The Efficacy and Harms of Pharmacological Interventions for Aggression After Traumatic Brain Injury—Systematic Review

Abstract

Background: Aggression is a commonly reported problem following traumatic brain injury (TBI). It may present as verbal insults or outbursts, physical assaults, and/or property destruction. Aggressive behavior can fracture relationships and impede participation in treatment as well as a broad range of vocational and social activities, thereby reducing the individual's quality of life. Pharmacological intervention is frequently used to control aggression following TBI. The aim of this systematic review was to critically evaluate the evidence regarding efficacy of pharmacological interventions for aggression following TBI in adults.Methods: We reviewed studies in English, available before December 2018. MEDLINE, PubMed, CINAHL, EMBASE, PsycINFO, and CENTRAL databases were searched, with additional searching of key journals, clinical trials registries, and international drug regulators. The primary outcomes of interest were reduction in the severity of aggression and occurrence of harms. The secondary outcomes of interest were changes in quality of life, participation, psychological health (e.g., depression, anxiety), and cognitive function. Evidence quality was assessed using the Cochrane Risk of Bias tool and the Joanna Briggs Institute Critical Appraisal Instruments.Results: Ten studies were identified, including five randomized controlled trials (RCTs) and five case series. There were positive, albeit mixed, findings for the RCTs examining the use of amantadine in reducing irritability (n = 2) and aggression (n = 2). There were some positive findings favoring methylphenidate in reducing anger (n = 1). The evidence for propranolol was weak (n = 1). Individual analysis revealed differential drug response across individuals for both methylphenidate and propranolol. The less rigorous studies administered carbamazepine (n = 2), valproic acid (n = 1), quetiapine (n = 1), and sertraline (n = 1), and all reported reductions in aggression. However, given the lack of a control group, it is difficult to discern treatment effects from natural change over time.Conclusions: This review concludes that a recommendation for use of amantadine to treat aggression and irritability in adults following TBI is appropriate. However, there is a need for further well-designed, adequately powered and controlled studies of pharmacological interventions for aggression following TBI.

Traumatic brain injury-induced submissive behavior in rats: link to depression and anxiety

“…Prevalence of any psychiatric illness in the first year after the injury has been observed at a rate of 49% following moderate to severe TBI and 34% following mild TBI, compared to 18% in those without TBI [ 2 ]. TBI sufferers are particularly susceptible to major depression [ 3 , 4 ], generalized anxiety disorder [ 5 ], post-traumatic stress disorder [ 2 , 6 ], social withdrawal [ 7 ], apathy [ 7 , 8 ], or aggression [ 9 , 10 ]. These conditions can persist for decades after brain injury [ 7 , 11 ] and delay rehabilitation and resumption of employment [ 12 , 13 ].…”

Current and Potential Pharmacologic Therapies for Traumatic Brain Injury

“…Carbamazepine and valproate are also used as mood stabilizers for psychomotor aggregation after TBI, but the effects are controversial [ 27 ]. A newer antiepileptic drug, levetiracetam, is commonly used as there is less drug interaction and it has an equal effect as phenytoin in preventing early seizures [ 28 ].…”

Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model

“…The majority of survivors of moderate and severe traumatic brain injury (TBI) suffer from chronic neuropsychiatric consequences, including cognitive defects, depression, anxiety, social withdrawal and aggression ( Tateno et al, 2003 ; McAllister, 2008 ; Jorge and Arciniegas, 2014 ; Hicks et al, 2019 ; Rauen et al, 2020 ). While these behavioral sequelae may at first be attributable to the emotional burdens of physical disability, these symptoms are not correlated with the severity of the initial injury or with pain ( Bodnar et al, 2019 ) and can persist for decades ( Hoofien et al, 2001 ; Koponen et al, 2002 ).…”

“…Neurological motor symptoms of TBI have been shown to be attenuated by decreasing glutamate levels or function in the brain with dextorphan ( Faden et al, 1989 ), N -methyl- D -aspartate (NMDA) antagonists ( Mei et al, 2018 ), stimulation of excitatory amino acid transporters (EAATs) ( Goodrich et al, 2013 ), or antibiotics and other drugs that block calcium channels or glutamate release ( McConeghy et al, 2012 ; Hicks et al, 2019 ). However, these treatments can also limit the essential effects of glutamate, leading to adverse side effects ( Ikonomidou and Turski, 2002 ; Hardingham and Bading, 2003 ; Muir, 2006 ).…”