Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders

• 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

• 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

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.

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).

• 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

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Inclusion Criteria:

• Triplication of glycine decarboxylase gene

Exclusion Criteria:

• Normal glycine decarboxylase copy number