Acute Glycine Pharmacodynamic Study

The purpose of this study is to use proton magnetic resonance spectroscopy (MRS) at 4 Tesla to measure brain glycine levels noninvasively at baseline and for 2 hours after a single oral dose of a concentrated glycine-containing beverage, and to compare MRS glycine measurements to glycine blood levels in samples obtained after each MRS spectrum. The investigators hypothesize that they will observe a high correlation between the magnitude increases in brain and plasma glycine levels over this time frame. The investigators also hypothesize that we will observe large intersubject variability in glycine uptake rates into brain and blood. The investigators also hypothesize that subjects with a glycine decarboxylase (GLDC) mutation (triplication) will have lower baseline plasma and brain glycine levels and will experience smaller brain and plasma glycine increases after glycine consumption than controls or family members without the GLDC mutation.

High doses of glycine (0.4-0.8 g/kg/day) administered orally along with certain antipsychotic medications can improve negative symptoms of schizophrenia (e.g., Heresco-Levy et al., 1999). The therapeutic effect appears to be due to glycine's co-agonist activity at glutamatergic N-methyl-D-aspartate receptors, which may correct the glutamatergic hypofunction associated with schizophrenia (e.g., Bergeron et al., 1998). Unfortunately, the therapeutic benefits of orally administered glycine are variable, in part because gut glycine absorption and resultant plasma (and presumably brain) glycine increases are variable (Silk et al., 1974). Even with intravenous glycine administration, which bypasses variability contributed by gut absorption and metabolism, between-subject variability in cerebrospinal fluid (CSF) glycine increments is large (D'Souza et al., 2000), suggesting that brain glycine uptake, metabolism, and turnover differ substantially among individuals. If brain glycine increments after oral glycine dosing are highly variable, those manifesting smaller or more transient brain glycine increments may not experience clinically significant effects. As a result, glycine's therapeutic efficacy could be underappreciated. Indeed, a multi-site glycine trial in schizophrenia subjects concluded that glycine is not a "…generally effective therapeutic option for treating negative symptoms or cognitive impairments", but included the caveat that "…it is not known if efficacy would have been achieved at substantially higher serum glycine levels" (Buchanan et al., 2007). Accordingly, we believe that it is important to fully characterize glycine's brain and plasma pharmacodynamic variability, which we will do in healthy subjects and in several members of a family with some members possessing a mutation in their glycine decarboxylase gene (GLDC), which may be associated with abnormal baseline brain and plasma glycine levels and increments after glycine administration. We will use an MRS method we developed to detect brain glycine increases after high-dose oral glycine administration (Prescot et al., 2006; Kaufman et al., 2009) along with standard analytical methods to determine plasma glycine levels.

Schizophrenia, Psychotic Disorders, N-methyl-D-aspartate receptor, Glycine augmentation, Glycine, Glycine Pharmacodynamics, Glycine Bioavailability, Magnetic Resonance Spectroscopy, Glycine Decarboxylase, Glycine Decarboxylase Mutation

Glycine will be administered once orally to all subjects to determine brain and plasma pharmacodynamics.

Glycine will be administered once as a 250 cc lemon-flavored beverage based on each subject's body weight. The drink concentration will be 0.4 g/kg glycine (not to exceed 30 grams). Subjects will have 10 minutes to consume the beverage.

Brain Glycine Increments After Oral Glycine Administration Measured With MRS as Glycine/Total Creatine, Normalized to the Glycine Dose Administered (g/kg).

Brain and plasma glycine levels are measured with proton magnetic resonance spectroscopy at 4T and analytically, respectively. Because glycine doses were limited to 30 g to avoid nausea and vomiting, some subjects with higher weights were administered lower doses per body weight of glycine (g/kg). Therefore, we corrected MRS data by the actual glycine dose administered (g/kg) to account for dosing differences.

Inclusion Criteria: Healthy Adult males Members of a family known to the research team with some members possessing a GLDC genetic mutation Exclusion Criteria: Contraindications to magnetic resonance scanning including metallic surgical implants or claustrophobia History of head injury with loss of consciousness > 5 minutes Brain structural abnormalities identified on MRI scan Known sensitivity or allergy to glycine History of taking glycine or other dietary supplements Healthy controls: history of psychiatric or substance use disorders; individuals taking prescription medications Pregnancy

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