BackgroundStudies have shown an association between depression and circulating metabolites, but the causal relationship between them has not been elucidated. The purpose of this study was to elucidate the causal relationship between circulating metabolites and depression and to explore the role of circulating metabolites in depression. MethodsIn this study, the top single-nucleotide polymorphisms (SNPs) associated with circulating metabolites (n = 24,925) and depression (n = 322,580) were obtained based on the publicly available genome-wide association study using two-sample Mendelian randomization (MR). SNP estimates were summarized through inverse variance weighted, MR Egger, weighted median, MR pleiotropy residual sum and outlier, and "leave-one-out" methods. ResultsApolipoprotein A-I (OR 0.990, 95% CI 981-0.999) and glutamine (OR 0.985, 95% CI 0.972-0.997) had protective causal effects on depression, whereas acetoacetate (OR 1.021, 95% CI 1.009-1.034), glycoproteins (OR 1.005, 95% CI 1.000-1.009), isoleucine (OR 1.013, 95% CI 1.002-1.024), and urea (OR 1.020, 95% CI 1.000-1.039) had an anti-protective effect on depression. Reversed MR showed no effect of depression on the seven circulating metabolites. ConclusionIn this study, MR analysis showed that apolipoprotein A-I and glutamine had a protective effect on depression, and acetoacetate, glycoprotein, isoleucine, glucose, and urea may be risk factors for depression. Therefore, further research must be conducted to translate the findings into practice.