Pharmacological Interventions to Assist with Cognitive Recovery Post ABI

Donepezil

The effectiveness of donepezil, a cholinesterase inhibitor, in improving cognitive and memory functions following brain injury has been assessed. Cognitive impairments affect one’s ability to return to work or school, as well as their ability to live alone (Masanic et al. 2001). When tested with individuals diagnosed with Alzheimer’s disease, donepezil has been found to be useful in treating memory problems (Morey et al. 2003; Walker et al. 2004). Its impact on cognitive function and memory in a TBI population is explored in the table below. 

Individual Studies

Table: Effect of Donepezil on Memory and Cognitive Functioning

Discussion

In a RCT, Zhang et al. (2004) demonstrated that donepezil was associated with improvements in tasks of sustained attention and short-term memory, and that these improvements were sustained even after the washout period. Benefits associated with donepezil were also documented in an open-label study by Masanic et al. (2001) who found that the treatment tended to improve both short- and long-term memory of patients living with TBI. Improvements in memory were also reported by Morey et al. (2003) in their retrospective study who demonstrated that donepezil led to significant benefits in visual memory function. 

Khateb et al. (2005) found only modest improvement on the various neuropsychological tests used to measure executive function, attention and learning and memory. Of note results from the learning phase of Rey Auditory Verbal Memory Test (RAVMT) showed significant improvement (p<0.05). To assess improvement in executive function, results from the Stroop-colour naming test showed significant changes (p<0.03). On the test for Attentional Performance (TAP) a significant change was noted on the divided attention (errors) subsection of the test.

Conclusions

Based on a single RCT, there is Level 1b evidence that donepezil improves attention and short-term memory post ABI.

Based on two non-RCTs, there is Level 4 evidence that donepezil is effective in improving short-term, long-term, and visual memory post ABI.

 

Donepezil helps to improve attention and short-term memory following brain injury.

 

Methylphenidate

Methylphenidate is a stimulant whose exact mechanism is unknown (Napolitano et al. 2005). One theory is that methylphenidate acts on the presynaptic nerve to prevent the reabsorption of serotonin and Norepinephrine, thereby increasing their concentrations within the synaptic cleft. This in turn leads to increased neurotransmission of serotonin and noreinephrine (Kim et al. 2006). Methylphenidate has been extensively used as a treatment for attention deficit disorder, as well as narcolepsy (Glenn 1998). A total of six RCTs examined the efficacy of methylphenidate as a treatment for the recovery of cognitive deficits post brain injury.

Individual Studies

Table: Effect of Methylphenidate on Cognitive Functioning

Discussion

In an RCT, Whyte et al. (2004) indicated that speed of processing, attentiveness during individual work tasks and caregiver ratings of attention were all significantly improved with methylphenidate treatment. No treatment related improvement was seen in divided or sustained attention, or in susceptibility to distraction. Similarly, Plenger et al. (1996) found methylphenidate significantly improved attention and concentration. 

Speech et al. (1993) conducted a double blind placebo controlled trial evaluating the effects of methylphenidate following closed head injury. In contrast to the results noted by Whyte et al. (2004) and Plenger et al. (1996), methylphenidate did not demonstrate significant differences compared to placebo on measures of attention, information processing speed, or learning. Kim et al. (2006) examined the effects of a single-dose treatment of methylphenidate and, although a trend was found in favour of improved working and visuospatial memory for the treatment group, these results did not reach significance. Recently, Kim et al. (2012) found that reaction time improved significantly while on the methylphenidate. This is in line with Willmott and Ponsford (2009) who found that administering methylphenidate to a group of patients during inpatient rehabilitation, did significantly improve the speed of information processing.

In a recent RCT conducted by Willmott et al. (2013), the authors hypothesized that an individuals’ response to methylphenidate depends on their genotype. More specifically, that individuals possessing the methionine (Met) allele at the catechol-O-methyltransferase (COMT) gene would confer greater response to methylphenidate compared to those with the valine (Val) allele. While both Met/Met and Val/Val carriers performed more poorly in various attentional tasks compared to healthy controls, Met/Met carriers did show greater improvements in strategic control in attention than Val/Val carriers. As well, the authors were able to identify one significant drug and genetic interaction between Met/Met carriers and performance on the Symbol Digit Modalities Test (SDMT). These findings suggest Met/Met carriers may in fact be more responsive to methylphenidate than 

Conclusions

There is conflicting evidence regarding the effectiveness of the administration of methylphenidate following brain injury for the improvement of cognitive functioning.

There is Level 1a evidence that methylphenidate improves reaction time of working memory.

Based on a single RCT, there is Level 1b evidence that an individual’s response to methylphenidate therapy may be dependent on his/her genotype of the catechol-O-methyltransferase gene.

 

The effectiveness of methylphenidate treatment to improve cognitive impairment following brain injury is unclear.

Methylphenidate is effective in improving reaction time for working memory.

Response to methylphenidate may depend on genotype.

 

Sertraline

Individual Studies

Table: Effect of Sertraline on Cognitive Functioning Post ABI.

Discussion

The effect of early administration of sertraline on cognitive functioning was evaluated by Banos et al. (2010) in a RCT. When comparing the sertraline group, who received 50mg per day, to a control group (placebo), there were no significant between group differences on any of the neuropsychological tests. The assessments examined attention and concentration, speed of processing, memory and executive function at 3, 6 and 12 months. Cognitive functioning was not found to improve following the administration of sertraline.

Conclusions

There is Level 1b evidence that sertraline does not improve cognitive functioning in individuals who have sustained a moderate to severe TBI.

 

Sertraline has not been shown to improve cognitive functioning within the first 12 months post injury.

 

Amantadine

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.

Individual Studies

Table: Effect of Amantadine on Executive Functioning Following Brain Injury

Discussion

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. 

Conclusions

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.

 

Pramiracetam

Pramiracetam is a nootropic or cognitive activator that is meant to facilitate learning and treat memory deficiencies and other cognitive problems. It produces an increased turnover of acetylcholine in hippocampal cholinergic nerve terminals and it is at least 100 times more potent than its original compound piracetam (McLean Jr. et al. 1991).

Individual Studies

Table: Effect of Pramiracetam on Memory Post ABI

Discussion

McLean Jr. et al. (1991) conducted a study evaluating Pramiracetam in a four males post brain injury. Improvements were found for memory and these improvements remained at one month following discontinuation of the drug. Given the small sample size and the lack of data reported to support the findings, future studies should be conducted.

Conclusions

Based on a single RCT, there is Level 1b evidence that pramiracetam produces significant clinical improvements on males’ memory.

 

Pramiracetam was shown to  improve memory in males; however, additional studies are needed.

 

Physostigmine

Physostigmine is a cholinergic agonist that temporarily stops acetylcholinesterase which in turn slows the destruction of, and thereby increases the concentration of, acetylcholine at the synapse. Its use in Alzheimer’s disease has been examined at length. It has been proposed to improve memory in patients with head injury (McLean et al. 1987).

Individual Studies

Table: Effect of Physostigmine on Memory Post ABI

Discussion

In a double-blind, placebo-controlled randomized trial, oral physostigmine was administered to males with TBI as an active treatment (Cardenas et al. 1994). The authors found that physostigmine led to significant improvements in long-term memory scores in 44% (n=16) of study participants. Those who responded favourably to the treatment, as indicated by their performance on the Selective Reminding Test, also demonstrated improved balance compared to non-responders (Cardenas et al. 1994).    

Conclusions

Based on a single RCT, there is Level 1b evidence that oral physostigmine improves long-term memory in men with TBI. 

 

Physostigmine improves memory in men with TBI.

 

Bromocriptine

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.

Individual Study

Table: Effect of Bromocriptine on Executive Functioning Following Brain Injury

Discussion

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, the Stroop test, the Wisconsin Card Sorting Test and the controlled oral word association test (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. 

Conclusions

Based on a 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.

 

Cerebrolysin

As explained by Alvarez et al. (2003), “Cerebrolysin (EBEWE Pharma, Unterach, Austria) is a peptide preparation obtained by standardized enzymatic breakdown of purified brain proteins, and comprises 25% low-molecular weight peptides and free amino acids” (pg. 272). Cerebrolysin has been demonstrated to have neuroprotective and neurotrophic effects, and has been linked to increased cognitive performance in an elderly population.

Individual Studies

Table: Effect of Cerebrolysin on Cognitive Functioning Following Brain Injury

Discussion

In an open-label trial of 20 patients with TBI Alvarez et al. (2003) found that cerebrolysin was associated with improved brain bioelectrical activity, as evidenced by a significant increase in fast beta frequencies. A brief neuropsychological battery (Syndrome Kurztest) consisting of nine subtests was administered to evaluate memory and attentional functions in patients undergoing treatment with cerebrolysin. There was an overall significant improvement in performance post treatment, suggesting patients experienced cognitive benefits from cerebrolysin treatment. Improvements were also seen in terms of recovery, as measured by the Glasgow Outcome Scale (Alvarez et al. 2003). Together these findings suggest that cerebroylsin may represent an effective neuroprotective therapy with tangible cognitive benefits for individuals living with an ABI. Controlled trials are necessary to further explore the efficacy of this drug. 

Conclusions

There is Level 4 evidence that cerebrolysin improves attention and memory function post ABI, as well as clinical outcome. 

 

Cerebrolysin may be beneficial for the improvement of clinical outcome and cognitive functioning following brain injury; however, controlled trials are needed to further evaluate its efficacy.