Depression Linked to Low Zinc Levels in Blood

People who are depressed have lower concentrations of zinc in their peripheral blood compared with nondepressed individuals, a meta-analysis suggests.

"The pathophysiological relationships between zinc status and depression, and the potential benefits of zinc supplementation in depressed patients, warrant further investigation," write Walter Swardfager, PhD, from the Sunnybrook Research Institute, University of Toronto, Canada, and colleagues.

Their findings were published in the December 15 issue of Biological Psychiatry.

Link to Zinc Deficiency
"A growing body of evidence demonstrates that experimental zinc deficiency can induce depressive-like behavior in animals, which can be effectively reversed by zinc supplementation," the authors write. Furthermore, preliminary clinical trials have suggested that zinc added to antidepressant therapy may produce more rapid or more effective improvement in depressive symptoms.

Many, although not all, studies that have measured zinc concentrations of peripheral blood in depressed and nondepressed individuals during the past several decades have suggested that depression might be associated with lower zinc concentrations in various population samples, the researchers note.

The aim of this meta-analysis was to determine whether the clinical evidence collectively supports lower zinc concentrations in depressed patients compared with nondepressed individuals.

The analysis included 17 studies that measured peripheral blood–zinc concentrations in 1643 depressed patients and 804 control participants. Ten of these studies reported on psychiatric inpatients, and 7 reported on community samples. Of the participants, 34.4% were male; the mean age was 37.7 years.

The researchers found that mean peripheral blood–zinc concentrations were lower by approximately 1.85 µmol/L in depressed individuals compared with control participants (95% confidence interval [CI], -2.51 to -1.19; P < .00001).

More severe depression was associated with greater differences in zinc levels between depressed and control participants (P = .026).

Further, the authors report that effect sizes were larger in studies of inpatients (weighted mean difference [WMD], -2.543; 95% CI, -3.522 to -1.564; P < .0001) vs community samples (WMD, -.943; 95% CI, -1.563 to -.323; P = .003) and in studies with higher methodologic quality (WMD, -2.354; 95% CI, -2.901 to -1.807; P < .0001).

Biologically Plausible
"Although association studies cannot determine the direction of causation, a causal association between zinc status and depression is biologically plausible," the authors write.

"Zinc has antioxidant properties, helps to maintain endocrine homeostasis and immune function, and plays multiple roles in regulating the hippocampal and cortical glutamatergic circuits that subserve affective regulation and cognitive function. Thus, changes in zinc homeostasis might compromise neuroplasticity and contribute to long-term neuropsychological and psychiatric decline," they write.

Zinc also plays an important role in immune function. Lower serum levels of zinc have been associated with disturbances in fatty acid metabolism and in serum lipid levels, which might affect brain function and vascular health. Lower zinc levels have also been associated cardiovascular disease, a common comorbidity of major depressive disorder (MDD), the authors note.

The investigators point out limitations of their study. The quality and risk of bias "were uneven among studies included in this meta-analysis," they write.

Not all studies reported demographic data "sufficiently to be included in investigations of heterogeneity, the use of antidepressants and other concomitant medications were not consistently reported, and data on diet and alcohol use were often not reported," the authors write.

Limitations notwithstanding, the authors conclude that their results suggest that depression is associated with reduced concentrations of zinc in peripheral blood.

"The findings suggest the need to further investigate potential roles of zinc in the pathophysiology of depression, the potential utility of zinc and related biomarkers in monitoring MDD and its clinical sequelae, and potential benefits of zinc supplementation in MDD patients," they conclude.

The study was supported by the Ontario Mental Health Foundation. Dr. Swardfager was supported by fellowships from the Heart and Stroke Foundation Center for Stroke Recovery and the Toronto Rehabilitation Institute. Dr. Swardfager and the other authors report no relevant financial relationships.