Discussion

The aim of the present study was to explore sex-specific associations of lifetime MDD and MDD recurrence status (i.e., MDD_S, vs. MDD_R) with obesity-related traits in an adult community sample. Specifically, the associations between MDD recurrence status and obesity-related traits revealed a consistent contrary pattern in women, but not in men. In women, MDD_S showed significant inverse associations with general (i.e., BMI) and central obesity (i.e., WC, WHR, and WHtR), while MDD_R exhibited significant positive associations with body weight; general (BMI) and central obesity (WC, HC, WHtR); and markers of body fat (FM, SAT, and VAT). Of note, only MDD recurrence status but not lifetime MDD showed significant associations with obesity-related traits in women. In men, just a few effects of lifetime MDD and MDD recurrence status on obesity-related traits were observed and limited to increases in SAT and VAT.

Consistent with established sex differences in lifetime prevalence [Reference Salk, Hyde and Abramson30], women in our cohort were at greater risk for lifetime MDD compared to men (23.8% vs. 14.5%), largely due to sex differences in MDD_R prevalence (16.9% vs. 9.0%). Results are further consistent with evidence linking MDD to anthropometric markers of obesity and weight gain in women [Reference Marcus, Kerber, Rush, Wisniewski, Nierenberg and Balasubramani15, Reference Jung, Woo, Cho, Park, Jeong and Lee20, Reference Zhao, Ford, Dhingra, Li, Strine and Mokdad31], which may partly be driven by women with MDD_R [Reference Frank, Carpenter and Kupfer21]. However, other studies did not report evidence of an effect modification by sex, MDD recurrence status, or their interaction [Reference Luppino, de Wit, Bouvy, Stijnen, Cuijpers and Penninx5]. Data on sex-specific links between MDD and direct measures of body fat are scarce and inconclusive, likely due to small sample sizes [Reference Stapel, Jelinic, Drummond, Hartung and Kahl32]. Previous population-based studies did not investigate the sex-specific effects of MDD or MDD recurrence status, but revealed positive associations between current depressive symptoms and VAT in women [Reference Murabito, Massaro, Clifford, Hoffmann and Fox33, Reference Cho, Lee, Rhee, Kim, Kim and Yoon34], men [Reference Remigio-Baker, Allison, Schreiner, Szklo, Crum and Leoutsakos35], and both sexes [Reference Alshehri, Boone, de Mutsert, Penninx, Rosendaal and le Cessie36]. We included current depressive symptoms (BDI-2 scores) in all MDD regression models and were able to show that, independent of lifetime MDD, current depressive symptoms exhibited significant positive associations with all obesity-related traits (except FFM) in women (Supplementary Table S2). In men, only the WHtR showed a positive relationship with current depressive symptoms. Importantly, the observed effects of MDD_S and MDD_R in our study were independent of current depressive symptoms. Thus, MDD recurrence status may exhibit distinct patterns of obesity-related traits in women, irrespective of current mood. We are not aware of any other population-based study investigating associations between MDD, MDD recurrence status, and body fat markers that simultaneously accounted for sex differences and MDD heterogeneity. It is particularly worth noting that our results suggest that women with MDD_R exhibit a pattern of obesity-related traits that is reminiscent of patients with “atypical” MDD, an MDD subtype which among other symptoms is characterized by hyperphagia (i.e., increased appetite). Indeed, epidemiological data suggest that, on average, women are two to three times more likely than men to present with symptoms consistent with the “atypical” MDD subtype [Reference Brailean, Curtis, Davis, Dregan and Hotopf37, Reference Blanco, Vesga-López, Stewart, Liu, Grant and Hasin38]. Additionally, and not taking the “atypical” MDD subtype into account, recent evidence from a GWAS suggests a female-specific link in the genetic association of MDD and obesity-related traits [Reference Silveira, Pokhvisneva, Howard and Meaney39]. These data converge to suggest that “atypical” MDD may constitute an MDD phenotype that is more characteristic for women than men [Reference Marcus, Kerber, Rush, Wisniewski, Nierenberg and Balasubramani15, Reference Frank, Carpenter and Kupfer21, Reference Silveira, Pokhvisneva, Howard and Meaney39]. We would further like to highlight that our results (summarized in Table S2) clearly show that current depressive symptoms (BDI-2), without taking the subtype of “atypical” MDD into account, show a clear pattern of sex-specific associations. Across all outcomes, depressive symptoms are significantly and positively associated with obesity-related traits in women, whereas in men only WHtR reveals a modest positive association. We (and others) therefore consider the label “atypical” problematic in this context. “Atypical” syndromes almost always refer to disease phenotypes that are more frequent in or more “typical” for women. This likely reflects a historical trend where males were largely overrepresented in clinical research and therefore defined the normative clinical presentation for most disease entities.

Given the well-documented obesogenic effects of antidepressants [Reference Domecq, Prutsky, Leppin, Sonbol, Altayar and Undavalli40–Reference Hiles, Révész, Lamers, Giltay and Penninx42], we conducted sensitivity analyses to exclude the possibility of confounding by the current intake of antidepressants. In participants without current antidepressant medication, most results remained unchanged (Supplementary Table S1) compared to the total sample. Of note, in women, associations of MDD_R with BMI and WHtR were no longer significant in sensitivity analyses, suggesting a potential mediation effect of antidepressants between MDD_R and anthropometric markers of obesity in women. Consistent with previous reports [Reference Domecq, Prutsky, Leppin, Sonbol, Altayar and Undavalli40–Reference Hiles, Révész, Lamers, Giltay and Penninx42], exploratory analyses in participants with current antidepressant intake revealed strong links of antidepressants with obesity-related traits (Supplementary Table S3), which were more pronounced in women than men, a finding that is consistent with previously published data on this topic [Reference de Vries, Denig, Ekhart, Burgers, Kleefstra and Mol43]. This finding further corroborates evidence indicating that the adverse effects of pharmacological agents, including antidepressants, disproportionately affect women [Reference Zucker and Prendergast44]. Furthermore, the frequent off-label use of antidepressants for other health problems, such as pain and sleep disorders and the rapid incline of prescription of antidepressants [Reference Skånland and Cieślar-Pobuda45] warrants careful consideration of the adverse drug reactions related to cardiometabolic health, with an emphasis on potential sex differences. Given the relatively small number of medicated participants, caution is warranted in drawing premature conclusions though. Nevertheless, we propose a systematic investigation of this effect in randomized controlled clinical trials, well-powered clinical trials, or population-based cohorts.

Given the growing public health challenges associated with rising MDD and obesity levels, and their associated cardiometabolic health risks in the general population, there is an urgent need to better understand their mechanistic links. Several excellent reviews [Reference Milaneschi, Simmons, van Rossum and Penninx8, Reference Fulton, Decarie-Spain, Fioramonti, Guiard and Nakajima46] provide insight into possible behavioral, molecular, neurobiological, neuroendocrine, and immunological pathways at the intersection of MDD and obesity-related traits, although sex and gender aspects are not systematically considered in this context. Meta-analytical evidence indicates that women with MDD are more likely than men with MDD to report increased appetite and subsequent weight gain [Reference Cavanagh, Wilson, Kavanagh and Caputi9]. Considering sex (but not MDD heterogeneity), a recent GWAS in a large predominantly white European sample revealed a sex-specific polygenic risk for MDD [Reference Silveira, Pokhvisneva, Howard and Meaney12]. Importantly, sex-specific polygenic MDD risk was associated with polygenic risk for obesity-related traits and metabolic features (i.e., body fat, WC, WHR, and triglycerides) in women, but not in men. Silveira et al. [Reference Silveira, Pokhvisneva, Howard and Meaney12] further identified expression regulation of the dopamine-receptor-D₂ gene (DRD2) as a depression-associated mechanism in women only. Given that deficient dopaminergic signaling has been identified in patients with disordered eating [Reference Leenaerts, Jongen, Ceccarini, Van Oudenhove and Vrieze47], obesity [Reference Volkow, Wang and Baler48], and MDD [Reference Belujon and Grace49], all of which occur more frequently in women, we speculate that this (genetically regulated) dopaminergic pathway may represent a female-biased mechanism linking MDD and obesity, particularly in MDD_R.

There are further plausible candidate mechanisms associated with cardiometabolic risk that exhibit significant sex differences and have well-established roles in both MDD and obesity [Reference Milaneschi, Simmons, van Rossum and Penninx8, Reference Fulton, Decarie-Spain, Fioramonti, Guiard and Nakajima46]. For instance, both inflammation and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis have been associated with MDD [Reference Dowlati, Herrmann, Swardfager, Liu, Sham and Reim50, Reference Zorn, Schür, Boks, Kahn, Joëls and Vinkers51] and obesity [Reference Rodriguez, Epel, White, Standen, Seckl and Tomiyama52, Reference Shoelson, Herrero and Naaz53]. While both the immune system [Reference Klein and Flanagan10] and the HPA axis [Reference Handa and Weiser13] show remarkable sex differences, their sex-differential roles in MDD, obesity, and their co-occurrence remains inconclusive. This lack of evidence warrants further systematic investigation of sex differences and additional factors that may interact with sex to predict differences in disease mechanisms relevant to MDD and obesity-related comorbidity which may (among others) include age, hormonal status (e.g., pregnancy, menopause), and exposure to childhood maltreatment.

There are several limitations in our analyses that we need to acknowledge. First, the cross-sectional observational study design does not permit the inference of causal pathways or longitudinal associations, which limits our ability to establish mechanistic or prospective associations (e.g., changes in weight and/or appetite) in the MDD-obesity relationship, which were mainly observed in women. Moreover, we cannot exclude the possibility of residual confounding by factors that we have not considered in statistical models or were not measured. As another limitation, our cohort is ethnically highly homogenous. All participants were white German nationals from a northeastern region of Germany (Western Pomerania). This circumstance limits the generalizability of our study to other populations of different ethnic, racial, cultural, or geographical background, where associations of MDD and obesity may systematically differ from the SHIP cohort.

A major strength of our study is the fact that in addition to standard anthropometric markers, we obtained direct measures of body fat through BIA and MRI in a large community-based sample. Given that body fat tissue, especially VAT, is associated with increased cardiometabolic risk in obese individuals [Reference Ibrahim54], the present study may provide important novel insights how MDD could contribute to an increased risk for chronic diseases in both men and women. As another strength, MDD diagnoses were established by trained clinicians in face-to-face sessions using structured clinical interviews and current depressive symptoms were accounted for in statistical models suggesting that MDD recurrence status and current depressive symptoms may be considered independent sex-specific predictors of obesity-related traits. Moreover, our stratification strategy accounts for sex and MDD heterogeneity and identified previously unreported associations, e.g., decreased general and central obesity in women with MDD_S. DSM-5-based criteria for MDD diagnosis include weight loss/gain and decreased or increased appetite [55]. Adequate stratification of MDD patients (e.g., based on MDD recurrence status) may help to establish greater diagnostic accuracy for subsamples of MDD patients with important treatment implications. For instance, inflammation is a hallmark feature of obesity and is associated with reduced treatment response to antidepressants [Reference Arteaga-Henríquez, Simon, Burger, Weidinger, Wijkhuijs and Arolt56]. Evidence from this study and others further suggests that MDD [Reference Marcus, Kerber, Rush, Wisniewski, Nierenberg and Balasubramani15, Reference Jung, Woo, Cho, Park, Jeong and Lee20], MDD recurrence status [Reference Frank, Carpenter and Kupfer21], and antidepressants [Reference Domecq, Prutsky, Leppin, Sonbol, Altayar and Undavalli40, Reference Serretti, Mandelli and Laura41] are associated with higher obesity risk, possibly more so in women. Together, these factors may contribute to increased cardiometabolic risk and reduced pharmacological treatment efficacy in subgroups of MDD patients and careful consideration of these issues may help to improve treatment outcomes, particularly for patients with MDD and obesity.

To conclude, by considering sex differences and MDD heterogeneity, we provide novel epidemiological insights into the intricate MDD–obesity relationship, which may help identify individuals with MDD at increased cardiometabolic risk associated with obesity.