Influence of Sex and Diagnosis on Clinical Variables and Neurocognitive Performance in Severe Mental Illness. Results From the PsyCourse Study.

Introduction Bipolar disorder (BD) and schizophrenia (SZ) are serious mental illnesses (SMI) with overlapping symptoms but distinct differences in onset and course. Sex differences are an area of growing interest in SMI. This study aims to examine potential interactions between sex and diagnosis across a broad range of variables, to compare males and females within SZ and BD, and to investigate sex-specific group differences.Methods A total of 1516 individuals were included in a cross-sectional study using baseline data from the multicenter PsyCourse Study, including BD (n = 543), SZ (n = 517), and healthy controls (HC) (n = 456). Sociodemographic characteristics, clinical symptoms, psychosocial functioning, quality of life, neurocognitive performance, and somatic comorbidities were assessed. Generalized linear models were used to analyze differences between groups and sexes. False Discovery Rate (FDR) and Bonferroni post hoc comparisons were performed.Results Significant interactions were identified in age (p = 0.001), age at treatment (p = 0.05), illness duration (p = 0.03), illicit drug use (p = 0.01), and smoking (p = 0.05). Differences in substance use were observed across groups and sexes, with the highest rates found in males with SZ. The BD group showed better functioning and neurocognitive performance compared with the SZ group. Within the BD group, females reported better performance in verbal memory (p = 0.003) and psychomotor speed (p < 0.001) than males. Moreover, both females and males with SMI showed higher rates of thyroid alterations compared with HC (p = 0.01 for females and p = 0.002 for males).Conclusions Significant sex differences were observed in substance use and somatic comorbidities. Interactions between diagnosis and sex underscore the importance of considering both factors in clinical assessments. These findings highlight the need to tailor sex-specific treatment for each patient. Further research is needed to explore the role of sex hormones and other biological and societal factors in the presentation and course of these disorders.