Unveiling the Interplay of EBV, HSV-1, and Inflammatory Biomarkers in Psychiatric Disorders

<b>Background/Objectives:</b> Schizophrenia (SCH), bipolar disorder (BPD), and major depressive disorder (MDD) are increasingly viewed as neuroimmune disorders shaped by viral exposure and inflammation. Disorder-specific immunovirological profiles, however, remain poorly defined. <b>Methods:</b> In this cross-sectional study, we assessed Epstein-Barr Virus (EBV) and Herpes Simplex Virus type 1 (HSV-1) seropositivity and measured serum CRP, IL-6, and IL-1β in 708 participants: 110 with SCH, 121 with BPD, 135 with MDD, and 342 healthy controls (HC). Statistical analyses included Shapiro-Wilk tests for normality; Kruskal-Wallis with Bonferroni-adjusted Dunn post hoc comparisons; and logistic regression adjusted for age, sex, and marital status. <b>Results:</b> EBV seropositivity was higher in SCH (90.9%) than in HC (78.9%) (OR = 3.46, 95% CI: 1.68-7.12; <i>p</i> = 0.001) but not in BPD or MDD. HSV-1 seropositivity was elevated in BPD (83.5%) versus HC (67.0%) (OR = 2.29, 95% CI: 1.34-3.92; <i>p</i> = 0.003), with no differences in SCH or MDD. Inflammatory biomarkers were significantly increased in SCH and MDD compared to HC (<i>p</i> < 0.001), while BPD showed no differences. <b>Conclusions:</b> The findings delineate distinct immunovirological patterns across major psychiatric disorders. Schizophrenia was characterized by EBV seropositivity accompanied by systemic inflammatory activation, bipolar disorder by HSV-1 seropositivity in the absence of inflammatory changes, and major depressive disorder by inflammatory dysregulation independent of viral exposure. These disorder-specific profiles highlight heterogeneity in neuroimmune pathways and underscore the potential relevance of biomarker-based stratification for generating hypotheses regarding targeted antiviral or anti-inflammatory interventions in psychiatric populations.