Acute Glycine Pharmacodynamic Study
Information source: Mclean Hospital
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Schizophrenia; Psychotic Disorders
Intervention: Glycine administration (Dietary Supplement)
Phase: N/A
Status: Completed
Sponsored by: Mclean Hospital Official(s) and/or principal investigator(s): Marc J. Kaufman, Ph.D., Principal Investigator, Affiliation: Mclean Hospital
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.
Clinical Details
Official title: Acute Glycine Pharmacodynamic Study
Study design: Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
Primary outcome: Glycine increments after oral glycine administration
Secondary outcome: Effects of the GLDC mutation on brain and plasma glycine increments after glycine administration
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.
Eligibility
Minimum age: 18 Years.
Maximum age: 55 Years.
Gender(s): Both.
Criteria:
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
Locations and Contacts
McLean Imaging Center, McLean Hospital, Belmont, Massachusetts 02478, United States
Additional Information
Brain and Behavior Research Foundation - Awarding NARSAD Grants
Related publications: Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry. 1999 Jan;56(1):29-36. Bergeron R, Meyer TM, Coyle JT, Greene RW. Modulation of N-methyl-D-aspartate receptor function by glycine transport. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15730-4. Silk DB, Kumar PJ, Perrett D, Clark ML, Dawson AM. Amino acid and peptide absorption in patients with coeliac disease and dermatitis herpetiformis. Gut. 1974 Jan;15(1):1-8. D'Souza DC, Gil R, Cassello K, Morrissey K, Abi-Saab D, White J, Sturwold R, Bennett A, Karper LP, Zuzarte E, Charney DS, Krystal JH. IV glycine and oral D-cycloserine effects on plasma and CSF amino acids in healthy humans. Biol Psychiatry. 2000 Mar 1;47(5):450-62. Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon RP, Heresco-Levy U, Carpenter WT. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. 2007 Oct;164(10):1593-602. Prescot AP, de B Frederick B, Wang L, Brown J, Jensen JE, Kaufman MJ, Renshaw PF. In vivo detection of brain glycine with echo-time-averaged (1)H magnetic resonance spectroscopy at 4.0 T. Magn Reson Med. 2006 Mar;55(3):681-6. Kaufman MJ, Prescot AP, Ongur D, Evins AE, Barros TL, Medeiros CL, Covell J, Wang L, Fava M, Renshaw PF. Oral glycine administration increases brain glycine/creatine ratios in men: a proton magnetic resonance spectroscopy study. Psychiatry Res. 2009 Aug 30;173(2):143-9. doi: 10.1016/j.pscychresns.2009.03.004. Epub 2009 Jun 24.
Starting date: July 2010
Last updated: March 25, 2014
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