Benefits of Methylphenidate for Long-Term Attention Problems After Traumatic Brain Injury in Childhood: A Randomized, Double-Masked, Placebo-Controlled, Dose-Titration, Crossover Trial

Abstract

Objective: To characterize the benefits and optimal dose of long-acting methylphenidate for management of long-term attention problems after childhood traumatic brain injury (TBI).

Design: Phase 2, randomized, double-masked, placebo-controlled, dose-titration, crossover clinical trial.

Setting: Outpatient, clinical research.

Participants: Twenty-six children aged 6 to 17 years who were at least 6 months post-TBI and met criteria for attention-deficit hyperactivity disorder (ADHD) at the time of enrollment.

Outcome measures: Vanderbilt Rating Scale of attention problems, Pittsburgh Side Effects Rating Scale, and vital signs.

Results: Among the 26 participants randomized, 20 completed the trial. The mean ages at injury and enrollment were 6.3 and 11.5 years, respectively. Eight participants had a severe TBI. On an optimal dose of medication, greater reductions were found on the Vanderbilt Parent Rating Scale for the medicated condition than for placebo (P = .022, effect size = 0.59). The mean optimal dose of methylphenidate was 40.5 mg (1.00 mg/kg/day). Preinjury ADHD diagnosis status was not associated with a differential medication response. Methylphenidate was associated with weight loss (∼1 kg), increased systolic blood pressure (∼3- to 6-point increase), and mild reported changes in appetite.

Conclusion: Findings support use of long-acting methylphenidate for management of long-term attention problems after pediatric TBI. Larger trials are warranted of stimulant medications, including comparative effectiveness and combination medication and nonmedication interventions.

Trial registration: ClinicalTrials.gov NCT01933217.

Conflict of interest statement

Disclosure Statement: All authors of this manuscript have no conflicts of interest to disclose.

Figures

Figure 1

CONSORT flow diagram

Figure 2. Study design

Baseline assessments were completed prior to randomization. At the end of the baseline assessment, each participant was randomized to medication or placebo and received the low dose condition at the end of the enrollment visit (week 0). Upward dose titration to medium and high dose conditions was completed during weeks 2 and 3. After week 3, medication effects and side effects were reviewed for each dose condition and the optimal dose was determine. At the end of week 4, outcomes were measured. Participants then crossed-over to the opposite condition and repeated the same procedures. The total duration of the trial was 8 weeks.

Figure 3. Vanderbilt outcomes

Graphs depicting mean ratings for Vanderbilt Parent Rating Scale Total Symptom Score (VAPRS TSS) and hyperactive and inattentive subscale items. The graph shows scores at the baseline visit, does-titration visits (weeks 1–3, and 5–7), and primary endpoints (week 4 and 8). Analyses included outcomes for the primary endpoints only. For the VAPRS TSS model (p=.022, t-value=2.52, effect size=.59), the placebo condition estimate was 1.47 with a standard error of .11 and medication condition estimate was 1.10 with standard error of .11. For the hyperactive symptom score model (p=.017, t-value=2.63, effect size=.62), the placebo condition estimate was 1.14 with a standard error of .11 and medication condition estimate was .84 with standard error of .11. For the inattentive symptom score model (p=.018, t-value = 2.48, effect size=.42), the placebo condition estimate was 1.79 with a standard error of .12 and medication condition estimate was 1.37 with standard error of .12. M=medication and P=Placebo condition.