While there is known to be an association between inflammation and depression, it is not known if there is cause and effect. Now, the power of the UK Biobank has been brought to bear to show that when all genetic, health and environmental factors are accounted for, people with depression have higher levels of inflammation in their bodies than controls.

The researchers say this is the first direct evidence that there is a specific biological mechanism by which inflammation causes depression.

"Our large scale analysis of data removed socioeconomic background, ill health, unhealthy habits, as well as genetic predisposition to immune dysfunction as the only explanations for the relationship between depression and inflammation. By this process of elimination, we show that there may be a core biological process that is behind the association between depression and increased inflammation," said Carmine Pariante, professor of biological psychiatry, psychology and neuroscience at King's College London.

Pariante is co-author of a paper in the American Journal of Psychiatry describing the research.

There is animal data -- and some limited clinical research -- showing the impact of inflammatory factors on the brain involves dopaminergic and glutamatergic pathways that regulate motivation and motor activity. The new findings are a spur to investigate further, said Pariante. "The key thing, and the next step, will be to understand the specific mechanism by which inflammation causes depression," he said. "If we can identify this process and uncover more detail about its role in the development of depression, we can pave the way for trialling new treatments for this widespread mental health disorder."

The case control study involved 26,894 people with a lifetime diagnosis of major depressive disorder who have contributed samples and medical records to UK Biobank. They were compared to 59,001 control subjects who had no mental health disorder and had not reported taking any antidepressant medication at the point they were recruited to the biobank.

In total, UK Biobank has data on 500,000 volunteers who were aged 40-69 years old when they were recruited between 2006-2010. The one-third depressed/two-thirds with no history of depression in the sample studied by Pariante and colleagues is similar to estimates of the global prevalence of depression.

The study used C-reactive protein (CRP) as a marker of inflammation, looking to see if CRP levels and depression are associated in UK Biobank; if CRP is associated with individual polygenic risk scores for depression; and if body mass index, smoking, early life trauma and socioeconomic status could fully explain the link between inflammation and depression.

Depressed participants had significantly raised levels of CRP, at 2.4 mg/L, compared to 2.1 mg/L in controls. They also were more likely to have low-grade inflammation, defined as CRP levels of 3 mg/L and above.

The increased inflammation, as reflected in CRP levels, was only partially explained by clinical and sociodemographic factors including age, sex, body mass index, smoking, alcohol consumption, exposure to early life trauma, socioeconomic status and self-reported health status.

Looking at polygenic risk scores estimating how likely an individual is to have a given trait based only on genetics, the researchers found an association between the genetic risk of depression and elevated CRP levels. However, this association was no longer present when body mass index and smoking, both causes of inflammation, were taken into account. In contrast, polygenic risk scores for the autoimmune disorders biliary cirrhosis, Crohn's disease and rheumatoid arthritis, all positively associated with CRP levels even after controlling for body mass index and smoking.

Showing that any genetic effects -- as captured by polygenic risk scores for depression -- are no longer significant once body mass index and smoking are regressed out begs the question, "What drives the increased inflammation in depression we detected?" the researchers say.

Response to therapy

There is some evidence that in the third of patients with depression who do respond to antidepressants, the reason may be that inflammatory factors tap into the same targets as antidepressant drugs. Based on this, there have been clinical trials of broad-spectrum anti-inflammatory drugs in combination with selective serotonin reuptake inhibitors in patients who are resistant to antidepressant treatment alone.

But the combination is problematic, given both classes of drugs make patients prone to gastric bleeding, and Pariante suggested elevated CRP levels could be used to stratify patients in clinical studies. In addition, the findings add weight to the use of CRP as an easily measured blood biomarker to identify patients who will not respond to current drug therapy, short circuiting the odyssey of trial and error treatment with one antidepressant after another.

Taken overall, the study showed depressed participants are more likely to have a high body mass index, to smoke and drink alcohol more, to have had more childhood trauma and to live in areas with high social deprivation. All these variables are associated with higher CRP levels.

However, although the association between depression and increased inflammation is reduced, it still remains significant after taking into account all the "candidate explanations", including immune gene pleiotropy, unhealthy lifestyle, adverse socioeconomic background or ill health.

"We suggest that the remaining association between depression and increased inflammation reflects, at least in part, a core biological process and thus possibly a crucial pathogenic mechanism leading to the depressive phenotype," the researchers conclude.