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.