Risk factors, protective factors, peripheral biomarkers, and neurocognitive markers associated with mood disorders: An umbrella review of 103 meta-analyses and systematic reviews

Brain Behav Immun Health. 2025 Jul 19;48:101068. doi: 10.1016/j.bbih.2025.101068. eCollection 2025 Oct.

ABSTRACT

BACKGROUND: Mood disorders, including bipolar disorder (BD) and major depressive disorder (MDD), are extensively studied regarding environmental risk factors, protective factors, peripheral biomarkers, and cognitive neurocognitive markers. Our umbrella review of observational studies aims to separately elucidate these associations with BD and MDD.

METHODS: A comprehensive search of PubMed, Embase, Web of Science, and Cochrane was conducted, with a search end date of October 17, 2024. We included systematic reviews that provided meta-analyses of observational studies that examined associations of potential environmental risk factors, environmental protective factors, peripheral biomarkers and neurocognitive markers with mood disorder. We synthesized data using summary effect estimates (e.g., odds ratio [OR], relative risk [RR]), evaluated quality with AMSTAR 2. This review is registered with PROSPERO (CRD42023439581).

RESULTS: Identified 103 articles from 2782 initially screened. In depression, we identified 95 risk factors, 18 protective factors, 19 biomarkers, and 10 neurocognitive markers. For MDD, evidence of association was convincing (class I) history of mental illness (OR 6.77, 95 %CI 5.07-9.04), perinatal domestic violence exposure (OR 3.14, 95 %CI 2.74-3.61), and Mediterranean diet adherence (OR 0.87, 95 %CI 0.84-0.91). For BD, evidence of association was suggestive (class Ⅲ) for cannabis use (OR 2.97, 95 %CI 1.80-4.90), obesity (OR 1.77, 95 %CI 1.40-2.23) were prominent risk factors. The evidence levels of biomarkers and cognitive neuro-markers for BD and MDD are at suggestive (class Ⅲ) or below.

CONCLUSION: This review highlights the complexity of the interrelationship between mood disorders and numerous risk and protective factors. However, the reviewed associations are not necessarily causal. Future research should prioritize prospective high-quality studies to establish causality and thus facilitate the development of targeted interventions and preventive measures for mood disorders.

PMID:40741164 | PMC:PMC12309926 | DOI:10.1016/j.bbih.2025.101068