Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine
NCT ID: NCT02304432
Last Updated: 2017-09-19
Study Results
Results available
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
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Recruitment Status
COMPLETED
Clinical Phase
EARLY_PHASE1
Total Enrollment
2 participants
Study Classification
INTERVENTIONAL
Study Start Date
2015-09-27
Study Completion Date
2017-07-31
Brief Summary
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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.
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
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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.
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.
Conditions
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Schizophrenia
Bipolar Disorder
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
CROSSOVER
Primary Study Purpose
TREATMENT
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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Open label DCS
Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule for 8 weeks.
Group Type
EXPERIMENTAL
D-cycloserine
Intervention Type
DRUG
Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
DCS or placebo
Randomized to DCS or placebo. Participants underwent double-blind placebo-controlled exposures to DCS for 6 weeks or placebo for 6 weeks. One participant received exposure to DCS for 6 weeks and then received placebo dosing for 6 weeks. The other participant received exposure to placebo dosing for 6 weeks and then DCS for 6 weeks.
Group Type
EXPERIMENTAL
D-cycloserine
Intervention Type
DRUG
Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
DCS or placebo
Intervention Type
DRUG
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.
Second open label DCS
Both participants received second open label exposures to D-cycloserine (seromycin), 50 mg/d capsule for 24 weeks.
Group Type
EXPERIMENTAL
D-cycloserine
Intervention Type
DRUG
Both participants received second open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Interventions
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D-cycloserine
Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Intervention Type
DRUG
DCS or placebo
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.
Intervention Type
DRUG
D-cycloserine
Both participants received second open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Intervention Type
DRUG
Other Intervention Names
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Seromycin (d-cycloserine)
Seromycin (d-cycloserine) or placebo
Seromycin (d-cycloserine)
Eligibility Criteria
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Inclusion Criteria
* Carriers of a triplication in the glycine decarboxylase gene
Exclusion Criteria
* Not carriers of a triplication in the glycine decarboxylase gene
Minimum Eligible Age
34 Years
Maximum Eligible Age
62 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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University of Minnesota
OTHER
Sponsor Role
collaborator
Mclean Hospital
OTHER
Sponsor Role
lead
Responsible Party
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Deborah L. Levy
Director, Psychology Research Laboratory
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Deborah L. Levy, Ph.D.
Role: PRINCIPAL_INVESTIGATOR
Mclean Hospital
References
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RESULT
Bodkin JA, Coleman MJ, Godfrey LJ, Carvalho CMB, Morgan CJ, Suckow RF, Anderson T, Ongur D, Kaufman MJ, Lewandowski KE, Siegel AJ, Waldstreicher E, Grochowski CM, Javitt DC, Rujescu D, Hebbring S, Weinshilboum R, Rodriguez SB, Kirchhoff C, Visscher T, Vuckovic A, Fialkowski A, McCarthy S, Malhotra D, Sebat J, Goff DC, Hudson JI, Lupski JR, Coyle JT, Rudolph U, Levy DL. Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene. Biol Psychiatry. 2019 Oct 1;86(7):523-535. doi: 10.1016/j.biopsych.2019.04.031. Epub 2019 May 9.
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DERIVED
Provided Documents
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Document Type: Informed Consent Form
Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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