Baseline Mismatch Negativity Amplitude Predicts Direction and Magnitude of Ketamine Effect in Healthy Volunteers: A Disordinal Effect.
Marco Cecchi, Jason Johannesen, Brandon J Farley, Michael C. Quirk, Mahdi Mahmoud-Zadeh, Jason M Uslaner, Ryan Terry-Lorenzo, Daniel G Smith, David A Ruhl, Michael Rotte, Austin L Reese, Patricio O'Donnell, Jennifer E Mollon, Christopher Missling, Yasuji Matsuoka, Michael J Marino, Susi Lee, Igor O Korolev, Daniel Klamer, Anna Jeong, Sokichi Honda, K C Fadem, Jim Doherty, Elan A. Cohen, Soren Christensen, Heramb Chadchankar, Derek L Buhl, Megumi Adachi, Deepak C D'Souza, Holly K. Hamilton, Mohini Ranganathan, Brian J Roach, Larry Ereshefsky, David P. Walling, William Z. Potter, Daniel C Javitt, Daniel H. Mathalon
Biological Psychiatry April 15, 2026 DOI: 10.1016/j.biopsych.2026.03.1008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Secondary analysis of three independent ERP studies plus a drug-free test-retest study Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Measures | Mismatch negativity (MMN) amplitude |
| Topics | Ketamine Esketamine |
| Keywords | Drug development Electroencephalography Event-related potentials Mismatch negativity Precision medicine |
| Key points | The authors report that baseline duration-deviant MMN amplitude predicted both the direction and magnitude of ketamine-induced MMN change across three independent ERP studies, which they describe as a "disordinal drug effect." They argue regression to the mean, estimated separately from a drug-free test-retest study, does not fully account for this crossover interaction. |
Abstract
Mismatch negativity (MMN) is a component of the auditory event-related potential (ERP) that is elicited during a passive oddball paradigm where task-irrelevant infrequent deviants are presented in a stream of more frequent standard stimuli. MMN is believed to index a preattentive stage of auditory information processing closely linked to NMDA receptor (NMDAR) function. Ketamine is thought to act primarily as an NMDAR antagonist, has been used in clinical trials to model the symptoms of schizophrenia, and is increasingly being used in the clinic to treat depression. Various studies have reported that ketamine reduces MMN amplitude, which in turn may reflect reduced function of NMDAR-mediated neurotransmission. Nonetheless, there is growing evidence showing MMN amplitude either having high variability or, paradoxically, moving in the opposite direction after ketamine in different individuals. We analyzed results from 3 independent ERP studies to test the hypothesis of a crossover interaction (disordinal drug effect) between the duration-deviant MMN amplitude at baseline (without ketamine) and the direction and magnitude of the ketamine effect. To rule out regression to the mean (RTM), a statistical phenomenon that may also partially explain this crossover interaction, we separately estimated RTM using a drug-free test-retest study. Our results are the first to statistically demonstrate the existence of a disordinal drug response to ketamine, where the direction and magnitude of ketamine-induced changes in MMN amplitude can be predicted by baseline MMN amplitude. These new insights may contribute to novel precision medicine approaches in the treatment of central nervous system disorders.
Comparable studies
Other observational and cohort studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Taming the Ketamine Tiger Volunteers from a prison population | 2010 | Observational study | n = 20 |
| Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin Humans | 2017 | Observational study | |
| Disruption of Frontal–Parietal Communication by Ketamine, Propofol, and Sevoflurane Surgical patients undergoing induction of anesthesia with intravenous ketamine | 2013 | Observational cohort | n = 30 |
| Do the dissociative side effects of ketamine mediate its antidepressant effects? Treatment-resistant inpatients with major depressive disorder or bipolar disorder | 2014 | Observational cohort | n = 108 |
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
Citations in the library
Cites 3
- Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions? American Journal of Psychiatry March 1, 2025
- 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
- Predicting treatment response to ketamine in treatment-resistant depression using auditory mismatch negativity: Study protocol. PLoS One 2024