In the largest study of its type to date, an analysis of 85,895 individuals in the UK shows that a greater risk of depression is associated with a higher level of inflammation in the body – potentially opening up another way of treating the mood disorder.
"Our study provides the most conclusive evidence to date that people with depression have proteins in their blood indicating activation of the inflammatory system," says psychologist Maria Pitharouli from King's College London in the UK.
"Furthermore, through in-depth analysis of data from 86,000 people, we have discovered more about the mechanisms that may be behind the relationship between inflammation and depression."
Through blood samples, genetic data, and physical and mental health questionnaires collected as part of the UK Biobank project, researchers were able to control for factors such as age, sex, body mass index (BMI), smoking, drinking alcohol, experiencing early life trauma, and socio-economic status.
Those other factors only partially explained the link between inflammation and depression. While the evidence here isn't enough to show that one directly causes the other, the researchers say that it suggests that there could be a direct biological link somewhere that's yet to be discovered.
Inflammation is one of the body's key defenses against attack, but left unchecked and unregulated it can cause plenty of damage of its own. Here, the team looked for the presence of an inflammation biomarker called C-reactive protein (CRP) in the blood.
CRP was found in higher levels in the roughly 31 percent of individuals who had reported experiencing major depressive disorder (MDD) at some point in their levels (a percentage which matches other studies), compared with those who hadn't.
The researchers also calculated a polygenic risk score for the study participants, which is a measure of how likely someone is to develop a condition based on genetics alone. While the polygenic risk score in those with some experience of MDD was strongly associated with levels of CRP, that association disappeared when controlling for BMI and smoking.
In other words, the genetic link to depression appears to be mostly down to body mass index and whether or not someone smokes. However, "the more the genetic loading for depression, the higher the CRP level," the team writes.
This association is similar in strength to that seen between inflammation and three autoimmune diseases: biliary cirrhosis, Crohn's disease, and rheumatoid arthritis.
"Our study highlights how genetics can be used as a tool for dissecting mental health disorders," says genetic epidemiologist Cathryn Lewis from King's College London.
"Here we've shown that the genetic contribution to inflammation in depression comes mostly from eating and smoking habits. That finding is important to help us understand depression better – and one further piece in the jigsaw puzzle towards improving care for people with depression."
The next stage for the researchers is to try and discover the link between inflammation and depression, if it exists. They acknowledge that "unknown or unmeasured psychosocial and clinical confounding factors", such as exposure to maternal depression during development in the womb, or unhealthy diets, could also explain the results that they've produced.
While inflammation and depression have been linked in several previous studies, what's behind that link remains something of a mystery – it may be that something yet to be discovered is causing both the inflammation and the depression, or that one is somehow increasing the risk of the other.
What the new study does is give scientists plenty of more data to work with, especially in terms of genetics and the risk of depression, which here seems to be mainly down to eating and smoking. If we have a better understanding of what underpins depression, we may be better able to target whatever the source is with treatments.
Other experts aren't so sure on the link between inflammation and depression, however, even with the new evidence to hand. Geneticist David Curtis from University College London in the UK, who wasn't involved in the study, said that he was "doubtful" that inflammation ends up playing a key role in depression.
"Certainly there is nothing to suggest that people should try to treat their depression with anti-inflammatory medications," says Curtis.
"As well as having no proven effect on depression, these medications have dangerous side effects whereas antidepressants are safe and effective. Anti-inflammatory medications are reckoned to be responsible for many thousands of deaths every year in the USA."
The research has been published in the American Journal of Psychiatry.