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.
|Study Design:||Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
|Official Title:||Acute Glycine Pharmacodynamic Study|
- Glycine increments after oral glycine administration [ Time Frame: For up to 2 hours ] [ Designated as safety issue: No ]Brain and plasma glycine levels will be measured with proton magnetic resonance spectroscopy at 4T and analytically, respectively.
- Effects of the GLDC mutation on brain and plasma glycine increments after glycine administration [ Time Frame: For up to 2 hours ] [ Designated as safety issue: No ]Brain glycine increments will be lower in subjects possessing the GLDC mutation.
|Study Start Date:||July 2010|
|Estimated Study Completion Date:||December 2013|
|Estimated Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Experimental: Glycine administration
Glycine will be administered once orally to all subjects to determine brain and plasma pharmacodynamics.
Dietary Supplement: Glycine administration
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.
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.
|United States, Massachusetts|
|McLean Imaging Center, McLean Hospital|
|Belmont, Massachusetts, United States, 02478|
|Principal Investigator:||Marc J. Kaufman, Ph.D.||Mclean Hospital|