Accepted Manuscript

Anxiety is Linked to New-onset Dyspepsia in the Swedish Population A 10 year

follow-up Study

Pertti Aro, Nicholas J. Talley, Sven-Erik Johansson, Lars Agrus, Jukka Ronkainen

PII: S0016-5085(15)00156-0
DOI: 10.1053/j.gastro.2015.01.039
Reference: YGAST 59591

To appear in: Gastroenterology

Accepted Date: 25 January 2015

Please cite this article as: Aro P, Talley NJ, Johansson S-E, Agrus L, Ronkainen J, Anxiety is Linked to
New-onset Dyspepsia in the Swedish Population A 10 year follow-up Study, Gastroenterology (2015),
doi: 10.1053/j.gastro.2015.01.039.

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Anxiety is Linked to New-onset Dyspepsia in the Swedish

Population A 10 year follow-up Study

Short title: Anxiety and upper gastrointestinal symptoms

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Pertti Aro1, Nicholas J Talley2, Sven-Erik Johansson1, Lars Agrus1, Jukka Ronkainen1,3,4
1

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Centre for Family Medicine, Karolinska Institutet, Stockholm, Sweden,
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Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia,

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Institute of Health Sciences, Medical Faculty, University of Oulu, Finland,
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Primary Health Care Centre, Tornio, Finland,

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Abbreviations: 99% CI 99% Confidence Interval, EGD - esophagogastroduodenoscopy,
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FD - Functional dyspepsia, H. pylori - Helicobacter pylori, IBS irritable bowel syndrome,

GERD Gastro-Esophageal Reflux Disease, GERS Gastro-Esophageal Reflux Symptoms,

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NSAID - Non Steroidal Anti Inflammatory Drug, OR odds ratio, PPI - Proton Pump
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Inhibitor
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Address for correspondence: Dr. Pertti Aro, Taimenkuja 4, SF-95410, Tornio Finland. Tel:

+358 (0)40 7548075. E-Mail: pertti.aro@fimnet.fi

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Grant support

This study was supported in part by the Swedish Research Council, the Swedish Society of
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Medicine, Norrbotten County Council (Sweden), Astra Zeneca R&D (Sweden), Orion
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Research Foundation (Finland), the Finnish Medical Foundation (Finland) and Vappu and

Oskari Yli-Perttulas Foundation (Finland).

The study sponsors did not have role in the study design in the collection, analysis, and

interpretation of data.

Disclosures
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The authors have nothing to disclose

Author Contributions

Pertti Aro: Constructing the study, performing the study and collecting the data, analysing the

data, writing and revising the article

Nicholas Talley: Constructing the study, supervising the study, writing and revising the article

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Sven-Erik Johansson: Analysing the data, revising the article

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Lars Agrus: Constructing the study, supervising the study, writing and revising the article

Jukka Ronkainen: Constructing the study, performing the study and collecting the data,

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writing and revising the article.

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ABSTRACT

Backgroud & Aims: Functional dyspepsia (FD) is associated with anxiety but it is not clear

if one causes the other. We investigated whether anxiety and depression precede the onset of

FD (based on the modified Rome III criteria) and gastroesophageal reflux symptoms (GERS)

in a population based follow-up study.

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Methods: Participants from the Kalixanda study (n=3000), randomly selected from the

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national population register of Sweden, were given the validated abdominal symptom

questionnaire (ASQ) 19982001; 1000 of these participants were then selected randomly to

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undergo esophagogastroduodenoscopy and were given the ASQ along with hospital anxiety

and depression scale (HADS) questionnaire. All eligible subjects who underwent endoscopy

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(n=887) were invited to a follow-up study in JuneAugust 2010 and were given the same
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questionnaires. Data were analyzed by logistic regression.
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Results: Of the 703 subjects who completed the follow-up questionnaires (79.3%); 110 were

found to have FD at baseline (15.6%) and 93 at the follow-up examination (13.3%); 48 of

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these were new cases of FD. GERS without organic disease was reported by 273 individuals
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(38.8%) at baseline and by 280 at follow-up examination (39.8%); 93 cases were new. Major

anxiety was associated with FD at follow-up (odds ratio [OD]=6.30; 99% confidence interval
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[CI], 1.6424.16). Anxiety was associated with post-prandial distress syndrome at baseline
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(OR=4.83; 99% CI, 1.2418.76) and at the follow-up examination (OR=8.12; 99% CI, 2.13
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30.85) but not with epigastric pain syndrome. Anxiety at baseline was associated with new-

onset FD at the follow-up examination (OR=7.61; 99% CI, 1.2147.73), but not with GERS.

Conclusions: In a study of the Swedish population, anxiety at baseline, but not depression,

increased risk for development of FD 7.6-fold in the next 10 years. Anxiety did not affect risk

for GERS.

Keywords: psychological factors; functional disorder; population study

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BACKGROUND & AIMS

Functional dyspepsia (FD) and gastroesophageal reflux symptoms (GERS) are common and

costly disorders in the adult population.(1-4) The prevalence of FD in different studies depends

on the definition used(5-7) but the prevalence of FD in the western world defined according to

the Rome III definition is between 11% and 20%(4, 8) whereas the prevalence of

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gastroesophageal reflux symptoms (GERS) once a week or more often is approximately

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20%.(9, 10)

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Psychological distress has been reported to be linked with dyspepsia(11-14) as has

depression.(15) In a multicenter study of uninvestigated dyspepsia, dyspeptic symptoms were

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reported to cause emotional distress.(16) We have earlier described the association of FD with
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anxiety(4) but longitudinal follow-up studies in the general population applying the Rome III
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definition are largely unavailable.(17) There is one 5-year follow-up study on FD patients

applying the Rome II definition showing an association of anxiety with FD(18) and another
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Australian 12-year follow-up study of functional gastrointestinal disorders (FGID) showing

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an association of anxiety with FGID overall but not dyspepsia.(19)

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A Norwegian population-based, cross-sectional, case-control study found a strong association

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of anxiety and depression with GERS(20) whereas Eslick and others in Australia did not find
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anxiety or depression to be risk factors for GERS.(21) Longitudinal follow-up studies to

determine if there is an association of psychological factors with GERS are not available.

Any link between GI symptoms and mental distress could be confounded by other

environmental risk factors such as smoking or alcohol use.(22-25) Smoking is linked to post

infectious FD(26) and to GERS(21) but whether this environmental factor drives new onset of
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symptoms is unknown. An association of non-steroidal anti-inflamatory drugs (NSAIDs) with

FD is controversial; a meta-analysis of uninvestigated dyspepsia identified an association for

some NSAIDs and for high dose of any NSAID(27) whereas an Italian population-based

endoscopic study failed to find any association of NSAIDs with FD.(8) There are also

inconsistent reports whether obesity and GI symptoms are linked.(28-30) There was no relation

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between body mass index and GERS in a Swedish population-based study(28) whereas others

have found that being overweight and obese are independent risk factors of GERS.(29)

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The aim of this study was to define whether there may be a causal relation between anxiety

and depression with functional dyspepsia and/or GERS. We also aimed to study the overlap

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of dyspepsia and GERS, and predictors for new onset of symptoms. We hypothesized that
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anxiety and/or depression drive FD and/or GERS and predict the new onset of dyspepsia.
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METHODS

The baseline data for the ten year follow-up study were gathered from a representative

random sample (n=3,000) of the general population in two Swedish communities between

1998 and 2001. At the baseline the participants were randomly selected from the national

population register which covers all inhabitants in Sweden and surveyed by a validated and

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widely used abdominal symptom questionnaire (ASQ).(31, 32) One thousand of them were

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randomly selected for esophagogastroduodenoscopy and for survey by a more comprehensive

ASQ assessing troublesome gastrointestinal symptoms and by the hospital anxiety and

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depression scale (HADS)(33) to define depression and anxiety. Organic reasons for dyspepsia

were excluded by esophagogastroduodenoscopy (EGD) and medical history the baseline

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Kalixanda study.(34) All eligible from this endoscoped cohort (n=887) were invited to a
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follow-up study in June-August 2010 with the same postal questionnaires ten years after the
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primary investigation (Figure 1). During these years the subjects could consult and be treated

as ordinary patients.(9, 34, 35)

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Aside from the individual symptoms from the questionnaires, the participants were asked

about their level of education, gastrointestinal (GI) medication and weight as well as their use
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of tobacco (smoking or moist snuff) and alcohol.

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The baseline study was approved by the Ume University ethics committee and the follow-up

study by the ethical approval committee of the Karolinska Institutet and conducted in

accordance with the revised Declaration of Helsinki in 1998.

Endoscopy at baseline
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The upper esophagogastroduodenoscopies (EGDs) were undertaken by three experienced

endoscopists, in the two clinics (Kalix and Haparanda), which gave sole medical cover to the

area. Internal validity was assessed by means of consensus sessions before the initiation of the

basic study. The endoscopists had been participating in regular quality assessment programs

over several years. The endoscopists were unaware of the symptoms of the subjects before

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endoscopy. Only topical anaesthesia was used.(34)

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Definitions of dyspepsia, gastroesophageal reflux symptoms and irritable bowel syndrome

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Functional dyspepsia (FD) was defined based on the Rome III definition: weekly bothersome

postprandial fullness or early satiation, or epigastric pain and/or epigastric burning without

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findings of esophagitis, peptic ulcer, celiac disease or cancer and no evidence of other
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structural disease at endoscopy that was likely to explain the symptoms. FD, according to the
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Rome III definition, was divided into:

1. Postprandial Distress Syndrome (PDS) consisting of bothersome postprandial fullness

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and/or early satiation.

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2. Epigastric Pain Syndrome (EPS) consisting of pain or burning localized to the epigastric

area and not generalized or localized to other abdominal or chest regions, and not
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relieved by defecation. Overlap between PDS and EPS was allowed in line with the

Rome III definition. The presence of heartburn/gastroesophageal reflux symptoms

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(GERS) or irritable bowel syndrome (IBS) did not exclude the diagnosis of FD.(7)
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The ASQ was designed before the Rome era but the questionnaire has been updated to meet

both the Rome II and III criteria and it measures all of the Rome III criteria aside from the

symptom onset (3 vs. 6 months).(31, 32)

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Gastroesophageal reflux symptoms (GERS) were defined as troublesome heartburn and/or

acid regurgitation over the past three months. The presence of FD or IBS did not exclude the

diagnosis of GERS.(36, 37)

Irritable bowel syndrome (IBS) was defined as troublesome abdominal pain or discomfort

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located at any site plus concomitant bowel habit disturbances (constipation, diarrhea, or

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alternating constipation and diarrhea). This simple definition has been used previously and

shown to produce results reasonably concordant with the Rome I criteria for IBS.(38-40)

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Definition of anxiety and depression

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A HADS score from 8 to less than 11 was used to define suspected anxiety and depression
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and 11 or more was used as cut off level for both clinically relevant (major) anxiety and

depression.(33)
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Definiton of obesity
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Body mass index (BMI) was calculated according to guidelines from WHO and it was

categorized as normal with BMI <25, overweight with a BMI between 25 and <30 and obesity
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with a BMI 30.(41)

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Covariates

All individuals were thoroughly interviewed face to face at the baseline study about their

smoking habits, use of alcohol and use of medication including use of non-steroidal anti-

inflammatory drugs (NSAIDs).

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These same questions were included also in the self-administrated ASQ-questionnaire at the

10-year follow-up study. The question about the dose of alcohol/week was also included. The

cut-off level for high consumption of alcohol was set at 100 grams absolute alcohol or

more/week.

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Statistics

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Logistic regression adjusting for age and gender was used in cross-sectional analyses both at

baseline and at follow-up to analyze associations of categorized BMI (normal weight,

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overweight, obesity), categorized anxiety (no anxiety, suspected anxiety and major anxiety),

categorized depression (no depression, suspected depression and major depression), use of

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proton pump inhibitors (PPIs), high consumption of alcohol, smoking, Helicobacter pylori (H.
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pylori) infection and use of NSAIDs and/or aspirin with FD, FDs subgroups (PDS, EPS and
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epigastric burning), GERS and IBS. Analyses were performed separately for different

gastrointestinal symptoms.
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Predictors for change in presentation of FD, PDS and EPS, GERS and IBS were analyzed in
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separate analyses by logistic regression adjusting for age and gender and including categorized

BMI, categorized anxiety, categorized depression, PPIs, smoking, H. pylori infection and use
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of NSAIDs and/or aspirin in the model. Unadjusted odds ratios (crude ORs) for association of

anxiety and depression with FD and GERS are also presented. Due to non-linearity, age was
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dichotomized with cut off at 60 years of age. Variables were chosen according to our

hypothesis and due to their clinical significance. Only statistically significant variables in

univariate anlysis were introduced into the basic model adjusted for age and gender. Model

selection was performed by dropping out statistically non-significant independent variables one

by one and the goodness of-fit of the new model was judged after each variable was removed

using the likelihood-ratio test. The reduced model was judged to be better if the p value of the
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likelihood-ratio test was >0.05. The goodness-of fit test was then performed after the chosen

model (Pearssons 2 test) and if the p-value was >0.05 the model was judged to fit the data.(42)

Fischers exact test was applied when number of observations was less than 10. The T-test was

used to analyze significances of differences in mean anxiety scores at baseline and follow-up in

individuals still having FD at follow-up and in individuals whose FD disappeared at follow-up.

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P-values were all two tailed and the alpha level of significance was set at 0.01. The results are

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shown as odds ratios (OR) with a 99% CI. The Intercooled STATA 9 program was used for

analyses.(43)

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RESULTS

Of the original study population (n=3,000), 2,860 were eligible for inclusion. The overall

response rate was 74.2 % (n=2,122) at baseline and 1,364 responders to the ASQ eligible for

upper endoscopy were invited in random order to EGD with a response rate of 73.3%

(n=1,000). Ten years after the baseline study, 887 subjects were eligible for the follow-up

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study: 113 individuals had deceased, moved away from Sweden, could not be reached for other

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reasons or had developed a serious mental or physical illness during the 10 year period so that

they could not answer the questionnaires. Overall 703 out of 887 subjects answered the postal

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questionnaires, a response rate of 79.3%. BMI could be defined in 575 individuals (81.8% of

the responders).

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Mean age at the baseline was 53.0 years and at the follow-up 63.2 years, and the proportion of
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women was 51.9 % in this follow-up cohort. Mean BMI was 26.3 both at the baseline and at

the follow up. Of those who were obese at the baseline (n=90), 74.4% were still obese (n=67).
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At baseline 14.4% were smokers and the respective figure at follow-up was 11.6%.
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At baseline 12.2% used 100 g/week or more alcohol compared to 7.2% at follow-up.

Treatment with PPIs over the 3 months prior to the baseline study was reported by 5.1%
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(n=36) and at the 10 year follow-up period such therapy was reported by 21.6% (n=145).
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FD was identified in 110 of these 703 individuals (15.6%) at the baseline study and by 93

individuals at follow-up (13.3%); these groups overlapped in 45 (6.4%) individuals. EPS was

reported by 35 (5.0%) and PDS by 87 (12.4%) individuals at baseline and there was overlap in

12 individuals. There were 21 EPS (3.0%) and 79 PDS cases (11.2%) at follow-up overlapping

in 7 (1%) individuals. Epigastric burning was reported by 11 (1.6%) individuals both at

baseline and at follow-up.

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In cross-sectional analysis, major anxiety, but not depression was associated with FD only at

follow-up. (Table 1) Smoking, being overweight or obese, H. pylori infection, use of alcohol

and use of NSAIDs or aspirin were not associated with FD. However, PDS was associated with

anxiety both at baseline (crude OR= 4.83; 99% CI 1.26-18.52, adjusted OR=4.83; 99% CI

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1.24-18.76) and at follow-up (crude OR= 9.65; 99% CI 3.87-24.06, adjusted OR=8.12; 99% CI

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2.13-30.85) but EPS and separately epigastric burning were not.

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GERS were reported by 273 individuals (38.8%) at baseline and by 280 individuals (39.8%) at

follow-up and the groups overlapped in 187 individuals. Suspected and major anxiety were not

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associated with GERS at baseline. Major anxiety was associated with GERS at follow-up both
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in unadjusted and adjusted analyses (Table 1). Being overweight was not associated with
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GERS at baseline (crude OR=1.19; 99% CI 0.71-1.99, adjusted OR= 1.35; 99% CI 0.84-2.18)

or at follow-up (crude OR= 1.50; 99% CI 0.90-2.52, adjusted OR= 1.54; 99% CI 0.86-2.75).
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Obesity at baseline was associated with GERS (crude OR= 1.86; 99% CI 1.03-3.37, adjusted
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OR=1.96; 99% CI 1.05-3.64) but not at follow-up (crude OR=1.43; 99% CI 0.74-2.77, adjusted

OR=1.39; 99% CI 0.66-2.93).

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FD and GERS did overlap in 69 individuals at baseline and in 68 individuals at follow-up. FD

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at baseline did also overlap with IBS in 56 individuals and at follow-up in 59 cases.

GERS overlapped with IBS in 112 individuals at baseline and in 117 individuals at follow-up.

Suspected and major anxiety were not associated with overlap of FD with GERS or IBS, nor

with overlap of GERS with IBS at baseline (Table 2). Major anxiety was associated with all

overlaps at follow-up (Table 3). Suspected depression or major depression, smoking, use of
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alcohol, H. pylori infection, use of NSAIDs or abnormal weight were not associated with

overlapping groups at baseline or at follow-up.

A total of 33 individuals changed from the FD group at baseline to GERS at follow-up and also

20 individuals changed from the FD group at baseline to IBS at follow-up (11 overlapping with

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change to GERS) 17 individuals from the GERS group changed to IBS. Change from FD at

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baseline to GERS at follow-up was associated with major anxiety at follow-up (crude

OR=50.40; 99% CI 2.85-889.42, adjusted OR=47.30; 99% CI 2.61-858.41, Fischers exact

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p<0.001). Major anxiety was also associated with change from FD at baseline to IBS at follow-

up (crude OR=13.16; 99% CI 1.77-98.05, adjusted OR=13.44; 99% CI 1.59-113.23, Fischers

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exact p=0.005) and with change from GERS to IBS (crude OR=28.64; 99% CI 2.39-342.88,
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adjusted OR= 7.35; 99% CI 2.21-338.23, Fischers exact p=0.002).
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Both suspected anxiety and major anxiety at baseline were associated with new onset FD
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(n=48) at follow-up (adjusted OR=3.97; 99% CI 1.20-13.20 and adjusted OR=7.61; 99% CI
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1.21-47.73, respectively) but not with new onset GERS (n=93) (adjusted OR=1.67; 99% CI

0.49-5.67 and adjusted OR=1.78; 99% CI 0.35-8.98, respectively). Depression, smoking, high
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consumption of alcohol H. pylori infection, use of NSAID/aspirin and obesity at baseline were

not associated with new onset FD or new onset GERS at follow-up.

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There were 14 new onset EPS and 37 new onset PDS and overlap of these occured in 3

individuals. Suspected and major anxiety at baseline were not associated with new onset PDS

(adjusted OR=3.71; 99% CI 0.99-14.03 and adjusted OR=6.48; 99% 0.91-45.75, respectively).

There were no associations of suspected or major anxiety at baseline with new onset EPS
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(adjusted OR=4.15; 99% CI 0.67-25.09 and adjusted OR=4.11; 99% CI 0.23-73.23,

respectively).

Mean anxiety score at baseline for cases where FD disappeared at follow-up was 4.4 and for

those cases still having FD the mean anxiety score at baseline was higher at 6.1 (p=0.021).

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Notably, the mean anxiety score at follow-up for those whose FD disappeared was 3.8 versus

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those still having FD where the mean anxiety score was significantly higher at 6.9

(p=0.0002).

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DISCUSSION

We have performed a prospective 10 year follow-up study in a well characterized cohort from a

clearly defined general population in Sweden who underwent a baseline endoscopy and

detailed symptom evaluation.(34) To our knowledge, this is the first follow-up of a general

population cohort where FD was defined according to the Rome III definition.(17) We found

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that anxiety at baseline was associated with over a seven fold risk of new onset FD symptoms

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but not GERS supporting a strong association with FD. Furthermore, a lower anxiety score at

follow-up was associated with the disappearance of FD. In addition, anxiety was associated

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with an increased risk of change of FD to GERS or IBS.

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Our results are in contrast to results from an Australian follow-up study where higher anxiety
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score did predict the onset of other functional gastrointestinal disorders but not onset of FD
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symptoms, although this may be explained by a type II error and none of these subjects had

systematically undergone prior endoscopy.(19) Our results are consistent with earlier
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observations from a population-based follow-up study applying the Rome II definition of

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FD.(18)
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The mechanisms by which anxiety may drive upper gastrointestinal symptoms are likely
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multifactorial and bidirectional. FD is associated with pathophysiological pertubations

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including delayed gastric emptying(44, 45) as well as reduced proximal gastric relaxation

postprandially.(46) Visceral hypersensitivity has also been identified in a subset,(47) although

the relationship between specific symptoms and gastric physiological changes has been

inconsistent.(44-46) Fischler et al. observed that epigastric pain and burning were significantly

associated with both hypersensitivity to gastric distension and the personality trait of

neuroticism which is closely related to anxiety.(48) Geeraerts et al. observed during induced
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anxiety by recalling a neutral or an anxious autobiographical experience that gastric

compliance significantly decreased with higher anxiety levels; intraballoon pressures inducing

discomfort during gastric distention were not altered, but the corresponding volume was

significantly lower. Meal-induced relaxation was inhibited during anxiety and this persisted

for the whole 60-minute measurement.(49) A Dutch study of 149 patients with FD showed that

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higher levels of state anxiety predicted lower discomfort and pain thresholds and lower

compliance applying the gastric barostat.(50) Thus the presence of anxiety may predispose to

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FD, and when pathophysiological abnormalities are induced for example by infectious

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gastroenteritis(51, 52), a vicious cycle may be set up inducing new upper gut symptoms that in

turn worsen anxiety and increase the perception of symptoms leading to the clinical syndrome

recognised as FD.
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We have earlier observed an association of duodenal eosinophilia with PDS and early satiation

in adults from the Kalixanda studies(53) now confirmed worldwide.(54, 55) In the present study
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we observed an association of anxiety with PDS both at baseline and at follow-up. Anxiety was
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not associated with the new onset PDS but the analysis was conservative (applying 99%

confidence limits) and the lack of association may represent a type II error once FD is
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subdivided. It is conceivable that anxiety induces a corticotrophin releasing hormone stress

response that in turn activates eosinophils, promotes eosinophil degranulation and leads to the
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release of cytokines such as TNF-alpha in FD, altering gastroduodenal function.(56, 57)

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Alternatively, anxiety might drive through the stress response immune activation from a TH1

to a TH2 response promoting an allergic diathesis in predisposed individuals leading to

eosinophil recruitment and degranulation, neuromuscular dysfunction and symptoms.(58) In

children, an association between anxiety and duodenal eosinophil density has been reported.(59)
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The data support the view anxiety may drive gut to brain as well as brain to gut mechanisms

that can result in or sustain symptoms of FD.(19, 60)

In this study 187 individuals had persistent GERS pointing to the chronicity of this condition.

We have earlier shown that GERS were more stable (81%), in comparison to the other

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gastrointestinal symptom groups in short term.(61) Based on earlier population-based cross-

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sectional studies, it is controversial whether an association of anxiety exists with

gastroesophageal reflux disease.(20, 21) Our study of a well characterized population cohort

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supports the finding of an association between anxiety and GERS in cross-sectional analyses

only at follow-up. However, importantly there appears not to be a causal link as anxiety did

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not precede GERS. There are data showing that anxiety heightens sensory perception in
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GERS and might reduce the symptomatic response to therapy.(20, 62) Sharma et al. for
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example observed in an experimental study of asymptomatic adult volunteers that anxiety

induction significantly increases the experienced magnitude of acid-induced esophageal

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hyperalgesia.(63)
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It is well established that FD, IBS and GERS overlap more than expected by chance but this

overlap remains unexplained.(61, 64) A link to post infectious gastroenteritis has been identified
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in some cases(51, 52) and a Korean study suggested that anxiety was linked to the overlap
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between GERD, dyspepsia and IBS.(65) Our findings at follow-up are consistent with these

results. We speculate the extent of immune activation in the small intestine after exposure to

infectious or food antigens may account for whether patients experience upper or lower

intestinal symptoms; if confined proximally, dyspepsia may be more likely. More distal

intestinal inflammation may induce IBS while while those having extensive proximal and distal
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involvement may be more likely to experience overlapping symptoms.(66, 67) If this is true,

anxiety through the stress response may play a key role in exaggerating the immune process

and increasing the probability of overlapping symptoms perhaps through alterations in

perception. This hypothesis needs further evaluation.

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We did not find an association of NSAIDs with FD. Overall 41 individuals out of 703 (5.8%)

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used NSAIDs at baseline, and only 11 of 110 individuals with FD (10%) in this cohort reported

use of NSAIDs at baseline. The low reported use of NSAIDs possibly explains the lack of

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association.

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The present population-based study had a number of strengths. A true general population
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based design was applied with a very high participation rate both at baseline and at the ten-
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year follow-up. Further, the questionnaires used have been found to be robust and

reproducible.(31-33) A possible weakness is that the ASQ was designed before the Rome era
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but the questionnaire has been updated to meet the Rome II and III criteria and it measures all
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of the Rome III criteria aside from the symptom onset (3 vs. 6 months).(31) The ASQ has also

been revalidated after being populated with the additional questions.(32) Performing the
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endoscopy only at baseline is a potential weakness but this method has been used earlier in

follow-up studies(14, 68) and ethically we couldnt perform an invasive procedure on the same
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population twice without a medical indication. Another possible weakness is a slightly lower

response rate to the question on present weight (81.8% of the responders and 82.8% of those

reporting GERS). This might have resulted in under-reporting high BMIs when analyzing the

association of obesity with GERS at follow-up. Another possible weakness is that we do not

have exact data on prescriptions of eradication therapy for H. pylori. However, the local

Swedish guidelines for eradication have remained very restricted (i.e. in peptic ulcer cases
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only). We did not have access to the medical records at the 10-year follow-up nor medicine

codes (ATC codes were available at baseline only) and therefore we could not check

treatment for anxiety and depression at follow-up. PPIs were available only by prescription at

baseline but could be bought over the counter at follow-up and the use of PPIs was markedly

increased at follow-up based on questionnaire responses. This fact might have influenced the

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reported EPS and GERS rates but not PDS; PPIs are not efficacious in dysmotility-like

dyspepsia which is equivalent to PDS.(69) A 10-year follow-up period leads to an information

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gap in data but this is not possible to avoid in a follow-up study of this kind. Finally, 99%

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confidence intervals were chosen to reduce type I errors but it is a conservative approach.

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In conclusion, anxiety but not depression precedes the onset of new FD but not GERS over a
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ten year follow-up suggesting a strong association. Further exploration of the mechanisms
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linking anxiety with FD may yield new approaches to interventions that reduce or eliminate

symptoms.
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FIGURE LEGENDS

Figure 1.

Flow-chart of the Kalixanda population-based study from 1998 to 2010.

Figure 2.

Gastrointestinal symptoms at baseline with overlap of symptoms

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Figure 3.

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Change of FD, GERS and IBS from baseline to follow-up

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Table 1. Association of anxiety and depression at baseline and at follow-up with FD and
GERS at baseline and at follow-up, respectively.
FD FD GERS GERS
at baseline at follow-up at baseline at follow-up
n=110 n=93 n=185 n=203
Suspected anxiety
Crude OR 2.44 1.96 2.00 1.79

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99% CI 1.02-5.87 0.71-5.41 0.95-4.20 0.79-4.06

Adusted OR 1.89 1.44 1.72 1.54

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99% CI 0.73-4.87 0.48-4.34 0.77-3.84 0.61-3.86
Major Anxiety
Crude OR 3.67 7.32 1.24 7.83

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99% CI 0.97-13.95 2.23-24.10 0.39-3.94 1.90-32.20

Adjusted OR 3.75 6.30 1.43 6.51

99% CI 0.97-14.49 1.64-24.16 0.43-4.73 1.47-28.78

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Suspected depression
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Crude OR 0.62 2.14 0.99 1.13
99% CI 0.12-3.11 0.63-7.25 0.36-2.75 0.39-3.23

Adjusted OR 0.57 2.24 1.00 1.27

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99% CI 0.10-3.17 0.55-9.09 0.33-2.97 0.36-4.44

Major depression
Crude OR 1.03 4.59 0.92 1.83
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99% CI 0.06-18.53 0.55-38.48 0.14-6.11 0.34-9.80

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Adjusted OR 0.99 5.74 0.94 2.12

99% CI 0.05-18.38 0.62-52.90 0.14-6.36 0.36-12.51
Use of PPI
Adjusted OR 7.92 5.45 4.92 9.21
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99% CI 2.57-24.45 2.53-11.74 1.67-14.52 4.67-18.16

Age 60
OR 0.61 0.49 1.03 0,71
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99% CI 0.31-1.21 0.24-0.98 0.65-1.63 0.43-1.18

Male gender
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OR 0.62 0.52 0.91 0.85

99% CI 0.33-1.14 0.25-1.06 0.59-1.42 0.52-1.39
PPI = proton pump inhibitor
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Table 2. Associations of overlapping FD, GERS and IBS at baseline 1998-2001

Overlap FD /GERS OverlapFD/IBS Overlap GERS/IBS

n=69 n=56 n=112
Suspected anxiety
Crude OR 2.94 3.09 3.54
99% CI 0.92-9.45 0.93-10.22 1.38-9.04

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Adjusted OR 2.78 2.15 2.66
99% CI 0.81-9.54 0.59-7.80 0.97-7.30

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Major anxiety
Crude OR 2.35 3.09 1.96
99% CI 0.39-13.96 0.53-18.05 0.45-8.56

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Adjusted OR 2.43 3.11 1.97
99% CI 0.40-14.90 0.51-18.85 0.45-8.67
Use of PPI

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Adjusted OR 28.84 8.21 15.05
99% CI 4.90-169.86 2.22 30.39 1.96-115.84
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Male gender
OR 0.43 0.37 0.72
99% CI 0.19-0 .96 0.16-0.88 0.39-1.33
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Age 60
OR 0.91 0.91 1.00
99% CI 0.40-2.07 0.39-2.14 0.52-1.92
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Table 3. Associations of overlapping FD, GERS and IBS at follow-up 2010

Overlap FD/GERS Overlap FD/IBS Overlap GERS/IBS

n=68 n=59 n=117
Suspected anxiety
Crude OR 1.90 2.07 1.74

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99% CI 0.55-6.62 0.66-6.54 0.64-4.74

Adjusted OR 1.47 1.61 1.27

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99% CI 0.35-6.10 0.48 5.43 0.41-3.98
Major anxiety
Crude OR 11.68 5.42 8.36

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99% CI 2,55-53.50 1.21-24.21 2.05-34.11

Adjusted OR 10.87 5.69 7.43

99% CI 1.58-74.78 1.12-28.90 1.37-40.14

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Use of PPI
Adjusted OR 10.04 3.34 11.43
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99% CI 4.05-24.88 1.43-7.80 5.06-25.80
Male gender
OR 0.40 0.29 0.44
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99% CI 0.16-1.00 0.12-0.69 0.22-0.88

Age 60
OR 0.43 0.39 0.44
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99% CI 0.18-1.01 0.17-0.87 0.22-0.88

PPI=proton pump inhibitor
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