Amantadine May Reduce Aggression in TBI Patients

The antiviral drug amantadine may reduce aggression in people with chronic traumatic brain injury (TBI)—defined as symptoms lasting for more than six months post-injury, according to a study published in the September/October issue of the Journal of Head Trauma Rehabilitation. The study did not find a beneficial effect on anger, another common behavioral symptom of chronic TBI.

“Several analyses of participant ratings demonstrated superior improvement in the magnitude and frequency of change in aggression” among individuals who took amantadine 100 mg twice daily compared with placebo, Flora M. Hammond, M.D., chair of the Indiana University School of Medicine Department of Physical Medicine and Rehabilitation, and colleagues wrote.

Each study participant was required to enlist an observer—someone close enough to the participant with TBI to have regular interactions and witness behavior—to answer questions about changes in aggression and anger over the course of the trial. According to the study, the reported decrease in aggression in the amantadine group was based on reports from the perspective of the person with brain injury, not from the observer.

“For observers, more so than for participants, the changes in aggressive behavior may need to be sustained over a longer time before observers are willing to conclude that the behavior has changed,” wrote Hammond in an email to Psychiatric News.

Substantial improvements were found in both amantadine and placebo groups (70 percent versus 56 percent), suggesting that participation the trial alone had a positive impact on the patients.

Aggression can have devastating effects on people’s lives and ability to function, Hammond said. “Having a variety of medications to choose from allows selection of the agent that may be most appropriate for the individual,” she wrote, adding that amantadine is cleared from the body by the kidneys and it should not be given to dialysis patients or individuals with inadequate creatinine clearance.

The study included 118 patients with TBI who had moderate to severe aggression at baseline. Of these, 61 were randomized to amantadine and 57 to placebo.

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. The NPI-A domain asks whether during the preceding month the person “got upset, resisted activities, shouted, cursed angrily, slammed doors, kicked furniture, threw things, hurt or hit others, or was stubborn, uncooperative, or hard to handle.”

Anger and aggression are related but are two distinct behaviors tested by the study. “Anger is a state of negative feeling that may be associated with hostile thoughts. Anger may be experienced internally or externally, but aggression is an externally expressed anger. Although anger and aggression may occur concurrently, they are not equivalent,” Hammond wrote.

“Aggression may have important links to arousal modulation and function. Thus, medications that enhance arousal could also have modulating effect on aggression. In contrast, anger is likely to be a more static condition, and possibly mediated in part by serotonin,” she commented.

The research was supported by the U.S. Department of Education, Office of Special Education and Rehabilitative Services, National Institute on Disability, Independent Living, and Rehabilitation Research grant. ■