{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:30:54Z","timestamp":1791855054576,"version":"4.3.4"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T00:00:00Z","timestamp":1585699200000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/www.nationalarchives.gov.uk\/doc\/open-government-licence\/version\/2\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["ZIAMH002857"],"award-info":[{"award-number":["ZIAMH002857"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["NCT02484456"],"award-info":[{"award-number":["NCT02484456"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied.<\/jats:p>\n                  <jats:p>ClinicalTrials.gov identifier: NCT02484456.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ijnp\/pyaa025","type":"journal-article","created":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T19:15:38Z","timestamp":1585595738000},"page":"417-425","source":"Crossref","is-referenced-by-count":63,"title":["A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression"],"prefix":"10.1093","volume":"23","author":[{"given":"Lawrence T","family":"Park","sequence":"first","affiliation":[{"name":"Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bashkim","family":"Kadriu","sequence":"additional","affiliation":[{"name":"Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd D","family":"Gould","sequence":"additional","affiliation":[{"name":"Veterans Affairs Maryland Health Care System, Baltimore, MD"},{"name":"Departments of Psychiatry, Pharmacology, Anatomy & Neurobiology and Physiology, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panos","family":"Zanos","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry, Pharmacology, Anatomy & Neurobiology and Physiology, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deanna","family":"Greenstein","sequence":"additional","affiliation":[{"name":"Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer W","family":"Evans","sequence":"additional","affiliation":[{"name":"Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peixiong","family":"Yuan","sequence":"additional","affiliation":[{"name":"Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristan A","family":"Farmer","sequence":"additional","affiliation":[{"name":"Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Oppenheimer","sequence":"additional","affiliation":[{"name":"Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jomy M","family":"George","sequence":"additional","affiliation":[{"name":"Clinical Pharmacokinetics Research Unit, Pharmacy Department, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian W","family":"Adeojo","sequence":"additional","affiliation":[{"name":"Clinical Pharmacokinetics Research Unit, Pharmacy Department, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H Ralph","family":"Snodgrass","sequence":"additional","affiliation":[{"name":"VistaGen Therapeutics, Inc., San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A","family":"Smith","sequence":"additional","affiliation":[{"name":"VistaGen Therapeutics, Inc., San Francisco, CA"},{"name":"Medical College of Georgia, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioline D","family":"Henter","sequence":"additional","affiliation":[{"name":"Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Machado-Vieira","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Science Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J","family":"Mannes","sequence":"additional","affiliation":[{"name":"Clinical Center, Department of Perioperative Medicine, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Carlos A","family":"Zarate","sequence":"additional","affiliation":[{"name":"Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,3,31]]},"reference":[{"key":"2020072901465997400_CIT0001","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.biopsych.2009.08.038","article-title":"Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression","volume":"67","author":"aan het Rot","year":"2010","journal-title":"Biol 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