NEW YORK—Interleukin-6 (IL-6) may be the key to unlocking the mystery of how depression increases the incidence and mortality of cardiovascular disease.
The association between depression, myocardial infarction (MI) and mortality is well documented. Upward of 30 different studies show clear and significant relationships. A widely publicized paper by Nancy Frazier Smith and colleagues at McGill University showed that high scores on the Beck Depression Inventory during the first week post-MI correlated strongly with reduced 5-year survival.
But until recently, little was known about the precise biochemical mechanisms by which depression precipitates cardiovascular events.
Gregory Miller, PhD, a psychologist at the University of British Columbia, Vancouver, has been searching for the biochemical link. His researches have led to the doorstep of IL-6, a powerful inflammatory signaling molecule. Speaking at a symposium sponsored by the National Association for Research on Schizophrenia and Depression, Dr. Miller outlined the ways in which depression contributes to the inflammatory process leading to coronary artery plaque rupture and, ultimately, MI.
“How does a so-called ‘brain’ disorder, a nebulous psychological state like depression, get into the body to increase the risk of something so physical as a heart attack?” questioned Dr. Miller. While there are likely several answers, he has been looking at the immune system, and inflammatory molecules involved in cardiovascular disease. “Coronary plaques form as a result of inflammation. We wondered whether depression somehow fosters this process.”
IL-6 and C-Reactive Protein
He began collecting blood from physically healthy but clinically depressed subjects in their 20s and 30s, as well as from healthy, non-depressed, age-matched controls. Both groups had equivalent psychiatric and medical histories, with no substance abuse or medication use in either cohort.
The investigators assayed a host of cytokines and immunomodulators, looking for differences between the two groups, and found something very suggestive: the level of IL-6, was 50% higher in the depressed versus non-depressed individuals. Similarly, the mean level of c-reactive protein (CRP), an accurate predictor of MI risk, was 40% higher in the depressed individuals.
The latter finding is disturbing because the depressed subjects had a mean CRP level of 3.5 mg/L, which puts them at high risk for CVD, according to current American Heart Association guidelines. Any CRP measurement over 3 mg/L is considered an indicator of high-risk. The finding is troubling, given that all subjects in the study were under age 40.
Dr. Miller stressed that he and his colleagues controlled for smoking, medication use, other diseases, and any other variable that might elevate CRP. “The only difference between the two groups was depression.”
He is now looking at depression and CRP levels in 70 post-infarction patients. Data gathered thus far indicate that post-infarction CRP levels track closely with Hamilton depression scores. Non-depressed people have a mean CRP of 2.5 mg/L; the most severely depressed have mean CRPs of 4 mg/L or greater.
Depression Promotes Inflammation Promotes Depression
Dr. Miller believes depression promotes inflammation, which in turn, increases CVD risk. But it may be a two-way process: increased inflammatory activity could promote depression. When rodents are injected with IL-6, they show a profound decline in sexual interest, a reduced interest in sugar-water, and reduced swim-test scores. These behavior patterns are rodent analogs of human depressive behavior.
His findings underscore a core principle of holistic medicine: that the dividing line between psyche and soma is highly permeable, if such a boundary truly exists at all. Psycho-emotional states manifest in the body, and likewise, physical changes have neurobehavioral correlates. Dr. Miller’s work also raises important questions, among them the question of whether more effective management of depression could lead to a reduction in cardiovascular disease. His ongoing work will, hopefully, shed further light.
