Is NMDA Receptor Hypofunction in Schizophrenia Associated With a Primary Hyperglutamatergic State?

In reply

Anand et al¹ recently reported that lamotrigine, an inhibitor of presynaptic glutamate (Glu) release, attenuates the psychotomimetic effects of ketamine.¹ They proposed that their findings are consistent with the N-methyl-D-aspartate (NMDA) receptor hypofunction (NRHypo) hypothesis of schizophrenia, a hypothesis that we, among others, have promulgated. Shim and Adityanjee,² in their letter to the editor, argue that the findings of Anand et al are not consistent with the NRHypo hypothesis because this hypothesis explains psychotic symptoms in terms of Glu hypofunction and predicts that drugs that promote Glu transmission will correct the Glu hypofunction, and will thereby correct a schizophrenic psychosis. Since lamotrigine would be expected to suppress rather than promote Glu transmission, Shim and Adityanjee argue that Anand et al are incorrect to suggest that their findings support the NRHypo hypothesis.