Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine
Condition: Schizophrenia; Bipolar Disorder
MeSH terms: Schizophrenia; Bipolar Disorder
Study type: Interventional
Phase: Early Phase 1

Summary: 
      The purpose of this study is to assess the efficacy of d-cycloserine (DCS) as an augmentation
      strategy in two psychotic patients with a triplication (4 copies) of the glycine
      decarboxylase (GLDC) gene. Subjects will first undergo an eight-week open-label arm of
      treatment with DCS (50 mg/d) followed by six 6-week double-blind placebo-controlled exposures
      to DCS or placebo. The length of each double-blind arm is limited to six weeks to minimize
      the length of symptom exacerbation experienced by the subjects when they are receiving
      placebo. The randomization scheme will allow two consecutive exposures to DCS, but will not
      allow two consecutive exposures to placebo, again to minimize the length of any symptom
      exacerbation. At the end of the open-label DCS trial, the following procedures will be
      carried out: structural MRI (3T), proton 1H MRS (4T), fMRI (3T), steady-state auditory evoked
      potentials, and electroretinogram recordings. In addition, 1H MRS (4T) for 2 hours after a
      single oral dose of a DCS will be assessed. Baseline data on all of these measures were
      previously obtained as part of a different study registered in clinical trials.gov -
      NCT01720316). 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. Pharmaceutical grade DCS) or placebo
      will be compounded and dispensed 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. DCS
      administration will increase brain glycine in the two carriers compared to baseline and
      treatment with glycine (0.8g/kg).

      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 DCS, but not placebo, will improve positive, negative
      and affective symptoms as well as neurocognitive function.

      The investigators also hypothesize that DCS 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. 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.

      There is an extensive literature on the effects of NMDA enhancing agents on positive,
      negative, and depressive symptoms and on neurocognitive function. Although many studies have
      reported positive results in at least one symptom domain, the results of other studies have
      been negative or ambiguous. 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 and individual differences in brain glycine uptake and
      metabolism . 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 DCS 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 DCS 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.
    

Intervention name(s): D-cycloserine; DCS or placebo; D-cycloserine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.; Double-blind placebo-controlled exposures to DCS or placebo x 6 weeks. One participant received exposure to DCS x 6 weeks and then received placebo dosing x 6 weeks. The other participant received exposure to placebo dosing x 6 weeks and then DCS x 6 weeks.; Both participants received second open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Other intervention name(s): Seromycin (d-cycloserine); Seromycin (d-cycloserine) or placebo; Seromycin (d-cycloserine)
Intervention MeSH terms: Cycloserine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: D-cycloserine; Glycine; Psychosis; Mutation; GABA