,Part 1: Project Description Persistent aggressive behavior is among the most prevalent problems for which children receive mental health services and it confers heightened risk for unfavorable outcomes throughout life. Among preadolescents, aggressive behavior most often develops in the context of impulse control deficits and affective instability. Most affected children fulfill diagnostic criteria for disruptive behavior disorders, with which ADHD is highly comorbid. Stimulant medication is first-line pharmacotherapy for ADHD and frequently also ameliorates associated aggression and other conduct problems. Yet, for many children receiving stimulant treatment, aggressive behavior and affective volatility remain significant impairments, leading clinicians to layer additional medications. In particular, use of antipsychotics and mood stabilizers for this purpose has risen sharply. Evidence currently cited to support their use, however, has not evaluated their efficacy as adjuvant therapy for children with ADHD whose aggression persists after adequate stimulant treatment. Without data evaluating these agents as adjuncts for children whose aggression is demonstrably refractory to stimulant monotherapy, the magnitude of their value as add-on treatment remains uncertain. We previously found that 51.5% of children with ADHD and high aggression experienced sustained remission of aggressive behavior after rigorous stimulant titration and a psychosocial intervention. Those whose aggression persisted participated in a controlled trial of adjunctive divalproex sodium (DVPX). Of those randomized to active DVPX, 52% experienced remission of aggression, compared to 12% of those who took placebo. While significant, this clinically moderate effect highlights the need to determine in a stepped design if widely-used antipsychotic treatment offers greater benefit. Therefore, we propose to evaluate the efficacy and safety of stimulant+antipsychotic and stimulant+DVPX strategies in ameliorating aggression among 6-12 year-olds with ADHD and ODD/CD who experience inadequate response to stimulant treatment and concurrent behavioral intervention. After an open lead-in of stimulant titration and behavioral therapy, the trial will randomly assign children whose aggression persists to adjunctive treatment with risperidone or DVPX for eight weeks. Children whose aggression remits will continue their regimen for 6 months to examine durability of response and tolerability. The study leverages our prior work that (1) estimated the rate of adequate response to stimulant alone, (2) gauged the effect of DVPX for stimulant-refractory aggression, 3) defined inclusion criteria likely to select children who will need adjunctive medication after stimulant monotherapy, and (4) established the feasibility of participant enrollment and retention through these study phases. Project summary/abstract project summary/Abstract,Part 2: Public Health Relevance Statement The proposed research stands to fill worrisome gaps in our knowledge on the sequencing, benefits, and liabilities of medication treatment strategies for highly impaired children. By helping to bridge the chasm from the rather improvisational character of current pharmacotherapy practice with this patient group to generalizable guidance from rigorous trials, this study will offer an important contribution to public health.
|Blader, Joseph C; Pliszka, Steven R; Kafantaris, Vivian et al. (2013) Callous-unemotional traits, proactive aggression, and treatment outcomes of aggressive children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 52:1281-93|