Sadness-Induced Inflammation May Up Comorbid Disease Risk

Fran Lowry

December 22, 2015

Experimentally induced feelings of sadness increased serum blood levels of the inflammatory protein interleukin-18 (IL-18) and also changed levels of stress-related opioids in the brain, but these effects were reduced when a neutral mood was induced.

The findings indicate that neuroimmune reactions involving IL-18 may have a mediating role and enhance susceptibility to certain medical comorbidities, such as diabetes, heart disease, and persistent pain states, especially in depressed individuals, investigators say.

The research was recently published in Molecular Psychiatry.

Heart Disease, Cancer

"Interleukin-18 is highly implicated in a whole host of medical conditions, including coronary artery disease, conditions that lead to stroke, and various other diseases, potentially even things like progression of breast cancer, so it's a very important homeostatic protein," lead author Alan Prossin, MD, from the University of Texas Health Science Center, Houston, told Medscape Medical News.

"The other important feature is that the effect was greater in depressed individuals, potentially showing that these people are more susceptible to changes in IL-18 and thereby are likely more susceptible to illnesses associated with this protein," Dr Prossin said.

In previous work, Dr Prossin and his colleagues found that IL-18 levels were increased in people with depression.

In the current study, the researchers induced sad and neutral mood states lasting 45 minutes each in 28 female volunteers (15 healthy control participants and 13 nonmedicated patients with major depressive disorder [MDD]) while the volunteers were undergoing PET neuroimaging.

Sad moods were induced by asking the volunteers to focus on the emotions they experienced during a prior event that was associated with profound sadness, such as the death of a loved one, the loss of a pet, or the end of a relationship.

Neutral moods were induced by asking the volunteers to focus only on the sensations they experienced in the PET scanner.

The researchers then obtained plasma samples of IL-18 at baseline, 45 minutes, and 90 minutes.

They also measured the relationship between plasma IL-18 levels and concurrent changes in opioid neurotransmitter release.

At their baseline scan, patients with MDD showed more opioid activity and serum concentrations of IL-18 were greater in comparison with the healthy control participants.

Greater Increase in IL-18 in Depression

The researchers found that sadness increased IL-18 significantly from baseline (P = 0.01) in both volunteer groups.

However, the sadness effect was more pronounced in patients with MDD than in the healthy volunteers (P = 0.03).

Focusing on sadness also increased the amounts of opioids that were released in the brain, and this opioid increase was proportional to increased concentrations of IL-18 in the blood.

Of note, neutral mood induction resulted in significantly reduced IL-18 serum levels in the MDD volunteers but had no effect on the healthy control participants (P < 0.001).

"Neutral mood did not affect IL-18 concentrations in healthy controls since their levels were normal to begin with. But the depressed individuals had higher levels of IL-18 to begin with, and these levels went down when we induced neutral mood," Dr Prossin said.

"We're using a cognitive type of technique to reduce a peripheral protein that is associated with medical illness. If these findings are validated elsewhere in bigger samples at many different centers, we could perhaps use behavioral techniques to alter peripheral proteins and thereby reduce risk for medical illnesses like cardiovascular disease," he said.

Complexity of the Brain

Commenting on the study for Medscape Medical News, Maurizio Fava, MD, executive vice chair, Department of Psychiatry, and executive director, Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, described the article as "a very interesting paper, as it shows that there is a connection between the inflammatory response and the opioid system.

"As you are inducing a negative mood, you are raising these inflammatory cytokines, and that stimulates a compensatory activation of the mu receptors in the opiate system," Dr Fava said.

The research is an example of the newer focus in the field of depression on systems other than the monoamines, he continued.

"This study is saying that other systems, such as the inflammatory cytokine system, are important in depression, and we know that we are starting to get some indications that treatments that are anti-inflammatory may act as antidepressants in some patients. We're also starting to see that opioid modulation is an important approach to the treatment of depression. This kind of study confirms that concept. It highlights the complexity of our brain function and of how different systems interact with each other."

Dr Prossin and Dr Fava report no relevant financial relationships.

Mol Psychiatry. Published online August 18, 2015. Full text

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