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The qEEG Signature of Selective NMDA NR2B Negative Allosteric Modulators; A Potential Translational Biomarker for
Deborah Keavy1, Linda J Bristow1, Digavalli V Sivarao1
1Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Company, Wallingford, CT, United States of America.
Plos One
|April 2, 2016
Summary
Quantitative electroencephalography (qEEG) revealed that beta and delta power changes may serve as biomarkers for NR2B NAMs, unlike gamma power changes seen with NMDA receptor blockers. This aids in developing new antidepressant therapies.
Area of Science:
- Neuroscience
- Pharmacology
- Biomarker Development
Background:
- Ketamine's antidepressant effects stem from NMDA receptor antagonism, prompting research into NR2B-selective negative allosteric modulators (NAMs).
- A translational pharmacodynamic biomarker is needed to assess brain penetration and NR2B receptor inhibition by NR2B NAMs in preclinical and human studies.
- Quantitative electroencephalography (qEEG) is a translational tool for measuring pharmacodynamic effects across species, with gamma power increases used for NMDA receptor antagonists.
Purpose of the Study:
- To investigate the effects of NR2B NAMs, traxoprodil and BMT-108908, on qEEG power spectra in nonhuman primates.
- To compare the qEEG effects of NR2B NAMs with NMDA receptor channel blockers, ketamine and lanicemine.
- To identify potential translational pharmacodynamic biomarkers for NR2B NAMs.
Main Methods:
- Cynomolgus monkeys were implanted with EEG radio-telemetry transmitters for qEEG measurements.
- qEEG power spectra were analyzed after administration of vehicle, ketamine, lanicemine, traxoprodil, or BMT-108908.
- Relative power in various frequency bands (gamma, beta, alpha, delta) was determined.
Main Results:
- Ketamine and lanicemine increased relative gamma power, consistent with NMDA receptor channel blockade.
- NR2B NAMs (traxoprodil, BMT-108908) did not affect gamma power.
- Ketamine, traxoprodil, and BMT-108908 all robustly decreased beta power, decreased alpha power, and increased delta power.
Conclusions:
- Measurement of beta and delta power spectra in qEEG may serve as a translational pharmacodynamic biomarker for functional effects of NR2B NAMs.
- This finding contrasts with the gamma power biomarker used for NMDA receptor antagonists.
- The study provides guidance for selecting qEEG measures for early clinical evaluation of NR2B NAMs in humans.
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