Inflammation Is Not Always Linked to Depression

Summary: In older adults, depression occurs independently of inflammation, a new study reports. However, the depression-inflammation link is a result of greater incidences of inflammatory disorders, like arthritis, which become more common as we age.

Source: University of Pennsylvania

Multiple prior studies have found higher levels of inflammation in older individuals with depression.

Now, a new Penn Medicine study has found that clinically depressed older individuals, on average, don’t have elevated levels of inflammation if they don’t already have other inflammatory conditions such as arthritis.

The new study, published recently in Nature Translational Psychiatry, suggests that depression occurs independently of inflammation for many older adults. Furthermore, depression-inflammation links are due to the greater incidence of inflammatory conditions, which in general are common in older people.

“It is still true that inflammatory illnesses can contribute to depression, but our findings suggest that there is a subset of individuals with late-life depression who do not have elevated levels of inflammation,” said study senior author Yvette Sheline, MD, McLure Professor of Psychiatry and Behavioral Research in the Perelman School of Medicine at the University of Pennsylvania.

National surveys in the United States suggest that, although depression is diagnosed more often among younger adults, about five percent of people who are at least 50 years old have had a major depressive episode in the past year.

Researchers suspect that many of these cases of late-life depression are caused by inflammation—in part because studies have found higher levels of inflammatory immune proteins in the blood of older people with depression, compared to non-depressed people of the same age.

Prior research also has shown that levels of inflammation markers generally tend to rise with increased age, as chronic illnesses set in and the body’s immune-regulating systems weaken. Based on such findings, doctors have tested anti-inflammatory drugs in patients with depression, and have found that they can improve outcomes when added to standard anti-depressant therapy.

The new study reveals, however, that the link between depression and inflammation is not as clear-cut as the prior literature suggests. Sheline and colleagues used online and in-person screening of over 1,100 depressed individuals to recruit a group of 63 individuals, age 50 to 80, who met criteria for major depressive disorder but did not have other inflammatory conditions.

Comparing this group to 29 healthy individuals of the same age, even with highly sensitive measurements, the researchers found no significant differences in bloodstream levels of 29 different inflammation-linked immune proteins.

The researchers then randomized 60 of the depressed patients to receive either a standard antidepressant drug, or the antidepressant plus an anti-inflammatory drug, or placebo, for eight weeks.

They found that while the two antidepressant-treated groups showed significant improvement in their depression ratings relative to placebo, there was no significant difference in outcome between the antidepressant and the antidepressant-plus-anti-inflammatory group.

Moreover, in all three groups, the subjects’ blood levels of inflammatory markers were low before treatment and did not drop significantly as a result of treatment. The researchers even tested the cerebrospinal fluid of the subjects for levels of the inflammatory protein IL-1β, and again found low levels both before and after treatment.

The study therefore suggests that, in many older adults, depression occurs independently of inflammation, and probably won’t be alleviated by anti-inflammatory treatments unless inflammation is present in addition to depression.

The researchers note, however, that because their study excluded late-life depression patients who have inflammatory disorders, it leaves open the possibility that inflammation from such disorders can contribute to depression.

“Our study supports the view that depression consists of different sub-categories, some with inflammation and some without,” said Sheline, who is also director of Penn’s Center for Neuromodulation in Depression and Stress.

“People who have depression should consult with their doctor to see if they have other illnesses that could cause inflammation, since there is evidence that increased inflammation can cause depressive symptoms.”

Additional co-authors include Eline Luning Prak, Thomas Brooks, Walid Makhoul, Joanne Beer, Ling Zhao, Tommaso Girelli, and Carsten Skarke.

Funding: The study was funded by the National Institute of Mental Health (R01 MH098260-02). Inflammatory biomarker assays were performed in the Penn Human Immunology Core facility.

Abstract

No increase in inflammation in late-life major depression screened to exclude physical illness

Depression is a common and debilitating disorder in the elderly. Late-life depression (LLD) has been associated with inflammation and elevated levels of proinflammatory cytokines including interleukin (IL)-1β, tumor necrosis factor-alpha, and IL-6, but often depressed individuals have comorbid medical conditions that are associated with immune dysregulation.

To determine whether depression has an association with inflammation independent of medical illness, 1120 adults were screened to identify individuals who had clinically significant depression but not medical conditions associated with systemic inflammation.

In total, 66 patients with LLD screened to exclude medical conditions associated with inflammation were studied in detail along with 26 age-matched controls (HC). At baseline, circulating cytokines were low and similar in LLD and HC individuals.

Furthermore, cytokines did not change significantly after treatment with either an antidepressant (escitalopram 20 mg/day) or an antidepressant plus a COX-2 inhibitor or placebo, even though depression scores improved in the non-placebo treatment arms. An analysis of cerebrospinal fluid in a subset of individuals for IL-1β using an ultrasensitive digital enzyme-linked immunosorbent assay revealed low levels in both LLD and HC at baseline.

Our results indicate that depression by itself does not result in systemic or intrathecal elevations in cytokines and that celecoxib does not appear to have an adjunctive antidepressant role in older patients who do not have medical reasons for having inflammation.

The negative finding for increased inflammation and the lack of a treatment effect for celecoxib in this carefully screened depressed population taken together with multiple positive results for inflammation in previous studies that did not screen out physical illness support a precision medicine approach to the treatment of depression that takes the medical causes for inflammation into account.