Current Glutamatergic Treatments and Future Directions for Glutamate-Based Management of Chronic Stress and Stress-Related Disorders

The recent Food and Drug Administration and European Medicine Agency regulatory approval of intranasal (S)-Ketamine for the treatment-resistant depression in adults and its quick introduction in everyday psychiatric practice might be considered as a second revolution in the field of neuropsychopharmacology after the first one, which started over 50 years ago with the discovery of the monoaminergic antidepressants. This chapter will present the critical antidepressant features of Ketamine, including its putative mechanisms of action and other Ketamine-like glutamatergic drugs in development for the treatment of chronic stress-related psychiatric disorders. First, a detailed picture of NMDA-dependent and independent glutamatergic mechanisms mediating Ketamine effects will be given. The following section will be dedicated to an in-depth description of cellular and molecular mechanisms which have been suggested to underlie the fast antidepressant properties of Ketamine. Alternative investigational therapeutic uses of Ketamine (besides as an antidepressant) will then be presented, followed by the description of other glutamatergic drugs which received significant attention for their potential antidepressant effects. The following part will be dedicated to limitations related to Ketamine use. Finally, we will share our insights and provide recommendations on the future perspectives in the prevention and early management of chronic stress and stressrelated disorders, focusing on glutamate-based aspects of proposed interventions.