Pharmacotherapy to Improve Cognitive Functioning After Acquired Brain Injury: A Meta-Analysis and Meta-Regression

Cognitive impairments, common sequelae of acquired brain injury (ABI), significantly affect rehabilitation and quality of life. Currently, there is no solid evidence-base for pharmacotherapy to improve cognitive functioning after ABI, nevertheless off-label use is widely applied in clinical practice. This meta-analysis and meta-regression aims to quantitatively aggregate the available evidence for the effects of pharmacological agents used in the treatment of cognitive impairments following ABI. We conducted a comprehensive search of Embase, Medline Ovid, and Cochrane Controlled Trials Register databases for randomized controlled and crossover trials. Meta-analytic effects were calculated for each pharmaceutical agent and targeted neuromodulator system. Cognitive outcome measures were aggregated across cognitive domains. Of 8,216 articles, 41 studies (4,434 patients) were included. The noradrenergic agent methylphenidate showed a small, significant positive effect on cognitive functioning in patients with traumatic brain injury (TBI; k = 14, d = 0.34, 95% confidence interval: 0.12-0.56, P = 0.003). Specifically, methylphenidate was found to improve cognitive functions related to executive memory, baseline speed, inhibitory control, and variability in responding. The cholinergic drug donepezil demonstrated a large effect size, albeit based on a limited number of studies (k = 3, d = 1.68, P = 0.03). No significant effects were observed for other agents. Additionally, meta-regression analysis did not identify significant sources of heterogeneity in treatment response. Our meta-analysis supports the use of methylphenidate for enhancing cognitive functioning in patients with TBI. Although donepezil shows potential, it warrants further research. These results could guide clinical decision making, inform practice guidelines, and direct future pharmacotherapeutic research in ABI.