How Antidepressants Work

27:40Yeah, 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've been getting way back machine. That's fun. OK, let's do it.

27:59To 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 alright that's one way to put it alright we're going to name these and these again might be things you saw if you're a A Gen Xer, you might have seen them in your grandparents' medicine cabinet even.

29:02Yeah, you probably associate these names with the smell of mothballs. That's right, exactly. Let me see here. Here's the first one.

29:12Nortriptyline. Nortriptyline. These are no SSRIs. Geez, I even practice these. Nortriptyline. Why am I getting all these? That's Pamelor. How about you take the next one? I can't. Yeah, sure you can. Uh, Maprotaline. Okay. That's Luteal, the, the brand name's even worse. Luteomil. Yeah. Uh, Desopramine, that's Norpermine is the brand name. Uh, Amitriptyline, Elevil. Good job. Yeah. Uh, 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.

29:59I 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 easier to overdose on. Yeah. And you're just not going to see them a lot for depression these days. They're still around. I think neuropathic pain is something they found use for.

30:41Yeah. And if you, you know, if you don't tolerate SSRIs, they might say, you know, they might pitch you a drug from the 1950s. 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 the way that I saw it explained is that if you're suicidal and you have depression, you're thinking of suicide, you may be too immobilized to actually carry it out. A tricyclic antidepressant may lift the depression just enough for you to act. And apparently there's a warning on the box that says that. So, yeah, tricyclics don't sound particularly desirable.

31:34But 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. Yes. We have SNRIs, serotonin, not just serotonin, but serotonin and norepinephrine reuptake inhibitors. They came around in the mid-90s, so after the SSRIs, a little bit after. And they do exactly what you would think. They block the reuptake of both of those in the same way. 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.

32:16Yeah. 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. Ben Lafixine. Ben Affleck's scene. That's right. What just happened? That was great, man. Ben Affleck'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. Oh, yeah. Have fun, fellas. Or else they turned this off a long time ago. Yeah.

33:00But 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 Venlaf vaccine. Yeah. Yeah. They came around in the, what, mid 80s? Yeah. 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.

33:48This 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? uh no oh okay so they're this like very like widespread class of drugs but they have a weird twist to them in that they um prevent you from breaking down something called tyramine which is an amino acid and tyramine is great because it regulates blood pressure but you don't want too much tyramine it gets out of whack and your blood pressure gets out of whack and tyramine is present a lot of different foods from like soy sauce to fish to sausage, aged cheese, the best cheese.

34:53Yeah. 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 MAOI is a monoamine oxidase inhibitor. That's right. So it prevents this thing from breaking down the monoamines, and that's why you can't eat aged cheese. 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.

35:39Well, 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 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.

36:15Yeah. So I think they started in 1958 with Marcellid, 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.

37:09Hi, I'm Dr. Priyanka Wally. And I'm Hari Kondabolu. It's a new year. And on the podcast Health Stuff, we're resetting the way we talk about our health. Which means being honest about what we know, what we don't know, and how messy it can all be. I like to sleep in late and sleep early. Is there a chronotype for that or am I just depressed? We talk to experts who share real experiences and insight. You just really need to find where it is that you can have an impact in your own life and just start doing that. We break down the topics you want to know more about. Sleep, stress, mental health, and how the world around us affects our overall health.

37:48We talk about all the ways to keep your body and mind, inside and out, healthy. We human beings, all we want is connection. We just want to connect with each other. Health stuff is about learning, laughing, and feeling a little less alone. Listen on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts. Hey there, this is Dr. Jesse Mills, director of the Men's Clinic at UCLA Health and host of the Mailroom Podcast. Each January, guys everywhere make the same resolutions. Get stronger, work harder, fix what's broken. But what if the real work isn't physical at all? To kick off the new year, I sat down with Dr.

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39:08New year, new goals, and in this economy, a better money plan is more necessary than ever. I am Matt. And I'm Joel. We are from the How to Money podcast, and every week we help you to spend smarter, save more, and make sense of what's going on out there. If you want 2026 to be the year you finally feel in control of your money, we're here to give you the tools and advice to help you make it happen. Listen to How to Money on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts. Hi, Kyle. Could you draw up a quick document with the basic business plan? Just one page as a Google Doc and send me the link.

39:41Thanks. Hey, just finished drawing up that quick one page business plan for you. Here's the link. But there was no link. There was no business plan. It's not his fault. I hadn't programmed Kyle to be able to do that yet. My name is Evan Ratliff. I decided to create Kyle, my AI co-founder, after hearing a lot of stuff like this from OpenAI CEO Sam Altman. There's this betting pool for the first year that there's a one-person billion-dollar company, which would have been unimaginable without AI, and now it will happen. I got to thinking, could I be that one person? I'd made AI agents before for my award-winning podcast, Shell Game.

40:17This season on Shell Game, I'm trying to build a real company with a real product run by fake people. Oh, hey, Evan. Good to have you join us. I found some really interesting data on adoption rates for AI agents and small to medium businesses. Listen to Shell Game on the iHeartRadio app or wherever you get your podcasts.

40:58Okay, 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.

41:43And 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.

42:23Yeah, 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. And I can buy it just over the counter.

42:59Then there can't be any side effects, right? But that's not true at all. There are side effects to supplements as well. And it can, you know, there have been plenty of situations where there's a supplement that becomes kind of the the all the rage. Yeah. And people just start like St. John's where it used to be when people were just like, hey, St. John's works 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 work when that. uh yeah i remember my parents even at one point signed up for one of the uh supplement uh 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 because they were teachers but um i specifically remember when i was a kid that we just had like a house full of this stuff for a while and i can't remember which system or brand this was but if someone wrote in and told me, I would be like, oh, yep, that's the one.

44:01Yeah, 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. 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.

44:40It also prevents the breakdown of antihistamines. It does all sorts of unwanted stuff. And that's just such a great 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.

45:29John'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 as 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.

46:14And 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. 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 take that up. Like a watered down version? Exactly. Yeah. That like, say, a geriatric person might take. Yeah, exactly.

46:55They started to develop ketamine in the 1960s in Belgium. And, you know, they've been, like you said, I think starting in 2000 is when they really started kind of looking into stuff. So it had a big jump on psilocybin. That's one that's just now starting to kind of people are starting to say, hey, you know, you know, magic mushrooms. I know it has a bad connotation for a lot of people. So let's call it psilocybin, you know, the medical or, you know, I guess, biological name. And let's let's study this stuff. 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.

47:39So 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.

48:25They didn't just wait two weeks to go to the next patient, I guess is what I'm saying. Yeah. So they found that the effects could last like a year, 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. Yeah. Do you know what what the dose was before I give this number? I think it was like melt your face. Half a bag. 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 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.

49:18And 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 it's pretty amazing. There was 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.

50:05That's right. So just real quick, because we'll probably go over this a little bit in the depression episode, but if you go in for treatment of depression, they're going to treat you in three different phases, two possibly, but probably three. The first is acute where you show up and you're like, I can't take this anymore. I need treatment. They're going to get you on SSR. Yeah, probably an 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.

50:46That 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 find an antidepressant that can manage your symptoms, you'll move into what's called the continuation phase. That's right.

51:24And 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. 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.

52:08Something like 50 to 85 percent 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. 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.

52:49Yeah, for sure. Which kind of all leads to the question, are these being prescribed too much? You can't hardly bring this up without hearing somebody say, yeah, they're just doctors are just willy-nilly prescribing this stuff to everybody. Like young children all the way to senior citizens, 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.

53:29So 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.

54:00And 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 percent in those two years.

54:49Kids pulled out of school and their entire social structure sometimes. Yeah. Yeah. Yeah. So it's also possible that 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.

55:34You 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.

56:13So 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.

56:51Yeah, 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 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. So if it's taking longer than usual, then usually a dose adjustment can help with that, But that could imbalance things even more.

57:37Yeah. 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, if you're on a lot of them, then it's some kind, sometimes can be hard to even tell what might be affecting what you had to get at a certain point.

58:16Right. Exactly. So that's it for antidepressants, right? You got anything else? 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 uh 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 have been lucid dreaming it's got to me uh 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.

59:30Often 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 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.

1:00:10Stuff You Should Know is a production of iHeart Radio. For more podcasts from iHeart Radio, visit the iHeart Radio app, Apple Podcasts, or wherever you listen to your favorite shows.

1:00:25Hey, it's Joel. And Matt. From HowToMoney. If your New Year's resolution is to finally get your finances in shape, we've got your back. Prices, they're still high, and the economy is all over the place. But 2026 is the year for you to get intentional and make real progress. That's right. Yeah, each week we break down what's happening with your money, the most important issues to focus on, and the small moves that make a big difference. Kick off the year with confidence. Listen to How to Money on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts. This is Dr. Jesse Mills, host of the Mailroom Podcast.

1:01:00Each January, men promise to get stronger, work harder, and fix what's broken. But what if the real work isn't physical at all? I sat down with psychologist Dr. Steve Poulter to unpack shame, anxiety, and the emotional pain men were never taught how to name. Part of the way through the valley of despair is realizing this has happened. and you have to make a choice whether you're going to stay in it or move forward. Our two-part conversation is available now. Listen to The Mailroom on the iHeartRadio app, Apple Podcasts, or wherever you get your favorite shows. I'm John Polk. For years, I was the poster boy of the conversion therapy movement, the ex-gay who married an ex-lesbian and traveled the world telling my story of how I changed my sexuality from gay to straight.

1:01:44You might have heard my story, but you've never heard the real story. John has never been anything but gay, but he really tried hard not to be. Listen to Atonement, the John Palk story on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts. Hi, I'm Dr. Priyanka Wally. And I'm Hari Kondabolu. It's a new year, and on the podcast Health Stuff, we're resetting the way we talk about our health. Which means being honest about what we know, what we don't know, and how messy it can all be. I like to sleep in late and sleep early. Is there a chronotype for that or am I just depressed?

1:02:23Health stuff is about learning, laughing, and feeling a little less alone. Listen on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts. This is an iHeart Podcast. Guaranteed human.