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Heart and Mind

January 2005

By William Davis, MD, FACC

Heart disease and depression often go hand in hand. Shared biochemical similarities between the two conditions suggest that common treatment strategies may address both illnesses. Here we provide a primer on nutritional supplements that may help navigate the complex interplay of these two major health issues.

Heart disease and clinical depression present with different symptoms and are conventionally managed with different treatments. While heart disease can be acutely life threatening, depression tends to be slow and insidious. How can the seemingly unrelated conditions of heart disease and depression possibly be related?

Emerging research indicates that the deeper we probe, the more alike the two disorders appear to be. While the ultimate manifestations of heart disease and depression differ, the underlying biochemical pathologies are surprisingly similar. Beneath the emotional surface of mood and depression can be a raging physical undercurrent of hormonal distortions, impaired immunity, and inflammation. These disturbances of physiology contribute to the growth and abnormal activity of coronary plaque, eventually leading to heart attack. Depressed people, in fact, suffer a fourfold greater risk of heart attack compared to non-depressed people.1,2

If the two seemingly disparate disorders of depression and coronary heart disease share common causes, can there also be common treatments? Exciting new insights suggest that strategies to address both conditions do exist. These therapies work by treating the shared metabolic origins of heart disease and depression. The good news is that some of these treatments are powerful nutritional therapeutics, readily available to all.

Depression: More than a Feeling

Everyone has had the experience of feeling sad or blue. How do these everyday feelings differ from clinical depression? Symptoms of depression include loss of interest in activities previously enjoyed, struggling to sleep or awakening early, difficulty concentrating, feelings of worthlessness or guilt, loss of appetite or weight, and suicidal thoughts. Symptoms that interfere with daily activities and that last longer than two weeks may signal clinical depression.

Far more than just a state of mind involving sadness or hopelessness, depression is a disease in the true organic sense, with measurable symptoms. In the last decade, clinical investigations have uncovered the myriad physical manifestations of depression. Until recently, these manifestations have been little understood, but growing evidence asserts that they have very real consequences.

Feeling good can hinge on a precarious balance of internal dialogue and external events. This balance can easily tip, setting the stage for negative emotions and the resulting metabolic consequences. At what point do negative emotions begin to add to risk for heart disease?

The line that separates depression from the more commonplace feelings of sadness and anger that are part of all our lives can be somewhat hazy. It is a matter of the degree and duration of symptoms. Full-blown depression is not necessary to increase heart disease risk, as even moderate feelings of hopelessness and sadness can more than double the risk of heart attack.2 People who chronically experience negative emotions—such as unexpressed anger, hostility, and resentment—also have a higher risk for heart attack. They experience a level of risk similar to that of the fully depressed.3

Metabolic Underpinnings of Depression

Beneath the surface of sadness and hopelessness blazes an inferno of metabolic phenomena. Increased levels of inflammatory proteins, such as interleukin one-beta (IL-1b) and tumor necrosis factor-alpha (TNF-a), circulate in the blood, suggesting that low-grade, body-wide inflammation accompanies depression. IL-1b and TNF-a levels correlate with the severity of depression, with higher levels of inflammatory proteins linked to more serious depression.4 C-reactive protein is another inflammatory protein found at higher levels in depressed persons. All these inflammatory mediators have been clearly linked to increased risk of heart attack.5,6 Extensive clinical trial data show that when the fires of inflammation are burning, coronary plaque is unstable and more prone to “rupture,” an event that can lead to heart attacks.7 (See also “Quenching the Flames of Inflammation” and “The Fires Within,” Life Extension, July 2004.)

Just as a life-threatening event such as a car accident triggers biochemical reactions in the body, depression activates the release of stress hormones. The feelings of anger, frustration, hostility, and anxiety are also associated with increased levels of stress hormones. Hypersecretion of corticotrophin-releasing hormone from the hypothalamus triggers the release of cortisol and norepinephrine, both of which are involved in the survival response that occurs when the human organism is threatened. These hormones are potent contributors to hypertension, insulin resistance, and diabetes, three well-established risks for coronary disease.8,9 When negative emotions become chronic and deeply rooted, the risk for developing pathological heart disease grows.

Cortisol and norepinephrine also contribute to development of metabolic syndrome, a combination of abdominal obesity, hypertension, low high-density lipoprotein (HDL), and higher blood sugar (above 110 mg/dL). The epidemic numbers of overweight and obese people in America are fueling a skyrocketing increase in metabolic syndrome, estimated to currently affect 47 million US adults. Metabolic syndrome is a rapidly growing cause of heart disease, and depressed people are particularly prone to develop the features of metabolic syndrome.10-12

During periods of depression, the “fight-or-flight” response of the sympathetic nervous system operates in a continuous state of heightened activation, releasing stress hormones into the bloodstream. The calming parasympathetic system is simultaneously suppressed. This reaction can be measured as blunted, beat-to-beat variation in heart rate, or heart-rate variability, even when the heart rate is normal. Decreased heart-rate variability predicts heightened potential for dangerous heart (ventricular) arrhythmias and sudden death.13


The common ground between coronary artery disease and depression is substantial. Consider that both states share:


Heart Disease


Inflammatory cytokines
(TNF-a, IL-1, IL-2)

increased levels

increased levels

Omega-3 fatty acids

decreased levels

decreased levels


increased levels

increased levels

Folic acid

decreased levels

decreased levels

Metabolic syndrome
(abdominal fat, hypertension,
low HDL, increased blood sugar)

increased levels

increased levels

Stress hormones
(cortisol, norepinephrine)

increased levels

increased levels

For years, epidemiologists have explored the unexpectedly low risk of both heart disease and depression in cultures in which fish is eaten in abundant quantities. The common thread seems to be the high content of omega-3 fatty acids in fish oils.14 Through his studies across numerous cultures, Dr. Joseph Hibbeln of the National Institutes of Health has documented the remarkable association between higher levels of fish consumption and lower rates of depression. He was also among the first to draw the connection between greater fish consumption and the lower likelihood of heart attack.

Indeed, both depression and heart disease are associated with low concentrations of omega-3 fatty acids in red blood cells. Conventional prescription antidepressant medication fails to correct an imbalance of omega-3 fatty acids.15 It is tempting to suggest that supplementation with fish oil rich in omega-3 fatty acids might provide a common therapy for both depression and heart disease. Research discussed later in this article suggests that it does.

Homocysteine represents another intriguing connection between depression and heart disease. Homocysteine, an amino acid associated with the deficiency of certain B vitamins, has been clearly and conclusively associated with increased risk of heart attack.16,17 Less well known is homocysteine’s role in emotions. Depression, poor response to antidepressant medication, and dysthymia (a lesser form of depression) have all been linked to low blood levels of folic acid. Folic acid deficiency causes high homocysteine blood levels. Folate-deficient people are also more likely to be deeply depressed and for longer periods.18 Up to 50% of depressed people have homocysteine levels that are significantly above normal, considered to be greater than 10 micromoles per liter (µmol/L) of blood.19,20 This variety of depression responds poorly to antidepressant medication, but does respond to folic acid. Studies examining depressed people in a number of settings have firmly established that folic acid replacement, resulting in reduced homocysteine blood levels, is an effective treatment for depression and a useful addition to prescription antidepressant therapies.21-23

Depression and feelings of anger, hostility, and anxiety share several biochemical traits that are similar to those that form the foundations of risk for heart disease. These include a tendency toward inflammation, increased levels of stress hormones, the presence of metabolic syndrome, blunted heart-rate variability, reduced levels of omega-3 fatty acids, and elevated homocysteine levels. Nutritional supplements may be powerful tools in managing the overlapping syndromes of depression and heart disease.