Over the years, medical research has increasingly pointed an accusatory finger at chronic inflammation as a primary cause of disease. It has been well-established that inflammation may occur throughout the body and that it contributes to atherosclerosis and heart attacks, asthma and diabetes. “There is growing evidence that inflammation in the body may be associated with inflammation in the brain,” says Dr. John H. Krystal, professor and chair of psychiatry at Yale University. And a study released in September has linked brain inflammation with certain forms of depression and, more specifically, suicidal thinking.

Published in the journal Biological Psychiatry, the study found that patients with major depressive disorder, or MDD, have increased levels of a marker of brain cell activation, a sign of inflammation. The increase in the inflammatory marker was present specifically in patients with MDD who were experiencing suicidal thoughts.

These results may signal a sea change in how some forms of depression are diagnosed and treated. “The field of medicine has become accustomed to thinking about mental illnesses as if they were dissociated from the processes that produce illness in the major organs of the body,” says Krystal, who also serves as editor of Biological Psychiatry.

“This is an important finding because there are some medications that produce anti-inflammatory effects,” Krystal says. “These medications are currently used to treat illnesses including psoriasis, rheumatoid arthritis, ulcerative colitis and other diseases.” With this new and growing evidence that inflammation, a pathological process that spans body and brain, is not only a signature of more forms of depression, but also contributes to the development of some forms of depression suicidality, perhaps these depression pathways can be targeted by anti-inflammatory treatments, Krystal says.

PET Scans Track Inflammation

In the study, the researchers used a recently developed technique to characterize inflammation in the brain. This technique involves positron emission tomography scan, which records very low doses of a radioactive tracer that binds to a protein expressed when a particular group of immune cells in the brain called microglia are inflamed. “Brain microglia aren’t activated under normal, healthy conditions,” says Dr. Peter S. Talbot, a senior lecturer in psychiatry at the Wolfson Molecular Imaging Centre at the University of Manchester in the U.K. and a co-author of the study. The study found “strong confirmatory evidence for the presence of microglial activation, and hence neuro-inflammation, during a serious depressive episode,” he says. The results, in fact, replicate a prior report that major depressive disorder patients showed evidence of inflammation in three brain regions involved in mood regulation: the anterior cingulate cortex, insula and prefrontal cortex.

Further, Talbot and his colleagues separated the depressed patients into two groups – those with current suicidal thinking and those without – and compared the inflammation levels between the two subgroups. “We found that the elevated levels in the depressed group as a whole was accounted for by those who had suicidal thinking. The subgroup without suicidal thinking didn’t have elevated levels despite having similar scores on depression rating scales,” Talbot says. Krystal believes that this tends to suggest that brain inflammation is a feature of the biology of depression, “particularly among patients who have the more severe forms of depression that are also associated with increased suicide risk.”

“Inseparable Links” Between Brain and Body

Defining the link between depression and inflammation is an active research subject, Talbot says. “I think these findings have the potential to focus future inflammation research more towards the most severe forms of depression, particularly those with prominent suicidal thinking. But they also reinforce the inseparable links between the mind, the brain and the body in depression. Treating depression effectively will always involve treating the whole person, and if we are to understand and treat inflammation as part of this, it will be vital to use a wide range of broadly anti-inflammatory strategies.”

These strategies are the same as those used to reduce inflammation to help prevent other diseases. Lifestyle changes like a low-sugar diet and more exercise make a significant difference, as do psychological therapies that focus on the chronic stresses that trigger stress hormones, which are an important cause of the inflammatory process. “We know that stress contributes to inflammation in the body by promoting the release of many substances by cells involved in immune response, including chemicals called cytokines that promote inflammation,” Krystal says.

There is still more work to do to better understand the implications of these findings, Krystal says. For instance, is inflammation a general predictor of more severe forms of depression, or does inflammation tend to uniquely contribute to suicide risk? Also, there are many markers of brain inflammation, so is the marker used in this study the most sensitive or most specific marker for depression or inflammation? And can this PET technique be used to measure brain changes during treatment?

“Well, PET scans for microglial activation aren’t yet at a point where they can be used diagnostically or to help guide treatment,” Talbot answers. “They are still very much a research tool at present. And although several pharmaceutical companies have anti-inflammatory drugs in development for trials in depression, these are not yet at a stage where they are ready for use in the clinic outside of the context of research trials."