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PROFESSOR: Good afternoon.
When we parted last time, I was --
you just did that demo with Sam, who was either collecting
stamps or lady's undergarments, depending.
And the point there was to describe the fact that any
behavior is going to be distributed across the
population in some fashion.
It may well be that the extreme of the population is
abnormal in some meaningful sense, maybe even pathological
in some sense, but that the border between what is normal
and what is abnormal is going to be necessarily ambiguous.
There's not going to be some nice, neat line that can be
drawn in all cases.
I was arguing that something like schizophrenia is a bit
more like that, where the abnormal state really does
look quite different from the normal state and less like
that it's on a continuum.
You will notice on your handout that it
says Lecture 20.
And those of you who are particularly observant will
say, last one was called Lecture 20.
And that's true.
I just liked 20.
No, this is really 21.
And with a bit of luck, I'll label the next one 22.
Otherwise it'll just turn out that there's 20A and 20B or
something like that.
Anyway, it really is the right handout.
You'll discover that it is closely related to the later
pages of the last handout that we didn't get to last time.
Yeah, it's kind of the same is what people are noting.
But I didn't have any faith that people would remember to
bring the real Lecture 20 handout.
Anyway, what I want to talk about, at least initially
here, is to talk a bit about how you would end up in this
abnormal bin of schizophrenia.
And one reasonable question to ask is,
well, it's on the handout.
It says, is there evidence for a genetic component?
And the answer is yes.
And the way you get one of the important sources of that
information is similar to the data that we were talking
about in intelligence testing.
Take a look at people who vary in the amount that they are
genetically related to each other.
Notably here, MZ stands for monozygotic or identical
single-egg twins.
And DZ stands for dizygotic two-egg twins who are no more
similar than siblings.
Concordance means what the chance is of Twin Two having
the disease if Twin One has it.
And so what you can see is that for monozygotic twins, if
one of a pair of identical twins becomes schizophrenic,
there's a 50% chance that the other one will, too.
That tells you two things.
Well, it only tells you two things if
you look at the dizygotic.
The dizygotic twins have a much lower concordance
rate of about 15%.
So that tells you first of all that there's a probable
genetic component there, and second of all,
that it's not absolute.
If you have the genetic mutation that makes you
color-blind or color anomalous,
you'll be color anomalous.
There's no big mystery at this point about that.
If you have whatever the genetic predisposition is for
schizophrenia, something else has to happen before you would
end up showing the disorder.
Now, these twin studies run into the same problem that the
intelligence testing twin studies did, which is that
monozygotic twins are simply more similar on
all sorts of things.
You know, they're treated more similarly and so on.
One way to look at whether or not there is a, you know, to
try parceling this out, is this third line here.
This was a population of dizygotic twins who thought
they were identical.
You know, they looked alike.
Presumably they're the same sex and stuff like that.
Thought they were identical.
You'll see that their concordance rate was less than
the 50% that the true monozygotic twins had.
So there does seem to be something to being really
genetically identical.
You can also do twins reared apart things.
But look, if you have a set of --
twins reared apart --
not common.
But all those twins have IQs.
You can always measure their IQs.
If you take twins reared apart and then take the cases where
one of them has schizophrenia and ask what the concordance
rate is, the answer is it's quite elevated.
But, you know, it's a really small population of people.
You know, twin reared apart and schizophrenic,
it's not a big crowd.
Now, when you go look for the genetic marker, since the late
'80s, there have been a slew of papers on genetic markers
for schizophrenia.
The way you look for this -- one of the typical ways to
look for this is that
schizophrenia runs in families.
And if you go and analyze the genetics of families, you can
find specific loci that seem to be abnormal in the
schizophrenic members of the family.
The difficulty or the interesting aspect of this
genetic story is that the story that works for this
family doesn't necessarily work for this family.
In the early days of this, there'd be some big article in
Science or Nature or something saying gene locus on
chromosome eight for schizophrenia or whatever.
I'm making it up.
And then, you know, either in the same issue or in the, you
know, next week, there'd be another thing saying, but not
in this family.
Clearly schizophrenic but not clearly
having the same defect.
It suggests that there are multiple roots, genetic
predispositions, to schizophrenia.
It's also possible that you need more
than one genetic insult.
That's jargon --
you don't say, you got an ugly gene.
You need to have perhaps more than one defect in order to
have the susceptibility to schizophrenia.
One of the curious little wrinkles that I dug up in my
reading on this -- and I've only read this
in a secondary source.
I have been unsuccessful in tracking
down the primary source.
But I'll tell you anyway --
is a study -- it turns out that there are two types of
identical twins.
There are, sort of, plain vanilla identical twins.
You know, Twin One is right-handed.
Twin Two is right-handed and so on.
And then there are so-called mirror twins.
They're genetically identical, but the phenotype, the actual
organism, is mirrored rather than identical or
something like that.
So if one's right-handed, the other is left-handed.
You know, swirl on the top of your head, if it swirls
clockwise for one twin, it swirls the other way for the
other twin and so on.
And the curious finding reported in this one
relatively small study, I think, is that the concordance
rates for identical identical twins, the right hand, right
hand identical twins, very high in this
study, like over 90%.
If one twin was schizophrenic, the other was schizophrenic.
The mirrored twins, the left, right ones, were concordance
rate down at about 25%.
Both of these are genetically identical pairs of twins.
It's abundantly unclear what it is that makes these two
groups different, if indeed that turns out to be a
reliable result.
I went hunting in the databases, and I think I found
the guy who did it.
So I sent him an email, but he didn't get back to me in time.
Oh, that reminds me.
It's a little late in the day to tell you this, but if you
discover that something that you're looking for in primary
source land, you know, you're looking for the Journal of
Hoozy Phoozy Results or whatever, and oh my god, MIT
doesn't carry it so you don't have access to it, it's often
very useful to go and see if you can find the website for
the lab where the work was done.
Because many, many of us post all of our publications, or as
many as we have PDFs for, on the website to be downloaded.
And so you can dig things up.
You can dig things up that way.
So anyway, there's pretty strong evidence
for a genetic component.
And then there's pretty strong evidence that that by itself
is not enough.
Unlike a variety of other neurological disorders, there
are plenty of neurological disorders where if you've got
this problem with your genome, it's going to munch up your
brain in the following fashion, you're going to have
this problem.
And fortunately most of these are very rare.
But they're straightforward genetic stories.
In schizophrenia, something about the environment seems to
be important to trip it off.
The leading notion is stress.
So, actually, does anybody remember?
The book used to go on at vast lengths about the stress
diathesis model of schizophrenia.
Does this sound familiar to anybody?
Has anybody looked at the relevant
parts of the book yet?
Nobody knows.
All right, well anyway, one of the leading notions about what
it is that actually produces the florid disease, is that
you need to have some genetic predisposition and then you
need something like stress to drop-kick you into pathology.
Now, this is an interesting --
this raises interesting problems for public policy.
I think we talked last time about, you know, when is it OK
to force somebody to be medicated, right?
This is a similar sort of problem.
Suppose you are applying to MIT this year.
Should I be able to --
should I go and suggest to the head of admissions that we
really should get little tubes of blood from everybody?
Because if we got little tubes blood from everybody, we could
genetically screen them.
And we know where --
we don't know exactly which loci are critical, but we know
a bunch of loci that seem to be related to family histories
of schizophrenia.
And anyway, there's all sorts of other interesting genetic
markers out there at this point.
We could screen the incoming population or the population
of applicants and systematically decide not to
admit people who had the genetic marker for
schizophrenia or for some other --
well, schizophrenia is a good example.
Why in the world would we do this?
Well, is there anybody currently present who believes
that MIT is a at least modestly stressful
environment?
All right.
Short of Guantanamo Bay or something, you know, it's
right up there.
All right.
The state of the art is that we know that stress is a
contributing factor to a variety of mental illnesses,
notably in this example schizophrenia.
If we admit people to an environment that we know is
highly stressful, we are asking for a certain number of
psychiatric problems.
Isn't it our responsibility to prevent that from happening?
Well, now, typically the --
I won't take a poll, but the typical answer is, no, that
doesn't sound right.
You know, that somehow that sounds a little too
paternalistic, too invasive for me to be
screening your genes.
And, you know, who knows?
Down the line, we take a look at this hunk of the genome and
we say, you know, sorry, you're just
never passing 18.03.
You know, what would we ever do with information like that?
But the disease case, it doesn't feel right
typically to people.
But on the other hand, we spend a lot of time worrying,
believe it or not, about your mental health.
The dean's office has substantial branches devoted
to mental health issues as does the medical department.
We know that university environments kick up a certain
amount of psychiatric problems.
And we know that that can be catastrophically bad for the
person and for people around them.
Wouldn't it be our responsibility to do something
about that?
Well, look, I'm not going to give you an answer to that,
and I promise not to ask on the exam, you know, should we
get blood samples from everybody and, you know, the
choices are yes, no, all of the above or
something like that.
I raise that as an issue to think about.
When you take a look at the brains of schizophrenics, by
the way, they don't look like the brains of healthy, normal
individuals.
So you get things like shrinkage of grey matter.
You get enlargement of the ventricles.
The ventricles are those nice, empty fluid-filled spaces in
your brain.
Great answer for a --
if you're looking at the multiple-choice question on
the final, and you're thinking, I'm going to go for,
you know, the third ventricle as the answer, you're probably
getting suckered here, right?
Because the ventricles are empty fluid-filled spaces.
It's not where any of the more important mental functions are
thought to be localized, at least not since the Middle
Ages, where people did think that memories were stored in
the ventricles, because after all they
looked like store rooms.
Anyway, the ventricles get bigger.
That's presumably not a good thing because it's reflecting
loss of brain tissue.
What's not absolutely clear is whether or not abnormalities
in brain structure precede disease.
You know, are they there somehow from birth?
Is part of what the gene is doing somehow changing the
structure of the brain in such a way that it makes it
vulnerable, or is it that having the disease itself is
bad for the brain?
In any case, the point to take away here is there are lots of
different routes into the kingdom of schizophrenia.
It's not a nice, clean simple diagnosis where you say, you
get this bacterium, you get this disease, we give you this
antibiotic, and you're OK.
Multiple routes in and treatment options are, you
know, getting better but remain difficult.
Let's see here.
Oh yes.
What I think I will do is switch gears and talk a bit
about depression.
But in order to talk about depression, what I want you to
do is to decide how you want to treat my three invented
patients on the handout.
The third one is on the back of the page.
So play with that for a second.
Kristen, can you do me a favor?
Go find me a bottle of water.
I'm going to expire today otherwise.
AUDIENCE: I have some.
Do you want some?
PROFESSOR: I don't know.
Do you got any interesting diseases?
AUDIENCE: No.
PROFESSOR: I don't want to steal yours.
Find me something somewhere.
Thank you.
I'm recovering from a cold still, and I can feel that I'm
going to run out of moisture.
And my tongue is going to get all big and
like a parrot or something.
I won't be able to talk.
All right, have you managed to do this?
Still working on it.
All right.
Don't cheat off your neighbors.
But I promise you this time, none of these guys are dealing
in lady's undergarments.
Here.
Let's collect some.
All right.
Let's collect us some data.
OK.
Everybody pretty much done here?
Make assenting noises or something.
OK, that's good.
That sounded very assenting.
OK, so Sarah had a bad day.
How many people would, let's see, so that --
slow numbers are the "no way, we're not going to medicate
this depression." How many people -- oh, that was quick.
That was good.
Thank you.
How many people are going to give her no meds?
Oh, OK.
So the answer is everybody, more or less.
Don't worry if you said, I'll give her a little bit of med.
That's OK, too.
But I won't bother asking about it.
These really are all the same, by the way.
There's no fifty-fifty split.
This is just straight up, normal.
I'm not tricking you this time.
OK.
And by contrast if we look at Sam, Sam's depressed, no
particular reason, just happens.
And he oscillates between manic and depressed states.
How many people think no treatment
or unlikely to medicate?
How many moderately like, you know, somewhere in the four to
seven department?
Well, a few people in there.
And you have all embodied the ethos of the
yeah, yeah, OK, good.
I mean, I don't know if it's good or not, but it's clearly
where medical science, I suppose, is these days, which
is that he would be a candidate for an
antidepressant in a way that she wouldn't.
Why not?
Why wouldn't you give her an antidepressant?
She's depressed.
AUDIENCE: It's normal for her to be depressed.
Like, anyone could be depressed in that situation,
but if you're depressed for no reason, then that
[UNINTELLIGIBLE]
problem in the brain that could be solved by medication,
whereas with her thing, all that needs to happen is the
problem's [? cured. ?]
PROFESSOR: There's a couple of things that are worth picking
up on here.
One is, I mentioned last time that the exact mapping between
cause and treatment shouldn't be seen as one to one.
So even if we take as correct for present purposes that
Sam's got something biochemical wrong with him, it
wouldn't necessarily be the case that the only way to deal
with this would be by a biochemical kind of treatment.
There isn't that necessary one-to-one mapping.
But it's not an unreasonable thought.
And the other part of that thought was, you know, she's
depressed for a reason.
And we don't want to shield her necessarily from that
depression.
Though this gets raised as an issue too now.
I talked last time about treatments for post-traumatic
stress disorder.
One of the notions is that you could give people medications
that would in a sense prevent them from feeling as bad about
something horrible as they normally would.
I mean, this is a real something horrible now, you
understand.
But we're going to get you --
something horrible has happened -- we're going to
give you a pill that is going to decrease, we hope, the
chance of you having a post-traumatic stress
disorder, but it's going to do that by blunting your
emotional response and your memory for that event.
Is that something that we want to get into?
Now, Sam I described as having this --
if this is now, oh, I suppose, mood --
Sam I described as having one of these oscillatory or
bipolar conditions where he bounces back and forth between
-- well, let's see, which end is this?
This can be the manic end and the depressed end.
You sometimes think that it might kind of be worth it,
right, because you have to put up with the depression, but
the manic energy thing would be good.
Well, the manic energy thing is kind of good here, maybe.
You know, you get all your problem sets done in ten
minutes or something.
But by the time you get out here, you are just as
abnormal, if you like, or just as crazy if we want to be
colloquial about this, out here as you are down here.
And you can be pretty hard on your friends and neighbors and
yourself, in fact.
I don't need --
I mean, this is very MIT, right --
I don't need to sleep anymore.
I can talk all night.
You don't want to listen to me?
Well, I'll talk anyway.
I remember reading a memoir by the child of a manic
depressive mother, who as I recall comes home --
the child comes home from school one day, discovers mom
has decided we're going to have a great old-fashioned
Christmas this year.
So she went out and bought like
thirty-five Christmas trees.
And you walk into the living room and it's just, you know,
forest in there.
She's stuffed the Christmas trees all over the --
and, you know, this is, I'm sorry, I'm glad you're feeling
really up, but this is nuts too.
It's not working.
It's an interesting observation.
There are interesting data suggesting that this sort of
bipolar disorder, this oscillation between deep
depression and this wild mania, that that's
overrepresented in at least some creative populations.
The notable one is poets.
It's notable because a woman named -- what is
her full name? --
well, anyway, Jamison is her last name.
I think it's spelled like this.
Anyway, she wrote a book called Touched by Fire where
what she did was she went and looked at the biographies of,
in particular, sort of the run of famous English poets.
And over and over in their biographies you get these
descriptions that --
you know, they didn't have the diagnosis in 18th century
England, but it sure sounds like a
manic depressive disorder.
You know, Shelley or Keats or somebody writes eight million
poems and then lies in bed for a month.
It's that sort of thing.
Now, great, you know.
I can be a famous poet.
All I have to do is put up with this.
The problem -- well, there are a number of
problems with this.
First of all, you become a little intolerable to your
immediate surroundings.
The other thing is that a very serious consequence of deep
depression is the threat of suicide.
Interestingly, you would think that this was a continuum
thing, right, that you go way, way down here and if you get
this far down into depression, that's when
people commit suicide.
Turns out not to be the case.
When people describe their really deep --
there's a huge genre here.
It's a very popular genre at the moment.
If you're into depression, your, you know, Christmas
reading list can be all set out because there's all sorts
of people who are happy to describe -- happy to describe
their depression? --
anyway, more than willing to describe their depression in
volumes thin or thick.
Jamison actually has a volume of her --
she got interested in this because she was a manic
depressive and trained in psychiatry.
So she's coming at it from every which way.
Anyway, she has a memoir --
I don't remember the title of it --
about her own depression that's actually nice and slim.
It's not a bad read.
But what the descriptions sound like is that when you're
really, really deeply depressed, you
just don't do anything.
You might in some sense want to be dead, but that's just
too much effort to do anything about that.
The danger for suicide in bipolar disorders turns out to
be -- well, let's get rid of this -- turns out to be when
you're on your way back out.
Still depressed, but now you're activated enough that
you can do stuff, but you're not convinced you're ever
really going to get better.
I mean, look, most of us have not been really clinically
depressed, but many of us can tap into this, into this
aspect in the sense of have you had the flu or some, you
know, relatively disgusting disorder of some variety where
you're sitting there thinking, "I know rationally that I'm
going to get better, but am I really going to get better, or
am I just going to be barfing forever?" So you're coming on
your way out, and that's where the suicide risk is high.
Now, that phenomenon may be related to something that hit
the news a lot this year, which was concerns about
giving antidepressants to children and adolescents.
Because there are data out there that say that the
suicide risk in depressed adolescents taking
antidepressants is elevated.
Exactly what you don't want to have happen, right?
What you really want to not have happen is people
committing suicide when they're depressed.
What is the cause of this?
Well, we don't actually know, I don't think.
At least I haven't seen anything definitive.
But there are a number --
one theory is that antidepressants work
differently in young brains than in older brains.
That's one possibility.
But the other possibility is that what the antidepressant
did was it moved the patient along to a point where they
weren't so paralyzed by the depression that
suicide became an option.
It sounds weird and disturbing, but that is one
possibility for where this elevated rate of suicide in
antidepressant treated young patients came from.
Let's see, what else do I want to say about
Sam and Emma here?
Oh, Emma's the one on the back.
All right, so how about Emma?
We need to collect some data on Emma.
Did I describe Emma as dysphoric?
Yes.
Emma is a dysphoric.
That's the opposite of euphoric.
So it's not depressed.
It would be sort of lying around here somewhere.
Just kind of flat.
All right.
So how many people voted that we'll leave her be?
OK.
How many people voted maybe?
And how many people voted sure?
Well, OK, we got a normal curve out of that.
Well, I could have gone --
it looked sort of like this to me.
So people are sort of unsure about -- oops.
Well, I guess it's going over there now.
People are sort of unsure about it.
So what are the issues here?
Why wouldn't you give it to her?
Yeah?
AUDIENCE: If she doesn't want it.
PROFESSOR: Oh, yes, yes.
Well, that's a separate issue.
Did I say anything about it?
No, no, no, this is just -- well, actually, we'll come
back to that.
That's an interesting problem.
But yes, I was not suggesting that we jam it down her
throat, which is by the way not the problem with Prozac.
Let's imagine that the antidepressant is Prozac here,
or one of its newer friends.
Prozac gets a lot of play in the public sphere.
Whoops.
Well, I'll put a P there now.
Uh oh.
C or K?
AUDIENCE: C.
PROFESSOR: C. Yes.
Thank you.
OK.
Prozac is a serotonin --
that's a neurotransmitter --
selective -- thank you, where was that coming --
AUDIENCE: It's first.
PROFESSOR: Oh, it's a selective serotonin, not
serotonin selective.
It's SS.
All right.
It's a serotonin selective -- reverse --
uptake, reuptake --
can I do reuptake?
AUDIENCE: [INAUDIBLE]
PROFESSOR: Yeah.
Yeah.
OK.
Reuptake inhibitor.
Or an SSRI, which makes it understandable how I would
have thought it might have been an SSRI
rather than an SSRI.
But let me explain what this is doing actually.
So remember that in schizophrenia, the first big
psychopharmacological breakthrough was the discovery
there's too much dopamine in bits of the brain.
If we block some dopamine receptors,
we reduce the symptoms.
In the case of at least some forms of depression, the
problem seems to be too little serotonin --
or a problem.
Seems to be too little serotonin in some
parts of the brain.
And so you've got a synapse.
And serotonin is being released here and binding to
the other side.
But now, in order to have this synapse be reusable, once
you've released some serotonin, you've got
to get rid of it.
You've got to get it out of the synapse so you can do it
again and again and again.
One of the techniques is to take the molecules and suck
them back into the originating neuron.
That's called reuptake.
Now, if you don't have enough serotonin here to do the job,
one thing to do is to slow down this reuptake so that the
serotonin hangs around here longer.
And that way you get more bang for your molecular buck.
And so that's what Prozac is doing.
The reason I put Emma on here is that Prozac seemed to do
good things for dysphoric patients, patients who did not
meet a clinical criterion for depression but who found --
I think in part because the drug manufacturer gave the
docs piles of free Prozac.
You know, patient comes through and says, "I feel kind
of down." So, "Oh yeah.
Try this.
This is new." You know, "All right.
Hey!
I feel better.
I feel a bunch better.
I'm not clinically depressed, but I really like this stuff.
And not only that, if I go off it, I go back to
my dysphoric state.
I go back to -- "
The example says something to the effect of, that's just the
way she is.
If she goes off Prozac, there are lots of reports even in
the popular literature of this, of people who said, you
know, if I'm off Prozac, I'm just, ughh.
But if I'm on Prozac, I'm just a better me.
Well, do you give them the drug?
Do you give them the drug?
Do you allow them to continue taking the drug for the rest
of their natural born days, particularly since we have no
idea since it's a new drug -- well, now it's
over a decade old.
But, you know, we don't know what happens if you take this
for twenty, thirty, forty years.
Who should pay for it?
You know, if you think that this drug makes you feel
better, that's lovely.
Should your insurance company pay for it on
a continuing basis?
So those are the Emma issues here.
The issues about whether or not it's OK to make somebody
better than they, in some sense, better than they were.
Are you the same person?
Is this, you know, is this the real Emma, or is this some
medicated Emma?
And, well, all right, now let's look back to the comment
about forcing them.
Well, you know what?
It works on kids, too.
And you know that there's a fairly substantial industry in
feeding psychiatric drugs to kids for
various and sundry problems.
Suppose, well, we know that shy --
how did I describe old Emma here?
Is she shy and withdrawn?
No, that was what's his name collecting the
underwear, wasn't it?
Oh well.
I could have described Emma as shy and quiet.
We know that the kid who's shy and quiet in first grade
doesn't get the same amount of attention that the bouncy,
active kid gets.
And in fact, there's some evidence that if you feed
something like Prozac to this kid, the kid will move from
here in the -- well, we've got to change the axis again.
You know, I don't know, what's the axis here?
Bounciness?
Technical term.
You know.
So the kid's going to move from being unbouncy to, you
know, Tigger is up here somewhere.
As are several -- couple of people out there
halfway up the --
so there's Tigger, I guess.
But, you know, move them up here, let's say.
Get them above average and the teacher's going to pay more
attention to them.
Is it OK to medicate your kid?
AUDIENCE: No.
PROFESSOR: If it's -- all right, it's not OK to
medicate your kid.
I'm not going to medicate my kid.
Uh oh.
The neighbors.
They're medicating their kids.
So what they've done -- my kid was right here.
He was average, right.
All right, now what the neighbors and the population
as a whole has done is they moved the whole
distribution over.
Because they're all handing out Prozac in the lunch box.
Now is it fair to my kid -- this is a hypothetical my kid.
This is not a real issue on my street
in case you're wondering.
But is it fair to my kid to not medicate him?
He's going to fall behind.
Is this systematically different, you know, is this
sort of morally or ethically different than the Kaplan or
Princeton Review approach to SAT tests?
What Princeton Review and stuff does is it takes the
population and it shoves it on --
everybody gets to gain those hundred points or whatever.
So is it OK for you to say, "My kid
doesn't need to do that.
I didn't do that when I was a kid, and no kid of mine's
going to go off and get tutored.
He'll do it on his own brains.
It's an aptitude test after all." Right.
You know, is there a difference between everybody
being signed up for Princeton Review versus everybody being
signed up, you know, going down to the nurse's office for
the daily Prozac dose?
Or is there a difference between just sitting there
saying, "I'm not going to go and make myself into a better
me by popping Prozac all the time.
I'll stick with --" What is that, Mountain Dew?
You know, twice the caffeine of whatever, right?
AUDIENCE: Late night last night.
PROFESSOR: Yeah.
OK, well, that's good.
You're vertical.
That's encouraging.
Give some to the guy next to you there.
He's gone.
[LAUGHTER FROM AUDIENCE]
I shouldn't have said that.
Anyway, we do this all the time, right?
We self-medicate.
We self-medicate, particularly with caffeine.
But perhaps with a variety of other things.
The use of alcohol as an antidepressant is probably a
mistake, but is not uncommon.
So when is this a sort of an unwarranted medicalization of
your life, and when is it, you know, a lifestyle choice?
And again, there's not going to be a question on the final
that says, "It's OK to drink Mountain Dew: yes, no, only if
it was a late night." But you can see that there are issues
to wrestle with.
And the doctors ended up with or have ended up with a
serious problem, which is what do you do with these patients
who you cannot in good conscience give a clinical
diagnosis of clinical depression to, but who say,
you know, if you don't give me my Prozac, I'm just going to
be so depressed, who really need that or who think that
they really need that.
Oh, by the way, OK, what's this?
Want to make sure that I do what it says.
Oh.
Well, OK.
Let's say something about how antidepressants work.
Here's a mystery for you.
Take Prozac.
It blocks the reuptake pathway within hours.
It doesn't take much time at all.
OK.
So you are down here, clinically depressed.
You come into the doctor's office.
He says, here's your Prozac.
You take the Prozac.
A few hours later, more serotonin
at all those synapses.
How do you feel?
Well, you feel depressed, actually.
It takes typically at least days, more like several weeks,
before an antidepressant of this sort has an effect,
beyond perhaps placebo effects.
There are placebo effects where you can take any old
damn thing and you feel a little better if you're
convinced that it's going to work.
But the main effect of antidepressants seems to take
a long time.
That's a mystery.
At least as far as I know, there's no neat, clean answer
to why it should be the case that the pharmacological
effect is there instantly almost and the psychological
effect takes a vastly longer time.
The reference that I put on the handout is a theory.
It's not proven.
But it's an interesting theory about what might be going on.
As I think I mentioned earlier in the course, one of the
interesting new findings in neuroscience is that we grow
new neurons.
We didn't used to think we grew new neurons.
But now it's pretty clear that you grow new neurons.
And there's a pretty strong suggestion that this
neurogenesis, as it's called, is depressed in depression.
You're not making those new neurons.
And one theory is that what an antidepressant is doing is
jump-starting the neurogenesis, that this is the
beginning of a cascade of events that leads eventually
to the birth of new cells, new neurons.
And only when you manage to sort of grow yourself a new
bit of brain, in a sense, does it help you to break out of
the depression.
The data on how well these things work is a little
depressing in its own right.
Antidepressants, like a lot of these --
antidepressants don't work as well once they go off patent.
It's a mysterious thing.
You want to worry about this.
Over and over again you get some cool
new drug like Prozac.
It's got no after effects.
It cures the disease like that.
And everybody is better, and it's a miracle drug.
Amazingly, by the time, you know, Eli Lilly or whoever's
patent has worn off, it now has side effects, doesn't work
all that well, but you want to try my new
amazing wonder drug.
So the last few reviews I've read of the effectiveness of
antidepressants have been, well, they've been sort of
depressing, actually, that they're not magic bullets.
Now, there are several ways to treat depression.
And how you treat it depends --
there are also several flavors of depression.
Not all depressions -- well, certainly not all are bipolar.
And there's evidence that they differ both in their symptoms
and in their neurochemistry.
So for instance, say, I think it says on the handout --
yeah, typical versus atypical depression.
I'm sure if I rummaged around I'd remember which was which.
But in some forms of depression, people sleep too
much and eat too much.
In other forms of depression, they sleep too little and eat
too little.
They're both depressions in terms of the mood, but they
are clinically distinct and
psychopharmacologically distinct.
Actually, bipolar disorders, the treatment of choice for
long before Prozac came on the scene was of all things
lithium chloride.
It's just the salt of lithium.
You know, just move right up from sodium chloride.
Jamison credits lithium with keeping her alive, that if she
had not been put on lithium as a treatment for her bipolar
disorder, that she thinks she probably would have ended up
committing suicide.
Anybody an expert on how lithium works?
No.
I think I don't know the answer to this.
I'm not sure it's known.
The last time I checked on it, we didn't know how it worked.
It was -- how was it discovered?
It was discovered in some bizarro fashion.
You know, where do you find lithium?
Like a salt --
I'm remembering some odd story about, you know --
AUDIENCE: Batteries?
PROFESSOR: Fine.
Batteries?
That people -- that's --
AUDIENCE: 7 Up.
PROFESSOR: 7 Up.
OK, if you dissolve your battery in 7 Up, I don't know
what happens but I don't imagine it's good because the
mercury and the rest of it probably isn't
really good for you.
The other treatment for --
now, sadly not all depressions are amenable to pharmacology.
Oh, first of all, the big mistake, which I think the
insurance people are growing out of, was the notion, OK,
now that we've got these cool pills, we'll pay for the
pills, but that's it.
So if it's going to take you several weeks for the medicine
to work, it turns out to be very helpful if you're
actually talking to somebody during this time, if there's
some psychotherapy of some sort going on.
Because if you are down here in the depths of the
depression and some genius hands you a pill
and says, "Go away.
Don't bother me no more." You know, if it's true that as
you're slowly coming out of the depression, that's when
the suicides take place, you know, this is
a recipe for disaster.
And if it takes a long time to work -- you know, if you take
a medicine and nothing happens for weeks, what do you do?
You stop taking the medicine.
And so what you really need typically as part of a
sensible treatment for a depression is not only
somebody who will give you the medicine, but somebody who
will talk to you about it too.
But even so there are depressions that are not
amenable --
or don't seem to respond well to any of the medicines that
we have at the moment.
And under the heading of even more unlikely treatments that
really turn out to work, more unlikely than feeding them
lithium salts, is what's known as ECT for
electroconvulsive therapy.
I talked about this a bit when we were talking about memory.
Remember this is little rats.
They step down.
You run electrical current through their heads.
You shock their little feet.
You run electrical current through their brains.
They don't remember that you shocked their feet, so they
step down again, you know.
Sound familiar?
OK, good.
Well, this is a treatment for depression.
Not abundantly clear why it works, but in my circle of
friends, I have a friend who actually went back to --
graduated college, went off, did a whole bunch of stuff,
then went back to med school, then became desperately
clinically depressed and had to be hospitalized.
And what got her through it was electroconvulsive therapy.
Not an entirely benign procedure.
It does have memory side effects.
But it used to be that nobody in an intro psych class
thought this was a good idea at all because everybody had
seen One Flew Over the Cuckoo's Nest.
How many people have seen that movie?
Oh, so still a fair number people have seen it.
That's a movie that does nothing good for the
reputation of electroconvulsive therapy.
Electroconvulsive therapy these days is, you know, you
give somebody a sedative.
They don't thrash around.
They don't hurt themselves.
It still has memory consequences, consolidation of
memory consequences, but it really does seem to
mysteriously break up depressions.
Now the latest wrinkle on this, you know, what boils
down to smack-them-up-th e-side-of-the-head treatments
of depression is the use of, very new, is the use of
transcranial magnetic stimulation, which I think I
also talked about earlier.
But basically what you do is you put a giant electromagnet
or strong electromagnet next to the skull.
You fire a big pulse of --
a big magnetic field that induces an electrical field
locally and knocks out neural activity locally.
And there's some evidence that properly applied, that this is
a sort of a kinder, gentler version of ECT, that it acts
to break up depressions.
I don't -- anybody know if there's a brilliant theory for
how that works?
Uh, who knows?
But it's very new.
But I expect that in a few years, I'll be lecturing more
about that.
Because it, at least initially,
sounds rather promising.
All right.
I think this would be a good time to take a break.
Let's take --
unless you're too depressed to get up, take a break.
AUDIENCE: I read Jamison's book.
PROFESSOR: Uh huh.
Which one?
AUDIENCE: Prozac Nation.
PROFESSOR: No.
Prozac Nation is somebody else's book.
AUDIENCE: Not Jamison?
PROFESSOR: No, that's somebody else.
I can't remember who wrote it, but yes, that's
a cool book, too.
AUDIENCE: Yes.
That's what I thought you were talking about.
PROFESSOR: Nope.
Nope.
But you'll come back and tell me who wrote it.
Because we're both forgetting who wrote it.
AUDIENCE: Have they ever done, what is it, using sugar pill
and Prozac and hand them out to patients and just seeing if
the sugar pill --
PROFESSOR: It's a big problem in mental illness in general
and certainly in depression, which is, particularly if
you've got a cycling depression, who's
going to get better?
Right?
And, yeah, the difference between placebos and Prozac
is, at least in some of the studies that I've read, a lot
less dramatic than you would think.
And the problem with a population like us is that
we're too well informed.
Placebos are great.
The side effects are really limited.
In the good old days, your doctor would come around, have
no clue, you know, how to treat you, but give you, you
know, Dr. Hoozy's magic elixir, and you'd feel better.
And it's a great pity that now if I fed you Dr. Hoozy's
elixir, the first thing you'd do is Google it and discover
that it's snake oil, and feel worse and sue me.
So, yeah, if you turn out to be particularly interested,
send me an email and I can send you a couple of the
references of things that depressed me when I read them.
Because they weren't that much good.
On the other hand, my mother absolutely
swears by this stuff.
She's had her own issues with depression and thinks that
Prozac is wonderful.
[PRIVATE CONVERSATION]
PROFESSOR: I want to talk about a couple of other
disease, you know, mental illness states, in part as a
way of illustrating --
I guess what I really want to illustrate in the last bit of
this lecture is the, sort of, mind and brain links.
We tend to like to make up theories that
are one or the other.
And the current popular trend is towards brain explanations.
Oh, you're depressed because you don't have enough
serotonin happening for you.
We'll boost up your serotonin.
You'll be fine.
It's a very brain kind of thing.
Freudian theories were very mind kinds of things.
But there's a number of cases that really illustrate, I
think, well, what you sort of know intuitively, right?
The brain isn't here and the mind is here.
It's, you know, waves and particles.
They're two manifestations of the same thing.
And brain stuff and mind stuff bounce back and forth
here all the time.
So let's think, for example, of panic attacks.
Which I didn't put on the handout at all, I see, but I
suddenly developed a need to talk about because I was
feeling really anxious and --
no.
So panic attack is this feeling of
anxiety out of the blue.
People report that they just suddenly feel very, very, very
fearful and anxious.
And it's scary and it's unpleasant and so on.
You may recall that Freud and his followers had a perfectly
nice notion about this, which was that anxiety was warning
you that you were about to tread on the super ego.
And it was the warning sign of the ego that was saying, don't
go and do that.
But that hasn't worked that well.
More modern notions tend to focus on the idea that it's
essentially neurochemical.
You get too much of some juice, some neurotransmitter.
It fires off the bits of your brain that are responsible for
the experience of anxiety.
And you feel this anxiety.
And this is a lovely case of looping back to a prior mode
of understanding.
The notion that you feel too anxious because you have too
much of this fluid, it's an awful lot like the notion that
you feel melancholic because you have too much black bile.
The difference of course is that we think we've got a
better scientific grounding than we had.
But the form of the argument is rather similar.
So is it the case that panic attacks, the clinical
condition of a panic attack, is just too
much of some juice.
It's possible to think about it as being somewhat more
complicated than that.
And, well, I didn't put that reference on the handout,
because I didn't.
But I'm stealing a story from --
who am I stealing it from?
Oh, Dave Barlow, who's over at BU.
This is a three-step route into panic attack.
And the first part of it is that you feel the visible
symptoms of anxiety.
Your heart starts --
remember the shaky bridge experiment all about
misattribution of arousal?
You're feeling "ooh-ooh-ooh" and you see her, and you just
think you're feeling "aah." Right?
So that can work in all sorts of ways.
Suppose that your heart is going through -- there are a
variety of things that cause your heart to go pitter-pat.
Suppose that you get these sort of symptoms and you don't
interpret it as love, you interpret it as "I feel
nervous about something.
I can't quite tell exactly what it is.
But I don't --"
People don't have panic attacks, by the way,
typically, when they're exercising vigorously.
Because they've got a good account of where that symptom
is coming from.
Your heart's pounding, you're sweating, and stuff like that.
Yeah, all right, fine.
If you're walking down the street and your heart is
pounding and you're sweating, you need a different
interpretation.
Now, this is unpleasant.
So you develop, flipping back to an earlier piece of the
course, you develop a conditioned
fear of these symptoms.
So you start avoiding situations that would produce
the symptoms, or that you think might
produce these symptoms.
And this can be quite unconscious, right?
This is good classical association learning or
something of that sort.
And that in turn -- that's sort of step two, is sort of a
learning story that is going to cause you to start --
you're going to act to avoid situations that
make you feel nervous.
But, all right, remember Pavlov?
Bell, tone.
Now I ring the bell by itself.
No.
Bell, tone.
That's stupid.
I'm not supposed to be the one who notices that first, guys.
You're supposed to -- "What's he talking about?" Anyway,
bell, food.
Bell, food.
Eventually the bell by itself produces salivation.
So you make this association in your own mind.
So when did this happen to me?
I was outside.
OK.
So now I'm outside, it doesn't happen to me.
But I feel --
I get the conditioned response in effect.
So now something else acts as a trigger for the panic.
The initial feeling of panic might have been, I don't know,
too many bottles of Mountain Dew, right.
You drink enough caffeine, and you'll get b-b-b-b.
Forget that you drank --
your brain doesn't remember the
caffeine part of the story.
And you're going b-b-b-b.
And you say, "Oh!
I'm having a panic attack." Then you don't want that --
this is an aversive event.
It's just like the business of the rat stepping down, right?
The rat steps down --
oh, all right.
Rat's up here, rat steps down, gets his little feet shocked.
That's unpleasant.
Rat's put back up here.
Does the rat step down again?
No.
Why?
Because he's got this anticipatory fear.
You can actually measure the fear physiologically.
All right, so you caffeine overdose or whatever.
You have this unpleasant experience.
Now you're in that environment again sometime later and you
have the experience again because it's a conditioned
response now, no caffeine involved.
You come to the reasonable, if perhaps unconscious,
conclusion that what makes me nervous is being outside in
public or being on shaky bridges or whatever.
Then you get step three, which is again learning theory kind
of stuff like Thorndike's Law of Effect.
You start doing things to avoid this punishment, right.
You're going to avoid the aversive stimulus.
So you can get secondary symptoms to the panic, like a
fear of open spaces, let's say, because you've now,
perhaps completely unconsciously, concluded, "If
I go out in public, the sky is so big.
I feel so small.
I get panicky.
And so now I'm not going to go outside."
And so what you end up with is the possibility that the
clinical thing that you see, what you get in your office if
you're the clinician, is somebody who says, "I have,
you know, I have uncontrollable
panic when I'm outdoors.
This is crippling my life because I don't go out
anymore." And what this may be is a cascade of events coming
from some sort of an initial physiological issue that you
then learned about, if you like, using the laws of animal
learning, in ways that that don't work well.
Well, what are you going to do about it?
Well, one thing you might do about it if you believed that
there was a significant learning component here is to
use learning theory kinds of things to treat it.
Now if it turns out that there really is a chemical imbalance
and every time the chemicals go out of whack, you feel
panicked, you might want to do something about the chemicals.
But if you've got one of these situations where the person
has basically scared themselves into maladaptive
behavior, you've now got to un-scare them.
So what are you going to do?
One of the standard techniques for these sort of disorders
would be desensitization methods.
Is it Barlow who was doing this?
So one of the versions -- you can imagine --
I did a version where you became scared of the outside.
Another version is you have a panic attack in an enclosed
space and you become very nervous about enclosed spaces.
You won't go into elevators and stuff like that.
I can't remember if it was Barlow --
I got a feeling it was -- whose technique for --
there are a variety of ways of using learning theory to get
around this.
One is the kinder, gentler one.
So you come to me.
You say, "I'm really afraid of being in enclosed spaces."
You say, "OK" --
the first cure out in this field that you've come to,
that I'm using for my doctor's office at the moment --
"Imagine that you're in a space.
Can you deal with that?"
"Oh, it's making me nervous, but, yeah, OK, I can deal with
that."
"OK, now we'll go to 10-250.
It's a big enclosed space.
And then we'll go to a smaller room and a smaller room.
And eventually we'll put you in a closet for a while.
And you'll discover -- what you'll do is un-learn the
response, in effect.
You'll learn nothing bad happened to me."
And this behaviorist sort of therapy does work to break up
these sorts of behaviors in many cases.
I think it's Barlow who has been advocating a much less
kinder, gentler version, which is to shut
people in car trunks.
So none of this business of doing it gradually.
This is known in the trade as flooding.
You just take the --
the guy says, "You know, I think if I'm in an enclosed
space, I'm going to die."
"All right.
Boom.
You dead yet?
No.
OK.
You're cured.
Good.
Out."
Well, it's not quite that simple, but the basic idea is
that if you have a patient who can actually deal with this,
that you can basically speed up the therapy rather
dramatically by not moving gradually to --
this is used for all sorts of phobias.
So, scared of snakes, you know, you're pathologically
scared of snakes.
OK, what we'll do is first we'll show you --
so the two versions are desensitization and flooding.
The desensitization story would be:
"We'll show you pictures of snakes."
"Ooh, I hate it.
I hate it."
"Are you dead?"
"No."
"Oh, OK." So now we'll go to the zoo. "And see that snake
cage way over there?
Are you dead yet?"
"No."
"OK, let's get closer.
OK, that's a snake, right.
OK, now you're going to get in with him.
Yeah."
"Aah."
All right.
"But I'm not dead."
And the flooding technique is "You're afraid of snakes?
Boom.
See those boas?
Are you dead?"
"Yes, actually."
[LAUGHTER FROM AUDIENCE]
So, anyway, the point from the panic attack example is that
it's possible that what you're seeing as the clinical entity
is a dance between physiology and learning, in effect, and
that what you learn --
and that a mode of treatment would be to unlearn.
Now, let's take another example which I did put on the
handout, which is obsessive compulsive disorders.
Obsessive compulsive disorders are, well, there's the
obsessive part and there's the compulsive part.
The obsessive part refers to obsessive thoughts.
What gets you into treatment is not some sort of obsessive
thought that "I love him.
I really love him.
Oh, I love him a lot.
Oh yeah, yeah, yeah.
I can't help but think about him." Yeah, it's a little
obsessive, but tough.
It's "Every time I look at him, I want to
rip his guts out.
I'm imagining the knife." You know, or something.
It's disturbing thoughts that somehow won't
get out of your brain.
That's the sort of obsession that people
seek treatment for.
And compulsive behaviors are behaviors where -- everybody
has some degree of this.
How many people here have left their room, gotten halfway
down the hall, said "Did I really lock it?", and gone
back to check?
Everybody does that sometime.
Or did I turn the stove off or something like that.
That's normal on compulsion land.
And almost always you have locked it, right?
Because the time you didn't lock it is the time you don't
go back to check, and somebody steals all your stuff.
Very annoying.
I donated a laptop to the criminal elements doing
exactly that.
Very annoying.
But anyway, if you have to go and, you know, get down the
hall, "Did I lock it?
Yep, it's locked.
Did I lock it?" You've got to do that forty or fifty times
and you can't get on with your life, literally.
You can't get to the next event in your life.
That's a compulsion that is likely to lead you to want to
do something about it.
It's interesting that these are compulsions --
rather like there are similarities in people's
narrative dreams --
that compulsions seem to be drawn from a limited
vocabulary of candidate compulsions.
I mean, I'm sure there's one of everything out there, but
there's lots of hand washers, right.
Actually, I can see my hands are covered in
chalk at the moment.
I should go wash them.
But, you know, why do you wash your hands?
Because your mother said so, right, and because there's
germs on them.
Can you see the germs?
No.
So you got to do the act and convince yourself
that you've done it.
OK, hands are clean.
Are they really clean?
I can't tell because there might be germs there.
I'm going to get sick.
I'll wash them again.
If you have to do this so often that your hands are
getting red and raw, that's a compulsion of some sort.
Now, you can treat OCD, as it's known in the trade, in a
number of different ways.
It turns out, for example, that Prozac is good against
obsessive compulsive disorders.
It breaks up the obsession, you know, the obsessive
quality here of this sort of thought that doesn't quite
work for you.
You can imagine that you've got some little circuit in the
brain somewhere that's a little checker.
You know, did I do what I was supposed to do?
And if that goes a little wacko on you, that that's got
too much serotonin or too little serotonin, I suppose,
or whatever, you know, you might end up in a sort of an
infinite loop where, "Got to check.
Got to check.
Got to check." And something chemical that gives
it a kick will help.
OK.
You can treat it that way.
You can also treat it using the same sort of behavioral
techniques that I was just talking about for phobias.
So let's do it for hand washing.
All right, Patient So and So, why do you have to wash?
"Well, I'm just really concerned that
my hands are dirty.
When I get dirt on my hands, I get all excited and
[NERVOUS SOUND]." Right.
All right.
So we can do the densitization business or we can do the
flooding business.
In the interests of time, we'll do flooding.
"All right.
See this?
This is dirt.
Put your hands in it." Right. "Are you dead yet?"
"No."
"All right.
How long can you leave them there?"
And you can basically desensitize this feeling of
deep anxiety about not cleaning your hands.
All right.
So that's mildly interesting.
What's interesting, the reason for raising this question or
this example, comes from this nice article, now more than a
decade old, by Baxter.
You can see obsessive compulsive
states in brain imaging.
There are little bits of brain specifically in the caudate.
It doesn't particularly matter for present purposes where
that might be.
But it's overactive.
You look at the brain of an obsessive compulsive sort, and
this little chunk of brain is busy, you
know, just going nuts.
If you give the patients Prozac, that chunk of brain
now doesn't look weird anymore.
It comes into the normal range.
If you'd go and do behavioral therapy on a patient with the
same story, the same piece of brain comes to look normal.
The point here is that you can reach this chunk of the brain,
if you like, either through the brain sort of
neurochemical route, or through the
psych behavioral route.
They're not necessarily either mutually exclusive or, you
know, one works and the other doesn't or
something like that.
This is a case where you can get to the source of the
problem, at least in a
neurolocalization kind of a way.
You can get to the source of the problem through either of
these routes.
And I suppose the bottom line here is that in disorder after
disorder, what you find is that there isn't just one way
of treating --
one problem is that in most mental illness situations,
there isn't one magic bullet treatment that automatically
works for you.
And then in many of these cases, there are both brain
and mind routes to therapy.
So when you're asking --
when you have like these patients we were cooking up,
when you have a particular patient, there's a spectrum of
choices that might potentially be of some use.
It says on the handout, "What happens when drugs make us
better than we ever were?" That was the example I was
talking about before of Emma, who feels better on Prozac
even though she wasn't technically --
didn't have a reasonable diagnosis of something being
wrong with her.
So we've already talked about that.
So I think I'll quit.
See you next week.