Re-Post - Signal Blues Stress and cytokine levels

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The Scientist

Volume 17 | Issue 16 | 24 | Aug. 25, 2003

Signal Blues Stress and cytokine levels underpin a

provocative theory of

depression | By Steve Bunk

In 1992, American writer , 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 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 cytokines.

Depression can be induced by external or internal

stressors, " says

psychiatry professor 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. 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, 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, , 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 cytokines.5

Another important contributor to this field,

psychiatry professor

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

. In an experimental model that has been applied

to hepatitis C and

malignant melanoma, has focused on the

depressive symptoms caused by

cytokines. For example, 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 :

" 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, discovered that depression did not

develop.7 However, there

was little effect on the nonspecific or

" neurovegetative " symptoms

corresponding to sickness behavior that

colloquially refers to as

feeling " blobbed. " This suggests different pathways

for the mood-related and

neurovegetative symptoms, which 's team is

currently exploring.8

CANCER AND CYTOKINES For the past three years,

Dantzer, , and others

have worked in a group led by Cleeland,

chairman of the Department

of Symptom Research at the University of Texas' M.D.

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.

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 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 animals. "

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 '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.

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. 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 changes.

" 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

when he says, " It's like the unified

theory of bad health. "

Steve Bunk (stevebunk@...) is a freelance

writer in San Francisco.

References

1. A. , 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.

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