Gender differences in depression prevalence: the role of inflammation and somatic symptoms

1. Introduction

Depression is a common mental disorder rated third in the World Health Organization Global Burden of Disease Study on causes of disability among women and fifth among men [1]. Although it is widely reported that depression is more prevalent among females compared to males beginning in adolescence [2, 3], an accepted explanation for this difference has not been found. One explanation is that the DSM overlooks a form of depression comprised of symptoms such as irritability that are prevalent among males [4]. To date, however, research needed to support the contention that these symptoms should be considered aspects of depression rather than of other disorders exhibited by men has not been published so even recent articles highly supportive of the concept note that the research support for the existence of male depression is limited [5]. This possibility will not be included here. One possible explanation of the higher prevalence of depression among women relates to inflammation. Inflammation is the main way in which the immune system defends against infections and injured tissue. An emerging body of research has found that increased levels of inflammation are associated with depressive disorders [6, 7]. The central argument presented here is that the gender difference in depressive prevalence results from women exhibiting a particular phenotype of depression and that this phenotype may result from inflammation

2. Somatic depression and gender differences in depression prevalence

The literature to date has described a few different depressive phenotypes that might explain the higher prevalence of depression among females [8]. For example, a pattern of results points to a disorder involving depression plus the somatic symptoms of disordered eating, body dysmorphia, headaches, insomnia, and fatigue that becomes particularly prevalent among women at adolescence. Multiple studies have demonstrated that women exhibit a higher prevalence of all of these somatic symptoms than do men beginning in adolescence. These somatic symptoms have been found to increase in frequency among females much more than among males beginning in adolescence. All of these somatic symptoms are more strongly related to depression among females than among males beginning in adolescence (for references, see [9]).

Several studies have compared the combination of depression with and without multiple somatic symptoms in relation to gender. Analyses of large representative epidemiological samples such as the Epidemiological Catchment Area Study [10], the National Comorbidity Survey [11], the National Comorbidity Survey- Replication, and the Zurich Study [12] defined somatic depression as meeting criteria for major depressive disorder and also exhibiting eating and sleep difficulties and fatigue (the somatic symptoms from the list above that were measured in these databases; the analysis of the Zurich Study also included headaches and body image issues in the criteria for somatic depression). These studies found a significant gender difference in the prevalence of depression accompanied by all three of these somatic symptoms but little or no gender difference in depression in the absence of reporting all three somatic symptoms [12]. Thus, the gender difference in the disorder currently labeled Major Depressive Disorder was found in several large representative studies due to the higher prevalence among women of a phenotype of depression combined with somatic symptoms.

In a representative sample of adolescents [13], the incidence of somatic depression increased from 7.4% to 13.3% during adolescence among females, compared to an increase of only from 2.2% to 3.5% among males. Neither gender exhibited an appreciable increase of nonsomatic depression during this same time frame. An analysis of data from the largest study of response to antidepressants, the STAR*D study, found that patients with somatic depression (defined as depression plus three or more of the following: disordered eating, body dysmorphia, headaches insomnia, and fatigue) responded more poorly to citalopram in level 1 and to the level 3 medications bupropion, lithium, mirtazapine, nortriptyline, sertraline, thyroid, and venlafaxine than patients who exhibited depression without three of these symptoms [14].

The studies cited above were published over many years but several fMRI studies published more recently found differences in brain functioning between people, particularly women, who exhibited somatic depression (defined as in the Star*D study described above) and those who exhibited depression with fewer somatic symptoms [15–18], providing strong support for the distinct diagnosis of somatic depression.

Although much research supports the existence of a depressive disorder that becomes prevalent among females at adolescence, to date no mechanism has been offered to explain the development of the particular symptoms of this disorder. Research published on inflammation may provide evidence for the physiological processes underlying somatic depression.

3. Inflammation and somatic depression

Our goal in this section is to present evidence across different measures of inflammatory processes linking them to somatic depression to stimulate additional research. Several studies have concluded that depression involving inflammation may constitute a distinct phenotype. For example, in a systematic review of studies of the effects of immune genes on depression, Barnes et al. [19] concluded that patients who exhibited increased mRNA expression for high levels of cytokines (inflammatory agents) exhibited a distinct phenotype of depression associated with inflammation. Similarly, based on a study of the relationship between levels of the inflammatory agent C-reactive protein (CRP) and depression scores on the General Health Questionnaire, Hughes and Kumari [20] postulated the existence of a distinct depressive subtype associated with inflammation, which is characterized by poor response to antidepressants. High levels of inflammation assessed before treatment with antidepressant medication have also been found to predict poor treatment response [21]. These studies are consistent with the Star*D study cited above that found somatic depression to exhibit poor response to antidepressants.

4. Inflammation and somatic depression resulting from low status/power

One intriguing possibility deserving of further study that might help explain the higher prevalence of somatic depression related to inflammation among women than men involves the role played by low status. John-Henderson et al. [34] found that college students who rated themselves as being of low social class and who associated lower class with more negative adjectives on an implicit association test showed significantly elevated levels of IL-6 compared to students who rated themselves as being of higher class. Two recent meta-analyses found that low socioeconomic status is significantly related to high levels of inflammatories [35, 36].

One way women recognize their lower status may be through their experience of discrimination. Kershaw et al. [37] studied random population samples of adults aged 45–84 recruited from six cities around the country Respondents filled out the nine-item Everyday Discrimination Scale. [38], which asks participants to report their experience of various forms of discrimination in their daily lives (e.g., “people act as if they think you are not smart”). Among women, but not among men, higher levels of reported discrimination were significantly associated with higher IL-6. Among women aged 42–52, Beatty et al. [39] found that overall scores on the Everyday Discrimination Scale predicted levels of the inflammatory CRP measured seven years later among women of “normal” body weight.

The recognition of the lower status and power among women is first manifested in adolescence [40], the period during which the higher prevalence of depression among females compared to males first appears. Klonoff et al. [41] found that female students at a state university who reported experiencing frequent inferior treatment due to their gender had significantly more depressive and somatic symptoms than men whereas women who reported little such treatment did not differ from men on these symptoms. Among high school and Freshman/Sophomore college students, somatic depression was significantly related to women’s feeling that their lives would be better if they were male, perceiving their mothers’ lives as limited by gender and seeing their fathers as favoring males. These findings were measured using multi-item scales with good inter-item reliability [42, 43]. Even more compelling are studies where somatic depression was found to be prevalent among females whose fathers reported believing males should have more power than females [44] and among females whose mothers reported feeling limited by their gender [45].

5. Discussion

This article has reviewed several bodies of research to offer a model hypothesized to at least partially explain the well-documented gender difference in the prevalence of depression from adolescence through adulthood. The model postulates that the gender difference in depression observed initially in adolescence is due to the greater prevalence of a distinct form of depression, somatic depression, Which is associated with inflammation, among women. Much additional research is needed to test the preliminary hypothesis offered here that the higher prevalence of inflammation-induced somatic depression among females compared to males might result from women’s experience of limitations in social status.

The review of research supporting each of the conclusions made here includes many studies demonstrating that the research findings have been highly replicated, including recently. This review might be considered to be part of a growing subfield that has been termed “social psychoneuroimmunology”, which postulates that there is significant crosstalk between the central nervous system and the immune system, such that psychological experiences can affect and be affected by the immune system [46].

One important implication for future research and practice that follows from the studies reviewed here is the possibility that current diagnostic classifications may be classifying distinct disorders as the single disorder “Major Depressive Disorder”. Many of the studies cited here, including several neuro-imaging studies, have found important differences between somatic versus nonsomatic depression. As a result of an unclarity in identifying diagnostic groups, the results of research using current diagnostic criteria on such aspects of depression as genetics, neurophysiology, and treatment may be misleading or uninterpretable. At the current time, such studies compare non-depressed control subjects to an experimental group possibly comprised of subjects suffering from distinct disorders but labeled as exhibiting a single disorder, major depression, greatly affecting measures of means and variance.

Another implication of the research reviewed here relates to the treatment of depression. Pharmacotherapy using anti-inflammatory agents may be particularly helpful in somatic depression, where depression and inflammation co-occur [22, 47]. Additional research is needed to balance the medical costs and benefits of this treatment. This is noteworthy in light of the poor response to antidepressant medication demonstrated for patients exhibiting somatic depression and those exhibiting inflammation.

The psychotherapy intervention literature indicates that family psychoeducation reduces the level of inflammation of low-SES African-American youth [48], and cognitive behavioral therapy and other psychosocial interventions have been effective in reducing depression and inflammation among women [49, 50]. These approaches deserve further study on somatic depression.

6. Conclusion

In summary, evidence is presented here supporting the inclusion of measures of somatic versus nonsomatic depression, inflammation, and possibly perceived low status in further research efforts attempting to explain the gender difference in the prevalence of depression.