OBJECTIVE: The effects of D-cycloserine added to clozapine were assessed and compared with previous results for D-cycloserine plus conventional neuroleptics. METHOD: Ten schizophrenic outpatients receiving clozapine entered consecutive 2-week trials of placebo and D- cycloserine at 5, 15, 50, and 250 mg/day. Clinical evaluations were videotaped and scored by a rater blind to the sequence of assessments. RESULTS: There was a significant dose effect of D-cycloserine on scores on the Scale for the Assessment of Negative Symptoms (SANS); the 50-mg dose produced a mean 21% increase in SANS score. The patients had significantly higher baseline serum glutamate concentrations than the patients receiving typical neuroleptics in the previous trial. Baseline glutamate level and change in glycine level significantly correlated with response of negative symptoms to 50-mg D-cycloserine. CONCLUSIONS: The improvement of negative symptoms with D-cycloserine previously observed in patients receiving typical neuroleptics did not occur in patients treated with clozapine.Abstract Teaser