Description
In this assignment, students will review a microbial journal article. Choose one article from a primary scientific literature source that uses a microbe as a model organism/system and write a comprehensive summary of the study that answers the following questions: Choose one article from a primary scientific literature source that uses a microbe as a model organism/system. NOTE: Many free articles may be obtained from http://www.pubmed.gov or visit the WCU library. Write a summary of the study that includes: 1. Why did the scientists perform the study (i.e., description of background)? 2. What was the hypothesis (or hypotheses) under investigation? 3. What were the major results and did they support or negate the hypothesis? Which key techniques were used to achieve these results? 4. Why are the results significant and do they point to further/future studies? In other words, why does this article matter and what should or could be done next? 5. Why did you choose this particular article to review? Was it interesting, informative, clearly written, or none of the above? Compose your review in APA format and include: • A title page • Answers to the questions above in paragraph format (2 or more pages) • A reference page with the reference for your article and any other sources used in your reviewP
risk of peptic ulcer disease (PUD) among patients with
depression has raised concern. This study determined the association
between depression and the subsequent development of PUD using
claims data.
Patients newly diagnosed with depression in 2000 to 2010 were
identified as depression cohort from the Taiwan National Health
Insurance Research Database. The comparison cohort was randomly
selected from subjects without depression, frequency matched by age
and gender and diagnosis date, with a size 2-fold of the size of the
depression cohort. The incidence of PUD was evaluated for both cohorts
by the end of 2011. We calculated the hazard ratios (HRs) and 95%
confidence intervals (CIs) of PUD using the Cox proportional hazards
regression model.
The depression cohort consisted of 23,536 subjects (129,751 personyears),
and the comparison cohort consisted of 47,069 subjects (285,592
person-years). The incidence of PUD was 2-fold higher in the depression
cohort than in the comparison cohort (33.2 vs 16.8 per 1000 personyears)
with an age adjusted HR of 1.97 (95% CI¼1.89–2.06) or a
multivariable adjusted HR of 1.35 (95% CI¼1.29–1.42).
Depression might increase the risk of developing PUD. Prospective
clinical studies of the relationship between depression and PUD are
warranted.
(Medicine 94(51):e2333)
Abbreviations: aHR = adjusted hazard ratio, BNHI = Bureau of
National Health Insurance, CI = confidence interval, LHID 2000 =
Longitudinal Health Insurance Database 2000, NERD = nonerosive
reflux disease, NHI = National Health Insurance, NHIA = National
Health Insurance Administration, NHIRD = National Health
Insurance Research Database, NHRI = National Health Research
Institutes, PUD = peptic ulcer disease (PUD).
INTRODUCTION
Depression, a type of mood disorder, is characterized by
emotional dysregulation and depressive cognition, which
induces distress in patients.1 In patients with depression, stress
not only plays a major role in pathogenesis but also is associated
with the disturbance of the hypothalamus-pituitary-adrenal
(HPA) axis.2 Additionally, patients with depression have been
reported to experience somatic consequences associated with
HPA axis dysregulation.3 Regarding the gastrointestinal (GI)
system, evidences have shown that depression is associated with
irritable bowel syndrome, ulcerative colitis, dyspepsia, and
gastroesophageal reflux disease.4–6 However, few studies have
reported evidence regarding the relationship between peptic
ulcer disease (PUD) and depression.
PUD, including gastric and peptic ulcers, is a prevalent GI
disease with a high mortality.7 Evidence has shown that both
physical stress and psychological stress are closely related to
PUD.8,9 Notably, PUD risk among schizophrenia or anxiety
disorder patients has been documented,10,11 but not for depression
patients. To make the diagnosis of unipolar depression,
patient should not have mania or hypomania, or their diagnosis
should be bipolar disorders (BD) instead.12 However, evidence
had shown that some patients with BD have unipolar depression
as their initial presentation, before mania or hypomania.13 Even
Editor: Thomas Polak.
Received: November 3, 2015; revised: November 18, 2015; accepted:
November 29, 2015.
From the Department of Psychiatry, Kaohsiung Veterans General Hospital,
Kaohsiung (C-CH.); Institute of Biomedical Sciences, Mackay Medical
College, New Taipei City (Y-CH.); Department of Medical Research,
Taichung Veterans General Hospital, Taichung (K-HC.); College of
Medicine, The School of Chinese Medicine for Post Baccalaureate, I-Shou
University (Yancho Campus) (C-YL.); Department of Chinese Medicine, EDA
Hospital, Kaohsiung (C-YL.); Division of Hepatology and Gastroenterology,
Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial
Hospital, Taipei (L-WC.); Management Office for Health Data, China
Medical University Hospital (C-LL); College of Medicine, China Medical
University (C-LL); Graduate Institute of Clinical Medical Science and School
of Medicine, College of Medicine, China Medical University (F-CS, C-HK.);
and Department of Nuclear Medicine and PET Center, China Medical
University Hospital, Taichung, Taiwan (C-HK), Department of Business
Administration, Tunghai University, Taichung, Taiwan (C-SS.).
Correspondence: Chia-Hung Kao, Graduate Institute of Clinical Medical
Science and School of Medicine, College of Medicine, China Medical
University, No. 2, Yuh-Der Road, Taichung, Taiwan (e-mail:
d10040@mail.cmuh.org.tw).
Author contributions: All authors have contributed significantly, and that all
authors are in agreement with the content of the manuscript. Conception/
design: Chih-Chao Hsu, Yi-Chao Hsu, Chia-Hung Kao; collection and/or
assembly of data: all authors; data analysis and interpretation: all authors;
manuscript writing: all authors; final approval of manuscript: all authors.
Chih-Chao Hsu and Yi-Chao Hsu contributed equally to this study.
Fung-Chang Sung and Chia-Hung Kao contributed equally to this study.
Funding: this study is supported in part by Taiwan Ministry of Health and
Welfare Clinical Trial and Research Center of Excellence (MOHW104-
TDU-B-212-113002); China Medical University Hospital, Academia
Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092);
NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039-006);
Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease
Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial
Funds, Japan; and CMU under the Aim for Top University Plan of
the Ministry of Education, Taiwan. The funders had no role in study
design, data collection and analysis, decision to publish, or preparation of
the manuscript. No additional external funding received for this study.
We appreciate the financial support by grants from Ministry of Science
and Technology (MOST103-2314-B-715- 001-MY2, and MOST104-
2314-B-715-003-MY3), Mackay Medical College (MMC 1012A10,
RD1010061, RD1020038, RD1020047, RD1012B13, RD1031B05,
RD1030053, RD1030076, RD1040109), and Mackay Memorial Hospital
(MMH-MM-10304, MMH-MM-10405).
The authors have no conflicts of interest to disclose.
Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved.
This is an open access article distributed under the Creative Commons
Attribution-NonCommercial-NoDerivatives License 4.0, where it is
permissible to download, share and reproduce the work in any medium,
provided it is properly cited. The work cannot be changed in any way or
used commercially.
ISSN: 0025-7974
DOI: 10.1097/MD.0000000000002333
Medicine®
OBSERVATIONAL STUDY
Medicine Volume 94, Number 51, December 2015 www.md-journal.com | 1
though the differential diagnosis between BD and unipolar
depression was challenging, they shared the common manifestation
of having depressive episode.14 Particularly, we have
previously demonstrated a positive association between BD and
PUD.15 However, we could not identify whether the depression,
mania, or hypomania predisposed the patients having subsequent
PUD. Therefore, we investigated the association
between depression and PUD. We hypothesized that if depression
was associated with subsequent PUD, more concern would
be raised among patients with unipolar depression or depressive
episode of BD.
To test the study hypothesis, we designed a nationwide
population-based study to compare the incidence raes of PUD
between cohorts with and without depression using longitudinal
insurance data.
METHODS
Data Source
Outpatient and inpatient claims data documented in the
Longitudinal Health Insurance Database (LHID) of Taiwan
were used in this study. The LHID containing annual claims
data from 1 million randomly selected insurants based on the
Taiwan National Health Insurance (NHI) program established in
1996 and updated annually by the National Health Research
Institutes (NHRI) thereafter. The NHI program is a universal
single-payer system that covers >99% of the 23.74 million
residents of Taiwan. The NHRI provided scrambled identification
numbers that were used to connect each person’s relevant
claims information, including sex and date of birth, registry for
medical services, and medication prescriptions. Disease definition
in the LHID is based on the International Classification of
Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
In accordance with the Personal Information Protection Act,
identification of beneficiaries was recoded by a computer. This
study was approved to follow the condition for exemption by the
Institutional Review Board (IRB) of China Medical University
(CMUH-104-REC2-115). The IRB had specifically waived the
consent requirement.
Study Cohorts Selection
This was a retrospective cohort study using the populationbased
insurance claims data to establish study cohorts. Patients
aged 20 years and older with newly diagnosed with depression
(ICD-9 codes 296.2, 296.3, 300.4, 311) from 2000 to 2010 and
free of PUD (ICD-9-CM codes 531–533) were identified and
selected into the depression cohort (Figure 1). The index date
was used and defined as the first date on which depression was
diagnosed from the medical records in LHID. The insured
population without the history of depression and PUD in the
LHID were randomly selected into the comparison cohort
frequency matched by age (within 5 years), gender, and index
date. The enrollment date for the subject in the comparison
cohort was matched with the same year and month of the subject
in the depression cohort, whereas the day was randomly
assigned. The sample size of the comparison cohort was 2-fold
of the depression cohort. Subjects without demographic information
at the baseline were excluded from the study cohorts.
Endpoint of Study
The major endpoint in this study was the development of
PUD (ICD-9-CM codes 531–533). Person-years of follow-up
were calculated for each person until PUD was diagnosed or
censored for death (119 and 129, respectively) and withdrawing
from the insurance system due to the loss of follow-up, moving
abroad or imprisonment, and so on, (2170 and 3205, respectively),
or the end of 2011.
Comorbidities and Medications
Comorbidities and medications were considered as
possible confounding factors. The examined comorbidities
FIGURE 1. Flowchart of establishing the study cohorts.
Hsu et al Medicine Volume 94, Number 51, December 2015
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were chronic liver disease and cirrhosis (ICD-9-CM code 571),
hypertension (HTN) (ICD-9-CM code 401–405), diabetes
mellitus (DM) (ICD-9-CM code 250), asthma (ICD-9-CM code
493), chronic kidney disease (CKD) (ICD-9-CM code 585),
coronary artery disease (CAD) (ICD-9-CM codes 410–414),
alcoholism (ICD-9-CM codes 291, 303, 305.00, 305.01, 305.02,
305.03, 790.3, and V11.3), tobacco dependency (ICD-9-CM
code 305.1), chronic obstructive pulmonary disease (COPD)
(ICD-9-CM codes 490, 491, 496), anxiety (ICD-9-CM code
300.0), and helicobacter pylori (ICD-9-CM code 041.86),
identified before the index date according to inpatient and
outpatient files. And the examined medications were nonsteroidal
anti-inflammatory drugs (NSAIDs), anxiolytics, and
benzodiazepines (BZDs) that were used before the index date
according to inpatient and outpatient files. Available antidepressants
were divided into 2 groups, selective serotonin
reuptake inhibitors (SSRIs) and non-SSRIs.
Statistical Analysis
The distributions of these 2 cohorts were presented by the
mean and standard deviation (SD) for age and frequency of
medical visits (per year during the study period) and numbers
and proportions for gender, occupation, monthly income
(NTD), comorbidities, and medication uses. Student’s t test
and chi square test were applied to test differences in the
continuous and categorical variables between the depression
and comparison cohorts. The cumulative incidence curves of
PUD were estimated for the 2 cohorts using the Kaplan–Meier
method, and the log-rank test was used to evaluate the difference
between the curves. The sex-, age-, tobacco dependency-,
NSAID-, and comorbidity-specific incidences of PUD per
1000 person-years of follow-up for each cohort were calculated.
We used Cox proportional hazards regression models to
examine the hazard ratios (HRs) with 95% confidence intervals
(CIs) of depression patients developing PUD relative to the
TABLE 1. Comparisons in Demographic Characteristics and Comorbidities in Patient With and Without Depression
Depression
No Yes
(N¼47069) (N¼23536) P Value
Gender 0.99
Women 28,846 (61.3) 14,424 (61.3)
Men 18,223 (38.7) 9112 (38.7)
Age stratified 0.99
49 19,870 (42.2) 9934 (42.2)
50–64 20,040 (42.6) 10,021 (42.6)
65þ 7159 (15.2) 3581 (15.2)
Age, meanSD 45.3 (16.7) 45.6 (16.6) 0.02
Frequency of medical visits/per year in the study period 14.7 (13.6) 29.0 (21.3) <0.001
Occupation <0.001
White collar 25,716 (54.6) 12,088 (51.4)
Blue collar 15,111 (32.1) 7369 (31.3)
Othersz 6242 (13.3) 4079 (17.3)
Monthly income (NTD)y <0.001
<15,000 12,026 (25.6) 6511 (27.7)
15,000–19,999 21,856 (46.4) 11,029 (46.9)
20,000 13,187 (28.0) 5396 (25.5)
Comorbidity
Chronic liver disease and cirrhosis 5000 (10.6) 4487 (19.1) <0.001
Hypertension 8797 (18.7) 6457 (27.4) <0.001
Diabetes mellitus 2391 (5.08) 1832 (7.78) <0.001
Asthma 1753 (3.72) 1457 (6.19) <0.001
Chronic kidney disease 300 (0.64) 281 (1.19) <0.001
Coronary artery disease 3415 (7.26) 3254 (13.8) <0.001
Alcoholism 215 (0.46) 857 (3.64) <0.001
Tobacco dependency 219 (0.47) 296 (1.26) <0.001
COPD 2297 (4.88) 1926 (8.18) <0.001
Anxiety 1066 (2.26) 4801 (20.4) <0.001
Helicobacter pylori 154 (0.33) 92 (0.39) 0.18
Medication <0.001
NSAID 41,167 (87.5) 22,208 (94.4) <0.001
Anxiolytics 29,576 (62.8) 22,875 (97.2) <0.001
Benzodiazepine 25,362 (53.9) 22,094(93.9) <0.001
COPD¼chronic obstructive pulmonary disease; NSAIDs¼nonsteroidal anti-inflammatory drugs; SD¼standard deviation.
Chi square test, t test.
y NTD: New Taiwan Dollars per month. One New Taiwan Dollar equals.0.03 US Dollar.
z Other occupations included primarily retired, unemployed, or low-income populations.
Medicine Volume 94, Number 51, December 2015 Depression and Peptic Ulcer Disease
Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com | 3
comparison cohort. We first adjusted for age in the Cox model.
The multivariable Cox model was then used controlling for age,
sex, and comorbidities of cirrhosis, HTN, DM, asthma, CKD,
CAD, alcoholism, COPD, and anxiety as well as the use of
NSAIDs, anxiolytics, and BZDs. The proportional hazard
model assumption was also examined using a test of scaled
Schoenfeld residuals. In the model evaluating the PUD risk
throughout overall follow-up period, results of the test revealed
a significant relationship between Schoenfeld residuals for
depression and follow-up time, suggesting that the proportionality
assumption was violated (P value¼0.002). In the subsequent
analyses, we stratified the follow-up duration to deal
with the violation of proportional hazard assumption. Data
management and statistical analysis were performed using
SAS 9.3 (SAS Institute, Cary, NC). The statistical significance
was defined as a (2-sided) P value<0.05.
RESULTS
The depression cohort consisted of 23,536 subjects (129,751
person-years), and the control cohort consisted of 47,069 subjects
without depression (285,592 person-years). (Table 1). The distributions
of gender and age were similar in both cohorts. Of the
study patients, 61.3%were women,with 42.2% being 49 years
old. The mean age of the depression cohort was 45.6 (SD¼16.6)
years, and the mean age of the comparison cohort was 45.3
(SD¼16.8) years. The prevalence rates of comorbidities and
medications were greater in the depression cohort than in the
comparison cohort (all P values<0.001). The mean follow-up
time was 5.51 (SD¼3.31) years for the depression cohort and
6.07(SD¼3.23) years for the comparison cohort.
After a 12-year follow-up, the Kaplan–Meier method
estimated cumulative incidence of PUD was 9.47% higher in
the depression cohort than that in the comparison cohort (27.0%
vs 17.53%; P<0.001) (Figure 2).
The incidence of PUD was 2-fold higher in the depression
cohort than in the comparison cohort (33.2 vs 16.8 per
1000 person-years) with an age adjusted HR of 1.97 (95%
CI¼1.89, 2.06) or a multivariable adjusted HR of 1.35 (95%
CI¼1.29–1.42) (Table 2). The incidence rate of PUD was
consistently higher in the depression cohort than in the
comparison cohort in each stratum by gender, age, NSAID
use, comorbidity, and follow-up year, except tobacco dependency.
The PUD incidence increased with age and decreased
with follow-up year. However, the depression cohort to the
comparison cohort relative HR decreased with age and follow-
up year. For those with tobacco dependency, the PUD
incidence was lower in the depression cohort than in controls,
but not significant.
Table 3 shows the PUD associations with socioeconomic
status. Subjects of nonwhite collar and middle income were at
significantly higher hazard of PUD. Almost all comorbidity and
drug use factors were related with greater PUD except
tobacco dependency.
Table 4 shows that among 23,536 depression cases, those
who did not receive any treatment had the highest incidence of
PUD, 55.2 per 1000 person-years with an adjusted HR of
2.27(95% CI 2.07, 2.48) for PUD compared to the comparison
cohort. Treatment reduced the incidence to 31.0 per 1000
person-years for those took SSRI.
Table 5 shows that depression patients were diagnosed
mainly in outpatient setting (84.70%) and by general physicians
(84.47%). The PUD incidence was higher in those to be
diagnosed as inpatients than as outpatients. Patients cared by
psychiatrists were associated with a lower risk of PUD.
DISCUSSION
This was the first population-based study, which examined
depression as a risk factor for PUD by using matched cohorts
and a long-term (12-y) follow-up period. As expected, results of
this study showed that patients with depression were at an
elevated risk of developing PUD. We hypothesized that the
possible mechanism may be associated with the HPA axis. The
HPA axis is closely related to stress, and a disturbed HPA axis
response has been noted in patients with depression, which
seems to be a stress-related disorder.16 In addition, psychological
stress has been considered as a risk factor for PUD.8 As a
type of psychological stress, depression is characterized by a
high risk of lifelong persistence and chronic course.17 Animal
models have shown that corticosterone may be ulcerogenic
under chronic stressful conditions.18 Consequently, depression
may increase the risk of PUD.
In the analyzed of risk factors associated with subsequent
PUD in patients with depression, we found that patients with
comorbidities, except tobacco dependency, were at a risk
of developing PUD. Studies have shown that there is a
dose–dependent relationship between chronic illness and
depression.19 In other words, the longer chronic comorbidities
persist, the higher the psychological stress patientsmay experience.
Consequently, patients with depression and the aforementioned
comorbidities may have an elevated risk of
subsequent PUD. On the other hand, patients with depression
were reported having positive association with tobacco dependence.
20 Tobacco use was seemed as self-medication for mood
disturbance and negative affectivity in patients with depression.
21 Although smokingwas a risk factor for PUD,22 smoking
was also reported slowing the progression of depression.23
Hence, further progression of the association between depression
and PUD may be delayed under the concern of this
paradoxical effect.
Alcohol use disorders have been reported as major problems
in patients with depression,24 and alcoholism is an
FIGURE 2. Cummulative incidence of peptic ulcer disease in
depression and comparison cohorts.
Hsu et al Medicine Volume 94, Number 51, December 2015
4 | www.md-journal.com Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved.
independent risk factor for PUD.25 In consideration of this close
relationship, this study also showed that patients with depression
and alcoholism had a higher risk of subsequent PUD than
those without alcoholism.
Depression has been associated with a neuroinflammatory
mechanism.26 However, the use of NSAIDs is a known risk
factor for PUD.25 Furthermore, patients with depression at high
stress levels are at a higher risk of inappropriate use of anxiolytics
and BZDs.27 Also, in depression, antidepressants were
used under the consideration of restoring the level of brainderived
neurotrophic factor and the prevention of further hippocampus
damage caused by disturbed HPA axis.28 However, the
animal model was reported that concurrent use of BZDs and
antidepressants would impair the neurogenesis of hippocampus.
29 As a result, the course of depression was affected,
and the risk of subsequent PUD increased.
Our study is the first longitudinal study using populationbased
data to examine depression as a risk factor for the
subsequent PUD occurrence. The strength of our study is the
age- and gender-matched design cohorts with and without
depression with a maximum of 12 years follow-up and adequate
adjustments for comorbidities and drug uses in data analysis.
However, our study has several limitations that are inherent in
the use of claims databases. First, the diagnoses of depression in
the NHIRD were based on ICD-9-CM codes. Thus, the severity
of depression as a risk factor for subsequent PUD was not
explored. Second, as mentioned above, unipolar depression still
had the possibility to reach the diagnosis of BD, if patients had
mania or hypomania after their depression.14 Hence, we could
not exactly confirm this condition, especially beyond our
follow-up years. Third, our further data analysis showed that
PUD were diagnosed mainly based on clinical symptoms
(79.4%) and few were diagnosed with oesophageal-gastroduodenoscopy
(OGD) (20.6%). However, the corresponding
adjusted HR of PUD for patients with depression was slightly
higher for those diagnosed with OGD than those diagnosed by
clinical symptoms. Fourth, the associations were assessed by
the chronological order in which these two diseases were
TABLE 2. Comparison of Incidence Densities of Peptic Ulcer Disease Hazard Ratio Between With and Without Depression by
Demographic Characteristics and Comorbidity
Depression
No Yes
Event PY IR Event PY IR
Age-adjusted HR
(95% CI)
Adjusted HRy
(95% CI)
All 4808 285,592 16.8 4312 129,751 33.2 1.97 (1.89, 2.06) 1.35 (1.29, 1.42)
Gender
Women 2866 177,413 16.2 2731 80,814 33.8 2.07 (1.97, 2.19) 1.40 (1.32, 1.49)
Men 1942 108,179 18.0 1581 48,937 32.3 1.82 (1.70, 1.94) 1.25 (1.16, 1.35)
Age, years
49 1069 127,157 8.41 1264 59,813 21.1 2.47 (2.27, 2.68) 1.48 (1.34, 1.64)
50–64 2311 122,378 18.9 2127 54,245 39.2 2.05 (1.94, 2.18) 1.36 (1.27, 1.46)
65þ 1428 36,057 39.6 921 15,693 58.7 1.46 (1.34, 1.58) 1.12 (1.02, 1.23)
Tobacco dependency
No 4790 284,889 16.8 4291 128,742 33.3 1.98 (1.90, 2.06) 1.24 (1.18, 1.30)
Yes 18 703 25.6 21 1009 20.8 0.93 (0.49, 1.76) 0.52 (0.24, 1.12)
NSAID
No 508 42,883 11.9 191 9306 20.5 1.84 (1.55, 2.17) 1.01 (0.81, 1.25)
Yes 4300 242,709 17.7 4121 120,445 34.2 1.93 (1.85, 2.02) 1.25 (1.19, 1.31)
Comorbidityz
No 2325 203,828 11.4 1339 61,266 21.9 2.12 (1.98, 2.27) 1.19(1.10, 1.29)
Yes 2483 81,764 30.4 2973 68,485 43.4 1.57 (1.48, 1.65) 1.13(1.07, 1.20)
Years of follow-up
1 889 46,262 19.2 1203 22,659 53.1 2.76 (2.53, 3.01) 1.61 (1.46, 1.78)
2–3 1517 81,603 18.6 1469 38,250 38.4 2.07 (1.93, 2.23) 1.43 (1.32, 1.56)
4–5 1074 64,726 16.6 793 29,068 27.3 1.67 (1.52, 1.83) 1.20 (1.08, 1.33)
5 1328 93,000 14.3 847 39,772 21.3 1.53 (1.40, 1.67) 1.19 (1.08, 1.32)
IR¼incidence rate, per 1000 person-years, NSAIDs¼nonsteroidal anti-inflammatory drugs, PY¼person years.
Age-adjusted HR: adjusted for age only.
yAdjusted HR: multivariable adjusted hazard ratio, mutually adjusted for age, gender, frequency of medical visits, occupation, monthly income, and
comorbidities of cirrhosis, hypertension, diabetes mellitus, asthma, chronic kidney disease, coronary artery disease, alcoholism, tobacco dependency,
COPD, anxiety, helicobacter pylori, and medicine of NSAID, anxiolytics, and benzodiazepine in Cox proportional hazards regression.
zComorbidity: patients with any one of the comorbidities cirrhosis, hypertension, diabetes mellitus, asthma, chronic kidney disease, coronary artery
disease, alcoholism, tobacco dependency, COPD, anxiety, and helicobacter pylori were classified as the comorbidity group.
P<0.05.
P<0.01.
P<0.001.
Medicine Volume 94, Number 51, December 2015 Depression and Peptic Ulcer Disease
Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com | 5
TABLE 3. Hazard Ratios of Peptic Ulcer Disease in Association With Gender, Age, and Comorbidities in Univariable and
Multivariable Cox Regression Models
Crude Adjustedy
Variable HR (95%CI) HR (95%CI)
Age, years 1.03 (1.02, 1.03) 1.02 (1.02, 1.02)
Sex (female vs male) 1.03 (0.99, 1.07) 1.05 (1.01, 1.10)
Frequency of medical visits/year 1.03 (1.02, 1.03) 1.02 (1.02, 1.02)
Occupation
White collar 1 (Reference) 1 (Reference)
Blue collar 1.47 (1.40, 1.54) 1.10 (1.04, 1.16)
Othersz 1.43 (1.35, 1.52) 1.12 (1.05, 1.19)
Monthly income (NTD)
< 15,000 1.13 (1.06, 1.19) 0.95 (0.89, 1.01)
15,000–19,999 1.22 (1.16, 1.28) 1.06 (1.00, 1.12)
20,000 1 (Reference) 1 (Reference)
Baseline comorbidities (yes vs no)
Chronic liver disease and cirrhosis 1.99 (1.90, 2.10) 1.31 (1.25, 1.38)
Hypertension 2.31 (2.21, 2.41) 1.07 (1.01, 1.13)
Diabetes mellitus 2.07 (1.93, 2.22) 0.95 (0.88, 1.02)
Asthma 1.78 (1.64, 1.93) 1.01 (0.93, 1.10)
Chronic kidney disease 3.02 (2.58, 3.54) 1.18 (1.00, 1.39)
Coronary artery disease 2.59 (2.45, 2.73) 1.12 (1.05, 1.19)
Alcoholism 1.56 (1.35, 1.81) 1.26 (1.08, 1.46)
Tobacco dependency 0.91 (0.67, 1.25) 0.73 (0.53, 1.00)
COPD 2.32 (2.17, 2.48) 1.04 (0.97, 1.12)
Anxiety 1.72 (1.61, 1.83) 1.03 (0.96, 1.10)
Helicobacter pylori 2.42 (1.93, 3.03) 2.22 (1.77, 2.77)
Medicine
NSAID 1.66 (1.54, 1.79) 1.10 (1.01, 1.19)
Anxiolytics 2.28 (2.15, 2.42) 1.12 (1.00, 1.25)
Benzodiazepine 2.23 (2.12, 2.35) 1.13 (1.02, 1.24)
CI¼confidence interval, COPD¼chronic obstructive pulmonary disease, NSAIDs¼nonsteroidal anti-inflammatory drugs, NTD¼New Taiwan
Dollars per month.
Crude HR: relative hazard ratio.
yAdjusted HR: adjusted hazard ratio, mutually adjusted for age, gender, frequency of medical visits, occupation, monthly income, and comorbidities
of cirrhosis, hypertension, diabetes mellitus, asthma, chronic kidney disease, coronary artery disease, alcoholism, tobacco dependency, COPD,
anxiety, Helicobacter pylori, and medicine of NSAID, anxiolytics, and benzodiazepine in Cox proportional hazard regression.
P<0.05.
P<0.01.
P<0.001.
TABLE 4. Incidence Rate and Hazard Ratio of Peptic Ulcer Disease Between Treatments for Depression
Variables N Event PY IR Age-adjusted HR (95% CI) Adjusted HRy (95% CI)
Without depression 47,069 4808 285,592 16.8 1 (Reference) 1 (Reference)
Depression
Without treatment 1919 527 9541 55.2 2.89 (2.64, 3.16) 2.27 (2.07, 2.48)
With treatment
Non-SSRI 5130 929 28,174 33.0 1.72 (1.61, 1.85) 1.19 (1.11, 1.29)
SSRI 16,487 2856 92,036 31.0 1.95 (1.86, 2.04) 1.28 (1.21, 1.35)
CI¼confidence interval, IR¼incidence rate (per 1000 person-years), SSRI¼selective serotonin reuptake inhibitors.
Age-adjusted HR: adjusted hazard ratio adjusted for age.
yAdjusted HR: adjusted hazard ratio, mutually adjusted for age, gender, frequency of medical visits, occupation, monthly income, and comorbidities
of cirrhosis, hypertension, diabetes mellitus, asthma, chronic kidney disease, coronary artery disease, alcoholism, tobacco dependency, COPD,
anxiety, helicobacter pylori, and medicine of NSAID, anxiolytics, and benzodiazepine in Cox proportional hazard regression.
P<0.05.
P<0.01.
P<0.001.
Hsu et al Medicine Volume 94, Number 51, December 2015
6 | www.md-journal.com Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved.
diagnosed. However, the possibility that PUD causes depression
cannot be entirely excluded. Finally, information regarding
many demographic variables, such as education, lifestyle,
and family history, was unavailable. We used alcoholism,
tobacco dependency, and COPD to substitute the drinking
and smoking behavior. Our results show that those with COPD
were also at a higher hazard of PUD.
Depression is a disorder often unrecognized and untreated.
The depression cohort identified in this study may not represent
the average mild ‘‘depressive’’ persons and may reflect a group
of persons with more severe depressive illness perhaps, or with
some personal characteristics that make them more likely to
seek medical attention and made claims. The findings thus may
not be readily generalized to people with milder depression,
depression uncomplicated by medical comorbidities, or the
healthy population of smaller size. However, this study compares
between 2 matched cohorts based on the same database
and adjusts related factors, and the real relationship between
depression and PUD risk is supposed to be revealed to a certain
degree even though the generalization is limited.
In conclusion, this study suggests that depression increases
the risk of developing PUD. On the basis of our data, we suggest
that greater attention should be focused on female and aging
patients, particularly those with comorbidities. Additional prospective
clinical studies on the relationship between depression
and PUD are warranted.
REFERENCES
1. Gotlib IH, Joormann J. Cognition and depression: current status and
future directions. Ann Rev Clin Psychol. 2010;6:285–312 PubMed
PMID: 20192795 Pubmed Central PMCID: PMC2845726 Epub
2010/03/03 eng.
2. Bao AM, Swaab DF. The stress systems in depression: a postmortem
study. Eur J Psychotraumatol. 2014;5:26521 PubMed PMID:
25511726 Epub 2014/12/17 eng.
3. Penninx BW, Milaneschi Y, Lamers F, et al. Understanding the
somatic consequences of depression: biological mechanisms and the
role of depression symptom profile. BMC Med. 2013;11:129 PubMed
PMID: 23672628 Pubmed Central PMCID: PMC3661358 Epub
2013/05/16 eng.
4. Shah E, Rezaie A, Riddle M, et al. Psychological disorders in
gastrointestinal disease: epiphenomenon, cause or consequence? Ann
Gastroenterol. 2014;27:224–230 PubMed PMID: 24974805 Pubmed
Central PMCID: PMC4073018 Epub 2014/07/01 Eng.
5. Fujiwara Y, Arakawa T. Overlap in patients with dyspepsia/
functional dyspepsia. J Neurogastroenterol Motil. 2014;20:447–457
PubMed PMID: 25257470 Pubmed Central PMCID: PMC4204405
Epub 2014/09/27 eng.
6. Chou PH, Lin CC, Lin CH, et al. Prevalence of gastroesophageal
reflux disease in major depressive disorder: a population-based
study. Psychosomatics. 2014;55:155–162 PubMed PMID: 23953172
Epub 2013/08/21 eng.
7. Prabhu V, Shivani A. An overview of history, pathogenesis and
treatment of perforated peptic ulcer disease with evaluation of
prognostic scoring in adults. Ann Med Health Sci Res. 2014;4:22–29
PubMed PMID: 24669326 Pubmed Central PMCID: PMC3952291
Epub 2014/03/29 eng.
8. Levenstein S, Rosenstock S, Jacobsen RK, et al. Psychological stress
increases risk for peptic ulcer, regardless of Helicobacter pylori
infection or use of nonsteroidal anti-inflammatory drugs. Clin
Gastroenterol Hepatol. 2014 PubMed PMID: 25111233 Epub 2014/
08/12 Eng.
9. Krag M, Perner A, Wetterslev J, et al. Stress ulcer prophylaxis in
the intensive care unit: is it indicated? A topical systematic review.
Acta Anaesthesiol Scand. 2013;57:835–847 PubMed PMID:
23495933 Epub 2013/03/19 eng.
10. Liao CH, Chang CS, Chang SN, et al. The association of peptic
ulcer and schizophrenia: a population-based study. J Psychosom
Res. 2014;77:541–546 PubMed PMID: 25199406 Epub 2014/09/10
eng.
11. Lim WY, Subramaniam M, Abdin E, et al. Peptic ulcer disease and
mental illnesses. Gen Hosp Psychiatry. 2014;36:63–67 PubMed
PMID: 24120385 Epub 2013/10/15 eng.
12. Hirschfeld RM. Differential diagnosis of bipolar disorder and major
depressive disorder. J Affect Disord. 2014;169(Suppl 1):S12–S16
PubMed PMID: 25533909 Epub 2014/12/24 eng.
TABLE 5. Incidence and Hazard Ratios of Peptic Ulcer Disease Measured for Outpatients and Inpatients and Patients Diagnosed
by General Physicians and Psychiatrists
Variables N Event Rate# Age-adjusted HR (95% CI) Adjusted HRy (95% CI)
Without depression 47,069 4808 16.8 1 (Reference) 1 (Reference)
Depression
Outpatient 19,936 3562 32.1 1.91 (1.83,1.99) 1.32 (1.25,1.39)
Inpatient 3600 750 40.1 2.36 (2.19,2.55) 1.52 (1.40,1.65)
Diagnosed by
General physicians 19,882 3731 33.8 1.96 (1.88,2.05) 1.35 (1.29,1.42)
Psychiatrists 3654 581 30.1 2.05 (1.88,2.24) 1.30 (1.19,1.43)
CI¼confidence interval.
#Rate, incidence rate, per 1000 person-years.
Age-adjusted HR, hazard ratio adjusted for age.
yAdjusted HR, hazard ratio mutually adjusted for age, gender, frequency of medical visits, occupation, monthly income, and comorbidities of
cirrhosis, hypertension, diabetes mellitus, asthma, chronic kidney disease, coronary artery disease, alcoholism, tobacco dependency, COPD, anxiety,
helicobacter pylori, and medicine of NSAID, anxiolytics, and benzodiazepine in Cox proportional hazards regression analysis.
P<0.05.
P<0.01.
P<0.001.
Medicine Volume 94, Number 51, December 2015 Depression and Peptic Ulcer Disease
Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com | 7
13. Pfennig A, Ritter PS, Hofler M, et al. Symptom characteristics of
depressive episodes prior to the onset of mania or hypomania. Acta
Psychiatr Scand. 2015 PubMed PMID: 26252885 Epub 2015/08/08
Eng.
14. Phillips ML, Kupfer DJ. Bipolar disorder diagnosis: challenges and
future directions. Lancet (London, England). 2013;381:1663–1671
PubMed PMID: 23663952 Epub 2013/05/15 eng.
15. Hsu YC, Hsu CC, Chang KH, et al. Increased subsequent risk
of peptic ulcer diseases in patients with bipolar disorders.
Medicine. 2015;94:e1203 PubMed PMID: 26200637 Epub 2015/
07/23 eng.
16. Hohne N, Poidinger M, Merz F, et al. Increased HPA axis response
to psychosocial stress in remitted depression is influenced by coping
style. Biol Psychol. 2014;103:267–275 PubMed PMID: 25263610
Epub 2014/09/30 Eng.
17. Kessler RC, Bromet EJ. The epidemiology of depression across
cultures. Ann Rev Public Health. 2013;34:119–138 PubMed PMID:
23514317 Pubmed Central PMCID: PMC4100461 Epub 2013/03/22
eng.
18. Zhang S, Xu Z, Gao Y, et al. Bidirectional crosstalk between stressinduced
gastric ulcer and depression under chronic stress. PloS One.
2012;7:e51148 PubMed PMID: 23251441 Pubmed Central PMCID:
PMC3521024 Epub 2012/12/20 eng.
19. Gunn JM, Ayton DR, Densley K, et al. The association between
chronic illness, multimorbidity and depressive symptoms in an
Australian primary care cohort. Soc Psychiatry Psychiatr Epidemiol.
2012;47:175–184 PubMed PMID: 21184214 Epub 2010/12/25 eng.
20. Edwards AC, Maes HH, Pedersen NL, et al. A population-based
twin study of the genetic and environmental relationship of major
depression, regular tobacco use and nicotine dependence. Psychol
Med. 2011;41:395–405 PubMed PMID: 20406522 Pubmed Central
PMCID: PMC3016459 Epub 2010/04/22 eng.
21. Carceller-Maicas N, Ariste S, Martinez-Hernaez A, et al. Smoking
as a form of self-medication for depression or anxiety in young
adults: results of a mixed-methods study. Adicciones. 2014;26:34–45
PubMed PMID: 24652397 Epub 2014/03/22 El consumo de tabaco
como automedicacion de depresion/ansiedad entre los jovenes:
resultados de un estudio con metodo mixto spa.
22. Li LF, Chan RL, Lu L, et al. Cigarette smoking and gastrointestinal
diseases: the causal relationship and underlying molecular mechanisms
(review). Int J Mol Med. 2014;34:372–380 PubMed PMID:
24859303 Epub 2014/05/27 eng.
23. Chaiton M, Cohen J, O’Loughlin J, et al. Use of cigarettes to
improve affect and depressive symptoms in a longitudinal study of
adolescents. Addict Behav. 2010;35:1054–1060 PubMed PMID:
20691543 Epub 2010/08/10 eng.
24. Boschloo L, Vogelzangs N, van den Brink W, et al. Depressive and
anxiety disorders predicting first incidence of alcohol use disorders:
results of the Netherlands Study of Depression and Anxiety
(NESDA). J Clin Psychiatry. 2013;74:1233–1240 PubMed PMID:
24434092 Epub 2014/01/18 eng.
25. Nagata N, Niikura R, Sekine K, et al. Risk of peptic ulcer bleeding
associated with Helicobacter pylori infection, NSAIDs, low-dose
aspirin, and antihypertensive drugs: a case-control study. J Gastroenterol
Hepatol. 2015;30:292–298 PubMed PMID: 25339607 Epub
2014/10/24 Eng.
26. Andrade C. Antidepressant augmentation with anti-inflammatory
agents. J Clin Psychiatry. 2014;75:975–977 PubMed PMID:
25295422 Epub 2014/10/09 eng.
27. Manthey L, van Veen T, Giltay EJ, et al. Correlates of (inappropriate)
benzodiazepine use: the Netherlands Study of Depression and
Anxiety (NESDA). Br J Clin Pharmacol. 2011;71:263–272 PubMed
PMID: 21219408 Pubmed Central PMCID: PMC3040548 Epub
2011/01/12 eng.
28. Masi G, Brovedani P. The hippocampus, neurotrophic factors and
depression: possible implications for the pharmacotherapy of depression.
CNS Drugs. 2011;25:913–931 PubMed PMID: 22054117 Epub
2011/11/08 eng.
29. Sun Y, Evans J, Russell B, et al. A benzodiazepine impairs the
neurogenic and behavioural effects of fluoxetine in a rodent model
of chronic stress. Neuropharmacology. 2013;72:20–28 PubMed
PMID: 23639432 Epub 2013/05/04 eng.
Hsu et al Medicine Volume 94, Number 51, December 2015
8 | www.md-journal.com Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved.
