Insulin Resistance and Leptin Dysregulation Impact In Vivo Brain Structure and Cognitive Functioning in Mood Disorders: A Multimodal Partial Least Squares Path Modeling Study

Background: Major depressive disorder (MDD) and bipolar disorder (BD) are associated with persistent cognitive deficits, but the biological mechanisms underlying these impairments remain unclear. Metabolic dysfunction, particularly insulin resistance (IR), may contribute to brain structural alterations and cognitive decline. However, diagnosis-specific metabolic effects on gray matter volumes (GMVs) and cognition have not been fully explored. Partial least squares path modeling was applied to examine associations among metabolic biomarkers, GMVs, and cognitive performance in mood disorders, stratifying by diagnosis. Methods: A total of 81 inpatients with BD (55 female, 26 male) and 78 inpatients with MDD (45 female, 33 male) underwent neuropsychological evaluation with the Brief Assessment of Cognition in Schizophrenia. T1-weighted magnetic resonance images were processed to extract GMVs. Blood samples were collected to assess metabolic markers. Results: In the whole sample, the metabolism latent construct negatively predicted both GMV and cognition, with the GMV factor positively affecting cognition. A significant diagnostic difference emerged for the metabolism-to-cognition path (p = .0196). Stratified analyses showed that in BD, metabolism was significantly associated with both reduced GMVs and poorer cognition, whereas no significant structural paths were identified in MDD. IR markers and leptin were the strongest positive contributors to the metabolism factor in both the whole sample and the BD group. The brain regions most affected encompassed areas central to cognitive and emotional regulation, characterized by a high density of insulin and leptin receptors. Conclusions: These findings highlight the role of IR and leptin in shaping cognition in mood disorders and underscore the potential of insulin-related pathways as therapeutic targets, especially in BD with metabolic comorbidities.