Inkwell: Authors and Artists

    
No disagreement there. 
  

    
I wouldn't say that Bipolar II is a catchall diagnosis, but it is
definitely easier to meet the criteria, and to stretch the case, than
it is with Bipolar I. Major depressive disorder is much more of a
catchall, and adjustment disorder withg depressed mood is, as near as I
can make out, actually designed to be a catchall.

And, as the study I mention above makes clear, just about anyone can
make all sorts of mischief with these diagnoses.
  

    
> Regulations? Consumer boycotts? Physician education?
 

The biggest single change that could be made would be to make medicine
nonprofit. That's never going to happen, but if it did, there would be
a lot less diseasemongering and perverse incentive out there.

Physician education is an interesting thought. As we all know, most
post-med sch9ool physician education is bought and paid for, and a
family doc is unlikely to leave a seminar sponsored by Pfizer with the
knowledge that, as a review article in Nature put it, depression is
"far from being a simple deficiency of monoamines [brain chemicals like
serotonin]." In fact, physician education started the depression
epidemic--that was the reason that Merck paid a doctor to write
Recognizing the Depressed Patient and then distributed it to 50000
doctors, who read that they should be much more liberal with their
diagnoses and not afraid to tell patients that they had a disease not
unlike any other physical illness. This was in 1962, before there was
any support (other than inferential) that biochemical imbalance caused
depression. The book was the idea of a marketing exec, who was
consciously trying to build a myth, or asw we would say today, doing
some viral marketing.

In my book, I suggest what else doctors could tell patients about
their depressions and antidepressantws that might make a
difference--about how the drugs might be a way to cope with an ever
more difficult world, etc. But for starters, it would make a huge
difference if doctors just stopped telling patients about their
biochemical imbalances, at least until such time as those imbalances
actually prove to exist. INstead, they could help pepole understand
taht they are altering their consciousnesses, and help them figure out
what that means in their lives.
  

    
But probably the single biggest change would be to hive off the
therapy profession from the psychiatry profession, a move that is
already under way, but to do it in a fashion that requires the
psychiatric industry to make good on their claim to scientific
authrity. The changes made starting with the revamping of the DSM have
been masterful uses of scientific rhetoric without very much substance
to back it up. Among themselves, doctors admit this--that, as I said
before, they've achieved reliability of diagnosis without improving
validity of diagnosis.

The same guy who said this out loud, Thomas Insel, head of Natl
INstitutes of Mental Health, thinks psychiatry should become clinical
neuroscience. I think i agree with this. But I think that whatever
dominion over whatever portion of our psychic lives this gives them, it
should be earned honestly. In my book, I tell the story of how a
prankster went into analysis with Freud and in the course of it
triumphantly brought Freud the news of shock treatments relieving
schizophrenia. Freud responded by saying, in so many words, that he
never said that mental suffering couldn't be neurochemical in origin
and that if doctors could get to the bottom of a problem that way, then
more power to them. I agree. And I think there is great promise in
pursuing the molecular biology of schizophrenia and bipolar disorder,
and maybe a few others. 

But I think as we approach the conditions that are both molecularly
and phenomenologically complex, we should be very cautious about what
comes under the gaze of medicine. Or I should say, they should be
cautious. Epistemological modesty should be the default mode when it
comes to advancing theories about human nature that could very easily
just be reifications. I believe that therapy, properly conducted, is
all abut epistemological modesty. It's a regular Church of I don't
Know, or at least it should be, much more about negative capability
than positive proof. 

I think this might mean it shouldn't be paid for with medical care
dollars, or at the very least there should be limits. But those limits
shouldn't be tied to diagnosis, except perhaps to say that some
diagnoses--those that the clinical neuroscientists have proven are in
their domain--ought to be treated like other illnesses, while the rest
should be subject to limiatations. Three years of therapy costs about
15 grand, real money to be sure, but not a bank=breaker. 
So maybe everyone gets a free pass for three years, and any more is on
you unless you have one of those clinical-neuroscience-diagnosed
diseases. 

I'm sure I'm dreaming here, and setting forth all sorts of
distinctions that can't reall y be made, but the point is if you take
the profit out of disease, if illnews is no longer a market, you will
also take away much of the incentive for the bad faith and outright
dishonesty that leads to disease mongering.
  

    
The distinction between reliability of diagnosis and validity of
diagnosis is a great one. 
  

    <scribbled by gberg Tue 9 Mar 10 16:40>
  

    
Right. I mean, homosexuality could be reliably diagnosed, but that
didn't make it a valid disease.

There's a whole story here that I won't bore you with (and that I had
to give up on putting in the book because I just couldn't make it
entertaining in the least, or even comprehensible) about how
statisticians used a statistic, the weighted kappa, to make the older
diagnostic categories seem less reliable, and the new ones more
reliable, than they really were, and then how reliability got
conflated with validity. It's too bad it hinges on arcana, because the
story is quite the scandal, and a great illustration of how scientific
rhetoric can substitute for science, to the detriment of some of us and
the advantage of others.
  

    
And speaking of serotonin deficiencies, an intersting article in the
journal Sleep introduces a guy who has a genetic defect that causes him
not to hae an enzyme crucial to the metabolism of solme monoamines.
Basically, he doesn't have anything like the normal amount of serotonin
or dopamine. He has, ande I quote, "mild hypersomnia with long sleep
time (704 min), ultradian sleep-wake rhythm (sleep occurred every 11.8
± 5.3 h), organic hyperphagia, attention/executive dysfunction, and no
depression." WAit! No serotonin and no depression? 

Not that I expect a one-to-one correspondence, but isn't that the
message of the antidepressant ads--that it's a deficiency of serotonin
that causes depression? 

It's interesting that he has some of the hallmark features of
depression--increased appetite and sleep and some kind of cognitive
impairment. This actually supports Irving Kirsch's hypothesis that the
mood change is the result of an amplified placebo effect, that what the
drugs do when they increase serotonin in a depressed person is to
create side effects, like moderating appetite and sleep, which in turn
not only makes a person feel better, but boosts the placebo effect. He
thinks, "The drug is working." Not sure I entirely buy this, but the
study is very intriguing.


The Sleep study is here
http://www.journalsleep.org/ViewAbstract.aspx?pid=27726
  

    
Yours is not the first story I've heard about statistical manipulation
for gain in the sciences.  I understand statistics only in general
terms - I'm good at grasping the concepts, but you wouldn't actually
want to rely on me for doing your stats.  Unfortunately, it is hard to
tell those stories, because the audience's eyes tend to glaze over very
quickly.
  

    
One aspect of diagnosis that is often overlooked is the change in
social attitudes toward and consequent psychological effects on the
diagnosed.  It's not all bad.  Before the disease model came along,
behavioral manifestations of what are now known as depression, bipolar,
ADD/ADHD, and autism were often attributed to deficits of character,
disposition, and parenting.
  

    
Facinating sleep study, thanks.  Just guessing here, but some balance
of serotonin and dopamine could still be involved in depression, since
levels of both were affected.  It is also worth noting that chronic
insomnia can lead to depression as well as cognitive impairment, and
that increases in serotonin, in this study as elsewhere, have led to
cognitive improvement as well as regulation of sleep and appetite.
  

    <scribbled by fingers Wed 10 Mar 10 00:58>
  

    
>Facinating sleep study, thanks.  Just guessing here, but some balance
of serotonin and dopamine could still be involved in depression, since
levels of both were affected.  

I don't think there's any doubt that when a person is depressed, it is
likely that his monoamine chemistry is different from when he is not.
It's even possible that AS a population depressed people's brain
chemistry is different in a consistent way from non-depressed people's.
THe real question is, waht does this mean? 

the Sleep paper only indicates what scientists already know, and what
I quoted earlier from the Nature article, which was a state-of-the-art
review of neuroscience about depression: that serotonin (or dopamine)
is the finger pointing to the mood. It's not the cause, but rather a
part of the very complex process that underlies depression. It happens
to be the thread we've tugged the hardest on. As my book details, this
is almost entirely a matter of historical accident, but out of it we've
woven this story about chemical imbalances. 

My favorite theory about the neurochemistry is the one that says that
lack of serotonin is an indicator of lack of hippocampal neurogenesis.
Depressed people, this theory says, are not growing new brain cells at
the rate they should be, especially in areas of the brain associated
with learning and memory. SErotonin may be a growth factor, or maybe
just a byproduct of neurogenesis. My favoring this theory is only
because I think it's rather beautiful and elegant. 

But even if this is true, we simply cannot say that the biochemistry
causes the depression, without claiming to know how mind and body are
related, whcih we just don't know.
  

    
>One aspect of diagnosis that is often overlooked is the change in
social attitudes toward and consequent psychological effects on the
diagnosed.  It's not all bad.  Before the disease model came along,
behavioral manifestations of what are now known as depression,
bipolar,
ADD/ADHD, and autism were often attributed to deficits of character,
disposition, and parenting.

 
This is what I mean when I say that calling something a disease is a
way to command social resources. In this case, the resource in question
is sympathy and other forms of understanding and acceptance, as well
as money, etc. for research and treatment. YOu can see this perhaps
most clearly in addiction, another disease that was invented as a
marketing tool (you can read about this in my previous book, The Noble
Lie), which has resulted in tremendous gains for addicts. 

On the other hand, I'm not sure it's unabmiguously a good thing to
have a disease story replace a story about character or history or
other biographical dimensions, or that the value is the same for ADD,
depression, and ASD. In fact, and I say this as the parent of a child
who could easily be diagnosed with ADD, deficits of character and
disposition, as well as parental errors and malfeasance, can indeed
contribute to, if not outright cause, those behavioral manifestations.
We've made grievous errors, including leaving my son in a school that
was simply unsuited to him because we were too clueless to understand
the depth of his learning disabilities, an error that resulted in a kid
who had behavior problems, espcially at home, that largely resolved
when we got him out of that school. What would have happened had we
gone with the ADD diagnosis and the drugs to go along with it? 

I don't mean to set up a false binary here, just to point out that the
destigmatization, so long as it hinges on a biochemical account of
suffering, has its own costs, largely that they determine the nature
and meaning of our biographies. It's not exactly a zero-sum game, in
which the more you have of one the less of the other, but we have to be
very aware of the tradeoffs, because they have chilling implications.
  

    

Interesting to me, I think obesity has not made that leap to disease model
and it is still seen as bad parenting, moral failing etc. - which doesn't
seem to be such a great place either.
  

    
I like the idea of making medicine non-profit. 
  

    
Really interesting discussions - I wish I had been paying attention
and arrived earlier.

One point about the nosology of disease is that it allows the
classification of pathologies based on hard-won mechanistic
understandings that then drive treatment. When dealing with the psyche,
the differential diagnosis is constructed from the phenomenology and
suggestive diagnostic testing to confirm clinical suspicions is
lacking.  This follows from the possibility that most of our so called
mechanistic understanding of the underlying pathology in what we might
call depression is complete bullshit - I'm in complete agreement here..

When folks fulfill criteria for depression, we are probably only
looking at the tail of a bell curve continuum of mood, where there is
enough dysfunction so that the phenomenology is relatively clear, even
accounting for various cultural and gender based biases in diagnosis.

I suspect that if depression is like most spectrum disorders, there
are probably a multitude of different physiochemical and possibly
structural aberrations that can lead to the expression of the disorder
as a final common pathway in the phenomenology - which then raises the
issue of how a clinician goes about trying to ameliorate the disorder
with little information on its true genesis. So we have the empiric
approach - let's try this and if it doesn't work let's try that.

The latter, coupled with more recent pharmacogenetic data on genetic
and possibly genetic x environmental factors altering response to
antidepressants, for example as illustrated in this article:

<http://www.nature.com/tpj/journal/v8/n2/abs/6500477a.html>

suggests to me that with more research we may get a better
understanding of the heterogeneous causes of the illness - which then
would drive "personalized" pharmacotherapy.

Gary, do you see any value in pharmacogenetic approaches to diagnosis
and treatment of depression, either now or in the future?

    
  

    
Well, to me, this whole field of individualized medicine is both very
promising and very spooky. There is no doubt that people respond
idiosyncratically to psychoactive drugs in general, and I don't think
that's entirely because of differing expectations or contexts for drug
use (set and setting). That's why I don't drink or take Xanax--these
drugs don't do anything for me, or at least nothing that I like. Other
drugs, which shall remain nameless, are much more friendly to my
personal biochemistry and history. (Actually, there's a section in my
book in which I give a firsthand look at the value of MDMA (Ecstasy) as
an antidepressant, so I've outed myself there.) For some people Prozac
is like rat poison, for others it's the key to the lock they've been
trying to open all their lives. It would be very nice to understand how
and why that is so, and some answer is at least potentially to be
found in individualized medicine, especially in its focus on the
translation of genetics via protein synthesis into phenotype. 

Similarly, even assuming that idiosyncratic drug response is mostly
about biochemistry, taht doesn't explain the heterogeneity of response
to antidepressants. If depression were homogeneous, biochemcially
speaking, You would still expect a stronger signal. So I think there
must be many pathways to the same experience. And here again, I;d put
my money not so much on figuring out the neural networks involved,
because that will be enormously difficult and require computational
heroics that I can't even imagine, but rather on figuring out the
crucial genetic and translational factors. 

(I emphasize translational because, as Nature also recently reported,
tjhe Genome Wide Association Study has been sort of a bust--very
loittle of our suffering can be located with any kind of confidence on
the genome, so attention has to turn to the way that genes do or don't
turn on, and to what happens next.)

So this is the promise. The spooky part is the granular level of
surveillance this puts us under, and the obvious advantage this gives
the medical industry in shaping norms and enforcing (although that's
probably too strong a word) them. The power granted to whoever
understands how, biochemically speaking, each individual comes to
experience the world is incalculable, and while most doctors (and for
that matter most drug company scientists, many of whom I have treated
because I work near Pfizer's main research site) are benevolent people,
I find this prospect a little unnerving.

I think what is needed to ensure a good outcome is a clear delineation
of waht all that biochemistry jazz gets at--that it is a correlate and
not a cause, that biography and biochemistry are connected,  parallel
tracks, irreducible to one another. Both approaches need to be wary of
epistemological hubris, which is just a fancy way of saying piety, or,
in other words, they need not to take themselves so seriously.
  

    
>So I think there must be many pathways to the same experience.

In total agreement. Also on the spooky aspects of personalized
medicine, especially in the context of un-universal health care.

Given the explosion of knowledge in genetic actuarial data - I can
foresee a time where a spot of DNA would give a pretty good picture of
health risk as far as a group - though not necessarily for a particular
individual. Nevertheless, the idea that an insurance company could
develop a genetic actuarial risk profile and then base premiums on it
is highly disconcerting.
  

    
What you say about some reactions to Prozac is interesting.  I've read
a fair number of addict narratives over the years, and it is amazing
how many of them start with first encountering the substance they
became addicted to and feeling that this was what they had been waiting
for their whole lives - the key turns in the lock.

That's one (of many) reasons I think our drug laws are insane.
  

    <scribbled by gberg Wed 10 Mar 10 08:45>
  

    
>What you say about some reactions to Prozac is interesting.  I've
read
a fair number of addict narratives over the years, and it is amazing
how many of them start with first encountering the substance they
became addicted to and feeling that this was what they had been
waiting
for their whole lives - the key turns in the lock.

>That's one (of many) reasons I think our drug laws are insane.

There are several coded messages in my book. One of them is taht the
drug laws are insane. I never come out and say this, at least I don't
think I do, but I chronicle the way that drug prohibition has driven
the antidepressant market by placing a premium on finding a disease for
the drugs so that they can be distinguished from other, less reputable
consciousness altering drugs.

The key-in-the-lock thing is only one of the ways that antidepressants
resemble recreational drugs. Earlier, someone (I think it was Gail)
talked about an antidepressant-using relative who might as well be
smoking a joint. She meant this as a criticism, which the relative may
well deserve. But I;m not sure the distinction between recreational
drugs and antidepressants is as sharp as we might like it to be, or as
the prescription/diagnosis regime makes it seem.

Consider the question of whether or not SSRIs ought to go over the
counter. It seems that two populations respond to the drugs: the
severely depressed, whose response shows up pretty well on clinical
trials (although if the FDA ever required head-to=head trials, I think
we'd see that the old antidepressants like imipramnine are better with
this group than Prozac), and the mildly or not at all depressed, the
walking wounded, whose response to the drugs was first detailed
anecdotally in Listening to Prozac, anbd who seem, in the small amoutn
of research done with them, to be experiencing personality changes that
make them less unhappy with themselves. Many in this second group are,
if we are honest, not diagnosable, or at least not diagnosable with
the disease that the clinical trials indicate the drugs can treat. 

Now, one thing we could do about this, and if we were a drug company
we'd have to at least consider it, is to get a good look at what the
drugs actually do for people in the second group and reverse engineer a
disease out of it. That's part of the story I tell about how
depression got manufactured in the first place, only in this case
they'd be manufacturing an illness closer to the old fashioned
neuroses, and that would probably be most honestly described as
Prozac-deficit disorder. But another approach would be to make the
drugs available over the counter. 

The original rationale for the prescription/otc distinction was all
about labeling. If instructions for safe use could be made clear in
layman's language on the label, then the drugs could be otc. Otherwise,
they had to be prescription. (This distinction was first made in 1937,
long before the FDA fkinally required (in 1962)drugmakers to prove
their drugs worked.) It's not a bad common sense approach. But it does
not mean that dangerous drugs can't go over the counter. Aspirin,
Tylenol, even Pepto-Bismol are dangerous drugs, much more dangerous, or
at l;east much easier to kill yourself with, than SSRIs. So they're
probgably safe enough to sell that way. And how does a doctor determine
whether you shold take Prozac or Paxil? Trial and error, based on your
account of how they make you feel. You don't actually need a doctor to
do that for you, just as you don't need a doctor to figure out if
sudafed (another dangerous one available otc, although not exactly
thanks to the methamphetamine industry) or zyrtec-d is best for your
allergies or which antacid you should take. 

I', not suggesting that this can or should happen (although I wouldn't
be sorry if it did), just pointing out that a good portion of the
rationale for keeping the drugs prescription-only is to strengthen the
distinction between one class of consciousness-altering drugs and
another.
  

    

>Interesting to me, I think obesity has not made that leap to disease
model
and it is still seen as bad parenting, moral failing etc. - which
doesn't
seem to be such a great place either.


Well, I don't know about moral failings, but obesity is, at least in
some cases, the result of conduct. There are many reasons that people
eat badly (and of course not everyone who lives on Whoppers and fries
is obese, while not everyone who is obese is eating badly), but some
of
them are about social matters like demoralization and lack of
resources--e.g., too many 7/11s, not enough Safeways in the inner
city.
Which is to say that even if we steer clear of blaming, biochemistry
isn't our only other choice. Understanding people at a molecular level
is in some ways the ultimate decontextualization, whcih is to say the
ultimate depoliciticization of our troubles. 

And not coincidentally, the molecular understanding of our discontents
tilts the playing field way toward the drug industry. Which reminds me
of a little story taht I never got to in the book. AS most of you
probably know, recently a group of neurotransmitters have been
isolated
that are responsive to THC. They're called endocannabinoids. And
obesity researchers have been very intersted in them, reasoning that
because munchies occur when you're stoned, the endocannabinoids must
be
involved in appetite regulation. It turned out not to be too terribly
hard to discover drugs that would block those receptors (called CB
receptors), and CB antagonists like Rimonabant went into clinical
trials for obesity treatment.

And guess what happened? As any stoner could have predicted, the
people taking the drugs got depressed. It turns out that if you block
the action of endocannabinoids, which obviously mediate pleasure in
some way, people get unhappy. Or to put it another way, they get
un-stoned. The drug makers (Pfizer and Merck, I think) halted the
trials and withdrew the application.

But there was a silver lining. AS one report put it, if blocking the
CB receptors brought on depression, then maybe stimulating them would
alleviate it, so maybe they should look to the CBs as targets for, you
guessed, it antidepressants. Of course, they seemed to have forgotten
that we already have one of those CB-targeted antidepressants in
widespread use. It;s an herbal remedy and sometimes it's smoked, but
it can be pretty darned effective.

 
  

    
Heh! The NIH/NIAAA spent millions of dollars (visualize dollar bills
on small wings flying away)  on a clinical trial looking at
CB-inhibitors to treat "alcoholism." In spite of the fact that the
resident clinical pharmacologist told the director that it was bad
science,  the animal studies suggested that the animals decreased all
oral intake, not just alcohol, that rats treated with CB-inhibitors had
a lot of problems "unlearning" behaviors once the paradigm changed,
which might translate across species as not helpful for someone trying
to change their behavior, and that early reports of dysphoria in the
obesity trials suggested that use in patients with post-alcoholic
dysphoria/sleep disorder that can last years probably would not be
useful.  Besides warning that Sanofi had not done any cardiovascular
safety studies which are now required before submitting an IND
application. 
  

    
The discovery of neurotransmitters leads almost immediately to the
search for drugs. They all look like targets to the drug industry. This
has been true from the beginning. AS I dexcribe in my book, serotonin
was first isolated in the late 1940s, and even before Abbott
Pharmaceuticals knew what it was or that it was in the brain, they sent
it out to scientists in hopes that they would figure it out and point
the drug designers ina  direction. One of the scientists who got a
sample was the first to identify it as a neurotransmitter and to locate
it in the mammalian brain. The rest is history.