A mind under seige
Could an overactive immune system be the trigger for some people's life-threatening depression? If so, we might just be on the way to a cure, says Phyllida Brown
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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