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Journal of Hypertension:
doi: 10.1097/HJH.0b013e328332d1d5
Editorial Commentaries

Depressive illness, the sympathetic nervous system and cardiac risk

Esler, Murray

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Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia

Correspondence to Professor Murray Esler, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne, VIC 8008, Australia Tel: +61 3 8532 1393; fax: +61 3 8532 1100; e-mail:

Cardiology was slow to recognize that depressive illness is a cause of coronary heart disease, the pivotal observation being made by a social scientist, Frasure-Smith [1], while working in a department of cardiology. This initial finding has been amply confirmed [2–5]. At one time the heart risk from depressive illness was attributed primarily to the loss of volition characteristic of the disorder leading to personal failure to adopt preventive health measures, but this is now discounted. Depressive illness is both a primary cause of coronary heart disease and, in addition, materially worsens the prognosis in the setting of existing heart disease, after myocardial infarction (MI) and in the presence of cardiac failure [1–5]. This elevated cardiac risk is independent of classical risk factors, and is similar in degree to that associated with smoking and hypercholesterolaemia.

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Sympathetic activity and cardiac risk in depressive illness

What might be the mediating mechanism of heart risk in patients with depressive illness? Perhaps it is the activation of the sympathetic nervous system, which characterizes the disorder [6], a phenomenon well demonstrated by Scalco et al. [7], in a study conducted in the University of Sao Paulo, and reported in this issue of the journal. The authors used clinical microneurography to measure multiunit sympathetic nerve firing rates in postganglionic fibres passing to the skeletal muscle vasculature in untreated patients with depressive illness and a control group of healthy men and women. Sympathetic nerve firing rates overall were directly related to the severity of the depressive illness, and higher in the more severely depressed patients than in both less depressed and healthy participants. Of particular relevance to the idea that sympathetic nervous activation in depressive illness may be the mechanism of cardiac risk is the earlier demonstration that, in addition to the skeletal muscle vascular sympathetic outflow, the sympathetic outflow to the heart is also activated in depression [8]. A causal relation of chronically activated cardiac sympathetic tone to adverse cardiac events does seem to generally apply, having been demonstrated in patients unexpectedly developing ventricular tachyarrhythmias [9], in patients with cardiac failure [10,11] and in end-stage renal disease [12].

The origins of sympathetic nervous activation in depressive illness remain unclear. Scalco et al. [7] link this to the severity of the depressive illness, as do Gold et al. [13], who found high sympathetic activity in severe, ‘melancholic’ depression only. This is contrary to the experience of Barton et al. [8], who found sympathetic activation independent of depression severity but linked to comorbid anxiety disorder. It had been hoped that analysis of the sympathetic nervous system in patients with depressive illness might provide clues which would help to ‘fathom’ the biology of this clearly heterogeneous psychiatric disorder, much as in earlier era when expectations were high that analysis of cortisol responses in depression would be the key to better the mechanistic understanding of the illness [14], but this has not happened. The specific central nervous system origins of the sympathetic activation remain totally unknown. Brain serotonin neurones are activated in depressive illness [15] but what relation this might have, if any, to the increased sympathetic tone is problematic.

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Why not hypertension in depressive illness?

The question might be put: ‘If patients with depressive illness have increased cardiac risk from sympathetic nervous activation, why do they not also have elevated blood pressure (BP)?’ There is unequivocal evidence that sympathetic nervous activation is one important mechanism by which the pressure elevation characterizing essential hypertension is generated [16], explicit evidence for this being recently provided in the antihypertensive effect of catheter-based radiofrequency ablation of the renal sympathetic nerves in patients with severe, difficult to control essential hypertension [17]. Perhaps the anomalous BP in depression derives from the pattern of sympathetic activation present. Sympathetic nervous system activation in the physiological responses of health and in disease is commonly not global, involving all outflows, but differentiated, with activation of outflows to some organs accompanying no change or sympathetic inhibition in other outflows [18]. Renal sympathetic activation, it seems from clinical observations [17,18] and the experience with renal denervation in experimental hypertension [19], is commonly crucial in the pathogenesis of hypertension. Perhaps the sympathetic activation of depressive illness spares the renal sympathetic outflow; this has not been tested. In the study of Scalco et al. [7], in harmony with this interpretation, muscle sympathetic nerve activity fell during chronic dosing with the selective serotonin reuptake blocker, sertraline, but BP did not change.

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No cardiac benefits from treatment of depressive illness to date: a place for cardioprotective antiadrenergic drugs?

There is now good evidence that treatment of depressive illness with selective serotonin reuptake-blocking drugs reduces sympathetic nervous system activity, evident in reduced sympathetic outflow to the skeletal muscle vasculature, as described by Scalco et al. [7], and also to the heart [8]. Whether this represents a direct pharmacological action of this drug class or is a consequence of the achieved therapeutic remission of the depression is uncertain. Given the occurrence of this sympathetic nervous system inhibition, it is surprising that to this point there is no demonstration that selective serotonin reuptake inhibitor (SSRI) drugs lower the rate of adverse cardiac events in treated patients with depressive illness [20]. An explanation may perhaps lie in the anticholinergic activity of this drug class, evident in the lowering of heart rate variability and reduction in arterial baroreflex sensitivity produced by SSRI drugs [21]. Perhaps the benefits of achieving remission in the depression and the lowering of sympathetic nervous activity are counterbalanced, in terms of cardiac risk, by the reduction in cardiac vagal activity.

The benefits in heart attack prevention achieved by blood cholesterol lowering with statins far outstrip those seen with treatment of depressive illness, which to this point are negligible or nonexistent. The Sertraline Antidepressant Heart Attack Randomized Trial study [20] demonstrated safety of serotonin reuptake-blocking drugs used to treat patients with depressive illness present after MI, but there was minimal reduction in re-infarction rates. The vagal blocking action of SSRI drugs might be the culprit [21].

The field is now at the crossroads, given this lack of clear evidence of benefit in terms of heart attack prevention from treatment of depressive illness. One view heard is that the pathophysiological mechanisms of cardiac risk in depressive illness might need to be better delineated, and these specifically targeted pharmacologically, beyond the treatment of the depressive illness itself. This idea is not fanciful, given that in many patients with depressive illness complete remission is not achieved with treatment. Evaluation of β-adrenergic blockade, or central sympathetic inhibition with imidazoline drugs such as moxonidine and rilmenidine for cardiac protection in treatment-resistant depressive illness would be a logical next step.

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21 Dawood T, Lambert EA, Barton DA, Laude D, Elghozi J-L, Esler MD, et al. Specific serotonin reuptake inhibition in major depressive disorder adversely affects novel markers of cardiac risk. Hypertens Res 2007; 30:285–293.

© 2009 Lippincott Williams & Wilkins, Inc.