Bipolar Disorder in Children and Adolescents: Diagnosis and

Treatment
Elizabeth B Weller, Sara M Calvert, Ronald A Weller

Curr Opin Psychiatry 16(4):383-388, 2003. 2003 Lippincott Williams & Wilkins

Posted 07/15/2003

Abstract and Introduction

Abstract

Purpose of Review: This article reviews current literature on the diagnosis and treatment of bipolar
disorder in children and adolescents. Controversies relating to diagnosis, common comorbid psychiatric
disorders, and the safety and efficacy of pharmocotherapy are summarized.
Recent Findings: The presentation of bipolar disorder in children and adolescents has been described
by some as 'atypical' in that (1) the predominant mood is often one of irritability, (2) the irritability may be
severe, persistent, and violent, (3) the pattern of cycling may be ultradian, (4) comorbid psychiatric
disorders and family history of bipolar disorder are common, and (5) poor treatment response and
recurrence are common. However, given the prevalence of mixed mania in adult bipolar disorder and the
similarities between childhood- and adolescent-onset bipolar disorder and mixed mania, some claim that
the child and adolescent variant may not be atypical after all. Adding to the confusion are the diverse
manifestations of bipolar symptoms at different developmental stages. Lithium, valproate, and
carbamazepine are the medications most commonly used to treat children and adolescents with bipolar
disorder. However, current practice parameters are based on preliminary evidence and/or studies using
adult patients. There is a need for randomized, double-blind, controlled trials to determine medication
safety and efficacy in children and adolescents with bipolar disorder.
Summary: An improved understanding of bipolar disorder should help clinicians in the accurate diagnosis
and treatment of children and adolescents with bipolar disorder. Clinicians should use preliminary
evidence and sound clinical judgment when working with patients who have, or may be at risk of, bipolar
disorder.

Introduction

Confusion and controversy surround the topic of bipolar disorder (BPD) in children and adolescents.
However, an appreciation of recent research on BPD should help clinicians more accurately diagnose and
treat children and adolescents with BPD. This article reviews the most current literature on the diagnosis
and treatment of BPD in children and adolescents, with an emphasis on the controversies relating to
diagnosis, common comorbid psychiatric disorders and pharmocotherapy. Recent studies have attempted
to define the specific symptomatology and phenomenology that distinguish BPD from (1) normal
developmental differences in behavior and (2) psychiatric conditions frequently diagnosed in children and
adolescents. Other studies have compared childhood/adolescent-onset and adult-onset BPD to
determine whether these are two separate and distinct disorders or whether they represent different
phases in the natural course of the same illness.

Diagnostic Issues

From the first description of a link between melancholia and mania, by Aretaeus of Cappadocia in the
second century AD, to the development of the various editions of the American Psychiatric Association's
Diagnostic and Statistical Manual (DSM), experts have argued over the definition and diagnosis of BPD.
[1**]
It is still debated whether BPD should be viewed as part of a spectrum of disorders ranging from
unipolar depression to psychotic disorders and schizophrenia or viewed as a group of distinct diagnostic
entities that includes two BPD types and cyclothymia. [2] Diverse manifestations of bipolar symptoms in
different developmental stages and in different comorbid conditions have further clouded the clinical
picture.

The Spectrum of Bipolar Disorder

Kraepelin[1**] was the first to categorize all affective disorders on a spectrum. More recently, there has
been an emerging viewpoint that BPD has a spectrum of its own in which only the 'classic' form of BPD,
BPD Type I (alternating episodes of mania and depression interspersed with periods of normal
functioning) is commonly recognized. [3**] In addition to BPD Type I, patients may also present with
symptoms classified by DSM-IV as BPD Type II (alternating episodes of hypomania and depression),
cyclothymia (alternating episodes of subthreshold mania and depression), schizoaffective disorder
(psychotic symptoms occurring between episodes of a DSM-IV affective disorder), and depression with
psychotic features (depression with concurrent psychotic symptoms). [3**]

A related issue is how child and adolescent BPD fits into the BPD spectrum and the larger constellation of
psychiatric disorders. Psychoanalytic theory, predominant in American psychiatry throughout the 1960s
and 1970s, led to rejection of the notion that children could be diagnosed with BPD 'because children lack
higher-level cognitive structures'.[1**, p. 448] Thus, numerous case reports published during this time were
disregarded. Campbell, who advocated the concept of a child and adolescent variant of BPD, described 'a
proclivity among psychiatrists to classify milder cyclothymic reactions in the psychoneurotic category and
the more severe manic and depressive reactions with schizophrenic classification disregarding the
possibility of manic-depressive psychosis in the younger age group'. [1**, p. 453]

Agreeing on a Definition of Child and Adolescent Bipolar Disorder

In a National Institute of Mental Health round-table discussion on prepubertal BPD, [4] experts agreed that
BPD could be diagnosed in prepubertal children by using DSM criteria, and that in addition to BPD Type I
and BPD Type II, BPD not otherwise specified (NOS) could be given as a 'working diagnosis' in children
and adolescents. These experts agreed that the most common type of adult-onset BPD with discrete
episodes of depression with clear onset and offset was not a common presentation in children. Instead,
the most frequent course was a long-duration episode with rapid cycling and mixed mania. [4] The
presentation has also been described as 'atypical' because the predominant mood is often one of
irritability as opposed to euphoria (in adults). [3**] A review by Weckerly[3**] noted that (1) the irritability may
be severe, persistent, and violent, (2) the pattern of cycling may be ultradian (involving at least 365
episodes per year in which mania occurs for at least 4 h at a time), (3) comorbid psychiatric disorders and
family history of BPD are common, and (4) poor treatment response and recurrence are common.
However, 'the atypicality of pediatric mania may only be atypical when "classic mania" is used as the point
of reference'.[3**, p. 47] Mixed mania (a variant in which the predominant mood symptom is irritability) has
been reported in 10-70% of adult patients with BPD, and a recent meta-analysis of 17 studies indicated
that 31% of patients with BPD experienced only mixed states. [3**] Mixed states in adults were associated
with younger age of onset, high rates of comorbidity, and family history of mood disorders. [3**] Comorbid
psychiatric disorders were prevalent in adult patients with BPD and were associated with an earlier age of
onset and more severe and frequent episodes. Weckerly[3**] concluded that these observations have led
some to conceptualize a 'virulent form' (p. 47) of the disorder in adults that is similar to the 'atypical'
childhood- and adolescent-onset BPD.

Another difficulty in diagnosis is how to account for developmental differences in patients with BPD.
Although many 'typical' symptoms of mania (e.g. grandiosity, motor restlessness, imaginative thinking)
may be considered normal childhood behavior, developmentally normal behavior and BPD symptoms can
be distinguished because 'children with mania do not respond to the appropriate contingencies of a
consistently applied behavior management program'. [3**, p. 49] Yet another problem is that similar actions may
be identified as a different category of behavior depending on a patient's age. For example, disruptive
behavior is often attributed to oppositional defiant disorder in children, while in adults it may be attributed
to BPD.[3**]

Geller et al.[5*] described developmental variants of five DSM-IV mania symptoms (euphoric mood,
grandiosity, decreased need for sleep, racing thoughts, hypersexuality) commonly seen in young patients
with BPD. They compared presentations of four of the five symptoms (manifestations of racing thoughts
were similar in all age groups) in normal children, manic children, and manic adults in an attempt to
describe 'pediatric age equivalents of adult symptoms of mania' (p. 4). For example, the authors stated
that elated mood is pathological when it is inappropriate to context and is associated with impairment, and
that grandiosity is pathological when acted out in real life (i.e. in the classroom) but not when it is in the
context of play. The authors hoped to provide such examples so that clinicians could have a set of
symptoms that can help rule in or rule out BPD in children and adolescents.

Comorbidity
Common comorbid psychiatric conditions seen in young BPD patients include attention-deficit
hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and anxiety disorders.

Comorbid ADHD complicates the diagnosis of BPD for two reasons: misdiagnosis and symptom overlap.
Geller et al.[6*] studied misdiagnosis by comparing young patients with BPD with those with ADHD and with
normal controls, using the Washington University in St Louis Kiddie Schedule for Affective Disorders and
Schizophrenia. The authors found that the BPD group had a significantly higher rate of five DSM-IV
mania-specific symptoms (elated mood, grandiosity, decreased need for sleep, racing thoughts,
hypersexuality) compared with the ADHD group. The authors also noted increased reporting of irritable
mood, sharpened thinking, and increased goal directedness in the BPD group. However, since the
occurrence of these symptoms was also high in the ADHD group, they were not useful in discriminating
between the two disorders in an individual patient. Hyperactivity, accelerated speech, and distractibility
were frequent in both groups and were not significantly different between the groups. Thus, these
symptoms were not useful in discriminating between the two diagnoses.

There is an asymmetrical overlap between the diagnosis of BPD and ADHD, as evidenced by a 91%
comorbidity rate of ADHD among children with primary mania (reported by Carlson et al.[7]) as opposed to
a 23% comorbidity rate of BPD among children with primary ADHD (reported by Biederman et al.[8]).[9*] To
determine whether ADHD was an artifact of symptom overlap with other psychiatric disorders, Milberger
et al.[10] studied 140 boys with ADHD, 15 of whom had a comorbid diagnosis of BPD. They used both a
subtraction method and a proportion method to correct for symptom overlap between BPD and ADHD
and found that seven (47%) and 12 (80%) of the children continued to meet criteria for BPD after the
subtraction and proportion methods, respectively, were applied; all 15 (100%) of the children with
comorbid ADHD and BPD continued to meet criteria for ADHD. Thus, the authors suggested that neither
ADHD nor BPD was an artifact of symptom overlap.

Comorbid occurrence of BPD and conduct disorder ranges from 41 to 74% in children with primary BPD
and is 40% in children with primary conduct disorder.[9*] Bipolar symptoms can be severe in young patients
and may be similar to the extreme behaviors seen in patients with conduct disorder. Irritability, hostility,
and impulsivity are common symptoms of both disorders. However, referring to a study by Bowring and
Kovacs, Kim and Miklowitz [9*] asserted that BPD tends to present with an abrupt onset whereas conduct
disorder is likely to present with a prodromal period and progressively worsen over time.

Birmaher et al.[11] investigated the relationship between panic disorder and BPD. Although this relationship
has not been well studied in children and adolescents, the authors noted that the occurrence of BPD
ranges from 13 to 23% in adult patients with primary panic disorder, and that comorbid panic disorder
occurs in 36 to 80% of adult patients with primary BPD. In their study of 5-18-year-olds, Birmaher et al.[11]
compared 42 with panic disorder, 407 with non-panic-disorder anxiety disorder, and 1576 psychiatric
controls without anxiety disorders and found that the patients with panic disorder had significantly more
comorbid BPD than the other two groups (19% versus 5.4% and 7.1%). The severity of panic symptoms
was not significantly different between patients with and without BPD, and the severity of manic
symptoms was similar in all BPD patients. However, the authors found that patients with both disorders
had significantly more psychotic symptoms and suicidal ideation than panic disorder patients who had
non-BPD comorbidities. The authors believed that in addition to an increased risk of comorbid BPD in
patients with primary panic disorder, patients with both disorders may have additional symptoms (e.g.
psychosis, suicidal ideation) that complicate management. Furthermore, the high risk of comorbid BPD in
panic disorder patients highlights the importance of screening for BPD in patients with panic disorder,
since selective seretonin reuptake inhibitors are commonly used to treat panic disorder but are also
thought to exacerbate manic symptoms.

Treatment of Bipolar Disorder in Children and Adolescents

Despite advances in the understanding of the symptomatology and phenomenology of BPD in children
and adolescents, there remains a dearth of information regarding pharmacotherapy for BPD. [12**] Current
practice parameters are based on preliminary evidence and/or studies using adult patients. General
guidelines indicate it is important for young patients with BPD to continue treatment for an extended
period of time in order to manage the frequent relapses of childhood- and adolescent-onset BPD.
However, there is a dire need for randomized, double-blind, controlled trials using child and adolescent
patients to determine the safety and efficacy of medications commonly used in the treatment of BPD and
to compare these agents with each other.
Lithium, valproate and carbamazepine have been the medications most commonly used to treat children
and adolescents with BPD.[12**] Kowatch et al.[13] performed the only open randomized trial comparing the
effectiveness of these three agents in children and adolescents with BPD. In their study, improvement
was defined as at least a 50% reduction in score from baseline on the Young Mania Rating Scale and a
Clinical Global Impression Improvement score (a modification of the Clinical Global Impressions (CGI)
scale) of 1 or 2. Based on the Young Mania Rating Scale and Clinical Global Impression Improvement
scores, response rates were 53 and 40% for valproate, 38 and 46% for lithium, and 38 and 31% for
carbamazepine.

Lithium

Lithium is the oldest and best-studied mood stabilizer in adult BPD. It is effective in treating acute manic
episodes and in preventing recurrent episodes of mania and depression in adults. [12**, 14] Geller et al.[15]
performed the only randomized, double-blind, placebo-controlled trial of lithium. They studied 25
adolescents with BPD and secondary substance abuse. Thirteen received lithium and 12 received a
placebo. The researchers found significant differences between the lithium and placebo groups on
psychopathology and substance abuse measures using both a completer and intent-to-treat analysis. In
the completer analysis, 6/10 (60%) of patients on lithium responded compared to 1/11 (9.1%) of patients
on the placebo. Similarly, in the intent-to-treat analysis, 6/13 (46.2%) of patients on lithium responded
compared to 1/12 (8.3%) of patients on the placebo. While this study may not be applicable to all young
patients with BPD, given that all subjects in this study had comorbid substance abuse, the results
provided preliminary evidence that supports the use of lithium in young BPD patients with comorbid
substance abuse. In their review, Weller et al.[12**] concluded that lithium may be effective, especially in
adolescent-onset BPD, although 'the overall response may be less than that for adults, possibly because
youth with mania often have mixed manic-depressive syndromes or a predominance of psychotic
symptoms, both of which are generally more refractory to treatment' (pp. 598-599).

Valproate

Valproate is an effective mood stabilizer in adult BPD, especially in mixed mania. [12**, 16] Thus, it was hoped
that it may be more efficacious in treating childhood- and adolescent-onset BPD, which often presents as
a mixed manic state. To date, there are no randomized controlled trials that provide adequate evidence to
support this hypothesis. Preliminary evidence was presented in an open-label, multicenter trial of
valproate reported by Wagner et al..[16] The authors studied 40 BPD patients aged 7-19 years and found
that 61% had at least a 50% score improvement from baseline on the Mania Rating Scale. Significant
decreases from baseline were also found on the Brief Psychiatric Rating Scale, on the Clinical Global
Impressions Severity scale, and on the Hamilton Rating Scale for Depression. Although symptom
improvement was rapid (in some cases within the first week), the authors emphasized that the duration of
treatment necessary for a maximal response may be longer than that for adult patients. There is some
concern that valproate use may be involved in a metabolic syndrome that includes obesity,
hyperinsulinemia, lipid abnormalities, polycystic ovaries, and hyperandrogenism and thus should be used
with caution in peripubertal and pubertal female patients. [12**]

Carbamazepine

Carbamazepine is effective in adult BPD and, in combination with lithium, may be more effective than
lithium alone for mixed mania and rapid-cycling mania. However, its use in children and adolescents with
BPD is poorly studied. In their review, Weller et al.[12**] suggested that carbamazepine may be a well-
tolerated and effective alternative or adjunct in children who do not respond to lithium. Serious side-
effects including aplastic anemia and agranulocytosis (which can present with symptoms such as sore
throat and fever) have been reported. Thus, parents and patients must be alerted to these side-effects,
and patients should receive routine complete blood counts and close monitoring. [12**]

Other Medications

In their review, Weller et al.[12**] stated that although novel anticonvulsants such as lamotrigine and
gabapentin currently have exciting prospects in the treatment of adult BPD, there are no relevant safety
or efficacy studies in young patients. In addition, their side-effect profiles, particularly the 'black-box'
warning for lamotrigine in patients younger than 16 years because of its high incidence of severe skin
rashes and Stevens-Johnson syndrome, [12**] currently make these medications suboptimal choices for
treating BPD in children and adolescents.
The use of antipsychotics in young patients with BPD may be reasonable in certain situations, as there is
a high prevalence of psychotic symptoms in young patients. [12**] At times it may be redundant to use
antipsychotic medications to treat these symptoms in young patients with BPD, as they frequently
improve with mood-stabilizing medications. However, studies have shown clozapine, quetiapine,
risperidone and olanzapine to be effective, especially as an adjunct to mood stabilizers or in patients who
do not respond to any of the mood stabilizers. [12**]

Further Considerations

Beyond the controversies surrounding the diagnostic criteria for BPD in children and adolescents, some
have discussed the issue of what assessment tools and information sources are most useful. The
accuracy of the General Behavior Index, [17] the Child Behavior Check List, [18] and agreement between
adolescent, parent and teacher reports to determine the most reliable sources of information [19] have been
studied. Also, the use of magnetic resonance imaging [20] and electroencephalograms[21] as adjunctive tools
in diagnosis have been examined.

In addition to the issues raised in this review regarding the comorbidity of BPD and ADHD, the diagnostic
and treatment questions presented by young patients who have both BPD and ADHD must be addressed.
For example, how can both disorders be optimally managed simultaneously [22*]? Is it safe to combine
mood stabilizers and stimulants in these patients? [22*, 23] Can treatment with stimulants complicate the
diagnosis and treatment of BPD in young patients with ADHD [24]?

The prognosis for children and adolescents with BPD is another topic of interest. Recent studies have
examined factors that may improve or worsen the outcome for young patients with BPD. Carlson et al.[25*]
found that both childhood psychopathology and age at onset were independent risk factors for outcome.
Geller et al.[26*] found that a low level of maternal warmth predicted relapse, and living with an intact
biological family predicted recovery. Other studies have begun to investigate the outcomes for children
whose parents have been diagnosed with BPD. These children at high risk have often been ignored. [27*]

Conclusion

Despite the acceptance of a child and adolescent variant of BPD, the diagnosis continues to be
controversial. Experts in the field have not yet agreed on all diagnostic criteria and treatment methods. In
our clinical experience, while underdiagnosis may have been a problem in the past, overdiagnosis is now
more prevalent and is exacerbated by the lack of agreement on diagnostic criteria. In this review, we have
discussed the most recent literature which views childhood- and adolescent-onset BPD as an 'atypical'
variant in the sense that predominant symptoms do not always fulfill criteria for BPD Type I ('classic
mania'). Beyond this, some authors have made an effort to view child and adolescent BPD within the
larger spectrum of BPD, relating it to BPD Type II with some developmental variations. Researchers are
now emphasizing the difficulty in distinguishing child and adolescent BPD from other psychiatric disorders
that are prevalent in this age group.

Treatment issues are of extreme importance given the increased recognition of BPD in children and
adolescents and the significant morbidity associated with the diagnosis. Unfortunately, few studies have
investigated the safety and efficacy, in children and adolescents, of the most common medications used
to treat BPD. The limited research to date has provided preliminary support for the use of lithium,
valproate and carbamazapine. Future multicenter studies investigating large samples of young patients in
a randomized, controlled fashion will determine whether treatment for the 'atypical' child and adolescent
variant of BPD also needs to be 'atypical'. Until then, clinicians must use preliminary evidence and sound
clinical judgment in formulating treatment plans for their patients.

References

Papers of particular interest, published within the annual period of review, have been highlighted as:

*of special interest

**of outstanding interest

1. Glovinsky I. A brief history of childhood-onset bipolar disorder through 1980. Child Adolesc
Psychiatr Clin N Am 2002; 11:443-60, vii.
**This is a very detailed review of the historical debates and discussions that are relevant to the
current controversies in diagnosing bipolar disorder in young patients.
2. Carlson GA, Kashani JH. What is new in bipolar disorder and major depressive disorder in
children and adolescents. Child Adolesc Psychiatr Clin N Am 2002; 11:xv-xxii.
3. Weckerly J. Pediatric bipolar mood disorder [review]. J Dev Behav Pediatr 2002; 23:42-56.
**This provides a thorough review of current literature on diagnosis and treatment of pediatric
bipolar disorder, with a thought-provoking discussion on classifying bipolar disorder as part of a
spectrum of psychiatric disorders.
4. National Institute of Mental Health research roundtable on prepubertal bipolar disorder. J Am
Acad Child Adolesc Psychiatry 2001; 40:871-878.
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bipolar disorder: examples of elated mood, grandiose behaviors, decreased need for sleep,
racing thoughts and hypersexuality. J Child Adolesc Psychopharmacol 2002; 12:3-9.
*This gives a concise, yet descriptive, discussion of the different manifestations of bipolar
symptoms in children as opposed to adults.
6. Geller B, Zimerman B, Williams M, et al DSM-IV mania symptoms in a prepubertal and early
adolescent bipolar disorder phenotype compared to attention-deficit hyperactive and normal
controls. J Child Adolesc Psychopharmacol 2002; 12:11-25.
*This study outlines distinct symptomatology that may be useful in distinguishing between ADHD
and bipolar disorder, with a nice discussion of symptoms that may be common to both disorders.
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**This is an excellent review of both common and novel treatments for child and adolescent
bipolar disorder, and includes a thorough discussion about the deficiencies in research on this
topic and recommendations for future research.
13. Kowatch RA, Suppes T, Carmody TJ, et al Effect size of lithium, divalproex sodium, and
carbamazepine in children and adolescents with bipolar disorder. J Am Acad Child Adolesc
Psychiatry 2000; 39:713-720.
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Pharmacokinet 2002; 41:639-660.
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adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc
Psychiatry 1998; 37:171-178.
16. Wagner KD, Weller EB, Carlson GA, et al An open-label trial of divalproex in children and
adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2002; 41:1224-1230.
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Behavior Inventory in juvenile bipolarity. Bipolar Disord 2002; 4:34-42.
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report CBCL. J Psychiatr Res 2002; 36:337-345.
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parent report, and teacher report of manic symptoms. J Child Adolesc Psychopharmacol 2002;
12:27-35.
20. Pillai JJ, Friedman L, Stuve TA, et al Increased presence of white matter hyperintensities in
adolescent patients with bipolar disorder. Psychiatry Res 2002; 114:51-56.
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22. State RC, Altshuler LL, Frye MA. Mania and attention deficit hyperactivity disorder in a
prepubertal child: diagnostic and treatment challenges. Am J Psychiatry 2002; 159:918-925.
*This is an elegant use of a case study to highlight important topics in diagnosing and treating
patients with comorbid ADHD and bipolar disorder.
 23. Soutullo CA, DelBello MP, Ochsner JE, et al Severity of bipolarity in hospitalized manic
adolescents with history of stimulant or antidepressant treatment. J Affect Disord 2002; 70:323-
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24. Sarampote CS, Efron LA, Robb AS, et al Can stimulant rebound mimic pediatric bipolar disorder?
J Child Adolesc Psychopharmacol 2002; 12:63-67.
25. Carlson GA, Bromet EJ, Driessens C, et al Age at onset, childhood psychopathology, and 2-year
outcome in psychotic bipolar disorder. Am J Psychiatry 2002; 159:307-309.
*This is a concise, yet quite informative, study of factors that affect the long-term outcomes of
children and adolescents with bipolar disorder.
26. Geller B, Craney JL, Bolhofner K, et al Two-year prospective follow-up of children with a
prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 2002; 159:927-
933.
*This is a very thorough naturalistic study of the long-term outcome for young patients with
bipolar disorder; it specifically investigates the roles of pharmacotherapy, psychotherapy and
family factors.
27. Hodgins S, Faucher B, Zarac A, Ellenbogen M. Children of parents with bipolar disorder. A
population at high risk for major affective disorders [review]. Child Adolesc Psychiatr Clin N Am
2002; 11:533-553 ix.
*This is a concise review of past studies of bipolar offspring and their psychopathology, with a
nice review of the authors' current prospective longitudinal study of bipolar offspring, a thoughtful
discussion of proper recognition and treatment of bipolar offspring, and recommendations for
future research.

Reprint Address

Correspondence to Elizabeth B. Weller MD, Department of Child and Adolescent Psychiatry, Children's
Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA Tel: +1 215 590
7573; fax: +1 215 590 7549; e-mail: weller@email.chop.edu

Elizabeth B Wellera; Sara M Calvertb; Ronald A Wellerc

Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia, 34th and Civic
a

Center Boulevard, Philadelphia, Pennsylvania, USA, bUniversity of Pennsylvania School of Medicine,

Philadelphia, Pennsylvania, USA, and cDepartment of Psychiatry, University of Pennsylvania,
Philadelphia, Pennsylvania, USA

http://www.medscape.com/viewarticle/457723