Traumatic brain injury: Pharmacotherapy options for cognitive deficits
Different medication classes improve different areas of cognitive function
Amantadine, 200 to 400 mg/d, has been shown to safely improve arousal and cognitive function in patients with moderate to severe TBI when started 3 days to 5 months after injury.9 Amantadine, 400 mg/d, also improves executive function measures without significant benefit in attention or memory in patients with mild to severe TBI 6 months post-injury.10
Memory responds to cholinesterase inhibitors. Memory deficits secondary to TBI affect immediate and delayed memory. The cholinesterase inhibitor donepezil is approved for treating Alzheimer’s disease (AD) in the United States and Canada, and research suggests memory deficits after TBI may be similar to those seen in AD.11 This includes deficits in long-term memory storage, which likely is associated with the cholinergic system.11 Post-mortem studies have found similarities in traumatically injured brains and those of AD patients.11
Three small prospective studies of done-pezil have shown improved memory and attention in TBI patients when cognition is the primary outcome, with 1 small negative open-label trial.7 In a study of 53 patients, Whelan et al12 found that donepezil improved patients’ intelligence quotient and clinician-based assessment of cognition over 2 years. Taverni et al13 found memory improvement in 2 TBI patients within 3 weeks of starting donepezil. These results suggest that donepezil may be used in acute and late phases of memory deficits following mild, moderate, or severe TBI.6 All studies titrated donepezil from 5 to 10 mg/d over several weeks. Dosing guidelines for donepezil in AD suggest 5 mg/d for 4 to 6 weeks, which may be increased to 10 mg/d if needed.8
Rivastigmine (3 to 6 mg/d) has been shown to be effective in mild TBI when started 1 year after injury and safe for 12 to 38 weeks of treatment.14,15 One retrospective cohort study of 111 patients with chronic TBI found no difference among donepezil, rivastigmine, or galantamine, with mean doses of 7.2 mg/d, 10 mg/d, and 2.3 mg/d, respectively.16 Sixty-one percent of patients showed improvement and the remainder had modest or no response. This study suggests that positive response on cognition may be similar among cholinesterase inhibitors. In case reports, physostigmine has offered some benefit17,18; however, cardiovascular and autonomic side effects restrict its use.11 Tacrine is associated with problematic gastrointestinal and hepatic side effects.11
Processing speed responds to stimulant catecholaminergics. Although the incidence of psychiatric illness is not correlated with TBI severity, evidence suggests that speed of processing mediates the relationship between injury severity and functional decline.19 Therefore, aggressively treating these deficits may help improve function.
Methylphenidate improves attention and processing speed after TBI. A review of 7 randomized trials and 2 nonrandomized trials indicated that patients with mild to severe, chronic TBI experienced significantly improved cognitive function after methylphenidate treatment.5 Willmott and Ponsford20 found significant enhancement in information processing speed within 2 weeks of methylphenidate treatment in 40 patients with moderate or severe TBI. Methylphenidate increased the rate of recovery and led to improvement in acute21 and post-acute phases.22 In addition, methylphenidate may improve processing speed even in the absence of significant changes in attention.23
The standard methylphenidate dose used in most studies, 0.3 mg/kg twice daily, is safe and effective. Dosing usually is started at 5 mg/d and titrated to symptomatic relief. Because methylphenidate does not lower the seizure threshold, it is safe for patients at high risk for seizure.24 Methylphenidate also significantly improves attention and speed of processing in pediatric head trauma.25,26
Dextroamphetamine also is used to treat speed of processing dysfunction after TBI, but is less studied than methylphenidate. Dextroamphetamine, 5 to 30 mg/d, was found to effectively treat attention problems that interfered with rehabilitation in patients with severe TBI.27
Table 3
Recommended treatments for mild TBI-related cognitive deficits
| Deficit | First-line medication | Side effects | Contraindications | Other treatments |
|---|---|---|---|---|
| Memory | Donepezil (5 to 10 mg/d) | Diarrhea, nausea, vomiting, muscle cramps, fatigue, anorexia | Hypersensitivity to donepezil or piperidine derivatives | Rivastigmine, galantamine, physostigmine, CDP-choline |
| Speed of processing | Methylphenidate (0.3 mg/kg twice daily) | Headache, insomnia, decreased appetite, nausea, vomiting, anxiety, irritability | Hypersensitivity to methylphenidate, glaucoma, history of Tourette syndrome or tics, use of MAOI within 14 days | Dextroamphetamine |
| Executive function | Amantadine (200 to 400 mg/d) | CNS depression, orthostatic hypotension, peripheral edema, agitation, nausea, anorexia | Hypersensitivity to amantadine | Bromocriptine, pramipexole, carbidopa/levodopa |
| CDP-choline: cytidinediphosphocholine; MAOI: monoamine oxidase inhibitor | ||||
| Source: Reference 8 | ||||
Nonpharmacologic treatments
In addition to pharmacotherapy, nonpharmacologic interventions also should be a mainstay of treatment. Compensatory training and cognitive exercise may improve patients’ cognitive deficits and return some sense of control. Individual and family psychotherapy, including cognitive-behavioral therapy, also may be beneficial.2 Review sources have identified the importance of validating patients’ symptoms and developing a goal-based treatment plan.6
