Association between Serum Homocysteine and Depression: A Systematic Review and Meta-analysis of Case-control and Cohort Study Designs

Depression is a heterogeneous disorder arising from complex interactions among various biological, psychological, and environmental factors.Hyperhomocysteinemia is known to cause direct neurotoxicity and vascular damage.However, the relationship between elevated homocysteine levels and depression remains inconclusive.This systematic review and meta-analysis aimed to evaluate the association between homocysteine levels and depression.From January 2024 PubMed, Ovid MEDLINE, and EMBASE were searched for case-control and cohort studies reporting homocysteine levels in individuals with depression and non-depressed controls.Randomized controlled trials,case reports,reviews, non-English publications were excluded.Risk of bias was assessed using the Newcastle-Ottawa Scale.A random-effects meta-analysis was performed using R (version 4.3.0),and standardized mean differences (SMDs) were calculated.Nine studies comprising 477 patients with depression and 378 controls were included.The pooled analysis demonstrated significantly higher homocysteine levels in individuals with depression (SMD = 1.02; 95% confidence interval: 0.40-1.63).However, substantial heterogeneity was observed (I 2 = 88.7%, 2 = 0.80, p ＜ 0.0001).Subgroup and sensitivity analyses indicated that heterogeneity was partly influenced by study characteristics and outlier effects.The prediction interval spanned both sides of the null, suggesting variability in the direction and magnitude of the association across populations.Most studies were case-control in design, limiting causal inference.Significant inter-study heterogeneity and limited sample sizes also affect the generalizability of results.Elevated homocysteine levels are associated with depression; however, the evidence is heterogeneous and observational.These findings should be considered hypothesis-generating.Further longitudinal and interventional studies are required to clarify causality and determine clinical relevance.