Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders
Condition: Schizo-affective Disorder; Bipolar Disorder
MeSH terms: Bipolar Disorder; Mood Disorders; Psychotic Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

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).
    

Intervention name(s): Glycine; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine
Intervention MeSH terms: Glycine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Glycine; Glycine decarboxylase; Psychosis; Mutation