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PROFESSOR JOHN GABRIELI:
Good afternoon.
So last time we talked about
neuropsychiatric disorder.
And I just want to remind you
that we talked about it in a
couple of context
of challenges.
That historically, different
cultures at different times
have interpreted unusual
behavior in
very different ways.
From trephination, where you
have to release evil spirits,
to possession, to what we would
now consider brutal
patterns of taking
people away from
society who behave unusually.
And that even in recent times,
things like in the Soviet
Union, the diagnosis of people
who protest at utilitarian
governments is a socially
defined diagnosis.
Obviously things like definition
of homosexuality is
a psychiatric disorder until
about 20 years ago.
It was a socially defined
disorder.
So there's a lot
of challenges.
On the other hand, there's a lot
of people suffering with a
huge range of neuropsychiatric
disorders.
So we're going to talk some
more about that today.
Think a little bit more about
issues of treatment, talk a
bit about depression,
and ADHD.
And I think of depression and
ADHD, attention deficit
hyperactivity disorder, as
kind of different as
schizophrenia.
So most of us, except for the
1% approximately who have
schizophrenia, don't
hear voices, right.
That's an unusual thing.
But all of us can be sad.
And many children are what we
would consider to be a bit
hyperactive, compared to a
teenager or an adult, right.
They won't sit still quietly in
a large classroom like this
for very long.
And so when we talk about
disorders like these.
These are in some ways
exaggerations, or extensions,
of what we consider typical
everyday behavior.
But moving into a realm that
makes life difficult for those
who get the diagnosis.
So when it comes to treatment,
there's sort of two giant
classes of them.
One of them is behavioral
treatment.
Broadly speaking, you could
call them talk therapies.
And the other one is medical
treatment with drugs.
Within psychotherapy, which
really covers all of the talk
therapies, people sometimes
make a distinction between
psychoanalysis and cognitive
behavioral therapy, or CBT.
So what is psychological
therapy?
So you might have a sense that
there's a lot of organization,
and rules, and regulations
about this.
But the truth of the matter is
that psychotherapy is a social
interaction in which a trained
professional tries to help
another person behave and
feel differently.
There's really no boundaries
on that.
OK.
There's no official rules.
There's more and less official
channels we're used to.
But it can be a very wide
sources of this.
And if you flip open--
this is an archaic thing--
yellow pages.
I realize a few years ago
people, yellow pages.
But they used to have things
called phones and phone books
that were tethered
to the wall.
And this is where you would
look for information about
people who list themselves as
providing psychotherapy.
All you have to do is put your
name in that listing, even
easier on the internet maybe.
A psychiatrist, the big
difference between
psychiatrist in one practical
sense and psychologist is
psychiatrist of course,
go to medical school.
And they have prescription
privileges.
They can write prescriptions
for drugs.
That's rare to nonexistent
currently among psychologists.
Psychoanalyst, here's Sigmund
Freud in the original
psychotherapy couch.
And I think we've barely
mentioned Freud so far in this
course, right?
Which is kind of a big
shock to many people.
You might have thought coming
into this course that there'd
be Freud, Freud, Freud.
And you know, that we would be
sitting there and that we'd be
discussing ideas about
Freudian theory.
I'll come back to that
in a moment.
Clinical psychologists can
provide psychotherapy.
Counseling psychologists in
schools, clinical social
workers, clergy, peer groups,
self-help books.
So let me just return to Freud
just for a moment.
Because intellectually, I think
most people will agree
that Freud was a giant mind.
And that in many ways, the
complexity of the modern human
mind, the idea that we're made
up of different parts,
different feelings, that we're
not just one simple operation
machine, but that we have
conflicts, different feelings,
and thoughts, and patterns
all within us.
Freud probably articulated that
thought more powerfully
than anybody else in many ways,
as a modern way in which
we view people, right.
People are not just
simple things.
They're complicated things, full
of tensions and desires.
They're all mixed together.
At the same time, the specific
ideas that Freud articulated
using psychodynamic theories
like free association,
resistance, transference,
interpretation, trying to have
a corrective emotional
experience, where you go back
to your youth and
you figure out
something bad that happened.
And if you can somehow grapple
with that, that will let you
be free of the consequences
of that early experience.
Almost none of that has
withstood the scrutiny of
practical science.
A lot of it, you don't
even know how you
could begin to test.
Now for those of you who become
physicians, and the
rest of you will be patients,
it's amazing how much of
medicine is not science-based.
It's amazing.
So you hear the cry all the time
in medicine, we need to
have science, or evidence-based
medicine.
And you might have thought,
well, what
else are they doing?
OK.
And the answer is they're
treated as best they can and
what works, works.
A lot of stuff they don't
understand exactly when and
why it works.
But they apply what they can.
There's a patient in distress.
Freudian ideas are everything
that you know about ids, and
electric complexes, and all
that kinds of stuff.
Hard to prove that they exist
in any scientific sense.
So weirdly, Freud is in many
ways marginalized in the
current scientific psychology.
That doesn't mean he wasn't a
creative mind that influenced
the way people think about the
human mind, and treating the
human mind.
But the specific ideas he has
are in many ways at the edge
of the field.
So more central to the field
is work called cognitive
behavioral therapy, or CBT.
This is Aaron Beck,
who's maybe the
foremost figure in that.
And that CBT was developed to
be exactly the opposite in
many senses of psychoanalysis.
So similar because it's about
behavior, and about the
interaction between a clinician
and a person seeking
a sort of happier, healthier
approach to things.
But the Woody Allen version of
psychotherapy, where you go
for 40 years weekly to your
psychiatrist on the west side
and talk through your
problems, OK.
That idea, people said, well,
that's fine if you do that.
But is that really what we mean
by treating somebody?
So Beck said, in things like
anxiety or depression, people
have dysfunctional beliefs that
the world is threatening,
that the world is hopeless.
These are sort of logical
thinking errors that you can
work yourself out of to make
yourself less depressed or
less anxious.
That you should focus not on
childhood causes of what
happened, but on current
problems you face day-to-day
and how to grapple with them.
Develop strategies that don't
make you get down and
depressed, or fearful
and anxious.
And that it should
be time limited.
Eight weeks or something, from
beginning to end period, not
an endless review of your life
and roots of your life.
And so people are like that
because of part, it's easy to
test in research studies.
It's been shown to be pretty
effective, pretty much on a
par with medications
in most studies.
And in some cases, better.
And a psychoanalysis
could go forever.
It's hard to experimentally
test that in many ways.
So there was questions about
whether psychotherapy works.
And if you're kind of a
scientist, you kind of like
biological stuff like pills,
not talking, right.
Although talk is
very powerful.
And now, and early on,
people say, well,
maybe it's all baloney.
And I would say that starting
around 1980 from this review,
people said, no, there's
a lot to it.
Although not everything
we wish it did.
So they performed
a meta-analysis.
You may have heard of these
kinds of things.
Where it was a quantitative
method for averaging results
of a large number of
different studies.
The ideas is that statistically,
if you combined
many different studies, you
might have a sort of an
overall picture.
It's not just describing them,
but taking their actual
statistics and combining them.
Looking for the effect size,
something about the consistent
size of, in this case, a
psychotherapy treatment.
And then asking what happens
in the terms
of the effect size.
And you come out with a picture
like this in the study.
That you have an average effect
side of a 0.7 that is
treated people.
This is getting better
this way.
We're on average better across
many different studies.
So the treatment seemed
to move people
in the right direction.
And that furthermore, about half
receiving psychotherapy,
the average person was better
off than 80% of the people who
didn't get it.
So not everybody benefits
greatly.
But many people benefit some.
About 10% got worse.
So this number says only
a few get worse.
A weirdly different thing, was
that people have always want
to develop very clear ideas
about which forms, of many
possible forms of behavioral
therapy are really powerful
for which difficulty, or
which kind of person.
It makes sense, right?
That the different problem
you're facing and the kind of
person you are, a different
kind of talk therapy,
different kind of CBT would
be powerful for you.
And that's been incredibly
hard to
demonstrate in most cases.
Shockingly hard to
demonstrate.
And part of that comes from
these kinds of studies.
So the best of these kinds
of studies have random
assignments and to different
kinds of treatment.
For psychotherapy, you might
have a wait list.
And you could be blinded as to
getting a good or bad version.
So again, here's another
meta-analysis.
And here's the kind
of big surprise.
Again in this next
meta-analysis, about 2:1
chance of improving, versus
control, if you sit there and
don't do anything.
So that's again, a good way to
go if you're in distress.
Here's kind of a surprise,
credentials don't matter,
Ph.D., M.D., no degree.
There might be something about
the kind of person who's a
more or less effective
therapists.
That's been hard to
scientifically demonstrate.
The degree you have has never
correlated with the
effectiveness of
the treatment.
Here's another big surprise,
the experience of the
therapist didn't matter.
Beginning, middle, end of
career, seen a lot of
patients, not seen a lot of
patients, that doesn't
consistently matter.
The type of therapy doesn't
consistently matter.
The length of therapy doesn't
matter in any way that people
have been able to show
scientifically.
What seems to matter is talking
to somebody who
listens to you on a
consistent basis.
Yeah?
AUDIENCE: [INAUDIBLE]
PROFESSOR JOHN GABRIELI: That's
for all these kinds of
things, right.
So on the one hand, you wouldn't
want to push it to an
absurdest thing because there
are humans involved.
You wouldn't want to say, well,
just for fun, let's take
somebody's who like a
three-year-old and send them
out to see what they
can do, right.
So I mean, there's a real
person involved
here in real distress.
But whenever they've
done these kinds of
things, they adjusted--
And CBT is the most consistently
studied because
it's very organized.
Psychotherapy, so many people
do so differently.
It's very hard to study.
And CBT is time-limited.
So that approach seems more
practical in some senses to
people's minds.
So most of the research on
behavioral therapy is focused
on CBT, but not exclusively.
But people never been able to
show that these things matter.
Maybe there is something about
the bedside manner so to
speak, of the clinitioner or the
person who talks with you.
But that's never been extracted
rigorously.
And then the other approach of
course is many different kinds
of medications that you read
about or hear about or
experience all the time.
It turned out, let me just say
it were, to be extraordinarily
hard to develop medications
for psychiatric diseases.
There's been a number that
have mostly been
discovered by accident.
Most of these were medications
developed for something else,
they kind of stumbled
on as useful
for psychiatric disorders.
In the last 20 years as people
have developed drugs more
systematically, it's been
brutally hard to develop drugs
for psychiatric disorders.
There's hardly been any major
new ones in the last 10 years.
And many pharmaceutical
companies are now abandoning
their current research programs
because they just
don't feel they're making
any traction on it.
So it's been really,
really hard.
I mean the mind and brain
is just so complicated.
And so you get all kinds of
partly political debates about
people who are concerned about
what's right for children.
Are we giving kids
too many drugs?
Of course, you're never
going to have a
scientific answer to that.
Some kids probably get
too many drugs.
Some kids probably
don't get enough.
We'll come back and
talk about ADHD.
So let's people let's pick for
a moment one disorder.
And then we'll pick OCD,
obsessive compulsive disorder.
So it's a kind of an anxiety
disorder that features
obsessions, recurrent
unwanted thoughts.
People are drawn to patterns
of thought that they don't
want to over and over again.
So the obsessions are mental
patterns of thought.
The compulsions are physical
repetitive behaviors, like
endless hand-washing, counting,
checking, and cleaning.
Done with such intensity and
ferocity that the person's
really trapped by these.
So let me show you one example
of an individual patient
describing her experience.
So the thing with these
disorders is we sometimes say
somebody's a little OCD because
they like to be extra
careful to brush their teeth
four times a day.
But in these cases, these
individuals are really trapped.
I mean they have a hard time
leaving their house, a hard
time functioning socially,
hard time getting jobs.
So people wonder, what's the
most helpful treatment?
And here's a example of a study
looking at how many
symptoms you have with OCD.
And these are individuals who
get, in blue, placebo.
So it's good to be low.
In green, a medication that's
used for the disorder.
And then these colors are
getting behavioral treatment,
or behavioral treatment
plus medication.
So at least in this context
for example, behavioral
treatment is more effective by
itself than the medication.
It would be easy to tell you
oh, there's a rule for
different disorders, that it's
behavioral treatment or
medication.
But it turns out on average,
it just vary considerably
depending on the medication,
depending on the particular
patients you see.
There's no real understanding
yet of which patient should
get which treatment under
what circumstances.
And here is some evidence
suggesting that if you get
medication only, this is the
percent who relapsed.
So a concern is there's active
treatment phase .
And how many people slide back
into the difficulty,
medication-only.
About half the people are
relapsing about a year later.
But if they get this sort of
behavioral treatment, there
sort of seems to be more
sustained benefits.
So people are thinking that
might be important.
And then people wonder, if we
treat your mind by behavioral
therapy, if we treat your brain
by drugs, now we're
going to reject that
distinction.
OK.
When I talk to you, if you
happen to remember anything I
say, I'm changing your brain.
OK.
Talk, or experience, or
thoughts, or imagination
change your brain as
much as any medical
substance does, right.
So it's a wrong way to think,
like the drugs change the
brain and the talk
changes the mind.
To change your mind is
to change your brain.
So but any case, you could ask
whether these forms of
treatment, in what ways are they
similar or dissimilar?
So here's PET scans of
patients with OCD
pre and post treatment.
And you can see that there's
sort of activation in the
basal ganglia in the caudate
that looks pretty similar
across the treatments, as if
both treatments were working
on that over activation
of the basal ganglia.
On the other hand, here's
looking at CBT and drug
treatment for depression.
And you can see these pictures
with these blue areas, and
these with these red areas, the
brain changes in response
to treatment, look
very different.
So there's no simple answer
about whether behavioral
therapy and drug therapy change
the same or different
things to help people.
Depends on the disorder,
depends on the drug.
And we just have a lot more
to learn about that.
But both of those things affect
the brain and can be
effective to help people.
So let's focus on depression
a little bit.
These are people with depression
who feel fearful,
gloomy, helpless, hopeless
in an extreme way.
So it's difficult to get out of
bed, difficult to do work,
relate to people.
Literature, Hamlet's description
of how weary,
stale, flat, and unprofitable
seem to me all the uses of
this world, describes often what
people with depression
roughly describe their
experiences like.
A typical episode,
it varies widely.
It's about 4 to 12 months
if untreated of intense
depression.
A pervasive dysphoria, just
sort of inability to feel
pleasure and intense
mental pain,
generalized loss of interest.
It's estimated to sometimes
affected some 5% of the
world's population.
That's a huge number
of individuals.
Average age of onset is 30.
But it goes across wide ages,
often unnoticed in children.
People are picking this up
more than they used to.
They used to think there's a
thought that children can't
really be depressed.
It's hard to know why that
happened exactly.
Psychiatric ideas are typically
developed in adults.
And it takes a while
for the field to
recognize them in children.
But it's rare to have a first
depressive episode after 60.
It's rare to have gone your life
and then get depression
in older age.
Kind of mysteriously at the
moment, women have depression
at two or three times the rate
of men in the United States,
and pretty much throughout
the world at a two
to threefold increase.
That's a pretty big one.
We'll talk later about ADHD.
There the numbers
kind of reverse.
It's 2 to 3 times more frequent
in boys than girls.
And about 70% of people who
will have one episode of
depression will have another
one later on.
So the diagnosis in the DSM book
requires at least three
of the following for a period.
Now what I wanted to give you
a feeling if you think about
this, you know you are the
doctor talking to somebody.
And you know, disturbed sleep,
but how disturbed
does it have to be?
Diminished appetite, but
how diminish, right?
Loss of energy?
Well, we all have periods where
we're more sluggish or
more focused, right?
I mean so usually depression,
these things are so extreme.
It's very obvious.
Sometimes it's at the edge.
And there's a range
of these things.
We know there's a genetic
predisposition.
If you have identical twins
50%, dizygotic 10%.
But we know there's
environmental factors.
So it's very hard to figure
out whether diseases are
getting more or less
common over time.
Because especially in
psychiatric diseases, the
criteria that defines those
diseased change over time.
So you don't know which it
is, sensitivity to it.
You know, 30 years ago teachers
never heard of autism.
Now every teacher in
kindergarten is watching out
for autism.
So it's spotted much more
quickly and consistently.
So people say it's going up.
Is it really going up?
Is it being detected
more often?
It's very hard to tell
those things apart.
But where evidence is available,
since 1940 there's
nearly a 10-year drop in the
average age of the first
instance of depression.
So is this 10-year drop that
people are getting better at
spotting it at adolescents,
instead of seeing an
adolescent or child as simply
moody, they're recognizing
depression?
Or is the increased pressures
in childhood driving
depression up at
an earlier age?
Very hard to tell.
So here's a video clip of some
patients describing their
experience in depression
So people have been trying to
understand by experiments,
what are the thought patterns
that are promoting depression?
One approach has been
this dot probe test.
We've talked about
that before.
I'll remind you in a moment
what that is.
But basically, it's to
experimentally test the idea
that there's a sort of cycle
of negative thought in
depression that reinforces
itself--
That you pay attention
to sad or bad things.
The more you think about bad
things, the worse you feel.
The worse you feel, the more
you think about bad things.
And this is sort of you know,
a downward spiral of
gloominess.
And another question that people
are very interested in
is, when you see these kind of
psychological mechanisms that
may contribute to depression,
are they there for somebody
who has never yet been
depressed, but it's a risk
factor for becoming depressed?
Or is it really a consequence
of the depression, right?
If you pay more attention to sad
things is that a risk for
becoming depressed
first time ever?
Or is that already part
of the disease process
itself once its hit?
So here's a dot probe test.
We talked about it before
in regards to aging.
You see two pictures.
A neutral one and a happy one.
They disappear.
A dot appears behind
one or the other.
And you push a button to
indicate which side it's on.
All you're doing is indicating
which side it's on.
Or you might get another pair
of faces with a negative
expression and a neutral
expression.
Beneath one of them, sometimes
it's a neutral,
sometime it's negative.
A dot appears.
And then you can look at the
response times, how quickly
people responded to the
dot depending on
where the face was.
And the idea is, the faster you
respond to a dot, the more
your attention was drawn to
a positive, neutral, or a
negative face, right.
Because if your attention is
sitting there already when the
dot appears, boom, you're
ready to go.
If your attention is somewhere
else, you'll
have a slower response.
And sure enough, in patients
with depression, specifically
for sad faces, they have
this bias response.
They tend to respond quickly
when the dot appears where the
negative face just has been.
So it's a way that there was
sort of the attention, even
for such a trivial thing is
drawn to the negative.
It sits on the negative.
And so now you can ask the
question, what about girls who
were born into families with
a history of depression?
So they're in a general way at
genetic risk for depression.
But they have never been
depressed themselves.
So now we can ask the question,
does this mode of
thinking, of dwelling on the
negative is it apparent in
these girls even before they
ever have depression?
And not all of them will.
But you don't yet which ones
will and which ones won't.
And sure enough, if looking at
sad or happy faces, and here
it gets pretty opposite, for the
young girls who have a low
likelihood of having depression,
no family history,
they tend to dwell on
the happy faces.
And for the girls who were
born in a family with
depression, they tend to dwell
on the negative faces.
So you can see this mechanism
of focusing on the negative,
dwelling on the negative already
even before the child
has ever a episode
of depression.
So just for a moment let's
discuss, does that mean it's
genetic or environmental?
Who are these girls who have
a high risk for getting
depression?
What does high mean?
Sorry to put you on the spot.
What does high mean?
They're in a family where they
have a parent with depression.
OK.
So you can't tell that maybe
having a parent with
depression ups the child's
focus on the negative.
Because they've had some
difficult things to deal with
in their family.
Maybe they have genes that draw
them to negative things,
or maybe both.
You can't tell that apart from
these kinds of studies.
Every once in while there's
sort of a success story in
brain sciences.
And why it's terribly important
is this, to this
day, as one of the speaker said,
there's people who think
psychiatric disorders are
just for sissies.
That you just stop
being depressed.
Just don't listen to those
voices, right.
Just stop washing your hands.
And what's very confusing about
this message is for
people for example, who are
addicted to substances or have
alcoholism, we ask them to stop
drinking and stop taking
drugs, with support.
But we say it's, we think
it's somewhere in
you to stop, right.
So with the right support,
we think it's
somewhere in you to stop.
So it's kind of hard.
Where is that line, right?
CBT is getting people to find
ways to think so they're not
anxious or not depressed.
Again, we think it's
in them with the
right kind of support.
So on the one hand we ask
people to get themselves
healthier with support, right.
So it's kind of tricky.
Where is the line of
responsibility?
But I think one of the triumphs
of modern brain
imaging is to make visible the
brain basis of psychiatric
disorders on average.
So because there's no broken
arm, no broken leg, no tumor
or anything like that, right.
That promotes discussion,
or consideration, is our
psychiatric disorders real
brain differences?
And I can also tell you that
unfortunately, we're not
anywhere near where a house
can put up a picture of
somebody's brain and say, oh,
this person's certainly has
depression, or schizophrenia,
or ADHD, or dyslexia, or any
difficulty that you know of.
Nobody can say that on the basis
of a single brain scan
for a single person.
We want to.
We're not there yet.
But we can see on average
differences between people who
have a diagnosis and
people who don't.
So here's a PET, positron
emission tomography, top of
the brain, bottom
of the brain.
They found less activation in
this so called subgenual
anterior cingulate.
The anterior cingulate is this
cortex that sits over the
corpus callosum.
And here in this bottom part
of the anterior cingulate,
less activation in patients
with depression
than control subjects.
And then, looking at structure
now, physical volume.
Also reduced volume in these
areas, in patients with both
unipolar and bipolar, in
this case, depression.
So now we have both
a structural
difference on average.
And a functional difference
on average.
Sometimes in psychiatry there'd
be a brain banks.
When patients passed
away, they'd donate
their brains to research.
And people said, let's go look
in this area in people who
have passed away so we can look
at the cellular level of
what's going on there.
We can't see with brain imaging
anything close to cells.
But with post-mortem
analysis we can.
And there was a big surprise.
The big surprise was when they
looked in this region, there
was a reduced number of cells,
which goes with the reduced
the volume, and the reduced
activation.
But it was in the neurons,
it was the glial.
And you go glial?
We haven't talked about
glial for a long time.
You know neurons are the stuff
that compute the mind.
We all agree with that.
Glial are essential for
brain function.
So we don't understand
what that means.
That these patients would have
an equal number of neurons but
a reduced number of glial.
We just don't know
what that means.
But it was a big surprise.
And over time I think maybe
we'll think about that.
And furthermore, imaging
studies looking at the
anterior cingulate found that
if you looked at the
pre-treatment activity in
this brain region--
I'll show another example
in a moment--
you could see not only changes
that occur with treatment, but
that differences predicted which
patients would benefit
more or less for treatment.
So all these conversion areas
about the importance of the
anterior cingulate cortex in
depression although nobody
thinks that's the whole story.
That the anterior cingulate is
part of a network of areas
that are compromised
in depression.
And another thing that I think
is sort of an exciting
direction is each dot here
is an individual person.
Here's how much they improved.
Better is down here.
This is the patients who
improved the most with
treatment, the least
with CBT treatment.
And this is the initial
activation.
So it's telling you maybe that
these are the patients who
really should get CBT.
And maybe these are
the patients who
didn't respond so much.
And maybe they should get, by
the initial brain measure,
some other form of treatment.
So that's I think an exciting
areas where we could develop
enough understanding of
diversity among patients to
understand which patient might
benefit for which treatment.
But we're just at
the beginning of
that kind of knowledge.
So what about treatments
for depression?
In 2005, that's some years ago
now, but there's an estimated
27 million people in the US.
There's $10billion now
and more in sales.
That's to drugs or CBT forms
of treatment of depression,
the most common forms
of treatment.
Even with these treatments--
so here's the message.
Everybody agrees I think and
reasonably, that if you know
somebody with depression, or
you're depressed yourself, or
anxiety, but we're talking about
depression, getting help
is a good idea.
Many people get helped.
But the help is not nearly
what we wish
it were in the field.
So in depression, about
half of patients
don't achieve remission.
They still are depressed
even after medicine
or behavioral treatment.
And even among those who improve
a lot, there's still
residual symptoms.
It's not as if patients
typically or often escape
entirely that.
But they can improve a lot.
But the other thing is since
nobody knows which approach to
take with which patient by any
scientific evidence, it's all
trial and error.
So finding a good
treatment for a
person could take months.
And by then some people just
give up and don't come back.
Because in the throes of the
diseases, or they just figure
they're not going
to be helped.
It's all hit and miss.
I have a colleague in CSAIL
the computer science
department.
And we're doing research
with her.
And we say, you know, if you
go to a doctor now with
depression, or anxiety, or
social anxiety disorder, it's
almost completely random whether
they assign you to one
treatment or another within
some broad constraints.
There's no scientific basis
for knowing what drug you
should get, or a drug plus
CBT, or CBT only.
It's completely random.
It's depending on the
physician's background and
intuitions.
There's no scientific basis
for knowing that.
So there's a lot to
be discovered.
So sometimes people are trying
to say, well, let's compare
placebo treatments to a
medicine treatment, to
cognitive behavioral therapy.
Here's responding to treatment,
improving.
So better than placebo
or both drugs, about
eight weeks, and CBT.
And then at 16 weeks there's
even more of a gain.
And they look very similar on
average across patients.
And if you look over time now,
after the treatment is over,
at how many people sort of what
the long-term picture is
because you care about that.
I mean there's two things,
getting people out of crises
and then keeping your
head above water.
It seems like the group that
maintains the best response
are the people who had the
CBT over longer periods.
So you might say, well
why don't we just
give everybody CBT?
And part of it is not everybody
responds to that.
Some patients for example, with
severe depression are
talking about suicide.
You don't feel like you can wait
8 weeks or 16 weeks to
let a CBT process happen.
Some patients just don't have
the energy to go to sessions
and work on things.
And you need to rescue
them from that.
So there's all kinds of issues
about what kinds of treatment
ultimately are practical and
effective for patients.
So in clinical trials when
they try a drug.
And I'll focus on drugs
for the moment.
There's a random assignment.
Patients with the diagnosis are
assigned either to or a
placebo or a drug.
The physicians are not supposed
to know what it is.
Response means just getting
better, which is valuable.
Remission means, that you don't
qualify for having the
disease anymore.
How people decide whether
you have depression?
They take a full history.
But they'll often use some
sort of rating scale.
One of the most common is a
Hamilton to say how severely
depressed are you.
So they can document
it at beginning.
Then give that to
you at the end.
And see how severely depressed
at the end.
So one thing to know that's
really interesting, and really
a problem from the field is
there's incredibly strong
placebo responses.
In many studies the placebo
responses rival the response
of the drug itself.
And people have had huge debates
to this day about what
that means.
And it's not well understood.
Some people say nobody is
getting better, that the
entire thing is regression to
the mean from study entry.
And what does that mean?
Well when people have a drug
trials for depression, they
say we want to treat people with
substantial depression.
That makes sense, right?
So you get people who are
substantially depressed.
Depression is inherently
a fluctuating disorder.
So from your understanding of
regression to the mean, what
happens to a patient when you
get them with a really bad
depression score?
What's likely to be
there score next
week, better or worse?
Better.
So you get people with really
low depression scores, you
just sit back, you don't
do anything.
And because it's a fluctuating
disorder, the chances are that
because you're getting them at
low points in, they're going
to get better next week.
OK.
That's not a treatment effect.
That's, you're getting at them
at a low moment by definition.
So some people say, wow, these
studies could be full of that.
We say, wow, look at
this drug effect.
Man, let's push it up.
Yeah, That's because you're
getting people
at their worst moment.
They're going to go back
to their average,
which will be better.
Or another really interesting
thing is could our brains have
incredibly powerful responses
to placebos?
Do we have in us naturally
occurring healing mechanisms?
That if we just really
believe in it, than
those can take over.
And could we harness that?
Could we harness these
naturally occurring
self-healing capacities in
people's minds and brains to
make themselves better?
So this is a kind of typical
average results.
Drug, psychotherapy,
about the same.
Placebo, pretty close.
And here's the no
treatment group.
But even this, kind
of the picture has
been challenged recently.
And let me tell you what the
challenges have been and then
let me tell you what I take
as the takeaway message.
But it's not scientifically
certain.
So one person did a
meta-analysis and
he's totally arguing--
and let me tell you, the
argument's pretty clever.
There's no effect of
a drug at all.
That typically, you get
about 75% of a drug
effect from the placebo.
That's huge.
75% from an inert substance,
sugar or something like that.
OK.
75% in treating a severe
psychiatric disorder.
And he says that that small
difference, that
25% is due to this.
And who even thinks of this
until you read this, if you
haven't been involved in a
drug study, that apparent
differences are due to patients
realizing they have
the active drug from
the side effects.
OK.
So most studies give
you the drug.
Most drugs that treat things
have unpleasant side effects.
Because they're potent
things, OK, that
are perfectly targeted.
So they're saying oh,
it's double blind.
You tell this patient,
here's your pills.
You don't know if they're
placebo or drug.
And here's your pills.
You don't know if they're
placebo or drugs.
But patient's are reasonably
smart.
Many have been through
treatment before.
And they know if they're feeling
nauseous, and yucky,
and all kinds of other stuff,
they got the drug.
And if they take it and they
don't feel anything funny,
they got the sugar placebo.
Does that make sense?
Because they figure out--
and 80% of the time they're
accurate, whether they got the
inert placebo or the drug.
Because this side effects tell
them that, not the drug effect
on the mind.
And that in the few studies
where they give you up a
placebo that has peripheral
effects, that make you
nauseous like the drug, then
in those couple of studies,
there's just been a couple,
there's no difference between
placebo and drug.
So here's a position that the
entire thing is placebo.
And an argument from this guy
that we should tell patients,
it's all placebo.
Now why do you think that it's
not necessarily a good idea to
tell patients even if it were
scientifically true?
Yeah?
AUDIENCE: Because if you
tell them it's a
placebo it could ruin--
PROFESSOR JOHN GABRIELI: Yeah.
There's a pretty good chance
you've ruined it.
If you hand them the pills and
you go, look, who know.
It's all sugar.
But you know give it
a go for a person
who's in misery, right.
So they have to kind
of believe.
And it's kind of interesting.
What is the biology
of that belief?
Right.
So that's one side
of the story.
Another slightly less drastic
interpretation, but also
pretty strong, is that in recent
meta-analysis is that
the drug effect of a placebo
only occurs for the most
severe depressions, the most
severe depressions.
And the Depression Center even
considered severe or moderate,
where you do want to help
people, there's no difference
between the placebo
and the drugs.
So my only fear in telling you
this is the last thing you
want to do if in your life, or
somebody you care about,
there's depression or anything
like that, get them help.
Because there are helped.
And if it's placebo,
that's OK too.
And if it's some unreputable
person without a degree but
they're really good at talking
to people, that's good too.
OK.
The evidence is overwhelming.
That getting help helps
many people.
And not getting help
out people at
greater and greater risks.
It's overwhelming.
Getting help is a really
good thing.
It's just that we don't
understand how the help works.
And we know it doesn't help
nearly powerfully enough on a
consistent basis.
So now we're going to switch
from depression to ADHD, a
disease of childhood.
These are children who have
inattention, hyperactive in
80% of cases, impulsive, moving
around, and jumpy.
The diagnosis, like everything,
is by exclusion.
They make sure that there's not
some other problem in the
child's life that's making
them inattentive or
impossible.
For example, like
abuse at home.
Its prevalence is 2
million or more.
It's tripled since 1981,
increased 2.5 times since '90.
So sort of like the discussions
you hear now about
autism, there was fantastic
debates about ADHD.
Does it exist at all?
Are people just medicating kids
to keep them lined up in
classrooms, quietly listening
to lectures like me?
Is there a real problem?
And there's incredibly
polarized
debates about these things.
So how does the clinician
make the diagnosis?
They look at the child.
They talk to parents,
teachers.
And they sort of fill out
questionnaires and have a list.
And I'll show you the kind of
a list the clinician has to
work against.
Depending on studies, and this
is kind of an interesting
number, ranges from about
2% to about 15%.
And you can say, well how could
it possibly do that?
Why can't researchers
get it right?
OK.
You could take a 1/2 a percent
off, or two or whatever it is.
And again, it depends
so much of your
criteria for the diagnosis.
Part of it too is over time
these things change as you
have different versions
of DSM.
And I mentioned also countries,
professions,
overnight in the same German
population doubled as DSM book
got revised and changed
its criteria.
OK.
Is this the correct criteria?
Are these the correct
criteria?
And how would you know if you
had the correct criteria?
How would you know if
you've got it right?
People just have to
have consensus as
best they can guess.
Because there's no objective
evidence beyond reasonable
interpretation.
So about 3-5% of school
age children.
And the reason that people take
it seriously beyond these
conceptual debates is that
children with ADHD that is not
treated struggle a lot.
To a huge variation of course,
but it predicts anti-social
behavior, substance abuse,
adverse occupational social
adjustments.
There are people with ADHD who
are phenomenally successful.
There's probably several of you
in the class who have been
diagnosed with that in
any group like this.
So it's not the certain thing,
but on average if you don't
have other talents, and
situations, and support, it's
a big risk factor for doing
badly in life by the ways that
most people want to do well.
The most common, but not the
only treatment, is a Ritalin
or methylphenidate.
The Ritalin is the commercial
name, methylphedidate the
generic name.
We know there's a genetic
piece about this.
You've heard it so many times.
7 times higher rate within
families, about a 0.76
heritability in twin studies.
Some candidate genes have been
identified and involved in the
dopaminergic systems
of the brain.
But like with all
neuropsychiatric diseases, in
kind of a weak way.
It's not like there's a
gene, if you have it,
you have the disorder.
Is just a little higher on
average in populations.
OK.
So here's the question,
a kid comes in to you.
You're the doctor.
And it's quite interesting to
talk to doctors about this.
Because in many medical settings
with the current
economic environment, doctors
are incredibly encouraged, and
by for example, their salaries,
to see patients
really fast.
The faster they see them, the
more the health systems says,
yeah, we're productive.
So here's what they have
to decide, do you had
inattention?
Because inattention was one
of the big criteria.
You have to have at least six
for at least six months to
agree that it's maladaptive
and age inappropriate.
Careless mistakes in school or
productivity, I'm sure none of
us ever make careless
mistakes, right.
Difficulty sustaining attention
in tasks or play,
does not seem to listen when
spoken to directly, not follow
instructions to finish tasks,
difficult organizing tasks and
activities.
Avoids, listen to this one,
avoids tasks engaging
sustained mental effort, OK.
Loses things, easily distracted
by extraneous
stimuli, forgetful in
daily activities.
What five-year-old is
not describable
in these ways, right?
So you see how challenging
it is?
And it's not to take
it lightly.
Because the kids who really
meet this, really
struggle over time.
There's been many longitudinal
studies.
That on average, children who
meet these criteria will
struggle in many ways.
But look at all of these.
There's nothing here like
hearing a voice, right?
It's just like a kid.
But a little more of
it for your age.
Hyperactivity, you fidget
or squirm in your seat.
You leave your seat
in the classroom.
You run about or climb
excessively.
You have difficulty
playing quietly.
You talk excessively.
Blurts out answers before
questions are completed.
So these are kids who are
tough on teachers in
classrooms.
The symptoms have to be present
before the age of
seven, persistent in two or
more settings, at home and
school for example, typically.
And then not because you don't
hear well, or because you have
allergies, or you have other
psychiatric disorders.
And sometimes people talk about
both, inattention and
hyperactivity, or the
combined type.
There is a thought that the more
frequent finding in boys
is because boys are more
frequently hyperactive.
So they're trouble making
in a classroom.
They're jumping up and down.
They're not listening
to the teacher.
And the girls might be more on
average inattentive, quiet and
dreamy, not taking stuff in.
That's not a problem for
classroom management.
So there's a thought the girls
might be under diagnosed
because of the way it's
expressed in boys and girls.
But there's a huge source
of evidence that if left
completely untreated, rates of
depression, anxiety, substance
abuse, academic failure, work
problems, family problems,
emotional distress are much
higher in children where
there's no attempt to treat
or manage ADHD.
There's a huge amount of
evidence for this.
So one of the sort of most
famous studies in
developmental psychiatry of
directly comparing individuals
on behavioral and
drug treatments.
It was a study called
the MTA study.
It was done in many different
sites all put together with a
huge number of children, 14
months, they got medication
management alone, behavioral
treatment alone, a combination
of both, or routine
community care.
So they said, what happens
when we give you better
behavioral treatment, or more
careful medical management on
the drugs, or you go back to
your standard community care?
And what people found was
this, that medication
management alone--
Here's what they did in
those conditions.
They saw a doctor monthly
for 30 minutes.
They would move the drugged
amount up or down.
They would titrate it if it
seemed to be sedating the
child too much, they'd
make it less.
If it was not working enough,
make it more.
And they will talk a lot with
a child and the parent.
So that was the medication
management.
More active than you typically
get people get at medical
interactions.
Behavioral treatments involved
an 8-week summer camp, or you
got the two of them together.
Or you were sent back to your
community and got the regular
care from a regular doctor that
people typically get.
So and the big outcomes were
that the best thing was to
have the medical management
alone, or a
combination of the two.
And in some cases, you would get
lower doses of medications
if you got the behavioral
treatment.
So you could say, and for many
years I heard lecturers who
were expert in this field
saying, the definitive thing
is the medication pretty
much does it all.
Maybe the behavioral treatment
had something, the behavioral
treatment by itself
didn't add much.
This was what everybody
was taught.
But they kept following
these people and
here's what they found.
Eight years later after the
study was over, no difference
in which group you were in.
About 60% of kids stopped taking
medication, the family
decided to stop, or the doctor
decided to stop.
And there's no difference
between those who did or did
not stop taking medication, in
terms of difficulties in life.
So now this is very
complicated.
Because people always say like,
what is the long-term
effects of taking Ritalin
in children?
What is the long-term effects?
And you go well, you
could say the first
interpretation is this.
Well, since it didn't make any
difference, the drug has no
effect at all, right.
You take the drug, you don't
take the drug, you have the
same outcome.
14-months was something.
But eight years, it
doesn't matter.
But of course, who's more likely
to stop taking the
medication?
Kids who are doing better or
kids who are doing worse?
Who's more likely to
stop probably?
On average, kids who are
doing better, right.
So maybe what you're really--
maybe no difference is some
kids were improving
for other reasons.
And so really, the kids who got
the medications caught up
with them because of
the medications.
And you can't tell those
two things apart.
So it's just incredibly hard
to know with certainty what
the right thing to do is
in any long-term view.
Because you can control for
14-months what people do, if
they're willing to
let you do that.
But you can't control
it over years.
They go back to their own
complicated lives.
And sorting out what the
treatment did, versus the rest
of their life is really hard.
So Charlie, if we could
do the VCR movie.
Here's a example of a kid
with ADHD and some
discussion about that.
You know, amazingly I can tell
you that even though they're
as good as it can do, there is
no behavioral test you can
give like this that's better
than 50/50 at separating an
ADHD child from other
children.
So you could be part
of the story.
But many, many, many children
will not be identified this
way even though they're having
real problems at
school and at home.
I want to say two things
about the video game.
People, as they noted
here, sometimes ADHD
diagnoses are tough.
Because when kids come into a
new situation, a doctor's
office, a new doctor,
an evaluation,
it gets their attention.
And they look more
focused, OK.
And people have noticed that
kids with ADHD seem to do
quite well when they have an
entertaining video game, which
is easier to enjoy, right,
than most things.
So they actually did the study
to ask how long does an ADHD
kid play a video game versus
a kid without ADHD.
And when they're both playing
video games, still the ADHD
kid plays for less long.
So it's not that it
takes it away.
But it in many ways, obfuscates
the difference.
So one interesting question
is what is the right dose?
Because we said the treatments
where they titrated the dose,
where you went to a doctor
frequently and they said let's
push it up, let's push it
down, let's get the dose
that's right for the child.
What is that number?
So here's a paper all the
way back from 1977.
Here's placebo, here's a small
dose, here's a large dose.
And they measured three
different things.
They measured how well
you did in terms
of the teacher ratings.
So a teacher say, how's
the kid doing?
That's the open bars, OK.
So the teacher said, here's
how the kid's doing.
They go, well, this
is even better.
And they go this is
even the best, OK.
So the teachers are saying,
the more drug the better.
Here's an objective measure of
learning performance by those
children, the same children.
Better, worse.
So you see, we go back to the
ideas that came out of the
prefrontal lobotomies,
completely different topic.
Everybody pretty much in the
field agrees that these drugs
help these kids on
average, OK.
But think about the
complications of what the
right dose is.
For the teacher, the biggest
dose is best.
And why do you think that's
likely to be?
For the teacher doing classroom
management with the 30 kids?
Why does a big dose seem best?
Yeah?
AUDIENCE: Because they want
the kids to be really
manageable.
PROFESSOR JOHN GABRIELI:
Yes Yeah, yeah.
You were going to say
the same thing.
Yeah.
For them it's the kid is not
fidgeting, not jumping around,
distracting the other kids.
So a slightly over-sedated
kid seems like a triumph.
And it can be to a parent also,
like listening to me.
But objective learning measures,
this is optimal.
And this is overdosing.
So I think we'd all agree.
This is the one that matters
most of all.
But you can see, you don't
often have this kind of
measurement.
Often the doctor says, what
does a teacher think?
What does the parent think?
And the kid will end up over
here because that's what seems
most correct to the eyes of the
teacher or the parent, the
biggest change in the
child's behavior.
So for the last couple of
minutes I want to talk about
brain imaging in regards
to ADHD.
So we talked about the idea that
the cerebral cortex, you
have too much of it, too many
neurons and over connected.
And that what it is to grow the
adult brain you have is to
eliminate neurons and synapses
that are not
functionally valuable.
You're picking out
the most valuable
players of your neurons.
And so you can say there's a
peak age at which you go up
and then you go down.
And you consider that peak to
be a sort of milestone of
development.
And you can see here in the
dorsal lateral prefrontal of
the cortex, here's the
front of the brain.
Here's the delay in
ADH children.
They take an average two years
longer to reach that peak than
do typically developing kids.
But there's no difference
at all in primary
somatosensory cortex.
So you might imagine it on
systems that are the inputs of
sensory stimulation
from the world, an
ADHD child is typical.
For parts of the brain that
regulate, like I'm not going
to pay attention to that or I'm
going to focus on this.
That's slower developing.
And you could see how that might
lead to inattention or
easy distractability.
So a two-year delay in the
development on average of
prefrontal cortex structure.
I talked with you before,
and I'm just going to
remind you of this.
That if we look at reward
systems, anticipation of a
reward coming up in a few
moments activates the nucleus
accumbens in animals
and humans.
This is in humans, anticipation
of a reward.
And the same system that's
measured here goes on to the
medial prefrontal cortex.
And that system turns on when
you get the reward.
So one thing anticipates.
And one thing responds when
you get the reward.
And there's been some slightly
divergent studies in ADHD.
But one suggestion
one is this.
So here's the control subjects
anticipating the reward.
Here's the ADHD individuals also
anticipating the reward
but not showing any
activation.
It's as if, now remember the
reward is this, you get a
signal that tells you in a few
moments if you push a button,
you're going to get $1.
This is not like study now, and
if you complete college,
you get to go to
medical school.
It's not delayed
gratification.
It's anticipating reward coming
up in about 10 seconds.
And at least in these
patients, it
doesn't drive the system.
It's as if delayed gratification
were not having
any attraction with
these brains.
On the other hand, then you find
out if you got it or not,
because sometimes they trick
you don't get it, orbital
frontal response and
controls, and much
more in ADHD patients.
If this picture is true, or at
least true for some patients,
imagine the consequences of
anticipating reward, but being
overly responsive to whether
you got it or not.
You'd be stimulus
bound, right.
You couldn't hold
yourself back.
It's not helping you develop
delayed gratification.
And here's one more thing
that people ask,
which is if you have--
because now there's some
evidence about this-- if you
give Ritalin for a while, does
it's slow the development of
the cerebral cortex?
And I won't go into
the details here.
But he answers is it does not.
So people are worried, like if
we keep giving Ritalin for
some more years are we affecting
brain structure?
And the evidence is clear.
Objectives of it is
that it is not.
So I think a lot of people feel
like if the medication's
helpful, there's very little
evidence there's
harmful side effects.
Weirdly enough, Ritalin--
and we'll come back to
this just in a --
is one of the least problematic
medications in
psychiatry, and frequently
helpful.
So the last FMRI study I want
to show you is this.
Let's say you gave Ritalin not
only to children with ADHD who
are taking it.
But also typically developing
children who've never taken
Ritalin because they're
typically developing.
And how do their brains
respond to that?
So here's some ADHD children,
and children without ADHD.
And here's the tasks
they perform.
Sometimes they push a button
every time a letter appears--
they're having a whole bunch of
letters here, push, push,
push, push.
But they're told when an
X appears, don't push.
So you're tricking
the subjects.
Because you're getting
a habit going.
What people call . prepotent
response.
So it's push, push,
push, push.
Oops, hold yourself back, OK.
What people call no
go, don't go.
And that's hard to
do for a kid.
It's harder to do for somebody
to do with ADHD, to control
the impulse to push.
And so you measure brain.
And here's the behavior.
And then let me tell
you the issue.
So here's the percent
of false alarms.
This is when you pushed for the
X, you should have held
yourself back.
Here's the control, here's the
ADHD children, making more
impulsive errors overall, harder
to control themselves
and stop themselves from pushing
for that X. When
they're off Ritalin they make
more mistakes when they're on.
But look at these kids who have
no ADHD and never took it
because they have no
reason to take it.
They perform better.
But look at the drug effect.
Just the same size.
And this is not the only study
that has found that giving
typical children Ritalin, will
make them perform better on
cognitively demanding tasks.
They are typically not done so
well by children as by adults.
So the psychiatrist we worked
with on the study said, wow,
we used to think that if we gave
somebody Ritalin and they
behaved better, we knew we
gave the right treatment.
But it's not clear that these
kids aren't behaving better.
OK.
They have no problem.
And there's no reason to give
them the medication.
And let me step through this.
If you look in the brains at
where the Ritalin's affecting
things, and lots of the brain,
the control subjects, and ADHD
children look alike.
The only part of their brain
that looks really different is
in the basal ganglia, part of
their brain that's involving
in habits and impulse
controls.
Also implicated in OCD that
we talked about before.
It's an area that's full of
dopaminergic systems.
It's an area that Ritalin
binds to.
When you look inside the brain
in animals, and here what was
found was this.
So this is a behavioral
difference you saw before.
So if you look in the basal
ganglia, here's the controlled
children off the medication,
and then on the medication.
Here's the ADHD showing this
opposite response.
So here's the only place where
the responses are different
between the controlled children
and the ADHD children.
And you can see in a way the
medication is so-called
normalizing the activation.
So here's typical kids just
being themselves, no Ritalin.
Here's children with
ADHD not treated.
And now you can see.
Now look how similar they
get with the treatment.
OK.
So in this part of the brain,
and its opposite effect when
the typical children get the
drug, the activation go down,
the ADHD children, it goes up.
So this part of the brain seems
like it's an important
part of the story.
And also of how the medication
influences somebody.
So last thing I want to talk
about for two minutes
including the chapter in this,
or three minutes is the
struggle that people have of,
what's the boundary between
treating an outright
disease and
manipulating normal variation?
So for example, here's the
average height in the US of
men and women.
Huge debate about whether people
who are on a very sort
of, are projected to have
a very short stature in
adulthood, should they get
growth hormone or not?
One argument is no, why
even think about it?
Some parents will feel like,
my kid might struggle.
Give the kid a break.
You can do something about it.
You don't have to do that.
How about sadness
and depression?
If you're somewhat sad,
should they get CBT?
Or do they have to be
and dark depression?
Where's the boundary between
shyness and social anxiety?
Or a kid doesn't follow
directions, when do you say
that's a kid not paying
attention to ADHD?
So one of the big surprises
has been that when people
have--and you guys can
tell me in a moment.
When people pole things,
you never know how
accurate these are.
In some polls 7% of university
students without ADHD say they
take methylphenidate to help
them focus and concentrate on
their studies.
And even more disturbing to
scientists, in one study in
nature, 20% percent of
scientists said they do it.
So I'm not asking you
to turn yourself in.
But this is my little poll of
undergraduates in the world
out there, because that's what
I read in the magazines.
So is there moderately
widespread use of it by people
who are not prescribed
directly themselves?
Or is it pretty rare?
Rare?
It could be rare, you know.
OK.
And then what is the
right thing?
Where in all this will people
debate about this?
I think there's no debate that
for people who are really
suffering, you want
to help them.
But where should the line be
drawn between you know,
helping those in despair and
boosting those in the middle.
So last example I want to give
you just for a minute is this
chapter from a man who mistook
his wife for a hat.
Because of this question about
boosting experience.
So this is a woman of
90, Natasha Kay.
She comes to the clinic.
And after her 88th birthday
she began to change.
She felt thrilled.
She was extremely well.
People said see had changed from
being shy to flirtatious,
giggling, telling
jokes at age 88.
She had this huge
transformation.
It turns out she has
syphilis, what she
calls cupid's disease.
But she's quite enjoying the
change in personality.
She's disinhibited and having
a good time, OK.
It's like the small bit of
alcohol that loosens you up
but all the time without any
of the downside, right.
And then they said well,
should we treat it?
Because she got the disease at
an age when penicillin was not
widely given.
And they discover happily that
if they treat the penicillin
it protects her medically.
But because the brain changed
from the neurosyphilis has
occurred, she remains very
happy all the time.
So you know, if somebody could
give you a drug that could
make you very happy all the
time, bad idea, good idea?
Anyway, so you could
think about it.
Thanks very much.
