Major depressive disorder (MDD) is a debilitating mental illness. For years, the research and development of drugs to be used in MDD focused on the monoaminergic system, leading to the introduction in the market of tricyclic antidepressants, selective serotonin/noradrenaline reuptake inhibitors and monoamine oxidase inhibitors. Nonetheless, patients continue to experience low remission rates, frequent relapses and persistent functional impairment. These drawbacks emphasize the need to studying alternative therapeutic targets in order to improve depression treatment efficacy. Herein, ascorbate role in the pathophysiology of MDD is discussed, particularly through the modulation of the glutamatergic system. Moreover, preclinical and clinical data regarding its antidepressant effect in affective disorders is reviewed. The electronic database Pubmed was searched from 2005 to the present date, using the following keywords: "ascorbate", "glutamate", "major depressive disorder", "depression", "ascorbic acid", and "vitamin C". Overall, 31 studies were retrieved, evidencing ascorbate efficacy on reversing depressive symptoms associated with MDD through the modulation of glutamatergic signalling, namely through the l-Arginine-NO-cGMP pathway. The present review supports the high potential of ascorbate in the research of new treatment strategies for MDD and it is expected to be very useful for the development of new target-antidepressant drugs.
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