Inkwell: Authors and Artists

    
This is increasingly fascinating to me, and I appreciate the detailed
explanations and anecdotes.  I'm guilty of not reading the book yet,
but I've ordered it and am looking forward to diving in.  I have
googled up a few articles and reviews that I think -- along with this
discussion -- have given me a good idea what the discussion is about,
something I didn't pick up on right away.

That said, I notice that there hasn't been much talk of "stress" in
discussing depression.  I ran across a recent lecture by Robert
Sapolsky, the Stanford biologist who has been studying stress for
something like 30 years, in which Sapolsky explains his take on the
most best-guess theory of depression.  Although he spends time
explaining the neurotransmitter theory, he states bluntly that anyone
who treats only the neurochemical aspect of depression is not going to
make anyone get better.  

The reason: research he refers to shows that psychosocial,
environmental, hereditary precursors are involved almost as catalysts
in the development of depression.  Among these precursors is, first and
foremost, stress.  (No surprise!)  What's more, especially highly
stressful -- call them traumatic -- events that set the brain up for a
kind of malignant feedback loop that makes the brain vulnerable to
depression.

If you care to watch his lecture -- or to check and make sure I
understand his hypothesis -- here's the URL: 

http://www.youtube.com/watch?v=NOAgplgTxfc

I'd love to get your take on this.  What feels, very often, like
depression to me is actually being overwhelmed by supercharged stress. 
Or, after being stressed out, I'll have a decidedly "down" period.  I
also have several "physical" chronic diseases that are commonly thought
to be aggravated by stress (Crohn's and Sjogren's syndrome in
particular), so the whole subject of stress -- and stress reduction --
has long been of great interest to me.  (It's also made me into a fan
of Sapolsky's work and writing -- to my layman's understanding, he
seems very solid in his science and very wise in his conclusions).

Sorry about the long request.  Thanks in advance.... 
  

    
I'm familiar with Sapolsky's work. He's a pretty brilliant guy, and he
clearly grasps not only the significance of stress, but also the
politics of it, the way that stress varies with social arrangements.

This is one of the truly vexed areas in the depression debate. Most of
the people I call in the book (perhaps unfairly, but you gotta have
your bad guys) "depression doctors" acknowledge the importance of
environmental stressors in depression. The result is a
"stress-diathesis" theory, a fancy way of saying that the outcome is
the result of interaction between your biological predisposition and
your lived experience. (I say most, because there are some who so swear
by the biological model that they discount entirely the role of
environment--I will ahve the pleasure of debating one of them, Lewis
Wolpert, tonight on BBC.) This is nothing more than the old
nature-nurture debate focused on a particular phenomenon, and the
explanation--it must be both--is both inescapable and unsatisfying.
Furthermore, most doctors seem to be giving lip service to the stress
side of the model--their interventions are on the side of diathesis,
whcih is to be expected because they are, after all, doctors and not
politicians or policy makers, and they are provided as if stress was
incidental. That's why doctors give the spiel about biochemical
imbalances to patients receiving antidepressants.

But anyway, the theory goes something like this. The biochemistry of
depression can be kindled by life events. You suffer a loss, you have
the normal reaction, which turns on a circuit in your brain, and then,
for reasons unknown but presumably genetic, the switch gets stuck in
the on position. The drugs help to turn off the circuitry, but once
this has happened you are vulnerable to depression for the rest of your
life, and should be treated as such. Which may mean ongoing medication
or simply getting on antidepressants (or learning the techniques of
cognitive-behavior modification) as soon as the earliest symptoms
arise. This is imperative because, the theory goes, the more that
circuitry is aroused, the more it is likely to turn on and stay on.
Untreated depression, they say, gets worse over the life span.

I think this theory has a certain common sense appeal. AS I've said
before, I think we have to be very careful about common sense, because
it tends to be ignorant of our blind spots. After all, it used to be
common sense to think that homosexuality was a disease or that cholera
was the result of bad air, and in both cases really significant social
prejudices were hidden in the common sense. My book details what could
be lurking in our common sense appraisal of depression as a
stress-diathesis disease--among other things, our prejudices against
unhappiness and consciousness-altering drugs, our difficulty in
understanding longing, our tendency to equate ongoing longing as a
failure to achieve fulfillment, etc. 

But let's just assume this view is correct. What are we to make of the
fact that increasing numbers of people are suffering depression? The
default explanation for this is increasing detection, better
monitoring, public education, etc. But is it possible that even if it
is a biochemical phenomenon, it is still also, and maybe primarily,
social, the result, say, of in utero or early life exposure to toxins
like heavy metals, which are undeniably an increasing part of our
environmental background? (I just read a book about mercury in the
environment, its decisive role in some illnesses throughout history,
its possible role in autism, and it's pretty worrisome stuff.) Or maybe
depression, the biochemical part of it, is an inflammatory illness,
onw of the many immune system afflictions that are also undeniably on
the increase, perhaps becasue of other background toxins. We can treat
those illnesses with corticosteroids or monoclonal antibodies or
antidepressants, but this doesn't mean that the inflammation or other
biochemical mechanism isn't a social problem.

And then of course there are the other stressors--the increasing
demands of modern life. IN a throwaway line in my book, I suggest that
our society demands more serotonin from us than our evolutionary
heritage prepares us for. I don't really believe this, but I do believe
that there are historically unique stressors impinging upon us, and
that they are getting bigger and stronger and weirder as time goes on.
This could mean that even if biochemistry is more or less stable across
time, still increasing numbers of us would be vulnerable. Here again,
the public health model, which I think Sapolsky is sympathetic to, is
valuable. As I said earlier, John Snow didn't have to know that cholera
was caused by a water-borne germ to understand that the best solution
was to take the handle off the pump. THe question raised by the
stress-diathesis model is perhaps not only what drugs should we take
but also which measures to take against the stressors. Or, to put it
another way, which handles should the vandals steal?
  

    
Why do you gotta have your bad guys, even at the cost of being unfair?
  

    
Another advance in genetics:

http://www.nytimes.com/2010/03/11/health/research/11gene.html
  

    
Well, I guess I walked into that one.

So I guess I have to explain that that was a moment of
self-deprecating humor, an acknowledgment of the limits of rhetoric. In
discussing the scientists and doctors who advocate for the disease
model, I generalize (by calling them a group even if they wouldn't
necessarily identify themselves as such) and use alliteration to give
the name I made up for them a little polemical punch. That's the part
that's unfair, because all generalization is unfair to the specific
parties and because naming a group that can't talk back is also unfair,
but the doctors can pretty much take care of themselves, so I'm not
exactly apologizing.

AS for why you gotta have bad guys, well, I didn't mean that entirely
straightforwardly either. That was a poke at the writer's craft and, to
a lesser extent, at the demands of the marketplace. In fact, my book,
mordant as it gets, is pretty careful to give credit where credit is
due, and expresses a great deal of respect for and even wonderment at
the discoveries that the depression doctors have made. I remain
critical of the way they've interpreted and implemented these
discoveries and of the power that they have gained thereby.

But as it happens, to the extent that there are bad guys and
malfeasance in my story, it is on the part of doctors who continue to
tell patients about their biochemical imbalances when they tell each
other that they have yet to find these imbalances and that if there;s
one thing they are sure of, it's that depression is not caused by an
imbalance of monoamines. This strikes me as just plain bad faith. 

Jennifer, may I ask if you have read my book?
  

    
I have not.  I have been responding to statements made here.  The
subject is of interest to me.  I am troubled by the use of informal
logical fallacy in making a case.  If it is done in ignorance, that
suggests a lack of rigor.  Done deliberately, it amounts to
intellectual dishonesty.
  

    
And the informal logical fallacies you're disturbed by are...?
  

    
Unfair but catchy labelling to discredit your opponents is ad hominem.
  

    
Well, of course that was why I added my little caveat above, although
obviously it backfired--I wanted to acknowledge that, taken out of the
context of my book "depression doctors" might sound unfair. Meantime,
read the book and tell me what you think about whether it lacks rigor
or intellectual honesty. I'd love to hear. 
  

    
I totally understand what you're saying about the writer's craft. 
  

    <scribbled by fingers>
  

    
In truth, what I have read here has dissuaded me from purchasing the
book.
  

    
Sapolsky also has one of the best beards in the business.

http://news-service.stanford.edu/news/2006/november8/stress-110806.html

Rivaled only by the beard of Aubrey de Grey, the life-extension
expert, which I described somewhere as looking like a hedgehog had
latched onto his chin. 

http://us.macmillan.com/author/aubreydegrey
  

    
Animal and some human studies suggest that chronically high cortisol
may exert neurotoxic effects, especially in the hippocampus by
suppressing neurogenesis - making the new neurons. Taken together with
the observation that different chemical classes of antidepressants
share the property of inducing neurogenesis leads to several possible
approaches to the mechanism. Maybe antidepressants alter perception of
anxiety - reduce stress and drop cortisol - maybe they are effective in
animals who have high cortisol - maybe they don't have much of an
effect if cortisol is otherwise low, etc.

The point being that studies seem be suggesting that chronic stress ->
more cortisol -> neurotoxicity.

A good example is structural studies showing hippocampal loss in vets
with PTSD, or in some women after treatment of lupus with high doses of
steroids. Assuming one believes in PTSD as a valid typing.

Sapolsky is one of this generation's resident geniuses. And a good
writer to boot.  I keep a few extra copies of his collection of essays
"The Trouble With Testosterone" collected from abebooks to hand out as
a way of introducing folks to his work.
  

    
"The Trouble With Testosterone"--that's an understatement.

AS I said a little while ago, that whole neurogenesis thing really
appeals. It explains some other things, like the way that
antidepressants can take a couple of weeks to work: it takes that long
for the new cell growth to manifest. Hippocampal volume is also
decreased in a small sample of patients who committed suicide. (on
autopsy, of cxourse.) 
  

    
Have you come across any data on neurogenesis and AMPA inhibitors or
acetam structure nootropics?
  

    
(Thanks for the insights on Sapolsky. That is one hell of a beard,
isn't it?) 
  

    

>Have you come across any data on neurogenesis and AMPA inhibitors or
acetam structure nootropics

No data, althougjh I'm sure it's out there. 

AMPA, by the way, refers to a subgroup of receptors called glutamates,
which are increasingly thought to be a better target than the
serotonin receptors for drugs to treat depression. And they are
implicated in neurogenesis, but I can't recall how we know that. 

Another type of glutamate receptor is NMDA, and one of the drugs that
has an affinity for that receptor is ketamine, which may be known to
some of you as a psychedelic or entheogenic drug. It has also been
studied as an antidepressant. People who took it had a rapid response.
I wrote about this study in my book in part becaues it illustrates the
brain-focus of many researchers. The scientist who conducted the study
never referred to ketamine's long history as a psychedelic, and never
talked about what the people who took it actually experienced (other
than that noting "adverse effects" that included euphoria and cognitive
distortion). 
  

    
Ketamine is weird - it is also a very potent and non-specific
monoamine reuptake inhibitor, hitting every class - serotonin,
dopamine, norepinephrine.
  

    
What they call a promiscuous chemical.

The article annoucing the depression/Ketamine study was a great
example of how the politics and economics of depression medicine
distort the science. The title was "A Randomized Trial of an
N-methyl-D-aspartate Antagonist in Treatment-Resistant Major
Depression," which immediately suggests that ketamine is another one of
these highly selective drugs that work like smart bombs going down
your brain chimney. This, as Paolo suggests above, is an exaggeration
(as it is for the serotonin drugs like Prozac, which are not really so
selective as they sound). As I mentioned above, there is no mention of
the actual psychological effects of the drug. There's also no reference
to its history of illicit use. ANd, most curiously, the author writes
the paper as if he figured out that NMDA was a likely antidepressant
target and then decided to use ketamine, distinguishing this line of
reasoning from the (presumably less scientific) empirical manner in
which SSRIs and tricyclics were discovered. But in fact, there's been a
long history of anecdotal reports, mostly from anesthesiologists,
about surgical patients who happen to be depressed who emerge from
ketamine anesthesia with reduced depressive symptoms. This also goes
unmentioned. So the results, which are strong and suggestive on their
own, are fluffed up by these omissions. 
  

    
Right - the one-drug one-receptor one-effect school is somewhat
simplistic. I've seen CSF values of monoamine metabolites after
ketamine and they are all astronomically high. Similar to that seen
after ECT.

I've always wondered if a good old fashioned orgasm might result in a
similar generalized release of monaomines and endorphins, enkephalins,
etc, though I'd bet that doing that study - spinal taps after an
orgasm, would probably experience accrual problems. Seriously though, I
think Wilhelm Reich may yet be proved correct wrt orgasm as a natural
antidepressant.
  

    
There was a movie in the 80s--Liquid Sky--in whcih the aliens fed on
people's endorphins. The aliens were thus attracted to people in 2
situations--shooting heroin and having sex. I remember some crude but
effective visuals, from the alien point of view, of the brain pulsing
with whatever it was that they were after. 
  

    
>though I'd bet that doing that study - spinal taps after an
orgasm, would probably experience accrual problems.

But researchers have, as Mary Roach details in Bonk, gotten couples to
climb into the MRI and get it on for science, and you can deduce from
blood flow patterns which neurochemicals are most active.
  

    
>the one-drug one-receptor one-effect school is somewhat
simplistic. 

It's also inaccurate, at least when it comes to antidepressants, even
the "selective" ones.

One of the themes in my book is the way that the magic bullet approach
to medicine has served as a guiding myth for the depression industry.
The idea that there is one chemical that can be targeted by one drug
and thereby depression can be cured has been irresistible from the
beginning of the magic bullet era--since, say, the turn of the 20th
century. A lot of the exaggeration and distortion that has occurred in
the science can be traced to the eagerness of scientists to have that
Eureka moment, which leads them to be uncharacteristically loose in
their reasoning, unusually willing to substitute inference for proof,
and prone to spin.

The ketamine study is an example. The author elides the illicit
history of the drug and claims that his discovery was a deduction from
theory rather than an empirical observation. This all has the force of
making the drug seem more like a magic bullet (and the disease more
like a target.)

A better example would be a paper that came out in 1965 called The
Catecholamine Hypothesis of Affective Disorders, lead author Joseph
Schildkraut. In it, he reviewed all the research up to that point and
concluded that depression was the result of deficiencies in the
catecholamines, chiefly norepinephrine and dopamine. Now, there's no
question that he overstated the case, and in fact, as subsequent
research showed, the more likely target was serotonin, which is not a
catecholamine. But even more interesting, his paper is not really an
account of affective disorders. It's an account of drug action--it's a
theory about how the drugs (which by then were in regular use even
though no one knew how they worked [and still no one does]) did what
they did. It's not unreasonable to move from that hypothesis to a
speculation about affective disorders, but that's not what the title
says the paper is about. So I think you can see the eagerness to have
that target just in his choice of title. And it worked--for many years,
the paper was among the most-cited in the psychiatric literature, 
repetition of the hypothesis substituting nicely for actual proof.
  

    
I re-read "repetition of the hypothesis substituting nicely for actual
proof" several times.  Sounds religious, almost!