Effects of Glycine on Mismatch Negativity and the Underlying Theta-Band Signature in the Ketamine Model of Schizophrenia in Healthy Men.
Stjepan Curic, Moritz Haaf, Darius Zokai, Tarik Korkutan, Saskia Rusche, Jonas Rauh, Christoph Mulert, Gregor Leicht
Schizophrenia Bulletin December 14, 2025 DOI: 10.1093/schbul/sbaf227 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Peer reviewed |
|---|---|
| Sample size | 25 |
| Population | Human participants |
| Interventions | Glycine Ketamine |
| Topics | Esketamine Ketamine |
| Keywords | EEG Nmdar modulation P3a |
| Key findings | Glycine prevented ketamine-induced reduction of theta power and phase consistency associated with duration MMN, and elevated theta activity predicted improvement in negative symptoms. |
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.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cites 14
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- The Standardized Psychometric Assessment of Altered States of Consciousness (ASCs) in Humans Pharmacopsychiatry July 1, 1998
- Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia JAMA Network Open May 1, 2020
- Glutamatergic Deficits in Schizophrenia – Biomarkers and Pharmacological Interventions within the Ketamine Model Current Pharmaceutical Biotechnology June 21, 2018
- Effects of Subanesthetic Ketamine Administration on Visual and Auditory Event-Related Potentials (ERP) in Humans: A Systematic Review Frontiers in Behavioral Neuroscience April 16, 2018
and 9 more in the library