Feeling sad can alter levels of stress-related opioids in the brain and increase levels of inflammatory proteins in the blood that are linked to increased risk of comorbid diseases including heart disease, stroke and metabolic syndrome, according to a study by researchers at The University of Texas Health Science Center at Houston (UTHealth).

The results were published in a recent issue of Molecular Psychiatry.

Previous studies have shown that major depression can be a contributing factor to other medical diseases, but researchers didn't know why. A team led by Alan Prossin, M.B.B.S., assistant professor in the Department of Psychiatry and Behavioral Sciences at the John P. and Kathrine G. McGovern Medical School, sought to find the answer.

When a person is under stress, brain neurotransmitters called opioids are released to reduce the impact of stress, said Prossin, the study's principal investigator. But when this stress response system is dysregulated, opioid neurotransmitters may have a negative impact on the body, altering the immune system response to stress, potentially increasing risk of other medical diseases.

Previous research by Prossin and colleagues had found that an inflammatory cytokine called interleukin-18 (IL-18), which has been associated with cardiovascular disease, is increased in depressed people.

Research subjects, both people suffering from a major depressive disorder and healthy controls, underwent positron emission tomography (PET) scans during the study, starting with a baseline scan.

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At baseline, depressed patients showed more opioid activity (and greater IL-18 concentration in the blood) than the healthy controls.

When asked to think about something neutral, opioid activity decreased in the brains of both groups and the opioid decrease was proportional to a decrease in IL-18 in the same people.

When asked to focus on the sadness they experienced during a sad event in their life, increased amounts of opioids were released in the brain and this opioid increase was proportional to increased IL-18 concentration in the blood.

"These effects were observed during sadness in both groups, but were much greater in people with major depression as compared to non-depressed, otherwise healthy people," Prossin said.

In the depressed group, following sadness, the level of IL-18 had increased, but not to the baseline concentration. In other words, thinking neutral thoughts had a lowering effect on IL-18 that persisted even after the same people were asked to think about sad things.

"Inducing a neutral affective state improved mood and lowered IL-18," Prossin said. "So if we could implement psychotherapies to improve mood in depressed people, then we could potentially normalize IL-18 and in the longer term, potentially reduce risk of various comorbid medical illnesses."

The researchers went on to compare the levels of IL-18 to more classic stress hormones such as cortisol and adrenocorticotropic. They found no correlation.

"This is potentially a new pathway associated with stress-related affective changes that could explain why treatments based on classic stress hormones may not be as effective in depressed people with stress-related mood changes," Prossin said.

Tatiana Barichello, Ph.D., assistant professor of psychiatry and behavioral health at UTHealth, is a co-author of the paper, "Acute experimental changes in mood state regulate immune function in relation to central opioid neurotransmission: a model of hman CNS-peripheral inflammation interaction."