Depression’s Dance With Inflammation

Depression’s Dance With Inflammation |

Despite numerous antidepressant drugs, as many as a third of patients don’t respond to medication. This has forced doctors to be more creative in finding different treatments for the condition.

In the past two decades, researchers have tied depression to a seemingly unrelated condition: inflammation, the body’s natural response to stress.

Some amount of inflammation is generally beneficial, as it ramps up production of cytokines, proteins that help us heal and protect us from the effects of overexertion.

But excessive cytokine levels, and the inflammation they bring on, could come at a cost: A number of studies suggest that high levels of cytokines could contribute to depression. 

Some studies even indicate that anti-inflammatory drugs could reduce those cytokine levels and help people recover from depression. 

Only a fraction of people with depression — an estimated 20 to 30 percent — have high inflammation (though for people with treatment-resistant depression, it’s 45 percent). No treatment guidelines yet exist to figure out who they are and how much they need. And treating depression patients who don’t have high inflammation with anti-inflammatory drugs could be detrimental.

Mounting Evidence

For years, doctors believed that depression weakens the immune system, making it harder for people to fight off infections and recover from an injury. But about 20 years ago, researchers started noticing that the levels of cytokines and T-cells, which help drive immune responses and secrete cytokines, were higher instead of lower in blood samples from people diagnosed with depression.

Since then, inflammation’s connection to depression has turned out to be even stronger. When people with skin cancer or chronic hepatitis C take a type of cytokine medication called interferon-alpha to spur their bodies’ immune systems, they often start having symptoms of depression. Numerous studies have also found that healthy adults who produce above-average levels of cytokines are more likely to develop depression later in life.

Cytokines can reach the brain several ways:

  • directly through the blood-brain barrier or
  • indirectly by binding to nerve fibers elsewhere, which send signals to the brain to produce the inflammation molecules.

In the brain, cytokines can disrupt the production and release of several important signaling chemicals, including serotonin, dopamine and glutamate, which help control emotion, appetite, sleep, learning and memory.

It’s thought that a lack of serotonin activity in the brain causes depression; most antidepressants increase the activity. But cytokines also have been shown to activate stress hormone signaling in the brain, which may also prime some to develop depression

Four small studies published between 2006 and 2012 by research groups in Europe and Iran found that adults diagnosed with depression who took aspirin or another anti-inflammatory drug called Celecoxib, along with an antidepressant, got more relief from feelings of sadness, hopelessness, guilt and fatigue compared with those taking an antidepressant alone.

Not so fast

None of them looked at whether the participants had to have high levels of cytokines before they’d see a benefit from anti-inflammatory drugs.

Andrew Miller, a professor of psychiatry at Emory University, and his colleagues wanted to see whether the effect of these drugs was limited to the subset of depression patients with high cytokine levels, or if it helped all people diagnosed with depression.

They naively assumed that using anti-inflammatory drugs to treat depression would take a one-size-fits-all approach. Instead, they found that the group of participants who received Infliximab were less likely to recover from depression than those who got the placebo.

“If you block inflammation in people who don’t have high levels of inflammation, you can do them a disservice,”

The study, published in 2013, shows that the role of inflammation in mental health might be more nuanced than once thought. It also helps make sense of other research suggesting that anti-inflammatory drugs may undermine depression treatment in some individuals

“For 20 years, we thought that only the higher side of the inflammatory processes in the body and brain are associated with depression,”

Now it seems like both the high and low levels could lead to depression.

As Yirmiya points out, these molecules at normal levels have many important brain functions associated with learning, forming memories and making new neurons.

Selective benefits

In Miller’s study, researchers measured levels of C-reactive protein (CRP), which our bodies make in response to high levels of cytokines.

Blood tests for CRP are already a routine part of monitoring and treating inflammation-related diseases.

One day, perhaps, depressed patients will come to a primary care office and have their blood drawn. If CRP is high, they will go straight to a combination of anti-inflammatory and antidepressant.


Here’s some basic information on cytokines from Wikipedia:


Cytokines are a broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling

They are released by cells and affect the behavior of other cells, and sometimes the releasing cell itself.

They act through receptors, and are especially important in the immune system;

they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways

They are different from hormones, which are also important cell signaling molecules, in that hormones circulate in much lower concentrations and hormones tend to be made by specific kinds of cells.

They are important in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction.

a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states.

Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signalling then alter cell functions. This may include the upregulation and/or downregulation of several genes and their transcription factors, resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by feedback inhibition.

Cytokines are crucial for fighting off infections and in other immune responses. However, they can become dysregulated and pathological in inflammation, trauma, and sepsis

Plasma levels of various cytokines may give information on the presence, or even predictive value of inflammatory processes involved in autoimmune diseases

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