Short-Term Functional Gains with Amantadine in Severe Traumatic Brain Injury Due to Diffuse Axonal Injury: A Triple-Blind Randomized Clinical Trial

Abstract Traumatic brain injury (TBI) is known to disrupt dopaminergic neurotransmission, leading to reduced dopamine turnover in the brain. Amantadine hydrochloride, a dopaminergic agent, has demonstrated potential in enhancing dopamine activity. This study aimed to assess the efficacy of amantadine hydrochloride in enhancing cognitive recovery in patients with diffuse axonal injury (DAI) following severe TBI. This randomized clinical trial included 57 patients with severe TBI (Glasgow Coma Scale [GCS] < 8) admitted to Imam Khomeini Hospital, Urmia, between March 2020 and March 2024. Patients were randomly assigned to two groups: the intervention group received amantadine hydrochloride (200 mg twice daily) in addition to standard care. In contrast, the control group received standard care with a placebo. Functional outcomes were assessed using the Disability Rating Scale (DRS) and the Glasgow Outcome Scale (GOS). Data were analyzed using SPSS software version 21. Among the participants, 28 patients were in the placebo group (mean age: 28.86 years, initial GCS: 5.25 ± 1.69, initial DRS: 20.42 ± 4.7, initial GOS: 2.71 ± 0.72, mortality rate: 10.71%). The amantadine group consisted of 29 patients (mean age: 29.79 years, initial GCS: 5.58 ± 1.54, initial DRS: 19.93 ± 5.2, initial GOS: 2.86 ± 0.73, mortality rate: 17.24%). At week 4, the amantadine group showed significantly lower DRS scores and higher GOS scores compared with the placebo group (p < 0.05), indicating faster functional recovery. However, by the 6th week, no statistically significant differences were observed between the two groups in either DRS or GOS scores. Mortality rates did not differ significantly between the groups. Amantadine hydrochloride appears to accelerate early cognitive and functional recovery, as reflected by improved DRS and GOS scores at week 4, in patients with DAI. Nonetheless, this benefit does not extend to long-term outcomes or survival, as no significant differences were found at the 6-week follow-up or in mortality rates.