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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: [email protected] (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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