Association between serum levels of essential elements (copper, zinc, and iron) and major depressive disorder: a systematic review and meta-analysis.

Abstract

Introduction: Trace elements such as zinc, iron, and copper are integral to neurochemical regulation, oxidative balance, and immune modulation. Their dysregulation has been increasingly implicated in the pathophysiology of Major Depressive Disorder (MDD). This systematic review and meta-analysis aimed to quantify differences in serum levels of zinc, iron, and copper between individuals with MDD and healthy controls.

Content: Sixteen observational studies were included following a comprehensive search of major databases. Data on serum concentrations of zinc, iron, and copper were extracted and pooled using a random-effects model. Standardized mean differences (SMDs) with 95 % confidence intervals (CIs) were calculated. Heterogeneity was assessed using the I² statistic, and publication bias was evaluated via funnel plots and Egger's regression. Sensitivity analyses were conducted to test the robustness of findings.

Summary: Meta-analysis revealed serum copper levels were significantly higher in patients with MDD compared to controls (SMD = +0.42; 95 % CI: +0.18 to +0.66; I²=67.4 %), while zinc (SMD = -0.62; 95 % CI: -0.78 to -0.46; I²=68.4 %) and iron (SMD = -0.36; 95 % CI: -0.52 to -0.20; I²=58.2 %) were lower in MDD patients. Evidence of publication bias was observed for zinc and copper, but adjusted estimates remained significant for zinc and iron.

Outlook: This study demonstrates consistent reductions in serum zinc and iron among individuals with MDD, supporting their potential role in depressive pathophysiology. While copper findings were inconclusive, the stability of zinc and iron results highlights the clinical relevance of micronutrient assessment in depression. These findings provide a foundation for future research in nutritional psychiatry and adjunctive treatment strategies.