[MUSIC PLAYING]
Stanford University.
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.
Oh no, come up to the front.
There's lots of room up here.
I see a couple
more seats up here.
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.
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?
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 psycho
motor retardation.
Everything is exhausting.
It's exhausting to do stuff.
It's exhausting think stuff.
You are there.
And you can't do the laundry
because, where's the basket?
And you gotta 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
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.
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, 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.
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.
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
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.
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
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.
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.
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
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
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.
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
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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