Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine (DCS)

September 18, 2017 updated by: Deborah L. Levy, Mclean Hospital

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

2

Phase

  • Early Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

34 years to 62 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Carriers of a triplication in the glycine decarboxylase gene

Exclusion Criteria:

  • Not carriers of a triplication in the glycine decarboxylase gene

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Open label DCS
Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule for 8 weeks.
Drug: D-cycloserine
Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Other Names:
  • Seromycin (d-cycloserine)
Drug: D-cycloserine
Both participants received second open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Other Names:
  • Seromycin (d-cycloserine)
Experimental: 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.
Drug: D-cycloserine
Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Other Names:
  • Seromycin (d-cycloserine)
Drug: D-cycloserine
Both participants received second open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Other Names:
  • Seromycin (d-cycloserine)
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.
Other Names:
  • Seromycin (d-cycloserine) or placebo
Experimental: Second open label DCS
Both participants received second open label exposures to D-cycloserine (seromycin), 50 mg/d capsule for 24 weeks.
Drug: D-cycloserine
Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Other Names:
  • Seromycin (d-cycloserine)
Drug: D-cycloserine
Both participants received second open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Other Names:
  • Seromycin (d-cycloserine)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Positive and Negative Symptom Scores
Time Frame: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.The sum of ratings for seven negative symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.
Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
Positive and Negative Symptom Scores
Time Frame: Baseline, 2, 4, & 6 weeks (crossover periods)
Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.The sum of ratings for seven negative symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.
Baseline, 2, 4, & 6 weeks (crossover periods)
Brief Psychiatric Rating Scale (BPRS) Scores
Time Frame: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms.
Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
Brief Psychiatric Rating Scale (BPRS) Scores
Time Frame: Baseline, 2, 4, & 6 weeks (crossover periods)
Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms.
Baseline, 2, 4, & 6 weeks (crossover periods)
Clinical Global Impression (CGI) Severity Scores
Time Frame: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
CGI severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients.
Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
Clinical Global Impression (CGI) Severity Scores
Time Frame: Baseline, 2, 4, & 6 weeks (crossover periods)
CGI severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients.
Baseline, 2, 4, & 6 weeks (crossover periods)
Mania Symptom Scores
Time Frame: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of the ratings for 7 symptoms of mania is measured on a scale of 0-4 and the sumof 4 symptoms of mania is measured on a scale of 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms.
Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
Depression Symptom Scores
Time Frame: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
Hamilton Depression Scale (HAM) measures severity of depression symptoms. The sum of the ratings for 9 depression symptoms is measured on a scale of 0-2 with 0 meaning no depression symptoms and 2 meaning some level of severity of that specific symptom. The rating for one depression symptom is measured on a scale of 0-3 with 0 meaning no depression symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms is measured on a scale of 0-4, with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65. Higher scores indicate worse depression symptoms.
Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
Mania Symptom Scores
Time Frame: Baseline, 2, 4, & 6 weeks (crossover periods)
Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of the ratings for 7 symptoms of mania is measured on a scale of 0-4 and the sumof 4 symptoms of mania is measured on a scale of 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms.
Baseline, 2, 4, & 6 weeks (crossover periods)
Depression Symptom Scores
Time Frame: Baseline, 2, 4, & 6 weeks (crossover periods)
Hamilton Depression Scale (HAM) measures severity of depression symptoms. The sum of the ratings for 9 depression symptoms is measured on a scale of 0-2 with 0 meaning no depression symptoms and 2 meaning some level of severity of that specific symptom. The rating for one depression symptom is measured on a scale of 0-3 with 0 meaning no depression symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms is measured on a scale of 0-4, with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65. Higher scores indicate worse depression symptoms.
Baseline, 2, 4, & 6 weeks (crossover periods)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neurocognitive Function
Time Frame: Baseline and Week 8 of open-label DCS treatment
Scores on each of 8 domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, social cognition, overall composite). Scores are T scores ranging from 0-100, with 50 representing the mean for a population based on a normal distribution, standard deviation of 10. Higher scores signify better functioning.
Baseline and Week 8 of open-label DCS treatment
Brain Glycine/CR Ratio
Time Frame: Baseline and Week 8 of DCS treatment
Proton magnetic resonance spectroscopy at 4T: brain glycine/CR ratio. Participants were assessed at baseline (pre-glycine challenge dose and 60, 80, 100 and 120 minutes post glycine dose) and in week 8 of of open-label DCS treatment: pre-DCS dose, and 60, 80, 100 and 120 minutes post DCS dose. Measured in posterior occipital cortex.
Baseline and Week 8 of DCS treatment
Auditory Evoked Potentials in Latency (Msec)
Time Frame: Baseline and Week 8 of DCS treatment
Auditory evoked potential latency: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz.
Baseline and Week 8 of DCS treatment
Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts)
Time Frame: Baseline and Week 8 of DCS treatment
Auditory evoked potential amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2; mismatch negativity (MMN) at fz and cz.
Baseline and Week 8 of DCS treatment
Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared)
Time Frame: Baseline and Week 8 of DCS treatment
Auditory evoked potential gamma: G40 hz phase locking at fz and cz; G30 hz phase locking at fz and cz; G20 hz phase locking at fz and cz
Baseline and Week 8 of DCS treatment
Auditory Evoked Potentials - P50 Ratio (P50 S2/S1) (Amplitude)
Time Frame: Baseline and Week 8 of DCS treatment
Auditory evoked potential amplitude: P50 ratio (P50 S2/S1)
Baseline and Week 8 of DCS treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mclean Hospital

Collaborators

University of Minnesota

Investigators

  • Principal Investigator: Deborah L. Levy, Ph.D., McLean Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 27, 2015

Primary Completion (Actual)

September 30, 2016

Study Completion (Actual)

July 31, 2017

Study Registration Dates

First Submitted

November 26, 2014

First Submitted That Met QC Criteria

December 1, 2014

First Posted (Estimate)

December 2, 2014

Study Record Updates

Last Update Posted (Actual)

September 19, 2017

Last Update Submitted That Met QC Criteria

September 18, 2017

Last Verified

September 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1R21MH105732 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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