Episode 126: Depression and Serotonin

[Music] Hello, you're listening to the Sites of Everything Podcast Episode 126, Serotonin and Depression. I'm your host, James Fodor. In this episode we're going to talk about the role of Serotonin and Depression. And this is obviously a serious and a bit of a sensitive topic, so I will recommend that listeners exercise their discretion and whether they want to continue listening on. I'm not primarily going to talk about the clinical manifestations of depression, although I will mention that a little bit at the start. For the most part I'm going to talk about the role of Serotonin specifically in Depression. I'll do another episode at some point in the future where I discuss major depressive disorder and dysthymia and other conditions, more generally and maybe look a bit more about other aspects of depression of which there are many. But here I want to focus a bit more narrowly on just the role of Serotonin and Depression. And particularly what I want to do is try to look at how we can understand the development of a very complex, high level phenomenon-like depression at a molecular biological level. And part of the interest in this is in understanding the connection between mood disorders like depression and psychopharmological treatment such as selective serotonin or reuptake inhibitors and other psychoactive drugs, which in some sense seem to have a very simplistic mechanism of action and yet have very complicated high level effects. So the question is how to draw this gap between the molecular level and the very high level cognitive effects. So that's what I want to do in this episode. It's a little bit different to normal in that I won't be trying to present a comprehensive overview of depression, but rather I'll be focusing on this specific question here. How do we go from a molecule to mood disorder? Recommended pre-listening is episode 38, neurons and synapses. That will be helpful for just providing general background because I'll be talking a lot about neurons and the nervous system in general. So that will be useful there. All right, so without further ado, let's begin. Depression is obviously a difficult thing to talk about and it's somewhat personal for me because I've suffered from depression before. I think I may mention that in a previous episode and it should also be said that depression is very complicated phenomenon partly because it manifests differently in different people. So I don't want to present an overly simplistic view or say that it's the same for everyone. That being said, there are commonalities, which I would discuss here. And before going ahead, I should also suggest that if anyone is suffering from some of the symptoms that I mentioned here, then you should really consider seeking professional advice. Now, to begin with a definition, depression is a debilitating condition characterized by low mood and feelings of helplessness, despair, loss of interest in life and the activities of life, as well as commonly changes in appetite and sleep schedule and difficulties in concentrating. So as you can tell from that, there is a rather wide range of symptoms. Key is the low mood or low of flat effect, which is very common as well as feelings of hopelessness and despair. Anxiety is very commonly co-occurring with depression, although it's not the same thing, although pretty much everyone who experiences depression does also experience anxiety to some extent, though not everyone who experiences anxiety is also depressed. There is a different stream depression, which is a symptom and major depressive disorder, which is a psychiatric disorder. Here, I'm going to be focusing on depression as the symptom, although typically this is occurs in the context of some other disorder, such as major depressive disorder or media, which I'll talk about more in another episode. Worldwide about 1 in 6 adults experience, at least 1 episode of depression at some point in their lifetime, which is certainly a lot, although it's also perhaps interesting to know that most people never experience an episode of depression. The risk of experiencing an episode of depression is about twice as high for women that it is for men. I don't know that it's understood why that is the case, but that seems fairly consistent cross culturally. Depression is estimated to be the second leading cause of healthy years of life lost to disability worldwide, so a major health burden around the world, and is a causative factor or contributing factor in about half of all suicides every year. So not all suicides are related to depression, but about half of them are. Unfortunately, compared to many other debilitating diseases, such as cancer or heart disease, depression is very poorly understood. Part of what I want to do in this episode is try to maybe clear up some people's thinking and help to clarify how we should think about depression, particularly the relationship between the biological, the cognitive and the sociological components of it. First of all, it will be helpful to talk a little bit more about the symptomology of depression, just to clarify a few issues, which I think are commonly misunderstood. Probably one of the most common misunderstandings is to equate depression with sadness. Sadness and depression are both, I guess you could call them emotional states, although I don't think it's correct to say that depression is an emotion. It's related to emotions, but it's not the same thing, whereas sadness is one of the basic emotions. But sadness is not really the same thing at all as depression. Depression may be sad, but they may also not be. It's better to characterize depression, or it's more accurate to characterize it as low mood, flat effect and feelings of helplessness and despair, loss of interest, loss of motivation. Not so much as being sad. Sadness often connotes an idea of being teary or upset as in after you maybe watch a sad movie, or you see an animal that's hurt or something like that. But those typically aren't the same subjective states as are associated with depression, which is much more of perhaps you could call it an emptiness feeling, or a feeling of just not caring about anything, which in itself is almost not even a feeling. It's more of a, as I said, flat effect is often a common term that's used because it's a description of sort of just being emotionally withdrawn and unable to respond in an appropriate way, but also feeling highly negative and often self-critical as well, which we'll talk about later. Depression is also not just a subjective state, it's also associated with particular cognitive aspects, which again we'll discuss more later, but people experiencing depression also tend to have very negative views about themselves, and often about others as well, but particularly towards themselves. They often have very low self-worth, believe that their troubles will continue indefinitely, and that there's very little that their future can offer them, and that often they feel this very little like and do to improve their situation. They also often lack motivation to help improve their situation, which of course leads to the perpetuation of the negative state, and they feel that all of their goals that they may still have are just both unattainable and also just don't really provide them with any pleasure or reward, or thinking about achieving them just doesn't really motivate them in the way that it used to. Likewise, other previously pleasurable activities often cease to have any sort of reward or feel valuable to people experiencing depression. Individuals with depression also typically display socially-versive behaviors, so they typically withdraw from social activity and spend a lot of time ruminating, that is sort of thinking over in a negative way and rehashing their problems and the reasons why they feel negatively or they feel negatively about themselves. Some people with depression also engage in various self-harming practices, and that doesn't just include things like cutting, but it can also include like sabotaging their own health or their relationships with others or recursive self-destructive thought behaviors, which are unhelpful. These are various forms of coping mechanisms, and unfortunately one of the typical symptoms of depression is an inability to think rationally and as you as a cognitive distortions, particularly about your own behaviors and your own future. And so unfortunately a lot of people with depression as part of that condition are not able to effectively deal with their depression because of those distortions, and that's something we'll talk about a little bit later. So having said the stage about a little bit about the symptomology of depression, bearing in mind of course that it is different for each person, but these are some of the general aspects that I've outlined here. We now want to try to explore what is the cause of depression with a particular eye on something called the monoamine hypothesis. And the monoamine hypothesis has been pretty much the leading scientific theory about the causes of depression for over 50 years now. The monoamine hypothesis is so named because according to this hypothesis it is the reduced activity of a certain type of neurotransmitter. A neurotransmitter is a molecule in the nervous system that helps neurons communicate with each other essentially. It's released after an action potential is fired by one neuron and diffuses across the gap between the neurons and is then taken up by the post-uneptic neuron to then trigger an action potential and that subsequent neuron. So it's effectively a chemical form of communication between neurons and there are many of these neurotransmitters that help to communicate signals between neurons in the brain and other parts of the body. Monoamines are one class of these. So monoamine transmitters include dopamine, neuroprinephyron and serotonin. Serotonin being the main one that gets a lot of attention and that I'm going to be talking a lot about, but monoamine transmitters are all sort of related to each other. So the theory of the monoamine hypothesis is that reduced activity of these monoamines, particularly serotonin, is a significant and indeed the leading factor of the onset of depression. So to put it crudely, if you have two little serotonin or your serotonin is insufficiently active, then that contributes to depressive symptoms or the onset of depression. Now this hypothesis is the basis for the usage of many of the most common pharmacological treatments for depression, particularly so-called SSRIs or selective serotonin reuptake inhibitors. Many of the most common drugs that are used to treat depression are in this category, although there are some others as well. Selective serotonin reuptake inhibitor essentially means that these drugs act to inhibitor. but the re-uptake of serotonin by neurons that release it. Remember I said that basically when you have an action potential firing in a neuron, if that neuron is a neuron that produces that releases serotonin, not all neurons do, but some of them do, then when that action potential arrives at the terminus of the axon for that neuron, it will release serotonin. The serotonin is contained in vesicles, these little essentially bubbles or containers that are waiting in the cytoplasm, ready to be released, they then diffuse across the space between the axon and the dendrites of the subsequent cell and then fuse with receptors on the subsequent cell and then trigger a signal in that. Because the brain doesn't want to have signaling all the time, there are mechanisms to re-uptake to take up again those serotonin molecules after they've done their work. A selective serotonin re-uptake inhibitor prevents or at least diminishes the re-uptake of the serotonin. So effectively it means the serotonin is around longer and has more of an effect. It increases the signaling of serotonin to the post-ynaptic neurons. So that's what a selective serotonin re-uptake inhibitor does. It's a bit of a mouthful of a name, but basically it just means more serotonin more often to put it very crudely. At least that's a way to help remember what the effect of an SSRI drug is. So the question is, why would we expect increasing the quantity of serotonin in certain neurons in the brain to have anything to do with such a very complicated, multifaceted high-level cognitive and emotional and social issue-like depression? It seems a bit strange if you sort of think about it that way. Some people have, I think, been misled into thinking about it as if serotonin somehow is depression, like having too little serotonin is the cause of depression, or it is depression somehow. But that's just clearly wrong. Depression is a cognitive and emotional and behavioral condition. It's not the same, or the same as, or attributable to any single molecule, or system of molecules operating in the brain. It's going to be far more complicated than that. But at the same time, we do want to understand the relationship between this some molecular level and the cognitive behavioral emotional level. And so that's what I want to talk more about in this episode. So in order to understand this better, it's useful to think in terms of a levels of analysis. So just like we might think about, say, what we talked about this before. So we might think of the operation of a cell in terms of levels of analysis. So you can look at the function of the cell as hollow. You can break it down into its organelles. And then you can look at the proteins and the nucleic acids and so forth. Then you could look at the chemistry of the component parts, the individual monomer parts of the macromolecules. Then you can zoom in further and look at the individual atoms. And you could zoom in even further and look at the electron orbitals and things like that. So you can look at different levels. And then you could even go above the cell level. You could look at the tissue level or the organ's level or the system level and so forth. So there's different levels of analysis that we can examine to try to understand systems better. And this is the same thing here with depression. So what we're going to do here is we're going to start the level of serotonin and ask questions like what do serotonin do and what is its importance in particularly the brain. And then we're going to move up from that level, moving up to moving through the molecular level, up to the cellular level, the systems level and finally at the cognitive level. And we're going to try to understand how there is any connection between serotonin and depress mood. And hopefully I think that that will serve to clarify how we might understand these connections. Not just in depression, although obviously that's the focus here. But also in other cases as well, and maybe other conditions like anxiety or even cognition more generally and emotion more generally to see how these connections might be understood. Obviously we don't know all of the answers here and a lot of what I'm going to say is based on it's based on scientific evidence, but it's still provisional. It's not as well understood as some of the other things we talk about on this show. So do bear that in mind. Okay, but let's start then talk by talking about the importance of serotonin. What does serotonin do? So serotonin, as I said, is a monochromic neurotransmitter. It's released by populations of neurons scattered widely across the cortex and various internal structures in the brain called the basal ganglia. So it's not like it's based in a single population of cells. It's pretty widely distributed. And it's implicated in a whole range of cognitive functions, particularly including the regulation of mood, the circadian rhythm, so that relates to sleep wake cycles, reward-related behaviors as well as learning. Now, this is interesting already because if you think about these functions, they are all quite closely related to depression. I didn't mention this before, but depression is quite closely associated with the circadian rhythm. So many people who are experienced depression also experience difficulty sleeping or other abnormal sleeping patterns. Depression is associated with seasonality and the amount of sunlight you get. So that's why seasonal effective disorder is a phenomenon whereby in particularly during the winter, when there's reduced daylight, you tend to have higher cases of depression. So the fact that the circadian rhythm is associated with serotonin is interesting, as well as regulation of mood. There's an obvious connection to depression there. And reward-related behaviors. So part of depression seems to be the fact that previously rewarding and fulfilling behaviors cease to be rewarding and fulfilling to people. And that's why you see the flat affect, you see the disinterest and feelings of emptiness and lack of meaning that the people experience typically. So that appears to be connected to this idea that there's something going wrong, some malfunction in the normal reward system that we get when we engage in rewarding behaviors. And rewarding behaviors can be anything from very basic, like eating yummy food to very high level, taking part in a social activity and a course that is something that provides you with meaning and you feel like it's contributing value to the water. And so on, any of those things can be rewarding behaviors. But it seems that serotonin is involved in those sorts of behaviors, which are also going wrong in some way in depression. And learning. Depression is certainly closely related to learning because, as we'll talk a bit a bit more about later, people who experience depression often learn or have learned various cognitive processes and maladaptive behaviors that reinforce, instigate depressive behaviors and maladaptive responses to those. So we'll talk a bit more about that later. But even at the outset, looking at the sort of things that serotonin is involved in, we can already see that there's a sort of a linkage here. But let's go into a bit more detail. So what specifically is serotonin doing then? Before we look at what exactly serotonin is doing at the molecular level, first it's important to understand that the evidence connecting serotonin to depression is quite strong. There are many different lines of evidence here. So let me just mention a few of them. Firstly, biochemical studies have shown that depressed patients do have lower concentrations of serotonin, as well as associated molecules, compared to healthy controls. So depressed patients have less serotonin. That's consistent with the monoamine hypothesis, which effectively says that two little serotonin leads to or can lead to depression. So second, patients who receive pharmacological treatments for depression, such as SSRIs, show increased levels of serotonin activity compared to beforehand. So that's exactly what the treatments are supposed to be doing. They're supposed to be increasing serotonin activity in the brain. And that is indeed what is found. Third, neuroimaging studies have found that binding efficacy of serotonin receptors is lower in depressed patients compared to healthy controls. So that's an indication that basically that serotonin is not the being as effective at triggering the activity of the post-ynaptic neuron as it is in normal patients. So that's again consistent with the monoamine hypothesis. Not so much less serotonin, but less effective serotonin in that case. Also, there are now a wide number, a large number of randomized placebo controlled studies that show that selectives serotonin and reuptake inhibited drugs are effective in treating depression. This has been somewhat controversial, although from my reading of the literature, the most recent studies are quite clear that and consistent in finding positive results here. It is true that SSRIs are certainly not effective for everyone. I think these sorts of drugs are effective in about half of patients. And that is a lot better than zero, but it's still not really that great. So a little bit more on that later, but there certainly is evidence that inhibiting the reuptake of serotonin does alleviate depression symptoms, at least in a large number of patients. So all of these pieces of evidence seem to confirm that there is a close connection between serotonin and depression. On the other hand of things, there are still major gaps and puzzles that raise questions as to exactly how to understand this relationship. So first of all, antidepressant medications, as I mentioned, are only effective in about half of depressed patients. So it certainly can't be the case that depression is caused by a lack of serotonin or at least a lack of the efficacy of serotonin in terms of binding efficacy, because four half of patients, improving that, doesn't really have any effect on their depression. So there's obviously more going on at least in about half of patients and possibly in all patients. Another issue is that experimental studies show that inhibiting the action of serotonin in healthy subjects does not give rise to two symptoms of depression. This is very important. What this means is that in depressed patients, we find lower concentrations and lower activity of serotonin. But in healthy subjects, when we induce those same symptoms, that is, we induce the reductions in serotonin or the reduction in binding efficacy, they don't become depressed. So it may be that a deficiency of serotonin can cause depression, but it doesn't always cause depression. There's obviously more going on. There's more to it than just the deficiency of serotonin. Third, it's well established from experimental and clinical observations that pharmacotherapeutic treatments, such as SSRIs, don't have any effect on the symptoms of depression for several weeks afterwards. But this is hard to understand because concentrations of serotonin increase almost immediately. So pretty much as soon as you start taking SSRIs, concentrations of serotonin and serotonin activity goes up. But depressive symptoms don't start to relieve when they are relieved until several weeks later. So this is indicating that it's not the serotonin directly that's causing changes in mood. It's some sort of downstream more complex metabolic or physiological process that serotonin is involved in, but it's certainly not sufficient for that. Because otherwise you would see this the symptoms begin to be relieved at the same time as serotonin increases, but that doesn't happen. So because of these reasons, it's fairly well established that serotonin does play a very important role in the development of the depression and the onset of depressive symptoms, at least in many cases. However, it's not really clear exactly what it is doing, and it's certainly not the case that serotonin is a direct cause of depression, as I said, because the timelines don't match up. And also, the levels of analysis don't really make sense. You can't identify or simply, or in a simple way, reduce a very complex phenomenon such as depression to the actions of a single neurotransmitter. So there's definitely more intermediating steps going on. And what we want to do, what I want to do in the rest of this episode, is to try to un-pick those a bit and try to explain what we know about how we can bridge the gap between this molecule and the mood disorder of depression, or the symptoms of depression. So let's talk a bit more now about what serotonin is doing at the molecular level. There are many classes, seven, in fact, of serotonin receptors that have been currently identified. So a receptor is just a molecule that's present on the cell membrane of a neuron in this case, which is a receptor. It's receptive to, or it responds to particular molecules. In this case, a serotonin receptor, by the nature of it, will bind to serotonin. So when serotonin is around, it will bind, literally, join up together and form a complex with the receptor. And that will then trigger some downstream function. So basically, you can think of it as kind of like dominoes falling over. It's a bit more complicated than that, but that gives you the idea. So the neurotransmitter, like the serotonin binds to the receptor, then the receptor binds to another protein. For example, a G protein. Don't worry if you don't know what that is, but that's an example of sort of an intermediating step. And then the G protein binds to an effect protein, and that then activates a secondary messenger that then has further effects on the cell. So there's a whole domino of sort of these metabolic processes happening inside the cell. I believe I did talk about these when we talked a bit about cell signaling in one of the previous episodes. I forget what number that was, but the details aren't too important here. The important thing to understand is that serotonin has an effect on what's happening inside the cell by triggering a cascade, that this is the way that she's a cascade of these molecular interactions, which then has an effect on stuff that's happening inside the cell. And serotonin has this effect on any, or can have this effect on any cells that have one or more of these different classes of serotonin receptors. And many, many cells have serotonin receptors. So there's many, many different things that serotonin can be doing. It's not like serotonin does one thing when it applies to a cell. No, there's many, many different complicated webs of interactions that can happen as a result of serotonin. So that's one issue that must be understood is that there's no particular connection. There's no simple straightforward connection between serotonin and mood. Serotonin has many, many effects depending on the types of receptor and depending on the state of that cell and what proteins it's expressing and so forth. So as I mentioned, pharmacological treatments for depression act by inhibiting the reuptake of serotonin. So that there's more serotonin that remains in the gap between neurons and therefore the serotonin receptors are active more often or more readily activated. And therefore, those serotonin receptors keep triggering or trigger to a higher extent. The metabolic changes that they instigate in the cell that they're on. So this is consistent with what I just said before that serotonin is not directly doing anything about depression. It's indirectly having an effect on it through various downstream interactions of metabolic processes. So that's exactly what we sort of expect, right? Serotonin is just a neurotransmitter. It's just triggering changes in the post-synaptic cell. It's those changes in the post-synaptic cell themselves that are then going to have that the effects on things like mood and behavior and such. And so we need to sort of trace that pathway forwards. So let's keep moving and look at the sort of next steps that are relevant here. Again, there are many that we could look at. This is, I'm going to focus on one that I think is particularly important here. And that is that there's something called this brain derived neurotrophic factor or BDNF is the short name for it. So this is a protein. We know what proteins are proteins are sort of the building blocks of cells and they're also enzymes that perform as catalysts mediating pretty much all of the reactions that occur in cells and help us stay alive. So brain derived neurotrophic factor is one of these proteins and it's very important as a sort of a signaling and regulatory protein to help the survival growth and plasticity of neurons as well as the growth of new neurons that neurogenesis in the brain. So that's why it's neurotrophic factor. It's particularly important for neurons. So BDNF is basically a signaling molecule that helps with the growth and survival of neurons. So it's very important for regular neural functioning and then keeping the brain working properly and so forth. There is a number of lines of evidence that link this BDNF to serotonin. First of all, clinical evidence in humans and also in rodents indicates that depression is associated with reduced levels of this brain derived neurotrophic factor, especially around the hippocampus. There are also studies that indicate that BDNF concentrations increase following antidepressant treatment. If we knock out certain serotonin receptors in rats, that means genetically modified rats that don't have these receptors or that they're not working. This has been shown to reduce levels of this brain derived neurotrophic factor around the hippocampus and the prefrontal cortex. Don't worry if you don't know some of these brain regions that I mentioned. I just mentioned them for the people who may be familiar with them. I'll talk a bit more about that later. Finally, brain derived neurotrophic factor is also known to affect the expression of genes that are relevant to cell growth and differentiation. I sort of mentioned this before and it does that again through a complicated process of these protein cell signaling molecular cascase interactions within the cell. That's happening here again. It's not just a straightforward one to one thing, but the point here of all this is that there seems to be a connection between serotonin and brain derived neurotrophic factors such that increased levels of serotonin allow for or promote in some way increased production of this brain derived neurotrophic factor, which in turn helps to promote the development, survival, and growth and maintain the health of neurons in the brain, particularly in certain regions of the brain that I mentioned like the hippocampus. Again, however, the evidence is clear that brain derived neurotrophic factor itself is not sufficient for generating depression. So if we knock out this protein, for example, in mice, that does not produce depressive symptoms. I should mention that there are models of depression in mice as well as in humans where the lack of interest in rewarding behaviors and a social behaviors and things like that are also manifested. I don't want to get into the details of that here, but I just wanted to mention when we talk about mice and rat studies, that's because we have analogs or models of various psychological conditions, including depression in these animals, which we can use to help study it in humans. But obviously, there are going to be differences. It's not precisely the same, but that's a discussion for another time. Anyway, so at this point, we understand that serotonin is a singling molecule, which is critical, it seems, for promoting the production and release of this neurotrophic factor, which helps to maintain the health and well-being and growth of neurons. So that's some way along the pathway, but we still need to understand exactly why this would lead to something like depression instead of just general cognitive deficits or something. So let's now move along from the molecular level and talk about a bit at the cellular level. So there are a number of lines of evidence which indicate that there are cellular level differences between depressed and normal brains. So there are a few lines of evidence that we can mention here. First of all, post-mortem analysis of depressed subjects has found that glial cell density and neuronal size is reduced in certain regions of the brain. Glial cells are not neurons, but they're sort of like helper cells. They help neurons to stay healthy and to transmit signals and things like that. We need to get into the details of that here. Look at some of the previous episodes I've done if you want more information about those. But the point is that there are differences in cell density and size between normal and depressed brains, as measured in post-mortem analysis. Furthermore, if we irradiate the hippocampus, that's one of the brain regions I mentioned before that's associated with both serotonin activity and depression as well. If we irradiate the hippocampus to destroy neurogenesis, the production of new neurons, if we do that in mice, that's actually been found to be sufficient to eliminate the behavioral effects of antidepressant medications. So basically, there's evidence that the function of the hippocampus is necessary in order for antidepressant medications to be beneficial. So something that's happening in the hippocampus that's relevant to the causal pathway by which selective serotonin and reuptake inhibitors helps with depressive symptoms. It's also been found that chronic administrations of providing serotonin, selective serotonin and reuptake inhibitors for a long period of time helps to increase adult neurogenesis in depress patients, so production of new neurons in the hippocampus. So a combination of evidence from humans and mice indicates that essentially depress patients have differing and typically reduced cell morphology and that there is an important role played by neurogenesis in the hippocampus, so production of new neurons in the hippocampus, and the effects of selective serotonin reuptake inhibitors. So whatever selective serotonin uptakes inhibitors are doing, whatever serotonin is doing, it seems to require the proper development of new cells and functioning of glial cells and so forth around the hippocampal regions. So I'll have bothers for this and this is not firmly established, but it seems reasonable. It's that brain-derived neurotrophic factor. Remember, that's the growth chemical that I mentioned that helps neurons to stay healthy and to grow. It is critical for the growth and survival of new neurons in the hippocampus and that it is through the maintaining appropriate levels of BDNF, brain-derived neurotrophic factor, that serotonin has its effect on neurogenesis and maintaining cell diversity and neural size and so forth. So there's a few lines of evidence that seem to support that. And this is interesting because this allows us to sort of see how chemicals such as serotonin or brain-derived neurotrophic factor actually have an effect at the cellular level because they're necessary, particularly brain-derived neurotrophic factor is necessary, for promoting cell growth, furthermore, it seems that brain-derived neurotrophic factor is also important for facilitating the alteration of the strength of connections between neurons in the hippocampus, which is important for memory formation and memory consolidation. So it appears that patients with depression have a reduced capacity for both neurogenesis or production of new neurons, as well as reduced capacity for neuroplasticity. So that's the alteration of the strengths of neural connections, particularly in the neuro campus, as a result of these reduced levels of brain-derived neurotrophic factor, which in turn seems to be partly at least due to a reduced activity of serotonin. Okay, so so far we've drawn a connection between serotonin and the levels of brain-derived neurotrophic factor and a connection between brain-derived neurotrophic factor and the plasticity and neurogenesis and general health of neurons in certain regions of the brain, including the hippocampus. But again, what is the connection between the activity and health of these cells in the in the hippocampus and the symptom of depression? So to see that, we need to move at a higher level and look at the system's level analysis. So particularly we want to look at different brain regions and see what the neural patterns of neural activity in these brain regions are doing. So neuroimaging studies have consistently shown that depressed patients exhibit changes in the structure and function of various brain regions compared to healthy controls. This has been observed in a number of different brain regions, particularly including, as I mentioned already, the hippocampus and also a brain structure called the amygdala, which is very highly associated with processing of emotions, especially fear responses and other negative emotional behaviors. And various parts of the prefrontal cortex, which is the front, out or most part of the brain that's involved in executive processing and so forth. Many of these regions are part of what's called the corticolimbic system. So this includes the amygdala and hippocampus and parts of the cortex, and it's involved in processing emotional responses and helps to regulate the top-down feedback that's received from other areas of the cortex. So essentially you can think of the corticolimbic system as being involved in the processing of cognitive responses and memories and stimuli and things like that and integrating them with our emotional response or how we feel about them or what sort of valence the significance they have to us. So it's theorized therefore that anti-depressant medications such as selective serotonin reuptake inhibitors may help to increase the plasticity of neurons in these regions. As we mentioned, that's through the effects of the brain drive neurotrophic factor, which in turn helps to remodel circuits in these regions, basically to improve the flexibility of neural growth and structuring connections within these brain regions, in the way that it sort of should allow us to properly respond and integrate these ideas, these experiences we have with our emotional responses. And there's something sort of goes awry with this, it seems, in depressed patients, partly because of the insufficient quantities of serotonin leading to insufficient brain drive neurotrophic factor, leading to a dysregulation of neural growth and plasticity in these regions. So effectively, this means that there's evidence that in certain brain regions such as hippocampus, amygdala, and certain parts of the cortex, circuits in these regions are not able to appropriately process the significance and the importance and the value and the emotional effects of stimuli that we experience as well as memories and other things. And therefore that can lead to depressed symptoms. But exactly what the connection is between these sort of brain processing regions and the actual symptomology of depression, we need to go further again and look at the cognitive level, which is sort of the functioning of the brain as a whole rather than sort of specific circuits. And when we do that, what we find is that there are many cognitive aspects of depression beyond simply flat affect or feeling down. And I mentioned some of these before, but I'll just talk briefly about them again. So in particular, it's been observed that many depressed patients experience a variety of cognitive distortions and deficits that are related to and help to propound and worsen their depressive symptoms. So some of these include selective abstraction. So this is essentially drawing generalizations and broad conclusions from only some of the aspects or elements of a situation. So typically what a depressed person is likely to do is emphasize the negative aspects of a situation and draw conclusions from those and sort of ignore or downplay the others. So that's how it's selectively abstracted. Minimization is a related aspect in which the positive aspects of a thought or situation or an emotion are downplayed minimized. Whereas the negative ones as through selective abstraction are sort of latched on and emphasized and often thought about repeatedly through cogitation and rumination. Personalization is another distortion, which involves attributing personal responsibility for things that aren't under the person's control typically for negative events. So this is sort of an it's all my fault. Another distortion is arbitrary inference. Basically this means drawing conclusions from little or no evidence. So an example of this might be that if someone makes a very minor remark or a very sort of insignificant behavior, then there's a tendency to isolate that aspect of the situation. That would be the selective abstraction part. But then draw strong inferences from that when there's just very little evidence. You might think that the person has a grudge against you or doesn't like you or is deliberately ignoring you, things like that. That will be an example of arbitrary inference. When the evidence is just not nearly sufficient to draw that conclusion. Magnification is another distortion which involves basically blowing something out of proportion. It's somewhat related to arbitrary inference. Except in this case it involves the involves overweighting the significance of fairly small events as opposed to drawing hasty conclusions from them, but they can go together. So the idea would be that a very very small behavior from another person might be selectively taken through selective abstraction. You identify that aspect. You minimize any positive aspects of the situation. You then use arbitrary inference to draw far stronger conclusions than a appropriate magnify the significance of this far in excess of what is appropriate. And then it should be personal responsibility for all of the negative aspects of the situation. Also tend to draw those implications very personally as in that you tend to think of yourself as responsible and a bad person and no one likes you and things like this. So you can see how these different cognitive distortions tend to go together and reinforce negative use about the self. And one way to think about this is in terms of what's called a triad, depressive triad. The triad here is negative use about the self, reinforce negative use about the world, which reinforce negative use about the future, which reinforce negative abuse about the self. So they're also sort of mutually reinforcing negative use which can potentially spiral downwards and lead to the person feeling worse and worse about themselves in the world and their general situation. These are all, as I mentioned, sort of reinforced and propounded by these cognitive distortions. There's also evidence that depressive patients have a bias processing for negative stimuli. So they focus on the negative and ignore or downplay the positive that that's sort of related to minimization and selective abstraction. I've also mentioned how depressive patients regularly engage in repetitive negative remination. So this involves self-referential thoughts, recall of negative memories and reflections on the negative aspects of yourself. So this is thinking about all the other day when I met this person, they did this thing, which indicates that they don't like me or they're ignoring me or whatever or that I'm a burden. I'm an annoyance to them. I just cause problems and it was all my fault and this is because I suck as a person and why would they want to talk to me and things like this. And these just go round and round and the thoughts continue and there's a focus on the thoughts and a neglect of things outside of that or neglect on other ways of looking at the situation. These sorts of depressive remination thoughts have been associated with something called the default mode network, which is a brain network, a connection of regions in the brain, which is involved in sort of conscious awareness and processing of stimuli. Neuroimaging studies have found that this brain network is particularly active, is extra active in depressed patients, compared to in control patients. So essentially, depressed patients have a greater activity of the default mode network, compared to other brain networks which are focused more on specific tasks. So you're if you're engaging in a motor task or a memory recall task or a visualization, you're recognizing a stimulus. There are particular brain regions that subserv those sort of tasks specific functions. But this default mode network is kind of a generalised network that is responsible for integration and reflection, as such is related to, or not exactly the same conscious reflection, conscious awareness. And this particular sort of default mode network is particularly active in depressed patients, which is an indication that they're typically less focused on what they're doing right now on the task or at least devoting fewer cognitive resources to that and more to this kind of ruminating activity. Now, rumination doesn't have to be negative per say, although in the case of depressed patients, it almost always is. So the proposal here then is that these cognitive distortions and ruminations and the reinforcing tried and so forth is that they all are product, they're all they're all they all arise as a result of defective circuitry in particular reasons of the brain, especially things regions like the amygdala and the hippocampus and certain regions of the cortex. And the defective activity and connectivity of these regions is manifest itself in these cognitive distortions. Effectively, the depressed persons are not appropriately integrating sensory stimuli and memories and not they're not thinking about it in a rational or an appropriate way and they're not appropriately integrating that in terms of their values. So that's why they tend to not see any value in things they tend to not find joint things because they're not appropriately responding to to reinforces that we mentioned before. The emotional, the positive emotional salience that we would normally get from a certain stimuli doesn't seem to be affected properly. So exactly how this works we don't fully understand, but there does seem to be something specific about these particular types of distortions and cognitive deficits and the malfunctioning or inappropriate functioning of particular circuitry and specific regions of the brain. We don't know the details of why this manifests in this particular way, but we can at least get the outlines of what must be happening or what seems to be going on. And this sort of connection between the molecular level and ultimately the cellular and the systems and cognitive level also seems to give a good explanation for why the most effective treatments for depression is a combination at at least in most patients is a combination of pharmacological treatments so that SSRIs and also behavioral treatments. Because effectively what most of the behavioral treatment is try to treat, try to overcome these cong negative distortions and negative rumination and things like that. So there's a variety of techniques for doing this. But essentially the idea is to try to direct patients towards some of these distortions and so that patients can understand better how they are consistently magnifying situations, overgeneralizing, minimizing the positive aspects, selectively abstracting and so forth, and how they're engaged in regular rumination and focusing on the negative aspects and so forth, and also how they're engaging self-destructive behaviors, which just cause them to, say, withdraw socially and isolate themselves and become more depressed. And instead focus on more helpful behaviors, things that help you to feel better, to focus on the positive aspects of the situation, to not overgeneralize and so forth. So basically therapies like this help to counter the cognitive deficits and problems that are associated with depression. At the same time, psychotherapeutic treatments, such as the SSRIs, help to alleviate some of the bottom-up aspects of the origin of depression by, as we've been talking about, increasing the activity of serotonin, which then seems to, among other things, increase the quantity of brain derived neurotrophic factor, which then helps with the neurogenesis, the production of new neurons, as well as promoting proper growth and plasticity of neurons in particular reasons of the brain, such as the hippocampus and make the lower and certain regions of the cortex. This then helps those circuits function better, more appropriately, which then subserves the cognitive tasks of helping to integrate evidence, integrate experiences and think about things and appraise the emotional significance and the rewards of certain states are in an appropriate way or more realistic way, a more adaptive way, as opposed to a focusing on the negative sides of things and overweighting negative aspects and not finding the rewards that we typically would in things. This integrated perspective and kind of a hierarchical way of thinking, I think makes best sense of the way in which these therapy and drugs can in together, at least for many people, provide effective treatments for depression. It must be said that this doesn't work for everyone and it's very common to have periods of depression relapse after a successful treatment and people can experience depressive symptoms on and off in a sort of a cycle for many years of their life. Although for other people, they'll have one, they'll have one episode and then that can be treated or may go away by itself and they'll have no further episodes in their life. So it varies a lot between persons and we may look more in detail about this in a future episode, but I'll talk about mood disorders more broadly and talk about more of the diagnostic side of things. But again, in this episode, I wanted to just focus on particularly the causes of depression with a focus on the monoamne hypothesis and the role of serotonin. So to conclude, hopefully I've given some of an idea about how we can draw this connection from a molecular level up to the level of a mood disorder like depression. And the essential idea here is to work in a hierarchical level to try to think about what's happening in each of these levels of analysis and then to put the pieces together. Obviously, we certainly don't have a full picture at the moment, but I think that I've on the basis of the literature that I've looked at offered a plausible integrative account that at least gives us a general idea of what's happening. So essentially, it seems that a deficit of serotonin or an insufficient activity of serotonin in particular brain regions results in a deficit of this brain derived neurotrophic factor, which in turn leads to a reduction in neurogenesis in the hippocampus as well as impairment of synoptic plasticity and normal functioning of neurons in certain brain regions, including hippocampus amygdala and parts of the cortex. This in turn leads to improper functioning and formation of memories, connections and processing in those in those brain regions and circuits, which in turn results in these various cognitive distortions and inappropriate integration of information and overrumination of negative aspects and those other cognitive behavioral aspects that I mentioned before. By treating in both directions at the molecular level and SSRIs and at the behavioral level through various types of psychotherapies, we can gain the best ability to intervene and relieve the symptoms of depression, at least in many patients, unfortunately, not all patients. The hope is that as we improve our understanding of the causes of depression at various levels of analysis, we'll be able to gradually improve our treatment regimens. There are other forms of treatment that I haven't mentioned here. Again, maybe I'll talk more about those in another episode. Also, it should be mentioned that serotonin and the monoamne hypothesis and cognitive distortions, that's not all there is to cause the depression. We know, for example, that depression is linked to the sleep weight cycle, so I mentioned that before. There's also linkages between there's no associations between depression and the immune system, as well as a connection between depressive symptoms and inflammation. I won't really go into the details of those here. They're relatively poorly understood compared to the monoamne hypothesis, but there's certainly more going on. It's not just a deficit of serotonin and that, of course, may explain why serotonin is not effective in treating depression in everyone, because there are other causes of problems as well, which can then lead to the symptomology of depression, but serotonin certainly is playing a large role, at least in a large number of patients. That's all there is today. Hopefully you found that interesting. 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