Auditory System Target Engagement During Plasticity-Based Interventions in Schizophrenia: A Focus on Modulation of N-Methyl-D-Aspartate–Type Glutamate Receptor Function

Joshua T. Kantrowitz, Neal R. Swerdlow, Walter Dunn, Sophia Vinogradov

Research output: Contribution to journalReview articlepeer-review

19 Scopus citations


Cognitive deficits are predictive of long-term social and occupational functional deficits in schizophrenia but are currently without gold-standard treatments. In particular, augmentation of auditory cortical neuroplasticity may represent a rate-limiting first step before addressing higher-order cognitive deficits. We review the rationale for N-methyl-D-aspartate–type glutamate receptor (NMDAR) modulators as treatments for auditory plasticity deficits in schizophrenia, along with potential serum and electroencephalographic target engagement biomarkers for NMDAR function. Several recently published NMDAR-modulating treatment studies are covered, involving D-serine, memantine, and transcranial direct current stimulation. While all three interventions appear to modulate auditory plasticity, direct agonists (D-serine) appear to have the largest and most consistent effects on plasticity, at least acutely. We hypothesize that there may be synergistic effects of combining procognitive NMDAR-modulating approaches with auditory cortical neuroplasticity cognitive training interventions. Future studies should assess biomarkers for target engagement and patient stratification, along with head-to-head studies comparing putative interventions and potential long-term versus acute effects.

Original languageEnglish (US)
Pages (from-to)581-590
Number of pages10
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
Issue number7
StatePublished - Jul 2018

Bibliographical note

Funding Information:
This work was supported in part by National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Grant No. UL1 RR024156 (to JTK); a Dr. Joseph E. and Lillian Pisetsky Young Investigator Award for Clinical Research in Serious Mental Illness (to JTK); Grant Nos. MH59803 and MH94320 (to NRS); the Brain & Behavior Research Foundation (to NRS); and Grant No. MH068725 (to SV).

Funding Information:
JTK reports having received consulting payments within the last 24 months from Krog & Partners Inc., Kinetix Group, Annenberg Center for Health Sciences at Eisenhower, Semantics MR Ltd., Transperfect, and Cowen and Company; conducted clinical research supported by the National Institute of Mental Health, the Stanley Foundation, Taisho, Lundbeck, Boehringer Ingelheim, NeuroRX, Merck, and Lilly within the last 24 months; and owning a small number of shares of common stock in GlaxoSmithKline. SV is a site investigator on a Small Business Innovation Research grant to Positscience Inc., a company with a commercial interest in cognitive training software; and is on the Scientific Advisory Board of Mindstrong and Alkermes. All other authors report no biomedical financial interests or potential conflicts of interest.

Publisher Copyright:
© 2018 Society of Biological Psychiatry


  • Biomarker
  • Cognition
  • MMN
  • NMDA
  • Plasticity
  • Schizophrenia
  • Treatment


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