Pharmaceutical Treatments

Pharmaceutical Treatments 

Memory dysfunction following an ABI is a common occurrence. The long term impairment of an ABI affects a person’s ability to return to work or school and may affect their ability to live alone (Katz et al. 1989). 

Difficulties Sustained Post ABI
 

Following an ABI, many individuals have been found to experience: personality changes, memory issues, judgement deficits, a lack of impulse control, and poor concentration. 

Goals of Treatment

  • To improve verbal reaction times
  • To improve the ability to concentrate and focus
  • To improve overall executive control
  • To improve working memory

Methylphenidate (Ritatlin)

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.

Table: Methylphenidate to Enhance Cognitive Skills   

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 individuals with the Val genotype. However, further studies are needed to draw firm conclusions.

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.

 

Donezepil

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. 

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.

 

 

Bromocriptine

Table: Effects of Bromocriptine on Executive Functioning

Discussion

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. 

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. 

Conclusions

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

 

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.

Table: Amantadine to Enhance Cognitive-Communication Skills

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. 

Conclusion

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.

 

Citicoline

Table: Citicoline to Enhance Cognitive-Communication Skills

Discussion

A study by Zafonte et al. (2012) explored the effectiveness of Citicoline in improving the functional and cognitive status of those who had sustain a TBI (mild to severe). This RCT compared the administration of citicoline to a placebo and found no significant differences between groups on any of the tools assessed in the TBI Clinical Trials Network Core Battery. The study concluded that there is a lack of utility of Citicoline in improving or enhancing cognitive functioning post TBI regardless of the severity (Zafonte et al. 2012).

Conclusions

There is Level 1b evidence that Citicoline does not enhance functional or cognitive functioning in individuals who have sustained a TBI.

 

Citicoline has not been found to enhance the functional and cognitive functioning in individuals who have sustained a TBI. The administration of the medication for this purpose appears to be under question.