In the January 1999 issue of the ARCHIVES, Farber et al1 provided a commentary on some of the current issues pertinent to the N-methyl-D-aspartate (NMDA) receptor hypofunction model of schizophrenia. It was appropriately stated that "a major underpinning of the hypothesis is that NMDA receptor hypofunction induced by various NMDA receptor antagonist drugs precipitates a transient psychotic state . . . "1(p13) The noncompetitive NMDA receptor antagonists evoke positive symptoms, negative symptoms, and cognitive impairments similar to the schizophrenia syndrome. The commentary further noted that NMDA receptor antagonists can induce excitotoxic cell death, most likely through the increased release of glutamate. This hypothesis provides no clear mechanism whereby NMDA receptor antagonists induce the schizophrenialike syndrome. Furthermore, a widespread increase in glutamate release would most likely result in seizures and complete loss of function.
Greene R, Bergeron R, McCarley R, Coyle JT, Grunze H. Short-term and Long-term Effects of N-Methyl-D-Aspartate Receptor Hypofunction. Arch Gen Psychiatry. 2000;57(12):1180-1181. doi:10.1001/archpsyc.57.12.1180