Schematic diagram of the glutamate synapse. Receptors most amenable to therapeutic manipulation include the AMPA and NMDA-type glutamate receptors; metabotropic type 2, 3, 5, and 7 receptors (mGluR2, mGluR3, mGluR5, and mGluR7); transporters for glutamate (GLT-1); glycine (GlyT1); and the cystine/glutamate antiporter (XC).

An example biomarker for glutamate-based drug development. (A) MMN is an event-related potential generated in primary auditory cortex. (B to D) Auditory-evoked field potentials (AEP), current source density (CSD), and multiunit activity (MUA) analyses show MMN-related activity in superficial layers of auditory cortex (B) and dose-dependent inhibition by local administration of the NMDAR antagonist PCP (C), leading to a reduction in local summed (SUMREC) current flow (D) (65). (E) In schizophrenia, reductions in MMN generation correlate with overall function, as reflected in the global assessment of function (GAF) score (60). (F) Deficits similar to those observed in schizophrenia are induced in volunteers by acute administration of ketamine (69). (G) Histological investigation of auditory cortex shows reduced glutamatergic pyramidal cell volume, consistent with underlying glutamatergic dysfunction (155). (A) to (D) is reprinted from (65). (E) is reprinted with permission from (60). (F) is reprinted with permission from (69). (G) is reprinted by permission from Macmillan Publishers Ltd. (155), copyright (2009).

(A and B) Effects of the NMDAR antagonist ketamine in unipolar (A) (138) and bipolar (B) depression, showing persistent effect. Adapted from (138) and (140).

Proposed glutamate-based treatment targets for drug abuse, including cystine/glutamate transporter (XC⁻) and the glutamate transporter (GLT-1). NAC, N-acetylcysteine; LTD, long-term depression. Updated from (32).

Schematic model of interactive drug development among academia, government, and pharma, designed to overcome barriers to translational drug development. In this model, biomarkers are developed in a precompetitive space, with pharma providing nonproprietary compounds, expertise, and financial support, which is matched by government and foundations. In addition, baseline genetic and consensus behavioral and biomarker data from clinical trials are pooled to permit comparison among disease states and genotype/phenotype investigation.