Psychiatry has a long history of treating mental illness with drugs that were developed for entirely different purposes.
Take depression medications: The first antidepressant was initially designed for tuberculosis. One of the newest treatments, ketamine, started as an anesthetic. Now, scientists are investigating whether anti-inflammatory drugs might benefit some patients. A medication for rheumatoid arthritis was the focus of a small study published last month, building on decades of research examining a connection between inflammation and depression.
Roughly 25 percent of people with depression have elevated levels of inflammatory proteins in their blood, and the inflammation seems to develop before the depression does. In studies where people were given a substance to stimulate inflammation, participants experienced feelings of depression and anxiety shortly after.
People with high inflammation are less likely to benefit from traditional antidepressants. “I don’t think that this is likely important for everyone with depression,” said Dr. David Goldsmith, an associate professor of psychiatry and behavioral sciences at the Emory University School of Medicine. But inflammation “may help explain why a lot of individuals don’t respond to first-line treatments for depression, like S.S.R.I.s,” he said.
Inflammation may also explain the association between depression and certain physical health conditions, such as metabolic or autoimmune diseases, said Dr. John Matthews, a senior psychiatrist at the Benson-Henry Institute for Mind Body Medicine at Mass General Brigham. The same goes for childhood trauma or chronic stress, he added. While there are most likely several factors that contribute to increased depression risk with these experiences, one may be that they increase inflammation.
Experts think the link between depression and inflammation stems from how inflammatory proteins affect the brain. These proteins can lead to lower levels of the neurotransmitters serotonin and dopamine, which are important for mood. They can also disrupt activity in some of the same areas of the brain that are altered in depression, including regions that process reward and motivation.
Depressed people with high levels of inflammation tend to have a specific subset of symptoms, called somatic symptoms, that reflect some of these brain changes. They include fatigue, lack of appetite and changes in sleep, as well as decreased motivation to seek out pleasurable experiences (sometimes called anhedonia).
“There are certain characteristics that set this group apart from all depression,” said Dr. Golam Khandaker, a professor of psychiatry at Bristol Medical School in England, adding that he had started calling this subgroup “inflamed depression.”
In one of the first studies testing an anti-inflammatory medication for depression, people were given either a drug typically used to treat Crohn’s disease or a placebo. When the researchers looked at all 60 patients together, the medication didn’t perform better than the placebo. But when they narrowed the analysis to include just patients who had the highest base-line levels of inflammation, there was a greater improvement in depression symptoms.
A handful of other small studies have come to similar conclusions, with only the participants who had signs of inflammation or a history of trauma seeing meaningful benefits.
The new study using a rheumatoid arthritis medication included 30 people with depression, all of whom had high levels of inflammation. The participants who took the medication saw a small reduction in their scores on a depression assessment, particularly on questions related to somatic symptoms. But the benefit wasn’t statistically significant when compared with the scores of those who received a placebo.
Dr. Khandaker, who led the trial, said the study was a “proof of concept” and too small to elicit significant results. Instead, the goal was to identify which depression symptoms might respond to the treatment and when patients might start to improve, in order to design a future larger trial.
Some scientists who work on the topic are puzzled by the inconsistent findings in the various studies. “It’s a mixed story and I don’t really know why that is,” said Dr. Michael Irwin, a professor of psychiatry and biobehavioral sciences at the David Geffen School of Medicine at the University of California, Los Angeles. The treatment studies “should be working,” he added, “because experimental data showing that inflammation drives this depression is really quite convincing.”
Dr. Goldsmith agreed “the evidence exists” for an inflammatory subtype of depression. But he added: “What eventually is going to be the right medicine to target inflammation, I think, remains an open question.”
The experts said it was premature to prescribe anti-inflammatory drugs for depression. But some psychiatrists, including Dr. Khandaker, have started testing patients’ blood inflammatory protein levels and recommending lifestyle changes, like exercise and diet, to help reduce them.
It may be a while before the theory that inflammation causes depression becomes mainstream.
Dr. Moira Rynn, the chair of psychiatry and behavioral sciences at Duke University School of Medicine, who does not specialize in inflammatory psychiatry research, called the idea “compelling.” Her clinic, which sees people with treatment-resistant depression, doesn’t typically take inflammation into account when caring for patients, but it’s something they’re considering, she said.
“The challenge,” she added, is “it’s not clear how to treat, given the current state of information.”
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