Abstract
Women have a consistently higher prevalence of major depressive disorder (MDD) than men. Hypotheses implicating hypothalamic-pituitary -adrenal, -gonadal, and -thyroid axes, immune response, genetic factors, and neurotransmitters have emerged to explain this difference. However, more evidence for these hypotheses is needed and new explanations must be explored. Here, we investigated sex differences in MDD markers using multiplex immunoassay measurements of 171 serum molecules in individuals enrolled in the Netherlands Study of Depression and Anxiety (NMDD = 231; Ncontrol = 365). We found 28 sex-dependent markers of MDD, as quantified by a significant interaction between sex and log2-transformed analyte concentration in a logistic regression with diagnosis (MDD/control) as the outcome variable (p<0.05; q<0.30). Among these were a number of male-specific associations between MDD and elevated levels of proteins involved in immune response, including C-reactive protein, trefoil factor 3, cystatin-C, fetuin-A, β2-microglobulin, CD5L, FASLG receptor, and tumor necrosis factor receptor 2. Furthermore, only male MDD could be classified with an accuracy greater than chance using the measured serum analytes (area under the ROC curve = 0.63). These findings may have consequences for the generalization of inflammatory hypotheses of depression to males and females and have important implications for the development of diagnostic biomarker tests for MDD. More studies are needed to validate these results, investigate a broader range of biological pathways, and integrate this data with brain imaging, genetic, and other relevant data.
Highlights
Major depressive disorder (MDD) is a highly prevalent and disabling condition with inadequate diagnosis and therapy [1]
insulin-like growth factor binding protein (IGFBP)-5 participates in biological processes including cell growth, glucose metabolism, and signal transduction, while MIP-3B and IL-2RA are involved in inflammatory response and regulation of T cell proliferation
Many of these are involved in defence, inflammatory, and immune response [trefoil factor 3 (TFF3), B2M, fetuin-A, cystatin-C, fatty acid-binding protein (FABP), C-reactive protein (CRP), CD5 antigen-like (CD5L), vascular cell adhesion molecule 1 (VCAM-1), tumor necrosis factor receptor 2 (TNFR2), FASLG receptor (FAS), eotaxin-1, C-peptide, macrophage derived chemokine (MDC), pulmonary and activation-regulated chemokine (PARC), and matrix metalloproteinase-7 (MMP-7)]
Summary
Major depressive disorder (MDD) is a highly prevalent and disabling condition with inadequate diagnosis and therapy [1]. A higher female prevalence of MDD has been observed consistently across several countries and cultural settings from late adolescence onwards [3,4]. Several hypotheses implicate biological factors in the increased risk of MDD in females. Sex hormones have been linked to the emergence of higher rates of female depression during puberty and rising hormone levels during this time have been linked to affective disturbances in girls [5,6]. No consistent reason for the higher rate of MDD in females has been found
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