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
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.
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
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.
- 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
- 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