Journal of Affective Disorders 175 (2015) 269–274
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A blunted sympathetic and accentuated parasympathetic response to postural change in subjects with depressive disorders Xiao-ling Jiang a,n, Zheng-gang Zhang b, Yuanyuan Chen a, Cui-Ping Ye a, Ying Lei a, Lei Wu a, Ying Zhang a, Zhong-ju Xiao b,n a b
Department of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangdong Province 510515, China Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangdong Province 510515, China
art ic l e i nf o
a b s t r a c t
Article history: Received 31 July 2014 Received in revised form 8 January 2015 Accepted 8 January 2015 Available online 15 January 2015
Background: In recent years, the bi-directional relationship between depression and ANS dysfunction has received considerable attention, but findings remain inconclusive. In this study, we aimed to examine the spectral HRV response to postural change in subjects with depressive disorders and in healthy controls, in order to gain insight into the characteristics of autonomic nervous system (ANS) response to postural change in subjects with depressive disorders. Methods: We compared HRV response to postural change between subjects with depressive disorders and healthy controls aged 20–37 years. Depression severity was assessed by the self-reported Beck Depression Inventory-II (BDI-II). Spectral HRV was analyzed at two moments: 10 min seated rest and 10 min at standing position, with spontaneous breathing. Results: No significant differences existed in the resting spectral HRV indices between subjects with depressive disorders and controls, however, following postural change, the increasing level of LF and LF/HF was lower and the decreasing level of HF power was higher, in the individuals with depression than that in healthy subjects. The differences in the LF power, HF power and the LF/HF ratio between seated rest before standing up and after postural change were found negatively correlated with depression severity. Conclusion: We found a blunted sympathetic and accentuated parasympathetic response to postural change in subjects with depressive disorder, suggesting that the autonomic impairment and early ANS dysfunction may exist among depressed individuals. These findings indicated that spectral analysis of HRV associated with postural change may be a more sensitive method than resting HRV analysis for detecting ANS dysfunction in depressive disorders. Limitations: Further studies are needed to expand the sample size and to clarify the mechanisms responsible for the autonomic dysfunction observed in individuals with depressive disorders. & 2015 Elsevier B.V. All rights reserved.
Keywords: Heart rate variability Depressive Postural change
1. Introduction It is increasingly being recognized that depressive disorders are independently associated with an increased risk of cardiovascular disease (including fatal arrhythmias and coronary artery disease) (Carney et al., 2005; Rabins et al., 1985; Tsuang et al., 1980). Autonomic disturbances have been thought to be responsible for the increased cardiovascular risk observed in patients with depression (Dekker et al., 2000; Liao et al., 1997; Tsuji et al., 1994). Specifically, it was thought that depressive disorders might be associated with increased sympathetic activity, which lowers the threshold for cardiovascular disease
n
Corresponding authors. Fax: 86 20 61648604. E-mail addresses: [email protected] (X.-l. Jiang), [email protected] (Z.-j. Xiao). http://dx.doi.org/10.1016/j.jad.2015.01.009 0165-0327/& 2015 Elsevier B.V. All rights reserved.
(Dalack and Roose, 1990; Eaker et al., 2005; Flaa et al., 2008; Glassman, 2008; Penninx et al., 2001; Veith et al., 1994). However, other studies have reported decreased SNS activity in subjects with depressive disorders or no association between psychopathology and SNS activity (Ahrens et al., 2008; Esler, 2004; Roth et al., 2008). Thus, findings about the bi-directional relationship between depression and ANS function remain inconclusive. Spectral analysis of resting heart rate variability (HRV) is a noninvasive method often used to assess cardiac autonomic nervous activity (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996; Akselrod et al., 1981). However, baseline autonomic functioning varies with age, sex, weight, emotional state, and environmental or physiological stimuli (Spiegelhalder et al., 2011). Thus, because studies have used different methodological designs, it has been impossible to draw firm conclusions.
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In recent years, the spectral HRV response to postural change has been hypothesized to be a more sensitive measure of cardiac autonomic modulation than resting spectral HRV because cardiac autonomic dysfunction is thought to occur primarily through impairment of sympathetic response to environmental or physiological stimuli (Guzzetti et al., 1988; Lombardi et al., 1996; Carnethon et al., 2002a). Normal HRV activity in response to postural change reflects a shift from parasympathetic predominance at rest to sympathetic control while standing(de Souza et al., 2014). Some studies have reported an attenuated or absent HRV response to postural change in subjects with chronic diseases such as hypertension (Guzzetti et al., 1988) and diabetes (Pagani et al., 1988), suggesting that autonomic impairment and early sympathetic dysfunction may be present in such individuals. However, to our knowledge, HRV response to postural change has not been examined in subjects with depressive disorders. In this study, we aimed to examine the HRV response to postural change in subjects with depressive disorders and in healthy controls. The primary purpose of this study was to gain insight into the possible bi-directional relationship between depression and ANS dysfunction and hence to discover whether ANS response to postural change could be a marker of autonomic dysfunction and early sympathetic dysfunction in depressive disorders.
2. Methods 2.1. Subjects The study sample consisted of two groups of adult subjects: subjects with depressive disorders (n¼42; age, 28.377.8 years; range, 20–36 years), and healthy controls (n¼ 49; age, 30.178.1 years; range, 20–37 years). All the depressive disorder patients were from the inpatients of School of Public Health and Tropical Medicine of Southern Medical University. Informed consent was obtained from all subjects prior to commencement of the study, and the Ethics Committee of School of Public Health and Tropical Medicine in Southern Medical University approved all the procedures. The psychiatric diagnosis of depressive disorder in each patient was verified by a psychiatrist using criteria based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV), and each subject's history of psychiatric illness, medical disease, and medication use was evaluated by an interview and a medical chart review carefully (Robles-Pina, 2011; Vignatelli et al., 2005). Subjects were screened and excluded if they suffered from other serious psychiatric, somatic or sleep disorders, or they had a comorbid substance-related disorder. They consumed no illicit, prescription or OTC (over-the-counter) drugs as confirmed by physical and mental examination and biological analysis. Subjects were also excluded if they had the habits of cigarette smoking or alcohol consumption, that have a documented effect on the autonomic nervous system (Carnethon et al., 2002a, 2002b; Shinozaki, et al. 2008; Quintana, et al., 2013). If subjects suffered from hypertension (presence of systolic blood pressure Z140 mmHg; diastolic blood pressure Z90 mmHg), diabetes (fasting glucose Z126 mg/dL), cardiovascular disease, severe cardiac arrhythmia, a frequent ectopic heartbeat, or an acute medical illness within 3 months of the start of the study, they were then excluded from the study. Any medications that have a documented effect on the autonomic nervous system (e.g. βblockade and anticholinergic drugs) were stopped at least 14 days prior to the recordings (Zhou et al., 2013). 2.2. Study design Volunteers were instructed to avoid consuming alcohol, caffeine, smoking and substances that influence the ANS for 24 h
before evaluation. All procedures necessary for the data collection were explained to the individuals. Data were collected between 8 and 12 a.m. in our laboratory under controlled temperature (21– 25 1C) and humidity (50–60%). Food intake also has effects on autonomic function (van Baak, 2008), so the postural change tests were conducted in a fasting state. After the initial evaluation the heart monitor belt was then placed over the thorax and aligned with the distal third of the sternum, and the polar heart rate receiver was placed on the wrist. The subject remained seated at rest with spontaneous breathing. After 10 min the volunteers quickly stood up from a seated position in up to three seconds according to verbal command and remained standing for 10 min (de Souza et al., 2014). Heart rate variability (HRV) was analyzed at two moments: 10 min seated rest with spontaneous breathing, and 10 min at standing position. The subjects were instructed to avoid talking and moving during the data collection. 2.3. Measures 2.3.1. Beck Depression Inventory (BDI) Depression severity was assessed by the self-reported Beck Depression Inventory-II (BDI-II) (Vanheule et al., 2008; Ward, 2006), which is one of the most commonly used self-report instruments for estimating the severity of depression. The total score indicates whether the individual presents a mild, moderate or major depression. The BDI-II consists of 21 items, each of which is scored on a scale from 0 to 3. The maximum score is 63. The recommended cutoff for minimal depression is 13, whereas a score of 14–19 indicates mild, 20–28 moderate and 29–63 serious depression.
2.3.2. Analysis of spectral HRV The R–R intervals (RRI) were computed from the electrocardiogram (ECG). All the QRS complexes were detected by Matlab (Matlab2007a) program, and the RRI time series were obtained. For maximum precision in measurement of the RRI data, artifacts were automatically detected using the following criteria: RRI o350 ms or RRI4 1500 ms (Barry et al., 1991; Brown et al., 2013). For calculation of the spectral indices we used the HRV Analysis software (Kubios HRV v.1.1 for Windows, Biomedical Signal Analysis Standard). Spectral HRV measures include high-frequency power (HF: 0.15–0.4 Hz), low-frequency power (LF: 0.04–0.15 Hz), and very-low-frequency power (VLF: 0.003–0.04 Hz). LF power is thought to be modulated by both sympathetic and parasympathetic activities, whereas HF power is mainly modulated by parasympathetic activity. The LF/HF ratio was computed as a measure of the sympathovagal balance towards sympathetic activity. The very low frequency (VLF) power is assumed to be due to long-term regulatory mechanisms such as humoral factors, temperature, and other slow components (Otzenberger et al., 1998; Stein and Pu, 2012). 2.4. Statistical analysis All participants were divided into two groups: depressive disorders and normal controls. Demographic variables were compared with a non-parametric test (Mann–Whitney U test) and Chisquared tests or student's t test. Analysis of variance (AVONA) and pairwise test comparisons were carried out to compare HRV responses to postural change in subjects with depressive disorders and those without. All variables were presented with standard deviations if there was no specified explanation (mean7SEM). All data calculations were performed with SPSS 13.0 (Chicago, IL, USA). A two-sided α-level of significance of 0.05 was used for all tests, and a value of Po0.05 was considered statistically significant.
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Table 1 Demographic data between depression disorder groups and normal control group. Depression disorder (n¼42) Controls (n¼ 49) P value Age, year Male/female Height (m) Weight (kg) BMI Heart rate (beats/min) SAP (mmHg) DAP(mmHg) Total BDI score
28.3 7 7.8 24/18 1.62 7 0.11 52.5 7 14.3 21.7 7 2.1 73.5 78.9 101.9 7 11.2 73.6 713.1 27.57 10.9n
30.1 78.1 29/20 1.63 7 0.09 52.9 7 15.7 22.1 72.6 72.9 79.2 103.5 7 13.6 74.17 11.9 4.1 73.8
0.315 0.642 0. 356 0.624 0.789 0.662 0.4787 0.512 0.000
Mean values ( 7 SE) for the indices of each group. n
Po 0.05 vs controls.
Table 2 Spectral HRV during seated rest between depression disorder groups and normal control group. Measure
Depression disorder (n ¼42) Controls (n ¼49) P value
Heart rate (beats/min) 73.5 7 8.9 VLF power, (ms2/Hz) 883.2 7 392.1 LF power, (ms2/Hz) 789.6 7 302.3 HF power, (ms2/Hz) 822.17 317.6 LF/HF 1.4 7 0.6
72.9 7 9.2 839.5 7 305.9 818.5 7 343.8 765.9 7 362.5 1.6 7 0.5
0.662 0.445 0.325 0.862 0.331
Mean values ( 7 SE) for the indices of each group.
3. Results 3.1. Demographic data The demographic data are presented in Table 1. The depressive disorder group and normal control group did not differ in terms of the age, gender ratio, BMI, heart rate and blood pressure. The depressive disorder group was rated higher on the BDI-II score than the normal control group (27.5 710.9 vs 4.1 73.8, P ¼0.000). 3.2. Spectral HRV at seated rest in the two groups For the spectral HRV at seated rest, no significant differences between two groups were detected for all the spectral HRV indices (Table 2). These results indicated that ANS activity in the depressive disorder group was not significantly different from that in the normal control group. 3.3. Spectral HRV observed with standing up in the two groups Table 3 presents data related to the spectral HRV indices observed with standing up in the depressive disorder group and normal control group. The heart rate increased significantly during standing in both groups (73.578.9–80.1710.3 vs 72.979.2–78.6711.6). As to spectral HRV indices, we observed that both the LF power and the LF/HF ratio increased and that the HF power decreased after standing up in the normal control group. No significant difference was observed in VLF power after standing up compared with seated rest in both groups. A significant increase in the LF/HF ratio and a decrease in HF power after standing up were observed in the depressive disorder group; no significant difference in LF power was observed. Differences in HRV between seated rest before standing up and during standing were compared across different degrees of depression severity in the depressive disorder group (Table 4). Using the self-reported Beck Depression Inventory-II (BDI-II), all the individuals were categorized as having one of four grades of depression: none, mild, moderate or serious depression. The D values, which are equal to the difference between the HRV value
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after standing up and the HRV value during seated rest, demonstrated that heart rate (HR), LF power, HF power and the LF/HF ratio varied with depression severity. Compared with the nondepressive (control) group, the mildly depressive group exhibited no significant difference in HR and spectral HRV indices, but moderate and serious depressive groups exhibited significant differences in HR and in most of the spectral HRV indices, with the exception of VLF power. The differences in the LF power, HF power and the LF/HF ratio between seated rest before standing up and after postural change exhibited negative correlations with depression severity, indicating that the increasing of sympathetic activity and sympathovagal balance to postural change is increasingly attenuated with increasing depression severity, and the decreasing of parasympathetic activity to postural change are increasingly accentuated with increasing depression severity.
4. Discussion The major findings of this study were the following: (a) no significant differences existed in the resting spectral HRV indices between subjects with depressive disorders and controls. (b) A blunted spectral sympathetic and accentuated parasympathetic response to postural change was identified in subjects with depressive disorders. In humans, the upright position challenges the cardiovascular system with the gravitational displacement of blood to lower parts of the body, and the cardiovascular system responds with an immediate translocation of blood toward the heart and a faster cardiac output response, resulting in a reduction in cerebral perfusion pressure (Carnethon et al., 2002a; Harms et al., 2010). Adjustment to the postural decrease in central blood volume involves increased systemic vascular resistance through autonomic reflex activity. However, subjects with autonomic dysfunction lack this ability to increase vasomotor tone and thus face an increasing risk of cardiovascular disease (Carnethon et al., 2002b; Smit et al., 1999). A large number of studies have demonstrated that depressive disorders are independently associated with cardiovascular diseases, and autonomic disturbances are thought to be responsible for the increased cardiovascular risk in patients with depression (Carney et al., 2005; Rabins et al., 1985; Tsuang et al., 1980). Thus, we assume that (a) the resting spectral HRV may be altered in patients with depression, and (b) the spectral HRV observed in response to postural change may be altered in patients with depression. The first hypothesis, that the altered spectral HRV may be altered in patients with depression, was not supported by our results. We compared HRV between subjects with depressive disorders and healthy controls aged 20–37 years in the state of seated rest during wakefulness, and we found no significant increase or decrease in spectral HRV in subjects with depressive disorders compared with (Table 2). These results differ from those obtained in most previous studies, which have reported that depressive disorders are associated with autonomic disturbances (Dalack and Roose, 1990; Eaker et al., 2005; Flaa et al., 2008; Glassman, 2008; Penninx et al., 2001). Resting HRV could be affected by many factors, such as age, sex, weight, emotional state and different experimental conditions (Spiegelhalder et al., 2011). Thus, it is possible that the results of different studies have been inconsistent because different methodological designs have been used in these studies. The second hypothesis, that the spectral HRV response may be altered in response to postural change in patients with depression, was supported by our results. The results obtained for the normal control group were consistent with the results of previous studies (Harms et al., 2010; Spiegelhalder et al., 2011; Wieling et al., 1993). Heart rate increased significantly after standing up compared with
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Table 3 HRV indices between before and after the PCM test in depression disorder group and normal control group. Index
Depression disorder (n¼ 42)
HR, beats/min VLF (ms2/Hz) LF (ms2/Hz) HF (ms2/Hz) LF/HF
P
Seated (d)
Standing (d)
73.5 7 8.9 883.2 7 392.1 789.6 7 302.3 822.17 317.6 1.4 7 0.6
80.1 710.3n 816.5 7368.9 815.6 7352.6 412.9 7269.8n 2.7 71.2n
P
Controls(n¼ 49)
0.027 0.228 0.486 0.035 0.029
Seated (c)
Standing (c)
72.9 79.2 839.5 7305.9 818.5 7343.8 765.9 7362.5 1.6 70.5
78.67 11.6# 889.7 7 453.2 993.97 396.8# 362.87 222.7# 3.17 2.1#
0.031 0.326 0.039 0.024 0.008
Mean values ( 7 SE) for the indices of each group. n
#
Po 0.05 vs seated (d). Po 0.05 vs seated (c).
Table 4 HRV indices differences between before and after the PCM test in different depression severity group and normal control group. Index
HR, beats/min LF (ms2/Hz) HF (ms2/Hz) LF/HF
P (AVONA)
Controls (n¼49)
Depression disorder
D (control)
D (total, n¼ 42)
D (mild, n¼ 12)
D (moderate, n ¼19)
D (serious, n¼ 11)
6.8 7 5.4 200.4 7 58.9 227.8 7 215.9 1.5 7 0.8
7.5 7 5.7n 144.7 7 45.1n 289.5 7 181.4n 0.9 7 0.7n
6.9 75.8 189.8 749.5 269.9 7209.5 1.3 70.9
7.8 75.6n 132.4 740.2n 287.3 7172.1n 0.8 70.6n
8.9 7 6.1n 110.9 7 48.2n 319.6 7 142.8nn 0.6 7 0.4n
0.028 0.038 0.021 0.019
Linear regression P value
R
0.036 0.029 0.041 0.035
0.621 0.593 0.428 0.477
Mean values ( 7 SE) for the indices of each group. D (mild) ¼ Standing (mild depression)-seated (mild depression). D (moderate)¼ Standing (moderate depression)-seated (moderate depression). D (serious) ¼ Standing (serious depression)-seated (serious depression). D (control) ¼ Standing(control)-seated (control). n
Po 0.05 vs D (control). Po 0.01 vs D (control).
nn
seated rest. Most of the spectral HRV indices, with the exception of VLF power, changed with the transition from sitting to standing. The observed increases in HR, LF power and the LF/HF ratio and the decrease in HF power reflected the shift in ANS activity from predominantly parasympathetic at rest to sympathetic control after standing up. Notably, a significant increase in the LF/HF ratio and a decrease in HF power were observed in the depressive disorder group after standing up, whereas no significant difference in the LF power was observed. Thus, the absence of change in LF power observed in depressive subjects differ from the increase in LF power observed in controls. Compared with the non-depressive (control) group, the mild depressive group exhibited no significant difference in the HR and spectral HRV indices, but the groups with moderate and serious depression exhibited significant differences in the HR and in most of the spectral HRV indices. The increase in LF power and in the LF/HF observed when an individual's postural changed from sitting to standing were lower in the depressive subjects than that in healthy subjects. The differences in the LF power and the LF/HF ratio between seated rest before standing up and after postural change were found negatively correlated with depression severity, indicating that the increases of sympathetic responses to postural change are attenuated with increasing severity of depression. The decrease in HF power observed when a individual's postural changed from sitting to standing was higher in the depressive subjects than that in healthy subjects. The difference in HF power was also found to be negatively correlated with depression severity, indicating that the decrease of parasympathetic responses to postural change is accentuated with increasing severity of depression. These results confirm that ANS responses to postural change are altered in subjects with depressive disorders, leading to the conclusion that autonomic dysfunction and early signs of ANS damage may exist in individuals with depressive disorders. Our study also indicated that spectral HRV in response to postural change may be a more sensitive method than resting HRV for evaluating ANS dysfunction in depressive disorders. The mechanisms responsible for altered spectral HRV in response to postural change in individuals with depressive disorders are
incompletely understood. Depressive disorders are generalized, systemic syndromes. A person having a depressive disorder not only exhibits a very low mood and multiple physical symptoms, such as insomnia, fatigue, headaches, or digestive problems, but also exhibits reduced sympathetic responses to multiple environmental or physiologic stimuli (Hays et al., 1995). Thus, it is not unexpected that decreased sympathetic responses to postural change should be found in depressive subjects. The greater extent to which parasympathetic responses are decreased in depressive subjects may partially be explained by the polyvagal theory (Porges, 1995), which relates lower vagal activity to certain behaviors and mental disorders (Porges, 2007; Porges and Furman, 2011). Furthermore, as observed in the study by Veith et al. (1983) and Stewart et al. (1992), plasma endocrine agents (such as nerepinephrine, dopamine and endothelin-1) that showed no significant differences in baseline function in subjects with depression or heart failure, demonstrated abnormal response to postural change. Because the concentration of plasma endocrine agents generally parallels the level of autonomic nervous system (ANS) activity, the observation partially explains our results that HRV disturbances could be present among the depressed subjects upon postural change although not present among the subjects in the resting position. Understanding the neural and endocrine mechanism underlying these changes may help us to elucidate the association between depressive disorders and changes in ANS function and to develop methods for regulating ANS function that could be used to treat depressive disorders (Gorman and Sloan, 2000). Further studies are needed to clarify the mechanisms responsible for the autonomic dysfunction observed in individuals with depressive disorders.
5. Limitation of the study Several limitations might have affected the results presented in this study. First, as this was a case-control study, the present results were limited to small sample size and possibility of selection bias due to various confounders (e.g., alcohol or smoking state) that led us to exclude some subjects. Further study should be undertaken to
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expand the sample size, and increase the age range of subjects, using a more stratified analysis. Second, our findings might be biased due to subjective reports. Third, evaluation of medical condition was based on interviews with patients and reviews of medical charts, so we could not exclude the possibility that subjects might have had undiagnosed medical conditions that could have affects on spectral HRV measures (Byrne et al., 2010; Nielsen et al., 2010). Fourth, in our study, the baseline measurements were performed sitting rather than supine, and the postural change measurements were performed from sitting to standing rather than supine to tilt or sitting. Using the endocrine challenge concept, we could anticipate observing even greater differences from normal if the studies were performed supine to standing and among more severely depressed patients. Further research will be undertaken on this point.
6. Conclusions Despite these limitations, we found that, following postural change, sympathetic responses are blunted and parasympathetic responses are accentuated in subjects with depressive disorders, suggesting that a relationship between depression disorders and ANS dysfunction exists. These findings lead to the conclusion that subjects with depressive disorders may have autonomic impairment and early signs of ANS dysfunction, and spectral analysis of HRV associated with postural change may be a more sensitive method than resting HRV analysis for detecting ANS dysfunction in depressive disorders. Role of funding source This work was supported by Grants from: 1. Key Laboratory of Psychiatric Disorders of Guangdong Province. 2. Program for Changjiang Scholars and Innovative Research Team in University (IRT1142). The role of the funding source was the following: 1. Fees for the subjects who participated and the staff of the laboratory. 2. Detection of ECG and analysis of HRV. 3. Payment for the relative materials.
Conflict of interest All authors declare no conflict of interest.
Acknowledgments The authors acknowledge all the subjects who participated and the staff of the laboratory for their hard work. Thanks are also due to Professors Chunquan Ou and Yaling Jiang for providing valuable suggestions on statistics and expression.
References Ahrens, T., Deuschle, M., Krumm, B., van der Pompe, G., den Boer, J.A., Lederbogen, F., 2008. Pituitary-adrenal and sympathetic nervous system responses to stress in women remitted from recurrent major depression. Psychosom. Med. 70, 461–467. Akselrod, S., Gordon, D., Ubel, F.A., Shannon, D.C., Berger, A.C., Cohen, R.J., 1981. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beatto-beat cardiovascular control. Science 213, 220–222. Barry, J., Campbell, S., Yeung, A.C., Raby, K.E., Selwyn, A.P., 1991. Waking and rising at night as a trigger of myocardial ischemia. Am. J. Cardiol. 67, 1067–1072. Brown, R.P., Gerbarg, P.L., Muench, F., 2013. Breathing practices for treatment of psychiatric and stress-related medical conditions. Psychiatr. Clin. N. Am. 36, 121–140. Byrne, M.L., Sheeber, L., Simmons, J.G., Davis, B., Shortt, J.W., Katz, L.F., Allen, N.B., 2010. Autonomic cardiac control in depressed adolescents. Depress. Anxiety 27, 1050–1056. Carnethon, M.R., Liao, D., Evans, G.W., Cascio, W.E., Chambless, L.E., Heiss, G., 2002a. Correlates of the shift in heart rate variability with an active postural change in a healthy population sample: the atherosclerosis risk in communities study. Am. Heart J. 143, 808–813.
273
Carnethon, M.R., Liao, D., Evans, G.W., Cascio, W.E., Chambless, L.E., Rosamond, W.D., Heiss, G., 2002b. Does the cardiac autonomic response to postural change predict incident coronary heart disease and mortality? The atherosclerosis risk in communities study. Am. J. Epidemiol. 155, 48–56. Carney, R.M., Freedland, K.E., Veith, R.C., 2005. Depression, the autonomic nervous system, and coronary heart disease. Psychosom. Med. 67 (Suppl 1), S29–S33. Dalack, G.W., Roose, S.P., 1990. Perspectives on the relationship between cardiovascular disease and affective disorder. J. Clin. Psychiatry 51 (Suppl. 4–9), 10–11. Dekker, J.M., Crow, R.S., Folsom, A.R., Hannan, P.J., Liao, D., Swenne, C.A., Schouten, E.G., 2000. Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC study. Atherosclerosis risk in communities. Circulation 102, 1239–1244. de Souza, A.C., Cisternas, J.R., de Abreu, L.C., Roque, A.L., Monteiro, C.B., Adami, F., Vanderlei, L.C., Sousa, F.H., Ferreira, L.L., Valenti, V.E, 2014. Fractal correlation property of heart rate variability in response to the postural change maneuver in healthy women. Int. Arch. Med. 7, 25. Eaker, E.D., Sullivan, L.M., Kelly-Hayes, M., D'Agostino, R.S., Benjamin, E.J., 2005. Tension and anxiety and the prediction of the 10-year incidence of coronary heart disease, atrial fibrillation, and total mortality: the Framingham offspring study. Psychosom. Med. 67, 692–696. Esler, M., 2004. An explanation of the unexpected efficacy of L-DOPS in pure autonomic failure. Clin. Auton. Res. 14, 356–357. Flaa, A., Eide, I.K., Kjeldsen, S.E., Rostrup, M., 2008. Sympathoadrenal stress reactivity is a predictor of future blood pressure: an 18-year follow-up study. Hypertension 52, 336–341. Glassman, A., 2008. Depression and cardiovascular disease. Pharmacopsychiatry 41, 221–225. Gorman, J.M., Sloan, R.P., 2000. Heart rate variability in depressive and anxiety disorders. Am. Heart J. 140, 77–83. Guzzetti, S., Piccaluga, E., Casati, R., Cerutti, S., Lombardi, F., Pagani, M., Malliani, A., 1988. Sympathetic predominance in essential hypertension: a study employing spectral analysis of heart rate variability. J. Hypertens. 6, 711–717. Harms, M.P., Wieling, W., Colier, W.N., Lenders, J.W., Secher, N.H., van Lieshout, J.J., 2010. Central and cerebrovascular effects of leg crossing in humans with sympathetic failure. Clin. Sci. 118, 573–581. Hays, R.D., Wells, K.B., Sherbourne, C.D., Rogers, W., Spritzer, K., 1995. Functioning and well-being outcomes of patients with depression compared with chronic general medical illnesses. Arch. Gen. Psychiatry 52, 11–19. Liao, D., Cai, J., Rosamond, W.D., Barnes, R.W., Hutchinson, R.G., Whitsel, E.A., Rautaharju, P., Heiss, G., 1997. Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study. The ARIC study. Atherosclerosis risk in communities study. Am. J. Epidemiol. 145, 696–706. Lombardi, F., Malliani, A., Pagani, M., Cerutti, S., 1996. Heart rate variability and its sympatho-vagal modulation. Cardiovasc. Res. 32, 208–216. Nielsen, T., Paquette, T., Solomonova, E., Lara-Carrasco, J., Colombo, R., Lanfranchi, P., 2010. Changes in cardiac variability after REM sleep deprivation in recurrent nightmares. Sleep 33, 113–122. Otzenberger, H., Gronfier, C., Simon, C., Charloux, A., Ehrhart, J., Piquard, F., Brandenberger, G., 1998. Dynamic heart rate variability: a tool for exploring sympathovagal balance continuously during sleep in men. Am. J. Physiol. 275, H946–H950. Pagani, M., Malfatto, G., Pierini, S., Casati, R., Masu, A.M., Poli, M., Guzzetti, S., Lombardi, F., Cerutti, S., Malliani, A., 1988. Spectral analysis of heart rate variability in the assessment of autonomic diabetic neuropathy. J. Auton. Nerv. Syst. 23, 143–153. Penninx, B.W., Beekman, A.T., Honig, A., Deeg, D.J., Schoevers, R.A., van Eijk, J.T., van Tilburg, W., 2001. Depression and cardiac mortality: results from a communitybased longitudinal study. Arch. Gen. Psychiatry 58, 221–227. Porges, S.W., 2007. The polyvagal perspective. Biol. Psychol. 74, 116–143. Porges, S.W., Furman, S.A., 2011. The early development of the autonomic nervous system provides a neural platform for social behavior: a polyvagal perspective. Infant Child Dev. 20, 106–118. Quintana, D.S., McGregor, I.S., Guastella, A.J., Malhi, G.S., Kemp, A.H., 2013. A metaanalysis on the impact of alcohol dependence on short-term resting-state heart rate variability: implications for cardiovascular risk. Alcohol.: Clin. Exp. Res. 37, E23–E29. Rabins, P.V., Harvis, K., Koven, S., 1985. High fatality rates of late-life depression associated with cardiovascular disease. J. Affect. Disord. 9, 165–167. Robles-Pina, R.A., 2011. Depression and self-concept: personality traits or coping styles in reaction to school retention of Hispanic adolescents. Depress. Res. Treat. (151469), 1-8. Roth, D.L., Ackerman, M.L., Okonkwo, O.C., Burgio, L.D., 2008. The four-factor model of depressive symptoms in dementia caregivers: a structural equation model of ethnic differences. Psychol. Aging 23, 567–576. Shinozaki, N, Yuasa, T, Takata, S., 2008. Cigarette smoking augments sympathetic nerve activity in patients with coronary heart disease. Int. Heart J. 49, 261–272. Smit, A.A., Halliwill, J.R., Low, P.A., Wieling, W., 1999. Pathophysiological basis of orthostatic hypotension in autonomic failure. J. Physiol. 519 (Pt 1), 1–10. Spiegelhalder, K., Fuchs, L., Ladwig, J., Kyle, S.D., Nissen, C., Voderholzer, U., Feige, B., Riemann, D., 2011. Heart rate and heart rate variability in subjectively reported insomnia. J. Sleep Res. 20, 137–145. Stein, P.K., Pu, Y., 2012. Heart rate variability, sleep and sleep disorders. Sleep Med. Rev. 16, 47–66. Stewart, D.J., Cernacek, P., Costello, K.B., Rouleau, J.L., 1992. Elevated endothelin-1 in heart failure and loss of normal response to postural change. Circulation 85, 510–517.
274
X.-l. Jiang et al. / Journal of Affective Disorders 175 (2015) 269–274
Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 93, 1043–1065. Tsuang, M.T., Woolson, R.F., Fleming, J.A., 1980. Premature deaths in schizophrenia and affective disorders. An analysis of survival curves and variables affecting the shortened survival. Arch. Gen. Psychiatry 37, 979–983. Tsuji, H., Venditti, F.J., Manders, E.S., Evans, J.C., Larson, M.G., Feldman, C.L., Levy, D., 1994. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham heart study. Circulation 90, 878–883. van Baak, M.A., 2008. Meal-induced activation of the sympathetic nervous system and its cardiovascular and thermogenic effects in man. Physiol Behav 94, 178–186. Vanheule, S., Desmet, M., Groenvynck, H., Rosseel, Y., Fontaine, J., 2008. The factor structure of the Beck Depression Inventory-II: an evaluation. Assessment 15, 177–187. Veith, RC, Raskind, MA, Barnes, RF, Gumbrecht, G, Ritchie, JL, Halter, JB, 1983. Tricyclic antidepressants and supine, standing, and exercise plasma norepinephrine levels. Clin. Pharmacol. Ther. 33, 763–769.
Veith, R.C., Lewis, N., Linares, O.A., Barnes, R.F., Raskind, M.A., Villacres, E.C., Murburg, M.M., Ashleigh, E.A., Castillo, S., Pascualy, M., Peskind, E.R., Halter, J. B, 1994. Sympathetic nervous system activity in major depression: Basal and desipramine-induced alterations in plasma norepinephrine kinet ics. Arch. Gen. Psychiatry. 51, 411–422. Vignatelli, L., Bisulli, F., Zaniboni, A., Naldi, I., Fares, J.E., Provini, F., Vetrugno, R., Plazzi, G., Tinuper, P., Montagna, P., 2005. Interobserver reliability of ICSD-R minimal diagnostic criteria for the parasomnias. J. Neurol. 252, 712–717. Ward, L.C., 2006. Comparison of factor structure models for the Beck Depression Inventory–II. Psychol. Assess. 18, 81–88. Wieling, W., van Lieshout, J.J., van Leeuwen, A.M., 1993. Physical manoeuvres that reduce postural hypotension in autonomic failure. Clin. Auton. Res. 3, 57–65. Zhou, L., Xiong, J., Lim, Y., Ruan, Y., Huang, C., Zhu, Y., Zhong, J.H., Xiao, Z., Zhou, X.F., 2013. Upregulation of blood proBDNF and its receptors in major depression. J. Affect. Disord. 150, 776–784.
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Research report
A blunted sympathetic and accentuated parasympathetic response to postural change in subjects with depressive disorders Xiao-ling Jiang a,n, Zheng-gang Zhang b, Yuanyuan Chen a, Cui-Ping Ye a, Ying Lei a, Lei Wu a, Ying Zhang a, Zhong-ju Xiao b,n a b
Department of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangdong Province 510515, China Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangdong Province 510515, China
art ic l e i nf o
a b s t r a c t
Article history: Received 31 July 2014 Received in revised form 8 January 2015 Accepted 8 January 2015 Available online 15 January 2015
Background: In recent years, the bi-directional relationship between depression and ANS dysfunction has received considerable attention, but findings remain inconclusive. In this study, we aimed to examine the spectral HRV response to postural change in subjects with depressive disorders and in healthy controls, in order to gain insight into the characteristics of autonomic nervous system (ANS) response to postural change in subjects with depressive disorders. Methods: We compared HRV response to postural change between subjects with depressive disorders and healthy controls aged 20–37 years. Depression severity was assessed by the self-reported Beck Depression Inventory-II (BDI-II). Spectral HRV was analyzed at two moments: 10 min seated rest and 10 min at standing position, with spontaneous breathing. Results: No significant differences existed in the resting spectral HRV indices between subjects with depressive disorders and controls, however, following postural change, the increasing level of LF and LF/HF was lower and the decreasing level of HF power was higher, in the individuals with depression than that in healthy subjects. The differences in the LF power, HF power and the LF/HF ratio between seated rest before standing up and after postural change were found negatively correlated with depression severity. Conclusion: We found a blunted sympathetic and accentuated parasympathetic response to postural change in subjects with depressive disorder, suggesting that the autonomic impairment and early ANS dysfunction may exist among depressed individuals. These findings indicated that spectral analysis of HRV associated with postural change may be a more sensitive method than resting HRV analysis for detecting ANS dysfunction in depressive disorders. Limitations: Further studies are needed to expand the sample size and to clarify the mechanisms responsible for the autonomic dysfunction observed in individuals with depressive disorders. & 2015 Elsevier B.V. All rights reserved.
Keywords: Heart rate variability Depressive Postural change
1. Introduction It is increasingly being recognized that depressive disorders are independently associated with an increased risk of cardiovascular disease (including fatal arrhythmias and coronary artery disease) (Carney et al., 2005; Rabins et al., 1985; Tsuang et al., 1980). Autonomic disturbances have been thought to be responsible for the increased cardiovascular risk observed in patients with depression (Dekker et al., 2000; Liao et al., 1997; Tsuji et al., 1994). Specifically, it was thought that depressive disorders might be associated with increased sympathetic activity, which lowers the threshold for cardiovascular disease
n
Corresponding authors. Fax: 86 20 61648604. E-mail addresses: [email protected] (X.-l. Jiang), [email protected] (Z.-j. Xiao). http://dx.doi.org/10.1016/j.jad.2015.01.009 0165-0327/& 2015 Elsevier B.V. All rights reserved.
(Dalack and Roose, 1990; Eaker et al., 2005; Flaa et al., 2008; Glassman, 2008; Penninx et al., 2001; Veith et al., 1994). However, other studies have reported decreased SNS activity in subjects with depressive disorders or no association between psychopathology and SNS activity (Ahrens et al., 2008; Esler, 2004; Roth et al., 2008). Thus, findings about the bi-directional relationship between depression and ANS function remain inconclusive. Spectral analysis of resting heart rate variability (HRV) is a noninvasive method often used to assess cardiac autonomic nervous activity (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996; Akselrod et al., 1981). However, baseline autonomic functioning varies with age, sex, weight, emotional state, and environmental or physiological stimuli (Spiegelhalder et al., 2011). Thus, because studies have used different methodological designs, it has been impossible to draw firm conclusions.
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In recent years, the spectral HRV response to postural change has been hypothesized to be a more sensitive measure of cardiac autonomic modulation than resting spectral HRV because cardiac autonomic dysfunction is thought to occur primarily through impairment of sympathetic response to environmental or physiological stimuli (Guzzetti et al., 1988; Lombardi et al., 1996; Carnethon et al., 2002a). Normal HRV activity in response to postural change reflects a shift from parasympathetic predominance at rest to sympathetic control while standing(de Souza et al., 2014). Some studies have reported an attenuated or absent HRV response to postural change in subjects with chronic diseases such as hypertension (Guzzetti et al., 1988) and diabetes (Pagani et al., 1988), suggesting that autonomic impairment and early sympathetic dysfunction may be present in such individuals. However, to our knowledge, HRV response to postural change has not been examined in subjects with depressive disorders. In this study, we aimed to examine the HRV response to postural change in subjects with depressive disorders and in healthy controls. The primary purpose of this study was to gain insight into the possible bi-directional relationship between depression and ANS dysfunction and hence to discover whether ANS response to postural change could be a marker of autonomic dysfunction and early sympathetic dysfunction in depressive disorders.
2. Methods 2.1. Subjects The study sample consisted of two groups of adult subjects: subjects with depressive disorders (n¼42; age, 28.377.8 years; range, 20–36 years), and healthy controls (n¼ 49; age, 30.178.1 years; range, 20–37 years). All the depressive disorder patients were from the inpatients of School of Public Health and Tropical Medicine of Southern Medical University. Informed consent was obtained from all subjects prior to commencement of the study, and the Ethics Committee of School of Public Health and Tropical Medicine in Southern Medical University approved all the procedures. The psychiatric diagnosis of depressive disorder in each patient was verified by a psychiatrist using criteria based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV), and each subject's history of psychiatric illness, medical disease, and medication use was evaluated by an interview and a medical chart review carefully (Robles-Pina, 2011; Vignatelli et al., 2005). Subjects were screened and excluded if they suffered from other serious psychiatric, somatic or sleep disorders, or they had a comorbid substance-related disorder. They consumed no illicit, prescription or OTC (over-the-counter) drugs as confirmed by physical and mental examination and biological analysis. Subjects were also excluded if they had the habits of cigarette smoking or alcohol consumption, that have a documented effect on the autonomic nervous system (Carnethon et al., 2002a, 2002b; Shinozaki, et al. 2008; Quintana, et al., 2013). If subjects suffered from hypertension (presence of systolic blood pressure Z140 mmHg; diastolic blood pressure Z90 mmHg), diabetes (fasting glucose Z126 mg/dL), cardiovascular disease, severe cardiac arrhythmia, a frequent ectopic heartbeat, or an acute medical illness within 3 months of the start of the study, they were then excluded from the study. Any medications that have a documented effect on the autonomic nervous system (e.g. βblockade and anticholinergic drugs) were stopped at least 14 days prior to the recordings (Zhou et al., 2013). 2.2. Study design Volunteers were instructed to avoid consuming alcohol, caffeine, smoking and substances that influence the ANS for 24 h
before evaluation. All procedures necessary for the data collection were explained to the individuals. Data were collected between 8 and 12 a.m. in our laboratory under controlled temperature (21– 25 1C) and humidity (50–60%). Food intake also has effects on autonomic function (van Baak, 2008), so the postural change tests were conducted in a fasting state. After the initial evaluation the heart monitor belt was then placed over the thorax and aligned with the distal third of the sternum, and the polar heart rate receiver was placed on the wrist. The subject remained seated at rest with spontaneous breathing. After 10 min the volunteers quickly stood up from a seated position in up to three seconds according to verbal command and remained standing for 10 min (de Souza et al., 2014). Heart rate variability (HRV) was analyzed at two moments: 10 min seated rest with spontaneous breathing, and 10 min at standing position. The subjects were instructed to avoid talking and moving during the data collection. 2.3. Measures 2.3.1. Beck Depression Inventory (BDI) Depression severity was assessed by the self-reported Beck Depression Inventory-II (BDI-II) (Vanheule et al., 2008; Ward, 2006), which is one of the most commonly used self-report instruments for estimating the severity of depression. The total score indicates whether the individual presents a mild, moderate or major depression. The BDI-II consists of 21 items, each of which is scored on a scale from 0 to 3. The maximum score is 63. The recommended cutoff for minimal depression is 13, whereas a score of 14–19 indicates mild, 20–28 moderate and 29–63 serious depression.
2.3.2. Analysis of spectral HRV The R–R intervals (RRI) were computed from the electrocardiogram (ECG). All the QRS complexes were detected by Matlab (Matlab2007a) program, and the RRI time series were obtained. For maximum precision in measurement of the RRI data, artifacts were automatically detected using the following criteria: RRI o350 ms or RRI4 1500 ms (Barry et al., 1991; Brown et al., 2013). For calculation of the spectral indices we used the HRV Analysis software (Kubios HRV v.1.1 for Windows, Biomedical Signal Analysis Standard). Spectral HRV measures include high-frequency power (HF: 0.15–0.4 Hz), low-frequency power (LF: 0.04–0.15 Hz), and very-low-frequency power (VLF: 0.003–0.04 Hz). LF power is thought to be modulated by both sympathetic and parasympathetic activities, whereas HF power is mainly modulated by parasympathetic activity. The LF/HF ratio was computed as a measure of the sympathovagal balance towards sympathetic activity. The very low frequency (VLF) power is assumed to be due to long-term regulatory mechanisms such as humoral factors, temperature, and other slow components (Otzenberger et al., 1998; Stein and Pu, 2012). 2.4. Statistical analysis All participants were divided into two groups: depressive disorders and normal controls. Demographic variables were compared with a non-parametric test (Mann–Whitney U test) and Chisquared tests or student's t test. Analysis of variance (AVONA) and pairwise test comparisons were carried out to compare HRV responses to postural change in subjects with depressive disorders and those without. All variables were presented with standard deviations if there was no specified explanation (mean7SEM). All data calculations were performed with SPSS 13.0 (Chicago, IL, USA). A two-sided α-level of significance of 0.05 was used for all tests, and a value of Po0.05 was considered statistically significant.
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Table 1 Demographic data between depression disorder groups and normal control group. Depression disorder (n¼42) Controls (n¼ 49) P value Age, year Male/female Height (m) Weight (kg) BMI Heart rate (beats/min) SAP (mmHg) DAP(mmHg) Total BDI score
28.3 7 7.8 24/18 1.62 7 0.11 52.5 7 14.3 21.7 7 2.1 73.5 78.9 101.9 7 11.2 73.6 713.1 27.57 10.9n
30.1 78.1 29/20 1.63 7 0.09 52.9 7 15.7 22.1 72.6 72.9 79.2 103.5 7 13.6 74.17 11.9 4.1 73.8
0.315 0.642 0. 356 0.624 0.789 0.662 0.4787 0.512 0.000
Mean values ( 7 SE) for the indices of each group. n
Po 0.05 vs controls.
Table 2 Spectral HRV during seated rest between depression disorder groups and normal control group. Measure
Depression disorder (n ¼42) Controls (n ¼49) P value
Heart rate (beats/min) 73.5 7 8.9 VLF power, (ms2/Hz) 883.2 7 392.1 LF power, (ms2/Hz) 789.6 7 302.3 HF power, (ms2/Hz) 822.17 317.6 LF/HF 1.4 7 0.6
72.9 7 9.2 839.5 7 305.9 818.5 7 343.8 765.9 7 362.5 1.6 7 0.5
0.662 0.445 0.325 0.862 0.331
Mean values ( 7 SE) for the indices of each group.
3. Results 3.1. Demographic data The demographic data are presented in Table 1. The depressive disorder group and normal control group did not differ in terms of the age, gender ratio, BMI, heart rate and blood pressure. The depressive disorder group was rated higher on the BDI-II score than the normal control group (27.5 710.9 vs 4.1 73.8, P ¼0.000). 3.2. Spectral HRV at seated rest in the two groups For the spectral HRV at seated rest, no significant differences between two groups were detected for all the spectral HRV indices (Table 2). These results indicated that ANS activity in the depressive disorder group was not significantly different from that in the normal control group. 3.3. Spectral HRV observed with standing up in the two groups Table 3 presents data related to the spectral HRV indices observed with standing up in the depressive disorder group and normal control group. The heart rate increased significantly during standing in both groups (73.578.9–80.1710.3 vs 72.979.2–78.6711.6). As to spectral HRV indices, we observed that both the LF power and the LF/HF ratio increased and that the HF power decreased after standing up in the normal control group. No significant difference was observed in VLF power after standing up compared with seated rest in both groups. A significant increase in the LF/HF ratio and a decrease in HF power after standing up were observed in the depressive disorder group; no significant difference in LF power was observed. Differences in HRV between seated rest before standing up and during standing were compared across different degrees of depression severity in the depressive disorder group (Table 4). Using the self-reported Beck Depression Inventory-II (BDI-II), all the individuals were categorized as having one of four grades of depression: none, mild, moderate or serious depression. The D values, which are equal to the difference between the HRV value
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after standing up and the HRV value during seated rest, demonstrated that heart rate (HR), LF power, HF power and the LF/HF ratio varied with depression severity. Compared with the nondepressive (control) group, the mildly depressive group exhibited no significant difference in HR and spectral HRV indices, but moderate and serious depressive groups exhibited significant differences in HR and in most of the spectral HRV indices, with the exception of VLF power. The differences in the LF power, HF power and the LF/HF ratio between seated rest before standing up and after postural change exhibited negative correlations with depression severity, indicating that the increasing of sympathetic activity and sympathovagal balance to postural change is increasingly attenuated with increasing depression severity, and the decreasing of parasympathetic activity to postural change are increasingly accentuated with increasing depression severity.
4. Discussion The major findings of this study were the following: (a) no significant differences existed in the resting spectral HRV indices between subjects with depressive disorders and controls. (b) A blunted spectral sympathetic and accentuated parasympathetic response to postural change was identified in subjects with depressive disorders. In humans, the upright position challenges the cardiovascular system with the gravitational displacement of blood to lower parts of the body, and the cardiovascular system responds with an immediate translocation of blood toward the heart and a faster cardiac output response, resulting in a reduction in cerebral perfusion pressure (Carnethon et al., 2002a; Harms et al., 2010). Adjustment to the postural decrease in central blood volume involves increased systemic vascular resistance through autonomic reflex activity. However, subjects with autonomic dysfunction lack this ability to increase vasomotor tone and thus face an increasing risk of cardiovascular disease (Carnethon et al., 2002b; Smit et al., 1999). A large number of studies have demonstrated that depressive disorders are independently associated with cardiovascular diseases, and autonomic disturbances are thought to be responsible for the increased cardiovascular risk in patients with depression (Carney et al., 2005; Rabins et al., 1985; Tsuang et al., 1980). Thus, we assume that (a) the resting spectral HRV may be altered in patients with depression, and (b) the spectral HRV observed in response to postural change may be altered in patients with depression. The first hypothesis, that the altered spectral HRV may be altered in patients with depression, was not supported by our results. We compared HRV between subjects with depressive disorders and healthy controls aged 20–37 years in the state of seated rest during wakefulness, and we found no significant increase or decrease in spectral HRV in subjects with depressive disorders compared with (Table 2). These results differ from those obtained in most previous studies, which have reported that depressive disorders are associated with autonomic disturbances (Dalack and Roose, 1990; Eaker et al., 2005; Flaa et al., 2008; Glassman, 2008; Penninx et al., 2001). Resting HRV could be affected by many factors, such as age, sex, weight, emotional state and different experimental conditions (Spiegelhalder et al., 2011). Thus, it is possible that the results of different studies have been inconsistent because different methodological designs have been used in these studies. The second hypothesis, that the spectral HRV response may be altered in response to postural change in patients with depression, was supported by our results. The results obtained for the normal control group were consistent with the results of previous studies (Harms et al., 2010; Spiegelhalder et al., 2011; Wieling et al., 1993). Heart rate increased significantly after standing up compared with
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Table 3 HRV indices between before and after the PCM test in depression disorder group and normal control group. Index
Depression disorder (n¼ 42)
HR, beats/min VLF (ms2/Hz) LF (ms2/Hz) HF (ms2/Hz) LF/HF
P
Seated (d)
Standing (d)
73.5 7 8.9 883.2 7 392.1 789.6 7 302.3 822.17 317.6 1.4 7 0.6
80.1 710.3n 816.5 7368.9 815.6 7352.6 412.9 7269.8n 2.7 71.2n
P
Controls(n¼ 49)
0.027 0.228 0.486 0.035 0.029
Seated (c)
Standing (c)
72.9 79.2 839.5 7305.9 818.5 7343.8 765.9 7362.5 1.6 70.5
78.67 11.6# 889.7 7 453.2 993.97 396.8# 362.87 222.7# 3.17 2.1#
0.031 0.326 0.039 0.024 0.008
Mean values ( 7 SE) for the indices of each group. n
#
Po 0.05 vs seated (d). Po 0.05 vs seated (c).
Table 4 HRV indices differences between before and after the PCM test in different depression severity group and normal control group. Index
HR, beats/min LF (ms2/Hz) HF (ms2/Hz) LF/HF
P (AVONA)
Controls (n¼49)
Depression disorder
D (control)
D (total, n¼ 42)
D (mild, n¼ 12)
D (moderate, n ¼19)
D (serious, n¼ 11)
6.8 7 5.4 200.4 7 58.9 227.8 7 215.9 1.5 7 0.8
7.5 7 5.7n 144.7 7 45.1n 289.5 7 181.4n 0.9 7 0.7n
6.9 75.8 189.8 749.5 269.9 7209.5 1.3 70.9
7.8 75.6n 132.4 740.2n 287.3 7172.1n 0.8 70.6n
8.9 7 6.1n 110.9 7 48.2n 319.6 7 142.8nn 0.6 7 0.4n
0.028 0.038 0.021 0.019
Linear regression P value
R
0.036 0.029 0.041 0.035
0.621 0.593 0.428 0.477
Mean values ( 7 SE) for the indices of each group. D (mild) ¼ Standing (mild depression)-seated (mild depression). D (moderate)¼ Standing (moderate depression)-seated (moderate depression). D (serious) ¼ Standing (serious depression)-seated (serious depression). D (control) ¼ Standing(control)-seated (control). n
Po 0.05 vs D (control). Po 0.01 vs D (control).
nn
seated rest. Most of the spectral HRV indices, with the exception of VLF power, changed with the transition from sitting to standing. The observed increases in HR, LF power and the LF/HF ratio and the decrease in HF power reflected the shift in ANS activity from predominantly parasympathetic at rest to sympathetic control after standing up. Notably, a significant increase in the LF/HF ratio and a decrease in HF power were observed in the depressive disorder group after standing up, whereas no significant difference in the LF power was observed. Thus, the absence of change in LF power observed in depressive subjects differ from the increase in LF power observed in controls. Compared with the non-depressive (control) group, the mild depressive group exhibited no significant difference in the HR and spectral HRV indices, but the groups with moderate and serious depression exhibited significant differences in the HR and in most of the spectral HRV indices. The increase in LF power and in the LF/HF observed when an individual's postural changed from sitting to standing were lower in the depressive subjects than that in healthy subjects. The differences in the LF power and the LF/HF ratio between seated rest before standing up and after postural change were found negatively correlated with depression severity, indicating that the increases of sympathetic responses to postural change are attenuated with increasing severity of depression. The decrease in HF power observed when a individual's postural changed from sitting to standing was higher in the depressive subjects than that in healthy subjects. The difference in HF power was also found to be negatively correlated with depression severity, indicating that the decrease of parasympathetic responses to postural change is accentuated with increasing severity of depression. These results confirm that ANS responses to postural change are altered in subjects with depressive disorders, leading to the conclusion that autonomic dysfunction and early signs of ANS damage may exist in individuals with depressive disorders. Our study also indicated that spectral HRV in response to postural change may be a more sensitive method than resting HRV for evaluating ANS dysfunction in depressive disorders. The mechanisms responsible for altered spectral HRV in response to postural change in individuals with depressive disorders are
incompletely understood. Depressive disorders are generalized, systemic syndromes. A person having a depressive disorder not only exhibits a very low mood and multiple physical symptoms, such as insomnia, fatigue, headaches, or digestive problems, but also exhibits reduced sympathetic responses to multiple environmental or physiologic stimuli (Hays et al., 1995). Thus, it is not unexpected that decreased sympathetic responses to postural change should be found in depressive subjects. The greater extent to which parasympathetic responses are decreased in depressive subjects may partially be explained by the polyvagal theory (Porges, 1995), which relates lower vagal activity to certain behaviors and mental disorders (Porges, 2007; Porges and Furman, 2011). Furthermore, as observed in the study by Veith et al. (1983) and Stewart et al. (1992), plasma endocrine agents (such as nerepinephrine, dopamine and endothelin-1) that showed no significant differences in baseline function in subjects with depression or heart failure, demonstrated abnormal response to postural change. Because the concentration of plasma endocrine agents generally parallels the level of autonomic nervous system (ANS) activity, the observation partially explains our results that HRV disturbances could be present among the depressed subjects upon postural change although not present among the subjects in the resting position. Understanding the neural and endocrine mechanism underlying these changes may help us to elucidate the association between depressive disorders and changes in ANS function and to develop methods for regulating ANS function that could be used to treat depressive disorders (Gorman and Sloan, 2000). Further studies are needed to clarify the mechanisms responsible for the autonomic dysfunction observed in individuals with depressive disorders.
5. Limitation of the study Several limitations might have affected the results presented in this study. First, as this was a case-control study, the present results were limited to small sample size and possibility of selection bias due to various confounders (e.g., alcohol or smoking state) that led us to exclude some subjects. Further study should be undertaken to
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expand the sample size, and increase the age range of subjects, using a more stratified analysis. Second, our findings might be biased due to subjective reports. Third, evaluation of medical condition was based on interviews with patients and reviews of medical charts, so we could not exclude the possibility that subjects might have had undiagnosed medical conditions that could have affects on spectral HRV measures (Byrne et al., 2010; Nielsen et al., 2010). Fourth, in our study, the baseline measurements were performed sitting rather than supine, and the postural change measurements were performed from sitting to standing rather than supine to tilt or sitting. Using the endocrine challenge concept, we could anticipate observing even greater differences from normal if the studies were performed supine to standing and among more severely depressed patients. Further research will be undertaken on this point.
6. Conclusions Despite these limitations, we found that, following postural change, sympathetic responses are blunted and parasympathetic responses are accentuated in subjects with depressive disorders, suggesting that a relationship between depression disorders and ANS dysfunction exists. These findings lead to the conclusion that subjects with depressive disorders may have autonomic impairment and early signs of ANS dysfunction, and spectral analysis of HRV associated with postural change may be a more sensitive method than resting HRV analysis for detecting ANS dysfunction in depressive disorders. Role of funding source This work was supported by Grants from: 1. Key Laboratory of Psychiatric Disorders of Guangdong Province. 2. Program for Changjiang Scholars and Innovative Research Team in University (IRT1142). The role of the funding source was the following: 1. Fees for the subjects who participated and the staff of the laboratory. 2. Detection of ECG and analysis of HRV. 3. Payment for the relative materials.
Conflict of interest All authors declare no conflict of interest.
Acknowledgments The authors acknowledge all the subjects who participated and the staff of the laboratory for their hard work. Thanks are also due to Professors Chunquan Ou and Yaling Jiang for providing valuable suggestions on statistics and expression.
References Ahrens, T., Deuschle, M., Krumm, B., van der Pompe, G., den Boer, J.A., Lederbogen, F., 2008. Pituitary-adrenal and sympathetic nervous system responses to stress in women remitted from recurrent major depression. Psychosom. Med. 70, 461–467. Akselrod, S., Gordon, D., Ubel, F.A., Shannon, D.C., Berger, A.C., Cohen, R.J., 1981. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beatto-beat cardiovascular control. Science 213, 220–222. Barry, J., Campbell, S., Yeung, A.C., Raby, K.E., Selwyn, A.P., 1991. Waking and rising at night as a trigger of myocardial ischemia. Am. J. Cardiol. 67, 1067–1072. Brown, R.P., Gerbarg, P.L., Muench, F., 2013. Breathing practices for treatment of psychiatric and stress-related medical conditions. Psychiatr. Clin. N. Am. 36, 121–140. Byrne, M.L., Sheeber, L., Simmons, J.G., Davis, B., Shortt, J.W., Katz, L.F., Allen, N.B., 2010. Autonomic cardiac control in depressed adolescents. Depress. Anxiety 27, 1050–1056. Carnethon, M.R., Liao, D., Evans, G.W., Cascio, W.E., Chambless, L.E., Heiss, G., 2002a. Correlates of the shift in heart rate variability with an active postural change in a healthy population sample: the atherosclerosis risk in communities study. Am. Heart J. 143, 808–813.
273
Carnethon, M.R., Liao, D., Evans, G.W., Cascio, W.E., Chambless, L.E., Rosamond, W.D., Heiss, G., 2002b. Does the cardiac autonomic response to postural change predict incident coronary heart disease and mortality? The atherosclerosis risk in communities study. Am. J. Epidemiol. 155, 48–56. Carney, R.M., Freedland, K.E., Veith, R.C., 2005. Depression, the autonomic nervous system, and coronary heart disease. Psychosom. Med. 67 (Suppl 1), S29–S33. Dalack, G.W., Roose, S.P., 1990. Perspectives on the relationship between cardiovascular disease and affective disorder. J. Clin. Psychiatry 51 (Suppl. 4–9), 10–11. Dekker, J.M., Crow, R.S., Folsom, A.R., Hannan, P.J., Liao, D., Swenne, C.A., Schouten, E.G., 2000. Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC study. Atherosclerosis risk in communities. Circulation 102, 1239–1244. de Souza, A.C., Cisternas, J.R., de Abreu, L.C., Roque, A.L., Monteiro, C.B., Adami, F., Vanderlei, L.C., Sousa, F.H., Ferreira, L.L., Valenti, V.E, 2014. Fractal correlation property of heart rate variability in response to the postural change maneuver in healthy women. Int. Arch. Med. 7, 25. Eaker, E.D., Sullivan, L.M., Kelly-Hayes, M., D'Agostino, R.S., Benjamin, E.J., 2005. Tension and anxiety and the prediction of the 10-year incidence of coronary heart disease, atrial fibrillation, and total mortality: the Framingham offspring study. Psychosom. Med. 67, 692–696. Esler, M., 2004. An explanation of the unexpected efficacy of L-DOPS in pure autonomic failure. Clin. Auton. Res. 14, 356–357. Flaa, A., Eide, I.K., Kjeldsen, S.E., Rostrup, M., 2008. Sympathoadrenal stress reactivity is a predictor of future blood pressure: an 18-year follow-up study. Hypertension 52, 336–341. Glassman, A., 2008. Depression and cardiovascular disease. Pharmacopsychiatry 41, 221–225. Gorman, J.M., Sloan, R.P., 2000. Heart rate variability in depressive and anxiety disorders. Am. Heart J. 140, 77–83. Guzzetti, S., Piccaluga, E., Casati, R., Cerutti, S., Lombardi, F., Pagani, M., Malliani, A., 1988. Sympathetic predominance in essential hypertension: a study employing spectral analysis of heart rate variability. J. Hypertens. 6, 711–717. Harms, M.P., Wieling, W., Colier, W.N., Lenders, J.W., Secher, N.H., van Lieshout, J.J., 2010. Central and cerebrovascular effects of leg crossing in humans with sympathetic failure. Clin. Sci. 118, 573–581. Hays, R.D., Wells, K.B., Sherbourne, C.D., Rogers, W., Spritzer, K., 1995. Functioning and well-being outcomes of patients with depression compared with chronic general medical illnesses. Arch. Gen. Psychiatry 52, 11–19. Liao, D., Cai, J., Rosamond, W.D., Barnes, R.W., Hutchinson, R.G., Whitsel, E.A., Rautaharju, P., Heiss, G., 1997. Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study. The ARIC study. Atherosclerosis risk in communities study. Am. J. Epidemiol. 145, 696–706. Lombardi, F., Malliani, A., Pagani, M., Cerutti, S., 1996. Heart rate variability and its sympatho-vagal modulation. Cardiovasc. Res. 32, 208–216. Nielsen, T., Paquette, T., Solomonova, E., Lara-Carrasco, J., Colombo, R., Lanfranchi, P., 2010. Changes in cardiac variability after REM sleep deprivation in recurrent nightmares. Sleep 33, 113–122. Otzenberger, H., Gronfier, C., Simon, C., Charloux, A., Ehrhart, J., Piquard, F., Brandenberger, G., 1998. Dynamic heart rate variability: a tool for exploring sympathovagal balance continuously during sleep in men. Am. J. Physiol. 275, H946–H950. Pagani, M., Malfatto, G., Pierini, S., Casati, R., Masu, A.M., Poli, M., Guzzetti, S., Lombardi, F., Cerutti, S., Malliani, A., 1988. Spectral analysis of heart rate variability in the assessment of autonomic diabetic neuropathy. J. Auton. Nerv. Syst. 23, 143–153. Penninx, B.W., Beekman, A.T., Honig, A., Deeg, D.J., Schoevers, R.A., van Eijk, J.T., van Tilburg, W., 2001. Depression and cardiac mortality: results from a communitybased longitudinal study. Arch. Gen. Psychiatry 58, 221–227. Porges, S.W., 2007. The polyvagal perspective. Biol. Psychol. 74, 116–143. Porges, S.W., Furman, S.A., 2011. The early development of the autonomic nervous system provides a neural platform for social behavior: a polyvagal perspective. Infant Child Dev. 20, 106–118. Quintana, D.S., McGregor, I.S., Guastella, A.J., Malhi, G.S., Kemp, A.H., 2013. A metaanalysis on the impact of alcohol dependence on short-term resting-state heart rate variability: implications for cardiovascular risk. Alcohol.: Clin. Exp. Res. 37, E23–E29. Rabins, P.V., Harvis, K., Koven, S., 1985. High fatality rates of late-life depression associated with cardiovascular disease. J. Affect. Disord. 9, 165–167. Robles-Pina, R.A., 2011. Depression and self-concept: personality traits or coping styles in reaction to school retention of Hispanic adolescents. Depress. Res. Treat. (151469), 1-8. Roth, D.L., Ackerman, M.L., Okonkwo, O.C., Burgio, L.D., 2008. The four-factor model of depressive symptoms in dementia caregivers: a structural equation model of ethnic differences. Psychol. Aging 23, 567–576. Shinozaki, N, Yuasa, T, Takata, S., 2008. Cigarette smoking augments sympathetic nerve activity in patients with coronary heart disease. Int. Heart J. 49, 261–272. Smit, A.A., Halliwill, J.R., Low, P.A., Wieling, W., 1999. Pathophysiological basis of orthostatic hypotension in autonomic failure. J. Physiol. 519 (Pt 1), 1–10. Spiegelhalder, K., Fuchs, L., Ladwig, J., Kyle, S.D., Nissen, C., Voderholzer, U., Feige, B., Riemann, D., 2011. Heart rate and heart rate variability in subjectively reported insomnia. J. Sleep Res. 20, 137–145. Stein, P.K., Pu, Y., 2012. Heart rate variability, sleep and sleep disorders. Sleep Med. Rev. 16, 47–66. Stewart, D.J., Cernacek, P., Costello, K.B., Rouleau, J.L., 1992. Elevated endothelin-1 in heart failure and loss of normal response to postural change. Circulation 85, 510–517.
274
X.-l. Jiang et al. / Journal of Affective Disorders 175 (2015) 269–274
Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 93, 1043–1065. Tsuang, M.T., Woolson, R.F., Fleming, J.A., 1980. Premature deaths in schizophrenia and affective disorders. An analysis of survival curves and variables affecting the shortened survival. Arch. Gen. Psychiatry 37, 979–983. Tsuji, H., Venditti, F.J., Manders, E.S., Evans, J.C., Larson, M.G., Feldman, C.L., Levy, D., 1994. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham heart study. Circulation 90, 878–883. van Baak, M.A., 2008. Meal-induced activation of the sympathetic nervous system and its cardiovascular and thermogenic effects in man. Physiol Behav 94, 178–186. Vanheule, S., Desmet, M., Groenvynck, H., Rosseel, Y., Fontaine, J., 2008. The factor structure of the Beck Depression Inventory-II: an evaluation. Assessment 15, 177–187. Veith, RC, Raskind, MA, Barnes, RF, Gumbrecht, G, Ritchie, JL, Halter, JB, 1983. Tricyclic antidepressants and supine, standing, and exercise plasma norepinephrine levels. Clin. Pharmacol. Ther. 33, 763–769.
Veith, R.C., Lewis, N., Linares, O.A., Barnes, R.F., Raskind, M.A., Villacres, E.C., Murburg, M.M., Ashleigh, E.A., Castillo, S., Pascualy, M., Peskind, E.R., Halter, J. B, 1994. Sympathetic nervous system activity in major depression: Basal and desipramine-induced alterations in plasma norepinephrine kinet ics. Arch. Gen. Psychiatry. 51, 411–422. Vignatelli, L., Bisulli, F., Zaniboni, A., Naldi, I., Fares, J.E., Provini, F., Vetrugno, R., Plazzi, G., Tinuper, P., Montagna, P., 2005. Interobserver reliability of ICSD-R minimal diagnostic criteria for the parasomnias. J. Neurol. 252, 712–717. Ward, L.C., 2006. Comparison of factor structure models for the Beck Depression Inventory–II. Psychol. Assess. 18, 81–88. Wieling, W., van Lieshout, J.J., van Leeuwen, A.M., 1993. Physical manoeuvres that reduce postural hypotension in autonomic failure. Clin. Auton. Res. 3, 57–65. Zhou, L., Xiong, J., Lim, Y., Ruan, Y., Huang, C., Zhu, Y., Zhong, J.H., Xiao, Z., Zhou, X.F., 2013. Upregulation of blood proBDNF and its receptors in major depression. J. Affect. Disord. 150, 776–784.
