Factors accounting for the association between anxiety and depression, and eczema: the Hordaland health study (HUSK)

The field of psychodermatology addresses the interaction between skin and mind, and the association between anxiety and depression, and eczema is well documented in the literature [1–8]. However, despite of numerous hypotheses, there is still surprisingly little empirical evidence for mechanisms involved in this association.

Omega-3 fatty acid level has been suggested to be a possible contributing factor in the association between depression and atopic eczema [7]. This hypothesis is inspired by reports of low levels of omega-3 fatty acids in blood and development of atopic disease [9], and reports of low dietary intake of omega-3 fatty acids and depression [10–12].

Timonen and colleagues have suggested that the association between atopic disorders and depression is limited to females only. This is based on their findings in two large, population-based studies, where women suffering from atopic diseases, compared with nonatopic subjects, were found to possess an elevated risk for developing depression [7, 13]. A corresponding association was not found among males. Timonen and colleagues also propose that parity and female hormones may contribute in the association between depression and atopic disorders such as eczema [7, 13]. This is based on reports of associations between parity and gestational age, and atopic disorders [14], and associations between multiparity, atopy, and depression [15].

A substantial part of the psychodermatological literature has focused on atopic forms of eczema, and many of the above referred hypotheses concerning possible explanatory factors for the association between anxiety and depression, and eczema presuppose the involvement of atopy (elevated levels of IgE, in addition to "atopic symptoms" [16]) as a part of the aetiological chain underlying this association. On this basis, we considered IgE levels as a possible explanatory factor in the association between anxiety, depression, and eczema, but we recently published that there is no association between IgE levels, and anxiety and depression [17]. On the basis of this nil finding, IgE levels cannot be a mediating or confounding factor in the association of interest. Therefore, we decided not to include analyses of IgE in this manuscript.

According to Koo and Lebwohl, disfiguring skin conditions can lead to psychological problems such as decreased self-esteem, that may lead to depression or symptoms of social phobia [1]. Several reports have emphasized psychological mechanisms beyond anxiety and depression, that may contribute in eczema: Eczema may be worsened by emotional stress [1], and some reports claim that eczema patients are more prone to express psychosomatic symptoms than normal controls [18]. According to a recent review by Gupta, a wide range of somatization-related symptoms are found in dermatological patients [19]. A according to the World Health Organisation (WHO)'s International Classification of Diseases, 10th revision (ICD-10), somatization is a mental disorder characterized by experience of somatic symptoms without known organic etiology, where symptoms often spread across organ systems, and vary over time [20]. Whereas, somatization disorder is rare in the general population, sub-clinical tendency of somatization is common. There are also reports of higher prevalence of hypochondria symptoms in eczema patients than in normal controls [21]. Hypochondria is an old clinical concept referring to exaggerated health anxiety (health-related worry and fear) and inadequate beliefs of suffering from a serious medical disease [22]. It is well known that anxiety and depression often are associated with both somatization and health anxiety [23–25], but, according to ICD-10, comorbidity with anxiety and/or depression is not a criterion for the diagnosis of somatization disorder. Due to the reported associations between eczema, and anxiety, depression, somatization and health anxiety, it is possible to suggest that somatization and health anxiety could be contributing factors in the association between anxiety and depression, and eczema, but as far as we know, this has not been previously investigated.

Most studies within the field of psychodermatology are based on clinical samples, commonly recruited from dermatological clinics. Such studies are often criticized for low statistical power and multiple selection biases. On the other hand, the advantage of clinical studies is the presumed good reliability of diagnoses of eczema, anxiety, and depression. Compared to clinical studies, epidemiological population-based studies are less vulnerable to selection bias and are commonly more generously powered. There are few epidemiological population-based studies within the psychodermatological field; among the exceptions are Timonen and colleagues [7, 8, 13, 26].

Despite the broad range of hypotheses concerning the association between anxiety and depression, and eczema, empirical support is scarce for most of them. The aim of the present study is therefore to examine the relevance of proposed contributing factors for the association between anxiety and depression, and eczema, including omega-3 fatty acid supplement, female gender, health anxiety, and somatization.

The present study confirmed previous findings of an association between anxiety and depression, and eczema [2–8, 47–49]. But more important, the study adds to the current knowledge on the understanding of possible contributing factors in this association. Somatization and health anxiety accounted for about half of the association between anxiety/depression, and eczema, and the associations of interest were insignificant after this adjustment. Female gender and omega-3 fatty acid supplements have in psychodermatological literature been proposed as contributing factors relevant for the association of between anxiety, depression, and eczema, but we were unable to provide empirical support for these hypotheses.

The present study has several strengths, one of them being the epidemiological population-based design avoiding selection biases commonly found in clinical contexts.

Among the most important limitations to our study is the self-report of eczema, which precludes sub-classification beyond report of body area involved. Theoretically, several forms of eczema could be included in the eczema group due to the general form of the eczema questions used in our study. It is not uncommon, however, to employ a wider definition of eczema in large epidemiological studies. In a study by Hanifin and Reed, [50] the term "empirical eczema" was defined by several skin symptoms that resemble the skin symptoms listed in the HUSK questionnaire used in our study. Further, the validity of several self-reported skin complaints against clinical signs was explored in a Norwegian, population-based, validation study [51], finding that self-reported skin complaints can be a valid tool for quantifying and exploring skin diseases at population level. The use of self-reported eczema represents a risk of misclassification (both false positive and false negative cases compared to the result of a clinical examination), resulting in an underestimation of the true strength of the association. Meding and colleagues reported good agreement between patients' self-report of hand eczema and dermatologists' judgements [37, 38]. Validation of the question "have you had hand eczema on any occasion during the last 12 months" indicated false negative answers among 10-12.5% of the participants [38]. This population survey is comparable to our present study, indicating similar extent of misclassification.

Another objection to our study, could be that hand eczema is a singular clinical entity, and that the reliability and validity of self-reported hand eczema cannot be generalized to eczema in other areas of the body. However, we have no reason to assume the validity to be poorer for other forms of self-reported eczema. In our analyses we compared face, hand and body eczema and their association to mental health, finding that the association was not restricted to special sub-types of eczema. Future studies of the validity of self-reported face and body eczema might be warranted, but while awaiting these, we have to assume that the validity of self-reported hand eczema can be generalized to other body areas.

The use of HADS for assessment of anxiety and depression also implies self-report rather than clinical examination. Misclassification cannot be excluded, but is likely to have been random; again resulting in an underestimation of the true association.

Another important limitation to our study is the use of a cross-sectional design, precluding inferences regarding causality for the association between anxiety and depression, and eczema. Employing a cross-sectional design, it is not possible to determine whether psychological symptoms can result from eczema, or if such symptoms are part of the causative chain for skin disease.

How can we interpret the finding that somatization and health anxiety explain most of the association between anxiety and depression, and eczema? One possibility is that health anxiety might represent selective attention to common somatic symptoms [52–54], which again might increase self-report of eczema. An alternative explanation could be that anxiety, depression, health anxiety and somatization are all a consequence of the burden of suffering from chronic eczematous conditions. Another explanation involves the possibility of a common factor in anxiety, depression, health anxiety and somatization which are correlated to eczema. In this perspective, our finding that somatization and health anxiety account for much of the association between anxiety/depression, and eczema might be regarded an artefact resulting from over-adjustments. However, the finding that somatization is more strongly associated to eczema than anxiety/depression makes us speculate that the association between anxiety/depression, and eczema is actually driven by somatization. Further, the large confounding effect of the somatization variable might indicate that it actually (at least partly) represents somatization, as primary adjustment for somatic diagnoses hardly attenuated the association. This does obviously not equivalence to clinical examinations. Adjustment for somatic diagnoses prior to symptoms of somatization, in the association of interest, was our attempt to exclude organic aetiology in somatization. Using an index based on questions derived from the somatization diagnostic criteria doesn't have the same validity as employing a validated instrument, but to the best of our knowledge, there is yet no well-validated and widely used instrument for somatization. Acknowledging the limitations of our measure; adjustment for somatization (on top of somatic diagnoses) explained about forty percent of the association of interest.

According to Koblenzer [55] the common origin of the skin and the central nervous system (CNS) from the embryonic neuro-ectoderm could explain the ongoing two-way physiologic communication between emotional input, CNS functioning, and cutaneous expression. Continuing Koblenzer's line of thought, it might be speculated that some forms of eczema and somatization may be mediated through a common immunological factor. A possible common immunological factor in eczema and somatization could be cytokines, which are known to be involved in the immunological mechanisms underlying eczema [56] and suggested by Dantzer [57] to underlie somatization. Dantzer suggests that stress (psychological included) can induce sensitization of the cytokine system in the brain, which further may lead to symptoms of mood disorders (anxiety and depression), and expression of somatic symptoms that resemble those seen in somatization [57]. According to ICD-10 [20], some skin symptoms (skin spots and discoloration of the skin) are already included in the symptom list for F45, somatization disorder. So, another possibility could be that somatization may lead to psychological stress reactions in the body, and psychological stress has been found to worsen or trigger outbursts of eczema [1].

Omega-3 fatty acid intake is also hypothesized to account for the association of interest [7, 12, 13], but our results provide no support for this hypothesis. It might be objected that omega-3 fatty acid intake was measured by self-report of dietary supplements (cod liver oil) only, and in fairly moderate doses, further omega-3 fatty acid content in regular diet was not accounted for. There are obvious limitations to our omega-3 fatty acid measure, possibly reducing expected effect sizes. However, if omega-3 fatty acid intake was a major factor in explaining the association, we would expect at least some attenuation of the association of interest. Further, we cannot exclude the possibility that a higher daily intake of omega-3 fatty acids than reported in this study is needed to demonstrate a mediating effect.

A gender-specific association between eczema and depression has been suggested by Timonen et al. [7, 13, 26]. Stratified analyses by gender, and testing of the interaction-term eczema by gender did not support this hypothesis, even if one significant gender-interaction was found across 12 analyses, but in this analysis the association between hand eczema and depression was stronger in men than in women, the opposite of Timonens hypothesis.

In the light of an epidemiological population-based study we have been able to examine several of the suggested contributing factors in the association between anxiety/depression, and eczema. The lack of support for different candidate explanations for the association of interest might be somewhat surprising. We note that somatization and health anxiety accounted for most of the association. The literature on somatization in eczema is scarce, and should be examined more thoroughly in future studies. Beyond the candidate explanatory factors discussed here, we are left with speculations as to biological mechanisms involved. Future research into the aetiology underlying the association between anxiety and depression, and eczema might benefit from including the concept of somatization and health anxiety.

The current study confirmed previous findings of an association between anxiety and depression, and eczema, but somatization and health anxiety accounted for more than half of the association of interest, and the association was insignificant after this adjustment.

We found no support for previously suggested contributing factors in the association between anxiety/depression, and eczema such as omega-3 fatty acid supplement and female gender.