title: Behavioral and cognitive effects of the N-methyl-D-aspartate receptor co-agonist D-serine in healthy humans: initial findings.
abstract: The efficacy of compounds having agonistic activity at the glycine site associated with the N-methyl-D-aspartate receptor (NMDAR) is presently assessed in psychiatric disorders. In contrast to NMDAR antagonists, the neuropsychiatric effects of NMDAR agonists in the healthy human organism are not known. We studied neuropsychiatric and neurochemical effects of the NMDAR-glycine site obligatory co-agonist d-serine (DSR) in healthy subjects using a randomized, controlled crossover challenge design including a baseline assessment day and two DSR/placebo administration days. Thirty-five subjects aged 23-29 years participated in the study and received a 2.1 g orally administered DSR dose. The main outcome measures were the changes in scores of mood-related Visual Analogue Scale (VAS), Continuous Performance Test-Identical Pairs (CPT-IP), and Rey Auditory Verbal Learning Test (RAVLT). DSR acute administration: (1) was well tolerated and resulted at 2 h in ≥ 200 times increase in DSR serum levels; (2) elicited reduced VAS-measured depression and anxiety feelings; (3) improved attention and vigilance as measured by CPT-IP D-prime score; (4) preferentially improved performance in RAVLT list 7 reflecting ability to retain information over interference; (5) had significant but nonspecific effects on Category Fluency and Benton Visual Retention tests; and (6) did not affect glycine and glutamate serum levels. These data indicate that in healthy subjects, DSR reduces subjective feelings of sadness and anxiety and has procognitive effects that are overall opposed to the known effects of NMDAR antagonists. The findings are relevant to translational research of NMDAR function and the development of NMDAR-glycine site treatments for specific psychiatric entities. ClinicalTrials.gov: Behavioral and Cognitive Effects of the N-methyl-D-aspartate Receptor (NMDAR) Co-agonist D-serine in Healthy Humans; http://www.clinicaltrials.gov/ct2/show/NCT02051426?term=NCT02051426&rank=1; NCT02051426.
authors.affiliation: Research and Psychiatry Departments, Ezrath Nashim-Herzog Memorial Hospital, Jerusalem, Israel.
authors.forename: Raz
authors.initials: R
authors.lastname: Levin
authors.affiliation: Hadassah Medical School, Hebrew University, Jerusalem, Israel.
authors.forename: Adi Ein
authors.initials: AE
authors.lastname: Dor-Abarbanel
authors.affiliation: Hadassah Medical School, Hebrew University, Jerusalem, Israel.
authors.forename: Shany
authors.initials: S
authors.lastname: Edelman
authors.affiliation: Research and Psychiatry Departments, Ezrath Nashim-Herzog Memorial Hospital, Jerusalem, Israel.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Durrant
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Nathan S. Kline Institute for Psychiatric Research and Columbia University, NY, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Javitt
authors.affiliation: Research and Psychiatry Departments, Ezrath Nashim-Herzog Memorial Hospital, Jerusalem, Israel; Hadassah Medical School, Hebrew University, Jerusalem, Israel. Electronic address: urielh@ekmd.huji.ac.il.
authors.forename: Uriel
authors.initials: U
authors.lastname: Heresco-Levy
mesh_terms: D000328:Adult; D000339:Affect / Q000187:drug effects*; D001007:Anxiety / Q000188:drug therapy* / Q000523:psychology; D003071:Cognition / Q000187:drug effects*; D018592:Cross-Over Studies; D005260:Female; D018698:Glutamic Acid / Q000097:blood; D005998:Glycine / Q000097:blood; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D012694:Serine / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome; D014706:Verbal Learning / Q000187:drug effects; D055815:Young Adult
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D012694:Serine; D005998:Glycine
keywords: Behavior; Cognition; N-methyl-d-aspartate receptor; d-serine