Amantadine Speeds Return to Consciousness After Brain Injury

A 4-week course of amantadine sped the rate of functional recovery in an international, randomized, double-blind, placebo-controlled trial of patients who had disorders of consciousness following traumatic brain injury.

Both patients given amantadine and those given placebo improved, but the rate of recovery was more rapid with the active drug. It affected "functionally meaningful behaviors such as consistent responses to commands, intelligible speech, reliable yes-or-no communication, and functional-object use," Joseph T. Giacino, Ph.D., of the JFK Johnson Rehabilitation Institute, Edison, N.J., and his associates reported in the March 1 issue of the New England Journal of Medicine.

The rate of recovery attenuated when treatment stopped, and scores on the Disability Rating Scale (DRS) were virtually indistinguishable between the treatment group and the control group 6 weeks later, indicating that the response was drug dependent.

"Practical and ethical constraints required the use of a brief treatment interval and a short-term assessment of the outcome [in this study], because we anticipated that caregivers would withdraw patients who were not making gains in order to try other treatments. Thus, our findings do not address the effects of prolonged treatment on long-term outcomes," the investigators noted.

"Whether treatment with amantadine, as compared with placebo, improves the long-term outcome or simply accelerates recovery en route to an equivalent level of function remains unknown."

The researchers conducted the trial after a pilot study indicated that amantadine improved functional outcomes after traumatic brain injury. They enrolled 184 patients aged 16-65 years who had sustained a nonpenetrating TBI 4-16 weeks previously and who were receiving usual inpatient rehabilitation at 11 medical centers in three countries.

Patients were diagnosed as being in a vegetative state, in which there was wakefulness without behavioral evidence of conscious awareness, or in a minimally conscious state, in which there was at least one clearly discernible behavioral sign of consciousness. All had scores above 11 on the DRS, which ranges from 0 (best) to 29 (worst); none were able to follow commands consistently or to engage in functional communication as assessed using the Coma Recovery Scale-Revised (CRS-R).

A total of 87 patients were randomly assigned to receive amantadine and 97 to receive a visually identical placebo for 4 weeks. They began at a dose of 100 mg twice daily, with escalations to 150 mg twice daily at week 3 and to 200 mg twice daily at week 4 if the DRS score had not improved by at least 2 points from baseline. Then the drug or placebo was tapered, and patients were assessed for another 6 weeks, according to Dr. Giacino and his associates. Dr. Giacino is also director of rehabilitation neuropsychology at the Spaulding Rehabilitation Hospital and is an associate professor in the department of physical medicine and rehabilitation at Harvard Medical School, both in Boston.

The primary outcome measure was the rate of improvement in the DRS score during treatment. DRS scores were assessed weekly by an interdisciplinary treatment team that was blinded to treatment assignment. Study personnel assessed clinically relevant behavioral benchmarks using the CRS-R.

Both study groups had significantly improved DRS scores at the end of the 4 weeks of treatment, but the amantadine group showed significantly faster improvement (–0.24 points/week more). In addition, at the final follow-up assessment, more patients in the amantadine group showed favorable outcomes on the DRS, fewer remained in a vegetative state, and more showed recovery of key behavioral benchmarks, Dr. Giacino and his colleagues said (N. Engl. J. Med. 2012;366:819-26). These benefits were consistent across all subgroups of patients. They were seen both in subjects in a minimally conscious state and in those in a vegetative state. And they were noted regardless of how long after the TBI injury the patients began treatment.

However, the treatment effect declined when drug therapy stopped, until there were no significant differences at the final follow-up assessment between patients who received the active drug and those who received placebo.

In particular, the proportion of patients who were able to engage in each of six clinically relevant behaviors was higher with amantadine during the month of therapy, but the difference between the two study groups was negligible at the final follow-up. These six behaviors were consistent command-following, object recognition, functional use of objects, intelligible verbalization, reliable yes-or-no communication, and sustained attention.

Amantadine "did not increase the risk of adverse medical, neurologic, or behavioral events, including those of greatest concern in this population (e.g., seizure)," the researchers noted.

The drug’s mechanism of action in these patients is uncertain. Amantadine is thought to promote dopaminergic activity "by facilitating presynaptic release and blocking reuptake postsynaptically." It may also enhance neurotransmission "in the dopamine-dependent nigrostriatal, mesolimbic, and frontostriatal circuits that are responsible for mediating arousal, drive, and attentional functions," they added.