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Allergic rhinitis in adolescence increases therisk of depression in later life: A nationwide

population-based prospective cohort study 

 Article  in  Journal of Aff ective Disorders · August 2012

Impact Factor: 3.38 · DOI: 10.1016/j.jad.2012.07.011 · Source: PubMed

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Research report

Allergic rhinitis in adolescence increases the risk of depression in later

life: A nationwide population-based prospective cohort study

Mu-Hong Chen a, Tung-Ping Su a,b, Ying-Sheue Chen a, Ju-Wei Hsu a, Kai-Lin Huang a,Wen-Han Chang a, Ya-Mei Bai a,b,n

a Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwanb Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan

a r t i c l e i n f o

 Article history:

Received 9 May 2012

Received in revised form

15 July 2012

Accepted 15 July 2012Available online 11 August 2012

Keywords:

Allergic rhinitis

Depression

Adolescence

Early adulthood

a b s t r a c t

Background: Many cross-sectional studies have suggested an association between allergic rhinitis (AR)

and depression, but the timing relationship was not determined. Using a nationwide population-based

prospective cohort study (1:4, age-/gender-matched), we hypothesized that AR in adolescence would

increase the risk of depression in later life.

Methods:   In all, 1673 adolescents aged 12–15 that had AR between 1996 and 2000 were recruited for

our study. Cases of major depressive disorder and any depressive disorder that occurred to the end of 

follow-up (December 31, 2010) were identified.

Result:  Adolescents with AR had a higher prevalence of major depression (2.5% vs. 1.2%, po0.001) and

any depressive disorder (4.9% vs. 2.8%, po0.001) and an earlier onset of major depression (19.3172.91

vs. 20.4372.71 years,   p¼0.038) and any depressive disorder (19.3572.63 vs. 20.4372.62 years,

 p¼0.002) compared with the controls. The Cox regression model showed that adolescents with AR had

increased HRs of major depression (HR: 1.59, 95% CI: 1.02–2.50) and any depressive disorder (HR: 1.42,

95% CI: 1.04–1.93) after controlling residence location and comorbid allergic diseases.

Limitations:  The prevalence of depressive disorder may be underestimated because only those who had

medicine-seeking behaviors were enrolled.

Conclusions:  This first cohort case–control study showed an association between AR in early adoles-cence and depression in late adolescence and early adulthood. Our results suggested that allergic

responses played important roles in the development of depression.

&  2012 Elsevier B.V. All rights reserved.

1. Introduction

Allergic rhinitis (AR) is one of the most common chronic allergic

disorders and impairs the sufferers’ quality of life, sleep, and work

performance (Dykewicz and Hamilos, 2010). The prevalence of AR 

in children and adolescents varies ranging from 1.4% to 39.7%, with

geographic difference (Strachan et al., 1997; Katelaris et al., 2012).

A trend toward an increasing prevalence of AR was noted world-

wide in the last decade (Arnedo-Pena et al., 2004; Lee et al., 2004).

The International Study of Asthma and Allergies in Childhood

(ISAAC) study estimated the time trend in the prevalence of AR 

and its geographic variations in 30,046 schoolchildren aged 13–14

years, and showed that the prevalence of AR increased in the past

10 year, with a geographical effect (Arnedo-Pena et al., 2004). Lee

et al. (2004) compared 4448 and 3618 children in 2001 and  1995,

respectively, and found that the prevalence of life-time AR (42.4%

vs. 38.9%,   po0.01) and current AR (37.4% vs. 35.1%,   po0.03)

increased significantly. In Taiwan, a national study from 2000 to

2007 showed that the mean 1-year and overall 8-year prevalence

rates of AR in children and adolescents were 11.3% and 37.8%,

respectively (Hwang et al., 2010).

Depressive disorder occurs usually in late adolescence and early

adulthood  (Paus et al., 2008). Some adverse events in early adoles-

cence, including physical diseases (i.e., arthritis and allergy), nega-

tive life events, and substance use increase the risk of depressive

disorder in late adolescence and early adulthood (Timonen et al.,

2002; Marmorstein, 2009; Tarakci et al., 2011; Espejo et al., 2012).

An association between allergies and depressive disorders has been

described in many reports. Previous evidence has shown that AR 

could lead to some psychological problems in the sufferers. Using

the Symptom Checklist-90 (SCL-90) and the Satisfaction with Life

Scale,  Bavbek et al. (2002) demonstrated that patients with AR had

significantly higher scores on all subscales of the SCL-90, especially

in the somatization and depression subscales, and lower scores for

life satisfaction, compared with the controls. Hurwitz et al.

Contents lists available at  SciVerse ScienceDirect

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

 Journal of Affective Disorders

0165-0327/$ - see front matter  &  2012 Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/j.jad.2012.07.011

n Corresponding author. Department of Psychiatry, No. 201, Shih-Pai Road,

Sec. 2, Taipei 11217, Taiwan. Tel./ fax:  þ886 2 28344012.

E-mail address:  ymbi@mail2000.com.tw (Y.-M. Bai).

 Journal of Affective Disorders 145 (2013) 49–53

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surveying 6836 patients on the comorbidity of allergy and depres-

sion, reported that subjects with a history of any allergy (i.e., asthma

or AR) were more likely to be diagnosed with major depression

(odds ratio [OR]¼1.58; 95% confidence interval [CI]: 1.13, 2.21). In a

large sample sized study of more than 85,000 individuals,  Cuffel

et al. (1999) found that AR patients had a 1.7 times greater chance of 

being diagnosed with depression than the controls. In a recent

systemic review, 10 out of 12 studies focusing on AR and depression

showed a positive relationship between allergies and depression(Sansone and Sansone, 2011). Most of those studies were cross-

sectional studies.

Longitudinal studies are important to clarify the timing rela-

tionship between AR and depression, but some limitations exist.

Timonen et al. (2002)   using the northern Finland 1966 birth

cohort with longitudinal follow-up to age 31, found that female

subjects with AR had a 1.8-fold greater risk of developing

depression than the control group. The researchers used ques-

tionnaires and skin tests to obtain the diagnoses of depression

and atopy, but could not confirm the diagnoses of specific allergic

diseases and depressive disorder. Another 8-year longitudinal

study found that subjects with non-food allergies had a slightly

higher probability of developing major depression (HR: 1.2, 95%

CI: 1.0–1.5), but the limitations of the study were the self-

reporting of the diagnosis of allergic diseases and the lack of a

specific diagnostic classification of the allergic diseases (Patten

et al., 2009).

In our study, using a nationwide database, a large number of 

adolescents who had AR, but no psychiatric disorder from 1996 to

2000, were identified. We followed the subjects to the end of 

2010, from adolescent to early adulthood. We hypothesized that

the AR in early adolescence would increase the risk of depressive

disorder in late adolescence and early adulthood.

2. Methods

 2.1. Data source

The National Health Insurance (NHI) program was implemen-

ted in Taiwan in 1995, and covers up to 99% of all 23,000,000

residents of Taiwan at this time. Demographic and medical

information on insured residents, including age, gender, residence

location, prescription drugs, prescription date, and the diagnosis

were recorded in the NHI Research Database (NHIRD). The

International Classification of Diseases, 9th revision, Clinical

Modification (ICD-9-CM) was used for the diagnosis. The com-

pleteness and accuracy of the NHIRD have been affirmed by the

Department of Health and the Bureau of NHI through audit. The

NHIRD has been used extensively in many epidemiologic studies

in Taiwan (Wu et al., 2011; Li et al., 2012).

 2.2. Inclusion criteria for the adolescents with AR and the control group

Adolescents aged 12–15 years with a diagnosis of AR (ICD-9-

CM code: 477) given by internists, family physicians, or pediatri-

cians, and without any psychiatric disorder (ICD-9-CM code: 299–

319) between January 1, 1996 and December 31, 2000, were

included in our study. The age- and gender-matched control

groups (four for every patient in the study cohort) was randomly

identified from the same cohort after eliminating adolescents

who had been given a diagnosis of AR and those with any

psychiatric disorder during 1996–2000. These subjects were

followed to December 31, 2010 for having diagnoses of major

depressive disorder (MDD) (ICD-9-CM codes: 296.2X and 296.3X)

and any depressive disorder (ICD-9-CM codes: 296.2X, 296.3X,

300.4, and 311) given by board-certificated psychiatrists. The

youngest patients with AR would have been about 22 years old in

2010 at the end of the follow-up period in the study. Because of 

the high comorbidity of other allergic diseases with AR, comorbid

allergic diseases, including asthma (ICD-9-CM codes: 493, 493.0,

493.1, or 493.9) diagnosed by internists, pulmonologists, rheu-

matologists, or pediatricians; atopic dermatitis (AD, ICD-9-CM

codes: 691 or 691.8) diagnosed by dermatologists or pediatri-

cians; and allergic conjunctivitis (AC, ICD-9-CM code: 372.05,

372.10, and 372.14) diagnosed by ophthalmologists, were identi-fied. Residence location was also assessed as a potential con-

founding factor in our study because the geographic effect on the

prevalence of AR was noted in the previous study ( Arnedo-Pena

et al., 2004).

 2.3. Statistical analysis

For between-group comparisons, the independent   t-test was

used for continuous variables and Pearson’s w2 test or Fisher’s

exact test for nominal variables, where appropriate. Two Cox

regression models were used to investigate the HR with 95% CI of 

MDD and any depressive disorder. The first model was adjusted

by residence location and the second model was adjusted by

residence location and comorbid allergic diseases. A two-tailed p-value of less than 0.05 was considered statistically significant.

All data processing and statistical analyses were performed with

Statistical Package for Social Science (SPSS) version 17 software

(SPSS Inc) and Statistical Analysis Software (SAS) version 9.1 (SAS

Institute, Cary, NC).

3. Results

 3.1. Demographic characteristics of patients with allergic rhinitis

and the control group

In all, 1673 adolescents with AR and a mean age 13.13 years

between 1996 and 2000 were recruited for our study ( Table 1).

The average follow-up duration was 11.3071.22 years. Adoles-cents with AR had greater prevalence of developing MDD (2.5% vs.

1.2%, po0.001) during the follow-up period, and an earlier MDD

onset (19.3172.91 vs. 20.4372.71 years,   p¼0.038) than the

controls. When broadening the diagnosis of MDD to any depres-

sive disorder, adolescents with AR still exhibited a higher rate of 

depression (4.9% vs. 2.8%,   po0.001) and earlier disease onset

(19.3572.63 vs. 20.4372.62 years,   p¼0.002) than the control

group. In addition, the prevalence of allergic comorbidities,

including asthma (20.9% vs. 1.3%,   po0.001), AD (9.4% vs. 3.2%,

 po0.001), and AC (38.4% vs. 17.3%,  po0.001) in the AR patient

group was higher than in the control group.

 3.2. Hazard ratio for MDD and depressive disorder 

Two Cox regression models were used to examine the risk of 

AR patients developing MDD and depressive disorder (Table 2).

Model 1 showed the adolescents with AR had increased HRs of 

developing both MDD (HR: 2.03, 95% CI: 1.39–2.95) and depres-

sive disorder (HR: 1.75, 95% CI: 1.35–2.67) in late adolescence and

early adulthood compared to the control group. Model 2 demon-

strated that a significantly increased HRs of developing both MDD

(HR: 1.59, 95% CI: 1.02–2.50) and depressive disorder (HR: 1.42,

95% CI: 1.04–1.93) still existed even after controlling for comorbid

allergic diseases. Furthermore, in the Cox regression model 2,

asthma (HR: 1.51, 95% CI: 0.84–2.72), AC (HR: 1.32, 95% CI: 0.88–

1.98), and AD(HR: 1.45, 95% CI: 0.74–2.82) did not exhibit

the elevated risk of developing major depression. But if broad-

ening the diagnostic criteria of depression, AC (HR: 1.43, 95%

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CI: 1.09–1.87), but asthma (HR: 1.42, 95% CI: 0.94–2.15) and AD

(HR: 1.13, 95% CI: 0.68–1.87) were prone to develop any depres-

sive disorder in the later life.  Fig. 1 showed the survival curves of 

major depression and any depressive disorder among adolescents

with or without AR after controlling for age, gender, residence

location, and comorbid allergic diseases.

4. Discussion

A relationship between allergic disease and depression has

been proposed for many years. Many cross-sectional studies have

proved this association, but those studies cannot clarified the

temporal relationship that determines which one or the other

diseases develops first and substantially impacts the other or

whether they develop simultaneously and interact together(Cuffel et al., 1999;   Timonen et al., 2002;  Patten and Williams,

2007; Sansone and Sansone, 2011; Slattery and Essex, 2011). The

longitudinal study provides an opportunity to clarify the possible

temporal sequence. Our results supported the study hypothesis

that adolescents with AR had an increased risk of depression in

late adolescence and early adulthood. The significance still

existed even after controlling for age, gender, residence location,

and comorbid allergic diseases.

Regarding the clinical aspects of AR and the related adverse

effects, Scadding and Williams (2008) demonstrated that patients

with AR reported an impact of AR on daily activities, and that

health-related quality of life (HRQoL) was negatively correlated

with disease severity. In a European multi-country study focusing

on the burden of AR, Canonica et al. (2007) assessed 1482 patients

with AR and showed that a large proportion of patients had

moderate-to-severe disease (67.2%) and persistent disease

(42.5%), and that the disease severity significantly impacted their

general well-being and HRQoL . The US survey reported similar

results that AR severity and the persistence of allergic symptoms

were significantly related to the impairment of HRQoL (Schatz,

2007). Stress from this chronic poor quality of life and the

disturbing allergic symptoms resulted in many cognitive and

emotional adverse events. Juniper et al. revealed that adolescents

with AR had more symptoms of attention difficulty, psychomotor

slowing, poor sleep, daytime tiredness, irritability, anxiety, and

depression ( Juniper and Guyatt, 1991; Juniper et al., 1994).

Another potential explanation, a shared genetic susceptibility

to both allergies and depression, may contribute to this phenom-

enon of comorbid AR and depression. Surveying the major

histocompatibility complex genes on chromosome 6,  Weitkamp

and Stancer (1989)  showed that HLA-region genes contribute to

the susceptibility to major depression.   Smeraldi et al. (1978)

studied several HLA genes and demonstrated that significant

increases were found in HLA-A29 and HLA-BW22 frequencies in

those with affective disorders when compared with the control

group. However, this genetic evidence cannot explain a core

question. If there is a shared genetic susceptibility, why do

allergic diseases develop first (usually during childhood and

adolescence) and depression follow sequentially (usually during

late adolescence and early adulthood)? Why don’t they occur

simultaneously? This unanswered question implies there are

some other mechanisms involved in the comorbidity between

allergic diseases and depression. A cytokine-related mechanism

has been proposed.

A chronic allergy response-related immune dysregulation

and abnormality, such as a predominantly T helper type 2 (Th2)

cytokine secretion, may contribute to the elevated vulnerability todepression (Kira, 2002;   Agrawal and Bharadwaj, 2005;   Bieber,

2008). Similar to allergic diseases, levels of circulating proinflam-

matory cytokines are usually elevated in depression; these

cytokines include interleukin 1 (IL-1), IL-6, and tumor necrosis

factor   a (Benson et al., 2001; Scavuzzo et al., 2003; Krishnan and

Nestler, 2010). But, the elevated cytokine profiles in depressive

disorder were not consistent in the previous studies (Raison and

Miller, 2011; Einvik et al., 2012). For example, Einvik et al.(2012)

failed to find significant difference in the levels of several

cytokines (i.e., IL-1b, IL-2, IL-6, and tumor necrosis factor-a)

between persons with and without MDD . Furthermore, some

evidence suggests that a dysregulated secretion of inflammatory

cytokines during an allergic response would pass the blood–

brain barrier (Yarlagadda et al., 2009) and activate abnormal

 Table 2

Cox regression models for major depression and depressive disorder.

Model 1a Model 2b

Major depression

HR 2.03 1.59

95% CI 1.39–2.95 1.02–2.50

 p-value   o0.001 0.043

Any depressive disorder

HR 1.75 1.42

95% CI 1.35–2.67 1.04–1.93

 p-value   o0.001 0.026

HR: hazard ratio, CI: confidence index.

Major depression: ICD-9-CM codes of 296.2X and 296.3X. Any depressive disorder:

ICD-9-CM codes of 296.2X, 296.3X, 300.4, or 311.a Adjusted by residence location.b Adjusted by residence location and comorbid allergic diseases.

 Table 1

Demographic characteristics of patients with allergic rhinitis and control group.

Patients (n¼1673) Controls (n¼6692)   p-Value

Age (year) 25.80(1.35) 25.80(1.35)

Gender (M, %) 932(55.7) 3728(55.7)

Age at recruitment (year) 13.13(1.30) 13.13(1.30)

Major depression (n, %) 41(2.5) 81(1.2)   o0.001

Age at diagnosis (year) 19.31(2.91) 20.43(2.71) 0.038

Duration between the enrollment and major depression (years) 6.37(2.92) 7.16(2.54) 0.125Any depressive disorder (n, %) 82(4.9) 190(2.8)   o0.001

Age at diagnosis (year) 19.35(2.63) 20.43(2.62) 0.002

Duration between the enrollment and any depressive disorder (years) 6.29(2.58) 7.15(2.41) 0.009

Allergic comorbidity (n, %)

Asthma 488(29.2) 87(1.3)   o0.001

Atopic dermatitis 157(9.4) 217(3.2)   o0.001

Allergic conjunctivitis 643(38.4) 1161(17.3)   o0.001

Major depression: ICD-9-CM codes of 296.2X and 296.3X.

Any depressive disorder: ICD-9-CM codes of 296.2X, 296.3X, 300.4, or 311.

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neuroimmune mechanisms involving some specific neural cir-

cuits related to emotional modulation (Raison et al., 2006). For

example,   Rosenkranz et al. (2005)   using functional magnetic

resonance (fMRI), demonstrated an activation of the anterior

cingulate cortex (ACC) and insula in patients suffering from

allergic episodes, compatible with what has been reported in

depression (Konarski et al., 2009). Ishiuji et al. (2009)  found that

patients with active atopic dermatitis exhibited bilateral activa-

tion of the ACC, posterior cingulate cortex (PCC), and dorsolateral

prefrontal cortex (DLPFC). Dysfunction of the DLPFC and ACC has

been suggested to play an important role in depression (Konarski

et al., 2007; Li et al., 2010; Hamani et al., 2011; Du et al., 2012;

Zeng et al., 2012). Moreover,   Reeves et al. (2007)  proposed a

possible link among allergic diseases, adolescent depression, and

suicide and described an increased rate of nonviolent suicide and

depression in females in spring, during intervals of high tree

pollen, compared with similar intervals of low tree pollen. In our

study, after adjusting for comorbid allergic diseases (i.e., asthma,

AD, and AC), adolescent with AR still had the elevated risk of 

developing major depression or any depressive disorder in their

late adolescence and early adulthood. Our results supported a

temporal association between allergic disease and depressive

disorder. Allergy-related neuroimmune changes, as in a vicious

cycle, take time to impair the specific brain function and neural

circuitry involved in emotional regulation and cognition, which

may explain the sequential phenomenon of allergic diseases

developing first and depression following. However, despite allparticipants having no any psychiatric disorder before the enroll-

ment time in our study, one more concern must be mentioned

that depression can be atypical in its clinical presentation and

more difficult to be diagnosed in children, which may be one of 

explanations why depressive disorder followed AR even if they

had the shared etiologic factors. Reeves et al.’s hypothesis and our

result may inspire further study to elucidate the impact of AR on

specific brain regions, and clarify the underlying mechanism of AR 

and the development of depression.

Some study limitations need to be addressed. First, the preva-

lence of depressive disorder may be underestimated because only

those who had medicine-seeking behaviors were enrolled. However,

the subjects enrolled in our study had board-certified physicians’

diagnoses, yielding better validity than the previous studies with

self-reported questionnaires. Second, the national health insurance

database did not provide some information, such as disease severity,

personal lifestyle, and environmental factors. Without this informa-

tion, we were unable to examine the influence of these factors.

Third, NHIRD is an anonymous database to protect personal medical

privacy. We cannot know who the parent or other family of specific

enrolled adolescent is. The information about parents, siblings, or

other family (i.e., the family history of psychiatric disorders or

allergic diseases, and the socioeconomic status of the parents) was

not provided.

5. Conclusion

This is the first longitudinal study to establish the association

between AR in early adolescence and depression in late adoles-

cence and early adulthood. Our results suggest that allergic

responses played important roles in the development of depres-

sion, and may inspire further study to investigate whether proper

treatment of allergic diseases could decrease the long-term risk of 

depression.

Role of funding source

Funding source: The study was supported by grant from Taipei Veterans

General Hospital (V101D-001-1).

Conflict of interest

There is no conflict of interest.

 Acknowledgment

We thank Dr. M.H.C. and Dr. Y.M.B., who designed the study, wrote the

protocol and manuscripts, Dr. Y.M.B., Dr. T.P.S., Dr. Y.S.C., Dr. J.W.H., and Dr. K.L.H.,

who assisted with the preparation and proof-reading of the manuscript, and

Dr. Y.M.B. and Ms. W.H.C. provided the advices on statistical analysis.

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