Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders

Abstract

Objective: The Food and Drug Administration currently requires the package inserts of most psychostimulant medications to list the presence of a tic disorder as a contraindication to their use. Approximately half of children with Tourette's syndrome experience comorbid attention-deficit/hyperactivity disorder (ADHD). We sought to determine the relative efficacy of different medications in treating ADHD and tic symptoms in children with both Tourette's syndrome and ADHD.

Method: We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of medications in the treatment of ADHD in the children with comorbid tics. We used a random effects meta-analysis with standardized mean difference as our primary outcome to estimate the effect size of pharmaceutical agents in the treatment of ADHD symptoms and tics.

Results: Our meta-analysis included nine studies involving 477 subjects. We assessed the efficacy of six medications-dextroamphetamine, methylphenidate, alpha-2 agonists (clonidine and guanfacine), desipramine, atomoxetine, and deprenyl. Methylphenidate, alpha-2 agonists, desipramine, and atomoxetine demonstrated efficacy in improving ADHD symptoms in children with comorbid tics. Alpha-2 agonists and atomoxetine significantly improved comorbid tic symptoms. Although there was evidence that supratherapeutic doses of dextroamphetamine worsens tics, there was no evidence that methylphenidate worsened tic severity in the short term.

Conclusions: Methylphenidate seems to offer the greatest and most immediate improvement of ADHD symptoms and does not seem to worsen tic symptoms. Alpha-2 agonists offer the best combined improvement in both tic and ADHD symptoms. Atomoxetine and desipramine offer additional evidence-based treatments of ADHD in children with comorbid tics. Supratherapeutic doses of dextroamphetamine should be avoided.

Fig. 1

A and B, Methylphenidate effect on ADHD and tic severity. Forrest plots of methylphenidate’s effect on ADHD (A) and tic severity (B). Methylphenidate significantly improved ADHD severity compared with placebo and improved tic symptoms at trend levels (Gadow et al.^, and Castellanos et al.). MPH = methylphenidate derivatives; TSSG = Tourette Syndrome Study Group.

Fig. 2

A and B, Alpha-2 agonists effect on ADHD and tic severity. Forrest plots of alpha-2 agonists’ effect on ADHD (A) and tic severity (B). Alpha-2 agonists significantly improved both ADHD and tic severity compared with placebo (Singer et al. and Scahill et al.). TSSG = Tourette Syndrome Study Group.

Fig. 3

Effectiveness of medications in treating ADHD and tic disorders. Bubbles represent point estimate and 95% confidence interval for medications in terms of effect size (ES) in treating ADHD and tic symptoms based on a meta-analysis of double-blind, placebo-controlled trials in children with ADHD and comorbid tic disorders. Effect size estimates in treating ADHD symptoms for pharmacological agents were methylphenidate (ES = 0.73; 95% CI 0.53–0.94), alpha-2 agonists (ES = 0.61; 95% CI 0.32–0.90), desipramine (ES = 0.80; 95% CI 0.02–0.91) and atomoxetine (ES = 0.51; 95% CI 0.27–0.74). Effect size estimates in treating tic symptoms for pharmacological agents were methylphenidate (ES = 0.28; 95% CI −0.03 to 0.58), alpha-2 agonists (ES = 0.74; 95% CI 0.44–1.04), desipramine (ES = 0.44; 95% CI −0.02 to 0.91), and atomoxetine (ES = 0.32; 95% CI 0.09–0.56). Supratherapeutic doses of dextroamphetamine modestly worsened tic symptoms (ES = −0.59; 95% CI −1.06 to−0.13) in a small crossover trial. These data are not depicted as there were no estimates for ADHD improvement in the trial. The ESs for deprenyl, a monoamine oxidase B inhibitor, that is not available in the United States and did not demonstrate efficacy in the treatment of ADHD or tics, is also not depicted in this figure. MAO-B = monoamine oxidase B; MPH = methylphenidate derivatives.