Immunometabolic Dysregulation and Cognitive Dysfunction in Major Depressive Disorder: The Role of Chronic Low-Grade Inflammation

Abstract

Major depressive disorder is a heterogeneous psychiatric condition frequently accompanied by persistent cognitive dysfunction involving executive function, attention, memory, processing speed, and motivational processes. Increasing evidence suggests that chronic low-grade inflammation and immunometabolic dysregulation may contribute to these alterations in a biologically distinct subgroup of patients. This study analyzed the relationship between systemic inflammatory activity, metabolic abnormalities, and cognitive impairment in depression through an integrative review based on the scientific method. Evidence from clinical studies, cohort investigations, systematic reviews, meta-analyses, and translational research was examined, with particular attention to C-reactive protein, interleukin-6, tumor necrosis factor-alpha, metabolic syndrome, insulin resistance, oxidative stress, dopaminergic dysfunction, and the tryptophan–kynurenine pathway. The results showed that elevated inflammatory activity is present in a substantial but non-universal proportion of patients with depression and is associated particularly with poorer executive functioning. The coexistence of depression and higher C-reactive protein was related to additional executive impairment, while the interaction between metabolic syndrome and inflammatory/oxidative dysregulation was associated with poorer global cognitive performance. Immune activation was also accompanied by increased kynurenine, reduced tryptophan, an elevated kynurenine-to-tryptophan ratio, and greater depressive symptom burden. Anti-inflammatory interventions showed modest improvements in depressive symptoms and anhedonia among individuals with elevated inflammatory activity, although direct evidence of cognitive improvement remains limited. Overall, the findings support an immunometabolic model in which inflammation interacts with metabolic and neurochemical abnormalities to influence cognitive vulnerability in selected patients with depression. Integrating inflammatory biomarkers, metabolic status, psychiatric assessment, and cognitive evaluation may contribute to more precise clinical stratification and guide future personalized therapeutic strategies.