Crucially, pro-inflammatory drugs can induce people to become depressed, which suggests a causative link. In one
seminal study published in the New England Journal of Medicine, Miller and his colleagues conducted a double-blind study of 40 cancer patients undergoing treatment with interferon-alpha, an inflammatory cytokine. Though none of the patients had depression to begin with, the inflammatory agent had a striking effect: Many became depressed, a finding that has been
consistently replicated. “The patients recognize pretty much immediately that, ‘Hey, you gave me something, and now I feel this way. I don’t know why I feel this way,’” Miller said.
Inflammation changes brain circuits and behavior
From an
evolutionary standpoint, inflammation may be a way for the immune system to communicate with the brain, Miller said. When animals were wounded or fighting off an infection, the brain and immune system would work in concert
to shut down the animal’s activities to allow for quicker recovery.
But for humans today, living in more sanitary environments and with relatively new sources of inflammation — unhealthy foods, sedentary lifestyles — this immune response may be less adaptive because the inflammation is less likely the result of an infection or wound.
“Now we live in an environment where we’re not terribly physically active, we eat a ton of carbs, we’re overweight by and large, and it’s killing us,” Miller said. “The inflammation is killing us. And one of the ways that it kills us is by affecting the brain.” But how inflammation influences depression is complex. Inflammation may be increasing
anhedonia, or the depressive symptom of reduced pleasure. It may also play a role in causing
psychomotor slowing, or the slowing down of thought and movement.
People receiving pro-inflammatory agents such as interferon-alpha had
blunted responses in brain areas associated with reward, such as the ventral striatum. Inflammation also seems to
decrease the release of dopamine, a neurotransmitter implicated in reward and movement. At the same time, inflammation
reduces the functional connections between the ventral striatum and the prefrontal cortex, which are important parts of the brain’s reward circuitry.
A leaky blood-brain barrier
Prolonged, elevated inflammation can lead to a
leakier blood-brain barrier, which normally protects the delicate brain from potentially harmful molecules in the blood. But when chronic inflammation is present, immune cells in the blood glue themselves to the barrier blood vessels, where they constantly release inflammatory molecules. These may activate the brain’s specialized immune cells on the other side of the barrier, called microglia, to release inflammatory agents of their own and cause neuroinflammation. “This will fragilize the blood-brain barrier,” said
Caroline Ménard, an assistant professor of psychiatry and neuroscience at Université Laval and CERVO Brain Research. “So eventually, you will have some tiny holes in the blood-brain barrier of the brain. And this will allow inflammation to pass from the blood into the brain, and this will eventually change the neurons and all the cells that create the behavior and who we are.”
Ménard and her colleagues
discovered, in one mouse study, that chronic stress and inflammation caused the blood-brain barrier to get leaky in specific areas involved in depression, such as the nucleus accumbens, a key structure in the ventral striatum. When the researchers examined the nucleus accumbens in postmortem brain tissue of depressed male patients in a
2020 study, they found similar molecular changes in the blood-brain barrier.
Interestingly, there are sex differences in how inflammation affects the blood-brain barrier. When the researchers ran similar experiments in female mice in a
2022 study, they found that chronic social stress caused the blood-brain barrier to be leaky in a different part of the brain — the prefrontal cortex, a mood-related hub. Postmortem brain tissue of depressed women exhibited similar vascular alterations in the blood-brain barrier near the prefrontal cortex.
These results suggest one possible mechanism for how inflammation, a whole-body process, could affect certain depression-relevant parts of the brain, such as the ventral striatum and prefrontal cortex, more than others: A leaky blood-brain barrier could cause neuroinflammatory changes to nearby neurons in the reward circuit. The coordinated involvement of the immune, vascular and nervous systems also underscores that depression is a whole-body problem that requires a whole-body approach to solving it. “I think we need to think outside the box, which is the brain and the neurons,” Ménard said. “When you’re stressed, you feel it all over your body, you don’t feel it only in your brain.”
Can treating inflammation treat depression?
If inflammation can induce or exacerbate depression and its symptoms, then reducing inflammation could provide relief. Even if inflammation is a disease modifier rather than the cause of the problem, “you have to take care of it in order for you to be able to get your therapeutics working to restore your circuitry and what’s happening in the mind,” said
Eleonore Beurel, a professor of psychiatry and behavioral sciences at the University of Miami Miller School of Medicine.
Anti-inflammatory drugs, used alone or in conjunction with a standard antidepressant, may help some depressed patients. A
2019 meta-analysis encompassing almost 10,000 patients from 36 randomized clinical trials found that different anti-inflammatory agents, including NSAIDs, cytokine inhibitors and statins, could improve depressive symptoms. But some
recent large clinical trials testing anti-inflammatory drugs have not found any noticeable impact on depressed patients.
Part of the issue is that anti-inflammatory treatments should target only patients with elevated inflammation — and not be used as a one-size-fits-all approach, because depression is so heterogeneous. Most clinical trials are not designed to compare inflammation levels of patients, but analyses run post-hoc suggest that anti-inflammatories have the largest effect on depressed patients with inflammation, Miller said. For example, one early
randomized controlled trial conducted by Miller and Raison found that giving a cytokine inhibitor to treatment-resistant depression patients helped only those with elevated inflammation.
Future research trials need to consider the heterogeneity of the patients and their different flavors of depression as well as their inflammatory profiles. Making more precise measurements of particular symptoms impacted by inflammation, such as anhedonia and psychosomatic slowing, may also tease apart subtle effects of different treatments. “We’ve come to the tipping point,” Miller said. “And we know enough at this point to begin to target the immune system and its downstream effects on the brain to treat depression. We are there.”
How to manage your own inflammation
Experts agreed that people should not take anti-inflammatories without talking with their health-care provider. Your doctor can order a
C-reactive protein blood test to measure your level of inflammation. “There are so many patients who do not respond to antidepressants,” said
Ole Köhler-Forsberg, a physician and associate professor of psychiatry at Aarhus University who has given anti-inflammatory drugs to his patients in addition to antidepressants. “So there is the issue of how can we improve the individual outcomes.” Tailoring treatment for each individual on a holistic basis may add some benefit.
More clinical tests for inflammatory markers may be a way to differentiate the effectiveness of antidepressant treatment. If confirmed, it would “be the first actual biomarker in psychiatry,” Raison said. “I mean, we’ve been looking for biomarkers for 50 years and had zero luck. And it’s ironic that it’s not a brain chemical.” In the meantime, “you get much more mileage out of the lifestyle changes than you would out of supplements or any other over-the-counter drugs at this point,” Miller said. These include:
Making lifestyle changes may be hard for severely depressed patients, Köhler-Forsberg said, but it could help build resilience and prevent relapse when they get better and have the energy to make these changes.
“Trying to reduce behavioral things that promote chronic inflammation is probably a smart move if one wants to reduce one’s depression,” Raison said.