Psychopharmacology of

B i p o l a r D i s o rd e r s in
C h i l d ren an d A d o l e s c e n t s
a, b
Ekaterina Stepanova, MD, PhD *, Robert L. Findling, MD, MBA

KEYWORDS
 Bipolar disorder  Pharmacotherapy  Children  Adolescents  Pediatric

KEY POINTS
 Bipolar disorder is a chronic condition that oftentimes requires pharmacologic
intervention.
 There are limited medication data available.
 Most studies targeted short-term treatment.

INTRODUCTION

Bipolar disorder is a chronic and debilitating illness that often begins early in life, with
the first episode frequently occurring in adolescence.1,2 Compared with adults, youth
diagnosed with bipolar disorder experience more severe symptoms and have poorer
prognosis.3 Bipolar disorder is estimated to be the fourth leading source of disability in
individuals of 10 to 24 years of age.4
The recommended treatment for bipolar disorder includes a combination of psycho-
pharmacological and psychosocial interventions.5 Until recently, very limited data per-
taining to pharmacologic management of pediatric bipolar disorder were available,
and children were essentially treated as “small adults,” with clinicians adapting

Disclosure Statement: Dr R.L. Findling receives or has received research support, acted as a
consultant and/or served on a speaker’s bureau for Actavis, Akili, Alcobra, American Academy
of Child & Adolescent Psychiatry, American Psychiatric Press, Bracket, CogCubed, Cognition
Group, Coronado Biosciences, Elsevier, Epharma Solutions, Forest, Genentech, GlaxoSmithK-
line, Guilford Press, Ironshore, Johns Hopkins University Press, KemPharm, Lundbeck, Medgen-
ics, Merck, NIH, Neurim, Novartis, Otsuka, PCORI, Pfizer, Physicians Postgraduate Press, Purdue,
Rhodes Pharmaceuticals, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals, Syneurx,
Takeda, Teva, Tris, Validus, and WebMD. Dr E. Stepanova receives research support from Psy-
chNostics, LLC.
a
Johns Hopkins University School of Medicine, Childrens’ Mental Health Center, 401 North
Caroline Street, Baltimore, MD 21231, USA; b Department of Psychiatry, Division of Child and
Adolescent Psychiatry Johns Hopkins University School of Medicine, 1800 Orleans Street, Balti-
more, MD 21287, USA
* Corresponding author.
E-mail address: estepan2@jhmi.edu

Pediatr Clin N Am - (2017) -–-

http://dx.doi.org/10.1016/j.pcl.2017.08.002 pediatric.theclinics.com
0031-3955/17/ª 2017 Elsevier Inc. All rights reserved.
2 Stepanova & Findling

information from clinical trials on adults. However, the efficacy and safety profiles of
pharmacologic interventions appear to be different in youth and adults.6
Pharmacotherapy of youth with bipolar disorder can be challenging. The choice of
medication mostly depends on the phase of illness (manic, depressive, or mainte-
nance treatment). In this review, we examine the current evidence for pharmacologic
management of bipolar disorder in youth based on the phase of illness. In addition, we
discuss medications currently approved by the Food and Drug Administration (FDA)
for the treatment of bipolar disorder (Table 1), and summarize studies directly
comparing monotherapy options (Table 2) and combinations of different classes of
medications (Table 3). Although the focus of this review is pharmacotherapy of pedi-
atric bipolar disorder, psychosocial interventions are important and should not be
discounted.

ACUTE MONOTHERAPY OF MANIC AND MIXED STATES

Lithium and Anticonvulsants
Lithium has been the gold standard for treatment of bipolar disorder in adults. It is also
the first medication approved by the FDA for pharmacotherapy of bipolar disorder in
children 12 years and older. At the time of its approval, all recommendations regarding
dosing, safety, and efficacy were adapted from adult data. In efforts to bridge this gap,
the Collaborative Lithium Trials (CoLT) examined dosing strategies, pharmacokinetics,
safety, and short-term and long-term efficacy of lithium in youth aged 7 to 17.7 In an
open-label trial, lithium was found to be reasonably effective in reducing symptoms of
a manic or mixed episode. Interestingly, only initial responders to lithium during the
first 8 weeks maintained mood stabilization over the next 16 weeks.8 The efficacy of
lithium as a treatment for bipolar disorder has been further documented in a
double-blind placebo-controlled trial9 (Table 4). Lithium was superior to placebo in
reducing symptoms during manic or mixed episode as well as increasing Clinical
Global Impression-Improvement scores.
The Treatment of Early Age Mania Study (TEAM) describes a direct comparison of
lithium, divalproex, and risperidone. In this randomized clinical trial, more youngsters
with bipolar disorder responded to risperidone than to lithium or divalproex.10,11 How-
ever, the risperidone group had higher rates of metabolic side effects.
Based on a randomized placebo-controlled trial and open-label studies discussed
previously, lithium has been shown to be effective for acute treatment of manic and
mixed states of pediatric bipolar disorder. However, acutely, it is less effective when
compared with antipsychotics. In addition, lithium requires careful monitoring due to
a narrow therapeutic window, which limits its use in some patients.

Table 1
Medications approved by the Food and Drug Administration for the treatment of pediatric
bipolar disorder

Medication Phase of Bipolar Disorder Age, y Daily Dose Range, mg/d

Lithium Mixed/manic 12–17 300–2400
Risperidone Mixed/manic 10–17 0.25–2.5
Olanzapine Mixed/manic 13–17 2.5–20
Aripiprazole Mixed/manic 10–17 2–30
Quetiapine Mixed/manic 10–17 50–600
Olanzapine/fluoxetine Depressive episode 10–17 3/25–12/50
combination
 Table 2
Select comparison studies

Number of
Medications Dose/Serum Level Study Design Age, y Subjects Results Common Side Effects
Lithium11 Lithium max 1.1–1.3 mEq/L; Controlled, 6–15 279 Mean CGI-BP-IM for Weight gain, increase in
Divalproex Divalproex randomized Risperidone (68.5), lithium prolactin level and
Risperidone 111–125 mg/mL; Risperidone (35.6), divalproex (24.0) thyrotropin with
4–6 mg/d risperidone.
Divalproex12 Divalproex 80–120 mg/mL; Double-blind, 12–18 50 No significant difference in No difference in rates of side
Quetiapine Quetiapine 400–600 mg/d randomized YMRS scores between effects between groups.
groups; more rapid
improvement in quetiapine
group
Lithium19 Maximum serum Open-label 6–18 42 Mean reduction in YMRS scores Nausea was the most common
Divalproex concentrations: lithium 0.8– was 14.53 for divalproex, side effect across all groups.

Psychopharmacology of Bipolar Disorders

Carbamazepine 1.2 mEq/L; divalproex
85–110 mg/mL;
carbamazepine 7–10 mg/L
Risperidone32 Risperidone 0.5–2 mg/d
Divalproex Divalproex 60–120 mg/mL
9.46 for lithium, 9.00 for Other side effects in lithium
carbamazepine group included increased
appetite, polyuria and
diarrhea; in divalproex
group, sedation; and in
carbamazepine group,
sedation, rash and dizziness.
Double-blind, 8–18 66 YMRS score decreased from Increased appetite, stomach
randomized 30.59 to 7.58 with discomfort, sleepiness and
risperidone; and from 25.09 fatigue was reported among
to 9.0 with divalproex both groups. Increased
irritability was reported with
divalproex.

Abbreviations: CGI-BP-IM, clinical global impressions for bipolar illness improvement-mania; YMRS, Young Mania Rating Scale.

3
 4
Stepanova & Findling
Table 3
Select medications for combination therapy

Phase of Bipolar Number of

Medications Dose Study Design Disorder Age, y Subjects Results Common Side Effects
Divalproex62 Divalproex 20 mg/kg Randomized, Acute manic/ 12–18 30 Combination treatment Sedation was more
Quetiapine Quetiapine 450 mg/d double-blind, mixed episode resulted in greater common with
placebo- reduction in YMRS combination treatment.
controlled scores compared with Nausea, headache,
divalproex 1 placebo gastrointestinal distress
occurred in both groups.
Lithium63 Serum levels: Lithium Open-label Acute manic/ 5–17 90 Significant reduction in Emesis, enuresis, stomach
Divalproex 0.6–1.2 mEq/L hypomanic YMRS (from 21.8 to 5.7), pain, tremor, increased
Divalproex 50–100 mg/mL episode CDRS (from 31.7 to 21.0) thirst, headache, nausea,
within 3 mo and CGAS (from 50.1 to sedation, increased
68.1) appetite, diarrhea.
Lithium1 Risperidone: up to 3 mg/d; Prospective Acute mixed/ 5–18 37 Mean reduction in YMRS Weight gain, sedation,
Risperidone65 Lithium serum level: open-label manic scores was 23.53 for nausea, increased
Divalproex1 0.6–1.0 mEq/L; episode lithium 1 risperidone; appetite, stomach pain,
Risperidone Divalproex serum level: and 22.0 for tremors occurred in both
50–120 mg/mL divalproex 1 risperidone groups.
Olanzapine47 6/25 Randomized, Depressive 10–17 255 Mean change in CDRS-R Weight gain, increased
Fluoxetine 12/50 placebo- episode score was greater in appetite, somnolence,
controlled active treatment group hyperlipidemia,
( 28.4) vs placebo increases in hepatic
( 23.4) analytes, prolactin, QTc.

Abbreviations: CDRS, children’s depression rating scale; CDRS-R, children’s depression rating scale, revised; CGAS, children’s global assessment scale; YMRS, Young
Mania Rating Scale.
 Table 4
Select acute randomized placebo-controlled trials for monotherapy in manic/mixed states of pediatric bipolar disorder

Number of
Medication Dose Age, y Subjects Results Common Side Effects
Lithium9 Serum level up 7–17 81 Mean change in YMRS scores greater for lithium Vomiting, nausea, headache, fatigue, increase in
to 1.4 mEq/L ( 14) vs placebo ( 7) TSH
Divalproex16 Serum level of 10–17 150 No significant difference in YMRS scores for No difference between groups
80–125 mg/mL divalproex ( 8.8) vs placebo ( 7.9)
Risperidone31 0.5–2.5 mg/d; 10–17 169 Mean change in YMRS scores greater for high Somnolence, headache, fatigue
3–6 mg/d dose of risperidone ( 16.5) and low dose of
risperidone ( 18.5) vs placebo ( 9.1)
Olanzapine33 2.5–20 mg 13–17 161 Mean change in YMRS scores greater for Olanzapine group had more weight gain, higher
olanzapine ( 17.65) vs placebo ( 9.99) levels of hepatic enzymes, prolactin, fasting
glucose, fasting total cholesterol, and uric acid

Psychopharmacology of Bipolar Disorders

Quetiapine34 400 mg 10–17 277 Mean change in YMRS scores greater for lower Sedation, dizziness, headache, and average
600 mg dose of quetiapine ( 14.25) and higher dose weight gain of 1.7 kg; notable increases in
of quetiapine ( 15.60) vs placebo ( 9.04) total cholesterol and triglycerides
Aripiprazole36 10 mg 10–17 296 Mean change in YMRS scores greater for lower EPS and somnolence
30 mg ( 14.2) and higher ( 16.5) doses of
aripiprazole vs placebo ( 8.2)
Ziprasidone37 40–160 mg/d 10–17 237 Mean change in YMRS greater for ziprasidone Sedation, headache, fatigue, nausea
( 13.83) vs placebo ( 8.61)
Asenapine39 5 mg/d 10–17 403 Mean change in YMRS scores greater for Somnolence, sedation, oral hypoesthesia and
10 mg/d asenapine 5 mg/d ( 12.8), asenapine 10 mg/d paresthesia, increased appetite, weight gain,
20 mg/d ( 14.9) and asenapine 20 mg/d ( 15.8) vs increase in fasting lipids and glucose
placebo ( 9.6)

Abbreviations: EPS, extrapyramidal symptoms; TSH, thyroid stimulating hormone; YMRS, Young Mania Rating Scale.

5
6 Stepanova & Findling

Anticonvulsants have been found to have mood-stabilizing properties in adults, but

available evidence is weaker in children. Divalproex is approved by the FDA for the
treatment of manic and/or mixed episodes in adults, but not in youth. There are several
positive open-label studies and a chart review suggesting the benefit of divalproex in
the treatment of manic/mixed states.12–14 A double-blind study compared divalproex
with quetiapine in treating acute mania and showed higher response with quetia-
pine.12 A randomized placebo-controlled study comparing lithium, divalproex, and
placebo demonstrated effectiveness of divalproex over placebo.15 However, a ran-
domized placebo-controlled, industry-sponsored trial of divalproex for the treatment
of acute mania failed to show separation from placebo during the first 4 weeks of treat-
ment.16 The discrepancy observed in the results of the 2 clinical trials was possibly
due to the use of different formulations of the medication. In addition, the number of
sites was larger in the negative study but so was the statistical power.
Although there is some evidence suggesting effectiveness of divalproex in the man-
agement of acute manic episodes, the available data are quite limited. In addition,
divalproex may be toxic at higher doses, requires serum drug level monitoring, and
has a potential for multiple drug interactions and teratogenic effects. Therefore, we
believe it should not be used as a first-line agent for the treatment of acute mania in
pediatric bipolar disorder.
Carbamazepine is currently approved by the FDA for the treatment of manic and
mixed episodes of bipolar disorder in adults but not in children. Although there are
no randomized, placebo-controlled clinical trials available to this date, several
open-label studies suggest variable benefit of carbamazepine in a pediatric popula-
tion. In a 26-week study of youth suffering from an acute manic or mixed episode,
there was a significant decrease of a Young Mania Rating Scale (YMRS) score.17 How-
ever, in another open-label study, many patients remained symptomatic despite treat-
ment.18 Carbamazepine was directly compared with divalproex and lithium in a small
open-label study of youth with bipolar disorder I or II.19 This study reported large effect
sizes for divalproex (1.63), lithium (1.06), and carbamazepine (1.00).
Given the lack of randomized placebo-controlled trials evaluating the effectiveness,
safety and pharmacokinetics of carbamazepine in the treatment of pediatric bipolar
disorder, it would be prudent to consider other mood stabilizers when treating manic
or mixed episode in children.
Lamotrigine is not approved by the FDA for the management of bipolar disorder in
children, but it has an indication for maintenance treatment in adults. At this time, there
are no randomized placebo-controlled trials of lamotrigine in the pediatric population,
in spite of several positive open-label studies.20 Currently, there is insufficient evi-
dence to recommend its use for the treatment of acute manic or mixed episode of pe-
diatric bipolar disorder.
Topiramate is currently not approved by the FDA for the treatment of bipolar disor-
der in children or adults. There are 2 chart reviews of adjunctive therapy with topira-
mate suggesting improvement in youth with manic/mixed episode.21,22 In a study
investigating the effect of topiramate on weight gain related to second-generation an-
tipsychotics, the use of topiramate was associated with lower YMRS scores.23
Adjunctive use of topiramate with olanzapine did not help reduce YMRS scores, but
it did lead to reduced weight gain compared with olanzapine alone.24 The only
double-blind, placebo-controlled trial was stopped before completion in pediatric pa-
tients due to failure to separate from placebo in adult studies. Yet, despite the low po-
wer, analysis of the data provided some evidence for possible effectiveness.25 Further
studies are needed to establish effectiveness of topiramate in the treatment of manic
episodes of bipolar disorder in children.
 Psychopharmacology of Bipolar Disorders 7

Although case reports suggested efficacy of oxcarbazepine in the treatment of pe-

diatric manic/mixed states,26 in a 7-week randomized controlled trial of 116 patients, it
failed to separate from placebo.27 Therefore, its use is not recommended in children
with bipolar disorder.
It has been our experience that gabapentin is sometimes prescribed by clinicians for
the treatment of bipolar disorder; nonetheless, there are only 2 case reports showing
some improvement in youth.28 To this date, there are no clinical trials examining the
effect of gabapentin in children. However, studies in an adult population did not sup-
port its use for bipolar disorder.29 Given the lack of evidence, gabapentin is not rec-
ommended for treatment of bipolar disorder.

Antipsychotics
Meta-analysis of pharmacologic treatments of bipolar disorder revealed that second-
generation antipsychotics are generally more effective than mood stabilizers, but have
greater burden of side effects (weight gain and metabolic changes).30 In addition, ris-
peridone, quetiapine, aripiprazole, and asenapine carry FDA approval for the treat-
ment of acute mixed and manic episodes of bipolar disorder in children based on
randomized placebo-controlled trials.
Haas and colleagues31 reported significant improvement in manic symptoms with
low (0.5–2.5 mg/d) and high (3–6 mg/d) doses of risperidone in a randomized
placebo-controlled trial. In a direct comparison with divalproex, the risperidone group
improved earlier and with a greater response and remission rates.32 In addition, the
discontinuation rate was lower in the risperidone group. As described earlier, the
response rate in the risperidone group was significantly higher than in divalproex
and lithium groups.11
Olanzapine is currently approved by the FDA for the treatment of acute manic/mixed
episodes in adolescents 13 to 17 years of age based on a 3-week double-blind study,
in which more patients on medication met response and remission criteria when
compared with placebo.33 However, there was a significant increase in weight in
the olanzapine group compared with placebo (3.7 kg vs 0.3 kg).
A randomized placebo-controlled trial of quetiapine demonstrated high response
rates with either 400 mg or 600 mg quetiapine compared with placebo.34 In a
double-blind, randomized study comparing divalproex and quetiapine in adolescents
12 to 18 years of age, the response and remission rates were greater in the quetiapine
group.12 In addition, youth receiving quetiapine improved faster compared with
divalproex.
An open-label, dose-escalation study of 20 mg, 25 mg, and 30 mg per day of aripi-
prazole showed safety and efficacy of aripiprazole in the treatment of youth with bipo-
lar disorder and schizophrenia.35 Two doses of aripiprazole (10 mg and 30 mg) were
given to youth ages 10 to 17 in a 4-week double-blind, placebo-controlled trial, which
showed significant reduction in manic symptoms when compared with placebo.36
Ziprasidone is approved by the FDA for the treatment of mania in adult but not pe-
diatric bipolar disorder. A randomized placebo-controlled trial, in which 237 subjects
10 to 17 years of age received flexible doses of ziprasidone or placebo, showed sig-
nificant changes in YMRS scores in the active medication group.37 Although electro-
cardiogram changes were minimal in this study, a different trial reported a notable
prolongation of QTc interval in youth.38
A randomized placebo-controlled study of 3 doses of asenapine (2.5 mg twice a
day, 5 mg twice a day, 10 mg twice a day) was conducted with 403 patients aged
10 to 17 years. During the course of the study, all groups showed significant improve-
ment in YMRS scores compared with placebo.39
8 Stepanova & Findling

To date, there are no randomized placebo-controlled trials of clozapine for the treat-
ment of pediatric bipolar disorder, but retrospective chart reviews suggested potential
benefit.40,41 Due to the severity of the side-effect profile and the lack of randomized
controlled trials, the use of clozapine in children with bipolar disorder is not
recommended.
There is only one prospective open-label study of paliperidone in the treatment of
pediatric bipolar disorder. Adolescents 16 to 17 years of age received monotherapy
with paliperidone for 8 weeks and had a significant improvement in YMRS scores.42
To date, there are no published clinical studies on the use of lurasidone and iloper-
idone for the treatment of mania in youth. A search of the clinical trials Web site (www.
clinicaltrials.gov) revealed an ongoing open-label study of lurasidone as a treatment
for mania in youth 6 to 17 years of age.

ACUTE TREATMENT OF DEPRESSIVE EPISODES

Depressive episodes are less common than manic or mixed states in the pediatric
population43 and fewer treatment studies are available to date. Although selective se-
rotonin reuptake inhibitors improve depressive symptoms in youth with bipolar disor-
der, they increase the risk of switching to a manic state.44,45 Antidepressants are
recommended only in addition to a mood stabilizer for the treatment of a depressive
episode.45,46 The only medication that is currently approved by the FDA for the treat-
ment of bipolar depression in youth of 10 to 17 years of age is olanzapine/fluoxetine
combination, which was superior to placebo in an 8-week randomized trial.47
There are no other trials of antidepressants in pediatric bipolar depression available
to date. However, a pilot study of youth with a genetic risk for bipolar disorder present-
ing with depressive symptoms was conducted.48 Children were randomized to receive
paroxetine or paroxetine/divalproex combination. Both treatment options were not
effective and more than 50% of patients had manic symptoms or suicidality, which
led to the early termination of the study.
Two randomized placebo-controlled studies of quetiapine for the treatment of bipo-
lar depression in children have been reported. In both studies, the response rates did
not demonstrate a significant separation from placebo.49,50 However, in one of the tri-
als, the response rate in the placebo group was high and could have contributed to the
lack of statistical significance.49
Open-label trials with lithium and lamotrigine demonstrated effectiveness for the
treatment of pediatric bipolar depression.51,52 Although these studies show some
promise, they should be interpreted with caution given the open-label design and
high YMRS scores before treatment. In addition, more randomized trials are needed
to establish efficacy and safety of antidepressants and other mood stabilizers for
the treatment of bipolar depression.

MAINTENANCE THERAPY

Bipolar disorder is a chronic and life-long illness, requiring not only treatment of acute
episodes, but also maintenance therapy to prevent relapse.5 There is a paucity of ran-
domized data available on maintenance treatment of youth with bipolar disorder. Trials
that exist focus mostly on open-label extension after acute treatment.8,37,53–57
Two randomized, double-blind, placebo-controlled trials of aripiprazole for mainte-
nance treatment of pediatric bipolar disorder have been performed. In a 30-week trial,
youth 10 to 17 years of age were first assigned to acute treatment for 4 weeks with
10 mg or 30 mg of aripiprazole or placebo, followed by 26 weeks of double-blind
extension.58 Both doses of medication resulted in a significant reduction of YMRS
 Psychopharmacology of Bipolar Disorders 9

scores. In another trial, children 4 to 9 years of age were randomized to receive pla-
cebo or aripiprazole for 72 weeks after the initial acute stabilization.59 The time to
discontinuation was longer in the active treatment group.
Two trials evaluated the efficacy of lamotrigine in maintenance treatment of pediat-
ric bipolar disorder. In an open-label trial, 46 pediatric patients, 8 to 18 years of age,
with manic/mixed or hypomanic episode received lamotrigine for 14 weeks with high
response and remission rates.60 Findling and colleagues61 conducted a discontinua-
tion study in which lamotrigine was investigated as an add-on to conventional treat-
ment in youth 10 to 17 years of age. Patients receiving a stable dose of lamotrigine
for 2 weeks were randomized to continue lamotrigine treatment or placebo for an addi-
tional 36 weeks. The overall time to occurrence of a bipolar event did not differ be-
tween groups, but was significantly longer in the subset of patients aged 13 to
17 years of age.
In summary, lithium, divalproex, aripiprazole, ziprasidone, asenapine, and lamotri-
gine have shown promising results in maintenance treatment of pediatric bipolar dis-
order. However, more randomized placebo-controlled studies are needed to evaluate
long-term safety and effectiveness of these pharmacologic interventions.

COMBINATION TREATMENT

Although many studies have reported significant symptom reduction during acute
manic episode with monotherapy, many children continue to be symptomatic despite
being treated. Several studies explored the possibility of combination therapy for
treatment-resistant youth.
A randomized placebo-controlled study of combination treatment with divalproex
and quetiapine showed greater symptom reduction when compared with divalproex
alone and placebo.62 Combination therapy of lithium and divalproex was effective in
an open-label trial of 90 youth presenting with manic or hypomanic episode within
3 months before the study.63,64
A significant reduction in YMRS scores was achieved in an open-label trial of com-
bination treatment with risperidone and either divalproex or lithium, respectively.65
Risperidone augmentation was also explored in a 12-month prospective open-label
trial.66 In this study, children with preschool onset of bipolar disorder, who did not
respond to lithium monotherapy or relapsed, showed decrease in manic symptoms
with addition of risperidone.
In general, the augmentation with an antipsychotic may improve manic symptoms
when monotherapy with an anticonvulsant or lithium has not been sufficient. However,
more studies are needed to evaluate the effectiveness of other antipsychotics in com-
bination treatments, as well as to assess the initial response to monotherapy versus
combination therapy.

SUMMARY

Despite an increasing interest in pharmacotherapy of pediatric bipolar disorder and

more clinical trials of second-generation antipsychotics published over the past
several years, there still remains a paucity of data to inform clinicians on the appro-
priate medication management. Based on the available data, initial monotherapy is
preferable when treating an acute mixed or manic state. Generally, atypical antipsy-
chotics have shown higher response rates when compared with lithium or anticon-
vulsants. However, higher efficacy is usually accompanied by metabolic side
effects. Lithium is effective and generally well tolerated. Results for divalproex in
the treatment of pediatric mania are mixed, but overall show some promise. Studies
10 Stepanova & Findling

of carbamazepine and topiramate show potential in children with bipolar disorder,

but randomized placebo-controlled trials are needed to establish efficacy. The use
of oxcarbazepine is not recommended.
Even fewer data are available on the treatment of bipolar depression. The olanza-
pine/fluoxetine combination was approved by the FDA after it was shown to be effec-
tive in a randomized placebo-controlled trial. Quetiapine failed to show efficacy in 2
randomized placebo-controlled trials.
There is only a modest amount of research available on maintenance treatment of
bipolar disorder in youth. Randomized placebo-controlled clinical trials were conduct-
ed with aripiprazole, which showed positive results. Lithium and divalproex are prom-
ising medications, but further studies are needed to evaluate the long-term efficacy.
Lamotrigine may be more effective in adolescents but not in younger children.
Despite the advances in pharmacotherapy of pediatric bipolar disorder over the
past 15 years, more research is needed to bridge the gap between clinical practice
and available data. Head-to-head comparison trials, as well as long-term studies,
can help guide medical decision making. Studies of combination treatment are prom-
ising and further research should focus on combining medications for more effective
management of bipolar disorder.

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