Application of Real-World Data and the REWARD Framework to Detect Unknown Benefits of Memantine and Identify Potential Disease Targets for New NMDA Receptor Antagonists

Background Observational data may inform novel drug development programs by identifying previously unappreciated, clinical benefits of existing drugs. Several preclinical and clinical studies have suggested emergent therapeutic utility of drugs acting on the N-methyl-d-aspartate (NMDA) receptor, a subtype of glutamate receptors, including the antidementia drug memantine. Methods Using a self-controlled cohort study design, the association of exposure to the NMDA receptor antagonist memantine with the incidence of all observed disease outcomes in four US administrative claims databases, spanning from January 2000 through January 2019, was assessed. The databases used in this study were the IBM MarketScan(R) Commercial Database (CCAE), the IBM MarketScan(R) Multi-State Medicaid Database (MDCD), the IBM MarketScan(R) Medicare Supplemental Database (MDCR), and the Optum De-Identified Clinformatics(R) Data Mart Database. Outcomes were defined according to the unique Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) classification system codes and required a diagnosis on two or more distinct dates. Of 20,953 outcomes assessed, only those for which memantine was associated with a >= 50% reduction in risk in two or more databases were included. A meta-analysis with random effects was used to pool data across the databases. Results Overall, 312,336 patients were exposed to memantine during the study. After removing conditions related to dementia and memory loss, 60 outcomes met the threshold criteria. Results fell into five disease categories: mental disorders, substance use disorders, pain, gastrointestinal and colon disorders, and demyelinating disease. The bulk of findings fell into the first two groups, with 28 outcomes related to mental disorders and 24 related to substance use disorders. Conclusion The present results confirm that NMDA receptor antagonism may have broader therapeutic utility than previously recognized. Further observational and clinical research may be warranted to explore the therapeutic benefit of NMDA antagonists for the outcomes found in this study.