Pediatric Bipolar Disorder or Disruptive Behavior Disorder?

Joseph Biederman, MD, Eric Mick, ScD, Stephen V. Faraone, PhD, and Janet Wozniak, MD

Dr. Biederman is professor of psychiatry at Harvard Medical School and chief of the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital in Boston.

Dr. Mick is assistant professor of psychiatry at Harvard Medical School and assistant director of research in the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital.

Dr. Faraone is professor in the Department of Epidemiology at Harvard School of Public Health, clinical professor of psychiatry at Harvard Medical School, and director of research in the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital.

Dr. Wozniak is assistant professor of psychiatry at Harvard Medical School and director of the bipolar program in the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital.

Disclosure: Dr. Biederman serves on the speaker’s bureaus for Cephalon, Eli Lilly, Novartis, Ortho-McNeil, Pfizer, Shire, and Wyeth; receives research support from Cephalon, Eli Lilly, Janssen, National Institute of Child Health and Human Development (NICHD), National Institute on Drug Abuse, National Institute of Mental Health (NIMH), Novartis, Pfizer, Shire, the Stanley Foundation, and Wyeth; and is on the advisory boards of CellTech, Cephalon, Eli Lilly, Janssen, Johnson & Johnson, Novartis, Noven, Ortho-McNeil, Pfizer, and Shire. Dr. Mick is a consultant for Janssen, receives grant and/or research support from NIMH, and receives honoraria and/or expenses from Ortho-McNeil. Dr. Faraone is a consultant for Eli Lilly, Noven, Ortho-McNeil, and Shire; serves on the speaker’s bureaus for Eli Lilly, Ortho-McNeil, and Shire; and receives research support from Eli Lilly, NICHD, NIMH, National Institute of Neurological Diseases and Stroke, Ortho-McNeil, and Shire. Dr. Wozniak is a consultant for Shire; serves on the speaker’s bureaus of Eli Lilly and Janssen; and receives grant and/or research support from Eli Lilly.

Funding/support: This work was supported in part by grant #98-325B from the Theodore and Vada Stanley Foundation awarded to Dr. Biederman.

Acknowledgment: Aspects of this work were presented at the conference, “Bipolar Disorder: From Preclinical to Clinical, Facing the New Millennium,” held January 19–21, 2000 in Scottsdale, Arizona. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted education grant provided by Eli Lilly.

Please direct all correspondence to: Joseph Biederman, MD, Pediatric Psychopharmacology Unit (ACC 725), Massachusetts General Hospital, 15 Parkman St, Boston, MA 02114-3139; Tel: 617-726-1731; Fax: 617-724-1540; E-mail: [email protected].

Abstract

Despite ongoing controversy, the view that pediatric mania is rare or nonexistent has been increasingly challenged by case reports and systematic research. This research suggests that pediatric mania is more common that previously assumed, although it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include a pattern of comorbidity that may be unique by adult standards, especially due to its overlap with attention-deficit/hyperactivity disorder and conduct disorder.

Introduction

The atypicality (by adult standards) of the clinical picture of childhood mania has long been recognized.^1,2 Notably, the literature consistently shows that mania in children is seldom characterized by euphoric mood.^3,4 Rather, the most common mood disturbance in manic children is severe irritability, with “affective storms,” or prolonged and aggressive temper outbursts.² This irritability observed in manic children is very severe, persistent, and often violent.⁵ The outbursts include threatening or attacking behavior toward family members, other children, adults, and teachers. In between outbursts, these children are described as constantly irritable or angry in mood.^3,4,6 Thus, it is not surprising that these children frequently receive the diagnosis of conduct disorder (CD). These aggressive symptoms may be the primary reason for the high rate of psychiatric hospitalization noted in manic children.⁵

In addition to the predominant abnormal mood in pediatric mania, its natural course is also atypical compared with the natural course of adult mania. The course of pediatric mania tends to be chronic and continuous rather than episodic and acute.^3,4,7,8 For example, in a recent review of the past 10 years of research on pediatric mania, Geller and Luby⁶ concluded that childhood-onset mania is a nonepisodic, chronic, rapid-cycling, mixed manic state. Such findings have also been reported by Wozniak and colleagues,⁵ who found that the overwhelming majority of 43 children from an outpatient psychopharmacology clinic who met diagnostic criteria for mania on a structured diagnostic interview presented with chronic and mixed presentation. Furthermore, Carlson and colleagues⁹ reported that early-onset manic subjects were more likely to have comorbid behavior disorders in childhood and to have fewer episodes of remission in a 2-year period than those with adult-onset cases of mania. Thus, pediatric mania appears to present with an atypical picture characterized by predominantly irritable mood, mania mixed with symptoms of major depression, and a chronic—as opposed to euphoric, biphasic, and episodic—course.

The chronicity of pediatric mania has been documented by an emerging, although limited, literature. Using data from a 2-year follow-up study, Geller and colleagues¹⁰ recently reported high levels of persistence and recurrence of manic symptomatology in children with bipolar disorder. Similar findings were reported by Biederman and colleagues¹¹ in a longitudinal sample of children with attention-deficit/hyperactivity disorder (ADHD) and comorbid bipolar disorder. These investigators documented that 90% of these children failed to attain euthymia over a 10-year course.¹¹ The findings suggest that pediatric cases with mania may develop into adults with mixed mania.

Bipolar Comorbidity with Attention-Deficit/Hyperactivity Disorder

A leading source of diagnostic confusion in childhood mania is its symptomatic overlap with ADHD. Systematic studies of children and adolescents show that rates of ADHD range from 60% to 90% in pediatric patients with mania.^5,12-14 Although the rates of ADHD in samples of youth with mania are universally high, the age of onset modifies the risk for comorbid ADHD. For example, while Wozniak and colleagues⁵ found that 90% of children with mania also had ADHD, West and colleagues¹⁴ reported that only 57% of adolescents with mania had comorbid ADHD. Examining further developmental aspects of pediatric mania, Faraone and colleagues¹⁵ found that adolescents with childhood-onset mania had the same rates of comorbid ADHD as manic children (90%) and that both of these groups had higher rates of ADHD than adolescents with adolescent-onset mania (60%). Most recently, Sachs and colleagues¹⁶ reported that, among adults with bipolar disorder, a history of comorbid ADHD was only evident in those subjects with onset of bipolar disorder before 19 years of age. The mean onset of bipolar disorder in those with a history of childhood ADHD was 12.1 years of age.¹⁶ Similarly, Chang and colleagues¹⁷ studied the offspring of patients with bipolar disorder and found that 80% of manic children had comorbid ADHD and that the onset of mania in adults with bipolar disorder and a history of ADHD was 11.3 years of age. These findings suggest that age of onset of mania, rather than chronological age at presentation, may be the critical developmental variable that identifies a highly virulent form of the disorder that is heavily comorbid with ADHD.

Although ADHD has a much earlier onset than pediatric mania, the symptomatic and syndromatic overlap between pediatric mania and ADHD raises a fundamental question: do children presenting symptoms that are suggestive of mania and ADHD have ADHD, mania, or both? One method to address these uncertainties has been to examine the transmission of comorbid disorders in families.^18,19 If ADHD and mania are associated due to shared familial etiologic factors, then family studies should find mania in families of ADHD patients and ADHD in families of manic patients.

Studies that have examined rates of ADHD (or attention-deficit disorder) among the offspring of adults with bipolar disorder all found higher rates of ADHD among these children compared with controls.²⁰ Although the difference in rates attained statistical significance in only one study, the meta-analysis of Faraone and colleagues²⁰ documented a statistical and bi-directional significant association between bipolar disorder in parents and ADHD in their offspring, as well as between ADHD in a child proband and mania in relatives.

Wozniak and colleagues²¹ used familial risk analysis to examine the association between ADHD and mania within families of manic children. They found that relatives of children with mania were at high risk for ADHD; this risk was indistinguishable from the risk in relatives of children with ADHD and no mania. However, rates of mania and comorbid ADHD selectively aggregated among relatives of manic youth were comparable to those of ADHD and comparison children.²¹ Almost identical findings were obtained in two independently defined family studies of ADHD probands with and without comorbid mania.^20,22 Taken together, this pattern of transmission in families suggests that mania in children might be a familially distinct subtype of either bipolar disorder or ADHD. The existence of a familial, developmental subtype is consistent with the work of Strober and colleagues,²³ Strober,²⁴ and Todd and colleagues,²⁵ who proposed that pediatric mania might be a distinct subtype of bipolar disorder with a high familial loading.

One problem facing studies of ADHD and mania is that these disorders share diagnostic criteria. Of seven Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R)²⁶ criteria for a manic episode, three are shared with DSM-III-R criteria for ADHD: distractibility, motoric hyperactivity, and talkativeness. To avoid counting symptoms twice toward the diagnosis of both ADHD and mania, two different techniques of correcting for overlapping diagnostic criteria have been used to evaluate the association between ADHD and pediatric mania.²⁷

In the first technique, the subtraction method, overlapping symptoms are simply not counted when making the diagnosis. In the proportion method, overlapping symptoms are not counted but the diagnostic threshold is lowered. However, the same proportion of symptoms is required in both the reduced set and the original diagnosis.²⁸ Using these methods, Biederman and colleagues²⁷ showed that 48% of children with mania continued to meet criteria by the subtraction method and 69% by the proportion method. Eighty-nine percent of children with mania maintained a full diagnosis of ADHD using the subtraction method and 93% maintained the ADHD diagnosis by the proportion method. These results suggest that the comorbidity between ADHD and pediatric mania is not a methodological artifact due to diagnostic criteria shared by the two disorders.

The potential for different rates of comorbidity with mania in the combined subtype, the inattentive subtype, and the hyperactive-impulsive subtype of ADHD is in need of further research. Faraone and colleagues²⁰ studied 301 ADHD children and adolescents consecutively referred to a pediatric psychopharmacology clinic. Among these, 185 (61%) had the combined type of ADHD, 89 (30%) had the inattentive type, and 27 (9%) had the hyperactive-impulsive type. Bipolar disorder was highest among combined-type youth (26.5%) but was also elevated among hyperactive-impulsive (14.3%) and inattentive (8.7%) youth.

Bipolar Comorbidity with Conduct Disorder

An emerging literature documents an elevated risk for CD among children with bipolar disorder. Kovacs and Pollock²⁹ reported a 69% rate of CD in a referred sample of bipolar youth. In that study, the presence of CD heralded a more complicated course of bipolar disorder. Similarly, Kutcher and colleagues³⁰ found that 42% of hospitalized youth with bipolar disorder had comorbid CD; Wozniak and colleagues⁵ showed that preadolescent children satisfying structured interview criteria for bipolar disorder very frequently had comorbid CD. Notably, an epidemiologic study of children and adolescents³¹ found high rates of comorbidity between bipolar and disruptive behavior disorders. These findings in children, which report a nearly 7-fold increase in the risk for bipolar disorder among individuals with antisocial personality disorder (ASPD), are consistent with those in adults.³²

While the reasons for these intriguing associations between CD and bipolar disorder remain unknown, a close inspection of the characteristics of juvenile bipolar disorder offers some clues. The literature indicates that juvenile bipolar disorder is frequently mixed, and that the most common mood disturbance in manic children is irritability, with “affective storms,” or prolonged, aggressive, and frequently violent temper outbursts.^2-4 The irritable outbursts include threatening or attacking behavior toward others, including family members, children, adults, and teachers.

In conceptualizing the overlap between bipolar disorder and CD, Kovacs and Pollock²⁹ suggested that the high prevalence of comorbid CD in bipolar youth might confuse the clinical presentation of childhood bipolar disorder and possibly account for some of the documented failure to detect bipolarity in children. Thus, the heterogeneity of bipolar disorder and that of CD may have important implications in helping to identify a subtype of bipolar disorder with early onset characterized by high levels of comorbid CD,²⁹ as well as a subtype of CD with high levels of dysphoria and explosiveness.

Although these aberrant behaviors are consistent with the diagnosis of CD, they may be due to the behavioral disinhibition of bipolar disorder, or the irritability and low frustration tolerance that frequently accompanies pediatric bipolar disorder. Considering the extreme severity of juvenile bipolar disorder, its emergence in CD children (and, conversely, the emergence of CD in bipolar children) seriously complicates their already compromised condition.

Biederman and colleagues³³ attempted to delineate this relationship between bipolar and CD in a series of studies. These studies relied on systematic evaluation of clinical correlates in affected youth and their relatives. Biederman and colleagues³³ first tested the hypothesis that subtypes of CD with and without bipolar disorder could be distinguished from one another in a family study of 140 ADHD probands and 120 controls without ADHD ascertained from psychiatric and pediatric clinics. All probands were Caucasian, non-Hispanic males who were 6–17 years of age. Of 140 ADHD probands, 38 (27%) also met diagnostic criteria for CD and 30 (23%) for bipolar disorder at either baseline or follow-up assessments; of those, 21 (55% of CD cases and 71% of bipolar disorder cases) had both CD and bipolar disorder. The researchers reexamined the degree of overlap in a larger sample of clinically referred children that were not selected to participate in a study of ADHD.³⁴ In this sample, the prevalence of bipolar disorder was 17% and the prevalence of CD was 18%. Of the pool of consecutively referred youth evaluated comprehensively with a structured diagnostic interview as described above, 186 subjects with mania and 192 subjects with CD were identified. Seventy-six patients satisfied criteria for both CD and bipolar disorder (ie, 40% of CD youth [76 of 192] and 41% of youth with bipolar disorder [76 of 186] also had the other disorder). This larger study of children with bipolar disorder and/or CD conducted outside the context of an ADHD sampling scheme³⁴ provided greater precision and more clearly demonstrates the bi-directional overlap of these two disorders in clinical samples.

Further examination of the symptoms of bipolar disorder and CD indicated that the presence of one disorder did not alter the presentation of the other.³⁴ The symptom profile of bipolar disorder was the same in bipolar disorder children and children with comorbid CD and bipolar disorder, just as the symptoms of CD were strikingly similar in children with bipolar disorder and CD irrespective of the comorbidity with the other disorder. Similarly, there were few differences in the frequency of CD symptoms between CD youth with and without comorbid bipolar disorder. These findings lend support to the notion that this may be true comorbidity and not simply the misdiagnosis of both conditions due to aggressive behavior endorsed in both modules of the interview. CD was also not found to modify the course of mania, with equal numbers of subjects reporting a chronic course (≥1 year duration) irrespective of the comorbidity with CD (65% versus 71% for bipolar disorder alone and comorbid bipolarity and CD, respectively).³⁴ This pattern of symptoms, onset, and course suggests that the disorders behave similarly whether they are comorbid or exist separately from each other, and do not necessarily overlap concurrently. Longitudinal studies that examine the course of the disorders repeatedly over brief intervals are needed to disentangle this difficult clinical diagnostic confusion.

Rates of psychiatric hospitalization also differed dramatically in CD youth with and without comorbid bipolar disorder, with children with both CD and bipolar disorder accounting for most of the psychiatric hospitalizations in youth with CD. Psychiatric hospitalization was very low outside the context of bipolar disorder. Since many children in psychiatric hospitals with the diagnosis of CD commonly have a profile of severe aggressiveness, it is likely that these children required psychiatric hospitalizations because of the manic picture and not necessarily due to the CD. More work is needed to better test this hypothesis and to determine other factors that lead to hospitalization in children with either CD or bipolar disorder.

Because both CD and bipolar disorder are known to be familial disorders, one useful approach to disentangling these diagnoses and answering questions regarding the nature of their association is the use of family aggregation data.^19,35-38 Such an approach can provide evidence external to the complicated diagnostic questions posed by the complex comorbid phenotype of individual patients. In other words, examining familial patterns of psychopathology can help answer whether children with a mix of mood and antisocial symptoms have bipolar disorder, CD, or both. Familial risk analysis showed that bipolar disorder probands had significantly higher rates of familial bipolar disorders and CD probands had higher rates of familial antisocial disorders compared with ADHD probands, irrespective of the presence of comorbidity with the other disorder.³³

Wozniak and colleagues³⁹ confirmed and expanded these findings in a second familial risk analysis that pooled resources from smaller studies in order to estimate the risk in relatives from a study with an increased sample size. This study pooled data from two samples of youth with DSM-III-R bipolar disorder (n=45) and their first-degree relatives (n=145), who were evaluated with identical methodologies. These were stratified into two proband groups defined by the presence or absence of CD and bipolar disorder. The first group contained 26 probands with both CD and bipolar disorder and 92 relatives, and the second group contained 19 probands with bipolar disorder without CD and 53 relatives. Compared with controls, the rate of bipolar disorder was significantly higher in relatives of both bipolar proband groups, irrespective of comorbidity with CD. The rate of CD/ASPD was significantly higher in relatives of both CD proband groups, irrespective of comorbidity with bipolar disorder. In addition, the rate of CD/ASPD in relatives of CD and bipolar disorder probands was nearly twice as large as the rate of CD/ASPD in relatives of CD probands (34% versus 19%, P<.05).^39,40

The researchers also found significant co-segregation between antisocial disorders and bipolar disorder among the relatives of CD and bipolar disorder probands. That is, nearly all the bipolar disorder among relatives of co-occurring CD and bipolar disorder probands occurred in those relatives who also had CD or ASPD (^c2=10.9, P=.001). Two types of CD/ASPD were identified in relatives of co-occurring CD and bipolar disorder probands: those with and those without comorbid bipolar disorder. While relatives of CD and bipolar disorder probands had almost exclusively the comorbid type of bipolar disorder, the overrepresentation of CD/ASPD in relatives of CD probands consisted exclusively of CD/ASPD individuals without comorbid bipolar disorder.³⁹ These findings were consistent with prior work suggesting a three-way familial association among bipolar disorder, CD/ASPD, and ADHD.²⁰ The results from these family studies support the concept of heterogeneity of bipolar disorder and CD and provide compelling evidence that subtypes of CD and of bipolar disorder can be identified based on patterns of comorbidity with the other disorder.

Treatment Implications

Biederman and colleagues⁴¹ systematically reviewed the clinical records of all pediatrically referred patients who, at initial intake, satisfied diagnostic criteria for mania based on a structured diagnostic interview with the mother. Mood stabilizers were frequently used in these children and their use was associated with significant improvement of manic-like symptoms (as recorded by their psychiatrists in the medical record). However, although treatment with mood stabilizers was associated with a statistically significant decrease in manic-like symptoms, this improvement was slow to develop and was associated with frequent relapses. Antidepressants, typical antipsychotics, and stimulants were not associated with improvement of manic-like symptoms.

Kowatch and colleagues,⁴² using an 8-week open study design, compared the effectiveness and tolerability of lithium carbonate, divalproex sodium, and carbamazepine in children with bipolar disorder. They found a 53% rate of improvement for divalproex sodium and much lower rates for lithium carbonate and carbamazepine. Likewise, Wagner and colleagues⁴³ reported similarly modest effects in another trial of divalproex sodium in pediatric bipolar disorder.

Recently, somewhat more optimistic findings have resulted from investigations of atypical neuroleptics in the treatment of juveniles with bipolar disorder. In a retrospective chart review study of 28 youths with bipolar disorder, 82% of subjects showed improvement in both manic and aggressive symptoms with risperidone treatment.⁴⁴ In contrast to the duration of treatment required for improvement with mood stabilizers, the average time to optimal response was 1.9±1.0 months of therapy. Moreover, no serious adverse effects were observed.

Similarly encouraging results were reported by Frazier and colleagues⁴⁵ in an open trial of olanzapine monotherapy. They found that treatment with olanzapine was associated with significant improvements in 23 manic children after 8 weeks of monotherapy on doses ranging from 2.5–20 mg/day, according to both the Children’s Depression Inventory and the Young Mania Rating scale. Using the same prospective 8-week open study design, Biederman and colleagues⁴⁶ reported that treatment with risperidone monotherapy improved both manic and depressive symptoms in youth with bipolar I, bipolar II, or bipolar spectrum disorder in youth. Also, DelBello and colleagues⁴⁷ recently reported results from a randomized clinical trial that documented that the combination of divalproex sodium plus quetiapine was superior to divalproex sodium alone in the treatment of an inpatient sample of adolescents with bipolar disorder.^47,48

Because pediatric bipolar disorder is frequently mixed and comorbid with ADHD, its pharmacologic management can be complicated, as treatments for bipolar disorder do not treat ADHD, treatments for ADHD do not treat bipolar disorder, and antidepressants can precipitate mania. Biederman and colleagues^41,49 used a novel chart review methodology to systematically evaluate the clinical records of psychiatrically referred youth with a diagnosis of bipolar disorder and comorbid ADHD. The results showed that the presence of mania interfered with the improvement of ADHD symptomatology during anti-ADHD pharmacotherapy and that ADHD symptoms were much more likely to improve after mood stabilization. These results suggest that the successful management of children with both mania and ADHD requires the deployment of disorder-specific treatments and that treatment of ADHD symptomatology is only possible after mood stabilization.⁴⁸ However, because of the severe disruption in functioning associated with exacerbation of manic symptoms, caution is needed in prescribing anti-ADHD treatments to ADHD children with mania.

The diagnosis of bipolar disorder in some CD children offers important therapeutic possibilities, since sociopathy and bipolar disorder may require very different treatment strategies. A series of controlled clinical trials^50-54 documented the efficacy of mood stabilizers (lithium carbonate and carbamazepine) in the treatment of aggressive CD children. However, these psychiatrically hospitalized CD youth were treated for severe, uncontrollable, and disorganized aggression and not necessarily for delinquency. Thus, it is possible that the therapeutic benefits observed in these children could have been due to the effects of these well known antimanic medications in treating aggressive manic children satisfying criteria for CD.^51,55

Findling and colleagues⁵⁶ recently reported that risperidone was effective in treating aggression in children with conduct disorder and Aman and colleagues⁵⁷ reported results from a double-blind study that documented that risperidone was superior to placebo in the treatment of youth with CD and subaverage intelligence. A recent secondary analysis of the study results of Aman and colleagues⁵⁷ documented the efficacy of risperidone in improving both manic and depressive symptoms in this population (Biederman and colleagues, unpublished data, 2004). Taken together, these initial results support the need for additional short- and long-term controlled trials of atypical neuroleptics in the treatment of juvenile bipolar disorder, either as monotherapy or in combination with mood stabilizers.

Conclusion

The emerging literature indicates that mania can be identified in a substantial number of referred children using systematic assessment methodology. Thus, this disorder may not be as rare as previously considered. Children with mania tend to show an atypical picture by adult standards, with a chronic course, severely irritable mood, and a mixed picture with depressive and manic symptoms co-occurring. Most children with childhood-onset mania may also have ADHD and CD, which requires additional treatment. Initial clinical evidence suggests that atypical neuroleptics may play a therapeutic role in the management of such youth. The high levels of comorbidity with other disorders is common, further requiring the cautious use of a combined pharmacotherapy approach. PP

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