Alright, here we are.
Another sip of that decaf coffee, Dr. Harvey.
Yeah, gotta have this McDonald's decaf coffee.
You're a little too hyper on this podcast, I'm worried.
I think so. If I keep talking about how much I love my McDonald's decaf coffee, do you think they'll like sponsor us or something like that? Because we really need a sponsor.
That would be a dream. That would be a dream. But I think we are years away from a sponsor.
I think we are.
And years and reality away from having a sponsor. But I noticed today you look like you're, I don't know, maybe it's just the decaf coffee, but you look like you're deep in thought.
I am. You know, I am deep in thought. There's been this topic that's been eating away at me that I've been thinking about very, very deeply.
Uh-oh. Thinking's not good.
It's not true that, yes.
What have you been thinking about? Yeah.
Well, yeah, so I've been, what I've been thinking about, I've been thinking about the serotonin hypothesis of the pathophysiology of major depressive disorder, you know, as one does.
I mean, we all are.
We all are, I think. I think we all wake up in the morning wondering about that. Yeah. And really, you know, it's not just the serotonin hypothesis, but, you know, more broadly or more generally, the monoamine hypothesis of major depressive disorder. So not Not just serotonin, but also norepinephrine and dopamine. Just the whole neurotransmitter thing with major depressive disorder.
And I guess, yeah, what are your thoughts on it?
Yeah, well, yeah, so lots of thoughts. But I think probably the place to start is, you know, I think we all kind of know where this hypothesis came from. And the place it came from is... is completely reasonable. So I think it was a reasonable thing for people to think, but now it looks like this hypothesis might not be true, but we'll kind of walk through that in just a little bit.
But, you know, we discovered antidepressant medications. When was that? Late 1950s, early 1960s, something like that. And... Those medications blocked the reuptake of the monoamines, whether it was serotonin, norepinephrine. Later on, some of the antidepressants boosted dopamine also. So medications that boost those monoamines, for some patients, that really worked well for depression. Some patients did get better with that. So I think when that happened, that really kind of changed everybody's thinking and kind of the working hypothesis or the working way to think about that was that we needed to boost those things to fix depression.
Yeah. Now, have you ever heard, this is a quote I love and I mentioned a lot in my teachings, all models are wrong, but some are useful.
Yes, yes, I've heard that. Yeah, and I think I love that saying because it's so true. It's so true. I mean, maybe someday we'll have a model that's right or at least better, but yeah.
Yeah, and that's the thing is that, you know, I personally don't think we'll ever have a model that's right. I think that's like epistemiologically impossible. I don't know if that's the right word, but I do think we'll get closer and closer approximations as to what's going on. And, you know, so... One thing, you mentioned like we all know where the hypothesis comes from. I actually, in residency, read one of like the main papers that kind of put forth, it actually initially was the catecholamine hypothesis.
So catecholamines being the norepinephrine, epinephrine, dopamine. The paper is like the 1965 paper, the Catecholamine Hypothesis of Affective Disorders, a Review of Supporting Evidence. If you take a look at it, it's really impressive. Because, you know, I always thought it was like as time has moved on, we've gotten more and more advanced science and more and more into the nitty-gritty of the different receptors and the different interactions, the molecules.
This paper is like super detailed and gives a lot of really good information in regards to the science on the catecholamines. Yeah. This paper is putting forth the catecholamine hypothesis. So it's more to do with the monoamines than serotonin specifically. But I actually want to read a quote from it because it's funny that we think of it as like, you know, the monoamine hypothesis kind of perfectly captures depression.
But this is one of the founding papers. And look at how specific they are. It's not been the aim of this paper to consider the important roles of personality, environmental, or genetic factors in the affective disorders. Many clinicians have observed, however, the significant effects which social and interpersonal factors have on the clinical response to antidepressant drugs. While our systematic knowledge in these areas is currently limited, their importance must be stressed and the need for further study emphasized.
So, I feel like we actually, like, Don't give credence to the fact that these people were doing hard, basic science. And even they were saying, like, this doesn't capture everything. And we're acknowledging that this is a piece of the puzzle.
Right, right. Yeah, yeah. Which is awfully realistic of them. Yeah.
Yeah. So even the people who were in the lab looking at this stuff, they weren't as simplistic as, like, you know, low catecholamines, depression. High catecholamines, good.
Right, yeah, yeah. And you hear that all the time. You know, sometimes people are like, oh, you know, I'm going to take a walk in the morning and boost my serotonin so I'll feel better. It's like, okay, it doesn't work that way. But yeah, yeah.
Yeah, yeah.
And I think, yeah. So I think, and I think, you know, kind of along the way, you know, we had these medicines that work for depression, but we, there are some things about the medicines that have kind of, I think we all, you know, in psychiatry, we kind of, we all knew that That the serotonin hypothesis or the monoamine hypothesis, we always kind of knew that those were half-truths.
You know, we always knew there was something wrong with that. And one way is, you know... If someone takes an antidepressant medicine and the medicine works, it takes three, four, five, six weeks for it to work. Whereas your serotonin is boosted that day. The serotonin is boosted right away and you don't have the improvement until much later. So there's that big time lag. So that kind of shows there's more to it than just boosting serotonin.
And the other thing is Occasionally we see people with something called serotonin syndrome which means because of too many medicines or the wrong mixture of medicines they get really severe side effects from too much boosting of serotonin and it's even possible for that to be fatal so if depression was because of a shortage of serotonin then these people with serotonin poisoning should be like really super duper happy I mean they should be like ecstatic they're like woohoo you know but they're not they're not they're sick and they're grumpy and confused and it's not not a fun thing it's like the opposite of fun yeah yeah yeah
Yeah, so, I mean, you call it a half-truth, and I agree, like, never in a single moment did I think, like, it was always known that it was an oversimplification. And sometimes it was helpful, because, you know, to think that something as complex as depression, which is, the human brain is the most complex thing in the universe. So to think it all boiled down to three levers of serotonin, norepinephrine, and dopamine,
come on. Yeah.
But I'm curious, do you have any knowledge in terms of like how they tested the, you know, whether or not serotonin, like what were the tests that kind of make, because recently there was that one paper, so I'm just curious if you could talk a little bit about that.
Oh, let's definitely, oh yeah, if we could, let's wait a couple minutes before we talk about that paper, but yeah, that's exactly the topic we want to talk about, is like have we tested this serotonin hypothesis? And the fact is, we have tested it, and it kind of failed the test. But yeah, let's talk about that in a little bit. But I think one thing is, you know, if we all knew this was a half-truth, how come it's so often quoted as being the truth?
Any thoughts about that?
Well, I do. I think it's a mixture, and I'm sure you're going to have a better answer than this, but... Doctors, you know, clinicians, we want to have explanations for things. And so if we find an explanation, it makes us feel good. And when it aligns with pharmaceutical desires in that, oh, the doctors feel good, so they prescribe it more, the patients feel like they understand it, the pharmaceutical company can put forth these theories and make them sound a little bit to be more true than they actually are.
And I'm not blaming pharmaceutical companies, but it's just that there's a Follow the money. And it makes doctors feel good. I can say, well, the reuptake of serotonin leads to an increase in serotonin. I'm very smart and learned. And the pharmaceutical companies make money. And the patients do often get better. So when all incentives align, it makes sense that maybe these oversimplifications come into the intellectual milieu.
Yeah, that makes a lot of sense to me. Yeah, I think so. And I think people want an explanation. I think people don't like it when they hear, we don't know, or it's unknown, or we don't know how that works. People are uncomfortable with that. So I think if we have some idea of how it might work, people really grasp at that and hold on to it tight, even if it's a half-truth.
And I think in the popular press, in the media, I think people who write articles for the popular press, they tend to oversimplify it in order to make it entertaining. I think people like reading articles that say, this is what causes it XYZ. And people don't like reading, well, it's complicated. Yeah, yeah.
I personally have seen the damage that these oversimplifications have done. I've heard patients who talk about like, oh, I can't do this because my dopamine's low.
And I have to be like, what are you talking about?
I've had a patient come to me with, they had a test done and it told me their exact levels of serotonin, dopamine, and norepinephrine in their brain. And I'm like, what the heck? Where did you get this?
Yeah.
So, yeah, there's always going to be someone who can make money and monopolize over simplifications.
It's ridiculous stuff. It's ridiculous stuff. And, you know, with TMS, you know, occasionally I have patients ask me like, oh, I guess TMS is boosting my serotonin. You know, it's like, nope, nope. Yeah, what do you say? Yeah, I say that TMS works in a different way. And we're going to be talking about that different way later on, too. But TMS works in a different way. And as far as we know, it's really not boosting serotonin and norepinephrine and everything like that.
But you know what? It's interesting because... There's a psychopharmacology textbook It's a textbook that probably both of us have read that we greatly respect It's a really good textbook And, you know, the older edition of the textbook, it said TMS works by boosting serotonin and norepinephrine And it's just not true But I think people are so stuck in that chemical soup way of looking at things that they think TMS has to work that way somehow, you know?
Yeah, yeah.
Now you mentioned, do you want to talk a little bit about that serotonin paper? Do you want to save that for our next episode?
Oh, let's talk about that because I love that paper. Yeah. Yes. Yeah. Let's jump right into that. So, yeah. So, you know, recently there was this very good paper that came out of Nature magazine that was kind of a systematic study of the evidence for the serotonin hypothesis. Wow. And it kind of walked through all the different experiments that have been done to see if the hypothesis is true.
And I mean, the bottom line is that mostly it failed those tests. You know, mostly time after time, you know, they kind of checked to see if the hypothesis is true and it just didn't turn out to be true. And so... I'll leave out all sorts of details here in the interest of time so people don't get bored. But the gist of it is one study that just looked at blood levels of serotonin versus whether or not people are depressed.
And no correlation, no connection. And then there was another study that looked at three spinal fluid, you know, CSF, looked at a metabolite of serotonin to see if that was correlated with depression or not. And it wasn't. Not correlated. You know, survey says. And then another one, you know, there's tryptophan. Tryptophan in our diet, you have to have tryptophan to make serotonin. So the idea of that study was if we give people a diet that's deficient in tryptophan, like has little or no tryptophan, then you'll be forcing people to have a shortage of serotonin in their body and maybe that will make people depressed.
So they tried that and no, it did not change the person's mood. It didn't seem to have any effect on mood. So So anyway, so kind of the bottom line is there have been all sorts of experiments to look at the serotonin hypothesis and mostly it fails. Yeah.
Yeah, and just the name of the paper that you're referring to is the Serotonin Theory of Depression, a Systemic, Systematic Umbrella Review of the Evidence. I remember when it was published in, I guess it was 2022, people, like the next day, people were acting like this was like the fatal blow to medications, not like, oh, look, this proves that like all medications don't work and that it's nonsense and like SSRIs are not going to hold up anymore.
And The analogy that I came up with in terms of how ridiculous that is, it would be like finding out gunpowder. The way it works is not what we thought it was. Like the mechanism of gunpowder wasn't what we initially thought and it's something totally different and that's what we initially thought was totally wrong. That doesn't mean you wake up and guns don't work anymore. Guns still will work the exact same amount regardless of if we know how much we know and how well we know how it works.
So this just showed us that our underlying understanding of mechanism. First off, as we said earlier, no self-respecting psychiatrist actually thought the simplistic view of serotonin, like high serotonin good, low serotonin depressed. But our understanding, whether or not it's correct, has no bearing on whether or not it works. And I think that's such an important point in that this was not a fatal blow to our medications.
This was just proof that the oversimplistic Hypothesis that no one actually believed. Turned out it was oversimplistic.
Yeah, right, right, right, yeah, yeah, very much so. Or, you know, I think another analogy is like penicillin, you know. We knew penicillin worked for a long time before we had any idea why it worked, you know. So, yeah, so people just kind of separate in their heads. There's does it work, yes or no, and then why does it work? And those are two separate questions. Absolutely.
You know, yeah, and frankly, you know, I mean, as someone who's trying to make people better— you know whether you know if a if a treatment works and I don't know why it work I'm kind of okay with that I mean it's cool to know why but if we know it works
that's great yeah yeah um well I mean do we have any other uh you know concluding comments before we wrap up this podcast
Oh, I think the only thing is, so I, you know, I think my view, and I think we share this view, is that the serotonin hypothesis was kind of an approximation of what the truth is. And as science advanced, we kind of found out that the serotonin hypothesis is less true than we thought. So we kind of need to move on from this whole chemical soup way of looking at the brain and look for other things and other better ways to understand the pathophysiology of depression.
Yeah. And I think we actually talked about this offline earlier. We need to learn from history in that we need to not throw the baby out with the bathwater. Psychoanalysis, I guess maybe we'll talk about this a little bit more, but we saw a progression from psychoanalysis to medications. And the people who started using medications who said, oh, psychoanalysis was all junk, they really missed out on something and lost something.
And we don't want to progress and then go all the medications and all the stuff we learned there is junk. We should be building up on our knowledge, not Finding the Right Thing. So I hope as we progress and find that next thing, we take the lessons that we learned throughout the history of psychiatry and keep adding rather than throwing out and replacing.
Right, yeah, absolutely, absolutely. And, you know, one thing that made me think of is I think part of the reason that people were so critical of psychoanalysis was that there were some people within psychoanalysis who took it too far, you know, who used, who were too confident in it and used psychoanalysis as like the explanation for, you know, for... Everything. Like for Crohn's disease even, you know, just everything.
And that turned out to be not true, you know. Yeah. But, and I think something similar with medications, you know, if you use the serotonin thing to try to explain everything in the world, it's like, well, okay, you know, you're taking it too far, but there's still truth there, you know, I mean, medicine still work, you know, and there's still something there with the serotonin, obviously. So, yeah, yeah.
So I think, and that's the good thing about science is, you know, when we find out we're wrong, Science people get kind of excited about that. Like, wow, we're wrong. Okay, let's do something better now.
I'm glad you bring that up. The scientific people, and I'm not saying I'm a scientist, but the people who follow these things are building up on their knowledge. And then the people who have money to be made now will hear people being like, oh, all meds are junk. Be careful. Be careful of those oversimplifications. Yeah.
Yeah, medicine still works. And you are a scientist, Dr. Maltzberg.
I don't think so. All right, Dr. Harvey. Yeah.
All right. All right. Well, that was fun. That was fun. Yeah. Hey, so I hope for all of you here listening, I hope you enjoyed the show. I'm glad you could be here to listen. And if you didn't enjoy the show, then just try listening some more and see if that works. All right.
Alright, have a good one, Dr. Harvey You too, have a good one