A randomized cross-over trial to define neurophysiological correlates of AV-101 N-methyl-D-aspartate receptor blockade in healthy veterans

Abstract

The kynurenine pathway (KP) is a strategic metabolic system that combines regulation of neuronal excitability via glutamate receptor function and neuroinflammation via other KP metabolites. This pathway has great promise in treatment of depression and suicidality. The KP modulator AV-101 (4-chlorokynurenine, 4-Cl-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), an N-methyl-D-aspartate receptor (NMDAR) glycine site antagonist, and of 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), a suppressor of NMDAR agonist quinolinic acid (QUIN), is a promising potential antidepressant that targets glutamate functioning via the KP. However, a recent placebo-controlled clinical trial of AV-101 in depression found negative results. This raises the question of whether AV-101 can penetrate the brain and engage the NMDAR and KP effectively. To address this problem, ten healthy US military veterans (mean age = 32.6 years ± 6.11; 1 female) completed a phase-1 randomized, double-blind, placebo-controlled, crossover study to examine dose-related effects of AV-101 (720 and 1440 mg) on NMDAR engagement measured by γ-frequency band auditory steady-state response (40 Hz ASSR) and resting EEG. Linear mixed models revealed that 1440 mg AV-101, but not 720 mg, increased 40 Hz ASSR and 40 Hz ASSR γ-inter-trial phase coherence relative to placebo. AV-101 also increased 4-Cl-KYN, 7-Cl-KYNA, 4-Cl-3-HAA, 3-HAA, and KYNA in a dose-dependent manner, without affecting KYN and QUIN. AV-101 was safe and well tolerated. These results corroborate brain target engagement of 1440 mg AV-101 in humans, consistent with blockade of interneuronal NMDAR blockade. Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.

Figures

Fig. 1. Summary of the measurements of γ-oscillations relative to AV-101 administration.

a 40 Hz ASSR γ-power at hourly intervals, displayed relative to baseline. b Grand average (across time) time-frequency power plot of the response to 40 Hz ASSR presentation for placebo, low, and high doses. c 40 Hz ASSR γ-inter-trial phase coherence (ITPC) at hourly intervals, displayed relative to baseline. d Grand average (across time) time-frequency ITPC plot of the response to 40 Hz ASSR presentation for placebo, low, and high doses. e Change in 10*log10 resting γ-power relative to baseline. f Resting-state power spectral density plot averaged across time, for placebo, low, and high doses.

Fig. 2. A summary of the blood metabolite findings with respect to their position on the microglial element of the kynurenine pathway.

Concentrations are displayed corrected to the baseline timepoint measurement. Variations in the concentration of metabolites during the placebo condition reflect diurnal fluctuations.

Fig. 3. A summary of the blood metabolite findings with respect to their position on kynurenine pathway.

Concentrations are displayed corrected to the baseline timepoint measurement.