Cytokines and Depression

Dave Bird dave at
Mon Dec 22 17:06:33 EST 2003

In article<3fe6804d at>, John H. <johnh at faraway.?>
>Stress and cytokine levels underpin a provocative theory of depression
>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.

 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 

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. 

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." 

By administering antidepressants to such patients before they began IFN-
a therapy, Miller discovered that depression did not develop.7 However,
there was little effect on the nonspecific or "neurovegetative" symptoms
corresponding to sickness behavior that Miller colloquially refers to as
feeling "blobbed." 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
mechanism.9 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.

  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

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. 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. 

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.

  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. 

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. 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." 

Steve Bunk (stevebunk at 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. 

 8====3  (O 0)    GROETEN --- PRINTZ XEMU EXTRAWL   no real OT has
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