Amantadine for Irritability After Traumatic Brain Injury

Summary and Comment |
December 23, 2013

Amantadine for Irritability After Traumatic Brain Injury

  1. Jonathan Silver, MD

It's a first-line option, according to a large single-center study.

  1. Jonathan Silver, MD

Of the many neuropsychiatric sequelae of traumatic brain injury (TBI), irritability and aggression most interfere with relationships and recovery. Yet, few double-blind, placebo-controlled efficacy studies of pharmacological interventions have been conducted (with most published studies focusing on beta blockers). Small studies have shown amantadine, a dopaminergic agent and N-methyl-D-aspartate channel antagonist, to decrease irritability and aggression. This single-center study — the second largest outpatient study (including multicenter studies) ever published on any TBI treatment — examines the efficacy of amantadine.

The 76 individuals, who had experienced TBI more than 6 months previously (mean, 5 years previously; moderate severity of injury on the Glasgow Coma Scale) and were at least moderately irritable, were randomized to amantadine (100 mg twice daily) or placebo for 28 days. The primary assessment was observer ratings of irritability and aggression; mood, fatigue, and global symptoms were also tracked.

Only four patients did not complete the study. In the amantadine group, 81% improved at least three points on an irritability scale, compared with 44% of the placebo group — a significant difference. Both frequency and intensity of episodes decreased significantly with amantadine. Overall, aggression levels did not change, but in an analysis of patients with significant baseline aggression, amantadine was associated with significant improvement. The drug was well tolerated.


Amantadine, a readily available, inexpensive, easy-to-administer medication, was effective for irritability in outpatients with chronic, moderate traumatic brain injury. Aggression in the whole group might not have significantly improved because of a ceiling effect. Although clinicians have several pharmacologic options for treating irritability, this study is the most rigorous completed thus far. Results of a multicenter, randomized trial should be available soon and, hopefully, will confirm these findings. Amantadine must now be considered a first-line medication for irritability after TBI.

Editor Disclosures at Time of Publication

  • Disclosures for Jonathan Silver, MD at time of publication Editorial boards Journal of Neurology, Neurosurgery and Psychiatry; Journal of Neuropsychiatry and Clinical Neuroscience; UpToDate Leadership positions in professional societies North American Brain Injury Association (Board Member) Editorial Boards Journal of Neurology, Neurosurgery & Psychiatry; Journal of Neuropsychiatry and Clinical Neurosciences


Reader Comments (1)

hanns ludwig, prof. of virology, fu- berlin, germany Fu Berlin; and Chongqing Medical Univerisity

The effect of amantadine might be de due to inhibition of replication of Borna disease virus. Did you check this?
See literature by Bode et al. and Ludwig et al., dealing with the (causal influence ???) contribution of BDV on mental diseases.

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