Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain Injury

JFK Johnson Rehabilitation Institute, Edison, NJ, USA.
New England Journal of Medicine (Impact Factor: 55.87). 03/2012; 366(9):819-26. DOI: 10.1056/NEJMoa1102609
Source: PubMed


Amantadine hydrochloride is one of the most commonly prescribed medications for patients with prolonged disorders of consciousness after traumatic brain injury. Preliminary studies have suggested that amantadine may promote functional recovery.
We enrolled 184 patients who were in a vegetative or minimally conscious state 4 to 16 weeks after traumatic brain injury and who were receiving inpatient rehabilitation. Patients were randomly assigned to receive amantadine or placebo for 4 weeks and were followed for 2 weeks after the treatment was discontinued. The rate of functional recovery on the Disability Rating Scale (DRS; range, 0 to 29, with higher scores indicating greater disability) was compared over the 4 weeks of treatment (primary outcome) and during the 2-week washout period with the use of mixed-effects regression models.
During the 4-week treatment period, recovery was significantly faster in the amantadine group than in the placebo group, as measured by the DRS score (difference in slope, 0.24 points per week; P=0.007), indicating a benefit with respect to the primary outcome measure. In a prespecified subgroup analysis, the treatment effect was similar for patients in a vegetative state and those in a minimally conscious state. The rate of improvement in the amantadine group slowed during the 2 weeks after treatment (weeks 5 and 6) and was significantly slower than the rate in the placebo group (difference in slope, 0.30 points per week; P=0.02). The overall improvement in DRS scores between baseline and week 6 (2 weeks after treatment was discontinued) was similar in the two groups. There were no significant differences in the incidence of serious adverse events.
Amantadine accelerated the pace of functional recovery during active treatment in patients with post-traumatic disorders of consciousness. (Funded by the National Institute on Disability and Rehabilitation Research; number, NCT00970944.).

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    • "Additionally, some reports argued that amantadine can suppress microglial activation and neuroinflammation [18] [19]. Recent studies documented how amantadine has been used extensively in clinical application for patients with post-traumatic disorders of consciousness and dysfunction [20] [21]. "
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    ABSTRACT: Traumatic brain injury (TBI) often results in multiple neuropsychiatric sequelae, including cognitive, emotional, and behavioral problems. Among them, depression is a common psychiatric symptom, and links to poorer recovery. Amantadine, as an antiparkinsonian, increases dopamine release, and blocks dopamine reuptake, but has recently received attention for its effectiveness as an antidepressant. In the present study, we first induced a post-TBI depression rat model to probe the efficacy of amantadine therapy in reducing post-TBI depression. The DA concentration in the striatum of the injured rats, as well as the degeneration and apoptosis of dopaminergic neurons in the substantia nigra (SN), were checked along with the depression-like behavior. The results showed that amantadine therapy could significantly ameliorate the depression-like behavior, improving the DA level in the striatum and decreasing the degeneration and apoptosis of dopaminergic neurons in the SN. The results indicated that the anti-depression effect may result from the increase of extracellular DA concentration in the striatum and/or the indirect neuroprotection on the dopaminergic neurons in the SN. We conclude that DA plays a critical role in post-TBI depression, and that amantadine shows its potential value in anti-depression treatment for TBI. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Nov 2014 · Behavioural Brain Research
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    • "Studies conducted with persons in a minimally conscious state and extensive motor impairment have reported four different intervention approaches in addition to pharmacological strategies (e.g., use of amantadine; see Schnakers et al., 2008; Oliveira and Fregni, 2011; Giacino et al., 2012a,b). The four intervention approaches involve general environmental stimulation (i.e., sensory stimulation including music, and social-tactile stimulation), transcranial magnetic stimulation (i.e., a procedure that uses magnetic fields to stimulate nerve cells in the brain), deep brain stimulation (i.e., electrical stimulation of the thalamus through implanted electrodes), and technology-based programs (i.e., procedures based on the use of assistive technology to monitor responding and follow it with relevant stimulation/events) (Giacino, 1996; Magee, 2005, 2007; Pape et al., 2009; Daveson, 2010; Georgiopoulos et al., 2010; Lancioni et al., 2010a; Hirschberg and Giacino, 2011; Piccione et al., 2011; O'Neill, 2012; Scherer, 2012). "
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    ABSTRACT: Post-coma persons in a minimally conscious state and with extensive motor impairment or emerging/emerged from such a state, but affected by lack of speech and motor impairment, tend to be passive and isolated. A way to help them develop functional responding to control environmental events and communication involves the use of intervention programs relying on assistive technology. This paper provides an overview of technology-based intervention programs for enabling the participants to (a) access brief periods of stimulation through one or two microswitches, (b) pursue stimulation and social contact through the combination of a microswitch and a sensor connected to a speech generating device (SGD) or through two SGD-related sensors, (c) control stimulation options through computer or radio systems and a microswitch, (d) communicate through modified messaging or telephone systems operated via microswitch, and (e) control combinations of leisure and communication options through computer systems operated via microswitch. Twenty-six studies, involving a total of 52 participants, were included in this paper. The intervention programs were carried out using single-subject methodology, and their outcomes were generally considered positive from the standpoint of the participants and their context. Practical implications of the programs are discussed.
    Full-text · Article · Feb 2014 · Frontiers in Human Neuroscience
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    • "Anatomic and functional studies have shown that the dopamine system may be vulnerable to TBI, and dopamine suppression after a TBI has been shown in previous studies [4], [5]. In addition, a significant pharmacotherapy that has consistently shown benefits to attention, behavioral outcomes, executive functions, and memory is dopaminergic (DA) therapy [6]–[8], but the aspect of TBI pathology targeted by DA therapy remains unclear. Pharmacological interventions to elucidate cognitive and behavioral deficits in patients with head injuries are now being performed clinically, although empirical studies supporting this practice are limited [9], [10], and the use of psychostimulant drugs (e.g., methylphenidate) for head injuries [11], [12] may indicate that cognitive and learning impairments are related to a deficiency in the dopamine system after head injury. "
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    ABSTRACT: To investigate the role of dopamine in cognitive and motor learning skill deficits after a traumatic brain injury (TBI), we investigated dopamine release and behavioral changes at a series of time points after fluid percussion injury, and explored the potential of amantadine hydrochloride as a chronic treatment to provide behavioral recovery. In this study, we sequentially investigated dopamine release at the striatum and behavioral changes at 1, 2, 4, 6, and 8 weeks after fluid percussion injury. Rats subjected to 6-Pa cerebral cortical fluid percussion injury were treated by using subcutaneous infusion pumps filled with either saline (sham group) or amantadine hydrochloride, with a releasing rate of 3.6mg/kg/hour for 8 weeks. The dopamine-releasing conditions and metabolism were analyzed sequentially by fast scan cyclic voltammetry (FSCV) and high-pressure liquid chromatography (HPLC). Novel object recognition (NOR) and fixed-speed rotarod (FSRR) behavioral tests were used to determine treatment effects on cognitive and motor deficits after injury. Sequential dopamine-release deficits were revealed in 6-Pa-fluid-percussion cerebral cortical injured animals. The reuptake rate (tau value) of dopamine in injured animals was prolonged, but the tau value became close to the value for the control group after amantadine therapy. Cognitive and motor learning impairments were shown evidenced by the NOR and FSRR behavioral tests after injury. Chronic amantadine therapy reversed dopamine-release deficits, and behavioral impairment after fluid percussion injuries were ameliorated in the rats treated by using amantadine-pumping infusion. Chronic treatment with amantadine hydrochloride can ameliorate dopamine-release deficits as well as cognitive and motor deficits caused by cerebral fluid-percussion injury.
    Full-text · Article · Jan 2014 · PLoS ONE
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