Treatment of Severe Childhood Aggression (The TOSCA Study)

• The NCBRF-TIQ Version Subscales [ Time Frame: Measured at baseline and Weeks 3, 5, 7, 9, 13, 17, 21, and 52 ] [ Designated as safety issue: No ]
• Clinical Global Impressions Scale for Improvement [ Time Frame: Measured at baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 13, 17, 21, and 52 ] [ Designated as safety issue: No ]
• Standard Observation Analogue Procedures [ Time Frame: Measured at baseline and Weeks 9 and 52 ] [ Designated as safety issue: No ]
• Antisocial Behavior Scale [ Time Frame: Measured at baseline and Weeks 9 and 52 ] [ Designated as safety issue: No ]
• Adverse Events Log [ Time Frame: Measured at baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 13, 17, 21, and 52 ] [ Designated as safety issue: Yes ]
• Cognitive Battery [ Time Frame: Measured at baseline and Weeks 3, 9, 21, and 52 ] [ Designated as safety issue: No ]

• The Nisonger Child Behavior Rating Form-Typical IQ Version Subscales [ Time Frame: Measured at baseline and Weeks 3, 5, 7, 9, 13, 17, 21, and 52 ] [ Designated as safety issue: No ]
• Clinical Global Impressions Scale for Improvement [ Time Frame: Measured at baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 13, 17, 21, and 52 ] [ Designated as safety issue: No ]
• Standard Observation Analogue Procedures [ Time Frame: Measured at baseline and Weeks 9 and 52 ] [ Designated as safety issue: No ]
• Antisocial Behavior Scale [ Time Frame: Measured at baseline and Weeks 9 and 52 ] [ Designated as safety issue: No ]
• Adverse Events Log [ Time Frame: Measured at baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 13, 17, 21, and 52 ] [ Designated as safety issue: Yes ]
• Cognitive Battery [ Time Frame: Measured at baseline and Weeks 3, 9, 21, and 52 ] [ Designated as safety issue: No ]

This study will determine the safety and effectiveness of two medications for treating aggression in children with attention deficit hyperactivity disorder (ADHD).

ADHD is characterized by inattention, impulsivity, and hyperactivity. Children with ADHD sometimes also have disruptive behavior disorders (DBDs), such as conduct disorder (CD), which is estimated to develop in 20% to 40% of children with ADHD, and oppositional defiant disorder (ODD), which is estimated to develop in 33% to 50% of children with ADHD. These two disorders place youth at risk of other psychiatric disorders, especially substance abuse disorders. Several medications have been tested to treat conduct disorders in aggressive children, and, among these, risperidone and methylphenidate hydrochloride (HCl) have relatively good records of safety and tolerability. Psychostimulants, such as methylphenidate HCl, can reduce the symptoms in some, but not all, children with DBDs. Combining methylphenidate HCl with risperidone may be one way to increase the effectiveness of drug treatments. This study will compare the effectiveness of methylphenidate HCl alone versus methylphenidate HCl combined with risperidone for treating aggressive behavior in children with ADHD. Participation in this study will last 1 year. The child participant and a parent will attend all study visits. Two initial visits will involve a battery of baseline tests, including a psychological clinical interview, physical examination, lab tests, and an electrocardiogram (ECG). The parents will undergo a parent education session and complete questionnaires about their child's behavior, emotions, and medication side effects. The child will have his or her vital signs measured and complete tests of verbal memory and attention and impulsiveness. After the second visit, the child participant will be randomly assigned to receive either methylphenidate HCl alone or methylphenidate HCl plus risperidone.

For the next 3 weeks, all child participants will take methylphenidate HCl at a dose that will start low and gradually be increased until the most effective dose is determined. For the next 6 weeks, child participants will add either risperidone or a placebo to their regimen of methylphenidate HCl. This second medication will also be started at a low dose and raised to appropriate levels of tolerability. During the 9 weeks of medication adjustment, participants will attend weekly study visits to complete questionnaires and have their vital signs measured. Parents will attend education sessions at each of these visits. The child's teacher will also fill out weekly questionnaires on the child's behavior. Every 3 weeks, child participants will be tested on verbal memory, attention, and impulsiveness. After the 9-week period, child participants will again undergo a physical exam, lab tests, and an ECG.

At this point, if the child's behavior has improved, the child will continue the same treatment for the next 3 months. Monthly study visits will include parent education sessions and recording of parent and teacher evaluations of the child. All participants will attend a 1-year follow-up visit that will include previous assessments.

• Drug: Methylphenidate HCl

  For children weighing less than 25 kg, the dose will be titrated at 18 mg for the first 7 days, 36 mg for the next 4 days, and, if needed, 54 mg for the next 4 days. For children weighing more than 25 kg, the dose will be titrated at 18 mg for the first 4 days, 36 mg for the next 3 days, 54 mg for the next 4 days, and 72 mg for the next 3 days.

  Once the child's optimal dose is established, he or she will continue on that dose for the rest of the 21-week trial.

  One pill is taken once daily.

  Other Name: Concerta
• Drug: Risperidone

  For children weighing less than 45 kg, the dose will start at 0.5 mg at night. After 4 days, the child's dose may be increased to 1 mg a day. On Day 8, the child's dose may be increased to 1.5 mg a day. On Day 16, the child's dose may be increased to 2.0 mg a day. On Day 22, the child's dose may be increased to 2.5 mg a day.

  For children weighing more than 45 kg, the dose will start at 0.5 mg at night. After 4 days, the child's dose may be increased to 1.0 mg a day. On Day 8, the child's dose may be increased to 1.5 mg a day. On Day 12, the child's dose may be increased to 2.0 mg a day. On Day 15, the child's dose may be increased to 2.5 mg a day. On Day 18, the child's dose may be increased to 3 mg a day. On Day 23, the child's dose may be increased to 3.5 mg a day.

  Other Name: Risperdal
• Behavioral: Parent Management Training (PMT)
  PMT will include individual parent sessions held weekly for 9 weeks, with two booster sessions to be completed during the 3-month extension. Sessions will include development of problem-solving skills and behavior management strategies, practice activities, and role-playing with the behavioral therapist.
  Other Name: Community Parent Education Program
• Drug: Placebo
  One pill will be taken once daily for the first 4 days and then twice daily until Week 21.

• Experimental: 1
  Children will receive active methylphenidate HCl and active risperidone. Parents will receive parent management training.
  Interventions:

  • Drug: Methylphenidate HCl
  • Drug: Risperidone
  • Behavioral: Parent Management Training (PMT)
• Active Comparator: 2
  Children will receive methylphenidate HCl and placebo instead of the active risperidone. Parents will receive parent management training.
  Interventions:

  • Drug: Methylphenidate HCl
  • Behavioral: Parent Management Training (PMT)
  • Drug: Placebo

Inclusion Criteria:

• DSM-IV diagnosis of ADHD, any subtype
• DSM-IV diagnosis of a disruptive behavior disorder, including CD or ODD
• Evidence of serious physical aggression, as rated on the Overt Aggression Scale-Modified, and as determined by parent or guardian ratings on the NCBRF D-Total Score. In addition, the blinded clinician must assign a clinical global impressions severity score of 4 or greater for aggression.
• Prior to random assignment, participants must be free of all psychotropic medicines for 2 weeks for most drugs (such as most antidepressants, alpha agonists, beta blockers, anxiolytics, mood stabilizers, and antihistamines), and 4 weeks for depot antipsychotics and fluoxetine.

Exclusion Criteria:

• Full-scale IQ below 71
• Pregnancy or a history of seizure disorder or other neurological or medical disorders for which medication may present a considerable risk
• Abnormal liver function
• Pervasive developmental disorder, schizophrenia or other psychotic disorders, or eating disorders
• Currently taking other psychotropic medications from which discontinuation would present a significant risk. Participants may not discontinue a satisfactory medication to participate.
• Presence or history of major depressive disorder
• Diagnosis of bipolar disorder
• A hypomanic/biphasic score of 36 or greater as rated by child's parent on the General Behavior Inventory and confirmed by clinician as indication of mood disorder
• Active substance abuse disorder or lack of control of substance use that does not allow for safe medication administration
• Evidence of current child abuse or neglect
• History of suicide attempt in the past year or current suicidal ideation with plan and/or intent
• Family history of type II diabetes in two or more first degree relatives, defined as biological parents and/or full biological siblings