Baseline Mismatch Negativity Amplitude Predicts Direction and Magnitude of Ketamine Effect in Healthy Volunteers -- A ''Disordinal '' Effect

BackgroundMismatch 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 pre-attentive stage of auditory information processing closely linked to N-methyl-D-aspartate receptors (NMDAR). 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 used in the clinic to treat depression. Various studies have reported that ketamine reduces MMN amplitude which, in turn, might 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. MethodsIn here, we analyzed results from three independent ERP studies to test the hypothesis of a cross-over interaction ("disordinal" drug effect) between the duration-deviant MMN 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 cross-over interaction, we separately estimated RTM using a drug-free test-retest study. ResultsOur 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. ConclusionsThese new insights may contribute to novel precision medicine approaches to treatment of CNS disorders.