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    A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression

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    Author
    Park, Lawrence T
    Kadriu, Bashkim
    Gould, Todd D
    Zanos, Panos
    Greenstein, Deanna
    Evans, Jennifer W
    Yuan, Peixiong
    Farmer, Cristan A
    Oppenheimer, Mark
    George, Jomy M
    Adeojo, Lilian W
    Snodgrass, H Ralph
    Smith, Mark A
    Henter, Ioline D
    Machado-Vieira, Rodrigo
    Mannes, Andrew J
    Zarate, Carlos A, Jr.
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    Date
    2020-03-31
    Journal
    International Journal of Neuropsychopharmacology
    Publisher
    Oxford University Press
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1093/ijnp/pyaa025
    Abstract
    BACKGROUND: Ketamine has rapid-acting antidepressant effects but is associated with psychotomimetic and other adverse effects. A 7-chlorokynurenic acid is a potent and specific glycine site N-methyl-d-aspartate receptor antagonist but crosses the blood-brain barrier inefficiently. Its prodrug, L-4-chlorokynurenine (4-Cl-KYN), exerts acute and sustained antidepressant-like effects in rodents and has no reported psychotomimetic effects in either rodents or healthy volunteers. This study examined whether 4-Cl-KYN has rapid antidepressant effects in individuals with treatment-resistant depression. METHODS: After a 2-week drug-free period, 19 participants with treatment-resistant depression were randomized to receive daily oral doses of 4-Cl-KYN monotherapy (1080 mg/d for 7 days, then 1440 mg/d for 7 days) or placebo for 14 days in a randomized, placebo-controlled, double-blind, crossover manner. The primary outcome measure was the Hamilton Depression Rating Scale score, assessed at several time points over a 2-week period; secondary outcome measures included additional rating scale scores. Pharmacokinetic measures of 7-chlorokynurenic acid and 4-Cl-KYN and pharmacodynamic assessments were obtained longitudinally and included 1H-magnetic resonance spectroscopy brain glutamate levels, resting-state functional magnetic resonance imaging, and plasma and cerebrospinal fluid measures of kynurenine metabolites and neurotrophic factors. RESULTS: Linear mixed models detected no treatment effects, as assessed by primary and secondary outcome measures. No difference was observed for any of the peripheral or central biological indices or for adverse effects at any time between groups. A 4-Cl-KYN was safe and well-tolerated, with generally minimal associated adverse events. CONCLUSIONS: In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied.ClinicalTrials.gov identifier: NCT02484456.
    Keyword
    4-Chlorokynurenine
    NMDA receptor
    depression
    glutamate
    glycine site antagonist
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13532
    ae974a485f413a2113503eed53cd6c53
    10.1093/ijnp/pyaa025
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