Baseline Mismatch Negativity Amplitude Predicts Direction and Magnitude of Ketamine Effect in Healthy Volunteers: A
Marco Cecchi1, Jason Johannesen2, Brandon Farley2
1Cognision, Louisville, Kentucky.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
These new insights may contribute to novel precision medicine approaches in the treatment of central nervous system disorders.
Insights
Ketamine
Area of Science:
- Neuroscience
- Psychopharmacology
Background:
- Mismatch negativity (MMN) indexes pre-attentive auditory processing linked to N-methyl-D-aspartate receptors (NMDAR).
- Ketamine, an NMDAR antagonist, is used to model schizophrenia and treat depression, with variable effects on MMN amplitude.
Purpose of the Study:
- Investigate the interaction between baseline MMN amplitude and ketamine's effect on MMN.
- Test for a "disordinal" drug effect where ketamine's impact varies based on initial MMN levels.
Main Methods:
- Analyzed data from three independent auditory event-related potential (ERP) studies.
- Controlled for regression to the mean (RTM) using a drug-free test-retest study.
Main Results:
- Statistically demonstrated a disordinal drug response to ketamine for MMN amplitude.
- Showed that baseline MMN amplitude predicts the direction and magnitude of ketamine's effects.
Conclusions:
- Ketamine's impact on MMN is dependent on individual baseline MMN.
- Findings support precision medicine approaches for central nervous system (CNS) disorders.
