A FIFTY-year-old woman living in Japan is infected with a potentially fatal
virus, hepatitis C. Doctors bombard her body with a powerful drug to boost her
immune response. The drug beats back the virus, but has horrific side effects.
She becomes inexplicably moody, rapidly sinking into a depression so savage that
the woman douses herself in oil and sets herself alight.
Fortunately, her suicide attempt fails and she recovers fully. But the
woman’s terrifying experience is not unique. Over the past few years, there’s
been a steady trickle of bizarre reports of people becoming suicidal after
taking alpha interferon and interleukin-2, two popular immune-boosting drugs.
Hundreds of others have become seriously depressed.
But here’s the rub. Patients and doctors are not rounding on the makers of
these drugs. Instead, everyone tends to think the psychological side effects are
a price worth paying for drugs that can combat cancer, hepatitis and other
life-threatening infections. Indeed even the terrible suicidal urges themselves
are now turning out to have a silver lining. They are awakening interest in one
of the most promising new avenues in depression research since Prozac left the
labs.
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Most of us associate depression with being run down and having poor immunity
to infections. The startling side effects of the immune-boosting drugs turn that
notion on its head. They suggest that some people who are depressed may actually
be suffering from an over-heated immune system, and that damping down
inflammation could offer a brand new way to treat routine clinical
depression—while making billions for the pharmaceuticals industry into the
bargain. It’s a theory that recasts depression—one of the great plagues of
our time—as a chronic inflammatory disease like rheumatoid arthritis.
In an inflammatory attack, immune cells rev each other up by pumping out
substances known as inflammatory cytokines. Drugs like interferon are simply
artificial versions of these substances. That’s why they boost immunity so
well—and why, according to the new “immune theory” of depression, they
also induce such dark moods in some patients. If the body’s own supplies of
cytokines stay too high for too long, maybe they too become toxic to mood and
trigger depression.
The case is far from proven but evidence is mounting. “At the beginning I was
very reluctant to get into this question because depression is such a can of
worms,” says neurobiologist Robert Dantzer of France’s national medical research
agency INSERM at the University of Bordeaux 2. “But when we saw the way these
drugs affected patients, it made me sure that it was worth it.”
The first inkling of a connection between mood and inflammation came around
1990. Michael Maes, a psychiatrist now at the University of Maastricht in the
Netherlands, was investigating claims that depressed people are unusually
vulnerable to infections and cancer, a theory that could be explained by a
lacklustre immune system. But when Maes looked at immune cells from depressed
people such as natural-killer cells, monocytes and macrophages, he found instead
that the cells were more active than normal, and spewed out more inflammatory
cytokines. “We had expected to find just the opposite,” admits Maes.
The surprise results did fit in with some other vague hints that depression
and inflammation are entwined. Depressed people tend to have slightly raised
temperatures, which suggests that they are suffering from some chronic
inflammation. They are also three times as likely to die of heart
disease—often caused by arteriosclerosis, itself an inflammatory condition
of the linings of arteries.
Still, Maes’s results languished in obscurity, being contradicted by other
studies almost as often as they were confirmed—until, that is, Dantzer
decided to take a second look at some old rat studies he had done in the late
1980s.
When you inject rats with parts of bacterial cell walls called
lipopolysaccharides, their temperatures rise, their sleep patterns change, they
become less sociable and stop eating. And it isn’t the bits of bacteria that
trigger this so-called “sickness behaviour”, but the immune response to those
bits. An injection of the cytokine interleukin-1 (IL-1), which marauding
macrophages produce when they meet bacteria, makes the animals behave in exactly
the same way. In other words, the rat studies showed that inflammatory cytokines
directly influence behaviour.
“For the first time it became clear,” says Dantzer. “Sickness behaviour is
like fear—it is a state that makes the animal reorganise its priorities.”
Just as the sight of a predator makes animals release hormones that drive the
“flight-or-fight” response, infection triggers the release of cytokines, which
make the animal rest and conserve its resources to fight the infection. And of
course, sickness behaviour is not exclusive to rats—think of the last time
you got flu.
At first, researchers were puzzled at how the cytokines could affect
behaviour. How could great big molecules like IL-1 get across the barrier that
protects the brain from all the potentially dangerous chemicals sloshing around
in the blood?
It turned out they didn’t need to. The exact mechanism is still a mystery,
but it seems that another set of far smaller signalling molecules, such as
nitric oxide and prostaglandins, tell the brain that a part of the body is
inflamed. Once in the inner sanctum, these molecules instruct the brain’s glial
cells to make their own supplies of inflammatory cytokines. These cytokines act
on receptors in areas of the brain such as the hippocampus, the cerebellum,
and—crucially—the hypothalamus, which is involved in regulating both
mood and temperature. “The brain builds a representation of the disease in the
body,” says Dantzer.
By the mid-1990s, Dantzer was wondering whether sickness behaviour wasn’t in
some way comparable with depression, and, if so, whether antidepressants could
prevent sickness behaviour. After all, some of the symptoms are similar to
depression— disturbed sleep, for instance, or a lack of interest in food
or sex.
Dantzer’s results were dramatic. He injected rats repeatedly with the
antidepressant tianeptine, before treating them with pieces of bacterial wall or
IL-1 (Psychopharmacology, vol 24, p 50). The antidepressant sharply reduced the
sickness behaviour created by the treatments. What’s more, the rats’ brains made
much smaller amounts of their own IL-1, and much larger amounts of another
cytokine, IL-10, which soothes inflammation. “It looks like some antidepressant
drugs are working like some anti-inflammatory agents,” concludes Dantzer.
The next piece in the puzzle was to take a closer look at those people who
get depressed while taking immune-boosting drugs. From about 1996 onwards, study
after study showed that about one-third of patients taking cytokine drugs get
depressed, sometimes seriously. The trouble is that they also have
life-threatening illnesses such as cancer or hepatitis so it’s hardly surprising
they should feel despair.
To get around that problem, Dantzer’s PhD student Lucile Capuron assessed the
psychological state of patients with advanced skin or kidney cancers before and
during treatment with interleukin-2 (IL-2) or alpha interferon. The results,
which appeared last year in the Journal of Clinical Oncology, left Dantzer in no
doubt.
Both drugs appeared to induce depression, but there were also some clear
differences. The patients on alpha interferon developed symptoms after a few
weeks, while people on IL-2 took only a few days. More subtly, the patients
taking alpha interferon tended to have slower reaction times, while patients on
IL-2 were more likely to have memory problems. To Danzter, such differences are
a telling sign that the depression is a specific side effect of the drugs,
rather than simply general despair at being ill.
Then, just this spring, Andrew Miller at Emory University in Atlanta
announced in The New England Journal of Medicine that a Prozac-like drug called
paroxetine actually protects people who take alpha interferon for skin cancer
from depression brought on by the immune-boosting drug.
“It’s exciting, because in psychiatry we don’t do a whole lot of prevention,”
says Miller. Miller even suspects that antidepressants could help a wider group
of hospital patients who may be exposed to sudden surges in their own levels of
inflammatory cytokines. For example, he says, inflammatory cytokines soar in
people who have major heart surgery as their immune systems respond to their
wounds. Up to 30 per cent get depressed soon after the operation. Treating them
with antidepressants before surgery could spare them this extra mental
suffering, says Miller.
Still, the bigger question remains: does inflammation also play a role in
depression that is triggered by more familiar messy circumstances like
bereavement, divorce, trauma and persistent stress?
To settle that question, neurobiologists will have to learn more about how
inflammatory cytokines interact with mood-altering neurotransmitters and
hormones. So far, there are tantalising hints that the cytokines could alter
those chemicals enough to help tip vulnerable minds over the edge (see “How can
the body’s immune system cause depression?”). But the puzzle is complex and
incomplete.
Another question is whether the link with inflammation is evidence of
something more disturbing—namely, that clinical depression is really
caused by some sort of mysterious infectious agent. To be fair, viruses can
cause inflammation, and a few years ago German researchers thought they had
found one that might trigger depression—a Borna virus that normally
infects the nervous systems of horses and sheep
(żěè¶ĚĘÓƵ, 27 July, 1996, p 14).
But the excitement evaporated as others failed to repeat the
German results, and today there is no evidence that you can “catch”
depression.
Of course for people with depression, the most pressing issue is better
treatments. One option is to try tackling depression with anti-inflammatory
drugs. There is no evidence that familiar anti-inflammatories such as ibuprofen
would help. But St John’s Wort, which many people take to combat symptoms of
depression, is also an anti-inflammatory. And over in Bordeaux, Dantzer says
there have been rumours that certain drugs that block inflammatory cytokines
significantly lift people’s mood. For example, an antibody called infliximab,
designed to ease joint pain in patients with rheumatoid arthritis, is rumoured
to induce a feeling of well-being even before the inflammation has begun to
subside.
At least one rheumatology expert emphatically endorses that claim. “I have
been consistently struck by the comments of patients on an enhanced sense of
well-being ever since we treated the first patients,” says Ravinder Maini, at
the Kennedy Institute of Rheumatology in London. Anecdotes aside, at least one
rheumatoid arthritis trial found patients scored higher on “vitality” and
“social functioning” after taking this type of drug (The New England Journal of
Medicine, vol 343, p 1594).
Drugs companies are understandably keen to find out whether these
“anti-cytokine” drugs can help depressed patients too. One in five of us will
get depressed at some point in our lives and, since older people are more
vulnerable, the figures are destined to climb as populations age. Yet existing
antidepressants are far from perfect and don’t work for everyone.
Even if anti-cytokines could help only some of the millions who get depressed
every year, that would still be a dramatic health gain and a multibillion-dollar
money spinner for the pharmaceuticals industry. And although researchers are
keeping quiet about the details, at least two groups are gearing up to start
trials within the year. “This will be the proof of the pudding,” says Miller.
“The need for these trials is tremendous.”
A lot of people’s health—and a lot of dollars for the drugs
companies—are resting on these results.
Links are emerging between the chemicals that underpin the inflammatory
reactions that help to control infection and brain chemicals that seem to govern
mood.
Take the neurotransmitter serotonin, the well-known target of Prozac.
Serotonin levels tend to be lower in the brains of depressed people. Serotonin
is made from tryptophan, and researchers have found that tryptophan levels are
depleted in people taking immune-boosting drugs such as interferon.
A second link involves cortisol. This is the stress hormone that makes your
heart pound and your pulse quicken.
Normally, cortisol turns itself off—meaning that a stressful event
usually triggers only a short, sharp surge of the hormone. Receptors in the
brain mop up the hormone and send signals to stop its production. But some
people with depression appear to have defective receptors, so their cortisol
levels stay artificially high.
As it happens, inflammatory cytokines also trigger cortisol secretion, while
cortisol itself dampens down the inflammatory cytokines, through receptors on
the immune cell.
If cortisol receptors in the brain are only firing on one cylinder in
depressed people, probably the cortisol receptors on their immune cells are also
working below par. That would mean that once an inflammatory response has
started, levels of the cytokines will rise higher than usual before they are
switched off. These, in turn, will trigger more cortisol to damp them down,
creating a vicious cycle that sends cortisol levels soaring, and could trip
depression.
How can the body’s immune system cause depression?
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Further reading:
Cytokines and depression: fortuitous or causal association?
by Robert Dantzer and others, Molecular Psychiatry, vol 4, p 328 (1999) - http://www.emory.edu/WHSC/MED/PSYCHIATRY/mindbody/IFNalpha.htm