Neurobiological Pathways between Depression and Cardio-Vascular Disease are Clarified

Depression has long had a popular link to cardiovascular disease and death. However, only during the last 15 years scientific evidence supporting this common wisdom has been available (Glassman et al., 2007a). Since the early 1990s studies have reported prevalences of major depression between 17% and 27% in hospitalized patients with coronary artery disease (CAD) (Rudisch & Nemeroff, 2003).

It is becoming clear that the comorbidity of depression and cardiovascular disease does not occur by chance but the mechanisms responsible for this relationship is poorly understood. Platelet abnormalities, autonomic tone, and health behaviors have all been implicated. There exists also the possibility that depression and vascular disease share certain vulnerability genes (McCaffery et al., 2006).

Moreover, it is now apparent that depression aggravates the course of multiple cardiovascular conditions (Glassman et al., 2007) and has regularly been shown to lower adherence to prescribed medication and secondary prevention measures (Glassman et al., 2007b).

Few randomized controlled trials have evaluated the efficacy of treatments for major depression in patients with coronary artery disease.

Depression and cardiovascular disease

• Depression observed following acute coronary syndrome (ACS) is common and associated with an increased risk of mortality. Medically healthy individuals who suffer from depression are at significantly increased risk of developing heart attacks and strokes later in life (Glassman et al., 2007).

• Acute coronary syndrome is both psychologically and physiologically stressful, and it is common to attribute depression observed following ACS to that stress (Glassman et al., 2006)

Furthermore, the Heart rate variability (HRV), a well-recognized measure reflecting fluctuations in autonomic activity, is an independent predictor of death. Earlier studies show that, after myocardial infarction, HRV values increase approximately 50% between 3- and 12-weeks. In post-ACS patients with depression, improvement in HRV could therefore result from the pharmacological action of an antidepressant drug, from an improving mood independent of the drug, or as a result of recovery from the acute cardiac injury.

Depression treatment among patients with coronary artery disease

Few adequately controlled trials evaluated whether antidepressant treatments are either safe or effective in patients with coronary artery disease (CAD). The largest of these, the Sertraline Antidepressant Heart Attack Trial (SADHART) (Glassman et al., 2002) was designed to evaluate the safety and efficacy of sertraline hydrochloride for treatment of MDD in ACS. No adverse cardiovascular effects of sertraline treatment were detected, sertraline was both safe and effective in post-MI depression and observed a reduction in death and recurrent myocardial infarction. Planned subgroup analyses showed a clear benefit of sertraline over placebo for patients with recurrent depression and those with more severe depression.

In addition, the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy, a randomized, controlled, 12-week, parallel-group trial (CREATE) (Lesperance et al., 2007), was the first trial specifically designed to evaluate the short-term efficacy and tolerability of 2 depression treatments in patients with CAD: citalopram, a first-line SSRI antidepressant and interpersonal psychotherapy (IPT), a short-term, manual-based psychotherapy focusing on the social context of depression. The trial documents the efficacy of citalopram administered in conjunction with weekly clinical management for major depression among patients with coronary artery disease and found no evidence of added value of IPT over clinical management. Similar to the results of SADHART CREATE found the benefits of SSRIs for patients with CAD to be clearer for recurrent episodes of major depression than for first episodes.

Clinical implications

•Depression is a painful state, and it should be treated aggressively when indicators of benefit are present; major depression following myocardial infarction is consistently associated with about a 3-fold increase in cardiac mortality and evidence continues to accumulate (Glassman et al., 2007b).

•Major depression severely impairs heart rate variability recovery following an acute coronary event. It is now clear, that depression is also associated with biological changes involving increased heart rate, inflammatory response, plasma norepinephrine, platelet reactivity, absent post-ACS HRV recovery – all of which is associated with life-threatening consequences. It also impairs compliance with doctors advice and health behaviors.

•Based on study results and those of previous trials, the selective serotonin-reuptake-inhibitors (SSRI) citalopram or sertraline plus clinical management should be considered as a first-step treatment for patients with CAD and major depression albeit there is still a clear need for additional studies evaluating interventions to prevent the cardiac prognostic impact of depression.

•From a clinician’s point of view, patients with depression after myocardial infarction, especially those with prior episodes, should be both carefully watched and aggressively treated, because they are at an elevated cardiac risk and less likely to get better spontaneousely.

References
Glassman AH. Depression and cardiovascular comorbidity. Dialogues Clin Neurosci 2007a;9(1):9-17

Glassman AH, Bigger JT, Gaffney M. Heart Rate Variability in Acute Coronary Syndrome Patients with Major Depression, influence of Sertraline and Mood Improvement. Arch Gen Psychiatry 2007b;64:9

Glassman AH, Bigger JT, Gaffney M, et al. Onset of major depression associated with acute coronary syndromes: relationship of onset, major depressive disorder history, and episode severity to sertraline benefit. Arch Gen Psychiatry 2006;63(3):283-8

Glassman AH, O'Connor CM, Califf RM, et al.; Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288(6):701-9

Lesperance F, Frasure-Smith N, Koszycki D, et al.; CREATE Investigators. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007;297(4):367-79

McCaffery JM, Frasure-Smith N, Dube MP, et al. Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of candidate genes related to inflammation and serotonin. Psychosom Med 2006;68(2):187-200

Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 2003;54:227-240.