Melatonin as a Treatment after Traumatic Brain Injury: A Systematic Review and Meta-Analysis of the Pre-Clinical and Clinical Literature

Traumatic brain injury (TBI) is common; however, effective treatments of the secondary brain injury are scarce. Melatonin is a potent, nonselective neuroprotective and anti-inflammatory agent that is showing promising results in neonatal brain injury. The aim of this study was to systematically evaluate the pre-clinical and clinical literature on the effectiveness of melatonin in improving outcome after TBI. Using the systematic review protocol for animal intervention studies (SYRCLE) and Cochrane methodology for clinical studies, a search of English-language articles was performed. Eligible studies were identified and data were extracted. Quality assessment was performed using the SYRCLE risk of bias tool. Meta-analyses were performed using standardized mean differences (SMD). Seventeen studies (15 pre-clinical, 2 clinical) met inclusion criteria. There was heterogeneity in the studies, and all had moderate-to-low risk of bias. Meta-analysis of pre-clinical data revealed an overall positive effect on neurobehavioural outcome with SMD of 1.51 (95% CI: 1.06-1.96). Melatonin treatment had a favorable effect on neurological status, by an SMD of 1.35 (95% CI: 0.83-1.88), and on cognition by an SMD of 1.16 (95% CI: 0.4-1.92). Melatonin decreased the size of the contusion by an SMD of 2.22 (95% CI: 0.8--3.59) and of cerebral edema by an SMD of 1.91 (95% CI: 1.08-2.74). Only two clinical studies were identified. They were of low quality, were used for symptom management, and were of uncertain significance. In conclusion, there is evidence that melatonin treatment after TBI significantly improves both behavioral outcomes and pathological outcomes; however, significant research gaps exist, especially in clinical populations.