How Antidepressants Work

Transcript

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Speaker 1 Welcome to Stuff You Should Know, a production of iHeartRadio.

Speaker 1 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? It's a dirty, dirty lie. What are you talking about?

Speaker 1 It's just me and Chuck.

Speaker 1 We're producing our own jam today, I guess you could say. And this is stuff you should know.

Speaker 32 That's right.

Speaker 35 And the listener will never hear where we edit out when Jerry bursts into the room in two minutes.

Speaker 36 We'll just cut that out.

Speaker 35 Nice and clean.

Speaker 1 We should just leave it in once just to really kind of share. Yeah.
Oh, hey, guys.

Speaker 1 She's got like a little bit of miso in the corner of her mouth.

Speaker 38 No, always a little crusty miso.

Speaker 1 So, Chuck,

Speaker 1 today we are doing something in grand stuff you should know fashion. We're doing a tangential

Speaker 1 episode where we haven't done like the core episode that it relates to.

Speaker 39 Have we never done one on depression, actually?

Speaker 1 I could not believe it. I looked on the stat sheet maintained by Joe Hurley, which is infallible.
I looked all over the internet.

Speaker 1 I sat there and had a conversation with myself.

Speaker 1 Nothing. It's not there.

Speaker 40 Yeah.

Speaker 37 I mean, that's so like us to hit stuff like bipolar first.

Speaker 1 Yeah. Yeah.
We did do bipolar. We've done PTSD.
We've done ADHD, obviously, all that. But

Speaker 1 we'll definitely do depression at some point.

Speaker 1 Okay.

Speaker 41 I think it makes sense maybe to cover this first.

Speaker 1 So how about that?

Speaker 1 Sure, stick it to me.

Speaker 44 Yeah, put that in your palm and wash it down with some water.

Speaker 36 How's that for a segue?

Speaker 1 Oh, that was a good one. That was great, man.
So, yeah, we're talking about antidepressants. That was a great one.
Thanks.

Speaker 1 And to talk about antidepressants, we really do have to kind of give at least the briefest overview of what depression is like.

Speaker 1 It's kind of everywhere. I saw something like 60 million adults in America, and I think they

Speaker 1 define that over age 18 these days for this kind of stuff,

Speaker 1 have some sort of diagnosed depression.

Speaker 1 I think 20

Speaker 1 million

Speaker 1 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.

Speaker 1 Unipolar is like just oppression.

Speaker 1 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,

Speaker 1 just the way that things are going. And everyone in the world is like, yeah, we know.

Speaker 1 And it just kind of is going from there.

Speaker 45 Yeah.

Speaker 47 I mean, that's a good overview, you know, without getting into the weeds as far as numbers go.

Speaker 49 Symptoms,

Speaker 50 as you might imagine, are

Speaker 9 they're sad disrupted sleep feeling like you're worthless

Speaker 54 sometimes it affects your concentration sometimes it affects your ability to even experience pleasure at all

Speaker 9 even you know when you're you know doing something that might ordinarily be fun for you it's not fun

Speaker 57 It's not

Speaker 33 being sad in a moment or being blue for a little while.

Speaker 45 It is a persistent thing where it disrupts your life.

Speaker 41 It interferes with your life.

Speaker 32 It can interfere with your relationships and interfere with your relationship with yourself in a big, big way.

Speaker 1 Yeah. And for a lot of people, I think for most people, statistically speaking, it's chronic or recurring.

Speaker 1 You don't just have one episode. It can keep coming back and back.

Speaker 1 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.

Speaker 1 But I mean, we used to call it melancholy, and they associated it with black bile all the way back to Hippocrates.

Speaker 1 And depending on what culture you were from, they would either say,

Speaker 1 tell you that you needed positive rewards, if, say, 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.

Speaker 1 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. Yeah.

Speaker 1 Like, if you have depression and you, you're not treating it, there's definitely hope. So please don't feel like there's not.
There's plenty of hope.

Speaker 1 And if anything, hopefully that's what we get across this, in this episode.

Speaker 1 But there used to be, they used to give people enemas, they used to give people baths,

Speaker 1 positive thinking, diet, exercise. And what's interesting, Chuck, is some of those are still prescribed today, depending on the severity of your depression.

Speaker 41 Yeah, for sure. And those things very much help.

Speaker 40 And I'm glad you said that, what you said just a second ago, because when I said, I sounded very, very

Speaker 53 down when I said that the symptoms are, and I paused and just said sad.

Speaker 36 It is. There is a lot of hope.

Speaker 48 But, you know, I have everybody you know has, if they don't suffer from the depression, you have people in your life and your family and your friends that do.

Speaker 3 And it makes me very sad because these are

Speaker 36 great people who have

Speaker 53 a hill they need to consistently hike up.

Speaker 41 And I imagine it is something that drains your life force.

Speaker 55 And we're here to talk about some of the ways that you can change that.

Speaker 1 Yeah.

Speaker 1 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.

Speaker 1 lars von trier of all people seems to have most accurately portrayed clinical depression great movie in that movie it is a great movie but she just does an amazing job um 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 yeah it's really so it's hard to watch that was a one-timer for me Yeah, uh, not the kind of movie you watch over and over, but uh, Lars been, uh, Lars Von Truer can make a great, great play.

Speaker 35 And I love Kirsten Dutch. She's great.

Speaker 1 For sure.

Speaker 1 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.

Speaker 1 Instead, they will prescribe you pills, antidepressants.

Speaker 1 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.

Speaker 1 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.

Speaker 1 They say you are depressed because you have low levels of serotonin. And that's been the dominant view for decades now.
That's how we treat depression is based on that presumption.

Speaker 61 Yeah, and it's accepted.

Speaker 52 And it's not like it's accepted with, you know, through gritted teeth.

Speaker 55 I think most people agree that's

Speaker 50 what most people agree on is they don't really understand

Speaker 47 what might be the underlying issue or the mechanism behind that is.

Speaker 58 We do know like a lot of the things that may lead to depression.

Speaker 33 If you're a woman, you're more likely to get,

Speaker 55 what did you call it, MDD?

Speaker 1 Yeah, major depressive disorder.

Speaker 65 Yeah, major depressive disorder.

Speaker 48 If you have suffered a loss or unresolved grief, And these are things that can compound.

Speaker 44 It's not like, again, that's different than being sad about, you know, losing a loved one or something like that.

Speaker 32 But it can help contribute to MDD.

Speaker 38 Same as if you suffer through a stress early in your life.

Speaker 44 That can all contribute.

Speaker 41 So we know some of those things, but we don't know that underlying mechanism that actually causes it.

Speaker 55 And because that, we don't exactly know how antidepressants work.

Speaker 47 We know that they do work and we know what they do.

Speaker 44 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.

Speaker 1 Yeah, so much so. We have so little of a grasp on how people become depressed, especially like MDD depressed.

Speaker 1 That

Speaker 1 studies show that people with MDD don't have, aren't likelier to have lower levels of serotonin than other people.

Speaker 1 Like, and that just throws out basically the whole premise of the biological model. And yet, we know that antidepressants work.
They work better than placebo. They're definitely doing something.

Speaker 1 And we know that by design, what they're doing is going in and messing with the concentration of neurotransmitters in your brain. We know they're doing that.

Speaker 1 We just don't know how that mechanism is treating the depression. We just know it works.
And I guess over the years,

Speaker 1 psychologists or psychiatrists and doctors have been like, let's just not ask questions.

Speaker 44 Well, thankfully, we know that's not 100% true because they are still studying and trying to figure this out.

Speaker 48 There was a study that I guess you dug this one up from last year from the University of Colorado, Go Buffaloes,

Speaker 40 that hypothesized that

Speaker 53 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.

Speaker 4 They are saying from the study that maybe it's helping to repair the neuroplasticity in the brain and just sort of like their brain circuits that become just sort of stuck and lodged in that depressed state.

Speaker 39 And it helps to unstick those.

Speaker 1 Yeah, that's a newish, from what I can tell, rival theory to the biological model.

Speaker 1 Even though it's biological itself, it's very, very confusing stuff. But

Speaker 1 the idea, remember you said earlier that like you differentiate, you know,

Speaker 1 MDD or even just non-major depression, but you know, diagnosable depression from just a passing

Speaker 1 feeling of the blues, right? For like a day or so.

Speaker 57 Yeah, or mood swings, you might call it whatever.

Speaker 1 Sure. So

Speaker 1 this theory basically says that thing that people normally come out of, people get stuck and it just seems to get worse and worse and worse worse the longer you're stuck in it or the harder you're stuck in it.

Speaker 1 So that's a, I love that theory. And there's actually support for it because

Speaker 1 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.

Speaker 1 And we know that psilocybin, for example, goes in and basically rewires your brain.

Speaker 1 So that would support the idea that it's a change in neuroplasticity that antidepressants create that helps treat depression.

Speaker 54 Yeah, for sure.

Speaker 66 And we also know, you know, you mentioned serotonin and norepinephrine and, you know, messing or balancing out the brain chemistry.

Speaker 44 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?

Speaker 1 By God, we are.

Speaker 57 They they interfere with what's what's called the synaptic transmission of these things of serotonin norepinephrine dopamine uh and that transmission is is the movement of neurotransmitters from one neuron to another they're 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 uh we know is what antidepressants affect.

Speaker 1 Right. That's where the money is.
They go to the horse's mouth. That's another word for the synapse.
That's what the neurologists call it, the horse's mouth.

Speaker 60 With the ultimate goal for all of these to increase levels of

Speaker 41 those things.

Speaker 30 Usually, I mean, some norepinephrine, as you'll see as we talk about, but more along the lines of serotonin.

Speaker 53 Right.

Speaker 1 Here's the twist to all that, though. Neurotransmitters do all sorts of other things besides, say, like regulate your mood.

Speaker 1 I think serotonin does all sorts of crazy stuff like um 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 uh does

Speaker 1 hence side effects yeah 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 uh

Speaker 43 that feels like a good breakpoint. That's a big old table setting.

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

Speaker 36 I don't know which is which, pal.

Speaker 63 Can you help me out?

Speaker 1 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.

Speaker 35 Well, no, I mean when I reach for the wrong one, just give my hand a little smack.

Speaker 1 I'll drive my dessert knife through your hand.

Speaker 10 Perfect. All right.

Speaker 63 Well, we'll be right back and start off with the star of the show, the SSRI.

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Speaker 30 All right, so we promised to start off with SSRIs, and we're starting off with that.

Speaker 44 We're kind of going to jump around starting with the most frequently prescribed sort of modern version of antidepressants, and then we'll jump back in time

Speaker 56 and talk about drugs that, you know, maybe your parents took.

Speaker 1 Who knows?

Speaker 58 But these came around in the mid-1980s.

Speaker 40 I think the very first one to became to become available was fluoxetine in 1988.

Speaker 46 And we're going to, 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.

Speaker 1 Yeah, so the people who take them can like be like, yeah. Yeah, exactly.

Speaker 60 Fluoxetine is Prozac.

Speaker 53 Peroxetine is Paxil.

Speaker 44 Sertraline is Zoloft.

Speaker 8 Fluvoxamine is Lubox.

Speaker 39 These are a challenge for me.

Speaker 17 You're doing great, man.

Speaker 10 I appreciate it.

Speaker 55 Citalopram is Selexa.

Speaker 58 And why don't you take that Lexapro for me?

Speaker 48 What is that?

Speaker 1 Escatalopram.

Speaker 36 Escatalopram. Oh, okay.

Speaker 67 I just had a little ES at the beginning of that.

Speaker 1 You did fantastic. My favorite out of all of them is fluvoxamine.

Speaker 1 Yeah, that's a good word.

Speaker 1 I like all those letters together like that. It's great.
Yeah, and I'm not saying the drug itself, just the words.

Speaker 38 Yeah, so these are the SSRIs that are going to block.

Speaker 64 They're called re-uptake inhibitors.

Speaker 53 And what that means is they're going to block that bus trip that serotonin takes back to that original cell, the presynaptic cell,

Speaker 9 the one who sent that transmission,

Speaker 47 and it leaves it floating around in that space in between.

Speaker 10 I believe that's probably you that said that's where all the action happens.

Speaker 55 Yes.

Speaker 49 But that's in what's called the synaptic cleft.

Speaker 44 So it sends that serotonin out.

Speaker 55 And when it comes back, instead of uptaking it or re-uptaking it, it blocks that from happening.

Speaker 64 So that just means there's more of it where you need it.

Speaker 1 They're just hanging out there like, where's my Uber?

Speaker 36 Yeah, exactly.

Speaker 1 So that was lame. I'm sorry, everybody.

Speaker 1 This is pretty good.

Speaker 1 It's an Uber share. 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.

Speaker 35 You're trying to wedge in jokes in an unfunny episode.

Speaker 1 Okay. Thank you for that.

Speaker 55 That's what we try and do. Wedge in jokes where they're not appropriate.

Speaker 1 So that's what, that's specifically what you just said, SSRIs do. And they live up to their name, essentially.

Speaker 49 Yeah, I don't think I even read out what it stands for, Selective Serotonin Reuptake Inhibitor, or I may have, but there it is again.

Speaker 1 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?

Speaker 1 So the great thing about SSRIs is that they work really, really, really well on most people with the fewest side effect.

Speaker 1 And it's in part because they selectively target serotonin.

Speaker 1 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.

Speaker 1 It depends on the brand. Not necessarily the brand, but the type of drug.
I mean, all of the SSRIs aren't exactly the same.

Speaker 1 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.

Speaker 1 But from what I can tell, SSRIs are essentially still today like basically the

Speaker 1 flagship antidepressant, if there is such a thing.

Speaker 3 Yeah, I think you're right. And I think that

Speaker 60 when it comes to getting that

Speaker 68 if you're on more than one, either that cocktail right or that single SSRI correct,

Speaker 41 that is where your doctor comes into play.

Speaker 28 But 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

Speaker 57 concert with your doctor.

Speaker 1 Right, for sure.

Speaker 17 Is that a good way to say that?

Speaker 1 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.

Speaker 1 Like, you're going to be armed with a lot of stuff on how to help yourself, too.

Speaker 1 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.

Speaker 1 It's crazy what it does. And 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.
Right.

Speaker 1 So on antidepressants,

Speaker 1 it increases the chances that you can exercise, and then that just makes it even more effective.

Speaker 54 Yeah,

Speaker 42 if you suffer from depression and you feel a little lost

Speaker 46 and you are a fan of comedy, I can highly, highly recommend the great comedian Gary Gullman.

Speaker 55 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.

Speaker 40 And then lately, he wrote about it in his book, which is great.

Speaker 55 I read the book.

Speaker 65 This is all about his childhood growing up.

Speaker 41 But lately on Instagram, he has been posting just daily things.

Speaker 44 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.

Speaker 41 But drilled down and got more specific. And

Speaker 62 advice on if you're a friend of someone, like what you can do, like it's really, really, really helpful. So Gary Goldman's awesome, and I encourage you to check out that Instagram.

Speaker 33 As silly as that sounds, it can really help.

Speaker 1 It doesn't sound silly at all.

Speaker 60 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?

Speaker 1 No, I still don't think it was silly. I think it was a great shout out for sure.
Good.

Speaker 1 So a couple more things real quick on SSRIs before we move on.

Speaker 1 They are, they have fluoxetine in particular, Prozac has a long

Speaker 1 half-life. Yeah.
So you can get away with just one dose, which you're like, who cares? One a day.

Speaker 1 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 a 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 um 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.

Speaker 68 All right. So, that's a quick overview of the SSRIs and how they work.

Speaker 3 Now, we're going to move on to we're going to jump back in time.

Speaker 35 Oh, we can get in the wayback machine. That's fun.

Speaker 1 Okay, let's do it.

Speaker 44 To the 1950s and 60s when tricyclic antidepressants made their debut?

Speaker 1 Yes, those were some of the first, but not the first, strangely.

Speaker 1 But these were really kind of early pioneering antidepressants that they worked on serotonin. That was kind of their goal.

Speaker 1 They were a re-uptake inhibitor as well. The problem with these things is that they

Speaker 1 weren't selective.

Speaker 1 That's why SSRIs are just so desirable tricyclic antidepressants are just like

Speaker 1 come here a 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 all right that's one way to put it uh all right we're gonna name these and these again might be things you saw if you're a

Speaker 49 gen xer you might have seen them in your in your grandparents'

Speaker 1 uh medicine cabinet even yeah you probably associate these names with the smell of mothballs.

Speaker 32 That's right, exactly.

Speaker 61 Uh, let me see here.

Speaker 38 Here's the first one:

Speaker 55 nortriptyline,

Speaker 1 nortriptyline, these are no SSRIs.

Speaker 61 Jeez, I even practice these.

Speaker 49 Nortriptyline, why am I getting all these?

Speaker 62 That's Pamela.

Speaker 65 How about you take the next one?

Speaker 1 I can't.

Speaker 1 Yeah, sure, you can.

Speaker 1 Meprotyline.

Speaker 1 That's

Speaker 1 the brand name's even worse. Ludiomil.
Yeah.

Speaker 1 desipramine that's norpramine is the brand name uh amitriptyline elevator job yeah

Speaker 1 clomipramine

Speaker 1 that does not roll off the tongue that's anaphrenil and then imipramine which is trophenil i've never heard of any of these um

Speaker 1 but they apparently work fairly well it's just the side effects that are really problematic.

Speaker 1 I mean, strangely, they treat it just as well as SSRIs, but again, they treat everything, all the neurotransmitters.

Speaker 1 And because, as we've seen, neurotransmitters perform more than one function in the body,

Speaker 1 they have a whole host of side effects that you just don't want. Yeah, I mean, yeah, we could go through them, but it sounds like one of those commercials.

Speaker 40 But you're way more likely to experience those with those than the SSRIs.

Speaker 67 It's also, they were the tricyclic were easy, easier to overdose on.

Speaker 1 Yeah.

Speaker 44 And you're just not going to see them a lot for depression these days.

Speaker 50 They're still around.

Speaker 44 I think neuropathic pain is something they found use for.

Speaker 1 Yeah.

Speaker 4 And if you, you know, if you don't tolerate SSRIs, they might say, you know, they might bitch you a drug from the 1950s.

Speaker 1 Right. That has,

Speaker 1 I saw a black box warning that the FDA slapped on it that says

Speaker 1 it can cause suicide.

Speaker 1 And I was like, how? How does that stuff happen?

Speaker 1 And

Speaker 1 the way that I saw it explained is that

Speaker 1 if you have, like, if you are,

Speaker 1 if you're suicidal and you have depression, you're thinking of suicide, you may be too immobilized to actually carry it out.

Speaker 1 A tricyclic antidepressant may lift the depression just enough for you to act. And apparently,

Speaker 1 there's a warning on the box that says that.

Speaker 1 So, yeah, tricyclics don't sound particularly desirable. Yeah.

Speaker 1 But they probably saved quite a few people in the 50s and 60s when they came out.

Speaker 53 I mean, that was a long time ago.

Speaker 44 So this was early sort of, you know, medicine at work.

Speaker 62 Yes.

Speaker 65 We have SNRIs, serotonin,

Speaker 44 not just serotonin, but serotonin and norepinephrine reuptake inhibitors.

Speaker 49 They came around in the mid-90s.

Speaker 68 So after the SSRIs, a little bit after, and they do exactly what you would think.

Speaker 3 They block the reuptake of both of those in the same way.

Speaker 1 Yeah, and what's weird is SNRIs.

Speaker 32 You think it's better, right?

Speaker 1 Yeah, despite selectively targeting two neurotransmitters, it's basically just as good as the SSRIs.

Speaker 1 Yeah,

Speaker 1 I think they have about the same number of side effects, too.

Speaker 49 Yeah, and those are, there's only a couple of those: Efexor and Symbalta.

Speaker 66 And in Symbalta's case, that's Duloxetine.

Speaker 1 And Effexor is

Speaker 60 Venlafexine.

Speaker 1 Not the best name ever.

Speaker 56 Vinlafaxine. Benafflexine.

Speaker 1 What just happened? That was great, man. And Ben Afflexine is Duncan.
Yeah, you're right. There's another related class called noradrenergic and specific

Speaker 1 serotonergic. I'll bet that psychiatrists are just laughing, laughing, laughing.
Have fun, fellas. Or else they turned this off a long time ago.
Yeah. But those type of antidepressants, NASSAs,

Speaker 1 lowercase A first. So I'm pretty sure there's no other, I guess you could say NASSAs.

Speaker 1 Surely people don't say that.

Speaker 17 NASAs?

Speaker 1 Sure. That's even better.
It's better than Venlofoxine.

They came around in the what, mid-80s?

Speaker 1 Yeah.

Speaker 1 They, the, the NASSAs have, they do the same thing, but they have different side effects. It's just so bizarre.
Yeah.

Speaker 1 Um, like you can experience experience weight gain and sedation rather than, say, sexual dysfunction like on a SNRI. But they're all doing the same thing.
But again,

Speaker 1 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.

Speaker 34 The next thing we're going to talk about are MAOIs or monoamine.

Speaker 32 Is that right?

Speaker 1 Monoamines.

Speaker 16 Monoamine, oxidase inhibitors.

Speaker 1 You got all fancy.

Speaker 60 And yeah, I don't think we've mentioned yet that that's what that group is called.

Speaker 46 Serotonin, norepinephrine, and dopamine are all monoamines

Speaker 48 because of the molecular structure of those things.

Speaker 1 Yes. So I've heard of MAOIs like basically my whole life, haven't you?

Speaker 3 No.

Speaker 1 Oh, okay. So they're this like very like...
widespread class of drugs, but they have a weird twist to them in that they

Speaker 1 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.

Speaker 1 It gets out of whack and your blood pressure gets out of whack. And tyramine is present in a lot of different foods, from like soy sauce to fish to sausage, aged cheese, the best cheese.

Speaker 1 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.

Speaker 1 So, what the monoamines get broken down by is monoamine oxidase, MAO,

Speaker 1 and the MAOI is a monoamine oxidase inhibitor. That's right.
So, it prevents this thing from breaking down the monoamines, and that's why you can't eat aged cheese.

Speaker 50 Do you think anyone ever goes in and they're like, can I just do the SSRIs?

Speaker 38 Because everyone kind of knows those.

Speaker 1 Right.

Speaker 41 Should we name check those?

Speaker 1 I've never heard of any of them, but sure, if you want.

Speaker 35 No, I don't feel the need to.

Speaker 1 Well, I think what's also interesting is that it was discovered by accident.

Speaker 45 Oh, no, that's right.

Speaker 57 This is one where

Speaker 60 I think it was in the early 1950s, they were testing drugs for TB, for tuberculosis.

Speaker 27 And it was one of those deals where they said, hey,

Speaker 2 these people over here taking this thing, they're sleeping pretty good.

Speaker 10 They have a good appetite.

Speaker 39 They're bouncing around the room.

Speaker 12 They seem pretty happy.

Speaker 37 And so that's how it was born.

Speaker 44 They found, I think, that when they gave it to patients with depression, that 70% of them showed an improvement.

Speaker 40 So they said, I guess we've got a new thing here.

Speaker 1 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.

Speaker 1 Got to have that cheese, Doc.

Speaker 1 Sure. I I mean, yeah, that'll make anybody depressed, not being able to eat aged cheese.

Speaker 42 I guess now we can jump over to, or should we take a break, or should we cover nutraceuticals?

Speaker 1 I think it's break time.

Speaker 55 All right, we'll take a break and then we'll come back and talk about

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Speaker 1 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.

Speaker 1 And in this case, people have long been seeking supplements to treat depression with,

Speaker 1 whether it's clinical or, you know, diagnosable or passing depression, who knows? People don't necessarily want to take pharmaceuticals, and it's tough to blame them.

Speaker 1 So they'll follow studies and they will read about new discoveries with people poking around trying to figure out what causes depression.

Speaker 1 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.

Speaker 1 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.

Speaker 1 But the problem is, in the United States, if it's a supplement, it's essentially totally unregulated.

Speaker 1 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.

Speaker 1 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.

Speaker 41 And, you know, this is a real shame because a lot of these studies on these have come back with some results that that look pretty good.

Speaker 49 Some of them show, you know, it 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.

Speaker 49 Others show it's not any better than a placebo.

Speaker 30 They can also have side effects. So it's not like, oh, it's just a supplement.

Speaker 44 So I don't, you know, I don't hear the commercial listing, you know, a laundry list of things that could go wrong.

Speaker 49 Then, and I can buy it just over the counter, then there can't be any side effects, right?

Speaker 54 But that's not true at all.

Speaker 30 There are side effects to supplements as well.

Speaker 65 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.

Speaker 55 Yeah. Um, and people just start like St.

Speaker 44 John's Wort used to be when people were just like, hey, St.

Speaker 62 John's wort's the best.

Speaker 35 We just should take tons of it.

Speaker 47 And that can result in its own set of issues.

Speaker 1 I remember that. That was our parents taking St.
John's wort, wasn't it?

Speaker 66 Yeah, I remember my parents even at one point signed up for one of the

Speaker 44 supplement

Speaker 1 pyramid schemes, I guess it was. No, really?

Speaker 60 Sort of like the Avon Laney, but it's supplements.

Speaker 39 I remember a short time.

Speaker 61 I mean, they were always trying to hustle some side gig because they were teachers, but I specifically remember when I was a kid that we just had like a house full of this stuff for a while.

Speaker 12 And I can't remember which

Speaker 27 system or brand this was, but if someone rode in and told me, I would be like, oh, yep, that's the one.

Speaker 1 Yeah, I can't bring it to mind either, but I'll bet I know what you're talking about. Yeah.

Speaker 1 So, yeah, St. John's Wart.
It was all the rage in the 80s. And I think one of the other things that lent it a lot of credibility is people have been using St.

Speaker 1 John's Wart to improve mood for probably thousands and thousands of years, if not longer. Yeah.

Speaker 1 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 Wart reduces the effectiveness of.

Speaker 1 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.

Speaker 1 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.

Speaker 1 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.

Speaker 1 Because

Speaker 1 I think most people do prefer something that you could conceivably consider more natural than a pharmaceutical. No, for sure.
The problem with that, though, is that

Speaker 1 we're not set up. The United States at least isn't set up to make a trillion dollars off of St.
John's wart.

Speaker 1 It's tough to do that as opposed to creating a new proprietary compound that treats depression.

Speaker 49 So, I mean, that leads very nicely into psychedelics.

Speaker 66 We promised talk of those earlier with ketamine and psilocybin.

Speaker 4 And here we are.

Speaker 10 They,

Speaker 27 at least for ketamine, that is one that is

Speaker 44 way out in front of psilocybin as far as like official studies and the government kind of getting behind some of this stuff.

Speaker 1 Yeah, they love K.

Speaker 36 Yeah, they love that K.

Speaker 49 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,

Speaker 30 we can fast track this through the approval process because we think it has so much potential.

Speaker 55 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.

Speaker 1 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 sketamine and apparently that to ketamine I've seen compared to CBD to THC right there were a couple double colons in there if you just pick that up a watered down version exactly that like say a geriatric person might take Yeah, exactly.

Speaker 27 They started to develop ketamine in the 1960s in Belgium.

Speaker 47 And,

Speaker 38 you know, they've been, like you said, I think starting in 2000 is when they really started kind of looking into stuff.

Speaker 66 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,

Speaker 49 you know, magic mushrooms now has a has a

Speaker 44 bad connotation for a lot of people.

Speaker 64 So let's call it psilocybin, you know, the medical or, you know, I guess biological name,

Speaker 17 and let's let's study this stuff.

Speaker 1 Yeah.

Speaker 1 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 right they're not as far as i know uh on the way to do that but who knows um but psilocybin in particular um

Speaker 1 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

Speaker 1 And so they gave each patient a dose of psilocybin two weeks apart. They didn't just wait two weeks to go to the next patient, I guess is what I'm saying.

Speaker 1 So they found that this, the effects could last like a year after a year from the second dose.

Speaker 1 They, they, and the effects were like just mind-blowing too, as far as the, the, I guess, quantifying the symptoms of depression, right?

Speaker 36 Yeah, do you know how, what, uh, what the dose was before I give this number?

Speaker 1 Um, I think it was like melt your face.

Speaker 45 Half a bag.

Speaker 1 Right. Two handfuls.

Speaker 48 I'm very curious, but um, this is, I think it was a depression rating scale they were using where 24 was severe and 7 or below was no depression.

Speaker 41 And before they had the psilocybin, they scored 22, an average of 22.8 out of 24 as far as being severely depressed.

Speaker 61 And then afterward, it went all the way down to 7.7, which is just a scosh above no depression.

Speaker 1 Yeah, and that 7.7 was that follow-up a year later. Yeah, that's remarkable.
Yeah, so that was 2022. I wonder if they check in with these people now, what the scores will be.

Speaker 1 You notice that do you have to take psilocybin every two years, twice over two weeks, and maintain control over depression? That's pretty amazing.

Speaker 1 There was another study from 2024 that found that psilocybin is at least as effective. at treating MDD as SSRIs, probably more.
Yeah.

Speaker 55 And I think they had did try to follow up with those people, but they got no self-service out there in Joshua Tree.

Speaker 1 So just real quick, there's,

Speaker 1 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.

Speaker 1 The first is acute, where you show up and you're like, I can't take this anymore. I need treatment.

Speaker 1 They're going to get you on SSRI, or yeah, probably an SSR, but they're going to get you on some antidepressant to start.

Speaker 1 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

Speaker 1 try an antidepressant for like four to six weeks. That was the, what was generally prescribed.
Like that's what all psychiatrists did.

Speaker 1 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.

Speaker 1 But I guess something happened to the psychiatry zeitgeist, and now they're waiting as long as six months to give it a chance,

Speaker 1 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

Speaker 1 once they find an antidepressant that can manage your symptoms, you'll move into what's called the continuation phase.

Speaker 49 That's right. And that's after remission has begun.

Speaker 38 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.

Speaker 4 After six months of that, if there's no relapse, then they may wean you down or completely off of something.

Speaker 61 You know, it just sort of depends.

Speaker 40 Like, again, like talk, talk a lot to your doctor through all this stuff.

Speaker 47 So you really have a good handle on what's going on.

Speaker 1 So I think I said most people will suffer multiple or chronic or recurring episodes of major depressive disorder once they have one.

Speaker 1 Something like 50 to 85% of people who have one will have another episode.

Speaker 1 So

Speaker 1 it's probable that your continuation phase will eventually turn into a maintenance phase where they'll just keep an eye on you.

Speaker 1 You'll probably keep up with, say, therapy or psychoanalysis or something like that.

Speaker 1 And if your episode starts to come back, they'll put you on the antidepressant that worked before.

Speaker 1 And this can go anywhere from a year to indefinite.

Speaker 1 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.

Speaker 44 Which kind of all leads to the question, are

Speaker 35 these being prescribed too much?

Speaker 59 That's, you know, you can't hardly bring this up without hearing somebody say, yeah, they're just doctors 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 uh there are critics who you know have valid points about stuff but you have to look at real numbers um as far as like an increase in prescriptions um if you if you look at the numbers part of it is that they are uh they are staying on something for longer so if so if they're keeping you on something for six months rather than just switching something out at six weeks, then the numbers for that prescription are going to be higher over a six-month period.

Speaker 44 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.

Speaker 1 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. Right.

Speaker 1 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.

Speaker 1 But dude, I saw a statistic that in the United States,

Speaker 1 people ages 12 to 25

Speaker 1 between 2016 and 2022, monthly prescriptions of antidepressants went up 66%.

Speaker 47 Yeah, I mean.

Speaker 55 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.

Speaker 36 So

Speaker 60 all of that stuff comes into play for sure.

Speaker 1 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.

Speaker 48 Kids pulled out of school and their entire social structure sometimes.

Speaker 4 Yep.

Speaker 1 Yeah.

Speaker 1 So it's also possible that

Speaker 1 the stigma has been reduced. Thank you, Gen Z, around seeking treatment for mental health and talking about your mental health.

Speaker 1 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.

Speaker 1 At the same time, some people are like, we're just, a lot of this is just pathologizing human sadness.

Speaker 1 And we need to, especially, so everybody agrees basically that if you have a low level diagnosable depression that's not MDD,

Speaker 1 then you should not start out with antidepressants. You should start out with lifestyle changes, like changes in your diet, exercise, again,

Speaker 1 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.

Speaker 42 Yeah, I was curious too about kids.

Speaker 38 I wondered if that was just a minimum age.

Speaker 1 And from what I found, each drug is FDA approved starting at a certain age what's the youngest you found uh mostly the youngest i found was seven years old i would have guessed five

Speaker 1 yeah i mean there that may be but uh i just found seven uh 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 right Because you would probably be bewildered if you were taking antidepressants and you're like, I actually feel way worse than I did before.

Speaker 1 And there's a whole kind of little suite of possible reasons for why that might happen.

Speaker 27 Yeah.

Speaker 38 I mean, you may be just, it may be simple misdiagnosis.

Speaker 43 It could be bipolar disorder.

Speaker 30 It could be BPD, which we've talked about, borderline personality disorder.

Speaker 47 But those are not the same things.

Speaker 61 So you just might be misdiagnosed. Yeah.

Speaker 1 You might have a chump for a doctor. Yeah.

Speaker 1 Genetics is also one. Apparently, that also determines whether you have

Speaker 1 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 SLC64A, the serotonin transporter gene, I think.

Speaker 1 There's a variation in that where you can actually

Speaker 1 feel worse after taking antidepressants because of that gene. Yeah.

Speaker 61 Your metabolism might affect it if some people just don't clear drugs out of their system as quickly.

Speaker 1 Yeah.

Speaker 38 So

Speaker 30 if it's taking longer than usual, then it usually a dose adjustment can help with that, but that could imbalance things even more.

Speaker 1 Yeah. And then being under 25 before your brain is fully developed, that's one.
There's something called ekathesia,

Speaker 1 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.

Speaker 1 And then just being on too many drugs, right?

Speaker 4 Yeah, polypharmacy, pretty good band name, but not a great thing to live with because,

Speaker 44 you know, things interacting with other drugs is a real thing.

Speaker 49 And 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

Speaker 63 at a certain point.

Speaker 1 Right, exactly.

Speaker 1 So that's it for antidepressants, right? You got anything else?

Speaker 17 I got nothing else.

Speaker 1 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.

Speaker 1 And since I said things can get a lot better, everybody, it's time for listener mail.

Speaker 4 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.

Speaker 36 Yeah.

Speaker 49 And specifically in this case, my

Speaker 62 inner monologue when I'm falling asleep getting really weird.

Speaker 52 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.

Speaker 41 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, it's because it's very common.

Speaker 56 But this person names it.

Speaker 3 There's a term called hypnagogic imagery,

Speaker 49 which I think we've talked about that in something. It might have been lucid dreaming.

Speaker 1 It's got to be.

Speaker 2 Which I learned about from Jeff Warren's awesome book, The Head Trip.

Speaker 4 It's basically the stage before falling asleep when our brains start to produce hallucination-like images.

Speaker 65 This happens to me, though I'm not consciously aware of it on nights when I fall asleep quickly.

Speaker 41 Often I'll drift into the hypnagogic stage and then catch myself and think that was weird,

Speaker 56 which is what happens to me, and then drift back in.

Speaker 30 Chuck described his experience as a series of nonsensical thoughts, so I wonder if his is truly verbal versus visual.

Speaker 4 I would love to hear more.

Speaker 49 I think mine are a little bit of both, Jill, and that is Jill in Connecticut.

Speaker 1 Thanks, Jill. That was a great one.
We love naming stuff that we experience and didn't know there was a name for, right? Right.

Speaker 1 So, okay. Well, if if you want to be like Jill, send us an email.
Send it off to stuffpodcast at iHeartRadio.com.

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How Antidepressants Work

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Transcript

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