Journal of Affective Disorders 246 (2019) 157–165

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research paper

Heart rate variability for treatment response between patients with major T
depressive disorder versus panic disorder: A 12-week follow-up study☆
Kwan Woo Choia,1, Eun Hye Jangb,1, Ah Young Kimb, Maurizio Favac, David Mischoulonc,
⁎ ⁎
George I. Papakostasc, Dong Jun Kimd, Kiwon Kima, Han Young Yub, , Hong Jin Jeona,d,
a
Department of Psychiatry, Depression Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
b
Bio-Medical IT Convergence Research Division, Electronics and Telecommunications Research Institute (ETRI), 218 Gajeong-ro, Daejeon, Korea
c
Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, USA
d
Department of Health Sciences & Technology, Department of Medical Device Management & Research, and Department of Clinical Research Design & Evaluation,
Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea

A R T I C LE I N FO A B S T R A C T

Keywords: Background: Heart Rate Variability (HRV) parameters have been used to evaluate the autonomic nervous
Heart rate variability system. We hypothesized that patients with major depressive disorder (MDD) and panic disorder (PD) showed
Major depression disorder different HRV profiles compared to healthy controls. We also hypothesized that we could predict the responder
Panic disorder groups in the MDD and PD patients, using differences in HRV indices between the stress and rest phases.
pNN50
Methods: 28 MDD patients and 29 PD patients were followed for 12 weeks, and we also followed 39 healthy
LF/HF ratio
control subjects. We measured HRV parameters at the rest, stress, and recovery phases.
Treatment response
Results: Patients with MDD and PD demonstrated lower pNN50 than controls during the stress (F = 7.49,
p = 0.001), and recovery phases (F = 9.43, p = 0.0001). Patients with MDD and PD also showed higher LF/HF
ratio than controls during the stress phase (F = 6.15, p = 0.002). Responders in the PD group presented a lower
level of LF/HF ratio during the stress phase compared to non-responders (F = 10.14, p = 0.002), while re-
sponders in the MDD group showed a lower level of heart rate during all three phases, compared to non-
responders. Additionally, we could predict treatment response in patients with MDD using ΔLF/HF ratio (OR:
1.33, 95% CI = 1.07–1.65, p = 0.011) and ΔpNN50 (OR: 1.49, 95% CI 1.09–1.77, p = 0.014).
Conclusion: The changes of HRV parameters of pNN50 and LF/HF ratio between the stress and recovery phase
may be clinical markers of predictors of treatment responsiveness in MDD and PD patients.

1. Introduction function (Bilchick and Berger, 2006). According to the neurovisceral

Major depressive disorder (MDD) and panic disorder (PD) are
known to increase the risk of cardiovascular morbidity and mortality
(Fleet et al., 2000; Barth et al., 2004; Albert et al., 2005; Nicholson
et al., 2006; Smoller et al., 2007; Katerndahl, 2008). Reduced heart rate
variability (HRV) is associated with the increased mortality in patients
with cardiovascular disease (Kleiger et al., 1987; Parati et al., 1995;
Tsuji et al., 1996; Liao et al., 1997). Lower HRV has been associated
with affective disorders such as depression and anxiety (Gorman and
Sloan, 2000; Kemp et al., 2010, 2012; Kemp and Quintana, 2013).
HRV is defined as fluctuation of the heart beat interval over time
(Roy-Byrne et al., 2000) and is known to be a quantitative index of ANS
integration (NVI) model, reduced HRV has been known to be a con-
sequence of reduced activation of central autonomic network (CAN).
CAN controls visceromotor, neuroendocrine, and behavioral flexibility
(Thayer and Lane, 2009; Smith et al., 2017). The output of the CAN has
connections to the sinoatrial node of the heart via the stellate ganglia
via vagus nerve (Benarroch, 1993).
Recently, HRV indices have attracted attention as a ‘transdiagnostic’
biomarker for psychopathology (Beauchaine and Thayer, 2015). For
example, there is lower resting HF-HRV and large reduction of HF-HRV
in depression (Rottenberg et al., 2002, 2005; Rottenberg, 2007) or
panic disorder (Asmundson and Stein, 1994). Previous meta-analysis
showed that patients with MDD displayed reduced vagal HRV indices

All authors have approved this submission.

☆
This material is original. It has not been previously published or submitted for publication elsewhere.
⁎
Corresponding authors.
E-mail address: jeonhj@skku.edu (H.J. Jeon).
1
These individuals contributed equally to this work as co-first authors.

https://doi.org/10.1016/j.jad.2018.12.048
Received 10 May 2018; Received in revised form 8 November 2018; Accepted 16 December 2018
Available online 18 December 2018
0165-0327/ © 2018 Elsevier B.V. All rights reserved.
K.W. Choi et al.
(Kemp et al., 2010). In patients with MDD, reductions in high frequency
(HF) variability, which is associated with parasympathetic modulation,
have been reported, in comparison to healthy control subjects (Licht
et al., 2009; Kemp et al., 2010). Consistent with these findings, the low
frequency (LF) to HF ratio is higher in these patients than in controls
(Udupa et al., 2007). Recently, subjects with MDD presented a lower
value of pNN50 compared to healthy controls (Wang et al., 2013b; Ha
et al., 2015).
Also, previous studies reported that patients with PD showed de-
creased parasympathetic activity, or an imbalance between the sym-
pathetic and parasympathetic system (Yeragani et al., 1993; Klein et al.,
1995). In patients with panic disorder (PD), significantly higher LF
power, lower HF power and higher LF/HF ratios were consistently
found, relative to healthy controls (Cohen et al., 2000; McCraty et al.,
2001; Kang et al., 2010; Martinez et al., 2010).
In clinical settings, comorbid MDD and PD are commonly seen
(Kessler et al., 1998; Roy-Byrne et al., 2000; Kessler et al., 2006).
Among MDD patients, more than half have a lifetime diagnosis of an
anxiety disorder (Gorman, 1996; Kessler et al., 1996, 2005). However,
there have been few attempts to differentiate MDD and PD using HRV
parameters (Kikuchi et al., 2009). Kikuchi et al. found that MDD pa-
tients had a relatively lower response to regular deep breathing method
in LF power and in LF/HF ratios, in comparison to normal controls and
PD patients (Kikuchi et al., 2009).
Also, there have been few studies that attempted to figure out
specific HRV indices, which could predict treatment respondents from
non-respondents in patients with MDD and PD (Khaykin et al., 1998;
Garakani et al., 2009; Kemp et al., 2010; Chang et al., 2018). Recently,
Pawlowski et al. attempted to distinguish the differences between de-
pressed patients and healthy subjects using the prefrontal theta cor-
dance and the REM sleep-derived HRV (Pawlowski et al., 2017).
In this study, we evaluated MDD and PD patients with healthy
control subjects during 12 weeks. We hypothesized that patients with
MDD and PD would exhibit increased sympathetic parameters (e.g.
increased LF/HF ratio) and decreased parasympathetic HRV indices
(e.g. decreased percentage of intervals greater than 50 ms, pNN50),
compared to healthy controls. We also hypothesized that responders in
MDD and PD would show increased LF/HF ratio and/or decreased
pNN50 during the rest, stress, and relaxation phase. We assumed that
there would be significant positive associations between treatment re-
sponse and the changes in LF/HF ratio and/or pNN50 between rest and
stress phase (stress phase – rest phase, ΔLF/HF ratio and/or ΔpNN50) in
MDD and PD patients.
2. Materials and methods
2.1. Subjects
As shown in Table 1, the MDD group consisted of 7 men and 21
Table 1
Baseline demographics (n = 96).
MDD (n = 28) PD (n = 29)
Age (years)* 42.07 ± 17.41 45.23 ± 12.82
Gender (M/F)¶ 7/21 12/17
Education (years)* 12.62 ± 3.60 15.48 ± 2.25
BMI (kg/m2)* 23.03 ± 3.64 23.79 ± 3.32
Smokers/Non-smokers¶ 5/23 5/24
Alcohol consumption, (g/week)* 2.15 ± 5.60 5.93 ± 18.22
HAM-D* 18.64 ± 6.28 13.52 ± 7.44
HAM-A* 17.46 ± 8.56 14.97 ± 8.26
PDSS* 2.68 ± 4.23 11.38 ± 6.51
MDD, Major depressive disorder; PD, Panic disorder; HC, Healthy controls; BMI, Body mass index; HAM-D, Hamilton depression rating score; HAM-A, Hamilton
anxiety rating score; PDSS, Panic disorder severity scale.
⁎
One-way ANOVA was used; Data are given as mean and standard deviation.
¶
Chi-square test was performed for the comparative analysis of gender and smoking.
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Journal of Affective Disorders 246 (2019) 157–165
women, and the PD group consisted of 12 men and 17 women. All
patients were recruited from the psychiatric outpatient clinic of Sam-
sung Medical Center from December 2015 to January 2017. They were
diagnosed with MDD or PD according to DSM-IV diagnostic criteria
(American Psychiatric Association, 1994). Psychiatrists with more than
three years of clinical experience evaluated the participants' psychiatric
and medical histories, and confirmed their eligibility. A trained psy-
chologist blinded to the psychiatrists' judgment separately investigated
the participants' psychiatric diagnoses and current mood states using
the Korean version of the Mini International Neuropsychiatric Inter-
view's (MINI) (Sheehan et al., 1998). Those who had bipolar disorder,
schizophrenia, other psychotic disorders, alcohol use disorders, organic
mental disorders, mental retardation, neurological illness including
epilepsy, and serious medical illnesses were excluded. Following defi-
nitive diagnoses, all the participants received standard psychiatric
pharmacotherapy for MDD or PD, i.e. standard antidepressant treat-
ment including selective serotonin reuptake inhibitors (SSRIs), ser-
otonin norepinephrine reuptake inhibitors (SNRIs), norepinephrine
dopamine reuptake inhibitors (NDRIs), and tricyclic antidepressants
(TCAs). Each treatment regimen was selected and modified depending
on individual clinical evaluation.
We also recruited normal healthy control (HC) group. The control
subjects consisted of 39 healthy volunteers (16 men and 23 women).
The control subjects had no personal or familial history of psychiatric or
neurological disease. All subjects provided written, informed consent.
This study was approved by the Institutional Review Board of Samsung
Medical Center.
2.2. Clinical measures
The duration of the study per each subject was twelve weeks
(Fig. 1). A total of five visits were completed: baseline, 2 weeks, 4
weeks, 8 weeks, and 12 weeks after screening.
All participants provided demographic data and clinical measures.
Demographic data included age, gender, and education years. Clinical
measures included Hamilton Depression Rating Scale (HAM-D)
(Hamilton, 1960, 1967), Hamilton Rating Scale for Anxiety (HAM-A)
(Hamilton, 1959), and the Panic Disorder Severity Scale (PDSS)
(Shear et al., 1997). These scales were evaluated at the baseline visit
and at the 12 week visit. We also evaluated subjects’ body mass index
(BMI), smoking and alcohol consumption, which were known to be
associated with changes in HRV parameters (Thayer et al., 2010;
Altuncu et al., 2012).
2.3. Data acquisition
The physiological data acquisition was done during the working
hours (9:00 a.m.−12:00 p.m. and 14:00 p.m.−18:00 p.m.) because
autonomic nervous systems are easily affected by physiological states of
HC (n = 39) Statistics F or X2 (p value) Post-hoc
41.22 ± 15.41 0.24 (0.790) ns
16/23 2.24 (0.326) ns
14.11 ± 2.67 6.22 (0.003) MDD < PD, HC
23.04 ± 2.92 0.66 (0.521) ns
6/33 0.08 (0.960) ns
8.62 ± 12.36 1.99 (0.142) ns
1.46 ± 1.50 95.76 (0.001) MDD > PD > HC
2.08 ± 2.17 59.94 (0.001) MDD, PD > HC
0.03 ± 0.16 75.99 (0.001) PD > MDD > HC
K.W. Choi et al.
Fig. 1. Study design.
subjects, such as time of the day, mood, rest state, etc. The psycho-
physiological assessment was completed on 5 separate occasions. Since
we hypothesized that we could predict treatment response at week 12
using baseline HRV parameters, we only used HRV parameters at the
first visit in this study. The experiment was performed under standard
conditions in a sound-attenuated room and stimuli, standard tempera-
ture 23 °C and humidity 45–55%. Prior to experiments, subjects were
instructed to sit comfortably in a special armchair and not to speak or
move unless necessary while the recording devices of physiological
signals were set and calibrated. For electrocardiographic (ECG) re-
cordings, each subject was seated in a chair with electrodes attached to
both wrists and left ankle. ECG recordings were acquired with a
ProComp Infiniti (SA7500, Computerized Biofeedback system, Thought
Technology. Ltd, Canada) using an ECG-Flex/Pro sensor. ECG elec-
trodes were placed on bilateral forearms, i.e. the negative lead was
placed on the right forearm while both the positive and ground leads
were placed on the left forearm. ECG signal was recorded at 256 Hz and
band-pass filtered (0.26–30 Hz).
An experimental design includes psychophysiological profile (PPP),
which is one of the assessment techniques of the autonomic response
influence upon behavior, consisting of the simultaneous registration of
some physiological parameters such as peripheral temperature (PT),
heart rate (HR), and HRV. These are generally divided into three con-
tinuative phases: at rest, stress presentation such as cognitive or per-
ceptual tasks and recovery (Hatch and Saito, 1990). PPP was used to
perform a physiological evaluation of the level of individual stress re-
activity (Hoehn et al., 1997; Diaz et al., 2003; Zarjam et al., 2013). For
stress presentation, we adapted the mental arithmetic task (MAT),
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Journal of Affective Disorders 246 (2019) 157–165
which consisted of continuous and serial subtraction of a digit number
from a number composed of three digits (500-7), in order to gradually
increase subjects’ mental load during task. The complete stress proce-
dure was performed by the two investigator-specialists, and only one
participant was examined in the clinical laboratory. Also, ECG was
recorded as physiological measure before, during, and after the MAT.
The ECG was recorded during the rest phase at baseline for 5 min, stress
phase performing MAT for 5 min, and recovery phase to rest for 5 min,
respectively. The experimental procedures of the study graphically are
shown in Fig. 1.
2.4. Heart rate variability feature analyses
The HRV analysis was performed by the CardioPro Infiniti HRV
Analysis Module Software (Thought Technology. Ltd, Canada). We
analyzed 3-min segments during each part of the testing procedure
(rest, stress and recovery phase). Also, the ECG signal was amplified
and digitized, and the RR interval time series was generated using the
automatic scheme to detect the R peak in the ECG. The most common
methods for HRV analysis are time-domain and frequency-domain. We
adopted multiple analysis methods to obtain more multidimensional
information about the HRV signals of the subjects.
We calculated HR and three features based on the RR intervals using
time-domain analysis, standard deviation of average normal-normal
intervals (SDNN), root mean square of successive differences (RMSSD)
and pNN50. SDNN reflects both sympathetic and parasympathetic ac-
tivities, while RMSSD and pNN50 are sensitive to parasympathetic
modulation. Frequency domain features indicates various spectral
K.W. Choi et al.
components, low frequency (LF: 0.04∼0.15 Hz), high frequency (HF:
0.15∼0.4 Hz) and LF/HF ratio. LF is modulated by sympathetic and
parasympathetic activities and HF is modulated by parasympathetic
activities. LF/HF ratio is ratio of LF and HF. It measures the balance
between sympathetic and parasympathetic activities (Thayer et al.,
2010; Kuang et al., 2017).
2.5. Statistical analysis
The HRV parameters of the three groups were individually calcu-
lated in each phase (rest, stress task, and recovery). We applied analysis
of covariance (ANCOVA) with age, gender, education years, smoking
and alcohol consumption to compare the differences of HRV responses
among three groups (MDD, PD, and HC) during the three phases. Also,
responder in MDD and PD group was defined as patient with a ≥ 50%
reduction of HAM-D or PDSS score of the last visit when compared to
the score of the baseline visit. The differences of HRV responses be-
tween responders and non-responders in each disorder group were
analyzed using ANCOVA with covariates of age, gender, education
years, smoking, and alcohol consumption. The post hoc tests of Fisher's
least significant difference (LSD) was used for each HRV variable. We
used a logistic regression analysis with the covariates age, gender,
education years, smoking, and alcohol consumption to verify whether
the changes of HRV rest and stress phase were significant variables
predicting the responder/non-responder status. All tests were two-
tailed with the adopted significance level of 0.05. In addition,
Bonferroni correction was used to solve the problem due to multiple
testing to test simultaneously HRV variables. Analyses were performed
using SPSS ver. 21.0 (IBM, USA).
3. Results
3.1. Demographic profiles and clinical measures of subjects with MDD, PD,
and healthy control groups
As shown in Table 1, the mean age was 42.07 ± 17.41 (mean ±
SD) years in MDD patients; 45.23 ± 12.82 in PD patients; and
41.22 ± 15.41 in HC subjects. There were no significant differences in
age among the three groups (F = 0.24, p = 0.790). Also, there were no
significant differences in gender (χ ² = 2.24, p = 0.326), BMI
(F = 0.66, p = 0.521), smoking (χ ² = 0.08, p = 0.521), and alcohol
consumption (F = 1.99, p = 0.142) between the three groups. The
MDD group reported significantly fewer education years than PD or HC
groups (F = 6.22, p < 0.05).
In the MDD group, mean HAM-D score was 18.64 ± 6.28 and mean
HAM-A score was 17.46 ± 8.56. In the PD group, mean PDSS score of
the PD group was 11.38 ± 6.51 and the mean HAM-A score was
14.97 ± 8.26. In the HC group, mean HAM-D, HAM-A and PDSS scores
were 1.46 ± 1.50, 2.08 ± 2.17 and 0.03 ± 0.16, respectively. We
found significant differences in three psychiatric measures between the
three groups (HAM-D: F = 95.76, p = 0.001; HAM-A: F = 57.94,
p = 0.001; PDSS: F = 75.99, p = 0.001).
3.2. Comparisons of HRV indices between MDD, PD, and healthy
controlgroups
Results of HRV analyses showed that there were significant differ-
ences (p < 0.0023, after adjusting for multiple comparison) for both
time and frequency domain parameters in rest, stress and recovery
phases among the three groups, after adjusting for age, gender, edu-
cation years, smoking, and alcohol consumption (Table 2). Patients
with MDD and PD showed significantly lower values of pNN50 than HC
during the stress and recovery phase. Compared to HC, patients with
MDD and PD had significantly lower values of pNN50 (F = 7.49,
p = 0.001) during the stress phase. During the recovery phase, patients
with MDD and PD also had significantly lower values of pNN50
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Journal of Affective Disorders 246 (2019) 157–165
(F = 9.43, p = 0.0001) than did HC.
There were significant differences in frequency domain parameters
among patients with MDD, PD, and HC (Table 2). During the stress
phase, patients with MDD and PD showed significantly higher values of
LF/HF ratio (F = 6.15, p = 0.002) than HC. Patients with MDD and PD
showed significantly higher values of HR than HC during the rest phase
and recovery phase.
3.3. Comparisons of psychological parameters and HRV indexes between
responders and non-responders of MDD and PD groups
As shown in Table 3, there were no significant differences in HAM-
D, HAM-A, and PDSS scores between responders and non-responders in
both the MDD and PD patients. After 12 weeks, there were significant
differences in HAM-D (responder: 6.56 ± 5.28; non-responder:
17.49 ± 8.49; p = 0.001), and HAM-A (responder: 5.88 ± 5.87, non-
responder: 14.39 ± 6.23; p = 0.003) scores between responders and
non-responders in patients with MDD. However, there were no sig-
nificant differences in HAM-D, HAM-A, and PDSS between responders
and non-responders in patients with PD.
Baseline HRV parameters between responders and non-responders
in MDD and PD groups were analyzed (Table 4). There was no sig-
nificant difference in timing of HRV tests between non-responders and
responders in subjects with MDD (Non-responders 12:43 ± 1:33/ Re-
sponders 12:37 ± 1:26; t = 0.169, p = 0.867) and PD (Non-responders
12:18 ± 1:17/ Responders 13:01 ± 1:47; t = 1.234, p = 0.228). In
the MDD group, responders showed significantly lower values of
baseline HR during all three phases than non-responders. Unlike the
MDD group, responders with PD had significantly lower values of LF/
HF ratio (responder: 2.64 ± 1.89, non-responder: 3.54 ± 3.41;
F = 10.14, p = 0.002) during the stress phase than non-responders with
PD.
3.4. Prediction of responder/non-responder status by the difference in HRV
parameters between stress phase and rest phase (stress phase – rest phase)
We used the changes in HRV parameters between rest and stress
phases (stress phase – rest phase, Δ) to predict the responder/non-re-
sponder status. Results of multivariate logistic regression analyses in-
cluding changes in HRV parameters for predicting response in two
disorder groups are shown in Table 5. Responders in the MDD group
showed a significant association (p < 0.0167, after adjusting for mul-
tiple comparison) with ΔLF/HF ratio (OR: 1.33, 95% CI: 1.07 to 1.65,
p = 0.011) and ΔpNN50 (OR: 1.49, 95% CI: 1.09 to 1.77, p = 0.014).
However, in the PD group, ΔpNN50 showed non-significant association
with treatment response. There was only a trend association with
treatment response (OR: 1.40, 95% CI: 1.02 to 1.91, p = 0.035).
4. Discussion
This study examines the association of various HRV parameters with
disease-specific changes and treatment response in MDD and PD pa-
tients, with repetitive and prospective follow-up. This study presents
three important findings. First, patients with MDD and PD showed
significantly higher LF/HF ratio and lower pNN50 than healthy con-
trols. Second, responders with PD showed a significantly lower level of
LF/HR ratio during the stress phase when compared to non-responders,
whereas responder subjects with MDD showed a lower level of heart
rate during all three phases. Third, we could predict treatment response
in patients with MDD using HRV parameters, such as changes in LF/HF
ratio or pNN50 between the stress phase and the rest phase.
This study showed that patients with MDD and PD had a sig-
nificantly higher LF/HF ratio after stress induction, and had lower
pNN50 during the stress, and recovery phase, when compared to
healthy controls. The LF/HF ratio is known to be associated with
sympathetic modulation (Reyes del Paso et al., 2013), whereas pNN50
K.W. Choi et al. Journal of Affective Disorders 246 (2019) 157–165

Table 2
Comparison of HRV during the rest, stress and recovery phases among MDD, PD, and healthy control groups at baseline (n = 96).
MDD (n = 28) PD (n = 29) HC (n = 39) ANCOVA*
Mean (SD) Mean (SD) Mean (SD) F (p value) Post-hoc

Rest phase
RMSSD (ms) 34.55 (42.99) 47.37 (115.25) 43.83 (44.30) 1.47 (0.230) ns
SDNN (ms) 35.59 (32.88) 44.67 (80.93) 43.69 (30.41) 1.34 (0.263) ns
LF (ms2/Hz) 283.93 (1202.58) 3774.92 (21672.64) 319.05 (711.63) 2.92 (0.055) ns
HF (ms2/Hz) 227.64 (755.96) 1548.94 (8818.03) 287.12 (750.53) 2.30 (0.102) ns
LF/HF ratio 2.68 (4.00) 2.32 (2.26) 1.88 (1.78) 3.97 (0.020) ns
pNN50 (%) 4.56 (7.24) 3.91 (8.19) 6.87 (8.29) 5.20 (0.006) ns
HR (bpm) 75.58 (11.91) 76.84 (13.95) 72.14 (9.51) 9.94 (0.0001)* MDD, PD > CON
Stress phase
RMSSD (ms) 39.17 (64.19) 46.68 (107.93) 49.04 (56.18) 0.92 (0.400) ns
SDNN (ms) 39.41 (44.00) 43.82 (74.38) 47.30 (36.68) 0.82 (0.440) ns
LF (ms2/Hz) 1475.53 (10930.39) 1782.47 (8616.56) 1137.85 (8587.24) 0.27 (0.761) ns
HF (ms2/Hz) 632.38 (3535.09) 1241.10 (6097.94) 534.93 (2054.57) 1.20 (0.304) ns
LF/HF ratio 2.94 (2.32) 3.08 (2.77) 2.30 (2.07) 6.15 (0.002)* MDD, PD > CON
pNN50 (%) 4.85 (6.88) 4.27 (8.32) 7.44 (8.41) 7.49 (0.001)* MDD, PD < CON
HR (bpm) 79.30 (12.02) 79.39 (13.56) 77.81 (11.36) 1.60 (0.203) ns
Recovery phase
RMSSD (ms) 39.17 (96.01) 35.92 (67.70) 44.59 (449.68) 0.67 (0.511) ns
SDNN (ms) 39.97 (73.75) 36.05 (45.96) 45.44 (35.41) 0.75 (0.472) ns
LF (ms2/Hz) 3630.66 (33390.06) 374.16 (2088.63) 329.42 (987.54) 0.98 (0.375) ns
HF (ms2/Hz) 1100.65 (8723.02) 410.41 (2052.12) 314.21 (900.83) 0.81 (0.445) ns
LF/HF ratio 2.75 (4.31) 2.12 (2.11) 2.06 (2.20) 5.19 (0.006) ns
pNN50 (%) 4.29 (7.01) 3.69 (7.60) 7.01 (7.88) 9.43 (0.0001)* MDD, PD < CON
HR (bpm) 75.67 (11.98) 76.09 (13.43) 71.75 (9.59) 9.88 (0.0001)* MDD, PD > CON

- Bonferroni correction for multiple comparison

⁎
p < 0.0023
- Adjusted for age, gender, education years, smoking, and alcohol consumption

Table 3
Comparisons of psychological parameters in responders and non-responders with MDD and PD at baseline, and after 12 weeks (n = 57).
MDD (n = 28) PD (n = 29)
Respondera (n = 16) Non-responderb (n = 12) t score (p-value) Respondera (n = 15) Non-responderb (n = 14) t score (p-value)

Baseline
HAM-D 20.19 (6.51) 18.90 (5.84) 1.45 (0.159) 14.80 (7.74) 12.14 (6.81) 0.98 (0.337)
HAM-A 17.06 (8.35) 17.45 (9.62) 0.27 (0.790) 17.27 (7.08) 12.50 (8.69) 1.63 (0.116)
PDSS 3.50 (5.10) 2.92 (2.57) 1.06 (0.299) 13.00 (6.22) 9.64 (6.37) 1.44 (0.163)
After 12 weeks
HAM-D 6.56 (5.28) 17.49 (8.49) 4.06 (0.001)* 6.82 (4.94) 11.50 (5.79) 1.69 (0.173)
HAM-A 5.88 (5.87) 14.39 (6.23) 3.36 (0.003)* 9.45 (4.44) 12.57 (10.39) 1.18 (0.133)
PDSS 1.00 (3.44) 1.20 (3.82) 0.18(0.857) 5.00 (4.74) 9.14 (7.06) 1.73 (0.098)

a
Responders: ≥ 50% improvement of HAM-D in MDD and PDSS in PD at 12-week follow-up.
b
Non-responders: < 50% improvement of HAM-D in MDD and PDSS in PD at 12-week follow-up.
⁎
p < 0.05.

Table 4
Comparisons of baseline HRV between responders and non-responders with MDD and PD (n = 57).
MDD (n = 28) PD (n = 29)
Respondera (n = 16) Non-responderb (n = 12) ANCOVA* F (p-value) Respondera (n = 15) Non-responderb (n = 14) ANCOVA* F (p-value)

Rest phase
pNN50 (%) 4.06 (6.97) 5.35 (7.73) 1.42 (0.235) 4.23 (9.21) 3.57 (7.01) 0.76 (0.386)
LF/HF ratio 2.23 (3.09) 3.35 (5.07) 5.21 (0.024) 2.15 (1.95) 2.50 (2.55) 1.05 (0.307)
HR (bpm) 72.85 (10.66) 80.04 (12.42) 11.81 (0.001)* 75.03 (13.77) 79.27 (14.01) 3.50 (0.063)
Stress phase
pNN50 (%) 4.42 (5.71) 5.50 (8.43) 0.64 (0.426) 5.27 (9.74) 3.21 (6.39) 2.87 (0.092)
LF/HF ratio 2.80 (1.92) 3.09 (2.76) 2.07 (0.163) 2.64 (1.89) 3.54 (3.41) 10.14 (0.002)*
HR (bpm) 76.50 (10.60) 83.96 (12.61) 8.63 (0.004)* 77.02 (13.35) 82.16 (13.64) 4.74 (0.031)
Recovery phase
pNN50 (%) 3.92 (6.23) 4.96 (8.42) 1.55 (0.216) 4.14 (9.52) 3.59 (6.59) 0.61 (0.438)
LF/HF ratio 2.69 (2.91) 3.68 (3.97) 6.34 (0.013) 2.58 (2.03) 3.23 (4.84) 2.50 (0.116)
HR (bpm) 72.89 (10.18) 80.23 (13.11) 9.63 (0.002)* 74.79 (14.16) 78.03 (12.70) 2.18 (0.143)

a
Responders: ≥ 50% improvement of HAM-D in MDD and PDSS in PD at 12-week follow-up
b
Non-responders: < 50% improvement of HAM-D in MDD and PDSS in PD at 12-week follow-up
- Bonferroni correction for multiple comparison
⁎
p < 0.0056
- Adjusted for age, gender, education years, smoking, and alcohol consumption

161
K.W. Choi et al. Journal of Affective Disorders 246 (2019) 157–165

is associated with HF (Electrophysiology, 1996), which reflects the

p-value

0.035
0.380
0.325
activity level of the parasympathetic tone (Berntson et al., 1997). Pre-
vious studies showed that patients with MDD had a higher LF/HF ratio
(Udupa et al., 2007), and a lower value of HF (Licht et al., 2009; Kemp
Wald χ2

et al., 2010), compared to healthy controls. Recent studies reported that

patients with MDD presented a lower value of pNN50 compared to
4.43
0.77
0.97
healthy controls (Wang et al., 2013b; Ha et al., 2015). In accordance
with previous studies with PD (Cohen et al., 2000; McCraty et al., 2001;
Wang et al., 2013a; Martinez et al., 2015), this study also revealed a
1.40 (1.02–1.91)
1.05 (0.95–1.15)
0.15 (0.01–5.03)

significantly higher LF/HF ratio in patients with PD, when compared to

OR (95% CI)

healthy controls. With these results, MDD and PD might be associated

with increased sympathetic function and decreased vagal tone via LF/
HF ratio and pNN50.
In this study, we investigated baseline HRV measures between
treatment responders and non-responders in patients with MDD.
Non-responder (n = 14)

Previous studies revealed that approximately half of MDD patients did

not respond to first-line antidepressant treatment through the
Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial
−0.37 (0.98)

(Rush et al., 2006; Trivedi et al., 2006; Sinyor et al., 2010). Similar to
1.40 (1.37)
3.01 (1.92)

these findings, we found that almost half of the MDD patients (16/28,
57.1%) showed more than 50% of improvement in the HAM-D scores
after 12 weeks. In patients with MDD, responders showed a sig-
nificantly lower HR during all three phases. Although there were no
Responder (n = 15)

significant differences in LF/HF ratio between responders and non-re-

sponders with MDD, responders with MDD had a relatively lower value
PD (n = 29)b

of LF/HF ratio during all three phases. Responders in MDD might have
0.49 (1.25)
0.95 (1.57)
1.87 (1.87)

relatively stable sympathetic regulation profiles compared to non-re-

sponders. We also investigated baseline HRV measures between treat-
ment responders and non-responders in patients with PD. Only half of
the PD patients showed more than 50% of improvement in the PDSS
scores after 12 weeks of follow-up. Responders in PD patients showed a
p-value

0.014*
0.011*
Changes of HRV parameters (stress phase – rest phase) and treatment response in MDD and PD patients (n = 57).

0.375

significantly lower value of LF/HF ratio than non-responders during the

stress phase. These results implicate that non-responders in PD showed
restricted autonomic flexibility than did responders, when applied to
the stress induction. These findings suggest that non-responders in PD
Wald χ2

Non-responders: < 50% improvement of HAM-D in MDD and PDSS in PD at 12-week follow-up

can be more sensitive to stress situations compared to PD responders,

6.03
6.44
0.79

and MDD subjects, thereby provoking an increase in anxiety and au-

Responders: ≥ 50% improvement of HAM-D in MDD and PDSS in PD at 12-week follow-up.

tonomic response (Gorman et al., 2000). In patients with PD, stressful

stimulus might activate fearful network and affect autonomic responses
0.12 (0.00–13.53)
1.49 (1.09−1.77)
1.33 (1.07–1.65)

(Gorman et al., 2000). On the contrary, patients with MDD might have
OR (95% CI)

sustained sympathetic predominance, so there could be no significant

- Adjusted for age, gender, education years, smoking, and alcohol consumption

change in LF/HF ratio during all phases. These results might implicate
that stress induces more apparent autonomic imbalance especially in
patients with PD in comparison with patients with MDD. These findings
may reflect different underlying neurobiological mechanisms between
Non-responder (n = 12)

MDD and PD.

Changes of HRV parameters at baseline (Stress phase - Rest phase)

In this study, we attempted to predict treatment outcome using

changes in pNN50, LF/HF ratio, and HR between stress phase and rest
−0.11 (2.52)

phase, in patients with MDD and PD. Due to the relatively low response
0.79 (1.63)
3.84 (3.94)

rate of antidepressants, many studies have attempted to differentiate

between treatment responders and non-responders in MDD using
- Bonferroni correction for multiple comparison

baseline HRV parameters (Fraguas et al., 2007; Jain et al., 2014).

Fraguas et al. showed that baseline changes in LF and LF/HF ratio in
response to the emotional stimuli were correlated with reduction in
Responder (n = 16)

MDD symptoms with subsequent fluoxetine treatment (Fraguas et al.,

MDD (n = 28)a

2007). Jain et al. also showed that baseline very low frequency (VLF)
0.73 (1.64)
1.16 (1.31)
3.51 (1.76)

power was negatively associated with depression improvement

(Jain et al., 2014). During yoga treatment, Shapiro et al. presented that
remitters with MDD had notably higher HF and lower LF when com-
pared to non-remitters (Shapiro et al., 2007). Consistent with these
findings, we found that ΔLF/HF ratio and ΔpNN50 in patients with
Δ LF/HF ratio
Δ pNN50 (%)

p < 0.0167

MDD was significantly associated with treatment response, while PD

Δ HR (bpm)

patients showed just a trend association between treatment response

and ΔpNN50. Evaluating HRV parameters at different phases (i.e. rest
Table 5

phase, and stress phase) enabled us to clarify, more accurately, the

b
a

differences between these response group and non-response group in

162
K.W. Choi et al.
MDD and PD. Recently, a similar study was conducted to distinguish
treatment response group from non-respondents using EEG and HRV
(Pawlowski et al., 2017). In this study, researchers did not predict
treatment outcome in depression using HRV parameters. However, they
found prefrontal theta cordance could predict treatment outcome in
depression (Pawlowski et al., 2017). Additionally, Minassian et al. have
shown that high LF/HF ratio (> 6.7) before deployment could predict
post-deployment posttraumatic stress disorder (PTSD) in active-duty
marines (Minassian et al., 2015), despite differences regarding diag-
nosis. In accordance with these results, the present study showed that
HRV parameters could predict treatment outcome in patients with
MDD.
Altered autonomic function is considered a serious mechanistic
candidate for increased risk of cardiovascular mortality in patients with
MDD and PD. Decreased vagal function is associated with reductions in
HRV and reductions in vagal function may be a consequence of reduced
activation of CAN, which includes the anterior cingulate, insular, and
ventromedial prefrontal cortices, the central nucleus of the amygdala,
the paraventricular and related nuclei of the hypothalamus, the peria-
queductal gray matter, the parabrachial nucleus, the nucleus of the
solitary tract, the nucleus ambiguus, the ventrolateral medulla, the
ventromedial medulla, and the medullary tegmental field (Benarroch,
1993; Thayer and Lane, 2000; Smith et al., 2017). There are both direct
and indirect pathways linking the frontal cortex to autonomic motor
circuits responsible for both the sympatho-excitatory and para-
sympatho-inhibitory effects on the heart (Thayer and Lane, 2009;
Thayer et al., 2010; Smith et al., 2017). Recent neuroimaging studies
have reported that decreased values of HRV are associated with de-
creased activation of several brain regions, including right superior
prefrontal, left rostral anterior cingulate, right dorsolateral prefrontal,
and right parietal cortices (Gianaros et al., 2004; Lane, 2008; Lane
et al., 2009; Thayer and Lane, 2009). Emotional arousal is associated
with a decrease in HRV and concomitant decrease in brain activation in
these regions. In the NVI model proposed by Thayer et al. (Thayer and
Lane, 2009), prefrontal cortical areas including the orbitofrontal cortex
(OFC) and medial prefrontal cortex (mPFC) have top-down inhibitory
and modulatory influences on subcortical affective centers that shape
subjective experience. It has been proposed that the prefrontal cortex is
switched off during threat to let automatic processes regulate behavior
(Arnsten and Goldman-Rakic, 1998). This prefrontal inactivation might
be adaptive by facilitating involuntary behaviors, which organize ap-
propriate amygdala responses without delay from the more deliberative
and consciously guided prefrontal cortex. Depression and panic dis-
order are associated with prefrontal cortex hypo-activity and the lack of
inhibitory neural mechanism with poor habituation to novel stimuli,
failure to recognize safety signals, and poor affective information pro-
cessing and regulation (Thayer and Lane, 2000, 2009; Thayer et al.,
2010; Beauchaine and Thayer, 2015; Smith et al., 2017). Hypoactivity
in prefrontal cortex could be related to dysfunctional cardiac adapta-
tion in patients with MDD and PD, specifically for treatment non-re-
spondents.
However, this study had several limitations. Firstly, the clinical
implications of changes in HRV associated with treatment response in
MDD and PD should be interpreted with caution. Due to the lack of
information on antidepressant use and cognitive behavioral therapy
(CBT), we could not evaluate the lowering effects of antidepressants or
CBT on the HRV parameters (Licht et al., 2008; O'Regan et al., 2015).
However, despite using antidepressant medication, we observed the
robust differences between responders and non-responders between
patients with MDD and PD. Secondly, due to the small sample size, we
could not evaluate the differences in HRV parameters between the
subtypes of MDD (e.g. melancholic vs. atypical depression) and PD (e.g.
panic disorder with agoraphobia vs. panic disorder without agor-
aphobia). Further studies will be needed to evaluate differences among
specific subtypes of these disorders. Thirdly, long-term follow-up data
for the time of complete remission and final wash-out from
163
Journal of Affective Disorders 246 (2019) 157–165
antidepressants are needed in future studies to confirm whether HRV
parameters have properties as a trait marker to indicate increased risk
of recurrent depression and panic disorder.
In conclusion, the HRV parameters of LF/HF ratio and pNN50 might
be used as clinical markers to differentiate between MDD and PD as
well as to predict treatment response in MDD and PD. Our results may
provide information for underlying autonomic dysfunction mechanisms
in MDD and PD. They might help us find the mechanistic differences
between response group and non-response group in MDD and PD.
Future research will be needed to find out more appropriate treatment
options for MDD and PD patients.
Acknowledgements
This work was supported by Institute for Information & commu-
nications Technology Promotion (IITP) grant funded by the Korea
government (MSIT) (No. 2015-0-00062, the development of skin ad-
hesive patches for the monitoring and prediction of mental disorders),
the Original Technology Research Program for Brain Science through
the National Research Foundation of Korea (NRF) funded by the
Ministry of Education, Science and Technology (No. NRF-
2016M3C7A1947307; PI HJJ), and by the Bio & Medical Technology
Development Program of the NRF funded by the Korean government,
MSIT (No. NRF-2017M3A9F1027323; PI HJJ).
Role of funding source
They had no further role in study design; in the collection, analysis
and interpretation of data; in the writing of the report; and in the de-
cision to submit the paper for publication.
Contributors
Prof. Hong Jin Jeon was a principal investigator of the Original
Technology Research Program for Brain Science through the National
Research Foundation of Korea (NRF) funded by the Ministry of
Education, Science and Technology (No. NRF-2016M3C7A1947307),
and by the Bio & Medical Technology Development Program of the NRF
funded by the Korean government, MSIT (No. NRF-
2017M3A9F1027323; PI HJJ). Dr. Han Young Yu was a principal in-
vestigator of Institute for Information & communications Technology
Promotion (IITP) grant funded by the Korea government (MSIT) (No.
B0132-15-1003, the development of skin adhesive patches for the
monitoring and prediction of mental disorders). Prof. Hong Jin Jeon,
and Doctor Han Young Yu designed the study, supervised the in-
vestigators, and checked the whole data. Dr. Eun Hye Jang and Dr.
Kwan Woo Choi analyzed the data, and wrote the manuscript. Ms. Ah
Young Kim and Mr. Dong Joon Kim evaluated the subjects and checked
their follow-up. Prof. Maurizio Fava, Prof. George Papakostas, Prof.
David Mischoulon, and Dr. Kiwon Kim supervised the data analysis and
manuscript writing.
Conflict of interest
The Authors have declared that there are no conflicts of interest in
relation to the subject of this study.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.jad.2018.12.048.
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