Acute Glycine Pharmacodynamic Study
Condition: Schizophrenia; Psychotic Disorders
MeSH terms: Schizophrenia; Mental Disorders; Psychotic Disorders
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Glycine administration
Intervention type(s): Dietary Supplement
Intervention description(s): 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.
Other intervention name(s): Aminoacetic Acid; Aminoethanoic Acid
Intervention MeSH terms: Glycine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Schizophrenia; Psychotic Disorders; N-methyl-D-aspartate receptor; Glycine augmentation; Glycine; Glycine Pharmacodynamics; Glycine Bioavailability; Magnetic Resonance Spectroscopy; Glycine Decarboxylase; Glycine Decarboxylase Mutation