N-methyl-d-aspartate-type glutamate receptor modulators and related medications for the enhancement of auditory system plasticity in schizophrenia

Deficits in N-methyl-d-aspartate-type (NMDAR) function contribute to cognitive deficits in schizophrenia, particularly dysfunction in neuroplasticity, defined as reduced learning during training on exercises that place implicit, increasing demands on early sensory (auditory and visual) information processing. Auditory mismatch negativity (MMN) can be both a target engagement biomarker for the NMDAR and a proxy measure of neurophysiological plasticity. This review covers the evidence for using NMDAR modulator and related compounds for enhancement of cognition, with a particular focus on early auditory processing/plasticity. Compounds covered include glycine site agonists, glycine and system A-type transporter inhibitors, d-amino acid oxidase inhibitors, memantine and nicotinic alpha-7 acetylcholine receptor agonists. As opposed to daily treatment studies focusing on schizophrenia in general, intermittent, non-daily treatment combining NMDAR modulators with neuroplasticity-based paradigms, using MMN as target-engagement biomarkers show promise as treatments to both remediate plasticity deficits and overall functional deficits.