title: Comorbid anxiety and social avoidance in treatment of severe childhood aggression: response to adding risperidone to stimulant and parent training; mediation of disruptive symptom response.
abstract: OBJECTIVE
  In the four-site Treatment of Severe Childhood Aggression (TOSCA) study, addition of risperidone to stimulant and parent training moderately improved parent-rated disruptive behavior disorder (DBD) symptoms. This secondary study explores outcomes other than DBD and attention-deficit/hyperactivity disorder (ADHD) as measured by the Child and Adolescent Symptom Inventory-4R (CASI-4R).
  
  
  METHODS
  A total of 168 children ages 6-12 with severe aggression (physical harm), DBD, and ADHD were randomized to parent training plus stimulant plus placebo (basic treatment) or parent training plus stimulant plus risperidone (augmented treatment) for 9 weeks. All received only parent training plus stimulant for the first 3 weeks, then those with room for improvement received a second drug (placebo or risperidone) for 6 weeks. CASI-4R category item means at baseline and week 9 were entered into linear mixed-effects models for repeated measures to evaluate group differences in changes. Mediation of the primary DBD outcome was explored.
  
  
  RESULTS
  Parent ratings were nonsignificant with small/negligible effects, but teacher ratings (n=46 with complete data) showed significant augmented treatment advantage for symptoms of anxiety (p=0.013, d=0.71), schizophrenia spectrum (p=0.017, d=0.45), and impairment in these domains (p=0.02, d=0.26), all remaining significant after false discovery rate correction for multiple tests. Improvement in teacher-rated anxiety significantly (p=0.001) mediated the effect of risperidone augmentation on the primary outcome, the Disruptive-total of the parent-rated Nisonger Child Behavior Rating Form.
  
  
  CONCLUSIONS
  Addition of risperidone to parent training plus stimulant improves not only parent-rated DBD as previously reported, but also teacher-rated anxiety-social avoidance. Improvement in anxiety mediates improvement in DBD, suggesting anxiety-driven fight-or-flight disruptive behavior with aggression, with implications for potential treatment strategies. Clinicians should attend to possible anxiety in children presenting with aggression and DBD.
  
  
  BACKGROUND
  Treatment of Severe Childhood Aggression (The TOSCA Study). NCT00796302. clinicaltrials.gov.
authors.affiliation: 1 Department of Psychiatry, Ohio State University , Columbus, Ohio.
authors.forename: L Eugene
authors.initials: LE
authors.lastname: Arnold
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Gadow
authors.forename: Cristan A
authors.initials: CA
authors.lastname: Farmer
authors.forename: Robert L
authors.initials: RL
authors.lastname: Findling
authors.forename: Oscar
authors.initials: O
authors.lastname: Bukstein
authors.forename: Brooke S G
authors.initials: BS
authors.lastname: Molina
authors.forename: Nicole V
authors.initials: NV
authors.lastname: Brown
authors.forename: Xiaobai
authors.initials: X
authors.lastname: Li
authors.forename: E Victoria
authors.initials: EV
authors.lastname: Rundberg-Rivera
authors.forename: Srihari
authors.initials: S
authors.lastname: Bangalore
authors.forename: Kristin
authors.initials: K
authors.lastname: Buchan-Page
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hurt
authors.forename: Robert
authors.initials: R
authors.lastname: Rice
authors.forename: Nora K
authors.initials: NK
authors.lastname: McNamara
authors.forename: Michael G
authors.initials: MG
authors.lastname: Aman
mesh_terms: D000374:Aggression / Q000187:drug effects*; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001008:Anxiety Disorders / Q000150:complications / Q000188:drug therapy*; D001289:Attention Deficit Disorder with Hyperactivity / Q000150:complications / Q000188:drug therapy*; D019958:Attention Deficit and Disruptive Behavior Disorders / Q000150:complications / Q000188:drug therapy*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000627:therapeutic use; D002648:Child; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D010290:Parents / Q000193:education; D018967:Risperidone / Q000008:administration & dosage / Q000627:therapeutic use; D012919:Social Behavior; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D018967:Risperidone