09/16/2022

Depression Isn’t Caused By Low Serotonin. So How Do Antidepressants Work?

17:02 minutes

A person stares down at a pill in their hands. A cloud that has folds like the brain reaches down over their head, darkening the frame.
Illustration by Jean Wei

In 2001, a now classic Zoloft commercial hit the airwaves—featuring a sad little blob with a rain cloud following it around. The commercial explains that “while the cause is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance.”

That theory of depression as a chemical imbalance is based on a simple premise: Depressed people’s brains lack serotonin. If a patient takes a serotonin reuptake inhibitor (SSRI), like Prozac or Zoloft, it boosts their serotonin levels, and their depression lifts. 

The trouble is that when researchers started testing this theory they found it didn’t hold up. Serotonin is certainly involved in depression. But it’s way more complicated than it originally seemed. 

To be clear, there is a body of research showing that antidepressants do work—it’s just unclear exactly how they work.  

A few months ago, a study was released which summarized decades of research debunking the overly simplistic chemical imbalance model. This left many depression researchers yawning and frustrated, as the field has long discarded the chemical imbalance theory of depression. However, the study did reveal that the public understanding of depression and antidepressants hasn’t kept up with the pace of scientific research. 

Ira talks with Dr. David Hellerstein, professor of clinical psychiatry at Columbia University, to break down what we do and don’t know about how antidepressants work and the future of medication treatment for depression. 


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Segment Guests

David Hellerstein

Dr. David Hellerstein is a professor of Clinical Psychiatry at Columbia University in New York, New York.

Segment Transcript

IRA FLATOW: This is Science Friday. I’m Ira Flatow. A quick programming note– our September book club is halfway through, but there’s still more ways to participate. You can join us in person in New York City or via livestream next Wednesday, September 21. We’re hosting a lively conversation about Vagina Obscura by Rachel E. Gross. Find out more and buy your ticket on our website, sciencefriday.com/bookclub. That’s sciencefriday.com/bookclub.

And for the rest of this hour, we’re going to be talking about antidepressants. About 13% of adults in the US take them every day. And we’re going to dig into what we do and don’t know about how they affect the brain and how scientists are working to improve pharmaceutical treatments for depression. Let me start off by asking you if you remember this commercial from the early 2000s. There’s that little sad blob with a rain cloud following it around.

SPEAKER: While the cause is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance.

IRA FLATOW: Antidepression medication was and is still a Madison Avenue staple. Just ask your doctor. That theory of depression as a chemical imbalance is based on a simple premise– depressed people’s brains lack serotonin. Give them an SSRI, or a Serotonin Reuptake Inhibitor, like Prozac or Zoloft, and serotonin increases, depression lifts.

Trouble is, when researchers started testing this theory, they found it didn’t hold up. Serotonin is involved in depression, but it’s way more complicated than it originally seemed. To be clear, there is a body of research showing that antidepressants do work. We just don’t know exactly how.

A few months ago, a study was released which summarized decades of research debunking this oversimplistic chemical imbalance model, which left many researchers in the field yawning, hey, we already knew this wasn’t true. But this study revealed that the public understanding of depression and antidepressants hasn’t kept up with the pace of scientific research. Joining me now to break down what we do and don’t know about how antidepressants work and the future of medication treatment for depression is my guest, Dr. David Hellerstein, professor of clinical psychiatry at Columbia University in New York. Welcome to Science Friday.

DAVID HELLERSTEIN: Ira, thank you for having me.

IRA FLATOW: Nice to have you. OK, let’s start off. Can you briefly explain how this chemical imbalance theory came to be?

DAVID HELLERSTEIN: I think it was an understandable early way of trying to summarize the effect of antidepressants. And it came out first when the tricyclic antidepressants were introduced in the 1950s and ’60s. And they blocked the re-uptake of some chemicals– serotonin and norepinephrine, particularly– and so a very simple way of thinking of that is, well, if it blocks the re-uptake, it must make more of these chemicals available in the brain. And therefore, it’s kind of logical to think maybe you just didn’t have enough. The gas tank was empty. You’re filling it up a bit. End of story.

IRA FLATOW: So that theory was a way to explain how antidepressants worked after the fact, right? Not an understanding of brain chemistry that led to antidepressants.

DAVID HELLERSTEIN: Right. And I think when the SSRI medications came out in the late 1980s, it was probably a pretty simple marketing message. And it resonated with people. Remember the book Listening to Prozac. Wow, it increases your serotonin and gets your depression, your panic, your anxiety better, and so on. Wonderful.

IRA FLATOW: And it was a wonderful profit maker for the pharmaceutical companies.

DAVID HELLERSTEIN: I think that’s an understatement.

IRA FLATOW: Anyone who’s taken an antidepressant can tell you that they don’t work immediately. What can this lag time help us better understand about how they work?

DAVID HELLERSTEIN: So, right, the antidepressants increase the serotonin available pretty immediately because they block the re-uptake, yet the effect takes several weeks to appear. So that is the question– why is that? And that’s led to a lot of complexity. There are some immediate effects of the medication, but the benefit takes a while to kick in. And so something happens in the brain that is a delayed process and clearly is much more complicated than just filling the tank with gas.

IRA FLATOW: So what are some of the alternative theories as to how antidepressants work?

DAVID HELLERSTEIN: So it’s interesting because the article that came out a couple months ago was making a very strong point as though the serotonin deficiency model was still what everybody believes. But it’s not. So I think that the reigning theory right now is a chronic stress model and that chronic stress and vulnerability– because some people have more risk for depression or anxiety or PTSD– chronic stress causes changes in the brain that are very difficult to undo except with some kind of treatment.

So the brain becomes actually shrunken. The size of the brain decreases. The number of synapses, connections between brain cells, decreases. And the presence or availability of brain growth factors decreases as well. So the brain is basically injured in the state of depression or anxiety disorders.

And therefore, the treatments that we use, to the degree that they’re effective, actually have an impact on the brain structure connectivity, brain health factors, and brain connectivity. So serotonin re-uptake inhibitors and other antidepressants actually do have an impact on this. But it takes a while for that to happen.

IRA FLATOW: And another theory. What other theories are there?

DAVID HELLERSTEIN: Well, so there’s an interesting other theory, which is sort of a bias theory, cognitive bias theory. So remember, people say, when someone is depressed, they see that the glass is half empty. And not only half empty, but the glass is cracked, right? So everything looks bad, and there seems like there’s no way to repair it.

So the antidepressants, interestingly, seem to change this cognitive bias in a positive direction. That seems to happen, actually, pretty quickly. So within the first few days that someone starts an antidepressant, their negative cognitive bias, their pessimism, hopelessness, seems to change even before their mood improves. So that’s an alternative theory, is that the antidepressants change this bias and that that enables the brain to start to recover from depression.

IRA FLATOW: Is there any evidence that talk therapy also might have the same kind of effect?

DAVID HELLERSTEIN: So, sure, the cognitive behavioral therapy is one of the evidence-based treatments for depression. And it actually tackles the negative bias, the sort of pessimism and hopelessness, pretty directly. And that has been shown to work clinically– it helps people– and also to have positive impact on brain connections and activity. So that’s kind of the other way to access these types of system.

IRA FLATOW: Now, I was surprised to find out that serotonin is not only found in the brain but is found in other parts of the body, like the gut.

DAVID HELLERSTEIN: Right, so I don’t know if you took an embryology course at some point in high school or college, but if you think back way, way long ago, the fetus grows out of three different layers– ectoderm, endoderm, and mesoderm. And the brain and the gut and a bunch of other tissues– skin– are formed from ectoderm. So there are receptors that are present in many, many tissues besides the brain.

So the serotonin receptors are present in the gut. They’re present in the skin. Someone who’s embarrassed will have a rash or hives sometimes, or they’ll flush, because they have receptors in the skin that are similar to the emotion responsiveness in the brain. Or your stomach– you’re upset and you’re nervous, well, you feel it in your stomach. Irritable bowel, classically, is something that comes along with anxiety. SSRI antidepressant medicines have some benefit for irritable bowel.

IRA FLATOW: So this might explain why SSRIs can work for other disorders.

DAVID HELLERSTEIN: Such as– pain would be another example. Right.

IRA FLATOW: Yeah. A lot of folks may be listening to this and saying to themselves, wow, if the scientists don’t even fully understand how antidepressants work, maybe I should think about not taking them anymore, just going cold turkey off my antidepressants. That’s not a great idea, is it?

DAVID HELLERSTEIN: No, definitely not. And I would say one kind of metaphor to think about is if you have a strep throat, and your doctor prescribes, say, penicillin or ampicillin, you need that to get better from your strep throat. It doesn’t mean the strep throat comes from a penicillin deficiency.

IRA FLATOW: That’s interesting. I want to talk a bit about the latest in depression drug research. And a lot of what we’re hearing these days is success with psychedelics– psilocybin, ketamine. For example, the FDA recently approved the use of a drug similar to ketamine for depression resistant to other treatments. This is a cutting-edge area, isn’t it?

DAVID HELLERSTEIN: Absolutely. One of the frontiers with depression treatment is trying to find rapid treatments that will affect the brain networks, connections, transmitters in a matter of hours or days rather than weeks or months. And so ketamine, a single dose of ketamine, can have a major impact on brain chemistry and mood.

And we’re part of some psilocybin studies here at Columbia. And the first large study was just completed and is about to be reported and looks like it’s pretty successful at having a single dose of psilocybin helping a significant number of people with treatment-resistant depression. Works within a couple of days. The effects last for most people for three weeks and then up to 12 weeks.

And so it’s really– we understand a lot more about depression. But the frontier is how do we get rapid onset of benefit and then how do we keep it, because ketamine, people get out of the depression, but we haven’t really figured out how to keep them non-depressed the best possible way.

IRA FLATOW: So it’s not resetting something in the brain. Is it doing something to brain circuitry?

DAVID HELLERSTEIN: Yeah, so psilocybin, for example, causes massive changes in brain activity. Parts of the brain talk to each other that don’t normally talk to each other. People would hear colors, see sounds, talk to God, see the beginning and end of the universe, these kind of extreme experiences because their brain circuits are firing off in a pretty intense kind of 4th of July way. And then, the days and weeks following the treatment, it looks like there’s reorganization of brain networks.

So one of the things that seems to happen for a lot of people with depression is kind of a broken record, for those of us who remember record players. You get a groove worn into a record which plays the same couple of notes over and over again. And the rapid-acting treatments, it’s thought, can get people out of those kind of broken-record cycles and help reconnect the brain in new ways. And there’s evidence that these drugs increase plasticity, or the ability of the adult brain to kind of reconnect and regrow connections.

IRA FLATOW: Did I hear you say, though, that it’s not a lasting effect?

DAVID HELLERSTEIN: Well, ketamine has a short acting effect. And then when you get the person out of the depression with ketamine, you have to figure out how to keep them out of the depression. So it doesn’t necessarily totally go away. It’s just that you give them kind of a boost out of the depression, and then you need to find the best ways to maintain that.

With psilocybin, most of the studies, the first studies, were doing two dosings. The current studies are just doing one dosing. And the question’s going to be, is that enough? For some people, it seems to be. Other people might need two doses. And then, how do you maintain the improvement after that?

So it’s not a slam dunk, boom, you’re better forever. It’s more of a jolt. You’re out of the state, and then how do you make the most of it?

IRA FLATOW: Right. You could be put on maintenance doses.

DAVID HELLERSTEIN: And actually– yes. And actually, the other thing that’s really interesting is, how do you best combine that with psychotherapy? Because if the brain is now more fluid, its connections are restructuring themselves or reconnecting, maybe that’s a time for enhanced learning and for people to find ways to reconnect with their activities, interests, other people, and to kind of break the broken-record cycles.

IRA FLATOW: This is Science Friday from WNYC Studios. If you’re just joining us, we’re talking with Dr. David Hellerstein, professor of clinical psychiatry at Columbia University, talking about what we know and don’t know about how antidepressants work. When do you think that this newer type, these newer types of drugs might replace SSRIs? Millions of people around the world take these drugs every day.

DAVID HELLERSTEIN: Well, the psychedelic drugs are just about to start phase 3 studies. So it’s going to be a couple years before they’re FDA approved, assuming that that happens. And they’re very labor intensive, so it’s going to be hard to scale up lots of treatments for lots of people. And so that’s going to be an ongoing challenge to figure out how to get– if they’re really as good as people think, which has to be actually proven, then it’s going to be a real process to figure out how to get them out to people.

Maybe psychedelic types of drugs but that don’t give a trip. That’s one alternative that might be actually– sounds kind of contradictory or impossible, but there are drugs that affect the same receptors that don’t give a trip. That might be an alternative that might not be so labor intensive.

IRA FLATOW: Do you think that the pharmaceutical companies are going to push back against this because they’re making so much money on these SSRIs?

DAVID HELLERSTEIN: I think the boat on SSRIs has sailed. Actually, the big drug companies have disinvested from psychiatric research. I really wish they would get back into the business because we need better drugs and new drugs, not just the psychedelics and the ketamines, but we need new allotted treatments that are more effective. And really, the new wave of psychedelic and ketamine studies is being funded mostly by small startup companies.

IRA FLATOW: Well, they could become big companies, could they not? I mean–

DAVID HELLERSTEIN: They could, or– it’s an interesting question. I’m not a business person. But sometimes they get acquired. That kind of thing tends to happen.

IRA FLATOW: But this is an optimistic future from what I’m hearing you say.

DAVID HELLERSTEIN: You know, I think that we’ve gotten out of the sort of lock box of the serotonin deficiency model. We think serotonin is involved with depression in a complicated way. But it’s not just, here’s what we do, we fill the gaps with serotonin, and that’s the end of the story. We see a complicated system but one that may have possible places to make an impact that could be rapid in onset and could have a significant impact. So I think it’s really– we’re actually in a very exciting period right now.

IRA FLATOW: Great to hear that, Dr. Hellerstein. Thank you for taking time to be with us today.

DAVID HELLERSTEIN: Oh, Ira, thank you so much for having me.

IRA FLATOW: You’re welcome. Dr. David Hellerstein, professor of clinical psychiatry at Columbia University in New York.

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