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