Acute Glycine Pharmacodynamic Study
| Status: | Completed |
|---|---|
| Conditions: | Schizophrenia, Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 55 |
| Updated: | 4/21/2016 |
| Start Date: | July 2010 |
| End Date: | December 2013 |
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.
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.
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.
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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