Depakote (Divalproex Sodium) for Children With Temper Dysregulation and Severe Mood Swings
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 7 - 11 |
| Updated: | 1/5/2017 |
| Start Date: | March 1997 |
| End Date: | March 2004 |
Double Blind Placebo Controlled Study of Depakote (Divalproex Sodium) in Children With Temper Outbursts and Severe Mood Swings
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.
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.
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.
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.
Inclusion Criteria:
- Age 7-11
- Meets Screening Criteria (i.e. "Explosive Mood Disorder") A) An explosive temper as
evidenced by four or more outbursts of rage, property destruction or fighting per
month on minimal provocation B) Mood lability as evidenced by multiple,
daily,distinct, shifts from normal to irritable mood with withdrawn or boisterous
behavior, occurring without a clear precipitant C) Duration of at least one year when
not treated D)Symptoms result in impairment in two or more areas including: school,
the law, family, substance use, peers, work E)Symptoms do not occur only during
substance toxicity or withdrawal. F)Symptoms not confined to a single setting or
context
- Parent and child willing to consent to study
- Inadequate response to an Adequate trial (8 weeks) of Psychotherapy and/or family
therapy
Exclusion Criteria:
- Meets criteria for Pervasive Developmental Disorder or Childhood Schizophrenia
- Seizure or other neurological disturbance
- Pregnancy
- Moderate to severe mental deficiency
- Physical exam or laboratory results with significant abnormalities
- Active suicidal or homicidal ideation or history of suicide attempts
- Use of Barbiturates
- Unequivocal manic or hypomanic episode
- Meets criteria for Attention Deficit Hyperactivity Disorder and has not failed a
trial of psychostimulants
- Meets criteria for Major Depression in prepuberty
- Sexually active females who are unwilling to use effective methods of contraception.
- Mitochondrial disease or family history of mitochondrial disease
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