Bipolar Disorder in Children/Adolescents:
New Pharmacological Studies
By Arline Kaplan © 2001 (All Rights Reserved)
Despite the increasing use of mood-stabilizing and antipsychotic agents in children
and adolescents with bipolar disorder, few studies have investigated the safety
and efficacy of these medications for this specific population. Fortunately,
new federal laws as well as psychiatric groups are encouraging drug studies
in children, so the picture is changing.
At the American Academy of Child and Adolescent Psychiatry’s (AACAP) annual
meeting in New York, Wagner and colleagues (2000) presented a poster on an open-label
study of divalproex (Depakote) in children and adolescents with bipolar disorder.
Just a few months earlier, Kowatch et al. (2000) published a pilot study aimed
at developing effect sizes for lithium, divalproex sodium and carbamazepine
(Tegretol) in the acute phase treatment of children and adolescents with bipolar
I or bipolar II disorder.
Currently, the medications most commonly used for children and adolescents with
bipolar disorder are the mood stabilizers (divalproex, lithium and carbamazepine)
followed by the newer atypical antipsychotics (olanzapine [Zyprexa] and risperidone
[Risperdal]), said Karen Dineen Wagner, M.D., Ph.D. She is vice chair of the
department of psychiatry and behavioral sciences and director of the division
of child and adolescent psychiatry at the University of Texas Medical Branch,
Galveston
"There isn’t a lot of data on the use of these drugs [in the pediatric
population], but I think in the next few years there will be a number of studies
to address which medications are the most effective in controlled settings,
and to identify the kinds of side effects we will see," Wagner said in
an interview. "It is important for clinicians to keep up-to-date with studies
that are either ongoing or have recently been completed so they know more about
…what will be successful in terms of treating these disorders."
Most of the reported studies have been open-label. They include, for example,
a seven-week trial of valproate for adolescent mania (Papatheodorou et al.,
1995), an eight-week flexible dose study of divalproex for adolescents with
mixed, manic or depressed bipolar states conducted by Zamvil and colleagues
(Zamvil and Frank, 1993), a study of olanzapine in the treatment of seven adolescents
with bipolar disorder manic episode (Soutullo et al., 1999) and a retrospective
chart review of 28 youths with bipolar disorder (25 mixed and three hypomanic)
given risperidone (Frazier et al., 1999).
Even with the older agent, lithium, Wagner said, there has been only one placebo-controlled
trial, a study conducted by Geller and colleagues (1998). In that study, 25
adolescents with bipolar disorder and a secondary substance dependency disorder
participated in a double-blind, placebo-controlled trial. The investigators
concluded that lithium treatment of bipolar disorder with secondary substance
dependency disorder in adolescents was "an efficacious treatment for both
disorders," and "these results warrant replication with a long-term
maintenance phase" (Geller et al., 1998). The adolescents treated with
lithium showed a significant decrease in their substance abuse and a significant
improvement in their global assessment scale.
"It was a good outcome, but small number of subjects," said Wagner.
"A large-scale, multisite study (anywhere from 150 to 200 children) would
certainly be reasonable [to conduct]."
For a further look at divalproex treatment for bipolar disorder in children
and adolescents, a large-scale, multicenter, double-blind study is now being
planned. It is a follow-up to the recently completed open-label study (Wagner
et al., 2000), Wagner said.
The open-label study involved 40 children and adolescents (aged 7 to 19 years).
To enter the study, they had to have a primary diagnosis of bipolar disorder
with a manic, hypomanic or mixed episode (based on the Diagnostic and Statistical
Manual for Mental Disorders, Fourth Edition) and a Mania Rating Scale (MRS)
score of 14 or greater from the Schedule for Affective Disorders and Schizophrenia-Change
Version (SADS-C). Potential subjects were excluded based on medical history
The study followed an open/discontinuation design in which all the patients
start on medication and then when they improve they are randomized to either
placebo or to medication.
"In
this case, we only analyzed the open data," she said, explaining that too
few subjects participated in the double-blind period to allow for statistical
analysis of efficacy.
In
the open-label phase, the young people generally were given a starting dosage
of divalproex of 15 mg/kg per day. The mean final dosage was 17.5 mg/kg per
day ± 8.2. Although participants were to be on no other medication, Wagner
said the investigators found during the course of the study that some of these
children had serious attention-deficit/hyperactivity disorder that was unmanageable
without medication.
"So, we made a decision to allow those who absolutely needed to have their
stimulant medication to be put on it," she said. "That’s an issue
that complicates studies of children with bipolar disorder—the comorbidity
rate between bipolar disorder and attention-deficit/hyperactivity disorder is
quite high."
Primary efficacy of divalproex was analyzed using the change from baseline scores
of the MRS. Other efficacy measures included change from baseline score for
the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression
(CGI) Severity Scale.
Twenty-two subjects (61%) showed a 50% or more improvement in MRS scores during
the open phase of treatment.
"A 50% improvement on that scale is considered a responder," Wagner
said.
MRS
scores declined (i.e., improved) within the first week of the study and continued
to decline throughout the open-label phase. Improvements in scores also occurred
on the BPRS and CGI-Severity scales.
The side effects experienced by the study participants "were quite mild,"
Wagner added. They included headache, nausea, vomiting, diarrhea and somnolence.
Six participants (15%) discontinued from the study because of adverse events.
Additionally, six discontinued because of ineffectiveness and six because of
noncompliance.
Overall, Wagner and her colleagues concluded that the study provided "preliminary
support for efficacy and safety of divalproex in the treatment of bipolar disorder
in children and adolescents."
(Concerns have been expressed about valproate [Depakote, Depakene] and the
risk of hyperandrogenism and polycystic ovary syndrome in females with epilepsy
[Isojarvi et al., 1993, as cited in Rasgon et al., 2000] and with bipolar disorder
[Soares, 2000]. A commentary by Piontek and Wisner [2000] provides recommendations
for appropriate clinical management of female adolescents and women taking valproate—Ed.)
Efficacy also was found for divalproex, as well as lithium and carbamazepine,
in the Kowatch et al. study (2000). In that study, 42 outpatients (20 with bipolar
I disorder and 22 with bipolar II) who were experiencing an acute manic or mixed
episode were randomly assigned to six weeks of open treatment with lithium (30
mg/kg/day), divalproex (20 mg/kg/day) or carbamazepine (15 mg/kg/day). Efficacy
was measured with the Bipolar Clinical Global Impression (CGI-BP) on the Improvement
Subscale and the Young Mania Rating Scale (Y-MRS).
With response defined as a 50% or more change from baseline to exit in the Y-MRS
scores, the effect size was 1.63 for divalproex, 1.06 for lithium and 1.00 for
carbamazepine. (An effect size greater than 0.8 is considered a large effect).
In the adequate trial sample of 32 study participants who had completed at least
five weeks of treatment, the carbamazepine group had the fewest responders (44%
using the CGI and the Y-MRS criteria). The divalproex sodium group had response
rates of 46% on the CGI and 54% on the Y-MRS, while the lithium group had response
rates of 50% on the CGI and 40% on the Y-MRS.
"The majority of side effects were mild to moderate and tolerated by most
subjects," the investigators reported. "There were no serious adverse
effects necessitating hospitalization."
While
most of the open-label studies have found improvement in manic symptoms with
mood stabilizers, psychiatrist Linda Zamvil, M.D., recently said in an interview
that she was most surprised by the improvement in depressive symptoms. She found
such improvement in a small study she and colleagues conducted using a loading
dose of divalproex for the rapid stabilization of acute mania in young patients
(Zamvil et al., 1999)
"My intention was to see if we could…rapidly get the kids feeling
better" without reliance on antipsychotics, said Zamvil who is assistant
clinical professor of psychiatry at Harvard Medical School and medical director
of the Massachusetts Behavioral Health Partnership. "We wanted to see how
rapidly they would improve as well as how sustainable their responses were over
the four weeks."
Zamvil and colleagues were seeking to replicate a loading-dose study conducted
by Hirschfeld et al. (1999). The differences were that Zamvil and colleagues
used an outpatient rather than inpatient setting and studied children and adolescents
(aged 10 to 16 years) rather than adults (aged 18 to 60 years).
In the Zamvil et al. study, four patients were given a single evening dose of
divalproex ranging from 20 mg/kg/day to 30 mg/kg/day. The therapeutic dose ranged
from 50 µg/mL to 125 µg/mL, and levels were checked at baseline,
day 5, 14 and 28. One patient was dropped from the study due to noncompliance
with laboratory procedures. All three patients who completed the study showed
good tolerability of the medication with minimal side effects.
Efficacy measures included the Young Mania Rating Scale, Overt Aggression Scale
(OAS), Beck Depression Inventory (BDI) and Children’s Global Assessment
Scale (CGAS).
"Not only did the manic symptoms diminish, but the depression improved
as well and was statistically significant," said Zamvil. Depressive symptoms
in all three patients dramatically decreased, with the mean BDI score dropping
from 28 at baseline to 11 on day 28.The decrease in the BDI was significant
at day 14 (t = 2.50, p = 0.05). Aggression scores also diminished while the
scores on the CGAS improved. Two of the three subjects who completed the study
were still on medication 18 months later.
For her own pediatric patients who present with depression, Zamvil starts with
either divalproex or lithium if she knows there is a family history of bipolar
disorder.
"In children and adolescents diagnosed with a major depressive disorder,
20% to 40% will eventually be bipolar, " Zamvil said. "I’m concerned
about the effects of exposure to antidepressants in this population."
She explained that while tricyclics are "notorious" for triggering
a manic state in a depressed bipolar patient, any antidepressant can do this
and can also worsen depressive symptoms.
Both Zamvil and colleagues’ divalproex loading study and the earlier dose-finding
study showed patient improvement on the Beck Depression Inventory (Zamvil et
al., 1999; Zamvil and Frank, 1993).
"So, when kids who have a family history of bipolar present as depressed
and not in a mixed state, I begin treatment with a mood stabilizer and not an
antidepressant. If a parent has had a good response to lithium I will recommend
lithium. If a relative has done well with Divalproex, I start this generally
at 15 mg/kg/day. In over a decade of practicing this way, I feel I may have
avoided iatrogenic reactions to antidepressants."
While one of Zamvil’s "pet concerns" is the overprescribing of
antidepressants to children with bipolar disorder, one of Wagner’s is accurate
diagnosis.
"Distinguishing bipolar disorder from ADHD [and]… knowing the features
of bipolar disorder in young children as contrasted to adolescents are important,"
Wagner said.
Increasing evidence exists that prepubertal children who develop bipolar disorder
often have rapid cycling of their mood and psychotic features, Wagner explained.
"In adults, we see periods of mania followed by an episode of depression.
With young children, the cycling can be within days or even a day," she
said. " It may be a more severe form of the illness in very young children."
It is also important for clinicians, Wagner said, to use agents that have been
tested with children and adolescents and to encourage compliance with these
medications, since bipolar disorder tends to be quite chronic.
"Issues of medication with children can sometimes be the timing of the
medication. If they have to take it in school, it gets more difficult. Usually,
the medications we use for treating this disorder can be taken once a day or
in the morning and evening. With young children, it is really incumbent on the
parents to give them their medication. Young children will either forget about
it or they might take a wrong dose. The compliance is actually easier with young
children, because the parents can more carefully regulate their schedule and
have them take the medication," Wagner said.
Issues of medication with adolescents can be more challenging, according to
Wagner.
"There
are some adolescents who don’t want to take medication, because they believe
that means there is something wrong with them. Helping them to understand the
medication can be beneficial to them is a major issue in dealing with these
adolescents with bipolar disorder," she said. "The other issue is
that sometimes adolescents who are very manic like that experience. They like
feeling high, they feel energetic, and they feel that they can do anything and
do it well …They may stop taking their medication when they don’t
feel that sense of being high in hopes of regaining it. But clinically, we see
that as mania, which can be so disruptive and devastating to their lives."
During the interview, Wagner was asked about the effects of the pediatric exclusivity
provision of the Food and Drug Administration Modernization Act that grants
pharmaceutical companies six months of marketing exclusivity for conducting
studies on children. The FDA published a list of approved drugs for which additional
pediatric information may produce health benefits in the pediatric populations.
On that list was divalproex, lithium, olanzapine and risperidone.
Wagner responded: "The FDA’s support of the incentives that have been
provided to industry to do these studies and some of the recent regulation in
terms of mandating some of these studies have been extremely helpful to the
field of child and adolescent psychopharmacology."
References
Frazier JA, Meyer MC, Biederman J et al. (1999), Risperidone treatment for juvenile
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Geller B, Cooper TB, Sun K et al. (1997), Double-blind and placebo-controlled
study of lithium for adolescent bipolar disorders with secondary substance dependency.
J Am Acad Child Adolesc Psychiatry 37(2):171-178.
Hirschfeld RMA, Allen MH, McEvoy J et al. (1999), Safety and tolerability of
oral loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry
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sodium, and carbamazepine in children and adolescents with bipolar disorder.
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Soutullo
CA, Sorter MT, Foster KD et al. (1999), Olanzapine in the treatment of adolescent
acute mania: a report of seven cases. J Affect Disorder 53(3):279-283.
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in childhood bipolar disorder. Poster. Presented at the 47th annual meeting
of the American Academy of Child and Adolescent Psychiatry. New York.
Zamvil L, Frank A (1993), Use of valproate with bipolar adolescents. Presented
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1(suppl 1)
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