Use of olanzapine to treat agitation in traumatic brain injury: study protocol for a randomised controlled trial

Abstract

Background: Agitation is common in the early stages of recovery from traumatic brain injury (TBI), when patients are in post-traumatic amnesia (PTA). Agitation is associated with risk of harm to patients and caregivers. Recent guidelines recommend that agitation during PTA is managed using environmental modifications. Agitation is also frequently treated pharmacologically, with the use of atypical antipsychotics such as olanzapine among the most common. This is despite a lack of well-designed studies to support the use of antipsychotics within this context. This study will be a double-blind, placebo-controlled randomised controlled trial. We will examine the efficacy, safety, cost-effectiveness and outcomes associated with the use of olanzapine for reducing agitation in patients in PTA following TBI over and above recommended environmental management. Methods: Fifty-eight TBI rehabilitation inpatients who are in PTA and are agitated will receive olanzapine or placebo for the duration of PTA. All participants will additionally receive optimal environmental management for agitation. Measures of agitation, PTA and health will be undertaken at baseline. Treatment administration will begin at a dose of 5 mg daily and may be escalated to a maximum dose of 20 mg per day. Throughout the treatment period, agitation and PTA will be measured daily, and adverse events monitored weekly. Efficacy will be assessed by treatment group comparison of average Agitated Behaviour Scale scores during PTA. Participants will cease treatment upon emergence from PTA. Agitation levels will continue to be monitored for a further 2 weeks, posttreatment measures of health will be undertaken and cognitive and functional status will be assessed. Level of agitation and functional health will be assessed at hospital discharge. At 3 months post-discharge, functional outcomes and health service utilisation will be measured.

Challenges of Delirium Management in Patients with Traumatic Brain Injury: From Pathophysiology to Clinical Practice

“…These guidelines also suggest not routinely using haloperidol or atypical antipsychotics to treat delirium. Notably, olanzapine has not been demonstrated to impair cognition after TBI and is currently the subject of a randomized controlled trial for post-traumatic agitation [ 167 ].…”

Agitation Following Severe Traumatic Brain Injury Is a Clinical Sign of Recovery of Consciousness

“…Moreover, suppression of dopaminergic neurotransmission can be unfavorable for posttraumatic arousal as clinical trials in amantadine have shown efficacy (12). The ongoing randomized controlled clinical trials using antipsychotics to treat posttraumatic agitation in subacute rehabilitation settings may shed light on the management of emotional dysregulation as a result of sTBI (23,24). The treatment of posttraumatic agitation in acute hospital setting requires further large-scale prospective randomized studies with long-term follow up.…”

“…These results suggest that dopaminergic suppression interferes with arousal and consequently recovery of consciousness. Currently, two randomized controlled clinical trials are being conducted to evaluate the safety and efficacy of antipsychotics in sTBI patients in rehabilitation settings (23,24). Results from these studies can shed light on the underlying mechanism of agitation during the early stage of recovery from sTBI.…”