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Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders

This study is ongoing, but not recruiting participants.
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Deborah L. Levy, Mclean Hospital Identifier:
First received: October 30, 2012
Last updated: January 26, 2017
Last verified: January 2017

The purpose of this study is to assess the efficacy of oral glycine as an augmentation strategy in two psychotic patients with a triplication (4 copies) of the gene glycine decarboxylase (GLDC). Subjects will first undergo a double-blind placebo-controlled clinical trial in which one 6-week arm will involve glycine (maximum daily dose of 0.8 g/kg, administered on a TID dosing schedule) and one 6-week arm will involve placebo. A 2-week period of no treatment will occur between treatment arms. A 6-week period of open-label glycine (maximum daily dose of 0.8 g/kg, administered on a TID dosing schedule) will follow the double-blind placebo-controlled clinical trial. Prior to the double-blind placebo-controlled clinical trial and at the end of the open-label glycine trial, the following procedures will be carried out: structural MRI (3T), Proton 1H MRS (4T), fMRI (3T), steady-state visual evoked potentials, and EEG. Positive, negative, and affective symptoms and neurocognitive function as well as plasma levels of large neutral and large and small neutral and excitatory amino acids and psychotropic drug levels will be assessed periodically. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a glycine-containing drink will be assessed at baseline. Pharmaceutical grade glycine powder (Ajinomoto) or placebo will be dissolved in 20% solution and prepared by the McLean Hospital Pharmacy.

Because the results of the double-blind placebo-controlled and open-label glycine treatment arms showed substantial clinical benefit to the participants, the study has been extended to include six months of chronic open-label glycine in order to determine 1) whether the clinical benefits achieved within 6 weeks previously recur, 2) the clinical benefits are lasting, and 3) additional clinical benefits occur with longer exposure. The glycine for this extension will be provided by Letco Medical.

The investigators hypothesize that mutation carriers will have reduced endogenous brain glycine and GABA levels and increased brain glutamate and glutamine levels. Glycine administration will increase brain glycine in the two carriers, but to a lesser extent than in non-carrier family members and controls.

The investigators hypothesize reduced activation of magnocellular pathways and abnormal ERPs modulated by NMDA in mutation carriers compared with non-carrier family members and controls.

The investigators hypothesize that glycine, but not placebo, will improve positive, negative and affective symptoms as well as neurocognitive function.

The investigators also hypothesize that open-label glycine will improve clinical and cognitive functioning, will partially normalize decreased baseline glycine and GABA and increased glutamate and glutamine, and will partially normalize magnocellular pathway activation and abnormal evoked potentials.

Condition Intervention Phase
Schizo-affective Disorder
Bipolar Disorder
Drug: glycine powder
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: Pilot Study of Glycine Augmentation in Carriers of a Mutation in the Gene Encoding Glycine Decarboxylase

Resource links provided by NLM:

Further study details as provided by Mclean Hospital:

Primary Outcome Measures:
  • Change in positive and negative symptoms compared with baseline [ Time Frame: 6 weeks per treatment arm ]
    Positive and Negative Symptom Scale (PANSS)

  • Change in clinical functioning compared with baseline [ Time Frame: 6 weeks per treatment arm ]
    Clinical Global Impression (CGI) Scale

  • Change in mood symptoms compared with baseline [ Time Frame: 6 weeks per treatment arm ]
    Young Mania Scale

  • Change in mood symptoms compared with baseline [ Time Frame: 6 weeks per treatment arm ]
    Hamilton Depression Scale

  • Change neurocognitive function compared with baseline [ Time Frame: 6 weeks per treatment arm ]
    MATRICS battery

  • Change in symptoms compared with baseline [ Time Frame: 6 weeks per treatment arm ]
    Brief Psychiatric Rating Scale (BPRS)

  • Change plasma amino acid levels compared with baseline [ Time Frame: 6 weeks per treatment arm ]
    Plasma amino acid levels

Secondary Outcome Measures:
  • Change in glycine metabolite levels post glycine treatment compared with baseline [ Time Frame: 6 weeks per treatment arm ]

  • Change in glutamate metabolite levels post glycine treatment compared with baseline [ Time Frame: 6 weeks per treatment arm ]

  • Change in GABA metabolite levels post glycine treatment compared with baseline [ Time Frame: 6 weeks per treatment arm ]

  • Change in glutamine metabolite levels post glycine treatment compared with baseline [ Time Frame: 6 weeks per treatment arm ]

  • Change in evoked potentials compared with baseline [ Time Frame: 6 weeks per treatment arm ]
    evoked potentials

  • Change in magnocellular pathway function compared with baseline [ Time Frame: 6 weeks per treatment arm ]
    functional magnetic resonance imaging

Enrollment: 2
Study Start Date: December 2012
Estimated Study Completion Date: May 2017
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: glycine
Glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks
Drug: glycine powder
Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine
Placebo Comparator: Placebo
placebo, TID dosing, 6 weeks
Drug: placebo

Detailed Description:

Multiple rare structural variants of relatively recent evolutionary origin are recognized as important risk factors for schizophrenia (SZ) and other neurodevelopmental disorders (e.g., autism spectrum disorders, mental retardation, epilepsy) with odds ratios as high as 7-30 (Sebat et al. 2009; Malhotra et al. 2011; Heinzen et al. 2010; Weiss et al. 2008; McCarthy et al. 2009). We have found a de novo structural rearrangement on chromosome 9p24.1 in two psychotic patients. One of the genes in this region is the gene encoding glycine decarboxylase (GLDC), which affects brain glycine metabolism. GLDC encodes the glycine decarboxylase or glycine cleavage system P-protein, which is involved in degradation of glycine in glia cells. Carriers of the GLDC triplication would be expected to have low levels of brain Gly, resulting in NMDA receptor-mediated hypofunction, which has been strongly implicated in the pathophysiology of schizophrenia (Olney & Farber, 1995; Coyle, 2006; Javitt, 2007).

There is an extensive literature on the effects of NMDA enhancing agents on positive, negative, and depressive symptoms and on neurocognitive function (see Tsai & Lin, 2010; Lin et al. 2011 for reviews). Although many studies have reported positive results in at least one symptom domain (Heresco-Levy et al. 1996, 1999, 2004; Tsai et al. 1998, 1999, 2004, 2006; Javitt et al. 2001; Goff et al. 1996; Lane et al. 2008), the results of other studies have been negative or ambiguous (Goff et al. 1999; Evins et al. 2000; Duncan et al. 2004; van Berckel et al. 1999). Factors likely to contribute to this variability include: mechanism of action of the agent, compliance, concurrent treatment with first- vs second generation antipsychotic drugs, baseline glycine blood levels, presence/absence of kynurenine pathway metabolic abnormalities (Wonodi et al. 2010; Erhardt et al. 2007) and individual differences in brain glycine uptake and metabolism (Kaufman et al. 2009; Buchanan et al. 2007). Genetic variants that impact the synthesis and breakdown of glycine, glutamate, or other modulators of NMDA receptor function are also likely to have significant effects. Although glycine augmentation has shown variable efficacy in patients unselected for having a mutation that would be expected to lower brain glycine levels, the GLDC triplication in the two carriers in this study would be expected to result in unusually low brain glycine levels, supporting its therapeutic potential as an augmentation strategy.

Thus, it is important to evaluate the therapeutic efficacy of glycine augmentation in individuals in whom there is a high prior probability of therapeutic benefit and to characterize the neurobiology of this mutation in terms of brain metabolites, brain function, and the pharmacokinetics of glycine metabolism using well-established methods (Kaufman et al. 2009; Prescot et al. 2006; Martinez et al. 2008; Butler et al. 2001; Jensen et al. 2009; Ongur et al. 2008).


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Triplication of glycine decarboxylase gene

Exclusion Criteria:

  • Normal glycine decarboxylase copy number
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Please refer to this study by its identifier: NCT01720316

United States, Massachusetts
McLean Hospital
Belmont, Massachusetts, United States, 02478
Sponsors and Collaborators
Mclean Hospital
National Institute of Mental Health (NIMH)
Principal Investigator: Deborah L Levy, PhD Mclean Hospital
  More Information

McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee YH, Vacic V, Gary S, Iakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, Derosse P, Steele J, Kassem L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR; Wellcome Trust Case Control Consortium., Craddock N, Owen MJ, O'Donovan MC, Shaikh TH, Susser E, Delisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL, King MC, Sebat J. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009 Nov;41(11):1223-7. doi: 10.1038/ng.474.

Responsible Party: Deborah L. Levy, Associate Professor, Mclean Hospital Identifier: NCT01720316     History of Changes
Other Study ID Numbers: 2012p001597
R21MH097470-01A1 ( US NIH Grant/Contract Award Number )
Study First Received: October 30, 2012
Last Updated: January 26, 2017

Keywords provided by Mclean Hospital:
Glycine decarboxylase

Additional relevant MeSH terms:
Bipolar Disorder
Mood Disorders
Psychotic Disorders
Pathologic Processes
Bipolar and Related Disorders
Mental Disorders
Schizophrenia Spectrum and Other Psychotic Disorders
Glycine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs processed this record on March 24, 2017