Acute Glycine Pharmacodynamic Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01610011
Recruitment Status : Completed
First Posted : June 1, 2012
Results First Posted : October 27, 2015
Last Update Posted : October 27, 2015
Brain & Behavior Research Foundation
Information provided by (Responsible Party):
Marc J. Kaufman, Mclean Hospital

Brief 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.

Condition or disease Intervention/treatment Phase
Schizophrenia Psychotic Disorders Dietary Supplement: Glycine administration Not Applicable

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Acute Glycine Pharmacodynamic Study
Study Start Date : July 2010
Actual Primary Completion Date : December 2013
Actual Study Completion Date : December 2013

Resource links provided by the National Library of Medicine

Drug Information available for: Glycine

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Brain Glycine Increments After Oral Glycine Administration Measured With MRS as Glycine/Total Creatine, Normalized to the Glycine Dose Administered (g/kg). [ Time Frame: For up to 2 hours ]
    Brain and plasma glycine levels are measured with proton magnetic resonance spectroscopy at 4T and analytically, respectively. Because glycine doses were limited to 30 g to avoid nausea and vomiting, some subjects with higher weights were administered lower doses per body weight of glycine (g/kg). Therefore, we corrected MRS data by the actual glycine dose administered (g/kg) to account for dosing differences.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01610011

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

Additional Information:

Responsible Party: Marc J. Kaufman, Director, Translational Imaging Laboratory, Mclean Hospital Identifier: NCT01610011     History of Changes
Other Study ID Numbers: 2010P001576
First Posted: June 1, 2012    Key Record Dates
Results First Posted: October 27, 2015
Last Update Posted: October 27, 2015
Last Verified: September 2015

Keywords provided by Marc J. Kaufman, Mclean Hospital:
Psychotic Disorders
N-methyl-D-aspartate receptor
Glycine augmentation
Glycine Pharmacodynamics
Glycine Bioavailability
Magnetic Resonance Spectroscopy
Glycine Decarboxylase
Glycine Decarboxylase Mutation

Additional relevant MeSH terms:
Mental Disorders
Psychotic Disorders
Schizophrenia Spectrum and Other Psychotic Disorders
Glycine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs