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.
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?" p
36). 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 (New Scientist, 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.-
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The role of corticotropin releasing factor
in depressive illness: a critical review
by
Mitchell AJ Department of Liaison Psychiatry,
Addenbrooke's Hospital,
Cambridge, UK.
Neurosci Biobehav Rev 1998 Sep; 22(5):635-51
Corticotropin-releasing factor (CRF) is the
principal neuropeptide involved in regulating the stress
response. When centrally administered to animals it produces
somatic changes analogous to those seen in both depression
and anxiety. In humans, it is capable of reproducing the
hormonal changes which are characteristically seen in
depressed patients.
