Robert Sapolsky: The Biology and Psychology of Depression

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Sh. Hi. My name is Robert Spolski. I'm a professor of biology, uh, neurology, and neurosurgery at Stanford University. Um, about 13 years ago, I gave a talk at Stanford on the biology of depression. Somebody taped it, and Stanford uploaded it to YouTube, and that has produced some good news, bad news. Good news is, in the year since, 5 million views or more for this lecture—in it's useful. Bad News: 5 million views or more telling you the magnitude of the problem out there with depression.

Now, of course, fortunately, there have been some new advances in the field since 13 years ago, and the purpose of this lecture is—it's a son of the 2010 lecture—it's an update on the information. Now I'm going to make the argument throughout that depression is among the worst medical catastrophes that can overwhelm someone, and we will get to that argument in considerable detail. Sense of what we're up against: World Health Organization sense that major depression is the number one or two leading cause of medical disability on this planet. Millions of people—best estimates 15 to 18% of people—will have a major depressive episode at some point. Now, worst news: about 80% of cases are never diagnosed, and of those that are, approximately one-third never respond to any medication; approximately one-third do, but the side effects are intolerable; and about a third are helped. In other words, we have massive, massive problems with oceans of people out there with this malady who are not being diagnosed or successfully treated. About 80% of people have multiple rounds of depression, and so that, as a starter, trying to impress—this is an important subject to know about.

Now, one of the more reliable, disturbing findings out there is that with each passing decade, the incidence of depression has been increasing. Okay, that may mean nothing at all; there may be all sorts of confounds. People today are more likely to admit that they feel depressed than people in the 1950s, and thus, artifactually, it looks like there's more cases. All sorts of very carefully controlled epidemiological studies showing cross-culturally the incidence of the disease has been increasing over the decades. Most informatively, where it's been increasing is among adolescence: with each passing year, more teenagers being recruited, roped into the lifelong cohort of people struggling with depression. Just so that it's not purely an adolescent thing, what's been seen also is increasing risks of depression over the years, over the decades, among elderly people. Now what you see is totally predictably who gets major depression: we will see just on a demographic level, low socioeconomic status is one of the biggest victors.

Okay, so I'm going to try to make three points in this lecture: three incredibly important points, and the first one is implicit in what I've been saying all along: depression is a medical disease. There is this incredibly toxic pull towards people who have no idea what it's like to say, "Oh, come on, we all get depressed, and people come out the other end. Pull yourself together, and stop babying yourself." Saying that to somebody with a major depression is like sitting down somebody with diabetes and saying, "Oh, come on, what's this? Stop babying yourself with this insulin stuff. Come on, just tough it through." Depression, as we will see, is as biological of a disorder as is diabetes—as we'll see, a very different type of biology nonetheless. We are talking about a medical disease.

Next critical point: if you learn about this, and all you learn is the biology—the brain chemistry and the hormones and the genes and what's connecting to what—all of that, you are never going to be able to effectively take on this disease. And the two parts of this lecture reflect that point: go learn all the biology, and you've got all those multicab terms down cold, and if you don't incorporate it with the psychology of depression, you're going to get nowhere at all.

Now, the third point being: why argue that this is among the worst of all diseases? And this sort of revolves around this totally bizarre thing that humans do. You've got terminal cancer, you've got crippling heart disease, you've lost a limb, whatever, and your life is obviously very constrained and very comp… and bizarrely, people find silver linings in these things on occasions. This is when you realize how much family means to you; this is where you realize you have found your God; this is what… whatever. We are capable of pulling satisfaction, pleasure, reward, contentment out of the most awful circumstances on Earth. Just ask anyone who came out of the concentration camp feeling like, in some ways, they were still glued together. It's a person. We humans can make the best of horrible situations; we can look on the bright side. Depression is a disease where you can no longer look on the bright side, and what could possibly be worse than that? And if I had to define depression in a single sentence, I would say it's a biochemical disorder with genetic components whose primary manifestation is: you lose the ability to be awed by rainbows and sunsets. So that makes her a pretty bad one.

Now, just starting off before we begin looking at the symptoms: some jargon. Yes, all of us get depressed. Everybody gets depressed in an everyday sense. Some disappointment happens, something unrequited, whatever, and what you wind up seeing is typically: come out the other end, and we heal. And what you see instead with the depression we'll be talking about today is not, "Oh, I've been down after this argument with a friend. From the next day, I just felt kind of mopy." This is a major biological disease that destroys people's lives, and once again, one of the leading causes of medical disability on this planet. Unfortunately, wow, crummy day, I feel depressed. And depression as a biological disorder—use the same term—we are only talking about this massive medical malady here.

Okay, so we start off before getting into the biology: what does the disease actually look like? The defining symptom of depression is anhedonia—anhedonism—the experience of pleasure; anil—anedonia—the inability to experience pleasure. And this is what the disease is all about. Something wonderful happens: you feel nothing. It is just a flatness; there is an emptying. This is the symptom that makes this among the worst diseases out there. We're going to get to how much more subtle stuff is going on than just the inability to feel pleasure. In addition, people with major depression are overwhelmed often by a sense of grief about things; trauma just resonates over and over; a sense of guilt over imagined wrongs you did at some point; a sense of guilt—one of the most pernicious versions is, "I've been so fortunate; I've been given so many gifts; I've been so privileged. All of that. Look at me wasting my life away feeling sad and feeling guilty as a result of that."

Now, another realm of symptoms of depression, and really informative of what's depression about: it's a disease of mood problems; it's also a disease of cognition, of thinking, and that winds up being really informative in the lecture to come. Cognition, on the simplest, like white-bread level, uh, depression involves cognitive problems. People's focus goes out the window; executive function, working memory—things like that—that's all the usual. What we're going to wrestle with coming down the line is: when somebody is not good at remembering eight-digit numbers or whatever, is because their cognition is compromised by the depression, or is because they're just not motivated—why bother?

Now, the realm in which depression is problematic with cognition leads us into the work of one of the giants in the field: this guy Aaron Beck, who framed depression as a disorder of cognitive distortion—not just of negative mood, not just an absence of positive mood, but depression as a disorder of cognitive distortion. What did Beck mean by this? And his insights became the backbone of arguably the most effective type of psychotherapy for depression: CBT—cognitive behavioral therapy. What is the cognitive distortion? There: yes, something awful happened to you; it's true; it's real; it's upsetting, but that's not the end of the world, and that's not your inevitable future, and that's not the rest of your life. And people with depression distortedly overgeneralize the negative into a worldview, as Beck turned it into a depressive triad—a negative triad—a depressive worldview about yourself, about the world, and about the future. So what does this look like when you see this in all sorts of cognitive realms? You ask somebody to remember things: tell me about this year from school when you were a kid or whatever, and in depression, you disproportionately generate, come up with negative memories. You give somebody a whole bunch of things to memorize, and you disproportionately remember the negative ones; you have a bias towards consolidating more negative memories. You interpret the things going on around you; you look at a picture of an absolutely neutral face, and you're asked to describe the mood of that person, and you have a bias in the direction of negativity. Your sensory processing even shows that—where you look. You show somebody pictures, and there's a negative one with a sort of sad context, positive—wondering where the eyes go in a fraction of a second—that bias—this negativity bias of memory retrieval, memory consolidation, interpretation of things, where you're looking to get sensory information from—this is permeating the disease.

Now, another way of describing this cognitive deficit in depression is: people fail to be able to do reappraisal. You feel bad about something; you get a bad result on a test, whatever, and a very healthy response is to reappraise, saying, "Okay, maybe I'm not so good at organic chemistry after all." Maybe you begin reappraising: "I wasn't so good on that particular day; maybe it had something to do with I got very poor sleep; maybe what I should keep in mind is there's a whole lot more to life than organic chemistry." You were changing your interpretation of the situation in a way to escape the negativity. People with depression have huge problems with reappraising a negative circumstance like that.

Now, an interesting thing with this in terms of people with depression having this more negative interpretation of the world—this really striking thing is: some of the time, by having a more negative interpretation, more accurate—they're more correct. And this has given rise to a sound bite in the field: sometimes people with depression are sadder but wiser. Because you look at your average person, and they are, on the average, delusionally over optimistic. When you ask people what's the likelihood of this thing happening or this great thing or that sort of stuff, and you see that people with depression are way more accurate. Okay, wait a second: I was just talking a few minutes ago about the cognitive problems, the distortions in depression. Something awful happened then in the past, and distortedly you decide this has to be your future; you're distorting stuff. Yet here people with depression are being more accurate than the average person—it's evaluating things in the world around you—when it's a distant thing, when it's an emotionally detached thing, people with depression are often sadder but wiser in terms of having more accurate, more realistic assessments about how the world actually works.

Okay, so that's looking a little bit of the cognition. Another major feature of depression as a symptom is rumination. You ruminate like a cow chewing its cud; you ruminate; you can't stop the sad thoughts; you can't stop the negativity; you can't dig your way out of this sad thing; reminds you of that sad thing, which… and you are just mired in it. It's really interesting neurobiology: we're going to hear about a part of the brain called the dorsal lateral prefrontal cortex. What that one's really good at is helping you control your thoughts, and what you see is the dlpfc has to work especially hard in people with depression. When you say to them, "Tell me about a happy childhood memory," it's really got to work to overcome the rumination. Likewise, this part of the brain has to work really hard when you're trying to stop the negative affect, the negative emotions. This—and we're going to be looking at this part of the brain, which atrophies, becomes less active in major depression—this part of the brain has a whole lot to do with that hellish symptom of depression: you can't stop the negative thoughts; they just go on and on and on, and they won't stop.

Now, another bunch of symptoms fall under this umbrella term called psychomotor retardation. Back to: major depression is not, "Oh, come on, just stop babying yourself." Major depression is a real disease. People with major depression, their bodies work differently—even when they're asleep, even when they're anesthetized—underlining again: this is a real biological disorder. And the psychomotor symptoms that you see in depression that sort of underlined this begin to tell you what's going on. Psychomotor: you slow down; your sensory processing speeds are impaired; everything is exhausting—to do, to think, to say, to get up in the morning and brush your teeth and figure out where you left the car keys—everything is exhausting, overwhelming. What becomes an issue that we will get to is: is this because you just don't have the energy to do whatever, or is this because you just don't have the motivation—why bother? Very intertwined there.

Now, along with that comes what are termed vegetative symptoms—where the body is working differently. People with major depression, their patterns of sleep are disrupted. Yeah, big surprise: we all have trouble falling asleep if we're depressed about something. With major depression, people tend to wake up earlier than normal—early morning wakening. Moreover, you get someone when they're asleep, and you put on like these EEG probes, and what you will see is the structure, the architecture of sleep—we go through different sleep stages and cycles of that—it's disrupted. The person is sound asleep, and their brain is working differently at that point. What you also see is appetite is altered. Lots of us, where we're depressed in an everyday sense, that's the time to eat Cheetos or Oreos or whatever, because high fat, high starch can decrease stress in us, and people actually understand how that works. Major depression: the tendency is towards loss of appetite, loss of the pleasure from food—part of the anedonia—part of the vegetative symptoms in the body there. Big surprise. Something else that goes down the tube is libido—interest in sex, sexual arousal, sexual repetitiveness, motivation, appetite—all of that. Like if you were just mired with endless, sad thoughts that won't stop, sex is kind of far down in your list.

Okay, what else is going on? Of course, adding all of this is the true nightmare of major depression, which is suicidality and self-harm. And major depression, because of this, is one of the most life-threatening diseases on this planet. Statistics: women with depression tend to attempt suicide much more frequently than men; men with depression tend to succeed at it much more frequently than women. What's your classic profile of impulsive suicidality? An older white guy, poorly educated, low socioeconomic status, who has access to a handgun.

Now, a really interesting thing about depressive suicidality: you get somebody who is massively depressed, and they're in your ward, in your psychiatric hospital, and you say, "Oh my God, they're so depressed, and depression is associated with suicide; we really need to keep an eye on this person to make sure they don't…" That's not when you worry about suicide with somebody with major depression, because this is somebody who is paralyzed with psychomotor; this is somebody who has to fight to get out of bed in the morning; they are so much a, you know, brine shrimp sitting there without any means of mobilizing; this is not someone who's going to figure out how to shred the mattress to make a new source, something like that. That's not when people are most at risk. You take someone who is severely, deeply depressed, and you start treating them with meds—whatever—we'll get to that—and they begin to get better, and in some cases the psycho-energy comes back; in some cases the person is still feeling the depression, but they get it together enough or mobilized or activated enough to go and kill themselves. This is when there is the danger of suicidality.

Now, one other vegetative feature of depression: when you look at the psychomotor stuff—person can't get out of bed; they're totally exhausted—you're, you're thinking of them as, again, being like some sort of invertebrate melting over the edge of the bed or something. You look at heart rate; you look at muscle tone; you look at various hormones going on in there, and what depression is about is a chronic activation of the neurochemistry of stress, of arousal, of vigilance, and we are going to see lots more about that. You are—if anything—that psychomotor exhaustion is coming from the fact that there is a battle going on 24/7 inside your head, and no wonder you don't have the energy to get up in the morning, let alone get up and put on a happy face.

Okay, another thing that underlines—we're talking about biology here—is there's more than one type of major depression; it comes in different flavors. One classic dichotomy—which people argue whether it actually is valid or if it's all in a continuum, that sort of thing—is the difference between reactive depression: something bad happens; everybody feels crummy, and you know, most people get better over the subsequent weeks, but some people sink into a major depression at that point. Reactive depression versus an endogenous depression: somebody falls into a depressive episode, and nothing bad has happened to them. Other versions, subtypes of depression: there's a subtype called atypical depression that is just dominated by the psychomotor stuff. These are people where just doing anything is overwhelming; they're less concerned, less bothered with the anhedonia, the rumination, all of that. And really interestingly, atypical depression seems to have a lot of biochemistry in common with chronic fatigue syndrome. Interesting, and first hints now that there may be some similarities with variants of long-haul COVID, the type that is still flattening you years later. So there's atypical depression; then there's psychotic depression—people who are so intensely delusional, and we will see sort of what that may be about, that they begin to be seriously thought-disordered. "Oh, oh, oh, I know this great promotion I just got; they're going to fire me at some point." That's cognitively distorted; that's not delusional in the sense of psychotic depression. Some people may remember this heartbreaking case: this woman Andrea Yates, a number of years ago, who, in a severe psychotic post-partum depression, drowned her children, and it took a number of trials for somebody to figure out this was somebody with a severe dis… Why did she drown her children? She was a fundamentalist Christian and raised in a school of thought that merely by birth her babies were nearly, you know, certainly damned to go to hell at this point, and drowning them would save them before they had the chance to become sinners. This is what psychotic depression looks like, because this is absolutely what she believed when she did this, and heartbreaking for everyone concerned. Different subtypes of depression: there are ones that have rhythms to that; there are rhythmic depressions where somebody has a depressive two or three weeks that are kind of incapacitating, goes away on its own, comes back after on its own, and just cycles like that. Another version is people who get depressive episodes only at certain times of year—what are called seasonal affective disorders—and it's mostly about people who fall into their annual depression each year during the winter months. Look at this: you got somebody with something awful happens to them in July, and they have a reactive depression; they feel awful; it's upsetting, whatever, and they see that this is not all of life, and they come out the other end. And then comes January, where everything's perfectly fine, yet for the nth year in a row they fall into a major depression and need to be hospitalized. Rhythms. And it turns out this seasonal affective disorder, SADs—these winter depressions—seem to have a lot to do with light exposure, a hormone called melatonin relevant to that.

Okay, what's the main point here? You take somebody who has a different subtype of depression, and it's neurochemically different from somebody with a different subtype. You take somebody with things are awful in the summer and they cope, and things are great in the winter and they go under… You're looking at not just a disease; you're looking at a whole family of diseases in this case. It's biological. This is: "Oh, come on, stop babying yourself."

Now, one additional point in terms of the presentation of depression, what it looks like, which is: depression very often goes hand in hand with an anxiety disorder. Now, what's that about? Anxiety: hyperarousal, a physiological state of agitation, a sense of forbidding, sort of anxious apprehension—as I check the exact term—and what you see is about 50% of people with a major anxiety disorder, particularly social anxiety, also have clinical depression; 50% of people with clinical depression also have a major problem with anxiety. The two of them overlap in all sorts of interesting ways. One way in which this has been interpreted is that these are both diseases of anhedonia. It's not fun having sad thoughts going through your head nonstop; it's not fun being anxious 24/7. What's the difference? Anxiety is anhedonia in a hyperaroused, vigilant state; depression is anhedonia without that.

Now, some more hints about this come from the fact that most often the anxiety comes first. One interpretation of this, which is: you could think of anxiety as this hyperaroused, frantic, urgent state, like a brush fire; that anxiety is just little flames popping up all over the place, and what depression is about is something responsive, comp… What depression is is a big old thick blanket that you throw on top of the fire to take the air out of it. Depression as a trying to contain the anxiety-related agitation by just flattening you out. That's one way of thinking about it—that is metaphorical in lots of ways. What that maps onto is another feature that you see with this transition of starting with anxiety leading into depression: anxiety—there is some upsetting challenge going on—lots of cases: you're a rat, you're a human, and they're shocking now and then, whatever—and what the anxiety is about is you're trying to cope; you try to cope 110 different ways at once, most of which are mutually contradictory; you keep trying to cope when the challenge is long over with this agitated attempt at: give me some control so I can make this challenge go away. What depression then is about is when you've given up; the challenge is still there, and you don't even bother. And we're going to be looking at this transition in the psychology section: anxiety is about really maladaptively trying to cope; depression is about you've learned to be helpless; you've learned to be hopeless, and in circumstances where you could cope and you could make things better, you don't even try; or if you stumble into doing it and it works, you don't even notice that it worked. So this heavy intertwining between depression and anxiety—I'm not going to be talking about the biology of anxiety today.

Okay, so we've gone through the symptoms, the comorbidities, all of that. What's going on in the brain during major depression? We start off with: what's the neurochemistry, the brain messengers, and depression? So for this, we've got to have the initial sort of slide that everybody taking Neuroscience 101 is exposed to: the picture of the synapse. You got two neurons; one neuron sends out a projection to the other; the other one has projections coming this way, and information flows from the first neuron to the second one. The first neuron hears some exciting gossip, and it gets all excited—a cell's version of getting excited—and it in turn passes on the excitation to the next neuron, and line the gossip spreads. Now, what you see in the diagram here—actually, this right now is just a green screen, so I'm not sure if I'm pointing to the diagram or not—but in any case, what you see is between those two NS, they don't actually touch; there's a gap in between called the synapse. What that means is the excitation from the first neuron on the left—all neurons go from left to right—the excitation coming down this way can't easily jump over the synapse and get the next neuron excited. The excitation, which is electrical, has to be translated into a different form of excitation. The first neuron there releases a chemical messenger that floats across the synapse and binds to specialized receptors there, and as a result, this neuron has now heard the gossip. These chemical messengers that are released are called neurotransmitters, and they're going to be real pertinent very soon to making sense of major depression.

Okay, little bit of housekeeping stuff, because that's going to be pertinent also: the first neuron is totally excited about whatever news and dumps a whole bunch of neurotransmitters into the synapse, and they float across, and they interact with receptors there, and they pass on the message. And that's to reflect what happens to those neurotransmitters afterward, because they eventually come off these receptors, and they're just floating around in the synapse. You got to clean up after yourself, and most broadly there's two ways that neurons do this. The first one is: if they're being ecologically minded, they recycle the neurotransmitter. That first neuron…

Pre-synaptic neuron has these specialized pumps that will get the neurotransmitter in here that's done its job and pump it back in, so you can reuse it. Or you can be totally wasteful and, sitting around in the synapsis, some enzyme breaks the neurotransmitter down, and you toss it into garbage. What's the garbage? Here, it gets into the synapse and then into the general brain and then your cerebrospinal fluid and your blood and your urine, so the people could measure levels of neurotransmitter breakdown products in your pee and get some sense of what's going on up there. Okay. So first neuron is excited, releases neurotransmitters that gets the next one excited. Or a twist on our story that can make the neuron here less excitable: an excitatory neurotransmitter or an inhibitory neurotransmitter. And then afterward you clean up, either with reuptake or degradation.

So with that in hand, we now look at particular neurotransmitters, and the one that comes up over and over and over again is serotonin. Twenty-five years ago, people would talk about this, and maybe serotonin would be the second or third neurotransmitter on the list. It is the number one neurotransmitter on the list: serotonin. Because the most effective class of anti-depressant drugs work on serotonin; a class of drugs called SSRIs, selective serotonin reuptake inhibitors. Most famous: Prozac, but a whole menagerie of them by now. SSRIs, selective serotonin reuptake—what do they do? This neuron dumps serotonin into the synapse, and it would normally be taken back up, but what something like Prozac does is it blocks the reuptake pump. What happens then? There's no reuptake, and the serotonin sticks around longer, and for lack of anything else to do, it hits the receptors a second time and a third time and the 100th time, and people tend to feel less depressed at that point. So what's the only possible interpretation that comes up with there? If you throw in a drug that causes serotonin to stick around in the synapse longer and buzzes the next neuron more often and somebody feels better, I bet the problem was too little serotonin in the first place. And thus the serotonin hypothesis, which dominates the entire field now. This is totally cool. What's one of the most interesting things about it is the serotonin is probably working in a part of your cortex that has a whole lot to do with blocking rumination, all of that.

Serotonin hypothesis: the problem in depression is too little of this neurotransmitter. SSRIs, selective—only working on the serotonin system—that's not actually true, but we will pretend that for the moment. Blocking reuptake—if the stuff sticks around in the synapse longer and buzzes here more and the person feels better—the only conclusion is I didn't have enough serotonin there in the first place, naturally. Two problems emerge. The first one is crazy-making for everybody in the business because you throw in something like an SSRI, and it's doing stuff to serotonin reuptake within minutes or hours, and typically people don't start feeling better for days to weeks. There's some sort of mismatch in the time course, and there's a model out there that might explain it, and it is so awful and confusing that I've consigned it to one of the, like, appendices in the back. You are for fools, Russian, if you want to go learn about that, but that's one of the problems: the time course problem. The other problem reflects this history of serotonin. It used to seem like the second or third most important neurotransmitter, and then it moved to being seen as the most important neurotransmitter. There's a problem, and then there became the temptation to decide it's the only neurotransmitter relevant to this disease. And what you see is this whole controversy these days is: serotonin problems necessary and sufficient to explain depression? Because you see lots of people where drugs that affect the serotonin system actually don't work, or where you see neurochemical problems elsewhere. This has led to, I think, a little bit of a sort of anarchist view that the whole serotonin story makes no sense, it's gibberish, and all of that. What do you know? It's not just one neurotransmitter, which brings us to the second neurotransmitter that's relevant: something called norepinephrine.

Norepinephrine and depression have been around in the scene for decades and decades. The very first drugs developed in the 1960s to treat depression, they weren't working on serotonin synapses; they were working on norepinephrine synapses. And what were they doing? One of them blocked the norepinephrine reuptake pump—something called a tricyclic anti-depressant. Another one of them kept the enzyme that breaks down norepinephrine from doing its thing. Both result in norepinephrine sticking around longer and having more of an effect here, and if the person begins to feel better—oh, I bet there's not enough norepinephrine either. The norepinephrine hypothesis. And this started in the 1960s and dominated until people learned a whole lot more about serotonin, but the exact same logic going on in there. And what you see is norepinephrine is probably most relevant in a part of the brain—do not write this down—called the locus coeruleus. I can't spell it right. After decades of obscurity, it's a part of the brain that has to do with arousal and vigilance and all of that. And you begin to get stressed, and you activate the system, and you deplete norepinephrine. Norepinephrine hypothesis: not enough of the stuff, you're short of norepinephrine, and what happens instead is you fall into psychomotor retardation. Lots of evidence for that. Third neurotransmitter that used to be at the top of everyone's list is interesting: a neurotransmitter called dopamine. Everybody knows about dopamine. Dopamine is about pleasure; it's about reward; it's about cocaine releasing dopamine; all sorts of euphoric drugs working on dopamine synapses. And what you see is: whoa, that's perfect—dopamine, reward, pleasure. And you begin to see some of the drugs that protect there, they block reuptake, they block degradation—oh, suddenly a person—there's not enough dopamine; that's where the anhedonia comes from, the loss of the capacity for pleasure because you don't have enough dopamine. Time to see a much more contemporary picture of what dopamine does. Yes, yes, yes. Dopamine is about pleasure. You take someone—you take a person, you take a monkey, you take a rat—and you give them a reward from out of nowhere, and dopamine neurons—we're going to hear about—release a lot of dopamine. Yes, it's about the rush of pleasure. Now you do something more subtle: take that person, monkey, rat, and you give them a training task. You put them in a room, and a light comes on, and every time the light comes on it means if you now press this lever 10 times you get a reward. You've had lots of practice at that. Light comes on, work, reward, signal, work, reward, works perfectly well. So you put someone in this sort of setting. When is dopamine released? If dopamine is just about reward—signal, work, reward—rise of dopamine—that's not what you see. Once somebody has learned this task, when does dopamine go up? When the signal comes on. What's that about? When it's dopamine being dumped from these neurons when the signal has come on and the person or rat is sitting there saying, "Yeah, the lights just come on; I know how this works; I'm all on top of this lever pressing; piece of cake; this is going to be terrific." Dopamine—yeah, it's about reward and pleasure, even more so it's about the anticipation of reward and pleasure. And amazingly you block that dopamine from being released, and you don't get the pressing of the lever. It's not just about the anticipation; it's the work you're willing to do at that point in order to get that reward. It's about the motivation; it's about goal-directed behavior. And what you see is during major depression there is depletion in this relevant part of the brain—we're going to hear about—and what you especially have is a loss of these spiky bursts of dopamine that come out. Dopamine is always doing a certain background thing with this anticipation, but you lose the ups, you lose the ups not of pleasure but of anticipation, of being willing to work to get it. And what you see is is not so much about the pursuit of happiness; it's much more about the happiness of pursuit, the anticipation.

Okay, so we've got those three neurotransmitters in there, and what you wind up seeing is—what do you know?—it's not just those three. I put up a slide here showing some of the other neurotransmitters that have been implicated. Do not write it down because this chart will probably be obsolete by the time I'm done with the select. There's all sorts of players in this; big surprise. It is not just serotonin; sometimes it looks like it isn't even serotonin. It's not just these big three; there's all sorts of other ones relevant. In the last few years, one of those minor players has started to seem more relevant because, again, we've got this time course problem. If you increase serotonin with one of those meds, if you do the same with norepinephrine, if you do the same with dopamine, you're changing stuff in the synapses within minutes or hours, and people take days to weeks to feel better. This mismatch in time is totally puzzling, and in recent years along has come a new drug, a new drug that has sort of revolutionized a lot of depression treatment: a drug called ketamine. Ketamine is turning out to be an anti-depressant; it's turning out to be one that works within minutes, and people are just beginning to learn about it, and it is relevant to a neurotransmitter called glutamate. So suddenly glutamate is on the scene as well.

Okay, so we've got all these players. To just broadly summarize, what's the serotonin problem about? It's probably the rumination, because SSRIs work on another disease that involves rumination: obsessive-compulsive disorder. Depression: you're ruminating on sadness, sadness, sadness. Obsessive-compulsive disorder: you're ruminating on, "Did I leave the oven on? Did I leave the oven on? Do I—I need to get the utensils perfectly straight." In both cases, somebody's feet are just stuck in a flytrap, kind of thing, in quicksand, and SSRIs help with that as well. So the serotonin piece of it, just to be totally simplistic, seems to have a lot to do with rumination. The norepinephrine part seems to have something to do with the psychomotor problems. The dopamine part seems to have something to do with the anhedonia. And glutamate—people are still figuring out—and like this is as clear as anybody can summarize all of this, and it is dreadfully oversimplified, blah blah blah. This is kind of where people are at in terms of studying the neurochemistry: where the most parsimonious thing in all these cases is there's a whole bunch of relevant neurotransmitters, and for some reason you're depleted of them, and some of the best drugs out there tend to reverse that process.

Okay, so this is looking at the biology of depression from the standpoint of brain chemicals and neurons talking to each other. What about the actual structure of the brain? Where is there problems? Where are there problems in the brain? What particular brain regions have problems in major depression? And a lecture like this 13 years ago or earlier than that, this would now be looking at this part of the brain and the evidence that there's something weird going on there, and then this part of the brain, this—and where there's been tremendous progress is recognizing that's not the most informative strategy. What you want to understand are the circuits that connect different brain regions, and that's where there's been some incredible insights there now. To appreciate this, we need to look at a classic model about how the brain works, and again you take Neuro 101 anytime in the last thousand years and you're going to learn about this: the Triune—TR-IU-NE—the Triune model of brain function; the three layers of brain function. This was a guy, Paul MacLean, pioneer in the 60s, who came up with the Triune model. It is a model that bears no relationship to which neurons are actually projecting to who in releasing neurotransmitters; it's just a way to conceptualize three layers of neural function. Layer number one: what MacLean called the reptilian brain, which is to say the parts of your reptilian brain. And you go out and you look at a lizard, and it's got basically the identical parts there, and it's the hypothalamus, the midbrain, the brainstem. What does the reptilian brain do? The sort of stuff that reptile brains do. You get hot, and you get all sweaty—if that's what reptiles do—but that's what we do. You get cold, you shiver; you get hungry; you get the brain telling you to release hormones that generate appetite. There, you lose a lot of blood, and the reptilian brain tightens up your blood vessels to make sure you're not hemorrhaging at all. What's the reptilian brain about? It's just about regulatory stuff, like little feedback loops. Then on top of it is the second layer, termed limbic system, and you don't see a lot of limbic system until you get to mammals. What's the limbic system about? Emotion. And this isn't surprising; reptiles are not famous for their emotional lives. It's only when you're getting up to mammals that you have a part of the brain that activates with sexual arousal, with fear, with anger. You take some wildebeest guy in his territory, and some other big male wildebeest shows up and is peeing all over there in a dominance action and challenge, and it's the limbic system that gets all crazed and hot and bothered at that point. Third layer, which you don't see much of until you get to primates: the cortex; the stuff on top that's about thinking, cognition, memory, evaluating information, doing or taxes, all of that. So yeah, we've got this totally simplistic model: reptilian, automatic, regulatory stuff; emotion; and thought. And of course what one sees is this is a totally false trichotomy or whatever in that all of these layers are talking to each other. For example, that scary wildebeest shows up and pees there, and your dominance is being threatened, and your emotions are all going crazy in that limbic layer, and one of the things that also happens is your heart starts beating faster. The emotional limbic brain is telling the regulatory reptilian brain to change its function. You're just standing there looking at this guy, this barbarian at the gates, and Layer Two tells Layer One to activate, not because you're running up a flight of stairs, but because you were simply emotionally aroused. So Layer Two can talk to Layer One; Layer Three can talk to Layer One. Now you just sit there and you're not seeing this big scary wildebeest show up; you're just before going to sleep thinking about that guy and how upsetting that was, and Layer Three activates the emotional limbic system, Layer Two, which gets your heart beating faster. This is just the means by which thought and memory can make your body work differently in all sorts of interesting ways. So there's lots of top-down regulation going on there. In addition to that, there's bottom-up: Layer One talking to Layer Two—just regulatory stuff changing your emotions. One example of this: when people are hungry, they tend to become less cooperative, less empathic, they cheat more in economic games. Layer One: "Oh, here's the news about your circulating blood glucose levels influencing emotion." There, Layer One influencing cortical judgment, cognition, sort of stuff. And the classic example of this: this amazing study some years ago looking at a whole bunch of judges making rulings on parole boards: either you give the guy good news—"Yes, you were freed"—or bad news—"You go back to jail again"—and over the course of hundreds and hundreds of judicial decisions there in this court system, what was the single biggest predictor of what a judge was going to decide—with this person go free, go back to jail?—how many hours it had been since the judge had eaten. Get somebody right after a meal, and you'd have about a 60% chance of being freed. By three, four hours later it's gone down to zero. Wait a second, your blood glucose levels has to do with your solic reasoning. You sit down some judge at that point and ask them why they freed this person but sent that one back to jail even though they had both done the same thing, and you're not going to get them telling you about blood glucose; they're going to go back to like freshman philosophy in a manual con or something. Layer One regulating Layer Three. By the way, as a footnote here, the judges—the hungry judges study—has gotten a huge amount of coverage in the media, which is great because it's a fantastically interesting study. There have been some challenges to it, people saying, "Here's a flaw, here's a confound," whatever, and for my money the original authors have swatted away every one of those objections. This is a very solid finding that has now been replicated. Finally, Layer Two can talk to Layer Three: emotions can talk to your cognitive brain. What's that about in a context of like everyday life? This is why when you're just frothing with emotion you make terrible decisions. This is why when we're all emotionally crazed about something we do some dumbass thing that we're going to regret for the rest of our lives, and we think it's brilliant at the time. Emotion marinates your supposedly nice rational cortex. And what's this about in depression? Your cortex can sit there and say, "No, actually, there's no reason why this is going to go poorly in the future, and here's why," and that emotive negative bias stuff is swelling up there on top and making you conclude, "This was my past, this is my present, this is my future," overwhelming there.

Okay, so we've got this broad orientation here, the Triune layers, and again this is just the metaphor. What we begin to look at now is some of the circuitry that's relevant. What we start off with—our first circuit—is one relevant to pleasure and anticipation and motivation and all of that, very relevant—you better bet—to both anhedonia and dopamine: a part of the brain called—do not write this down—the mesolimbic dopamine system. And it consists—again, I'm guessing where the slide is showing it—consists of these two brain areas: the ventral tegmental area, the nucleus accumbens. Do not write these down. This is the part of the brain that drives the anticipation, all of that stuff, and thus if there's a shortage of dopamine in there or if the neurons in there become less responsive to dopamine, you're seeing loss of anticipation, loss of motivation, loss of pleasure, anhedonia. Where is this coming from in depression? You see overactivity from two inputs into the mesolimbic dopamine system. First brain region: the amygdala. The amygdala activates in response to unpleasantries, fear, threat, challenge; it drives aggression. All of that negative stimuli activate the amygdala, and what you see is the amygdala input into the mesolimbic system is overactive in depression. And what's the effect of that input? It tends to inhibit the dopamine system there, so that's bad news. One interesting thing with that: you take somebody, you put them in a brain scanner, and if it's somebody without depression you flash up a picture of something scary, and in a fraction of a second the amygdala activates. You put somebody with depression in a brain scanner, and it doesn't activate when you show them scary pictures. The amygdala activates when you show them sad pictures. It's rewired to a different function. Until you think about it, if what the amygdala is about is responding to scary things, and you are majorly depressed, the scariest thing on Earth is anything that might come along that makes you even sadder. So the amygdala has simply put into there. Meanwhile, this other part of the body—the ACC, the anterior cingulate cortex—totally cool brain area. What does it do? It's about empathy, as follows: you take somebody, put them in a brain scanner, and poke their finger with a pin, and all sorts of parts of the brain activate, saying, "It was my finger, not my toe," and that sort of stuff, and the ACC also activates; it codes a representation of pain. Now take someone, put them in the brain scanner, and don't poke their finger with a needle; make them watch their loved one's finger get poked, and the anterior cingulate cortex activates. These are neurons that literally cannot distinguish between their pain that you were feeling and your own pain: empathy. And what people find is the anterior cingulate tends to be overactive in major depression. And what is it doing? It is also fueling inhibitory signals going down to that whole dopamine system.

Okay, so let's step back from like modern science and turn this into like some idiotic, like, metaphor. Anterior cingulate in the cortex, and what's going on with depression is the ACC is like thinking all these sad thoughts all the time, and those are cognitions, and somehow it's whispering it to the limbic system and turning it into emotional sad thoughts and getting the reptilian brain that the ACC, through feeling the pains of the world, are driving all sorts of stuff down south. So this brings up a totally idiotic idea: whoa, so you have somebody with depression, and the ACC is too active, which is what is exactly is shown. What would be a great solution? Go in there and snip just below the ACC and make it impossible for it to talk to the limbic system and down below. Depression gone! Shazam! Idiotic. And amazingly it works. Desperate, desperate final measure with the most severe depressions out there that have resisted every conceivable treatment is to do a singulotomy—cut the projections there—so that metaphorically your ACC can't be wallowing in bad thoughts and then get the rest of the brain to go along as if it's for real. In terms of actual circuitry, so that the ACC isn't able to deplete the mesolimbic dopamine system of dopamine, and this procedure, which is a desperate Hail Mary, seems to work in about 50% of severe, treatment-resistant cases.

Okay, so wait. What we'll notice one more thing on that diagram: both the ACC and the amygdala messing with the mesolimbic dopamine system by way of LH—a part of the brain I knew once for a final in psych—the lateral habenula. And when you activate it, it inhibits the dopamine system. And okay, so that's part of the story, and there's all sorts of evidence that it's overactive in depression and thus inhibiting the dopamine system, all of that. What's the neurotransmitter that the lateral habenula is using heavily? That neurotransmitter: glutamate; the one that ketamine works on within minutes as an anti-depressant. This is the part of the circuit that is right near where you really want to be affecting stuff; maybe that's why manipulating this and you feel better within minutes or hours, and fussing with some of the others with slower-acting medications and it takes days to months. Suddenly lateral habenula and glutamate on the map in terms of making sense of the circuit.

Okay, so that's the circuit telling us something about loss of pleasure, loss of anticipation, inhibition, suppression, depletion, discouragement of this whole dopamine system down there in response to things like painful empathy, negative stimuli, etc. We move to our second circuit now, and our second one is relevant to the rumination—the sad thoughts won't go away—and this has to do with a network in the brain called the default mode network. You put somebody in a brain scanner, and you're looking—when you do this, this part of the brain activates, and you do that to them, and this part goes quiet or whatever, and you—MTH—things out and just pain in the neck feature of it is you do nothing to the person, and there's just all sorts of background activity; different parts of the brain just sort of mumbling there in the background all the time. And this used to be viewed as background noise, and when you would analyze your experiment you'd have to subtract out this like irritating meaningless background noise until people figured out that this wasn't just background noise; this was this default mode network that's always rumbling along there. What is it doing? It's keeping their sense of self going, a sense of sort of autobiographical stuff. The default mode network is responding to sensory—it's just this background kind of hum there—and what you see is it's a default pathway to getting to the mesolimbic dopamine system. And if what you're doing is daydreaming with your default network—which is one of the things is most important about—if you're sitting there daydreaming about sad stuff, this is another way to get to the mesolimbic system. So where does the rumination come from? This is just this resonating circuit and goes over and over and all this sort of thing. Who's talking to it during depression more than usual? The anterior cingulate, the amygdala, the amygdala by way of anterior singular, lateral—all of that—you access the circuit that way, and that gums you up in ruminative thoughts there. That's what that one is about. Now that brings us to our third circuit, which is the most important one from the standpoint of rumination: you got the amygdala too active, and the ACC is too active, and this default mode network is too active, so that you're ruminating on negative stuff. Isn't there some part of the brain that can tell them to—

Stop. That can tell them to slow down, to stop it with all this negativity. And this is that part of the brain I mentioned before: the frontal cortex, in the prefrontal cortex, a sub-area called the dorsal lateral prefrontal cortex. What is it good at? It's good at breaking rumination. It's good at getting your default mode mumbling in the background to suddenly stop as you sort of focus on stuff. The prefrontal cortex, the dlPFC, is really good at blocking negative thoughts and coming up with counteractive, positive ones and reappraisal, all of that. And you better bet where we're going right now: the dlPFC is less active than normal in people with major depression. And we look at big-time, chronic major depression, and this dlPFC even atrophies a little bit. This is the part of the brain which tells you to do things like, "Don't steal the money," or, "Don't say this outrageous thing, even though you're feeling tempted," and don't. It blocks all sorts of emotive stuff. It's the one that would normally be able to say, "Stop the thoughts here, stop the negativity," and it is weakened during depression.

Two more circuits that are relevant: one of them brings us back to that business about stress before, and we're going to hear so much about stress when we get to the psychology section. Stress. You look at the body of somebody with depression, and there's a whole brain circuit that has to do with arousal and emergency and anxiety, and all sorts of these stress circuits are overactive in depression, and we'll see about some of the homeworks there. One additional part of the brain—okay, this is stuff in a part of the brain called the hypothalamus—and it talks to the locus coeruleus and the midbrain and all of that. So this is the circuit by which being mired in a major depression bears a lot of resemblance to being chronically stressed.

Final circuit, and this is one where I am confessing: a part of the brain called the hippocampus. I've spent my entire life studying the hippocampus. It's a brain region that has something to do with memory; it's totally cool, all of that. And I spent years studying what the hippocampus has to do with depression, and what I kind of have come to is it's not really one of the most interesting parts; it's really involved in depression in all sorts of ways, but it's not central to the anhedonia, the psychomotor, the rumination. You know Benjamin Disraeli, the famous British 19th-century politician-neurochemist, said, "Youth is about blunders; old age is about regret," and I now regret my decades wasted on the hippocampus. Why even think about it in terms of stress and depression? With chronic depression, the hippocampus shrinks; the neurons in there shrivel up, their synapses at an extreme; neurons even die there. The hippocampus isn't able to make new neurons, and all sorts of treatments for depression are meant to focus on getting the hippocampus to grow new connections again. And the hippocampal problems probably have something to do with why your working memory goes down the tube with depression. This is my confession here: I don't think the hippocampus is as important as I'm used to. With all of this, I've published in a journal called *Hippocampus*, for God's sake. It's not central to the really important stuff: the anhedonia, the rumination that just goes on and on, the thoughts that might stop, the psychomotor exhaustion. It's got something to do with the cognitive problems there. There's all sorts of people who will believe that I've now, like, blasphemed beyond any hope.

Okay, so we've just seen the neurochemistry; we've just seen the neuroanatomy, the circuitry, the where those neurotransmitters are being relevant when this area talks to this one, or this one doesn't talk to this one as much as it used to, all of that. One additional piece of it: hormones, all throughout those glands in your body, getting up into your brain and affecting function there. So where are hormones relevant to depression? One that's really important, but I'll go over very quickly because I actually don't find it very interesting—oh, another confession—hormones related to your thyroid gland. Thyroid hormones keep your metabolic rate up, all of that, and it turns out a lot of people who look like they have a major depression, especially an atypical one dominated by psychomotor retardation, you check, and what the real problem is is that they've got a hypothyroid disease of some sort; they've got too low of levels of thyroid hormone. And there's a little bit of hints in the literature that that may have some antidepressant effects if you give someone replacement thyroid hormones. What's most important about this? What's going wrong in depression is not just the job of a psychiatrist, and what's going wrong in the thyroid gland is not just the job of a thyroidologist, because, like, you can't take the pieces apart. This part of the body that's very, very relevant to your metabolic rate, if it's running out of its hormones and you're running on one cylinder, depression, psychomotor especially, is one of the consequences.

Next hormone that is interesting, and this is a hormone that I love more than any on Earth because it's the major stress hormone: we've all heard of adrenaline. Adrenaline is garbage; it's Teflon-reputation; it's way, way oversold. What's really interesting is a class of stress hormones called glucocorticoids. I have sung about glucocorticoids; they are so wonderful. They're hormones that come out of your adrenal gland. Wait, wait, wait—adrenaline comes out of your adrenals; different class of hormones. Class of hormones that come out of your adrenal gland: glucocorticoids; human version called cortisol, hydrocortisone; rodent version, corticosterone; all sorts of synthetic versions of the steroid hormone: dexamethasone, prednisone, all of that. And there's real problems going on in the glucocorticoid stress system during depression. You've already heard about it, which is, in lots of ways, what's going on in the brain. Chronic depression is a picture of a chronic stress response at the hormonal level, the same thing: excessive glucocorticoid in the bloodstream. And a huge, major finding in the early 60s was that it's of a particular type: the glucocorticoid stress system has trouble turning off once a stressor is over with; it has trouble recovering, getting back to baseline. That seems to be its problem, and we understand a little bit about what that's about. And a classic clinical test, something called the dexamethasone suppression test, DST. Dexamethasone, a synthetic glucocorticoid; they give it to you, and this is a way of testing whether your system is resistant to turning off after the end of stress. Do you just go on secreting corticoids long after it's over? The DST is the standard test for this. The DST was invented in the early 60s, and I remember my friends and I were so excited about it, the potential of the DST; we were all in kindergarten at the time, because this might have been the Holy Grail of psychiatry. Forget talking to the person; just give me a blood test where I can diagnose this, and then psychiatry could be another branch of, like, chest-thumping medicine and not have to be embarrassed anymore. Aha, the DST—that's going to be the diagnostic test. You give somebody the DST, and you see if they keep secreting glucocorticoids, and that's how we're going to diagnose the disease. We never have to talk to somebody with depression again. And of course, that turned out not to be remotely specific enough; there's other psychiatric disorders where you get a problem. Disappointment, all of that. By first grade, I had come to terms with it. Nonetheless, what you see with the glucocorticoid system is, just as in the brain, your hormonal system is suggestive of chronic depression: chronic activation of the stress response.

Now we move to our final hormone system, and the one that is probably most interesting here to lots of people, which is ovarian hormones. Steroid hormones coming out of the ovaries, like estrogen, progesterone, are super relevant to depression. How do you know? The first evidence comes from just demographic studies, epidemiological studies: women are about twice as likely as men to have a major depression. They're not twice as likely to have bipolar disorder, manic depression—totally different disorder; we're not talking about—but about two to three times the rate that men do, cross-culturally, all sorts of societies looked at. Whoa, why are women so vulnerable to depression? Maybe they're not; maybe there's all sorts of confounds there; maybe women are more likely to go and seek help for a depressive state that turns out to be the case; maybe women are more likely to be able to do the reflection on emotions needed to sort of come out the other end, and reflection is part of what gets them in there in the first place. We will see more about that. Maybe there's something else going on, and this has always been a confound in the field. A lot of people who have major depression self-medicate because they haven't been diagnosed; nobody's given them meds, and a way to very temporarily deal with your depression is with alcohol—temporarily, because you're going to be worse off afterward than before you started. Men have higher rates of alcoholism; maybe a lot of men who were classified as alcoholic what they're actually doing is self-medicating a depressive disorder. Go into insanely careful cross-cultural epidemiological studies, and what you see is women are like two to three times more likely as men to have a major depressive disorder.

Okay, so how can you begin to explain this? We can try to do this on a level of social behavior, socialization, and you begin to see a very relevant sort of first array of sex differences right off the bat: a difference. Males, men tend to become more at risk for depression in circumstances where they are lacking control in their lives. Women, in contrast, are more likely, on the average—when they are lacking social support. Women get more of their sense of self-esteem and self-worth from their social connections than, like, what their salary is in the corporation. You see differences like that; maybe that's got something to do with it. You see differences in other realms: on the average—not everybody—but on the average, women are more sensitive to social rejection than are men, and that's certainly relevant to a lot of this. There are other aspects of it, and this is like one of the great ironic findings in the whole field: social support. We're going to hear about that; social support is helpful to buffer from depression. How about marriage? And what you see is, like, men who are married are more resistant to depression than are men who aren't married—cool. And then you see women who are married have higher rates of depression than women who are not married. As it has been said, from a neurochemical psychiatric standpoint, marriage is toxic for women and protective for men.

Okay, so all these possible hints as to why you have different rates, having to do with social environments. Then there's temperament, cognitive stuff: women, on the average, are much more ruminative than are men; they are more likely to get caught up into loops of negative affect. Men, on the average, are much more likely to use an avoidance strategy: "I don't want to think about it; I don't want to talk about it," he can't talk about his emotions, whatnot. And that is a consistent sex difference in populations by sex, on the average, all of that rumination puts you closer to that edge of just getting mired in the quicksand of rumination. So that's a possibility. So, let's look at how much control you have in society and how much social support and how ruminative you are and prone towards anxiety, because women have much higher rates of anxiety as well. So all of that. But then let's look at the biology, because all of those ovarian sex hormones are doing all sorts of interesting stuff in the brain. Where does the biology come in? First off, estrogen. Estrogen makes some parts of the brain more sensitive to some of those stress hormones, and this one part of the brain—don't write this down—the locus coeruleus, that responds to the stress neurotransmitter called CRH. CRH can make the locus coeruleus depressed, and estrogen makes this locus coeruleus area relevant to psychomotor; it makes it more sensitive to this neurotransmitter. Lots of estrogen around, and the same amount of CRH is more depressogenic on this part of the brain. Whoa, maybe you could make a drug that would block the effects here. And people went and looked, and all sorts of rat studies, and the conclusion is, "Nah, not really." There's an oopsy in that literature, which is virtually all of the studies were done on male rats. Ooh, my bad; a little bit of a problem there. All of them should have been done on female rats, because estrogen is very powerfully potentiating this pathway.

Okay, so estrogen does that. What are the things that it does? Meds: various antidepressant medications work to different extents in different genders, depending on hormone levels, things like that. So we got some biology going on there. Then go and look at people's genes; look at people with and without depression, females versus males, and what you see is there's about 50 genes that go in opposite directions of activation: 25 of them are turned on, 25 of them are turned off, but where it's going in opposite directions depending on whether you are looking at a man with major depression or a woman. There's differences in genetic regulation. Now, in lots of ways, the thing that most screams biology with the sex differences is it's only certain times of life where women show higher rates of depression than do men. Now, what this immediately brings us into is the menstrual cycle and menses, menstruation, and jargon: premenstrual syndrome. What is clear by now is it's perimenstrual; it's the time just before and just after, rather than only after. And what one sees is most of what has been thought about premenstrual changes in mood and stuff are myths in terms of the magnitude, the amount of mood changes. There are about the same as in men over the course of, like, an average month or two; it's just that it's coupled to this time period. And what you see is all sorts of suggestions that premenstrual syndrome—your average person has some degree of anhedonia and some degree of rumination—and then you get severe premenstrual syndromes rather than just symptoms, and these are people where everything is completely thrown out of whack. All along there have been all of these great social anthropology theories about what menstruation is about and why people feel sad; then it's because you're in a culture that's uptight about sex, and if you went to some cool Polynesian culture, you never see perimenstrual mood shifts. It's all over the planet. And what really tells you that we're looking at biology here is you look at a female baboon, and her likelihood of social interactions goes down when she's menstruating; she becomes socially withdrawn at that time. She sure does not know about whether her culture's ethos is about being, like, sex and bodies are beautiful or they're uptight and sinful. We're not the only species that shows a perimenstrual decrease in positive affect.

Now, the other time of life where you see a big increase in the incidence of depression in women—a much higher rate where it goes through the roof in terms of comparison to males generally—is after giving birth: postpartum depression, in the days, weeks, months afterward. A subset of women fall into major depression at that point. Now, what's going on there? The first thing is the mythic versions: it used to be stated—and I stated this in my sleep, in my lectures—that the period after giving birth is the time of life when humans are most at risk for major depression. That turns out probably not to be the case. The postpartum period is the time of life where humans are most vulnerable to their first episode of major depression; that appears to be the case. And what does postpartum depression look like? All sorts of things: in brain scanning, and you hear the voice of your baby, and you don't secrete dopamine; you hear your child that's crying, and you don't get changes in your pupillary stuff and your blood pressure. It's detachment; it's that. So what is postpartum depression about? There's some hints out there having to do with another hormone that comes out of the ovaries along with estrogen: progest-estrone, progesterone. You secrete tons of during pregnancy; it is progestational. And what happens right around the time of giving birth? These extremely high progesterone levels go crashing down right after birth; they go crashing down like a thousandfold change in the level in your bloodstream. And there's some major hints out there that a subset of people who are vulnerable towards postpartum depression, where this happens to them, birth and pregnancy after pregnancy, and this is what was going on with Andrea Yates with her psychotic depression, drowning her children. There's a lot of evidence to suggest these are people who have a bigger drop of progesterone than average and/or have their brains be more sensitive to a drop in progesterone. And this has given rise to the newest drug in treatment of depression; it was just approved a month ago—this right now is August 2023—a drug called zuranolone. No, I've got to look it up because I had to write it out. Oh, I've just ruined all my—oh, that is what it's called: zuranolone. Okay, this was news to me because I don't know much about the postpartum part of the story. Zuranolone, zuranolone, every—it was up this by now; it was just in the news. It's the first antidepressant that was approved by the FDA for having effects specifically for postpartum depression. It has a drug that works a little bit like progesterone on the brain, and people are just beginning to figure this one out. More hints in terms of postpartum depression: people see all sorts of folks who have normal levels of progesterone, yet they fall into postpartum depression, and you see they've got variance of their genes related to estrogen, estrogen receptors, progesterone receptors, things like that, where it's different than most other people. So there's genetic vulnerability there. Over and over and over, what we're screaming here is biology, biology. And what you see is every neurotransmitter system you could think of—dopamine, serotonin, norepinephrine, glutamate—is affected by estrogen and affected by progesterone, and they are ways to tap into every synapse relevant to depression.

One other biological piece of it: inflammation. People who have chronic inflammatory disorders are more at risk for depression. Well, no wonder. You got some crappy chronic inflammatory disorder; you control—you compare them to people with some other chronic disease that's just as awful and disruptive—and inflammation in and of itself puts people more at risk for depression. You give people drugs that mimic aspects of inflammation, and this is done for some cancer patients, and they catastrophically fall into major depressions. You look at the brains of people with depression postmortem, and you see markers of chronic neuroinflammation and some interesting parts of the brain. So you have evidence that inflammation can increase the risk of depression, and then you see that depression increases activation of the inflammatory system. You've got a vicious cycle there, very similar to what you see with glucocorticoids and stress. Elevated glucocorticoid levels; you give somebody a lot of artificial, synthetic glucocorticoids for some disease; they're more at risk with depression. You get a disease called Cushing's disease, where you're secreting way too much glucocorticoid; you're at risk with glucocorticoids. And stress can cause depression; depression activates the secretion of glucocorticoids—a loop there all on its own. And what you get is, after a while, you transition from major depressive episodes tend to come after periods of extreme stress, trigger this, and what you begin to see—oh, another major stressor—and somewhere around the third or fourth major stressor triggering a depressive episode, you begin to see the system running on its own; it runs with its own internal, endogenous rhythm—jargon for what goes on there. This is called kindling—kindling, like firewood that you set fire to; that burst. This is when the relationship between stress and depression suddenly kindles and takes off on its own. Now, in much the same way, what you see: inflammation chronically can cause—inflammation can cause depression, and depression activates the inflammatory system—once again, a loop there. You may be wondering this digression I just had into glucocorticoids and kindling; that's because I suddenly remembered I forgot to mention in the previous section, so, like, record the last two minutes and splice it back into there. But what we see is another example of a vicious cycle where the peripheral biological aspects of things aren't great, make depression more likely, which produces more of that biological profile in your body. Couple other things: your gut, the bacteria in your gut has something to do with risk of depression; people are doing all sorts of interesting stuff on that, and for some reason I always fall asleep reading those papers.

Okay, what have we gotten to now? Ending the first of these two lectures, we have now learned about the neurochemistry of depression and the neuroanatomy and the circuitry and the neuroendocrinology and the neuroinflammatory aspects, and at this point you are a card-carrying biological psych-psychiatrist because you've got all this knowledge about every contemporary bit of biology relevant to this disease. And at this point, if this is all you know, you're going to get nowhere in really making substantive, sort of, advances in treating somebody's depression, because what we've seen here is only one half of the story: the biological components, all of the stuff we've gone over. And the next lecture of this pair: how it interacts with the psychological components of depression. If you're not studying the interactions between the two, you are never going to get a fundamental understanding of this disease. So if you're still interested in this pair of lectures, the next one is looking at psychological aspects of depression, and most importantly, how these two bodies of knowledge interact in an amazingly interesting way in explaining what's going on with depression. So perhaps we will all resume after I get a snack.

Welcome to the second part of this talk. Now, one of the occupational hazards of professing stuff and lecturing is you go through a whole lecture, and then it's 2 in the morning that night, you suddenly remember, "Oh, I left out this or that in the lecture today," and I've messed up. And this is what we dread. And of course, after finishing the previous lecture and going and eating some cookies or whatever and saying, "Oh, no, I left out a whole section," which I will touch very briefly here, after going through everything before: the neurochemistry, neuroanatomy, neuros-circuitry, neuroendocrinology, neuroimmunology, all of that—um, I was going to briefly discuss: so what were the effective treatments around these days that address the biology of what we just learned about depression? And that's the array of standard drugs: SSRIs, like Prozac; drugs like Wellbutrin; other ones that are boosting up serotonin signaling, norepinephrine signaling, dopamine signaling. This drug that's supposed to only work on this system turns out to do a little bit on this one; people are still sorting it out. You give people combinations of multiple drugs, orchestrations, to try to address all three of these systems, or ketamine, and addressing that other glutamate neurotransmitter. So these drugs are there, and they are miraculous when they work, and as I noted at the beginning, about one-third of people are treatment-resistant to any of the conventional drugs. And of the people who are responsive to antidepressant drugs, about half of them have to stop because the side effects are intolerable. And so, yeah, hooray for drugs—um, it's limited; it's limited as to how much they can do; they don't cure every case, not even remotely. Then there's this whole realm of, like, untraditional antidepressants that people have been working on: ones that block the stress response, ones that block inflammation, ones that do something or other to how your gut is working, ones that replace thyroid hormone. Collectively, each one of these—people are totally excited about—none of them have hit the big time yet; they all have some effects; they help a little bit; they help with this type of depression more than that type, all of that; they, at this stage, are still second-tier.

What other treatments? You get someone who has been resistant to every type of medication you've tried out there on their depression, and they're really, really depressed, like they're hospitalized because they're not functioning anymore, and you get really desperate at this point, and you look into the next line of defense against depression: ECT, electroconvulsive therapy, electroshock therapy. Eighteen seconds on its history: it's a treatment where you zap people's brains with electricity. Scientists, doctors stumbled into it purely by chance that it had antidepressant effects. And during its heyday, when people were so excited about it, they were using way too much electricity and too many rounds and doing it to people they had no business giving ECT to and causing all sorts of brain damage and memory loss. And some years ago, people in Berkeley—on the other side of the bay for me—who believe in all sorts of nonsense and debris that I deeply agree with, even attempted to have a referendum that would ban ECT within Berkeley. ECT, in its modern form, you do a limited number of rounds; you do not use a whole lot of electricity. I had a big professional investment in showing that ECT caused permanent...

Brain damage, and I couldn't find it. And so what's it doing? Metaphor: it breaks the back of a major treatment-resistant depression. What's it doing in the brain where you zap someone with some strong electrical pulses? There. What's it doing in the brain? Nobody is absolutely sure. ECT has been around for like a century now. It does stuff in the hippocampus; it makes the hippocampus make new neurons, and I was so excited about that. Is that part of the story? Who knows? It does everything to every single neurotransmitter we heard about. It's very effective for desperate, severe cases, and we still don't really understand how it works.

And I have a close friend who's a psychiatrist who said every time he gets a patient who is severely depressed and he looks at them and says, "Okay, before we're over with, the only thing that's going to help this person is ECT," they are so frustrated because they have to waste 6 months of trying out the various meds on them, which they know are not going to work, until they can conclude the meds didn't work. Okay, let's try ECT. He is crazed by how, on the average, there's months of additional suffering before this could come in. Amid that, ECT has a horrible reputation: Jack Nicholson, *One Flew Over the Cuckoo's Nest*, a history of being abused. In its modern version, it is safe; it does not cause permanent brain damage. Damage, in most cases—the vast majority of cases—it does not cause permanent memory loss, and it helps for severe depressions, even though, like, who knows what it's doing?

One final realm of contemporary treatment, and this is a realm encompassed by: you put an electrode into a part of the brain and stimulate it so it becomes more active than it would be otherwise, like the mesolimbic dopamine system. You do something that is called DBS, deep brain stimulation; that's one cutting-edge approach. Another one: you essentially do the same thing with magnetic waves on the surface of the skull—transcranial magnetic stimulation, TMS. And another one: there's a nerve going into the brain called the vagus nerve that stimulates there. These are exciting; these are some new approaches. Tons and tons more work needed. Once again, in the framework of: 15% of all the people in the world will have an incapacitating depression at some point, and all of the stuff I just mentioned—the conventional meds, the new waves of meds, the ECT, these brain stimulation ones—all of that, and only about 20% of people are ever diagnosed for their depression, and of those who are, none of these work in like roughly a third of the cases. We desperately need more treatments.

Okay, so this is where we should have finished the previous lecture, and all this neurobiology stuff that you now know. And if you're one of those people who decided you hated biology in ninth grade, you turned off this lecture 10 minutes into it. You know all this stuff, and my final point was: if that's all you know—the nuts and bolts biology—you're really not going to understand this disease because you have to integrate it into the psychology of depression. And a great way of framing this is: you're not going to understand how a part of the brain works, or a single neuron works, or a single synapse works; you're never going to really understand it if you don't consider it in the context of the entire brain and the person in whom that brain sits and the society in which that person sits, because all of those factors—psychological, cultural, etc.—all of those impact every one of those synapses. And that's where we're going to see our integration between the biology of depression and the psychology of it.

Now, the realm of the psychology of depression: people have thought about for a long time, and God help me from mentioning his name, Freud had some really interesting, insightful, moving things to say about depression, mid all the other problems he caused. Um, but Freud—a famous essay of his, *Mourning and Melancholia*. Mourning: you mourn someone. Turn-of-the-century Viennese term for what we would all call a reactive depression: something bad happens, you get depressed for a while, you recover. Melancholia: old Viennese term for what we would now call a major chronic depression. What's the difference between the two? Because that's the question started with all of us. We mourn at times, and a large percentage of us wind up coming at the other end; we heal. What is it about the subset of us who instead fall into Melancholia, fall into major depression? And Freud's explanation was built on all sorts of fori and nonsense that nonetheless kind of has a right intuitive feel to it. So Freud—according to Freud—we have loved object; objects, people we love, ideas we love, whatever. We have loved objects, and Freud—inevitability—we have mixed feelings about them; we have a love-hate relationship with our loved object; we are—we have ambivalence about them, all of that. So in Freud's thinking, you lose a loved one, you lose a love object, someone has died, whatever, who really matters to you, and Freudian sort of requirement: you have mixed feelings about them, and love-hate, and all of that. And most people, when they are in this period of mourning their lost one, what they're able to do is put aside the negative feelings, the hatred, all of that, and just focus on the love. And by focusing on the love that you can focus on, then by doing that, that is how somebody comes out the other end and heals. Where does major depression come from? Where does somebody lose a lost someone and fall instead into Melancholia? In Freud's view, these are people who are not able to put aside the anger and the hatred and the negativity and not be able to experience the pure love you felt for them. Instead, the ambivalence is still going on, and his view, that's where somebody doesn't heal; that's where somebody goes into a major depression. Lots of ways in which that just feel—feels right, but it's very hard to do modern biology on it.

And one of the really sort of interesting ideas that Freud came up with about depression is: depression is anger turned inward. And you've lost a loved one, and you loved him, but you hated him, and you're all this ambivalence, and all of that, and you've just lost the opportunity to ever tell them the things you wanted to, to ever hear them say what you always yearned for, all of that, and you love them, and you're angry at them, and all of that, and you love and ha, and all of this is going on inside. No wonder you're chronically activating the stress response, and it's hard to get out of bed in the morning. Something about this Freudian formulation just has a right feel to it, but nonetheless, you cannot figure out what like ratio of love to hate have to do with ratios of estrogen to progesterone. It's hard to do modern biology. Where we get the most insights into the psychology of depression—contemporary insights—is by looking at the role of stress. Now I've already said stress a whole bunch of times in here: stress in the endocrine sense, stress in the neurochemical sense, all of that, stress in the psychological sense. And when we begin to see—see first is the epidemiological evidence: major stressors at a very higher than expected rate precede somebody's first depressive episode. They come out the other end of it, and they're likely to be fine for the rest of their life, just like everybody else. Have a second major stressor a week later, a decade later, who knows what, and they fall into a major depression. Have a third one: major depression. And it's around that point that it begins to run on its own, when the kindling occurs, when you're stuck in this vicious cycle, and you don't see a major stressor being the precipitant of depression anymore. So that's one way of seeing where stress comes into it: stress is a major, major predisposing factor towards major depression, especially stress in childhood. And all sorts of studies showing things like loss early in life: lose a parent to death while you were still a child, and when studies show is: for the rest of your life you are now significantly more at risk for major depression. Stress can plummet you into a depression; stress can set you up with the brain now where, for the rest of your life, you're a little bit more at risk.

Now, what's this about stress? Stress because lions are chasing you, stressed because of tornadoes, all of that. What we're talking about mostly is psychological stress, and we have entered here a very, very primate realm because we primates specialized in psychological stress. I spent 33 summers studying wild baboons in East Africa trying to understand who had the best stressed-he responses and the healthiest bodies and what it had to do with this or that. And baboons were great to study; they live in these big, complex social groups, and they got giant teas that the lions mess with them maybe once a year, and they only have to spend about three hours a day getting their day calories foraging, all of that. And what that means is your average baboon has nine hours of free time every day for generating psychological stress in somebody else: harassment, dominance interactions, pity, displacing of aggression because you're in a bad mood. They are all about psychological stress, just like us. Again, we have the Westernized luxury of spending most of our days feeling stressed not by tree predators but by psychosocial factors. And what you begin to see then is psychological stress is an entity all its own. Like, cut somebody's arm off, they're going to have a stress response; you know, starve someone, they have a stress response; chasing with a machete, whatever physical stressors—reptilian brain, all of that from before—psychologically stress somebody, and your brain and body can do the same thing. And this is our first steps towards: lots of psychological stress producing a disease—depression—in which a lot of your parts in your brain and a lot of your hormones look as if you were chronically activating a stress response. So, of course, this brings it to: what makes stress psychologically stressful? What is it that constitutes psychological stress for the same external reality? What are the mediators that make some of us more likely get stressed? What is psychological stress? And some beautiful, elegant studies going back half a century have shown exactly what the building blocks are of psychological stress: lack of control. You take a rat who has been lever pressing, and it gets reward, and lever pressing, and it doesn't get a shock, and it's on top of its great, and suddenly the lever stops working; it has lost control, and it has a massive stress response. Same thing with college freshmen in Psych 101 who come in and volunteer, and they're doing a lever that makes it less likely that they get some mild shock, and the lever stops working, and they get a stress response. Loss of control; loss of the sense that you are the captain of your ship in any sense at all. And what you see is: you take people now where volunteers, and they get a shock every now and then, and you tell them by pressing this lever you're less likely to get a shock; it doesn't actually do anything; you still get the exact same frequency, but because they feel like they have control, they have less of a stress response. Next building block of psychological stress: loss of predictability. When a stressor comes along, you are much more up the creek in terms of feeling stress, secreting stress hormones, etc., etc., if you don't know when it's going to happen, and you don't know how bad it's going to be, and you don't know when it's going to end. And thus really like insightful studies where you take somebody and they get a shock now and then; each time they get a shock they turn on stress response, but then give them predictive information 10 seconds before each shock—a little warning light comes on—and they don't have as much of a stress response. A sense of control; a sense of predictability. What are the other building blocks? Lack of outlets. You are at the bottom of a hierarchy, and you were getting dumped on left and right, and what you see there is: you can't dump on anybody else, and you don't have outlets, and you don't have social support, and you don't have—what does that look like in a baboon? If you were a low-ranking baboon, you lack control, you lack predictability, and you lack outlets because somebody beats on you because they're in a bad mood, and you really can't go over and tell somebody else you feel badly; could they groom you? Nobody grooms you; nobody will have sex with you; you can't beat up anyone smaller because you're the smallest ones there. And interestingly, what many years of work on my part showed that if you a low-ranking baboon in terms of stress hormones and physiology and all of that, you bear a lot of resemblance to a clinically depressed human. So lack of outlets; implicit in what I've been saying all along: lack of social support. Have somebody's shoulder to cry on, or studies as like straightforward and reductive as something: stress—all shocks now and then—and you get to hold the hand of somebody you know and trust, and you don't get as much of a stress response. All of this feeding into all the stuff we heard before: in men, depression is disproportionately about lack of control; in women, it's disproportionately about lack of social support. It's about—always one of the big four—there are all of them: lack of control, lack of predictability, lack of outlets, and lack of social support. And the same external misery is far more likely to make you activate a stress response, and the same external misery under those circumstances, if it happens enough times over and over and over and over, is more likely to make you fall into a major depression. Depression is a disease of chronic psychological stress, and enough of it over the years, and eventually kindling happens, and the system runs on its own.

Where does this fit in? The way to conceptualize psychological stress is this extremely powerful model of depression called learned helplessness. And we go back to our scenario: you got the rat that's getting shocks now and then, but it's pressing a lever, and it's fine; it's preventing the shocks, and it's great at efficacy and agency and all of that, and suddenly the lever stops working, and you get the rat go into an anxious phase where what's going on in his body is just like a human having an anxiety attack and all of that, and it's trying to cope; it's pressing the lever 10 times more than normal, and it's pressing the lever with its feet, and it's pressing the lever while wearing its lucky socks and all, and it's just attempting to cope, attempting to cope, and the shocks keep coming, and the lever does nothing, and eventually the rat gives up; it has become helpless; it has become hopeless. And what a lot of people think of as the transition of anxiety preceding depression is that transition into crazed maladaptive attempts at sort of coping and vigilance 24/7 and not recognizing when you're safe and all of that into: there's nothing I can do about it, and helplessness. And what you see is: when you produce an animal version of learned helplessness, you get depletion serotonin and dopamine, and antidepressants could be protective, and that's one of the pathways to it. So what we see here is: stress—lots of stress—stress early in life, especially psychological stress, sets you up for increased vulnerability forever after to major depression. And we see what it's about in terms of the psychological, cognitive comp components is this transition to: why even bother? It's hopeless; I'm helpless. And it's here that we get some insight into the type of psychotherapy that is most likely to succeed with major depression: CBT—cognitive behavioral therapy. What it's about is exactly what we talked about before: depression is a cognitive overgeneralization. Yes, that awful thing did happen to me back when; yes, I failed; yes, they abandoned me; yes, I was unloved, whatever. But most of us mourn and come out the other end; most of us can do reappraisal; most of us would—we come out and we say that was awful, but that's not the whole world, and that's not the rest of my life, and you can build a wall about it. And what we saw was: in lots of ways, to impressive cognitive distortions is: you decide the reality back when has no walls, and it just spreads, and this is inevitably your present and your future and all of that. And this is the picture of psychological stress getting to the point where you've learned to be helpless. Yes, I lacked control then; I lacked outlets; I lacked predictability; I lacked support. And this transition to overgeneralizing into this being a globalized view—this is sort of the cognitive pathway into a major depression. And what cognitive behavioral therapy tries to do is break that pathway: say yes, yes, yes, that was awful; no one is denying that; why it's valid; it is appropriate for you to feel devastated; that that has shaped you, all of that, etc., etc. But did you notice you did this thing the other day, and that terrible outcome didn't happen? It's not inevitable. And try this; try this tomorrow; one where you're convinced it's going to be a disaster because of back when, and try, and maybe it won't happen. And you slowly begin to learn the ways in which you were cognitively overgeneralizing and distorting, and you were gradually being given the tools by the therapist as to what are the best ways of keeping a wall around it and doing reappraisal: that was then; this is different now; all of that. And this gives you a lot of insight into why early life stress sets you up for increased risk of depression ever after. What is a lot of childhood about? What is a lot of adolescence about? It's you learning what things you can and can't control in the world out there; how much efficacy you have; how—how much agency. And if you spend your childhood mired and lessons of: you got no control, you got no outlets, you got no predictability, any of that stuff; if you spent childhood being trained to be helpless, no wonder for the rest of your life. And in lots of ways, that explains one of the strongest predictors of major depression: childhood low socioeconomic status—poverty. If you want to socially subordinate someone, like no non-human primate could ever dream of inventing hierarchy and invent unequal distribution and invent poverty, and poverty for kids is a grinding, permanent lesson in helplessness, and that's one of the biggest predictors of falling into major depression later in life.

Okay, so how do we put all these pieces together? How do we get from psychological stress—loss of control, loss of predictability—to your lateral habenula, if you remember that term from before, starts doing something screwy? What you see is: stress, especially early life stress, when you secrete lots of those glucocorticoids, they have all sorts of effects on the developing brain. Lots of stress early in life, and you make fewer dopamine neurons in your mesolimbic dopamine system as an adult; you are more vulnerable to anhedonia. Lots of early life stress, and your amygdala is going to be bigger and more hysterically hyperreactive, and thus more likely to access the default mode network, and you were just ruminating on negativity and get into the mesolimbic system. All that early life—a lot of what you're doing is learning how much control I have over the world; learning how much control I have over the world translates into: your amygdala is going to work differently, and your mesolimbic system is going to work differently. And we even know like how that works—why this part of the brain gets bigger, why this prod is going to be more sluggish forever after. This is where all of that psychological stuff turns out to have exact parallels in all of that nuts and bolts biology we're hearing about before; we're beginning to see hints of how they integrate.

Final piece that shows us just how dramatically we can think about the biological and the psychological intersecting now. In the previous part one of this lecture, we talked about hormones; we talked about neurotransmitters; we talked about brain structure; we talk about all this stuff. One biological thing we never got around to, you may have noted, is: we never talked about genes. What do genes have to do with depression? Because it turns out major depression runs in families: greatly increased risk if you have another family member. You look at adoption studies, and depression risk transfers from the biological parents who didn't raise you, regardless of the depression status of the adoptive parents. Also, what do genes have to do with it? And right off the bat: genes do not cause depression; genes are not deterministic in that way; in the same way that genes determine very few things. What genes do is interact with environment; in other words, in different environments, the same gene works differently; the same variant, the same flavor—ice cream flavor—of this gene works differently. And here's where we get a massive insight: a way of saying that a gene has different effects in different environments is saying that its effects are context-dependent. And one of the most important studies ever done as biological psychiatry showed a magnificent version of this. This has to do with a gene that codes for something: 5-HTTLPR. What—what is this coding for? The serotonin and re-uptake pump. Back to the last lecture: remember release serotonin and buzzes there, and you give somebody SSRIs so that you have less of this happening—less re-uptake—and the person feels better. Oh, you've boosted up serotonin; maybe had a serotonin depletion. And this is the gene coding for that re-uptake pump, and it comes in different flavors—different variants. X percentage of the population has this version; Y percentage has that version. And what you see is: one version is better at removing serotonin from the synapse than another version. Ooh, you now make predictions: there's a vulnerability variant of the serotonin transporter gene, and there's a resistance—depression resistance—version of it. And what you should immediately say is: aha, people who have the bad news gene variant should have higher rates of depression. And this massive study—longitudinal, following thousands of people from infancy into early adulthood—looked at: does the flavor of this serotonin transporter gene—does your flavor of it—influence your likelihood of depression? If you've got the bad news—vulnerability—one, are you more likely to have a history of major depression? And the answer was not necessarily. Overall, in the population, which version you had had no effect on your depression risk. And now comes in the context dependency—the interaction and environment. Having the bad news version of that gene when you're just sitting there having a perfectly mundane life doesn't increase your depression risk, but if instead you have a history of abuse during—during childhood—childhood adversity, the more adversity there was in childhood, the more having the bad news version puts you at risk for depression. In other words, having the bad news version doesn't put you more risk of depression; it puts you more at risk if you suffered—suffered huge amounts of childhood abuse. In that environment, this variant sets you up for the biology that we've learned about. What this is telling you is: this is a way of putting together hard-ass biology—genes and environments—psychological stress, loss of control, predictability, childhood adversity, and hard-ass biology and adulthood and all of that. And what you see here is: this is where the pieces come together of huge importance. It turns out that glucocorticoids affect this gene and affect them differently depending on which flavor you have, and thus you can get permanent changes in the working of this if and only if you've got glucocorticoids because of abuse, all of that. This is an environment-gene interaction model. Important thing: this particular finding has been mired in controversy; all sorts of people saying it's an artifact; it's not really true; here's how they analyze their data wrong; other people—replications out the wazoo. I love this finding, and I think it is absolutely legitimate and solid, and all the sort of challenges to it, I think it is held up. And for my money, one of the greatest things that reinforces that this thing is for real: in that monkeys come with multiple versions of this gene, and monkeys have adult versions of depression, and if you're a monkey with the same bad news version of this gene that we—some of us—have, are you more at risk for depression? Only if you had an abusive mother during childhood—the same exact interaction. And my bias is: show the exact same thing in another primate, and you're seeing the real thing going on there. This is for real. Whether or not this particular finding replicates solidly, uh, what you see is: by now there's a whole bunch of genes that have been implicated—genes implicated in the stress response, genes implicated in the birth of new neurons and the construction of the brain—a whole bunch of genes where they come in different versions, and a priori sitting there, this version looks like it might be the bad news version—better, worse—than this other version. And in all…

Cases the bad new, ver bad news version only is manifested if it's coupled with stress early in life, that sort of thing. So what we're getting to at the end here is a vulnerability model: biology, genes, genes not as destiny, genes not as inevitability, but genes as potentials, genes as vulnerabilities. In this case, you have a genetic vulnerability towards depression, and if life is hunky-dory from there, you never have consequences of it. But if it's coupled with lots of stress, particularly early in life—when you're putting together your dopamine system and your frontal cortex and all that sort of thing, when you're building the system—lots of stress early in life, with abuse, with childhood adversity, and it's then that that gene variant is going to have effects forever after on all the little pieces we've seen here. This is where the psychology of stress, especially psychological stress, especially psychological stress early in life interacts with all the biology we've seen here.

So what have we gotten to at the end? The same points I emphasized from the very beginning, which is this is a biological disorder. We've just spent like two hours looking at the biology of it and how it interacts with psychology. This is biology; this is a real disease. Somebody with diabetes isn't babying themselves. The other thing, theme that came through all of this, is again the song and dance: you know, I can wear a lab coat and pass for just thinking about this end of things. If all you're thinking about is the biological part, you're not going to understand what's going on. Moreover, if all you're thinking about is the psychological part, blah blah—the same exact thing. This is one where you have to look at the interactions between biological vulnerabilities, environmental triggers, environments that teach you efficacy or coping strategies or give you lifelong abilities to get social support and things of that sort—the interaction between the two.

The most important point about these lectures, these two, is one that comes out of the: it's real biology. You don't tell a diabetic, "Stop it with the insulin stuff." What you see here is major depression, like every other psychiatric disorder out there, has a massive social stigma. Being mentally ill has a massive stigma, and it terrifies the crap out of us, getting that label, and we recoil from people with that label. And we are only talking about best estimates like 30% of humans have some sort of psychiatric disorder at some point or other, with depression and anxiety at the top of the list. Oh, this is not about them and their diseases, their mental illnesses; this is about all of us and our loved ones and people we encounter every single day. This is a ubiquitous feature of the human condition. And if we're capable, with our human brains, of knowing we will die someday, if we're capable of imagining awful things happening to those you love, if we're capable of any of that stuff, no wonder we're the species that is most vulnerable to depression and anxiety. Punchline there: biological disease. If this is you, you are not alone. If this is you, get help, because you have one of the most life-threatening diseases out there. If this is a loved one around you, take everything you've heard in these last two hours and do something to turn this from a stigmatized mental illness problem to: here's the biology of what's going wrong, and get them help, because most people don't get it. So, on that note, thanks for your patience and good luck for dealing with some of the challenges of life that we appro—with that we approach with primate brains, for better and worse.