Journal of Affective Disorders 335 (2023) 49–56

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Journal of Affective Disorders

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

Inverse association between changes in systolic and diastolic blood pressure

and risk of depression: A nationally representative cohort study
Yohwan Lim a, 1, Bo Chang Kim a, 1, Sung Soo Yoon a, Hye Jun Kim a, Sang Jun Lee a,
Myeong Hoon Lee a, Ju Hee Kim a, Sun Jae Park c, Seogsong Jeong a, *, Hyun Wook Han a, b, *
a
Department of Biomedical Informatics, CHA University School of Medicine, CHA University, 335 Pangyo-ro, Seongnam 13448, Republic of Korea
b
Institute of Biomedical Informatics, CHA University School of Medicine, CHA University, 335 Pangyo-ro, Seongnam 13448, Republic of Korea
c
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

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

Keywords: Background: Depression is one of complex mental disorders with diverse etiological factors but the association
Blood pressure between blood pressure (BP) and depression is unknown. We aimed to investigate the association between
Systolic pressure changes in BP (systolic and diastolic) and incident depression.
Diastolic pressure
Methods: From the National Health Insurance Service-Health Screening Cohort (NHIS-HEALS), 224,192 partic­
Depression
ipants who underwent biennial health screenings from period I (2004–05) and II (2006–07) were included in the
study. Systolic BP (SBP) and diastolic BP (DBP) categories were defined as follows: SBP into 5 categories (<90
mmHg, 90 mmHg − 119 mmHg, 120 mmHg − 129 mmHg, 130 mmHg − 139 mmHg, ≥140 mmHg) and DBP into
4 categories (<60 mmHg, 60 mmHg − 79 mmHg, 80 mmHg − 89 mmHg, ≥90 mmHg). Also, BP levels were
classified into 5 groups: normal, elevated BP, stage 1 BP, stage 2 BP, hypotension. Using the Cox proportional
hazards regression, changes in SBP and DBP between two screening periods and the risk of depression were
calculated by adjusted hazard ratio (aHR) and 95 % confidence interval (CI).
Results: There were 17,780 depression events during 1.5 million person-year of follow-up. Compared to the
participants with SBP ≥ 140 mmHg or DBP ≥ 90 mmHg from both periods, those who decreased SBP from ≥140
mmHg to 120 mmHg–129 mmHg (aHR 1.13; 95 % CI 1.04–1.24; P = 0.001) and those who decreased DBP from
≥90 mmHg to 60 mmHg–79 mmHg (aHR 1.10; 95 % CI 1.02–1.20; P = 0.020) showed a higher risk of
depression, respectively.
Conclusions: Changes in SBP and DBP showed an inverse relationship with depression risk.

1. Introduction compared to the normal population, suggesting a bidirectional rela­

Depression is one of the common but complex mental disorders with
diverse etiological factors that result in both physical and psychological
symptoms. The World Health Organization reported that depression is
ranked first as the single largest contributor to global disability, result­
ing 4.4 % of the global population suffering from depression regardless
of gender or age (World Health, 2017).
Known risk factors for depression include life stressors, personality,
and environmental factors but also share common risk factors, such as
smoking, physical activity, obesity, and hypertension (Hammen, 2018;
Maier et al., 2021). In addition, patients with depression are more likely
to have cardiovascular diseases (CVD) and a higher CVD mortality rate
tionship (Hare et al., 2014; Meng et al., 2020). Therefore, investigating
the relationship between depression and blood pressure is important to
understand the underlying mechanism between depression and CVD.
Many studies investigated the association between blood pressure (BP)
and depression, but the results were not consistent. Some studies re­
ported that low BP had a higher risk or showed no association with
depression (Akbaraly et al., 2011; Barrett-Connor and Palinkas, 1994;
Godin et al., 2012; Siennicki-Lantz et al., 2013; Yang et al., 2015). For
example, Godin et al. (Godin et al., 2012) reported that low BP (systolic
BP [SBP] < 120 mmHg or diastolic BP [DBP] < 75 mmHg) showed a
higher risk of depression compared with normal BP group (adjusted
hazard ratio (aHR) 1.63, 95 % CI 1.23–2.36). Conversely, Jeon et al.

* Corresponding authors at: Department of Biomedical Informatics, CHA University School of Medicine, 335 Pangyo-ro, Seongnam 13448, Republic of Korea.
E-mail addresses: seoksong@mensakorea.org (S. Jeong), stepano7@gmail.com (H.W. Han).
1
These authors contributed equally.

https://doi.org/10.1016/j.jad.2023.04.107
Received 26 September 2022; Received in revised form 23 April 2023; Accepted 28 April 2023
Available online 1 May 2023
0165-0327/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Y. Lim et al.
(2020) reported that low BP levels did not show any meaningful results
but only high BP level (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg) lowered
the risk of depression (aHR 0.77, 95 % CI 0.66–0.99). Chronic symptoms
of relative hypotension, such as fatigue and light-headedness, can lead to
depression through accumulated psychological stress. However, these
studies have evaluated the relationship only by a single measurement
and the association of changes in BP has been neglected. Therefore, we
examined the association of changes in BP who underwent two
consecutive biennial health screenings with the risk of incident
depression using the National Health Insurance Service-Health
Screening Cohort (NHIS-HEALS) database.
2. Methods
2.1. Study population
The NHIS is a non-profit institution which is responsible for man­
aging health insurance services in South Korea. The NHIS-HEALS is a
nationally representative cohort comprising 514,866 participants aged
40 years or older who underwent a health screening between 2002 and
2003 and were followed up until December 31, 2013. It provides soci­
odemographic and clinical data, such as serological characteristics,
medical history, drug prescription, and disease history. Detailed infor­
mation about the NHIS-HEALS is provided in the previous study (Seong
et al., 2017). Our study was conducted in accordance with the STROBE
guidelines and was approved by the Institutional Review Board of CHA
Bundang Hospital (No.: CHAMC 2022-04-041) (Elm et al., 2007).
Informed consent was waived because the NHIS-HEALS data has been
strictly anonymized according to the Personal Data Protection Act
guidelines.
There were 263,776 participants who underwent two consecutive
biennial health screenings (period I: 2004–05 and period II: 2006–07).
All participants were followed up from 1 January 2008 until the diag­
nosis of depression or 31 December 2013. Next, we excluded those who
were already diagnosed with depression before the index date (n =
17,995), missing values for SBP or DBP (n = 146), and missing values for
other key variables (n = 21,443). Therefore, 224,192 participants were
finally included for the analysis (Fig. S1).
2.2. Measurement and classification of BP
BP was measured on the bare upper arm after at least 5 min of rest by
either sphygmomanometers or oscillometric measuring devices,
whichever is available. Appropriate cuff size was chosen by the medical
experts and was measured at least twice for accurate BP value and the
average value of each BP was registered in the health screening data. If
SBP was below 60 mmHg or above 400 mmHg and DBP was below 30
mmHg or above 250 mmHg, NHIS-HEALS processed each BP as a null
value regarding as an incorrect input data.
The classification of BP was based on the 2017 American College of
Cardiology-American Heart Association Hypertension Guideline
(Whelton et al., 2018). Hypotension was additionally defined based on
the previous study (Jeon et al., 2020). Therefore, BP was classified into 5
groups as follows: normal (90 mmHg ≤ SBP < 120 mmHg and 60 mmHg
≤ DBP < 80 mmHg), elevated BP (120 mmHg ≤ SBP < 130 mmHg and
60 mmHg ≤ DBP < 80 mmHg), stage 1 BP (130 mmHg ≤ SBP < 140
mmHg or 80 mmHg ≤ SBP < 90 mmHg), stage 2 BP (SBP ≥ 140 mmHg
or DBP ≥ 90 mmHg), and hypotension (SBP < 90 mmHg or DBP < 60
mmHg from those classified as normal BP). Similarly, SBP and DBP were
classified based on the BP classification as follows: SBP into 5 categories
(<90 mmHg, 90 mmHg to 119 mmHg, 120 mmHg to 129 mmHg, 130
mmHg to 139 mmHg, ≥140 mmHg) and DBP into 4 categories (<60
mmHg, 60 mmHg to 79 mmHg, 80 mmHg to 89 mmHg, ≥90 mmHg).
50
Journal of Affective Disorders 335 (2023) 49–56
2.3. Incident depression
Participants with incident depression were defined as any first-ever
admission or outpatient visit registered by the International Classifica­
tion of Diseases 10th revision (ICD-10) codes of F32-F33 as described in
previous studies (Kim et al., 2022; Park et al., 2020).
2.4. Key variables for adjustment and subgroup analyses
Key variables were extracted from the health screenings through
questionnaires and anthropometric measurements. The following vari­
ables were considered for the adjustment: age (continuous; years), sex
(categorical; male and female), household income (categorical; quar­
tiles), body mass index (continuous; kg/m2), fasting serum glucose
(continuous; mg/dL), cigarette smoking (categorical; never, former, and
current), alcohol consumption (categorical; 0, 1–2, 3–4, ≥5 times/
week), total cholesterol (continuous; mg/dL), disability (categorical; yes
and no), physical activity (categorical; 0, 1–2, 3–4, 5–6, and ≥7 times/
week), history of sleep disorder and anxiety (categorical; yes and no),
antihypertensive medication (e.g., angiotensin-converting enzyme in­
hibitors, calcium channel blockers; categorical; yes and no), antide­
pressant medication (e.g., selective serotonin reuptake inhibitors,
tricyclic antidepressants; categorical; yes and no), and Charlson co­
morbidity index (CCI; categorical; 0, 1, and ≥2). Household income was
calculated based on the insurance premium of the NHIS. Definitions of
CCI and each key variables are described in previous studies (Kim et al.,
2019; Quan et al., 2005). The Korea Drug codes for antihypertensive and
antidepressant medication used in the analyses are described in Table S1
and S2. Diabetes was defined as ICD-10 code (E10–E14) and the use of
antidiabetic medication. Hyperlipidemia was defined as total choles­
terol ≥240 mg/dL or use of lipid-lowering medication. History of sleep
disorder (F51, G47) and anxiety (F41) was defined based on ICD-10
code.
2.5. Statistical analysis
The follow-up started from 1 January 2008 and ended on 31
December 2013. Each participant was censored when diagnosed with
depression during the follow-up period. Categorical variables are pre­
sented as n (%) and continuous variables are presented as medians
(interquartile range). Crude rate was calculated by the total number of
depression events divided by 1000 person-years (PY). The
multivariable-adjusted hazard ratio (aHR) and 95 % confidence interval
(CI) were calculated using the Cox proportional hazards regression after
adjustments for the key variables. First, the adjusted HRs and 95 % CIs
were calculated by the BP measured at period I to assess the association
of single-point BP with incident depression. Next, adjusted HRs and 95
% CIs were calculated according to changes BP from the period I to II to
assess the association in consecutive periods. The first model was
minimally adjusted for age and sex. The second model was adjusted for
age, sex, household income, body mass index (BMI), fasting serum
glucose, cigarette smoking, alcohol consumption, total cholesterol,
disability, physical activity, history of sleep disorder and anxiety, anti­
hypertensive medication, antidepressant medication, and Charlson co­
morbidity index. In addition, the association was additionally calculated
by stratifying the model with BP classification at period I to assess the
interaction between BP classification and depression.
For subgroup analyses, we stratified the participants by age (<60,
≥60 years), sex (male, female), household income (lower half, upper
half), cigarette smoking (never, former, and current), alcohol con­
sumption (yes, no), physical activity (yes, no), history of sleep disorder
and anxiety (yes, no), antihypertensive medication (yes, no), antide­
pressant medication (yes, no), and CCI (<2, ≥2). To account for the data
uncertainties, sensitivity analyses were performed by (1) excluding the
participants with one, three, and five years of follow-up, respectively,
(2) excluding the participants with hypotension at period I. Restricted
Y. Lim et al. Journal of Affective Disorders 335 (2023) 49–56

cubic splines based on 3 knots of consecutive aHR were drawn to Table 1

examine the association of continuous SBP and DBP with risk of Baseline characteristics of participants at the period II (2006–07).
depression. A P value of <0.05 was considered statistically significant. Characteristic Total
All data preprocessing and statistical analyses were carried out using
(n = 224,192)
SAS version 9.4 (SAS Institute Inc.) and R Project for Statistical
Computing (https://www.r-project.org/). Age, years 55 (50–63)
Male 132,424 (59.1)
Household incomea, n (%)
3. Results 1Q 55,911 (24.9)
2Q 54,797 (24.4)
3.1. Participant characteristics 3Q 63,685 (28.4)
4Q 49,799 (22.2)
Blood pressure classificationb, n (%)
In total, 224,192 participants (male; n = 132,424 [59.1 %]) with a Hypotension 3147 (1.4)
median (interquartile range) age of 55 (50–63) years were included in Normal 60,424 (27.0)
the analysis. Participants with lower SBP and DBP categories showed Elevated 22,806 (10.2)
lower BMI, lower total cholesterol, higher household income, lower Stage 1 87,410 (39.0)
Stage 2 50,405 (22.5)
fasting serum glucose, lower frequency rate of alcohol consumption, and Body mass index, kg/m2 23.8 (22.0–25.7)
lower use of antihypertensive and antidepressant medications. Pro­ Total cholesterol, mg/dL 196 (85–104)
portions of participants with SBP < 90 mmHg and DBP < 60 mmHg were Fasting serum glucose, mg/dL 94 (85–104)
relatively low compared to other categories (0.1 % and 1.4 %, respec­ Cigarette smoking, n (%)
Never smoker 158,653 (70.8)
tively). Other descriptive characteristics of the participants are listed in
Former smoker 21,782 (9.7)
Tables 1 and S3. Current smoker 43,757 (19.5)
Alcohol consumption, n (%)
3.2. Association of SBP and DBP categories with risk of depression at the None 128,920 (57.5)
period I (2004–05) 1–2 times/week 73,937 (33.0)
3–4 times/week 14,059 (6.3)
≥5 times/week 7276 (3.3)
There were 17,780 depression events during 1.5 million PY of follow- Physical activity, n (%)
up. After the adjustment of key variables including socioeconomic fac­ Physically inactive 105,044 (46.9)
tors, anthropometric measurements, medical history, and comorbidities, 1–2 times/week 65,549 (29.2)
3–4 times/week 30,691 (13.7)
the participants with SBP 120–129 mmHg (aHR 0.94; 95 % CI
5–6 times/week 7665 (3.4)
0.91–0.98; P = 0.003), 130–139 mmHg (aHR 0.89; 95 % CI 0.86–0.94; P ≥7 times/week 15,243 (6.8)
< 0.001) and ≥140 mmHg (HR 0.84; 95 % CI 0.81–0.88; P < 0.001) Baseline comorbidities, n (%)
showed a lower risk of depression compared with SBP 90–110 mmHg. Hyperlipidemiac 40,408 (18.0)
Also, the participants with DBP 80–89 mmHg (aHR 0.94; 95 % CI Diabetesd 10,033 (4.5)
Sleep disordere 7353 (3.3)
0.91–0.97; P < 0.001) and ≥90 mmHg (HR 0.88; 95 % CI 0.85–0.92; P < Anxietyf 10,031 (4.5)
0.001) showed a lower risk of depression compared with DBP 60–79 Charlson comorbidity index, n (%)
mmHg (Table S4). Both SBP and DBP showed a significant, dose- 0 113,320 (50.5)
dependent association with depression. 1 54,744 (24.4)
≥2 56,139 (25.0)
Disabilityg, n (%) 1457 (0.7)
3.3. Association between changes of SBP categories from the period I Use of medication, n (%)
(2004–05) to II (2006–07) with risk of depression Antihypertensive medication 47,396 (21.1)
Antidepressant medication 9486 (4.2)
From the participants with SBP 90–119 mmHg at the period I, those Data are presented as median (interquartile range) unless otherwise specified.
who increased SBP to ≥140 mmHg at the period II showed a lower risk Acronyms: BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic
of depression (aHR 0.88; 95 % CI 0.78–0.98; P = 0.020). Also, from the blood pressure; ICD-10, the 10th revision of the International Statistical Clas­
participants with SBP ≥ 140 mmHg at the period I, those who decreased sification of Diseases and Related Health Problems.
a
SBP to 120–129 mmHg at the period II showed a higher risk of Proxy for socioeconomic status based on the insurance premium of the
depression (aHR 1.13; 95 % CI 1.04–1.24; P = 0.001; Table 2). The non- National Health Insurance Service.
b
linear association between changes of SBP values with risk of depression Definitions of blood pressure classification were based on the 2017
American College of Cardiology-American Heart Association Hypertension
is depicted by a restricted cubic spline curve in Fig. 1. SBP < 90 mmHg at
Guideline (Whelton et al., 2018) and included hypotension criteria as follows:
period I was not depicted due to small sample size.
normal BP, SBP < 120 mmHg and DBP < 80 mmHg; elevated BP, 120 mmHg ≤
SBP < 130 mmHg and 60 mmHg ≤ DBP < 80 mmHg; stage 1 BP, 130 mmHg ≤
3.4. Association between changes of DBP categories from the period I SBP < 140 mmHg or 80 mmHg ≤ DBP < 90 mmHg; stage 2 BP, SBP ≥ 140
(2004–05) to II (2006–07) with risk of depression mmHg or DBP ≥ 90 mmHg; hypotension, SBP < 90 mmHg or DBP < 60 mmHg
from those classified as normal BP.
From the participants with DBP < 60 mmHg at the period I, those c
Defined as total cholesterol ≥240 mg/dL or use of lipid-lowering
who increased DBP to 60–79 mmHg at the period II showed a lower risk medication.
d
of depression (aHR 0.65; 95 % CI 0.47–0.89; P = 0.008). Also, from the Defined as ICD-10 code (E10-E14) and use of antidiabetic medication.
e
participants with DBP 80–89 mmHg at the period I, those who decreased Defined as ICD-10 code (F51, G47).
f
DBP to 60–79 mmHg at the screening period II showed a higher risk of Defined as ICD-10 code (F41).
g
Based on the enrollment records from the National Health Insurance
depression (aHR 1.06; 95 % CI 1.01–1.12; P = 0.023). From those with
Service.
hypotension (DBP < 60 mmHg & SBP 90–119 mmHg) at the period I,
increased DBP to 60–79 mmHg at the period II showed a lower risk of
depression (aHR 0.67; 95 % CI 0.47–0.94; P = 0.020). Similarly, from The non-linear association between changes of DBP values with risk of
the participants with stage 2 BP (DBP 60–79 mmHg & SBP ≥140 mmHg) depression is depicted by restricted cubic spline curve in Fig. 2. DBP <
at the period I, those who increased DBP to ≥90 mmHg showed a lower 60 mmHg at period I was not depicted due to small sample size.
risk of depression (aHR 0.70; 95 % CI 0.50–0.97; P = 0.040; Table 3).

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Y. Lim et al. Journal of Affective Disorders 335 (2023) 49–56

Table 2
Association between changes in SBP categories from the period I (2004–05) to II (2006–07) and risk of depression stratified by blood pressure classification.
Blood pressure classification Event/total SBP (mmHg) at the period II (2006–07)

<90 90–119 120–129 130–139 ≥140 P for trend

SBP (mmHg) at the period I (2004–05)

Overall
<90 46/434 1.00 (reference) 0.55 (0.12–2.47) 0.49 (0.09–2.69) 0.41 (0.05–3.41) 1.58 (0.20–12.68) 0.57
90–119 5563/67,330 1.08 (0.72–1.61) 1.00 (reference) 0.97 (0.91–1.04) 1.02 (0.95–1.10) 0.88 (0.78–0.98)a 0.15
120–129 4102/53,253 0.35 (0.05–2.51) 1.07 (0.99–1.16) 1.00 (reference) 0.99 (0.91–1.08) 1.04 (0.94–1.15) 0.22
130–139 4069/53,562 0.87 (0.22–3.48) 1.04 (0.95–1.13) 1.00 (0.92–1.09) 1.00 (reference) 0.96 (0.88–1.05) 0.62
≥140 4000/49,613 NA 1.05 (0.94–1.17) 1.13 (1.04–1.24)b 1.05 (0.98–1.14) 1.00 (reference) 0.10
Hypotension
SBP < 90 & DBP < 60 26/287 1.00 (reference) 0.46 (0.05–3.93) 0.50 (0.05–5.36) NA NA 0.13
SBP < 90 & DBP 60–79 20/146 1.00 (reference) 0.90 (0.08–10.48) 0.14 (0.01–3.33) NA NA 0.46
SBP 90–119 & DBP < 60 248/2820 1.00 (reference) 0.86 (0.32–2.32) 0.84 (0.30–2.36) 1.02 (0.35–2.96) 0.59 (0.17–2.00) 0.73
Normal
SBP 90–119 & DBP 60–79 4695/56,465 1.14 (0.74–1.78) 1.00 (reference) 0.98 (0.91–1.05) 1.03 (0.94–1.11) 0.89 (0.78–1.02) 0.33
Elevated
SBP 120–129 & DBP 60–79 1712/20,784 NA 1.04 (0.92–1.17) 1.00 (reference) 0.91 (0.80–1.04) 1.06 (0.90–1.24) 0.27
Stage 1
SBP 90–119 & DBP 80–89 592/7698 NA 1.00 (reference) 0.92 (0.75–1.12) 0.96 (0.77–1.20) 0.81 (0.59–1.10) 0.70
SBP 120–129 & DBP 80–89 2208/29,856 1.46 (0.21–10.41) 1.09 (0.98–1.22) 1.00 (reference) 1.04 (0.93–1.17) 1.05 (0.92–1.21) 0.63
SBP 130–139 & DBP 60–79 884/9863 NA 0.96 (0.80–1.15) 0.96 (0.80–1.14) 1.00 (reference) 0.89 (0.74–1.07) 0.82
SBP 130–139 & DBP 80–89 2380/32,438 1.40 (0.35–5.60) 1.11 (0.99–1.24) 1.01 (0.90–1.12) 1.00 (reference) 0.99 (0.89–1.11) 0.37
Stage 2
SBP 90–119 & DBP ≥ 90 28/347 NA 1.00 (reference) 0.77 (0.26–2.26) 0.75 (0.26–2.11) 0.68 (0.19–2.39) 0.92
SBP 120–129 & DBP ≥ 90 166/2445 NA 1.12 (0.73–1.71) 1.00 (reference) 1.22 (0.81–1.84) 0.86 (0.52–1.41) 0.66
SBP 130–139 & DBP ≥ 90 800/11,196 NA 0.92 (0.75–1.14) 1.03 (0.86–1.24) 1.00 (reference) 0.93 (0.78–1.12) 0.80
SBP ≥ 140 & DBP 60–79 319/3003 NA 1.45 (1.01–2.08)a 0.97 (0.69–1.38) 1.37 (1.06–1.79)a 1.00 (reference) 0.03
SBP ≥ 140 & DBP 80–89 1130/12,498 NA 1.04 (0.85–1.27) 1.30 (1.11–1.53)b 1.00 (0.87–1.16) 1.00 (reference) 0.02
SBP ≥ 140 & DBP ≥ 90 2545/34,074 NA 0.99 (0.86–1.14) 1.08 (0.96–1.20) 1.07 (0.95–1.14) 1.00 (reference) 0.73

Data are adjusted hazard ratio calculated using the Cox proportional hazards model after adjustments for age, sex, household income, body mass index, fasting serum
glucose, cigarette smoking, alcohol consumption, total cholesterol, disability, physical activity, history of sleep disorder and anxiety, antihypertensive medication,
antidepressant medication and Charlson comorbidity index.
Acronyms: SBP, systolic blood pressure; DBP, diastolic blood pressure; NA, not applicable.
a
p < 0.05.
b
p < 0.01.

3.5. Subgroup analysis
We stratified the participants with age, sex, household income,
cigarette smoking, alcohol consumption, physical activity, history of
sleep disorder and anxiety, antihypertensive medication, antidepressant
medication, and CCI score. The inverse association was maintained
among the participants with no history of sleep disorder and anxiety.
Other subgroup analysis showed no significant difference in the sub­
groups (Table S5 and S6).
3.6. Sensitivity analysis
The trend of inverse association between changes in BP and
depression was similar to the main analysis when excluding the follow-
up years at the selected latent time periods (Tables S7, S8). Also, when
excluding the hypotension criterion, the trend and effect size were
consistent with the main analysis (Tables S9, S10).
4. Discussion
In a large-scale and nationally representative cohort, we discovered
that changes in SBP and DBP were associated with risk of depression.
The inverse association between SBP and DBP levels with incident
depression was significant at single-point measurements. When
measuring BP trajectories, the risk of depression increased when SBP
and DBP decreased to normal BP levels among participants with stage 2
hypertension.
There were several previous studies investigating the relationship
between BP and depression, but the results were inconsistent. Incon­
sistency between the results of previous studies could be due to the
differences in the sample size, BP measurement, or dissimilarities with
key variables. A cross-sectional study of 9294 participants showed that
depressive participants were found to have decreased SBP and DBP in
both male (SBP: 148.2 versus 151.8 mmHg; DBP: 83.0 versus 84.7
mmHg) and female (SBP: 141.7 versus 144.7 mmHg; DBP: 80.7 versus
81.4 mmHg) compared with non-depressive participants (Lenoir et al.,
2008). However, the participant’s SBP/DBP characteristics (Male:
150.8/84.0, female: 143.9/81.0) and proportions of antihypertensive
medications (Male: 49.4 %, female: 49.5 %) were higher compared to
our study. Thus, comparing the results with our study needs to be
interpreted with caution . On the contrary, a 6-year cohort study with
5232 participants showed no association between high BP and incident
depression (Akbaraly et al., 2009). Akbaraly et al. defined hypertension
as SBP ≥ 135 mmHg or DBP ≥ 85 mmHg, thus the association with
depression could have been mitigated. In a prospective cohort study,
Jeon et al. investigated 183,448 participants without baseline depres­
sion and reported that higher BP (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg)
lowered the risk of depression (aHR 0.77, 95 % CI 0.66–0.99), which is
similar with our result (Jeon et al., 2020). However, they investigated
the risk only with normal BP as reference, therefore, the association with
other BP levels needs to be investigated.
In a long-term follow-up study, BP was inversely association with the
risk of depression, which is similar to our study (Godin et al., 2012).
They divided BP into 3 categories (low: SBP < 120 mmHg or DBP < 75
mmHg, high: SBP ≥ 140 mmHg or DBP ≥ 90 mmHg or use of antihy­
pertensive medication, otherwise as normal). Compared with normal
BP, those with low BP showed a 63 % increase in the depression risk
(aHR 1.63, 95 % CI 1.23–2.36) while those with high BP didn’t show any
relationship. Because the participants with high BP included those
having antihypertensive medication, the association between actual BP
and the depression risk could have been confounded. Indeed, a pro­
spective cohort of 276,244 adults showed a reduced risk in hypertensive

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Y. Lim et al. Journal of Affective Disorders 335 (2023) 49–56

Fig. 1. Association between systolic blood pressure categories from screening period I (2004–05) to period II (2006–07) and risk of depression. Restricted cubic
spline curves were drawn using aHR, calculated with Cox proportional hazards regression after adjustments age, sex, household income, body mass index, fasting
serum glucose, cigarette smoking, alcohol consumption, total cholesterol, disability, physical activity, history of sleep disorder and anxiety, antihypertensive
medication, antidepressant medication and Charlson comorbidity index. Blue curve indicates aHR and the beige region indicates the 95 % CI. (A) 90–119 mmHg at
period I (2004–05). (B) 120–129 mmHg at period I (2004–05). (C) 130–139 mmHg at period I (2004–05). (D) ≥140 mmHg at period I (2004–05). Systolic blood
pressure < 90 mmHg at period I was not depicted due to small sample size. (For interpretation of the references to color in this figure legend, the reader is referred to
the web version of this article.)

group (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg; aHR 0.77, 95 % CI
0.66–0.99) when compared with normal BP group (Jeon et al., 2020).
Possible mechanisms that account for the association between BP
and depression include the alteration of neuropeptide Y (NPY) level that
is responsible for the regulation of BP and emotional state. Many re­
searchers suggested that NPY could be a common factor that links low
BP and depression (Hildrum et al., 2007; Jeon et al., 2020; Licht et al.,
2009). NPY is distributed widely from peripheral to central nervous
systems and its levels are decreased in plasma and CSF from depressive
patients (Hou et al., 2006; Sharma et al., 2022). Increased levels of NPY
plays an antidepressant-like activity via a serotonergic-dependent
pathway (Morales-Medina et al., 2010; Redrobe et al., 2005). Surpris­
ingly, there are rising evidence that NPY is associated with pathophys­
iology of atherosclerotic cardiovascular disease (ASCVD). When NPY
acts in peripheral regions, due to its nature of sympathetic co-
transmitter, it increases peripheral vascular resistance and induces
vasoconstriction in a dose-dependent manner, thereby inducing hyper­
tension that can lead to risking ASCVD (Tan et al., 2018; Zhu et al.,
2016). However, there are insufficient studies dealing with the causal
relationship of NPY between BP and depression. Therefore, deeper
neuroendocrine mechanism of BP and depression with regard to NPY
needs further investigation on whether the direction of association is
uni- or bidirectional.
Because our results showed that decreased BP elevated the risk of
depression, some might be intrigued to think whether treatment for
hypertension can be harmful to mental health. However, depression it­
self is a significant risk factor for CVD and other chronic illnesses and the
evidence for discontinuing antihypertensive treatment is lacking. In
addition, the pathophysiology of hypertension and depression is
different from which hypertension is a slowly progressing chronic dis­
ease, whereas depression is an episodic disease that repeats remission,
relapse, and recurrence. Therefore, further research is needed to set
optimal BP range for preventing new onset depression and lowering the
complications of hypertension.
There were several limitations in our study. First, the tool for
measuring BP could not be unified due to difference of each hospital
equipment statuses and the detailed information was not recorded in the
cohort data. However, due to diverse hospitals that are engaged in na­
tional health screenings, it is very difficult to have the same device for
measuring BP. Nevertheless, the quality of the BP measurement is very
high due to the 3-year national quality assessment according to the Basic
Act on General Health Screening Program (Shin et al., 2022). Also, BP
was averaged through repeated measurements, and the mean differ­
ences between the aneroid and the oscillometric measurement method
are reported to be very small in a comparative analysis (Kroke et al.,
1998; McGrady and Higgins, 1990). Therefore, many previous studies
used the same standard of BP measurements with our study (Choi et al.,
2018; Kwon et al., 2021; Son et al., 2018). Second, due to some limits
with our data, we only assessed depression using ICD-10 codes of hos­
pital admission or outpatient visit and failed to stratify by its subtypes or
clinical symptoms. However, the diagnosis of depression based on ICD-
10 codes are highly reliable outcome since every diagnosis is claimed by
expert physicians. Also, the case definition of depression by adminis­
trative data is demonstrated by several studies (Doktorchik et al., 2019;

53
Y. Lim et al. Journal of Affective Disorders 335 (2023) 49–56

Table 3
Association between changes in DBP categories from the period I (2004–05) to II (2006–07) and risk of depression stratified by blood pressure classification.
Blood pressure classification Event/total DBP (mmHg) at the period II (2006–07)

<60 60–79 80–89 ≥90 P for trend

DBP (mmHg) at the period I (2004–05)

Overall
<60 301/3378 1.00 (reference) 0.65 (0.47–0.89)b 0.70 (0.46–1.06) 0.78 (0.40–1.49) 0.06
60–79 7630/90,261 1.10 (0.96–1.26) 1.00 (reference) 1.01 (0.96–1.06) 0.94 (0.86–1.02) 0.24
80–89 6310/82,490 0.99 (0.73–1.34) 1.06 (1.01–1.12)a 1.00 (reference) 0.98 (0.91–1.05) 0.06
≥90 3539/48,063 0.61 (0.25–1.47) 1.10 (1.02–1.20)a 1.07 (0.99–1.16) 1.00 (reference) 0.10
Hypotension
DBP < 60 & SBP < 90 26/287 1.00 (reference) 0.33 (0.11–1.00) 0.85 (0.21–3.48) NA 0.20
DBP < 60 & SBP 90–119 248/2820 1.00 (reference) 0.67 (0.47–0.94)a 0.67 (0.42–1.07) 0.75 (0.34–1.63) 0.13
DBP 60–79 & SBP < 90 20/146 0.43 (0.04–4.22) 1.00 (reference) 1.06 (0.26–4.31) NA 0.91
Normal
DBP 60–79 & SBP 90–119 4695/56,465 1.12 (0.96–1.31) 1.00 (reference) 1.02 (0.95–1.09) 0.94 (0.83–1.08) 0.37
Elevated
DBP 60–79 & SBP 120–129 1712/20,784 0.96 (0.65–1.42) 1.00 (reference) 0.97 (0.88–1.08) 1.04 (0.88–1.24) 0.88
Stage 1
DBP 60–79 & SBP 130–139 884/9863 1.00 (0.51–1.93) 1.00 (reference) 1.06 (0.92–1.23) 0.98 (0.79–1.22) 0.82
DBP 80–89 & SBP 90–119 592/7698 0.52 (0.19–1.40) 1.13 (0.95–1.35) 1.00 (reference) 0.87 (0.64–1.19) 0.12
DBP 80–89 & SBP 120–129 2208/29,856 1.27 (0.82–1.95) 1.08 (0.99–1.19) 1.00 (reference) 1.05 (0.92–1.19) 0.30
DBP 80–89 & SBP 130–139 2380/32,438 0.65 (0.31–1.36) 1.05 (0.96–1.15) 1.00 (reference) 1.01 (0.90–1.12) 0.44
Stage 2
DBP 60–79 & SBP ≥ 140 319/3003 1.28 (0.52–3.15) 1.00 (reference) 0.96 (0.76–1.23) 0.70 (0.50–0.97)a 0.15
DBP 80–89 & SBP ≥ 140 1130/12,498 1.25 (0.65–2.42) 0.98 (0.86–1.12) 1.00 (reference) 0.87 (0.75–1.01) 0.24
DBP ≥ 90 & SBP 90–119 28/347 NA 1.40 (0.42–4.72) 1.16 (0.37–3.69) 1.00 (reference) 0.95
DBP ≥ 90 & SBP 120–129 166/2445 NA 1.14 (0.73–1.77) 1.23 (0.81–1.86) 1.00 (reference) 0.82
DBP ≥ 90 & SBP 130–139 800/11,196 0.47 (0.07–3.35) 1.07 (0.89–1.30) 1.10 (0.92–1.31) 1.00 (reference) 0.61
DBP ≥ 90 & SBP ≥ 140 2545/34,074 0.73 (0.27–1.96) 1.08 (0.97–1.20) 1.05 (0.96–1.15) 1.00 (reference) 0.45

Data are adjusted hazard ratio calculated using the Cox proportional hazards model after adjustments for age, sex, household income, body mass index, fasting serum
glucose, cigarette smoking, alcohol consumption, total cholesterol, disability, physical activity, history of sleep disorder and anxiety, antihypertensive medication,
antidepressant medication and Charlson comorbidity index.
Acronyms: SBP, systolic blood pressure; DBP, diastolic blood pressure; NA, not applicable.
a
p < 0.05.
b
p < 0.01.

Fig. 2. Association between diastolic blood pressure categories from screening period I (2004–05) to period II (2006–07) and risk of depression. Restricted cubic
spline curves were drawn using aHR, calculated with Cox proportional hazards regression after adjustments age, sex, household income, body mass index, fasting
serum glucose, cigarette smoking, alcohol consumption, total cholesterol, disability, physical activit, history of sleep disorder and anxiety, antihypertensive medi­
cation, antidepressant medication and Charlson comorbidity index. Blue curve indicates aHR and the beige region indicates the 95 % CI. (A) 60–79 mmHg at period I
(2004–05). (B) 80–89 mmHg at period I (2004–05). (C) ≥90 mmHg at period I (2004–05). Diastolic blood pressure < 60 mmHg at period I was not depicted due to
small sample size. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fiest et al., 2014). In addition, there were absence of variables such as
marital status that could lead to false associations. However, we used
similar covariates associated with the risk of depression to previous
studies (Baek et al., 2021; Jeon et al., 2020; Lee et al., 2021). Third, the
association of SBP lower than 90 mmHg and DBP lower than 60 mmHg
with depression is neglected due to unbalanced population. However,
the sample size of low BP achieved adequate power of >90 % (alpha =
0.05) to detect the association. Fourth, our study could not investigate
the association with the participants below 40 years of age due to age
limit of Korea’s general health screening program while prevalence of
depression is widely distributed throughout the lifespan. Therefore, a
follow-up study is needed to investigate the association including
younger ages with balanced population. Lastly, there were participants
with very low pulse pressure (<30 mmHg), which needs to be fully
considered. 312 participants (stage 2 [SBP 90–119 mmHg & DBP ≥ 90
mmHg] or hypotension [SBP < 90 mmHg & DBP 60–79 mmHg] at
period I) showed very low pulse pressure. The median (interquartile
range) of systolic and blood pressure at period I and II were 120
(106.5–130) vs 110 (88–114) mmHg and 78 (68–80) vs 90 (64.5–90)
mmHg, respectively. Since the BP was drastically changed from period I
to II, it could be due to decreased cardiac function resulted by impaired
health-promoting behaviors, or measurement bias affected by alcohol,
coffee, or smoking even though medical experts notified the precautions
of the procedure. However, the participants comprised of <0.01 %
among total participants, therefore, the association with changes in BP
and depression may not be confounded by the low pulse pressure

54
Y. Lim et al.
participants. Despite the limitations, the significance of our results is
that our study analyzed the change in BP with two consecutive health
screening periods, compared to most of the previous studies which only
analyzed with a single assessment. Investigating the association with
consecutive time frame allows us to statistically understand the impact
of controlled or uncontrolled state of BP and raise a question of under­
lying mechanisms of BP with depression.
In conclusion, the findings of our study indicate an inverse associa­
tion between BP and incident depression. Our results give epidemio­
logical evidence for further investigation on finding neurobiological
mechanisms of depression associated with cardiovascular risk factors.
Funding
This research was supported by a grant of the MD-Phd/Medical
Scientist Training Program through the Korea Health Industry Devel­
opment Institute (KHIDI), funded by the Ministry of Health & Welfare,
Republic of Korea. This research was supported by the Bio Industry
Technology Development Program (No. 20015086) funded by the
Ministry of Trade, Industry, & Energy (MOTIE, Korea). This work was
supported by National Research Foundation of Korea (NRF) grant fun­
ded by the Korea government (MSIT) (NRF-2019M3C7A1032262).
CRediT authorship contribution statement
Yohwan Lim: Conceptualization, Data curation, Formal analysis,
Methodology, Writing – original draft, Writing – review & editing. Bo
Chang Kim: Conceptualization, Data curation, Writing – original draft,
Writing – review & editing. Sung Soo Yoon: Conceptualization, Meth­
odology, Writing – review & editing. Hye Jun Kim: Conceptualization,
Data curation, Formal analysis, Methodology, Writing – original draft,
Writing – review & editing. Sang Jun Lee: Conceptualization, Meth­
odology, Writing – review & editing. Myeong Hoon Lee: Data curation,
Methodology, Writing – review & editing. Ju Hee Kim: Methodology,
Writing – review & editing. Sun Jae Park: Data curation, Writing –
review & editing. Seogsong Jeong: Conceptualization, Data curation,
Formal analysis, Methodology, Writing – original draft, Writing – review
& editing. Hyun Wook Han: Conceptualization, Data curation, Meth­
odology, Supervision, Writing – original draft, Writing – review &
editing.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
No additional data available. Only authorized researchers were
received permission to access the National Health Insurance Service
(NHIS) database at the Big Data Research Center of the Big Data Steering
Department in the Republic of Korea.
Acknowledgements
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jad.2023.04.107.
55
Journal of Affective Disorders 335 (2023) 49–56
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