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.
Highlights
The kynurenine pathway (KP) links excitatory amino acid transmission and neuroinflammation, and is a promising target for treatment of depression and suicidality
The KP modulator AV101 (4-chlorokynurenine, 4-Cl-KYN) is an oral prodrug of 7chlorokynurenic acid (7-Cl-KYNA), which is converted by kynurenine aminotransferase (KAT)-rich astrocytes [1, 2] and which acts as a high-affinity N-methyl-D-aspartate receptor (NMDAR) strychnine-insensitive glycine-binding site competitive antagonist [3,4,5] that strongly inhibits NMDAR activation [5]
A neurophysiological marker will help to determine whether the lack of clinical effects recently reported [9] might be due to insufficient NMDA inhibition because of subtherapeutic dosing of AV-101 and will be valuable in assessing the roles of NMDA receptors in behavior and treatment. In this phase-1 randomized, double-blind, placebo-controlled, crossover study in healthy military veterans, we examined doserelated effects of AV-101 (720 and 1440 mg) on KP regulation, AV101 metabolites, and NMDAR target engagement measured by γ-band EEG, assessed by the 40 Hz auditory steady-state response (ASSR) and during rest
Summary
Ethical statement This study is registered at ClinicalTrials.gov (NCT03583554). Study procedures were approved by the Baylor College of Medicine Institutional Review Board and the Research and Development Committee of the Michael E. Randomization was performed by a research pharmacist, who had no patient contact, by randomly permuting the three dose conditions for each subject to generate the dose for the first week. Drugs were given on three separate test days with at least 5 days (median interval: 13 days; range: 5–77 days) between doses. EEG, blood samples for pharmacokinetic analyses, and the Profile of Mood States (POMS) [28] were collected before (pretreatment baseline) and at hourly intervals for 5 h after drug intake. To monitor participant engagement/attention, subjects counted randomly presented oddball click trains (eleven 2000 Hz tones); oddball trials were not used in the final data analysis. For KP metabolites, vital signs, and POMS, LMM analyses were performed across 1–5 h post administration with pretreatment baseline measurement as covariate. Data collection and analyses were conducted blind to treatment condition
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