Chronic illness can be tough on mental health. Depression affects 42 percent of cancer patients, according to the Centers for Diseases Control and Prevention, as many as 42 percent of people with rheumatoid arthritis, 27 percent with diabetes, 17 percent with cardiovascular disease, and 11 percent of Alzheimer’s patients.
There is something else those diseases share: inflammation. And that’s not a coincidence. In many cases, scientists are finding that inflammation exacerbates mental health beyond the challenges of living with a chronic illness.
As scientists dig into the biological connections between inflammation and depression, the work is leading to new targets for medications and new insights into how people can manage their own inflammation to improve mental health. The work offers hope, especially for the large number of people with depression who don’t improve with current medication options.
“We’re at the stage where we have a number of different types of evidence that all point toward either a heightened inflammatory response or at least an altered immune response being involved in our future risk of depression, our current state of depression, and our response to treatment for depression,” says Deakin University’s Wolfgang Marx. “All along the pathway of that clinical course of depression, inflammation seems to play at least some sort of role.”
From inflammation to depression
Depression was, for a long time, considered to be a simple story of neurotransmitters gone wrong, Marx says. Serotonin and dopamine are two particularly important neurotransmitters, or messenger molecules in the brain, that help regulate mood, motivation, and emotions. The thinking was that when those molecules got out of whack, mental health problems followed.
In the last few decades, however, multiple lines of evidence have converged to suggest that, while neurotransmitters matter, the immune system also plays a role in affecting mental health and that inflammation in the body can alter mood in the brain. As early as 1980, researchers noted that people with psychosis had elevated levels of T cells and B cells in their blood. As scientific knowledge has exploded about the number of molecules involved in the inflammatory process, so too have studies linking a variety of inflammatory cytokines with major depressive disorder, as well as bipolar disorder and schizophrenia.
Some of the strongest evidence that inflammation can wreak havoc in the brain comes from research on a drug called interferon alpha. Secreted by infected cells in the human body, interferon is an inflammatory cytokine that works as a powerful antiviral. Human-made versions of the molecule are used as a drug to treat hepatitis C, malignant melanomas, and other conditions. But side effects of these inflammation-inducing medications include psychosis and depression. A quarter of people who take interferon alpha for hepatitis C develop major depression, studies find.
Uncovering how exactly inflammation damages mental health is a work in progress, and scientists are investigating several hypotheses. Among them, Marx says, is that chronic inflammation may impair the production of serotonin and other neurotransmitters, inhibit the body’s ability to make new brain cells, or damage the ability of brain cells to make new connections with each other. Impacts are particularly notable in the hippocampus, the part of the brain that is responsible for memory, emotional regulation, and mood.
On a more fine-grained level, scientists are looking at the activity of specific molecules involved in inflammation and how they might affect processes in the brain. Some studies, for example, show that certain kinds of T cells and cytokines cross the blood-brain barrier and affect microglia, the central nervous system’s immune cells. Normally, microglia repair damage and destroy injured cells, but when stimulated by inflammation, they appear to damage neurons instead, essentially eating up parts required for neuronal functioning, says Eléonore Beurel, a biochemist at the University of Miami Miller School of Medicine in Florida.
In her lab, she is researching the role that inflammation plays in interrupting a balance between inflammatory molecules and immune cells that repair brain cells and those that interfere with the beneficial activity of immune cells in the brain. “We are still trying to put the puzzle together,” she says.
The early roots
To understand how inflammation-related depression develops, some researchers are looking to key risk factors for depression in the earliest stages of life. Scientists have known for decades that a history of trauma in childhood raises the risk for adult depression in general and treatment-resistant depression in particular. Inflammation may help explain the association and might be the key to mitigating it, says Andrea Danese, a child and adolescent psychiatrist at King’s College London in the U.K.
Kids who experience abuse and neglect in the first decade of life show elevated levels of several inflammatory molecules by the time they are in their early thirties, Danese has found in his work. Childhood maltreatment—and chronic inflammation—are also associated with a heightened risk for cardiovascular disease, type 2 diabetes, and other physical health conditions.
Danese suspects that early life stress related to childhood maltreatment might affect brain development in multiple ways—through activated inflammatory pathways—that lead to long-lasting impacts. Exacerbating that connection are substance misuse, unbalanced diet, poor sleep, and other behaviors related to maltreatment that can also increase inflammation.
Results of this stress-induced elevated inflammation might include altered functioning of microglia, as well as impaired production or functioning of neurotransmitters and cortisol, a hormone that regulates the stress response. Cortisol has powerful anti-inflammatory effects; synthetic versions of it, called corticosteroids, are used to treat inflammatory disorders such as rheumatoid arthritis and lupus. But in mice experimentally exposed to early-life stress, the hormone appears less effective at reducing inflammation.
Chronic stress activates inflammatory circuits at any age, studies show, but exposure to stress at an early age appears to cause more stubborn forms of depression, Danese says. Identifying the pathways involved provides a window into opportunities to buffer the damaging effects of childhood maltreatment and improve treatments for people with a history of depression.
“Individuals who have a history of childhood maltreatment tend to have more chronic and more persistent types of depression and they also tend to respond more poorly to conventional treatment,” he says. “Inflammation may definitely be one of the biological reasons for why this happens.”
Fighting inflammation to fight depression
As scientists unravel the details of inflammation’s role in mental health, they are looking for ways to fight depression by controlling inflammation. The strategy appears to be most promising for the 5mg/L.” rel=”noopener noreferrer” target=”_blank”>estimated 30 percent of people with depression who don’t respond to standard anti-depressants. This group, studies show, tend to have the most elevated inflammation levels.
Many mood stabilizers and mental-health medications already have anti-inflammatory effects. And a wide variety of anti-inflammatory medications appear to ease depression, found a 2019 review of research, with data from 26 studies that included more than 1,600 people. Compared with people who took a placebo, the review found, those who took medications or supplements with anti-inflammatory effects—including NSAIDs, statins, omega-3 fatty acids, and antibiotics—reported reduced depressive symptoms, especially when they combined the anti-inflammatories with anti-depressants.
Now, scientists are turning to their increasingly detailed understanding of the molecules involved in inflammation to search for drugs that could more specifically target inflammatory molecules most closely linked to depression in the people that need it most.
For example, some research is focused on a drug called infliximab, which is used to treat auto-immune disorders such as rheumatoid arthritis, psoriasis, and Crohn’s disease, but may have anti-depressant effects too. In one trial of 60 people who were randomly assigned to get infliximab or a placebo, those who got the drug reported twice as much improvement in depressive symptoms as those who got the placebo, scientists reported in 2013.
As in other studies since then, though, the anti-inflammatory only worked as an anti-depressant in people who had elevated levels of inflammation to begin with. In another study, a 12-week course of infliximab helped treat depression only in a subset of patients who had endured physical abuse as children. And more recent trials of the drug, for bipolar disorder and depression, have been less supportive.
Infliximab works by lowering levels of a pro-inflammatory cytokine called TNF-alpha. Beurel is interested in another cytokine called interleukin 17A, which is also elevated in people with depression. In her work, she has shown that injections of the cells that produce this inflammatory molecule lead to depression-like symptoms in mice, causing them to cease interacting with other mice or stop trying to escape uncomfortable situations. At the Icahn School of Medicine at Mount Sinai in New York, researchers are now conducting a clinical trial to see whether a drug called ixekizumab that targets IL-17A might help people with treatment-resistant depression.
Multiple approaches are welcome, Marx says, because mental health is complicated. The risk for depression is tied to genetics, biology, environmental factors, and life experience, and mood is wrapped up in many processes in the brain and body. Inflammation is only part of the story; it is elevated in at most half of people with depression. And it probably goes both ways, Marx adds, with depression leading to inflammation, too. But the strong and growing evidence linking inflammation with depression suggests that many people could benefit from addressing chronic inflammation as a mental-health strategy. And medications aren’t always necessary.
Eating away at depression
Among lifestyle changes that can affect mental health, including exercise, diet might be one powerful way to intervene, Marx says. Mediterranean-style eating, in particular, has been linked through multiple studies to a reduction in depression symptoms, Marx and colleagues reported in a 2020 review of research.
For one trial, researchers at his institution included 67 people with diagnosed depression. Half were assigned to work with a dietician, who helped them revise their diets. They were coached to eat more produce, legumes, low-fat dairy, fish, raw nuts, whole grains, and other foods typically found in Mediterranean diets, with fewer processed, refined, fried, and fast foods. After 12 weeks, 32 percent of people in the diet-support group had achieved a state of remission from clinical depression, compared with 8 percent who didn’t get any dietary coaching.
A variety of mechanisms are implicated in the link between diet and depression, Marx says. But inflammation has some of the strongest evidence behind it. The microbiome is one of the factors that appear to regulate the immune response, Beurel adds. Through both diet and exercise, studies show, it is possible to alter the microbiome in ways that influence inflammation and enhance the benefits of antidepressants.
Evidence also supports sufficient sleep, spending time outside, and reducing stress through meditation as ways to lower inflammation and in turn, boost mood.
“As we learn more about the role that lifestyle factors have to play in our mental health and also in inflammation, I think that provides quite an empowering message,” Marx says. “By exercising, by engaging with nature, by eating healthily, we can actually make a pretty substantial difference—not only in physical outcomes, but also our mental health.”