A Cochrane review included 18 studies with a total of 358 subjects. In all trials, glycine, D-serine, D-cycloserine, or ampakine CX516 were used to augment the effect of antipsychotic drugs. All were short-term trials with a maximum duration of 12 weeks. NMDA receptor co-agonists glycine and D-serine showed some effects in reducing the negative symptoms of schizophrenia (SMD –0.66, CI –1.0 to –0.3, n=132). When responder rates rather than mean scores of negative symptoms were analysed the data were inconsistent: there was no difference in responder rates between glycine and the control in terms of more than 20% improvement of negative symptoms (RR 0.70, CI 0.3 to 1.71, n=62) and only a borderline significant superiority in terms of more than 50% improvement (RR 0.87, CI 0.8 to 1.00, n=62). There were also some effects in favour of glycine and/or D-serine in terms of overall and general symptoms, but they did not have a statistically significant effect on positive symptoms and cognitive functioning.
Comment: The level of evidence is downgraded by sparse and inconsistent data. Many participants in the included trials were treatment-resistant which may have reduced treatment response.