This study demonstrated that, when compared with a healthy control group, patients hospitalized for clinical depression exhibit altered cardiac nervous function, evidenced by a lower high frequency domain index and a higher low frequency domain index and LF/HF ratio. Increases in the severity of depressive symptoms were shown to exacerbate these trends. Arrhythmias, particularly supraventricular arrhythmias, were over-represented in depressed patients when compared to those without. The findings from this study are consistent with the hypothesis that cardiac autonomic dysfunction is experienced by individuals with depression, especially decreased parasympathetic nerve activity (as evidenced by decreased values of the time domain indexes). This is supported by other studies of patients with depression that have applied other assessment techniques. For example, Bi et.al [28] found that patients with depression experienced autonomic nervous dysfunction using sympathetic skin response measures.

There may be a number of explanations for this finding. A mood disorder may trigger a series of adverse cardiovascular factors that evoke pathophysiological changes, which have been detailed previously [29]. These study [2–4] have demonstrated a significant relationship between depression and cardiovascular risk factors that are known to lead to adverse outcomes. Battacharyya et al. [30] hypothesized that the relationship between depression and cardiovascular risk may be explained by enhanced parasympathetic control. We suggest that the decreased HF and increased LF and LF/HF ratio observed in our study (using frequency domain analysis) is indicative of reduced parasympathetic nerve activities and the imbalance of sympathetic and parasympathetic innervation, which may reflect dysregulation of sympathetic and parasympathetic coordination in depression. LF reflects the influence of sympathetic and parasympathetic nervous activity on heart rate fluctuation, and has relevance to vessel baroreflex effects. As such, enhanced vascular baroreceptor reflex resulting from emotional stress can induce increased LF. This is consistent with clinical manifestations in patients with depression who experience excessive tension, palpitation, chest tightness and other physical symptoms. HF may represent both vagus nerve activity and respiratory activity. However, Berger [31] found that while vagus activity was reduced in their group of depressed patients, there was no relationship between parasympathetic nervous activity and the frequency and rhythm of respiration. As there is a direct effect on HRV [32], where HRV is smaller if parasympathetic activity is lower and vice versa, we propose that parasympathetic nervous activity predominantly influences cardioregulatory function. Pathophysiological links between depression and cardiovascular system dysfunction include reduced HRV, changed sympathetic nerve activity, arrhythmia, and altered ventricular electrophysiological properties [15]. In examining HRV in depressed patients in our study, we speculated that the relative increase in sympathetic tone and corresponding reduction of parasympathetic tone may be a mechanism associated with this phenomenon and arrhythmia induction.

Our finding that a linear relationship exists between depression severity and HRV is consistent with previous research. Stein [33] found that cardiac patients with severe depression experienced significantly reduced HRV and increased mortality; a linear relationship between depression severity and level of cardiac autonomic dysfunction was observed. Agatisa [34] reported that recurrent episodes of elevated depressive symptoms were related to a greater risk of coronary and aortic atherosclerosis among those not yet diagnosed as having coronary disease. Some reports suggest the cardiac autonomic dysfunction in depressed patients may increase the risk of arrhythmia; which itself is a risk factor for coronary and other cardiovascular disorders. Indeed, we demonstrated a higher prevalence of arrhythmia in depressed patients compared with controls; a finding that may go some way to partially identifying a pathway by which depressed individuals are at increased susceptibility to CVD onset. That people with depression are more vulnerable to arrhythmias, especially supraventricular arrhythmias, such as single atrial premature beats, paired atrial premature beats and single ventricular premature beats, is in general agreement with the concept that there is a relationship between arrhythmia and emotional turbulence [35], which may be related to increased sympathetic nervous system activity [36]. Adrenergic secretion can increase the auto-rhythmicity of heart purkinje fibers, reducing the excited domain of the diastolic period and inducing sympathetic excitability. As a result, it may increase the probability of ventricular arrhythmia. Hyper-responsivity of sympathetic nervous activity may also constitute a risk factor for the development or progression of CVD [36].

Some of the inconsistencies in the evidence base surrounding the relationship between HRV and depression may be explained by variance in study design, assessment techniques and/or markers of autonomic functions used across studies [37]. In this study, we analyzed HRV and evaluated autonomic function through analysis of the time-domain indexes SDNN, SDANN, RMSSD and PNN50. The domain parameters of HRV used in this study are considered a reliable indicator for risk of malignant ventricular arrhythmias and sudden cardiac death when compared with ventricular late potentials, left ventricular ejection fraction, QT dispersion and the level of cardiac function [38, 39]. Altered HRV may therefore be useful for predicting arrhythmia risk in patients with depression.

We acknowledge several limitations of this study. Ours was a sample taken from patients undergoing hospitalization and subsequent treatment for major depression. Based on the pre-determined selection criteria, they had few anxiety symptoms, a low risk of suicide, and an absence of acute myocardial infarction. While these criteria were employed in order to reduce the impact of confounding variables on our outcome of interest, this selection bias may affect the generalizability of our results. Secondly, the sample size was relatively small, limiting our ability to analyse the relationship between depression severity and HRV and perform meaningful sub-group analyses. Although it should be acknowledged that the markers of autonomic function are indirect measures, the comprehensiveness of the data including gold standard measures of depression using diagnostic psychiatric interviewing and HRV using domain parameters are strengths of this study. Thirdly, the cross sectional nature of the study does not allow examination of autonomic dysfunction across the disease course to determine whether remission affects this marker. Lastly, multiple comparisons were not undertaken as part of our statistical analyses; for example the effects of medication usage remain undetermined as all patients in the depressed group were receiving medication. We do acknowledge that SSRI have been shown to impact on cardiac rhythm, thus it is possible that using a sample comprising those on antidepressants may have diluted or alternatively, magnified our findings, compared with a sample from the general population, or using depressed individuals who were not on medication. Therefore, results should be interpreted with caution.