Journal of Affective Disorders 267 (2020) 297–306

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Journal of Affective Disorders

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

Review article

Heart rate variability changes in patients with panic disorder T

a,# b,# b a b,⁎
Yuan Zhang , Bo Zhou , Jian Qiu , Lijuan Zhang , Zhili Zou
a
Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, PR
China
b
Psychosomatic department, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Chengdu 610072, PR China

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

Keywords: Background: This review aimed to evaluate whether patients with panic disorder (PD) exhibit different heart rate
Panic disorder variability (HRV) compared to healthy controls and to determine whether HRV is different in patients with PD
Heart rate variability after treatment.
Panic attack Methods: Literature databases were searched for studies comparing resting-state HRV between drug-naïve pa-
Systematic review
tients with PD and healthy controls. Parameters from the short-term frequency-domain and long-term time
Meta-analysis
domain were included.
Cardiovascular disease
Results: In the low frequency (LF) analysis, no significant association was found between LF and PD (standar-
dised mean difference [SMD] = −0.0443, 95% confidence interval [CI]: −0.1765 to 0.0879). In the high
frequency (HF) analysis, no significant association was found between HF and PD (SMD = −0.1269, 95% CI:
−0.2598 to 0.0059). In the LF/HF analysis, a significantly higher LF/HF ratio was found in cases than in
controls, but the effect was moderate (SMD = 0.1390, 95% CI: 0.0180 to 0.2600). For the standard deviation of
normal-to-normal intervals, a significantly lower value was observed in cases than in controls (SMD = −0.3133,
95% CI: −0.5459 to −0.0808).
Limitations: Limited sample size in the time-domain and treatment effect analyses.
Conclusions: Patients with PD had a higher short-term LF/HF ratio, indicating impaired sympathovagal balance.
The LF/HF ratio findings were more consistent compared with LF and HF alone, making it a better parameter to
interpret the LF and HF in conjunction. HRV may be a promising biomarker for predicting antidepressant re-
sponse.

1. Introduction
Panic disorder (PD) is the most common anxiety disorder char-
acterised by recurrent and unexpected panic attacks. One cross-national
epidemiology study reported that the lifetime prevalence of panic at-
tacks was 13.2% (de Jonge et al., 2016). The clinical presentation of PD
includes multiple symptoms of autonomic nervous system (ANS) dis-
turbance such as palpitations, tachycardia, sweating, shaking, shortness
of breath, and chest pain (Hasan and Mooney, 1986). Therefore, pa-
tients with PD most frequently seek care in medical settings, e.g. a
cardiovascular or emergency department (Simpson and Pasic, 2016).
PD causes substantial suffering and increased economic costs to both
patients and society (Na et al., 2011). Additionally, PD is closely related
to heart disease. On one hand, the symptoms of a panic attack overlap
with those typical of a myocardial infarction (MI) and angina pectoris.
On the other hand, a previous study found that PD was associated with
an elevated risk for subsequent coronary heart disease (CHD)
(Tully et al., 2015). However, the relationship between PD and CHD
remains tenuous.
Heart rate variability (HRV) measures beat-to-beat changes in heart
rate by electrocardiography. HRV analysis methods comprise a time
and a frequency domain. The time domain measures generally include
the mean normal-to-normal (NN) interval, standard deviation of NN
(SDNN) interval, which reflects the total HRV for the period of interest

Abbreviations: PD, panic disorder; ANS, autonomic nervous system; NS, nervous system; MI, myocardial infarction; CHD, coronary heart disease; HRV, heart rate
variability; SDNN, standard deviation of NN of normal-to-normal intervals; RMSSD, square root of the mean squared difference of successive NN intervals; pNN50,
percent of successive differences of intervals between normal heart beats >50 ms; LF, low frequency; HF, high frequency; LF/HF, ratio of LF to HF; CVD, cardio-
vascular disease; CI, confidence interval; SD, standard deviation; SMD, standardised mean difference; CBT, cognitive behavioural therapy; PNS, parasympathetic
nervous system; SSRIs, selective serotonin reuptake inhibitors
⁎
Corresponding author.
E-mail address: zou_zhili@hotmail.com (Z. Zou).
#
These authors contributed equally to this study and should be considered co-first authors.

https://doi.org/10.1016/j.jad.2020.01.132
Received 20 August 2019; Received in revised form 19 November 2019; Accepted 21 January 2020
Available online 25 January 2020
0165-0327/ © 2020 Published by Elsevier B.V.
Y. Zhang, et al.
and is the most commonly used measure of HRV, the square root of the
mean squared difference of successive NN intervals, and the percentage
of successive differences >50 ms in intervals between normal heart
beats. The last two measures reflect the parasympathetic control of
heart rate when the rhythm is normal (Friedman and Thayer, 1998).
The frequency domain typically includes three measures: very low
frequency (≤0.04 Hz), low frequency (LF, 0.04–0.15 Hz), and high
frequency (HF, 0.15–0.4 Hz). The HF component measures vagal ac-
tivity, while the LF component is related to a combination of both vagal
and sympathetic activities, and ratio of LF to HF (LF/HF) reflects the
cardiac sympathovagal balance (Gorman and Sloan, 2000). Reduced
HRV has been shown to be one of the strongest clinical predictors of
fatal cardiac arrhythmia in patients with MI. In addition, multiple
studies found reduced HRV has been observed in patients with mood
and anxiety disorders (Chalmers et al., 2014; Alvares et al., 2016;
Clamor et al., 2019; Mestanikova et al., 2019; O'Neil et al., 2019). These
findings may contribute to the underlying causes for the relationship
between PD and cardiovascular disease (CVD).
To date, previous studies have found that patients with PD have
reduced HRV when compared to healthy controls, but results have been
inconsistent (Ito et al., 1999; Yeragani et al., 2000; Kemp et al., 2012;
Petrowski et al., 2017). For example, Ito et al. found no differences in
HF and LF measures between patients with PD and controls (Ito et al.,
1999). Petrowski et al. also reported no differences in time domain
measures between patients with PD and controls (Petrowski et al.,
2017). These inconsistent findings highlight the need for a meta-ana-
lysis. A previous meta-analysis, which analysed HRV in various anxiety
disorders including PD, generalised anxiety disorder, post-traumatic
stress disorder, and social anxiety disorder concluded that a significant
reduction was found in the time domain, LF, and HF parameters of HRV
in patients with PD (Chalmers et al., 2014). However, this meta-analysis
did not have any limitations on medication status and physical illness,
including CVD or other comorbidities, which we believe could con-
tribute largely to study heterogeneity. Moreover, this meta-analysis did
not investigate the LF/HF ratio, which we believe is an important
component of HRV analysis. Therefore, we conducted a meta-analysis
and systematic review focusing on PD with an evaluation of the time
domain (SDNN parameters), frequency domain (LF, HF, and LF/HF
parameters), and changes in HRV before and after treatment. The aims
of this study were to evaluate whether drug-naive patients with PD
exhibit different HRV in the resting state relative to controls, and to
determine whether HRV is different in patients with PD after treatment
(Fig. 1).
2. Methods
The Preferred Reporting Items for Systematic Reviews and Meta-
Analyses were followed to ensure the quality of this review.
2.1. Search criteria and identification of relevant studies
Pubmed, Embase, Medline, Cochrane Library, and China National
Knowledge Infrastructure databases were searched for English and
Chinese literature from database inception until June 2019 using the
search terms ‘panic disorder OR panic attack AND heart rate varia-
bility’. Studies that met the following criteria were included: (1) clinical
studies comparing HRV in patients with a diagnosis of PD and a control
group without mental disorders or history of cardiac disorder; (2) pa-
tients not taking medication with an effect on the ANS; and (3) ade-
quate reporting of statistics (i.e. the number of cases and controls,
mean, standard deviation [SD], and p-value). Reviews, duplicate stu-
dies, and animal experiments were excluded. Ultimately, LF, HF, and
LF/HF ratio from the frequency domain and SDNN from the time do-
main were included since there was an adequate number of eligible
studies to perform meta-analyses of such parameters. The potentially
relevant articles retrieved from databases were reviewed by two
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Journal of Affective Disorders 267 (2020) 297–306
independent authors and disagreement on inclusion was resolved by
discussion between the two authors.
2.2. Data extraction
The following information from each eligible article was recorded:
the name of the first author; year of publication; country where the
participants were recruited from; criteria used for diagnosing PD; type
of HRV analysis; number of cases and controls; HRV measures reported;
mean and SD of LF, HF, LF/HF, and SDNN; and conclusions.
2.3. Data analysis
The ‘Meta’ packages of R (version 3.5.1; The R Foundation for
Statistical Computing, Vienna, Austria) were used to aggregate in-
dividual studies. The standardised mean difference (SMD, also known
as Hedge's g) was used to express all HRV outcomes. The significance of
SMD was determined using 95% confidence internals (CIs).
Heterogeneity between studies was calculated using the chi-square-
based Q test and inconsistency value (I2). A p-value <0.05 for the Q
statistic or I2 ≥50% was considered significant for heterogeneity. Data
from eligible studies were combined using inverse variance by a
random-effects model if I2 ≥50%; otherwise, a fixed-effect model was
used. Begg's adjusted rank correlation test and Egger's regression test
were used to assess potential publication bias. Sensitivity analysis,
where one study is excluded at a time, was conducted to assess the
effect of each study. A p-value <0.05 was considered statistically sig-
nificant.
3. Results
3.1. Included studies
The literature search yielded 803 studies. After screening the titles,
152 studies were identified for further assessment. After reading the
abstracts, 58 studies’ full texts were retrieved. After analysing the full
texts, we found that 28 studies investigated the impact of PD on HRV,
and we created a summary table of studies reporting comparisons in
HRV between patients with PD and controls (Tables 1–3). Among these
24 studies, 21 with LF analysis, 22 with HF analysis, 22 with LF/HF
analysis and 6 with SDNN analysis were included (Fig. 2).
3.2. Results of the meta-analysis
Meta-analyses of the pooled mean differences for short-term vari-
ables (LF, HF, and LF/HF) and the long-term variable (SDNN) of HRV
were performed to determine whether there was an overall difference in
any of the variables between cases and controls. Initially, 21 studies
were pooled for the meta-analysis of LF; the results showed no differ-
ence between cases and controls (SMD = −0.1347, 95% CI:
−0.5124–0.2429), p = 0.4844, random-effects model). As hetero-
geneity was high (I2 = 88.7%), a meta-sensitivity analysis was per-
formed. After removing studies that contributed significantly to the
heterogeneity, 17 studies remained, which did not change the results
(SMD = −0.0443, 95% CI: −0.1765–0.0879), p = 0.5114, fixed-ef-
fects model). The forest plot of the LF analysis is displayed in Fig. 3.
For the HF analysis, 22 studies were initially pooled for the meta-
analysis, which revealed lower HF in cases than in the controls
(SMD = −0.4457, 95% CI: −0.8578 to −0.0336, p = 0.0340,
random-effects model). However, the heterogeneity was high
(I2 = 90.8%); after meta-sensitivity analysis, in which 2 studies were
removed, the difference became nonsignificant (SMD = −0.1269, 95%
CI: −0.2598–0.0059, p = 0.0612, fixed-effects model). The forest plot
of the HF analysis is presented in Fig. 4.
For the LF/HF analysis, the difference between cases and controls
was nonsignificant when including all the 22 studies (SMD = 0.1282,
Y. Zhang, et al.
Fig. 1. How heart rate variability works and the differences in health and panic disorders.
95% CI: −0.3240–0.5804, p = 0.5785, random-effects model) and
there was high heterogeneity (I2 = 93.2%). After the meta-sensitivity
analysis, in which 4 studies were removed, the I2 value fell to an ac-
ceptable range (I2 = 47.0%), and the difference became significant
(SMD = 0.1390, 95% CI: 0.0180–0.2600, p = 0.0244, fixed-effect
models), indicating that the cases displayed a higher LF/HF than con-
trols. The forest plot of the pooled LF/HF analysis is shown in Fig. 5.
For the long-term measure of HRV, 5 studies analysing SDNN were
pooled, and a significantly lower SDNN was seen in cases than in
controls (SMD = −0.3133, 95% CI: −0.5459 to −0.0808, p = 0.0083,
fixed-effects model). No meta-sensitivity analysis was performed be-
cause heterogeneity was low (I2 = 38.2%). The forest plot of the SDNN
analysis is displayed in Fig. 6.
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Journal of Affective Disorders 267 (2020) 297–306
3.3. Publication bias
The meta-analysis of LF showed potential publication bias according
to Egger's regression test (p = 0.008). Therefore, the Duval and
Tweedie trim and fill procedure was used to adjust for any suspected
publication bias using a random-effects model. The result remained
nonsignificant (SMD = −0.1594, 95% CI: −0.3417–0.0229),
p = 0.0866). No publication bias was observed in Begg's adjusted rank
correlation test and Egger's regression test for the other three meta-
analyses.
3.4. HRV before and after treatment
Six studies investigated HRV before and after treatment and 5
 Table 1
Y. Zhang, et al.

The characteristic of the studies reporting comparisons in HRV (short-term) between patients and controls.
Author Year Country Criteria Subjects HRV-related Measures NP NC Significance between PD and Controls 1

Vikram K. Yeragani 1992 USA DSM-III-R PD (supine vs standing & LF, MF, HF 21 21 No difference between PD and controls
standing+deep breathing)
Vikram K. Yeragani 1994 USA DSM-III-R PD (pre-isoproterenol & post- LF, MF, HF, MF/HF 6 11 No difference between PD and controls before isoproterenol
isoproterenol) administration
Vikram K. Yeragani 1994 USA DSM-III-R PD (placebo & lactate) MF, HF 6 9 No difference between PD and controls taking placebo
FRIED ECKART SEIER 1997 Germany DSM-III PD (pre-infusion & infusion & post- LF (0.01~0.05 Hz), MF (0.05~0.15 Hz), 9 11 No difference between PD and controls before saline infusion
infusion) HF, LF/HF, MF/HF
Bruce H. Friedman 1998 USA DSM-III-R PD/blood phobia students HF, LF/HF 16 15 Lower LF, and higher LF/HF in PD than controls
TAKASHI ITO 1999 Japan DSM-IV PD (supine & tilt) total power, LF, HF, LF/HF 8 13 No difference between PD and controls in supine position
Vikram K. Yeragani 2000 USA DSM-III-R PD (supine & standing) total power, ULF, LF, HF, LF/HF 27 21 No difference between PD and controls in supine position
Hagit Cohen 2000 Israel DSM-III-R PD and PTSD Mean RR interval, LF, HF, LFnorm, 11 25 Higher LFnorm, LF/HF and lower HFnorm in PD than controls, but no
HFnorm, LF/HF difference of LF and HF between PD and controls
Rollin McCraty 2001 USA DSM-IV PD VLF, LF, HF, LF/HF, LFnorm, HFnorm, 38 38 Lower lnLF, ln(LF/HF) and normalized LF (nu) and higher
criteria normalized HF (nu) in PD than controls.
B.R. Slaap 2004 Netherlands DSM-IV PD and OCD TP, LF, HF, LF/HF 53 54 No difference between PD and controls
MARLIES E. ALVARENGA 2006 Australia DSM-IV PD (unmedicated) LF, HF, LF/HF 25 20 Lower HF and higher LF/HF in PD than controls
Amir Garakani 2009 USA DSM-IV PD Mean RR interval, PNN50, LF, HF, LF/HF 42 11 Lower mean-RRI and PNN50 in PD than controls. No difference of LF,
HF, LF/HF between PD and controls
Eun-Ho Kang 2009 Korea DSM-IV PD Mean RR interval, SDNN, RMSSD, HF, LF, 45 30 Lower HF and higher LF/HF in PD than controls. No difference of
LF/HF, HFnorm, LFnorm Mean RR interval, SDNN, RMSSD, HF% (nu) and LF% (nu) between
PD and controls
JOSE M. MARTINEZ 2010 USA DSM-III PD (baseline & tilt) Mean RR interval, PNN50, LFnorm, 30 10 Higher LFnorm, LF/HF in PD than controls at baseline
HFnorm, LF/HF

300
Mitsuru Kikuchi 2010 Japan DSM-IV PD and MDD (supine rest & supine deep RR interval, In LF, In HF, LF/HF 17 15 No difference between PD and control group
breathing
Vikki Wise 2011 Australia DSM-IV PD (resting eyes-open and resting eyes- RR, Var, LF/HF 52 104 Lower RR and HRV in PD than controls in both conditions
close)
Hsin-An Chang 2013 Taiwan DSM-IV PD RR interval, Var, LF, HF, LF/HF 48 202 Lower RR interval, HRV, HF and LF in PD than controls. No difference
of LF/HF between PD and controls
Sheng-Min Wang 2013 Korea DSM-IV PD (resting state & threatening stimuli) LFnorm, HFnorm, LF/HF 27 20 No difference between PD and controls at the resting state. Higher LF
and LF/HF, lower HF in PD than controls during threatening stimuli
Huaixi Bie 2013 China CCMD-III PD/GAD SDNN, LF/HF 35 35 Higher LF/HF in PD than controls. No different of SDNN between PD
and controls
Jose M. Martinez 2015 USA DSM-IV PD (pre- and post- saline injection & pre- LFnorm, HFnorm, Total power, LF/HF 15 30 No difference between PD and control group in pre- saline injection
and post- doxapram injection)
Katja Petrowski 2016 Germany DSM-IV PD (prior to, during and post- stress) HF, LF, LF/HF, RMSSD square root of 38 23 No difference between PD and controls
successive R–R interval differences
Xiuli Liu 2016 China CCMD-III PD SDNN, SDANN, PNN50, RMSSD, HF, LF, 60 60 All the parameters were lower in PD than controls
VLF, LF/HF
Antonia Kotianova 2018 Slovak Republic ICD-10 PD SD of R–R intervals, VLF, LF, HF, LF/HF 33 33 Lower VLF in PD than controls at baseline period, and higher LF/HF
ratio in PD than controls during mental task
Kwan Woo Choia 2018 Korea DSM-IV PD and MDD (rest phase & stress phase & LF, HF, LF/HF 29 39 Higher LF/HF in PD than controls in rest phase
recovery phase

TP, Total power; VLF, Very low frequency; ULF, Ultra low frequency; LF, Low frequency; MF, Mid frequency; HF, High frequency; LFnorm, Normalized LF, LF/(TP−VLF) × 100; HFnorm, Normalized HF, HF/
(TP−VLF) × 100; Mean-RRI, Mean R to R wave interval; PNN50, Percent of differences between adjacent NN intervals greater than 50 ms; SDNN, Mean of five minute standard deviation of NN intervals; RMSSD, Root
mean square of successive NN interval differences; Var, Variance; SDANA, Standard deviation of sequential 5 min RR interval; DSM, The diagnostic and statistical manual of mental disorders; ICD, International
classification of diseases; CCMD, Chinese classification and diagnostic criteria of mental disorders; PD, Panic disorder; PTSD, Post traumatic stress disorder; OCD, obsessive compulsive disorder; MDD, Major depressive
disorder; GAD, Generalized anxiety disorder; NP, Number of patients; NC, Number of controls.
Journal of Affective Disorders 267 (2020) 297–306
Y. Zhang, et al. Journal of Affective Disorders 267 (2020) 297–306

reported HRV changes after treatment. All patients in these studies used

No difference between PD and controls in supine

Lower pNN50 in PD than controls in rest phase

Lower ULF in PD than controls when awake.
medications or medication and cognitive behavioural therapy (CBT);

Lower SDNN, VLF, LF in PD than controls

All the parameters were lower in PD than

the only study which reported no changes before and after treatment
Significance between PD and Controls

included patients who used only CBT.

No difference between two groups

Lower SDNN in PD than controls
4. Discussion

The association between PD and CVD has been extensively studied

since the 1990s, but no causal hypothesis has been well established.
According to a review which assessed possible causes of a connection
between PD and CVD, a pleiotropic gene related to glycolysis and
position

vascular growth/modelling, autonomic inflexibility, lifestyle factors

controls

such as smoking and being overweight, atherosclerosis, mental stress,

and myocardial perfusion defects were found to be possible mediating
NC

factors (Machado et al., 2017). The use of HRV in psychiatric illness has
23
21

38

17
30

39

24

been adopted to monitor ANS function; reduced HRV has been seen as a
NP

29
27

38

17
30

29

32

risk factor for increased incidence of CVD (Yeragani et al., 1998). Nu-
Mean RR interval, SDNN, SDANN, SDNN, RMSSD, Total power, Total Power,

merous studies have found associations between PD and diminished

Average R-R, Total power, VLF, LF, HF, LFnorm, HFnorm, LF/HF, SDNN,

HRV, reduced HF power, increased LF power, and elevated LF/HF

(Yeragani et al., 1993; Garakani et al., 2009; Kang et al., 2010;
Martinez et al., 2010; Chang et al., 2013). However, other studies have
reported a lack of evidence between PD and HRV (Slaap et al., 2004;
Kikuchi et al., 2009; Petrowski et al., 2017; Choi et al., 2019). These
inconsistent results make the application of HRV measures in patients
with PD to predict sudden cardiac death controversial. In the present
study, we did not find any significant differences in the short-term
frequency domain measures (LF and HF) between patients with PD and
SDNN, SDANN, PNN50, RMSSD, HF, LF

healthy controls. Our study's results might be partly attributable to the

different study selection criteria, such as drug-naïve patients with a
total power, ULF, LF, HF, LF/HF

SDANN, SDNN, RMSSD, pNN50

primary diagnosis of PD and different HRV measurement settings and

calculations. However, this study found a higher LF/HF ratio in patients
ULF, VLF, LF, HF, LF/HF

with PD that reached significance and had a moderate effect size. This
RMSSD, SDNN, pNN50
HRV-related Measures

finding is in line with most recent studies which reported that patients
The characteristic of the studies reporting comparisons in HRV (long-term) between patients and controls.

with PD presented with a significantly higher LF/HF (Cohen et al.,

2000; McCraty et al., 2001; Martinez et al., 2010; Wang et al., 2013).
The LF/HF ratio is associated with sympathetic modulation
(Reyes, et al., 2013); panic attacks are often characterised by sympa-
SDNN
ULF

thetic excitation and PD might be associated with increased sympa-

thetic function and decreased vagal tone. Thus, there may be an im-
paired sympathovagal balance in patients with PD in comparison to
PD and MDD (rest phase & stress phase &

healthy controls. Additionally, Choi et al. found that patients with PD

showed significantly higher values of LF/HF than healthy controls
during the stress phase, but not the during the rest phase (Choi et al.,
2019). These results suggest that mental stress induces more apparent
autonomic imbalance in patients with PD, which reflects complex im-
paired neurocardiac and emotional integrity. Further studies may be
PD (awake & sleep)

PD (awake & sleep)

PD (awake & sleep)

needed to verify this association in a larger sample size or other eth-

recovery phase

nicities. In addition, sex, occupation, duration of PD, and disease se-

PD (supine)

verity should be considered.

Subjects

Notably, in our study, the long-term time domain parameter (SDNN)

PD

PD

was significantly different between patients with PD and healthy con-

trols. Despite the sample size discrepancy between the short- and long-
DSM-III-R
DSM-III-R

CCMD-III
DSM-IV

DSM-IV

DSM-IV

DSM-IV
Criteria

term analyses, which was expected since the long-term analysis is more
time-consuming and expensive, we suggest two possible reasons for our
findings: 1) Short- and long-term analyses both have advantages and
Country

Turkey

disadvantages. The advantages of the short-term analysis are that it is

China

Korea
USA
USA

USA

USA

easy and fast to perform the tests and confounding factors, such as body
position, physical activity, respiration and environmental factors, are
1997
2000

2001

2007
2016

2018

2018
Year

more readily adjusted, making the results more accurate. However,

numerous confounding variables could have biased the results taken
Gözde Şirin DURDU
Vikram K. Yeragani
Vikram K. Yeragani

from short-term analysis. For example, the age and sex of the partici-
Kwan Woo Choia
Deane E. Aikins
Rollin McCraty

pants were not clearly specified in these studies, which could have af-
Chunjie Shan

fected the results, as the ANS function varies according to sex and age
(Li et al., 2019). Generally, women have higher total and HF parameters
Author
Table 2

and lower LF and LF/HF than men. HRV indices also decrease with age
(Young and Leicht, 2011; Voss et al., 2015). The time point when the

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 Y. Zhang, et al.

Table 3
The characteristic of the studies reporting comparisons in HRV between patients before and after treatment.
Author Year Country PD criteria Subjects Type Therapy HRV-related NP Conclusions
measures

Middleton HC 1995 UK DSM-III-R PD short-term 9 for congnitive therapy 11 for impramine therapy ~0.1 Hz 20 Recovery was associated with a significant rise in overall heart
rate variability.
Tucker, P. 1997 USA DSM-III-R PD short-term Paroxetine at 20 mg/day for 4 weeks LF, HF, LF/HF 24 After paroxetine treatment, patients’ total sympathetic activity
was decreased while parasympathetic activity was increased,
whereas the baroreflex response was preserved.
Vikram K. Yeragani 1999 USA DSM-III-R PD long-term All 16 patients were receiving paroxetine. The dose of TP, ULF, VLF, 16 Lower HF and LF after Paroxetine treatment due to the
paroxetine was 19.7 ± 4.7 mg/day. The mean duration of LF, HF, LF/HF antimuscarinic effect of Paroxetine
treatment was 105 ± 37 days
Prasko J 2011 Czech ICD-10 PD short-term 6 weeks treatment with antidepressants combined with VLF, LF, HF, LF/ 19 There were highly statistical significant differences between
Republic cognitive behavioural therapy HF panic patients and control group in all components of power

302
spectral analysis in 2nd (VLF, LF and H in standing) and in two
component of 3rd (LF and HF in supine) positions. There was also
a statistically significant difference between these two groups in
LF/HF ratio in standing position (2nd)
Jennifer Lara Maria 2019 Germany ICD-10 PD short-term CBT three exposure sessions RMSSD, HF, Var 73 No changes in HR and HRV were observed throughout therapy.
Mumma
Kwan Woo Choia 2019 Korea DSM-IV PD and short-term standard antidepressant treatment pNN50, LF/HF 29 Responders in the PD group presented a lower level of LF/HF
MDD and long- ratio during the stress phase compared to non-responders
term (F = 10.14, p = 0.002)

TP, total power; VLF, Very low frequency; ULF, Ultra low frequency; LF, Low frequency; MF, Mid frequency; HF, High frequency; LFnorm, Normalized LF, LF/(TP−VLF) × 100; HFnorm, Normalized HF, HF/
(TP−VLF) × 100; Mean-RRI, Mean R to R wave interval; PNN50, Percent of differences between adjacent NN intervals greater than 50 ms; SDNN, Mean of five minute standard deviation of NN intervals; RMSSD, Root
mean square of successive NN interval differences; Var, Variance; SDANA, Standard deviation of sequential 5 min RR interval; DSM, The diagnostic and statistical manual of mental disorders; ICD, International
classification of diseases; CCMD, Chinese classification and diagnostic criteria of mental disorders; PD, Panic disorder; PTSD, Post traumatic stress disorder; OCD, Obsessive compulsive disorder; MDD, Major depressive
disorder; GAD, Generalized anxiety disorder; NP, Number of patients; NC, Number of controls.
Journal of Affective Disorders 267 (2020) 297–306
Y. Zhang, et al. Journal of Affective Disorders 267 (2020) 297–306

Fig. 2. Flowchart of literature search.

short-term analysis was performed could also affect the results since the criteria of control recruitment, and participant posture and instructions
ANS responds differently to physiological activity during the day. (Quintana et al., 2016). This may be why the results from each study of
Moreover, HRV could vary depending on the severity level of PD, short-term variables were variable and displayed great heterogeneity

Fig. 3. Meta-analysis of HRV LF of panic disorder patients compared with controls (FRIED ECKART SEIER 1997, Rollin McCraty 2001, JOSE M. MARTINEZ 2010 and
Xiuli Liu 2016 were excluded).

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Fig. 4. Meta-analysis of HRV HF of panic disorder patients compared with controls (Hsin-An Chang 2013 and Xiuli Liu 2016 were excluded).

Fig. 5. Meta-analysis of HRV LF/HF of panic disorder patients compared with controls (Hagit Cohen 2000, JOSE M. MARTINEZ 2010, Huaixi Bie 2013, Xiuli Liu
2016 were excluded).

Fig. 6. Meta-analysis of HRV SDNN of panic disorder patients compared with controls.

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Y. Zhang, et al.
and why the results from studies of long-term variables were more
stable and displayed smaller heterogeneity. 2) The parasympathetic
nervous system (PNS) is the balancing force to the sympathetic nervous
system. The main role of PNS is ‘sleep and digest’; patients with PD are
known for their ANS imbalance with overaction of the sympathetic
nervous system while the PNS is compromised. This imbalance might be
exaggerated during sleep; this is supported by the fact that approxi-
mately half of patients with PD reported experiencing sleep panic at-
tacks at some point during the course of their illness (Krystal et al.,
1991). Currently, only 24-hour measurements of HRV are able to detect
this abnormality. Accordingly, two studies which compared HRV in
patients with PD during awake and sleep periods found a more pro-
nounced reduction in HRV during sleep (Yeragani et al., 1998;
Aikins and Craske, 2008).
In the 7 studies which investigated HRV before and after treatment,
5 out of 6 (83.3%) reported HRV changes after treatment. One study in
which patients used only CBT did not find any significant changes in
HRV. This result suggests that medication may have a more profound
effect on HRV than CBT and that HRV could be used as a predictor of
treatment response. Moreover, among the 7 studies investigating HRV
before and after treatment, 4 analysed LF/HF parameters and 3 re-
ported significant lower short-term LF/HF after antidepressant treat-
ment (with or without CBT), suggesting this parameter may be a pro-
mising biomarker for antidepressant treatment response, while only 1
study which used long-term LF/HF parameters instead reported an in-
creased LF/HF ratio after treatment (Tucker et al., 1997; Yeragani et al.,
1999; Prasko et al., 2011; Choi et al., 2019). This discrepancy may be
due to the antimuscarinic effect of antidepressive medication (in this
case, paroxetine), which may become more profound during sleep.
Moreover, environmental factors other than medication use could not
be excluded (Voss et al., 2013). Similar results have been observed for
depressed patients treated with selective serotonin reuptake inhibitors
(SSRIs); a significant increase in short-term time domain HRV measures
was observed after treatment with SSRIs, whereas a slight decrease in
long-term time domain HRV measures was seen after treatment with
SSRIs (Kemp et al., 2010). As there was only one such study in our
review, further research is needed to validate this result.
4.1. Limitations
The limitation of this study is its small sample size in the long-term
time domain and treatment effect analyses. Thus, further investigation
into these topics with a larger sample size is needed in the future.
4.2. Conclusions
Patients with PD displayed impaired sympathovagal balance and
decreased overall autonomic nervous system activity, which were de-
monstrated in the short-term LF/HF and long-term SDNN parameters.
The LF/HF ratio findings were more consistent compared with LF and
HF alone, making it a better parameter to interpret the LF and HF in
conjunction. Using HRV to predict drug response may be promising but
needs further investigation.
Funding
This study is funded by the National Science Foundation for Young
Scientists of China (Grant no. 81801360) and the National Key
Specialty Construction Project of Clinical Pharmacy (Grant no.
30305030698).
CRediT authorship contribution statement
Yuan Zhang: Methodology, Writing - original draft. Bo Zhou:
Conceptualization, Funding acquisition, Writing - review & editing.
Jian Qiu: Data curation. Lijuan Zhang: Data curation. Zhili Zou:
305
Journal of Affective Disorders 267 (2020) 297–306
Conceptualization, Funding acquisition, Writing - review & editing.
Declaration of Competing Interest
The authors (Yuan Zhang, Bo Zhou, Jian Qiu, Lijuan Zhang, Zhili
Zou) report no conflict of interest in submitting the manuscript titled
“Heart Rate Variability Alterations in Patients with Panic Disorder”.
Acknowledgements
None.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.jad.2020.01.132.
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