Recent data suggests that the glutamatergic system is involved in the pathophysiology and treatment of major depressive disorder (MDD) and that the N-

Introduction: Current antidepressant therapies exhibit low therapeutic efficiency and delayed onset of antidepressant action. Thus, the search for better acting agents is a continuous process. One of the primary targets for the development of new antidepressant drugs is the glutamate N-methyl-D-aspartate (NMDA) receptor. Areas covered: The present review aims to summarize and provide an update on published preclinical data evaluating the antidepressant efficacy of various NMDA antagonists and their mechanisms of action. The review also provides an update on the clinical efficacy of ketamine and esketamine as well as other NMDA receptor antagonists based on published results from clinical studies. Expert opinion: The recent approval of esketamine by the FDA for the treatment of major depressive disorder (MDD) culminates the almost 30 years of research focused on the NMDA receptor as a target for the development of antidepressants. This action gives hope to patients who do not respond to currently available pharmacotherapy. While knowledge of the mechanism of action of ketamine/esketamine will pave the way for the creation of a new class of antidepressants, recent results have shown that several issues regarding the use of these compounds or other NMDA receptor antagonists must be clarified.

The results from numerous studies have shown that an imbalance between particular neurotransmitters may lead to brain circuit dysfunction and development of many pathological states. The significance of glutamate pathways for the functioning of the nervous system is equivocal. On the one hand, glutamate transmission is necessary for neuroplasticity, synaptogenesis, or cell survival, but on the other hand an excessive and long-lasting increased level of glutamate in the synapse may lead to cell death. Under clinical conditions, hyperactivity of the glutamate system is associated with ischemia, epilepsy, and neurodegenerative diseases such as Alzheimer’s, Huntington’s, and many others. The achievement of glutamate activity in the physiological range requires efficient control by endogenous regulatory factors. Due to the fact that the free pool of ion Zn²⁺is a cotransmitter in some glutamate neurons; the role of this element in the pathophysiology of a neurodegenerative diseases has been intensively studied. There is a lot of evidence for Zn²⁺dyshomeostasis and glutamate system abnormalities in ischemic and neurodegenerative disorders. However, the precise interaction between Zn²⁺regulative function and the glutamate system is still not fully understood. This review describes the relationship between Zn²⁺and glutamate dependent signaling pathways under selected pathological central nervous system (CNS) conditions.

(2014). NMDA antagonists under investigation for the treatment of major depressive disorder. Expert Opinion on Investigational Drugs: Vol. 23, No. 9, pp. 1181-1192.