Drug development in schizophrenia: are glutamatergic targets still worth aiming at?

The ketamine model has dominated drug discovery in schizophrenia over the past decade, supported by genetic and postmortem evidence implicating glutamatergic transmission. This review assesses recent successes and disappointments of glutamatergic agents and identifies promising new directions.

Strategies focused on enhancing activity of the N-methyl D-aspartate (NMDA) receptor via direct agonists at the glycine site or by inhibition of glycine reuptake have produced modest and often inconsistent evidence of efficacy, as have approaches to reduce excessive glutamate release by lamotrigine or by mGluR2/3 agonists. Strategies targeting α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors have also met with only limited success. Newer approaches include selective allosteric modulation of NMDA receptor subunits and of mGluR5 receptors. In addition, intracellular pathways downstream of NMDA receptors may also provide new treatment targets, as exemplified by phosphodiesterase (PDE) inhibitors.

Targeting glutamatergic transmission remains one of the most promising strategies in schizophrenia, particularly early in the course of illness, but therapeutic approaches may require greater specificity for receptor subtype type, illness phase, and individual biology in order to enhance efficacy and overcome problems with reproducibility of clinical results.