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Trial record 21 of 120 for:    Anti-Bacterial | CYCLOSERINE OR SEROMYCIN

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

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ClinicalTrials.gov Identifier: NCT02304432
Recruitment Status : Completed
First Posted : December 2, 2014
Results First Posted : September 19, 2017
Last Update Posted : September 19, 2017
Sponsor:
Collaborator:
University of Minnesota - Clinical and Translational Science Institute
Information provided by (Responsible Party):
Deborah L. Levy, Mclean Hospital

Brief 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.


Condition or disease Intervention/treatment Phase
Schizophrenia Bipolar Disorder Drug: D-cycloserine Drug: DCS or placebo Early Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine
Actual Study Start Date : September 27, 2015
Actual Primary Completion Date : September 30, 2016
Actual Study Completion Date : July 31, 2017

Resource links provided by the National Library of Medicine


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 Name: 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 Name: 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 Name: 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 second open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Other Name: Seromycin (d-cycloserine)




Primary Outcome Measures :
  1. 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.

  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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   34 Years to 62 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Carriers of a triplication in the glycine decarboxylase gene

Exclusion Criteria:

  • Not carriers of a triplication in the glycine decarboxylase gene

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02304432


Sponsors and Collaborators
Mclean Hospital
University of Minnesota - Clinical and Translational Science Institute
Investigators
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Principal Investigator: Deborah L. Levy, Ph.D. Mclean Hospital
  Study Documents (Full-Text)

Documents provided by Deborah L. Levy, Mclean Hospital:
Informed Consent Form  [PDF] April 9, 2015
Study Protocol  [PDF] April 9, 2015
Statistical Analysis Plan  [PDF] February 27, 2015


Publications of Results:
Other Publications:
McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee YH, Vacic V, Gary S, Iakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, Derosse P, Steele J, Kassem L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR; Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O'Donovan MC, Shaikh TH, Susser E, Delisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL, King MC, Sebat J. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009 Nov;41(11):1223-7. doi: 10.1038/ng.474. Epub 2009 Oct 25.

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Responsible Party: Deborah L. Levy, Director, Psychology Research Laboratory, Mclean Hospital
ClinicalTrials.gov Identifier: NCT02304432     History of Changes
Other Study ID Numbers: 1R21MH105732 ( U.S. NIH Grant/Contract )
First Posted: December 2, 2014    Key Record Dates
Results First Posted: September 19, 2017
Last Update Posted: September 19, 2017
Last Verified: September 2017

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Deborah L. Levy, Mclean Hospital:
D-cycloserine
Glycine
Psychosis
Mutation
GABA

Additional relevant MeSH terms:
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Cycloserine
Antibiotics, Antitubercular
Anti-Bacterial Agents
Schizophrenia
Bipolar Disorder
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Bipolar and Related Disorders
Glycine
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Antitubercular Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs