Amantadine Effect on Perceptions of Irritability after Traumatic Brain Injury: Results of the Amantadine Irritability Multisite Study

Flora M Hammond, Mark Sherer, James F Malec, Ross D Zafonte, Marybeth Whitney, Kathleen Bell, Sureyya Dikmen, Jennifer Bogner, Jerry Mysiw, Rashmi Pershad, Amantadine Irritability Multisite Study Group, Flora M Hammond, Mark Sherer, James F Malec, Ross D Zafonte, Marybeth Whitney, Kathleen Bell, Sureyya Dikmen, Jennifer Bogner, Jerry Mysiw, Rashmi Pershad, Amantadine Irritability Multisite Study Group

Abstract

This study examines the effect of amantadine on irritability in persons in the post-acute period after traumatic brain injury (TBI). There were 168 persons ≥6 months post-TBI with irritability who were enrolled in a parallel-group, randomized, double-blind, placebo-controlled trial receiving either amantadine 100 mg twice daily or equivalent placebo for 60 days. Subjects were assessed at baseline and days 28 (primary end-point) and 60 of treatment using observer-rated and participant-rated Neuropsychiatric Inventory (NPI-I) Most Problematic item (primary outcome), NPI Most Aberrant item, and NPI-I Distress Scores, as well as physician-rated Clinical Global Impressions (CGI) scale. Observer ratings between the two groups were not statistically significantly different at day 28 or 60; however, observers rated the majority in both groups as having improved at both intervals. Participant ratings for day 60 demonstrated improvements in both groups with greater improvement in the amantadine group on NPI-I Most Problematic (p<0.04) and NPI-I Distress (p<0.04). These results were not significant with correction for multiple comparisons. CGI demonstrated greater improvement for amantadine than the placebo group (p<0.04). Adverse event occurrence did not differ between the two groups. While observers in both groups reported large improvements, significant group differences were not found for the primary outcome (observer ratings) at either day 28 or 60. This large placebo or nonspecific effect may have masked detection of a treatment effect. The result of this study of amantadine 100 mg every morning and noon to reduce irritability was not positive from the observer perspective, although there are indications of improvement at day 60 from the perspective of persons with TBI and clinicians that may warrant further investigation.

Trial registration: ClinicalTrials.gov NCT00779324.

Keywords: aggression; agitation; amantadine; brain injuries; irritability.

Figures

FIG. 1.
FIG. 1.
Consort diagram showing study flow.
FIG. 2.
FIG. 2.
Mean Observer and Participant ratings for Neuropsychiatric Inventory-Irritability Most Problematic at baseline, day 28, and day 60.
FIG. 3.
FIG. 3.
Meta-analysis of difference in probability between treatment and control groups (risk difference) of >2 point decrease in Neuropsychiatric Inventory-I Observer Most Problematic at day 28.

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Source: PubMed

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