Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia - A randomized, double-blind, placebo-controlled study

Context: Agents that enhance N-methyl-D-aspartate (NMDA) function through the glycine modulatory site (D-serine, glycine, or D-cycloserine) or through glycine transporter 1 (sarcosine) improve the symptoms of patients with stable chronic schizophrenia. Objective: To determine whether NMDA-glycine site agonists or glycine transporter-1 inhibitors have better efficacy and whether NMDA receptor-enhancing agents have beneficial effects for acute exacerbation of schizophrenia. Design: Randomized, double-blind, placebo-controlled trial. Setting: Inpatient units of 2 major medical centers in Taiwan. Patients: Sixty-five schizophrenic inpatients with acute exacerbation. Interventions: Six weeks of treatment with sarcosine (2 g/d), D-serine (2 g/d), or placebo and concomitant optimal risperidone therapy. Main Outcome Measures: Positive and Negative Syndrome Scale (PANSS) and Scale for the Assessment of Negative Symptoms (SANS) (20 and 17 items) total scores. Results: The sarcosine group revealed more reductions in PANSS total scores than the placebo (P=.04) and D-serine (P <.001) groups. Sarcosine adjunctive treatment was also superior to placebo in reducing SANS-20 (P=.007) and SANS-17 (P=.003) scores and to D-serine in decreasing SANS-20 (P=.006) and SANS-17 (P=.002) scores. The PANSS-general, PANSS-cognitive, and PANSS-depressive symptoms scores and SANS-alogia and SANS-blunted affect scores improved significantly more in sarcosine-cotreated patients than in risperidone monotherapy patients (P <=.02 for all). Sarcosine adjunctive therapy also surpassed D-Serine in terms of PANSS-general, PANSS-positive, PANSS-negative, and PANSS-depressive symptoms scores (P <=.04 for all). D-Serine and risperidone cotreatment did not differ significantly from risperidone monotherapy in all efficacy domains. Conclusions: This first short-term treatment study on NMDA receptor-enhancing agents suggests that sarcosine, superior to D-serine, can benefit not only patients with long-term stable disease but also acutely ill persons with schizophrenia. This finding indicates that a glycine transporter 1 inhibitor may be more efficacious than NMDA-glycine site agonists for adjuvant treatment of schizophrenia, at least during the acute phase. Further studies are needed.