Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain Injury

JFK Johnson Rehabilitation Institute, Edison, NJ, USA.
New England Journal of Medicine (Impact Factor: 54.42). 03/2012; 366(9):819-26. DOI: 10.1056/NEJMoa1102609
Source: PubMed

ABSTRACT 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.
    Behavioural Brain Research 11/2014; 279. DOI:10.1016/j.bbr.2014.10.037 · 3.39 Impact Factor
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    • "For example, medial thalamic stimulation has proven beneficial for the recovery of responsiveness in some MCS patients (Schiff, Giacino et al. 2007), suggesting an important role for the thalamus in consciousness. Amantadine, a dopaminergic drug (Giacino, Whyte et al. 2012), and surprisingly zolpidem, a GABAergic agonist (Whyte and Myers 2009), have also proven beneficial in some cases of VS or MCS. While the foregoing progress is indeed encouraging, considerable research is still needed in this field. "
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    ABSTRACT: This joint article reflects the authors' personal views regarding noteworthy advances in the neuroscience of consciousness in the last 10 years, and suggests what we feel may be promising future directions. It is based on a small conference at the Samoset Resort in Rockport, Maine, USA, in July of 2012, organized by the Mind Science Foundation of San Antonio, Texas. Here, we summarize recent advances in our understanding of subjectivity in humans and other animals, including empirical, applied, technical, and conceptual insights. These include the evidence for the importance of fronto-parietal connectivity and of "top-down" processes, both of which enable information to travel across distant cortical areas effectively, as well as numerous dissociations between consciousness and cognitive functions, such as attention, in humans. In addition, we describe the development of mental imagery paradigms, which made it possible to identify covert awareness in non-responsive subjects. Non-human animal consciousness research has also witnessed substantial advances on the specific role of cortical areas and higher order thalamus for consciousness, thanks to important technological enhancements. In addition, much progress has been made in the understanding of non-vertebrate cognition relevant to possible conscious states. Finally, major advances have been made in theories of consciousness, and also in their comparison with the available evidence. Along with reviewing these findings, each author suggests future avenues for research in their field of investigation.
    Frontiers in Psychology 10/2013; 4:625. DOI:10.3389/fpsyg.2013.00625 · 2.80 Impact Factor
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    • "A placebo-controlled trial has shown a favorable effect of amantadine on recovery of patients with UWS and in a MCS (Giacino et al., 2012a). Amantadine , facilitating dopamine presynaptic release and blocking its reuptake, may promote dopaminergic neurotransmission in the nigrostriatal, mesolimbic, and frontostriatal circuits, which are involved in arousal and attentional functions (Giacino et al., 2012a). Another study reported an increase in cerebral flow perfusion after zolpidem administration in patients with UWS without brainstem involvement (Du et al., 2013). "
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    ABSTRACT: Unresponsive wakefulness syndrome (UWS, previously known as vegetative state) occurs after patients survive a severe brain injury. Patients suffering from UWS have lost awareness of themselves and of the external environment and do not retain any trace of their subjective experience. Current data demonstrate that neuronal functions subtending consciousness are not completely reset in UWS; however, they are reduced below the threshold required to experience consciousness. The critical factor that determines whether patients will recover consciousness is the distance of their neuronal functions from this threshold level. Recovery of consciousness occurs through functional and/or structural changes in the brain, i.e., through neuronal plasticity. Although some of these changes may occur spontaneously, a growing body of evidence indicates that rehabilitative interventions can improve functional outcome by promoting adaptive functional and structural plasticity in the brain, especially if evidence from a comprehensive neurophysiological theory of consciousness is followed. In this review we will focus on the pathophysiological mechanisms involved in UWS and on the plastic changes operating on the recovery of consciousness.
    Neuroscience & Biobehavioral Reviews 09/2013; 37(10). DOI:10.1016/j.neubiorev.2013.09.007 · 10.28 Impact Factor
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