N-Methyl-D-aspartate (NMDA) receptor-based treatment approaches in schizophrenia: the first decade

The study of excitatory amino acids (EAA) [e.g. glutamate (Glu), aspartate] as neurotransmitters has resulted in many new and fundamental concepts in neuroscience. Much of this progress centres upon the role of N-methyl-D-aspartate (NMDA) subtype of Glu receptors in central nervous system synaptic transmission and plasticity. A leading hypothesis suggests that deficits in NMDA receptor-mediated neurotransmission may be central to the pathophysiology of schizophrenia. The conceptual foundation of this hypothesis derives from the clinical effects of NMDA receptor antagonists, such as phencyclidine (PCP) and ketamine and from post-mortem findings in brain samples of schizophrenia patients. Consequently, at present there is an intense search for pharmacological strategies capable of facilitating NMDA receptor function in this illness. During the last decade, a first generation of small clinical studies has focused on assessing the therapeutic potential of glycine-(Gly) site agonists of the NMDA receptor, such as Gly, D-serine and D-cycloserine. The results of these studies indicate that this type of compound may reduce negative symptoms and executive cognitive deficits in schizophrenia patients. Furthermore, preliminary findings suggest that patients having low serum Gly levels may represent the population of choice for treatment with Gly-site agonists. Additional potential schizophrenia treatments that may affect mainly NMDA receptor neurotransmission are : (i) other full and partial Gly-site agonists - in course of development for clinical use, and (ii) Gly transport antagonists that can inhibit Gly reuptake from neuronal synapses. Moreover, the antipsychotic action of some typical and atypical neuroleptics may be mediated by their agonistic activity at the strychnine-insensitive NMDA receptor-associated Gly site. After decades of relative neglect, the role of glutamatergic neurotransmission in the pathophysiology and therapeutics of schizophrenia is presently in process of conceptualization. In this context, it is likely that the development of NMDA receptor-based approaches for the treatment of this illness will continue. This trend is already supported by available clinical findings with Gly-site agonists and may herald an important, innovative development in the pharmacological treatment of neuropsychiatric syndromes.