Inflammation a Core Feature of Depression

Sarah Edmonds

May 14, 2021

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

New research suggests that depression and inflammation are biologically linked ― a finding that may have important implications for patients whose condition fails to respond to treatment with antidepressants.

In the largest-ever examination of genetic, environmental, lifestyle, and medical drivers of inflammation in major depressive disorder (MDD), levels of the key inflammation marker C-reactive protein (CRP) were higher in patients with depression than in those with no mental disorder.

This was true after adjusting for sociodemographic factors such as age, sex, body mass index (BMI), alcohol consumption, early-life trauma, socioeconomic status, and physical health ― evidence a core biological mechanism is at work.

The study's joint senior author, Carmine Pariante, MD, Kings College London, London, United Kingdom, said there may be elements of cause and effect in the presence of inflammation in depressed patients.

"We know that patients with depression can have profound changes in all aspects of the body, mostly associated with the stress responses. So the activation of the immune system is present in depression, possibly because it's together with other stress responses," he told a news briefing

The study was published online May 14 in the American Journal of Psychiatry.

Breaking a Vicious Cycle

In animal models, stress stimulates the entire immune system, bone marrow included, which leads to the hyperactive production of immune cells.

Humans with depression also produce more white blood cells, particularly monocytes. The release of these important immune cells into the bloodstream prompts further response elsewhere in the body.

Inflammation is an immune response to infection or other stresses on the body. High inflammation levels are associated with autoimmune disorders and can be risk factors for cardiovascular illness or other ailments.

"Then the immune factors they have circulated, they are able to go back and influence the brain. They either change the blood-brain barrier, or move across the blood-brain barrier, or transmit the signal ― the information ― across the blood-brain barrier and perpetuate the depressive systems by changing the function of brain areas responsible for interpretation of emotions," said Pariante, professor of biological psychiatry at the Institute of Psychiatry, Psychology and Neuroscience, Kings College London.

All this results in a negative feedback loop in which inflammation makes the body believe it is under threat, produces a more robust immune response, and perpetuates or exacerbates depressive symptoms.

"That's why it's so important to understand what is happening but also to break this vicious cycle, because then we could really change the outcome and potentially improve the treatment of these patients," he said.

The findings indicate there may be a benefit in including anti-inflammatories in the treatment regimens of patients with MDD whose condition does not respond to antidepressants. Changes to lifestyle and diet, such as adding high-dose fish oil supplements, and increased exercise could help as well, Pariante said.

In part, this is because inflammation dampens the effectiveness of antidepressants by reducing the brain's production of mood-determining chemicals such as serotonin.

"We need to remember that around one third of depressed patients don't respond to any of the available medication, so we are a long way from having a silver bullet that can help all depressed patients," he said.

He noted that even if only some patients with MDD could be helped by the addition of an anti-inflammatory, that would be a "really important step forward."

A New Finding

For the study, the investigators analyzed blood samples, genetic data, and physical and health questionnaires collected by the UK Biobank, a database of information from more than half a million UK participants who were recruited from 2006 to 2010.

The study compared 26,894 patients who had received a lifetime diagnosis of MDD with 59,001 control persons who had no known mental disorder.

Although the researchers found a link between the genetic predisposition for depression ― as indicated by a polygenic risk score ― and higher levels of inflammation, this association disappeared when higher BMI and smoking were removed from the analysis.

This contrasted with autoimmune disorders such as rheumatoid arthritis, in which the association between genetic risk and inflammation remained after correcting for behavioral factors.

Pariante said this was a new finding.

"Here we've shown that the genetic contribution to inflammation in depression comes mostly from eating and smoking habits," said joint senior author Prof Cathryn Lewis, head of the Social, Genetic and Developmental Psychiatry Center at the Institute of Psychiatry, Psychology and Neuroscience, King's College London.

"That finding is important to help us understand depression better," she said.

Previous studies have shown that patients with depression have high levels of inflammation, but no study has been as large as the current one or has dealt with such a wide range of causative factors.

Pariante said the results may also have implications for long-COVID patients, many of whom suffer exhaustion or depression.

"The research on long COVID-19 is still at the beginning. There's much more discussion than actual data," he said in response to a question from Medscape Medical News. Some studies have indicated that patients who experience higher levels of inflammation during SARS-CoV-2 infection were more likely to suffer mental disorders 3 to 6 months after having COVID-19.

"So it is definitely this biological pathway through which high levels of inflammation change brain functioning, induce symptoms...that are relevant to fatigue, for example, or to lack of motivation or lack of willingness to engage in social activity. This could be relevant to some people with long-COVID," Pariante said.

As previously reported by Medscape Medical News, a study published online April 6 in The Lancet showed that one third of 236,379 COVID-19 survivors in a US database were diagnosed with at least 1 of 14 psychiatric or neurologic disorders within a 6-month span. The rates of illnesses ranging from depression to stroke were much higher among those who required hospital admission.

The authors cited several limitations of the study, including the fact that lifetime depression was diagnosed in participants 6 to 10 years after the collection of blood samples and that CRP analysis was based on a single blood sample.

Am J Psychiatry. Published online May 14, 2021. Abstract

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