Overcoming antidepressant treatment resistance: Focus on glutamate

Current antidepressant treatments have a delayed onset of action and limitations in efficacy, particularly for patients who fail to respond to 2 or more antidepressant trials. Translational neuroscience offers the potential for the development of a new generation of antidepressants with novel mechanisms of action. Antidepressants with targets outside the monoamine system may offer the potential for more rapid onset of action and improved efficacy in treatment-resistant patients. There is now compelling evidence for glutamatergic dysfunction in the pathophysiology of major depression. These findings have prompted vigorous investigation of the glutamate system as a central target for antidepressant drug discovery. In particular, there is now substantial initial evidence for rapid-onset antidepressant properties of the N-methyl-D-aspartate glutamate receptor antagonist ketamine. Ongoing research aims to characterize the safety, feasibility, and efficacy of single-dose and repeated-dose intravenous ketamine, and will explore optimal delivery methods, means to minimize neuropsychiatric side effects, and relapse prevention. Strategies understanding the mechanism of therapeutic benefit of ketamine is an important research goal, with functional neuroimaging investigations implicating the anterior cingulate cortex. More broadly, neuroimaging techniques may help identify depression biomarkers associated with response, and may thereby facilitate rational drug discovery.