On this episode of Psychiatric News Special Report, host Dr. Adrian Preda talks with psychiatrist and neuroscientist Dr. Chloe Page about what modern brain science really tells us about major depressive disorder. Drawing on the December 2025 Special Report, they walk through the rise and limits of the “chemical imbalance” story, how media coverage of the Moncrieff serotonin review fueled public mistrust, and why a neuroplasticity framework offers a richer and more accurate way to understand depression. Along the way, they explore how stress, genetics, inflammation and brain circuits converge on reduced plasticity, why antidepressants can help even when serotonin is not the whole story, and how psychotherapy, exercise, neuromodulation and medication can work together to get a “stuck” brain moving again. The conversation highlights the power of metaphors, honest communication and shared decision making to rebuild trust and help patients make sense of both the science and their own experience of depression.

Read the full Special Report here: https://www.psychiatryonline.org/doi/10.1176/appi.pn.2025.12.12.2

PsychNews Special Report is a production of Psychiatric News, a media platform dedicated to serving as the primary and most trusted source of information for APA members, other psychiatrists and physicians, health professionals, and the public about developments in the field of psychiatry and mental health that impact clinical care and professional practice. Learn more at psychiatryonline.org/journal/pn

Transcript

Dr. Adrian Preda (00:11) Welcome to the Psychiatric News Special Report Podcast, a monthly podcast produced by Psychiatric News for the APS Medical Minds channel. I'm your host, Dr. Adrian Preda, Editor-in-Chief of Psychiatric News and Professor of Clinical Psychiatry and Human Behavior at University of California Irvine School of Medicine. Today, we are really taking a high-level view on the science of major depressive disorder, or MDD. Our main source... is the December 2025 Psychiatric News Special Report titled Neuroplasticity, Communicating the Major Depressive Disorder Framework. And this is in part a report about neurobiology, but really the point of this special report is a powerful argument. It argues that the way professionals understand what depression is about is in fact now drastically different from how the public understands depression. And that gap discrepancy is causing some real problems. To discuss ⁓ all of this and more, I'm delighted to welcome Dr. Chloe Page. Dr. Page is an assistant professor of psychiatry at University of Colorado Anschutz School of Medicine and the author of the special report coming up in our December issue. Dr. Page, welcome. Happy to have you here on our podcast.

Dr. Chloe Page (01:34) Thank you so much for having me. really happy to be here.

Dr. Adrian Preda (01:37) All right, so let's start with the big picture. It's a huge issue, I think. I mean, if you ask most people, maybe even some of my junior colleagues, medical students, most of them medical students, but even maybe some of my junior residents, probably if I ask them what causes depression, they will say, it's a chemical imbalance, the serotonin deficit, right? So what about the serotonin deficit hypothesis?

Dr. Chloe Page (02:01) Mm-hmm, yes. Yes, it's still very prevalent in our understanding of depression. I think it's because it's really easy to understand. It's really easy to be able to say that you have major depressive disorder because you don't have enough of this neurotransmitter and treatments like antidepressants, SSRIs, give you more of this neurotransmitter or this sort of happy chemical. ⁓ and that makes you feel better. Yeah, so that's really easy to understand. And I also think it helps de-stigmatize patients who have major depressive disorder and maybe feel like they have some responsibility for their illness. But if there's a biological explanation like serotonin to point to that, that takes some of that feeling of responsibility off and helps de-stigmatize mental illness. So it has those strengths of accessibility and de-stigmatization. But there's also a lot of problems to it because of its inaccuracy and inadequacy for explaining major depressive disorder.

Dr. Adrian Preda (03:09) So it's a neat story for sure. It's easy, which is great, but it's not scientifically sufficient or accurate.

Dr. Chloe Page (03:19) Yeah, exactly. You might be able to just say, we can't expect patients to totally understand a very accurate scientific explanation anyway, so maybe we'll just go with the serotonin deficit hypothesis and that's good enough. But I think that it's played out that that's really problematic and dangerous because what happened and what was the impetus for the article that my colleagues and I wrote in molecular psychiatry about this and that we then wrote the, that I wrote the special report about was based on a publication in, it came out online in 2022 and then was published in press in 2023 by Joanna Moncrief and her team. And this was an umbrella review saying that there's insufficient evidence for the serotonin deficit hypothesis. And that in and of itself was not problematic. I think many psychiatrists and neuroscientists have known this to be true for a while. But the problem was twofold. One, the article implied that because there's insufficient evidence for the serotonin deficit hypothesis, there's not a strong enough evidence base for prescribing serotonergic antidepressants because depression doesn't relate to serotonin. So a treatment that focuses on serotonin is not going to treat depression. So that was one problem with the article. And then the other problem with the article was the media response that really picked up on it and articulated it to the public as if this major theory of depression had just been totally debunked and psychiatrists and researchers were totally. following this line of thinking for decades and now it's all been blown apart and we sort of don't know what we're talking about. So when we have the media communicating science to the public, that's when it can get dangerous if an accurate portrayal of the science and the medicine is not being represented there.

Dr. Adrian Preda (05:33) That's such an important point. So one of the things that I think it's worth spending some time on is this perception that that was big news for the field, right? Yes. knew that there is something that's not explained by the serotonin deficit. And that's a big surprise plot for the neuroscientists and psychiatrists and everybody else. Such a big discovery. So the Monkrieff paper was an important paper, but the way it was perceived, was as if nobody knew that before. And that's the point that you are making. When in fact the reality is that if you are to talk to a neuropsychiatrist, not now, but 10 years ago, and you would have said, you know, what's going on with depression? Is this erotone story all there is? And they would have probably said, well, that's part of it. It's not all there is.

Dr. Chloe Page (06:21) Exactly. So that is not new.

Dr. Adrian Preda (06:25) Maybe that's not new. I think it would be really interesting to look at the beginning of this. Where does this story start? The Serotonin Hypothesis story?

Dr. Chloe Page (06:40) Yeah, it starts back in the 50s by accident. There were serendipitous findings. I think people were trying to treat hypertension. And they found that drugs that increased levels of monoamines like serotonin and norepinephrine had antidepressant effects, pro-energizing effects, mild euphoria. And by contrast, drugs that lowered levels of those monoamines had pro-depressive effects could induce depression-like symptoms. So that led to the chemical imbalance hypothesis of depression and the development of SSRIs. And it really came to focus on serotonin, I think really with the popularization of these drugs like Zoloft through pharmaceutical advertising. about the chemical imbalance. remember in the 90s, I don't know if you remember these, but these little commercials with a sad little Zoloft blob bouncing around and then talks about how Zoloft gives you more of this chemical, treats this chemical imbalance, and then the little Zoloft ball gets happy again. I think those really stuck.

Dr. Adrian Preda (07:56) So the first point here is that the fifties were almost like 75 years ago. So we're talking about, right? So in 25 years, we have 100 years. It's a century of like this hypothesis being around and that's important to understand. You know, the serendipitous thing. I always love that there are so many things that actually major changes in medicine that were serendipitous. But there are these drugs that were changing monoamines. And I think that's a

Dr. Chloe Page (08:02) Gosh, yeah it is.

Dr. Adrian Preda (08:25) point that maybe that's worth unpacking a bit because ⁓ serotonin is a monoamine but it's not the only monoamine. there are three monoamines, serotonin is one of them, is nifline and there is dopamine. And those drugs were found to have some antidepressant effects. And that's the beginning of the story. It made for an explanation, which was nice because back then, really, we didn't have a clear biological explanation of what was happening. not with depression, but in general with any of the major psychiatric disorders. And that was kind of a nice thing to hold on to. That led to the discovery actually and use of the first generation of antidepressants. Now those antidepressants, and that's another point maybe worth emphasizing, they are not serotonin-ergic. They are serotonin-ergic and they are doing some other things, right? The older antidepressants, the tricyclics and the mono-amine oxidase inhibitors. But then going to the 90s story, pharma got interested in actually developing better drugs with regards to first-order ability because the other drugs were pretty heavy-handed when it came to the first-order And these newer drugs turned out to be serotonin reuptake inhibitors, in essence, really kind of much more focused serotonin-ergic drugs. And that's where the Zoloft ad comes in and many other ads like that that were really persuasive. And you would see them on big billboards and newspapers and eventually they made it on TV. And that was, we have an explanation. And that's how the public started to become aware of this, maybe about 20 years into the making of the story. And what really brought the story forward to the public eye was a pretty well put together marketing campaign that was now very clearly and nicely explaining depression in terms of biological terms to the public.

Dr. Chloe Page (10:22) Yeah, and I think that was really needed. I think it really played a role during that time because there was and still is to a large extent a stigma around mental illness and a lack of understanding, not just in how these disorders work in the brain, but from the perspective of patients and their families, what they're experiencing. And I do think there was a benefit to this focus on the chemical imbalance at the time to help point to a biological explanation and say this is not people's fault. And I don't want to lose that as we try to communicate something that's more accurate.

Dr. Adrian Preda (11:03) So stigma was a significant issue, not only associated with depression, but with mental disorders in general. And depression is prevalent. So lots of people out there were shamed and felt that it was their fault. Clearly there was good news, right? So the stigmatizing matters, it was ⁓ straightforward and easy to follow explanation. But the issue though was that clinical findings and then findings from neuroscience showed us that That hypothesis was not explaining some of the things that we are seeing both on the neurosciens side and also in the clinical trenches when we are treating depression. So one of the things that you are mentioning in your report was the fact that when we start an antidepressant, they don't work right away. And that's not what you would expect if serotonin would be the culprit, is it?

Dr. Chloe Page (11:56) Yeah, because it's been shown that these serotonergic antidepressants actually increase levels of serotonin in the brain pretty quickly. And if depression was a simple deficit, you would expect that increasing levels of serotonin correlates pretty well temporally with alleviation of depression symptoms. But that's not the case. These drugs take about two weeks or more to have antidepressant efficacy.

Dr. Adrian Preda (12:23) So the relief should be almost immediate, but in fact we see a lag, which kind of tells us that there is some other slower, deeper process than just releasing a chemical.

Dr. Chloe Page (12:35) Exactly. Yeah, there's something more that serotonin is involved with.

Dr. Adrian Preda (12:40) That's a huge point and the research that followed only complicated it further. What about the genetic findings?

Dr. Chloe Page (12:47) There was a genetic finding that a polymorphism of the serotonin transporter increased serotonin uptake, so helped clear it from the synapse. So you have less serotonin transmission, pretty much the opposite of what serotonin reuptake inhibitors do, which is block that reuptake of serotonin from the synapse to increase serotonin transmission. And these people who had this genetic variant of the serotonin transporter that decreased serotonin reuptake had decreased risk of depression. And that's not what you would expect. If it's doing the opposite of what an antidepressant is doing, you would think that it would increase your risk for depression, but they actually had a decreased risk. So this was another opposing finding that there's something more complicated going on with serotonin.

Dr. Adrian Preda (13:40) So in this case, it's almost like lower serotonin transmission was linked to less depression, which is not what you would predict based on the serotonin hypothesis. That really completely upends the simple idea that less serotonin equals more depression.

Dr. Chloe Page (13:52) Exactly. Exactly. Yeah, so there were definitely clues pretty early on that something more is going on here than a simple serotonin deficit.

Dr. Adrian Preda (14:08) So, okay, so the scientific community has known this for years. This is like, this is not 2022 that we are talking about new findings. ⁓ So the field has been moving, has been moving on from a simple model to this firestorm in 2022 for like no clear reasons. The Moncrief review that you mentioned, right, which in effect stated that there was insufficient evidence for the serotonin hypothesis. and then explosive headline.

Dr. Chloe Page (14:41) Yeah. And that really showed that there's been a disconnect somewhere along this entire historic trajectory between what science and medicine has known and has been discovering about the causes of depression and what the public understands. Because if that disconnect in communication hadn't been there, this article wouldn't have made a splash. There wouldn't have been this messaging that this major hypothesis has just been debunked and we kind of need to go back to the drawing board with depression.

Dr. Adrian Preda (15:15) You actually in your report, you quote some of this, I think it's fair to characterize them as sensationalist headlines. So I'm just going to name a few here. So the economist, so following the Mancreef paper, they had an article titled, a popular medical explanation for depression is rebuffed. And then having them post their title was your depression might not be due to a chemical imbalance after all. And then BBC, I really like this one. Did we all believe a myth about depression? So media was really taking this on. And I think the question here, were they accurately representing what was happening at the time? Were they spinning off things? I what do you think was going on?

Dr. Chloe Page (16:04) I think they are spinning off of the science, but they are accurately representing where the public is at with understanding of depression. And as I sort of keep alluding to, I think that is the problem because there is already a distrust of science and medicine. was really exacerbated by COVID. It's always been, I think, especially true in the realm of psychiatry. That's probably something you can speak even more to as a psychiatrist and a clinician. I'm sure in your career, you faced anti-psychiatry sentiments and mistrust of the psychiatric system.

Dr. Adrian Preda (16:49) Yeah, so nothing new, right? There has been an anti-psychiatry movement around for a long time. And by the way, there are also benefits that came from the anti-psychiatry movement and that's been followed by critical psychiatry. And I think as a field, we learn a lot from our criticism. But that being said, is this perception that, misperception that psychiatry just make up psychiatric illnesses because... We are instruments that society use for oppression and control, which couldn't be farther away from the truth. Mental pain and suffering is, as we all know, very real.

Dr. Chloe Page (17:27) Yeah. And also I think an impression that it's just a machine of the pharmaceutical industry to prescribe and sell more medication.

Dr. Adrian Preda (17:40) Exactly. know, it's been psychiatrists has been just paid off and everybody's on pharma's payroll and it's about just pushing pills, pushing pills, pushing pills. So there is this narrative out there. And I think that you're right to point out that ⁓ so far as the timing of that 2022 was just two years after the COVID pandemic. So the timing probably also matters because during COVID as well now there was a level of distrust in medicine and science. So that's sort of, know, sort of been taking off. And then we had the Moon Creek paper that came in with the long history that we discussed and then adding the sort of ⁓ post-COVID context. And that it's almost like that ignited a fire. ⁓ In all these issues that were maybe somewhere, you know, somewhat covered, they exploded. And there was finger pointing and saying, first, you know, do we even know what we are doing? And secondly, then is anything that we are doing, you know, even remotely justified. These are, of course, extreme interpretations.

Dr. Chloe Page (18:43) Yeah, I think there's a lot of reasons why people think that, yeah. And sending the message that this hypothesis has just been totally debunked and there's no basis for prescribing antidepressants just really reinforces that in a way that I think is quite dangerous.

Dr. Adrian Preda (19:03) Yeah, and that's the point, right? Because it sort of resulted in a level of distrust that then in turn affected people perception of what could be in many ways an effective treatment. So one thing led to another. And then we had patients coming to see us and saying, you know, hey, why do you even prescribe these medications? You know, I've seen it out there, right? In the economist and having them, you know, post-entend. It's been over the place there is any benefit in my taking these medications. So a real problem because even when the hypothesis in many ways as we are discussing is limited, on the other hand what we know is that we have an effective treatment. So we might not have the best way to explain it, especially to the serotonin hypothesis. And there are actually many other explanations that we will discuss and the field has been aware of. But what's happened is that the perception was that that was the explanation, the explanation no longer holds, therefore the treatment couldn't be effective, which is in fact again, not factual, the treatments do work. We have clinical trials results, have decades of very solid research that showed that we have effective treatments for depression. So it was a little bit like throwing the baby away with the bathwater.

Dr. Chloe Page (20:23) It absolutely was. antidepressants don't work for everybody, that's true, but they work for a lot of people and it's undeniable that they've saved lives of people with major depressive disorder. So this is getting to the complexity of this, that there is a role for serotonin in depression. That's not just that these medications help people. But the fact that these medications still help people is still a clue that there is a role for serotonin in depression. But it's not accurate to consider it just purely a simple deficit. That's completely insufficient for understanding depression. So how do you reconcile that complexity is a real challenge for communicating this.

Dr. Adrian Preda (21:12) And you are talking about corrective communication, right? Maybe that's the best way to understand it. And the point here is that when simple becomes simplistic, that's a problem. And it seems like that's what happened here with the Selotonian hypothesis. It went from a simple explanation that explains some of the things into really being the explanation that was a simplistic explanation. And then at the end of the day, that really backfired in a big way, right?

Dr. Chloe Page (21:19) Yeah.

Dr. Adrian Preda (21:41) And maybe as a field, you know, the question that we should honestly ask is that did we play a role in sort of supporting what at the end of the day was miscommunication, as opposed to engaging with the real complexity that's out there, which is hard. Complexity is always hard. Complexity equals complicated and nobody likes complicated. But at the same time, complexity is real and complexity in this case will result in an accurate communication. and at the end of the day is going to do more good. So let's talk about corrective communication, which then brings us to, know, serotonin considered, the serotonin changes considered, what else is going on in

Dr. Chloe Page (22:22) Yeah, I really like that phrase, corrective communication, because it really is trying to, like I've said, bridge this gap between what we understand as psychiatrists and neuroscientists versus what the public understands. And we do have to try to strike this balance between what is accurate and what is accessible, because if we don't, then that gap in understanding can be filled by misinformation and sensationalism as we've seen. So the question is, how do we communicate the role that serotonin plays and what other components there are to major depressive disorder without making it completely inaccessible for patients? But on the flip side of that, not assuming that they can't understand any complexity, beyond it's just a simple deficit in serotonin and here's a drug to increase that.

Dr. Adrian Preda (23:25) Right. then, you know, so that's going to go ahead.

Dr. Chloe Page (23:29) I was just going to say that some of this complexity too is just that depression is a really heterogeneous condition. It doesn't present the same way for everybody. are core symptoms of depressed mood or lack of interest or pleasure in things, but some people sleep more, some people sleep less, some people eat more, some people eat less, some people have suicidality, others don't. And there's also lots of contributing factors to depression, like genetic, environmental, medical conditions. So it doesn't present the same way for everybody, nor does it have the same underlying drivers for everybody, which also speaks to its complexity and all of these other things that are going on in depression beyond serotonin. And how do we communicate that?

Dr. Adrian Preda (24:25) So there are many components at work and obviously we have a limited time here and I just want to not fall into the temptation of simplifying at our end as well. you know, so the point is that there are, right? But there are many causes and I think one of the things that it's important to understand is that of course there is the biology but there is a whole psychosocial environment component and they all matter. what matters in the environment, their relationships, the way people cope, psychosocial component, prior experiences with stress and trauma, all this is going to come back to changing the risk for depression. Now, on the biological side, a way to conceptualize all these different components would be probably to think about stress components. And there is a lot of evidence for chronic stress actually contributing and changing the risk. So that is a model and I think again it's important to emphasize that's probably again an important component but a component as opposed to the explanation. But just on that side I think you know that's a very different perspective than just a neurochemical imbalance. So stress could result in changing the risk for neuroinflammation and ⁓ neuroinflammation has been linked again in very complex way to neuroplasticity.

Dr. Chloe Page (25:31) Mm-hmm.

Dr. Adrian Preda (25:49) Neuroplasticity, you discussed that in your report and maybe we should just take a very high level view for our listeners out there to kind of explain what is it that we know about the neuroplasticity ⁓ changes that have been associated with deflection.

Dr. Chloe Page (26:06) Yeah, think neuroplasticity is pretty key to understanding depression and to communicating what we know about depression. Stress being a contributing factor to depression, I think, is a great example of this because you can almost think of depression as a learning from stress, that you've been exposed chronically to really stressful environments and your brain learns that the world is threatening to pay more attention to negative stimuli. you might have genetic vulnerabilities or something like that that make you more prone to these stress responses and to these states of focusing on negativity that reinforce that learning. that plasticity is a component to that learning. Your brain learns. When something like stress or genetic vulnerabilities to depressive symptoms really lead to a clinical condition like major depressive disorder is when people get stuck in certain states of information processing cognitively and emotionally. And there are these changes that are reflected at different levels, like the behavioral, the network, and the cellular, but they all relate to impairments in neuroplasticity that leave brains in these kind of stuck states that are indicative of depression.

Dr. Adrian Preda (27:41) So you have genetics, trauma, inflammations, other medical issues. They are all playing a role. But the common pathway seems to be that there are neuroplastic changes. The good news is that we have neuroplastic, and actually that is relatively new in neuroscience. But the plain is neuroplastic. That seems to be somewhat decreased in depression. That's the stock. state that you are talking about. And I like it because I think it sort of brings home the message. how does, so stuck means that we're looking at maybe narrow unhelpful patterns of processing information. That's what it's coming down to.

Dr. Chloe Page (28:21) Yeah. Yeah, I think there are a couple of pretty indicative behavioral patterns of this stuck state. And one that really characterizes depression is the negativity bias, just an increased ability to pay attention and respond to negative information and to punishment and decrease reactiveness to positive and rewarding. stimuli and I think this is a pretty pretty universal feature of depression.

Dr. Adrian Preda (28:53) Yeah, and that's, know, summarizing lots of data. But in essence, we have an indication, we have pretty clear indications that the shows less of a neural response to good things. Is that the way to understand it? ⁓ To things that are positive or rewarding, but it shows a much bigger response to negative things, which would be like punishment and threat.

Dr. Chloe Page (29:17) Exactly. I think it's most simply reflected in amygdala activation, which of course responds to emotional stimuli. You do see increased reactivity to negative or punishing information in the amygdala, but then you see decreased responsiveness to something rewarding or pleasurable when you present the amygdala with different types of emotional stimuli.

Dr. Adrian Preda (29:44) So increased reactivity, it's almost like a constant survey of programs for bad news. And then when the good news come in, they're kind of discarded.

Dr. Chloe Page (29:54) Yeah, and this bias is really self-reinforcing too because if you have brain circuits that are stuck in a state where they're more receptive and more alert to negative stimuli, then that's also what you see in your environment and what you pay attention to. People with depression can get to the point where the good stuff just doesn't even really register anymore.

Dr. Adrian Preda (30:19) So first, negativity, then negativity bias. And secondly, in your paper, you discuss the cognitive and emotional inflexibility. What's that about?

Dr. Chloe Page (30:30) I really like this one and how it depicts a kind of stuck brain state. Cognitive and emotional flexibility are really fundamental processes, and decreased cognitive flexibility is an inability to adapt to changing rules in processing information or a changing environment. Studies, a way they test this is with something called the Wisconsin card sorting task, for instance. And a participant will get a deck of cards with different shapes and colors and numbers of symbols on them, and they have to sort these cards according to some rule that they're not told about. So the rule might be all the yellow cards go in one pile and the other colors don't matter, but you're not told this rule. So you just have to get the feedback when you saw a card was that correct or incorrect. And then you deduce what the rule is. And then at some point, the rule will change. Now it'll be sort all of the cards with the squares on them. That's the salient piece of information. And people with high cognitive flexibility can adapt when the rules change very quickly. But decreased cognitive flexibility means it takes a lot longer to realize that your circumstances have changed. And people with depression actually do show poorer performance on this card sorting task. It takes them longer to adapt to a changing environment. And then there's an emotional component of it too that I think is really relevant to depression.

Dr. Adrian Preda (32:15) And then, you know, based on that, actually the Wisconsin, ⁓ card sorting test is actually mapping to the prefrontal circuits in the brain. what's nice about, ⁓ about this evidence, it's also bring brings it improves our understanding of what the neurocircuitry that might be involved in the different components of depression is at the same time. So we talked about amygdala, we talked about PFC. So there are a number of brain regions actually that we can match. based on experimental evidence that are contributing to the risk for depression.

Dr. Chloe Page (32:49) Yeah, there's so many regions of the brain that are involved in depression, so this is by no means comprehensive. But yeah, some of the core ones are the prefrontal cortex, which like you said is really important for cognitive flexibility. And then the amygdala, just really important for processing emotional responses. And we also see decreased emotional flexibility in amygdala responses. when I was talking about the amygdala being less reactive to positive stimuli and more reactive to negative stimuli in someone who has decreased emotional flexibility, they've also done studies showing that it takes longer for amygdala activity to switch between. valence stimuli. So if you present someone with with negative information, then positive information, someone with high emotional flexibility can readily shift between those emotional states and respond appropriately. But someone with decreased emotional flexibility, it takes a lot longer for them to, to start showing any kind of response to positive stimuli, and they stay like stuck in that, in that negative reactiveness. So in that sense, the emotional inflexibility and the negativity bias are really connected and reflect this kind of state that the brain is in.

Dr. Adrian Preda (34:18) So this is kind of a higher level view in which we talk about neurocircuits, abnormalities that are associated with depression. But then we can take this further down from the circuits to the actual cells, because there are actually changes at the synapse and the neurons level. So maybe we can just spend a little time discussing that. What about the synaptic dysfunction?

Dr. Chloe Page (34:45) This has been really pioneering work by people like Bruce McEwen, Ron Dooman, Carol Wellman, who looked at pyramidal neurons in the prefrontal cortex and hippocampus especially, which is also shown to be decreased in the activities decreased in depression. And the hippocampus is of course really important for learning and memory and cognitive and emotional functioning. So decreased activity. in this region also drives these symptoms of depression. What these researchers have seen at the level of the cells in these regions is that they have reduced dendritic arborization, reduced spine density, where excitatory synapses from other neurons communicate, and they're less excitable. This is a cellular substrate for this decreased activity and decreased communication both within brain regions and between brain regions. So thinking of the brain from a network perspective, all of these different hubs, like the prefrontal cortex, the amygdala, the hippocampus, the nucleus accumbens as well, which is important for reward processing, they're less able to regulate each other because at the level of the cells, those cells are less active and not communicating as well. with each other. So this also drives this really stuck state where each brain region is kind of just in its own rut of information processing and less receptive to being influenced by network-wide communication from other brain regions.

Dr. Adrian Preda (36:30) So there are the brain regions and then the brain cells, the neurons, they also have the fewer branches and the fewer contact points, which in turn literally decreases the physical infrastructure that's needed for communication.

Dr. Chloe Page (36:48) Yeah, exactly. And then that scales all the way up to the behavioral level where we get the other negativity bias, the inflexibility.

Dr. Adrian Preda (36:53) this. Yeah. And there are many things that are at play here, right? But one of the things that you discuss is the fact that a key component here, a key player is probably a combination of neurotrophic factors. These are chemicals that actually help the neurons stay healthy and grow and develop connections. And you're actually talking about the role of BDNF. So what about BDNF in the question?

Dr. Chloe Page (37:22) BDNF is the really big one, brain-drive neurotrophic factor. So BDNF helps initiate signaling pathways within the cells that facilitate neuroplasticity. So BDNF will be released by other cells, bind to a receptor, and then trigger intracellular signaling pathways like the MAP kinase signaling pathway that trigger the the synthesis of proteins involved in helping restructure these cells. So the actual physical protein substrates for dendritic arborization and increased dendritic spine density forming new synapses. BDNF is a huge driver of that by initiating cellular streams necessary for this. So if you have decreased BDNF, you just have decreased production of building blocks that are necessary for neuroplasticity to take place. And if you have less of that infrastructure, again, you have cells and networks and behaviors that are stuck.

Dr. Adrian Preda (38:33) Great. So to put it all together, this is already a much more complex model than the serotonin hypothesis, but what we're talking about is a combination of different risk factors, genes, stress, inflammation, and they all seem to converge down on lowering neurotrophic factors. We talked about BDNF as an example, which in turn leads to the physical shrinking of synapses in key brain regions. which then causes those circuits to get stuck in those negative inflexible patterns. And that is the state of being stuck that we call MDD.

Dr. Chloe Page (39:13) Yes, yeah. it is, I'm glad you summarized it that way, because when you do get into these details like BDNF and these intracellular signaling pathways, it does start to sound complex, but conceptually, it doesn't have to be, because there are all of these, like you said, these different risk factors, these drivers of MDD and these proteins and cells and networks that are involved, but they converge on this concept of decreased neuroplasticity in key brain regions important for cognitive and emotional processing and therefore these ruts of cognitive and emotional information processing.

Dr. Adrian Preda (39:59) And I think, you know, what's important about this formulation is that it's not just some dry theoretical thing, but it's, you know, if we think of MDT as being fundamentally a disease of, how should I put it, low neuroplastic capacity. That means that if the problem is a low capacity for change, then the goal of any treatment has to be to engage neuroplasticity, to literally help alter those synapses, rewire those circuits and get the brain unstuck. It's about restoring the potential for change, isn't it?

Dr. Chloe Page (40:33) Yeah, there's an analogy I really like with heart rate variability. So heart rate variability is used as a measure of stress responsiveness. And a higher heart rate variability is actually a good thing. It's indicative of adaptability. You don't have a physiological state that's stuck in like high heart rate or low heart rate. High variability means you're shifting between different activation states appropriately according to your environment. But then low heart rate variability means you're just kind of stuck in one state. And I think that conceptually matches very well to this understanding of major depressive disorder and what the goal is with treatment. It's increasing this neuroplastic capability. so you can have variability in how you process information and respond to the world.

Dr. Adrian Preda (41:36) And the other part that I think it's important to consider about this model, which is a more complex model, that then it improves our understanding of why psychotherapy works. Because psychotherapy works on this sort of negative bias and cognitive inflexibility, but also it helps understand why treatments that have nothing to do with serotonin are also effective. So we have evidence about all these glutamine-ergic interventions for depression. than neuromodulation and this other mechanism of actions actually could be better conceptualized in the context of this neuroplasticity model.

Dr. Chloe Page (42:16) Yeah, I think about it now that serotonin is just one pathway into neuroplastic changes for treating depression. And in that way, serotonin is still relevant. You can't just totally disregard its role in depression because serotonergic activity is one way to stimulate BDNF and these downstream signaling pathways that support neuroplasticity. And that's how antidepressants are thought to work. But to your point, it's not the only pathway into activating these neuroplastic mechanisms. They can also be activated by glutamatergic drugs, just pure electrical stimulation of the brain like in neuromodulation, ⁓ and by psychotherapeutic techniques and by combinations of these approaches as well.

Dr. Adrian Preda (43:13) And actually we know that even sustained aerobic exercise and meditation have been shown to increase BDNF levels.

Dr. Chloe Page (43:22) It really is and it kind of gives a framework for understanding kind of how these less tangible mechanisms like exercise or psychotherapy can still have antidepressant effects even though it's not like a chemical substrate like serotonin. So yeah, I think it's really helpful to consider neuroplasticity as a kind of convergent goal for all of these desperate therapeutic mechanisms of which serotonin is one of them.

Dr. Adrian Preda (43:57) So, you know, it seems like we have a number of like sort of ways of getting that these biological treatments will get the neuroplasticity engine started, so to speak, because they create this capacity for change. But how do you make sure that the brain uses this newfound flexibility to then build good healthy connections instead of just, you know, dig back into the old roots even deeper?

Dr. Chloe Page (44:25) Yeah, that's a really good point because in the context of depression, neuroplasticity is positive. It has a lot of potential for therapeutic change, but neuroplasticity isn't inherently a good thing. It can open the window for change in the brain, but that needs to be accompanied by positive experiences to actually help. get the brain out of this negativity bias and in flexibility and into more adaptive states.

Dr. Adrian Preda (45:01) And that's, think that's important to emphasize, right? Because neuroplasticity in itself is something that can be used, but how we're going to use it is going to matter when it comes to improving depression. So, go ahead.

Dr. Chloe Page (45:16) If you just think about neuroplasticity as the brain's ability to change, that can of course be shaped to therapeutic end. you have a more, a brain that's made more malleable by antidepressants, for example, then psychotherapy has more potential to be effective. But if you have a brain that is more susceptible to change and you're continuously in stressful environment that can actually just reinforce the learning of a threatening negative world. There's a really interesting study on this in mice that a stressed environment plus antidepressant medication in mice just reinforces depressive behaviors because it's like increasing their capacity to learn that the world is stressful.

Dr. Adrian Preda (46:15) be pessimistic and down. It's almost like you open the gates of being able to remodel the brain in different levels. You then need to make sure that the remodeling is going to be done properly because remodeling will happen and if you're going to have that flexibility and if you don't use it for good, in fact it could result in more problems.

Dr. Chloe Page (46:17) Yeah. Exactly. Another example of this is the increased susceptibility for stress-related mental health conditions for people who are in a critical developmental window of plasticity, like early childhood or puberty, when the brain is more plastic. But if you experience stress, adverse conditions, trauma during those times, it can really shape the brain in in pathological ways.

Dr. Adrian Preda (47:14) Yeah, you have a great metaphor in your report. You're comparing MDD with breaking your leg, right? And you make the point that after the immediate trauma, the leg is still stiff, it's inflexible, you have limited range of motion. And the medication, you could think about it as an anti-pain, anti-inflammatory type of medication. It could help with the biological ⁓ healing, but you need physical therapy, right?

Dr. Chloe Page (47:40) Mm-hmm. Yeah, that metaphor is really great too. And that one comes from my colleague and co-author on the paper, Andy Novik. The rehabilitation metaphor really focuses on how medication or some kind of like, quote unquote, biological intervention combined with a therapeutic intervention is the gold standard for treating these conditions. Because you can have something like an SSRI that increases the ability for change and then you have psychotherapy coming in to actually help shape that change in a healthy direction just like physical therapy for an injured leg.

Dr. Adrian Preda (48:24) Absolutely, absolutely. think that's a very powerful metaphor. So in that metaphor, so, you know, it's funny because the physical therapy is the psychological therapy for us, right? Yeah. The point is that all these different components are important. And in fact, you know, the whole one way treatment, I'm going to do medication, so I'm just going to be psychotherapy with this model. It actually, you know, the evidence points out that it makes sense to in fact combine. biological interventions and psychotherapy.

Dr. Chloe Page (48:55) Yeah, because if you just then take try to take a psychotherapeutic approach, if you don't have a capacity for change in the first place, it simply just isn't going to it can only help so much. Just like if you have a broken leg, if you don't actually reduce the pain, reduce the inflammation, reset the bone, whatever, if you don't do that first, the psychotherapy or the physical therapy rather is just going to just going to potentially make things worse if you don't have a baseline level enough of of healing and flexibility to respond to the therapy.

Dr. Adrian Preda (49:38) So think ⁓ to summarize what we've been talking about is how moving from what's no longer just a simple but a simplistic model, the serotonin hypothesis to this much more nuanced model that discusses neuroplasticity with the different components with the different perspectives, communicating that to our patients, at times using metaphors. That's a way to get the patients on board. and actually empower our patients because it provides a real context of why treatments work the way they work, why is it that they take time, why is it that we combine things. And it combats that whole narrative that depression is just a chemical impact.

Dr. Chloe Page (50:19) I am really a fan of metaphors and stories for trying to communicate this complexity because I think they are really accessible and they give people ⁓ something to hold on to that they can really relate to. I think most people can probably relate to some kind of physical injury, but they also don't have to understand all of this neurobiological complexity like BDNF and downstream signaling cascades and dendritic spines. That doesn't have to be an essential component of the scientific communication, but you can still communicate what that complexity indicates through these metaphors and stories to patients. So I think they have a lot of power for for integrating accessibility and accuracy.

Dr. Adrian Preda (51:17) Absolutely. And I think the other point that's worth emphasizing is that complexity is real. And that being the case, it's important to be honest. It's important to state what is it that we know and it's equally important to state what we don't know. Because it goes back to making sure that we have trust in our relationship with our patients. So simplification, yes, it could help maybe some education, but if you are not going to... to be honest about what is it that you know and you don't know that could result in over time in an ⁓ erosion of trust, which could create further problems down the road.

Dr. Chloe Page (51:54) That's so important. And I think that's another really key component of this scientific communication. You're trying to strive for accuracy, but you still want it to be accessible. And then you also want it to be adaptable. You don't want to give the impression that this explanation is the be-all, end-all understanding of this condition, because we're always discovering new things. That's how science works. It's important too to communicate to the public and to patients that things are always evolving. But just because we incorporate new information into our understanding doesn't mean that we don't know what's going on or are having to completely start from scratch or anything like that. Yeah, including that piece that we don't know everything, we're still learning new information is so important for trust. And I think it's another strength of this neuroplasticity framework that kind of uses this metaphor of being stuck, because it doesn't, that conceptualization doesn't inherently depend on like one particular mechanism like serotonin. So then if we find there's not enough evidence for serotonin's role, doesn't undermine the whole framework. We can still adapt new findings into this model that helps communicate convergent mechanisms of depression and its treatment.

Dr. Adrian Preda (53:37) Dr. Page, thank you so much for this insightful discussion on neuroplasticity and on communicating what we know about neuroplasticity and depression to our patients and really on what communicating what we know and we don't know when it comes to what we treat with our patients. Because communication as it turns out is key. It's the foundation of trust and trust is going to be the foundation of effective intervention, really. So thank you so much for being here today. was a very illuminating discussion. And thank you all for listening to the Psychiatric News Special Report podcast. You can read the full December report at psychnews.org. We've posted a link to the article in the episode description. If you enjoyed today's episode, please take a moment to subscribe, rate and review it. It helps others discover these important conversations. Until then, stay informed, stay compassionate and take care.

Dr. Chloe Page (54:07) Thank you so much for having me. you