Chronic aggressive behavior among preadolescents heightens their risk for unfavorable outcomes that extend well beyond youth into later life (1
). Ramifications are family strain and the child's extrusion from ordinary socialization experiences, leading to progressive social marginalization. High prevalence of these detriments to children's development and to those around them places aggression among the most frequent concerns for which children obtain mental health treatment (3
Aggressive behavior may constitute a symptom, an associated feature, or complication of numerous psychiatric and developmental disorders (4
). Because diverse factors influence the emergence of children's aggressive behavior (5
), practice guidelines recommend that clinicians plan pharmacotherapy in the context of the specific psychopathology thought to give rise to the behavior (7
). Preadolescents who exhibit chronic aggressive behavior most often fulfill diagnostic criteria for a disruptive disorder (oppositional defiant disorder, conduct disorder) and for attention deficit hyperactivity disorder (ADHD) (8
). Stimulant medications for ADHD demonstrate strong efficacy for its core symptoms and often ameliorate comorbid disruptive disorders (10
). Accordingly, guidelines for the pharmacotherapy of aggressive children with ADHD propose that initial pharmacotherapy hew to strategies recommended for ADHD (12
However, a substantial proportion of children with ADHD do not experience satisfactory reductions in aggressive behavior with stimulant treatment (13
). High rates of multiagent treatment in the clinical care of children with ADHD and conduct problems (14
) also suggest that suboptimal stimulant response is common.
Chronic aggression among children with ADHD that is refractory to stimulant treatment therefore poses a common clinical challenge. Faced with insufficient response to stimulant monotherapy, one prevalent strategy is to, in effect, “layer” additional agents in pursuit of behavioral stability (14
). Prescription of antipsychotic and antimanic mood stabilizing medications for this purpose has surged in the past decade (19
Controlled-trial evidence for these compounds as antiaggressive agents in youth comes chiefly from evaluations of monotherapy with the antipsychotic risperidone (20
), the antimanic/anticonvulsant divalproex (23
), and lithium (25
). Studies have involved patients with diverse psychopathology, including developmental disorders, disruptive disorders, and “explosive temper.” Some studies include aggressive behavior specifically as a treatment outcome, while in others, antiaggressive effects are inferred from evaluations of a broader spectrum of conduct or affective disturbances (e.g., irritability). Although studies with adults indicate the benefit of fluoxetine in treating intermittent explosive disorder (28
), antidepressants currently do not have a major role in treating childhood aggression.
Although contributing important data, these studies do not specifically address the value of these agents for aggressive behavior in the large number of preadolescents with ADHD and a disruptive disorder who experience insufficient response to adequate first-line stimulant treatment. Two placebo-controlled trials of risperidone for children with mental retardation or borderline IQs permitted those receiving a stimulant before enrollment to continue the same regimen (20
). Among children with concurrent stimulant treatment, the addition of risperidone was more efficacious than the addition of placebo (29
). However, stimulant doses were not titrated to insure that they represented the child's optimal dose.
In the present study, we examined the efficacy of divalproex in reducing aggressive behavior that was demonstrably refractory to stimulant monotherapy among children with ADHD. During the trial's development, guidelines proposed divalproex as an adjunctive option for aggression that was underresponsive to stimulant treatment (30
). However, the magnitude of divalproex's benefit as cotherapy in this context was unexamined. Emerging data for divalproex's efficacy as monotherapy in reducing aggression in youths with diverse psychopathology (23
) support a randomized, controlled trial to fill this evidentiary gap.
Treatment began with an open lead-in phase of stimulant monotherapy along with family-focused behavioral management treatment. Systematic titration and monitoring were designed to optimize children's overall stimulant response. Children whose aggressive behavior persisted after this stimulant monotherapy phase were eligible for random assignment to adjunctive, double-blind treatment with divalproex or placebo for 8 weeks.