Depression

OK, there are all sorts of interesting diseases out there. And lots of them are
quite exotic. You've got elephant man syndrome. And you've got progeria, which is the
disease where you basically die of old age when you're about 10 years old. Then you've
got cannibals eating brains and getting prion diseases. And those are very exciting. And
they're great and great junior high school papers about disease and such. So there are
all sorts of these great made for TV movie disease out there. But when you want to
come to basic meat and potatoes of human medical misery, there is nothing out there
like depression.

Depression is absolutely crippling. Depression is incredibly pervasive, and thus

important to talk about. I'll make the argument here today, a number of things, but one
critical thing being that basically depression is like the worst disease you can get. And I'll
make the argument for that in a bit. It is devastating. It is wildly common. Current
estimate are 15% of us in this room will have a major depression at some point or other
in our lives. So that is not good. What is also clear is it is worldwide. Currently, World
Health Organization says depression is the number four cause of disability on this
planet. And by the year 2025 it's going to number two, after obesity, diabetes-related
disorders. So it is bad news. And it is becoming more common.

OK, so what I'm going to talk about today are seemingly two very, very different
topics, and tie them together at the end. And what the main is if you live inside only one
of those topics, you're not going to understand this disease at all - first topic being what
does biology have to do with depression? Second topic being, what does psychology
have to do with it?

OK, so starting off, first giving a sense of symptoms. Symptoms and right off the
bat, we've got a systematic problem, which is we all use the word depression in an
everyday sense. You get some bad news about something. You have to replace the
transmission in your car. Somebody disappoints you enormously. And you feel bummed.
You feel depressed. You are down for a few days. That's not the version of depression I'll
be talking about. Next version, you do have some sort of large, legitimate loss, setback,
whatever, losing a job, unemployment, death of a loved one. And you are extremely
impaired by a sense of malaise for weeks afterward. And then you come out the other
end. That's sort of what I'll be talking about. But even more so what I'll focus on is the
subset of individuals who, when something like that occurs, falls into this depressive
state. And weeks and months later, they still have not come out the other end.
Terminology - the everyday depression that we all have now and then, that sort of
version. The second one, the something awful happens and you feel terrible for a while,
and then come out the other end, a reactive depression. The third version, where you
are flattened by it for long periods afterward, a major depression. And what you also see
with people with major depression after a while is as doesn't take something awful
externally to trigger one of those again.

OK, so what are the symptoms about? If I had to define major depression in one
sentence, I would say, it's a lot biochemical disorder with a genetic component, and
early experience influences, where somebody can't appreciate sunsets. And that's what
this disease is about. And when you think about it, that is a very sad thing. You look at
some of our major diseases, somebody with cancer, somebody crippled by heart
disease, and you see the most unlikely things out there. You see somebody saying, well,
obviously I'm not glad I'm dying of cancer. But without this disease, I never would have
realized the importance of friends. I never would have reconciled with my family
members. I never would have found my God. On a completely weird level, I'm almost
glad this has happened to me. Humans have this astonishing capacity to derive pleasure
out of the most unlikely domains. What could possibly be worse than a disease whose
defining symptom is the inability to feel pleasure?

- Anhedonia
- Grief
- Self-injury
- Psychomotor retardation
- Vegetative symptoms: - sleep disorder
- appetite disorder
- stress hormones

Thus, at the top of the list, Anhedonia - hedonism, the pursuit of pleasure,
anhedonia the inability to feel pleasure. That is what a depression is about. And you get
someone who has just had some enormous good luck; a long-sought relationship works
out well, whatever. And they feel nothing, an inability to feel pleasure, way at the top
list. What else? Grief - guilt, and that's where we've got the semantic problem again,
which is the everyday sort of depression. Something happens, bums us out, and by
definition we are feeling some version of grief. Often, we started obsessing at that point
over some miserable thing we did somebody 12 years ago and sort of despair in that.
When you're talking about major depression, the grief and the guilt can be so severe
that it actually takes on a delusional quality. OK, not delusional in the sense of a
schizophrenic with delusions hearing voices thought disorder, but a certain style with
extreme depression.
 Let me give you an example.
You have late middle aged guy, perfectly healthy, and suddenly out of nowhere he has a
major heart attack. He's lying there in the hospital. And the reality is, he's going to
recover. He's going to have to make some changes in his lifestyle. But he's going to
recover. He, instead, falls into a major depression. This has transformed his sense of
who he is. Suddenly, he's an old man. Suddenly there's all these things he can't do. He
falls into a major depression. Yet, he's recovering. Every day, his family is in there,
saying: “Look, you're just depressed. You're getting stronger. The doctors are saying
you're getting stronger. You're just depressed”. It happens the hospital is circular.
It has a corridor that forms a circle in it. And one day, the family is in there saying:
“You're getting stronger. Look, the nurses said yesterday you did one loop around the
hospital. And today you did two loops. You're getting better. You're getting stronger”.
And the person says: “No, no, you don't understand. They're doing some construction.
Last night, they closed down the outer corridor. And they opened up a new little. So the
two versions of this one, two loops there is shorter than the large one. I'm getting
weaker. I'm getting weaker. I'm going to die. I'm hopeless”. This is like someone
expecting to believe that last night there were beavers digging through the walls there
making this new - this was the father of an acquaintance of mine, a structural engineer.
This is what a structural engineer looks like when they're delusional to the point of
saying that this is a world in which everything is inevitably getting worse, depression
built around that.

Next, of course, one of the most dramatic and one of the most awful symptoms
of depression - Self-injury. Depressives mutilating themselves at a high rate, and of
course most notoriously, suicide, risks of suicide. And that is absolutely tragic. And
teenagers, early adults, that along with accidents is the leading cause of death - major
bad news. Another set of symptoms that wind up being informative, something called
Psychomotor retardation. Everything is exhausting. It's exhausting to do stuff. It is
exhausting think stuff. You are there. And you can't do the laundry because, where's the
basket? And you got to find change for the machine. And you've got to go detergent.
And it's too much. Everything is too much. And you fall into this paralyzed state.
Something very interesting in that regard - you get someone who is severely depressed,
like to the point of hospitalization, and when they are absolutely crippled with
psychomotor retardation, that's not when you worry about suicide. This is someone
who's having enough trouble getting out of bed and getting dressed each day. They're
not going to figure out how to shred the hospital mattress and make a noose out of it.
Where you've got your problems is when somebody begins to get better from a severe
depression. When they're starting to come out, that's where the psychomotor
retardation relieves enough that suddenly they've got the energy to do something
catastrophic. That's when people are on suicide watches, when you have clinicians who
are oriented well.
Next - something really interesting, and in lots of ways the single point I want to
hammer in here over, and over, and over, is something that people with depression
constantly battle with. Back to semantics, we all get depressed. Bad stuff happens to us.
We all get depressed. We feel lousy. We feel withdrawn. We feel a sense of grief. And
we're not taking much pleasure. And we withdraw. And then we get better. We cope.
We heal. We deal with things in life. What's the deal with you that you can't do that?
And there's this lurking sense given that all of us have periods of being depressed and
come out the other end. When you look at people who instead go down and stay down
there to this crippling extent, there's always this little voice between the lines there of,
come on. Pull yourself together. We all deal with this sort of thing. I will make the
argument throughout here vegetative symptoms that depression is as real of a
biological disorder as is juvenile diabetes. And you don't sit down a diabetic and say, oh,
come on, what's with this insulin stuff? Stop babying yourself. Pull it together. You will
see this is just as much a biological disorder. Part of what makes that clear are a bunch
of symptoms called vegetative symptoms. The bodies of major depressives work
differently. First set of symptoms - no surprise, lots of people have trouble sleeping
when they're having every day off the rack depression. There's a certain pattern with
people with major depression. What would you think - you're depressed, you have
trouble falling asleep, toss and turn. That's not what you see with a major depressive.
Instead, you wake up early. You wake up four in the morning, five in the morning. You're
exhausted. But you're not going to sleep. Early morning wakening-- you wind up in an
emergency room somewhere deeply depressed. And the clinician there better ask you
at some point, how's your sleep been? Do you tend to wake up early in the day? Early
morning wakening, classic sign. Additional thing, sleeping - sleep is not this monolithic
process. There's all these different stages of sleep, slow wave sleep, deep sleep, REM
sleep, all of that. There's a structure, an architecture, to how we sleep, sort of 90-
minute cycles as you go through the different phases. You look at the brain of somebody
with depression while they're sleeping. And these different phases are completely
disordered. The whole structure of sleep goes down the tubes. Look at somebody when
they're sound asleep. And their brain sleeps differently. This is not oh, come on, stop
babying yourself. This screams biology. More versions of it - most of us, what we do
when we're feeling kind of down is we eat more out of this general belief that when you
feel unloved carbohydrates make you feel better. And bizarrely, there's actually a brain
chemistry of it of carbohydrates decrease stress hormone release. So for most of us,
you're feeling bummed out about things, you eat more. That's not what you see in
major depression - decreased appetite. Another thing you see is activation of the stress
response. Stress response A class of stress hormones are highly elevated in people with
major depression. You also have over-activation of something that's called the
sympathetic nervous system, adrenaline. Overactivity of these components of the stress
response, and that's really important. Because you look at someone with a major
depression who's just mired in this psychomotor retardation stuff, and there's this
temptation to start thinking about them as some sort of sea sponge, some invertebrate
thing, where you're just so wiped out. You can't even get out of bed. It is just
debilitating in that sense. That's not what's going on during depression. What you have
instead is somebody whose body is blasting through there, over-activated stress
response, this enormous battle, all of it going on internally. And the fact that you see
changes like these tell you this is not, oh, just so wiped out you can't even activate. This
is someone whose body is having a massive stress response 24/7. There's a huge battle
going on. And it's all internally - increased metabolic rate, increased muscle tone, all of
this again screaming biology.

The final thing that says tons of biology is lots of people with major depression
have rhythmic patterns to the depression. You will get somebody where they will fall
into a depression where it will have two months of extreme severe symptoms,
debilitating, and come out the other end. And a year and a half later, the exact same
pattern, a year and a half later, exact same thing. You have some people who only get
their depressions during the winter, something known as seasonal affective disorders,
SADs. And this is someone where something horrible happens to them in June. And they
feel sort of sad for a couple of weeks. And they come out the other end. And nothing
happens in January. And they fall into a depression. And they're hospitalized for a
month and a half, just like every January for the last 10 years. Biological clocks And you
see that. And that is all about biological clocks that are out of whack there. It's biology.
This is not, oh, come on, pull it together.

OK, so hopefully what that begins to introduce is the notion amid all these
debilitating symptoms, these are ones that are about biology. These are bodies working
differently. So starting to focus in more on the biology of it - what's going on in the brain
in major depression? What I'll start off with is the chemistry of it.
OK, what we've got here-- do not panic if you are not familiar with this and have not
wanted to think about science since high school
sort of thing. You've got two brain cells. You've got two neurons. The way they talk to
each other, they don't actually
touch each other. In order for one neuron to send a message to another one, it needs to
release a chemical messenger that goes floating
over here and does something or other to this neuron, chemical messenger called a
neurotransmitter.
And here we have a case of this. And by law, all neurons go from left to right. So this is a
cell that continues down this way.
It's all excited. It's trying to pass on some news to this neuron.
There's a space in between called a synapse. And what this one is doing, because it's all
excited, it has these little water balloons
filled with neurotransmitters. Excitation signal comes along, dumps the
neurotransmitters.
They go floating across the synapse, bind to a receptor there. And then, suddenly,
something changes in this neuron.
That's how neurons talk to each other. How many different types of neurotransmitters
there are,
probably hundreds. And what will be pertinent here is in depression, there's just a
handful of them that seem to be implicated.
norepinephrine
First neurotransmitter-- something called norepinephrine. Norepinephrine first got
implicated in depression
in the early '60s. What was the evidence? Around that time, the first generation
of antidepressant drugs had been developed, something called MAO inhibitors.
What do they do? OK, so you got your neurotransmitters released. This neuron is
excited. What do you have to do?
It comes out. It does its thing with the receptors. And then you have to clean up after
yourself. You've dumped all the stuff in the synapse.
What do you do then? You got two options. You can take the neurotransmitter. And you
can be green in your orientation.
You can recycle. You can take it back up in here and stick it back into one of these. You
can do this recycling business.
Or you could be terrible and carbon footprint. You can throw out your neurotransmitter.
There's enzymes sitting around here
that break it up and flush it down the toilet. What's the toilet? Out into your cerebral
spinal fluid,
your bloodstream, your urine, whatever. So either recycling or degrade this stuff.
So what do these MAO inhibitors do? They inhibit the activity of this enzyme that
breaks down norepinephrine. OK, so what's the logic there? So you inhibit the activity of
this enzyme.
You don't break down norepinephrine. So it's just floating around there. And for lack of
anything else to do,
it hits the receptor a second time, and a third time, and a gazillionth time. And,
suddenly, somebody's depression goes away.
What's your theory have to be at that point? Oh, I bet there wasn't enough
norepinephrine coming out.
You find a means to increase the signaling. Somebody gets better. And you now
hypothesize there's a problem
with too little norepinephrine. By the late '60s another class of antidepressants
tricyclic antidepressants
came in called tricyclic antidepressants. What do they do? Essentially the same exact
thing.
What they do is they gum up this pump that recycles the stuff.
Norepinephrine doesn't get removed from the synapse, has nothing else to do, hits the
receptor a second, third, tenth time.
Person feels better, oh, I think the problem in my theory is too little norepinephrine
coming out-- thus,
the norepinephrine hypothesis. More evidence for it-- there are classes of drugs that
will decrease your norepinephrine release.
Why would you want to do that? In some parts of the body, an excess of norepinephrine
has something to do with high blood pressure.
So you take a class of drugs, something called reserpine. And what it does is it
disintegrates these things.
And, thus, you don't dump as much norepinephrine. Major side effect in lowering
somebody's blood pressure
that way is they fall into a depression. So you take a depressed person. You find a way of
boosting up there norepinephrine signaling.
They feel better. You take a normal person. You drive down their norepinephrine
signaling. They get depressed.
There's gotta be a problem here of too little norepinephrine. So that's incredibly
convincing.
So at this point, what you've got to say is, OK, great. That's convincing. That's
irrefutable. What does norepinephrine do?
And people figured it out in the '50s. And it's got something to do with this.
Take a rat. And take a certain part of the brain. You put an electrode down in there
where you can stimulate the neurons.
You can force them to talk to each other when otherwise they have nothing to say.
Stimulate this pathway, and what you do
is you make a rat unbelievably happy. So, of course, the question is, how do you
tell when a rat is unbelievably happy? And what you do is you make it work in order
to get stimulated there. It presses a lever. And it presses a lever 25 times. And it gets a
little buzz there.
And it does another. And rats will work themselves to death to get stimulated in this
area.
It is better than food. It is better than sex. If they're addicted to a drug and going
through withdrawal,
it is better than the drug. And what you see is these mediates pure pleasure.
And this was called the pleasure pathway in the 1950s. So, of course, you look at it.
pleasure pathway
And then what you have to then say is, oh, do we have the same pathway? Can I get a
new one? Can I get a second one?
Shortly after that, people went looking, and saw the exact same thing in humans. And
this would be during neurosurgery-- classical
neurosurgical techniques. You don't anesthetize the person. The brain doesn't feel pain.
Once you've witnessed the skin and the skull, you get through there. And you can
actually keep somebody awake during surgery.
And they used to need to need to do that, because you put your little needle down in
one part of the brain. d the person flaps their arm.
And another part and they say the Pledge of Allegiance or whatever. And then you look
at your little roadmap. And it says, OK, go three neurons and make a left.
People had to do that. So it was around the early '60s that people started stimulating
the same area in the human brain.
And it is unbelievable what you got. There were transcripts of some of these. And you
read it.
And the person is going on. And they're saying stuff like, oh that's great. That's great.
That's kind of like sex. But you know when you have this itch and finally you get to
scratch it? And, oh, it's like getting back into bed.
And remember how in the fall you'd go out and play in the leaves, and mom would call
you in, and she made cookies, and then you
get into your jammies with the feet on? They just go on like this. It's like, where can you
sign up and have this happen?
The same exact sort of these as in a rat. And it was around that time that people
discovered that in this pathway it uses norepinephrine.
So if you've got a shortage of norepinephrine
problems began to emerge
in that part of the brain, what have you just explained? That's the loss of pleasure.
Great, utterly convincing-- here's all the reasons why you shouldn't be convinced.
Problems began to emerge.
First problem was there's something weird with the time course. You throw in any of
the drugs I just talked about
and norepinephrine signaling is changing within like an hour. You put a depressed
person on those drugs
and they don't get better for a couple of weeks. Something isn't working there.
So that was mysterious. Next problem was it turned out norepinephrine is useful in this
pathway.
Another neurotransmitter turned out to be even more important, a neurotransmitter
called dopamine.
Dopamine-- cocaine works on dopamine systems. So, suddenly, norepinephrine is just a
minor player
in this pleasure pathway stuff. But the biggest problem came in the late '80s with the
introduction of Prozac.
Prozac, which is an SSRI, a Selective Serotonin Re-uptake
Inhibitor-- what that does is work on a completely different neurotransmitter system,
this neurotransmitter
called serotonin. What that drug does is it does the same deal. It stops the Re-uptake
Increased Serotonin Signaling.
And then what's your hypothesis? You give somebody a Prozac SSRI. They feel better.
I bet you there was too little serotonin. So it was during this period where there was just
endless tragic drive-by shootings
of norepinephrine people by the serotonin crowd, or the other way around-- huge, huge
controversy.
And, of course, the middle of the road liberals are like, why can't we all get along?
Which starts suggesting that maybe it's got something
to do with norepinephrine, and serotonin, and dopamine, and everybody hold hands.
And that's absolutely what's going on. The best evidence at this point, to be insanely
simplistic,
is that dopamine has something to do with the anhedonia, an absence of dopamine.
The absence of norepinephrine has something to do with the psychomotor retardation.
The absence of serotonin is this obsessive sense of grief.
And, interestingly, supporting that notion is you can have an obsessive sense of
something else.
You could have an obsessive need to keep your utensils perfectly symmetrical and
obsessively wash your hands eight hours a day.
Obsessive compulsive disorder, that's helped by SSRIs like Prozac as well.
Whatever it is you are just perseverating over like mad, increasing serotonin signaling
can help.
So you've got at least three different neurotransmitters relevant to the pleasure, the
psychomotor retardation, all
of this, all sorts of other leads floating around in the field. There's a neurotransmitter
called substance P.
And what substance P is about is pain. Like, poke your finger and your spinal cord,
there's neurons there are releasing substance, talking to each other. It's about pain. It's
about chronic pain syndrome, which
is about whole body burns. Everybody knew this. And then it was discovered that if you
get a drug that decreases substance P signaling,
sometimes depressives get better. What does that suggest? It is not just a metaphor of
depression as psychic pain.
Your body is using the same brain chemistry to feel this psychic pain of depression
as just telling you, oh, I just stubbed my toe-- interesting similarities there. OK, so we've
got something about the neurochemistry.
How about the neuroanatomy, the structure in the brain? And what you've got here is
this is the human brain.
This is exactly what it looks like. It comes in three colors. And this was this formulation
that came out during the '40s called the triune brain concept, which
winds up being really, really explanatory. Down here at the bottom, you've got the really
boring nuts
and bolts part of the brain. And as it was termed, this is the reptilian part of the brain.
Take a lizard, and its' basically the exact same stuff
down there. What does this part of the brain do, like regulatory boring things?
It measures your blood glucose levels. Or if your blood pressure has dropped, it sends
out a signal to tighten up your blood vessels--
just hope total boring plumbing-type issues. Sitting on top of it is a much more
interesting brain region
called the limbic system. Limbic system is about emotion. You don't see a big limbic
system
until you get to mammals. Lizards are not famous for their emotional lives. Limbic
system is much more about emotive stuff-- fear, and lust,
and anger, and rage, and poignance, and God knows what. What you've got there are all
sorts
of ways where the limbic system talks to this part of the brain.
And what it does is rather than you being hemmoraged-- oh, [INAUDIBLE], your body
getting cold, whatever, you're some elk.
And there's some scary other elk there that's got you all upset. And you start secreting
stress hormones.
That's your limbic system saying, oh, I don't like the smell of that guy talking down
there-- all sorts of means by which your emotional part of the brain
can talk to stuff down here. Then you've got the really interesting area
up on top-- the cortex. Cortex, all sorts of creatures out there have cortexes.
We got more than anybody. It is this hugely expanded area in primates.
We proportionally have the biggest one out there. What does cortex do? It makes you
do your taxes.
And it does processing visual information, and tells you, that's punk rock.
And that's not Beethoven, and all sorts of sensory stuff, associative cortex things.
But then there's an interesting part of the cortex that's very relevant to all of this.
What is depression
Suppose you finish the lecture. You go outside. Unexpectedly, you are gored by an
elephant.
What are you going to do? You are going to activate your stress response.
You may feel a sense of grief at that point. You may kind of hunker down at that point,
a little psychomotor retardation. Appetite, there goes the dinner arrangements.
Sex may not be the most appealing thing under that context. You are having a stress
response in response
to the sort of insult that this part of the brain is thinking about. So what's a depression?
You sit there. And you think about kids in refugee camps. You think about the inevitable
mortality of your loved ones.
You think about whatever. And, suddenly, your body does the exact same thing
as if you were gored by an elephant. And what's going on there is you get the feelings,
the abstract sort of depressive stuff there. And this part of the brain is able to make
the rest of the brain go along with it, as if this was an elephant goring you. On a certain,
totally simplistic level
what depression is about is the cortex whispering in the ear of the rest of the brain,
saying,
this is as real as you were just physically assaulted by some sort of predator, whatever.
And you turn on the exact same thing. On a very simplistic level, what a depression is,
is the cortex having too many sad thoughts and getting the rest of the brain to go along
with it.
OK, so if that's how you think about depression, which is insanely simplistic, you could
come up with an insanely simplistic treatment for depression,
which is get yourself a pair of scissors and just kind of cut through there. And separate
that part of the brain from the rest of it.
And you're home free. Oh, yeah, right, well, that's certainly an advance in medicine.
That is a medical procedure. It is called a cingulotomy, the part of the cortex
is called the anterior cingulate. A cingulotomy, or a cingulome bundle cut. And what you
do is you sever this pathway.
When do people get less depressed
And people get less depressed at that point. OK, when does this happen?
This is someone where every type of medication, and every type of therapy, and
electroshock interventions,
and all of that has been tried in every combination. Are they're still in the back ward of
the state hospital slashing their wrists every three months.
That's when people try this. And the amazing thing with this desperate measure is
people get less depressed at this point.
OK, so at that point, you may want to look at that and say, well, anything else about
these people when you've gone through there and just snipped away?
Mind you, this not a frontal lobotomy. Frontal lobotomy is doing something very
undefined up there.
But instead, you're disconnecting here. What else is up with somebody when you've just
disconnected part of their cortex
from the rest of the brain? Insofar as the cortex can come up with abstractly sad
thoughts
and get the rest of the brain to go along with it, maybe the cortex also comes up with
abstractly pleasurable thoughts and gets the rest of the brain--
have you just wiped out somebody's ability to have abstract pleasure? Absolutely.
So, suddenly, you are off and running with a great philosophy term paper. It's important
that we have pain in order to have pleasure.
This is nonsense. You get someone who is a candidate for this procedure back in the
state hospital there with their wrists scarred over.
And this is not somebody feeling a whole lot of abstract pleasure anyway. So what does
this tell us?
You come up with some ridiculously simplistic explanation, that you make it impossible
for this sad part
of the brain to whisper sad thoughts to the rest of the brain, the best people in the field
thinking about this can't come up with anything a lot more
sophisticated than that. So that tells you something about the brain structure
with depression. Final bit of biology here-- hormones, what do hormones have to do
with it?
One very important domain of hormones-- you take somebody. And they're having
problems with a class
Hormones
of hormones, thyroid hormones. What thyroid hormones are about is maintaining your
metabolism,
keeping your body warm enough, all that sort of stuff. If you have a severe shortage of
thyroid hormone, lots of things
happen, including you fall into a major depression. Hypothyroidism is associated with
major depression.
There's an autoimmune disease called Hashimoto's Disease, which involves problems
with secreting thyroid hormone.
And that's a basic feature of it. And somebody comes in. And you diagnose it. And you
give them normal levels of thyroid hormone.
And away goes their depression. Lots of lessons with that. First one is best estimates are
about 20% of major depressions
are undiagnosed hypothyroid syndromes instead. The next one that demonstrates is
you better,
when somebody is thinking about your psychiatric state, you better have somebody
there who's thinking about your nutrition, your hormone levels,
your-- nothing about what's going on here is independent of the rest of the body.
So a big role for thyroid hormones. Next domain of hormones being relevant-- you take
women.
And they have a higher incidence of major depression than men do-- approximately
twice the rate.
In addition, women have their highest vulnerability to depression at certain points in
their reproductive life
histories. After you've given birth, a post-parturition depression. Around the time of
your period, around the time
of your menopause, all of these scream biology. So you look at why women have
elevated rates of Depression.
And there's biology. There's all sorts of other schools of thought that have gone into it.
There are ones having more sociological framework.
Lack of control can cause depression. In society after society, women traditionally
have less control. No wonder they fall into more depression. There's another school that
focuses
on a certain style of emotional differences you see between the genders. On the
average, women tend to ruminate more
on emotionally upsetting things to focus in on more. And this sounds totally
stereotypical.
And when you do the studies, there's overlaps between individuals. But nonetheless, on
the average, what you see
is these sorts of studies where you get someone after they've just had a fight with a
close friend.
And what do women do when they give a choice of a whole bunch of activities? They
choose to fill out questionnaires
about how they met their friend, and what the nature of the relationship is, and does
the friend have a good marriage?
And all of that. You do it to guys. And they fill out questionnaires about trivia questions
about the Civil War.
Oh my God. They can't express their emotions. No wonder they're impossible. And, of
course, again, individual variation, this
is highly stereotyping. On the average, though, women ruminate more on upsetting
emotions than men do.
So that is solid science. What is completely unsolid science is the speculation at that
point that if you
ruminate on bad feelings, you're more prone to a depression. So that's a whole
emotional regulation argument.
But you come back to that business of, women are most at risk for a depression in the
two weeks
after giving birth, around the period of their periods, menopause. And that's all about
hormones.
And by now, there's a huge literature having to do with the effects on all of that stuff
over there
of estrogen, and progesterone, and probably most importantly the ratio of estrogen
progesterone.
And what's going on around giving birth, period? Levels of this stuff is just shooting
around all
over the place. And the sense is something goes out of whack with the ratios there. And
everything about estrogen, progesterone, and the ratio
can change the number of receptors for these neurotransmitters, the extent to which
you do this re-uptake pump.
Whatever depression is going to turn out to be on this nuts and bolts level,
estrogen and progesterone can do something to it. Final class of hormones that are
relevant-- a class of hormones
released during stress. OK, what's the most famous stress hormone on Earth?
Adrenaline is this vastly overrated hormone that I despise because there's a much more
important stress
hormone out there to which I've devoted the last 30 years of my life, class of stress
hormones called glucocorticoids.
They come out of your adrenal gland during stress. The human version is
hydrocortisone, also
known as cortisol. All sorts of other species out there, you secrete these glucocorticoids
Stress and Depression
when you are stressed. You look at people with major depression. And about half of
them have elevated levels
of glucocorticoids through the roof. There's something out of whack with the regulation
of this stress hormone during depression. What's that about? That's back to people with
depression are not
invertebrates sitting on their beds. These are bodies undergoing massive stress
responses.
There's a huge emotional battle going on, all of it inside their heads.
So elevated stress hormone levels-- what's very clear is you get exposed to a lot of
glucocorticoids,
and you're more at risk now for depression. You can see this epidemiologically. You get
people, and statistically
before their first major depressive episode, something awful stressful occurs.
And that's where this happens. And this is the subset of people who stay down there far
longer.
Have one of those first depressive episodes due to some stressful event, you come out
the other side
eventually. You are no more at risk for depression than anybody else. Along comes a
second major stressor.
And you fall into a depression. Come out the other end, no more at risk than anyone
else
for depression. Somewhere around the fourth or fifth stress-induced depression,
something happens.
And things start cycling on their own there. And you no longer need a major stressor to
cause you to get depressed like that.
That's when the clocks are often running. That's the transition. OK, so major stress can
predispose you
towards depression. More evidence-- there's a disease called Cushing's disease, where
people secrete boatload
of this glucocorticoid stuff. People with Cushing's fall into depressions.
There's a whole bunch of diseases where people have to be treated with lots of
glucocorticoids. They fall into depression.
What are glucocorticoids doing? A whole lot of them, and your brain gets depleted of
dopamine.
And you're right back in this domain. That's probably the neurochemistry of how you get
there.
OK, so what do we get at this point? We've got something about brain chemistry and
depression. We've got something about the structure of the brain.
We've got something about hormones. You are a card-carrying biological psychiatrist.
And that's all you need to know about the subject.
And if that's all you know about the subject, you are going to be pitifully bad in making
anybody get better, because all of this knowledge winds
up being effective for treating maybe 30%, 40% of depressives. Vast majority of people,
the antidepressant drugs
don't do a whole lot there. All you've got there is modern, cutting edge biology stuff.
And that's not enough. So what I'll transition to here is now talking about the
psychology of depression,
because you better have that piece in the story. Or else you're absolutely useless.
Starting off with, I make apologies here.
But I actually have to say the name of Sigmund Freud here, because he winds up being
very relevant to depression.
The Psychology of Depression
Freud back when dealt with this puzzle of the difference between we all get depressed
and come out the other end,
and the subset of people who crash. The turn of the century Viennese term for people
who come out the other side, mourning.
You mourn something and you recover. Term of the century Viennese term for major
depression, melancholia.
And Freud and this famous essay said, why is it that a subset of us fall into it?
What's the difference between mourning and melancholia? And he came up with a
really interesting model.
OK, according to Freud, you have mixed feelings, ambivalencies about everybody you
love out there.
You love them. And you hate them. And you resent them. And you reject them, and all
that Freudian stuff.
So in this Freudian view, you have lost a loved one. That can also be a loved concept, a
loved goal.
You have lost a loved one. What happens then is, in most people,
you are able to focus on the love and the sense of loss. You mourn.
And you come out the other end. In Freud's view, what melancholia is about is the
subset of people who
can't put the negative feelings in the background. And instead, you are awash in the
love, and the hate,
and the regret, and the pain, and the delight, and all of that. And what a depression is, is
this wallowing,
this melancholic loss, and the ambivalencies you have about the lost loved one.
It explains tons. No wonder you have the grief. Lose somebody and go through the
mourning business.
And only one thing is wrong. You've lost this loved one. Lose somebody with
melancholia, and two things have happened.
You've lost the loved one. And you have now lost the opportunity to ever make things
better with them.
No wonder you have the guilt. You're sitting there saying, thank God, I'm finally done
with this person.
They are never gonna control my-- how can I think such a thing like that? Sudden,
crippling guilt, all sorts of other symptoms.
And out of this came this wonderful soundbite-- depression is aggression turned inward,
because you've
got nobody else out there to have these arguments with. This is the person who you
have most loved, but most hated.
And you've never said the things you needed to hear, and pounding at the door to get
them to finally to e able to tell them.
And now you have lost that opportunity forever. And all you can do is internalize all of
that-- aggression turned inward.
No wonder you're not feeling a whole lot of pleasure. No wonder you're secreting stress
hormones. No wonder you're not getting out of bed
all that readily with the psychomotor retardation stuff-- this really powerful soundbite
of aggression
turned inward. That's great. What isn't great is how in the hell
do you turn Freudian ambivalent feelings into something about neurochemistry?
Or what do estrogen progesterone ratios have to do with love hate ratios?
It's great. It feels very intuitive. You can't do modern science on it, which is the problem
with the best parts of Freud.
So instead, you need to shift over to looking at experimental psychology, and
understanding
what is the psychology of stress? What is it that makes psychological stressors stressful?
And an enormous literature now shows
that for the same external misery, you feel more stressed, you turn on a stress
response, you
are more at risk for a stress-related disease if you don't have outlets for the frustration
caused
by the stressor, if you feel like you have no control over what's happening, you have no
predictability as to when it's occurring,
and you don't have anybody's shoulder to cry on. This is what psychological stress is
about. And what a depression is, is pathological extremes of this.
You fall into the cognitive psychology soundbite of what a depression is, it's learned
helplessness.
It is learning to be helpless. Something bad happens to you. You a rat, getting some
shocks now and then,
you a human experience some loss, and the logical thing you should do is learn, this is
awful.
When I'm in this situation, there's not a damn thing I can do about it. It's awful. I feel
terrible.
But this is not the whole world. And what a major depression is about is you sit there.
And you're that rat. And in this setting, you get uncontrollable shocks. But put you in
another setting and just
by hitting the lever a couple of times you avoid the shocks. You don't bother doing it
because you've learned to be helpless, just like a human depression.
What depression, what learned helplessness is, is taking a circumstance where by any
logic, again,
you should be saying, this is awful. But it is not the whole world. And do this cognitive
distortion.
And decide, this is, indeed, the entire world. And I have no control.
I am always helpless. I am always hopeless. This is the psychology of what a depression
is about.
At that point, you don't have a whole lot of trouble seeing how you wind up in here.
Stress affects on some dopamine, all that sort of stuff.
So we've got two extremely different viewpoints here as to what depression is about--
modern, biological stuff,
and this totally different world of psychology, loss, lack
of control. One version of it, one of the most reliable findings in the whole epidemiology
of depression
is lose a parent to death when you are under 10 years of age, and for the rest of you life
you are more at
risk for a major depression. This makes perfect sense. What is a lot of what's going on
during your first 10
Genetics and Depression
years of life? You are learning about cause and effect. You're learning, is this a world out
there
where I have any sort of efficacy, where I have any sort of control? And you have just
learned in the most big time, awful way,
there are things you can't control. And sometimes they are awful. And what have you
just learned?
There's all sorts of reasons where one can be helpless. And you're that much closer to
the edge
of this learned helplessness cliff for the rest of your life-- extremely powerful model
here of that. So you got all the biology stuff. You've got this weird Freudian aggression
turned inwards,
which just feels right. But you can't do modern science on it. You've got this whole
world.
How do you begin to put this world and that world together? And the critical link turns
out to be stress.
Stress is the intersection of the two in a very interesting domain.
OK, depression is a genetic disorder. What do I mean by that?
Depression has some degree of heritability. Depression tends to run in families.
Depression runs more reliably as you look at closer and closer relatives. And you
eventually look at identical twins.
And if one of them has depression, the other has a 50% chance. Full siblings who are not
identical
twins, 25% chance, half sibling about 8%, person off the street, about a 2%.
50% chance when they share the identical genes. What does that do? That tells you this
is a disorder that
has a genetic component. What does that also tell you? If you've got 50% likelihood-- if
you've
got all the genes in common, and you've got a 50% chance of not getting the
depression-- it tells you
genes are important. But they're not more important than any other component. So
genes and depression are not about inevitability.
They're about vulnerabilities. So what is the vulnerability about? A few years ago,
people discovered a particular gene
that's really relevant to whether or not you get depression. What was exciting about
that?
It was a very clear finding. It has since been replicated. What else was exciting about it?
It made sense. This was not some weirdo gene having something to do with how your
big toe functions.
This was a gene having something to do with serotonin. And this was a gene relative to
this whole re-uptake pumping
business, all of that. The main point of it is this gene comes in two different flavors.
Each one of us has one of the two versions. And you immediately get this prediction,
one
of the versions by all logic should be predisposing to depression. One of them is the one
that should get you in more trouble
here. So what does it look like when you go and study it? First paper that reported this a
few years ago--
and this, I suspect, is going to wind up being viewed as the most important paper in
biological psychiatry for a quarter century.
This was this massive study where a bunch of researchers looked at 17,000 kids growing
up in New Zealand,
following them year after year, and looking at the genetic makeup of these individuals.
And then asking in their early '20s, who's got problems with major depression? And then
asking this critical question,
what does it have to do with this gene? Does the version of that gene that gets you into
trouble,
by all logic, is that going to set you up for more of a depression? Are you more at risk for
a depression
if you've got the bad version of the gene. And back comes the finding which is no, no, it
doesn't increase your risk. You look here. And what's your likelihood of depression?
And you've got the good version. And it's this likely. And you've got the bad version. And
it's this likely.
It doesn't make a difference, unless something else is going on, unless you have a
history of exposure
to major stressors. And what you are able to do is quantify how many major stressors
somebody
has had during their childhood, their development. And that involves parental divorce,
and physical abuse,
and death of family member, all that sort of thing. And what you see is in the folks who
have the good version of the gene,
as you have more and more of a history of major stressors, our risk of depression goes
up, absolutely.
Now you look at the people with the bad version of the gene. And as you have more and
more of history of stress,
your risk of depression does this. And when you look at the major history of stressors,
a thirty fold difference in the likelihood. This is not about genes control our brains.
And genes control our behavior. This is a gene that's relevant to how readily we pick
ourselves up after life has dumped us on our rear ends, how readily we recover from
stressors.
What's the final piece of that story? Glucocorticoids regulate the function of this gene.
All the pieces fall into place there-- wonderfully logical. And, suddenly, you have a way
of taking
this whole world of psychological components of stress, and tying it into all that
biochemistry-- wonderfully
integrated model. OK, so in lots of ways, this is where the field is at this point.
And what should mostly have come through here amid all this minutia, and factoids, and
all of that,
is the role of stress, and the intersection of the biology, and the psychological stuff, and
childhood as a very important
time to imprint how vulnerable you are to depression for the rest of your life. But, again,
the single thing I want
to emphasize over and over implicit on everything on that left side of the board there,
which is this is not,
oh, pull yourself together. We all get depressed. This is as real of a biological disorder as
is diabetes.
And that's the thing I most want you guys to take off from here. And in the context of a
university
setting is rife with major depression. A community of high achieving, type A individuals
is rife with major depression. It is all around us. And amid it being all around us, there
is this weird, corrosive inhibition, embarrassment, discomfort we have with the world of
psychiatric diseases.
One of the greatest things-- if you're a researcher with a disease, one of the things you
pray for is to for some powerful Senator
have their loved one come down with your disease because they're going to setup a
foundation, and get special funding.
And there's advocacy groups and all of that. Not for a psychiatric disorder, that's the one
where people don't talk about it.
And amid this screaming biology, and this is a devastating disease, and all of that, in any
place,
and especially in a community like this where everyone is supposed to be golden, and
functioning, and flawless, and just gliding through life,
this is one of the hardest diseases for people to admit to. So it is there. It's all over the
place.
And it's biology. And you should be no more inhibited about admitting that you've got
something going on that's
funny with this type of gene than you would be to admit that your pancreas isn't
secreting insulin.
So let me stop at this point. And, again, unfortunately, I got to spring out the door.
Otherwise, I would take questions, but thanks.
[APPLAUSE]
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