Cardiovascular Effects of Agomelatine and Escitalopram in Patients With Major Depressive Disorder

There is strong evidence that patients with major depressive disorder (MDD) are at increased risk of developing coronary heart disease (CHD). This elevated risk is independent of classical risk factors such as smoking, obesity, hypercholesterolemia, diabetes and hypertension. The risk of CHD is increased 1½-2 fold in those with minor depression and 3-4½ fold in subjects with MDD. Put simply, the relative risk of developing CHD is proportional to the severity of the depression. While the mechanism of increased cardiac risk attributable to MDD is not known disturbances in autonomic function most likely do play a part.

In untreated patients with MDD (with no underlying CHD) the investigators have identified that a marked sympathetic nervous activation and diminution in heart rate variability (HRV) occurs in a proportion (approximately one third) of patients. Diminished heart rate variability has been linked to increased incidence rates of acute cardiac events in conditions such as hypertension, diabetes and myocardial infarction. Importantly, whether treating depression actually improves the risk of: (1) CHD development or (2) recurrence of cardiac events in patients with existing CHD remains unknown.

The investigators, and others, have provided a growing body of evidence linking elevated sympathetic activity and exaggerated sympathetic responses to stress to early stages of end organ dysfunction and markers of disease development. Of particular note, in addition to possible effects on HRV is the association of chronic sympathetic nervous activation to: (a) abnormal blood pressure regulation and (b) the development of insulin resistance.

The investigators therefore plan to examine the cardiovascular effects of two different anti-depressant medications, agomelatine and escitalopram, in patients with major depressive disorder using a randomized, parallel group design. In addition, the investigators plan to investigate the effects these two medications have on sympathetic nervous system activity, blood pressure, HRV, endothelial function, metabolic and psychological effects.

This study will involve a detailed screening, clinical and psychometric assessment at baseline to confirm clinical phenotype. There are two major study points, one at study entry (week 0) and the other at the study conclusion (week 12) following 12 weeks of treatment with either agomelatine or escitalopram. The major components of the two study points is a detailed assessment of the sympathetic nervous system with a mental stress test, non-invasive measures of endothelial function, an oral glucose tolerance test, psychometric testing and assessment of blood pressure and HRV. Blood and urine tests for biochemistry and hematology will be taken and a pregnancy test performed.

Findings from this study will assist us to identify of biological correlates of sympathetic nervous activation which will enable us to: (1) identify those at potentially increased cardiac risk, and (2) potentially implement additional therapeutic strategies in addition to antidepressants in order to reduce cardiac risk. Indeed, it is not known whether antidepressant treatment alone would be sufficient to reverse any adverse effects of sympathetic nervous activation. This study aims to answer this important clinical question.