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.
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Acknowledgements This study was supported by PHS RO1 MH54245, K24 MH02025, and P50 MH60450.