Speaker 1: My name is Will and my experience with ssriyes and
Speaker 1: esenriyes started when I was in pharmacy school. Actually, I
Speaker 1: was diagnosed with both anxiety and depression at the same time,
Speaker 1: which was a lot of fun, especially when I was
Speaker 1: in a doctorate program and my doctor started me on
Speaker 1: s a telegram on lexaprob. It worked fairly well for
Speaker 1: a while, needed a little bit of help from buse
Speaker 1: Peronne to get through the anxiety, but I did okay.
Speaker 1: That said, I still had some breakthrough symptoms and I
Speaker 1: especially had side effects. I had a lot of the
Speaker 1: sexual dysfunction side effects, and I also gained about thirty pounds,
Speaker 1: so I swapped off of that for a while when
Speaker 1: I'm a little bit of a vacation, but then my
Speaker 1: symptoms started coming back and getting worse. So I got
Speaker 1: started on wellbutrin bupropion, and I did a lot better
Speaker 1: symptom wise on it, but again I had really really
Speaker 1: bad side effects. And it wasn't so much suicidal ideation
Speaker 1: as it was just an acute knowledge of my own mortality,
Speaker 1: which is not great when you had anxiety and depression.
Speaker 1: So at that point I had the wherewithal because of
Speaker 1: my education as a pharmacist to ask my doctor to
Speaker 1: go on and do genetic testing, which I'm glad I
Speaker 1: did because when we got the results back, it turned
Speaker 1: out that there were only about two antidepressants and a
Speaker 1: couple of anxiolytics that were on my green as go list.
Speaker 1: That is to say, you know that my hepatic enzyme
Speaker 1: is going to metabolize without giving me two bad side effects.
Speaker 1: And that is kind of the journey of how I
Speaker 1: found pristique des been the fact sine that is the
Speaker 1: miracle drug that worked for me. But I still can't
Speaker 1: help but wonder how long it would have taken me
Speaker 1: to find my miracle drug if we did it kind
Speaker 1: of the old fashioned way. If I hadn't known to
Speaker 1: ask for this genetic testing, I could have been trying
Speaker 1: and failing SSRIs and SNRIs for years, years before I
Speaker 1: found the drug that worked for me. So you know,
Speaker 1: I try and advocate for the genetic testing and for
Speaker 1: being your own advocate as a patient whenever I can,
Speaker 1: because I just I know that there are a ton
Speaker 1: of people that don't have the same sort of background
Speaker 1: as I had the good fortune of having. So as
Speaker 1: a fellow health professional, I definitely tell patients all the time,
Speaker 1: make sure you're advocating for yourself, even if it's just
Speaker 1: asking questions.
Speaker 2: Taking SSRIs is the best thing I've ever done. I've
Speaker 2: always had trouble with OCD in terminal anxiety from a
Speaker 2: young age, probably as long as I can remember. I
Speaker 2: would have like a baseline level of anxiety and OCD,
Speaker 2: and then every so often I'd have these periods where
Speaker 2: it got so much worse and it was all consuming.
Speaker 2: I spent all my time in my own head, worrying, ruminate,
Speaker 2: in doom, mental compulsions. I struggled to eat, or sleep
Speaker 2: or socialize, and it really started to have an effect
Speaker 2: on my personal life. I managed to get through work
Speaker 2: and other commitments without most people noticing, but I wasn't
Speaker 2: present and it was really horrible to endure. I felt
Speaker 2: like I didn't deserve anything nice or for my family
Speaker 2: to be even sympathetic to me because of these awful,
Speaker 2: intrusive thoughts I was having. These periods were so difficult
Speaker 2: that when they subsided, I was so grateful that I
Speaker 2: didn't even notice the baseline level of anxiety I had
Speaker 2: all the time, and how much of an impact that
Speaker 2: was having on my life. Last October, I had an
Speaker 2: OCD flare up, and it was the worst it's ever been.
Speaker 2: I was in a really dark place. My therapist recommended
Speaker 2: taking fla woxatine, and I was so desperate to feel
Speaker 2: better I would have taken anything. Within a few weeks,
Speaker 2: I started to feel more myself again. The thoughts quietened,
Speaker 2: and I remember getting really emotional because it was so
Speaker 2: strange for me to feel like that, my mind being
Speaker 2: quiet for once. I can't emphasize enough how much of
Speaker 2: a sitive impact they've had on my life. It was
Speaker 2: the first time in my life I'd actually felt content
Speaker 2: in myself and excited for the future. I'm so much
Speaker 2: happier now and just enjoying life to the fun. I'm
Speaker 2: so grateful that I don't have to feel that permanent
Speaker 2: level of anxiety and intrusive thoughts anymore.
Speaker 3: I've literally never felt.
Speaker 2: Like this in my life before, and it really hammered
Speaker 2: home how much I'd been struggling on a daily basis
Speaker 2: and didn't even notice. The tablets alongside the therapy were
Speaker 2: like a helping hand to pull me out of a
Speaker 2: really dark hole. My only regret is not taking them.
Speaker 2: Any sooner.
Speaker 4: Thank you so much for providing your first hand account.
Speaker 4: That really means it means so much. I know we
Speaker 4: say it all the time, but it always does. It
Speaker 4: really does.
Speaker 5: It means so much every single time, honestly, So thank you,
Speaker 5: and thank you to everyone who wrote in. We really
Speaker 5: really do appreciate it.
Speaker 3: We do.
Speaker 5: Hi.
Speaker 3: I'm Aaron Welsh.
Speaker 5: And I'm Erin Alman Updike and this is this podcast
Speaker 5: will kill You. And today we're talking about SSRIs.
Speaker 4: About SSRIs, and next week we're talking about SSRSR. Yeah,
Speaker 4: I mean, it really does warrant at least two full episodes,
Speaker 4: Like there's so much there in the history, in the
Speaker 4: biology and sort of the current the discourse.
Speaker 3: James, we did not plan that, No, we did. That's thrilling.
Speaker 3: Just shows that we're best friends.
Speaker 5: Like yeah, and we spent way too much time like
Speaker 5: thinking about this too and with each other.
Speaker 3: Yeah yeah, yeah.
Speaker 5: But yeah, So we're gonna do a two parter this week.
Speaker 5: Aaron Welsh's gonna tell me all about the history because
Speaker 5: I don't know it other than like we had MAOIs
Speaker 5: and then TCAs and now SSRI's what I've done. Next
Speaker 5: episode and then next week, I'll get into what we
Speaker 5: think we know about how SSRIs actually work and their mechanism,
Speaker 5: and then yeah, I'm excited to tell you what I know,
Speaker 5: and then some of the yeah, the current discourse.
Speaker 3: Current.
Speaker 4: But before we get into all all of that, it
Speaker 4: is of course quarantine.
Speaker 5: Quarantin any time or should we say plusy berrita time.
Speaker 4: This week we've been like mixing it up and every
Speaker 4: now and then it's like, what do you what do
Speaker 4: you feel like doing plasy parita This week we'll do
Speaker 4: this one. Yeah, this week is the serotonin sprits.
Speaker 5: Couldn't be anything else. It could have been Actually we
Speaker 5: thought about other things.
Speaker 4: We were like, this is as bad as it is.
Speaker 4: It's the best we can do.
Speaker 3: Saraton sprits. It's pretty simple.
Speaker 4: It's it's got soda water, hence the sprits. It's got
Speaker 4: sparkling apple cider and some pineapple juice. And it's tasty.
Speaker 4: It's simple, it's refreshing.
Speaker 5: Yeah, for a warm or a cold day.
Speaker 4: Yeah, sure, jack of all trades anyway.
Speaker 5: The full recipe on our website, this podcast with kill
Speaker 5: you dot com and our socials. Are you following us there?
Speaker 5: Because you could and should be. We're on Instagram, TikTok,
Speaker 5: the Facebook, loose Sky. We're also online on a website
Speaker 5: called This Podcast Will Kill You dot com. Have you
Speaker 5: checked it out yet, because if you haven't, what a
Speaker 5: wealth of things you'll find there.
Speaker 3: So many things.
Speaker 5: The bookshop dot org affiliate list account that we have.
Speaker 5: You're doing you're doing it, thank you, good reads list, transcripts,
Speaker 5: We've got Bloodmobile. We've got sources from every single one
Speaker 5: of our episodes, including this one.
Speaker 3: What else is now on Instagram?
Speaker 5: So oh really that's exciting.
Speaker 3: Check them out.
Speaker 5: Check we've got merch We've got a link to our
Speaker 5: Patreon account. If you haven't yet dropped a what do
Speaker 5: you call it? Rate and review and subscribe. I'm trying
Speaker 5: to do too much.
Speaker 3: Be sure to do that. Do it?
Speaker 5: Okay, we're on YouTube.
Speaker 1: There we go.
Speaker 3: Let's just try to take a little off your plate.
Speaker 3: Thank you.
Speaker 5: My plate is done.
Speaker 4: The end, the end, and the beginning. Let's take a
Speaker 4: quick break and get started.
Speaker 5: I can't wait.
Speaker 4: In December nineteen eighty seven, the FDA approved Prozac for
Speaker 4: treatment of depression, and it became the first ssri to
Speaker 4: hit the US market. The following January within two years,
Speaker 4: pharmacies were filing one million prescriptions each month.
Speaker 5: Wow in the US.
Speaker 3: In the US Wow.
Speaker 4: Today, global numbers are hard to pin down. I'm sure
Speaker 4: you'll do some Aaron math maybe, but no, I won't. Sorry, well,
Speaker 4: they're really hard to find. I mean, googled for like
Speaker 4: five minutes and no, it was longer than that.
Speaker 5: Was I believe it was substantially longer than that.
Speaker 4: But I did find one estimate from the CDC from
Speaker 4: twenty eighteen where they suggested that thirteen percent of people
Speaker 4: in the US are on antidepressants, which comes out to
Speaker 4: around forty two million people, and this is likely an
Speaker 4: underestimate since prescriptions have increased in recent years. As antidepressant
Speaker 4: use has grown, so has the controversy surrounding these medications.
Speaker 4: RFK Junior, the Secretary of the US Department of Health
Speaker 4: and Human Services, despite having zero medical training, has made
Speaker 4: claims that SSRIs are more harmful and addictive than heroin,
Speaker 4: so claims not supported by any data, and has proposed
Speaker 4: limiting their use, instead sending people to quote unquote wellness farms. Yeah,
Speaker 4: I mean we could do an entire Yeah.
Speaker 5: I'm sorry, it's just so unseerious, but it's very very serious.
Speaker 5: He's very much in charge of everything right now. But
Speaker 5: it's one of those you laugh or you just break
Speaker 5: down and give up on everything.
Speaker 3: Is I laugh?
Speaker 4: I mean I'm scared every day and it feels surreal
Speaker 4: every day.
Speaker 5: And yeah, yep, I mean.
Speaker 3: This is like.
Speaker 4: Wellness farms are not a new concept, and it's never
Speaker 4: been a good concept. We could do an entire episode
Speaker 4: in the dark history of wellness farms or the ones
Speaker 4: similar to the ones that he presumably has in mind,
Speaker 4: my guess, and how ablest and racist and sexist and
Speaker 4: classist they are.
Speaker 5: It's dark. It's dark.
Speaker 3: It's dark.
Speaker 4: But this controversy extends beyond conspiracy theories and conspiracy theorists
Speaker 4: like RFK Junior, with some psychiatrists and researchers expressing reservations
Speaker 4: about the way that we use or think about antidepressants
Speaker 4: and mental health disorders, prompting the popular media to release
Speaker 4: articles exploring this controversy with headlines like the risks and
Speaker 4: Rewards of antidepressants and do antidepressants work better than Placebo?
Speaker 3: Despite all the.
Speaker 4: Progress that has been made in raising awareness and being
Speaker 4: open about mental illness, it is still a taboo subject
Speaker 4: in many ways, very much so. Acknowledging that you struggle
Speaker 4: and seeking help because of that is perceived by some
Speaker 4: as or by many, as a weakness.
Speaker 3: Oh we all.
Speaker 4: Get a little blue here and there. You don't need meds.
Speaker 4: Just think on the bright side, go get some fresh air,
Speaker 4: just take a walk, take a nice little stroll. Or yeah,
Speaker 4: I get anxious too. Sometimes I just try not to
Speaker 4: think about it.
Speaker 3: Just kind of put it in a box, put it away.
Speaker 3: Just stop.
Speaker 5: Yeah, just stop to stop. Just stop being anxious and depressed.
Speaker 3: That's easy, that's easy.
Speaker 4: The stigma surrounding mental health disorders also extends to the
Speaker 4: treatments that people seek, whether that's an SSRI or therapy,
Speaker 4: and the stigma, no doubt, contributes to the constant questioning
Speaker 4: of antidepressants by the general public. However, the skepticism that
Speaker 4: some researchers or healthcare practitioners express towards SSRIs, while likely
Speaker 4: influenced by this overarching doubt, is also informed by the
Speaker 4: gaps in our scientific knowledge about the causes of mental
Speaker 4: illness and the mechanisms by which SSRIs may work to
Speaker 4: improve symptoms. So, in other words, like what do these
Speaker 4: medications do and how do they do it? And next week, Aaron,
Speaker 4: I know that you're going to take us through the
Speaker 4: long answers to these questions, but the short answer is
Speaker 4: that we don't really know.
Speaker 5: Yeah, I mean, that's the conclusion of next week's episode.
Speaker 4: Yeah, yeah, yeah, I mean we have some ideas, and
Speaker 4: those ideas have changed over the decades, but we don't
Speaker 4: know for certain how these medications work. And that's partly
Speaker 4: because we don't understand the underpinnings of depression, of anxiety,
Speaker 4: of obsessive compulsive disorder, and of other mental health disorders. Yeah,
Speaker 4: and at first glance that maybe that sounds a little strange,
Speaker 4: like what do you mean we use these antidepressants but
Speaker 4: we don't quite know how they work.
Speaker 5: It doesn't sound strange if you work in medicine.
Speaker 4: Aaron I was gonna say, there are still there's so
Speaker 4: many medications that are also mysterious. There's acetaminifin paracetamol. We
Speaker 4: don't know why or how it reduces pain and fever.
Speaker 4: Met Foreman is still a bit of a black box.
Speaker 4: Even a few of our general anesthetics holds some mystery.
Speaker 5: There is probably more medicines that we do not fully understand.
Speaker 5: And I don't just mean like how they work, like
Speaker 5: a lot of things we know, like it binds to
Speaker 5: this receptor and this mechanism happens. That does not mean
Speaker 5: that we understand how like why do they improve the
Speaker 5: thing that they improve, because we use a lot of
Speaker 5: medicines for a whole bunch of different stuff, Like I'm
Speaker 5: going to get into it next week more as well too,
Speaker 5: like this concept and the way that we talk about
Speaker 5: these medicines for depression versus other medicines that we don't understand.
Speaker 5: But yeah, it's it is not just SSRIs.
Speaker 3: It's not it's not.
Speaker 4: And I think that this speaks to how our approach
Speaker 4: to drug development is not always guided by a find
Speaker 4: the specific problem, engineer the targeted solution mindset, Like that's
Speaker 4: just not the way that drug development often works, and
Speaker 4: maybe maybe that's the ideal way, but like that rarely
Speaker 4: rarely happens, or it doesn't happen, and we think that
Speaker 4: we've found the solution, but it's like, well, we didn't
Speaker 4: quite understand the problem in the first place.
Speaker 5: That's the thing. You have to know the problem very
Speaker 5: clearly to be able to do that kind of targeted development.
Speaker 5: So we have that for some situations, right, for some cancers,
Speaker 5: for example, Yes, but not for a lot of other
Speaker 5: disorder that are more nebulous, that have multiple factors that
Speaker 5: contribute to their development. Right.
Speaker 4: I mean it's kind of it's kind of amazing, like
Speaker 4: and just just how much serendipity can play a huge
Speaker 4: role in bridging these gaps of like, we here's this problem.
Speaker 3: What's the solution? Right?
Speaker 4: We don't have the information, But then something comes along
Speaker 4: and it's like, hey, that seems to work.
Speaker 5: How does it work? How does We'll figure that out
Speaker 5: later right now? Yeah, it's what is it doing first?
Speaker 5: And then how does it work? How does it We
Speaker 5: don't have the how does it work for a lot
Speaker 5: of things?
Speaker 3: Yes? Yeah?
Speaker 4: And so what I want to do in this episode
Speaker 4: is take us through the story of SSRIs, starting with
Speaker 4: serotonin itself and how the first antidepressants were developed, and
Speaker 4: then ultimately ending with kind of a small reflection of
Speaker 4: how these medications have led a revolution in our understanding
Speaker 4: and perception of mental illness. That's the good, the bad,
Speaker 4: and everything in between.
Speaker 5: I can't wait.
Speaker 4: So let's start at the beginning with serotonin. The neurotransmitter
Speaker 4: and cellular messenger. That's the star of this episode.
Speaker 5: I can't wait.
Speaker 3: Which to do.
Speaker 4: This means that we have to start pretty far back, Okay,
Speaker 4: billions of years back.
Speaker 3: You know.
Speaker 5: I love it when you go deep time a time.
Speaker 4: I mean, I'm not going to stay deep for very long,
Speaker 4: but it's okay, it is.
Speaker 3: I was so.
Speaker 4: Surprised to learn how ancient serotonin serotonin, I mean two
Speaker 4: to three billion years ago.
Speaker 5: Wow.
Speaker 4: It can basically be found in all walks of life,
Speaker 4: from bacteria to protozoans, leeches, worms, fishes, birds, plants. Did
Speaker 4: you know that plants make serotonin?
Speaker 5: No? But that makes me so happy.
Speaker 3: I know why I don't know dogs humans?
Speaker 4: I mean basically yeah, I mean dogs make sense. Plants
Speaker 4: is a little more like it's a little what so
Speaker 4: basically everything. It exists in all the organs of the
Speaker 4: human body, which is pretty fascinating, but not as fascinating
Speaker 4: as the fact that it's found in basically every living
Speaker 4: organism on this planet.
Speaker 3: Wow, So what does this tell us?
Speaker 4: Like, it's so widespread and so ancient that it means
Speaker 4: that a this serotonin is got to be really important,
Speaker 4: super important, and be just how many ways. It is important,
Speaker 4: like the varied roles that it can play.
Speaker 5: It's obviously not just doing one thing exactly.
Speaker 4: It's not just oh, this is the depression neurotransmitter in
Speaker 4: humans only, right, Yeah, I mean, and we tend to
Speaker 4: think of and describe serotonin as a neurotransmitter, which it is,
Speaker 4: but it also existed before neurons did.
Speaker 5: Oh my gosh, stop.
Speaker 3: Isn't that wild?
Speaker 5: Well, yeah, because if you're talking about bacteria have serotonin,
Speaker 5: I didn't know that. Yeah, yeah, you don't have neurons exactly,
Speaker 5: You're just one cell.
Speaker 4: This neurotransmitter existed before it could be transmitted by neurons.
Speaker 3: Like, what is so cool? It's so cool?
Speaker 5: Do we know what that does in bacteria?
Speaker 4: I'm watching a lot of it is like energy capture
Speaker 4: or regulation or management. Sometimes there's like intracellular or like
Speaker 4: a signaling between.
Speaker 5: Different still signal what it is for us? Okay, okay, yeah, yeah.
Speaker 3: I mean it is involved.
Speaker 4: Like these are just some of the things that it's
Speaker 4: involved in just across life, which is regulating cell activity
Speaker 4: and signaling. Development and plasticity plays a huge role generation,
Speaker 4: energy consumption, metamorphosis, embryogenesis, digestion, feeding behaviors, motor activities, sleep regulation,
Speaker 4: neurological development, decision making, stress responses, mood behavior, social dynamics, anxiety, learning,
Speaker 4: and memory, just to name a few, just a few.
Speaker 4: It's everywhere does everything. Yeah, and so Aarin, I know
Speaker 4: that next week you'll tell us more about what seratonin's
Speaker 4: role is thought to be in humans, or like at
Speaker 4: least some of the things that we know it does, right,
Speaker 4: But I wanted to share just a couple of fun
Speaker 4: tidbits that I discovered in researching for this. I can't
Speaker 4: not on the non human side of things. Okay, So
Speaker 4: we love leeches, we do, and we.
Speaker 3: Love kissing bugs.
Speaker 4: Is love is not the right word, But we are
Speaker 4: intrigued by kissing gigs.
Speaker 5: Appreciate their They are interesting.
Speaker 4: Creatures, yes, and we have episodes that feature both of
Speaker 4: these creatures. In these two In medicinal leeches and kissing bugs,
Speaker 4: serotonin acts as a signal to expand their stomach so
Speaker 4: that they can eat many, many, many more times their
Speaker 4: body size blood.
Speaker 5: It's what, lets just suck all of our blood.
Speaker 4: Yep yep, just expand expand. It also seems to help
Speaker 4: leeches swim.
Speaker 5: Oh.
Speaker 4: In some species of worms, it stimulates development and egg laying.
Speaker 4: In certain marine molluscs, environmental serotonin is needed to induce
Speaker 4: metamorphosis from the larval to the adult stage, and so
Speaker 4: it's thought that the serotonin is produced by algae which
Speaker 4: the mollusks feed on. And so if you are detecting
Speaker 4: not high enough levels of serotonin and you're a mollusk
Speaker 4: and you're like, wait, where's the serotonin the environment and
Speaker 4: it's a little low, that could signal a resource poor area.
Speaker 4: So it's like, don't metamorphose here, you won't get enough
Speaker 4: to eat. What serotonin?
Speaker 5: Serotonin?
Speaker 4: It's incredible, I mean, and we could spend forever talking
Speaker 4: about what serotonin does in different species or tissues or organs.
Speaker 4: But do you know what else is fascinating about serotonin?
Speaker 4: I want to how it was discovered, Okay, okay. I
Speaker 4: was surprised that how much serotonin history. I was like, okay,
Speaker 4: I got to start at the beginning. What's the story
Speaker 4: of serotonin?
Speaker 5: Right?
Speaker 4: And then I was like, actually, this is fascinating. But
Speaker 4: I've thought about serotonin in isolation, like I've always thought
Speaker 4: about it in the context of SSRIs or in mental
Speaker 4: health disorders and like, what does it do in humans?
Speaker 4: Without thinking of it? It's a broader picture. Yeah, yeah, okay,
Speaker 4: So serotonin discovery. The early decades of the twentieth century
Speaker 4: were an exciting time to be a molecular biologist because
Speaker 4: what they found was that these increasingly sensitive bioassays allowed
Speaker 4: them to tease apart the functions of the tiny compounds
Speaker 4: that are constantly flitting around within the bodies of animals,
Speaker 4: humans and other animals, things like hormones or antibodies, vitamins,
Speaker 4: and of course neurotransmitters. What do these different molecules do,
Speaker 4: how do they interact with one another, what happens if
Speaker 4: things go awry? And how can we use all this
Speaker 4: knowledge to develop medications to treat certain conditions. These were
Speaker 4: the types of questions that motivated many researchers in the
Speaker 4: nineteen thirties, among them an Italian physiologist and pharmacologist named
Speaker 4: Vittorio or Spammer.
Speaker 3: We'll try that.
Speaker 4: I say his name a bunch more times, so great,
Speaker 4: but Erspimer had a particular interest in deriving pharmacologically active
Speaker 4: substances from nature to use in medications because he so
Speaker 4: he would be like, what is this plant alkaloid. Can
Speaker 4: we use this as a medication? What does it do
Speaker 4: these sorts of things? Okay, it was a very hot
Speaker 4: time for that. If you think also of things like
Speaker 4: willow and aspirin, and you think of quinine malaria, that's
Speaker 4: sort of right anyway.
Speaker 3: So his work.
Speaker 4: Erspimer's work centered around the smooth muscle of animals and
Speaker 4: trying to figure out which substances caused it to constrict
Speaker 4: or contract. So he looked at the skins and intestines
Speaker 4: of rabbits, of molluks, of molluscs it's a hard word
Speaker 4: to say, and of frogs to name a few, and
Speaker 4: substance found in a certain type of cells in the
Speaker 4: gut caught his eye. When he isolated it and tested
Speaker 4: it out. He observed that it caused smooth muscle contraction,
Speaker 4: and it didn't seem to be any of the recently
Speaker 4: discovered usual suspects. It was something completely undescribed at that point,
Speaker 4: and so he named it enteramine in his nineteen thirty
Speaker 4: seven paper.
Speaker 5: Okay.
Speaker 4: In the subsequent years, he found the substance in many
Speaker 4: other organisms and tissues, mollus cart octopus, salivary glands like
Speaker 4: I guess had a particular bent towards ocean creatures. Yeah, creatures,
Speaker 4: and he seemed quite enamored with it. In a letter
Speaker 4: that he wrote at eighty nine years old, so way
Speaker 4: way later, he described it as quote unquote my firstborn daughter, Okay,
Speaker 4: really loved enter remine.
Speaker 3: Yeah.
Speaker 4: But where Erstimer was actively looking for this stuff, another
Speaker 4: research group which was comprised of researchers Maurice, Rapport, Arta Green,
Speaker 4: and Irvine Page, they were looking for how to get
Speaker 4: rid of it. So since nineteen forty eight they had
Speaker 4: been investigating the cause of hypertension in the hopes of
Speaker 4: developing a drug and kept coming across the substance in
Speaker 4: their clotted blood samples, where it seemed to act as
Speaker 4: a vasoconstrictor interesting erin. Yeah, and so they were like, gosh,
Speaker 4: this is like one collaborator later said, Yeah, the group
Speaker 4: just kind of thought of it as a contaminant, and
Speaker 4: they were like, how can we identify this so that
Speaker 4: we can get rid of it, get rid of it
Speaker 4: out of our samples, I mean, And that might be
Speaker 4: underestimating their interest or understating their interest, because they ended
Speaker 4: up isolating, synthesizing and then producing an elemental analysis of
Speaker 4: the serum vasoconstrictor, which they named seratonin in nineteen forty eight,
Speaker 4: not knowing that it already had a name.
Speaker 5: Right, Yeah, they went out.
Speaker 4: They yeah, they won out. I mean, and I think
Speaker 4: they won out because it was the serum part. The
Speaker 4: pharmaceutical company liked the name sarah like SCR to indicate
Speaker 4: that it was found in the serum.
Speaker 3: I don't know first they named it.
Speaker 4: Yeah, five hydroxy trip trip to mean. But the pharmaceutical company, yeah,
Speaker 4: they were like serotonin.
Speaker 5: I mean, that is still what it is called. It's
Speaker 5: like five hydrox yeah, five h yeah yeah, five ht yes.
Speaker 4: But they yeah, they wanted a catchier which I appreciate.
Speaker 4: I five hydroxy trip to mean is a hard is
Speaker 4: a harder one to say, for sure. But within a
Speaker 4: few years this research group realized that, oh wait a second,
Speaker 4: this thing already like has been described, and so enter
Speaker 4: I mean and serotonin actually the same thing. And then
Speaker 4: they published this in a paper saying like, hey, these
Speaker 4: these two things are the same. And this kind of
Speaker 4: like expanded the interest and sort of the knowledge base
Speaker 4: of what this thing does. Right, But at the time
Speaker 4: it was still thought of as primarily a vasoconstrictor and
Speaker 4: involved in smooth muscle contraction. Its role as a neurotransmitter
Speaker 4: had not yet been uncovered, and when it was, it
Speaker 4: would launch serotonin out of the realm of like cool
Speaker 4: physiological things like this is neat, maybe this does something
Speaker 4: in mollusks and into the burgeoning field of brain chemistry.
Speaker 4: There was a researcher named Betty Tuurog who had been
Speaker 4: interested in understanding a phenomenon in the muscles of muscles. Okay, yeah,
Speaker 4: the organized the vibe out and she had identified serotonin
Speaker 4: as a likely candidate for were the mystery neurotransmitter that
Speaker 4: that she had suspected of playing a role. The structures
Speaker 4: seemed to match, and analyzes confirmed her hypothesis, making serotonin
Speaker 4: a neurotransmitter. But this landmark finding had trouble getting published
Speaker 4: because the editor of the journal that she submitted to
Speaker 4: sat on it for two years because he was like,
Speaker 4: this is not worthy of review two years, and he
Speaker 4: only sent it out for review after her advisor was like, hey, man, like,
Speaker 4: what's the deal.
Speaker 3: Can you please review this? This might be a.
Speaker 4: Pretty huge finding. Yeah, And it was. It didn't get
Speaker 4: a ton of traction. It's funny because it came out
Speaker 4: I think after another paper that got a lot more traction,
Speaker 4: which makes sense. But anyway, so TWAA didn't stop there
Speaker 4: with just this like this is a neurotransmitter. She reasoned
Speaker 4: that if saratonin was an important neurotransmitter in invertebrates like muscles,
Speaker 4: it was probably invertebrates too. One of her advisors was like,
Speaker 4: I don't so, I think this is just a this
Speaker 4: is just just an invert thing. Yeah, just an invert thing,
Speaker 4: just like a very you know, like primitive transmitter of course, right, Yeah,
Speaker 4: but she got the last laugh because she isolated serotonin
Speaker 4: not only from muscle nervous tissue like in the bivalve,
Speaker 4: but from mammalian brain as well, and her resulting nineteen
Speaker 4: fifty three publications started a new chapter or even a
Speaker 4: new book really on serotonin in brain function and mental illness.
Speaker 5: Fascinating.
Speaker 4: So that is how serotonin was like discovered and then
Speaker 4: discovered to be a neurotransmitter in the mammalian brain.
Speaker 5: Something that was in the mammalian brain that potentially was
Speaker 5: having effects. Yes, in the mammalian brain.
Speaker 3: What do we do with this?
Speaker 5: Yeah?
Speaker 4: So since the nineteen forties, LSD fascinated those who knew
Speaker 4: about it, of course that dead who also wondered at
Speaker 4: its psychedelic properties. So a couple of these researchers, Dilworth
Speaker 4: Woolley and Elliott Shaw followed these developments on serotonin with
Speaker 4: great interest because the neurotransmitter was structurally very similar to LSD.
Speaker 4: So when they like, when that chemical structure was published
Speaker 4: by that first group, they were like, this is this
Speaker 4: is really interesting and they thought, Okay, maybe because it's
Speaker 4: so structurally similar to LSD, does this mean that LSD
Speaker 4: could act as a block, like fitting into serotonin's receptors
Speaker 4: and preventing it from working. Okay, And this concept of
Speaker 4: like a lock and key for neurotransmitters would form the
Speaker 4: basis for understanding how drugs could act as either mimicking
Speaker 4: a natural substance like a neurotransmitter or a hormone, or
Speaker 4: blocking its action like LSD did to serotonin. So it
Speaker 4: was like, what does this do? Can this either flood
Speaker 4: brain with more of the same and then there are
Speaker 4: all the receptors are filled in the way that it
Speaker 4: normally and things continued to act the way they would,
Speaker 4: but maybe like kind of elevated elevated or would it
Speaker 4: block block the action exactly? Yeah, And so sure enough,
Speaker 4: when it came to LSD, that is exactly what happened
Speaker 4: when someone tried it out. It blocked serotonin and so
Speaker 4: receptors receptors, and so for Woolley and Shaw, this raised
Speaker 4: the question of whether serotonin could play a role in
Speaker 4: mental illness because they had observed that people who were
Speaker 4: on LSD could experience mental disturbances that looked very similar
Speaker 4: to something like schizophrenia, for example, And so what if
Speaker 4: those disturbances were the results of the drug blocking serotonin.
Speaker 4: So maybe, to extend this even further, they thought, Okay,
Speaker 4: maybe it's not just about someone on LSD and these disturbances,
Speaker 4: but what if mental illnesses, mental health disorders like schizophrenia,
Speaker 4: are actually some sort of mismatch or decrease in serotonin serotonin. Yeah,
Speaker 4: And so subsequent experiments and closer scrutiny in this idea
Speaker 4: showed that it didn't quite work out that way, particularly
Speaker 4: when it came to schizophrenia, But there was something to
Speaker 4: the idea, and researchers began testing other drugs that could
Speaker 4: either deplete or replenish stores of serotonin.
Speaker 5: Okay.
Speaker 4: One of these serotonin depleters was recurpene.
Speaker 3: Does this sound familiar? Yeah?
Speaker 5: Okay, did we talk about it on the podcast or
Speaker 5: you the podcast?
Speaker 3: Yeah?
Speaker 4: Because I was like, this sounds familiar, So I did
Speaker 4: a control f of our transcripts.
Speaker 3: Sure enough, and yeah.
Speaker 4: So recurping is an alkaloid from the snake wood plant
Speaker 4: Rau Wolfia serpentina, and it was examined as a possible
Speaker 4: treatment for hypertension. And then but this is not this
Speaker 4: is not when we I'll tell you about it in
Speaker 4: a second, okay, Okay, Okay, First I'm going to get
Speaker 4: to like the serotonin part. So researchers found that people
Speaker 4: were given recurping, uh, and then they tended to become depressed,
Speaker 4: which was resolved if treatment stopped. So they were like,
Speaker 4: what is recurping doing that is causing these symptoms of depression?
Speaker 4: And it seems very clearly resurping because it stops with
Speaker 4: stopping the treatment.
Speaker 3: Stopping treatment.
Speaker 4: Yeah okay, And so in tests carried out on rabbits,
Speaker 4: resurping was found not only two deplete stores of serotonin,
Speaker 4: which was a big contender, but also nouropinephrin, and a
Speaker 4: newly discovered neurotransmitter called dopamine.
Speaker 5: Dopamine.
Speaker 4: Yes, so we talked about this in our Parkinson's arkansans.
Speaker 4: This is how el dopa was found because they they
Speaker 4: found that when you when you gave rabbits high doses
Speaker 4: of recurping, they tended to exhibit some of like paraals symptoms.
Speaker 5: Similar to Parkins.
Speaker 4: And then they added el dopa and that sort of
Speaker 4: snapped them out of it, ultimately meaning the researchers to
Speaker 4: discover dopamine.
Speaker 3: Wow.
Speaker 4: Okay, but what does this all mean for depression and
Speaker 4: under and other mental health disorders? Like talked about Parkinson's,
Speaker 4: I've talked about hypertension, I've talked about schizophrenia. We haven't
Speaker 4: really talked about depression yet. Okay, the precise mechanism wasn't clear,
Speaker 4: but researchers hypothesized that maybe it was depletion of serotonin, dopamine,
Speaker 4: and nouropinephrine that underlay the development of depression, and that
Speaker 4: accesses might also lead to psychosis, especially when it came
Speaker 4: to dopamine. So, in other words, mental illness might be
Speaker 4: a result not of psychological imbalances, but rather chemical ones.
Speaker 4: And so this is really when like the imbalance sort
Speaker 4: of notion of mental health illnesses began.
Speaker 5: And specific imbalances of those three like monozines.
Speaker 4: Yeah, the monoamine or catacholamine hypothesis of depression was essentially
Speaker 4: born out of these experiments.
Speaker 5: Okay, okay, yeah, okay.
Speaker 4: So I want to take a second here to ground
Speaker 4: ourselves in what depression meant. At the time this research
Speaker 4: was happening, this is the nineteen fifties, nineteen sixties or so,
Speaker 4: it was rarely diagnosed. It wasn't often even included as
Speaker 4: a separate category of diagnosis. Like there was really like
Speaker 4: depression as a diagnosis. When patients expressed symptoms that today
Speaker 4: we would associate with depression, so despondent, low energy, chronically sad,
Speaker 4: something that would interfere with their everyday life, they were
Speaker 4: usually ascribed to an expression of someone's anxiety, so like
Speaker 4: anxiety was thought to be at the heart of most
Speaker 4: mental health disorders at the time, some clinicians felt that
Speaker 4: depressive symptoms were like a self defense against anxiety. Oh,
Speaker 4: I can't work too much if I just become apathetic.
Speaker 5: That was sort of like.
Speaker 4: The idea that I think decission fell into Yeah, it is.
Speaker 4: It is really interesting, especially considering like today sort of
Speaker 4: the lines between anxiety and depression and the yeah.
Speaker 5: Yeah, I mean there is. There is so much overlap
Speaker 5: with anxiety symptoms of anxiety and depression, and a lot
Speaker 5: of times depression is a lot harder to treat if
Speaker 5: there is an anxiety component versus if there isn't.
Speaker 3: Yeah.
Speaker 5: So that's really interesting, it is.
Speaker 4: It's yeah, the history of anyway we could yeah.
Speaker 5: I know that, like the history of psychiatry. Wo oh,
Speaker 5: that's not this episode.
Speaker 3: That not this episode. Yeah.
Speaker 4: And so there was a distinct diagnosis for depression separate
Speaker 4: from anxiety, but it was reserved for extreme, like really
Speaker 4: severe cases that involved psychosis.
Speaker 5: Okay. Interesting.
Speaker 4: So from the nineteen fifty two DSM describing quote unquote
Speaker 4: psychotic depression reaction quote, these patients are severely depressed and
Speaker 4: manifest evidence of gross misinterpretation of reality, including at times
Speaker 4: delusions and hallucinations end quote. Okay, so it's it's not again,
Speaker 4: it's a very narrow definition compared to what we have today, exactly. Yeah,
Speaker 4: And things like melancholia or melancholy had also been a
Speaker 4: popular diagnosis in the late eighteen hundreds and into the
Speaker 4: nineteen hundreds, and it was believed to have a biological
Speaker 4: basis until Freud. That biological basis and melancholia in general
Speaker 4: kind of fell out of favor as Freudian theory took over,
Speaker 4: which held that biology had nothing to do with it.
Speaker 5: Yeah, it was all your mom and stuff.
Speaker 3: It's all your mom.
Speaker 5: Yeah, that's the conclusion of freud the end.
Speaker 4: So all this is to say that in the nineteen
Speaker 4: fifties and nineteen sixties, depression was not the widespread, broadly
Speaker 4: defined cli entity that we think of today, and so
Speaker 4: it really wasn't seen as a major problem warranting extensive
Speaker 4: searches for effective treatment or better understanding of its underlying cause. Wow,
Speaker 4: the framing of it really prevented interest. I think, yeah,
Speaker 4: and like consideration.
Speaker 3: Yeah.
Speaker 4: And some treatments did exist, such as electroconvulsive therapy, which
Speaker 4: was used for severely depressed patients with psychosis in the
Speaker 4: nineteen forties, and it seemed effective in the short term,
Speaker 4: but no one knew why, and it quickly fell out
Speaker 4: of favor as long term negative effects emerged, like extreme
Speaker 4: memory loss and other things. Amphetamines were prescribed for the
Speaker 4: Blues in the nineteen forties and the nineteen fifties.
Speaker 5: Okay.
Speaker 4: And then there were combination amphetamines sedatives to treat anxiety
Speaker 4: and the depressive symptoms that came with it.
Speaker 5: Oh gosh, okay, upper runed downer, mix it all up, Okay, great, yep.
Speaker 4: But again none of these drugs were antidepressants. They were
Speaker 4: treating what was understood at the time to be a
Speaker 4: symptom of anxiety. What turned things around was tuberculosis.
Speaker 5: Stop it, everything is tuberculosis.
Speaker 3: I was just, yeah, I have here.
Speaker 4: John Green was right, everything really is tuberculosis.
Speaker 5: Stop it, yes, tell me more, Okay, okay.
Speaker 4: So, as the nineteen fifties rolled around, the hunt for
Speaker 4: an effective tuberculosis treatment had been going on for decades
Speaker 4: with how much success. And then a new drug called
Speaker 4: iproniazid okay, m hmm came on the scene. And if
Speaker 4: you listen to our book club episode on the Black
Speaker 4: Angels by Maria Smilios, this is one of the new
Speaker 4: anti tuberculosis drugs that the nurses at Seaview Hospital on
Speaker 4: Staten Island tested out on their patients.
Speaker 5: Okay.
Speaker 4: And when these patients, when these tuberculosis patients were getting
Speaker 4: this drug, their moods improved, their appetite increased. There were
Speaker 4: even reports of dancing in the wards. Whoa yep. Initially,
Speaker 4: these positive side effects of euphoria, psychostimulation, increased appetite, improved
Speaker 4: sleep weren't of much interest to the drug manufacturer, especially
Speaker 4: since ipronized It only did so so when it came
Speaker 4: to treating tuberculosis, its sister drug, ionized It did much better.
Speaker 4: But the pictures of dancing patients that seeview caught the
Speaker 4: attention of one psychiatrist, doctor Nathan Klein, who wondered whether
Speaker 4: ipronized It held the answer to a question that had
Speaker 4: long interested him. If something like schizophrenia was caused by
Speaker 4: an excess of psychic energy quote unquote, which is kind
Speaker 4: of the idea at the time, could depression be caused
Speaker 4: by a lack of it? Could this tuberculosis drug, with
Speaker 4: its euphoric effects increase psychic energy. So began a trial
Speaker 4: using Iproniazid to treat his patients who had severe depression
Speaker 4: at the state hospital where he worked. He detected an
Speaker 4: improvement in seventy percent of them, wow, which he reported
Speaker 4: in nineteen fifty seven, and so with this, iproniazid came
Speaker 4: the became the first of our modern antidepressants on the
Speaker 4: market ANDI or a monoamine oxidase inhibitor. Isn't that unbelievable
Speaker 4: from tuberculosculosis.
Speaker 5: Wow, Jock Green had it right.
Speaker 3: He had it right.
Speaker 4: I just I love that it was this researcher, the
Speaker 4: psychiatrist who saw these pictures and was.
Speaker 5: Like, whoa they seem pressed?
Speaker 1: Ye?
Speaker 3: Can we use this?
Speaker 5: How interesting?
Speaker 3: Yeah, that's it's amazing. Yeah.
Speaker 4: And the popularity of iproniazid and other similar MAOIs that
Speaker 4: quickly appeared at following iproniazid in the late nineteen fifties,
Speaker 4: it was they were fairly lived as a as a
Speaker 4: popular antidepressant because while they did seem to be effective
Speaker 4: in treating depression, they came with some pretty nasty side
Speaker 4: effects constipation, difficulty urinating, even jaundice. Death could occur if
Speaker 4: someone eat cheese or chocolate.
Speaker 5: Yeah, and drug tresines.
Speaker 4: Drug companies withdrew the drug and it would soon be
Speaker 4: replaced by another class of drugs, the tricyclic antidepressants or TCAs,
Speaker 4: which were approved.
Speaker 3: In nineteen fifty nine.
Speaker 4: And these had first been tested as a possible treatment
Speaker 4: for schizophrenia, where they were found to be not effective. No,
Speaker 4: but definitely not definitely not Again it was all like depletion,
Speaker 4: you know, that great sort of the sea cell of
Speaker 4: what do we want the balance? Yeah, exactly, But these
Speaker 4: these TCAs did show some positive impact for people with
Speaker 4: depressive symptoms. At side effects again left something to be desired, dizziness,
Speaker 4: memory impairment, drowsing, et cetera. But I just think it's
Speaker 4: amazing that we keep finding antidepressants when we're not looking,
Speaker 4: which speaks to this phenomenon that I mentioned at the
Speaker 4: very beginning, like sometimes we have these drugs that are
Speaker 4: effective for certain conditions we don't know why, right, And
Speaker 4: stories like MAOIs and TCAs show us that we don't
Speaker 4: necessarily have to know how something works to develop effective treatments.
Speaker 4: And even if we think we know, like we thought
Speaker 4: we did with SSRIs, because this was like this was
Speaker 4: a more targeted drug development, and we're proven wrong about
Speaker 4: our initial hypothesis or not totally right, we can still
Speaker 4: make a difference.
Speaker 5: Yeah.
Speaker 4: Yeah, Okay, so we're finally at the point in the
Speaker 4: story where SSRIs.
Speaker 3: Come onto the scene.
Speaker 4: Okay, it's taken us a little bit to get here,
Speaker 4: but I feel like it was important to understand the
Speaker 4: big picture, like, oh yeah, it's just fascinating, you know,
Speaker 4: from two billion, three billion years ago all the way to.
Speaker 5: Till the day in nineteen sixties.
Speaker 3: Nineteen sixties, there you go.
Speaker 4: And so the advent and effectiveness of MAOIs and TCAs
Speaker 4: kind of lent support to the idea that depression and
Speaker 4: other mental health disorders are related in some way to serotonin, orpinephrine,
Speaker 4: and dopamine. So like there's something to the monoamine hypothesis
Speaker 4: of depression, right, And how exactly they were involved was
Speaker 4: unclear since they both worked in different ways TCAs and MAOIs, Right,
Speaker 4: they both led to kind of the same end result.
Speaker 5: Right, you're increasing the amount of these neurotransmitters.
Speaker 4: Exactly, and how you're doing that, that's not really sure.
Speaker 4: And how is it improving your symptoms?
Speaker 5: I would really know. No.
Speaker 4: And so it seemed like antidepressants were on a trajectory
Speaker 4: of incremental improvements. But like we talked about, those two
Speaker 4: existing classes had some serious drawbacks with their prevalent and
Speaker 4: sometimes serious or deadly side effects, which were due in
Speaker 4: part to how they weren't super specific. They were kind
Speaker 4: of ramping up all of those three dopamine, norpinephrin, serotonin.
Speaker 4: It was kind of just like across the board. And so,
Speaker 4: you know, some researchers thought, well, what if we could
Speaker 4: make these more specific, What if you could target just
Speaker 4: one of these neurotransmitters, Maybe that would help with the
Speaker 4: side effects, Maybe that would get to the root underlying
Speaker 4: cause of these disorders. And so by the late nineteen sixties,
Speaker 4: interest had gathered specifically on the role that serotonin might
Speaker 4: play in depression. Specifically, again it's depletion, with the logic
Speaker 4: following that if you could restore serotonin, you could alleviate depression.
Speaker 4: We know that that's.
Speaker 3: Not the case.
Speaker 5: It's not exactly the truth.
Speaker 4: It's not exactly the truth, but it was a it
Speaker 4: was a hypothesis. Yeah, it's not Yeah, it's anyway, there's
Speaker 4: a lot of us were starting points, the starting point exactly.
Speaker 5: Yeah, And so.
Speaker 4: Pharmaceutical companies set their sites on making a compound that
Speaker 4: prevented the reuptake of serotonin at serotonin transporters, specifically, meaning
Speaker 4: that it had reduced affinity for Nora Bernephrin. So put
Speaker 4: that jargon another way, and you've got a selective serotonin
Speaker 4: reuptake inhibitor SSR.
Speaker 5: Yeah.
Speaker 4: Eli Lilly found success in nineteen seventy two with a
Speaker 4: compound that they called fluoxetine, and thirteen years later it
Speaker 4: became the first SSRI approved by the FDA under the
Speaker 4: trade name Prozac. And it is interesting to me that
Speaker 4: with Prozac with fluoxetine, we did have this plan, here's
Speaker 4: what the drug that we want to make, and here's
Speaker 4: what we're going to do, and here's how we think
Speaker 4: it works. Right, And it still didn't work out, but
Speaker 4: it still had some effect. And it's just different than
Speaker 4: like ipronize it, which was like, oh, tuberculosis, right.
Speaker 5: It was much more like intentional.
Speaker 3: It was an intentional design. Okay.
Speaker 4: So in the time between PROZACX development and its approval,
Speaker 4: which is, you know, decade and a half, depression had
Speaker 4: time long time. Depression had undergone quite a transformation really,
Speaker 4: so beginning in the late nineteen sixties, clinicians started to
Speaker 4: think of it as separate from anxiety, or that what
Speaker 4: had been thought of as anxiety was actually depression. So
Speaker 4: the depression was both increasing in its prevalence as well
Speaker 4: as broadening in its definition. Okay, So the WHO in
Speaker 4: nineteen seventy four declared depression much more widespread than previously thought,
Speaker 4: affecting one fifth of the global population.
Speaker 2: Wow.
Speaker 3: Yeah in nineteen seventy four.
Speaker 5: In nineteen seventy four, Wow okay, huh.
Speaker 4: And part of this transformation, and also what made such
Speaker 4: estimates possible, was the creation of standardized scales by which
Speaker 4: to measure and diagnose depression. These scales allowed researchers to
Speaker 4: conduct clinical trials where they could track depression symptoms over
Speaker 4: time and with or without treatment, and these trials revealed
Speaker 4: that by and large, antidepressants were effective in alleviating symptoms
Speaker 4: of depression, with some differences among formulations and of course
Speaker 4: among different individuals, and their efficacy held whether someone could
Speaker 4: identify specific reasons for their depression, like this thing is
Speaker 4: going on in my life or this you know, my
Speaker 4: dog died, my car broke down, my house was foreclosed upon,
Speaker 4: or if they couldn't right so, in response like to
Speaker 4: this sort of depression happens, antidepressants work whether or not
Speaker 4: you can define a specific incident. The DSM was like,
Speaker 4: we need to make some adjustments, and so the three
Speaker 4: published in nineteen eighty removed any questions about life circumstances,
Speaker 4: family history, triggers, and so forth, and its description of depression.
Speaker 5: Ooh interesting.
Speaker 4: Yeah, so instead it just provided a checklist of symptoms. Yeah, okay,
Speaker 4: so because previously diagnoses depended more on whether you could
Speaker 4: pinpoint fact life life situations.
Speaker 5: That's so interesting, especially thinking about now, like when you
Speaker 5: have life stressors a lot of times you're less likely
Speaker 5: to diagnose depression real till yeah, I mean because a
Speaker 5: certain amount of depressive symptoms are to be expected with
Speaker 5: significant life events, right, and so then it's like a
Speaker 5: grief reaction which you then have to separate out from depression.
Speaker 5: So that's interesting. I mean, it can certainly lead to depression,
Speaker 5: but it just sort of it complicates a picture more
Speaker 5: and it sounds like in the past it was like, no,
Speaker 5: you need to have that in order to be depressed.
Speaker 5: How interesting.
Speaker 4: The transformation's huge, yeah, huge, huge, And so this shift though,
Speaker 4: what it did was it it really increased diagnoses across
Speaker 4: the board, because now you don't have to say, oh, well,
Speaker 4: I don't think I think you're just I think you're
Speaker 4: just a little bored, or I think you're just a
Speaker 4: little bumped, you know what I mean, Like, I'm not
Speaker 4: saying that's exactly what was said, but I think legitimized
Speaker 4: no cases of depression where it was like nonspecific right,
Speaker 4: life events, Yeah, right. And so when Prozac hit the
Speaker 4: market in January nineteen eighty eight, there were many more
Speaker 4: people who sought prescriptions for this new antidepressant than there
Speaker 4: had been in past decades. Not necessarily because depression overall
Speaker 4: was on the rise, like because which it may may
Speaker 4: have been just because of the world or whatever, but
Speaker 4: also because our framing and perception of the condition had broadened.
Speaker 4: People now had the vocabulary to describe the things that
Speaker 4: they felt, and then they were often, though not always,
Speaker 4: taken more seriously about the impact of this on their
Speaker 4: day to day functioning.
Speaker 5: Right.
Speaker 4: By nineteen ninety, this is just two years. Within two
Speaker 4: years of its release in the US, Prozac became the
Speaker 4: most widely prescribed drug in North America.
Speaker 5: Wow, and just a.
Speaker 4: Few years later, the second most sold drug in the world.
Speaker 5: Wow W.
Speaker 3: This was unexpected. I don't think it illiglally anticipated.
Speaker 4: This Prozac was not the first antidepressant or even the
Speaker 4: first SSRI. There were other previous SSRIs but they were
Speaker 4: never approved for the US market, and they seemed to
Speaker 4: have more side effects, but prozac had fewer side effects,
Speaker 4: and so it was considered a safer drug compared to
Speaker 4: like TCAs, which meant that physicians were more likely or
Speaker 4: felt better about prescribing it not only to their patients
Speaker 4: who had like severe depression, but also those with milder symptoms.
Speaker 4: The continued pop popularity of prozac and later SSRIs showed
Speaker 4: that clearly these medications were working, but how were they working?
Speaker 4: Even before their release, researchers knew that these SSRIs were
Speaker 4: not acting under the hypothesis of low or imbalanced serotonin
Speaker 4: equals depression. That idea had been rejected decades before.
Speaker 5: It's just so fascinating that that doesn't like that is
Speaker 5: so often left out of the story.
Speaker 4: It doesn't get translated. It's like, yeah, people are like, oh,
Speaker 4: serotonin is not the only thing related to depression, you know,
Speaker 4: scream the headlines and it's yeah. All the researchers are like,
Speaker 4: what year.
Speaker 3: Is this right? We've known this, I was taught this.
Speaker 5: Said that, who said that it was sorry said that.
Speaker 3: It was Yeah.
Speaker 4: It's a straw man argument, because if that was the hypothesis,
Speaker 4: then they would have expected to see You would expect
Speaker 4: to see improvement in symptoms in someone very soon after
Speaker 4: someone starts taking SSRIs, not after weeks, which is the
Speaker 4: timeline that we usually see. But given that these drugs
Speaker 4: are effective, serotonin likely plays some role in depression and
Speaker 4: other mental health disorders, maybe in like a regulatory capacity.
Speaker 4: But even though researchers had long acknowledged that the biological
Speaker 4: underpinnings of depression are more complicated than just serotonin.
Speaker 5: Add serotonin, yeh, sprinkle some serotonin.
Speaker 4: Well, serotonin on top, this message didn't reach the general
Speaker 4: public until I feel like, relatively recently, you've got again,
Speaker 4: like popular media articles or TikTok saying things like you've
Speaker 4: been lied to. Antidepressants don't do what we think, and
Speaker 4: it's like yeah, or the final nail in the depression
Speaker 4: serotonin coffin?
Speaker 5: Is that a real headline?
Speaker 4: Narin, I don't remember it, Okay, I think it actually,
Speaker 4: I think it was because researchers again were like, final nail.
Speaker 4: That thing's been dead for decades, it's been buried. What
Speaker 4: are you talking about? But a few promoted or even
Speaker 4: we're behind this misrepresentation of the science of SSRIs. You know,
Speaker 4: this is where like this again the serotonin hypothesis as
Speaker 4: the straw man argument against these medications, right, and this
Speaker 4: I mean to go, I don't want to go too
Speaker 4: much into like the motivations or the reasons for this misrepresentation,
Speaker 4: because I do think that there is like an anti
Speaker 4: psychiatry movement that you don't need drugs, You just need
Speaker 4: to pull yourself up by the bootstraps, bootstraps and work hard.
Speaker 4: Just get out of bed, clean your house, just do it,
Speaker 4: just push.
Speaker 5: Do it, just do it, right. I mean, that's the
Speaker 5: same thing as before anyone recognized that depression was a thing, Right,
Speaker 5: It's the same, that's the same end result.
Speaker 3: It's the same end result.
Speaker 4: The thing is this, this misrepresentation saying that scientists think
Speaker 4: that SSRIs work on depression in this way and they're wrong.
Speaker 4: That has the capacity to do real damage.
Speaker 5: Especially to people who are on SSRIs, who have benefited
Speaker 5: from SSRIs, who are now in charge of regulating our SSRIs.
Speaker 4: It has or could encourage people to stop treatment under
Speaker 4: these false pretenses. And it also just overall deepens mistrust
Speaker 4: in science and medicine. The truth is that the general
Speaker 4: public has been lied to, or at least not been
Speaker 4: told the whole truth about our understanding of SSRIs and depression. Ads,
Speaker 4: like pharmaceutical ads, which should be outlawed in my opinion,
Speaker 4: for antidepressants, have long claimed that the drugs work by
Speaker 4: correcting a chemical imbalance, and these ads reduce these complicated
Speaker 4: disorders to a simple issue of brain chemistry. It's a
Speaker 4: catchy thing. You got, you know, thirty seconds for an ad.
Speaker 4: Of course you're going to say the simplest thing possible.
Speaker 4: And what company wants to be like, we don't know.
Speaker 3: How this works.
Speaker 4: Of course they're going to say something like it's a
Speaker 4: chemical imbalance. But I think that that under represents or
Speaker 4: falsely represents the complexity of the issue and how much
Speaker 4: we know or don't know about this. And I think
Speaker 4: this trickles down into physicians who will use the same
Speaker 4: language when explaining the medications to their patients. Again, not
Speaker 4: wanting to sit there in an office, you have five
Speaker 4: minutes to talk to your patient, and you don't want
Speaker 4: to say we don't know how this works.
Speaker 3: Number one.
Speaker 4: Number two, let me tell you about how serotonin receptors
Speaker 4: work in your brain.
Speaker 3: And your gut. Right, I know. So it's laughing chemistry.
Speaker 3: It's an imbalance.
Speaker 5: I'm laughing so much erin because I it's my favorite
Speaker 5: thing when I get to explain mechanisms to my patients.
Speaker 5: So you're in the office or you get to be like, Okay,
Speaker 5: this is too detailed, but just give me one and
Speaker 5: then and then at the end be like, yes, so
Speaker 5: we don't know how it works, but.
Speaker 3: Right, but it's yeah, but no, but most people.
Speaker 5: Don't do that. Yeah, yeah, most people. We also don't
Speaker 5: do that, and like, yeah, okay, we learned the mechanism
Speaker 5: in med school and then you obviously forget it because
Speaker 5: there is way too much to know. And what you
Speaker 5: really need to know is do I have something that
Speaker 5: can help my patient or not? Right exactly so.
Speaker 3: And I think that, like you know, I was thinking.
Speaker 4: I just I've spent so much time thinking about SSRIs,
Speaker 4: like in a very focused, directed way where I'm like, okay,
Speaker 4: this these ads for example, or this message I'll say,
Speaker 4: whether it's in an ad or in your doctor's office
Speaker 4: or wherever, about depression and other mental health disorders being
Speaker 4: a result of an imbalance in your brain chemistry. That
Speaker 4: message has been really important for reducing stigma and for
Speaker 4: underscoring the idea that these disorders are real and that
Speaker 4: they can be treated with medical solutions. But by framing
Speaker 4: it in this unnuanced way, by not acknowledging that there
Speaker 4: are still unknowns, it ignores the need for more research
Speaker 4: both on SSRIs as well as depression and other mental
Speaker 4: health disorders. It disregards the experiences of many people for
Speaker 4: whom these medications don't work, and it minimizes the importance
Speaker 4: of non pharmaceutical interventions such as therapy. And it does
Speaker 4: a disservice to everyone who uses, prescribes, or researches these
Speaker 4: medications or alternative treatments for depression and other mental health disorders.
Speaker 4: There is no question that in the decades since Prozac's release,
Speaker 4: SSRIs have completely changed the landscape of depression. They have
Speaker 4: provided relief to so many people. They've been a life
Speaker 4: saving to so many people. They have helped to reduce
Speaker 4: stigma surrounding depression and other mental health disorders. They have
Speaker 4: forced us to reconsider how we think of mental illness.
Speaker 4: They are not perfect, but I don't know anyone who
Speaker 4: claims they are, besides maybe the pharmaceutical companies.
Speaker 5: Don't know any neat drug that is perfect.
Speaker 3: No drug, you're perfect.
Speaker 4: Yeah, But I'm I'm excited though for next week, Arin,
Speaker 4: when you get to tell me about more about how
Speaker 4: much we don't know and how much we do know
Speaker 4: about these medications and how we can make them maybe
Speaker 4: not perfect but better.
Speaker 5: Hmmm, that's a good one. I probably won't answer that question,
Speaker 5: but I will provide quite a lot of data to
Speaker 5: support what we do and don't know. And then a
Speaker 5: little bit in my opinions about how we talk about
Speaker 5: all of this too.
Speaker 3: Oh love it?
Speaker 5: Okay, next week more next subscribe so that you don't
Speaker 5: miss an.
Speaker 4: Episode, never miss an EPP. And in the meantime, how
Speaker 4: about some reading?
Speaker 5: How about some reading? I'd love to do more reading, Aaron.
Speaker 4: I have a bunch of sources, but I'm going to
Speaker 4: shout out three in particular. There's by Whittaker as Media
Speaker 4: in nineteen ninety nine, The Discovery of serotonin and its
Speaker 4: role in neuroscience from Hillhouse and Porter twenty fifteen, A
Speaker 4: brief history of the development of interdepressant drugs from Monoa
Speaker 4: means to glutamate, and then kind of just the broad scope,
Speaker 4: big picture of depression and the advent of SSRIs and
Speaker 4: how that changed the landscape. There was a couple great
Speaker 4: chapters in a book called Mind Fixers Psychiatry's Troubled Search
Speaker 4: for the Biology of Mental Illness by Anne Harrington, and
Speaker 4: I've got more I'll post.
Speaker 3: Them on our website.
Speaker 4: This podcast will kill you dot Com.
Speaker 5: Thank you again so much to the providers of our
Speaker 5: first hand account. We appreciate you so so so much.
Speaker 5: And thank you to everybody who wrote in to share
Speaker 5: your story about SSRIs. We really appreciate it.
Speaker 3: Yeah, thank you, Thank you.
Speaker 4: Thank you also to Bloodmobile now on Instagram for the
Speaker 4: music that you provide for this episode in all of
Speaker 4: our episodes.
Speaker 5: Thank you to Leanna and Tom and Brent and Pete
Speaker 5: and Mike and Jess and everybody exactly right for all
Speaker 5: your help making these episodes happen.
Speaker 4: Yes, thank you, and thank you to you listeners and
Speaker 4: watchers and anyone who partakes in the podcast in some way.
Speaker 3: We really appreciate it that we do. Thank you. Thank you.
Speaker 5: Thank you as always to to our patrons for your
Speaker 5: support over on Patreon. We really really appreciate it. It means
Speaker 5: a lot.
Speaker 3: We do well.
Speaker 5: Until next time, wash your hands, you filthy animals,