Abstract

Treatment-resistant depression (TRD) occurs in about 30% of patients with major depressive disorder who have not achieved an adequate therapeutic response after two or more lines of treatment with antidepressants, provided that they have taken each selected antidepressant for a sufficient period of time and at the appropriate dose. Numerous factors are associated with the etiopathogenesis of TRD, one of the significant ones being the neurotransmitter glutamate. In excessive concentrations in the extracellular space, glutamate causes excitotoxicity, further leading to the release of proinflammatory cytokines and the development of neuroinflammation. This results in damage to neurons in brain regions responsible for emotional behavior and mood regulation, which may clinically manifest as TRD. Treating TRD poses a great challenge for clinicians because, despite the numerous current pharmacological and non-pharmacological treatment methods, there is a great need for new and more effective treatment strategies. Esketamine represents a new therapeutic possibility in the treatment of TRD. Unlike traditional antidepressants, it acts as an antagonist to glutamatergic NMDA receptors, it is administered intranasally, and has acute effects. Due to its unique mechanism of action, it can be effective in treating TRD by enhancing the signaling of neurotrophic factors and synaptogenesis. Esketamine is increasingly considered as a welcome new pharmacological strategy in the treatment of TRD, while the inhibition of the excitotoxic effects of glutamate places this neurotransmitter increasingly at the center of scientific research.