Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis Harri J. Tuominen a,b , Jari Tiihonen a,c , Kristian Wahlbeck b,d, * a Department of Psychiatry, University of Helsinki, P.O. Box 320, FIN-00029 Helsinki University Central Hospital, Finland b National Research and Development Centre for Welfare and Health (STAKES), P.O. Box 220, FIN-00531 Helsinki, Finland c Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital, FIN-70240 Kuopio, Finland d Psychiatric Unit, Vaasa Central Hospital, FIN-65130 Vaasa, Finland Received 19 January 2004; received in revised form 9 May 2004; accepted 16 May 2004 Available online 19 July 2004 Abstract Objective: To evaluate the efficacy of glutamatergic drugs, acting agonistically on the N-methyl-d-aspartate (NMDA) or the non-NMDA receptors, in schizophrenia. Method: All relevant randomized controlled trials of glutamatergic drugs for schizophrenia were obtained from the Cochrane Schizophrenia Group’s Register of Trials without any language or year limitations. Trials were classified according to their methodological quality. For binary and continuous data, relative risks and weighted (WMD) or standardized mean differences (SMD) were calculated, respectively. Results: Eighteen short-term trials with 343 randomized patients were included in the meta-analysis. In all of these trials, glycine, d-serine, d-cycloserine or ampakine CX516 was used to augment antipsychotics. NMDA receptor co-agonists glycine and d-serine are effective in reducing negative symptoms (N=132, fixed effect model SMD=À0.66, 95% CI À1.02 to À0.29, p =0.0004) of schizophrenia, the magnitude of the effect is moderate. d-Cycloserine, a partial agonist of NMDA receptors, is less effective towards negative symptoms (N=119, fixed effect model SMD=À0.11, 95% CI À0.48 to 0.25, p =0.6). Positive symptoms fail to respond to glutamatergic medication. Available derived data on cognitive functioning do not indicate a significant effect of glycine or d-serine (N=80, random effect model WMD=À2.79, 95% CI À6.17 to 0.60, p =0.11). Conclusions: In the current limited data set, a moderate amelioration of negative symptoms of schizophrenia was found, but no other statistically significant beneficial effects on symptoms of schizophrenia. D 2004 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Systematic review; Meta-analysis; Glycine; d-Serine; d-Cycloserine 1. Introduction Systematic reviews have been developed to sup- port evidence-based decision-making in medicine as 0920-9964/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2004.05.005 * Corresponding author. National Research and Development Centre for Welfare and Health (STAKES), P.O. Box 220, FIN- 00531 Helsinki, Finland. Tel.: +358 9 3967 2300; fax: +358 9 3967 2155. E-mail address: kristian.wahlbeck@stakes.fi (K. Wahlbeck). Schizophrenia Research 72 (2005) 225 – 234 www.elsevier.com/locate/schres