d-Cycloserine is a partial agonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor. Results have been inconsistent in trials on the efficacy of d-Cycloserine in patients with schizophrenia. We examined the efficacy of d-Cycloserine against negative and cognitive symptoms (primary and co-primary outcomes). Secondary outcomes were efficacy of d-Cycloserine against positive symptoms and the examination of early treatment outcomes. A systematic literature search was carried out using following selection criteria: Population = Patients with Schizophrenia; Intervention = Trials using d-Cycloserine either as monotherapy or adjuvant therapy; Comparison = Placebo or active comparator; Outcome = Change in negative symptoms, cognitive symptoms and positive symptoms; Study design = Randomized controlled trials with parallel design. We used the Cochrane Collaboration tool for risk of bias for study quality appraisal. Effect sizes for trials were calculated separately for negative, positive and cognitive symptom dimensions using the DerSimonian–Laird random effects model. Seven studies (pooled N = 413) provided data for meta-analysis. The pooled Standardized Mean Difference (SMD) for negative, cognitive, and positive symptom change scores were − 0.32 (95% CI, − 0.75 to 0.11), − 0.05 (95% CI, − 0.91 to 0.81), and − 0.08 (95% CI, − 0.37 to 0.20), respectively. No significant improvement was noted with regard to early outcome. I2 values for heterogeneity were 61%, 67%, and 0% for studies assessing negative, cognitive, and positive symptom ratings, respectively. d-Cycloserine did not exhibit significant efficacy in treating negative, cognitive, or positive symptoms of schizophrenia at either study-defined endpoint (4–36 weeks) or at four weeks (early outcome).
