Effects of Glycine on Mismatch Negativity and the Underlying Theta-Band Signature in the Ketamine Model of Schizophrenia in Healthy Men.

Deficits in automatic auditory processing, measured by mismatch negativity (MMN), are linked to poor outcomes in schizophrenia and involve glutamate dysfunction. In a placebo-controlled crossover EEG study with 25 participants, ketamine—which induces schizophrenia-like symptoms—reduced MMN amplitudes, theta power, and P3a. Pretreatment with glycine, an NMDAR coagonist, did not prevent ketamine's effects on MMN or P3a amplitude but did block ketamine's reduction of theta power and phase consistency associated with duration deviant MMN. Elevated theta activity due to glycine predicted improvement in negative symptoms. The findings confirm the glutamate system's role in pre-attentive auditory processing deficits and suggest MMN's theta signature may help identify patients responsive to glutamatergic treatments.

Study at a glance

Abstract

Pre-attentive information processing deficits are associated with poor outcomes in schizophrenia. The auditory mismatch negativity (MMN), observed when an auditory signal changes, is reduced in schizophrenia, related to glutamatergic dysfunction and is considered a response biomarker. We hypothesized that glycine, an N-methyl-d-aspartate receptor (NMDAR) coagonist, could reverse the NMDAR-antagonistic effects of ketamine, which produces schizophrenia-like clinical symptoms and neurophysiological changes. Using a placebo-controlled crossover design, this 64-channel electroencephalography (EEG) study assessed psychopathological changes using the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness (5D-ASC) scale in 25 participants. MMN responses to duration (dMMN) and frequency deviant tones, their underlying theta-band activity and sources, P3a, and associations were examined. Ketamine induced schizophrenia-like symptoms, and reduced MMN amplitudes, theta power, and P3a. While glycine did not modulate ketamine's effect on the (time-domain) MMN or P3a amplitude, it did prevent the effect of ketamine on dMMN-associated theta power and phase consistency. The underlying theta power was associated with auditory alterations, and elevated theta activity due to glycine pretreatment predicted a clinically relevant improvement in negative symptoms. This is the first study in humans to investigate the effects of glycine on the MMN in the ketamine model of schizophrenia. The results confirm a key role of the glutamate system for pre-attentive auditory processing deficits underlying the symptoms of schizophrenia. From a translational perspective, the MMN and its theta-band signature may serve as biomarkers to identify patients who may benefit from glutamatergic treatment options.