Journal of Psychiatric Research 144 (2021) 110–117

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Journal of Psychiatric Research

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

Ethnic discrimination and depressed mood: The role of

autonomic regulation
Julia M. Hagen a, *, Arjen L. Sutterland a, Didier Collard b, Carien D.E. de Jonge a,
Mirjam van Zuiden a, c, d, Jasper B. Zantvoord a, Hanno L. Tan c, e, f, Irene G.M. van Valkengoed c,
Bert Jan H. van den Born b, c, Aeilko H. Zwinderman c, g, Lieuwe de Haan a, h, Anja Lok a, c, i
a
Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Meibergdreef 9, Amsterdam, the Netherlands
b
Amsterdam UMC, University of Amsterdam, Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, the Netherlands
c
Amsterdam UMC, University of Amsterdam, Department of Public and Occupational Health, Amsterdam Public Health research institute, Meibergdreef 9, Amsterdam,
the Netherlands
d
Amsterdam Neuroscience research institute, Amsterdam, the Netherlands
e
Netherlands Heart Institute, Moreelsepark 1, Utrecht, the Netherlands
f
Amsterdam UMC, University of Amsterdam, Department of Cardiology, Heart Center, Meibergdreef 9, Amsterdam, the Netherlands
g
Amsterdam UMC, University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Meibergdreef 9, Amsterdam, the Netherlands
h
Arkin Mental Health Institute, Amsterdam, the Netherlands
i
Center for Urban Mental Health, University of Amsterdam, the Netherlands

A R T I C L E I N F O A B S T R A C T

Keywords: Perceived ethnic discrimination (PED) is thought to underlie increased prevalence of depressed mood in ethnic
Depressive disorders minorities. Depression is associated with increased sympathetic and decreased parasympathetic activity. We
Depression investigated a biopsychosocial model linking PED, disrupted sympathovagal balance and depressed mood.
Ethnic discrimination
Baseline data of HELIUS, a cohort study on health among a multi-ethnic population, was used. Heart rate
Racial discrimination
Autonomic nervous system
variability (HRV), baroreflex sensitivity (BRS), PED (evaluated with the Everyday Discrimination Scale) and
Heart rate variability presence of depressed mood (evaluated with the Patient Health Questionnaire-9) were assessed. Associations of
PED, HRV/BRS and depressed mood were analyzed with linear and logistic regression analyses. Mediation of the
association of PED and depressed mood by HRV/BRS was assessed in a potential outcomes model and four steps
mediation analysis. Of 9492 included participants, 14.7% fulfilled criteria for depressed mood. Higher PED was
associated with depressed mood (P < .001). Lower autonomic regulation indexes were associated with depressed
mood (deltaR2 = 0.4–1.1%, P < .001) and at most weakly with PED (deltaR2 = 0.2–0.3%, P < .001). A very
modest mediating effect by HRV/BRS in the association between PED and depressed mood was attenuated after
adjustment for socioeconomic status. To conclude, we found no support for the hypothesis that autonomic
regulation relevantly mediates the association between PED and depression.

1. Introduction
Globally, over 300 million people suffer from depression (WHO
2018), making it the leading cause of disability and a major contributor
to the global burden of disease. However, prevalence of depression does
not seem to be equally distributed between ethnic minority and majority
groups (Williams et al., 2007; de Wit et al., 2008; Missinne and Bracke
2012). Within the HELIUS cohort, a large prospective study of a
multi-ethnic cohort in the Netherlands, it was previously observed that
persons from ethnic minorities were 2–4 times more likely to have a
depressed mood than those of Dutch descent (Ikram et al., 2015).
An important factor thought to underlie depressed mood in ethnic
minorities is ethnic discrimination (Budhwani et al., 2015). Indeed, in
HELIUS, perceived exposure to ethnic discrimination showed a robust
association with depressed mood in various ethnic minorities (Ikram
et al., 2015). This is in line with the hypothesis that stressors such as
perceived discrimination can induce a biological response that in turn
causes symptoms of depression (McEwen 2008). Disruption of the
sympathovagal balance, characterized by persistent higher activity of
the sympathetic branch of the autonomic nervous system and lowered

* Corresponding author.
E-mail address: julie.hagen@arkin.nl (J.M. Hagen).

https://doi.org/10.1016/j.jpsychires.2021.09.048
Received 5 May 2021; Received in revised form 9 August 2021; Accepted 22 September 2021
Available online 23 September 2021
0022-3956/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
J.M. Hagen et al.
activity of the parasympathetic branch, has been suggested as a bio­
logical pathway linking psychological stressors to depression (Udupa
et al., 2007). Prolonged imbalance of autonomic regulation at the
expense of parasympathetic tone is thought to amplify inflammation
through impairment of the cholinergic anti-inflammatory response, a
mechanism that links autonomic dysregulation to the pathophysiology
of depressive disorders (Tracey 2002; Huston and Tracey 2011).
Two important, non-invasive indexes of autonomic regulation are
heart rate variability (HRV) and baroreflex sensitivity (BRS). HRV
constitutes the beat-to-beat variation in the heart rate and is modulated
primarily by the vagus nerve, a major component of the para­
sympathetic nervous system. BRS captures the magnitude of change in
heart rate in response to a change in systolic blood pressure. It has
convincingly been demonstrated that lower HRV and BRS, reflecting
relatively lower parasympathetic and higher sympathetic activity, pre­
dict cardiovascular morbidity and mortality post myocardial infarction
(Farrell et al., 1991; La Rovere et al., 1998; Perkiomaki et al., 2008;
Huikuri and Stein 2013) and in the general population (Kubota et al.,
2017). Lower HRV has been associated to psychological stress and
stressor frequency, although there has been inconsistency of findings
(Hill et al., 2017; Kim et al., 2018). More consistent are reports of an
association of lower HRV with depressive symptoms and major
depressive disorder (Agelink et al., 2002; De Jonge et al., 2007; Koschke
et al., 2009; Kemp et al., 2010). It has been suggested that lower HRV
precedes worsening of depressive symptoms (Jandackova et al., 2016;
Huang WL et al. 2017). However, in a more recent observational study,
no association between depressive disorder and HRV was found (Kemp
et al., 2014) and it has been suggested that low HRV is primarily caused
by antidepressant medication (Licht et al., 2008).
Although associations between PED and several biological markers
have been investigated (Hill et al., 2017; Ikram et al., 2017; Schmengler
et al., 2017; Panza et al., 2019), a biopsychosocial model linking the
response of the autonomic nervous system to PED with depression has
not previously been explored. The investigation of HRV and BRS in the
association of PED and current depressed mood might increase our un­
derstanding of the biological link between sociopsychological factors
and depression. We hypothesize that high PED is associated with
increased sympathetic tone, as indicated by low HRV/BRS, and that
increased sympathetic tone is associated with depressed mood. Also, we
hypothesize that imbalance in autonomic regulation mediates the as­
sociation between PED and depressed mood. To test these hypotheses,
we investigated the associations between PED and HRV/BRS, and be­
tween HRV/BRS and depressed mood in a large, multi-ethnic popula­
tion. In addition, we assessed whether HRV/BRS mediated the
association between PED and depressed mood.
2. Material and methods
2.1. Participants
For the current study, baseline data of HELIUS (HEalthy LIfe in an
Urban Setting) was used. This is a prospective cohort study carried out in
Amsterdam, the Netherlands. HELIUS aims to unravel the causes of the
unequal burden of disease across ethnic groups, to improve prevention
strategies and health care. Procedures have been reported elsewhere
(Stronks et al., 2013; Snijder et al., 2017). In brief, from 2011 to 2015,
participants in the age range of 18–70 years were randomly sampled
stratified by ethnic origin through the municipality registry of Amster­
dam. Also, up to three of their family members living in Amsterdam
were invited to participate. At baseline, 24,789 participants (28% of
those invited) of Dutch, African Surinamese, South-Asian Surinamese,
Ghanaian, Turkish and Moroccan descent were included. HELIUS is
conducted according to the principles of the Declaration of Helsinki and
approved by the medical ethical committee of Amsterdam University
Medical Centers, location AMC. Written informed consent was obtained
from all participants.
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Journal of Psychiatric Research 144 (2021) 110–117
For the current analyses, participants were included if outcomes of
the Everyday Discrimination Scale (EDS) and the Patient Health
Questionnaire-9 (PHQ-9), and HRV and BRS measurements were
available. Participants reporting the use of beta-blockers were excluded
because of the sympatholytic effects of these agents.
2.2. Measures
2.2.1. Perceived ethnic discrimination
PED was assessed using the Everyday Discrimination Scale (EDS)
(Williams et al., 1997), a widely-used self-report instrument (Bastos
et al., 2010) that assesses the frequency of discriminatory experiences in
daily life, using nine items, with a five-point Likert scale (1, ‘never’ to 5,
‘very often’). In HELIUS, the EDS was adapted by inquiring about ex­
periences of discrimination specifically because of (ethnic) background.
A mean score of the nine items was used in the analyses.
2.2.2. Depressed mood
Depressed mood was assessed using the PHQ-9 (Kroenke et al.,
2010), a validated nine-item self-report questionnaire that assesses the
presence of depressive symptoms during the past two weeks, using a
four-point Likert scale (0, ‘not at all’ to 3, ‘almost every day’). Within
HELIUS, PHQ-9 was found to function similarly in the different ethnic
groups (Galenkamp et al., 2017). A binary score indicating presence of
depressed mood, as indicated by PHQ-9 larger than or equal to 10 (with
sensitivity and specificity for diagnosing major depressive disorder both
estimated at 88% (Kroenke et al., 2001)), was used in the analyses..
In case of one missing item of EDS or PHQ-9, the mean score of the
other items was used to replace the missing item. If more than one item
was missing, the variable was considered missing.
2.2.3. Autonomic regulation indexes
A subset of 13,726 participants in HELIUS was subjected to contin­
uous blood pressure measurement by finger plethysmography using the
Nexfin device (Edwards Lifesciences, Irvine, CA). Finger blood pressure
measurements were obtained for 3–5 min in the supine position after a
10-min rest using a sample frequency of 200 Hz. Study participants
visited the research location in the morning after an overnight fast and
refrained from smoking in the morning prior to the visit. Automated
analysis of the hemodynamic data was performed using custom written
software in Matlab (R2018b, The MathWorks, Inc. Natick) as described
elsewhere (Bakema et al., 2020). In brief, in order to remove noise and
possible ectopic beats, the beat to beat dataset was filtered to determine
normal-to-normal intervals (NN) using a local moving median filter with
a length of 9 beats. Beats with a duration that deviated by more than
25% of the mean interbeat interval (IBI) from the local median IBI were
removed. Participants more than 20% removed beats were excluded. In
addition, recordings from participants without a sinus rhythm (which
was assessed with an electrocardiogram performed during the same
visit, using a MAC 1600 System (GE Healthcare)) were excluded. This
yielded 10,252 participants with good quality HRV and BRS data.
2.2.4. Heart rate variability
To assess the sympathovagal balance, we computed the following
HRV parameters from the finger blood pressure measurements: the
square root of the mean squared successive differences between adjacent
normal-to-normal (NN) intervals (HRVrMSSD) and the standard deviation
of NN intervals (HRVSDNN). HRVSDNN is used to determine the overall
heart rate variability, while HRVrMSSD reflects the short-term changes in
heart rate, which has been related to mainly activity of the para­
sympathetic branch of the autonomic nervous system (Shaffer and
Ginsberg 2017). During short-time recordings of 3–5 min, high HRVSDNN
and HRVrMSSD reflect a high beat to beat variation of heart rate, mostly
resulting from relatively high parasympathetic activity compared to
sympathetic activity.
J.M. Hagen et al.
2.2.5. Baroreflex sensitivity
Cross-correlation estimations of BRS (xBRS) (Wesseling et al., 2017)
were used to assess the cardiac baroreflex, which is a physiological
mechanism to counter-regulate sudden changes in blood pressure. xBRS
was determined as the geometric mean of the correlation between
different 10 s intervals of systolic blood pressure and interbeat intervals
as described in Westerhof et al. (2004). A low xBRS indicates relatively
high sympathetic and low parasympathetic activity.
2.3. Covariates
Information regarding demographics, physical health, lifestyle and
education were obtained through questionnaires. Mastery, i.e., the
extent to which one perceives to be in control of one’s life, has been
previously demonstrated to significantly moderate and mediate the as­
sociation between PED and depressed mood (Slotman et al., 2017).
Mastery was measured using an adapted version of the Pearlin-Schooler
Mastery Scale (Pearlin and Schooler 1978), described in detail else­
where (Slotman et al., 2017). Anthropometric measurements were
conducted by a research nurse. Serum glucose and lipid spectrum levels
were obtained from fasting blood samples. Current medication use was
recorded using the Anatomical Therapeutic Chemical Classification
System (WHO Collaborating Centre for Drug Statistics Methodology
[WHO] 2019).
2.4. Statistical analyses
Analyses were performed in R, version 3.6.3. Between-group com­
parisons of characteristics of cases with depressed mood versus controls
and of included versus excluded participants were conducted using
unpaired t-tests, Mann-Whitney U tests and X2 tests for normal
distributed, non-normal distributed and categorical data, respectively.
Missing values concerning covariates were imputed using multiple
imputation by chained equations (R-package “mice”) (van Buuren and
Groothuis-Oudshoorn, 2011). Five imputations were performed and
number of iterations was set at 20.
2.4.1. Primary analyses
Three sets of regression analyses were performed to assess the cross-
sectional associations between PED and depressed mood (A), between
PED and indexes of autonomic regulation (HRVrMSSD, HRVSDNN and
Fig. 1. Diagram of associations investigated in the four steps mediation analyses, adapted from http://towardsdatascience.com (Fuchs 2019). Investigated mediators
are HRVrMSSD, HRVSDNN and BRS.
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xBRS, separately) (B), and finally, between the indexes and depressed
mood (C). Although the former analysis was previously performed in a
subset of the HELIUS cohort (Ikram et al., 2015), the analysis was
repeated for the purpose of this mediation analysis. All three indexes
were log-transformed. The proportion of variance explained by the
variable of interest was calculated. To investigate potential mediation of
the association between PED and depressed mood by each of the in­
dexes, two sets of analyses were performed: total, direct and causal
mediation effects and mediated proportion were calculated in a poten­
tial outcomes framework (D1), using R-package “mediation”. Number of
simulations was set at 500. Control and treatment values of the mediator
were set at the mean minus and plus 1 SD of each autonomic regulation
index. Also, a mediation analysis according to the four steps method by
Baron and Kenny (1986) was performed (D2). See Fig. 1 for a diagram of
the four steps and the supplementary material for a detailed description.
For analyses of associations of and mediation by the three investi­
gated indexes of autonomic regulation (HRVrMSSD, HRVSDNN and xBRS),
levels of significance was set at 0.05/3 = 0.01667 to adjust for multiple
comparisons.
Covariates were hierarchically added to all analyses, creating 3 pri­
mary models. In model 0, analyses were adjusted for age and sex. In
model 1, analyses were further adjusted for level of education and
occupational level (indicating socio-economic status). In model 2, an
interaction term of mastery*PED was added to analysis B (autonomic
regulation index ~ PED) and to the mediation models D1 and D2.
2.4.2. Secondary analyses
In a secondary analysis, 2 additional sets of covariates were adjusted
for in analysis C (depressed mood ~ autonomic regulation index). In
model 3, analyses were adjusted for age, sex, level of education, occu­
pational level and cardiometabolic risk factors. Analyses in model 4
were additionally adjusted for self-reported medical history of somatic
morbidities (see the supplementary material for included covariates).
We chose to perform these as a secondary analysis, because it is unclear
whether these covariates might act as confounders of the association
between depressed mood and HRV/BRS or whether they are associated
as cause or consequence of either of these variables.
2.4.3. Sensitivity, additional and post-hoc analyses
Several sensitivity analyses were performed. First, analyses were
repeated after exclusion of participants using tricyclic antidepressants
J.M. Hagen et al.
(TCAs), selective serotonin reuptake inhibitors (SSRIs) or serotonin and
norepinephrine reuptake inhibitors (SNRIs), because these drugs have
been demonstrated to lower HRV (Licht et al., 2010; Kemp et al., 2014;
O’Regan et al., 2015). Also, to investigate the possible existence of un­
observed confounders in the mediation analyses, the effects of a corre­
lation between residuals of the associations between PED and the
mediators and between PED and depressed mood on the mediation and
direct effects were assessed. Furthermore, to investigate the probability
of reverse causation in this cross-sectional mediation model of PED, HRV
and BRS and depressed mood, the mediation analyses were repeated
with depressed mood as mediator in the association between PED and
autonomic regulation indexes.
Post-hoc, analyses were repeated for a subset of only participants of
non-Dutch descent, because the report of ethnic discrimination by native
Dutch participants might not be comparable to that by non-native par­
ticipants. Also, to minimize risk of measurement error affecting results,
analyses were repeated on a subsample excluding outliers, defined as
above the top 2.5% or below the bottom 2.5% of the analyzed HRV/BRS
index.
3. Results
3.1. Participants
Of 10,252 participants with available good quality HRV and BRS
data, PHQ-9 and EDS scores were available in 10,087. The exclusion of
Fig. 2. Data points and predictions of PED and HRVrMSSD, HRVrMSSD and depressed mood and PED and depressed mood, corrected for HRVrMSSD, in a 45-year-
old female.
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586 participants using beta-blockers resulted in 9492 participants in the
final study cohort. Characteristics of included participants were similar
to those individuals excluded due to incomplete data or beta-blocker
use, although included participants more often had a higher level of
education and employment (Table S1 in the supplementary material). Of
included participants, 1396 (14.7%) fitted the case definition for
depressed mood. Compared to non-depressed participants, cases were
more often female and of Turkish or Moroccan ethnicity, were more
often unemployed or unfit for work due to medical incapacity, had more
often received no or only elementary education, more often were current
smokers and reported more somatic morbidities (Table S2 in the sup­
plementary material).
3.2. Association of PED and depressed mood (A)
Higher PED was associated with increased odds for current depressed
mood in all models (adjusted for age and sex (model 0), socioeconomic
status (model 1) and mastery as moderator (model 2)). In model 2, the
interaction term PED*mastery was a significant predictor (Table S3 in
the supplementary material). See Fig. 2 for a graphic representation of
data points and predictions of investigated associations.
3.3. Association of PED and autonomic regulation indexes (B)
Although higher PED was associated with lower HRVSDNN in all
models (Table 1), explained variance by PED was smaller than 0.3%.
J.M. Hagen et al. Journal of Psychiatric Research 144 (2021) 110–117

Table 1
Coefficient for PED and (delta) adjusted R2 in a multivariate linear regression model of (log-transformed) autonomic function indexes (B).
Outcome Model† Predictor B (95% CI) p value‡ adjusted R2 delta R2

log(HRVrMSSD) 0 PED − 0.014 (− 0.027–− 0.001) .04 21.0% 0.0%

1 PED − 0.005 (− 0.019 - 0.008) .43 21.5% 0.0%
2 PED − 0.001 (− 0.015 - 0.013) .94 21.6% 0.0%
PED*mastery 0.001 (0.000–0.003) .015
log(HRVSDNN) 0 PED − 0.032 (− 0.043–− 0.021) < .001 15.7% 0.3%
1 PED − 0.018 (− 0.029–− 0.007) .002 17.5% 0.1%
2 PED − 0.017 (− 0.028–− 0.005) .005 17.5% 0.0%
PED*mastery 0.000 (− 0.001 - 0.001) .52
log(xBRS) 0 PED − 0.033 (− 0.046–− 0.020) < .001 34.6% 0.2%
1 PED − 0.015 (− 0.028–− 0.002) .03 36.6% 0.0%
2 PED − 0.008 (− 0.022 - 0.005) .24 36.6% 0.1%
PED*mastery 0.002 (0.001–0.003) < .001

Model 1: + level of education + occupational level.

Model 2: + mastery*PED.
†
Model 0: age + sex.
‡
Significant p values at Bonferoni-corrected level (p < .05/3) are in bold.

Higher PED was associated with lower xBRS in model 0, but not in model
1. In model 2, the interaction PED*mastery was significant, indicating Table 3
Estimates of total, direct and mediated effects in model of depressed mood with
that the negative effect of PED on xBRS is diminished with higher levels
predictor mean EDS and autonomic function indexes as mediators (D1).
of mastery. Again, explained variance by PED was smaller than 0.2% in
all models. The regression of HRVrMSSD failed to show PED as a signifi­ Mediator Model1,2

cant predictor. 0 1 2

log(HRVrMSSD) total effect 0.122 0.112 0.053

3.4. Association of autonomic regulation indexes and depressed mood (C) causal mediation effect 0.001 0.000 0.000
direct effect 0.121 0.112 0.053
proportion mediated 0.6% 0.2% 0.0%
Lower HRV and BRS were associated with increased odds for current log(HRVSDNN) total effect 0.123 0.112 0.053
depressed mood in all models (Table 2). Explained variance by the in­ causal mediation effect 0.002 0.001 0.000
dexes ranged from 0.1 to 1.1%. In the secondary analyses with addi­ direct effect 0.121 0.112 0.053
tional adjustment for cardiometabolic parameters (model 3) and proportion mediated 1.2% 0.5% 0.5%
log(xBRS) total effect 0.123 0.113 0.053
somatic morbidities (model 4), associations for HRV measures were no
causal mediation effect 0.002 0.001 0.000
longer significant (Table S4 in the supplementary material). Coefficients direct effect 0.120 0.112 0.053
of xBRS were only minimally reduced and remained significant in the proportion mediated 2.0% 0.7% 0.7%
fully adjusted model.
Model 1: + level of education + occupational level.
Model 2: + mastery*PED.
3.5. Mediation analyses (D1 and D2) 1
Estimates significant at Bonferoni-corrected level (p < .05/3) are in bold.
2
Model 0: age + sex.
The potential outcomes model (D1) showed a significant total and
direct effect of PED on depressed mood in all models (Table 3), indi­ showed similar results to our main analyses (n = 9,173, Tables S5–S7,
cating an association between PED and depressed mood that is not data of four steps analysis not shown). Because no mediation effect was
completely mediated by HRV/BRS. The mediation effect was significant observed in our fully adjusted model, analyses of the effect of correlation
in model 0 (adjusted for age and sex) for HRVrmsdd and xBRS, with an between the residuals of the mediator and outcome regressions on the
estimated 1.2–2.0% (the mediated proportion) of the total effect medi­ mediation effect could not be performed.
ated by HRV/BRS. The mediation effect of all mediators was attenuated After repeating the mediation analyses with depressed mood as
after adjustment for socioeconomic status (model 1). The four steps mediator and PED as predictor, no significant total or direct effects were
mediation analysis (D2), showed similar results (see the supplementary shown for HRVrMSSD in a potential outcomes framework. For HRVSDNN,
material) and are depicted in Fig. 1, S1 and S2. significant total and direct effects were detected in all 3 models. For
xBRS, this was only the case in model 0 (adjusted for age and sex). Model
3.6. Sensitivity and additional analyses 0 and 1 (additionally adjusted for sociodemographic parameters)
showed a significant mediation effect by depressed mood for all
Analyses after exclusion of participants using TCAs, SSRIs or SNRIs,

Table 2
Coefficient for (log-transformed) autonomic function index and (delta) Nagelkerke R2 in a multivariate logistic regression model of depressed mood (C).
Predictor Model† OR (95% CI) p value‡ Nagelkerke R2 delta R2

log(HRVrMSSD) 0 0.750 (0.669–0.842) < .001 1.9% 0.4%

1 0.796 (0.709–0.895) < .001 5.0% 0.3%
log(HRVSDNN) 0 0.726 (0.633–0.833) < .001 1.9% 0.4%
1 0.827 (0.719–0.950) .007 4.8% 0.1%
log(xBRS) 0 0.640 (0.571–0.718) < .001 2.6% 1.1%
1 0.722 (0.642–0.812) < .001 5.3% 0.5%

Model 1: + level of education + occupational level.

†
Model 0: age + sex.
‡
Significant p values at Bonferoni-corrected level (p < .05/3) are in bold.

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J.M. Hagen et al.
outcomes, as did model 2 (also adjusted for mastery as moderator) for
outcomes HRVSDNN and xBRS (Table S8). Results of the four steps
mediation analyses showed a significant mediation effect by depressed
mood in all models but model 1 for HRVSDNN (data not shown).
3.7. Post-hoc analyses
After exclusion of participants of Dutch descent, the association be­
tween HRV/BRS and depressed mood showed similar results, except for
analysis A: in this subgroup (n = 7552), no association between PED and
HRV/BRS was found in any model, except model 2 (adjusted for mastery
as moderator) for HRVrMSSD. Results of the analyses with exclusion of
outliers were similar to the main analyses, although coefficients of in­
dividual regressions were smaller (n = 9,016, data not shown).
4. Discussion
4.1. Main findings
This is the first study to examine the relation between perceived
ethnic discrimination, autonomic regulation and prevalence of current
depressed mood. In this cross-sectional study of a large multi-ethnic
cohort, we found a significant association of PED with autonomic
regulation, operationalized as HRV and BRS, although effect sizes were
small. A stronger association was found between lower HRV/BRS,
indicating higher sympathetic tone, and prevalence of depressed mood.
This was most prominent for xBRS, of which the association with
depressed mood was independent of sociodemographic factors, car­
diometabolic parameters and somatic morbidities. Finally, the media­
tion analysis showed a very modest mediation effect of HRV/BRS on the
association between PED and depressed mood in the unadjusted models,
but not after adjustment for socioeconomic status. Therefore, we
conclude the results do not support the hypothesis of a biopsychosocial
model in which the association between PED and depressed mood is
relevantly mediated by dysregulation of the autonomic nervous system.
Previous reports on the association between autonomic regulation
and chronic psychological stressors have been inconsistent. In line with
our findings, three recent studies of HRV and various psychological
stressors (child maltreatment, negative life events and job strain) re­
ported weak or absent associations after adjustment for sociodemo­
graphic factors (Oliveira Junior et al., 2019; Bakema et al., 2020;
Klosowska et al., 2020). In contrast, a negative association between job
strain and HRV has been reported in 3290 white-collar workers in
London (Chandola et al., 2008), but only for the combination of pro­
longed high job strain and social isolation. In our analyses, associations
between PED as psychological stressor and HRV or BRS are weak. The
lack of an association in participants of non-Dutch descent in our
post-hoc analyses (presuming invalidity of the EDS in Dutch majority
groups) disputes the hypothesis of an association between PED and
sympathovagal balance.
As for the observed association between autonomic regulation and
depressed mood, our results are partly in line with findings of a lower
HRV in 524 patients suffering from major depressive disorder compared
to 1075 healthy controls was reported, although differences in this case-
control study were mainly driven by use of antidepressant medication
(Licht et al., 2008). The latter is in contrast with findings of our sensi­
tivity analyses in which after exclusion of users of TCAs, SSRIs and/or
SNRIs the magnitude of the association between HRV and depressed
mood was only minimally reduced and remained significant. In support
of our findings, a recent meta-analysis of HRV in major depressive dis­
order, excluding users of antidepressants, reported significantly lower
HRV in patients suffering from depression compared to healthy controls
(Koch et al., 2019). Studies of BRS in relation to depression are scarce,
but a negative association with (late-life) depression has been reported
in a small case-control study (Vasudev et al., 2011). Overall, reports are
in line with current findings of a link between depressed mood and lower
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Journal of Psychiatric Research 144 (2021) 110–117
HRV/BRS, indicating increased sympathetic tone.
Neither the results of our primary analyses, nor of our sensitivity and
post-hoc analyses are in support of a biopsychosocial model that links
PED and depressed mood through a biological pathway: the autonomic
nervous system. Alternative mechanisms that might explain the link
between ethnic discrimination and depression, such as the effects of
repeated assaults on one’s self-image or of socioeconomic deprivation
resulting from discrimination, have not been investigated in the current
study. We did find an indication of reverse causation: the (weak) asso­
ciation between PED and HRV/BRS was mediated by depressed mood. In
literature, both directions of the pathway between HRV and depression
have been proposed (Jandackova et al., 2016), although decreased HRV
is suggested to be mostly driven by antidepressant use (Huang M et al.,
2018; Hu et al., 2019), a theory that is not supported by our findings.
4.2. Limitations
Although the risk of reverse causation in the mediation analyses was
addressed, the restrictions of the cross-sectional design should be
recognized: conclusions about the direction of investigated associations
cannot be made. Most importantly, we used 3 to 5-min continuous blood
pressure recordings to determine HRV and BRS, performed using stan­
dardized procedures in the morning. Earlier studies have shown that this
is sufficient to determine a valid and consistent estimate of automatic
regulation. However, we were not able to capture variations within a
day using our technique. This is less of a problem for BRS, because BRS
reflects a response of the autonomic nervous system to blood pressure
change and is less prone to random variations over the day. Even so, our
results could be complemented by repeated measures, and by measures
of HRV in response to a stimulus (Kuang et al., 2017). Furthermore, the
effects of physical activity (of which the assessment was shown to be
insufficiently reliable and valid (Nicolaou et al., 2016)), alcohol use
(more prevalent amongst controls compared to cases), or other lifestyle
factors known to affect autonomic regulation were not taken into ac­
count in this study. Finally, frequency of perceived discriminatory ex­
periences does not necessarily translate to the psychological stress
associated with these experiences. Focusing on psychological impact of
discrimination, an alternative to assessing frequency of PED, could
additionally be informative.
5. Conclusion
We observed that lower HRV and BRS, indexes of autonomic regu­
lation, were associated with depressed mood and at most weakly with
PED. However, we found no evidence that autonomic regulation medi­
ated the relation between PED and depression. Our findings do not
support the biopsychosocial hypothesis that an imbalance of autonomic
regulation in response to ethnic discrimination increases the likelihood
of depressed mood.
CRediT authorship contribution statement
Julia M. Hagen: Conceptualization, Methodology, Formal analysis,
Writing – original draft, Writing – review & editing, Visualization. Arjen
L. Sutterland: Conceptualization, Methodology, Formal analysis,
Writing – original draft, Writing – review & editing. Didier Collard:
Methodology, Writing – review & editing. Carien D.E. de Jonge:
Writing – review & editing. Mirjam van Zuiden: Methodology, Writing
– review & editing. Jasper B. Zantvoord: Methodology, Writing – re­
view & editing. Hanno L. Tan: Methodology, Writing – review & edit­
ing. Irene G.M. van Valkengoed: Methodology, Writing – review &
editing. Bert Jan H. van den Born: Methodology, Writing – review &
editing. Aeilko H. Zwinderman: Methodology, Formal analysis,
Writing – review & editing. Lieuwe de Haan: Conceptualization,
Methodology, Writing – review & editing, Supervision. Anja Lok:
Conceptualization, Methodology, Writing – review & editing,
J.M. Hagen et al.
Supervision.
Declaration of Competing Interest
Dr. A. Lok is a member of the advisory board on suicidality for
Janssen. Other authors report no conflict of interest.
Acknowledgements
The HELIUS study is conducted by the Amsterdam UMC, location
AMC and the Public Health Service of Amsterdam. Both organizations
provided core support for HELIUS. The HELIUS study is also funded by
the Dutch Heart Foundation, the Netherlands Organization for Health
Research and Development (ZonMw), the European Union (FP-7), and
the European Fund for the Integration of non-EU immigrants (EIF). We
are most grateful to the participants of the HELIUS study and the man­
agement team, research nurses, interviewers, research assistants and
other staff who have taken part in gathering the data of this study. We
want to thank Noelle Acton, for writing the first draft of the proposal.
Finally, we would specifically like to acknowledge prof. dr. R. Peters for
initiating cardiological research in the HELIUS Study.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jpsychires.2021.09.048.
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