Elsevier

Schizophrenia Research

Volume 72, Issues 2–3, 1 January 2005, Pages 225-234
Schizophrenia Research

Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis

https://doi.org/10.1016/j.schres.2004.05.005Get rights and content

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=−0.66, 95% CI −1.02 to −0.29, 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=−0.11, 95% CI −0.48 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=−2.79, 95% CI −6.17 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.

Introduction

Systematic reviews have been developed to support evidence-based decision-making in medicine as well as in other sciences. Whenever appropriate, meta-analysis is conducted to pool the results of studies (Petticrew, 2001). The aim of a systematic review is to avoid biases. This is achieved by systematic literature searches and by using a team of researchers to assess the methodological quality of trials (Sterne et al., 2001). For example, inadequate allocation into treatment groups (Schulz and Grimes, 2002b) and shortcomings in allocation concealment (Schulz and Grimes, 2002a) may bias outcome of controlled trials and therefore these aspects are inspected carefully. Several small experimental trials on the efficacy of glutamatergic drugs in schizophrenia have been performed, and a systematic review and synthesis of the topic are now timely.

The dopamine hypothesis has been, and remains, the leading theory on the pathophysiology of schizophrenia. However, new evidence shows that other monoamines as well as glutamate and γ-aminobyturic acid (GABA) also play a role. Glutamatergic neurons influence dopaminergic neurotransmission and findings of clinical studies in which glutamate antagonists (such as PCP [phencyclidine, ‘angel dust’], MK-801 or ketamine) provoked schizophrenia-like symptoms have shifted research towards a multifactorial view (Carlsson et al., 2000, Goff and Coyle, 2001).

In the central nervous system, glutamate is an excitatory amino acid neurotransmitter acting on ionotropic and metabotropic receptors. Ionotropic receptors include the N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) and kainate receptors. The NMDA receptors function together with the AMPA and kainate receptors, collectively named the non-NMDA receptors, which are needed to activate the NMDA receptors. Activation of the NMDA receptors also requires an endogenous co-agonist glycine or d-serine to be bound to its binding site on the NMDA receptor complex (Goff and Coyle, 2001, Snyder and Kim, 2000).

Negative symptoms and cognitive deficiencies of schizophrenia have been associated with downregulation of the dopaminergic mesocortical tract (Davis et al., 1991). On the other hand, it has been proposed that disinhibition of excitatory glutamatergic neurons projecting from subcortical regions to target glutamatergic association pathways (pyramidal cells) in the cortex excites cortical neurons excessively (Farber et al., 2002) and may contribute to schizophrenia symptoms. Additionally, in the prefrontal cortex, hypofunction of NMDA receptors located on GABA interneurons inactivates these inhibitory GABA neurons. This in turn leads to a stimulation of glutamatergic cortical neurons and to a neurotoxic increase of glutamate release in pyramidal cells, linked hypothetically to the symptoms of schizophrenia (Farber et al., 1998). For the time being, the question whether schizophrenia is a hyperglutamatergic or hypoglutamatergic state remains unresolved. It is thus plausible that stimulation of NMDA receptors (Farber et al., 1999), inhibition of presynaptic glutamate release by, e.g., lamotrigine (Anand et al., 2000), or non-NMDA receptor antagonism (Farber et al., 2002) may result in beneficial effects in schizophrenia. Glutamatergic agents, including glycine (Diaz et al., 2002, Evins et al., 2000, Heresco-Levy et al., 1999, Javitt et al., 1994, Javitt et al., 2001, Potkin et al., 1992, Potkin et al., 1999), d-serine (Tsai et al., 1998, Tsai et al., 1999), d-cycloserine (Duncan et al., 2002, Goff et al., 1999a, Goff et al., 1999b, Heresco-Levy et al., 1998, Heresco-Levy et al., 2002, Rosse et al., 1996, van Berckel et al., 1999) and ampakine CX516 (Goff et al., 2001), have therefore been clinically investigated to determine whether they could reduce the symptoms of schizophrenia.

The aim of this study was to evaluate whether administration of glutamate receptor agonistic drugs has an effect on the symptoms of people with schizophrenia. We were especially interested in the amelioration of negative symptoms and cognitive deficits for which conventional (Javitt, 1999, Kirkpatrick et al., 2001) and to a lesser degree atypical (Harvey and Keefe, 2001, Leucht et al., 1999) antipsychotics are less satisfactory.

Section snippets

Method

Randomized controlled double-blind trials on glutamatergic drugs for people with schizophrenia, with a minimum trial duration of 2 weeks, were considered for this review. Glutamatergic drugs were limited to those acting in an agonistic fashion on NMDA, AMPA or kainate receptors. No limitations were applied regarding patients' use of antipsychotic medication, i.e. both conventional and atypical antipsychotics were accepted.

An electronic search was performed of the Cochrane Schizophrenia Group's

Results

Electronic search of the Cochrane Schizophrenia Group's Register of Trials yielded 104 citations (June 2002). Reference list searches and communication with trialists yielded an additional 19 citations. Sixty-seven citations were not relevant to this review, leaving 56 citations for more careful inspection. Twenty-four citations were excluded because they were not reports of controlled trials or, e.g., because they did not fulfill inclusion criteria for duration of trial or allocation

Discussion

To our best knowledge, this is the first systematic review and meta-analysis of glutamatergic drugs for schizophrenia. We found a beneficial treatment effect on negative symptoms of schizophrenia only by glycine and d-serine. The treatment effect on negative symptoms, if measured by the PANSS-negative subscale, approximately equals a four-point decrease. Although this can be seen as a moderate effect, it needs to be taken into consideration that this effect is added on any existing beneficial

Acknowledgements

This study was supported by the Wilhelm and Else Stockmann Foundation and by Special Government Funding (EVO). The following researchers are acknowledged for their replies to our inquiries: Dr. S. Akhondzadeh, Dr. B. van Berckel, Dr. R. Bilder, Dr. P. Diaz, Dr. E. Duncan, Dr. A. E. Evins, Dr. D. Goff, Dr. D. Javitt, Dr. K. Kee, Dr. S. Potkin and Dr. R. Rosse. Mika Sampo is also thanked for helpful comments on the manuscript.

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