Effect of Antidepressants on the Neuroimmunological Networks of Peripheral Leukocytes in Patients with Major Depressive Disorder

• Grant number: 24/22162-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2025
• End date: May 31, 2029
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Otávio Cabral Marques
• Grantee: Roseane Galdioli Nava
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Major depressive disorder (MDD) is increasingly associated with immune dysregulation, including pro-inflammatory cytokine activity and altered interferon signaling. These systemic changes affect central nervous system function via neuroimmune pathways, contributing to neuroinflammation and mood disturbances. However, the immunomodulatory impact of antidepressants remains unclear. We conducted a transcriptomic meta-analysis to investigate how antidepressants modulate cytokine and interferon pathways in MDD, using peripheral blood leukocyte data from three paired microarray datasets (GSE128387, GSE146446, and GSE32280). After normalization and batch correction (ComBat, SVA), differentially expressed genes were identified using limma. Functional enrichment (GO, KEGG), ligand-receptor mapping, and interferon-stimulated gene profiling (Interferome) were applied. Antidepressant treatment downregulated pro-inflammatory mediators (IL1B, TNF, IFNG) while upregulating regulatory cytokines (IL10, IL4) and their receptors, indicating a Th2-like immune shift. Cytokine-receptor analysis revealed enhanced IL-10/IL-4 signaling. Interferon pathway analysis showed upregulation of ISGs (IFIT1, OAS3, IFI6), supporting activation of antiviral and immunoregulatory programs without excessive inflammation. Network analysis revealed convergence of immune and neural processes, including cytokine signaling, synaptic modulation, microglial activation, and interferon-beta production. These findings suggest that antidepressants induce neuroimmune reprogramming to promote homeostasis. This integrative transcriptomic study highlights the role of antidepressants in reshaping cytokine and interferon networks in MDD, revealing potential targets for precision psychiatry. (AU)