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Donald C. Goff, MD; Guochuan Tsai, MD, PhD; James Levitt, MD; Edward Amico, MEd; Dara Manoach, PhD; David A. Schoenfeld, PhD; Doug L. Hayden, MA; Robert McCarley, MD; Joseph T. Coyle, MD

Arch Gen Psychiatry. 1999;56:21-27.

Background  In a preliminary dose-finding study, D-cycloserine, a partial agonist at the glycine modulatory site of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, improved negative symptoms and cognitive function when added to conventional neuroleptics at a dose of 50 mg/d.

Methods  Forty-seven patients with schizophrenia meeting criteria for deficit syndrome were randomized to D-cycloserine, 50 mg/d (n=23) or placebo (n=24) added to their conventional neuroleptic for an 8-week, double-blind trial. Clinical assessments were performed at baseline and at weeks 1, 2, 4, 6, and 8. Serum concentrations of D-cycloserine, relevant amino acids, and homovanillic acid were assayed at baseline and at weeks 4 and 8. A cognitive battery was performed at baseline and at week 8.

Results  Thirty-nine patients completed the 8-week trial. Seven dropouts occurred in the D-cycloserine group and 1 in the placebo group. The mean reduction in negative symptoms with D-cycloserine (23%) was significantly greater than with placebo (7%) as calculated by slopes representing Scale for the Assessment of Negative Symptoms (SANS) total scores. Improvement of negative symptoms was predicted by low neuroleptic dose and low baseline SANS total score. No differences were found in performance on any cognitive test between groups or in changes in any other clinical measure. Clinical response did not correlate significantly with serum amino acid concentrations at baseline or with concentrations of D-cycloserine at weeks 4 and 8.

Conclusion  These results support the hypothesis that agents acting at the glycine modulatory site of the NMDA receptor improve primary negative symptoms.

From the Psychotic Disorders and Biostatistics Programs, Massachusetts General Hospital, Boston; the Brockton VA Schizophrenia Biological Research Center, Brockton, Mass; and the Harvard Consolidated Department of Psychiatry, Boston.

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