Depakote (Divalproex Sodium) for Children With Temper Dysregulation and Severe Mood Swings
Condition: Irritable Aggression
MeSH terms: Aggression
Study type: Interventional
Phase: Phase 4

Summary: 
      Though the Disruptive Disorders of Childhood and Adolescence are a major source of morbidity
      and fill a large proportion of special education slots, specific pharmacologic treatment is
      available only for those children with Attention Deficit/Hyperactivity Disorder. Other
      disruptive children are usually said to "have" Oppositional Defiant or Conduct Disorder.
      These diagnoses are useful descriptively but they do not have specific treatment implications
      In the course of treating adolescents with explosive tempers and severe mood swings with
      Depakote (divalproex sodium), the investigators learned that younger children manifest
      symptoms that seemed identical to those constituting the adolescent disorder. They were in
      special education programs and not responding to psychostimulants.

      The investigators systematically collected data on these children using the same screening
      criteria as in our studies of adolescents. Since Depakote has been used to treat seizures in
      children for more than twenty years, a great deal was known about its safety profile in the
      pediatric population. The investigators treated 7 children, age 7-12, whose recurrent temper
      outbursts and chronic mood lability did not respond to individual/family therapy. After
      parents signed informed consent and children gave assent, these subjects would receive open
      label Depakote in doses sufficient to reach a blood level between 50-100 micrograms/ml for
      six weeks. The family received supportive therapy.
    

Detailed description: 
      The hypothesis to be tested is whether children below age thirteen with the same symptom
      cluster targeted in that protocol (explosive temper outbursts and severe mood swings,
      Explosive Mood Disorder) will show the same response to open label Depakote that the
      adolescents showed. An addition in this protocol is to see if this hypothesis holds under
      double blind placebo controlled conditions.

      The investigators have now completed open treatment with six children and have found that the
      same criteria that selected a treatment responsive group of adolescents and adults also
      worked for five of these six children. The investigators now propose to test these findings
      under double blind conditions. There is no change in the overall safety profile of the
      treatment. The only change is the addition of a placebo phase. All children will receive
      active treatment at some point.

      In addition, the investigators hypothesize that the clinical syndrome of temper and
      irritability will tend to resolve with development and that families will not exhibit
      bipolarity in first degree relatives but will exhibit temper outbursts. This hypothesis will
      be studied in a follow-up study.

      Data Summary

      OPEN TRIAL

      Patient Age Dose Acute Outcome Long Term Outcome

        1. age 10 1000mgs Good Excellent

        2. 12 1000mgs Fair-good Poor (non-compliant

        3. 10 1000mgs Excellent Good

        4. 9 1000mgs Excellent Very good

        5. 12 1000mgs Poor Poor

        6. 7 500mgs Excellent Good-excellent 7 11 500 mgs Dropped out after 3 weeks; never took
           meds Poor

      BACKGROUND The disruptive disorders of childhood and adolescence are conduct,
      oppositional-defiant, and attention deficit hyperactivity disorders. Of these, only the
      latter has a specific pharmacologic treatment. The other two reliably describe problem
      behaviors of special education classes, chemical dependency units and family courts but have
      few treatment implications. In a previous communications, the investigators described
      adolescent subjects with temper outburst and severe mood swings. The investigators labeled
      the syndrome Explosive Mood Disorder (EMD) and drafted tentative criteria for temper outburst
      and irritable mood swings (see Inclusion Criteria for EMD). The goal of this study is to
      demonstrate that Depakote can help a certain type of problem child, one whose disruptiveness
      is associated with mood dysregulation.

      The investigators hypothesized the subjects' mood dysregulation and aggressive disinhibition
      to be "limbic" pathology. The limbic system is heavily implicated in behavior and emotion,
      and work by previous investigators suggested episodic dyscontrol can result from limbic
      irritability. Since carbamazapine and valproic acid are used in limbic seizures and bipolar
      spectrum disorders, the investigators predicted subjects would improve on divalproex sodium
      (Depakote), the enteric coated form of valproic acid. The investigators treated thirteen
      patients meeting the above criteria criteria with open label divalproex sodium. In all cases,
      there were strikingly beneficial results, including a sharp decline in the frequency and
      severity of temper outbursts and the severity of mood swings.

      The typical patient would progress from irritation to screaming, door-slamming, property
      destruction or fighting explosively, i.e., without intermediate steps. When not exploding,
      the patient's affect and frustration tolerance would fluctuate throughout the day. The mood
      could be irritable, normal or silly but always unpredictable. The patients had chronic
      interpersonal difficulties, especially with authority figures, thus serious problems with
      family, school and work were common. They tended to end up with deviant peers, since others
      could not tolerate the unpredictable interactions. Though some of patients met criteria for
      Conduct or Oppositional Defiant Disorder, these diagnoses were too heterogeneous to describe
      the Depakote responders. Cyclothymia and Bipolar II Disorder did not capture the chronic,
      maladaptive interactions with peers and authority figures. Intermittent Explosive Disorder
      missed the above plus the connection to mood dysregulation. Borderline Personality implied a
      specific type of interpersonal pathology (idealization, devaluation, manipulation) that was
      not necessarily present.

      The closest match the investigators found in the literature to our patients was "Emotionally
      Unstable Character Disorder" (EUCD). This diagnosis described young adults with extreme
      irritability, mood swings, chronic maladaptive behaviors, and a clear response to a mood
      stabilizing agent (lithium carbonate). However, even this diagnosis does not capture the
      explosiveness which is prominent in the sample of Depakote responders. The investigators
      therefore decided to use the term Explosive Mood Disorder (EMD) to capture the temper
      outbursts and the mood lability.

      Campbell reported hospitalized conduct disordered children with affective (as opposed to
      predatory) aggression improvement on lithium and Findling reported similar findings in
      similar outpatients treated with risperidone. The key feature of irritable mood swings is not
      directly addressed in these studies. In addition, other studies of childhood aggression in
      Autism, Tourette Syndrome, Bipolar Disorder and mental deficiency suggest a role for
      risperidone. Nonetheless, it is still not clear what alternative pharmacological treatments
      for temper driven by irritable mood swings are available.

      The investigators treated ten subjects who met screening criteria for EMD with open label
      Depakote 1000mgs. Baseline evaluation included a full medical and psychiatric interview, the
      Structured Clinical Interview for Diagnostic and Statistical Manual of Psychiatry-III-R and a
      record of the total number of explosions during the previous week and thirty days. The latter
      estimate was obtained from as many sources as possible. At minimum, the patient and one
      parent had to each give an estimate. As many other sources as possible were also asked to
      estimate the lability of the patient's mood during the previous week and thirty days. Each
      week the same information would be obtained about the previous week and a global assessment
      made as to whether the patient was unimproved, minimally improved, much improved or very much
      improved.

      Twelve adolescents agreed to participate, and two dropped out before receiving an adequate
      trial. The other ten adolescents showed clear improvement in mood and number of explosions,
      with the latter typically declining by 90-100%. All ten adolescent patients were judged at
      least much improved by the psychiatrist, parents and patient. These results were later
      replicated under double-blind, placebo controlled conditions.

      Teachers and parents approached the investigators with children under the age of 13 and asked
      us to treat them. The investigators obtained permission to collect open label data on those
      youngsters. The completion of open-label data has led to the current study.
    

Intervention name(s): Divalproex
Intervention type(s): Drug
Intervention description(s): Patients were randomly assigned to receive divalproex or placebo first, follow by the converse treatment, for six weeks each
Other intervention name(s): Divalproex (Depakote)
Intervention MeSH terms: Valproic Acid
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: temper outbursts; pediatric aggression; irritability