Although it is a very small and simple molecule, dopamine fulfills many functions in the brain. It acts as a neurotransmitter activating dopamine receptors and when released by the hypothalamus it inhibits the release of prolactin from the anterior lobe of the pituitary gland. Dopaminergic medications are often used by individuals with Parkinson’s disease and those who have sustained an ABI.
Amantadine in Acute Care
Amantadine is a dopamine agonist that acts both pre- and post-synaptically to enhance dopamine activity (Meythaler et al. 2002). Dopamine is thought to be involved in frontal lobe stimulation and plays a role in behavior, mood, language, motor control, hypothalamic function and arousal (Sawyer et al. 2008). Amantadine was initially developed for prophylactic use as an antiviral agent in the prevention of influenza A, but is now commonly used in the treatment of Parkinson’s disease. Amantadine’s properties as a potential neuro-active agent were quickly recognized (Zafonte et al. 2001). Researchers believe that amantadine could significantly improve arousal in comatose patients. Potential side effects include over-stimulation, peripheral edema, livedo reticularis, and lowering of the seizure threshold (Schneider et al. 1999). The favourable risk-benefit profile of amantadine suggests that it may be an attractive treatment option for inducing arousal from coma (Hughes et al. 2005).
Neither the American Association of Neurological Surgeons nor the European Brain Injury Consortium has made recommendations regarding amantadine use in ABI management.
A single RCT explores amantadine’s effectiveness for improving consciousness in adults. Meythaler and colleagues (2002) found that patients who received amantadine initially made significant gains on the Disability Rating Scale, Mini Mental Status Exam, Functional Independence measure-Cognitive domain, and the Galveston Orientation and Amnesia Test, with no further gains made during the placebo phase. Interestingly, patients receiving the placebo first made smaller, but still significant gains. Of note, these patients made further improvements on all measures when switched to amantadine (Meythaler et al. 2002). The authors note that while patients receiving placebo initially made some natural recovery, patients receiving amantadine made more pronounced improvements. Furthermore, the improvements made by patients receiving amantadine in the second six week period suggests that amantadine aids in recovery at various stages of recovery. Other studies have also shown that Amantadine reduces DRS scores (Whyte et al. 2005) and improves GCS scores compared to standard therapy alone (Saniova et al. 2004).
When examining the use of Amantadine for children, two RCTs have been conducted. Amantadine was compared to a placebo in a cross-over study by McMahon et al. (2009). Although no significant differences were noted between the drugs in terms of recovery using standardized measures, physicians noted greater improvements in consciousness when amantadine was administered. It is possible the benefits of amantadine were not shown due to the small sample size of this study (n=7) and the fact two patients dropped out. A child was withdrawn due to medical complications and another was removed because the family requested unblinded administration of amantadine in the second three weeks.
In the second RCT, Patrick et al. (2006) compared amantadine to pramipexole (both dopamine agonists) for children and adolescents who remained in a low-responsive state one month post injury. Patients in both groups made significant improvements on the Coma/ Near Coma Scale (CNCS), the Western NeuroSensory Stimulation Profile (WNSSP), and the DRS weekly gains. Patients also improved on Rancho Los Amigos Scale (RLAS) level. There were no significant side effects to treatment which, combined with the positive results, suggest that dopamine agonists may be a viable option for coma arousal in children and adolescents. However, the lack of control group and small sample size warrant further study before conclusions are drawn.
Green et al. (2004) evaluated the safety of amantadine in a paediatric population. In this study, five out of 54 patients experienced side effects which were all readily reversible. The significant change in RLAS level in the treatment group was questionable due to differences in baseline. There were no significant differences in post-traumatic amnesia (PTA) or length of stay. The subjective improvements reported were difficult to distinguish from natural recovery.
There is Level 1b evidence that pramipexole, and Level 1a evidence that amantadine, are effective in improving levels of consciousness in children with ABI.
Based on a single RCT, there is Level 1b evidence that amantadine improves levels of consciousness and cognitive function in adult patients in various stages of coma.
Amantadine improves consciousness and cognitive function in comatose adult ABI patients.
Amantadine and pramipexole are effective in improving levels of consciousness in children post TBI.
Amantadine and Cognitive Rehabilitation
Amantadine is a non-competitive N-methyl-D-aspartate receptor antagonist and has been used as an antiviral agent, as a prophylaxis for influenza A, for the treatment of neurological diseases such as Parkinson’s Disease, and in the treatment of neuroleptic side-effects such as dystonia, akinthesia and neuroleptic malignant syndrome (Schneider et al. 1999). It is also thought to work pre- and post-synaptically by increasing the amount of dopamine (Napolitano et al. 2005). One study was identified that investigated the effectiveness of amantadine as a treatment for the remediation of learning and memory deficits and cognitive functioning following brain injury.
In a small sample RCT by Schneider et al. (1999) the effects of Amantadine on cognition and behaviours was assessed. In this six week cross-over study, patients received both placebo and amantadine. Although the study found that patients improved over the six week study period, statistical comparison of results evaluating the five subsets of attention, executive/flexibility, memory, behaviour and orientation did not demonstrate any significant effect for the use of Amantadine. Similarly, Kraus et al. (2005) demonstrated that the administration of amantadine over a 12-week treatment period does not improve memory deficits or attention; however, significant improvements in executive functioning were observed. Given the quality and sample size of the current studies, future studies exploring the efficacy of amantadine for learning and memory are warranted.
There is Level 2 evidence that Amantadine does not help to improve learning and memory deficits.
Amantadine has been shown to be ineffective in improving attention and memory deficits. Its impact on executive functioning should be studied further.
Dopamine Medications used in the Paediatric Population
Patrick et al. (2003) examined the effect of a number of dopamine enhancing medications on improvement in arousal and awareness for individuals in a low response state. This study suggests a positive relationship between rate of recovery for children in a low response state and administration of dopamine-enhancing drugs. Limitations of this study include: a retrospective design, a small sample size (n=10), and multiple medications being studied.
There is Level 4 evidence that dopamine-enhancing drugs may accelerate the rate of recovery from a low response state for children post TBI.
Dopamine enhancing drugs may accelerate the rate of recovery from a low response state post TBI in children.
Bromocriptine is a dopaminergic agonist which primarily affects D2 receptors (Whyte et al. 2008). It has been suggested that dopamine is an important neurotransmitter for prefrontal function (McDowell et al. 1998). In a study looking at the effects of bromocriptine on rats, Kline et al. (2002) noted that the animals showed improvement in working memory and spatial learning; however, this improvement was not seen in motor abilities. Three studies have been identified investigating the use of bromocriptine as an adequate treatment for the recovery of cognitive impairments following brain injury.
The question of whether bromocriptine improves cognitive function in patients with ABI was explored in two RCTs (McDowell et al. 1998; Whyte et al. 2008) and a case series (Powell et al. 1996). In an earlier investigation, low-dose bromocriptine (2.5 mg daily) improved functioning on tests of executive control including a dual task, Trail Making Test (TMT), the Stroop test, the Wisconsin Card Sorting Test (WCST) and the controlled oral word association test (COWAT) (McDowell et al. 1998). However, bromocriptine did not significantly influence working memory tasks. Further, a study by Whyte et al. (2008) found that bromocriptine had little effect on attention. It was noted that several participants did experience moderate to severe drug effects and withdrew or were withdrawn from the study.
Although McDowell et al. (1998) demonstrated some benefits following administration of bromocriptine, there was only a single administration of bromocriptine and the dose was considerably lower than that given by Whyte et al. (2008). Spontaneous recovery may have been a factor leading to the improved abilities in individuals receiving a single dose (2.5mg daily) of the medication; however, study results did not answer this question. Results from Whyte et al. (2008) noted that the placebo group demonstrated better (although not significant) trends in improvement on the various tasks administered. Powell et al. (1996) conducted a multiple baseline design on 11 patients with TBI or subarachnoid hemorrhage who received bromocriptine. Improvements were found on all measures assessed except mood.
Based on two RCTs, there is conflicting evidence supporting the use of bromocriptine to enhance cognitive functioning.
There is Level 4 evidence that bromocriptine improves all motivational deficits except mood.
Bromocriptine improves some executive cognitive functions such as dual task performance and motivational deficits but it does not consistently improve memory. More research is needed before the benefits of using bromocriptine to enhance cognitive functioning are known.