How Antidepressants Work

Summary

Podcast Summary: Stuff You Should Know – "How Antidepressants Work"

Release Date: March 13, 2025
Hosts: Josh Clark and Chuck Bryant
Produced by: iHeartPodcasts

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Introduction: Addressing the Overlooked Topic of Depression

In this insightful episode of Stuff You Should Know, hosts Josh Clark and Chuck Bryant delve into the complex world of antidepressants—a topic they realized they had yet to explore in depth. Recognizing the widespread impact of depression, they aim to educate listeners on how these medications work, their various types, and the broader context of treating depression.

Understanding Depression

Prevalence and Definitions

Josh begins by highlighting the staggering statistics surrounding depression. "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" (02:28). Among these, approximately 20 million grapple with Major Depressive Disorder (MDD), also known as clinical or unipolar depression, distinct from bipolar disorder which includes both manic and depressive episodes.

Symptoms and Impact

Chuck elaborates on the debilitating symptoms of depression: persistent sadness, disrupted sleep, feelings of worthlessness, impaired concentration, and anhedonia—the inability to experience pleasure. "It's 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" (03:56).

The Biological Model: How Antidepressants Work

Neurotransmitter Imbalance

Josh introduces the biological model as the foundation for modern antidepressant treatment. "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" (07:40).

Challenging the Premise

However, Chuck points out the complexities and uncertainties within this model. "We don't know the underlying mechanism that actually causes it. And because that we don't exactly know how antidepressants work... we just know it works" (08:53). This underscores the ongoing research and debate in the field.

Classes of Antidepressants

1. Selective Serotonin Reuptake Inhibitors (SSRIs)

Introduction and Examples

Josh and Chuck discuss SSRIs as the cornerstone of modern antidepressant therapy. "SSRIs are basically the flagship antidepressant, if there is such a thing" (19:13). Examples include:

• Fluoxetine (Prozac)
• Paroxetine (Paxil)
• Sertraline (Zoloft)
• Fluvoxamine (Luvox)
• Citalopram (Celexa)
• Escitalopram (Lexapro)

Mechanism of Action

Chuck explains, "They're gonna block that bus trip that serotonin takes back to that original cell... and it leaves it floating around in that space in between" (17:28). By inhibiting the reuptake of serotonin, SSRIs increase its availability in the synaptic cleft, enhancing mood.

Advantages and Side Effects

SSRIs are favored for their efficacy and relatively fewer side effects. Josh notes, "they work really, really, really well on most people with the fewest side effects." However, potential side effects include anxiety, sexual dysfunction, and vertigo (20:29).

2. Tricyclic Antidepressants (TCAs)

Historical Context and Examples

Chuck takes listeners back to the 1950s and '60s, discussing TCAs like Nortriptyline and Amitriptyline. "They were easier to overdose on and you're just not gonna see them a lot for depression these days" (25:09).

Mechanism and Challenges

Unlike SSRIs, TCAs are non-selective, affecting multiple neurotransmitters, which leads to a higher incidence of side effects. This lack of specificity made them less desirable compared to newer medications.

3. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

Introduction and Examples

Emerging in the mid-1990s, SNRIs like Venlafaxine (Effexor) and Duloxetine (Cymbalta) target both serotonin and norepinephrine. "They're basically just as good as the SSRIs... they have about the same number of side effects, too" (26:55).

Efficacy and Side Effects

While SNRIs offer an alternative for those who might not respond to SSRIs, they don't significantly outperform them in terms of effectiveness and come with a similar side effect profile.

4. Monoamine Oxidase Inhibitors (MAOIs)

Historical Discovery and Risks

Josh introduces MAOIs, explaining their accidental discovery in the 1950s. These inhibitors prevent the breakdown of monoamines, including tyramine, leading to the infamous "cheese reaction"—a hypertensive crisis triggered by consuming tyramine-rich foods like aged cheese (30:07).

Current Use and Limitations

Due to dietary restrictions and potential severe side effects, MAOIs are rarely prescribed today and are typically reserved for cases resistant to other treatments.

Alternative Treatments: Nutraceuticals and Psychedelics

Nutraceuticals: Supplements as Antidepressants

Josh discusses the rise of nutraceuticals—over-the-counter supplements touted for treating depression. While some, like St. John's Wort, have historical usage and supporting studies, the lack of regulation in the U.S. poses significant risks. "There's no one checking out, like, to make sure that the dose is the same pill to pill" (33:48).

Risks and Efficacy

Supplement quality varies, and interactions with other medications can lead to adverse effects. Josh emphasizes the importance of caution: "St. John's Wort reduces the effectiveness of... birth control pills" (35:58).

Psychedelics: The Emerging Frontier

Chuck and Josh explore the potential of psychedelics like ketamine and psilocybin in treating depression. Recent studies show remarkable efficacy, with psilocybin demonstrating long-lasting effects after just a couple of doses. "After a year from the second dose, they... the effects were like, just mind blowing" (40:50).

Clinical Approval and Future Prospects

Esketamine, a derivative of ketamine, received FDA approval in 2019 as a breakthrough treatment. Meanwhile, psilocybin continues to gain traction through ongoing research, promising transformative results for those with treatment-resistant depression.

Treatment Phases and Prescription Trends

Phased Approach to Treatment

Josh outlines the typical treatment trajectory for depression:

1. Acute Phase: Immediate intervention with antidepressants to alleviate severe symptoms.
2. Continuation Phase: Stabilizing and eliminating remaining symptoms over six months.
3. Maintenance Phase: Ongoing treatment to prevent relapse, often lasting indefinitely.

"Once they find an antidepressant that can manage your symptoms, you'll move into what's called the continuation phase" (42:49).

Increasing Prescription Rates

Chuck addresses concerns about the rising number of antidepressant prescriptions, particularly among young people. "In the United States, people ages 12 to 25, between 2016 and 2022, monthly prescriptions of antidepressants went up 66%" (45:47). Factors include heightened stress levels from global events like the COVID-19 pandemic and reduced stigma surrounding mental health care.

Potential Adverse Effects: When Antidepressants May Worsen Depression

Possible Reasons for Deterioration

While antidepressants are generally effective, some individuals may experience worsening symptoms due to:

• Misdiagnosis: Conditions like bipolar disorder or borderline personality disorder may be incorrectly treated with antidepressants.
• Genetic Factors: Variations in genes like SLC64A can affect individual responses, sometimes making symptoms worse (48:45).
• Side Effects: Issues like akathisia (internal restlessness) and interactions from polypharmacy can exacerbate depression (49:02).

Importance of Medical Oversight

Josh emphasizes the necessity of working closely with healthcare providers to tailor treatments and monitor responses, ensuring that antidepressants are both safe and effective for each individual.

Listener Mail: Exploring Hypnagogic Imagery

Towards the episode's end, Josh and Chuck share a listener's experience with hypnagogic imagery—the vivid, often nonsensical thoughts and hallucinations that occur as one falls asleep. This segment highlights the podcast's dedication to addressing a wide range of mental experiences and offering relatable insights.

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Conclusion: Encouraging Open Dialogue and Seeking Help

Both hosts reiterate the importance of recognizing depression as a treatable condition. "If you have depression and you're not treating it, there's definitely hope" (04:51). They encourage listeners to seek professional help and stay informed about the various treatment options available, whether pharmaceutical or alternative.

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Transcript

[Chuck Bryant]

Welcome to Stuff youf Should Know, a production of iHeartRadio.

[Josh Clark]

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

[Chuck Bryant]

What are you talking about?

[Josh Clark]

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.

[Chuck Bryant]

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.

[Josh Clark]

We should just leave it in once, just to really punish her. Yeah. Oh, hey, guys. She's got, like, a little bit of miso in the corner of her mouth.

[Chuck Bryant]

Always a little crusty miso.

[Josh Clark]

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.

[Chuck Bryant]

Have we never done one on depression officially?

[Josh Clark]

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.

[Chuck Bryant]

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

[Josh Clark]

Yeah, 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.

[Chuck Bryant]

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

[Josh Clark]

Sure. Stick it to me.

[Chuck Bryant]

Yeah, put that in your palm and wash it down with some water. How's that for a segue?

[Josh Clark]

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. 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 oppression.

[Chuck Bryant]

Yeah.

[Josh Clark]

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

[Chuck Bryant]

Yeah. I mean, that's a good overview 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 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.

[Josh Clark]

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

[Chuck Bryant]

Yeah.

[Josh Clark]

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. 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.

[Chuck Bryant]

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 are here to talk about some of the ways that you can change that.

[Josh Clark]

Yeah. Just as an aside, every time I think of depression being really accurately portrayed, I think of Kirsten Dunst in Melancholia, the Lars von Trier movie. Lars von Trier, of all people, seems to 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 from being so depressed that like she can barely crawl into a bath. Yeah, it's really. So it's hard to watch.

[Chuck Bryant]

That was a one timer for me.

[Josh Clark]

Yeah.

[Chuck Bryant]

Not the kind of movie you watch over and over. But Lars Ben. Lars von Trier can make a great, great flick. And I love Kirsten Dutch. She's great, for sure.

[Josh Clark]

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

[Chuck Bryant]

Yeah. And it's accepted. And it's not like it's accepted 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 a lot of the things that may lead to depression. If you're a woman, you're more likely to get. What'd you call it? Mdd?

[Josh Clark]

Yeah. Major Depressive Disorder.

[Chuck Bryant]

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 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.

[Josh Clark]

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 likelier 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, 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.

[Chuck Bryant]

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 hypothesize 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 that become just sort of stuck and lodged in that depressed state and it helps to unstick those.

[Josh Clark]

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

[Chuck Bryant]

Yeah. Or mood swings, you might call it. Whatever.

[Josh Clark]

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, 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.

[Chuck Bryant]

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 gonna talk about, I guess, all of them, probably. Right.

[Josh Clark]

By God we are.

[Chuck Bryant]

They interfere with what's called the synaptic transmission of these things, of serotonin, norepinephrine, dopamine. And that transmission is. Is the movement of neurotransmitters from one neuron to another. They're 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.

[Josh Clark]

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

[Chuck Bryant]

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.

[Josh Clark]

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.

[Chuck Bryant]

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

[Josh Clark]

Yeah, yeah, yeah. We've got a dessert knife and a butter knife.

[Chuck Bryant]

I don't know which is which. Pal, can you help me out.

[Josh Clark]

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

[Chuck Bryant]

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

[Josh Clark]

I'll drive my dessert knife through your hand. How about that?

[Chuck Bryant]

Perfect. All right, well, we'll be right back and start off with the star of the show, the ssri. Geico's motorcycle expertise means I'm covered by people who know bikes like I do. I'm happy as a clam.

[Jerry]

Disclaimer. No. Conclusive scientific research has shown clams can experience happiness.

[Chuck Bryant]

It just meant that I feel really good about my coverage.

[Jerry]

I mean, even if you took the clam out for the best day ever, visiting the zoo, taking a scenic ride, knowing you're insured by specialists, and sharing a strawberry ice cream cone together, the clam would not feel happy, and your strawberry cone would taste sort of clammy. Geico's motorcycle specialists who know bikes like you do, assume no liability for clammy ice cream cones. Geico expertise for your motorcycle.

[Chuck Bryant]

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 gonna. I guess we'll say both their regular name and their trade name or trademark name, just so everyone knows kind of what we're talking about.

[Josh Clark]

Yeah. So the people who take them can, like, be like.

[Chuck Bryant]

Yeah, yeah. Fluoxetine is Prozac. Paroxetine is Paxil. Sertraline is Zoloft. Fluvoxamine is Luvox. These are a challenge for me.

[Josh Clark]

You're doing great, man.

[Chuck Bryant]

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

[Josh Clark]

Escitalopram.

[Chuck Bryant]

Escitalopram. Oh, okay. I just had a little Es at the beginning of that.

[Josh Clark]

You did? Fantastic. My favorite out of all of them is Fluvoxamine.

[Chuck Bryant]

Yeah, that's a good word.

[Josh Clark]

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

[Chuck Bryant]

Yeah. So these are the SSRIs that are gonna block. They're called reuptake inhibitors. And what that means is they're gonna block that bus trip that serotonin takes back to that original cell, the presynaptic 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 synaptic cleft. So it sends that serotonin out, and when it comes back, instead of uptaking it or re. Uptaking it, it blocks that from happening. So that just means there's more of it where you need it.

[Josh Clark]

They're just hanging out there. Like, where's my Uber?

[Chuck Bryant]

Yeah, exactly.

[Josh Clark]

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

[Chuck Bryant]

That's pretty good. It's an Uber share.

[Josh Clark]

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

[Chuck Bryant]

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

[Josh Clark]

Okay, thank you for that.

[Chuck Bryant]

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

[Josh Clark]

So that's specifically what you just said SSRI is to. And they live up to their name, essentially.

[Chuck Bryant]

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.

[Josh Clark]

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

[Chuck Bryant]

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.

[Josh Clark]

Right. For sure.

[Chuck Bryant]

Is that a good way to say that?

[Josh Clark]

It is. And patient education is a really important part of treating depression. Like, it's not one of those things where you just turn up and say, 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.

[Chuck Bryant]

Yeah.

[Josh Clark]

It's crazy what it does.

[Chuck Bryant]

Yeah.

[Josh Clark]

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

[Chuck Bryant]

Right.

[Josh Clark]

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

[Chuck Bryant]

Yeah. 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 Gulman. 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 and one sort of set where he really, really dug into this. And one special. And then lately he wrote about it in his book, which is great. I read the book. This is all about his childhood growing up. But lately on Instagram, he has been posting just daily things. He's kind of written down on a paper that helped him when he was at his darkest and, you know, take a walk, things like that, but. But drilled down and got more 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 Goleman's awesome and I encourage you to check out that Instagram. As silly as that sounds, it can really help.

[Josh Clark]

It doesn't sound silly at all.

[Chuck Bryant]

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?

[Josh Clark]

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

[Chuck Bryant]

Good.

[Josh Clark]

So a couple more things real quick. On SSRIs. Before we move on, they are. They have Fluoxetine in particular. Prozac has a long half life.

[Chuck Bryant]

Yeah.

[Josh Clark]

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

[Chuck Bryant]

One a day.

[Josh Clark]

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

[Chuck Bryant]

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

[Josh Clark]

Oh, okay, let's do it.

[Chuck Bryant]

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

[Josh Clark]

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

[Chuck Bryant]

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.

[Josh Clark]

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

[Chuck Bryant]

That's right, exactly. Let me see here. Here's the first one. Nortriptyline. Nortriptyline.

[Josh Clark]

These are no SSRIs. Geez.

[Chuck Bryant]

I even practice these. Nortriptyline. Why am I getting all these? That's Pamelaure. How about you take the next one?

[Josh Clark]

I can't.

[Chuck Bryant]

Yeah, sure you can.

[Josh Clark]

Mepretylene, that's. The brand name's even worse. Luteomyl.

[Chuck Bryant]

Yeah.

[Josh Clark]

Desipramine, that's Norepramine is the brand name. Amitriptyline. Good job.

[Chuck Bryant]

Yeah.

[Josh Clark]

Clomipramine, that does not roll off the tongue. That's Anaphranil. And then imipramine, which is Trophanil. 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.

[Chuck Bryant]

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 easier to overdose on and you're just not gonna see em a lot for depression these days. They're still around. I think neuropathic pain is something they found use for. Yeah. And if you don't tolerate SSRIs, they might say, they might pitch you a drug from the 1950s.

[Josh Clark]

Right. I saw a black box warning that the FDA slapped on it that says, oh, wow, really can cause suicide. And I was like, how, how does that stuff happen? And the, the way that I saw it explained is that if you have, like, if you are, if you're suicidal and you have depression, you're thinking of suicide, you may be too immobilized to actually carry it out. A tricyclic antidepressant may lift the depression just enough for you to act. And apparently there's a warning on the box that says that. So, yeah, tricyclics don't sound particularly desirable, but they probably saved quite a few people in the 50s and 60s when they came out.

[Chuck Bryant]

Yeah, for sure. I mean, that was a long time ago. So this was early sort of 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.

[Josh Clark]

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.

[Chuck Bryant]

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.

[Josh Clark]

Not the best name ever.

[Chuck Bryant]

Venlafaxine. Ben Affleck's scene.

[Josh Clark]

That's right.

[Chuck Bryant]

What just happened?

[Josh Clark]

That was great, man. Ben Affleck's scene is Duncan.

[Chuck Bryant]

Yeah, you're right.

[Josh Clark]

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

[Chuck Bryant]

Have fun, fellas.

[Josh Clark]

Or else they turned this off a long time ago. But those type of antidepressants. N, a SSAs, lowercase A first, so I'm pretty sure there's no other. I guess you could say na, SSAs. Surely people don't say that.

[Chuck Bryant]

NASA's sure.

[Josh Clark]

That's even better. It's better than Venlafaxine.

[Chuck Bryant]

Yeah. Yeah. That came around in the, what, mid-80s?

[Josh Clark]

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

[Chuck Bryant]

By the way, the next thing we're gonna talk about are maois or monoamine. Is that right?

[Josh Clark]

Monoamines.

[Chuck Bryant]

Monoamine oxidase inhibitors.

[Josh Clark]

You got all fancy.

[Chuck Bryant]

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.

[Josh Clark]

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

[Chuck Bryant]

No.

[Josh Clark]

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

[Chuck Bryant]

Yeah.

[Josh Clark]

And as a matter of fact, it's called the cheese reaction, where people get hyper. Hypertensive from taking maois and accidentally eating the wrong food. So what the monoamines get broken down by is monoamine oxidase mao. And the MAOI is a monoamine oxidase inhibitor.

[Chuck Bryant]

That's right.

[Josh Clark]

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

[Chuck Bryant]

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?

[Josh Clark]

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

[Chuck Bryant]

No, I don't feel the need to.

[Josh Clark]

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

[Chuck Bryant]

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

[Josh Clark]

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

[Chuck Bryant]

Gotta have that cheese, doc.

[Josh Clark]

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

[Chuck Bryant]

I guess now we can jump over to. Or should we take a break? Or should we cover Nutraceuticals?

[Josh Clark]

I think it's break time.

[Chuck Bryant]

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.

[Josh Clark]

Okay, Chuck. So we started talking about Nutraceuticals. And that's just a fancy name for a supplement that you could conceivably use to treat a malady. And in this case, people have long been seeking supplements to treat depression with, whether it's clinical or, 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.

[Chuck Bryant]

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 are. 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 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.

[Josh Clark]

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

[Chuck Bryant]

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 that I remember a short time I Mean, they were always trying to hustle some side gig cause 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.

[Josh Clark]

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

[Chuck Bryant]

Yeah.

[Josh Clark]

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.

[Chuck Bryant]

Yeah.

[Josh Clark]

The problem 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.

[Chuck Bryant]

Right.

[Josh Clark]

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

[Chuck Bryant]

No, for sure.

[Josh Clark]

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.

[Chuck Bryant]

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.

[Josh Clark]

Yeah, they love K. Yeah, they love.

[Chuck Bryant]

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. Um, 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.

[Josh Clark]

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

[Chuck Bryant]

Right.

[Josh Clark]

There were a couple double colons in there if you didn't.

[Chuck Bryant]

A watered down version.

[Josh Clark]

Exactly. That like say a geriatric person might take.

[Chuck Bryant]

Yeah, exactly. They started to develop ketamine in the 1960s in Belgium. And, you know, they've been like you said, I think starting in 2000 is when they really started kind of looking into stuff. So it had a big jump on psilocybin. That's one that's just now starting to kind of. People are starting to say, hey, 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.

[Josh Clark]

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

[Chuck Bryant]

Right.

[Josh Clark]

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

[Chuck Bryant]

Yeah.

[Josh Clark]

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

[Chuck Bryant]

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

[Josh Clark]

I think it was like melt your.

[Chuck Bryant]

Face half a bag.

[Josh Clark]

Right. Two handfuls.

[Chuck Bryant]

I'm very Curious. But this is. I think it was a depression rating scale they were using where 24 was severe and 7 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.

[Josh Clark]

Yeah. And that 7.7 was that follow up a year later.

[Chuck Bryant]

Yeah. That's remarkable.

[Josh Clark]

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

[Chuck Bryant]

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

[Josh Clark]

That's right. So just real quick, there's. 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 the. 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.

[Chuck Bryant]

That's right. And that's after remission has begun. And that is when they're trying to 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. It just sort of depends. Again, talk a lot to your doctor through all this stuff so you really have a good handle on what's going on.

[Josh Clark]

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

[Chuck Bryant]

Yeah.

[Josh Clark]

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

[Chuck Bryant]

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 who are just willy nilly prescribing this stuff to everybody, like young children, all the way to senior citizens. Like they'll just throw anyone on that. And that's just a very sort of dumbed down way to look at this. There are critics who 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.

[Josh Clark]

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

[Chuck Bryant]

Right.

[Josh Clark]

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

[Chuck Bryant]

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.

[Josh Clark]

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

[Chuck Bryant]

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

[Josh Clark]

Yep. 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.

[Chuck Bryant]

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

[Josh Clark]

What's the youngest you found?

[Chuck Bryant]

Mostly the youngest I found was seven years old.

[Josh Clark]

I would have guessed five.

[Chuck Bryant]

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

[Josh Clark]

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

[Chuck Bryant]

Right.

[Josh Clark]

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.

[Chuck Bryant]

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.

[Josh Clark]

Yeah. You might have a chump for a doctor.

[Chuck Bryant]

Yeah.

[Josh Clark]

Genetics is also one apparently. That also determines whether you have. Whether a risk factor, like you said earlier, like grief or something like that, pushes you into major depressive disorder. There's a gene, the SLC64A, the serotonin transporter gene. I think there's a variation in that where you can actually feel worse after taking antidepressants because of that gene.

[Chuck Bryant]

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

[Josh Clark]

Yeah.

[Chuck Bryant]

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

[Josh Clark]

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?

[Chuck Bryant]

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's some kind. Sometimes can be hard to even tell what might be affecting what at a certain point.

[Josh Clark]

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

[Chuck Bryant]

I got nothing else.

[Josh Clark]

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

[Chuck Bryant]

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.

[Josh Clark]

Yeah.

[Chuck Bryant]

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

[Josh Clark]

It's gotta be.

[Chuck Bryant]

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 as 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.

[Josh Clark]

Thanks Jill. That was a great one. We love naming stuff that we experience and didn't know there was a name for. Right, right. So okay, well, if you want to be like Jill, send us an email. Send it off to [e-mail].

[Chuck Bryant]

Stuff youf Should Know is a production of iHeartRadio. For more podcasts My Heart Radio, visit the iHeartRadio app. Apple Podcasts are wherever you listen to your favorite show.