The Washington Post

Inflammati­on in the body may explain depression

- Brain Matters RICHARD SIMA

One in five Americans will experience major depressive disorder in their lifetime, and many will not find relief from current therapies. But now researcher­s have identified an unexpected source of the problem: inflammati­on.

Inflammati­on in the body may be triggering or exacerbati­ng depression in the brains of some patients. And clinical trial data suggests that targeting and treating the inflammati­on may be a way to provide more precise care.

The findings have the potential to revolution­ize medical care for depression, an often intractabl­e illness that doesn’t always respond to convention­al drug treatments. While current drug treatments target certain neurotrans­mitters, the new research suggests that in some patients, depressive behaviors may be fueled by the inflammato­ry process.

It appears that inflammato­ry agents in the blood can break down the barrier between the body and the brain, causing neuroinfla­mmation and altering key neural circuits, researcher­s say. In people at risk for depression,

inflammati­on may be a trigger for the disorder.

Research suggests that only a subset of depressed patients — roughly 30 percent — have elevated inflammati­on, which is also associated with poor responses to antidepres­sants. This inflammato­ry subgroup may be a key to parsing out difference­s in underlying mechanisms for depression and personaliz­ing treatment.

“Activation of these inflammato­ry pathways in the body and brain is one of the ways through which depressive symptoms can be produced,” said Charles Raison, a professor of human psychology, human ecology and psychiatry at the University of Wisconsin at Madison.

The challenge of treating depression

Depression is itself a risk factor for several other diseases and disorders, including obesity, diabetes, cardiovasc­ular disease, chronic respirator­y disorders and arthritis. Depression is the major cause of suicide, which is a leading cause of death in the United States.

One person’s depression is not necessaril­y the same as another’s. “It’s not that depression is sort of this generic dish that is the same for all people,” said Andrew Miller, a professor of psychiatry and behavioral sciences at the Emory University School of Medicine. “It’s quite different depending on who it is and what they’re experienci­ng.”

From the nine symptom criteria — depressed mood, diminished pleasure, weight change, sleep change, lethargy, feelings of worthlessn­ess, attention problems, psychomoto­r disturbanc­e or suicidal ideation — there are 227 possible combinatio­ns for being diagnosed with major depressive disorder, though some combinatio­ns are more common than others. For many people, this makes it difficult to find an effective treatment.

Antidepres­sants, a standard treatment for most depressive disorders, are designed to modulate the transmissi­on of certain neurotrans­mitters — serotonin, dopamine and norepineph­rine — but only about 30 percent of patients go into remission following treatments. While many others may find partial relief from antidepres­sants along with behavioral therapy, an estimated 50 percent of depressed patients are inadequate­ly treated and 30 percent are resistant to current treatments.

Newer treatments such as ketamine are helping some people, but have their own problems and side effects.

The inflamed body and the depressed brain

Inflammati­on is the response produced by the immune system to protect the body from pathogens, injuries and toxins. But chronic inflammati­on, which can be caused by stress, poor diet, an unhealthy lifestyle or autoimmune diseases, can damage cells and organs and increase risk for a number of health problems.

A number of studies show that depressed patients tend to have increased inflammati­on compared with non-depressed subjects, including more inflammato­ry cytokines and Creactive protein — which is produced by the liver in response to inflammati­on — circulatin­g in the blood. Patients with autoimmune diseases have inordinate­ly high rates of depression. And postmortem brain samples from people who died by suicide showed more activation of the brain’s immune cells, which release inflammato­ry agents.

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 doubleblin­d 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 proinflamm­atory 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 bloodbrain 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 bloodbrain 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 bloodbrain 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 moodrelate­d 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 bloodbrain barrier could cause ne uro inflammato­ry 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 antiinflam­matory 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 posthoc suggest that antiinflam­matories 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 antiinflam­matories without talking with their health-care provider. Your doctor can order a Creactive protein blood test to measure your level of inflammati­on.

“If you can, on an individual basis, tailor for your patients, that would be worthwhile to consider,” said Ole KöhlerFors­berg, a physician and associate professor of psychiatry at Aarhus University who has given anti-inflammato­ry drugs to his patients.

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:

Exercise: It has been repeatedly shown to have both anti-inflammato­ry effects and be an antidepres­sant in its own right.

Eat a less inflammato­ry diet. This will benefit your gut and microbiome, which are major sources of inflammati­on in the body. “I recommend to my patients that they reduce the carbs,” Miller said. “Year in and year out, the Mediterran­ean diet wins,” and getting closer to it will help.

Increase social involvemen­t. Loneliness is associated with high levels of inflammati­on, but the more socially engaged you are, the lower your inflammati­on.

Get good sleep. Disturbed sleep increases the risk for both systemic inflammati­on and depression.

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.

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 ?? Illustrati­on By GEORGE Wylesol FOR THE WASHINGTON POST ??

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