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Potential Impact of Amantadine on Aggression in Chronic Traumatic Brain Injury

Hammond, Flora M. MD; Malec, James F. PhD; Zafonte, Ross D. DO; Sherer, Mark PhD; Bogner, Jennifer PhD; Dikmen, Sureyya PhD; Whitney, Marybeth P. RN; Bell, Kathleen R. MD; Perkins, Susan M. PhD; Moser, Elizabeth A. MS

Section Editor(s): Neumann, Dawn PhD

The Journal of Head Trauma Rehabilitation: September/October 2017 - Volume 32 - Issue 5 - p 308–318
doi: 10.1097/HTR.0000000000000342
Original Articles

Objective: To assess the effects of amantadine on anger and aggression among individuals with a chronic traumatic brain injury (TBI).

Methods: A cohort of 118 persons with chronic TBI (>6 months postinjury) and moderate-severe aggression selected from a larger cohort of 168 participants enrolled in a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100 mg twice daily (n = 82) versus placebo (n = 86) for treatment of irritability were studied. Anger and aggression were measured at treatment days 0, 28, and 60 using observer-rated and participant-rated State-Trait Anger Expression Inventory-2 (STAXI-2) and Neuropsychiatric Inventory-Agitation/Aggression domain (NPI-A) Most Problematic and Distress scores.

Results: Participant-rated day 60 NPI-A Most Problematic (adjusted P = .0118) and NPI-A Distress (adjusted P = .0118) were statistically significant between the 2 groups, but STAXI-2 differences were not significant after adjustment for multiple comparisons. Substantial improvements were noted in both amantadine and placebo groups (70% vs 56% improving at least 3 points on day 60 Observer NPI-A; P = .11).

Conclusion: Amantadine 100 mg twice daily in this population with chronic TBI appears to be beneficial in decreasing aggression from the perspective of the individual with TBI. No beneficial impact on anger was found.

Trial Registration: Identifier: NCT00779324;

Supplemental Digital Content is Available in the Text.

Indiana University School of Medicine, Indianapolis, Indiana (Drs Hammond, Malec, and Perkins and Ms Moser); Rehabilitation Hospital of Indiana, Indianapolis, Indiana (Drs Hammond and Malec); Spaulding Rehabilitation Hospital, Harvard Medical School, Massachusetts General Hospital, and Brigham and Women's Hospital, Boston, Massachusetts (Dr Zafonte); TIRR Memorial Hermann, Houston, Texas (Dr Sherer); Department of Physical Medicine and Rehabilitation, The Ohio State University, Columbus, Ohio (Dr Bogner); University of Washington, Seattle, Washington (Drs Dikmen and Bell); Department of Physical Medicine and Rehabilitation, Carolinas Rehabilitation, Carolinas HealthCare System, Charlotte, North Carolina (Ms Whitney); and University of Texas Southwestern Medical School, Dallas, Texas (Dr Bell).

Corresponding Author: Flora M. Hammond, MD, Indiana University School of Medicine, 4141 Shore Dr, Indianapolis, IN 46254 (

The authors gratefully acknowledge the work of the Amantadine Irritability Multisite Study Group, Data Safety and Monitoring Board, study site coinvestigators, study coordinators, and other project staff.

The research reported in this article was supported by US Department of Education, Office of Special Education and Rehabilitative Services, National Institute on Disability, Independent Living, and Rehabilitation Research grant H133A080035. This support included the funds to purchase amantadine. The study sponsor had no role in the design and conduct of this study; the collection, management, analysis, and interpretation of the data; or the preparation review, or approval of the manuscript.

Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (

The authors declare no conflicts of interest.

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