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 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 fibres 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 neurotransmitters, including serotonin, dopamine, and glutamate, which help control emotion, appetite, sleep, learning and memory.
Generally, it’s thought that a lack of serotonin activity in the brain causes depression; and most antidepressants increase that activity in a variety of different ways. But cytokines also have been shown to activate stress hormone signalling in the brain, which may also prime some people to develop depression.
With all the evidence implicating inflammation in depression, doctors have been anxious to test anti-inflammatory drugs as a potential treatment. 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 - selecozib - along with an antidepressant, got more relief from feelings of sadness, hopelessness, guilt and fatigue compared with those taking an antidepressant alone.
However, Andrew Miller, a professor of psychiatry at Emory University, noticed something amiss with these small-scale studies as 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.
His research group 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 looked at a cohort of 60 depressed adults who were otherwise healthy - if they weren't healthy there would be a risk of people showing heightened levels of cytokines due to infection or illness rather than depression. They then divided them into two groups. One group received a potent anti-inflammatory drug called Infliximab, and the other group got a placebo. Among the participants with high inflammation, those who received Infliximab experienced a reduction in their symptoms. Somewhat to be expected considering what is already known.
But then things got interesting. When they analyzed the group with normal inflammation, they were taken aback. They had assumed that using anti-inflammatory drugs to treat depression would take a one-size-fits-all approach. Instead, they found that this group of participants who received Infliximab were less likely to recover from depression than those who got the placebo.
It appears that blocking inflammation in those who don't have pre-existing high levels of depression is detrimental. It also highlights the intriguing idea that a certain level of inflammatory cytokines is needed to help the brain function normally.
The study, published in 2013, shows that the role of inflammation in mental health might be more complex than once thought. It also helps make sense of other research suggesting that anti-inflammatory drugs may undermine depression treatment in some individuals. One recent analysis of more than 1,500 people found that those who took an anti-inflammatory drug along with an antidepressant were less likely to overcome their depression than those who only took an antidepressant.
Over the past 20 years the idea that high levels of inflammation in the body and brain were associated with depression have been the norm. This one-size-fits-all theory has now been well and truly thrown out of the metaphorical window as it now seems likely that both high and low levels could lead to depression.
While Professor Miller’s study indicates that anti-inflammatory drugs aren’t a perfect cure for depression, it does give clues about how to use the medication effectively for specific groups. The key lies in identifying depressed individuals with high levels of inflammation.
Blood tests are routinely used to measure levels of something called C-reactive protein (or CRP) in people who have a variety of inflammation-related diseases, such as heart disease and arthritis. CRP is made when our bodies have high levels of cytokines so high levels of CRP are a good indicator of high levels of cytokines. Researchers are now anticipating that CRP testing could be extended to those suffering from depression to identify individuals who would possibly benefit from anti-inflammatory medication.
Hopefully this will make the pharmacological treatment of depression less hit-and-miss. Currently people with depression experience a titration schedule of prescription medications. If the first antidepressant doesn't work, then let’s try the next, if that doesn't work then let’s move onto the next and so on.
Through my own experience of working with people with depression, I for one have always felt that the word depression is just an all-encompassing term that covers a group of similar, yet distinct conditions - hence the difficulties in treating it. This research further entrenches this belief for me, and hopefully opens up a new wave of research that steps outside the box to enable better and more specific treatment options for patients.
For those who want to read Professor Millers original research:
Raison, C. L., Rutherford, R. E., Woolwine, B. J., Shuo, C., Schettler, P., Drake, D. F., Haroon E and Miller A H (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers JAMA Psychiatry 70(1): 31-41