Use of Olanzapine to Treat Agitation in Traumatic Brain Injury: A Series of N-of-One Trials

Abstract

Agitation is common during post-traumatic amnesia (PTA) following traumatic brain injury (TBI) and is associated with risk of harm to patients and caregivers. Antipsychotics are frequently used to manage agitation in early TBI recovery despite limited evidence to support their efficacy, safety, and impact upon patient outcomes. The sedating and cognitive side effects of these agents are theorized to exacerbate confusion during PTA, leading to prolonged PTA duration and increased agitation. This study, conducted in a subacute inpatient rehabilitation setting, describes the results of a double-blind, randomized, placebo-controlled trial investigating the efficacy of olanzapine for agitation management during PTA, analyzed as an n-of-1 series. Group comparisons were additionally conducted, examining level of agitation; number of agitated days; agitation at discharge, duration, and depth of PTA; length of hospitalization; cognitive outcome; adverse events; and rescue medication use. Eleven agitated participants in PTA (mean [M] age = 39.82 years, standard deviation [SD] = 20.06; mean time post-injury = 46.09 days, SD = 32.75) received oral olanzapine (n = 5) or placebo (n = 6) for the duration of PTA, beginning at a dose of 5 mg/day and titrated every 3 to 4 days to a maximum dose of 20 mg/day. All participants received recommended environmental management for agitation. A significant decrease in agitation with moderate to very large effect (Tau-U effect size = 0.37-0.86) was observed for three of five participants receiving olanzapine, while no significant reduction in agitation over the PTA period was observed for any participant receiving placebo. Effective olanzapine dose ranged from 5-20 mg. Response to treatment was characterized by lower level of agitation and response to treatment within 3 days. In group analyses, participants receiving olanzapine demonstrated poorer orientation and memory during PTA with large effect size (olanzapine, mean = 9.32, SD = 0.69; placebo, M = 10.68, SD = 0.30; p = .009, d = -2.16), and a trend toward longer PTA duration with large effect size (olanzapine, M = 71.96 days, SD = 20.31; placebo, M = 47.50 days, SD = 11.27; p = 0.072, d = 1.26). No further group comparisons were statistically significant. These results suggest that olanzapine can be effective in reducing agitation during PTA, but not universally so. Importantly, administration of olanzapine during PTA may lead to increased patient confusion, possibly prolonging PTA. When utilizing olanzapine, physicians must therefore balance the possible advantages of agitation management with the possibility that the patient may never respond to the medication and may experience increased confusion, longer PTA and potentially poorer outcomes. Further high-quality research is required to support these findings and the efficacy and outcomes associated with the use of any pharmacological agent for the management of agitation during the PTA period.

Keywords: agitation; antipsychotic; inpatient care; olanzapine; post-traumatic amnesia; traumatic brain injury.