Proton magnetic resonance spectroscopy ((1)H MRS) measures glutamatergic metabolites namely glutamate and glutamine located in neurons and astrocytes respectively. In this meta-analysis the contribution of glutamatergic neurotransmission to depressive symptoms was evaluated together with other putative prefrontal metabolites described in the pathogenesis of mood disorders, and in relation to treatment effects. A comprehensive literature search up to 2014 identified 17 reports which measured absolute concentrations of neurometabolites in the prefrontal cortex with (1)H MRS meeting criteria for inclusion in this meta-analysis. Excess of heterogeneity was investigated with meta-regressions. The analyses showed an exclusive reduction in absolute values of the composite measure of Glutamine and Glutamate (Glx) in the prefrontal cortex in depression, correlating in meta-regression analyses with treatment severity. Glutamate measurements in isolation did not differ vs. healthy controls or in relation to treatment and/or clinical improvement. Similarly there were no significant changes in other neurometabolites at baseline and following treatment. The analysis supports a role for glutamatergic dysfunction in the pathogeneses of mood dysregulation. The reduction in the absolute Glx values in the absence of changes in glutamate levels, suggests a possible modulatory role of astrocytes in the pathophysiology of depression.