Behavioral and cognitive effects of the N-methyl-d-aspartate receptor co-agonist d-serine in healthy humans: Initial findings

• Published in: Journal of psychiatric research Vol. 61; pp. 188 - 195
• Main Authors: Levin, Raz, Dor-Abarbanel, Adi Ein, Edelman, Shany, Durrant, Andrea R., Hashimoto, Kenji, Javitt, Daniel C., Heresco-Levy, Uriel
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2015
• Subjects: Adult; Affect - drug effects; Anxiety - drug therapy; Anxiety - psychology; Behavior; Cognition; Cognition - drug effects; Cross-Over Studies; d-serine; Female; Glutamic Acid - blood; Glycine - blood; Humans; Male; N-methyl-d-aspartate receptor; Neuropsychological Tests; Psychiatry; Receptors, N-Methyl-D-Aspartate - agonists; Serine - administration & dosage; Serine - pharmacology; Treatment Outcome; Verbal Learning - drug effects; Young Adult; Cognition; Behavior; N-methyl-d-aspartate receptor; d-serine; N-methyl- d-aspartate receptor
• ISSN: 0022-3956; 1879-1379; 1879-1379
• DOI: 10.1016/j.jpsychires.2014.12.007

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. •Agonism at the N-methyl-d-aspartate receptor (NMDAR) represents a new pharmacological mechanism.•We examined the acute effects of the NMDAR agonist d-serine in healthy individuals.•d-serine administration was well tolerated and resulted in significantly increased d-serine serum levels.•d-serine reduced depression and anxiety feelings and improved cognitive performance parameters.•NMDAR agonists may be beneficial in the treatment of neuropsychiatric disorders.