The Role of Noncompetitive Antagonists of the N-Methyl-d-aspartate (NMDA) Receptors in Treatment-Resistant Depression

Emerging evidence indicates that non-monominergic drugs could hold promise as novel antidepressants, particularly in the case of treatment resistance. Particular attention has recently been focused on the NMDA antagonist ketamine, as a useful clinical agent in cases of severe intractable depression and suicidal risk. Importantly, ketamine works rapidly in many such patients; however, the drug is not devoid of adverse effects. Hence, it is of critical importance to develop alternate NMDA or other novel antidepressants as well as possible combinatorial drug approaches to treat depression. For instance, novel agents that target AMPA receptors are currently being explored; it has been found that compounds able to exert neurotrophic effects and anti-inflammatory drugs might be useful as add-on (or adjuvants) with traditional antidepressants. Whatever the case, it is clear that future antidepressant approaches will target a variety of parallel and overlapping processes that ultimately contribute to the unique profile of symptoms that each patient exhibits