Abstract
The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in preclinical species and humans. Quantitative electroencephalography (qEEG) is a translational measure that can be used to demonstrate pharmacodynamic effects across species. NMDA receptor channel blockers, such as ketamine and phencyclidine, increase the EEG gamma power band, which has been used as a pharmacodynamic biomarker in the development of NMDA receptor antagonists. However, detailed qEEG studies with ketamine or NR2B NAMs are lacking in nonhuman primates. The aim of the present study was to determine the effects on the qEEG power spectra of the NR2B NAMs traxoprodil (CP-101,606) and BMT-108908 in nonhuman primates, and to compare them to the NMDA receptor channel blockers, ketamine and lanicemine. Cynomolgus monkeys were surgically implanted with EEG radio-telemetry transmitters, and qEEG was measured after vehicle or drug administration. The relative power for a number of frequency bands was determined. Ketamine and lanicemine increased relative gamma power, whereas the NR2B NAMs traxoprodil and BMT-108908 had no effect. Robust decreases in beta power were elicited by ketamine, traxoprodil and BMT-108908; and these agents also produced decreases in alpha power and increases in delta power at the doses tested. These results suggest that measurement of power spectra in the beta and delta bands may represent a translational pharmacodynamic biomarker to demonstrate functional effects of NR2B NAMs. The results of these studies may help guide the selection of qEEG measures that can be incorporated into early clinical evaluation of NR2B NAMs in healthy humans.
Highlights
Major Depressive Disorder (MDD) is a heterogeneous condition characterized by the core symptoms of pervasive, sustained, low mood and/or loss of interest in the environment accompanied by a constellation of other symptoms involving alterations in sleep, appetite, energy level, psychomotor function and cognition [1]
Area under the curve (AUC) is calculated as relative power change from baseline for each animal at each dose and compared to the respective vehicle using a 1-way RM ANOVA with the factor of treatment
The present studies are the first to demonstrate the effect of NR2B selective negative allosteric modulators (NAMs) as well as the NMDA receptor channel blockers ketamine and lanicemine, on quantitative EEG in nonhuman primates including a full range of clinically relevant frequency bands
Summary
Major Depressive Disorder (MDD) is a heterogeneous condition characterized by the core symptoms of pervasive, sustained, low mood and/or loss of interest in the environment accompanied by a constellation of other symptoms involving alterations in sleep, appetite, energy level, psychomotor function and cognition [1]. The monoamine system has been the focus of MDD research for many years and numerous antidepressant drugs of this class are available, MDD symptoms are poorly treated in most patients. The glutaminergic system, including N-methyl-D-aspartate (NMDA) receptors, has been an area of research interest in the neurobiology of MDD [3, 4]. Berman et al, (2000) were the first to publish a small (n = 7) novel, proof-of-concept clinical trial showing the non-selective NMDA receptor antagonist ketamine had rapid anti-depressant effects in patients with treatment-resistant depression (TRD) [5]. Zarate et al, (2006) confirmed these findings by demonstrating the robust, rapid (within 2 hrs) and sustained (more than 1 week) anti-depressant effects of a single dose of ketamine (0.5 mg/kg, i.v. infusion for 40 min) in TRD patients [6]
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