Researchers at Louisville, Kentucky-based Cognision, working through the EEG/ERP Biomarker Qualification Consortium, report that an individual's baseline mismatch negativity amplitude — a ketamine EEG biomarker measured before drug administration — predicts not only the magnitude but the direction of ketamine's neurophysiological effect, according to a study published in Biological Psychiatry. The finding suggests that previously reported inconsistencies in ketamine brain effects across studies may reflect a statistical artifact of averaging subjects whose brains respond in opposite directions.
The study, published in Biological Psychiatry, found that mismatch negativity (MMN) amplitude measured before ketamine administration predicted whether the drug increased or decreased MMN following treatment. According to the authors, the effect represents a "disordinal interaction" in which participants with low baseline MMN values showed increases after ketamine, while those with high baseline values showed decreases.
The finding suggests that many previous ketamine studies may have obscured biologically meaningful effects by averaging together participants whose responses moved in opposite directions. Under conventional group-level analyses, these opposing responses can cancel one another out, producing weak or inconsistent average effects.
The effect was first identified in a randomized, placebo-controlled crossover study involving 24 healthy volunteers (NCT04928703), in which participants received sub-anesthetic ketamine and placebo on separate visits. EEG recordings were collected before and after dosing, and the primary analysis found that baseline MMN amplitude significantly influenced the direction of ketamine's effect.
To determine whether the finding generalized beyond the initial cohort, the researchers subsequently replicated the analysis across three additional datasets, including studies sponsored by pharmaceutical companies participating in the Consortium. The combined dataset included 105 participants across four studies, including 70 individuals exposed to ketamine and a separate test-retest cohort used to evaluate regression-to-the-mean effects.
MMN is an EEG-derived event-related potential generated when the brain detects an unexpected auditory stimulus. Because it depends on NMDA receptor signaling, it has long been studied as a biomarker of glutamatergic function in disorders such as schizophrenia. Ketamine, an NMDA receptor antagonist, acts on the same pathway and has been widely used in experimental models of psychosis and depression.
The authors propose that baseline differences in cortical excitation-inhibition balance may explain the divergent responses. Individuals with lower baseline MMN amplitudes may respond differently to NMDA receptor blockade than those with stronger baseline signaling, resulting in opposite neurophysiological outcomes despite receiving the same dose.