A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia.

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 may play a role in clozapine's efficacy for negative symptoms.