
Speaker 3 (28:18):
So it's like then that's interesting. Okay. So a couple
of questions, Okay, how more oh before we go there? Yeah,
how long does that compensatory reaction take? How long does
it take for the the machine to stop pumping out
serotonin and the batter to stop swinging at every ball?
Speaker 4 (28:40):
That's a good question. I don't know the answer to that.
I don't know the timeline per se. Okay, yeah, did
you have another before? I keep going on what we say, okay, okay, okay.
So but from that we can see that while we
know this is the mechanism, like we know this is
what this drug is doing and where it is binding. Yeah,
but that is not alone what is helping depression? So
(29:03):
what else is going on? And the more that we
have started to look at it, what we also see
is these downstream effects because it turns out that SSRIs
and a lot of other antidepressants, they end up modulating
by one degree our gene expression. Okay, okay, let me
(29:26):
tell you what I mean by this. Yeah, okay, Because
serotonin and other monoamines are involved in so many different processes.
Down the line, antidepressant drugs seem to have effects on
adjusting the upregulation and down regulation of other factors that
(29:48):
are produced in our brain. So the drug is not
doing this but downstream over time. I know your face
is like, this makes no sense.
Speaker 3 (29:59):
I'm just trying to I'm trying to keep everything in line.
Speaker 4 (30:02):
I know it's not in line, and there's no baseball
analogy for this one. Okay, we'll say about that, but basically,
and we don't know, Like this is where it gets
very complicated, Aaron, because we don't know exactly what is
doing this. But what we know is that in people
on antidepressants or in animal studies of antidepressants, we see
(30:22):
changes in gene expression. We see increases in things like
brain derived neurotropic factor or BDNF, as well as other
growth factors, vascular endothelial growth factor, genes that are linked
to neuroplasticity, activity dependent genes, other signaling molecules, and antidepressant
(30:43):
treatment is associated with a wide array of changes in
gene expression, and we think that some of these might
be mediated by other serotonin receptors, not the transporter that
is being affected by the drug itself, but by various
other serotonin receptors, because there are literally dozens of different
(31:04):
types of serotonin receptors in different parts of our brain
and different parts of our body who do different things. Okay,
so once you've then increased the amount of serotonin down
the line, what other receptors are some of these serotonins
acting on that is changing other pathways in our brain.
Speaker 3 (31:25):
And these other pathways are serotonin related, but not the
specific receptor or they're just pathways.
Speaker 4 (31:33):
They are may they may be serotonin receptor related, so
like other not the serotonin receptor that gets the most
attention in SSRIs, and not the transporter protein that's being
blocked by SSRIs yep, but by other ones. And some
additional evidence that's pointing to these kinds of gene expression
(31:54):
pathways as being important are investigations into other types of
antidepressants that are more like psilocybin as well as ketamine,
which has a lot of really great data for it,
especially with treatment resistant depression. Both of these have actions
on a lot of different receptors and are not mediated
directly through serotonin, but they do seem to have action
(32:17):
on other types of serotonin receptors that more directly modulate
things like neuroplasticity. And the more that we look at
things like neuroplasticity, which is your brain's ability to kind
of change and like continue to change over time, the
more that we think that that is very, very involved
in depression and anxiety.
Speaker 3 (32:38):
To begin with, Okay, I just want to put a
quick plug in for an Advances and Care episode on
psychedelics and psilocybin and some of these other formulations. Super fascinating.
Go check it out.
Speaker 4 (32:50):
Very interesting.
Speaker 3 (32:51):
So it's really it's really interesting research. Okay, So before
we keep going, though, I just want to make sure
I understand. Yes again, so we've got we've got this
specific receptor targeted action that it's doing with this one
serotonin transport transporter. And then that's not the only thing
that there are other things that are being affected in
(33:13):
ways that we don't quite understand, that we can't quite predict.
But it has to do something with serotonin, these pathways
that are other serotonin type receptors. Yes, okay, so it
would be like, here's my baseball analogy if we could,
if we could continue, it would be like if you're
changing the settings on that pitching machine, and that pitching
machine is then being like send out fewer balls in
(33:38):
decrease frequency. Wait, and then those settings though, are also
somehow impacting the tennis court and the soccer ball court
or the soccer field, and the basketball court and the
pickleball because everyone's into pickleball. It's all of those things.
Speaker 4 (33:54):
Are all of these courts are being affected by by
blocking the Yeah, catcher.
Speaker 3 (34:01):
But it was unexpected. It was like, whoa, this is
only supposed to affect right this.
Speaker 4 (34:06):
Okay, let's let's say that that's close.
Speaker 3 (34:09):
Okay, thank you for that, promea bone.
Speaker 4 (34:14):
I'm actually very curious to hear from like someone who
really studies this if that's a good analogy. Can some
of us know?
Speaker 3 (34:19):
Because that's I'm nearly certain it's not, and I apologize.
I like the idea of it. Thank you.
Speaker 4 (34:26):
I will also say, like, this is one potential hypothesis,
right that it's like through this gene expression, through these
other you know, pathways. There are other hypotheses as well.
There is also some evidence, or some hypotheses with some
evidence to support them, that SSRIs don't necessarily improve our
(34:47):
mood per se, but do induce a shift in our
perceptive state. Right, So, like how we perceive positive versus
negative stimuli, which then makes it easier for our brains
to are interpreting things with a positive bias rather than
a negative bias in our emotional processing. And we can
actually see some of that like positive versus negative stimuli
(35:09):
bias change even with like short term, like really short term,
like like a couple of days or like one dose
of SSRIs and so then is it that change in
bias over time that allows us our brain to but
we don't know. Okay, this is some of our ideas. Okay,
So that's what we know about SSRIs and how they work.
(35:32):
Can Can I be done with the brain part for now? Okay?
Speaker 3 (35:35):
I'll allow it.
Speaker 4 (35:36):
No, because what I want to move into next is
the idea or the question of do they work? Because
for some reason this is still a question out there.
The answer in short is yes, they work, and also
(35:59):
they might not always work.
Speaker 3 (36:02):
Yeah, I think again, not a new.
Speaker 4 (36:06):
Not a new concept, but I'm going to get into
detail on it. Yes, there's more than a few nuances
because first, there there's so many levels of this AARIN.
So first, some people who are experiencing depression will get
better on their own without any treatment or intervention. What
do I mean by get better? Great question. There's two
(36:27):
metrics that we tend to look at when we're looking
at depression. There's remission, meaning that your depression scale, your
depression score, it's usually the Hamilton Depression Rating scale. It
drops below a threshold usually seven. It means you don't
really have any symptoms of depression. There's also response, and
response means that you've got a fifty percent reduction in
(36:50):
your score or in your symptoms. Okay, so there's two
different metrics remission and response. Neither of these specifically address
the fact that depression is defined by its effects on
your life and function.
Speaker 3 (37:06):
But right it's just the score. It's score related.
Speaker 4 (37:09):
Or related, and that is what we do.
Speaker 3 (37:11):
Okay, Okay, so just a quick question. So this is
that final question of is this impacting your life? Could
still be a yes, but if the other symptoms are
if your score is reduced because the other checklists are
different than you, so then you could be shown to
(37:31):
have a response response but still impacted.
Speaker 4 (37:35):
Absolutely, absolutely, especially when we look at response with remission,
it really should be like your symptoms are essentially gone,
you're scoring very low and so presumably hopefully that's not
impacting your life. But we're not necessarily looking at that
part of it. We're looking at the score. So in
the short term, studies that have looked at this, and
all of these studies are so flawed, Aaron, There's so
many ways that all of these studies are flawed. But
(37:55):
I'm just going to give you the data that we
have in studies that have looked at people on like
a wait list or what they call care as usual,
which I'm not even sure exactly what that entails. Basically,
people who are in a study about depression but who
are not getting any specific depression treatment. Short term rates
(38:17):
of remission over like three months or twelve weeks or
so range from about twelve to twenty percent. So about
twelve to twenty percent of people who are in a
study about depression not receiving treatment will get better, will
have remission. Long term, we think that about half of
people fifty percent or so will have remission of their symptoms.
Speaker 3 (38:42):
In with without.
Speaker 4 (38:43):
Without treatment, without treatment.
Speaker 3 (38:45):
Okay, not just SSRII, but any form of.
Speaker 4 (38:48):
Truth without without any without any therapy, without any treatment.
This is what we think based on studies. Now, depression
is also a very like waxing and waning and remitting
type of disease, and so something like seventy percent of
people who have an episode of depression might have a
second episode at some point in their lives. Okay, Then
if we look at placebo controlled studies, because all of
(39:10):
these pills had to be tested against placebo pills, sugar pills,
and there is so much out there about the placebo response,
but in these studies, placebos tend to have a response rate,
so that means a reduction in your symptoms at twelve weeks.
Because almost all these studies are short term of about
(39:32):
thirty five to forty percent on average, so thirty five
to forty percent of people in a clinical trial that
are given a sugar pill to treat their depression might
improve in their symptoms. Only about twenty percent might meet
that remission threshold.
Speaker 3 (39:50):
And this is these are short term studies to term studies,
and so we don't know anything about sustained improvement correct
correct SSRI across the board. And there are a lot
of different SSRIs and we don't have great data to
tease them all apart. But SSRIs across the board tend
to have response rates of fifty to sixty percent and
(40:11):
remission rates around forty to forty five percent. So what
does that mean overall? What it means is that on
the whole, SSRIs are consistently and significantly better than placebos alone.
Speaker 4 (40:31):
Yeah, and they are statistically and significantly better than no
treatment at all or care as usual, meaning no specific
treatment for your depression. When we look at other types
of treatment like psychotherapies, Cognitive behavioral therapy is the best studied,
(40:52):
but other psychotherapies have been studies as well. Usually we
see about a forty one percent response rate and a
thirty percent remittance rate rate at eight weeks or so. Okay,
so better than placebo again and relatively comparable honestly to SSRIs.
Speaker 3 (41:09):
What about SSRIs and combination with CBT.
Speaker 4 (41:12):
Great question. They tend to do a little bit better.
There's not quite as many studies like comparing those directly
in things, but they tend to do well. The other
thing though, Okay, there's a lot. There's so many things.
Speaker 3 (41:23):
I have so much, so.
Speaker 4 (41:24):
Many others already. Yeah. The other thing to consider is
that the studies that look at these different types of
therapies might sometimes be different. For example, all of these
studies are going to have a lot of exclusion criteria
because these are studies that are looking at a pill
(41:47):
versus a no pill or something like that, or a
therapy versus a waiting list. The studies, especially that use
waiting list controls, tend to not include people who have
very severe depression. Certainly, they don't include people who have
SEU sitle ideation, because that would not be considered safe
to like not offer someone any treatment ethical, Yeah, And
so similarly, like there can be a lot of variation,
(42:09):
there's also a ton of variation in like how people
are doing these studies, like the settings and everything. And
when we're thinking about placebo responses, which is a combination
of the effect of someone taking a pill that doesn't
actually have anything in it. That's the placebo effect part, okay,
but the response that we see is also the setting
(42:33):
of a clinical trial where participants having regular and frequent
contact with a healthcare environment, where someone is asking them,
often on a weekly basis, how are you, How is
your mood? Please fill out this questionnaire about how your
mood is. Check in with yourself, chork in with yourself,
(42:53):
check in with me who's asking you these questions. You're
also having an expect dictation that something could help, right,
and so we know that all of that is going
to like, I mean from the data that those things
are effective for some people in improving symptoms of depression
(43:17):
and anxiety. And still on the whole, the improvement rate
of SSRIs over placebos is significant in terms of whether
you're looking at effect size, whether you're looking at the
response and remission rates in terms of percentages, the other
thing that we can calculate from this, And I think
this is an important number because some people with depression
(43:39):
or anxiety will improve on their own without any treatment.
Some people with depression or anxiety will improve if you
give them a pill or a something that says this
will help you. And some people will improve because of
the effects of the SSRIs.
Speaker 3 (43:58):
And some people won't improve at all.
Speaker 4 (44:01):
Some people won't improve at all. So we can calculate
what's called a number needed to treat, to try and
estimate how many people have to be given SSRIs to
get one person to experience remission who would not have
otherwise remitted on their own. Interesting and for we can
(44:22):
do this for therapies, and we can do this for
SSRI psychotherapy and SSRI okay, And most of the studies
big picture estimate a number needed to treat for therapy
of about five. So for every five people who are
in therapy or who are prescribed therapy for their depression,
one person will improve who would not have approved otherwise.
(44:42):
And for SSRIs it's like seven to nine.
Speaker 3 (44:46):
Interesting, Okay, Okay.
Speaker 4 (44:47):
Now here's another big problem with all of those studies.
They are not the real world.
Speaker 3 (44:55):
That's okay, yeah, and are any looking long term?
Speaker 4 (45:02):
There are long term studies. They're not great and so
I don't I don't have like, I don't have great
numbers for you on that. In all honesty and new
all right, we do know that relapse rates tend to
be higher if somebody stops. If someone is started on
an SSRI and improves, they are much more likely to
(45:22):
relapse if that SSRI is stopped before six to twelve
months of therapy. Okay, so there is good data to
suggest that you want to continue therapy for at least
six to twelve months to reduce the rate of relapse.
It does not mean that someone wouldn't have another episode
in the future, but that can kind of help to
prevent that.
Speaker 3 (45:40):
And just to clarify, you mean taking an SSRI, not psychotherapy.
Speaker 4 (45:44):
Correct and psychotherapy. We have better data that like a
fixed term of therapy like say twelve weeks or whatever
timeframe it is, can have long term benefits, whereas with SSRIs,
even if you see improvement at twelve weeks, if you
then stop, it not going to continue to see that
improvement a year from now, but you would if you
continued it for a year and then tapered off, you'd
(46:05):
be more likely to see sustained improvement. But there is
a big study that was a pretty huge moment in
like depression research that tried to look at more real
world scenarios. And I'm not going to dig like super
super deep on this study design. I do link to it,
and there's been a ton of papers published from it.
It was called the star D Trial, and this was
(46:28):
pretty huge because A it was a very large study.
B It included a much more realistic sample of people
who were experiencing depression. It was like community based kind
of where it wasn't just you know, it included people
who had comorbidities, who had other mental health disorders, who
had substance use disorders like it just a more realistic
(46:50):
sample than was usually included in these pharmaceutical trials. And
then it walked them through this kind of step wise
therapy where we see, we give everybody one drug, and
then we see who responds and who doesn't, and then
if they don't respond, then we randomize them. It wasn't
perfectly landom but we randomize them to a bunch of
different possible treatments, either stop that and switch to something new,
(47:12):
or add things or add therapy or whatever it was.
And then after level two they go to level three,
level four. There was like four levels overall. Bottom line
results from this were that about one third of people
reached remission with only the first line SSRI, which was
satalopram in this case. Okay, by the end of the
(47:35):
second stage, the cumulative remission rate was fifty percent, and
by the end of the study about seventy percent of people.
So if you went through all these different possibilities, about
seventy percent of people had remission. Again, that doesn't mean
they might never relapse, but it certainly is meaningful. Now,
(47:55):
before you even ask a question, I have to caveat
this because the study is old at the point and
a more recent kind of renalysis, and I will say
by people who seem to not like SSRIs based on
all their other published papers, but they reanalyzed this data
and actually estimated a slightly lower remission rate. So they said, no,
(48:15):
it wasn't you know, a third of people. It was
actually like twenty five and a half percent after that
first level. So one SSRI trial and then they estimated
only about a forty percent response rate by the end
rather than seventy percent. Interesting hm, but either way, it
is a much more realistic, real world trial that tells
(48:38):
us a few things. One, it tells us that not
everyone is going to respond to the first SSRI that
they try. Yeah, period, we know this very true. It
tells us that they are still effective for a substantial
portion of people. Like some might say, twenty five is
not that much, but if you are in that twenty
(48:58):
five percent and your depression is is remitted because of this,
and usually on a much faster time frame than what
we would expect if someone has no treatment whatsoever. Yeah, right,
that is meaningful, right totally. What were you gonna ask, Karin?
Speaker 3 (49:16):
Okay, first question that came to mind is, and I
know you said you weren't going to talk about the
differences in SSRIs, but broadly speaking, what are some differences
between these different SSRs?
Speaker 4 (49:29):
Great question. So, there there's a bunch of different SSRIs
that are licensed in the US, and there are some
that are licensed in the US that are or some
in Europe in the UK that aren't used in the US.
And then There's also s NRIs, which are serotonin selective
serotonin reuptake and nor epinephrine reuptake inhibitors, so they do
both the differences between them, some of them are going
(49:54):
to be more sedating and some of them are going
to be less sedating. Some of them make you sleepy,
some of them make you less sleepy. We know why, no, no, no,
we don't know why for any of these. Some of
them are gonna some of them can cause weight gain,
and some of them have much less seem to cause
much less weight gain. Some of them, like cetalapram, for example,
(50:16):
at higher doses and especially in elderly populations, we have
seen that it can cause some effects on your heart.
It can prolong your QT interval, which means it could
potentially put you at higher risk for a heart condition
in the future. We don't see that with all of
the ssries. And then in terms of so a lot
of it comes down to the side effects, So the
side effect profiles can be different for different, you know,
(50:39):
specific ones.
Speaker 3 (50:41):
And then in.
Speaker 4 (50:41):
Terms of efficacy, there was a big study that came
out that tried to compare, you know, between looking at
all of these different placebo trials and the head to
head trials that exist because there are some of those.
Are there any that kind of come out on top?
And the answer is like, maybe there are a few,
Like scetalopram, which is lexipro brand name. Often it comes
(51:03):
out higher. Sirtraline tends to be like well tolerated compared
to its effect size, if that makes sense, because they
were comparing like side effects versus efficacy. Yes, yeah, but
there is not like a oh my gosh, this is
the clear winner or anything like that.
Speaker 3 (51:20):
Well, and it's so it's so individual, like so person
to do we know anything about the individual variation and
receptivity to SSRIZ or efficacy?
Speaker 4 (51:29):
And like I remember there.
Speaker 3 (51:30):
Was is there something about genetic testing?
Speaker 4 (51:33):
Yeah, I didn't get deep. I didn't get into that,
but there is a lot of interest in that, Like
can we do any sort of genetic analysis to try
and identify who might be more likely to respond to which,
because one thing that we see is that like there
is familial clustering sometimes like if you're like, oh, my
sister was on seartraline and she did really well on it,
(51:55):
then you might be more likely to also do well
on searchralein. But is that again part because of an
expectation and because of a familiarity, or is it because
of some genetic predisposition things like that.
Speaker 3 (52:07):
So there are it, and you read the wrong testimonial like, yeah,
lexipro ruined my life, and then someone else is like
that was the best thing that's ever happened to be.
Speaker 4 (52:16):
And both are true, but they're true, are true.
Speaker 3 (52:19):
Absolutely, Yeah.
Speaker 4 (52:20):
There are certainly side effects to SSRIs on the whole,
their safety profiles are really quite good, especially compared to
our older antidepressants like the TCAs and the MAOIs. But
the two biggest side effects of SSRIs are gi side effects,
so nausea, vomiting diarrhea, probably because of all the serotonin
in your guts your gut, yeah, and that tends to
(52:42):
be transient. Usually improves. Sexual dysfunction, though can be a
huge downside to SSRIs, and this can affect any part
of like your sexual cycle, from like desire or libido
to ability to achieve an erection or to achieve orgasm,
which can be pretty debilitating, especially because depression and anxiety
(53:04):
can also affect sexual sexual functioning. It does not, though,
happen to everyone who is on an SSRI, and we
can't predict who it's going to happen to and who
it won't. It usually does not get better though while
you're on it, in contrast to the GI side effects.
Speaker 3 (53:22):
Oh interesting.
Speaker 4 (53:23):
Yeah, and there are some reports of sexual dysfunction persisting
after discontinuation, But as of right now, it's not like
a well studied or well recognized phenomenon like in the
medical literature. But I know there's a lot of interest
in studying it more deeply in people who are depressed
like in a depressive episode, but perhaps actually have undiagnosed
(53:44):
bipolar disorder. SSRIs can potentially precipitate a manic episode, and
so they're not usually used in bipolar depression and there
are caveats to every role when it comes to that.
But probably the most headline generating warning or side effect
as it relates to SSRIs is its relationship with suicide
and suicidal ideation. Yeah, an increase in suicidal ideation is
(54:10):
often it's a black box warning now on all SSRIs.
The data suggests that this might this association might exist
like exposure to SSRIs and an increase in suicidal thoughts
or attempts at suicide might exist for pediatric and adolescent populations, right, Yeah,
(54:31):
the evidence in adult populations looks like there is actually
a decreased risk of suicide, especially in the older populations,
like in our older adult populations over sixty five, but
in adults over age twenty five, twenty five is the cutoff.
There is not an increased risk of suicide that we
(54:52):
see with SSRIs. There may be in those under twenty five,
and that still doesn't mean that we don't ever prescribe
them because in some cases they still can really help
with all of the other symptoms of anxiety and depression.
So yeah, but it is like it's an important that
is why it's a black box warning, and it's an
(55:13):
important thing that people are really looking into. There are
a lot of other potential harms that have been scrutinized
very deeply in their literature in these like large scale
observational studies to try and figure out long term are
there other detrimental effects to SSRIs, And all of the
rest of them don't hold up to scrutiny, They don't
(55:34):
hold up to the statistical analyzes. There's like, is there
effects on autism rates or ADHD rates? In people who
are pregnant who are on SSRIs. So far, those don't
hold up to the statistical analyses. It doesn't mean there's
not some suggestion, but there's there's not like a clear
consensus at this point.
Speaker 3 (55:53):
What about dementia was another one that I saw, I
came across and nothing that holds up again too, you
didn't get yet.
Speaker 4 (55:59):
Yeah, at least all the meta analyzes that I read.
Speaker 3 (56:02):
Right, What about serotonin syndrome are you gonna great question?
Speaker 4 (56:07):
So, serotonin syndrome is an important potential effect of overdosing
essentially on SSRIs, and importantly because self harm and suicide,
which overdoses one mechanism that people might try to attempt
a suicide. SSRIs are actually much safer in overdose compared
to TCAs or MAOIs or like benzodiazepines that we use
(56:30):
for anxiety for example. We don't use them very often,
but we do sometimes. But serotonin syndrome can absolutely be
a thing. And that is something where you basically just
have way too much serotonin. And then there's a mnemonic
that I'm sure I learned in med school, but I
didn't write it down, so I can't tell you the
exact symptoms of it, but it's like it can be
quite dangerous. It's an emergency room situation. It is still
(56:53):
safer again than overdoses of other older antidepressants, and it
is a treatable condition. But one concern is not necessarily
like overdose. But when a person is on multiple serotonergic medications.
Speaker 3 (57:08):
Because what else would they be a lot.
Speaker 4 (57:10):
Of our medicines actually have some serotonin effects. Zofran so
adansitron or I think that's how you pronounce it, which
is a medicine we use for nausea, trazodone, which is
like an antidepressant that no one uses for depression, but
we use it for insomnia. There are so many gabapentin,
so many medications that we use for a whole bunch
of different things. Tricyclics we use a lot actually for
(57:33):
migraine and sometimes for neuropathic pain or for ibs. And
so if you're taking multiple different medications, which we very
often see in our elderly populations, you do have to
think about how many of these might have effects at
some point on serotonin or on serotonin receptors. Because some
of them, like zofrin, acts on serotonin receptors.
Speaker 3 (57:55):
Right right, Okay, Okay, so.
Speaker 4 (57:57):
Yeah, it is something that we have to kind of
keep in mind, but on they are really pretty safe
medications on the whole, especially compared to what we had previously. Yeah,
for me, though, do you have any other questions aarin
about like the nitty gritty, because that's my end of
nitty gritty, and I want to tell you what I
feel like.
Speaker 3 (58:16):
I mean, let me think about the nitty gritty. I
think the thing that like in reading all these papers
and reading the research is that because the effects of
SSRIs are so broad, because the way that we measure
those effects are so broad and so imperfect, imperfect, and
so varied, and because the number of conditions that SSRIs
(58:40):
are used for can also be very varied, people can
draw whatever conclusions they want almost out of this. And
that is I think what makes there's so much noise
around SSRIs. There's so much noise, and I think what
gets lost in that noise is the signal that for
(59:02):
many people, SSRIs are very effective. For many people, maybe
they want to weigh the pros and cons of SSRIs,
but it's like there are these sweeping statements yes that
research groups I think there are one in particular I'm
thinking of wants to make and that are harmful. Yeah,
(59:25):
SSRIs are not more effective than placebo, which is not.
Speaker 4 (59:28):
True, not true, not true, Yeah, the end of the day,
not true.
Speaker 3 (59:32):
I mean it can be true if you cherry pick
your studies and you, you know, throw out the ones
that don't suit your end agenda.
Speaker 4 (59:40):
But I also think for me, there's a few different
things I feel like are really left out a lot
of a lot of these conversations that are happening about SSRIs,
and really like it's left out of the conversations that
we're having about how we treat major depressive disorder, how
we treat generalized anxiety disorder, any of these affective or
mental health disorders, a lot of which we treat with
(01:00:02):
SSRIs or other medicines. Right, we do not understand the
biology of these conditions. We do not know what these
mechanisms are. We do not have biomarkers or tests that
we can run to diagnose these conditions. We don't even
have a measurement that is not subjective, right, because these
(01:00:23):
are disorders that we diagnose based on timeframes, based on
questionnaires of symptoms, and based on their effect on our
daily lives and our ability to function. So of course
we cannot expect to fully understand how a drug is
working if we don't understand the disease that we're treating. Yeah,
and at the exact same time, we cannot ignore, refuse
(01:00:48):
to treat, or withhold effective treatment from millions of people
just because we don't understand the mechanism. So I really
want to provide everyone a compare contrast. And some people
might get mad and say that's apples and oranges, to
which I say, those are both fruit, Okay, so allow
me to tell it.
Speaker 3 (01:01:08):
Orange is a vegetable, and I'm just kidding.
Speaker 4 (01:01:10):
Scared me for a second. Eighty five to ninety five
percent of cases of hypertension or high blood pressure are
what is called essential hypertension, which is our fancy way
in medicine of saying we have no idea what causes it.
And yet we have dozens of different drugs that work
on very disparate mechanisms, from diuretics to calcium channel blockers
(01:01:33):
to angiotens interceptor blockers, none of which not a single
one is targeting the primary cause of hypertension. Because we
do not know what the cause of hypertension is and
it goes further erin not everyone who receives the same
benefit from one anti hypertensive is going to receive it
the same way. In fact, only twenty five to thirty
(01:01:55):
percent of people with hypertension are going to have their
blood pressure controlled with a single agent. Most people are
going to require at least two, if not three. The
same can be said for antidepressants. No, we don't understand
how they work, because we don't understand depression, but we
do know that a substantial proportion of people who try
one will derive benefit from it, and those that don't
(01:02:18):
might benefit from a different version of one or a
different type of antidepressant. And this is not just because
of a placebo effect.
Speaker 3 (01:02:26):
Yes, it's I mean, I feel like I've saw it
described somewhere which I really like. And using the hypertension analogy,
is that hypertension is not caused by a lack of
anti hypertensive right, depression is not caused by a lack
(01:02:47):
of serotonin. But we have drugs anti hypertensive antidepressants SSRIs
that have an impact for some people and so that
it's not like a one to one. Here's the problem
here's the solution, but it is here is a problem,
and here's an imperfect solution. That's some that can work
(01:03:10):
for some people.
Speaker 4 (01:03:11):
One hundred percent, Aaron, one hundred percent. And I will
also say too that like there is a lot of
discussion of like, oh, mild versus moderate versus severe depression,
and like most of the guidelines from the European societies,
from the American societies actually recommend psychotherapies like cognitive behavioral
therapies for mild to moderate depression over SSRIs. But realistically,
(01:03:35):
a lot of people either do not want that, or
are not ready for that, or cannot do it because
their insurance won't cover it because they always going to
provide her because they don't have a time right.
Speaker 3 (01:03:45):
So it's sort of like, oh, you need in order
to be prescribed ASSROS, you need to undergo six months
of therapy first. Yeah, how are you going to take
time to do?
Speaker 2 (01:03:55):
That?
Speaker 3 (01:03:55):
Happens for some people, maybe that's realistic. For other people,
it absolutely is not possible, exactly.
Speaker 4 (01:04:02):
And I think a lot of this, like a lot
of this discussion comes down to the stigma that we
have when it comes to mental health disorders. I think
another part of the problem, which is in part due
to the stigma, is that when it comes to something
like hypertension, we have really great data on if we
control blood pressure by whatever means, we can prevent death
(01:04:22):
from cardiovascular disease long term. That's a pretty big deal.
That's probably worth it. Right. We don't have as good
of data on the long term effects of treatment versus
non treatment and things like that when it comes to
depression and anxiety because who's going to fund those studies?
Who's going to put up the money for that? Right?
So that I think is another part of this problem
is that there is a lot more data that needs
(01:04:43):
to be gathered and a lot more understating that we
need of these medicines and alternatives because treatment resistant depression
is very real and affects a huge proportion of people.
So yeah, there's still a lot but SSRIs are safe
and they're effective for a life people.
Speaker 3 (01:05:02):
I mean, it's like we we just come to the
same conclusion in every episode. More research is needed, a
more nuanced view is crucial, and transparency.
Speaker 4 (01:05:19):
Wouldn't that be great? Aaron?
Speaker 3 (01:05:21):
Yeah, I think it's it's been very interesting to like explore,
to get like so.
Speaker 4 (01:05:33):
Over my head deep in this literature and still feel
like I don't have a great handle on it.
Speaker 3 (01:05:38):
Honestly, I think that in itself is the lesson. Yeah.
It's like, who has a really who can raise their
hand and say, I know how they work for each person,
whether that person has derived benefit or has it you know,
described that they have had benefits or is treatment resistant
right now, it's like.
Speaker 4 (01:05:58):
Or has had only side of right or yes, benefit
but also side effects that we're bad enough that it's
not worth it, right, yeah, and that we absolutely see
all the time yea, And I mean looking forward, like
I would not be surprised if there is a time
when SSRIs are almost entirely replaced, like the same way
that m aois or TCAs are not really used very commonly.
(01:06:23):
But that needs to come because we have found better,
more effective alternatives, because we've invested in mental health research
and in expanding access to services, in normalizing therapy, in
taking time off work to do these other things, and
because we come to a better understanding of the causes
of depression and we have safer, more effective medicines. Not
because we lie and say that SSRIs are addictive, They
(01:06:45):
are not there is no data for that that they're
dangerous like Heroin. They are not right like they. This
needs to happen for good reason, not just taking something
away that has been life saving for a lot of people,
even though it is imperfect.
Speaker 3 (01:06:59):
Yeah, it's it's a real bizarre, it's a real it's
it's an ugly new manifestation of the stigma that has
long been with us.
Speaker 4 (01:07:08):
When it comes to health one hundred. It's an ugly manifestation.
If that's that stigma, I really don't like it.
Speaker 3 (01:07:15):
No.
Speaker 4 (01:07:16):
No, So if you want to read more and get
as deep as I did, I cannot. This was such
a big episode for me aarin that I actually tried
to organize all my sources. Usually they're just like a
I throw them all into a spreadsheet. This was like,
I have a whole section for papers on the mechanism
(01:07:36):
of action. I've got a whole section for papers about
the guidelines, who's making these guidelines. I've got a huge
section on the efficacy and effectiveness studies. I've got a
separate section on looking at the placebo responses versus efficacy studies,
another section on papers specific to children and adolescents. Because
(01:07:59):
it is a very different kind when we're talking about
these medicines and children and adolescents and we have less data,
and like I said, there's more potential for risk, and
that doesn't mean they're not used. I have a few
papers on long term data, not great, but I have some.
I have more than I realized actually, And then other
papers on untreated depression. I'm just scrolling through all of
these areas.
Speaker 3 (01:08:18):
Love this. I mean, you have just made life so
much easier for someone writing a term paper.
Speaker 4 (01:08:22):
Seriously, could someone like take all these and write a paper.
I also have separate section. I should move this up
to the top about what we know of depression and anxiety,
like what we think about their neurobiology. Yeah, some papers
on the epidemiology, and then a few that I call mythbusting.
And then those you mentioned Aaron the like very controversial
straw Man argument about serotonin and whether or not it's involved.
(01:08:45):
I included that paper and all of the responses to it.
Speaker 3 (01:08:48):
Oh my god, there are so many responses.
Speaker 4 (01:08:50):
Yeah, you can read about it on our website. This
podcast will kill you dot com.
Speaker 3 (01:08:56):
Thank you again so much to the providers of our
first hand accounts for these episodes and all of our episodes. Really,
it really means so much to hear these perspectives and
your experiences. So thank you, thank you.
Speaker 4 (01:09:09):
Yeah, thank you so much. Thank you also to Bloodmobile,
who provides the music for this episode and all of
our episodes now on Instagram, now on Instagram.
Speaker 3 (01:09:18):
Thank you to everyone at Exactly Right who helps us
make this podcast, Tom, Leanna, Brent, Pete, Jess, you know everyone.
There's so so many, so many people. So thank you,
thank you.
Speaker 4 (01:09:31):
Thank you, and thank you to you listeners. Hopefully you
liked this two part deep dive. Yeah, did you tell
us genuinely? Also, how about that baseball on analogy?
Speaker 3 (01:09:42):
Yeah? Sorry about that. Thank you. Also to our wonderful,
generous patrons. We appreciate your support. It means the world
to us, it really does.
Speaker 2 (01:09:53):
Thank you.
Speaker 4 (01:09:54):
Well.
Speaker 3 (01:09:55):
Until next time, wash your hands, filthy animals.
Speaker 5 (01:10:04):
Bomba bonba bumba bumbo bo