Bidirectional relationship between human herpes virus reactivation and depression: a systematic review and meta-analysis

BACKGROUND: Human herpesviruses (HHVs) are lifelong pathogens that can reactivate under stress or immunological changes. Depression has been implicated as both a potential trigger for and a consequence of HHV reactivation. This study investigates the bidirectional relationship between HHV reactivation and depression through a systematic review and meta-analysis. METHODS: This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD42024565616). A search of PubMed, Web of Science, Embase, and Scopus identified studies published through March 5, 2024. RESULTS: Nineteen studies, representing a total sample size of 94,194 participants, were included in the meta-analysis. The pooled odds ratio (OR) demonstrated a significant association between HHV reactivation and depression (OR = 1.33; 95% CI: 1.07-1.64; p < 0.001; I2 = 92%). Subgroup analyses revealed significant associations for Epstein-Barr virus (EBV) (OR = 1.99; 95% CI: 1.80-2.20) and herpes simplex virus 2 (HSV-2) (OR = 1.83; 95% CI: 1.32-2.55), while cytomegalovirus (CMV) and HSV-1 showed non-significant associations. A secondary meta-analysis found a significant association between pre-morbid depression and EBV reactivation (OR = 2.18; 95% CI: 1.48-3.21) as well as varicella-zoster virus (VZV) reactivation (HR = 1.09; 95% CI: 1.06-1.13). Sensitivity analyses confirmed the robustness of the findings, and no substantial publication bias was detected. CONCLUSION: This study provides evidence of a bidirectional relationship between HHV reactivation and depression, highlighting depression as both a risk factor for and a potential consequence of HHV reactivation.