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PROFESSOR: So today and next time we're going to talk about
psychopathology--
people whose minds, brain, and behavior are atypical more
often than not.
But we'll talk about this in a moment.
These people face struggles, difficulties, and huge goals
to try to help such individuals.
So we'll talk a little bit about the history of ideas in
psychiatry and psychopathology, a little bit
about the ideas of diagnosis and labels.
And I'll do a little film of a patient with schizophrenia.
But there's an intuition in some places and some lives are
led that psychopathology is rare.
Here's a list of not all psychiatric
diagnoses but some of them--
schizophrenia; bipolar disorder; depression;
substance abuse (drugs and alcohol); anxiety; panic
disorder; phobia; developmental ones like
autism, ADHD, and dyslexia; obsessive compulsive disorder.
Tomorrow, I'm reviewing a lot of research grants for
anorexia and bulimia.
So if we take this list that you just saw and heard and ask
how many of us in this room know somebody
that we care about--
could be yourself, could be a family
member, could be a friend--
know somebody who is touched by one of these diagnoses?
If you're willing to put up your hand, who's touched?
Look around the room.
Right?
An incredible number of people are touched by this.
And so it's a terribly important topic to understand
and to help individuals and families who are struggling
with these things.
And in fact it's estimated--
we'll talk about these labels exactly-- that about half of
all individuals, at some moment in their life, will
qualify, men or women, at least for a brief period of
meeting some psychiatric disorder.
It can be rare and devastating.
Like schizophrenia--
1% of the population worldwide, typically
devastating in its consequences.
It can be potentially milder like depression which ranges
from very severe to somewhat moderate and, interestingly,
occurs considerably more often in women than men.
And we'll talk about that next time.
There was a recent survey done-- a public health survey,
5,000 young adults, half of them in college like you, have
them out of college.
They surveyed them and talk with them.
And about half qualified to have some sort of psychiatric
disorder within the last year.
Whether they were in or out of college didn't make a
difference in this study.
But fewer than a quarter of those who met some criteria
went and sought help.
So how through recent history have people thought about
people who behave differently, who are so depressed they
can't get out of bed, who hear hallucinations, who behave in
agitated ways, and bipolar disorder?
And it's as much a history story and a story of culture
and tolerance and intolerance as it is anything else.
And so unusual or mad behavior, behavior that's very
disturbing, and atypical--
now there's debates about all of this.
And so, for example, some people have argued that
everything that we call psychiatric disorders is
nothing but the labels we give to behaviors that we find
uncomfortable or unproductive.
OK?
It's nothing but that.
It's just variation.
Some people are taller and shorter.
Some people like vanilla or chocolate ice cream.
And some people do or do not have bipolar disorder.
All right?
It's a label that's given for just
variation in human ability--
and we'll talk about that-- or human performance.
And there's many consequences of that.
Others think that there's a humanitarian need to
understand the disorders to help people.
So as you think about these two sort of perspectives, you
can think that when people behaved very unusually--
I'll show you a picture of this that we think some time
ago that people would literally trephinate, that is,
make a hole in the skull of individuals to attempt to let
out the demons.
That was the interpretation of the time.
There's a thought that the witch hunts in the 16th and
17th centuries, the Salem trials in the United States
may have involved patients with things like Huntington's
or Tourette's.
People didn't know how to interpret unusual behavior.
And so label it as possession or label it as witchcraft or
something like that.
Insanity began to be understood as some sort of a
disease but without any approach to treating it or
helping individuals.
Basically, the process was to segregate individuals away.
And you would have very large, pretty scary institutions with
people literally chained and living in filthy conditions.
There was nobody to care or protect for them.
In a London zoo you could go pay a penny and watch the
humans in the cages.
They had not as many visitors as are in London now for the
royal wedding.
But they had 96,000 in 1814.
It wasn't a rare thing to go pay your penny and look at the
scary people.
More recently we understand there's an organic illness and
a psychological illness.
And we'll talk about all that.
But all this is a huge point that how we understand unusual
behaviors and people is tremendously influenced by the
historical context that you're in.
And we'd like to think we're making progress on this.
I think we are.
But a generation from now people might look back and
say, how sad that in 2011 people at MIT were teaching
stuff like this.
Right?
Because if they were that wrong, how certain are we that
we're that right?
So one has to be a little cautious about very strong
positions on these things, I think.
Here are skulls that were discovered with the
trephination and some evidence that the person actually
survived this kind of radical neurosurgery.
But you understand at the time when somebody behaved very,
very unusually, people had tried to explain what's going
on and tried to do what they can.
Here's pretty monstrous looking devices, heads in
boxes and things kind of like this, where people were trying
to treat, if you want to call it, or control individuals who
were having very unusual behaviors.
Here's a huge hospital.
It had thousands and thousands.
The name of the hospital is Bedlam.
And that's what led to the word bedlam now, more
generally used for sort of wildness or craziness.
And paintings like this one from Goya showing a madhouse.
Because at that time, don't forget, when people-- there
was no drug treatment, no behavioral treatment.
People were behaving in scary ways.
And they were sort of put off to the side to be out of the
range of disturbing other people.
Now the first step towards teaching psychiatric diseases
turns out to be a giant misstep.
But it took a long time for that to be understood as a
giant misstep.
This is Egas Moniz who did something that all of us as
scientists would be happy to have happen to us.
He won the Nobel Prize in physiology
and medicine in 1949--
the pinnacle of scientific respect throughout the world.
And he introduced what's now called frontal lobotomies or
prefrontal lobotomies as a treatment for severe
psychiatric disorders.
And then in the United States, Freeman and
Watts picked it up.
And they went around the country taking basically ice
picks, going inside, and making various
cuts inside the skulls.
By 1942, there were 5,000 people per year worldwide
documented, probably more than that.
These were cases.
And we now look at it as a terrible idea.
But at the time, this is all they could imagine.
And that seemed better than putting people in boxes or
cages was to attempt to treat it.
And even a kind of a nascent understanding that very
unusual behaviors went with something
to do with the brain.
We now understand these front frontal lobotomies or
prefrontal lobotomies, surgery to sever the connection to the
frontal lobes, as not treating the disorder but simply
sedating and controlling individuals.
When you made a person who was very agitated, hard to deal
with, hard to control, hard to reason with, you give a
procedure like this, all of a sudden they were easier to
deal with for the doctors and nurses and family members.
And that seemed like progress.
And we now understand that simply making somebody behave
in a sedated, controllable way is not what we
mean really by treatment.
But we'll come back to this in a minute because many
individuals who get medications don't like to take
their medications.
Some of you may have that experience.
They feel they're dulled down in many cases,
not themselves anymore.
And so it's a really tricky issue at what level some
medications start to approach that same issue of just making
people behave in ways that other people find comfortable.
So a nice example of this or challenging example of this is
from your book where there's a guy named Ray.
He has Tourette's syndrome.
So we classified that as a neurological disorder but has
a sort of psychiatric pieces.
You know Tourette's syndrome.
If you don't know from your own life some way or another,
you know it from movies.
And TV shows love Tourette's syndrome like law shows with
courts because what do patients with Tourette's
syndrome do?
They have involuntary physical tics.
And part of what they have is they, during those tics, they
curse in pretty horrific ways, in an uncontrollable way.
So that's ideal for television plot lines.
It's unbelievably hard for the children and adults who have
it because they're often perceived as being scary and
dangerous if they're not in a controlled state.
So here's a guy named Ray who has tics every few seconds
since age four.
Imagine if you haven't been--
maybe some of you have gone through this or know somebody.
It's very tough on children to have that problem, tough on
adults but really tough on children.
By the time he's an adult, he's a weekend drummer.
He loves to play ping-pong.
But he's not doing too well in terms of jobs.
He loses his jobs all the time.
And his home life is pretty miserable.
He has a pretty miserable life at work and at home.
He tries Haldol which is a drug that can help with
Tourette's.
And what happens to him?
Is he instantly cured of his tics and the
happiest person around?
Have any of you glanced at this?
Yeah?
AUDIENCE: Life seemed to slow down.
And he keeps trying to do things he used
to do with his tics.
And he hurts himself, because his eyes--
PROFESSOR: Yeah, because it's slowing his--
he feels slowed down.
Exactly.
So he comes back with a black eye and a broken nose.
So now, in a controlled, voluntary way he
curses at the doctor.
And he says, like just trying to go through a revolving
door, his timing is so off that he injures himself
because the drug has changed, in some sense, who he is.
And he feels that.
He's not himself anymore.
He stays on the drug for three months.
It starts to work.
Over the next nine years he has a steady jobs.
His familial relations improve.
He's successfully treated by sort of
every objective measure--
happiness at home with your family, holding a job, the
sort of two practical things.
But he likes to live a life as two Rays.
On the weekends, he likes to go off his medication and be
himself and be the fast drummer and ping-pong player
that he enjoyed for his early life.
And then he'll take the medication and be the sober,
slow, somewhat sedated individual who is valued at
the workplace and that can work things out with this
family more easily.
It's always this interesting thing about how you're
changing people in order to help them.
And then, what's that line between changing them to fit
in versus helping them?
So what is abnormal?
And we mean in a very statistical sense here, just
being at the tail end of distributions.
Some things we value being abnormal, at one end of the
distribution in terms of success in life.
So what's a mental disorder?
It's a clinically significant behavioral or psychological
syndrome or pattern that occurs in a person and that is
associated with present distress or disability or with
significantly increased risk of suffering death, pain,
disability, or important loss of freedom.
So when I talk with psychiatrists-- and I
collaborate a lot with them on research--
they emphasize, again, the functional consequence.
Can you lead a happy personal life?
Can you lead a reasonably successful professional life?
And that's almost the most important
thing beyond anything.
And there's amazing stories that make you think about
sources of apparent madness or insanity.
And a powerful story for me is the story of Semmelweis.
So he noticed, as a physician in 1840's, that the rate of
death of childhood fever in a ward served by physicians was
four times as high as mothers in a ward in the same hospital
served by midwives.
At that time practically every physician was a male.
And every midwife was a female.
But you were four times more likely to die.
That's a big increase in his death if you were in a ward
that physicians served compared to midwives.
So he wondered what that was about.
And he tended to know, furthermore, that the deaths
tended to occur in women serially who were in one bed
next to the other.
There were physical clusters of these.
And so he began to think, well, for example, if the
priest comes to give the last rites to this person, does
that psychologically discourage the next person?
And he also found out that didn't seem to tell the story.
And then he asked, was the same doctor
going from bed to bed?
And the answer was yes.
It makes sense, right?
Bed to bed, the same doctors going down the line of women.
And what he began to notice is that the physicians we're
reluctant to wash their hands.
Now this sounds ridiculous.
But this is 1840 medicine.
And when he asked them why they didn't wash their hands,
which we would now consider pretty fundamental in a
medical environment.
The basic response was that it was unmanly.
Like, men didn't wash their hands.
I'm a doctor.
I'm a man.
I don't wash my hands.
I'll come back to this in a couple minutes.
So he asked them to wash their hands in a solution of
chlorine and lime.
The deaths fell from 12% to about 1% in 15 months.
All right, many lives were saved because the physicians
simply washed their hands and did not carry infections from
one person to another down the row of child-bearing women.
1848--
there's a revolution in Austria.
He's fired from his job.
The doctors--
you would think this would be better world-- but the doctors
immediately are happy they no longer have
to wash their hands.
And the death rate goes right back up.
Joseph Lister in 1880 figured out the formula of Listerine.
But Lister--
what was going on in terms of cleanliness and sanitation.
Semmelweis in Austria becomes crazy.
He runs around to people in the street, telling them to
wash their hands and avoid physicians.
And he dies in a mental institution in 1865.
And imagine if you were walking here.
And sometimes when you do walk on the street, you run into
people with psychiatric difficulties.
And it can be a bit scary.
Imagine somebody runs up to you and tells you, God sakes,
avoid physicians and please wash your hands.
Most of us would shrink back a little bit.
It would be unusually slightly scary, right?
But is he-- who's the crazy person, right?
And he's tragically feeling that if he could just tell
doctors to wash their hands, he would save lives that day
and into the future.
So but more recently there's a compelling story for
checklists.
I don't know if any of you have seen this book.
So in an emergency room-- you think, OK, that's 1840.
But now we're modern-day USA.
We know what we're doing and doctors do and other
professionals wash their hands.
More recently there's a best seller, couple years ago about
checklists.
So this is what's done in emergency rooms.
And you may know that there's an unfortunately high rate of
errors in hospitals, even among highly skilled
physicians in the best of academic hospitals.
There's just miscommunications between doctors and nurses,
changes of shifts, and so on.
Mistakes happen.
And they began to use, as an experiment, a small checklist,
like five items.
Did you do the following five things about the catheter or
replacing needles or so on?
And almost instantly, there was opposition from the
physicians.
They said, we're doctors.
And some of this was at Johns Hopkins which is, as you know,
a famous academic place.
But I think it would apply at every hospital.
We're doctors-- now men and women doctors.
OK?
We don't need a checklist.
I went to college.
I went to medical school.
I've been through my residency.
I got my specialty and my boards.
I don't need a checklist.
That's for the intern, right?
So they really opposed it.
But they got almost instantly far better results of safety.
And including saving lives almost instantly from the
checklists.
But the physicians still don't like it
because it seems childish.
So even to this day, it's a bit of a challenge to get
professionals with pride to do certain things that go against
the grain, even if it helps people's health.
So, again, we talked about that some people think that
mental illness is nothing but labeling that which we find
unpleasant or difficult, non-conforming, or deviant.
On the other hand, there's two things.
One is-- again, so many hands were up.
I think if you're around it, you know that for many, many
psychiatric diagnoses there's a lot of misery involved for
the patient, for the family.
It's not just a conceptual argument.
And then for many diseases, like for schizophrenia for
example, in very different cultures around the world the
rates are strikingly similar around 1%.
We'll talk about disorders like autism and ADHD where the
numbers have gone up.
But in schizophrenia, for as long as people have roughly
had a definition, around the world is roughly
1%, which is a lot--
1 out of 100 for a very, very severe, life-altering disease.
So the challenges of diagnosis are huge because no brain
disorder for all these neuropsychiatric disorders
that affect so many people can be spotted by a blood test or
a brain image.
None, zero to this day.
Everybody's working on it for many years.
And that corner may turn.
Or a genetic test--
none.
So everything is a discussion between the physician and the
patient and the family.
Everything's a discussion like that.
You can use your common sense and do a good job.
But there's risks.
So here's a famous study that psychiatrists
get really mad about.
I'll tell you, OK?
And you'll hear why in a moment.
So this is David Rosenhan, a psychologist at Stanford.
And what he did is he and his graduate students became
pseudopatients.
They pretended to hear voices, which is one of the signal
symptoms of schizophrenia, to hear
voices telling you things.
And of course if you go to an emergency room and say you're
hearing voices telling you to do things, you get admitted.
You get a psych consult.
And then what they did is once they were admitted into a
psychiatry ward, they just became themselves again.
OK?
But now they had the label that they had a behavior at
the check-in at the moment of admission that look like
schizophrenia.
Seven of eight of these people were diagnosed as
schizophrenia by the physicians and
nurses who saw them.
And it took them anywhere from three weeks to two months to
be released.
And every behavior they did--
like taking notes because they were doing it for
the research paper--
they were frequently interpreted as another sign of
their disorder like abnormal writing behavior.
And if they got a little bit better they would say
schizophrenia but now in remission because, you
understand, once you have that perspective on somebody then
every behavior can be interpreted as a momentary
abatement or, if you're sitting there scribbling
something, unusual writing behavior.
So one pseudopatient described that he had a close
relationship with his mother but was rather remote from his
father during early childhood.
During adolescence and beyond, his father became a close
friend while his relationship cooled with his mother.
OK, so that happens, right?
His present relationship with his wife was
characteristically close and warm.
Apart from occasional angry exchanges,
friction was minimal.
The children had rarely been spanked.
This is what he told them.
This is the truth.
Nothing's remarkable in this story, right?
OK.
But because you're a health professional who's now trying
to figure out why did this person hear voices, the notes
were this white 39-year-old male manifests a long history
of considerable ambivalence and close relationships which
began in early childhood.
A warm relationship with his mother cools during his
adolescence.
A distant relationship to his father is described as
becoming very intense.
Affective stability is absent.
His attempts to control emotionality with his wife and
children are punctuated by angry outbursts and, in the
case of children, spankings.
I mean, this is human.
This is not--
OK?
Because once you have a take on somebody, you keep
connecting the dots.
And while he says that he has several good friends, one
senses considerable ambivalence embedded in those
relationships also.
OK, you understand that the interpret--
and you could say, but this is just the problem of
psychiatric diagnoses--
all discussion and interpretation.
Finally, they were remitted.
Patient resumes writing behavior, oral fixation.
It's a little too good to be almost true.
But there's some stories where other patients were skeptical.
One patient said quote, "You're not crazy.
You're a journalist or professor--
referring to the continual note-taking.
You're checking up on the hospital." As if the freed-up
up patients.
Now this is a little bit of a fable because this makes a
psychiatric disorder sound like we have a better sense of
reality on the world.
And I don't think anybody thinks that in a deep way.
But it just shows you how far off the health
professionals were.
So you tell this story to psychiatrists, and they get
really mad at you.
I mean, it's a true story.
It shows you the difficulty of diagnosis.
The psychiatrists I talk with say, well, they could fake any
disease they wanted to and go pretty far because if you know
the medical symptoms and you go and tell doctor those
things, a non-psychiatric disease, you could get pretty
far in terms of treatment before they figure out
something's not there, if you know what to say.
So they just think it's nothing specific about
psychiatry.
But, in any case, diagnosis--
so what are the criteria for diagnostic categories?
Signs are what the examiner sees in symptoms, what the
patient says.
And a syndrome is a cluster of signs and symptoms.
Everyone neuropsychiatric psychiatric disorder is
basically a syndrome.
It's a cluster of things that tend to go together.
But individual patient, individual patient, individual
patient, shows a different picture than other people.
They want diagnosis that can be relatively reliably
assessed, consistently assessed.
Some sense that there's some validity to this.
But all of this is sort of thinking things through.
And then finally all these thoughts are organized by
experts meeting in hotel rooms around the country in
conferences.
And they produce a book called the Diagnostic and Statistical
Manual of the American Psychiatric Association--
DSM-IV.
DSM-V is about to come out in a little bit.
This is the official list of diagnoses.
These are the lists that all doctors use, school systems
use, health insurers use.
You have to meet the criteria in this
book to get a diagnosis.
It looks like that.
People like to point out that if you pile up the original
DSMs with each version, the lists get bigger and bigger.
All of these lists are debated in various ways.
Let me give you a sense of a couple of the ones.
And you can see the ambivalence and
the dangers of this.
So psychiatrists in the Soviet Union, before the Soviet Union
fell, were thrown out of the worldwide psychiatric
associations because they would regularly diagnose
protesters of the Soviet Union as being crazy and had to be
put into mental institutions and given anti-psychotic
medications because only a crazy person would fail to
recognize the correctness of Marxist principles in the
Soviet Union and the incorrectness of all other
competing systems.
All right?
Now that's what we consider to be politically abusive, in the
worst sense.
I think some of that is thought to go on a bit in
China still and other countries.
But it was manifest in the Soviet Union.
So that we can throw out as really bad.
But it just shows you that the dominant powers in a culture
could make these decisions.
About 20 years ago, if you were a homosexual, you had a
diagnosis in this book as a psychiatric disorder.
On a lighter side people--
not always lighter side, maybe--
people would have debated whether video game addiction
should count as a real addiction.
People debate all the time.
What is the borderline between addictions that almost
everybody agrees in terms of alcoholism and drug dependency
count as full-scale addictions versus other things.
What would it take for a person not to leave the room
ever playing video games to count as an addiction?
There's debates now in autism spectrum disorders.
They're about to eliminate the separate
listings of two diagnoses.
One of them called Asperger's which is sort of the milder
form of autism, in general.
They're about to eliminate that distinction.
Many patients and families with
Asperger's don't like that.
And also something called-- here's a bad label--
PDD-NOS, pervasive developmental disorder not
otherwise specified.
Imagine if you have a child with difficulty.
And the doctor tells you, your child has pervasive
developmental disorder not otherwise specified.
That's a child, basically, who has two of the three
components of a diagnosis for autism.
So why draw the line there?
And so psychiatrist, I think, reasonably are saying, we
don't really understand the lines.
We're going to call all of these
autism spectrum disorders.
But you could see these things are shifting over time.
These labels move as people think about things.
And there's no definitive evidence one way or the other
besides best attempts by people to figure out
what's going on.
And not everybody agrees.
Also--
I'll talk about this next time--
when one DSM switched to another, for example, the
number of children in Germany who qualified for ADHD
diagnosis doubled overnight because the diagnostic
criteria changed.
That doesn't mean that the--
which is the better one.
You couldn't even begin to prove which
is the better one--
the original or the one that had admitted more
children into it.
So these are tough calls.
And you could say, well it's all kind of a little bit
arbitrary and a bit subjective.
And it's true.
On the other hand, you've got to help people.
So why have these labels if there's all kinds of issues?
Well first, allocation of resources.
If a person usually needs such a diagnostic label to get
services at school, to get medical services in hospitals,
to have insurers support them, and that's independent of the
kind of medical service you have.
Right?
Second, if you have a label that's somewhat useful for--
that helps you know what kind of service is needed,
different services are needed for a child with ADHD versus
an adult with depression or an adult with obsessive
compulsive disorder.
Different things are needed.
A label is needed to even begin to figure out
which way to go.
And then people also want to understand a little bit what
can they predict about the future course of that person--
a little bit of treatment and their fine, a lot of treatment
and monitoring needed?
You have to do something practical.
And the labels help you organize around that with all
the risks of these labels.
So we're going to focus a little bit on schizophrenia.
And I'll describe it a little bit.
And then we'll see a film.
So sometimes the word schizophrenia is used in kind
of a medically incorrect way which is like multiple
personality disorder.
That's not what schizophrenia is.
It was described by Bleuler as a splitting of mental
functions; disintegration of emotions,
thoughts, and actions.
About 1% worldwide, another 2% to 3% have a partial version
of schizophrenia.
Practically for every disorder there's patients
who meet the disorder.
And there's patients who come close.
And what that exact dividing line should be and what the
value of it is is constantly struggled with.
Similar around the world, a slight tendency from birth in
winter or spring--
people don't know why schizophrenia happens.
It makes them think about a virus as part of the story.
Patients with schizophrenia are defined as having
psychosis, an alteration in thoughts, perception, and
consciousness.
The thoughts are disconnected and loose.
They've unusual beliefs or delusions, often of
persecution.
Somebody else is possessing their thought.
They can have abnormal experiences in terms of
auditory hallucinations, mood disorders, motor alteration.
You'll see in the movie, it was a restless, purposeless
overactivity.
Can have impoverished social function.
For a while, people thought a really important distinction
of schizophrenia was between what they called negative and
positive symptoms.
So the negative ones were they did less of what a person
typically does--
poverty of speech, poor attention, flat affect, lack
of motivation.
Sorry, that's negative.
And the positive were active things that people don't
usually do-- delusions, hallucinations, bizarre or
disorganized behaviors.
Biologically, it's been hard to show that that's kind of a
distinction that matters.
And so what happens with patients with schizophrenia,
very mysteriously the clinical onset in most cases is late
adolescence and early adulthood.
And nobody understands this.
So typically it's in your 18, 20, 22, 24.
How is that such a psychiatric disorder waits that long and
not much longer in the vast majority of cases?
What biological thing is ticking in a person that will
lead to a psychotic break with reality?
A huge amount of research now is to try to look at
individuals who are in their teens and step in and stop
somebody before they have a psychotic episode.
The positive symptoms are most evident in this acute
schizophrenic episode.
Negative symptoms often predominate in the long run.
Huge variability from one person to the other.
In terms of outcome, the outcome often responds
positively to anti-psychotic drugs.
It's estimated about a quarter of patients make a pretty
strong recovery.
About a quarter remain very disturbed.
And about half are going back and forth,
fluctuating over the years.
So a picture that people will use is there's premorbid
functioning, and then somewhere in the late teens,
early 20s some dramatically bad thing happens, and then
some sort of stable condition with occasional relapses.
And a lot has to do with the challenge of individuals like
this taking their medications, partly being organized enough
to take them, partly again feeling like their real selves
often is not what the medicated self is.
You may know the movie Beautiful Mind with John Nash.
And it's just an example how psychiatric disorders
challenge people of every mental caliber.
So he won the 1994 Nobel Prize in Economics.
And if you've seen the movie--
although it's interesting if you've seen the movie, also
you could go up on YouTube and see him talking about the
movie because they sanitized him somewhat to make him more
popular with the movie-going public because they made it a
more charming disorder than everybody says it was,
including himself.
But he had a terrific aptitude for math, went to the Carnegie
Mellon, Princeton for his Ph.D., famous for bargaining
problem and non-cooperative games theory, came to MIT in
1951 as an instructor.
And then, after doing his fantastic work that won him
the Nobel Prize, developed acute schizophrenia.
So why don't we watch the movie.
Tyler, can we do that?
Let me do this.
So here's a fairly typical patient.
Yeah?
AUDIENCE: [INAUDIBLE]
PROFESSOR: Sorry?
AUDIENCE: [INAUDIBLE]
PROFESSOR: I have no idea.
Is there any different rate of schizophrenia in people who--
AUDIENCE: I was just wondering about the voices, hearing
voices in their head.
But if you--
PROFESSOR: That's a--
that's a good--
somebody who were deaf, would they hear voices in their
schizophrenia?
AUDIENCE: [INAUDIBLE]
PROFESSOR: It's a fascinating question
because I have no idea.
I've never thought about that.
It's rare.
Its combination of the two are moderately rare,
just numbers wise.
But that'd be an interesting question.
I don't know.
Any other?
I saw another hand, or no?
OK.
So we know one thing that practically for every
neuropsychiatric disorder, there's strong familial
evidence that there's a genetic component to the
disorder and a big one.
So here are four--
this is a very touching picture, in a way.
These are identical quadruplets, four girls, who
all grew up to have schizophrenia.
Not every identical twin will do that.
So if one twin has schizophrenia, half the time
the second twin will have schizophrenia.
If it's dizygotic, it's still higher than 1%.
But it gets down to 15%.
But I think people have rethought this because very
often the sibling or the twin, if you look a little bit more
carefully, they won't meet the diagnostic criteria.
But they often have struggles of some kind, as well.
The lifetime probability in a first degree relative
is 10% versus 1%.
If one parent is 13%, two parents 50%.
So all this is lots of suggestions that there's a
genetic basis.
Concordance rates for monozygotic twins, for
identical twins, is almost identical whether they're
reared together or apart-- again, suggesting a very
strong genetic basis.
Being adopted away from relatives does
not reduce the risk.
Having said that, if it's not 100% concordance, there's got
to be something else going on besides the
simple genes at birth.
It is higher in urban areas, areas that we think have more
stress in them.
People have noticed that often times
when people move cultures--
for example, African communities in London were of
recent immigres.
They kind of seemed to notice a higher rate, as well, as if
a big cultural move can put you at risk.
And so everybody pretty much agrees that there's what
people would call multifactorial
polygenic-environmental threshold model.
That is, there's a lot of different genes, plus
environmental stressors that come together in some way we
don't understand.
And you would think that with the human genome decoded to a
large extent and so on, that we have some clarity on this.
It's been-- you can debate this.
And certainly identifying the genes that put you at risk for
these disorders is a hugely important topic.
The progress in identifying certain genes for any of these
psychiatric disorders has been horrible.
Genes are identified one year and the next five studies
don't replicate it and so on.
So people at the Broad Institute across the street
now say for them to believe that a gene is associated with
schizophrenia, they think you have to have samples of 10,000
patients with schizophrenia and 10,000 people without it.
What does that mean?
That means there's nothing like a smoking gun gene--
10,000 to have enough statistics to support a
difference.
That means many, many of the 10,000 don't have that gene
who have schizophrenia.
If it were one gene, one disorder you don't need 10,000
people to get a statistic.
You need five people.
So it's been a shock to people that there's been so slow
progress, given that all the things they can decode the
genome, to find the genes that are at the heart of
psychiatric diseases.
And that's true for practically all of them.
So there's something complex about genes and environment
and people that far exceeds their understanding at the
moment at every level.
And so people could be modelled like this because it
makes us feel better.
And there's something probably right about it.
There's an amount of stress in your life that can come up
from socioeconomic risk, health problems, family
situations.
There's a predisposition that's genetically based.
And some combination of them determines whether you
manifest the disorder or don't.
So we said there's no definitive biological marker
for schizophrenia, as there isn't for every other
psychiatric disease.
There's no blood test, no brain test, no nothing that
definitively tells you if a person has a diagnosis.
But people have been studying things that are, on average,
different in brains.
And I'll show you some of the most consistent findings about
ventricles, about hippocampal involvement, PET scans.
I'll show you this.
And I'll show you a few examples in schizophrenia.
So one thing people have noticed is that if they
compare-- these are identical twins.
And you can see the ventricle, the fluid filled space, is
somewhat larger in the twin with the
diagnosis than without.
That's about the least specific brain marker
we could ever have.
The ventricle just means that there's tissue
missing around it.
OK?
It's just this fluid-filled space.
There should be a bit more tissue.
It's very far from any specific
biology of the disorder.
And here's the actual twins with their actual MRIs.
So we don't think it's the size of the ventricle.
That makes no sense.
But that somehow roughly correlated over the brain
basis of the disorder is.
And then people have shown-- and these are relatively
extreme examples, post-mortem samples.
Here's the hippocampus in healthy individuals.
Here you can see a somewhat shrunken in patients with a
diagnosis of schizophrenia.
And if you look at those pictures that are kind of
picked, you could say, well that's easy.
Give me the MRI and I'll tell you who has it.
But statistically it doesn't work that way at all.
There's tremendous overlap in the size of the hippocampus
between people without a diagnosis and people with
schizophrenia.
So it's a statistical thing.
People have also noticed the cellular organization
sometimes looks somehow better in the typical people than
people with schizophrenia.
Again, a suggestion about a developmental history
underlying this for the risk but
without any kind of certainty.
When they've done studies looking at resting scanning
metabolism--
you just laying there.
This is a PET scan.
It's just where is the blood flowing.
You can see that this is a healthy person.
A lot of our blood flows as we sit there
to the frontal cortex.
And you can see it's kind of diminished in schizophrenia.
But, again, you cannot put a patient in and say this
patient has schizophrenia because many patients will
look like many controls.
But the average can look like this.
Here's a task now of a working memory task.
So people see in the easy condition,
letters are running along.
And every time there's an X, they push a button.
That's the easy condition.
Here, letters are presented rapidly.
And every time the current letter is identical to the one
you saw two letters ago, you push a button.
So this is harder mental work, harder working memory demands.
And then here's what you see in one data set.
So as they're doing this task, they turn on a lot of frontal
cortex, working memory, thinking.
You're used to that.
Here's controls--
how much they turn it on, the front of the brain
viewed from the top.
Here's relatives who don't have the diagnosis.
And here's patients who do have the diagnosis.
These are relatives of these patients.
And take a look at it.
You can see they're growing.
So this is this issue of is more
activation better or worse?
Well it all depends.
The way we interpret this is for a typical person, here's
how much they have to push the pedal to accomplish that
working memory task.
If you're a patient, you have to push it a lot
more to do the task.
And you still make more mistakes.
If you are a relative without a diagnosis of schizophrenia,
you're somewhere in between.
And those relatives are accurate as controls.
But they perform somewhat more slowly.
This is a kind of interesting thing.
And practically every disorder, if you take the
relatives of people with the diagnosis, they often look
like they have a kind of a milder version of that.
But they may have no problems in their lives.
They may be doing flourishingly well in every
regard that you could think of.
But they harbor some of the same genes.
To be a relative means to share genes.
And so that can make--
there's something about that happening here or in some
subset of those individuals.
Practically every study that's done, if you take the
relatives of people with a diagnosis, there's some
in-betweenness compared to people picked in families
without any history of that disorder.
But what matters is the boundary.
Right?
I mean, this difference doesn't matter if this person
is doing well.
This difference is associated with something that really
makes a big difference in the person's life.
The question about auditory hallucinations and the deaf--
this is kind of like that.
But this is people hearing people.
But one of things you can do with imaging is ask.
Some patients with schizophrenia have rapidly
psyching auditory hallucinations.
Most don't.
Most is every here and there.
But some have it pretty often.
So you can put them in a scanner and when they hear a
voice, they push a button.
And you can ask, when they hear a voice is their auditory
cortex active?
At the level of the brain is it as if they were really
hearing a voice?
And here's the auditory cortex active in the individuals at
the moment they're experiencing the
hallucination.
It's real to them because somehow it's engaging the
auditory cortex that really hears the world.
That's why it's so powerful.
And it's somehow engaging the very same tissue by which you
really hear the world.
How about treatment?
So next session we'll talk a lot about
different kinds of treatment.
Neuroleptics are the most common treatment for
schizophrenia.
They block--
I'll talk a bit about this--
post-synaptic dopamine receptors.
The drug is fully effective within hours.
The maximum clinical effect takes weeks and then the
effect remains after treatment stops.
A huge problem in schizophrenia are side effects
of these kinds of drugs.
So early on, you induce a bit of Parkinson's disease in
patients who never had Parkinson's disease with these
typical drugs.
Because atypical drugs, they have their problems.
I'll just focus on the typical drugs.
I'll tell you why in a minute.
And then later on, this becomes known as tardive
dyskinesia in about 20% of patients.
That's a lot of patients.
You're producing, by the drug, abnormal and involuntary
movements-- smacking of lips, chewing, and tongue
protrusion.
And there's some drugs that don't do it.
But they have other problems.
And there is evidence that behavioral therapy can be
surprisingly useful in schizophrenia.
Most of us hardcore biologists we thing that drugs
got to be the deal.
I think there's more evidence than you would imagine that
behavioral therapy or the combination of the two can be
very helpful for people.
So you may know now--
you wouldn't know this, I know this because I am constantly
in the fund raising business as a researcher--
drug companies have almost stopped working on developing
treatments for psychiatric diseases.
And they've almost stopped because it's been so
unsuccessful.
The drugs that were found were almost always by
happenstance--
drugs that were almost randomly tried for various
disorders or various groups and worked.
None of them are rationally done in any biotechnology
sense or molecular chemistry design sense.
Practically all of them are happenstance applications of
quasi-random drugs.
And then people noticed it helped individuals.
And so in the last 28 years, where there was much more
rational development of drugs, it's been spectacularly hard
to develop new drugs for psychiatric disorders.
And so most pharmaceutical companies have basically
stopped in the last couple years.
They've just given up.
We remain optimistic that everybody thinks they'll come
back into the picture when some academics produce some
things that look good.
But it's turned out to be really hard.
And, furthermore, many of the medications that are effective
have all these side effects, very undesirable
side effects sometimes.
At the same time, the fact that these drugs affect the
disorder sort of promoted various theories.
So once people noticed that the anti-psychotic
medications, medications that diminish the psychosis of
schizophrenia, act on the dopamine system, that led to
the dopamine theory of schizophrenia.
So you say, well if the drug is pushing down dopamine and
that's helping people be less psychotic, then maybe what
that real problem is that there's too much dopamine
flowing in the brain of individuals with
schizophrenia.
And that got supported by studies that if you give
typical people overdoses of amphetamine, you induce
something that looks a bit, in a typical person, like the
paranoia of schizophrenia.
And so let's talk about this idea of drug
action versus disease.
So if you have a headache, what do you take to help
yourself with the headache?
Ibuprofen or aspirin or something like that?
Does that mean the medical problem was you didn't have
enough aspirin in your blood?
Were you "hypoasperinemia?" No, right?
The aspirin is doing something else to counteract the
headache, or the ibuprofen.
It's not that you were short on Tylenol.
OK?
But it treats the problem.
So if a drug treats schizophrenia by acting on the
dopamine system, does that mean dopamine was the culprit?
And the answer is probably not or it's hard to figure out.
But the original assumption that the way the drug works
gives you a direct insight into what the cause of the
disease is, people have pretty much dismissed.
But what drew them to it, of course, is still these
anti-psychotics.
The way they work is they block the
receptors that take dopamine.
And, therefore, dopamine gets catabolized here and is not
used in neurotransmission.
And, furthermore, amphetamine, which produces a somewhat
schizophrenia-like syndrome in some healthy individuals, that
accelerates the production of dopamine.
So that seemed to favor the story.
But, again, that's sort of not taken very broadly now.
Again, what favored the story was the more powerfully a drug
bound to dopamine receptors, the less drug
you had to give patients.
All of that, you could see, made people
think, this is the story.
And it may be that dopamine is a part of the story.
But everybody understands now that just because a drug acts
on a disease, does not mean it's treating the disease in
the most direct way.
And now why do patients get tardive dyskinesia?
Why is it an inadvertent consequence of treating
schizophrenia, producing a version
of Parkinson's disease?
It's because the drugs are too nonspecific.
So we know the ventral tegmental area in the brain
stem sends dopamine into the basal ganglia and into the
prefrontal cortex.
Conceptually, what we understand we're trying to
achieve with schizophrenia is something like diminishing
something about this pathway.
But the drug can't just block this.
It also affects the basal ganglia.
And what Parkinson's diseases is is a shortage of dopamine
in the basal ganglia.
In the case of Parkinson's disease, it's because of death
of substantial nigral cells.
But you're producing a pharmacological version of
Parkinson's disease in the effort to treat schizophrenia.
Not in all patients, not as severe as Parkinson's disease,
but a big side effect in many patients.
And there's other drugs.
They have their problems.
There's almost no drug that's completely successful and pure
in any treatment sense for the patient.
Despite that, there's been a fantastic effect.
We talked about that when people were
behaving very oddly--
and certainly schizophrenia is perhaps the scariest set of
behaviors, if you have to pick one disorder in that way--
then once they began to have drugs that diminished the
unusual behavior, people were let out of state and
government hospitals where they had been sort of secluded
in many ways and not helped in many ways.
And people viewed this as a tremendous success.
And I think it is to let people back into the
community, interacting in a sort of more typical way, as
opposed to being segregated in areas that were
often not the best.
But there was a fantastic consequence, which is now
these people, as you may know, have no safety net.
They're back in the community.
And if they don't have people who care for them or follow
them, there are risks for themselves.
So it's great to give a medication to
let somebody out.
Everybody agrees on that.
But then if you don't have a kind of a safety net of
physicians and family and so on, a person's out on their
own, they stop taking their medication, who's
there to help them?
So it's a societal challenge on top of that.
So next time I'm going to talk about treatments for
neuropsychiatric disorders.
But for just one minute I'll ask you, do you have any
questions or thoughts about this whole topic?
Yeah?
AUDIENCE: [INAUDIBLE]
I read somewhere that 90% of schizophrenics [INAUDIBLE]
PROFESSOR: There's a fantastic--
the question was, why is there such a fantastically high rate
of smoking-- which there is-- in patients with schizophrenia
and bipolar?
So people will use phrases like they're self-medicating
in some way.
But I don't think there's--
you could make up a little bit of a story,
but it is very striking.
I don't know a deeper story than that.
There might be.
But it's very striking.
AUDIENCE: [INAUDIBLE]
One girl said she had a schizophrenic episode and
started smoking afterwards [INAUDIBLE]
it made the voices go away.
PROFESSOR: It made the voices go away?
Yeah.
I don't know.
I mean there's--
But it's very--
there's a phenomenal high rate of smoking among
patients like that.
OK, thanks very much.