Major depressive disorder is reported to be associated with increased cardiovascular mortality and morbidity, and it is a significant risk factor for increased mortality after myocardial infarction (MI) 1,2. The cardiac autonomic imbalance in major depression has been established to be a focus of interest in these disorders; specifically, it was thought that major depression might be associated with decreased parasympathetic and increased sympathetic modulations, which lower the threshold for lethal arrhythmias 3,4.
Heart rate variability (HRV) refers to the degree of fluctuation in the length of the interval between heart beats 5. Two people could exactly have the same average heart rate, and yet when the variation is precisely measured in milliseconds (ms), it can be demonstrated that there is variance between individual beats and that the degree of variance is different for different individuals under different conditions. This degree of variance between different beats is called HRV. Although it has been known for quite some time that HRV exists, it is only in the past 35 years or so that it is has been discovered that beat-to-beat variations is a measure of health of the cardiovascular system and that a variability in the heart rate is the reflection of a healthy, well-developed autonomic nervous system (ANS) 6.
Although cardiac automaticity is intrinsic to various pacemaker tissues, heart rate and rhythm are largely under the control of ANS 4,7. The parasympathetic influence on heart rate is mediated by release of acetylcholine by the vagus nerve. Muscarinic acetylcholine receptors respond to this release mostly by an increase in cell membrane K+ conductance. The sympathetic influence on the heart rate is mediated by release of epinephrine and norepinephrine. Activation of adrenergic receptors results in cyclic AMP-mediated phosphorylation of membrane proteins. Under resting condition, vagal tone prevails, and variation in heart period is largely dependent on vagal modulation 8. The vagal and sympathetic activities constantly interact. Many medications and therapeutic protocols are supposed to affect the autonomic modulation of the heart, such as β-adrenergic blockers 9, scopolamine and atropine 10, antiarrhythmic drugs 11, thrombolytic drugs 12, and exercise training 13.
HRV has been the subject of numerous clinical studies investigating a wide spectrum of cardiological and noncardiological diseases and clinical conduction 2,14. A general consensus of the practical use of HRV in adult medicine has not been reached, and future HRV studies should enhance our understanding of physiological phenomenon, the actions of medications, and the disease mechanisms 15.
The aim of this work is to throw light on the issue of HRV as an indicator of cardiac autonomic imbalance in major depression and also to see what changes occur in HRV measures with depression treatment.
Patients and methods
The patients for this study were recruited from neuropsychiatry and cardiology department, Tanta Faculty of Medicine. Written consent was obtained for all the patients of the research.
Group I: Twenty patients (13 males and seven females, mean age=46.3, SD=3.3) met the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria of major depressive disorder, recurrent episode. Those included in the study were having normal findings on physical examination and not having any cardiovascular, pulmonary, or endocrinal diseases. ECG and routine laboratory investigation findings were normal. This group was further classified into two subgroups (10 patients each):
- Group I-A was put on a full therapeutic trial of selective serotonin reuptake inhibitors (SSRI) for 3 months (on medical treatment only).
- Group I-B was put on medical treatment plus physical exercise protocol (walking or light jugging for 50 min three times/week with intervening mild aerobic exercises) for 3 months (on medical treatment plus physical exercise).
Group II: Ten patients in the post-MI period, i.e., in the first year after an episode of MI (six males and four females, mean age±SD: 48.1±3.3 years). Those included in the study were meant to be not having any mental disorder.
Group III: Ten healthy volunteers not having any physical or mental disorder were included in this group, where five were males and five females, with mean age±SD of 46.5±2.9 years.
At baseline, all participants of the research were subjected to the following:
Complete physical examination
- Psychiatric interview based on the Structured Clinical Interviews for DSM-IV axis I disorders, patient edition 16.
- ECG, echocardiogram, and routine laboratory tests (complete blood count, liver function tests, renal function tests, serum lipids, blood sugar, and serum electrolytes).
- Montogomry–Asperg Depression Rating Scalefor measuring depression severity 17.
Heart rate variability measures
- Three months later, only patients of group I-A and those of group I-B were assessed regarding depression severity and HRV.
Heart rate variability measuring procedures
- ECG recording were obtained for all patients in the same quite room between 10:00 a.m. and 12:00 p.m. to avoid diurnal effect. One unfiltered ECG limb lead was digitized online with 16-bit signal resolution at 1000 Hz by using computerized system. A well-tested algorithm that uses a template and a threshold was chosen by the operator before recording to localize the fiducial point of every heart beat intervals real time.
- The point-wise correlation dimension ‘PD2’ estimates of heart beat intervals (RR) were calculated according to the algorithm developed by Skinner et al. 18 as follows: state space was constructed through the method of time delays, that is, RRi=[RR (ti), RR (ti+ (m−1)t], for successive embedding dimensions from m=1 to m=16, where t=1 was taken as the most reasonable choice for delay (as longer lags may induce undue loss of spatial correlation between points). Starting with the initial point in the series, the local correlation integral C (r) of the point was calculated, that is, all vector differences (r) relative to this point were calculated rank-ordered from the smallest to the largest, plotting C (r) as a function of r on a log–log scale results in a sigmoid-shaped curve. The slope over the largest linear range was then measured (with a regression coefficient ≥0.98); this was done for successive m values to look for a plateau beyond a certain m. This plateau was considered as the PD2 estimate, and its value was calculated with weighted average technique (each value in the plateau was weighted by the variance of its underlying slope calculations). Then, the algorithm was stepped to the next point in the series, and the whole procedure was repeated until the entire file was exhausted.
Data collected were introduced to personal computer, and statistical analysis was done with EPIS and SPSS program. Statistical significance was accepted at P less than 0.05 level. All values were expressed as means and SDs.
There is no significant difference between groups of major depression and post-MI group regarding measures of HRV but major depression group has significantly higher depression rating scores than those of post-MI group (Tables 1 and 2).
HRV measures were significantly lower and depression rating scores were significantly higher in patients with major depression than those of healthy comparison patients (Table 3).
After 3 months, major depression subgroup I-A (on medication only) showed significant lowering of their depression ratings but their HRV measure showed no significant difference than those at baseline (Table 4).
After 3 months, major depression subgroup I-B (on medication plus physical exercise) showed significant lowering of their depression ratings and also significant rise of their HRV measure than those at baseline (Figs 1–6).
The aim of this study is to highlight the issue of HRV in physically healthy patients with major depression by comparing their HRV measures (point-wise correlation dimension PD2) with those of mentally healthy post-MI patients and physically and mentally healthy comparison subjects. It was found that PD2 measures (an estimate of the RR interval) in patients with major depression were comparable with those of post-MI patients, that is, no significant difference between HRV measures of both groups (t=0.62 and 0.76, P=0.55 and 0.47) (Table 1). On the contrary, HRV measures showed significantly lower values when comparing major depression groups with healthy comparison individuals. These significantly lower measures were also shown when comparing post-MI patients with the healthy individuals. Surprisingly, these results emphasize that patients with major depression were indistinguishable from post-MI patients regarding measures of HRV. As it has not been established whether lowered HRV is a part of the mechanism of increased post-MI mortality or is merely a marker of poor prognosis, it is suggested that lowered HRV is not a simple reflection of the sympathetic overdrive and/or vagal withdrawal owing to poor ventricular performance, but that it also reflects depressed vagal activity, which has a strong association with the pathogenesis of ventricular arrhythmias and sudden cardiac death 19. Lowered HRV can be considered a powerful predictor of mortality and of arrhythmic complications in patients following MI 19,20. Cardiac autonomic imbalance is also represented in patients having major depressive disorder and who are well known not to be experiencing any physical diseases, including any heart problems 14,21. Studies investigated the possible higher risk for cardiac mortality and morbidity in patients either having major depression alone or heart disease 22. In most of these studies, lowered HRV was one of the most powerful indicators of this increased risk 21,22.
Depressed patients in this study were already on treatment. Those on the SSRIs were only included in the study to avoid the heterogeneity of the sample and also because SSRIs are the commonly used antidepressants nowadays. Tricyclic antidepressants were excluded because of potential cardiotoxic effects. We optimized the treatment regimen for each patient for 3 months in both major depression groups (groups I-A and I-B). Group I-B patients were assigned to a physical exercise program in addition to the antidepressant medication during the 3-month period. After the 3 months, we found that Montogomry–Asperg Depression Rating Scale depression scores were significantly lower than baseline scores for both groups (I-A and I-B t=11.3 and 14.6, respectively, P=0.000). Moreover, HRV measures were nearly normalized in group I-B (on medication and physical exercise), that is, significantly lower PD2 measures after 3 months when compared with baseline scores (t=7.61 P=0.000). On the contrary, group I-A (on medication only) showed no significant changes in HRV measure after 3 months when compared with baseline scores (t=2.2, P=0.54). This was in spite of the significant improvement in depression scores. SSRIs have been presumed to have minimal effects on the ANS. Paroxetine, which has some anticholinergic activity, might affect HRV measures. However, many studies have demonstrated that therapeutic doses of SSRIs (including paroxetine) given to depressed patients do not alter HRV measures 15,23.
Exercise training is reported to decrease cardiovascular mortality and sudden cardiac death. Regular exercise training is also thought to be capable of modifying the autonomic balance, improving vagal sensitivity, and modifying sympathetic response, leading to an increased overall responsiveness to autonomic modulation 13,24,25. Moreover, exercise training in post-MI patients was found to reduce the incidence of cardiac mortality and morbidity, but this should be done very tentatively under the supervision of a professional cardiorehabilitation specialist 26.
Conclusion and recommendations
Improvement of HRV measures in patients with major depression with physical exercise when added to the treatment regimen but not with SSRIs alone raises the question of the feasibility of antidepressant treatment in readjusting the HRV in patients at risk and whether HRV can be considered as a state marker of depression or not.
Large prospective longitudinal studies are needed to determine the sensitivity, specificity, and predictive values of HRV in the identification of individuals at risk for subsequent morbid and mortal events.
Recognition of those problems led the European Society of Cardiology and the North American Society of Pacing and Electrophysiology to constitute a task force charged with the responsibility of developing appropriate standards. The specific goals of this task force were to standardize nomenclature and develop definitions of terms, specify standard methods of measurement, define physiological and pathophysiological correlates, describe currently appropriate clinical applications, and identify areas of future research.
The authors of this research would like to express the greatest gratitude to Professor Dr. Ayman M. El-Said, professor of cardiology, Tanta Faculty of Medicine, for his participation in recruiting patients of the research (post-MI) and for his valuable help in the HRV procedures.
Conflicts of interest
There are no conflicts of interest.
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