CHAPTER 4:Glutamatergic Approaches for the Treatment of Schizophrenia

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system and plays a key role in most aspects of normal brain function including cognition, learning and memory. Dysfunction of glutamatergic neurotransmission has been implicated in a number of neurological and psychiatric disorders with a growing body of evidence suggesting that hypofunction of glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor plays an important role in the pathophysiology of schizophrenia. It thus follows that potentiation of NMDA receptor function via pharmacological manipulation may provide therapeutic utility for the treatment of schizophrenia and a number of different approaches are currently being pursued by the pharmaceutical industry with this aim in mind. These include strategies that target the glycine/d-serine site of the NMDA receptor (glycine transporter GlyT1, d-serine transporter ASC-1 and d-amino acid oxidase (DAAO) inhibitors) together with those aimed at enhancing glutamatergic neurotransmission via modulation of AMPA receptor and metabotropic glutamate receptor function. Such efforts are now beginning to bear fruit with compounds such as the GlyT1 inhibitor RG1678 and mGlu2 agonist LY2140023 proving to have clinical meaningful effects in phase II clinical trials. While more studies are required to confirm long-term efficacy, functional outcome and safety in schizophrenic agents, these agents hold real promise for addressing unmet medical needs, in particular refractory negative and cognitive symptoms, not currently addressed by existing antipsychotic agents.