New Findings Further Explain Strong Link Between Depression, Heart Disease, and Stroke

Pauline Anderson

February 18, 2009

February 18, 2009 — New findings confirming the presence of elevated levels of 2 inflammatory markers in physically healthy patients with depression and the identification of another marker not previously strongly associated with inflammation may further explain the robust link between depression and cardiovascular disease and stroke.

The study also found that although levels of these inflammatory markers were not significantly lowered in patients who took an antidepressant for 8 weeks, there were indications that they would normalize after a longer period of time.

These results, published online December 31, 2008 in the World Journal of Biological Psychiatry, suggest physicians should not be too quick to take patients off antidepressant medications, as these drugs could be protecting them from persistent low-grade inflammation, which has been linked to heart disease and stroke, study investigator Angelos Halaris, MD, from the Stritch School of Medicine at Loyola University Medical Center, in Maywood, Illinois, told Medscape Psychiatry.

The study consisted of 2 parts. In the first, researchers measured 5 inflammatory biomarkers — tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-1beta (IL-1β), cell determinant-40 ligand (CD-40L), and C-reactive protein (CRP) — in the blood of 22 patients with major depressive disorder (MDD) who did not have coronary artery disease (CAD), arthritis, diabetes, or hypertension.

The researchers then compared these levels with 17 age- and sex-matched subjects who were also physically healthy who did not have depression. They found that baseline levels of TNF-α, IL-1β, and MCP-1 were significantly higher in the MDD patients than controls, but there were no significant differences in levels of the other biomarkers.

Markers Take Longer than Mood to Normalize

Although TNF-α and IL-1β had previously been associated with depression, this is the first time elevated MCP-1 levels were clearly linked to this disorder, said Dr. Halaris. "This substance is involved rather early in the process of inflammation," he said. "I'm excited about this finding; this substance in particular, in conjunction with the other 2 markers [TNF-α and IL-1β], could be viewed as a harbinger of worse things to come if nothing is done preventively."

In the second part of the study, 17 patients with MDD took the selective serotonin- and norepinephrine-reuptake inhibitor venlafaxine (Effexor, Wyeth Pharmaceuticals) for 8 weeks. All subjects had a therapeutic response, with at least a 50% reduction in Hamilton Rating Scale for Depression (HAM-D) scores.

However, levels of TNF-α, IL-1β, and MCP-1 all remained elevated. "In spite of the fact that these patients recovered from their depression, these markers did not return to normal at the same time that their mood improved," said Dr. Halaris.

However, in those patients who continued on the therapy beyond 8 weeks, inflammatory-marker levels did go down.

"The surprise was that it didn't coincide timewise with the mood normalization," said Dr. Halaris. "I think that after 6 months, maybe a little longer, all markers would return to normal, assuming the patient continued to take the medication and didn't suffer a relapse for some other reason."

These findings suggest physicians should think twice before giving in to pressure from patients who are feeling better and want to come off antidepressants, said Dr. Halaris.

It's important to point out to patients, he said, that the inflammatory markers take longer than the depression itself to normalize. "The patient may feel better, but you can tell that patient that the inflammatory changes that were occurring along with their depression take about 3 times as long to return to normal."

Inflammatory markers are an indication of responses to infection, injury, or stress. Elevated levels of these markers are linked to plaque formation, cardiac irritation, and CAD. The authors point out that the markers examined in this study are known to be high in various cardiovascular disease states.

For example, previous research has found that plasma TNF-α levels are 2.4-fold higher in patients with stable heart failure than in healthy controls and that plasma IL-1β levels are 3.8-fold higher in patients with angina and 4.5-fold higher in patients with congestive heart failure than in normal controls.

Routine Cardiovascular Screening Recommended

The inflammatory process begins with chronic stress. In vulnerable individuals, chronic stress can topple the "fine balance" between the sympathetic and parasympathetic nervous systems, explained Dr. Halaris. "There's a persistent sympathetic overdrive, with the resulting diminution of parasympathetic tone."

When the parasympathetic tone is diminished in a "persistent static way," the body loses its ability to control inflammation, he added. "When inflammatory responses that are actually healthy and necessary to combat infection, tissue injuries, etc, become and remain elevated, homeostasis can no longer be achieved, and then we've got the situation of chronic persistent low- to moderate-grade inflammation in the body."

The sympathetic overdrive activates platelets responsible for clotting. Clots get lodged on the endothelium and in small clumps in the lining of the arteries. As the clots form plaques, over time, these plaques cause atherosclerosis. A chronic inflammatory state "eventually literally erodes the lining of the blood vessels and leads to plaque formation, and then eventually you get your heart attack or stroke," said Dr. Halaris.

It is not entirely clear why some individuals with depression go on to develop heart disease while others do not. However, what is clear is that having depression is a major cardiovascular risk factor. "Depression has been shown to be perhaps the highest risk factor of all known factors for cardiovascular disease, raising the risk 2- to 3-fold. It's a bigger risk factor than even smoking and hypertension," he said.

The study findings highlight the role of routine screening for heart disease in people with depression. In addition, he said, new screening tests are on the horizon. "We hope that in the not-too-distant future, blood tests that specifically assess the body's inflammation status, such as the so-called proinflammatory cytokines, will also become a reimbursable routine blood test."

Depression affects an estimated 18 million adults, or about 9% of the US population.

The authors report no conflicts of interest.

World J Biol Psychiatry. Published online December 31, 2008. Abstract

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