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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, in one preliminary dose-finding study, worsened negative symptoms when added to clozapine.

Seventeen schizophrenia outpatients treated with clozapine were assigned in random order to 6-week trials of d-cycloserine 50 mg/day and placebo in a crossover design separated by a 1 week placebo washout.

Eleven patients competed the 13-week study. d-Cycloserine significantly worsened ratings of negative symptoms compared to placebo but did not significantly affect ratings of psychotic symptoms.

The differing effects of d-cycloserine on negative symptoms when added to clozapine compared to conventional antipsychotics suggests that activation of the glycine recognition site …