PNRR-MAD-2022-12375859_OSR

Post-COVID-19 syndrome has unveiled intricate connections between inflammation, depressive psychopathology, and cognitive impairment. This study investigates these relationships in 101 COVID-19 survivors, focusing on sex-specific variations. Utilizing path modelling techniques, we analysed the interplay of one-month 48-biomarker inflammatory panel, on three-month depressive symptoms and cognitive performance. The findings indicate that cognitive impairment is influenced by both inflammation and depression in the overall cohort. However, sex-specific differences emerged prominently. In females, residual dysregulated immune-inflammatory response significantly affects cognitive functioning also showing a trend of association with depressive burden thus suggesting that a mixed anti- and pro-inflammatory profile could foster these outcomes. Conversely, in males, inflammation was inversely associated with depression severity, with protective effects from regulatory mediators (IL-2, IL-4, IL-6, IL-15, LIF, TNF-α, β-NGF) on depression. Cognitive impairment in males was primarily influenced by depression, not inflammation. These results highlight distinct sex-specific pathways in immune and inflammatory responses post-COVID-19, potentially shaped by endocrine mechanisms. The findings emphasize the persistent impact of inflammation on the brain and underscore the need for sex-tailored therapeutic strategies to mitigate the long-term neuropsychiatric burden of COVID-19.

Introduction: Depressive disorders are a leading cause of global disease burden, particularly with the challenge of treatment-resistant depression (TRD). Research points to a complex bidirectional relationship between cardiovascular (CV) risk factors and TRD, with CV risk negatively impacting brain structure and potentially influencing antidepressant resistance. Moreover, the association between depression and the genetic vulnerability to cardiovascular disease suggests a shared pathophysiological process between the two. This study investigates the mediating role of brain structural alterations in the relationship between CV and cerebrovascular (CeV) risk and treatment resistance in depression. Methods: We assessed 165 inpatients with Major depressive disorder. Each patient's CV risk was assessed via the QRISK 3 calculator. For a subset of patients, CV and CeV disease polygenic risk scores (PRS) were obtained. All patients underwent a 3 T MRI scan, and white matter hyperintensities estimates and indicators of brain trophic state were obtained. Results: Both CV risk and CV disease PRSs are associated with treatment resistance status, white matter hyperintensities, and indicators of brain atrophy. Mediation analyses suggested that CV-induced brain alterations might underlie the relation between CV genetic and phenotypic risk and antidepressant treatment resistance. Conclusion: These results underscore the need to explore cardiovascular risk management as part of treatment strategies for depression, pointing toward a shared pathophysiological process linking heart and brain health in treatment-resistant depression.