The aim of this updated systematic review was to assess the efficacy and safety of pharmacological agents in the management of agitated behaviors following traumatic brain injury (TBI). We updated a 2019 systematic review, which originally included 21 studies, by performing a search strategy in MedLine, Embase, PsychInfo, Cinhal, Directory of Open Access Journals, and Latin American and Caribbean Literature on Health Sciences Literature (up to Jan 7th, 2025) for evidence on the risks and benefits of nine medication classes used to control agitated behaviors following TBI. We included all randomized controlled trials, quasi-experimental and observational studies examining the effects of medications administered to control agitated behaviors in TBI patients. Of the 58 studies screened in full-text, 11 additional studies were added to the 21 original studies for a total of 32 studies. Of these new studies, three studies evaluating dexmedetomidine suggested some potential benefits in reducing agitation. New studies on risperidone, olanzapine, carbamazepine, and valproic acid failed to show efficacy compared with control groups. Among studies identified in the first review, propranolol did reduce intensity of agitation but not its frequency. In conclusion, there remain insufficient data to recommend the use of any medications for the management of agitation following TBI. Dexmedetomidine may have potential benefit in an acute setting, and the benefits of antipsychotics, carbamazepine, and amantadine remain unclear. Beta-blockers and valproic have shown benefits, but results are inconsistent. More studies in the acute, rehabilitation, and outpatient settings are needed to assess the efficacy and safety of pharmacological agents for the management of agitated behaviors.
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