The same chemicals that can induce the body to fight infection can also sicken the brain: a growing body of evidence suggests that inflammation may be linked to depression.

Studies in animals “demonstrate quite convincingly that signals from the immune system get into the brain,” says Andrew Miller, professor of psychiatry at Emory University.

Miller says the signaling molecules, or cytokines, can alter the levels of neurotransmitters such as dopamine and serotonin in the brain. In animals, an increase in the level of cytokines can induce 'sickness behavior'—the animal equivalent of depression.

Scientists have known for more than a decade that cytokines such as interferon-alpha and interleukin-2 can cause depression in cancer patients. Miller's work also suggests that antidepressants given before cytokine therapy can stave off depression. In that study, only 11% of cancer patients who took the antidepressant paroxetine two weeks before starting cytokine therapy developed depression, compared with 45% on placebo (N. Engl. J. Med. 344, 961–966; 2001).

More recently, another study showed that treating cancer patients with cytokines lowers blood levels of tryptophan—an essential amino acid that is a precursor of the mood-stabilizing neurotransmitter serotonin. About one-third of patients on the medications became depressed (Mol. Psychiatry 7, 468–473; 2002).

In those patients, the lower the levels of tryptophan, the more severe the depression, says lead investigator Robert Dantzer, director of the Center for Integrative Neurobiology in Bordeaux, France. Dantzer says the cytokines might be activating an enzyme that breaks down tryptophan.

What isn't clear is whether it is byproducts of the enzyme's actions on tryptophan or tryptophan itself that cause the behavioral changes.

In fact, both processes might be responsible. Depression is a complex disorder that appears to involve several separate brain systems. For instance, cytokines can activate the corticotropin-releasing factor pathway, which regulates the stress response. Depression may also involve the dopamine system, which is implicated in addictive behaviors.

“People are starting to talk about different symptom complexes being mediated by different pathways of neurocircuitry,” says Miller.

Even if it is established as causing depression, inflammation is unlikely to account for all cases of depression. There is also little research on whether circumstances such as job loss or divorce can exacerbate inflammation.

That the immune system contributes to depression in some cases is becoming “incontrovertible,” says Philip Gold, chief of neuroendocrinology at the US National Institute of Mental Health. “But the idea has not been generally accepted because there hasn't been a smoking gun.”

A system as complex as this is going to yield contradictory data. Philip Gold, US National Institute of Mental Health

Proof of the theory would require reversing brain inflammation with treatment, “but we haven't shown that yet,” Gold says. “A system as complex as this is going to yield contradictory data,” he adds. “But I really believe [the link] is there. There are too many pieces that are beginning to fit together.”