Cytokines and Depression
k p Collins
kpaulc at [----------]earthlink.net
Tue Dec 23 01:04:50 EST 2003
I tried to access the article, but couldn't, so
thank you for posting it(?). I'll provide some
analysis below. [If it's not the same article to
which John referred, it doesn't matter.]
"Dave Bird" <dave at nospam.xemu.demon.co.uk> wrote in message
news:OR7BRTApr25$EwNB at xemu.demon.co.uk...
> In article<3fe6804d at dnews.tpgi.com.au>, John H. <johnh at faraway.?>
> >Stress and cytokine levels underpin a provocative theory of depression
> >Maes helped to establish the notion that overexpression of
> >cytokines, in particular, can disrupt the stress response system's
> >elements: the hypothalamic-pituitary-adrenal (HPA) axis and the
> >monoaminergic system, including the hormones serotonin and
> >Among the stressors that can overstimulate these proinflammatory
> >are infections and melancholy. Although the pathophysiology of depression
> >remains unclear, Maes is among those researchers who assert that it is a
> >psychoneuroimmunological disorder.
> Yes there is undoubtedly a deep connection between high immune response
> states such as a physical illness and depression. I'm not sure this
> article takes us that much forrarder in understanding how.
> Signal BluesStress and cytokine levels underpin a provocative theory of
> depression | By Steve Bunk
> In 1992, American writer Andrew Solomon, then in his late-20s, was about
> to publish his first novel when he unexpectedly slid into a major
> depression. In a subsequent book, he wrote that the experience is
> "almost unimaginable" to the uninitiated. Describing it, he likened
> himself to an oak being strangled by a vine, "a sucking thing that had
> wrapped itself around me, ugly and more alive than I." He called up the
> image of falling into an abyss: "You hit invisible things over and over
> again, until you are shredded." And he mentioned the fleeting terror
> anyone feels who trips and is about to fall: "I felt that way hour after
> hour after hour."1
All that was going on, here, were the dynamics of
"rendering useless" [as they are discussed in AoK,
and, in particular, Ap8] left uncomprehended.
When =anyone= works on a 'project' relatively-
exclusively, their relatively-exclusive focus results
in TD E/I-minimization convergence occurring
within their nervous systems in a commensurately-
relatively-exclusive way. While in this 'focussed
state', everything's taken care of by 'normal'
Then the project is completed, and justification for
the relatively-exclusive 'focus' 'disappears' - 'poof' -
but the "biological mass" - the microscopic trophic
modifications that were physically constructed within
the individual's nervous system under the artificially-
narrow constraints of the relatively-exclusive focus -
When this happens, there's a =temporary= 'state' in
which the tight "finitization" that was acchieved within
the artifically-delimited TD E/I-minimization limits of
the relatively-exclusive focus rapidly 'disappears. This
happens be-cause, when the project is completed, the
justification for the artificially-narrow TD E/I-minimiza-
tion focus ceases to have any rationality to underpin it.
This is experienced as an innundation of TD E/I-min-
imization work that was just 'cast aside' while the
individual was in the midst of the project's artificially-
delimited focus. All manner of 'normal' stuff impinges
upon the nervous system's TD E/I-minimization dyn-
amics, but, because of the relatively-intensely-focus
that was given to the project's delimited subset of
'normal' experience, and be-cause TD E/I-minimization
occurred in accord with such, when the project is de-
clared to be 'finished',the individual's nervous system is
relatively-quickly confronted with TD E/I-minimization
work that was left undone while the relatively-exclusive
focus of the project was being 'enforced' [by a
correlated "prefrontal constellation", AoK, Ap7].
Beyond the prevailing absence-of-understanding of what's
going on within the nervous system, it's no 'big deal'.
The analogous thing occurs routinely within common
experience with respect to all manner of "rendering
useless" instances - loss of employment, loss of Love,
loss of Loved ones by Death, natural catastrophes [such
as the forrest fires in the western U. S. last summer, and
the earthquake that occurred in California earlier today(?),
which come replete with modern News coverage of folks
being in the midst of the "rendering useless" that's been
catastrophically-imposed upon their nervous systems. All
that underpins their 'confused states' is the fact that the
TD E/I-minimization capabilities that their nervous systems
developed during the courses of their prior experiences
have been rendered relatively inadequate be-cause a lot
of the external-stimulus-correlates in which TD E/I-
minimization formerly derived has 'just' 'disappeared'.
Of course, the loss is real, but the 'confused states' of the
folks involved are not at all 'abnormal'.
The =only= 'problem' has been that what's going on within
the nervous systems involved has 'just' not been compre-
And it's a particularly-Tragic instance of absence-of-
understanding when 'helpers' who haven't bothered to
understand nervous system function declare folks who
are 'just' experiencing catastrophic "rendering useless"
to be 'ill', and pump them full of drugs that only act to
assure that the doing of the necessary TD E/I-minimization
work within folks' nervous systems will be delayed.
What's 'hilarious' is that these 'helpers' get paid to inflict
such drug-induced delay upon nervous system function [and,
of course, the pharmaceutical companies get rich pedalling
all of the useless stuff that gets pumped into nervous systems,
only to the detriment of the folks who are subjected to such.]
Why not just understand what's going on in-there, and take
action in understanding in a way that empowers the innate
brilliance of 'the' nervous system?
> Even as Solomon struggled with his demon, scientists were undertaking an
> effort to describe depression in terms of molecular biology. Evidence is
> growing that a key mechanism underlying major depression--a sometimes
> heritable, often lifetime illness, with repeated remissions and
> relapses--involves dysregulation of the signaling proteins called
> "Depression can be induced by external or internal stressors," says
> psychiatry professor Michael Maes, University of Maastricht,
> Netherlands. "So, depression is probably a symptom or a syndrome of
> stress." A principal architect of the cytokine dysregulation hypothesis,
> Maes helped to establish the notion that overexpression of
> proinflammatory cytokines, in particular, can disrupt the stress
> response system's primary elements: the hypothalamic-pituitary-adrenal
> (HPA) axis and the monoaminergic system, including the hormones
> serotonin and norepinephrine. Among the stressors that can overstimulate
> these proinflammatory cytokines are infections and melancholy. Although
> the pathophysiology of depression remains unclear, Maes is among those
> researchers who assert that it is a psychoneuroimmunological disorder.
> Others are not so sure. Robert Dantzer, a key figure in cytokine and
> mood research, rejects the exclusiveness of Maes' theory. "Cytokines can
> be at the origin of mood disorders, just like any other psychosocial
> life event that does not necessarily activate the brain cytokine
> system," says Dantzer, director of the Laboratory of Integrative
> Neurobiology at the National Institute for Health and Medical Research
> (INSERM) in Bordeaux, France.
> Another school of thought: Cytokine dysregulation does not lead to mood
> disorders, but could increase the susceptibility of an already depressed
> patient to immunity-related illnesses.3 The debate stems, in part, from
> animal studies upon which most of the cytokine data is based.
> Contradictory results, differing methodologies, and the nagging question
> of the relevance of animal depression models to the human experience
> keep the debate alive. (Try, for instance, to measure symptoms such as
> guilt or suicidal thoughts in a rodent.)
> But human studies present their own challenges. Multiple factors,
> including genetic susceptibilities, body mass index, diet (ingested
> omega-3 polyunsaturated fatty acids, for example, can have anti-
> inflammatory effects), smoking, recent infectious diseases, and
> medications, can confound cytokine measurements. Yet, none of this
> complexity diminishes the attractiveness of focusing on stress mediators
> as potential targets to treat or prevent depression. And chief among
> those mediators are cytokines.
> SICKNESS BEHAVIOR In 1988, Benjamin Hart unwittingly provided a thematic
> framework for investigations of depression and cytokine dysregulation.
> Hart, a professor in the School of Veterinary Medicine at the University
> of California, Davis, recognized that factors such as appetite loss,
> decreased grooming behavior, and lethargy in sick animals are evolved,
> adaptive strategies that save energy for recovery.4 In 1992, INSERM's
> Dantzer put this concept into perspective for mood disorders by
> providing evidence that sickness behavior is mediated by brain
> Another important contributor to this field, psychiatry professor Andrew
> Miller of Emory University in Atlanta, declares that Hart "got everybody
> thinking" about the possible connections between inflammatory responses
> to infection and behavioral changes, which are now well established.
> Hart, unaware until being interviewed for this article that his paper
> inspired an approach to studying depression, says his reading and
> observations led to the conclusion that the behavior of sick animals
> "increases their capability to meet demands of the fever response, which
> are costly."
> Numerous inflammatory diseases, infectious and noninfectious, now have
> been associated with both cytokine dysregulation and depressive
> symptoms.6 The infectious diseases include HIV and hepatitis C; the
> noninfectious conditions include stroke and autoimmune diseases such as
> diabetes mellitus and rheumatoid arthritis. Depression also is
> frequently comorbid with heart disease and cancer.
Illness =always= exerts "rendering useless", simply be-cause it
incapacitates 'normal' behavior.
The absence-of-understanding that imposes further "rendering
useless" upon folks who've suffered illness-imposed "rendering
useless" has to be replaced by understanding that actually =helps=
folks who've suffered illness-induced "rendering useless", instead
of artificially compounding the "rendering useless" with completely-
unfounded, Erroneous presumptions that derive in absence-of-
understanding with respect to the fundamentals of nervous system
At this juncture, Failure to remedy this situation constitutes institu-
tionalized "Mad 'science'" run amok.
All that's necessary is to lift thos who've suffered illness-induced
"rendering useless" up in an understanding of what's going on
within their nervous systems.
Inflicting psychoactive substances upon a nervous system that's
in the midst of experiencing "rendering useless" is the exact
opposite of what needs to be done.
> Most research to date has focused on depression in medically ill
> patients, in whom it is five to 10 times more prevalent than in healthy
> people, says Miller. In an experimental model that has been applied to
> hepatitis C and malignant melanoma, Miller has focused on the depressive
> symptoms caused by cytokines. For example, Miller says IFN
> (interferon)-a, which he has used to treat patients with hepatitis C and
> malignant melanoma, will induce depression in 30% to 50% of patients,
> depending on the dosage. Says Miller: "It's a wonderful model, where we
> have a tremendous amount of control over mood problems as they develop."
Good grief! This's all B.S.
There are myriad molecular dynamics that alter in the midst of
"rendering useless" - muck around with any of them, and the
engineered-in mechanism of 'depression' is, itself, "rendered useless".
Why not just optimize the innate information-processing dynamics
by lifting nervous systems up in an understanding of them?
> By administering antidepressants to such patients before they began IFN-
> a therapy, Miller discovered that depression did not develop.7
Somehting's 'missing' here - a complete, long-term analysis of
behavior under the influence of the 'anti-depressants'. I predict that,
when such analysis is done [and not omitted or excised from publications],
it will be observed that 'normal' nervous system information-processing
capabilities have become diminished, and will remain so while the
psychoactive substances are being imposed upon nervous system
> there was little effect on the nonspecific or "neurovegetative" symptoms
> corresponding to sickness behavior that Miller colloquially refers to as
> feeling "blobbed."
The "feeling 'bobbled'" is the stuff I addressed in my comments
immediately above. the "feeling 'bobbled'" is drug-induced.
> This suggests different pathways for the mood-related
> and neurovegetative symptoms, which Miller's team is currently
> CANCER AND CYTOKINES For the past three years, Dantzer, Miller, and
> others have worked in a group led by Charles Cleeland, chairman of the
> Department of Symptom Research at the University of Texas' M.D. Anderson
> Cancer Center in Houston. The group has applied the sickness behavior
> concept to symptoms of various cancers, including melanoma, renal cell
> carcinoma, and chronic myelogenous leukemia, and to the side effects of
> cytokine treatment. Their hypothesis is that at least some symptoms of
> both the disease and its treatment stem from the same biological
Illness "renders useless".
Understand how such happens within nervous systems, and, then,
=help= patients by helping them understand how such happens
within nervous systems, and why it does, and how it exists as a
Greatly-Loving "cradle" for folks who've experienced "rendering
Anything else only exacerbates the dynamics of "rendering useless".
> Accordingly, the group asserts that cytokine dysregulation
> can be a primary cause of cancer. "It's a simple idea and we've already
> been criticized for it, but you have to start somewhere," Cleeland says.
I'm unable to comment, one way or the other, here, except with respect
to my long-former discussions of micro-nutrient deficits being involved
in the onset of Cancer. =Of course= such micro-nutrient deficits will
impact upon, and ramify within, 'normal' molecular dynamics.
> STRESS BY DESIGN: This simplified schematic of the stress system's
> central and peripheral components shows the system's functional
> interrelations, and their connections, to other central systems involved
> in the stress response. (Redrawn from C.M. Pariante, A.H. Miller, Biol
> Psychiat, 49:391-404, 2001.)
> The group plans to perform initial studies that correlate tumor cell
> growth and disease symptoms to changes in cytokine levels, and then to
> mount the first placebo-controlled trial of a specific cytokine
> inhibitor to control a given cancer. "There are three [cytokines] that
> we would put our money on: IL-1, IL-6, and TNF-a," Cleeland says.
> Interleukin-1 is implicated in numerous cancers and in major depression,
> while interleukin-6 is a good predictor of survival and response in lung
> cancer. Tumor necrosis factor-a figures prominently in graft-versus-host
> disease, he explains.
> Clinical trials have yet to be conducted for cytokine receptor
> antagonists, or to test anti-inflammatory agents (such as antalarmin, an
> inhibitor of corticotropin-releasing hormone, which stimulates HPA axis
> activity), or for blockers of cytokine-induced downstream mediators of
> depression, Cleeland says. The latter targets include prostaglandins,
> substance P, and nitric oxide. Another promising intervention involves
> the essential amino acid L-tryptophan, the precursor of serotonin. Its
> availability in the brain is controlled by an enzyme, indoleamine
> 2,3-dioxygenase, which is inducible by the cytokine interferon-a.
> FUZZY SYMPTOMS A major difficulty of fundamental research remains in
> matching clinical descriptions of depression to neurobiological
> functions, says Steven Maier of the multidisciplinary Center for
> Neuroscience at the University of Colorado, Boulder. "There may be
> nothing in the brain that corresponds to what the clinical psychiatrist
> describes as a major depression." He suggests that while a
> psychoneuroimmunological route to depression is likely, it probably is
> not the only one. He points to a line of thinking that downstream
> changes in molecules critical to neurotrophic signaling cascades, such
> as cyclic adenosine monophosphate (cAMP), could be important. Everyone
> might be right, he says. "It's not like talking about a medical
> condition that's clearly defined, like a lesion or an ulcer."
> He and his colleagues showed that the psychological stressor of socially
> isolating rats causes a conditioned freezing behavior and raises IL-1
> levels in some regions of the uninjured brain.10 Although Maier
> concentrates on brain function rather than on a particular pathology, he
> declares that every aspect of human depression, including the different
> effects of acute and chronic stressors, which are just beginning to be
> studied, can be modeled in rodents, except for feelings such as guilt or
> worthlessness. "The only hurdle, really, is that you can't talk to
"Stressors" -> "rendering useless".
Understand how nervous systems have engineered-in
mechanisms that act to guide nervous systems through
'stressful' environmental circumstances, take action in
such understanding, and that's all that can be done,
which, in light of the Eroneous 'diagnoses' that have
prevailed, is a =lot=.
> Psychology professor Raz Yirmiya, Hebrew University of Jerusalem, has
> shown that activation of the immune system in rodents, when they are
> given an endotoxin, induces depression-like characteristics, including
> less interest in saccharine solutions.
'Illness' induces "rendering useless", even when the
'illness' is artificially-induced.
> That behavior corresponds to
> human anhedonia (the inability to gain pleasure from normally
> pleasurable experiences), if controls are used to discard nonspecific
> effects on general activity and fluid intake. The animals exhibited a
> range of other depressive traits, such as reduced social interaction and
> psychomotor slowing, all of which were attenuated or eliminated by
> giving them antidepressants.11 This work inspired Miller's clinical
> studies with IFN-a and antidepressants.
Again, long-term assessment of raw information-
processing capacities are 'missing' here.
The position I'm taking predicts that, when such
long-term assessment is done, the drugged subjects
will be assed as being 'dumbed-down' relative to
It's Testable [requires complete objectivity, as
Science always does, but I feel the Need to
emphasize it in this discussion because of the
influence of 'profit'-seeking within 'scientific'
> Although cytokine-induced depression affects both the monoaminergic
> system and the HPA axis, the question of which is the more critical
> dysregulation remains unresolved, Yirmiya thinks. "The neurochemistry of
> depression is very complex, and even without considering cytokines as a
> factor, it is not so clear what the specific role of any
> neurotransmitter or neuromodulator is, with respect to other mediators
> and with respect to the syndrome in general," he says.
These comments are =IMPORTANT=.
> UNDER PRESSURE: The detrimental effects of chronic stress on adipose
> tissue metabolism and bone mass. The solid lines indicate stimulation;
> dashed lines indicate inhibition. (Redrawn from C.M. Pariante, A.H.
> Miller, Biol Psychiat, 49:391-404, 2001.)
> PREDICTING CHD Researchers say that to answer such questions, brain
> imaging and technologies in the genetics of risk, including single
> nucleotide polymorphisms, will be increasingly employed. Another
> approach being pursued by at least one scientist is the study of
> volunteers who are both physically and mentally healthy. Edward Suarez,
> a Duke University associate research professor of medical psychiatry,
> says he strove for 12 years before obtaining funds to measure cytokine
> levels and other stress-induced monocyte markers in healthy people. He
> attributes his change of fortune to the mounting evidence in the 1990s
> of a relationship between depression and cytokine dysregulation. Now
> starting the third year of a five-year study funded by the National
> Institutes of Health, he has several papers in press, he says. An
> overall goal is to discover if severity of depressive symptoms--a
> predictor of coronary heart disease (CHD)--will still foretell CHD onset
> in people who are neither clinically depressed nor physically sick.
Illness -> "rendering useless" -> activation of 'depression's
mechanism -> the best-that-can-be-given-the-"rendering useless"
that's been induced by the illness's "rendering useless" of behavioral
capabilities [which, in heart disease] are generalized across all of
behavior - the "rendering useless" is generalized be-cause oxygenation
is diminished throughout the body and, hence, in everything that the
body does, which occurs as a "rendering useless" of everything the
body can do relative to what the body could do before the onset of
the heart disease.
Attacking the mechanism of 'depression' in the midst of such is
'just' absence-of-understanding of nervous system function run
Instead of working to thwart the mechanism of 'depression',
understand it, help folks to understand it, and, then work on
heart disease, which is the wellspring of the "rendering useless"
with respect to which the mechanism of 'depression' acts
[Folks =need= to learn about stuff that acts Lovingly, instead of
presuming it to be 'pathological', which totally mucks-up the Love
that's built right into nervous systems.]
> His recruitment method involves screening thousands of potential
> participants for a wide range of confounding factors, such as
> cholesterol levels, obesity, hypertension, smoking, sports injuries,
> allergies, estradiol levels, and oral contraceptive use. Even people
> with a bruise are rejected, and no medications can be taken during the
> two weeks prior to the screening, including low-dose aspirin. His female
> recruits are premenopausal; Suarez says women are twice as likely as men
> to have depression and that significant changes in cytokine levels can
> follow menopause.
More 'normal' "rendering useless".
> He and colleagues have published a study of 53
> apparently healthy men that demonstrates an association between
> increases in severity of depressive symptoms and in proinflammatory
> cytokine levels.12 He is now asking subjects to recall stressful life
> events, in an attempt to determine how stress triggers these biochemical
> "A certain percentage of diseases can be promoted by the way we act and
> think, the way we struggle with ourselves," Suarez observes. For him,
> the boundaries of mood disorders are far wider than
> psychoneuroimmunological mechanisms. As he cast for a description of
> depression, he sounds like Andrew Solomon when he says, "It's like the
> unified theory of bad health."
It's all just "rendering useless", the nervous system's innate
RU-handling mechanisms, and their being thwarted, to
varying degrees, by folks who don't understand how
nervous systems process information.
Of course I've great Sorrow as I post this.
Not only because having to read all of this stuff induces me
to 'mourn' the victims of the absence-of-understanding that's
been imposed upon their nervosu systems' functionings, but
be-cause, just posting it will result in the imposition of more
"rendering useless" upon myself as others, with long-standing
vested interests in the 'depression'-as'pathology' view, 'move
away from' me [more].
Oh well :-]
I'll have more to say with respect to 'depression' in another
post this night.
ken [K. P. Collins]
> Steve Bunk (stevebunk at sbcglobal.net) is a freelance writer in San
> 1. A. Solomon, The Noonday Demon: An Atlas of Depression, New York:
> Scribner, 2001.
> 2. M. Maes et al., "Depression related disturbances in mitogen-induced
> lymphocyte responses and IL-1 beta and soluble IL-2 receptor
> production," Acta Psychiatrica Scandanavica, 84:379-86, 1991.
> 3. P.W. Gold, G.P. Chrousos, "Organization of the stress system and its
> dysregulation in melancholic and atypical depression: high vs. low
> CRH/NE states," Mol Psychiat, 7:254-75, 2002.
> 4. B.L. Hart, "Biological basis of the behavior of sick animals,"
> Neurosci Biobehav Rev, 12:123-37, 1988.
> 5. S. Kent et al., "Sickness behavior as a new target for drug
> development," Trends Pharmacol Sci, 12:24-8, 1992.
> 6. Y. Pollack, R. Yirmiya, "Cytokine-induced changes in mood and
> behavior: implications for 'depression due to a general medical
> condition', immunotherapy and antidepressive treatment," Int J
> Neuropsychopharmacol, 5:388-99, 2002.
> 7. L. Capuron et al., "Neurobehavioral effects of interferon-a in cancer
> patients: phenomenology and paroxetine responsiveness of symptom
> dimensions," Neuropsychopharmacol, 26:643-52, 2002.
> 8. L. Capuron et al., "Association of exaggerated HPA axis response to
> the initial injection of interferon-a with development of depression
> during interferon-a therapy," Am J Psychiat, 160:1342-5, July 2003.
> 9. C.S. Cleeland et al., "Are the symptoms of cancer and cancer
> treatment due to a shared biologic mechanism? A cytokine-immunologic
> model of cancer systems," Cancer, 97:2919-25, 2003.
> 10. C.R. Pugh et al., "Role of interleukin-1 beta in impairment of
> contextual fear conditioning caused by social isolation," Behav Brain
> Res, 106:109-18, 1999.
> 11. R. Yirmiya, "Endotoxin produces a depressive-like episode in rats,"
> Brain Res, 711:163-74, 1996.
> 12. E.C. Suarez et al., "The relation of severity of depressive symptoms
> to monocyte-associated proinflammatory cytokines and chemokines in
> apparently healthy men," Psychosom Med, 65:362-8, 2003.
> FUCK THE SKULL OF HUBBARD, AND BUGGER THE DWARF HE RODE IN ON!!
> 8====3 (O 0) GROETEN --- PRINTZ XEMU EXTRAWL no real OT has
> |n| (COMMANDER, FIFTH INVADER FORCE) ever existed
> A society without a religion is like a maniac without a chainsaw.
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