A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients.

RATIONALE: D-Cycloserine, a partial agonist at the glycine site of the N-methyl-D-aspartate receptor, has demonstrated inconsistent efficacy for negative and cognitive symptoms of schizophrenia. The strongest evidence for efficacy has come from studies using D-cycloserine at a dose of 50 mg/day added to conventional antipsychotics in trials of 8 weeks duration or less. OBJECTIVE: To assess the efficacy for negative symptoms and cognitive impairment of D-cycloserine augmentation of conventional antipsychotics in a 6-month trial. METHODS: Fifty-five schizophrenia patients with prominent negative symptoms, treated with conventional antipsychotics, were randomly assigned to treatment with D-cycloserine 50 mg/day or placebo for 6 months in a double-blind, parallel group design. RESULTS: Twenty-six subjects completed the 6-month trial; drop-out rates did not differ between treatment groups. D-Cycloserine treatment did not differ from placebo treatment on any primary outcome measure at 8 or 24 weeks, including response of negative symptoms and performance on a cognitive battery. Serum D-cycloserine concentrations did not correlate with response of negative symptoms. CONCLUSION: D-Cycloserine did not exhibit therapeutic effects in this trial, possibly reflecting the high drop-out rate, a narrow range of therapeutic serum concentrations, a modest magnitude of therapeutic effect for the selected outcome measures, or loss of efficacy over time. Because D-cycloserine is a partial agonist with relatively low affinity for the glycine site, the magnitude of potential therapeutic effect may be smaller than that achieved by the higher-affinity full agonists, glycine and D-serine.

D-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia.

BACKGROUND: D-Cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor has previously been shown to improve negative symptoms when added to conventional antipsychotics and to worsen negative symptoms when added to clozapine. The purpose of this study was to examine the effects of D-cycloserine when added to risperidone on negative symptoms of schizophrenia. METHOD: Ten patients with schizophrenia who were treated with risperidone completed consecutive two week trials of placebo and four doses of D-cycloserine. Clinical assessments were videotaped and were scored by a rater who was blind to temporal sequence. RESULTS: D-Cycloserine at a dose of 50mg/day was associated with significant reduction in negative symptoms (mean=10%). Ratings of depression, extrapyramidal side effects, and cognitive function were unchanged. Serum concentrations of glutamate and serine increased significantly on this dose of D-cycloserine. CONCLUSIONS: This preliminary study suggests that combination of D-cycloserine, 50mg/day, with risperidone may improve negative symptoms of schizophrenia over a narrow dose range. The degree of improvement appears to be intermediate between improvement of negative symptoms observed with combination of D-cycloserine with conventional antipsychotics and worsening of negative symptoms observed with combination of D-cycloserine with clozapine in previous trials of identical design.