Robert Sapolsky: The Biology and Psychology of Depression
(gentle music) – Hi, my name is Robert Sapolsky. I’m a professor of biology, neurology, and neurosurgery at Stanford University. 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 years since
five million views or more for this lecture, suggesting it’s useful. Bad news, five 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 and considerable detail. Sense of what we’re up against, World Health Organization, says 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 worse news, about 80% of cases are never diagnosed, and of those that are approximately 1/3 never respond to any medication, approximately 1/3 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 artifact 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 adolescents. With each passing year, more
teenagers being recruited into the lifelong cohort of people struggling with depression. It’s just so it is 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 as
one of the biggest predictors. 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 poll 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 and pull yourself together
and stop babying yourself and don’t indulge yourself.” Saying that to somebody
with a major depression is like sitting down somebody
with diabetes and say, “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 about 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
multi-syllabic terms down cold, and if you don’t incorporate it with the psychology of depression, you are 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 compromised, 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 where, 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 as 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 for 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. For the next day, I just
felt kind of moody.” 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 mally 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, and hedonism, the experience of pleasure, anhed tells you this. Anhedonia, 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 empty ink. 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 imagine wrongs you did at some point, a sense of guilt, and 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, oh, what’s depression about
is 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, depression involves cognitive problems, people’s focus go off 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 as 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, it 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
distort over generalize the negative into a worldview. As Beck termed 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 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 one, and where the eyes go, and a fraction the 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 and 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, and 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, they’re more accurate,
they’re more correct, and this is given rise to
a soundbite in the field. Sometimes people with
depression are sadder but wiser. Because you look at your average person and they are on the average,
dilution over optimistic when you ask people what’s the likelihood of this thing happening or this great or that sort of stuff
and you see the 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 distort decided 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 it. 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 we want 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. Psycho-motor, 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, your 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 awakening. 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 anhedonia, 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 appetitiveness,
motivation, appetite, all of that. Like if you were just mired
with endless sad, sad thoughts that won’t stop, sex is kind
of far down in your list. Okay, what else is going on? Of course, embedding 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’s paralyzed with psychomotor retard. This is somebody who has to fight to get out of bed in the morning. They are so much a 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 noose or 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 will get to that
and they begin to get better and in some cases the
psychomotor 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, a person can’t get out of bed,
they’re totally exhausted. 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 and get up
and put on a happy face. Okay, another thing that underlies, 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 on a
continuum, that sort of thing, is the difference between
reactive depression. Something bad happens,
everybody feels crummy and 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 subtypes of depression, there’s a subtype called
atypical depression that is just dominated
by the psychomotor stuff. These are people we’re just
doing anything is overwhelming, they’re less concerned, less bothered with the anhedonia, 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 variance 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 cognitive distorted. That’s not delusional in the
sense of psychotic depression. Some people may remember
this heartbreaking case, this woman, Andrea Yates,
number of years ago, who in a severe psychotic
postpartum depression drowned her children, and it took a number of trials
for somebody to figure out this was somebody with a severe disorder. Why did she drown her children? She was fundamentalist Christian and raised in a school of
thought that merely by birth, her babies were nearly 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 years. 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 where 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 it then comes January, where
everything’s perfectly fine yet for the eighth year in a row they fall into a major depression and need to be hospitalized, rhythms, and it out this seasonal
affective disorder, SAD. 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 the 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 hyper aroused, frantic urchin 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, what depression is is
a big old thick blanket that you threw 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 mats 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 in lots of cases. You are a rat, you are a human, and there are shocking
you now and then whatever. And what the anxiety is about
is you are trying to cope. You try to cope elevendy
different ways at once, most of which you’re
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 you 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 of 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. Here’s some exciting gossip
and it gets all excited. A cells version of getting excited and in turn passes on the excitation to the next neuron in line. The gossip spreads. And 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 names, 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 called
neurotransmitters. And they’re going to be
real pertinent very soon to making sense of major depression. Okay, little bit of housekeeping stuff, ’cause 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 terrific. 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, the 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 that breaks the neurotransmitter down and you toss it in the 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 that
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 and
excitatory neurotransmitter or an inhibitory neurotransmitter. And then afterward you clean up either with re-uptake 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. 25 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 antidepressant drugs work on serotonin. 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 synapse and it would normally be taken back up, but what something like Prozac does is it blocks the re-uptake pump. What happens then? There’s no re-uptake 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 a hundredth 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 buzz 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. So serotonin, hypothesis, the problem in depression is too little of this neurotransmitter. SSRI’s selective only working
on the serotonin system. That’s not actually true, but we will pretend that for the moment. Blocking re-uptake, 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 re-uptake 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 born fools rushing 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 and is
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 and was seen 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 antidepressant. 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. 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 this stuff. You’re short of norepinephrine and what happens instead is you fall into the 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 euphoriant 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 re-uptake,
they block degradation. Oh, suddenly a person,
there’s not enough dope. 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 ’em
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 ’em in a room
and the 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 had lots of practice at that. light comes on, work, reforward, 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 this signal comes on. What’s that about? When is dopamine being
dumped from these neurons when the signal has come on and the person or rat signal you’re 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 do you specially have is a loss of these spiky bursts of
dopamine that come out. Dopamine is always doing
a certain background thing with its 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 this lecture. 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 and 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 antidepressant. 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. Alright, 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 are ruminating on
did I leave the oven on, did I leave the oven on? Do I need to get the
utensils perfectly straight? In both cases, somebody’s
feet just stuck in a fly trap 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 the 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
are 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 their problems? Where are their 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 or the evidence that there’s
something weird going on there. And then this part of the brain and 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 here to learn about this. The triune, T-R-I-U-N-E, the triune model of brain function, the three layers of brain function. This was a guy, Paul MacLean
pioneering guy 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 and 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 mid brain, the brain stem. 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? Is just about regulatory stuff
like little feedback loops. Then on top of it is the second layer, term, the 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 get up to mammals that you have a part of the brain that activates with sexual
arousal, with fear, with anger. You take some will to
be guy in his territory and some other big male
wildebeest shows up and is peeing all over there in a dominant 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 your 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 are 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, ooh, 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 parole, 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 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 cont 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, ’cause 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
rule 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 are
just frothing with emotion, you make terrible decisions. This is why when we’re all emotionally crazed about something, we do some dumb ass 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 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’s 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 ’em 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 and 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 to
simply put into the, meanwhile this other part of the brain, the ACC, the anterior cingulate cortex, totally cool brain area, what does it do? It’s about empathy. As follows, you take
somebody brain scanner and poke their finger with a pin and all sorts of parts of
the brain activates saying, there’s my finger, not my
toe, and that sort of stuff. And the ACC also activates, it codes for representation of pain. Now take someone, put
’em in the brain scanner and don’t poke their finger with a needle. Make ’em 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 in 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 cortex. And what’s going on in
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 cingulotomy to
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 note is 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 exam, 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 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 antidepressant. 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 futzing with some of the others with slower acting medications
and it takes days to months. Suddenly lateral habenula
and glutamate on the back 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 and such. 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 quieter, whatever, and you map things out and just in the next 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 your sense of self going, a sense of sort of autobiographical stuff, that 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 map 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 that’s 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 cingulate, lateral, all of that. You access the circuit that
way and that gums you up and 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. Wait, wait, wait, wait. You got the amygdala is 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 in the frontal cortex,
in the prefrontal cortex, a subarea called the dorsal
lateral prefrontal cortex. What is it good at? It’s good at raking rumination. It’s good at getting your
default mode mumbling in the background to suddenly stop as you sort of focus on
stuff that prefrontal cortex. The DOPFC is really good at
blocking negative thoughts and coming up with
counteracting 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 you 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 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, it brings us back to that
business about stress before. And we are 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 will see about some
of the hormones there. One additional part of the brain, okay? This is stuff in a part of
the brain called 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, there’s a lot of resemblance
to being chronically stressed. Final circuit, and this is one where I am confessing 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 synapsis, at an extreme, neurons even die there. The hippocampus isn’t
able to make new neurons and all sorts of treatments for depression were 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 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
before beyond any hope. Okay, so we’ve just
seen the neurochemistry. We’ve just seen the
neuroanatomy, the circuitry, 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. 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 in 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, a 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 psychiatrist,
is not just the job of, and what’s going wrong
in the thyroid gland is not just the job of thyroidologist, becomes 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 are hormones that come
out of your adrenal gland. But 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 glucocorticoids
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 with. The DST is the standard test for this. The DST was inventing 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 problem, disappointment, all of that. By first grade, I had
come to terms with it. Nonetheless, what you see
with glucocorticoid system is just as in the brain,
your hormonal system is suggestive of chronic depression, is 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 get 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 the reflection is 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 is 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 the 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 than 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-definition 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 sort relevant to a lot of this in there. Other aspects of it and this is like one of the great ironic
findings in the whole field. Social support, we’re 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’re 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
quicksand of rumination. So that’s a possibility. So that’s how much control
you have in society and how much social support
and how ruminative you are and prone towards anxiety, ’cause 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 this stress
neurotransmitter called CRH, and 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
in all sorts of rat studies and the conclusion is nah, not really. There’s an oopsie in that literature, which is virtually all of this 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? The meds, various
antidepressant medications work to different extents
in different genders there depending on hormone
levels, things like that. So we’ve 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 is 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
perimenstrual syndromes rather than just symptoms. And these are people where everything is completely thrown
out of whack with them. All along there have
been all of these great social anthropology theories about what menstruation is about
and why people feel sad. And it’s because you are in a culture that’s uptight about sex. And if you went to some
cool Polynesian culture, you’d 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
embodies, or beautiful, or their 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 general state 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 that 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. Post parturition period is at
the time the life of 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’s crying and you don’t get changes
in your pupillary stuff, in your blood pressure. It’s detachment. It’s that. So what is post parturition
depression about? There’s some hints out there, having to do with another hormone that comes out of the ovaries along with estrogen, progesterone. Progesterone, you secrete
tons of during pregnancy, it is progestational. And what happens right around
the time of giving birth is extremely high progesterone levels go crashing down right after birth. They go crashing down like
a thousand fold changes in the level in your bloodstream. And there’s some major hints out there that a subset of people who are vulnerable towards post parturition 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 is 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
’cause I had to write it out. Oh, I’ve just ruined all my, oh, that is what it’s called zuranolone. zuranolone. Okay, this was news to me because I don’t know much
about the post parturition part of the story, zuranolone. Zuranolone, zuranolone
everybody knows 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 post parturition depression. It has a drug that works a
little bit like progesterone in the brain and people are just beginning to figure this one out. More hints in terms of post
parturition depression. People see all sorts of
folks who have normal levels of progesterone yet they
fall into post parturition. And you see they’ve got
variants 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 glucocorticoid 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 disease where you’re secreting way
too much glucocorticoid. You at risk with glucocorticoids and stress can cause depression. Depression activates the
secretion of glucocorticoids, a loop, they’re 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 the 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, chronic 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 are the 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 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 are going to get nowhere
and really making substantive sort of advances in treating
somebody’s depression. Because what we’ve seen here
is only 1/2 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,
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 at two in the morning that night, you suddenly remember, oh,
I left out this or that and a 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 with everything
before the neurochemistry, neuroanatomy, neurocircuitry,
neuroendocrinology, neuroimmunology, all of that. I was going to briefly discuss, so what are 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 and 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 addressing that other
glutamate neurotransmitter. So these drugs there and they
are miraculous when they work. And as I noted at the beginning, about 1/3 of people are resistant, 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, 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 when working on ones that block the stress response, ones that block inflammation, ones that do something or other
to how your good is working, ones that replace thyroid
hormone and 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 have 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, 18 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 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, the people in Berkeley on the
other side of the Bay from me who believe in all sorts of nonsense and gibberish 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’s 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’re so frustrated because they have to waste six 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’s 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 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 devious 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 on 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, once 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 are 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, et cetera, 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 for mentioning his name. Freud had some really
interesting, insightful, moving things to say about depression, amid all the other problems he caused. But Freud a famous essay of his, mourning and melancholia. Mourning, you mourn someone, turn the century Vietnamese term for what we would all call
a reactive depression. Something bad happens, you get depressed for
a while, you recover. Melancholia, old Vietnamese term for what we would now call
a major chronic depression. What’s the difference between the two? Because that’s the
question we started with. All of us mourn at times and a large percentage of us wind up coming out the other end, we heal. What is it about the subset of us who instead fall into melancholia fallen into major depression? And Freud’s explanation was built on all sorts of Freudian nonsense, that nonetheless kind of has
a right intuitive feel to it. So Freud, according to Freud, we have love to objects, people we love ideas, we love whatever. We have loved objects and
Freudian inevitability, we have mixed feelings about them. We have a love hate relationship
with our loved object. 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 or 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 ambivalences 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 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 ’em and hate ’em, 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 ratios 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 what we begin to see first is the epidemiological evidence. Major stressors at a very
higher than expected rate proceed 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 predispose 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 even to a depression. Stress can set you up with a 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. Stress because of tornadoes, all of that. What we’re talking about
mostly is psychological stress. And we have reentered here
a very, very primate realm because we primates specialize
in psychological stress. I spent 33 summers studying wild baboons in East Africa trying to understand who had the best stressed health responses in 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 teeth that the lions mess with ’em maybe once a year. And we have to spend
about three hours a day getting their days calories,
forging, all of that. And what that means is
your average fat wound has nine hours of free time every day for generating psychological
stress in somebody else. Harassment, dominance, interactions, petty displacement of aggression ’cause you are 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 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, starve someone there and
have stress response, chase ’em 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 of 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 to 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 it’s great and suddenly the lever stops working, it is 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 of 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 ’em 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,
et cetera, et cetera. 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 are 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 are a low ranking
baboon, you lack control, you lack predictability
and you lack outlets, ’cause somebody beats on you
’cause 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 were the smallest ones there. And interestingly, what many years of work
on my heart showed that if you are 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 stressful, 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 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 is pressing a lever and it’s fine. It’s preventing the shocks and it’s great and 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 liver 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 attempt 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 components is this transition to why even bother? It’s hopeless, 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 wouldn’t. 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, depressives 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
have learned to be helpless. Yes, I lacked control
that 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, et cetera, et cetera. 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 it, 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 them. 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 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 spend 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, invent 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 less more likely to access
the default mode network. And you were just
ruminating on negativity, 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 talked 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 it affects
our context dependent. And one of the most important studies ever done in biological psychiatry showed up magnificent version of this. This has to do with the gene
that codes for something. Five HTPP what? What is this coding for? The serotonin 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. Ooh, you’ve boosted up serotonin. Maybe you 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. Then another version, ooh, you now make predictions. There’s a vulnerability variant of the serotonin transporter chain 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 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 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 new version doesn’t put you more at
risk with the depression. It puts you more at risk if you suffered huge
amounts of childhood abuse. In that environment, this variant sets you up for human biology that we’ve learned about. What this is telling you is this is a way of putting
together hardass biology, genes and environments, psychological stress, loss of control, predictability, childhood diversity, and hardass 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 childhood abuse, all of that. This is an environment
chain 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 at the Wazo. I love this finding and I think it is absolutely
legitimate and solid, and all the sort of challenges to it. I think it has 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 are 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, 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, in the construction of the brain, a whole bunch of genes where they come in different versions. An apriori sitting there, this version looks like it
might be the bad news version, better or worse than this other version. And in all cases, the 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, this 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 is 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. Ooh, 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 where 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 approach
with primate brains, for better and worse.
Stanford Professor Robert Sapolsky gives an overview of both the biology and psychology of depression, with the key points being that depression is as a real of a disease as is diabetes, and that you can’t begin to understand depression without seeing how the biological and psychological are one and the same. This is a 2023 update of his 2009 lecture, incorporating scientific advances since that time.
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