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Objective This study aimed to assess the association between homocysteine (Hcy) levels and cognitive function in individuals with depression using a systematic review and meta-analysis. Methods We searched PubMed, Web of Science, EMBASE, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and the Chinese Science and Technology Journal Database (VIP) for studies reporting Hcy levels and cognitive outcomes in patients with depression from inception to December 2025. Methodological quality was assessed using the Agency for Healthcare Research and Quality (AHRQ) checklist, evidence certainty was evaluated using the GRADE approach, and meta-analyzes were performed using random-effects models in Stata 17.0. Results A total of 13 studies involving 1,269 patients with depression were included. The meta-analysis showed a significant inverse association between Hcy levels and cognitive scores ( r = −0.41, 95% CI: −0.57 to −0.22, p 0.001). High Hcy levels were associated with poorer cognitive performance (SMD = −0.37, 95% CI: −0.62 to −0.13, p = 0.003). Patients with cognitive impairment (CogI) also had higher Hcy levels than cognitively normal (CogN) individuals (SMD = 2.44, 95% CI: 0.86 to 4.01, p = 0.003). Conclusions Hcy levels are associated with CogI in patients with depression, and subgroup analyzes and leave-one-out sensitivity analyzes indicate that the direction of the association is generally consistent. Further prospective studies are needed to clarify the clinical relevance of Hcy and whether it may contribute to the assessment of cognitive impairment in depression. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420251206956.
Liu et al. (Wed,) studied this question.