Risperidone Augmentation for Treatment-Resistant Aggression in ADHD
Condition: Aggression
MeSH terms: Aggression
Study type: Interventional
Phase: Phase 4

Summary: 
      Primary objectives:

        1. To assess the short-term efficacy of risperidone augmentation for treatment-resistant
           aggression in children with ADHD.

        2. To assess the short-term safety and tolerability of risperidone augmentation in the same
           group of subjects.
    

Detailed description: 
      Methods and Procedures:

      Study Design

      The study will be a double-blind placebo-controlled trial of risperidone as an augmenting
      agent in 40 children, 7-12 years of age, with ADHD. All subjects would have been treated
      first with a stimulant medication as a single agent, but continue to present impulsive
      aggression. The active phase of treatment will be four weeks long, during which risperidone
      or placebo will be added to a constant dose of stimulant medication. The study will include a
      four weeks continuation phase where placebo nonresponders will have the opportunity to
      receive risperidone on an open basis.

      Subject recruitment

      Special time and effort will be devoted to subject recruitment since we recognize that it is
      crucial to the study. Our primary recruitment sites are the Child and Adolescent Psychiatry
      (CAP) outpatient clinic, the psychiatry crisis unit, and the child and adolescent psychiatry
      inpatient unit. Clinical staff will identify and refer to the research team potential
      candidates for the study. Community referrals will be sought after by means of professional
      liaisons and academic presentations at local psychiatric facilities. Possible subjects will
      then be scheduled for a full evaluation after telephone screening for inclusion and exclusion
      criteria. Recruitment will be continuous until the total number of proposed subjects (N=40),
      complete the study.

      Inclusion criteria

        1. Boys and girls ages 7 to 12 years, inclusive

        2. Medical/neurological clearance

        3. Meets DSM-IV diagnosis of ADHD

        4. Treatment with a stimulant medication during the last three weeks

        5. Failure to respond to stimulant medication as documented by:

             1. Three acts of aggression in the past week, two of which must be acts of physical
                aggression against other people, objects, or self

             2. Aggression Questionnaire (AQ) Predatory-Affective index score of 0 or below. This
                indicates primarily an affective or impulsive subtype of aggression

             3. Minimum CGI scale rating of 4 (moderately ill)

        6. IQ > 75

      Exclusion criteria

        1. Major medical problems such as cardiac, renal, thyroid diseases, and seizure disorder

        2. History of alcohol or substance abuse within the last 4 weeks

        3. Previous adequate treatment with risperidone (2 mg/day for at least 4 weeks)

        4. Acutely suicidal or homicidal

        5. Unable to sign informed consent

      Assessment Instruments and Scales

        1. Aggression

           Understanding an aggressive episode is clearly complicated by the need to numerically
           quantify it. Being a low frequency behavior, aggression presents a challenge to the
           systematic assessment required in a research study. We will employ the Children's
           Aggression Scale, Parent (CAS-P) and Teacher (CAS-T) versions (Halperin et al., 2002) to
           measure retrospectively the frequency and severity of four categories of aggression: (1)
           verbal aggression, (2) aggression against objects and animals, (3) provoked physical
           aggression, and (4) initiated physical aggression. Responders complete a Likert scale to
           evaluate the frequency of an act. A distinction is made between aggressive acts directed
           toward persons who live in the home and those who do not, and also between acts directed
           toward peers and those directed towards adults. The frequency of aggressive events is
           multiplied by its designated severity weight factor and then summed to yield a total
           score. We modified the instrument so that only the occurrence of impulsive aggressive
           events over the previous one-week period is rated (see Appendix). These "event" types of
           variables fall in the category of "impulsive aggression" as defined above.
           Parents/guardians and teachers will be the respondents for this scale.

           Vitiello and associates (1990, 1997) studied aggressive behaviors in children and
           adolescents and developed the Aggression Questionnaire (AQ) to classify aggression into
           "predatory" and "affective" subtypes. Subsequently, Malone et al., (1998) modified the
           instrument by making it a parent interview and increasing the range of scoring. The
           modified version, which will be used in this study, is a 16-item scale consisting of
           eight items that assess predatory aggression and eight items that assess affective
           aggression. Items are scored as not true (0), partly true (1), or very true (2).
           Predatory and affective scores are obtained by adding the corresponding items with a
           possible range from 0 to 16. The Predatory-Affective index is calculated by subtracting
           the affective score from the predatory score. Higher index scores indicate a
           predominantly predatory type of aggression while lower scores indicate primarily an
           affective subtype. This affective aggression is viewed as an overreaction to a minor
           provocation often accompanied by disinhibition and behavioral dyscontrol,
           characteristically impulsive. The AQ differentiated responders from nonresponders to
           lithium treatment in a group of aggressive conduct-disordered children (Malone et al.,
           1998).

        2. ADHD Symptoms

      The Continuous Performance Test (CPT; Conners, 1995) consists of a series of letters
      presented on a computer screen in rapid succession. The subject is required to press a key
      whenever a target stimulus is presented, and to refrain from pressing the key when the
      nontarget stimulus is presented. The CPT generates separate measures of inattention and
      impulsivity. The impulsivity score is derived from a combination of commission errors and hit
      reaction times. T-scores of 60 or above on commission errors and hit reaction times will be
      considered as an indication of impulsivity.

      The ADHD Index (Conners, 1997) - Because of its brevity (12 items) and excellent psychometric
      properties, this index is well suited for repeated measures in clinical drug trials. The ADHD
      Index will help us understand if the effect of risperidone treatment on impulsive aggression
      is independent of any effect it may have on ADHD symptomatology.

      Initial visit

      The initial visit will take place at the CAP outpatient clinic where the rest of the study
      will be conducted. The study will be fully explained and a written informed consent will be
      obtained from the parent(s) while an assent from will be obtained from the subject. Parent(s)
      and subject will undergo the following assessments:

        1. Parent/Staff:

             1. Structured psychiatric interview employing the computerized Diagnostic Interview
                Schedule for Children IV (Generic C-DISC 4; Shaffer et al., 2000) - This is a
                comprehensive, structured interview that covers 36 mental health disorders for
                children and adolescents, using DSM-IV criteria. Extensive reliability data on this
                instrument are available. The instrument produces a series of reports including a
                diagnostic report that indicates endorsed symptoms, criteria, and diagnoses.
                Comorbidity in the sample will be clearly identified. The parent version is
                suitable for caretakers of 6 to 17 year olds. Raters will be required to
                participate in a two-day training session by a Columbia DISC trainer.

             2. Complete social history and review of environmental stressors

             3. Medical review of systems

             4. CAS-P, ADHD index, and AQ

        2. Subject:

             1. Structured psychiatric interview employing the Generic C-DISC 4. The youth version
                is suitable for children aged 9 to 17 years. The parent and youth interviews will
                be performed in parallel except for children ages 7 and 8 years for which only the
                parent interview is valid.

             2. Continuous Performance Test

             3. Kaufman Brief Intelligence Test (K-BIT; Kaufman and Kaufman 1990) - The K-BIT is a
                brief, individually administered measure of verbal and nonverbal intelligence.
                While it is not intended to substitute for a comprehensive measure of intelligence,
                it is adequate for our screening purposes. The K-BIT IQ composite score was
                correlated .80 with the WISC-R full scale IQ

             4. Clinical Global Impressions (CGI) - A four-item scale widely used in clinical drug
                trials, involving both adult and pediatric patients.

             5. Laboratory studies will include complete blood cell count (CBC) and differential,
                electrolytes, thyroid and kidney function tests. These will be repeated at
                endpoint.

             6. Urine analysis for toxicology and pregnancy (females)

        3. Teacher:

      The teacher will be given the Children's Aggression Scale-Teacher Version (CAS-T) (Halperin
      et al., 2002) to evaluate the frequency and severity of aggressive acts, as distinct from
      oppositional and defiant behaviors. In addition, the teacher will be given the ADHD index.
      The teacher who best knows the patient will complete both scales.

      The research team will discuss all information collected to arrive at a preliminary consensus
      diagnosis. After reviewing inclusion and exclusion criteria, subjects who are eligible will
      be invited to participate in the study.

      Phase I

      This phase will last 4 weeks. Subjects that meet inclusion criteria will be randomized to
      receive study medication (risperidone or placebo) as augmenting treatment to stimulant
      medication. The dose of the stimulant will remain constant during this phase. Janssen
      Pharmaceutica will supply risperidone 0.5 mg and identical placebos. All research staff and
      subjects will be blind as to the study medication to be administered. The dose of the study
      medication will be started at 0.5 mg/day. The dose for each child will be individually
      regulated until optimum efficacy or until the side effects become unacceptable. The guiding
      principle will be to achieve control of symptoms with the lowest possible dose in order to
      minimize undue side effects. The medication dose can be gradually increased by 0.5mg weekly
      to a maximum of 2 mg/day. Dose reduction for adverse events may occur at any time and be made
      in any multiple of 0.5 mg as deemed clinically necessary. No other concomitant medication
      will be permitted. Subjects will attend the research clinic on a weekly basis for behavioral
      assessments and medication distribution.

      At the end of Phase I, the blind will be broken on every subject and the study medication
      will be identified. Subjects that received placebo and continue to present aggressive
      behaviors, as defined by inclusion criteria, will be eligible to continue to Phase II. All
      other subjects will be treated as clinically indicated.

      Phase II

      This phase will last 4 weeks. Subjects that received placebo during Phase I and continue to
      present aggressive behaviors will receive risperidone on an open basis. All visits, dosing,
      and assessment instruments will be the same as in Phase I. This represents an opportunity to
      identify all potential responders to risperidone as an augmenting agent.

      Safety Evaluations

        -  Baseline, week 4, and week 8 if applicable: Blood-cell-count (CBC) and differential,
           electrolytes, thyroid and kidney function tests, and urine pregnancy test.

        -  Vital signs and weight; baseline and weekly thereafter

        -  Side-effect questionnaire; baseline and weekly thereafter

      Drug Accountability

      A medication log will be maintained for each subject detailing dose and schedule on a daily
      basis. At each weekly visit subjects will be provided with enough medication for one-week of
      treatment plus an additional 2 days supply for safety. They will be required to return any
      unused medication at the end of each week. All drug supplies will be stored in a locked
      cabinet.
    

Intervention name(s): Risperidone
Intervention type(s): Drug
Intervention MeSH terms: Risperidone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Aggression; ADHD; Antipsychotic