Stepped Treatment for Attention-Deficit/Hyperactivity Disorder and Aggressive Behavior: A Randomized, Controlled Trial of Adjunctive Risperidone, Divalproex Sodium, or Placebo After Stimulant Medication Optimization

Abstract Objective Stimulant medications are the most prevalent first-line pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD), but children with aggressive behavior often receive multi-agent treatment. There is sparse evidence for the benefits of adjunctive medications when stimulant monotherapy has proved inadequate, yet the adverse effects of common adjuncts are well-established. This study compared the efficacy in reducing aggressive behavior of risperidone (RISP), divalproex sodium (DVPX), and placebo (PBO) added to stimulant medication among children whose symptoms persisted after individually-optimized stimulant treatment. Method This trial enrolled 6-12-year-olds with ADHD, a disruptive disorder, significant aggressive behavior, and prior stimulant treatment. Open, systematically titrated stimulant treatment identified patients with inadequate reductions in aggressive behavior, who were then randomized to receive adjunctive RISP, DVPX, or PBO under double-blind conditions for 8 weeks. Family-based behavioral treatment was offered throughout the trial. The primary outcome was the parent-completed Retrospective-Modified Overt Aggression Scale. Results 175 children participated, mean [ sd ] age 9.48 [2.04] years, 19% female. 151 participants completed the stimulant optimization phase, with aggression remitting among 96 (63%), and 45 were randomized to adjunctive treatment groups. The adjunctive RISP group showed greater reductions in aggression ratings than the PBO group; least squares means difference [ΔLSM], -2.33 (95% confidence interval [CI], -3.83 – -0.82; effect size [ES], -1.32), as did those receiving DVPX (ΔLSM, -1.60; 95% CI, -3.18 – -0.03; ES, -0.91). Mean standardized body mass index scores increased more among RISP-treated patients than those receiving -PBO (ΔLSM, 1.54; 95% CI, 0.68 – 2.40; ES = 0.58). Conclusion High response rate during the trial’s open stimulant optimization phase suggests that rigorous titration of stimulant medication and concurrent behavioral therapy may avert the need for additional medications. Among nonremitters, RISP and DVPX were efficacious adjunctive treatments although RISP was associated with weight gain.