Association between total cholesterol and depression or depressive symptoms: A systematic review and meta-analysis accounting for comparator comorbidity.

BACKGROUND

The association between total cholesterol (TC) and depression remains uncertain because study populations, depression ascertainment, comparator groups, metabolic comorbidity, and study precision vary substantially. We conducted a systematic review and meta-analysis to quantify group differences in TC and to evaluate the influence of comparator comorbidity, study characteristics, and small-study effects.

METHODS

PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to January 9, 2026. Observational studies reporting TC in participants with depression or depressive symptoms and a comparator group were included. Hedges'g was pooled using random-effects models with Hartung-Knapp-Sidik-Jonkman (HKSJ) inference. We report 95% confidence intervals (CIs), prediction intervals (PIs), and heterogeneity statistics. Prespecified analyses considered reported cardiovascular disease (CVD), diabetes mellitus (DM), depression ascertainment, study design, population characteristics, and potential overlap among database-derived studies. Random-effects meta-regression evaluated associations of effect size with standard error and log-transformed sample size.

RESULTS

Forty-four studies involving 491,854 participants were included. Among studies without reported CVD or DM in either group, the pooled SMD was 0.43 (95% CI, 0.05 to 0.81; 95% PI, -1.54 to 2.40; I2 = 99.84%). The association was not statistically significant in studies reporting CVD (SMD = 0.14, 95% CI, -0.12 to 0.41) or DM (SMD = 0.55, 95% CI, -0.17 to 1.27). In studies with CVD-matched controls, the pooled SMD was 0.08 (95% CI, -0.20 to 0.37). Effect size was positively associated with study standard error, whereas its association with log-transformed sample size was not statistically significant.

CONCLUSIONS

The pooled average TC difference was positive but should be interpreted cautiously because of extreme heterogeneity, wide prediction intervals, heterogeneous comparator definitions, and possible small-study effects. Current aggregate-data evidence does not establish a consistent or clinically meaningful depression-specific difference in TC or support its use as a depression-specific biomarker. Nonlinear or range-specific associations cannot be excluded.