Neural Correlates of Diagnostic-Relevant Emotional Processing in Schizophrenia and Major Depressive Disorder: Insights from a Replication of fMRI and Self-Report Scales

BACKGROUND: Accurate differentiation between major depressive disorder (MDD) and schizophrenia (SZ) remains a clinical challenge due to overlapping symptoms and limitations of traditional diagnostic methods. Integrating neurobiological markers, especially functional magnetic resonance imaging (fMRI), with clinical assessments holds promise for improving diagnostic specificity. Recently, a translational cross-validation paradigm integrated the von Zerssen Paranoid-Depression Scale (a clinical self-assessment scale) with simultaneous fMRI data acquisition to cross-validate evaluations of psychopathology using neuroimaging techniques, allowing direct comparison of subjective symptom-related processing with corresponding neural activation patterns. Hence, we sought to replicate this method in an independent Chinese cohort. METHODS: A sample of 62 participants, comprising 32 MDD and 30 SZ patients, underwent task-based fMRI scanning using a paradigm with statements of diagnostically neutral (DN), depressive-specific (DS), and paranoid-specific (PS) content. After preprocessing, the number was reduced to 57 (30 MDD and 27 SZ). Neural responses were analyzed using the PS versus DS contrast to isolate paranoia- versus depression-related processing. Brain activation patterns were compared across the two patient groups. Mixed-effects Analysis of Variance (ANOVA) was used to test main effects and interactions. RESULTS: In SZ relative to MDD, processing paranoia-relevant content (PS > DS) was associated with greater activation in the bilateral supplementary motor area (SMA), left middle cingulate cortex (MCC), right precentral gyrus, and right superior frontal gyrus, indicating differential neural engagement during paranoia-specific processing. The second-level mixed-effects ANOVA revealed a significant main effect of condition (PS versus DS) across both groups in the precuneus/calcarine cortex, left frontal cortex, and hippocampal regions, indicating task-related modulation of neural activity. Importantly, a significant group × condition interaction was identified in fronto-cingulate, motor, temporal, and prefrontal regions, suggesting differential neural responses to paranoia-related processing between SZ and MDD. CONCLUSIONS: Integrating task-based fMRI with clinical self-assessment scales offers a robust approach to delineate neurofunctional differences between SZ and MDD. Combining self-report scales with fMRI data contributes to the development of objective neurobiological markers, enhances the reliability of the differential diagnosis, and provides a neurobiological basis for more precise clinical assessments.