Efficacy of methylphenidate in the rehabilitation of attention following traumatic brain injury: a randomised, crossover, double blind, placebo controlled inpatient trial

Psychology Department, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Clayton, Victoria, Australia.
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 6.81). 04/2009; 80(5):552-7. DOI: 10.1136/jnnp.2008.159632
Source: PubMed

ABSTRACT Most previous studies evaluating the use of methylphenidate following traumatic brain injury (TBI) have been conducted many years post-injury. This study evaluated the efficacy of methylphenidate in facilitating cognitive function in the inpatient rehabilitation phase.
40 participants with moderate-severe TBI (mean 68 days post-injury) were recruited into a randomised, crossover, double blind, placebo controlled trial. Methylphenidate was administered at a dose of 0.3 mg/kg twice daily and lactose in identical capsules served as placebo. Methylphenidate and placebo administration was randomised in a crossover design across six sessions over a 2 week period. Primary efficacy outcomes were neuropsychological tests of attention.
No participants were withdrawn because of side effects or adverse events. Methylphenidate significantly increased speed of information processing on the Symbol Digit Modalities Test (95% CI 0.30 to 2.95, Cohen's d = 0.39, p = 0.02), Ruff 2 and 7 Test-Automatic Condition (95% CI 1.38 to 6.12, Cohen's d = 0.51, p = 0.003), Simple Selective Attention Task (95% CI -58.35 to -17.43, Cohen's d = 0.59, p = 0.001) and Dissimilar Compatible (95% CI -70.13 to -15.38, Cohen's d = 0.51, p = 0.003) and Similar Compatible (95% CI -74.82 to -19.06, Cohen's d = 0.55, p = 0.002) conditions of the Four Choice Reaction Time Task. Those with more severe injuries and slower baseline information processing speed demonstrated a greater drug response.
Methylphenidate enhances information processing speed in the inpatient rehabilitation phase following TBI. This trial is registered with the Australian New Zealand Clinical Trials Registry (12607000503426).

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    • "Six of eight trials using physical rehabilitation also showed positive treatment effects, and nutrition and acupuncture were found to be beneficial in the single trials conducted thus far. Potential TBI pharmacotherapies were tested in 11 post-acute RCTs, with positive treatment effects reported in six studies, including for methylphenidate (Whyte et al., 2004; Willmott and Ponsford, 2009), CDP-choline (Calatayud Maldonado et al., 1991) and pyritinol (Kitamura, 1981). A trial of phenytoin and carbamazepine was negative (Smith et al., 1994), and sertraline, carbamazepine, rivsatigmine and modafinil were found to have no significant treatment effects (Banos et al., 2010; Jha et al., 2008; Novack et al., 2009; Tenovuo et al., 2009). "
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    • "Healthy participants perceived more errors consciously when they were under the influence of MPH than in the placebo condition. MPH has also proven to be effective in the treatment of cognitive deficits that can be observed after traumatic brain injury (Willmott and Ponsford, 2009), which have been associated with reduced awareness (O'Keeffe et al., 2004). Since MPH is a DA and NE reuptake inhibitor, it can be seen as indirect DA agonist (cf. "
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    • "Pharmacological manipulations of error-related brain activity have shown that enhancing catecholamines with amphetamine (de Bruijn et al., 2004; de Bruijn et al., 2006) or the ␣2 adrenoceptor antagonist yohimbine (Riba et al., 2005) increased the amplitude of the error-related negativity (ERN). Methylphenidate (MPH) has also been shown to be effective in treating the cognitive deficits associated with TBI (Willmott and Ponsford, 2009), in which there is a fundamental problem of reduced awareness (O'Keeffe et al., 2004). In contrast, the D 2 receptor antagonist haloperidol (Zirnheld et al., 2004) and the GABA A /benzodiazepine receptor modulators lorazepam and oxazepam (Johannes et al., 2001; de Bruijn et al., 2004) have been shown to decrease error-related dACC activity. "
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