http://www.sciencenews.org/view/feature/id/33835/title/Sick_and_down
Sick and down
By Amy Maxmen
July 4th, 2008
To fight off an infection or illness, the body ****fts into a slow-down
mode that mirrors some symptoms of depression. In fact, scientists now
think the immune response itself may even cause the mood disorder.
When one of psychiatrist Andrew Miller=E2=80=99s patients asked about
receiving the best drug available for treating hepatitis C, Miller
said: =E2=80=9CNo way.=E2=80=9D The patient=E2=80=89=E2=80=94=E2=80=89in
hi=
s early 20s and accompanied by his
mom to the appointment=E2=80=89=E2=80=94=E2=80=89had no job, few friends
an=
d a history of
depression. While Miller knows that hepatitis C patients often benefit
from the new generation of immune-boosting treatments, he=E2=80=99s keenly
aware that those same immune therapies have a strong tendency to bring
people down=E2=80=89=E2=80=94=E2=80=89and, in people predisposed to
depress=
ion, dangerously
down.
Certain immune proteins in the body appear to mess with the minds of
otherwise healthy, but depressed people as well. Those who suffer from
major depression have higher levels of cytokines, immune proteins the
body makes to fend off infections and to patrol the body for disease,
and which laboratories mimic. Excess cytokines have also been found
lurking in the postmortem brains of suicide victims. =E2=80=9CIt raises
the
issue, how much of how we feel=E2=80=89=E2=80=94=E2=80=89how much of who
we=
are as people=E2=80=89=E2=80=94=E2=80=89is
dictated in terms of our immune system?=E2=80=9D says Miller, a researcher
=
at
Emory University in Atlanta.
Though the connection between the body=E2=80=99s immune response and
depression has only gained firm sup****t in the last five years,
it=E2=80=99=
s
already catalyzing a revolution in antidepressant drug development. In
hindsight, an emotional reaction to surging immune molecules does not
seem so surprising. Cytokines are among the first immune proteins to
respond to infection. Some direct swelling and fevers. Others order
the body to rest, and so the sick take to the bed and decline party
invitations, showers and even homemade dinners. The powerful molecules
influence wants and needs by altering levels of substances like
s*****onin in the brain. Essentially, cytokines command the body to
conserve energy when it=E2=80=99s sick. =E2=80=9CA little depressed
behavio=
r is a
survival mechanism in that sense,=E2=80=9D Miller says. But when
inflammati=
on
is artificially or erroneously triggered, prolonged sickness behavior
may morph into depression and do more harm than good.
Figuring out the biology behind depression should help doctors combat
the disorder, which strikes an estimated 14.8 million American adults
each year, according to the National Institute of Mental Health. More
than one in six individuals will experience major depression in their
lifetime. And when depression coincides with chronic diseases like
multiple sclerosis, cancer or diabetes, patients=E2=80=99 conditions are
le=
ss
likely to improve.
Psychiatrists and pharmaceutical companies have noted the downpour of
evidence linking inflammation to depression. Miller says he and his
colleagues have considered creating a new diagnostic category: Major
Depressive Disorder with Increased Inflammation. To combat this
depression, he says, researchers must find a way to alter the
body=E2=80=99=
s
immune response. It is a risky strategy but one that offers hope to
the nearly 30 percent of all depressed patients who don=E2=80=99t respond
t=
o
the antidepressants currently on the market.
Jekyll-and-Hyde changes
Cytokines emerged as the primary suspects for what=E2=80=99s since become
known as inflammation-induced depression after Miller and others
noticed that cancer patients became inexplicably upset during
treatment with synthetic type 1 interferons, cytokines that block
viral replication in infected cells. One of these, interferon-alpha,
is among the most effective drugs for patients battling cancer and the
hepatitis C virus. Yet the treatment has become notorious for causing
major depression and other behavioral changes in more than half of
these patients, depending on the dose of the immune booster.
Miller describes a =E2=80=9CJekyll-and-Hyde=E2=80=93 type change=E2=80=9D
i=
n one of his
patients after interferon therapy. Eight weeks into it, the patient
dumped his girlfriend, began dressing in black and grew a goatee. And
there was another woman, Miller recalls, who took a drastic downward
turn. =E2=80=9COne of my most positive patients had been battling cancer
fo=
r
years, yet four weeks into the cytokine therapy she was distraught,=E2=80=
=9D
he says. =E2=80=9CShe told me, =E2=80=98I love my husband and my children,
=
but I don=E2=80=99t
want to be around them. I want to be left alone, and I don=E2=80=99t know
why.=E2=80=99=E2=80=89=E2=80=9D
As observations of sadness, irritability, insomnia, fatigue and loss
of appetite=E2=80=89=E2=80=94=E2=80=89all classic symptoms of
depression=E2=
=80=89=E2=80=94=E2=80=89mounted in patients
treated with immune boosters in the 1990s, papers published nearly a
decade earlier in veterinary journals resurfaced. Benjamin Hart had
been writing about the behavior of sick animals since the mid-1980s.
=E2=80=9CDepression was the first sign we had that an animal was sick,=E2=
=80=9D says
Hart, an animal behavior researcher at the University of California,
Davis. In a seminal 1985 paper in the Journal of the American
Veterinary Medical Association, he put forth the argument that animal
malaise serves a purpose.
=E2=80=9CPeople would call in and say that the dog is sleeping more than
usual. They give the dog its favorite treat, and it only nibbles at it
and then drops it, or they=E2=80=99d say the cat looks scruffy,=E2=80=9D
Ha=
rt
explains. =E2=80=9CCats usually groom all the time.=E2=80=9D He says that
w=
hen he ran
blood and urine tests on such animals, he usually discovered signs of
bacterial or viral infection. Instead of assuming the pet acted sad
because it wasn=E2=80=99t feeling well, he suggested that the
pet=E2=80=99s=
behavior
was part of its immune response. Fido=E2=80=99s body forced the animal to
devote its energy to battling illness, instead of to chasing
squirrels.
Furthermore, since all mammals act similarly when sick, Hart suggested
that the behavior had been inherited from a common ancestor who
survived infection better than other animals who had not evolved the
behavioral response.
In the 1990s, researchers in the Netherlands re****ted that patients
with major depression showed signs of inflammation, with elevated
levels of cytokines in their blood and cerebrospinal fluid. And in
2001, Robert Dantzer, now at the University of Illinois at Urbana-
Champaign, injected rats with cytokines. Sure enough, Dantzer says,
the rats lost interest in previous pleasures and activities: They
didn=E2=80=99t care for sugary water, they didn=E2=80=99t run on the wheel
=
and, when
placed in a pool of water they swam lethargically, barely keeping
their heads above water.
Miller compares this sickness behavior to =E2=80=9Choling up in a
cave.=E2=
=80=9D
Although the animal has little drive to do much of anything, it does
stay alert to major threats. =E2=80=9CWhile in the cave, the organism
rests
but keeps one eye open,=E2=80=9D he says. That may explain why people with
=
the
flu, as well as people with depression, neither leave the couch nor
get the deep sleep they crave.
Connecting body to mind
Like army generals, innate immune cytokines order inflammatory
molecules to prepare for war when the body is under threat from
invasive bacteria or viruses, or under perceived threat in the form of
stress or chronic disease. In these situations, cytokine levels rise.
=E2=80=9CIt=E2=80=99s a good thing if you=E2=80=99re running from a
tiger,=
=E2=80=9D explained
psychiatrist Dominique Musselman in May at a meeting in Wa****ngton,
D.C., of the American Psychiatric Association. =E2=80=9CYou=E2=80=99d want
=
to rev up
your immune system to prepare for an injury.=E2=80=9D Nowadays, however,
an=
gry
bosses, aggressive creditors and disappointed spouses have replaced
vicious predators, she said. And as those stressors are less likely to
bite, the subsequent immune response, which had evolved to heal
injuries and fight infection, seems a vestige of the distant past.
=E2=80=9CThe fact that stress can activate the innate immune response has
b=
een
a major breakthrough,=E2=80=9D Miller notes. Add this to one more piece of
=
the
puzzle: Stress often leads to depression. The immune system may
explain why.
In mapping out the molecular pathway between elevated cytokines in the
body and chemical changes in the brain, scientists aim to provide
targets for drugs intended to treat depression caused by inflammation.
In the last few years, researchers have identified primary suspects.
Many cytokine proteins, including tumor necrosis factor-alpha,
interleukin-6 and the type 1 interferons (IFN-alpha and IFN-beta),
have been accused of being the principal perpetrators in sickness
behavior. They respond rapidly to foreign intruders, circulate in the
bloodstream and initiate a response in the central nervous system.
Cytokines manufactured in the body can send messages through the
central nervous system to induce production of cytokines in the brain.
That message may be relayed when cytokines sneak into the brain
through leaky regions in the blood-brain barrier, a series of
structures that block most substances. In the brain, cytokines
activate inflammatory middlemen who tag-team their way to affecting
emotion-regulating neurotransmitters. As neurotransmitter levels
change, so can mood. =E2=80=9CAmong other things, we see a drop in levels
o=
f
s*****onin, the feel-good chemical,=E2=80=9D Miller says.
Attempts are underway to treat depression by blocking specific
cytokines or the messages they send. A 2006 clinical trial funded in
part by the biotech company Amgen found that depressed patients who
suffered from psoriasis, an autoimmune skin disease associated with
increased levels of cytokines, felt happier after taking the cytokine
blocker etanercept (brand name Enbrel), which affects tumor necrosis
factor-alpha. Another TNF-alpha blocker, infliximab (Remicade), is
being tested for use in depressed patients who don=E2=80=99t respond to
antidepressants such as the selective s*****onin reuptake inhibitors
Prozac and Zoloft. Those results should be ready by 2010, says Charles
Raison, a research psychiatrist at Emory University who heads the
project.
Anti-inflammatory drugs like aspirin and ibuprofen haven=E2=80=99t been
sho=
wn
to affect mood. But another anti-inflammatory, celecoxib (Celebrex),
that more specifically blocks the inflammatory molecule COX-2, helped
heal depression in a small clinical trial in Germany. Norbert M=C3=BCller,
a psychiatrist on that study from Ludwig-Maximilians-University
Munich, suggests that a high dose of aspirin would be needed to
inhibit COX-2 as strongly as celecoxib. And that, he says, =E2=80=9Cwould
provoke a high rate of side effects, mainly gastrointestinal pain and
possibly bleeding.=E2=80=9D
Developing these types of treatments isn=E2=80=99t easy, warns Dantzer.
Compounds that interfere with immune responses have the dangerous
potential to compromise the body=E2=80=99s resistance to infection. The
goa=
l
is to temper inflammatory molecules in the brain, not the body.
Researchers will have to identify safe points to alter along the
molecular pathway that runs between bodily cytokines, molecular
middlemen and neurotransmitters in the brain. =E2=80=9CThe further
upstream
you go towards the cytokines, the more far-reaching the effects on the
body. If you move downstream to block cells that are activated by the
inflammation, you may have a drug that is less toxic,=E2=80=9D Miller
says.
Custom-made meds
Another problem is identifying the cases in which the immune system is
to blame. =E2=80=9CThe evidence is clear at this point that inflammation
events can lead to a depressed mood,=E2=80=9D says neuroscientist Steven
Ma=
ier
of the University of Colorado at Boulder. =E2=80=9CThe issue is how often
t=
his
is the case.=E2=80=9D
Not all people are sensitive to surges in cytokines. Some recover from
the side effects of interferon therapy as gracefully as some lovers
rebound from heartbreak. Variations in a couple of genes may help
doctors to predict who is most susceptible to immune-related
depression. Miller and collaborators found that patients with
hepatitis C were more resistant to interferon-induced depression if
they possessed a slight variation in the gene encoding the s*****onin
trans****ter 5-HTT, which is known to be involved in psychiatric
disorders, as well as another small variation in a gene that codes for
the cytokine interleukin-6. The fact that the interleukin-6 gene,
involved with inflammation, has an emotional impact provides more
evidence of how the body and mind interact, the researchers re****t in
the May 6 Molecular Psychiatry.
Identifying these genes is part of a larger effort by doctors to
tailor treatment to the individual. =E2=80=9CIdeally there could be a drug
where one size fits all, but that doesn=E2=80=99t seem to be the case,=E2=
=80=9D Miller
says. He thinks that while s*****onin reuptake inhibitors like Prozac
work for certain people, others might need an immunological approach
to combat depression. =E2=80=9CWe want to bring to people=E2=80=99s
attenti=
on the
interaction between factors,=E2=80=9D he says. =E2=80=9CThis is the idea
be=
hind
personalized medicine.=E2=80=9D
Others agree that depressed patients unaided by standard treatments
may be good candidates for an immune approach. =E2=80=9CPeople who don=E2=
=80=99t
respond to those [therapies] seem to have increased levels of
inflammatory markers,=E2=80=9D Raison says.
As logic, and misfortune, would have it, depression caused by
inflammation is most prevalent in patients who have diseases
associated with increased inflammation. Rates of depression are five
to 10 times higher than average in patients with disorders that
involve the immune system, including infectious diseases, cancer and
autoimmune disorders, say Miller and Raison in a March re****t that
appeared online in FOCUS. Inflammation is also a risk factor for
diabetes and cardiovascular disease. When these diseases coincide with
depression, patient outcomes can worsen.
Sickness behavior leads to grumbling under the covers. And grumbling
under the covers hinders the hope and drive that patients need to
follow doctors=E2=80=99 orders. Depressed patents are more likely to skip
appointments and stop taking their medication, Musselman said at the
APA meeting. And depressed smokers are more likely to continue smoking
after bypass surgery.
By treating those susceptible to depression early on, doctors may
increase their patients=E2=80=99 chances of surviving disease.
=E2=80=9CThe=
idea,=E2=80=9D
Maier says, =E2=80=9Cis to cut depression off at the pass.=E2=80=9D
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