Treatment of Severe Childhood Aggression (The TOSCA Study)

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.

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