Inflammation in the body may explain depression
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 disease 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 C-reactive 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 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.
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 KöhlerForsberg, 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:
• 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.