title: Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence.
abstract: Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, D-serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors.
authors: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06516, USA. deepak.dsouza@yale.edu
authors: Deepak Cyril
authors: DC
authors: D'Souza
authors: Nagendra
authors: N
authors: Singh
authors: Jacqueline
authors: J
authors: Elander
authors: Michelle
authors: M
authors: Carbuto
authors: Brian
authors: B
authors: Pittman
authors: Joanna
authors: J
authors: Udo de Haes
authors: Magnus
authors: M
authors: Sjogren
authors: Pierre
authors: P
authors: Peeters
authors: Mohini
authors: M
authors: Ranganathan
authors: Jacques
authors: J
authors: Schipper
mesh_terms: D000328:Adult; D000778:Anesthetics, Dissociative / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D018592:Cross-Over Studies; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D008297:Male; D010865:Pilot Projects; D011605:Psychoses, Substance-Induced / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D000778:Anesthetics, Dissociative; D050487:Glycine Plasma Membrane Transport Proteins; C520612:N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)aminomethylcarboxylic acid; C493268:SLC6A9 protein, human; D013764:Tetrahydronaphthalenes; D007649:Ketamine