Sex-stratified associations between depressive symptoms and cognitive impairment in treatment-resistant vs. non-resistant schizophrenia.

BACKGROUND: Treatment-resistant schizophrenia (TRS), affecting approximately 30% of schizophrenia patients, is frequently accompanied by depressive symptoms, which exacerbate cognitive and socio-emotional deficits. However, it remains unclear whether the impact of depressive symptoms on cognition differs by sex in TRS patients. METHODS: We evaluated 344 schizophrenia patients (112 TRS, 232 non-TRS) at Tianjin Anding Hospital. Depressive symptoms were assessed with the Hamilton Depression Rating Scale (HAMD), cognitive function with the Repeatable Battery for Neuropsychological Status (RBANS), and alexithymia with the Toronto Alexithymia Scale-26 (TAS-26). Two-way ANCOVA examined diagnosis-by-sex interactions, and partial correlation analyses assessed sex-stratified associations between depressive symptoms and cognitive and emotional measures. FDR correction was applied for all partial correlation analyses. RESULTS: Compared to females, males showed better performance on verbal tasks and higher TAS-26 scores, specifically in identifying, describing, and externally orienting emotions (all ps < 0.05), but higher levels of hopelessness (p < 0.001). After FDR correction, sex-stratified correlation patterns were observed. In men, depressive measures showed consistent positive correlations with TAS-26 indices (hopelessness-TAS total: r = 0.316, adjusted p < 0.001; total HAMD-DDF: r = 0.291, adjusted p = 0.004), without significant associations with neurocognition. In women, depressive dimensions correlated positively with TAS-26 subscales (anxiety/somatization-DDF: r = 0.256, adjusted p = 0.013) and negatively with multiple RBANS domains (hopelessness-RBANS total: r = - 0.252, adjusted p = 0.013). Stratified analysis by sex and TRS status detected significant depression-TAS-26 correlations only in male TRS patients (hopelessness-TAS total: r = 0.407, adjusted p = 0.050); no meaningful associations survived adjustment in the remaining three subgroups. CONCLUSION: Our findings indicate that the associations between depressive symptoms and alexithymia differ between males and females in schizophrenia, with distinct patterns observed across TRS and non-TRS patients.