Depression, Heart Disease: Links Remain Elusive

More than metaphor links hearts and minds, but is the relationship between depression and heart disease one of cause or coincidence?

Epidemiology shows a clear association. Between one-fifth and one-third of people with heart disease also have depression, and depression predicts development of cardiovascular disease in healthy people and increased mortality in patients who have had heart attacks. Even those with depressive symptoms but not clinically diagnosed major depression did worse than those without such symptoms.

However, behavioral scientists and cardiologists are still searching for definitive studies to prove causation and show that treating depression can reduce cardiovascular mortality.

In short, even after years of research, the connection remains suggestive but shadowy, said Nancy Frasure-Smith, Ph.D., of McGill University and the University of Montreal, in a lecture at APA's 2005 annual meeting in Atlanta. That ambiguity suggests that concern for depression rates low among cardiologists.

“Depression is off the radar of cardiac care,” said Frasure-Smith.

Cardiology has indeed been slow to acknowledge depression's role in cardiovascular disease, agreed Christopher O'Connor, M.D., a professor of medicine and director of the heart-failure program at Duke University Medical Center, in an interview. Depression shows up rarely in the cardiological literature, and cardiologists rarely screen for it, he said.

“Cardiologists think that when patients come in with cardiac events, some depression is normal and that the patient will eventually get better,” O'Connor told Psychiatric News. “This is partly true, but depressive symptoms in the hospital are a risk factor even if the patient returns to baseline two weeks later.”

Connecting depression and heart disease evolved in stages. Work by several researchers in the 1970s showed a link between life stress and sudden death. Frasure-Smith later analyzed results of an intervention trial testing a distress-reducing intervention. There was no difference in outcomes between the two arms, but she found that distress levels in the usual-care group predicted cardiac mortality.

“The symptoms of distress that were most linked to prognosis were complaints of poor concentration, feelings of unhappiness, not enjoying activities, and other symptoms that seemed to be related to depression,” she said. “This led my colleague François Lespérance and me to look specifically at the importance of depression, but we were not the first to consider the importance of depression.”

She credits others, including Robert Carney, Ph.D., and Kenneth Freedland, Ph.D., of the Department of Psychiatry at Washington University in St. Louis with first concluding in the late 1980s that “major depressive disorder is an important independent risk factor for the occurrence of major cardiac events in patients with coronary artery disease.”

Is Depression Cause or Effect?

Depression's relationship to heart disease meets many of the criteria for causality laid out by Austin Bradford Hill, Ph.D., D.Sc., said Frasure-Smith, but it has been hard to discern cause and effect in either direction. A systematic review she conducted with Lespérance found 64 prospective studies that used recognized measures of depression and included objective recorded outcomes. They noted problems with sample sizes and characteristics and with definitions of depression and outcome measures.

“Despite these issues,” they wrote in the May-June supplement to the journal Psychosomatic Medicine, “the bulk of the data from protective studies with recognized indices of depression and objective outcome measures is supportive of depression as a cardiac risk factor.”

In their own studies of heart attack and stable angina patients, she and Lespérance found that depressed patients are more seriously ill than other heart patients and that depression predicts mortality independently of ejection fraction, hypertension, and heart failure severity.

Large, long-term studies are needed to determine whether depression causes or worsens heart disease, said Frasure-Smith at APA's annual meeting. Any valid explanation would also have to demonstrate biologically plausible mechanisms by which depression caused heart disease and demonstrate that treating depression reduced morbidity and mortality.

Hypotheses Remain Unproven

Many hypotheses have been put forth for how depression might harm the cardiovascular system, although none is proven, said Frasure-Smith. Some have suggested behavioral influences: depressed people are less likely to get treatment or take their medications, for example.

Others have hypothesized a physiological connection by way of the autonomic nervous system, which controls heart rate. Depressed people often have higher heart rates, and a higher resting heart rate increases risk of sudden cardiac death. Also, depressed patients have lower heart-rate variability, which also carries an increased risk of death. Indicators of platelet activity and inflammation are higher among depressed individuals. Researchers have noted improved mood in patients taking lipophilic statin drugs, which reduce some inflammatory marker levels.

Studies have found that people who eat more fish containing omega-3 fatty acids have lower incidence of major depression. Omega-3 fatty acids are also antiarrhythmic and antithrombogenic and increase heart-rate variability.

Cardiologists are more attuned to physiological than behavioral explanations, said John Rumsfeld, M.D., Ph.D., an associate professor of cardiology at the University of Colorado Health Sciences Center and the Denver Veterans Affairs Medical Center.

“To date, cardiologists have embraced hypertension, diabetes, and cholesterol levels as established risk factors and now treat them as part of the standard of care,” said Rumsfeld in an interview. “But depression has remained wholly separate from the cardiovascular world. There's no formal recommendation for when and how to screen for depression.”

Rumsfeld said he is starting to screen patients using the Patient Health Questionnaire-9 (PHQ-9) in his office waiting room. He argued that treating depression can be justified to improve the patient's quality of life and to improve adherence to cardiac-care recommendations, even in the absence of evidence of benefits to cardiovascular physiology.

Only two treatment trials have attempted to solve the final part of the puzzle— whether treating depressed heart patients for depression affects cardiovascular outcomes.

“We don't know yet whether treating depression will reduce the cardiac-event rate, which is why cardiologists haven't jumped on board,” said O'Connor. They may also have had bad experiences in the 1980s when they prescribed tricyclic antidepressants, which are now known to be cardiotoxic.

SADHART (Sertraline AntiDepressant Heart Attack Trial) tested the SSRI sertraline against placebo but found no significant differences in outcome over the 24 weeks of the trial. The study was designed as a safety test and was too small and too short to draw useful conclusions, said Frasure-Smith.

However, every site in SADHART had both a cardiologist and a psychiatrist on the study team—a first, said O'Connor, who worked on the trial.

The ENRICHD (Enhancing Recovery in Coronary Heart Disease) study found that patients who got cognitive-behavioral therapy and were followed for a mean of 29 months recorded a two-point difference on the Hamilton Depression Rating Scale. That difference was statistically significant but there was no impact on survival, said Frasure-Smith.

A recent secondary analysis of the ENRICHD data concluded that treating depression reduced risk of death or recurrent heart attack in patients who had already had a heart attack. After adjustment for baseline depression and cardiac risk, use of SSRI antidepressants was associated with a 43 percent reduced risk of all-cause mortality and death or recurrent heart attack, according to a report by C. Barr Taylor, M.D., of Stanford Medical Center and colleagues in the July Archives of General Psychiatry. They cautioned, however, that their analysis was post hoc and observational, based on patient self-report of SSRI dosage and use, and may have been confounded by use of cognitive-behavioral therapy in half the patients.

“The results of this substudy are suggestive, but far from being confirmatory,” said Frasure-Smith in an interview. “Without randomization, there is no way of assuring that the people with and without SSRIs were identical in important background factors that may have influenced outcome. Another randomized study would be needed to assess whether SSRIs really causally influence cardiac events.”

More than one large, well-designed trial will be needed to prove to both psychiatrists and cardiologists that treating depression can save heart patients' lives, she said.

“If any one treatment improved prognosis in coronary heart disease, we would know it was due to the therapy but not necessarily that was due to reducing depression,” she said. “But if trials of several different therapies improved outcomes then we'd be closer to knowing that changing depression changes risk.”

Planning is under way for a new version of SADHART that would recruit 3,000 to 4,000 patients with major and minor depression and test the effects of cognitive-behavioral therapy and sertraline on cardiovascular outcomes, said O'Connor. The Veterans Affairs medical system will soon begin a push to recognize and treat depression in its disease-management program for heart failure, said Rumsfeld.

All of that is good news to Frasure-Smith, who would like to see better coordination between psychiatrists and cardiologists as they plan and run clinical trials.

“There is little evidence from clinical trials that we can change depression in coronary artery disease patients, but there is enough evidence to support additional trials,” she said. “Trials to assess mood should judge other cardiovascular factors, and trials of cardiovascular treatments should assess mood.”

More information is available online in “From Feeling Blue to Clinical Depression: Exploring the Pathogenicity of Depressive Symptoms and Their Management in Cardiac Practice” at<www.psychosomaticmedicine.org/cgi/content/full/67/Supplement_1/S2> and “Reflections on Depression as a Cardiac Risk Factor” at<www.psychosomaticmedicine.org/cgi/content/full/67/Supplement_1/S19>.▪

Psychosom Med 2005 67 S2

Psychosom Med 2005 67 S19