For years, researchers theorized that depression may be caused by inflammation.
Years of evidence linked inflammation to the illness. However, anti-inflammatory drugs repeatedly failed to treat depression when tested in trials.
How could both be true?
Now, a new proof-of-concept clinical trial published in JAMA Psychiatry is offering an answer.
“This pilot trial provides early evidence that, for people with depression who also have raised inflammation, targeting the immune system may improve symptoms,” Éimear M. Foley, the study’s first author and a clinical research fellow at the University of Bristol, told The Epoch Times in an email.
The findings are preliminary, but they suggest that the problem with earlier studies may not have been the theory itself—but rather the assumption that all depression is the same.
The Inflammation Theory
The case for inflammation began with a cluster of complaints.
Many people with depression share the same set of symptoms: feeling utterly drained, thinking and moving more slowly, sleeping more, losing interest in things they once enjoyed. It closely resembles what scientists call “sickness behavior,” the body’s way of conserving energy while fighting infection.
Beginning in the late 1990s, biological evidence began to accumulate. Study after study repeatedly found that people with elevated C-reactive protein (CRP), a blood marker of inflammation, were at higher risk of developing depression.
“We were seeing a lot of data to support that inflammation may play a role in depression,” Dr. Andrew Miller, a professor of psychiatry and behavioral sciences at Emory University who was among the first scientists to build the case, told The Epoch Times.
People living with chronic inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease, as well as people recovering from serious infections, were also more likely to develop depression.
Then came an observation that convinced even the skeptics.
Cancer patients receiving interferon-alpha, an immune-stimulating treatment, began developing symptoms that looked like major depression. People who had never experienced depression suddenly reported profound fatigue, social withdrawal, and low mood.
“Amazingly, they were depressed just like the patients we see in clinic,” Miller said.
The findings suggested that inflammation does more than accompany depression. It drives it.
The Right Idea, the Wrong Patients
However, when Miller and his colleagues tested their theory by giving patients with depressive symptoms a powerful anti-inflammatory—it didn’t work.
“The drug did not separate from placebo,” he said. “We were crushed.”
But when the researchers dug back into the data, they noticed a pattern. The treatment had failed overall, yet not everyone responded the same way—some did show benefit.
People who entered the study with the highest levels of inflammation saw the greatest benefit. In that group, depression scores fell several points more than in similar patients on placebo, an effect size on par with what researchers typically see when an antidepressant works.
The finding raised a new possibility in our understanding of depression: Depression is not a single condition. In a subset of people, inflammation is the driver.
Roughly one-third of people with depression have elevated inflammatory markers in their blood. Coincidentally—or perhaps not—about one-third of patients also fail to achieve adequate relief from antidepressant medications.
However, by grouping all depressed patients together, researchers were effectively diluting any signal the treatment might have produced.
According to Dr. Manish Jha, an associate professor of psychiatry at UT Southwestern Medical Center, selecting patients with elevated inflammatory markers is essential when testing immune-targeted therapies. Those markers, he told The Epoch Times via email, can identify the subgroup of people whose depression “may be underpinned” by immune-system dysfunction.
Testing the Theory
With the failed lesson, the new Insight Study made sure to enroll only patients whose depression symptoms were highly likely to be driven by inflammation.
Foley and colleagues enrolled 30 adults whose depression had not improved despite trying at least two antidepressant medications and who also showed persistent low-grade inflammation, indicated through repeated abnormally high CRP blood tests, alongside low energy and physical symptoms.
Participants received either tocilizumab—an immune-modulating drug commonly used to treat inflammatory diseases such as rheumatoid arthritis—or a placebo. Tocilizumab lowered CRP levels into the normal range.
Over the following month, those who received the drug also showed steady, stepwise improvements in their symptoms: depression severity, fatigue, anxiety, and overall quality of life ratings all improved into ranges regarded as clinically meaningful. By the fourth week, half of the people given tocilizumab no longer met the criteria for major depression—they achieved depression remission.
“This study is the first to show rapid antidepressant effects [after] using a single intravenous injection of a powerful anti-inflammatory drug,” Carmine Pariante, a professor of biological psychiatry at King’s College London, told The Epoch Times in an email.
“The symptoms that respond are symptoms related to energy, motivation and fatigue,” Miller said. “Those symptoms map directly onto what we know inflammation does to the brain.”
Among the improvements, Jha noted, the strongest signals were seen in improving fatigue.
How Inflammation Alters the Brain
For decades, depression has largely been blamed on a chemical imbalance in the brain, especially involving serotonin, often described as one of the brain’s feel-good chemicals. That idea helped inspire the development of selective serotonin reuptake inhibitors, or SSRIs, drugs designed to keep more serotonin available.
However, the serotonin theory has long been controversial: in addition to not working in one-third of patients, serotonin levels do not consistently match depressive symptoms.
“When you talk to psychiatrists, they don’t know how much we do know about how inflammation affects the brain,” Miller said. “What circuits, what neurotransmitter systems, and what behaviors.”
This study targeted interleukin-6 (IL-6), a molecule that can interact with specific brain circuits involved in motivation, reward, and energy. When these circuits are hit by inflammation, people slow down.
Elevated IL-6 has repeatedly been linked to depression, with patients often reporting fatigue, low energy, and physical complaints.
Inflammation also interferes with dopamine. While dopamine is often linked to pleasure, researchers say one of its most important jobs is helping us decide whether something is worth the effort in the first place.
When dopamine goes down, motivation goes down. People lose interest and enjoyment in things that once felt meaningful, also known as anhedonia—a symptom many experts consider one of the defining features of depression.
These changes shift the brain into a state designed to conserve energy. While the response can be beneficial in the short-term, such as when recovering from a cold, when inflammation becomes chronic, the brain can get stuck running the same program—even though there’s no infection to fight.
Precision Psychiatry
The broader significance of the small pilot trial extends well beyond any single drug. It tests a new way of thinking about how depression should be treated.
Today, two people can receive the same diagnosis of major depression despite having different symptoms, life experiences, and underlying biology. Yet both are typically treated with the same medications, often through months of trial and error—with no guarantee of relief.
However, the biology of inflammation isn’t always one pathway or another. Some people may respond to antidepressants while still experiencing lingering fatigue because inflammation is also contributing to their depression. More than one biological process can be shaping a person’s depression at the same time.
Within psychiatry, there is a growing movement known as precision psychiatry, whose goal is to identify biologically meaningful subtypes of mental illness and match people to treatments that target the mechanisms driving their symptoms, rather than relying on a one-size-fits-all drug or combination of pills.
The study’s finding validates this growing movement.
“This study confirms the notion of an inflammatory subtype of depression that can be best identified using blood C-reactive protein and that responds to anti-inflammatories,” Pariante said.
In terms of diagnosis, that could mean using a simple blood test, such as a CRP test, to identify patients whose symptoms are driven, at least in part, by immune-system activity. “CRP is a simple, low-cost blood test that is already widely used in routine [medical] practice,” Foley said.
Several leading researchers, including Miller, Jha, and Pariante, are advocating for the addition of an inflammatory subtype of depression in the upcoming editions of the Diagnostic and Statistical Manual of Mental Disorders.
Larger studies will be needed to determine whether inflammatory markers can reliably identify patients who benefit from targeted treatments and whether those benefits can be sustained over time.
For patients whose symptoms have long resisted standard treatments, that possibility offers something earlier research could not: an explanation for why depression can behave so differently from one person to the next.
“It’s going to happen,” Miller said. “It may take time, but I think the field is ready to hear the story.”