In the last decades, multiple studies have suggested evidences of disturbances within the glutamate system in depressed patients. The first clinical study using ketamine in depression treatment was conduct fifteen years ago. Since then several studies tried to understand the mechanisms underlying the antidepressant effects of ketamine, as well as discover new drugs with better pharmacodynamic profiles.

Review the literature on the role of glutamate system in depression and novel approaches with glutamate N–methyl–D–aspartate receptor antagonists in depression.

Search and review of scientific literature on PubMed database with the keywords.

“major depressive disorder”, “depression”, “ketamine”, “glutamate”, “NMDA”, “neuroplasticity”.

Abnormalities of the glutamate clearance at synaptic space and astrocytic dysfunction associated with glutamate metabolism have been associated with depressive symptomatology. In depressed patients, reduced levels of glutamate have been described by magnetic resonance spectroscopy in multiple cortical areas, amygdala and hippocampus, supportting the hypothesis of glutamate system involvement in the neurobiology of depression. Indeed, in the last 15 years, multiple clinical studies using ketamine provided some evidence that glutamate N–methyl–D–aspartate receptor antagonism could be an approach for refractory forms of depression. However, regardless all of the evidences, no drug targeting specifically the glutamate system has been approved for depression treatment.

The glutaminergic system plays a role in the pathophysiology of depression, why it's a possible therapeutic target. So, it's of utmost importance that future studies keep the focus in this area, looking for new drugs active in this system.