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Glycine and D-Cycloserine in Schizophrenia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00000372
Recruitment Status : Withdrawn (Pairing D-Cycloserine with Clozapine was found to worsen negative side effects in patients with Schizophrenia, so the study was suspended.)
First Posted : November 3, 1999
Last Update Posted : June 12, 2014
Sponsor:
Information provided by (Responsible Party):
Donald C. Goff, MD, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE November 2, 1999
First Posted Date  ICMJE November 3, 1999
Last Update Posted Date June 12, 2014
Study Start Date  ICMJE March 1998
Actual Primary Completion Date November 2005   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2014)
Change in SANS Total Score from Baseline to Week 8 [ Time Frame: Baseline, Week 8 ]
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00000372 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2014)
Change in Positive and Negative Syndrome Score from Baseline to Week 8 [ Time Frame: Baseline, Week 8 ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: June 11, 2014)
  • Change in Brief Psychotic Rating Scale from Baseline to Week 8 [ Time Frame: Baseline, Week 8 ]
  • Change in Global Assessment Scale from Baseline to Week 8 [ Time Frame: Baseline, Week 8 ]
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Glycine and D-Cycloserine in Schizophrenia
Official Title  ICMJE A Placebo Controlled Trial of Glycine Added to Clozapine in Schizophrenia
Brief Summary

The purpose of this study is to compare the effects of D-cycloserine and glycine for treating negative symptoms (such as loss of interest, loss of energy, loss of warmth, and loss of humor) which occur between phases of positive symptoms (marked by hallucinations, delusions, and thought confusions) in schizophrenics.

Clozapine is currently the most effective treatment for negative symptoms of schizophrenia. Two other drugs, D-cycloserine and glycine, are being investigated as new treatments. D-cycloserine improves negative symptoms when added to some drugs, but may worsen these symptoms when given with clozapine. Glycine also improves negative symptoms and may still be able to improve these symptoms when given with clozapine. This study gives either D-cycloserine or glycine (or an inactive placebo) with clozapine to determine which is the best combination.

Patients will be assigned to 1 of 3 groups. Group 1 will receive D-cycloserine plus clozapine. Group 2 will receive glycine plus clozapine. Group 3 will receive an inactive placebo plus clozapine. Patients will receive these medications for 8 weeks. Negative symptoms of schizophrenia will be monitored through the Scale for the Assessment of Negative Symptoms, Positive symptoms will be monitored through the Positive and Negative Syndrome Scale, and additionally subjects will complete the Brief Psychiatric Rating Scale and the Global Assessment Scale.

An individual may be eligible for this study if he/she is 18 to 65 years old and has been diagnosed with schizophrenia.

Detailed Description

To determine if glycine produces improvement in negative symptoms and D-cycloserine produces worsening in symptoms compared to placebo, patients will undergo a double blind study of d-cycloserine and glycine treatment added to clozapine.

Clozapine is more effective for negative symptoms of schizophrenia than conventional neuroleptics, but the neurochemical actions contributing to this superior clinical efficacy remain unclear. Recent evidence points to a role for glutamatergic dysregulation in schizophrenia, as well as important differences between conventional agents and clozapine in effects upon glutamatergic systems. D-cycloserine, a partial agonist at the glycine modulatory site of the N-methyl-D-aspartate (NMDA) receptor, improves negative symptoms when added to conventional agents and worsens negative symptoms when added to clozapine. High-dose glycine also improves negative symptoms and has provided preliminary evidence suggesting that glycine improves negative symptoms when added to clozapine. Serum concentrations of glycine predicted response to both high-dose glycine and D-cycloserine. Both clozapine and D-cycloserine may improve negative symptoms by activation of the glycine modulatory site of the NMDA receptor complex. Because D-cycloserine is a partial agonist, it may act as an antagonist at the glycine site in the presence of clozapine, whereas the full agonist, glycine, would not be expected to worsen negative symptoms in the presence of clozapine.

This study proposes to administer a fixed-dose of D-cycloserine, glycine, or placebo added to clozapine in 45 patients with schizophrenia. Because assessments are standardized between studies, results from this study can be compared with results from a previous study of D-cycloserine added to conventional neuroleptic.

The study was ultimately suspended before participants were enrolled, due to definitive findings indicating that pairing treatment of D-cycloserine with Clozapine resulted in worsening of negative symptoms.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Schizophrenia
Intervention  ICMJE
  • Drug: D-cycloserine
  • Drug: Glycine
  • Drug: Clozapine
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: Glycine
    The patients will undergo a 2 week single blind placebo lead in followed by an 8 week randomly assigned double blind treatment phase with 30 grams of glycine in 7 ounces of lemonade twice a day in addition to clozapine treatment.
    Interventions:
    • Drug: Glycine
    • Drug: Clozapine
  • Placebo Comparator: Placebo
    The patients will undergo a 2 week single blind placebo lead in followed by an 8 week randomly assigned double blind treatment phase with 30 grams of placebo powder in 7 ounces of lemonade twice a day in addition to clozapine treatment.
    Interventions:
    • Drug: Clozapine
    • Drug: Placebo
  • Experimental: D-Cycloserine
    The patients will undergo a 2 week single blind placebo lead in followed by an 8 week randomly assigned double blind treatment phase with D-cycloserine in addition to clozapine treatment.
    Interventions:
    • Drug: D-cycloserine
    • Drug: Clozapine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Withdrawn
Actual Enrollment  ICMJE
 (submitted: June 11, 2014)
0
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE November 2005
Actual Primary Completion Date November 2005   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of Schizophrenia
  • Score of 27 or greater on the Scale for the Assessment of Negative Symptoms (SANS)
  • Treatment with stable dose of clozapine for at least 4 weeks
  • Between 18 and 65 years old

Exclusion Criteria:

  • No other antipsychotic medications in oral for for at least 3 months or in depot form for 6 months
  • Current major depressive episode
  • Current substance abuse diagnosis
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00000372
Other Study ID Numbers  ICMJE R01MH057708-02( U.S. NIH Grant/Contract )
DSIR
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Donald C. Goff, MD, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Donald Goff, MD
PRS Account Massachusetts General Hospital
Verification Date June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP