Herpes simplex reactivation triggers symptom exacerbation in patients with major depressive disorder

• Herpes simplex virus infection and consequent inflammation affects psychiatric symptom severity. • Infection recurrence leads to changes in plasma levels of inflammation-associated proteins IFN-γ and sICAM-1. • Effect of infection on sICAM-1 is dependent on major depressive disorder diagnosis. • Plasma levels of anti-inflammatory cytokines IL-10 and IL-13 are positively correlated with depressive symptom severity. Herpes Simplex Virus (HSV) infection has been linked to depression, but the underlying mechanism remains largely unknown. We hypothesized that recurring HSV infection could exacerbate depressive symptomatology via activation of the immune response and the kynurenine pathway in patients with Major Depressive Disorder (MDD). 32 MDD patients and 17 psychiatrically healthy individuals with a history of HSV recurrence were enrolled into the study. Blood samples were obtained, and psychiatric symptom severity was assessed at three separate visits- asymptomatic, active infection, and follow-up. Plasma levels of tryptophan metabolite levels were measured using ultra-high performance liquid chromatography-mass spectrometry (LC-MS), and inflammation-associated proteins were measured using high sensitivity electrochemiluminescence. There was a significant effect of infection recurrence on IFN-γ and sICAM-1 levels, the latter being influenced by MDD diagnosis. This indicates that the effect of infection on sICAM-1 levels differs between control and depressed groups, although post hoc analysis suggests that interaction effect might be subtle. Infection recurrence had a significant effect on the reactivity of psychiatric symptoms. Finally, there was a positive correlation between levels of anti-inflammatory cytokines IL-10 and IL-13 and depression severity in the cohort during infection recurrence. Relatively small sample size, limited number of male participants, and the relatively weak inflammatory stimuli studied. MDD patients might react with an exacerbation of symptoms along with elevations of inflammatory markers during HSV recurrence. Further, the association with symptom severity indicates that therapeutic modulation of inflammation may be beneficial in patients with MDD, especially during active infections. Created in BioRender. Anis, E. (2024) BioRender.com/j18t976