Previous studies have revealed that the presence of depressive symptoms increases both the risk of coronary heart disease and its mortality rate.[1, 2] Reduced parasympathetic activity reflected in abnormal heart rate variability (HRV) measures has been reported to underlie this comorbidity. Change in HRV is now considered to be the link between depression and heart disease.
In addition, it has been revealed that depression itself, without heart complications, also manifests HRV changes, including reduced vagal modulation.[4, 5] A recent review supports this perspective. The severity of depressive symptoms has been correlated with a reduction of parasympathetic activity. Psychological studies have further reported that affective changes occurring not only in depression but also in normal subjects are accompanied by HRV changes. HRV measures serve as parameters for analyzing depressive states.
Because autonomic complaints, including appetite and weight loss, are frequently observed in depression, HRV, heart rate (HR) and the like are natural measures for evaluating the clinical symptoms of depressive states. Because HRV is also related to arousal changes, such as sleep/wakefulness,[9, 10] it is possible to use HRV measures to analyze not only the autonomic condition but also the arousal state of patients.
In most previous studies on depression, HRV has been evaluated under resting conditions, with decreases in vagal activity having been reported. In some studies, reduced vagal activity has been ascertained during procedures designed to activate the parasympathetic system, including deep breathing and the Valsalva maneuver.[5, 11] Depressive patients have shown a lower response of HRV parameters to regular deep breathing.[12, 13] In a study using motor tasks, reduction of the parasympathetic index during a handgrip task was attenuated in the presence of depression. Because recording data during various behavioral states adds information regarding the control of arousal, it would be important to analyze not only the resting state but also the activated state.
Autonomic activity is modulated in response to various behavioral changes. During the aroused condition, balance is shifted toward sympathetic activation. In contrast, when the subject is at rest, parasympathetic activity overwhelms sympathetic activity. This natural reactivity of the autonomic system in response to arousal changes is of interest and should be confirmed in depression. Because disturbed reactivity of the autonomic and arousal systems is possibly related to various somatic and psychological symptoms of depression, assessment of reactivity can add new insights into pathophysiological analysis.
The present study on depression focused on the reactivity of HRV and HR, which were measured both at rest and in a task condition, to evaluate responsiveness to the task execution. Rest parameters were recorded not only during the initial rest condition before the task but also during the period following the task to investigate the effects of task execution on the subsequent rest condition. The autonomic measures during the initial rest condition, during the task execution and during the post-task rest condition were compared between the depressed and control subjects.
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The subjects were 22 drug-naïve patients (39.5 ± 10.6 years old, mean ± SD; 10 men and 12 women) diagnosed as having depression based on DSM-IV criteria and 47 age- and sex-matched control subjects (40.7 ± 12.2 years old; 21 men and 26 women). The control subjects had no history of psychiatric, neurological or cardiac disorders. There was no difference in the ratio of smokers between the depressed (n = 3) and the control subjects (n = 6, χ2-test = 0.019, P = 0.89). None of the subjects drank alcohol or coffee from the previous day of HRV measurement. The smokers did not smoke on the day of measurement. The severities of symptomatology were assessed using the Self-Rating Depression Scale (SDS) and the State and Trait Anxiety Inventory (STAI). Written informed consent to participate in this study was obtained from all subjects. The protocol of the study was approved by the ethics committee of Shizuoka Saiseikai General Hospital.
Electrocardiograms (ECG) were measured conventionally with a gain of 10 000 and time constant of 0.1 s, and the signals were stored on a computer for off-line analysis (Makin2, GMS, Japan). R peaks were used to create the R–R interval trend data, and their fluctuations were analyzed using the maximum entropy method (MemCalc, GMS, Japan). The maximum entropy method was selected for the power spectrum analysis because it has been successfully applied to trend data with a minimum duration of 30 s and is useful for studies incorporating measurements of multiple behavioral states. Using the R–R interval data, low-frequency (LF) and high-frequency (HF) components of the spectrum were measured every 2 s by integrating the power at corresponding frequency intervals (0.04–0.15 Hz for LF, 0.15–0.4 Hz for HF) for the preceding 30-s period. R–R intervals were also converted to HR every 2 s (/min). Previous pharmacological studies have shown that HF and LF/HF reflect parasympathetic and sympathetic activities, respectively.
During the experiment, the subject was seated on a chair with the ECG electrodes attached to the chest or the arm. ECG was recorded in three different conditions: initial rest, task and post-task rest conditions. First, the subjects were instructed to relax as much as possible in the chair for approximately 100 s (the initial rest condition). Then, the subjects were engaged in a random number generation task for 100 s (the task condition). After the task, ECG was recorded for another 2-min period in the relaxed state (the post-task rest condition). Figure 1a illustrates one example of a control subject. The data show a decrease of HF and an increase of LF/HF and HR during the task condition (‘Task’ in Fig. 1a) followed by recovery in the post-task rest condition (‘After’ in Fig. 1a). Respiration was monitored, and its frequency was confirmed to be within the range of 0.15–0.4 Hz in each subject, as previously reported.[19, 21, 22]
Figure 1. (a) An example of control heart-rate variability (HRV) data. High frequency (HF) component decreases in response to task execution, whereas the ratio of low-frequency (LF) component to HF and heart rate (HR) increase. (b) HRV parameters during the initial rest condition (Rest), the task execution (Task) and the rest condition after the task (After), in the control and the depressed groups. Data from the same subject are connected. Statistically significant differences from the control data are indicated by asterisks on the depression data (t-test, P < 0.05). The increase of HF after the task in the depressed subjects is indicated by a filled triangle.
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HF, LF/HF and HR were averaged in the interval from 30 s to 60 s after the onset of each condition to exclude any data at the beginning of each new period that might still reflect the previous condition. The data during the task and the post-task resting conditions were also expressed as ratios to the resting condition (i.e., the Task/Rest ratio and the After/Rest ratio); similarly, the post-task rest condition was also expressed as a ratio to the task condition (i.e., the After/Task ratio). The effect of condition on each group was evaluated using anova with repeated measures with the post-hoc Newman–Keuls test (Statistica, Statsoft Japan, Tokyo, Japan). Differences between the control and depressed groups were evaluated using the Student's t-test, and correlations between parameters were examined using Pearson's correlation coefficient (Prism 5, Graph Pad, La Jolla, CA, USA).
In the random number generation task, the subjects were instructed to orally generate a random series of 100 digits using the numbers 0–9 at the rate of 1 Hz, as if they were repeatedly casting a die. The generation rate was indicated by a metronome click sound. They were requested to concentrate on this task as much as possible. To evaluate randomness in the generated digit series, counting bias (CB; frequency of counting up or down), interval bias (IB; frequency of same inter-digit intervals) and random number generation index (RNG; frequency of same digit pairs) were calculated according to our previous study.
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For the control subjects, the results clearly showed that the sympathetic index (LF/HF) increases and the parasympathetic index (HF) decreases during the task condition (Fig. 1a,b). Both indices return to initial levels during the rest condition after the task. This HRV profile is a confirmation of previous knowledge about the autonomic system, which has been shown to exhibit a shift of balance toward sympathetic activation with arousal elevation. HR reacts in the same way as LF/HF. The present study has clearly shown that HRV measurement is useful in analyzing autonomic activity and reactivity and is suitable for assessing the autonomic and arousal changes found in psychiatric disorders, including depression. It is also possible to record these HRV and HR parameters over the course of treatment to evaluate changes in clinical states. HRV analysis in depression may also be used as a risk factor measure in preventive medicine. Median values in the patients' data may be helpful in determining the standard ranges, since mean values are sometimes affected by the extreme data.
Expanding on previous HRV findings on depression that indicate reduced parasympathetic activity in the rest condition,[4-6] the present study has further revealed that HRV parameters for depressed subjects are different from those for control subjects during the task performance condition and during the rest condition after the task. Both the absolute values of the HRV parameters and the ratios showing relative changes exhibit differences between the depressed patients and the controls, and both are found to be useful in understanding pathophysiological phenomena. The effects of medication have been reported, but were excluded in this study because all patients were drug-naïve. Although a previous study has suggested a possible influence of smoking on HRV, such an influence is improbable in the present study because the ratios of smokers in the depression and control groups were not different.
In the resting condition, depressive patients demonstrated low HF, high LF/HF and high HR. These changes in HRV in the rest condition can be regarded as increments of baseline arousal level when subjects try to stay relaxed. Although behavioral activity is reduced in depression, the existence of a state of hyperarousal is suggested and may be related to symptoms such as insomnia and irritability. However, the presence of high parasympathetic activity in some patients suggests that a subset of depressed patients exhibit underarousal, indicating that depression is not homogeneous with respect to arousal state.
During the task condition, depressed subjects did not show significant autonomic reactivity. HF did not decrease and LF/HF and HR did not increase when the patients performed the random number generation task (Fig. 2). This disturbance in reactivity should not be totally attributed to sympathetic activation in the rest condition because some patients showing high HF and low LF/HF in the rest condition also exhibited a lack of reactivity (Fig. 1b). It is also interesting to see that HR increased significantly during the task condition for the patients, indicating that HRV is more useful than HR in analyzing the autonomic dysregulation found in depression. Because no differences in randomness scores were observed between the two groups, task performance could not be attributed to these results. Although the depressed patients performed the task equivalently, their autonomic systems did not react identically. For the depressed patients, the RNG score was positively correlated with LF/HF values in the initial resting condition, which suggests that excessive arousal before the start of the task may have disturbed the task performance for some patients.
In the post-task rest condition, LF/HF did not return to the initial rest level but, instead, remained high. Because sympathetic activation was maintained throughout the paradigm, elevated arousal level would seem to underlie depressive illness. HF in the post-task rest condition even increased in comparison with the initial state in some subjects. This rebound-like phenomenon was also observed among the control subjects; however, its incidence was significantly higher among the depressed subjects (Fig. 2). The average After/Rest ratio in depression was 1.913, indicating that the HF value almost doubled from its initial value. This increase was still present in the post-task rest condition from 60 s to 90 s but was not observed during the 90–120-s interval after the end of the task, showing that this phenomenon lasted only for a short period of time. This transient activation of the parasympathetic system for the patients was accompanied by sustained sympathetic activation, indicated by the increase of LF/HF. Its clinical significance has not yet been elucidated but could be related to somatic symptoms caused by autonomic dysregulation; simultaneous activation of sympathetic and parasympathetic systems with opposite functional directions can disturb the autonomic balance, leading to somatic symptoms.
The alteration of autonomic reactivity in depression is an interesting finding in the present study. When a normal subject is required to shift from a relaxation condition to execution of a task, responses of autonomic and arousal functions are elicited to engage somatic and psychological conditions during the behavioral activation. The present findings suggest that depressed patients are not competent in adjusting their mental and physical conditions to such a change in their behavioral state. Anergic and anhedonic states, fatigue and loss of concentration in addition to somatic symptoms, including digestive and cardiovascular ones, can be related to this autonomic and arousal dysfunction. HRV unresponsiveness in the present study provides a good measure by which to assess pathophysiology.
Limitations of the present study may come from the methodology. The obtained data fundamentally belong to autonomic activity. The arousal dysfunction was assessed through the autonomic dysfunction revealed as HRV abnormality. EEG and other measures on the central nervous activity can give us more direct view on the state of arousal. However, HRV measurement has an advantage as the data are simple and easy to evaluate. It would be interesting to use both the central and autonomic measure to investigate the arousal dysfunction of depression in a future study.
Previous studies on HRV have also indicated that, in addition to depression, panic disorder and schizophrenia show differences in HRV measures.[26, 27] It would be important in future studies to apply the present HRV paradigm to other psychiatric disorders to assess the specificity of the findings.
With respect to associations with self-rated psychological conditions, only HR reactivity was found to correlate with depression and anxiety scores. This result, showing a relation between increased reactivity and depressive symptoms, is different from the HRV finding showing less reactivity in depression. In contrast to a previous report, the present study did not reveal a relation between the reduction of HF and the severity of clinical symptoms. It will be important to further examine the usefulness of HRV analysis in analyzing the clinical condition of depression.
Age is negatively related with HF, as has previously been reported. In the present study, this relation was observed not only among the controls but also among the depressed patients. It is necessary to take age into account when HRV parameters are used in the clinical practice.
Respiration rate is known to affect HRV parameters related to parasympathetic activity, and should be incorporated into HRV analysis.[21, 22] In the present study, respiration rate during measurements was confirmed to be within the designated range used in the HRV analysis for HF (0.15–0.4 Hz), which was used as a parasympathetic index. It is important to check respiration rate in HRV studies.