Background: Based on the NMDA deficit hypothesis of schizophrenia, it has been proposed that facilitation of NMDA receptor function may have therapeutic potential in schizophrenia. Agonists of the strychnine-insensitive NMDA receptor glycine site offer a safe method to facilitate NMDA receptor function. Clinical trials with glycine added to neuroleptics show promise in the treatment of negative symptoms and cognitive deficits associated with schizophrenia. However, there are limitations to the interpretation of clinical trials. Further, clinical trials do not offer insight into the mechanism of action of glycine' therapeutic efficacy. The noncompetitive NMDA receptor antagonist ketamine, induces symptoms in healthy individuals resembling several aspects of schizophrenia. Preclinical studies suggest that glycine site agonists reverse the effects of non-competitive NMDA receptor antagonists. The ketamine paradigm offers a safe, feasible and clearly interpretable method to clarify the therapeutic potential of glycine and provide insight into the mechanistic underpinnings of its clinical efficacy.
Aims : Does glycine pretreatment reduce ketamine-induced: 1) the perceptual alterations, 2) negative symptoms and 3) amnestic effects in healthy subjects. A secondary exploratory aim is to determine whether the effects of glycine are dose-related. Methods: Healthy subjects (n = 42) will complete 6 test days during which they will be administered intravenous glycine (0.1 g/kg), (0.2 g/kg) or placebo (normal saline) pretreatment followed by ketamine or placebo in a randomized, double-blind, counterbalanced order. Behavioral ratings for perceptual alterations (Clinician Administered Dissociative Symptom Scale), negative and positive symptoms of psychosis (Brief Psychiatric Rating Scale), recall (Hopkins Verbal Learning Test) and working memory will be administered. Ketamine levels will also be measured. Behavioral measures and drug levels will be subjected to a repeated measures analysis of variance (RMANOVA) with within subject factors of ketamine (ketamine vs. placebo), glycine (glycine vs. placebo), and time. Cognitive measures (HVLT, working memory) that are administered only once per test day, the RMANOVA performed on these data will just include within subjects factors of ketamine and glycine. Relevant covariates including age, weight, baseline WAIS-R scores, education level, drug levels will be included into the analyses. Pilot Data: Ketamine induces a schizophrenia-like syndrome in healthy humans that includes perceptual alterations, negative symptoms and amnestic effects have previously been reported. The central bioavailability and dose-related effects of intravenous glycine in healthy subjects will also be studied. Pilot data (n=12) towards this proposal suggests that glycine reduces ketamine-induced perceptual alterations, negative symptoms and impairments on recall without worsening positive symptoms.
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