How Antidepressants Work

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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? It's just me and Chuck.
We're producing our own jam today, I guess you could say, and this is Stuff You Should Know. 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. We should just leave it in once just to really kind of sure.
Yeah. Oh, hey, guys.
She's got like a little bit of miso in the corner of her mouth. Always a little crusty miso.
So, Chuck, today we are doing something in grand stuff you should know fashion. We're doing a tangential episode where we haven't done like the core episode that it relates to.
Have we never done one on depression officially? I could not believe it. I looked on the stat sheet maintained by Jill Hurley, which is infallible.
I looked all over the internet. I sat there and had a conversation with myself.
Nothing. It's not there.
Yeah. I mean, that's so like us to hit stuff like bipolar first.
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.
I think it makes sense maybe to cover this first. So how about that? Sure.
Stick it to me. Yeah.
Put that in your palm and wash it down with some water. How's that for a segue?

Oh, that was a good one.

That was great, man.

So, yeah, we're talking about antidepressants. That was a great one.
Thanks. 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 define that over age 18 these days for this kind of stuff, have some sort of diagnosed depression.

I think 20 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.
Yeah. 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. 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 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.
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, say, you lived in Pers in the 9th century.
Or if you were in medieval Europe, they might burn you at the stake or something like that. Luckily, we've come a long way with treating depression.
That's the, I think we should say here at the outset, that's the message we're trying to say. Like, it is highly treatable.
Yeah. Like, if you have depression and you're not treating it, there's definitely hope.
So please don't feel like there's not. There's plenty of hope.
And if anything, hopefully that's what we get across this in this episode. but there used to be they used to give people enemas 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. 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.
It is. 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 and your family and your friends that do. 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 is something that drains your life force. And we're here to talk about some of the ways that you can change that.
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.
Yeah. 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. Like there's a part where she's just in physical pain, such physical pain.
Wow. From being so depressed that like she can barely crawl into a bath.

Yeah. It's really, it's hard to watch.
That was a one-timer for me. Yeah.
Not the kind of movie you watch over and over, but Lars von Trier can make a great, great flick. And I love Kirsten Dunst.
She's great. 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.

In the biology of the study, 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. And that's been the dominant view for decades now.
That's how we treat depression is based on that presumption. 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 would you call it? MDD. Yeah.
Major depressive disorder. 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. Yeah, so much so.
We have so little of a grasp on how people become depressed, especially like MDD depressed. That studies show that people with MDD don't have aren't likely to have lower levels of serotonin than other people 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. 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. 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.
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 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.

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 just a passing feeling of the blues, right? For like a day or so. Yeah, or mood swings, you might call it, whatever.
Sure. So 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 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. Yeah, for sure.
And we also know, you know, you mentioned serotonin and norepinephrine 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? By God, we are.
They interfere with what's called the synaptic transmission of these things, of serotonin, norepinephrine, dopamine. And that transmission is the movement of neurotransmitters from one neuron to another.
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.
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. That's right, with the ultimate goal for all of these to increase levels of those things.
Usually, I mean, some norepinephrine, as you'll see as we talk about, but more along the lines of serotonin. Right.
Here's the twist to all that, though. Neurotransmitters do all sorts of other things besides, say, like, regulate your mood.
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.
That feels like a good break point. That's a big old table setting.
Yeah. Yeah? Yeah, we've got a dessert knife and a butter knife.
I don't know which is which, pal. Can you help me out? 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. Well, I know.
I mean, when I reach for the wrong one, just just give my hand a little smack. I'll drive my dessert knife through your hand.
Perfect. All right.
Well, we'll be right back and start off with the star of the show, the SSRI. All right.
Thank you. so you can find your way back to solid ground.
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All right, so we promised to start off with SSRIs, and we're starting off with that. 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 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 become available was fluoxetine in 1988.
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. Yeah, so the people who take them can be like, yeah, Paxil.
Fluoxetine is Prozac. Paroxetine is Paxil.
Sertraline is Zoloft. Fluvoxamine is Luvox.
These are a challenge for me. You're doing great, man.
I appreciate it. Citalopram is Celexa.
And why don't you take that Lexapro for me? What is that? Escatalopram. Escatalopram.
Oh, okay. I just had a little ES at the beginning of that.
You did fantastic. My favorite out of all of them is fluvoxamine.
Yeah, that's a good word. I like all those letters together like that.
It's great. Yeah, and I'm not saying the drug itself, just the word.
Yeah, so these are the SSRIs that are going to block. They're called reuptake inhibitors.
And what that means is they're going to block 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. Yes.
But that's in the, what's called the synapticft. So it sends that that serotonin out.
And when it comes back, instead of uptaking it or reuptaking it, it blocks that from happening. So that just means there there's more of it where you need it.
They're just hanging out there like, where's my Uber? Yeah, exactly. So that was lame.
I'm sorry, everybody. That's pretty good.
It's an Uber share 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. You're trying to wedge in jokes in an unfunny episode.
Okay. Thank you for that.
That's what we try and do. Wedge in jokes where they're not appropriate.
So that's specifically what you just said SSRIs do, and they live up to their name, essentially. 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.
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.
I mean, all of the SSRIs aren't exactly the same. So if one's not working for you, you can try another one and another one and 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. Yeah, I think you're right.
And I think that when it comes to getting that, 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 even though I've never been through this, 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.

Right, for sure.

Is that a good way to say that?

Thank you. where you come into play, though, as advocating for yourself in concert with your doctor.
Right. For sure.
Is that a good way to say that? 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. 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.
So on antidepressants, you are you the increases the chances that you can exercise. And then that just makes it even more effective.
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 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 drill down and got more 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 Goldman's awesome.
And I encourage you to check out that Instagram as silly as that sounds. It can really help.
It doesn't sound silly at all. 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? No, I still don't think it was silly.
I think it was a great shout out for sure. Good.
So a couple more things real quick on SSRIs before we move on. They are, fluoxetine in particular, Prozac has a long half-life.
Yeah. So you can get away with just one dose, which you're like, who cares? One a day.
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 need to go into understanding what you're facing. But a good psychiatrist or doctor will be like, OK, let's just do this a little at a time to get you on your feet as gently as possible.
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.
I'll be getting the Wayback Machine. That's fun.
Oh, OK. Let's do it.
To the 1950s and 60s when tricyclic antidepressants made their debut. 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 why SSRIs are just so desirable. Tricyclic antidepressants are just like, kill me your 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.
All right. We're going to name these.
And these, again, might be things you saw if you're a Gen Xer. You might have seen them in your grandparents' medicine cabinet even.
Yeah. You probably associate these names with the smell of mothballs.
That's right, exactly.

Let me see here.

Here's the first one.

Nortriptoline.

Nortriptoline.

These are no SSRIs.

Jeez, I even practice these.

Nortriptoline.

Why am I getting all these?

That's Pamelor.

How about you take the next one?

I can't.

Yeah, sure you can.

Maprotoline. Okay.
That's L that's the the brand name's even worse luteomil yeah uh desopramine that's norpermine is the brand name uh amitriptyline good job yeah clomipramine that does not roll off the tongue that's anaphernal and then imipramine, which is trophenil. I've never heard of any of these, 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. Yeah.
I mean, yeah, we could go through them, but it sounds like one of those commercials. But you're way more likely to experience those with those than the SSRIs.
It's also, they were, the tricyclic were easy, easier to overdose on. Yeah.
And you're just not going to see them a lot for depression these days. They're, they're still around.
I think neuropathic pain is something they found use for. Yeah.
And if you, you know, if you don't tolerate SSRIs, they might say, you know say they might pitch you a drug from the 1950s.

Right. I saw a black box warning that the FDA slapped on it that says it can cause suicide.
And I was like, how? How does that stuff happen? and um the the way that i saw it explained is that um if you have like if you are um

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.
Yeah. But they probably saved quite a few people in the 50s and 60s when they came out.
Yeah, for sure. I mean, that was a long time ago.
So this was early sort of, you know, medicine at work. We have SNRI, serotonin,

not just serotonin, but serotonin and norepinephrine reuptake inhibitors. They came around in the mid 90s.
So after the SSRI is a little bit after. And they do exactly what you would think.
They block the reuptake of both of those in the same way. Yeah.
And what's weird is SNRIs. You think it's better, right? Yeah.
Despite selectively targeting two neurotransmitters, it's basically just as good as the SSRIs. Yeah.
I think they have about the same number of side effects, too. 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. Not the best name ever.
Venlafaxine. Benaflexine.
That's right. What just happened? That was great, man.
Benaflexck's scene is dunking. Yeah, you're right.

There's another related class called noradrenergic and specific serotonergic.

I'll bet the 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, lowercase a first.
So I'm pretty sure there's no other, I guess you could say not SSAs. Surely people don't say that.
NASAs? Sure. That's even better.
It's better than Venlafaxine. Yeah.
Yeah. They came around in the, what, mid 80s? Yeah.
They, the NASSAs have, they do the same thing, but they have different side effects. It's just so bizarre.
Yeah. 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. The next thing we're going to talk about are MAOIs or monoamine.
Is that right? Monoamines? Monoamine, oxidase inhibitors. You got all fancy.
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 because of the molecular structure of those things.
Yes. So I've heard of MAOIs like basically my whole life, haven't you? No.
Oh, okay. So they're this like like, widespread class of drugs, but they have a weird twist to them in that they 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.
And tyramine is present in a lot of different foods from like soy sauce to fish to sausage, aged cheese, the best cheese. Yeah.
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 MAOI is a monoamine oxidase inhibitor.
So it prevents this thing from breaking down the monoamines. And that's why you can't eat aged cheese.
Do you think anyone ever goes in and they're like, can I just do the SSRIs because everyone kind of knows those? Right. Should we name check those? I've never heard of any of them, but sure, if you want.
No, I don't feel the need to. Well, I think what's also interesting is that it was discovered by accident.
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 taking this thing, they're sleeping pretty good.
They have a good appetite. They're they're bouncing around the room.
They seem pretty happy. And so that's that's how 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.
Yeah. So I think they started in 1958 with Marcilid, the first ever MAOI antidepressant.
But again, because you can't eat aged cheese, people don't usually prescribe that as an antidepressant anymore. Got to have that cheese, Doc.
Sure. I mean, yeah, that'll make anybody depressed not being able to eat aged cheese.
I guess now we can jump over to, or should we take a break or should we cover nutraceuticals? I think it's break time.

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.

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IBM, let's create. 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, you know, 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.
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. Yeah, for sure.
And, you know, this is a real shame because a lot of these studies on these have come back with some results that look pretty good. Some of them show, you know, can kind of be all over the place again, maybe because it's not regulated is the reason.
Because some studies show that results can treat MDD pretty effectively. Others show it's not any better than a placebo.
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, all the rage. 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.
I remember that. That was our parents taking St.
John's Wort, wasn't it? Yeah. I remember my parents even at one point signed up for one of the supplement, you know, pyramid schemes, I guess it was.
No, really? Sort of like the Avon Laney, but it's supplements. I remember a short time.
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.
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.
Yeah, I can't bring it to mind either, but I'll bet I know what you're talking about.

So, yeah, St. John's Wort, 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. John's Wort to improve mood for probably thousands and thousands of years, if not longer.

Yeah.

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.
Right. 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, you know, 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 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. It's tough to do that as opposed to creating a new proprietary compound that treats depression.
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 ketamine, that is one that is way out in front of psilocybin as far as like official studies in the government kind of getting behind some of this stuff. Yeah, they love K.
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 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.
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.

Right.

There were a couple double colons in there if you didn't pick that up. Like a watered-down version? Exactly.
Yeah. That, like, say, a geriatric person might take.
Yeah, exactly. They started to develop ketamine in the 1960s in Belgium.
them and um you know they've been like you said i think uh starting in 2000 um 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, you know, magic mushrooms, I know has a bad connotation for a lot of people. So let's call it psilocybin, the medical or, I guess, biological name.

And let's study this stuff.

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.

Right.

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.
They didn't

just wait two weeks to go to the next patient, I guess is what I'm saying. So they found that

the effects could last like a year, a year from the second dose. And the effects were like just

mind-blowing too, as far as the, I guess, quantifying the symptoms of depression, right?

Yeah.

Do you know what the dose was before I give this number?

I think it was, like, melt your face.

Half a bag?

Right.

Two handfuls.

I'm very curious.

But 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.

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.

You know, does it do you have to take psilocybin every two years, twice, over two weeks, and

maintain control over depression?

That'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.

Yeah.

And I think they did try to follow up with those people, but they got no self-service out there in Joshua Tree. 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 SS or yeah, probably an SSRI, 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 what was generally prescribed.
Like that's what all psychiatrists

did. 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.

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. 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 what's going on.
So I think I said most people will suffer multiple or chronic or recurring episodes of major depressive disorder once they have one. Something like 50 to 85 percent of people who have one will have another episode.
So 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. And this can go anywhere from a year to indefinite.
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.
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 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 staying on something for longer. 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.
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. 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.
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 percent. 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. Yeah, I think from 2020 to 2022, if you just look in that window, especially for, I think, girls and women age 12 to 25, it went up like 150% in those two years.
Kids pulled out of school in their entire social structure sometimes. Yeah.
Yeah. 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, 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.

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.

What's the youngest you found? Mostly the youngest I found was seven years old. I would have guessed five.
Yeah, I mean, that may be, but I just found seven. 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.
And there's a whole kind of little suite of possible reasons for why that might happen. 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. Yeah.
You might have a chump for a doctor. Yeah.
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 SLC64A, 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. Yeah.
Your metabolism might affect it if some people just don't clear drugs out of their system as quickly. Yeah.
So if it's taking longer than usual, then usually a dose adjustment can help with that, but that could imbalance things even more. Yeah.
And then being under 25 before your brain is fully developed, that's one. There's something called akathisia, 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? 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 on a lot of them, then it sometimes can be hard to even tell what might be affecting what at a certain point.
Right, exactly. So that's it for antidepressants, right? You got anything else? I got nothing else.
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.
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.
Yeah. 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. Right.
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've been lucid dreaming.
It's got to me. 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.

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.

So, okay.

Well, if you want to be like Jill, send us an email.

Send it off to stuffpodcasts at iheartradio.com. Stuff You Should Know is a production of iHeart Radio.
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