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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
Authors
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Authors Affiliations
  1. 1. Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
  2. 2. Student Research Committee, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
  3. 3. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. School of Medicine, Islamic Azad University of Medical Sciences, Tehran, Iran
  5. 5. School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  6. 6. Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran

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.
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