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Glycine and D-Cycloserine in Schizophrenia

This study has been withdrawn prior to enrollment.
(Pairing D-Cycloserine with Clozapine was found to worsen negative side effects in patients with Schizophrenia, so the study was suspended.)
Sponsor:
ClinicalTrials.gov Identifier:
NCT00000372
First Posted: November 3, 1999
Last Update Posted: June 12, 2014
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.
Information provided by (Responsible Party):
Donald C. Goff, MD, Massachusetts General Hospital
  Purpose

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.


Condition Intervention Phase
Schizophrenia Drug: D-cycloserine Drug: Glycine Drug: Clozapine Drug: Placebo Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Placebo Controlled Trial of Glycine Added to Clozapine in Schizophrenia

Resource links provided by NLM:


Further study details as provided by Donald C. Goff, MD, Massachusetts General Hospital:

Primary Outcome Measures:
  • Change in SANS Total Score from Baseline to Week 8 [ Time Frame: Baseline, Week 8 ]

Secondary Outcome Measures:
  • Change in Positive and Negative Syndrome Score from Baseline to Week 8 [ Time Frame: Baseline, Week 8 ]

Other Outcome Measures:
  • 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 ]

Enrollment: 0
Study Start Date: March 1998
Study Completion Date: November 2005
Primary Completion Date: November 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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.
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.
Drug: D-cycloserine Drug: Clozapine

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.

  Eligibility

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.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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): NCT00000372


Locations
United States, Massachusetts
Freedom Trail Clinic
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
Principal Investigator: Donald Goff, MD
  More Information

Responsible Party: Donald C. Goff, MD, Director of the Schizophrenia Clinical and Research Program, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00000372     History of Changes
Other Study ID Numbers: R01MH057708-02 ( U.S. NIH Grant/Contract )
DSIR
First Submitted: November 2, 1999
First Posted: November 3, 1999
Last Update Posted: June 12, 2014
Last Verified: June 2014

Keywords provided by Donald C. Goff, MD, Massachusetts General Hospital:
Adult
Amino Acids
Cycloserine
Female
Glycine
Human
Male
N-Methylaspartate
Placebos
Schizophrenia
Amino Acids -- blood
Cycloserine -- *therapeutic use
Glycine -- *therapeutic use
Schizophrenia -- *drug therapy
Schizophrenia -- physiopathology

Additional relevant MeSH terms:
Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Cycloserine
Clozapine
Glycine
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
GABA Antagonists
GABA Agents
Glycine Agents