Objective Pharmacological therapies aimed at modulating catecholaminergic and cholinergic neuronal dysfunction caused by brain trauma have been tried to improve cognitive function post TBI. This systematic review aims to evaluate effectiveness of catecholamingeric and cholinergic drugs used to improve cognitive deficits in adults with TBI.

Method Medline, EMBASE and PsycINFO were searched for randomised control trials (RCTs), open label, case control studies or case series with 10 or more subjects, assessing effectiveness of catecholaminergic or cholinergic drugs or both, in adults who had TBI at least 2 weeks ago (post-acute phase). All eligible studies required at least one outcome that assessed attention or memory using standardised test. Any study involving children, non-TBI, adults with minimal conscious states or neurodegenerative diseases, less than 10 subjects or single dose treatment was excluded.

Results The studies were pooled using narrative synthesis with results grouped according to the type of medication used. 19 studies (n=823) were selected: 12 RCTs (n=434), 1 single blind randomised study (n=115), 1 case control study (n=36), 3 open label prospective studies (n=175), 1 case series (n=10) and 1 retrospective study (n=53). Catecholaminergics (9 studies): Methylphenidate showed significant improvement in speed of information processing and attention in survivors of TBI in three RCTs as compared to placebo, while no significant difference was found between the two groups in other RCT. One RCT showed possible role of amantadine in cognitive recovery in early stages of TBI, while the other two studies did not support these findings. Bromocriptine in low dose was shown to improve executive function in one RCT, but its effects on attention and memory improvement were less promising. Cholinergics (10 studies): All but one (case control study) of the 6 studies (1 RCT, 3 open label and 1 case series) reported positive effect on sustained attention and short term memory with donepezil. The level 1 evidence based on one large multi-centric RCT does not support use of rivastigmine for cognitive augmentation post-TBI. Results for the use of choline and physotigmine on cognitive recovery after TBI from two RCTs are inconsistent.

Conclusion Heterogeneity of TBI population, methodological difficulties, variation in the dose, duration and timing of the medication and use of various psychometric tests to measure cognitive changes confound the results of these studies. Pharmacotherapy of cognitive symptoms following TBI remains a common practice although robust evidence to support this practice is limited. Further research in this area is warranted.