Amantadine Did Not Positively Impact Cognition in Chronic Traumatic Brain Injury: A Multi-Site, Randomized, Controlled Trial

Flora M Hammond, Mark Sherer, James F Malec, Ross D Zafonte, Sureyya Dikmen, Jennifer Bogner, Kathleen R Bell, Jason Barber, Nancy Temkin, Flora M Hammond, Mark Sherer, James F Malec, Ross D Zafonte, Sureyya Dikmen, Jennifer Bogner, Kathleen R Bell, Jason Barber, Nancy Temkin

Abstract

Despite limited evidence to support the use of amantadine to enhance cognitive function after traumatic brain injury (TBI), the clinical use for this purpose is highly prevalent and is often based on inferred belief systems. The aim of this study was to assess effect of amantadine on cognition among individuals with a history of TBI and behavioral disturbance using a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100 mg twice-daily versus placebo for 60 days. Included in the study were 119 individuals with two or more neuropsychological measures greater than 1 standard deviation below normative means from a larger study of 168 individuals with chronic TBI (>6 months post-injury) and irritability. Cognitive function was measured at treatment days 0, 28, and 60 with a battery of neuropsychological tests. Composite indices were generated: General Cognitive Index (included all measures), a Learning Memory Index (learning/memory measures), and Attention/Processing Speed Index (attention and executive function measures). Repeated-measures analysis of variance revealed statistically significant between-group differences favoring the placebo group at day 28 for General Cognitive Index (p = 0.002) and Learning Memory Index (p = 0.001), but not Attention/Processing Speed Index (p = 0.25), whereas no statistically significant between-group differences were found at day 60. There were no statistically significant between-group differences on adverse events. Cognitive function in individuals with chronic TBI is not improved by amantadine 100 mg twice-daily. In the first 28 days of use, amantadine may impede cognitive processing. However, the effect size was small and mean scores for both groups were generally within expectations for persons with history of complicated mild-to-severe TBI, suggesting that changes observed across assessments may not have functional significance. The use of amantadine to enhance cognitive function is not supported by these findings.

Trial registration: ClinicalTrials.gov NCT00779324.

Keywords: amantadine; attention; brain injuries; cognition; executive function; memory.

Conflict of interest statement

The participant institutions received funding for the project from the U.S. Department of Education, Office of Special Education and Rehabilitative Services, National Institute on Disability and Rehabilitation Research grant H133A080035. Dr. Hammond has served on the Avanir PRISM II Steering Committee, the Avanir Scientific Advisory Board, and has stock ownership (Stock ownership in health care companies include: ABBVIE INC SHS, AMGEN INC COM, ASTRAZENECA PLC SPND ADR, EDWARDS LIFESCIENCES CRP, GW PHARMACEUTICALS PLC ADR, INTUITIVE SURGICAL INC NEW, KONINKL PHIL NV SH NEW, MERCK AND CO INC SHS, PFIZER INC, SANOFI, THERMO FISCHER SCIENTIFIC INC, UNITED HEALTH GROUP, and ZOETIS INC), outside the submitted work. Dr. Bell serves on the Avanir Scientific Advisory Board and receives grant funding from Microtransponder, Inc. The other authors do not have any other relevant financial disclosures.

Figures

FIG. 1.
FIG. 1.
Participant flow diagram. SD, standard deviation.

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