0:00 - Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a Professor of Neurobiology and Ophthalmology at Stanford School of Medicine. This month, we're talking all about disorders of the mind, things like depression, attention deficit disorders, eating disorders, schizophrenia, and bipolar disorder. During the course of this month, we are going to discuss the psychological and biological underpinnings of mood disorders of all kinds. You'll learn a lot of science. You'll also learn a lot about the various treatments that exist and that are in development for these various mood disorders. We will talk about behavioral tools, things like exercise,
0:47 meditation, breath work, but also prescription drugs, supplements and novel compounds that are now being tested in various clinical trials. Across the month, I think you'll start to realize that there are common pathways underlying many mood disorders. In fact, mood disorders that look quite different from one another often depend on the action of the same neurochemicals or neural circuits in the brain and body. That actually should be a point of great relief because what it means is that by understanding the biology of one mood disorder or understanding how one treatment or behavioral intervention can impact a mood disorder, we gain insight into other mood disorders as well. As always, we will discuss science and science related tools that people could implement should they choose.
1:33 Before we dive into today's topic, I'd like to discuss a very particular set of scientific findings that relate to today's topic, and that are important for understanding all mood disorders and all states of motivation, happiness, and sadness, as well as depression. Basically, I'm going to paraphrase a brief segment of my discussion with Dr. Anna Lembke, who I sat down with to discuss addiction and the biological basis of addiction and addiction treatment. A very important aspect of that discussion was when Dr. Lembke described the pleasure pain balance, literally the circuits in our brains that control our sense of pleasure and pain, and ultimately whether or not we remain happy
2:19 in our pursuit of pleasure or not. This is an absolutely crucial aspect to the way that we function in everyday life, and especially under conditions of mood disorders. The pathway that she was describing is the so-called pleasure system. However, what most people don't realize is that the pleasure system is also directly associated with, and in fact is the very same system that modulates mental or psychological anguish and pain. Essentially what she described is that whenever we pursue something that we think will bring us pleasure, and that could be anything that we think will bring us pleasure from food, to video games, to sex, to a particular job or goal, short-term or long-term, that we experience release of the neuromodulator dopamine.
3:09 Now, dopamine is associated with increased levels of motivation and drive. It is not the molecule of reward, it is the molecule of craving motivation and drive. However, as Dr. Lembke pointed out, when we are in pursuit of something, there is a release of dopamine in our brain that makes us feel motivated, and in general, it makes us feel good. But very shortly thereafter and beneath our conscious awareness, there is a tilt of the pleasure pain balance in the brain, literally a shift in the neural circuits that underlie pleasure and pain, such that every bit of pleasure or pleasure seeking that causes release of dopamine will be balanced out by a little bit of pain. And we don't experience this as physical pain,
3:56 at least not at first, we experience it as craving for more of the thing that brought us pleasure. Now, that sounds pretty good. You get pleasure and then you get a little bit of pain to balance it out. It's subconscious and you experience it as the desire to seek out more pleasure. However, it's actually more diabolical than that. And we really need to keep an eye on this if we are to remain happy, if we are to remain in pursuit of our goals. The crucial thing to understand is that if we remain in constant pursuit of pleasure, the pain side of the balance tips so that each time we are in pursuit of that pleasureful thing, activity, or substance, we are going to experience, we literally achieve less dopamine release each subsequent time. So we get less pleasure and the amount of craving increases.
4:45 Now, after a certain point or threshold, we call that addiction. And the way to reset the balance, and this is very important, the way to reset the balance is actually to enter into states in which we are not in pursuit of pleasure, to literally enter states in which we are bored, maybe even a little bored and anxious, and that resets the pleasure pain balance so that we can return to our pursuit of pleasure in a way that's healthy, and then in an ongoing way, won't lead to this over tipping or this increase in the amount of pain or addiction. So this is very important. And if this seemed vague, what this means is we should always be cautious of any state of mind or body or any pursuit that leads to very large increases in dopamine.
5:30 And if it does, we should be very careful to not pursue that repeatedly over time. During today's episode, I'm going to give an example, a real life example of a discussion that I've been in with a young man who's 21 years old who's dealing with a disruption in this pleasure pain balance. He is essentially depressed and he's depressed because of his ongoing pursuit of a particular activity that initially led to a lot of dopamine, but over time has led to less and less dopamine and more and more of this pain side of the balance. We could call him addicted to that particular activity. Whether or not he's addicted by clinical standards or not, really, isn't important. What is important is that he experiences this as depression, as low affect as it's called or anhedonia,
6:18 an inability to experience pleasure from that thing or from anything else. And he's currently undergoing treatment through a rebalancing of his pleasure pain pathway. So while I can't reveal his identity to you, that wouldn't be appropriate. He did give me permission to reveal the general architecture of what he's coping with. And I spent some hours with him on the phone this week, talking to him as well as to the various people that he's working with to really understand what's going on here 'cause I think it can illustrate the relationship between dopamine, pleasure, and pain for sake of addiction, but also for understanding how to avoid depressive states, how to remove ourselves from depressive states. And as you'll see today, as we discussed depression, many of the molecules and neural pathways and biological mechanisms that we know can be used
7:04 to counter depression, feed back onto this pleasure pain balance. Before we begin, I'd like to say that this podcast is separate from my teaching and research roles at Stanford. It is however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from blood and DNA to help you better understand your body and help you reach your health goals. I've long been a believer in getting regular blood work done for the simple reason that many of the factors that impact our immediate and long-term health can only be detected from a quality blood test. The problem with most blood tests, however,
7:51 is that you get information back about hormone levels, metabolic factors, et cetera, but you don't really know what to do with that information. Some things might be flagged as too high or too low, but really interpreting those data and taking action to bring those numbers into the ranges that you want is what it's really about. An InsideTracker makes all that very easy. They have a platform, it's a dashboard that will tell you for instance, what sorts of dietary changes or supplementation changes or exercise changes will help you bring various hormones, metabolic factors, and other factors into the ranges that are right for you. If you'd like to try InsideTracker, you can go to insidetracker.com/huberman. And if you do that, you'll get 25% off any of InsideTracker's plans.
8:36 Just use the code "huberman" at checkout. Today's episode is also brought to us by Athletic Greens. Athletic Greens is an all-in-one vitamin mineral probiotic drink. I've been using athletic greens since way back in 2012. And so I'm delighted that they're sponsoring the podcast. The reason I started taking Athletic Greens and that I still take Athletic Greens is that it really covers all of my foundational nutrient and micronutrient needs. It has vitamins, minerals, and the thing that's especially important to me these days is the probiotics, because there are so many data that show that having a healthy gut microbiome is vital to having a healthy immune system and for healthy gut brain axis, literally the functioning of your brain, your mood, various aspects of brain inflammation or limiting brain inflammation are facilitated
9:23 by having a healthy gut microbiome. And that's facilitated by getting the proper probiotics. If you'd like to try Athletic Greens, you can go to athleticgreens.com/huberman. And if you do that, you can claim their special offer. The special offer is five free travel packs, which make it very easy to mix up Athletic Greens while you're on the road or in the car, and a year supply of vitamin D3K2. Vitamin D3K2 have been shown to have a number of different positive health effects on hormones, on cardiovascular health, and so on. Again, that's athleticgreens.com/huberman to claim their special offer. Today's episode is also brought to us by Belcampo. Belcampo is a regenerative farm in Northern California that raises organic, grass fed, and finished certified humane meats. I don't need a lot of meat. Typically my diet regime is one in which I fast
10:10 until about noon, and then I have a lunch which is fairly low carbs. So I'll have some piece of meat or chicken or fish and some salad typically. And then in the evening is when I tend to emphasize carbohydrates. That helps me be really alert during the day and sleep well at night. When I do eat meat, I insist that the meat be of the very highest quality and that it is sourced in humane ways. Belcampo's animals graze on open pastures and seasonal grasses, and that results in meat that is higher in nutrients and healthy fats. There are now a lot of data pointing to the fact that high levels of omega-3 fatty acids are vital for mood, for cardiovascular health and various aspects of maintaining what's called a healthy Inflammatone, the various things in our brain and body that maintain a healthy inflammation response,
10:56 but one that doesn't go out of whack or get unchecked in any way that is detrimental to us. If you'd like to try Belcampo, first-time customers can get 20% off by going to belcampo.com/huberman and using the code "Huberman" at checkout. That's belcampo.com/huberman for 20% off and use the code "Huberman" at checkout. Today we're discussing depression. In particular, we're going to talk about major depression. The phrase major depression is used to distinguish one form of depression from the other, the other one being bipolar depression. Bipolar depression, sometimes called bipolar disorder, is really characterized by manic highs. So where people aren't sleeping and they're talking very fast, and they're buying things and pursuing resources
11:43 that they can't afford, they're starting relationships left and right, they're manic, followed by periods of crashes of feeling very low, lethargic, and so on. Bipolar depression is an absolutely crucial thing for us to discuss. And therefore we are going to have an entire separate episode related to bipolar depression. Today, we're going to talk about major depression, also sometimes called unipolar depression, just because it doesn't have the highs and lows. It's more characterized by the lows. We're going to talk about the biology, the psychology, and the various treatments, behavioral, drug, supplementation, diet, exercise, all of that. Before we go forward into the material, I just want to emphasize that any discussion about mood disorders carries with it
12:29 a particular sensitivity, and that sensitivity is one related to self-diagnosis. Today's episode, and indeed in the future episodes for this month on mood disorders, you're going to hear various symptomologies that are used to diagnose and characterize these disorders. If you recognize some of these symptomologies in yourself or in others that you know, that's an important thing to take note of. However, accurate diagnosis really should be done by a qualified healthcare professional. So at once I'm saying, keep your eyes and your ears up for things that sound familiar to you that might be of concern. And at the same time, I'm saying don't necessarily leap to conclusions. Take those flags of concern if they're there and bring them to a qualified healthcare professional,
13:16 and they'll be able to properly diagnose you as having a particular mood disorder or diagnose somebody as having a particular mood disorder or not. And that's an essential step. I don't say this to protect us, I said this really to protect you. Okay, let's have a fact-based discussion about depression. And I promise you that where we don't know certain things about depression, I will be clear to tell you. In fact, we are going to talk about some treatments for depression that are looking very promising, and that right now are actually being used more and more. And from my read of the mechanistic literature, we're still a bit in the dark as to how these work. That's actually a common theme of medicine. Many times there are treatments that seem promising or that look really terrific.
14:01 And there isn't a lot of understanding about mechanism. However, any good discussion about neuroscience and in particular about mood disorders, has to get into mechanisms. So we're going to do that. And in doing that, we're going to frame the discussion for the tools of how to keep depression at bay and how to deal with it if you happen to find yourself depressed, or if you know somebody else who's depressed. What is this thing we call depression? Was I mentioned before, it has two forms, bipolar depression, which we're not talking about today, and major depression, also called unipolar depression is the other. Major depression impacts 5% of the population. That is any enormous number. That means if you're in a class of 100 people,
14:46 five of them are dealing with major depression or have at some point. Look around you in any environment and you can be sure that a good portion of the people that you're surrounded by is impacted by depression, or will be at some point. So this is something we really have to take seriously and that we want to understand. It is the number four cause of disability. A lot of people miss work, miss school, and before then likely perform poorly in work or school due to major depression. Now there's a very serious challenge in having a discussion about depression and it relates directly to the challenges in diagnosing depression. Earlier, I did an episode with Dr. Karl Deisseroth, who is indeed a medical doctor and a PhD.
15:33 He's a psychiatrist. And he made a very important point, which is that the field of psychiatry and psychology are confronted with a challenge, which is they're trying to understand what's going on within the stuff that's in our brains that's deep to our skulls. We don't have access to that without brain imaging and electrodes and things like that. Someone just comes into the office and the dissection tool for depression so to speak is language. In order to determine if somebody has depression or not, we have to use language, how they talk about things, also how they carry their body. Also some general patterns of health. So let's talk about depression the way that clinicians talk about depression, because one of the issues is that we use the word depression loosely.
16:19 A lot of people say, "Oh, I'm so depressed. "I didn't get this job or I'm so depressed. "I just don't know, I had a really rough week "or I'm exhausted. "I'm so depressed or I'm so depressed "I thought I was going to go on vacation "and then they canceled the flight." Okay. That is not clinical depression. That's called being bummed out, being sad or disappointed. Now that person might be depressed, but clinical depression actually has some very specific criteria. And those criteria are mainly characterized by the presence of certain things and the absence of a few particular things. So let's talk about the things that are present in somebody that has major depression. First of all, there tends to be a lot of grief. There tends to be a lot of sadness.
17:05 That's no surprise. The threshold to cry is often a signature of depression. Now that doesn't mean that if you cry easily, that you're depressed. Some people cry more easily than others, but if you're somebody who typically didn't cry easily and suddenly you find yourself crying very easily, that could be a sign of depression. And I want to emphasize, could. There's also this thing that we call anhedonia, a general lack of ability to enjoy things, things that typically or previously we enjoyed. Things like food, things like sex, things like exercise, things like social gatherings, a kind of lack of enjoyment from those things. Sometimes that lack of enjoyment is sad, and sometimes it's just flat, it's just kind of neutral. It doesn't feel good because nothing there. It's like bland food.
17:51 It's like these experiences are analogous to biting into your favorite article of food and it just not tasting very good. It just doesn't taste like anything at all. And that's a common symptom of major depression. The other one is guilt. Oftentimes people with depression will feel very guilty about things they have done in the past, or they'll just generally feel badly about themselves. And we're going to talk about this because it relates to some of the more serious symptomology seen in depression sometimes, things like self harm, mutilation, or even suicide. But for the time being, we want to frame up anhedonia, this lack of ability to achieve or experience pleasure, or kind of a flat affect as it's called. Sometimes even delusional thinking,
18:37 negative delusional thinking, and in particular anti-self confabulation. What is anti-self confabulation? Well, first of all, confabulation is an incredible aspect of our mind and our nervous system. You sometimes see other forms of confabulation in people who have memory deficits either because they have brain damage or they have age-related dementia. A good example of this would be someone with age related dementia sometimes will find themselves in a location in the house and not know how they got there. And if you ask them, "Oh, what are you doing here?" They will create these elaborate stories. "Oh, I was thinking about going to the shopping today, "and I was going to take the bus, "and then I was going to do this." They create these elaborate stories, they confabulate.
19:23 And yet that person hasn't left the house in weeks and that person doesn't have a driver's license. And so they're really just creating this stuff. They're not lying to get out of anything, they're confabulating. It's as if a brain circuit that writes stories, just starts generating content. In major depression, there's often a state of delusional anti-self confabulation, where the confabulation are not directly or completely linked to reality, but they are ones that make the self, the person describing them, seem sick or in some way not well. A good example would be somebody who experiences a physical injury perhaps. Maybe they break their ankle, maybe it's an athlete, and they also happen to become depressed. And you'll talk to them and say, "How are things going? "How's your rehab though?"
20:09 And they go, "Oh, it's okay. And I don't know. "I feel like I'm getting weaker and weaker by the day. "I'm just not performing well." And then you'll talk to the person that they're working with, their kinesiologist or whoever the physical therapist is. And they'll say, "No, they're actually really improving. "And I tell them they're improving, "but somehow they're not seeing that improvement, "they're not registering that improvement." You notice that sometimes it's subtle and sometimes it's severe, but they'll start confabulating. You'll say, "I actually heard you're doing much better. "You're getting better, you're taking multiple trips "around the building now "before you could barely get out of bed." And they'll say, "Yeah, well basically, they changed some things "about the parking lot that make it easier to move around. "So it's not really me." And these aren't people that are just explaining away their accomplishments
20:54 'cause they're trying to brush off praise. They are viewing themselves and they're confabulating according to a view that is very self-deprecating to the point where it doesn't match up with reality. It's not what other people see and it's actually not matched up with reality. And that's a symptom of depression that I think we don't often think about or conceptualize enough. So it's not just telling people, "oh yeah, it's not as good as it seems. Everything's bad." These people really believe that and it becomes disconnected from reality. So it's if they're sort of sinking into a pit and they're losing touch with the realities of the world, including data about themselves, their ability to move and get around it, for example, in that particular instance that I used as an example, but there are others as well.
21:41 The other common symptomology of major depression is what they call vegetative symptoms, okay? So vegetative symptoms are symptoms that occur without any thinking, without any doing, or without any confabulation. These are things that are related to our core physiology. The word vegetative, you might know it sounds like vegetable. It actually relates to a system in the body that nowadays is more commonly called the autonomic nervous system. The vegetative nervous system and the autonomic nervous system, historically were considered sort of one in the same. And it relates to things like the stress response or to our ability to sleep. So vegetative symptoms be things like constantly being exhausted. The person just feels exhausted.
22:26 It's not because they exercise too much, it's not necessarily because of a life event, it could be, but they're just worn out. They don't have the energy they once had. So it's not in their heads, it's probably, and now I think we have good data to support the fact that there's something off, something is disrupted in the autonomic or so-called vegetative nervous system. And one of the most common symptoms of people with major depression, one of the signs of major depression is early waking and not being able to fall back asleep despite being exhausted. So waking up at 3:00 AM or 4:00 AM or 5:00 AM just spontaneously and not being able to go back to sleep. I want to emphasize that that could happen for other reasons as well, but it is a common symptom
23:12 or warning sign of major depression. So let's talk more about sleep and depression. It's well-known that the architecture of sleep is disrupted in depression. What's the architecture of sleep? I've done entire episodes about this, but very briefly in two sentences, although they're probably be run on sentences, early in the night, you tend to have slow wave sleep more than REM sleep or Rapid Eye Movement sleep. As the night goes on, you tend to have more Rapid Eye Movement sleep. That architecture of slow wave sleep preceding Rapid Eye Movement sleep is radically disrupted in major depression. In addition, the pattern of activity in the brain during particular phases of sleep is disrupted. Now this is during sleep. So this can't be that people
23:57 are creating this situation for themselves. These are real physiological signs that something is off in this so-called autonomic or vegetative nervous system. And then there are some other things that relate to the autonomic nervous system, but that we normally think of as more voluntary in nature. And these are things like decreased appetite. So you can imagine that one could have decreased appetite because of the anhedonia, the lack of pleasure from food, right? If you don't enjoy food, then you might be less motivated to eat it. That makes sense. As well because of these disruptions in the autonomic nervous system, these vegetative symptoms, as they're called, you can imagine that someone would have decreased appetite because some of the hormones associated with appetite, hypocretin orexin and things of that sort, ghrelin,
24:43 that those will be disrupted. And if those names of hypocretin orexin and ghrelin don't make any sense to you, don't worry about it. What those are just hormones that impact when we eat, when we feel hungry, and when we crave food more, as well as when we feel full, we have enough so-called satiety. If you want to learn more about those, we did entire episodes on eating and metabolism. So you can see that the symptomology of major depression impacts us at multiple levels. There's the conscious level of how excited we are generally. Well, that's reduced. There's grief, there's guilt, there's crying, but then there's also these vegetative things. There's disruptions in sleep, which of course make everything more challenging when we're awake. We know that sleep is so vital for resetting. You're waking up early, you can't get back to sleep.
25:29 That's going to adjust your affect, your emotions in negative ways. We know this. And appetite is off. And there are hormones that get disrupted. So cortisol levels are increased. In particular, there's a signature pattern of depression whereby cortisol, the stress hormone that normally is released in a healthy way only in the early part of the day is shifted to late in the day. In fact, a 9:00 PM peak in cortisol is one of the physiological signatures of depressive like states. It's not the only one, but it is an important one. So there are a lot of things going on in major depression. And by now you're probably thinking, goodness, this is dreadful. Like there's all this terrible stuff. And indeed it is terrible.
26:14 It is a terrible thing to find oneself in a mode where things feel sad, you feel guilty, you're exhausted. And oftentimes there's also an association with the anxiety system. So just because people are exhausted and lethargic and they don't enjoy things, doesn't necessarily mean that there's an absence of anxiety. There can also be a lot of anxiety about what's going to happen to me. Am I going to be able to achieve my goals in life? Will I ever get out of this state? And so things really start to layer on. And if this sounds depressing to you, it is indeed depressing. This is really the place that many people find themselves. And it's a pit that they just don't know how to climb out of. So let's just take a few minutes and talk about some of the underlying biology that creates this cloud or this constellation
27:01 of symptomology. I think that's really important to do because if we want to understand the various treatments, how they work and why they work and how to implement them, we have to understand some of the underlying biology. So let's spend a few minutes talking about the biology of depression, what's known and what's not known. Because in doing that, I think you'll get a much clearer picture about why certain tools work to relieve depression and why others might not. So one of the most important early findings in the search for a biological basis of depression was this finding that there are drugs that relieve some of the symptoms of depression. Those drugs generally fall into three major categories, but the first set of ones that were discovered
27:48 were the so-called tricyclic antidepressants, and the MAO inhibitors, the monoamine oxidase inhibitors. You don't need to understand that nomenclature, but I'm going to give you a little bit of detail so that if you want to understand it, you can. Most of this work took place in the late 1950s and in the 1960s, and continued well until the 1980s when new classes of drugs were discovered. And these tricyclic antidepressants and the MAO inhibitors largely worked by increasing levels of norepinephrine in the brain, as well as in the body, in some cases. And they were discovered through a kind of odd set of circumstances. We don't have time to go into all the history, but suffice to say that they were discovered
28:34 because of the exploration for drugs that alter blood pressure. Norepinephrine impacts blood pressure, and drugs that lower blood pressure reduce levels of norepinephrine. And that in many cases, was shown to lead to depression or depressive like symptoms. And so these drugs, these tricyclic drugs, and the MAO inhibitors actually increase norepinephrine. And frankly, they do quite a good job of relieving some, if not all of the symptoms of major depression. However, they carry with the many side effects. Some of those side effects are side effects related to blood pressure itself, by increasing noradrenaline, norepinephrine as it's called, you raise blood pressure. That can be dangerous, that can be uncomfortable.
29:21 But they also have a lot of other side effects. The reason they have other side effects is because they impact systems in the brain and in the body that impact things like libido, appetite, digestion, and others. And we'll talk about each of those in sequence. Okay, so the experience that clinicians had of observing some relief for depression with the tricyclic antidepressants and with MAO inhibitors was terrific, but there were all these side effects, side effects that people really did not like, they didn't like these drugs at all. A lot of people get dry mouth, I mentioned the low libido, they'd have sleep issues, appetite issues, weight gain. They made some people so uncomfortable that they preferred not to take them, even though when they didn't take them, they had a worsening or a maintenance
30:06 of their depressive symptoms. A decade or so later, there was the discovery of the so-called pleasure pathways in the brain. These are pathways, literally groups of neurons that reside in different locations in the brain but connect to one another. So it's a circuit. And when you stimulate these neurons with certain behaviors or with electrical stimulation in an experiment, believe it or not, that's been done in both animals and humans, animals and humans become very, very motivated to get more stimulation of these pathways. So this pleasure pathway or these circuits for pleasure are very what we call reinforcing. In fact, animals and humans will work hard to get stimulation of these brain areas
30:54 even more than they will work to obtain sex, drugs, or even if they are addicted to a particular drug and they are in a state of withdrawal, the ultimate state of craving, if given a choice, a person or an animal will select to have stimulation of this pleasure pathway instead of the drug itself. And that is a major and significant finding. This pleasure pathway, as it's sometimes called, involves areas like the nucleus accumbens and the ventral tegmental area. These are areas of the brain that are rich with neurons that make dopamine. And if you think to the symptoms of depression, of anhedonia, lack of pleasure, a lack of ability to experience pleasure, well, that was a smoking gun that there's something wrong
31:39 with the dopamine pathway in depression. And indeed that's the case. So it's not just norepinephrine, it's also the dopamine or pleasure pathway is somehow disrupted. And then in the 1980s, there was the discovery of the so-called SSRIs Most people are now familiar with the SSRIs, the Selective Serotonin Re-Uptake Inhibitors. The SSRIs worked by distinct mechanisms from the tricyclic antidepressants and the MAO inhibitors. As their name suggests, SSRI, Selective Serotonin Re-Uptake Inhibitors prevent serotonin from being wiped up from the synapse after two neurons talk to one another. What do I mean by that? Well, here's some very basic Neurobiology 101. If you don't know any neurobiology, you're going to know some in about 15 seconds.
32:26 Neurons communicate with one another by spitting out chemicals into the little gap between them. The little gap between them is called the synapse or by the Brits, the synapse. Those chemicals bind to the neuron on the opposite side and cause changes in the electrical activity of that neuron on the other side of the synapse. Serotonin is one such neurotransmitter or more specifically, it's a neuromodulator, can change the activity of large groups of neurons in very meaningful ways. Selective serotonin re-uptake inhibitor means when a person takes this drug, some of those drugs include things like Prozac or Zoloft, the more typical names or more generic names are things like fluoxetine, when people take those, more serotonin hangs out
33:12 in the synapse and is able to be taken up by the neuron on the opposite side because of this selective re-uptake inhibition. It prevents the clearance of serotonin from the synapse and thereby more serotonin can have an effect. So SSRIs don't increase the total amount of serotonin in the brain. They change how effective the serotonin that's already in the brain is at changing the activity of neurons, okay? So they don't increase serotonin, they increase the efficacy or the function of serotonin in the way that I just described. So that was more than 15 seconds, but now you understand how SSRIs work. And I wouldn't be talking about SSRIs
33:58 if they didn't in fact work. Yes, there are many problems with SSRIs. They do carry certain side effects in many individuals. Also, about a third of people that take SSRIs don't derive any benefit, it doesn't relieve their symptoms of depression. However, for the other two thirds, there's often a relief of some, if not all of the symptoms of major depression. The problem is the side effects that accompany those SSRIs. And so these days SSRIs are a complicated topic. It's sort of what I would call a barbed wire topic because we often hear about all the problems with them, but these drugs also have saved a lot of lives. They've also improved a lot of lives. The issue is that they tend to have varying effects on different individuals,
34:43 and sometimes varying effects over time. So they'll work for awhile then they won't work for a while. There are also a lot of mysteries about the SSRIs, and those mysteries bother people. What mysteries am I referring to? Well, SSRIs increase the amount of serotonin or more specifically, they increase the efficacy of serotonin at the synapse, that happens immediately, or very soon after people start taking SSRIs. But people generally don't start experiencing any relief from their symptoms of depression if they're going to experience them at all, until about two weeks after they start taking these drugs. So there's something going on there that's not clear. One idea is that the SSRIs actually can improve symptoms of depression or even remove symptoms of depression
35:30 through so-called neuro-plasticity by changing the way that neural circuits function. And there are many on this, but the main categories of studies on SSRIs that relate to neuroplasticity fall into two camps. One is that the ways in which SSRIs might, and I want to emphasize, might be able to trigger the production of more neurons in the brain, in particular areas of the hippocampus called the dentate gyrus and others, that impact memory. This is important. We're going to come back to memory. The other is that the SSRIs have been shown in various scientific studies to reopen critical periods of plasticity. I'll just briefly describe one of those studies. There was a study done by Lamberto Maffei's group in Pisa, that explored brain plasticity
36:16 that's known to be present in young animals and disappear in older animals. And this is also true in humans that younger humans have a far more plastic brain that can change in many more ways more easily than can the older brain. And what they showed was that fluoxetine, Prozac, given to adult animals can reopen this incredible period of plasticity, can allow more plasticity to occur. That was interesting. I mean, it's purely through increases in serotonin transmission. And there are other studies showing that fluoxetine can increase the number of new neurons that are born into the adult brain, so called neurogenesis, the production of new neurons. So it's very clear that there are at least three major chemical systems in the brain; norepinephrine, dopamine, and serotonin that relate to
37:05 and can adjust the symptoms of depression. And those actually can be divided into separate categories. So for instance, epinephrin or norepinephrine is thought to relate to the so-called psychomotor defects, sometimes called psychomotor retardation. This is the lethargy, this is the exhaustion, this is the inability to get out of bed in the morning. Dopamine is thought to relate to the anhedonia, or I should say lack of dopamine in depressive patients is thought to lead to the anhedonia. The lack of ability to experience pleasure. And serotonin is thought to relate to the grief, the guilt, some of the more cognitive or more emotional aspects of depression. So we've got the norepinephrine system related to activity and alertness,
37:52 the dopamine system relating to motivation, pleasure, and the ability to seek and experience pleasure, and then the serotonin system that's related to grief. And unfortunately, brains and organisms don't work in a simple mathematical way where you just say, oh, well, this person's experiencing a lot of grief, but they don't have any problems with lethargy. And so let's just boost up their serotonin. On paper it works, but oftentimes it doesn't work clinically. And another patient, you might get somebody who can't experience pleasure, but they're kind of anxious. They don't have any trouble sleeping, but they're just much more anxious and frustrated than they normally are, and they meet the symptoms of depression. Well, you might think, oh, well, do you just give that person some drugs increase dopamine and everything will be better?
38:38 And indeed, in some cases that's true. There are drugs like Wellbutrin, which function more specifically on the dopamine system to increase dopamine and they also increase norepinephrine. Many people get great relief from things like Wellbutrin. They don't really impact the serotonin system so much. And therefore you don't get a lot of the serotonergic or serotonin related side effects. However, some people feel far too anxious on those drugs, some people get addicted to those drugs in a way, because a lot of those drugs that increase dopamine make you want more of those drugs. So you start to realize that what makes sense on paper doesn't always make sense clinically. And this is why it's complicated. And a really good psychologist and a really good psychiatrist will work with someone to try and pull and push on these various systems to find the combination of drugs that may be
39:25 or may not be correct for them. There's a fourth aspect of the chemistry of depression that's really important to understand. And that's pain. We've talked about pain on this podcast before, but even if you didn't hear the episode on pleasure and pain, just want to emphasize that pain is something that we experience in our body, no surprise there, an injury, a cut, et cetera, but that we also experience emotional pain. And those systems are linked in very intricate ways. There's actually some data showing that pain relievers, Tylenol, Aspirin, these sorts of things, can help certain people with emotional pain. Now I'm not recommending people run out and take those things for emotional pain. But actually, if you think about it, that shouldn't come as any surprise. given the enormous number of people that take painkillers, opioids and things like them to try and relieve
40:11 their psychological pain. And as we know, those drugs are very, very problematic for many individuals. They can help certain individuals, but they are very prone to abuse and they can induce addiction very easily in a number of people. There's a substance that's literally called substance P, the letter P, that's manufactured by neurons in our brain and body, which underlies our sensation of pain. And indeed substance P inhibitors have been used to treat depression, and in some cases works. A lot of people with depression are hypersensitive to pain, and of course they could have multiple things going on. They could have chronic pain or chronic injury and major depression. So you start to get the constellation of the many things that could happen. So that's all I want to say today about the chemistry
40:57 underlying depression or major depression. There's a lot more there, but I think if you understand the norepinephrine system and that it relates to some of these things like lethargy, the psychomotor defects, as they're called, dopamine and how it relates to motivation and lack of motivation and lack of dopamine and depression, and serotonin and its relationship to grief, and that low serotonin can lead to extreme grief and shame and higher serotonin levels can sometimes restore a sense of wellbeing and safety and feeling good about oneself. If you understand that and you understand that physical pain is somehow involved in certain cases, I think you will know more about depression and its underlying chemistry than most all people out there. And if you'd like to learn more, I invite you to pursue searching those terms
41:44 further on the internet. And we'll certainly go into them in more depth. But that really sets the stage for where we're headed next. So next I'd like to talk about hormones and how they relate to depression. And I'd also like to talk about stress and how it relates to depression, as well as talk about some of the genetics or the predispositions to depression. And for those of you that are thinking, hey, I want the tools. I want to know how to fix depression. I understand the desire for that. I will just ask if you hang in here with me a little bit longer, not only will you learn a lot more about how this complicated mood disorder works, some of the more interesting things about it, but it will also position you to get a lot more out of the tools that we will describe. You always have the option to skip forward of course, but I think it's important to understand some of the hormonal and stress-related
42:29 aspects of depression. So let's talk about hormones. 20% of people that have major depression have low thyroid hormone. Thyroid hormone is related to metabolism. Oftentimes we think about thyroid is only related to having a fast metabolism, but thyroid is related to all forms of metabolism, including our ability to synthesize new tissues like protein and repair injuries. I did a whole episode on thyroid and growth hormone. If you want to check that out, all of that is archived at hubermanlab.com. It's all timestamped, et cetera. You can find on YouTube, Apple, Spotify, all those places. So if you're curious about thyroid hormone and growth hormone, and you want to do the deep dive on those, and you want to learn how to alter their levels using various approaches, check that out.
43:15 But 20% of people with major depression are hypo thyroidal. They don't make enough thyroid. And that leads to low energy, low metabolism in the brain and body. And there's a condition called Hashimoto's, which is essentially low thyroid output. And again, I don't want to get into all the tools related to thyroid. Sometimes a psychiatrists will prescribe thyroid medication to increase thyroid output in people that are depressed and that will work to relieve the symptoms. So there isn't necessarily a direct problem with serotonin, dopamine, and norepinephrine or substance abuse. Sometimes it's a thyroid problem. So there are certain situations or conditions that can impact the thyroid hormone system and make people more susceptible to depression or make a pre-existing depression worse.
44:02 And those are things like childbirth. So it's well-known that women who give birth can often undergo what's called postpartum depression. It actually comes from the word post parturition depression. They give birth, what's happier, what's more joyful than the birth of a new healthy child, and they will lapse into a depression. And that's thought to be hormonally related, either directly to the thyroid system or perhaps to the cortisol system as well. We'll talk about cortisol in a moment. As well, certain women during certain phases of their menstrual cycle experience symptoms that are very much like clinical depression, and oftentimes are diagnosed with clinical depression appropriately. And of course the menstrual cycle is associated with shifts in hormone levels. As well, menopausal and post-menopausal women
44:48 are more susceptible to major depression, regardless of whether or not they've had that major depression earlier in their life. So these are things to be on the lookout for and to definitely talk to a doctor and get a blood panel that hopefully includes measures of thyroid hormone and cortisol hormone. Why cortisol hormone? Well more stress is correlated with more bouts of major depression across the lifespan. How many bouts? Well, it turns out that as you go from having one to two to three, well, when you hit four to five bouts of really intense, stressful episodes in life, these tend to be long-term stressful episodes, your risk for major depression goes way up. So whether or not you have a genetic predisposition to depression or not, one of the best things you can do to try and avoid getting depressed
45:34 is to learn to control your stress system, to not go from short-term stress, which everybody experiences, we all have short-term stressors, to medium term stress to long-term stress, and to not have too many bouts of long-term stress because that probability of getting depressed goes way, way up. And this is something I've seen over and over again, not just in my scientific career, but just throughout life. People in all sorts of domains, young and old, I've seen that people will go through a very intense relationship, a breakup, sometimes it's the staying together that stressful, sometimes it's a graduate school that can be stressful, sometimes it's some other event. And then some months later they become depressed. And that's because the stress system is associated with the release of cortisol. The cortisol system can dramatically impact
46:21 the way that these different neuromodulators, dopamine, norepinephrine and serotonin function. And so there's this kind of latent or longer lasting impact on the systems that impact mood and wellbeing. So learning how to control your stress is really key. If you're not depressed or you're somebody that has not lapsed into a depression recently, take control of your stress system. And we did an entire episode on how to conquer stress, and that involves dealing with stress in the short term, the medium term, and in the long-term. And there are a lot of different ways to do that. One of the more important reasons for learning how to counter stress in order to offset depression is that there is a genetic predisposition that certain people carry to become depressed. There are these studies now of many, many thousands of individuals,
47:08 these were mainly done in New Zealand, but these studies have now been done elsewhere, looking at many tens of thousands of individuals who carry particular copies of genes, what they call polymorphisms, in particular of a gene called 5HTTLPR, which is a serotonin transporter. So this is a gene that controls or regulates how much serotonin is available in the brain. If you have this gene, this polymorphism, it doesn't necessarily mean that you will be depressed, but it greatly shifts your susceptibility to depression under conditions of stress. So I realize some people are listening to this and some people are watching it on YouTube. So I'm going to describe this in a way that doesn't require looking at any graphs. What I want you to imagine is a very, shallow hill,
47:56 like a very mellow hill. It's just a ramp set at about 10 or 15 degrees, okay. What we're plotting there in your mind is that with each about of serious stress, so that could be trying to finish a degree or a relationship breakup, or a family member that's sick, or the loss of a loved one or a pet, with each about of stress, the probability that you will experience a major depression goes up. However, if you carry this gene, this HTTLPR gene, the steepness of that curve goes way, way up where it's actually more like a line such that you need far fewer bouts of stress in order to lapse into a major depression, okay?
48:42 So if the typical person who doesn't carry this polymorphism has to experience two or three or four or five bouts of stress before they lapse into a depression, somebody with this gene is susceptible to getting depression after just one about or two bouts of intense stress, okay? So that's how these genes work. They don't preordain or determine you to be depressed. They raise a susceptibility. And many genes, many things related to heritability in general, work in that way. And we know there's a strong genetic component to depression. How do we know? Well, in what are called concordant monozygotic twins. So these will be identical twins. And they can either be in one biological sack or two biological sacks while in utero,
49:30 what's called monochorionic or dichorionic. Well, typically it's monochorionic. And identical twins, for which one of those twins goes on to have major depression, there's a 50% probability that the other one will have major depression. So it's not 100%, it's not 100% inherited, it's not 100% generic, as you might say, but there's a much higher predisposition for depression. Whereas in fraternal twins, that number drops, and in siblings, that number drops to about 25%, and in half siblings, it's about 10%. The numbers vary from study to study, but basically the more closely related you are to somebody who has major depression, the more likely it is that you will also get major depression. And therefore, if you haven't gotten major depression,
50:17 the more likely it is that you should take steps to learn to mitigate stress because stress is the major factor that can trigger one of these depressive episodes. So we've covered a lot related to the stress and the hormones and the neurochemistry of depression. In fact, I think this is probably the deepest I've ever gone into the biology of any topic on this podcast before getting to any specific tools. I mentioned that learning how to mitigate stress and deal with stress, learning how to measure and adjust your thyroid hormone, those might be useful. But next I'd like to turn to some very specific tools that people who both have depression or who are prone to depression, as well as people who don't have depression and simply want to maintain a good mood,
51:02 who want to maintain a positive affect and pursuit of things in life, what are the things that you can do? It turns out there are things that you can do and all of the biology that underlies the utility of those things. Meaning the reasons those things work will now make sense to you because they adjust things like serotonin and dopamine, and they adjust them through very specific pathways. I know for many people learning about mechanism is kind of grueling. I realized this podcast isn't necessarily one that you can listen to passively while doing other things. Although I would hope that you could do that and still enjoy it and extract the information. Why mechanism? Mechanism is so key because mechanism is a little bit like understanding some of the chemistry of cooking. If you read a recipe and you can follow a recipe,
51:48 you often hear people say, oh, I can follow a recipe. That means that if you have every ingredient in that recipe, you're good. You likely can make that dish. You can make that meal. However, if you understand a little bit of the chemistry of why salt has to be added third and not first, or why the heat has to be adjusted at a particular time, well then not only can you follow a recipe, but that also gives you flexibility for when salt isn't available, or when you want to adjust the flavor of the dish, or when you want to try a new dish, or you want to get experimental. So when you understand mechanism, it puts you in a tremendous place of power to work with your system. So it's not just plug and chug, like take 12 milligrams of this, you either feel better or you don't. You can really start to understand how prescription drugs,
52:37 supplements, nutrition, behavioral tools, how those things weave together to either work for you or not work for you and get you to paths of healthy mind and body. So let's think about why any tool would work to relieve depression. We've talked about how some of the drugs that impact these different chemical systems might work and why they create some of the problems they create. Problems are mainly created by the fact that they impact lots of systems in the brain and body. So you take a drug to increase serotonin, but that serotonin is also related, not just to mood, but to things related to libido and appetite. And so you start disrupting multiple systems. The same could be said for behavioral tools, right? That any behavioral tool that adjusts the levels
53:22 of a particular chemical ought to perhaps, provide some relief for some of the symptoms of major depression. Let's take an example that I've talked about before on the podcast, which is, if you get into a very cold shower, you take an ice bath, you will release norepinephrine and epinephrine in your brain and body. There's no question about that. I don't think anyone can really escape that. It's a kind of a universal response to being in cold water. Well, if some aspects of depression are related to low levels of norepinephrine, will taking cold showers relieve your depression? Perhaps it might even relieve certain aspects of that depression. Is it a cure? Well, that's going to depend on the individual. Will exercise help? Well, if you go out for a run, you're going to increase the amount of norepinephrine
54:07 in your body. If you enjoy that run, it's likely that you'll increase the levels of dopamine and probably serotonin in your brain and body as well. Will that cure your depression? Well, there are a lot of studies exploring how exercise can impact depression. And indeed, regular exercise is known to be a protective behavior against depression, but it also can help relieve some of the symptoms of depression. So you may ask yourself, why would you need drugs at all? Why would there be prescription drugs or the need for supplementation or other things to alleviate the symptoms of depression? Ah, well, that's the diabolical nature of depression, which is if people are far enough along in this thing, this sometimes called disease, sometimes called disorder, but major depression, oftentimes they can't get the energy
54:57 to even get up and take a bath or a shower. They have no motivation to do it, they have no desire to go for a run. So you say, "Come on, let's go, you'll feel better. "I know you feel better, it generates all these chemicals "I heard on the whatever podcast, Huberman Lab podcast, "or another podcast that getting into action "does all these things." And they just don't want to do it. And to you, a person who's not experiencing depression, that perhaps could just seem like the most frustrating and confusing thing in the world. But it's very important to highlight the fact that these circuits that are accessible to some of us, the circuits for happiness, for pursuit of pleasure, for exercise, for getting in a cold shower, if that's your thing, that those circuits are present in all people, but for certain people that are experiencing major depression
55:44 and are really in the depths of their depression, they can't really access those circuits in the same way that people who are not suffering from depression can. So I hope that makes it clear. It's not offering any excuses for them. And indeed, I think those behaviors would help jolt them out of some of the symptomology of depression, but they're just not accessible to everybody. So let's talk about the things that people can do to deal with depression. And again, anytime you add a behavior or a tool or a supplement, or subtract a behavior, tool, supplement, drug, et cetera, you absolutely should talk to your physician, especially if you're somebody that's dealing with major depression. I want to focus on the stress system. And I'm not just going to tell you
56:29 to get sunlight in your eyes and to get a good night's sleep, although I think everybody should do that on a regular basis, ideally every day, talked about those ad nauseum on this podcast. They will help your sleep, they will help you alleviate stress. I think you should have tools to deal with stress in real time, et cetera. But let's look at depression from the standpoint of a deeper biological phenomenon, which is inflammation and the immune system. There's growing evidence now that many forms of major depression, if not all of them, relate to excessive inflammation. Now inflammation plays an important role in wound healing. It is a positive aspect of our immune system. Our ability to combat wounds, combat illnesses, et cetera, but inflammation gone unchecked,
57:15 inflammation that lasts too long, or is of too high amplitude, meaning too many anti-inflammatory or inflammatory cytokines and things of that sort in the body is bad. And there's decent evidence now that inflammation can lead to or exacerbate depression. And that if we want to control depression, or limit or eliminate depression, that focusing on reducing inflammation and its associated pathways is a really good thing to do. And I think this is a really good thing for everybody to do regardless of whether or not you suffer from depression or not. And today we're going to talk about exactly how depression comes about through the inflammation pathway. So, first of all, who are the major players in creating chronic inflammation in the brain and body?
58:02 They are the inflammatory cytokines. Things like IL-6, interleukin-6, things like Tumor Necrosis Alpha, TNF alpha, things like C reactive protein, alright? Not all of these are cytokines. You have interferons and prostoglandins and a lot of these things. But when we are stressed, chronically stressed, we get inflamed, our brain and various locations of the brain become inflamed because certain classes of cells, in particular, those glial cells, the cells that are typically thought to just be support cells, those cells and their biochemistry and their dialogue with the neurons of the brain and body starts to become disrupted. I may have mentioned it earlier, I don't recall. But I certainly mentioned it in an earlier podcast that adrenaline epinephrin, when it's released in the body,
58:50 it doesn't cross the blood brain barrier, but there are certain things that are able to cross the blood-brain barrier when we are stressed. Things like the E2 prostoglandins, those cross the blood brain barrier. And our blood and our brain, therefore our brain and our body can communicate because certain things can pass through this barrier we call the BBB or the Blood Brain Barrier. And also we have something called the glymphatic system, which is really a plumbing system that links the brain and body. It's the link between the immune system and the brain. Well, there is a set of actions that we can take in order to limit inflammation. And this has been shown in several quality peer reviewed studies now to reduce inflammation and to relieve some, and in some cases, all of the symptoms of major depression.
59:37 One of those approaches is to increase our intake of so-called EPAs or Essential Fatty Acids. There's now a very long list of papers in quality peer review journals showing that when people ingest a certain level of EPA omega-3 fatty acids, the relief from depressive symptoms matches the SSRIs. That's incredible, right? That essential fatty acids could relieve symptoms of depression, as well as some of the prescription antidepressants. Now, this doesn't necessarily mean you run off and stop taking your antidepressants if you've been prescribed them, please don't do that. Please talk to your physician. And I should mention that some of the same studies have shown that increasing our intake
1:00:24 of these essential fatty acids, in particular, the EPA variety of omega-3s, can lower the effective dose of things like SSRIs. Meaning if we required a 50 milligram or 40 milligram dose of fluoxetine, that one can get by on a lower dose and thereby perhaps not experience as many
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