Research Reports - Pharmacotherapy for chronic cognitive impairment in traumatic brain injury
Cochrane Database Syst Rev. 2015 Dec 1;12:CD009221. doi:
Dougall D(1), Poole N, Agrawal N.
BACKGROUND: Traumatic brain injury (TBI) is a major cause of chronic disability.
Worldwide, it is the leading cause of disability in the under 40s, resulting in
severe disability in some 150 to 200 million people per annum. In addition to
mood and behavioural problems, cognition-particularly memory, attention and
executive function-are commonly impaired by TBI. Cognitive problems following TBI
are one of the most important factors in determining people's subjective
well-being and their quality of life. Drugs are widely used in an attempt to
improve cognitive functions. Whilst cholinergic agents in TBI have been reviewed,
there has not yet been a systematic review or meta-analysis of the effect on
chronic cognitive problems of all centrally acting pharmacological agents.
OBJECTIVES: To assess the effects of centrally acting pharmacological agents for
treatment of chronic cognitive impairment subsequent to traumatic brain injury in
SEARCH METHODS: We searched ALOIS-the Cochrane Dementia and Cognitive Improvement
Group's Specialised Register-on 16 November 2013, 23 February 2013, 20 January
2014, and 30 December 2014 using the terms: traumatic OR TBI OR "brain injury" OR
"brain injuries" OR TBIs OR "axonal injury" OR "axonal injuries". ALOIS contains
records of clinical trials identified from monthly searches of a number of major
healthcare databases, numerous trial registries and grey literature sources.
Supplementary searches were also performed in MEDLINE, EMBASE, PsycINFO, The
Cochrane Library, CINAHL, LILACs, ClinicalTrials.gov, the World Health
Organization (WHO) Portal (ICTRP) and Web of Science with conference proceedings.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing the
effectiveness of any one centrally acting pharmacological agent that affects one
or more of the main neurotransmitter systems in people with chronic traumatic
brain injury; and there had to be a minimum of 12 months between the injury and
entry into the trial.
DATA COLLECTION AND ANALYSIS: Two review authors examined titles and abstracts of
citations obtained from the search. Relevant articles were retrieved for further
assessment. A bibliographic search of relevant papers was conducted. We extracted
data using a standardised tool, which included data on the incidence of adverse
effects. Where necessary we requested additional unpublished data from study
authors. Risk of bias was assessed by a single author.
MAIN RESULTS: Only four studies met the criteria for inclusion, with a total of
274 participants. Four pharmacological agents were investigated: modafinil (51
participants); (-)-OSU6162, a monoamine stabiliser (12 participants of which six
had a TBI); atomoxetine (60 participants); and rivastigmine (157 participants). A
meta-analysis could not be performed due to the small number and heterogeneity of
the studies.All studies examined cognitive performance, with the majority of the
psychometric sub-tests showing no difference between treatment and placebo (n =
274, very low quality evidence). For (-)-OSU6162 modest superiority over placebo
was demonstrated on three measures, but markedly inferior performance on another.
Rivastigmine was better than placebo on one primary measure, and a single
cognitive outcome in a secondary analysis of a subgroup with more severe memory
impairment at baseline. The study of modafinil assessed clinical global
improvement (n = 51, low quality evidence), and did not find any difference
between treatment and placebo. Safety, as measured by adverse events, was
reported by all studies (n = 274, very low quality evidence), with significantly
more nausea reported by participants who received rivastigmine compared to
placebo. There were no other differences in safety between treatment and placebo.
No studies reported any deaths.
AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether
pharmacological treatment is effective in chronic cognitive impairment in TBI.
Whilst there is a positive finding for rivastigmine on one primary measure, all
other primary measures were not better than placebo. The positive findings for
(-)-OSU6162 are interpreted cautiously as the study was small (n = 6). For
modafinil and atomoxetine no positive effects were found. All four drugs appear
to be relatively well tolerated, although evidence is sparse.