Bidirectional Relationship Between Human Herpes Virus Reactivation and Depression: A Systematic Review and Meta-Analysis Publisher



Shafiee A¹ ; Nakhaee Z² ; Amini MJ¹ ; Abianeh FE³ ; Goodarzi M³ ; Omran SP³ ; Hajishah H⁴ ; Sadeghi D⁵ ; Nejad AR³ ; Bakhtiyari M⁶
Source: Journal of NeuroVirology Published:2025

Abstract

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. © The Author(s) under exclusive licence to The Journal of NeuroVirology, Inc. 2025.