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Depression, Dissected

New research illuminates the role of inflammation in the common mood disorder.

Evgeny Atamanenko / Shutterstock

Depression research has become something of a downer. The first drug to ease the torments of those afflicted with the disorder hit the market more than half a century ago, and since then dozens more have emerged. All essentially operate on the same elements of brain biology—the neurotransmitters serotonin, norepinephrine, and dopamine—and for many people, they work quite well. Yet none has altered the stubborn fact that one-third of patients don’t get better no matter how many meds they try. With 16 million Americans estimated to have suffered a major depressive episode in the past year according to the National Institute of Mental Health, that adds up to a lot of unmitigated suffering—and a lot of psychiatrists frustrated by their inability to help.

Enter inflammation, which has been associated with depression since at least the 1990s, although the nature of the connection has been unclear and the research focus on it marginal. “It never had enough traction to grab the field’s attention,” says psychiatrist Andrew Miller of Emory University.

That may be changing. For five years, research on inflammation and depression has been accelerating, pulling it from the periphery into the spotlight, and the pace has increased markedly in just the past year. Although there’s still no tidy illustration of how the two conditions are linked, there’s a growing confidence that inflammation has a significant role in the depression equation. In a field that Miller describes as being at “a crisis point looking for new ideas and conceptual frameworks that might yield more effective treatments,” emerging findings about inflammation have been received “like the Second Coming.”

As a physiological process, inflammation might seem like an unlikely facet of what’s commonly perceived as a disease of the mind. Inflammation evolved to defend the body against injury and infection—chemical compounds released by white blood cells usher blood to the scene, provoke swelling to immobilize injured tissue, and raise the temperature to kill invading microbes. The same chemicals induce the malaise of illness, forcing the injured or infected body to conserve energy for healing.

But the process can go very wrong, attacking the body’s own tissues in autoimmune diseases such as rheumatoid arthritis, psoriasis, and ulcerative colitis. In recent years, research has connected chronic low-level inflammation with a growing list of unlikely ills, such as heart disease and diabetes, and brain disorders, including schizophrenia and Alzheimer’s disease.

The evidence for a link to depression is particularly compelling. Patients with a medical illness where inflammation is prominent have long been observed to suffer high depression rates. Injecting healthy people with inflammatory messenger chemicals such as cytokines provokes depressive symptoms. And depressed individuals tend to have elevated blood levels of the proteins that signal chronic inflammation.

But beyond these intriguing correlations, basic questions remain unanswered: Is inflammation the horse or the cart, a cause or effect of depression? Or does it simply signify some more fundamental malfunction? “At the end of the day, you have to show that people get better when you block inflammation, and no definitive studies have done that,” Miller says. Drug trials have been on the whole disappointing: A 2014 meta-analysis of 14 of them found some benefits in adding anti-inflammatories to antidepressants, but they were modest and uneven.

A big part of the problem, Miller says, has been a failure to appreciate that inflammation is likely only a piece of the depression story. “Hidden in the data are subgroups of patients who have increased inflammation—between a third and a half.” Identifying these subgroups, he says, “is the cutting edge of where the field is right now.”

In the past year, a number of studies have explored this territory, shedding light on underlying processes that might yield novel treatments. Data from the decades-long Avon Longitudinal Study of Parents and Children, which has been charting the health of 14,500 families in Bristol, England, since 1991, strongly support the hypothesis that a hyped-up inflammatory response predisposes to depression. In a paper published last year, investigators reported that healthy children who at age 9 had high levels of the cytokine interleukin-6, or IL-6, were 50 percent more likely to be depressed when they were 18—and the higher their IL-6 level, the greater the depression risk.

This is not to say chronic inflammation caused depression in these youngsters, but “it’s almost certainly a risk factor,” says psychiatrist Golam Khandaker of the University of Cambridge, who led the study. “There are various pieces to the puzzle that must come together. The study highlights that inflammation is one of the most important pieces.”

Stress, long established as a risk factor for depression, is apparently another piece; a study at Mt. Sinai School of Medicine last year traced inflammation as at least part of the connection between the two. In an experiment, mice were subjected to the social stress of repeated confinement with an aggressive mouse. Some lapsed into a depression-like state of avoidance and withdrawal, while others sailed through the experience unaffected. White blood cells from the stress-sensitive mice produced more IL-6 when stimulated, even before they had been exposed to stress. As with the children in the Avon Study, a naturally elevated inflammatory response left certain mice vulnerable.

A follow-up experiment confirmed the link: Transplanting bone marrow that had been genetically engineered to produce extra IL-6 made resilient mice susceptible to stress, while bone marrow modified to produce no IL-6 made vulnerable mice resilient.

“A lot of people have thought that inflammatory biomarkers in the blood reflect something occurring in the brain,” says neuroscientist Scott Russo, senior author of the study. “Our most important finding was that inflammatory factors in the peripheral circulation could cause brain pathology.”

The exact mechanism is open to conjecture. “Cytokines like IL-6 can squeeze through the blood-brain barrier, and peripheral leukocytes”—the white blood cells that are the war horses of the immune system—“can be transported into the brain,” Russo observed. Within the brain, cytokines may interfere with basic communication processes, such as neurotransmitter release and reception, and with connections between brain regions.

Interestingly, for all the indirect links, no one has actually shown inflammation to occur within the brains of depressed people. “The absence of brain evidence has been a key weakness of the theory,” says psychiatrist and neuroscientist Jeffrey Meyer of the University of Toronto’s Centre for Addiction and Mental Health.

Until now. In a study published earlier this year, Meyer’s research group announced that it had found such evidence, having used positron emission tomography (PET) scans to show higher concentrations of translocator protein in the brains of depressed individuals compared to controls. This protein, he proposed, reflects the activation of microglia, brain cells that can, like white blood cells, release inflammatory chemicals. Increased activity was especially marked in brain regions linked to depression symptoms.

As in other studies, the correlation between inflammation and depression was not complete. Translocator protein was elevated in about half of the patients and in 15 percent of the nondepressed controls. “It’s possible it takes several biological and psychological changes to tip someone into a depressive episode,” Meyer says.

Identifying appropriate subgroups of depression sufferers is essential if research is to bear practical fruit, Andrew Miller argued recently in JAMA Psychiatry. For all the promise of using them to address depression, drugs that target inflammation are unlikely to help depressed patients who don’t actually show signs of inflammation. The failure to make such distinctions, he maintains, may be the reason the results of anti-inflammatory drug trials in relation to depression have so far been tepid at best.

A study Miller and colleagues published two years ago in fact found that a drug used to block tumor necrosis factor, an inflammatory mediator, failed overall to help patients with treatment-resistant depression—but significantly improved symptoms in the subgroup whose blood tests indicated high levels of inflammation.

Another recent study corroborated the importance of isolating a target group using omega-3 fatty acids, a nutrient with anti-inflammatory effects found in fish and other foods. Omega-3s have been effective against depression in some studies but not others. The researchers, at Harvard and Emory University, showed that EPA, a key omega-3, reduced depression symptoms more than a placebo, but only in patients who started out with elevations of one or more inflammatory chemicals. The more elevated biomarkers they had, the better their response.

Patients without evidence of inflammation, on the other hand, did worse with EPA than a placebo. “The key point is that omega-3 fatty acids may not be for everyone,” says Harvard researcher David Mischoulon. “Those with high inflammatory status may be good candidates, but those whose biomarkers are normal or low are not.”

Bench-to-bedside translation of inflammation research to depression treatment is quite foreseeable, Miller says. Right now, work is under way investigating compounds that target cytokines prominent in depression, such as drugs already approved for ulcerative colitis and rheumatoid arthritis. Effective interventions might also include natural inflammation-reducers such as exercise and weight loss, and the findings could guide a physician’s choice among conventional antidepressants to focus on brain regions affected by inflammation.

The Avon study linking signs of inflammation in childhood with later depression suggests that a better understanding of the process could generate strategies to prevent the condition altogether. “We’re not quite there yet,” Miller says. “But the data are mounting quickly enough that within the next five years, we might expect to see clinical recommendations based on how inflammation affects the brain.”