Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders
Condition: Schizo-affective Disorder; Bipolar Disorder
MeSH terms: Bipolar Disorder; Mood Disorders; Psychotic Disorders
Intervention: Glycine; placebo
Intervention description: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine
Intervention MeSH terms: Glycine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Glycine; Glycine decarboxylase; Psychosis; Mutation

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Triplication of glycine decarboxylase gene

        Exclusion Criteria:

          -  Normal glycine decarboxylase copy number