Multiple Sclerosis, Depression, and Sex Differences: An Enduring Conundrum

Objective: No clear sex difference in depressive symptoms has been observed among people with multiple sclerosis (MS), unlike for the general population in which females have higher depression rates. MS, however, is heterogeneous. The authors evaluated whether the influence of sex on depressive symptoms in MS varies across age, disease-related variables, or testing year. Methods: Data were gathered from 1,731 adults with MS assessed at a neuropsychiatry clinic between 2006 and 2025 and stratified by age (18–45, 46–55, and ≥56 years), disease duration (0–4, 5–9, and ≥10 years), Expanded Disability Status Scale (EDSS) scores (0.0–1.0, 1.5–2.5, and ≥3.0), illness subtype (primary progressive, secondary progressive, and relapsing remitting), and testing year (2006–2015, 2016–2020, and 2021–2025). Depressive symptoms were measured with the Hospital Anxiety and Depression Scale depression subscale (HADS-D). Analyses of covariance, controlled for education, were conducted to test for a sex difference in HADS-D scores and whether the influence of sex varied according to stratified subgroups. Results: The mean±SD participant age was 43.5±11.0 years; 73% were women; and the median EDSS score was 2.0 (interquartile range 1.5–3.5). HADS-D scores did not significantly differ between men (mean=7.2±4.2) and women (mean=6.9±4.0). In analyses controlled for education, the effect of sex on HADS-D scores did not significantly differ by age (η 2 p =0.001), disease duration (η 2 p =0.003), EDSS score (η 2 p <0.001), illness subtype (η 2 p =0.003), or testing year (η 2 p =0.001). Conclusions: Across various disease-related characteristics and cross-sectional periods, depressive symptoms did not significantly differ between men and women with MS.