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.

OBJECTIVE: Stimulant medications are the most prevalent first-line pharmacotherapy for attention-deficit/hyperactivity disorder, but children with aggressive behavior often receive multiagent treatment. There is sparse evidence for the benefits of adjunctive medications when stimulant monotherapy provides inadequate benefit for aggressive behavior, 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 childrenwhose symptoms persisted after individually optimized stimulant treatment. METHOD: This trial enrolled 6- to 12-year-old with attention-deficit/hyperactivity disorder, 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 randomly assigned to receive adjunctive RISP, DVPX, or PBO under double-blinded 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: Participants included 175 children (mean [SD] age 9.48 [2.04] years, 19% female). Of participants, 151 completed the stimulant optimization phase, with aggression remitting among 96 (63%), and 45 were randomly assigned 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% CI, -3.83 to -0.82; effect size [ES], -1.32), as did the DVPX group (ΔLSM, -1.60; 95% CI, -3.18 to -0.03; ES, -0.91). Mean standardized body mass index scores increased more among RISP-treated participants than participants receiving PBO (ΔLSM, 1.54; 95% CI, 0.68 to 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. CLINICAL TRIAL REGISTRATION INFORMATION: Effectiveness of Combined Medication Treatment for Aggression in Children With Attention Deficit With Hyperactivity Disorder (The SPICY Study); https://www.clinicaltrials.gov; NCT00794625.

Prevalence and Treatment Outcomes of Persistent Negative Mood Among Children with Attention-Deficit/Hyperactivity Disorder and Aggressive Behavior.

OBJECTIVE: Diagnostic criteria for disruptive mood dysregulation disorder (DMDD) require 1) periodic rageful outbursts and 2) disturbed mood (anger or irritability) that persists most of the time in between outbursts. Stimulant monotherapy, methodically titrated, often culminates in remission of severe aggressive behavior, but it is unclear whether those with persistent mood symptoms benefit less.This study examined the association between the presence of persistent mood disturbances and treatment outcomes among children with attention-deficit/hyperactivity disorder (ADHD) and periodic aggressive, rageful outbursts. METHODS: Within a cohort of children with ADHD and aggressive behavior (n = 156), the prevalence of persistent mood symptoms was evaluated at baseline and after completion of a treatment protocol that provided stimulant monotherapy and family-based behavioral treatment (duration mean [SD] = 70.04 [37.83] days). The relationship of persistent mood symptoms on posttreatment aggressive behavior was assessed, as well as changes in mood symptoms. RESULTS: Aggressive behavior and periodic rageful outbursts remitted among 51% of the participants. Persistent mood symptoms at baseline did not affect the odds that aggressive behavior would remit during treatment. Reductions in symptoms of sustained mood disturbance accompanied reductions in periodic outbursts. Children who at baseline had high irritability but low depression ratings showed elevated aggression scores at baseline and after treatment; however, they still displayed large reductions in aggression. CONCLUSIONS: Among aggressive children with ADHD, aggressive behaviors are just as likely to decrease following stimulant monotherapy and behavioral treatment among those with sustained mood symptoms and those without. Improvements in mood problems are evident as well. Therefore, the abnormalities in persistent mood described by DMDD's criteria do not contraindicate stimulant therapy as initial treatment among those with comorbid ADHD. Rather, substantial improvements may be anticipated, and remission of both behavioral and mood symptoms seems achievable for a proportion of patients. TRIAL REGISTRATION: ClinicalTrials.gov (U.S.); IDs: NCT00228046 and NCT00794625; www.clinicaltrials.gov.

Callous-unemotional traits, proactive aggression, and treatment outcomes of aggressive children with attention-deficit/hyperactivity disorder.

OBJECTIVE: Stimulant treatment improves impulse control among children with attention-deficit/hyperactivity disorder (ADHD). Decreased aggression often accompanies stimulant pharmacotherapy, suggesting that impulsiveness is integral to aggressive behavior in these children. However, children with high callous-unemotional (CU) traits and proactive aggression may benefit less from ADHD pharmacotherapy, because their aggressive behavior seems more purposeful and deliberate. This study's objective was to determine whether pretreatment CU traits and proactive aggression affect treatment outcomes among aggressive children with ADHD receiving stimulant monotherapy. METHOD: We implemented a stimulant optimization protocol with 160 children 6 to 13 years of age (mean [SD] age of 9.31 [2.02] years; 78.75% male) with ADHD, oppositional defiant or conduct disorder, and significant aggressive behavior. Family-focused behavioral intervention was provided concurrently. The primary outcome was the Retrospective Modified Overt Aggression Scale. The Antisocial Process Screening Device and the Aggression Scale, also completed by parents, measured CU traits and proactive aggression, respectively. Analyses examined moderating effects of CU traits and proactive aggression on outcomes. RESULTS: In all, 82 children (51%) experienced remission of aggressive behavior. Neither CU traits nor proactive aggression predicted remission (CU traits: odds ratio [OR] = 0.94, 95% CI = 0.80-1.11; proactive aggression, OR = 1.05, 95% CI = 0.86-1.29). Children whose overall aggression remitted showed decreases in CU traits (effect size = -0.379, 95% CI = -0.60 to -0.16) and proactive aggression (effect size = -0.463, 95% CI = -0.69 to -0.23). CONCLUSIONS: Findings suggest that pretreatment CU traits and proactive aggression do not forecast worse outcomes for aggressive children with ADHD receiving optimized stimulant pharmacotherapy. With such treatment, CU traits and proactive aggression may decline alongside other behavioral improvements. Clinical trial registration information--Medication Strategies for Treating Aggressive Behavior in Youth With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00228046; and Effectiveness of Combined Medication Treatment for Aggression in Children With Attention Deficit With Hyperactivity Disorder (The SPICY Study); http://clinicaltrials.gov/; NCT00794625.

Can antidepressants be used to treat the schizophrenia prodrome? Results of a prospective, naturalistic treatment study of adolescents.

OBJECTIVE: This study reports the results of a prospective, naturalistic treatment study of adolescents considered to be in the prodromal (i.e., prepsychotic) phase of schizophrenia. METHOD: Forty-eight adolescents (mean age = 15.8 years) participating in the initial phase of the Recognition and Prevention (RAP) program (1998-2005) were included in the current report. Individuals were selected from the overall sample (N = 152) if they had: (1) displayed attenuated positive symptoms, (2) been treated pharmacologically for at least 8 weeks, and (3) been followed up for at least 6 months (mean follow-up = 30.5 months). RESULTS: Two types of medication were naturalistically prescribed: antidepressants (N = 20) or second-generation antipsychotics (N = 28), with polypharmacy common. The 2 treatment groups did not differ in baseline symptom profiles, with the exception of disorganized thinking, which was more severe in second-generation antipsychotic-treated adolescents. Twelve of the 48 adolescents (25%) developed a psychotic disorder, with all converters having been prescribed second-generation antipsychotics. There were no conversions among antidepressant-treated adolescents (log-rank chi(2) = 7.36, df = 1, p = .007). Treatment outcome, however, was confounded, since 11 of the 12 converters were nonadherent. Adolescents, in general, were more likely to be nonadherent to second-generation antipsychotics (61%, 17/28) than to antidepressants (20%, 4/20; chi(2) = 7.86, p = .005). Improvement in 3 of 5 positive symptoms over time was significant (p < .001) and similar for both medications. Disorganized thought, however, did not improve regardless of treatment. CONCLUSIONS: Nonrandom assignment limits comparisons between antidepressants and anti-psychotics in this study. However, with follow-up, a number of adolescents meeting criteria for prodromal schizophrenia were successfully treated with antidepressants. At present, a substantial number of false positives among the antidepressant-treated subgroup cannot be ruled out. However, the findings suggest that, in some cases, it might be preferable to begin treatment with antidepressants and progress to antipsychotics once symptoms intensify, since adherence to the latter is difficult to maintain.