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Despite the tremendous personal agony and societal burden associated with major depressive disorder (MDD), we have not been able to significantly improve the effectiveness of our treatments for more than 5 decades. Large real-world studies, such as the Sequenced Treatment Alternatives to Relieve Depression (STAR*D),1 have presented us with humbling data on the relatively low rates of sustained remission associated with our current armamentarium of therapeutic options and have led many in the field to suggest that future targets for antidepressant drug development should be based on a deeper understanding of the pathophysiologic mechanisms underlying the disorder and not the “me-too” approach that has dominated the field. Accumulating evidence now suggests that dysregulation of the glutamatergic neurotransmitter system and its effects on neuroplasticity may play a critical role in the pathophysiology of depression and may thus provide a viable target for future drug development.2
Sanacora G. What Are We Learning From Early-Phase Clinical Trials With Glutamate Targeting Medications for the Treatment of Major Depressive Disorder. JAMA Psychiatry. 2016;73(7):651-652. doi:10.1001/jamapsychiatry.2016.0780