Effective Treatment of Traumatic Brain Injury

Abstract

IN THIS ISSUE OF JAMA, ZAFONTE AND COLLEAGUES 1 PREsent the findings of the Citicoline Brain Injury Treatment Trial (COBRIT), a phase 3, double-blind study comparing citicoline vs placebo. In this trial, 1213 study participants with complicated mild, moderate, or severe traumatic brain injury (TBI) were randomized to receive 2000 mg of citicoline or placebo daily for 90 days. The study, which did not demonstrate any benefits of citicholine treatment, is likely to have implications not only for the use of citicoline in patients with TBI but also for the design of future trials of TBI therapies. Traumatic brain injury is an important national and global health issue for civilian and military populations. Recent estimates for the United States indicate that each year 235 000 patients are hospitalized for nonfatal TBI, 1.1 million are treated in emergency departments, and 53 000 die. Trauma, which often includes TBI, is the leading cause of non–cancerrelated deaths among Americans younger than 40 years. A population-based study conducted in Olmsted County, Minnesota, found that the incidence of TBI requiring medical attention was 558 per 100 000 person-years. Following hospitalization for TBI, approximately 43% of patients in the United States have residual disability; 3.2 million Americans are now living with disability following hospitalization for TBI. A birth cohort study in New Zealand indicated that 32% of people had experienced an episode of TBI requiring medical attention by age 25 years. Clearly, TBI is a potentially severe and disabling health condition, but these estimates of morbidity, mortality, and disability do not consider the large number of mild TBI events for which patients do not seek immediate medical attention but can be associated with persistent problems such as headache. Moreover, US veterans with combat-associated mild TBI often have posttraumatic stress disorder, which can complicate reentry into civilian life. The main causes of TBI are motor vehicle crashes, sports injuries, falls, work-related injuries, assaults, and intentional and unintentional injuries involving firearms, explosives, and other weapons. Traumatic brain injury–related fatalities have declined the past 10 to 15 years in part because of improvements in protection of occupants in motor vehicles, protective helmet design, and other preventive measures. However, there remains an imperative need to further reduce the incidence of TBI. In addition, reducing the severity of TBI morbidity once trauma has occurred and improving the rate and extent of recovery from TBI are major challenges. Experimental therapies have shown some promise. For example, among a few carefully selected individuals with severe TBI who were in a state of minimal consciousness, electrical stimulation of the interstitial thalamic nuclei was associated with improved ability to participate and respond to cognitive and motor therapy. In a double-blind, placebo-controlled trial, amantadine improved the rate of recovery from severe TBI, although improvement attributed to amantadine was incomplete and only applicable for patients with severe TBI. There currently are no effective treatments to reduce the severity of TBI-related deficits among patients with complicated mild or moderate TBI. Therefore, the results of the COBRIT study of citicoline therapy were anticipated with great hope. Citicoline is an intermediate in the generation of phosphatidylcholine from choline. The brain uses choline to synthesize the neurotransmitter acetylcholine and the essential membrane components phosphatidylcholine and sphingomyelin. Citicoline increases choline availability for acetylcholine synthesis and membrane synthesis and repair. Citicoline has little toxicity in humans at doses up to 2000 mg daily. There have been encouraging findings in animal studies and preliminary clinical pilot studies using citicoline to reduce cerebral injury caused by TBI, ischemia, and aging. However, similar to the TBI study by Zafonte et al, a multicenter placebo-controlled study found that citicoline did not improve the extent or speed of recovery following acute stroke. There are several possible explanations for differences in the results of animal and human clinical studies in the efficacy of citicoline to reduce brain injury associated with trauma or ischemia. First, differences between animal and