| The association between atopic disorders and depression: The Northern Finland 1966 Birth Cohort Study | ||
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The findings of this thesis, based on extensive birth cohort data, show that there is an association between atopic disorders and depression at epidemiological level: In general, the existence of an atopic disorder increases the risk of both self-reported lifetime and hospital-treated depression about two- to three-fold when compared with an absence of atopic disorders. Thus, the results of this thesis provide firm support to the findings of previous studies concerning the association between these two disorders (Nasr et al. 1981, Sugerman et al. 1982, Bell et al. 1991, Wamboldt et al. 1996, 1998, 2000, Hashiro & Okumura 1997, 1998, Cuffel et al. 1999, Hurwitz & Morgenstern 1999, Brown et al. 2000, Centanni et al. 2000, Goethe et al. 2001).
The interpretation of the results of different earlier studies concerning the association between atopic disorders and depression is hampered because of several methodological discrepancies in the study designs and case definitions for both depression/depressive symptoms and atopic disorders. The present study was the first general population birth cohort study to demonstrate an association between atopy and depression. Since it is also known that during recent decades the occurrence of atopic disorders has been increasing (Konsensuslausuma 1998, Pekkanen et al. 2001a, Savolainen 2001, Hannuksela 2002), while the prevalence of depression has remained rather stable despite the increasing use of antidepressant medication and an upward trend in depression-related disability (Lehtinen & Joukamaa 1994, Salminen et al. 1997, Isometsä et al. 2000, Herva 2002, Pirkola et al. 2002), there are some difficulties between the present and earlier studies with regard to interpreting the results.
However, the results of this thesis are in accordance with the findings of the few earlier studies, which were based on non-clinical samples: In a sample of college students, Bell et al. (1991) found that the proportion of self-reported professionally diagnosed allergic disorders was about two times higher among subjects with professionally diagnosed depression than in subjects without depression. Albeit that the occurrence of atopic disorders have been increasing during recent years, the results of the present thesis are in line with the findings of Bell and colleagues (1991). More recently, Cohen et al. (1998) followed prospectively a cohort of randomly selected children and found that the preceding atopic disorders increased the probability of subsequent depressive disorders about two-fold from childhood to adulthood. Thus, the results of the present thesis parallel also these findings, which show strong positive associations between atopic disorders and depression. The findings of the present thesis are also on a par with the findings of Cuffel et al. (1999), who by using an enormous database of over 600 000 privately insured persons, found that allergic rhinitis was associated with increased, nearly two-fold rates of depression. Finally, in a cross-sectional analysis of a large adult database, Hurwitz and Morgenstern (1999) found that subjects with asthma or hay fever were twice as likely to have been diagnosed with major depression in the past 12 months than those without these illnesses. Thus, the present findings are also consistent with these results. Accordingly, an association between atopic disorders and depression has now also been confirmed to exist by using a large, genetically homogeneous birth cohort data set.
With the exception of the studies of Wamboldt and colleagues, concerning juvenile (Wamboldt et al. 1998) and adult twins (Wamboldt et al. 2000), the results of which are discussed in chapter 6.2.3, the other earlier studies have been conducted in connection with selected, relatively small clinical data settings, in which the association between the two disorders has been investigated by studying patients suffering from either depressive or atopic symptoms. Thus, the results of this unbiased large general population database are not comparable with them.
The comparison of the results of the association between atopy and depression (reported in this thesis) with earlier studies addressing the associations between other physical disorders and depression is very difficult due to methodological discrepancies. However, the probability of the presence of depression was shown to be two-fold in patients with diabetes (Anderson et al. 2001, Katon 2003), which was similar to that found in atopic cohort members in this study. The proportion of major depression in patients with coronary artery disease have reported to vary between 17% and 27% (Rudisch & Nemeroff 2003), which is in accordance to the proportions of the most severe manifestations of depression found in subjects with atopy in this thesis. Further, similar or even greater prevalences of major depression have been observed in patients with Parkinson’s disease (20%–30%) and multiple sclerosis (16%–30%) (Katon 2003). Since congruent or greater risks of developing depression have been noted in connection with many other physical diseases as well, the association between atopic disorders and depression may be non-specific in regard to atopic disorders. To investigate the associations between other physical disorders and depression was, however, beyond the scope of this thesis.
This thesis adds some important considerations to the earlier literature, one of them being the gender difference with regard to the association between atopy and self-reported doctor-diagnosed lifetime depression. At epidemiological level, skin prick test positive females exhibited an up to 1.8-fold greater risk of developing self-reported doctor-diagnosed lifetime depression when compared with prick test negative subjects. Further, the corresponding risk increased up to 2.7-fold in females, who had positive skin prick tests together with self-reported allergic symptoms, when compared with skin prick test negative females without self-reported allergic symptoms. The corresponding associations were not found among male cohort members. Thus, the findings of this thesis are consistent with those of Centanni et al. (2000), who also found a gender difference while showing increased prevalence of depressive symptoms among asthmatic patients with women having higher depression scores than men.
The severity of the depressive symptoms was assessed in the original publication III with the help of the HSCL-25 depression subscale (Derogatis et al. 1973, Winocur et al. 1984). In atopic females, the risk of depression increased in line with the increased severity of depressive symptoms, the odds ratios ranging from 3.0 to 4.7-fold. In the earlier literature, no previous findings were reported with regard to gender differences in the context of different degrees of severity of depression. Putative explanations for the gender differences are discussed in the theoretical discussion of this thesis.
In males the association between atopic disorders and depression was seen only in the most severe manifestations of depression: In the original publication I, it was found that hospital-treated atopic disorders increased the probability of hospital-treated depression up to three-fold, independently of the subject’s gender and sociodemographic characteristics. Likewise, in the original publication III, the atopy-depression association was seen only in the highest depression scores, the risk for depression in atopic males being over six-fold.
Whether the strength of the association between atopic disorders and depression is dependent on the severity of the depression is a very sparsely studied area. Previously, Bell et al. (1991) found that self-reported frequency of asthma was higher among those, who were most frequently depressed when compared with those, who reported to have had current depressions less often. Thus the results of the original publication III are in line with these findings. However, in contradiction to the findings presented in the original publication III, Bell and colleagues (1991) also found that subjects with differing degrees of self-rated current depression did not differ statistically significantly in the overall presence or absence of allergic disorders (i.e., hay fever, asthma, eczema, and hives (i.e., urticaria)). The definitions of atopic allergies differed, however, to some extent between the present thesis and the study carried out by Bell and colleagues.
In the present thesis the highest odds for the atopy-depression association were to some extent above those of the findings of earlier studies (Bell et al. 1991, Cohen et al. 1998, Cuffel et al. 1999, Hurwitz & Morgenstern 1999). It must be, however, kept in mind that the highest odds in the present thesis reflected the most severe manifestations and symptoms of depression. Thus, these differences between the results can be explained by the differences of the case definitions between the present and the earlier studies.
The major finding of the original publication IV was that maternal atopy or atopies in both parents combined with a subject’s own atopy were the most important predictors of a female proband’s depression, the odds ratios being over 4-fold. Maternal atopy alone almost doubled the risk of lifetime depression in female probands when compared with families in which no maternal atopy existed. Thus, these findings are on a par with previous studies in which an association between atopic disorders and depression has been noted to exist between first degree relatives (Davis 1977, Wamboldt et al. 1996). These earlier studies, however, analysed the prevalence of depression among first degree relatives (Wamboldt et al. 1996) or among mothers (Davis 1977) of children with asthma. With regard to the other atopic disorders, corresponding findings are not reported in the earlier literature. Likewise, there exist no previous studies in which the association between parental atopy and a proband’s depression would have been investigated.
Since neither parental nor siblings’ atopies predicted any type of depression in male probands, it could be suggested that the putative genetic association (between parental atopic disorders and a child’s depression) involves female probands only. Thus, the results of this thesis are in support of recent findings that point to genetic factors playing a greater role in the etiology of depression in women than in men (Bierut et al. 1999, Kendler et al. 2001a).
In addition, the results of this thesis extend the earlier findings of Wamboldt et al. (1998, 2000), who suggested that a common additive genetic effect accounts for the majority of the covariance between atopic and depressive symptoms. Based on the findings of this thesis it could be assumed that regarding heritability, it is specifically the maternal link, which is stronger than the paternal one. Since in the literature reviewed, no earlier findings were reported with regard to the association between maternal or parental atopy and a proband’s depression, the putative explanations for these findings are discussed in the theoretical discussion of this thesis. It must, however, be kept in mind that also the findings of this thesis about the familial atopy as a predictor for female proband’s depression may be a non-specific finding. It could be speculated that e.g., a mother’s other chronic illnesses such as coronary hearth disease, for instance, might also predispose her child to become depressed.
According to the CHAID-analysis, a proband’s regular daily smoking was the strongest factor associated with both self-reported doctor-diagnosed lifetime and hospital-treated depression in males. Correspondingly, in females with a parental history of atopic conditions, doctor-diagnosed lifetime depression among regular daily smokers (12.7%) was over two times more common than the overall prevalence of depression in females (4.9%). Several previous studies have also indicated an association between smoking/nicotine dependence and depression (Brown et al. 1996, Hanna & Grant 1999, Dierker et al. 2002), but, as reviewed by Upadhyaya et al. (2002), there is more evidence that major depression can be regarded a risk factor of smoking than vice versa.
Whether the presence of parental atopy would have an explanatory role to play with regard to the association between smoking and depression, was behind the scope of this thesis. Also, this far, little is known about the mechanism of co-morbidity between smoking and depression. It has been suggested that depression may result from neurochemical changes brought on by smoking, or that depression may cause smoking by increasing the likelihood that individuals will self-medicate negative feelings with nicotine. In addition, it has been suggested that there may exist a third factor – either genetic or environmental in nature – which would increase the risk of having both of the earlier conditions, as reviewed by Dierker et al. (2002).
With regard to the association between the effect of exposure to tobacco smoke and atopic sensibilization, the existing evidence is also to some extent controversial: In some recent studies both exposure to tobacco smoke in utero, and current own smoking have been shown to be associated with atopic disorders (Backer et al. 2002, Devereux et al. 2002). On the contrary, the prevalence of allergic asthma and allergic rhino-conjunctivitis has been shown to be decreased with increasing exposure to tobacco smoke (Hjern et al. 2001), and children who had been exposed to tobacco smoke in childhood have been noted to have lower risks of atopic disorders (Hjern et al. 2001, von Linstow et al. 2002).
In females, if there existed no parental history of atopy, then living in an urban area was a significant predictor of depression: doctor-diagnosed lifetime depression for citydwellers (6.0%) was 2.5 times more common than for those living in the countryside (2.4%). This finding is in accordance with the findings of previous Finnish surveys, in which depression has been shown to be most prevalent in the most heavily populated areas of the country/in cities (Väisänen 1975, Lehtinen & Joukamaa 1994). Worthy of note is the fact that among females with no parental history of atopy, a city dweller’s own atopy was a significant predictor of depression; Since a cohort female’s atopy did not predict depression in those individuals living in the country, it could be speculated that the same etiological factors might play a role behind the pathophysiology of the atopy-depression association, and are the cause of the fact that living in a farm environment during childhood/being a farmer’s child is associated with a decreased risk of atopic allergies (Kilpeläinen et al. 2000, Pekkanen et al. 2001b).