Effectiveness of Amantadine Hydrochloride in the Reduction of Chronic Traumatic Brain Injury Irritability and Aggression

Background: Following traumatic brain injury (TBI), individuals may experience chronic problems with irritability or aggression, which may need treatment to minimize the negative impact on their relationships, home life, social interactions, community participation, and employment. Objective: To test the a priori hypothesis that amantadine reduces irritability (primary hypothesis) and aggression (secondary hypothesis) among individuals greater than 6 months post-TBI. Methods: A total of 76 individuals greater than 6 months post-TBI referred for irritability management were enrolled in a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine (n = 38) versus placebo (n = 38). Study participants were randomly assigned to receive amantadine hydrochloride 100 mg twice daily versus equivalent placebo for 28 days. Symptoms of irritability and aggression were measured before and after treatment using the Neuropsychiatric Inventory Irritability (NPI-I) and Aggression (NPI-A) domains, as well as the NPI-Distress for these domains. Results: In the amantadine group, 80.56% improved at least 3 points on the NPI-I, compared with 44.44% in the group that received placebo (P = .0016). Mean change in NPI-I was -4.3 in the amantadine group and -2.6 in the placebo group (P = .0085). When excluding individuals with minimal to no baseline aggression, mean change in NPI-A was -4.56 in the amantadine group and -2.46 in the placebo group (P = .046). Mean changes in NPI-I and NPI-A Distress were not statistically significant between the amantadine and placebo groups. Adverse event occurrence did not differ between the 2 groups. Conclusions: Amantadine 100 mg every morning and at noon appears an effective and safe means of reducing frequency and severity of irritability and aggression among individuals with TBI and sufficient creatinine clearance.