Intuniv vs Placebo in the Treatment of Childhood Intermittent Explosive Disorder

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.

Inclusion Criteria:

1. Age 6-12

2. Meets DSM-IV TR Criteria for Intermittent Explosive Disorder

1. several discreet episodes of failure to resist aggressive impulses that result in
serious assaultive acts or destruction of property

2. the degree of aggressiveness is grossly out of proportion to any precipitating
psychosocial stressors

3. the aggressive episode is not better accounted for by another mental disorder

4. duration of at least six months

5. impairment in home, peer relations and / or school

3. Modified Overt Aggression Scale (MOAS) score > 15

4. Parent and child willing to consent to study

5. Inadequate response to psycho-social interventions (including school interventions)

6. Medically healthy with

1. weight > 55 lb (25 kg)

2. body mass index < 35

3. normal blood pressure as defined by National Heart Lung and Blood Institute
(below 95th percentile for age height and weight)

4. normal response to orthostatic changes (no persistent fall in systolic/diastolic
BP > 20/10 mm Hg within 3 minutes of assuming the upright position)

5. normal electrocardiogram

6. normal vital signs

7. no history of intolerance of guanfacine.

7. If on another medication, willingness to discontinue if medication is judged
ineffective after adequate trial or to remain on a constant optimized dose if it is
partially effective

Exclusion Criteria:

1. Current Treatment with another alpha 2 blocker e.g. clonidine

2. Puberty

3. Meets criteria for Pervasive Developmental Disorder or Childhood schizophrenia

4. MOAS score > 50

5. weight < 55 lb or body mass index > 35

6. hypertension (Blood Pressure above 95th percentile for age height and weight)

7. Chronic hypotension (Blood Pressure at or below 5th percentile for age height and
weight)

8. Orthostatic Hypotension fall in systolic/diastolic BP > 20/10 mm Hg within 3 minutes
of assuming the upright position

9. QTc interval of > 440 milliseconds; Bradycardia; heart block diagnosed

10. history of seizure during the past 2 years (exclusive of febrile seizures)

11. Patients who had taken an investigational drug within 28 days

12. Intelligence Quotient < 70

13. Physical exam, EKG or laboratory results with any other significant abnormalities
until reviewed by medicine.

14. Active suicidal or homicidal ideation or history of suicide attempts

15. Unequivocal manic or hypomanic Episode

16. Patients who meet criteria for Major Depression in pre-puberty will not be eligible
for this study.

17. Axis I disorders that are current, severe and uncontrolled. Children with moderate
Axis I pathology will be evaluated on a case by case basis and excluded if the other
diagnosis is not ADHD but could still be the cause of the temper dyscontrol and the
treatment is judged substandard.

18. Any other history of cardiovascular dysfunction

19. Positive Urine Toxicology

20. Children who have experienced prior adverse effects (physical or psychological) to
either Tenex or clonidine

21. Any child who previously received Tenex and either did not tolerate it, or failed to
respond to an adequate trial