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Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders

This study is enrolling participants by invitation only.
Sponsor:
Information provided by (Responsible Party):
Deborah L. Levy, Mclean Hospital
ClinicalTrials.gov Identifier:
NCT01720316
First received: October 30, 2012
Last updated: November 14, 2014
Last verified: November 2014

October 30, 2012
November 14, 2014
December 2012
August 2015   (final data collection date for primary outcome measure)
  • Change in positive and negative symptoms compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    Positive and Negative Symptom Scale (PANSS)
  • Change in clinical functioning compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    Clinical Global Impression (CGI) Scale
  • Change in mood symptoms compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    Young Mania Scale
  • Change in mood symptoms compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    Hamilton Depression Scale
  • Change neurocognitive function compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    MATRICS battery
  • Change in symptoms compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    Brief Psychiatric Rating Scale (BPRS)
  • Change plasma amino acid levels compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    Plasma amino acid levels
Same as current
Complete list of historical versions of study NCT01720316 on ClinicalTrials.gov Archive Site
  • Change in glycine metabolite levels post glycine treatment compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    spectroscopy
  • Change in glutamate metabolite levels post glycine treatment compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    spectroscopy
  • Change in GABA metabolite levels post glycine treatment compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    spectroscopy
  • Change in glutamine metabolite levels post glycine treatment compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    spectroscopy
  • Change in evoked potentials compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    evoked potentials
  • Change in magnocellular pathway function compared with baseline [ Time Frame: 6 weeks per treatment arm ] [ Designated as safety issue: No ]
    functional magnetic resonance imaging
Same as current
Not Provided
Not Provided
 
Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders
Pilot Study of Glycine Augmentation in Carriers of a Mutation in the Gene Encoding Glycine Decarboxylase

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.

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).

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Schizo-affective Disorder
  • Bipolar Disorder
  • Drug: glycine powder
    Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine
  • Drug: placebo
  • Active Comparator: glycine
    Glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks
    Intervention: Drug: glycine powder
  • Placebo Comparator: Placebo
    placebo, TID dosing, 6 weeks
    Intervention: Drug: placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Enrolling by invitation
2
August 2015
August 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Triplication of glycine decarboxylase gene

Exclusion Criteria:

  • Normal glycine decarboxylase copy number
Both
18 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01720316
2012p001597, R21MH097470-01A1
Yes
Deborah L. Levy, Mclean Hospital
Mclean Hospital
Not Provided
Principal Investigator: Deborah L Levy, PhD Mclean Hospital
Mclean Hospital
November 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP