The Neuroprotective Role of Melatonin in Intracerebral Hemorrhage: Lessons from an Observational Study

<b>Background/Objectives:</b> Growing evidence is underscoring the neuroprotective properties of melatonin, particularly its anti-inflammatory, anti-apoptotic, and antioxidant effects. Preliminary findings suggest that it has the potential to attenuate secondary brain injury following intracerebral hemorrhage (ICH). This observational study aimed to investigate the effect of melatonin on post-ICH mortality and functional outcomes. <b>Methods:</b> We conducted an exploratory analysis of data from a single-center, non-randomized, prospective cohort study involving 177 non-ventilated patients with spontaneous ICH consecutively admitted to the Stroke Unit at the University Hospital of Tübingen, Germany, between December 2015 and December 2020. Patients received either the best standard of care (control group) or the best standard of care plus melatonin (2 mg nightly), initiated within 24 h of symptom onset and continued until discharge. The primary endpoint was mortality at discharge, while secondary endpoints included mortality at 90 days and favorable outcomes (modified Rankin Scale [mRS] ≤ 2) at both discharge and a 90-day follow-up. To minimize baseline differences, propensity score matching (PSM) was employed in the secondary analysis. Additionally, ordinal mRS shift analysis was performed to assess the patients' functional status at discharge. <b>Results:</b> In the full cohort (84 melatonin-treated patients vs. 93 controls), melatonin was not associated with any of the primary or secondary outcomes. In the PSM cohort (38 melatonin-treated patients vs. 38 controls), mortality at discharge was three times lower in the melatonin group compared to the control group (2.6% vs. 7.9%), although this trend did not reach statistical significance (ORadj: 0.372; 95% CI: 0.036-3.843; <i>p</i> = 0.407). Ordinal mRS analysis revealed no significant association between melatonin and functional status at discharge (common OR: 0.762; 95% CI: 0.327-1.773; <i>p</i> = 0.527). Similarly, the melatonin treatment was not associated with 90-day mortality (ORadj: 1.519; 95% CI: 0.295-7.826; <i>p</i> = 0.617) or the functional outcome at 90 days (ORadj: 0.626; 95% CI: 0.198-1.983; <i>p</i> = 0.426). <b>Conclusions:</b> Although 2 mg of melatonin daily did not significantly reduce mortality or improve functional outcomes in ICH patients, robust preclinical evidence and the favorable safety profile of melatonin warrant its further exploration in adequately powered, randomized-controlled clinical trials to evaluate optimized dosing regimens.