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Recent advances in research on depression have confirmed that it is common, recurrent and disabling mental disorder affecting millions of individuals worldwide. Current medications for the treatment of depression have limited efficacy and delayed onset of therapeutic action. Existing antidepressants used to treat these disorders are insufficient for many. Patients continue to have low remission rates, delayed onset of action, residual subsyndromal symptoms, and relapses. New therapeutic agents able to exert faster and more sustained antidepressant effects are urgently needed to treat these disorders. Multiple lines of evidence suggest that inşammation and glutamate dysfunction contribute to the pathophysiology of depression. Excess levels of inşammatory mediators occur in a subgroup of depressed patients. Patients with depression have been found to exhibit increased blood inşammatory biomarkers, including inşammatory cytokines, which have been shown to be involved in depression. Activation of inşammatory pathways is believed to contribute to a conşuence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with findings that characterize depressive disorders. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) are involved in the pathogenesis of mood disorders and in the action of at least some drugs. It has been shown that serum BDNF levels are decreased in patients with depressive disorder and antidepressant treatment induces BDNF expression. In this context, the glutamatergic system has been implicated in the pathophysiology of depression in unique clinical and neurobiological ways. The data from depressed patients, suggest that inhibiting proinşammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. The past decade of efforts to find improved treatment for depression has been dominated by genome-driven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. To date, the monoaminergic systems (serotonin, norepinephrine, and dopamine) have received the most attention in the neurobiology of depression, and all classes of antidepressants target these monoaminergic systems. Accumulating evidence suggests that the glutamatergic system plays an important role in the neurobiology and treatment of depression. Many reports have highlighted alterations in glutamate signaling as well as changes in the expression of AMPA or NMDA receptor subunits in depression. In parallel, there is growing interest in the non-competitive NMDA receptor antagonist, ketamine, which produces a rapid and sustained antidepressant response in patients with treatment-resistant depression. Importantly, such effects of ketamine are seen at subpsychomimetic doses of the drug. Moreover, ketamine produces a profound reduction in suicidality. Based on findings with ketamine, there is interest in developing subtype-selective NMDA antagonists, particularly those that act through allosteric mechanisms. A final glutamatergic strategy for treating depression may be through modulating metabotropic (G protein-coupled) glutamate (mGlu) receptors. During the last 10 years, several selective mGlu receptor competitive antagonists and potentiators have been discovered. Selective mGlu receptor antagonists are among the most promising agents under development for the treatment of depression. Overall, this system holds considerable promise for developing the next generation of therapeutics for the treatment of depression.