In this issue of the journal, Barton et al.  present a remarkable study on the activation of the sympathetic nervous system in patients with major depressive disorder (MDD) and a potential beneficial effect of selective serotonin reuptake inhibitors (SSRIs). The authors applied elaborate state of the art techniques to assess sympathetic nervous system activity. Using noradrenaline isotope dilution techniques, they measured whole body and cardiac sympathetic nerve activity. Moreover, they assessed muscle sympathetic nerve activity by microneurography at the peroneal nerve. Thus, different parameters of regional and global sympathetic nerve activity were available. Representative samples were studied, 39 patients with MDD and 76 healthy controls. Interestingly, patients with MDD as whole group did not display elevated sympathetic activity compared to healthy subjects. However, the authors were able to demonstrate a bimodal distribution of cardiac and whole body sympathetic nerve activity in the patients with MDD. They were able to define a subgroup with marked sympathetic activation and a subgroup with low sympathetic activity.
In contrast to the findings of Barton et al., previous studies suggest that, in patients with MDD, there is a dysregulation of autonomic cardiovascular control. Cardiac vagal modulation appears to be normal  or suppressed . On the other hand, cardiac sympathetic activation and an elevated resting heart rate have been reported [3,4]. Agelink et al.  suggest that the autonomic dysregulation originates in the central nervous system, central activation of sympathetic outflow being a hallmark of MDD. Equivocal findings with respect to sympathetic activation in MDD may be the result of the different methodology applied in the studies. Previous studies mainly used an analysis of heart rate variability to assess cardiac autonomic control. In addition, measurements of noradrenaline concentrations, which have been reported to be increased in MDD , provide a less reliable assessment of sympathetic activation than the elaborate techniques applied in the study by Barton et al. .
It has been consistently shown that patients with MDD have an increased risk of cardiovascular complications, which is even independent from pre-existing cardiovascular disease . It is tempting to speculate that sympathetic activation, at least in a subset of patients with MDD, is responsible for the increased cardiovascular risk associated with MDD. In several clinical conditions characterized by sympathetic overactivity, such as heart failure  or renal failure , increased sympathetic outflow is related to increased cardiovascular morbidity and mortality.
The study by Barton et al.  does not allow a relationship to be established between increased sympathetic outflow and increased cardiovascular risk in their patient collective. From the study design, it is not possible to conclude that those patients with MDD who have increased sympathetic nerve activity are patients with a higher likelihood of cardiovascular complications. However, it should be noted that Barton et al.  found that increased sympathetic activity was present in those patients with MDD who also had comorbid panic disorder. Also, other studies have described increased sympathetic activity in patients with panic disorder. There is substantial evidence that patients with panic disorder have significantly increased morbidity and mortality from ischemic heart disease . Thus, patients with MDD and comorbid panic disorder, who have increased sympathetic nerve activity, may comprise a patient group with a particularly increased cardiovascular risk. Longitudinal studies are warranted to assess a potential cause–effect relationship between increased sympathetic outflow and cardiovascular disease in patients with MDD.
An issue of major importance is whether disturbed autonomic control in patients with MDD can be improved by antipsychotic treatment. Changes in heart rate variability with psychotherapy, electrotherapy and drug therapy have been reported with equivocal results . Importantly, the drugs used for the pharmacotherapy of MDD interfere with central catecholamine metabolism and may even increase catecholamine concentrations in the central nervous system. To date, studies on the effects of central psychotropic drugs on autonomic nervous system regulation, and particularly on sympathetic nerve activity, are scant. Therefore, the effects of antidepressants on sympathetic outflow need to be investigated. The study by Barton et al. , who used elaborate methods to measure sympathetic nerve activity before and during treatment with SSRIs in patients with MDD, is an important contribution. The subgroup of patients with elevated sympathetic nerve activity displayed reduced whole body and cardiac sympathetic activity with SSRI treatment. By contrast, SSRIs had no effect on sympathetic outflow in patients with low baseline sympathetic nerve activity. These results suggest that SSRIs may correct sympathetic overactivity in a subgroup of patients with MDD. Unfortunately, Barton et al.  did not include a control group of patients not treated with SSRIs in whom sympathetic outflow was assessed longitudinally. Therefore, their study does not allow any definite conclusions to be made as to whether SSRIs specifically suppress sympathetic nerve activity in MDD. The differential sympatholytic effect of SSRIs in patients with and without elevated baseline sympathetic activity suggests such a specific sympathoinhibitory effect.
Assuming that SSRIs effectively reduce elevated sympathetic nerve activity in patients with MDD, this leaves the unresolved issue whether these drugs will also improve cardiovascular outcome in MDD. Interestingly, the study group of Barton and coworkers recently also published a study on the cardiovascular effects of SSRIs . In that study, they observed that SSRIs caused a reduction in baroreflex sensitivity and heart rate variability, along with increases in pulse pressure and C-reactive protein, in patients with MDD . Thus, SSRI treatment influenced these parameters in a manner likely to be associated with an increase in cardiovascular risk. The issue of potential cardiovascular complications attributable to antidepressant drugs is not yet resolved. Antidepressant drugs, notably SSRIs, may increase serum glucose and cholesterol levels . Cohen et al.  found the use of tricyclic antidepressants to be associated with a substantially increased risk of myocardial infarction, whereas SSRIs had no negative influence on coronary artery disease. Goodnick et al.  did not observe any negative effect of SSRIs on the QTc interval . Moreover, a recent meta-analysis by Rampello et al.  showed that SSRIs can be safely used in patients after stroke. Therefore, the present evidence suggests that SSRIs do not cause adverse cardiovascular events in patients and that they can be safely used in patients with cardiovascular and cerebrovascular disease. However, additional controlled long-term studies are warranted to address this issue.
In summary, the study by Barton et al.  contributes a systematic assessment of sympathetic nerve activity in patients with MDD to the existing literature. The major strength of their study is the multimodal assessment of sympathetic activity using elaborate state of the art methods. However, further controlled studies are warranted to address several important questions. Do depressive patients with increased sympathetic activity represent a subgroup with increased cardiovascular risk? Do SSRIs provide a specific suppression of sympathetic activity in patients at risk? Do SSRIs improve cardiovascular outcome in patients with MDD and is a potential improvement of cardiovascular outcome related to a reduction of sympathetic nerve activity?
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