Do NMDA-R Antagonists Re-Create Patterns of Spontaneous Gamma-Band Activity in Schizophrenia? A Systematic Review and Perspective

Introduction

Bianciardi and colleagues situate their review within the debate over the role of N-methyl-D-aspartate receptor (NMDA-R) hypofunction in the pathophysiology of schizophrenia. Earlier research has shown that NMDA-R antagonists such as ketamine and phencyclidine can transiently produce a range of schizophrenia-like symptoms and cognitive deficits in healthy volunteers, and post-mortem, genetic and imaging data implicate NMDA-R abnormalities—including reductions in NR1 subunits and effects on interneurons enriched for GAD67—in the disorder. Because parvalbumin-positive GABAergic interneurons and NMDA/AMPA receptor interactions are central to generating gamma-band oscillations (approximately 30–200 Hz), the authors reason that NMDA-R hypofunction could perturb excitation/inhibition (E/I) balance and thereby alter spontaneous gamma-band amplitude and network organisation. To test whether pharmacological NMDA-R hypofunction recreates the gamma-band signatures reported in schizophrenia, the study reports a systematic review comparing effects of NMDA-R antagonists on spontaneous gamma-band power and functional connectivity in preclinical and human studies with resting-state EEG/MEG findings from clinical high-risk, first-episode and chronic schizophrenia samples. The primary aim was to establish consistency between antagonist-induced changes and patient data; a secondary aim examined effects on functional connectivity. The review included 24 preclinical studies, 9 human NMDA-R antagonist studies, and 27 resting-state EEG/MEG studies in schizophrenia patients.