N-Methyl-D-Aspartate receptor antagonist treatment in traumatic brain injury: a systematic review of the clinical studies

Traumatic brain injury (TBI) is a leading cause of long-term disability. N-methyl-D-aspartate receptor (NMDAR) signaling constitutes an important target for pharmacological treatment options. The authors have systematically reviewed primary clinical literature reporting on FDA-approved NMDAR antagonist treatment in TBI, based on a set of pre-defined eligibility criteria. Risk of bias assessment was performed using Scottish Intercollegiate Guidelines Network (SIGN) recommendations. Patient characteristics, treatment conditions, and outcomes were reported according to PRISMA guidelines. This review of five clinical literature databases identified 32 eligible studies. Of 1,827 included patients, the majority (74.8%) experienced severe TBI (weighted mean baseline GCS 6.35). Amantadine (24 studies) variably influenced functional recovery and was linked to adverse effects. Ketamine (five studies) variably lowered intracranial pressure and suppressed spreading depolarization. Memantine and dextromethorphan (2 and 1 studies, respectively) showed favorable safety profiles, though data were limited. Across controlled studies, there was a 0.46 (95% CI: 0.16–0.76) weighted mean difference between control and intervention, favoring NMDAR antagonist treatment. Future trials should incorporate mechanism-driven biomarkers and must expand research on safe, well-tolerated drugs to improve efficacy and mitigate adverse effects. <b>PROSPERO registration number</b>: CRD42024539051.