Intuniv vs Placebo in the Treatment of Childhood Intermittent Explosive Disorder
Condition: Intermittent Explosive Disorder; Childhood Aggression; Oppositional Defiant Disorder; Attention Deficit Disorder
MeSH terms: Attention Deficit Disorder with Hyperactivity; Aggression; Attention Deficit and Disruptive Behavior Disorders; Disruptive, Impulse Control, and Conduct Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      Children with explosive aggression are often rejected by their peers, placed in special
      classroom, and contribute to family discord. When psychotherapy and family therapy is
      unsuccessful, medications are often used. Current medications are stimulants (e.g.
      methylphenidate, dextroamphetamine), anticonvulsants (e.g. Divalproex) and antipsychotics
      (olanzapine, risperidone). At this time, the available medications are of limited usefulness,
      either because they do not always work or because they have side effects such as weight gain
      or insomnia. There is a clear need for new medications to treat explosive aggression when
      psychotherapy is unsuccessful.

      The hypothesis of this study is the medication Intuniv when combined with psychotherapy will
      be more helpful to children with explosive aggression than placebo combined with
      psychotherapy. Intuniv is a long acting form of guanfacine, a medication approved by the FDA
      for treatment of Attention Deficit Hyperactivity Disorder. Intuniv is not a stimulant, nor is
      it an anticonvulsant, nor is it an antipsychotic.

      The children in this study will be between the ages of 6 and 12 and meet Diagnostic and
      Statistical Manual of Psychiatry Fourth Edition, Text Revision (DSM-IV-TR) criteria for
      Intermittent Explosive Disorder.
    

Detailed description: 
      Aggressive children are often alienated from parents, separated from peers, placed in special
      education and segregated with other aggressive children. While predatory (i.e. planned, goal
      directed, reward driven) aggression is not responsive to pharmacologic treatment, non
      predatory (impulsive, paranoid, irritable) aggression (DSM-IV-TR "Intermittent Explosive
      Disorder") often is. Intermittent Explosive Disorder is characterized by discrete episodes of
      failure to resist aggressive impulses resulting in serious assaults or destruction of
      property. In children, due to their limited ability to damage or hurt others, the seriousness
      of the aggressive impulses are indicated by (a) the frequency and severity of tantrums (b)
      the fact that the severity is out of proportion to the provocation, and (c) the intent to
      damage and hurt is present and (d) this pattern of events causes impairment.

      The level of aggression being studied is equivalent to that in moderate to severe
      Oppositional Defiant Disorder with the severity due to the tantrums rather than passive
      aggression (Modified Overt Aggression Score between 15-50). For 20 years a blood pressure
      medication, guanfacine (Tenex), has also been used for impulse control (e.g. in Attention
      Deficit Disorder, in Tourette's Syndrome) and to calm the sympathetic nervous system when it
      is hyper-aroused (e.g. in opiate and nicotine withdrawal]. Both impulsivity and hyper arousal
      can also promote intermittent explosive aggression. If guanfacine treats impulsivity and
      hyper arousal, it is logical to ask if guanfacine can treat intermittent explosive
      aggression.

      Shire Pharmaceuticals modified the guanfacine molecule to create a long acting preparation
      (Intuniv) that the FDA recently judged safe and effective for Attention Deficit Hyperactivity
      Disorder (ADHD) in children ages 6-17. Secondary analysis of data from the pivotal studies
      that led to this indication revealed that in ADHD children, Intuniv also reduced
      oppositional-defiant symptoms. Better impulse control (these were all ADHD children) and/or
      decreased sympathetic arousal (common to all intermittent explosive aggression) are plausible
      explanations.

      This Investigator Sponsor Protocol (ISP) seeks to replicate prospectively the anti-aggression
      finding. Since Intuniv could benefit non-ADHD aggressive children, any child with mild to
      moderate Intermittent Explosive Disorder is eligible. Anti-psychotic and anti-convulsant
      medications (current treatments for Intermittent Explosive Disorder) have serious side
      effects (weight gain, metabolic syndrome) and are not always effective. Intuniv is neither a
      stimulant, nor an antipsychotic, nor an anticonvulsant. Intuniv is not FDA approved for
      treatment of Intermittent Explosive Disorder.

      In addition to medication or placebo, all children will receive a modified form of Parent
      Management Training, the standard psychotherapy for oppositional symptoms, administered by a
      child psychiatrist. It addresses the coercive reciprocal social interactions that
      characterize microenvironment of oppositional children.

      Fifty children, ages 6-12 with Intermittent Explosive Disorder will be randomly assigned to
      eight weeks of double blind Intuniv plus Parent Management Training or placebo Parent
      Management Training. Titrated over four weeks to a maximum dose of 4 mgs or .09-.12
      mgs/kg/day, they will be maintained on that dose for four weeks. At the end of treatment, the
      treating physician will break the blind and offer open label treatment for eight weeks.
    

Intervention name(s): Parent Management Training; Placebo; Intuniv
Intervention type(s): Behavioral; Other; Drug
Intervention description(s): This is a psychological treatment that focuses on decreasing tantrums and outbursts by reducing the ability of the tantrum to coerce parents into giving in to the demand that precipitated the tantrum.; Weekly dispensation of pills matching Intuniv but without the active medication; Weekly administration of medication in doses as per protocol
Other intervention name(s): PMT; Extended release Guanfacine
Intervention MeSH terms: Guanfacine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: childhood; temper; explosive; aggression; tantrums; oppositional; defiant; conduct; disruptive; emotional dysregulation; special education