Low D-serine Levels in Schizophrenia: A Systematic Review and Meta-analysis

An increasing amount of evidence indicates that d-serine, a potent and selective endogenous coagonist of the N-methyl-d-aspartate receptor (NMDAR), is efficacious in the treatment of schizophrenia. Although the therapeutic efficacy of d-serine supplementation is based on the d-serine deficit and NMDAR hypofunction hypothesis, it has not been confirmed whether d-serine levels are decreased in patients with schizophrenia compared to healthy controls. We searched the following electronic databases: Embase, Ovid Medline, and the Cochrane Library. A total of 20 studies were included in our meta-analysis. Serum d-serine levels were significantly decreased in patients with schizophrenia (standardized mean difference (SMD)=-1.008, 95% CI=-1.827 to -0.190). In the meta-regression analysis, male gender was positively correlated with serum d-serine levels (coefficient=0.190, 95% CI=0.070 to 0.311). d-Serine therapy combined with antipsychotics significantly improved negative (SMD=-0.319, 95% CI=-0.576 to -0.061) and positive (SMD=-0.211, 95% CI=-0.413 to -0.009) symptoms in patients with schizophrenia. Our results suggest that decreased d-serine availability may justify combining d-serine therapy with antipsychotics in patients with schizophrenia. However, clinical methodological heterogeneity across studies should be considered a major limitation of this analysis.