Acute Glycine Pharmacodynamic Study

This study has been completed.
Sponsor:
Collaborator:
Brain & Behavior Research Foundation
Information provided by (Responsible Party):
Marc J. Kaufman, Mclean Hospital
ClinicalTrials.gov Identifier:
NCT01610011
First received: May 28, 2012
Last updated: March 25, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention
Schizophrenia
Psychotic Disorders
Dietary Supplement: Glycine administration

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Acute Glycine Pharmacodynamic Study

Resource links provided by NLM:


Further study details as provided by Mclean Hospital:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 21
Study Start Date: July 2010
Study Completion Date: December 2013
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Other Names:
  • Aminoacetic Acid
  • Aminoethanoic Acid

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

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01610011

Locations
United States, Massachusetts
McLean Imaging Center, McLean Hospital
Belmont, Massachusetts, United States, 02478
Sponsors and Collaborators
Mclean Hospital
Brain & Behavior Research Foundation
Investigators
Principal Investigator: Marc J. Kaufman, Ph.D. Mclean Hospital
  More Information

Additional Information:
Publications:

Responsible Party: Marc J. Kaufman, Director, Translational Imaging Laboratory, Mclean Hospital
ClinicalTrials.gov Identifier: NCT01610011     History of Changes
Other Study ID Numbers: 2010P001576
Study First Received: May 28, 2012
Last Updated: March 25, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Mclean Hospital:
Schizophrenia
Psychotic Disorders
N-methyl-D-aspartate receptor
Glycine augmentation
Glycine
Glycine Pharmacodynamics
Glycine Bioavailability
Magnetic Resonance Spectroscopy
Glycine Decarboxylase
Glycine Decarboxylase Mutation

Additional relevant MeSH terms:
Schizophrenia
Psychotic Disorders
Mental Disorders
Schizophrenia and Disorders with Psychotic Features
Glycine
Glycine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 18, 2014