Acute Glycine Pharmacodynamic Study

September 25, 2015 updated by: Marc J. Kaufman, Mclean Hospital

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 Overview

Status

Completed

Conditions

Intervention / Treatment

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

Enrollment (Actual)

21

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Belmont, Massachusetts, United States, 02478
        • McLean Imaging Center, McLean Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 51 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
For up to 2 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mclean Hospital

Collaborators

Brain & Behavior Research Foundation

Investigators

  • Principal Investigator: Marc J. Kaufman, Ph.D., McLean Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2010

Primary Completion (Actual)

December 1, 2013

Study Completion (Actual)

December 1, 2013

Study Registration Dates

First Submitted

May 28, 2012

First Submitted That Met QC Criteria

May 31, 2012

First Posted (Estimate)

June 1, 2012

Study Record Updates

Last Update Posted (Estimate)

October 27, 2015

Last Update Submitted That Met QC Criteria

September 25, 2015

Last Verified

September 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2010P001576

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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