Memantine as an Augmentation Treatment for Schizophrenia: Limitations of Meta-Analysis for Evidence-Based Evaluation of Research.

The action of memantine on N-methyl-D-aspartate (NMDA) glutamatergic receptors and the other pharmacodynamic actions of this drug suggest that it may benefit patients with schizophrenia. Many randomized controlled trials (RCTs) have examined this possibility. These RCTs have been meta-analyzed by at least 2 groups of authors. In one meta-analysis (8 RCTs, pooled N = 448), memantine (20 mg/d for 6-12 weeks) augmentation of antipsychotic drug therapy was found to attenuate the severity of negative symptoms and improve cognitive functioning; in both regards, the effect was large. Memantine was also associated with a small but statistically significant reduction in general psychopathology. Whereas memantine did not significantly attenuate positive symptom, depression, total psychopathology, and global illness ratings, it was also not associated with an increased risk of individual adverse events, discontinuation due to adverse events, or all-cause discontinuation. The findings of the other meta-analysis, which examined much the same body of literature, were largely similar. On the surface, these results suggest that memantine may be considered for the reduction of negative symptoms and cognitive impairment in schizophrenia. However, an examination of the individual RCTs and a careful look at the findings of the meta-analyses identify so many important concerns that it is probably premature to draw conclusions about the usefulness of memantine as an augmentation strategy in schizophrenia. At best, it may be stated that there is a signal that supports the study of memantine in schizophrenia patients who are specifically impaired by negative symptoms and cognitive complaints. This is a good example of a situation in which meta-analysis did not provide a trustable evidence-based interpretation of literature.