Copper Dysregulation in Major Depression: A Systematic Review and Meta-Analytic Evidence for a Putative Trait Marker

Major depressive disorder (MDD) is a leading contributor to global disability. Despite advances in neurobiological research, no reliable peripheral biomarkers are currently available for diagnosis or monitoring. Copper (Cu), an essential trace element involved in redox balance and monoamine metabolism, has been repeatedly associated with MDD, though evidence remains inconsistent. To systematically evaluate and quantify differences in serum Cu concentrations between individuals with MDD and healthy controls, and to explore potential moderators, including sex, age, and analytical methodology. We conducted a systematic review and meta-analysis of observational studies reporting serum Cu levels in MDD patients versus controls. Data were extracted regarding diagnostic criteria, measurement methods, sample characteristics, and study quality. Subgroup and sensitivity analyses were performed based on demographic and methodological variables. Twenty-four studies, including 8617 participants (2736 MDD, 5881 controls), were analyzed. The pooled analysis revealed significantly higher Cu levels in MDD patients (Mean Difference (MD) = 2.22 µmol/L; 95% CI: 0.97-3.48; p = 0.001), although heterogeneity was high (I² = 98.6%). Sub-analysis in females confirmed the association (MD = 1.39 µmol/L; 95% CI: 0.65-2.12; p = 0.009). Results remained robust in sensitivity analyses. Begg's test did not indicate possible publication bias. Our findings support an association between altered Cu homeostasis and MDD. Elevated Cu levels were observed in most studies, including among females and in subclinical cases, suggesting a potential role as a trait biomarker. Standardization in measurement and longitudinal designs is needed to confirm Cu's clinical utility.