Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine
Information source: Mclean Hospital
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Schizophrenia; Bipolar Disorder
Intervention: D-cycloserine (Drug); placebo (Drug)
Phase: Phase 0
Status: Enrolling by invitation
Sponsored by: Mclean Hospital Official(s) and/or principal investigator(s): Deborah L. Levy, Ph.D., Principal Investigator, Affiliation: Mclean Hospital
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.
Clinical Details
Official title: Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Clinical and neurocognitive response to DCS augmentation; change in amino acid levels with DCS augmentationBrain and plasma glycine levels will be measured with proton magnetic resonance spectroscopy at 4T and analytically, respectively
Secondary outcome: Change in glycine levels after oral DCS administration
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.
Eligibility
Minimum age: 33 Years.
Maximum age: 62 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Carriers of a triplication in the glycine decarboxylase gene
Exclusion Criteria:
- Not carriers of a triplication in the glycine decarboxylase gene
Locations and Contacts
Additional Information
Starting date: January 2015
Last updated: July 9, 2015
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