How Antidepressants Work

The good news is that we know antidepressants can treat major depression, helping millions of people live healthier lives. The bad news is that we don’t really know how they do that. Check out the theories on how antidepressants work in this episode. See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Speaker 00

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• 0:04Josh Clark?

  Curious people ask great questions, and here's one. What's something you wish there was an app for? Well, with Base44, you can build it yourself. Maybe it's a tool to organize a project, or track a hobby, or share knowledge, or solve a problem that's always bugged you. Just describe what you want in your own words. No coding required. Base44 handles the database, login, backend, and hosting. Try it for free. Go to base44.com to get started. Buy smart, drive for less, and trade for more. That's Toyota affordability, and it starts with a great deal on an off-road-ready Tacoma or half-ton Tundra, two of Toyota's longest-lasting trucks, combining power for work, tech for adventures, and style in between. And they're built on a reputation for quality and reliability,

• 0:48Josh Clark?

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• 1:59Speaker 04

  Welcome to Stuff You Should Know, a production of iHeart Radio.

• 2:09Josh Clark?

  Hey and welcome to the podcast. I'm Josh and there's Chuck and Jerry's here too. Well, actually, that's not true, is it Chuck? That's a dirty, dirty lie.

• 2:17Speaker 03

  What are you talking about?

• 2:18Josh Clark?

  It's just me and Chuck. We're, we're producing our own jam today, I guess you could say. And this is stuff you should know.

• 2:26Speaker 03

  That's right. And the listener will never hear where we edit out when Jerry bursts into the room in two minutes. We'll just cut that out, nice and clean.

• 2:36Josh Clark?

  We should just leave it in once, just to really punish her.

• 2:39Speaker 03

  Yeah. Oh, hey, guys.

• 2:43Josh Clark?

  She's got like a little bit of miso in the corner of her mouth.

• 2:45Speaker 03

  Oh, always a little crusty miso.

• 2:48Josh Clark?

  So Chuck, today, we are doing something in grand Stuff You Should Know fashion. We're doing a tangential

• 2:59Josh Clark?

  episode where we haven't done like the core episode that it relates to.

• 3:05Speaker 03

  Have we never done one on depression officially?

• 3:08Josh Clark?

  I could not believe, I, I looked on the stat sheet maintained by Jill Hurley, which is infallible. I looked all over the internet.

• 3:18Josh Clark?

  I sat there and had a conversation with myself. Nothing. It's not there.

• 3:25Speaker 03

  Yeah. I mean, that's so like us to hit stuff like bipolar first.

• 3:29Josh Clark?

  Yeah. Yeah. We did do bipolar. We've done PTSD. We've done ADHD, obviously, all that. But we'll definitely do depression at some point. Okay?

• 3:40Speaker 03

  I think it makes sense maybe to cover this first. So how about that?

• 3:44Josh Clark?

  Sure. Stick it to me.

• 3:46Speaker 03

  Yeah. Put that in your palm and wash it down with some water.

• 3:51Speaker 03

  How's that for a segue?

• 3:52Josh Clark?

  Oh, that was a good one. That was great, man. So yeah, we're talking about antidepressants. That was a great one.

• 3:58Speaker 03

  Thanks.

• 3:58Josh Clark?

  And to talk about antidepressants, we really do have to kind of give at least the briefest overview of what depression is like. It's kind of everywhere. I saw something like 60 million adults in America. And I think they, they define that over age 18 these days for this kind of stuff. Have some sort of diagnosed depression.

• 4:21Josh Clark?

  I think twenty million of those have major depressive disorder, which also is called clinical depression or unipolar depression. As opposed to say like bipolar where you have ups and downs, mania and depression. Unipolar is like just depression.

• 4:41Speaker 03

  Yeah.

• 4:42Josh Clark?

  And it apparently is picking up so much that the World Health Organization is saying like, hey, guys, by 2030, that will be the leading disease essentially in the entire world. Depression will be just the way that things are going. And everyone in the world is like, yeah, we know. And it just kind of is going from there.

• 5:03Speaker 03

  Yeah, I mean, that's a good overview, you know, without getting into the weeds as far as numbers go. Symptoms, as you might imagine, are.

• 5:17Speaker 03

  They're sad, disrupted sleep, feeling like you're worthless. Sometimes it affects your concentration. Sometimes it affects your ability to even experience pleasure at all. Even, you know, when you're, you know, doing something that might ordinarily be fun for you. It's not fun. It's not being sad in a moment or being blue for a little while. It is a persistent thing where it disrupts your life. It interferes with your life. It can interfere with your relationships and interfere with your relationship with yourself in a big, big way.

• 5:54Josh Clark?

  Yeah, and for a lot of people, I think for most people, statistically speaking, it's chronic or recurring. You don't just have one episode. It can keep coming back and back. And it's nothing new, like depression is not new, although it does, it has really kind of picked up as far as diagnoses and prescriptions go. But, I mean, we used to call it melancholy and they associated it with black bile. All the way back to Hippocrates. And depending on what culture you were from, they would either say, tell you that you needed positive rewards. If they. You lived in Persia in the ninth century. Or if you were in medieval Europe, they might burn you at the stake or something like that.

• 6:39Josh Clark?

  Luckily, we've come a long way with treating depression. That's the, that's, I think we should say here at the outset, that's the message we're trying to say. Like, it is highly treatable.

• 6:50Speaker 03

  Yeah.

• 6:50Josh Clark?

  Like, if you have depression and you're, you're not treating it, there's definitely hope. So please don't feel like there's not. There's plenty of hope. If anything, hopefully, that's what we get across this, in this episode. But there used to be, they used to give people edemas, they used to give people baths. Positive thinking, diet, exercise. And what's interesting, Chuck, is some of those are still prescribed today, depending on the severity of your depression.

• 7:18Speaker 03

  Yeah, for sure. And those things very much help. And I'm glad you said that, what you said just a second ago, because when I said, I sounded very, very down when I said that the symptoms are, and I paused and just said sad.

• 7:31Josh Clark?

  It is.

• 7:32Speaker 03

  There is a lot of hope, but, you know, I have, everybody you know has, if they don't suffer from the depression, you have people in your life, in your family, in your friends that do. And it, and it makes me very sad, because these are, you know, great people who have a hill they need to consistently hike up. And I imagine it, it is something that drains your life force. And we're here to talk about some of the ways that you can change that.

• 8:01Josh Clark?

  Yeah. Just as an aside, every time I think of depression being like really accurately portrayed, I think of Kirsten Dunst in Melancholia, the Lars von Trier movie.

• 8:13Speaker 03

  Yeah.

• 8:14Josh Clark?

  Lars von Trier, of all people, seems to have most accurately portrayed clinical depression.

• 8:19Speaker 03

  Great movie.

• 8:19Josh Clark?

  In that movie. It is a great movie, but she just does an amazing job. Like, there's a part where she's just in physical pain, such physical pain from being so depressed that like she can barely crawl into a bath.

• 8:34Speaker 03

  Yeah.

• 8:34Josh Clark?

  It's really, it's hard to watch.

• 8:36Speaker 03

  That was a one-timer for me.

• 8:38Josh Clark?

  Yeah.

• 8:39Speaker 03

  Uh, not the kind of movie you watch over and over, but Lars, been, Lars von Trier can make a great, great flick. And I love Kirsten Dunst, she's great.

• 8:47Josh Clark?

  For sure. So we should say that you rarely will get an enema when you present yourself to a physician and are diagnosed with clinical depression, major depressive disorder. Instead, they will prescribe you pills, antidepressants. And the reason that they will prescribe you antidepressants is because ever since the 70s, people have kind of basically treated depression based on what's called the biological model. And the biological model says that you're depressed because there's an imbalance of neurotransmitters, chemicals in your brain. And usually, they zero in on serotonin. They say you are depressed because you have low levels of serotonin.

• 9:31Josh Clark?

  And that's been the dominant view for decades now. That's how we treat depression is based on that presumption.

• 9:38Speaker 03

  Yeah, and it's accepted, and it's not like it's accepted with, you know, through gritted teeth. I think most people agree that's... What most people agree on is they don't really understand what might be the underlying issue or the mechanism behind that is. We do know like a lot of the things that may lead to depression. If you're a woman, you're more likely to get, what'd you call it, MDD?

• 10:05Josh Clark?

  Yeah, major depressive disorder.

• 10:08Speaker 03

  Yeah, major depressive disorder. If you have suffered a loss or unresolved grief. And these are things that can compound. It's not like, again, that's different than being sad about, you know, losing a loved one or something like that. But it can help contribute to MDD, same as if you suffer through a stress early in your life, that can all contribute. So we know some of those things, but we don't know that underlying mechanism that actually causes it. And because that, we don't exactly know how antidepressants work. We know that they do work, and we know what they do. But if you really don't know the underlying cause, you can't just say like, yeah, we have antidepressants completely figured out because we know they work and we know how they function.

• 10:51Josh Clark?

  Yeah, so much so, we have so little of a grasp on how people become depressed, especially like MDD depressed.

• 11:01Josh Clark?

  That studies show that people with MDD don't have, aren't likelier to have lower levels of serotonin than other people. Like, and that just throws out basically

• 11:14Speaker 03

  I know.

• 11:14Josh Clark?

  The whole premise of the biological model. And yet, we know that antidepressants work. They work better than placebo. They're definitely doing something. And we know that by design, what they're doing is going in and messing with the concentration of neurotransmitters in your brain.

• 11:31Speaker 03

  Mm hmm.

• 11:31Josh Clark?

  We know they're doing that. We just don't know how that mechanism is treating the depression. We just know it works. And I guess over the years, psychologists or psychiatrists and doctors have been like, let's just not ask questions.

• 11:47Speaker 03

  Well, thankfully, we know that's not 100% true because they are still studying and trying to figure this out. There was a study that, I guess you dug this one up from last year, from the University of Colorado, go Buffaloes, that hypothesized that increasing, well, increasing serotonin, we know that alleviates symptoms, but it's not like it's just rebalancing your brain and picking up a level that you had that was low. They are saying from the study that maybe it's helping to repair the neuroplasticity in the brain.

• 12:24Josh Clark?

  Mm hmm.

• 12:25Speaker 03

  And just sort of like their brain circuits have become just sort of stuck and lodged in that depressed state and it helps to unstick those.

• 12:33Josh Clark?

  Yeah, that's a newish, from what I can tell, rival theory to the biological model. Even though it's biological itself, it's very, very confusing stuff. But the idea, remember you said earlier that like you differentiate, you know, MDD or even just non-major depression, but you know, diagnosable depression from, from just a passing feeling of the blues, right? For like a day or so.

• 13:02Speaker 03

  Yeah, or mood swings, you might call it, whatever.

• 13:04Josh Clark?

  Sure. So this theory basically says that thing that people normally come out of,

• 13:10Josh Clark?

  People get stuck and it just seems to get worse and worse and worse the longer you're stuck in it. Or the harder you're stuck in it. So that's a, I love that theory and there's actually support for it. Because some of the newer, more far out treatments psychedelics in particular like ketamine and psilocybin. They have been basically irrefutably shown to treat major depressive disorder really well. And we know that psilocybin, for example, goes in and basically rewires your brain. So that would support the idea that it's a change in neuroplasticity that antidepressants create that helps treat depression.

• 13:54Speaker 03

  Yeah, for sure. And we also know, you know, you mentioned serotonin and norepinephrine and and, you know, messing or balancing out the brain chemistry. What's literally going on and what they're designed to do, antidepressants that is, and we're going to talk about, I guess, all of them probably, right?

• 14:11Josh Clark?

  By God, we are.

• 14:13Speaker 03

  They interfere with what's called the synaptic transmission of these things of serotonin, norepinephrine, dopamine. And that transmission is, is the movement of neurotransmitters from one neuron to another. They're they're leaping from one to another. They're talking to each other. They're getting to know one another. And it's that transmission that we know is what antidepressants affect.

• 14:39Josh Clark?

  Right. That's where the money is. They go to the horse's mouth. That's another word for the synapse. That's what neurologists call it, the horse's mouth.

• 14:49Speaker 03

  That's right. With the ultimate goal for all of these to increase levels of, of those things. Usually, I mean, some norepinephrine, as you'll see as we talk about, but more along the lines of serotonin.

• 15:03Josh Clark?

  Right. Here's the twist to all that, though. Neurotransmitters do all sorts of other things besides, say, like, regulate your mood.

• 15:12Josh Clark?

  I think serotonin does all sorts of crazy stuff like it helps regulate sleep, digestion, nausea, blood clotting, bone growth. It does everything, right? So if you start messing with the serotonin in your brain, it can also start to mess with the other functions that serotonin does, hence side effects. And so those are something that we are still figuring out too. But luckily, that's another thing we're getting a handle on is the side effects.

• 15:42Speaker 03

  Uh, that feels like a good breakpoint. That's a big old table setting.

• 15:46Josh Clark?

  Yeah.

• 15:47Speaker 03

  Yeah?

• 15:48Josh Clark?

  Yeah, we've got a dessert knife and a butter knife.

• 15:52Speaker 03

  I don't know which is which, pal. Can you help me out?

• 15:54Josh Clark?

  The dessert knife is a little smaller, fancier. It's got a kind of a sharp, pointy end that you could easily drive through the hand of the person sitting next to you at the table.

• 16:04Speaker 03

  Well, no, I mean, when I reach for the wrong one, just, just give my hand a little smack.

• 16:07Josh Clark?

  I'll drive my dessert knife through your hand.

• 16:10Speaker 03

  Perfect. All right. Well, we'll be right back and start off with the star of the show, the SSRI.

• 16:30Josh Clark?

  Curious people ask great questions, and here's one. What's something you wish there was an app for? Well, with Base44, you can build it yourself. Maybe it's a tool to organize a project, or track a hobby, or share knowledge, or solve a problem that's always bugged you. Just describe what you want in your own words. No coding required. Base44 handles the database, login, backend, and hosting. Try it for free. Go to base44.com to get started.

• 16:59Speaker 02

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• 17:29Josh Clark?

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• 20:01Speaker 03

  All right, so we promised to start off with SSRIs and we're starting off with that. We're kind of gonna jump around, starting with the most frequently prescribed sort of modern version of antidepressants, and then we'll jump back in time and talk about drugs that, you know, maybe your parents took, who knows? But these came around in the mid 1980s. I think the very first one to became, to become available was fluoxetine in 1988. And we're gonna, I guess we'll say both their regular name and their trade name or trademark name, just so everyone knows kind of what we're talking about.

• 20:41Josh Clark?

  Yeah, so the people who take them can like be like, "Yeah."

• 20:43Speaker 03

  Yeah, exactly. Fluoxetine is Prozac, paroxetine is Paxil, sertraline is Zoloft, fluvoxamine is Luvox. These are a challenge for me.

• 20:59Josh Clark?

  You're doing great, man.

• 21:00Speaker 03

  I appreciate it. Citalopram is Celexa. And why don't you take that Lexapro for me? What is that?

• 21:10Josh Clark?

  Eschatolopram.

• 21:11Speaker 03

  Eschatolopram, okay. I just had a little "yes" at the beginning of that.

• 21:14Josh Clark?

  You did fantastic. My favorite out of all of them is fluvoxamine.

• 21:18Speaker 03

  Yeah, that's a good word.

• 21:21Josh Clark?

  I like all those letters together like that, it's great. Yeah, and I'm not saying the drug itself, just the words.

• 21:27Speaker 03

  Yeah, so these are the SSRIs that are gonna block, they're called reuptake inhibitors, and what that means is they're gonna block that, that bus trip that serotonin takes back to that original cell, the pre-synaptic cell, the one who sent that transmission. And it leaves it floating around in that space in between, I believe that's probably you that said, "That's where all the action happens."

• 21:52Josh Clark?

  Yes.

• 21:52Speaker 03

  But that's in the, what's called the synaptic cleft, so it sends that, that serotonin out, and when it comes back, instead of up-taking it or re-up-taking it, it blocks that from happening, so that just means there, there's more of it where you need it.

• 22:05Josh Clark?

  They're just hanging out there like, "Where's my Uber?"

• 22:08Speaker 03

  Yeah, exactly.

• 22:10Josh Clark?

  So that was lame. I'm sorry, everybody.

• 22:13Speaker 03

  Pretty good. It's like, it's an Uber share.

• 22:16Josh Clark?

  There is so many other things I could have said, and I just, I don't know. I couldn't come up with anything better.

• 22:21Speaker 03

  You're trying to wedge in jokes in a unfunny episode.

• 22:25Josh Clark?

  Okay, thank you for that.

• 22:26Speaker 03

  That's what we try and do. Wedge in jokes where they're not appropriate.

• 22:31Josh Clark?

  So that's what, that's specifically what you just said SSRIs do, and they live up to their name essentially.

• 22:38Speaker 03

  Yeah, I don't think I even read out what it stands for, selective serotonin reuptake inhibitor, or it may have, but there it is again.

• 22:44Josh Clark?

  I think you did, but yes, so they specifically focus on serotonin and they prevent its reuptake from the synapse that sent it, or the neuron that sent it out, right? So the great thing about SSRIs is that they work really, really, really well on most people with the fewest side effect. And it's in part because they selectively target serotonin. And despite the fact that there's fewer side effects in fewer people than other types of antidepressants, some people do not respond particularly well to it. It depends on the brand, not necessarily the brand, but the type of drug.

• 23:27Josh Clark?

  I mean, all of the SSRIs aren't exactly the same.

• 23:30Speaker 03

  Right.

• 23:30Josh Clark?

  So if one's not working for you, you can try another one and another one, another one. And if that doesn't work, then you might move on to another class of antidepressants. But from what I can tell, SSRIs are essentially still today, like basically the flagship antidepressant, if there is such a thing.

• 23:50Speaker 03

  Yeah, I think you're right. And I think that when it comes to getting that,

• 23:56Speaker 03

  if you're on more than one, either that cocktail right or that single SSRI correct, that is where your doctor comes into play. But that, even though I've never been through this, I've been, I know plenty of people who have. I believe it's safe to say that's also where you come into play, though, as advocating for yourself in concert with your doctor.

• 24:17Josh Clark?

  Right, for sure.

• 24:19Speaker 03

  Is that a good way to say that?

• 24:20Josh Clark?

  It is, and patient education is a really important part of treating depression. Like, it's not one of those things where you just turn up and say, "Well, you know, here, treat me." Like, you're going to be armed with a lot of stuff on how to help yourself, too. And I guarantee you, they're going to say, "Exercise every day for 20, 30 minutes a day" will be one of the things that they say, because it works so well.

• 24:43Speaker 03

  Yeah.

• 24:44Josh Clark?

  It's crazy what it does.

• 24:45Speaker 03

  Yeah.

• 24:46Josh Clark?

  And that's, that's part of also treating things with antidepressants is, if you are suffering from major depressive disorder, you probably can't get yourself up and exercise.

• 24:56Speaker 03

  Right.

• 24:57Josh Clark?

  So on antidepressants, you are, you, the, it increases the chances that you can exercise, and then that just makes it even more effective.

• 25:06Speaker 03

  Yeah, I, if you suffer from depression and you feel a little lost, and you are a fan of comedy, I can highly, highly recommend the great comedian Gary Gullman. He's a comedian who has, he's been around a long, long time, and it's not like that's his act, but he did have one tour and one sort of set where he really, really dug into this, and one special. And then lately, he wrote about it in his book, which is great, I read the book, this is all about his childhood growing up, but lately on Instagram, he has been posting just daily things, he's kind of written down on a paper, that helped him when he was at his darkest, and, you know, take a walk, things like that, but, but drilled down and got more

• 25:48Speaker 03

  specific, and advice on if you're a friend of someone, like, what you can do, like, it's really, really, really helpful. So Gary Gullman's awesome, and I encourage you to check out that Instagram. As silly as that sounds, it can really help.

• 26:03Josh Clark?

  It doesn't sound silly at all.

• 26:05Speaker 03

  Well, anytime you're like, "Oh, go to a social media thing and look at what this comedian said," but, you know what I mean?

• 26:11Josh Clark?

  Uh, no, I still don't think it was silly. I think it was a great shout out for sure.

• 26:15Speaker 03

  Good.

• 26:16Josh Clark?

  So a couple more things real quick on SSRIs before we move on. They are, they, fluoxetine in particular, Prozac has a long half-life.

• 26:26Speaker 03

  Yeah.

• 26:27Josh Clark?

  So you can get away with just one dose, which you're like, who cares?

• 26:30Speaker 03

  One a day.

• 26:31Josh Clark?

  Yeah, but that actually decreases your chances of missing a dose. So that's a good thing. And then one of the other things too is when you go to the doctor, especially if you're a kid, they start treating you with antidepressants. They're going to start at really, really low dose and just kind of slowly move it up. And as you get adjusted to it, it cuts down on the chances of side effects, but there can be side effects with SSRIs from anxiety to sexual dysfunction to vertigo. So, I mean, you, you need to go into understanding what you're facing, but a good psychiatrist or doctor will be like, okay, let's just do this a little at a time to get you on your feet as gently as possible.

• 27:09Speaker 03

  Yeah, for sure. All right. So that's a quick overview of the SSRIs and how they work. Now we're going to move on to, we're going to jump back in time. Oh, we can get in the wayback machine. That's fun.

• 27:20Josh Clark?

  Oh, okay. Let's do it.

• 27:29Speaker 03

  To the 1950s and 60s when tricyclic antidepressants made their debut.

• 27:36Josh Clark?

  Yes, those were some of the first, but not the first strangely, but these were really kind of early pioneering antidepressants that they worked on serotonin. That was kind of their goal. They were a reuptake inhibitor as well. The problem with these things are, is that they weren't selective. That's, that's why SSRIs are just so desirable. Tricyclic antidepressants are just like, come here neurotransmitter and they kind of dry hump the neurotransmitter, no matter what kind of neurotransmitter it is, and prevent it from being taken back up again.

• 28:17Speaker 03

  All right. That's one way to put it. All right. We're going to name these and these again, might be things you saw if you're a Gen Xer. You might've seen them in your, in your grandparents. Medicine cabinet even.

• 28:31Josh Clark?

  Yeah, you probably associate these names with the smell of mothballs.

• 28:34Speaker 03

  That's right, exactly. Let me see here, here's the first one. Nor- Nortri- Nortryptiline. Nortryptiline.

• 28:44Josh Clark?

  These are no SSRIs.

• 28:46Speaker 03

  Geez, I even practiced these. Nortryptiline, why am I getting all these? That's Pamela Laura, how about you take the next one?

• 28:51Josh Clark?

  I, I can't.

• 28:52Speaker 03

  Yeah, sure you can.

• 28:54Josh Clark?

  Uh, Maprotiline. That's the, the, the brand name's even worse. Ludiomil.

• 29:01Speaker 03

  Yeah.

• 29:02Josh Clark?

  Uh, Desaprimine, that's Norpermine is the brand name. Amitriptiline.

• 29:07Speaker 03

  Do a good job, yeah.

• 29:09Josh Clark?

  Uh, Clamiprimine? That does not roll off the tongue. That's Anaphrenil. And then Imiprimine, which is Trofenil. I've never heard of any of these.

• 29:22Josh Clark?

  But they apparently work fairly well. It's just the side effects that are really problematic. I mean, strangely, they treat it just as well as SSRIs. But again, they treat everything, all the neurotransmitters. And because as we've seen, neurotransmitters perform more than one function in the body. They have a whole host of side effects that you just don't want.

• 29:46Speaker 03

  Yeah, I mean, yeah, we could go through them, but it sounds like one of those commercials. Uh, but you're way more likely to experience those, with those than the SSRIs. Uh, it's also, they were, uh, the tricyclic were easy, easier, easier to overdose on.

• 30:01Josh Clark?

  Yeah.

• 30:02Speaker 03

  Uh, and you're just not gonna see them a lot for depression these days. They're, they're still around. Uh, I think neuropathic pain is something they found use for.

• 30:09Josh Clark?

  Yeah.

• 30:10Speaker 03

  Uh, and if you, you know, if you don't tolerate SSRIs, they might say, you know, they might pitch you a drug from the 1950s.

• 30:17Josh Clark?

  Right, that has, I saw a black box warning that the FDA slapped on it.

• 30:22Speaker 03

  Oh wow, really?

• 30:24Josh Clark?

  Can cause suicide. Uh, and I was like, how? How does that stuff happen? And the way that I saw it explained is that if you have, like, if you are, if you're suicidal and you have depression, you're thinking of suicide, you may be too immobilized to actually carry it out. A tricyclic antidepressant may lift the depression just enough for you to act. And apparently, there's a warning on the box that says that. So, yeah, tricyclics don't sound particularly desirable.

• 31:02Speaker 03

  Yeah.

• 31:03Josh Clark?

  But they probably saved quite a few people in the 50s and 60s when they came out.

• 31:08Speaker 03

  Yeah, for sure. I mean, that was a long time ago. So this was early, sort of, you know, medicine at work.

• 31:13Josh Clark?

  Yes.

• 31:13Speaker 03

  We have SNRI, serotonin, not just serotonin, but serotonin and norepinephrine reuptake inhibitors. They came around in the mid 90s, so after the SSRIs, a little bit after. And they do exactly what you would think. They block the reuptake of both of those in the same way.

• 31:32Josh Clark?

  Yeah, and what's weird is SNRI's.

• 31:36Speaker 03

  You think it's better, right?

• 31:37Josh Clark?

  Yeah, despite selectively targeting two neurotransmitters, it's basically just as good as the SSRIs.

• 31:45Speaker 03

  Yeah.

• 31:46Josh Clark?

  I think they have about the same number of side effects, too.

• 31:50Speaker 03

  Yeah, and those are, there's only a couple of those, Effexor and Cymbalta. And in Cymbalta's case, that's duloxetine, and Effexor is venlafaxine.

• 32:03Josh Clark?

  Not the best name ever.

• 32:05Speaker 03

  Venlafaxine, Benathlexine.

• 32:10Speaker 03

  What just happened?

• 32:11Josh Clark?

  That was great, man. Benathlexine is Duncan.

• 32:14Speaker 03

  Yeah, you're right.

• 32:15Josh Clark?

  There's another related class called noradrenergic and specific serotonergic. I'll bet the psychiatrists are just laughing, laughing, laughing.

• 32:25Speaker 03

  Have fun, fellas.

• 32:27Josh Clark?

  Or else they turned this off a long time ago.

• 32:29Speaker 03

  Yeah.

• 32:29Josh Clark?

  But those type of antidepressants, NASSAs, lowercase a first, so I'm pretty sure there's no other, I guess you could say NASSAs? Surely, people don't say that.

• 32:42Speaker 03

  NASSAs?

• 32:44Josh Clark?

  Sure, that's even better. It's better than venlafaxine.

• 32:49Speaker 03

  Yeah, yeah, they came around in the, what, mid 80s?

• 32:52Josh Clark?

  Yeah, they, the, the NASAs have, they do the same thing, but they have different side effects. It's just so bizarre.

• 33:01Speaker 03

  Yeah.

• 33:01Josh Clark?

  Like, you can experience weight gain and sedation, rather than, say, sexual dysfunction, like, on a SNRI. But they're all doing the same thing. But again, none of them seem to be any better than SSRIs, and SSRIs have the fewest side effects. This episode is brought to you by SSRIs, by the way.

• 33:21Speaker 03

  Uh, the next thing we're gonna talk about are MAOIs, or monoamines, is that right?

• 33:28Josh Clark?

  Monoamines?

• 33:29Speaker 03

  Monoamine, oxidase inhibitors.

• 33:32Josh Clark?

  You got all fancy.

• 33:33Speaker 03

  And, yeah, I don't think we've mentioned yet that, that's what that group is called. Serotonin, norepinephrine, and dopamine are all monoamines.

• 33:40Josh Clark?

  Mm-hmm.

• 33:41Speaker 03

  Uh, because of the molecular structure of those things.

• 33:44Josh Clark?

  Yes. So, I've heard of MAOIs, like, basically my whole life, haven't you?

• 33:49Speaker 03

  Uh, no.

• 33:51Josh Clark?

  Oh, okay. So, they're this, like, very, like, widespread class of drugs, but they have a weird twist to them, in that they, um, prevent you from breaking down something called tyramine, which is an amino acid. And tyramine is great, because it regulates blood pressure, but you don't want too much tyramine. It gets out of whack, and your blood pressure gets out of whack.

• 34:13Speaker 03

  Mm-hmm.

• 34:13Josh Clark?

  And tyramine is present in a lot of different foods.

• 34:16Speaker 03

  Mm-hmm.

• 34:16Josh Clark?

  From, like, soy sauce, to fish, to sausage, aged cheese, the best cheese.

• 34:22Speaker 03

  Yeah.

• 34:22Josh Clark?

  Um, and as a matter of fact, it's called the cheese reaction, where people get hypertensive from taking MAOIs and accidentally eating the wrong food. So, what the monoamines get broken down by is monoamine oxidase, MAO, and a MAOI is a monoamine oxidase inhibitor.

• 34:44Speaker 03

  That's right.

• 34:44Josh Clark?

  So, it prevents this thing from breaking down the monoamines, and that's why you can't eat aged cheese.

• 34:53Speaker 03

  Do you think anyone ever goes in, and they're like, "Can I just do the SSRIs? Because everyone kind of knows those?"

• 34:58Josh Clark?

  Right.

• 35:01Speaker 03

  Should we name check those?

• 35:04Josh Clark?

  I've never heard of any of them, but sure, if you want.

• 35:06Speaker 03

  No, I don't feel the need to.

• 35:08Josh Clark?

  Well, I think what's also interesting is that it was discovered by accident.

• 35:13Speaker 03

  Oh, yeah, that's right. This is one where, I think it was in the early 1950s, they were testing drugs for TB, for tuberculosis. And it was one of those deals where they said, hey, these people over here are taking this thing, they're sleeping pretty good, they have a good appetite, they're bouncing around the room, they seem pretty happy.

• 35:34Speaker 03

  And so that's how it was born. They found that, I think, that when they gave it to patients with depression, that 70% of them showed an improvement. So they said, I guess we've got a new thing here.

• 35:44Josh Clark?

  Yeah, so I think they started in 1958 with Marcelid, the first ever MAOI antidepressant. But again, because you can't eat aged cheese, people don't usually prescribe that as an antidepressant anymore.

• 35:59Speaker 03

  Kind of had that cheese, doc?

• 36:01Josh Clark?

  Sure. I mean, yeah, that'll make anybody depressed, not being able to eat aged cheese.

• 36:07Speaker 03

  I guess now we can jump over to, or should we take a break, or should we cover nutraceuticals?

• 36:14Josh Clark?

  I think it's, I think it's break time.

• 36:17Speaker 03

  All right, we'll take a break and then we'll come back and talk about something that you can just get over the counter. It's called a nutraceutical, right after this.

• 36:38Josh Clark?

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• 37:37Josh Clark?

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• 37:59Josh Clark?

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• 38:15Speaker 03

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• 38:40Josh Clark?

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• 38:51Speaker 03

  Oh?

• 38:52Josh Clark?

  Mm-hmm.

• 38:53Speaker 03

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• 39:04Josh Clark?

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• 39:14Speaker 03

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• 40:00Josh Clark?

  Okay, Chuck, so we started talking about nutraceuticals. And that's just a fancy name for a supplement that you could conceivably use to treat a malady. And in this case, people have long been seeking supplements to treat depression with, whether it's clinical or diagnosable or passing depression, who knows? People don't necessarily want to take pharmaceuticals and it's tough to blame them. So they'll follow studies and they will read about new discoveries with people poking around, trying to figure out what causes depression. And very often they'll turn up some specific amino acid or something like that, that they show that there's low levels of that in the brain of people with depression.

• 40:45Josh Clark?

  And so they'll go off and test this amino acid and they'll show like, yep, actually it improves symptoms. And then people go out and buy tons of that supplement. But the problem is in the United States, if it's a supplement, it's essentially totally unregulated. So there's no one checking out like to make sure that the dose is the same pill to pill, that they actually have what they say they have in them, that they don't have old newspapers ground up with it. Like it's just the Wild West when it comes to supplements, which makes it really a tricky thing to treat your depression with, even though I totally understand how somebody would not want to take pharmaceuticals if they don't have to.

• 41:25Speaker 03

  Yeah, for sure. And you know, this is a real shame because a lot of these studies on these have come back with some, some results that are, that look pretty good. Some of them show, you know, can kind of be over the, all over the place again, maybe because it's not regulated is the reason, because some studies show that results can, can treat MDD pretty effectively. Others show it's not any better than a placebo.

• 41:50Speaker 03

  They can also have side effects, so it's not like, oh, it's just a supplement. So I don't, you know, I don't hear the commercial listing, you know, a laundry list of things that could go wrong. Then, and I can buy it just over the counter, then there can't be any side effects, right? But that's not true at all. There are side effects to supplements as well. And it can, you know, there have been plenty of situations where there's a supplement that becomes kind of the, the, all the rage.

• 42:15Josh Clark?

  Yeah.

• 42:16Speaker 03

  And people just start like St. John's Wort used to be when people were just like, hey, St. John's Wort's the best. We just should take tons of it. And that can result in its own set of issues.

• 42:26Josh Clark?

  I remember that. That was our parents taking St. John's Wort, wasn't it?

• 42:31Speaker 03

  Yeah, I, I remember my parents even at one point signed up for one of the supplement, you know, pyramid schemes, I guess it was.

• 42:41Josh Clark?

  No, really?

• 42:42Speaker 03

  Sort of like the Avon Laney, but it's supplements. That I remember a short time. I mean, they were always trying to hustle some side gig because they were teachers, but um, I specifically remember when I was a kid that we just had like a house full of this stuff for a while. And I can't remember which system or brand this was, but if someone wrote in and told me, I would be like, oh, yep, that's the one.

• 43:03Josh Clark?

  Yeah, I, I can't bring it to mind either, but I'll bet I, I know what you're talking about.

• 43:08Speaker 03

  Yeah.

• 43:09Josh Clark?

  So yeah, St. John's Wort, it was all the rage in the eighties. And I think one of the other things that lent it a lot of credibility is people have been using St. John's Wort to improve mood for probably thousands and thousands of years, if not longer.

• 43:22Speaker 03

  Yeah.

• 43:24Josh Clark?

  The problem is, is all that time through history, people weren't also taking like birth control pills or pharmaceutical antidepressants, both of which St. John's Wort reduces the effectiveness of.

• 43:35Speaker 03

  Right.

• 43:36Josh Clark?

  You don't really want to reduce the effectiveness of your birth control pills if you're trying not to get pregnant at that time. It also breaks down, it also prevents the breakdown of antihistamines. It does all sorts of unwanted stuff. And that's just such a great, like stellar lesson in the problems with using a supplement to treat something like major depressive disorder. But it's also a lesson in just how far we need to go to look into non-pharmaceutical treatments for stuff and actually study them and figure out exactly how to do it and start producing that treatment as well. Because I, you know, I think most people do prefer something that you could conceivably consider more natural than a pharmaceutical.

• 44:22Speaker 03

  No, for sure.

• 44:23Josh Clark?

  The problem with that, though, is, is that it's, we're not set up, the United States at least, isn't set up to make a trillion dollars off of St. John's Wort.

• 44:32Speaker 03

  Yeah.

• 44:32Josh Clark?

  It's tough to do that, that, as opposed to creating a new proprietary compound that, that treats depression.

• 44:40Speaker 03

  Yeah, for sure. So, I mean, that leads very nicely into psychedelics. We promised talk of those earlier with ketamine and psilocybin, and here we are. They, at least for, for ketamine, that is one that is way out in front of psilocybin as far as like official studies and the government kind of getting behind some of this stuff.

• 45:00Josh Clark?

  Yeah, they love K.

• 45:01Speaker 03

  Yeah, they love that K. They're being tested, ketamine, that is, as a breakthrough treatment, and breakthrough is a label or a designation, rather, that the FDA says, hey, we can fast-track this through the approval process because we think it has so much potential. And these, still though, even though like ketamine has shown a lot of promise, it's still looked at and studied as a last resort if you're resistant to other more traditional treatments.

• 45:26Josh Clark?

  Yeah, so the government was all about, I should say, the FDA, back in 2019, they prescribed, or they approved, sorry, a prescription version of ketamine called esketamine. And apparently, that to ketamine, I've seen compared to CBD to THC.

• 45:45Speaker 03

  Right.

• 45:46Josh Clark?

  There were a couple of double colons in there if you didn't pick that up.

• 45:49Speaker 03

  A watered down version?

• 45:51Josh Clark?

  Exactly. That like, say, a geriatric person might take.

• 45:55Speaker 03

  Yeah, exactly. They started to develop ketamine in the 1960s in Belgium. And, you know, they've been, like you said, I think, starting in 2000 is when they really started kind of looking into stuff. So it had a big jump on psilocybin. That's one that's just now starting to kind of, people are starting to say, hey, you know, magic mushrooms, I know has a bad connotation for a lot of people. So let's call it psilocybin, you know, the medical or, you know, I guess biological name. And let's, let's study this stuff.

• 46:31Josh Clark?

  Yeah, so psilocybin is just gangbusters at treating depression. Ketamine is too. We should say also that psychiatrists are like, we need a more potent version of ketamine. So please approve that FDA.

• 46:44Speaker 03

  Right.

• 46:44Josh Clark?

  They're not, as far as I know, on the way to do that, but who knows? But psilocybin in particular, there's just study after study after study that's like, this stuff really works. And it works in, like, you don't have to stay on it. You don't have to take mushrooms every day for the rest of your life, which, you know. But you only take them a couple of times and it can have effects that last up to a year. There was a, I think a Johns Hopkins study from 2022, where they gave two doses of psilocybin to patients two weeks apart. And so they gave each patient a dose of psilocybin two weeks apart.

• 47:27Josh Clark?

  They didn't just wait two weeks to go to the next patient, I guess is what I'm saying.

• 47:31Speaker 03

  Yeah.

• 47:31Josh Clark?

  So they found that this, the effects could last like a year, after, a year from the second dose. They, they, and the effects were like just mind blowing too, as far as the, I guess, quantifying the symptoms of depression, right?

• 47:50Speaker 03

  Yeah. Do you know how, what, what the dose was before I give this number?

• 47:54Josh Clark?

  I think it was like melt your face.

• 47:58Speaker 03

  Half a bag?

• 47:59Josh Clark?

  You're right, two handfuls.

• 48:01Speaker 03

  I'm very curious, but um, this is a, I think it was a depression rating scale they were using where 24 was severe and seven or below was no depression. And before they had the psilocybin, they scored 22, an average of 22.8 out of 24, as far as being severely depressed. And then afterward, it went all the way down to 7.7, which is just a skosh above no depression.

• 48:27Josh Clark?

  Yeah, and that 7.7 was that follow-up a year later.

• 48:30Speaker 03

  Yeah, that's remarkable.

• 48:32Josh Clark?

  Yeah, so that was 2022. I wonder if they check in with these people now, what the scores will be, you know, does it? Do you have to take psilocybin every two years, twice, over two weeks? And maintain control over depression? That's, it's pretty amazing. There's another study from 2024 that found that psilocybin is at least as effective at treating MDD as SSRIs, probably more.

• 49:01Speaker 03

  Yeah, and I think they had, did try to follow up those people, but they got no cell service out there in Joshua Tree.

• 49:07Josh Clark?

  Yeah, that's right. So, just real quick, there's, we, because we'll probably go over this a little bit in the depression episode, but if you go in for treatment of depression, they're going to treat you in three different phases, two possibly, but probably three. The first is acute, where you show up and you're like, I can't take this anymore, I need treatment. They're going to get you on SSR, yeah, probably an SSR, but they're going to get you on some antidepressant to start. They're going to try to work their way up while also balancing getting you feeling better as soon as possible. And time was, they would try an antidepressant for like four to six weeks. That was the, what was generally prescribed, like that's what all psychiatrists did.

• 49:53Josh Clark?

  And if after four to six weeks, there wasn't more than a 25% reduction in symptoms, they would say, this isn't working for you, let's try another one. But I guess something happened to the psychiatry zeitgeist, and now they're waiting as long as six months to give it a chance. Which has got to be tough when you're suffering from major depressive disorder, but that's the acute phase. And once they get a, once they find an antidepressant that can manage your symptoms, you'll move into what's called the continuation phase.

• 50:26Speaker 03

  That's right. And that's after remission has begun. And that is when they're trying to, you know, knock down or outright eliminate the symptoms that are still sticking around and get you back to where you were before your MDD episode. After six months of that, if there's no relapse, then they may wean you down or completely off of something.

• 50:49Josh Clark?

  Mm hmm.

• 50:50Speaker 03

  You know, it just sort of depends. Like, again, like, talk, talk a lot to your doctor through all this stuff. So you really have a good handle on what's going on.

• 51:00Josh Clark?

  So I think I said, most people will suffer multiple or chronic or recurring episodes of major depressive disorder, once they have one.

• 51:10Speaker 03

  Yeah.

• 51:11Josh Clark?

  Something like 50 to 85% of people who have one will have another episode. So there's, it's probable that your continuation phase will eventually turn into a maintenance phase where they'll just keep an eye on you. You'll probably keep up with, say, therapy or psychoanalysis or something like that. And if your episode starts to come back, they'll put you on the antidepressant that worked before.

• 51:37Speaker 03

  Yeah.

• 51:37Josh Clark?

  And this can go anywhere from a year to indefinite.

• 51:41Speaker 03

  Mm hmm.

• 51:42Josh Clark?

  The just, the point is to stay on top of your symptoms so that you don't have another episode. Or if one starts to come along, they nip it in the bud very quickly.

• 51:51Speaker 03

  Yeah, for sure. Which kind of all leads to the question, are these being prescribed too much? That's, you know, you can't hardly bring this up without hearing somebody say, yeah, they're just doctors are just willy nilly prescribing this stuff to everybody. Like, young children all the way to senior citizens, like, they'll just throw anyone on that. And that's just a very, sort of dumbed down way to look at this. There are Critics who, you know, have valid points about stuff, but you have to look at real numbers as far as like an increase in prescriptions. If you look at the numbers, part of it is that they are, they are staying on something for longer. So if they're keeping you on something for six months, rather than just switching something

• 52:35Speaker 03

  out at six weeks, then the numbers for that prescription are going to be higher over a six month period. So there's just a lot more nuance in those numbers as far as there's been a big increase, like a sweeping statement, like there's been a big increase in the number of prescriptions.

• 52:50Josh Clark?

  Right. Plus, if you're just counting prescriptions of antidepressants, you might miss that. Say the tricyclic antidepressants are now being prescribed for neuropathic pain.

• 52:59Speaker 03

  Right.

• 53:00Josh Clark?

  So that would get lumped into that as well. And yet you can totally get the viewpoint of people who are like, yeah, that probably accounts for some of it, but dude, I saw a statistic that in the United States, people ages 12 to 25, between 2016 and 2022, monthly prescriptions of antidepressants went up 66%.

• 53:22Speaker 03

  Yeah. I mean, 2016 to 2022 is also a period of a lot of upheaval in the United States and starting in 2020 with COVID around the world. So all of that stuff comes into play for sure.

• 53:38Josh Clark?

  Yeah, I think from 2020 to 2022, if you just look in that window, especially for, I think, girls and women aged 12 to 25, it went up like 150% in those two years.

• 53:51Speaker 03

  Kids pulled out of school and their entire social structure sometimes.

• 53:54Josh Clark?

  Yep.

• 53:55Speaker 03

  Yeah.

• 53:56Josh Clark?

  Yeah. So it's also possible that the stigma has been reduced, thank you, Gen Z, around seeking treatment for mental health and talking about your mental health. So more people could be seeking help, which could lead to a higher increase in diagnoses, which would of course lead to an increase in prescriptions. At the same time, some people are like, we're just, a lot of this is just pathologizing human sadness. And we need to, especially, so everybody agrees basically that if you have a low level diagnosable depression, that's not MDD. Then you should not start out with antidepressants. You should start out with lifestyle changes, like changes in your diet, exercise again.

• 54:41Speaker 03

  Right.

• 54:42Josh Clark?

  Getting good sleep, just stuff you can do without pharmaceuticals. Everyone agrees, except I'm sure for the pharmaceutical companies that you should not start with that for like low level depression.

• 54:54Speaker 03

  Yeah, I was curious too about kids about, I wondered if there was just a minimum age. And from what I found, each drug is FDA approved, starting at a certain age.

• 55:05Josh Clark?

  What's the youngest you found?

• 55:06Speaker 03

  Mostly the youngest I found was seven years old.

• 55:10Josh Clark?

  I would have guessed five.

• 55:11Speaker 03

  Yeah, I mean, that may be, but I just found seven.

• 55:15Josh Clark?

  So there's just a couple of other things we want to cover real quick that fall under the umbrella of antidepressants making depression worse.

• 55:23Speaker 03

  Right.

• 55:24Josh Clark?

  Cause you would probably be bewildered if you were taking antidepressants and you're like, I actually feel way worse than I did before. And there's a whole kind of little suite of possible reasons for why that might happen.

• 55:37Speaker 03

  Yeah, I mean, you may be just, it may be simple misdiagnosis. It could be bipolar disorder, it could be BPD, which we've talked about borderline personality disorder. But those are not the same things, so you just might be misdiagnosed.

• 55:53Josh Clark?

  Yeah, you might have a chump for a doctor.

• 55:55Speaker 03

  Yeah.

• 55:56Josh Clark?

  Genetics is also one, apparently that also determines whether you have, whether a risk factor like you said earlier, like grief or something like that. Pushes you into major depressive disorder. There's a gene, the SLC 64A, the serotonin transporter gene, I think. There's a variation in that where you can actually get, feel worse after taking antidepressants because of that gene.

• 56:22Speaker 03

  Yeah, your metabolism might affect it if some people just don't clear drugs out of their system as quickly.

• 56:28Josh Clark?

  Yeah.

• 56:30Speaker 03

  So if it's taking longer than usual, then it usually a dose adjustment can help with that, but that could imbalance things even more.

• 56:39Josh Clark?

  Yeah, and then being under 25 before your brain is fully developed, that's one, there's something called akathisia.

• 56:47Josh Clark?

  Which it's basically just an internal restlessness that keeps you from sleeping, makes you anxious, and then those will make your depression symptoms worse. And then just being on too many drugs, right?

• 57:00Speaker 03

  Yeah, polypharmacy, pretty good band name, but not a great thing to live with because, you know, things interacting with other drugs is a real thing. And if you're, if you're on a lot of them, then it's some kind, sometimes can be hard to even tell what might be affecting what you had to get at a certain point.

• 57:18Josh Clark?

  Right, exactly. So that's it for antidepressants, right? You got anything else?

• 57:24Speaker 03

  Got nothing else.

• 57:25Josh Clark?

  Okay, well, go forth and seek treatment if you have depression, especially if you think you have major depressive disorder. Go get help. Things can get a lot better. And since I said things can get a lot better, everybody, it's time for listener mail.

• 57:42Speaker 03

  This is one of a couple I'm going to read in the next few episodes about the inner monologue episode. We heard a lot from people about that.

• 57:49Josh Clark?

  Yeah.

• 57:50Speaker 03

  And specifically in this case, my inner monologue when I'm falling asleep, getting really weird. Hey, guys, Chuck mentioned before falling asleep, his thoughts start to get weird, and that's how he knows he's falling asleep. Right away, I knew what he was talking about. And the reason I read this one, because I had dozens and dozens of people that have the same thing.

• 58:09Josh Clark?

  Right.

• 58:09Speaker 03

  It's because it's very common. But this person names it. There's a term called hypnagogic imagery. Which I think we've talked about that in something. It might have been lucid dreaming.

• 58:18Josh Clark?

  It's got to be.

• 58:19Speaker 03

  Which I learned about from Jeff Warren's awesome book, The Head Trip. It's basically the stage before falling asleep when our brains start to produce hallucination-like images. This happens to me, though I'm not consciously aware of it, on nights when I fall asleep quickly. Often I'll drift into the hypnagogic stage and then catch myself and think, that was weird, which is what happens to me, and then drift back in. Chuck described his experience as a series of nonsensical thoughts, so I wonder if his is truly verbal versus visual. I would love to hear more. I think mine are a little bit of both, Jill, and that is Jill in Connecticut.

• 58:53Josh Clark?

  Thanks, Jill. That was a great one. We love naming stuff that we experience and didn't know there was a name for, right?

• 58:59Speaker 03

  Right.

• 59:01Josh Clark?

  So, okay, well, if you want to be like Jill, send us an email. Send it off to [email protected].

• 59:12Speaker 04

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