Several studies have suggested an association between IgE-mediated atopic allergies and depression. The present study extends our understanding about putative gender differences of this association and provides further epidemiological evidence for our previous finding that the association between atopy and depression may be characteristic for females only. In order to clearly determine the presence of atopic disorders and depression, we used more valid tools than had been employed earlier and we had access to a database (the Northern Finland 1966 Birth Cohort), in which individuals were followed up prospectively until the age of 31 years. The information on allergic symptoms, verified by skin-prick tests and comprising data of 5518 individuals, was used to ascertain the presence of atopy. Depression was assessed with the help of Hopkins' Symptom Checklist-25 and self-reported doctor-diagnosed depression. After adjusting for a father's social class, mother's parity, and place of residence, logistic regression analyses showed that the risk of developing depression increased in parallel with the increasing severity of depression and, when compared with nonatopic subjects, was 3.0 to 4.7-fold up in atopic females and statistically significant. In atopic males, the association between atopy and depression was statistically significant only in the highest depression scores, the odds ratio being 6.3-fold. The results indicate that females suffering from atopic diseases might possess an elevated risk of developing depression already during early adulthood. In males, the association between these two disorders is evident only among the most severe manifestations of depression. Possible background theories, that is, genetic abnormalities in serotonin metabolism, HPA-axis dysfunction, and histamine theory are discussed.
Several lines of evidence suggest that there exists an association between depression and atopic allergies (ie, asthma, atopic eczema and allergic rhinitis).1,2,3,4 An excess of IgE-mediated allergies has been found in patients with depression,1 and conversely, increased amounts of depressive symptoms have been reported in patients suffering from atopic disorders.2,3 Since atopic allergy itself is an IgE-mediated immune system disorder and depression has been shown to be associated with changes in altered immunity,5,6,7,8,9 it has been postulated that certain immune mediators, for example cytokines, contribute to the mechanism behind both allergic and depressive symptoms.10,11,12,13
First-degree relatives of asthmatic children apparently exhibit high rates of depression.14,15 Wamboldt et al16 have provided support for the hypothesis of a shared genetic factor between atopy and behavioral as well as emotional symptoms in a study of juvenile twins, and later between atopy and depression involving an adult twin sample.13
We have previously demonstrated, at epidemiological level, that hospital-treated atopic disorders increase the risk of developing a severe, hospital-treated depression up to three-fold in males and females,17 and that clinically manifest atopic disorders increase the risk of self-reported doctor-diagnosed depression up to 2.7-fold in females, but not in males.18 These findings urged us to investigate now for the first time, whether the sex-specific association between atopic disorders and depression is dependent on the severity of depression. In the present study, we were able to use more accurate tools to define the presence of atopic disorders and depression. The presence of atopy was verified by skin-prick tests and by questionnaires. The severity of depressive symptoms in cohort members, who had been suffering from self-reported doctor-diagnosed depression, was assessed with the Hopkins' Symptom Checklist-25 (HSCL-25). These diagnostic tools and an access to the genetically homogenous Northern Finland 1966 Birth Cohort database enabled us to carry out the research.
Materials and methods
The Northern Finland 1966 Birth Cohort study is comprised of an unselected, genetically homogenous general population: in the two northernmost Finnish provinces, that is, Oulu and Lapland, 96% of all women (n=12 068), with an expected date of delivery falling between 1st January and 31st December in 1966, were evaluated and they gave birth to 12 058 live infants. A variety of biological, socioeconomic and health-related conditions, as well as living habits and family characteristics of the cohort members, were collected prospectively through prenatal stages up to the age of 31 years. A detailed description of the data has been presented in several previous studies.19,20 In connection with a 31-year follow-up survey, written consent from all cohort members was requested. The Ethics Committee of the Faculty of Medicine, University of Oulu (Finland), approved the study.
In the 31-year follow-up during 1997–98, 8463 cohort members, who were living in northern Finland or in the capital area, were sent postal questionnaires and invited to undergo a clinical examination; 6025 (71.2 %) attended. Skin-prick tests to three of the most common allergens in Finland (ie, cat, birch, and timothy grass) and the house dust mite (Dermatophagoides pteronyssinus) were carried out. In these tests, histamine dihydrochloride (10 mg per ml) and diluent of the allergen extracts were used as positive and negative controls, respectively. After 15 min, skin reactions to each allergen were recorded as the average of the maximum wheal diameter and the diameter perpendicular to the maximum. Subjects with a wheal reaction ≥3 mm to one or more of the four allergens tested were considered to be prick-test positive. Of all the prick-tested persons, 36 with positive reactions to the negative control were excluded. All subjects had a positive reaction to histamine.
In clinical practice, the presence of atopy requires not only positive skin-prick tests but also clinical symptoms of allergy.16 Therefore, we utilized additional data on a cohort member's history of allergic diseases, which were obtained through the above-mentioned postal questionnaires. Each person was asked to give his/her own estimate of the presence (yes/no) of the following allergic disorders/symptoms: asthma, allergic rhinitis, atopic eczema, and/or allergic conjunctivitis. Symptoms of allergies were considered to be present if a cohort member had at least one of these allergic disorders/symptoms.
Information of depression was determined through HSCL-25, which is a 25-item shortened version of an originally 90-item questionnaire designed by Degoratis et al.21 A depression subscale consists of 13 items. Cohort members recorded their estimate of severity of their depressive symptoms on a scale ranging from 1 (‘not at all’) to 4 (‘extremely’). Responses were summed and divided by the number of answered items to generate a depression mean score ranging from 1.0 to 4.0. This mean score was utilized to assign the cohort members to subgroups according to the severity of their depressive symptoms. In addition to the two commonly used mean scores of 1.55 and 1.75,22,23 a cutoff point of 2.01 was also used. This cutoff point was included into statistical analyses, because it is known that the duration of symptoms is an essential factor in the diagnoses of major depressive disorders, and because Winokur et al24 have found that patients, who were considered to be highly symptomatic (ie, had a score >2.0), showed more consistent ratings over a whole follow-up period than subjects with lower cutoff points.
Data on self-reported doctor-diagnosed lifetime depression was also obtained from these postal questionnaires: a cohort member was asked ‘whether he/she had ever been diagnosed by a doctor as having depression’ (yes/no).
In previous studies, socioeconomic status, dwelling place and mother's parity, were shown to be associated with atopic disorders25,26,27 and depression.28,29,30 Therefore, dwelling place and father's social class in 1966, as well as mother's parity were evaluated as potential confounding variables.31
The final number of cohort members, who had not denied the use of the collected data on them for scientific purposes and whose completed variable information was available, was 5518 (2735 males, 2783 females). The continuation ratio model was used to estimate the association between outcome and allergic symptoms verified by skin-prick tests. This model partitions the analysis of the outcome variable into three different logistic regression models for dichotomous responses.32 Nondepressive subjects in the outcome variable consisted of those cohort members who had neither self-reported doctor-diagnosed lifetime depression nor depressive symptoms in the HSCL-25 depression subscale (mean score=1.0). The final models used odds ratios (ORs) and 95% confidence intervals (95% CI) after controlling for dwelling place, father's socioeconomic status and mother's parity in 1966. The data were subjected to statistical analyses using the SAS software (version 8e) for Windows.
Table 1 demonstrates the proportions of depressive cohort members in each exposure group according to HSCL-25 depression subscale scores separately for males and females. In females, an association between depression and atopy was clearly apparent: those suffering from allergic symptoms, verified by skin-prick tests, always had higher proportions of self-reported doctor-diagnosed depressions than prick-test-negative females without allergic symptoms. In males, the same association was only seen in the highest HSCL-25 subgroup (mean HSCL-25 scores >2.0).
After adjusting for confounders, the results of the logistic regression analyses (when three different cutoff points for the HSCL-25 subscale for depression were utilized) showed that the risk of self-reported doctor-diagnosed depression ranged from 3.0 to 4.7-fold in females, when compared with skin-prick test-negative subjects without allergic symptoms (Table 2). This adjusted risk rose, furthermore, in line with the increased severity of depression in atopic but not in nonatopic females. Among males the corresponding statistically significant association was seen only in the highest depression scores (mean HSCL-25 score over 2.0), the adjusted OR being even 6.3-fold.
Our findings, based on data from the Northern Finland 1966 Birth Cohort, provide firm support to the findings of previous studies13,14,15,16,17,18 concerning an association between depression and atopic disorders. The results of this 31-year prospective follow-up, moreover, suggest that in females the presence of atopic symptoms, verified by skin-prick tests, increase the risk of depression up to 4.7-fold when compared with nonatopic female cohort members. The phenomenon was even apparent with less severe depressions determined through the lower commonly used cutoff point of the HSCL-25.
Some biological explanations are possible: cytokines play a critical role in the pathogenesis of allergic diseases.33,34 Besides acting as chemical messengers between immune cells, cytokines can serve as mediators between the immune system and the brain.33,35 In atopic states, there exists a shift from T helper (Th) 1 to Th2 responses from Th lymphocyte precursors.36 Of the cytokines produced by Th2 cells,33,34 interleukin-4 (IL-4) is an essential mediator of immediate hypersensitivity favoring the production of immunoglobulin E.37 IL-4 has, furthermore, been shown to have an effect on the serotonin (5-HT) metabolism, but different regulatory effects on different serotonin transporter (5-HTT) genotypes.12 Because 5-HT is an important mediator of bidirectional interactions between the nervous and the immune systems,12,38 and because the genetic polymorphism in the 5-HTT gene promoter has been found to be associated with depression,39 our findings might be explained by an altered 5-HT metabolism in the brain because of some immunological reactions during atopy.
At the time of an immune response, brain and immune system communicate with each other in order to maintain homeostasis in the body.33,40 Two major pathways, the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS), are involved in this bidirectional interaction.38,40 During allergic hypersensitivity reactions, proinflammatory cytokines such as IL-1β and IL-6 are released by the IgE-mediated stimulation of tissue mast cells and basophils.37,41 In addition to contributing to allergic inflammation, these proinflammatory cytokines are capable of activating both the SNS and the HPA axis.40,41 The end products of this ‘stress system’—glucocorticoids and catecholamines—cause a selective suppression of Th1 responses and a Th2 shift by inhibiting the production of IL-12 and by favoring the production of IL-10.40,42 Proinflammatory cytokines themselves can cause dysfunction of corticosteroid receptors,43,44,45 which together with hypercortisolism are usually present in states of depression.46,47 In addition, both IL-1β and IL-6 have the capacity to induce a syndrome of ‘sickness behavior’ that shares many features with major depression, including anhedonia, fatigue, anorexia, reduced activity, and altered sleep patterns.35,44 On the other hand, there is also evidence that psychosocial stress can suppress cellular immunity, but boost humoral immunity by causing a Th2 shift via these same stress hormones, that is, glucocorticoids and catecholamines.42
The histamine metabolism could also have been involved, for histamine is released from the cytoplasmic granules of activated mast cells during immediate hypersensitivity reaction. As a biogenic amine, histamine is mediating a variety of biological effects:37 via stimulation of H2-receptors, histamine has been shown to be capable of suppressing IL-12 and stimulating IL-10 secretion,48 thereby causing a shift of the Th1/Th2 balance toward Th2-dominance.40,49 It is, furthermore, known that histamine has various physiological roles as a neurotransmitter in the brain and that in the histaminergic neuronal system three different receptors exist:50 postsynaptic histamine H1 and H2 as well as presynaptic H3. Histamine turnover in the diencephalon has been suggested to be related to the pathology of the depressive state by Ito et al51 and histamine H3 receptor antagonists have been shown to possess antidepressive effects.50 Furthermore, H1 receptor antagonists, commonly called antihistamines, also have (a) immunological effects since they inhibit the immediate wheal and flare response to intradermal allergens37 and (b) psychological effects, for they are known to decrease the anxiety state of a person.50
Changes in polyunsaturated fatty acid (PUFA) intake or metabolism can also be linked to the findings: because PUFAs are either precursors of eicosanoids, such as prostaglandins, or affect eicosanoid and cytokine formation, they have important effects on immune and inflammatory processes. An increased ratio of omega-6 to omega-3 PUFAs may lead to an overproduction of inflammatory cytokines and eicosanoids, which contribute to the allergic inflammation, and which are also associated with major depression.34,43 Evidence has been accumulating that diminished omega-3 fatty acid intake or concentrations are associated with depressive disorders,52,53,54 and persons with atopic disorder have been noted to have low levels of omega-3 fatty acids in their plasma and red cell membranes.55 On the other hand, fatty acids of omega-3 type have anti-inflammatory effects by reducing the production of inflammatory cytokines/eicosanoids, which forms the basis for their use in the management of inflammatory diseases.34 Correspondingly, highly purified ethyl eicosapentaenoic acid, an omega-3 fatty acid, has also been shown to be effective in improving major depression even in two randomized, placebo-controlled studies.56,57 Unfortunately, fatty acid intake was not used as a confounding factor in this study, but we recommend that it should be taken into account in future studies of this nature.
Among atopic males, the only statistically significant association was seen in those cohort members suffering from the most severe manifestation of depression measured with HSCL-25. In these men, the risk of depression was extremely high, adjusted OR reaching up to six-fold higher level. These results extend our earlier findings on gender differences in the depression–atopy association. Only recently we had noted that atopic disorders, verified with the help of skin tests, were associated with depression only in females, but the severity of the depression was not measured in that study.18
There are some explanations for the gender difference, that is, the fact that in females the association between the disorders is evident independent of the severity of depression and that among males it is only seen in the presence of the most severe manifestations. It has been suggested that atopic disorders and depression share a common genetic etiology.13 Since there is evidence that in women genetic factors play a greater role in the etiology of depression than in men,58,59 we speculate that even the pathophysiology of the atopy-depression association could have arisen from different origins in females and males. For example, with respect to the serotonin metabolism, Enoch et al60 have recently established that the 5-HT(2A) promoter polymorphism is associated with affective disorders in women but not in men. Because IL-4 has been shown to have an effect on the 5-HT metabolism,12 it can be hypothesized that there might be an association between immediate hypersensitivity reactions with serotonin-related mental disorders and the female gender. On the other hand, there is evidence that subtypes of depression may differ with respect to some immune parameters.7 Thus, it could be possible that in men, minor depression could have different pathophysiological roots than those of major depression, which could explain the lack of the atopy association among less depressive men. In addition, it is also possible that men have under-reported depression and/or were unable to recognize their symptoms correctly and this could have caused a bias in our results. In this same set of birth cohort data, it has previously been possible to show that the prevalence of alexithymia was higher in men (9.4%) than in women (5.2%).61 Further, since alcohol abuse and violent behavior, for example, can be signs of psychosocial distress,62 we think that ‘masked depression’ might be a manifestation of minor depression in predominantly men rather than in women.
The major limitations of our study were that self-report rating scales such as the HSCL-25 conducted at one time point (in this study at the age of 31 years) give a very limited approximation of lifetime depression of cohort members, and does not provide a specific depression diagnosis. Also, questionnaire studies might be biased because of the interindividual differences in reporting about symptoms. However, in addition to HSCL-scores we were able to use the self-reported doctor-diagnosed lifetime depression data. In spite of the fact that we were not aware of the exact diagnosis of the self-reported depression or when exactly a cohort member had been treated by a doctor owing to depression, our findings about the highly symptomatic cohort members (that is, having HSCL-25 depression subscale scores in excess of 2.0) together with the doctor-diagnosed depression mean that those cohort members have very likely had before the age of 32 years, a major depression—either a single episode or a recurrent one. In statistical analyses, false-positive depression cases may exist because of other psychiatric disorders such as personality disorders and substance use disorders. In addition, data on IgE or cytokine and other immunomediator profiles were also lacking.
The strengths of our study were that firstly, it was based on a large, unbiased and genetically homogenous prospectively followed-up birth cohort. Secondly, skin-prick tests are one of the best objective assessments for demonstrating an IgE-mediated mechanism underlying clinical atopic symptoms.63 In our study material, the detection of atopic disorders was based on positive responses from skin-prick tests. We, therefore, can expect that, with regard to atopy, only a very small number of false-positive cases may have been included. Thirdly, HSCL-25 has proved to be an acceptable screening scale in obtaining information on symptoms of depression in the normal population.23
In conclusion, we found in both genders a strong association between atopic disorders and depression, verified by high scores of the HSCL-25 depression subscale. Thus, it is possible that our findings, related to the gender differences, are a reflection of some psychosocial factors such as possible differences in treatment seeking between males and females suffering from minor depression. Because of the fact that in females the association between atopy and depression was seen independent of the severity of depressive symptoms measured with HSCL-25, we strongly suggest that in future studies the gender difference should be taken into account while investigating the association between these two disorders.
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This study was supported by grants from the Allergiatutkimussäätiö (Foundation of Allergy Research).
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Timonen, M., Jokelainen, J., Hakko, H. et al. Atopy and depression: results from the Northern Finland 1966 Birth Cohort Study. Mol Psychiatry 8, 738–744 (2003). https://doi.org/10.1038/sj.mp.4001274
- cohort study
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