Janet Wozniak, MD

CME credit for this article is now expired. It appears here for informational purposes only.

of the article and the author's financial disclosure at the time of publication (December 2011). Some of the material may have changed.

After reading this article, readers should be able to:

• Better appreciate the familial role in ADHD
• Recognize the implications of ADHD and bipolar comorbidity
• Understand the overlapping psychopathology and diagnostic issues associated with ADHD and bipolar comorbidity
• Comprehend the psychopharmacological response in comorbid ADHD and bipolar disorder
• Initiate a treatment strategy that may include mood stabilizers and stimulant medications



Who will benefit from reading this article?


Psychiatrists, child and adolescent psychiatrists, psychologists, primary care physicians, nurse practitioners, and other health care professionals.

Is bipolar disorder overdiagnosed in youths? Public and scientific debates have focused on the controversial topic of whether some children with emotional and behavioral problems are receiving an incorrect diagnosis of bipolar disorder and are being exposed unnecessarily to the adverse effects of mood stabilizing medications.On the other hand, it may be that because of skepticism and diagnostic confusion, bipolar disorder has been, and continues to be, underdiagnosed in youths, with many children left untreated despite FDA approval of potentially useful medications for children as young as 10 years.Thus, efforts to better understand the issues of diagnostic confusion are of extremely high clinical, scientific, and public health importance.

A major component of the debate regarding the validity of the diagnosis of bipolar disorder in youths rests with its high overlap with ADHD.

 Distractibility, physical hyperactivity, and talkativeness are symptoms of both ADHD and mania. Arguably, all the symptoms of ADHD, including inattention, impatience, disorganization, and restlessness, could be part of the mania component of bipolar disorder.

By the same token, many of the symptoms of mania, such as euphoria (giddy, silly) or irritability (low frustration tolerance), reckless impulsivity, and racing thoughts, could be construed to occur at least some of the time as part of ADHD.

 ADHD also can include a component of emotional dysregulation, which further complicates the diagnosis.

Epidemiology of ADHD and bipolar disorder

While not all training programs include education in pediatric bipolar disorder, all child and adolescent psychiatry residents and most pediatricians are well acquainted with the diagnosis of ADHD, which is one of the most common reasons for psychiatric treatment in pediatric patients. ADHD is a highly morbid, well-characterized, and valid disorder with onset in childhood; it affects more than 5% of youths.

While bipolar disorder in adults has long been considered to be one of the most disabling conditions seen in psychiatric practice, the condition in children has only recently been the focus of research to establish its validity. Because of a lack of accurate epidemiological reports, researchers had estimated, based on indirect evidence, that bipolar disorder affects approximately 1% of children and adolescents. However, a recent epidemiological study of more than 10,000 US adolescents reports a rate of 2.9% (2.6% are severely impaired).

A recent meta-analysis performed by Van Meter and colleagues

 of international epidemiological studies of pediatric bipolar disorder from 1985 through 2007 showed an overall prevalence of 1.8%. The researchers noted that there was no significant difference in the rates between US and non-US studies, and there was no evidence of an increase in the community over time.

While mania can present as either euphoria or extreme irritability, findings suggest that irritability may be the more common manic mood symptom in youths.

 While a case can be made that the irritability of mania is distinctly and qualitatively different from other forms of irritability, when present in a child with ADHD, irritability or angry outbursts may be misattributed to the frustration of living with ADHD and attendant impulsivity rather than to co-occurring mania.

 Conversely, inattention, distractibility, and talkative-ness in a child or adolescent with bipolar disorder may erroneously be attributed to residual mania rather than ADHD.

According to diagnostic criteria, episodicity is a definitional feature of bipolar disorder and can be a useful marker of mania, just as chronicity or cross-situationality is a diagnostic feature of ADHD. However, the documented chronicity and complex/rapid cycling of bipolar disorder in youths often renders the notion of classic episodicity as a distinguishing feature of mania functionally impracticable.

 While many adults with bipolar disorder present with chronicity, mixed states, and irritability as the clinical picture, this presentation has been the subject of debate when it occurs in children.

 Whether this presentation is valid for bipolar disorder for some patients remains a scientific and clinical question.

In clinical practice, the question of whether mood-dysregulated, hyperactive, and inattentive youths have bipolar disorder, ADHD, or both has critical clinical and therapeutic implications. Medications for ADHD may worsen mania, and medications for mania are fraught with adverse effects and may not be effective for the treatment of ADHD. Because ADHD and mania exhibit similar symptoms, there is a risk of unintentional overdiagnosis or underdiagnosis of one or the other. Milberger and colleagues

 demonstrated that most of the children in their study with the combined disorders continued to meet criteria for both mania and ADHD after overlapping symptoms were discounted. This suggests that bipolar disorder and ADHD comorbidity is not a methodological artifact that results from shared diagnostic criteria.

The co-occurrence of bipolar disorder and ADHD has long been an “orphan” condition, neglected in adults because of past skepticism regarding the continuity of ADHD into adulthood and neglected in children because of the now debunked concept that bipolar disorder does not occur in the young.

A bidirectional overlap is well documented between ADHD and bipolar disorder. Among children with bipolar disorder, rates of co-occurring ADHD range from 57% to 98%, with higher, almost universal rates among prepubertal children.10 ADHD has also been reported in samples of adults with bipolar disorder.

 In a longitudinal study of boys with ADHD, 17% were found to have co-occurring bipolar disorder at baseline.

 Other studies of ADHD, such as the Multimodal Treatment of ADHD (MTA) study, found rates of any mood disorder, depression or bipolar, to be too low for hypothesis testing, possibly an outcome related to exclusionary criteria for bipolar disorder (as well as psychosis, suicidality, and homocidality).

 found higher rates of ADHD in persons with childhood-onset bipolar disorder than in persons with adolescent-onset bipolar disorder. Those findings were consistent with a report from West and colleagues

 that 57% of adolescents with bipolar disorder also had ADHD. The prevalence reported in preadolescent samples is much higher and ranges from 70% to 98%.

 These results suggest that co-occurrence with ADHD is a marker of preadolescent-onset mania. This form of very early–onset mania may represent a developmental subtype of the disorder.

The clinical features of mania in children with comorbid ADHD and bipolar disorder provide further evidence that this subtype represents a developmentally distinct variant. Mania in these children is more often characterized by violent irritability and prolonged and aggressive temper outbursts, rather than euphoric mood.

 The type of irritability observed in manic children is very severe, persistent, and often violent.

 It is distinctly different in quality and severity from other forms of irritability, such as the low frustration tolerance of ADHD or the “mad, cranky” irritability of childhood depression.

The natural course of bipolar disorder in pediatric cases tends to be chronic, complex/rapid cycling, and continuous (and mixed with depression) rather than episodic and acute.

 This is due in part to the complex and continous cycling of mania and depression (with switches in polarity and the melancholy and lower level irritability of depression and the euphoria and extreme irritability of mania) as well as the interplay of bipolar disorder with its comorbid conditions, notably ADHD. Thus, children with comorbid bipolar disorder and ADHD are rarely “well.”

In a review of 10 years of research on pediatric mania, Geller and Luby

 concluded that childhood-onset mania is a nonepisodic, chronic, rapid cycling, mixed manic state. Similar findings also suggest that in the overwhelming majority of bipolar children, the disorder is chronic (they are seldom well) and the presentation is mixed.

 A follow-up study showed that the youths (N = 78) continued to experience persistent disorder, including depression and subthreshold states of mania. Only 6.4% were euthymic without treatment at 4 years.

The Course and Outcome of Bipolar Illness in Youth (COBY) study demonstrated an episodic course with spontaneous improvements and deteriorations in mood and energy. On average, patients were ill for 60% of the follow-up time. Most patients (81.4%) recovered from their index episode, but time to recovery was a median of nearly 2.5 years. Of those who recovered, 62.5% had a full syndromal recurrence a median of 1.4 years following symptom remission.

Because of overlapping features, comorbid bipolar disorder and ADHD is difficult to diagnose. In addition to the full symptom profiles of both mania and ADHD, the comorbid condition has correlates of both disorders.

 Children who meet the criteria for ADHD show high rates of conduct and oppositional defiant disorders and of learning disorders and need for academic support. Depression and psychosis as well as poor functioning-all common correlates of bipolar disorder-are also usually present.

While ADHD and mania have been found to co-occur in pediatric populations, the National Comorbidity Survey Replication epidemiological study also has documented high bidirectional comorbidity between bipolar disorder and ADHD in adults. Study results showed significantly higher rates of bipolar disorder in adults with ADHD than in those without ADHD (19.4% vs 3.1%). Equally high rates of ADHD were seen in adults with bipolar disorder compared with those without bipolar disorder (21.2% vs 3.5%).

Although the mechanisms that mediate the association between bipolar disorder and ADHD are not entirely clear, ADHD and bipolar disorder individually and together are known to have strong familial links. Children of bipolar parents have an elevated risk of ADHD, and relatives of children with ADHD are at increased risk for bipolar disorder.

 However, the combined condition appears to be common in these families. In children of bipolar parents, the risk of ADHD is higher in children with bipolar disorder.

Consistent with the notion of a subtype, relatives of patients who have comorbid bipolar disorder and ADHD are at increased risk for the combined condition.

 This suggests that the disorders are transmitted together and not independently. Faraone and colleagues

 studied the familial transmission of these disorders in children with ADHD. The pattern of transmission seen in the studies supported the hypothesis that the comorbid condition could represent a distinct condition.

Studies of adults with bipolar disorder suggest that comorbid ADHD may be a marker for an early-onset subtype. Winokur and colleagues

 found that bipolar adults were more likely to have shown traits of hyperactivity in childhood. Sachs and colleagues

 reported that among adults with bipolar disorder, a history of comorbid ADHD was only evident in those 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.

Nierenberg and colleagues11 reported that adults with comorbid bipolar disorder and ADHD had distinct features of bipolar disorder, including early onset, shorter periods of wellness (chronicity), greater comorbidity, and a worse course overall. These features are frequently characteristic of the bipolar disorder seen in children.

Consistent with the documented association of comorbid ADHD almost exclusively with early-onset bipolar disorder, a relatively low lifetime prevalence (9.5%) of comorbid ADHD has been reported in adults with bipolar disorder with heterogeneous age at onset.

 found that 65% of adults with bipolar disorder in a large sample (N = 1000) had early onset of the disorder (younger than 18 years). In the adults who had early onset, there were greater rates of comorbid anxiety disorders and substance abuse, more recurrences, shorter periods of euthymia, and a greater likelihood of suicide attempts and violence. The rate of ADHD was 20.7% among the earliest-onset group (younger than 13 years), 7.6% in the intermediate-onset group (13 to 18 years), and 5.7% in those with onset after 18 years. The age at bipolar onset appears to modify the risk of comorbid ADHD. The researchers concluded that age of onset may cleave a distinct form of bipolar disorder, which is more likely to be comorbid with ADHD.

 of children of parents with bipolar disorder supports this notion. The findings suggest that bipolar disorder in high-risk children is associated with early-onset bipolar disorder in the parent and a parental history of ADHD. The age at onset of mania in adults with bipolar disorder and a history of ADHD was 11.3 years. The study by Geller and coworkers

 showed similar results-bipolar disorder comorbid with ADHD was a proxy for early onset.

Further highlighting the importance of age at onset are the findings of Lin and colleagues.

 The results of their study showed that relatives of patients with early-onset bipolar disorder were more likely to also have early-onset bipolar disorder. The pattern of transmission seen in families suggests that early-onset mania, which is largely associated with ADHD, might be a familially distinct subtype of bipolar disorder.

 used familial risk analysis to examine the association between ADHD and mania. They found that relatives of children with comorbid ADHD and bipolar disorder were at high risk for ADHD that was indistinguishable from the risk in relatives of children with ADHD and no bipolar disorder. However, comorbid bipolar disorder and ADHD and bi-polar disorder alone selectively aggregated among relatives of youths with bipolar disorder compared with those with ADHD but without bipolar disorder.

Almost identical findings were obtained in the family study by Wozniak and colleagues.

 Bipolar parents of children with comorbid ADHD and bipolar disorder had a childhood history of ADHD, a mixed manic presentation, and juvenile-onset bipolar disorder.

Emerging neurobiological correlates are the focus of recent research, and a wide array of FDA-approved treatments is available for ADHD. While the recognition and treatment of ADHD in adults has lagged, research documenting the continuity of ADHD into adulthood has established ADHD as a disorder with lifelong implications.

Pediatric bipolar disorder, a long-neglected diagnosis, is gaining acceptance in the clinical and research community as a valid clinical entity. The FDA has approved 5 medications (risperidone, aripiprazole, quetiapine, olanzapine, and lithium) for treatment of bipolar disorder in youths-with some medications approved for children as young as 10 years. Findings from clinical practice indicate that the use of atypical antipsychotics for the treatment of mania and mixed states is common in pediatric patients.

Although empirical evidence for the psychopharmacological response in comorbid bipolar disorder and ADHD is limited, many youths with bipolar disorder also receive treatment for comorbid ADHD. In a recent chart review of psychopharmacological interventions in clinically referred youths with bipolar disorder, 60% were treated for ADHD with stimulants and atomoxetine. ADHD symptom improvement was seen in 56% of the patients.

Stimulant medications may increase the risk of exacerbating mania; thus, clinical good sense dictates that the treatment of ADHD be addressed only after the symptoms of bipolar disorder are stabilized. In mood-stabilized youths who have bipolar disorder, ADHD symptoms often become the second most severe presenting complaint. The decision to treat comorbid ADHD following stabilization of mania should be guided by clinically determining the level of impairment associated with ADHD.

Lamotrigine and divalproex are FDA-approved for use in bipolar adults, but they do not have a psychiatric indication for youths. However, emerging research suggests that lamotrigine may be useful in youths with bipolar disorder.

 Carbamazepine (used off-label) has been evaluated, with positive results.

 Divalproex, on the other hand, has not shown therapeutic efficacy in youths with bipolar disorder.

 The efficacy of antimanic medication for bipolar disorder has been confirmed in more than 2500 pediatric patients.

Antimanic and mood stabilizing agents on their own may have anti-ADHD effects. Carbamazepine and risperidone improve ADHD symptoms in youths with bipolar disorder, although this improvement may be attributable to the overlapping symptoms of ADHD and mania.

 In a recent controlled trial of youths with bipolar disorder, aripiprazole was not found to be superior to placebo in improving ADHD symptoms.

 The response to lithium and divalproex is greater in youths with comorbid bipolar disorder and ADHD than in those without comorbid ADHD.

 The subtype of comorbid bipolar disorder and ADHD may have unique treatment requirements.

While concern exists regarding the mood destabilizing effects of stimulant medication in bipolar disorder, a controlled trial found adjunctive mixed amphetamine salts to be safe and efficacious for the treatment of ADHD in patients with bipolar disorder whose symptoms have been stabilized with divalproex.

 reported that concomitant treatment with methylphenidate (MPH) improved symptoms of ADHD without destabilization of mood in youths with bipolar disorder.

MPH adjunctive therapy for ADHD in bipolar youths who have been stabilized with aripiprazole was not superior to placebo, and in 1 patient who received MPH and aripiprazole, severe mood destabilization developed.

 reported that atomoxetine added to antimanic agents was well tolerated and efficacious in the treatment of ADHD in a small sample (N = 12) of youths with comorbid bipolar disorder. ADHD symptoms in adults with comorbid bipolar disorder and ADHD improved with bupropion treatment, without activation of mania.

 These aggregate data suggest that ADHD can be safely and effectively treated in patients with stabilized bipolar disorder, although caution is always indicated.

The relationship between bipolar disorder and ADHD remains unclear; however, this combined condition may represent an important genetic and clinical subtype with distinct psychopathology, familiality, and treatment response. Further research to examine the distinct nature of comorbid bipolar disorder and ADHD is needed.

Using DSM-IV criteria, comorbid bipolar disorder and ADHD has been identified in pediatric and adult samples, despite overlapping symptoms. Clinical trials point to the safety and efficacy of using combined pharmacotherapy to address both disorders. Heterogeneity in bipolar disorder is well accepted; stratifying by comorbidity with ADHD may mark an early-onset subtype of bipolar disorder worthy of independent study.

Milberger S, Biederman J, Faraone SV, et al. Attention deficit hyperactivity disorder and comorbid disorders: issues of overlapping symptoms. 

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. 

 Anastopoulos AD, Smith TF, Garrett ME, et al. Self-regulation of emotion, functional impairment, and comorbidity among children with AD/HD. 

 Merikangas KR, He JP, Burstein M, et al. Lifetime prevalence of mental disorders in US adolescents: results from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A). 

 Van Meter AR, Moreira AL, Youngstrom EA. Meta-analysis of epidemiologic studies of pediatric bipolar disorder. 

 Wozniak J. Pediatric bipolar disorder: the new perspective on severe mood dysfunction in children

 Leibenluft E, Charney DS, Towbin KE, et al. Defining clinical phenotypes of juvenile mania

 Geller B, Sun K, Zimerman B, et al. Complex and rapid-cycling in bipolar children and adolescents: a preliminary study. 

Faraone SV, Biederman J, Wozniak J, et al. Is comorbidity with ADHD a marker for juvenile-onset mania? 

 Nierenberg AA, Miyahara S, Spencer T, et al; STEP-BD Investiga-tors. Clinical and diagnostic implications of lifetime attention-deficit/hyperactivity disorder comorbidity in adults with bipolar disorder: data from the first 1000 STEP-BD participants. 

 Biederman J, Mick E, Faraone SV, et al. A prospective follow-up study of pediatric bipolar disorder in boys with attention-deficit/hyperactivity disorder. 

 A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. 

 West SA, McElroy SL, Strakowski SM, et al. Attention deficit hyperactivity disorder in adolescent mania. 

Wozniak J, Biederman J, Kiely K, et al. Mania-like symptoms suggestive of childhood onset bipolar disorder in clinically referred children. 

 Biederman J, Mick E, Faraone SV, et al. Pediatric mania: a developmental subtype of bipolar disorder? 

 Mick E, Spencer T, Wozniak J, Biederman J. Heterogeneity of irritability in attention-deficit/hyperactivity disorder subjects with and without mood disorders. 

 Geller B, Luby J. Child and adolescent bipolar disorder: a review of the past 10 years [published correction appears in 

 Wozniak J, Biederman J, Kwon A, et al. How cardinal are cardinal symptoms in pediatric bipolar disorder? An examination of clinical correlates. 

 Findling RL, Gracious BL, McNamara NK, et al. Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. 

 Wozniak J, Petty CR, Schreck M, et al. High level of persistence of pediatric bipolar-I disorder from childhood onto adolescent years: a four year prospective longitudinal follow-up study. 

 Birmaher B, Axelson D, Goldstein B, et al. Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. 

 Wozniak J, Biederman J, Faraone SV, et al. Heterogeneity of childhood conduct disorder: further evidence of a subtype of conduct disorder linked to bipolar disorder. 

 Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. 

Articles

The relationship between bipolar disorder and ADHD remains unclear; however, this combined condition may represent an important genetic and clinical subtype with distinct psychopathology, familiality, and treatment response. 

The Clinical and Treatment Implications of Co-Occurring Mania and ADHD in Youths

Recent work has established that, contrary to being uncommon, childhood-onset bipolar disorder (BD) may account for a significant number of child psychiatry referrals (Faedda et al., 1995; Geller and Luby, 1997; Weller et al., 1995; Weller et al., 1986). Studies indicate that up to 16% of youth in child psychiatry clinics may have BD (Wozniak et al., 1995). Moreover, children with major depression are at high risk to develop BD (Geller et al., 1994; Strober and Carlson, 1982). Bipolar disorder in children and adolescents is often familial (Chang et al., 2000; Strober, 1992; Strober et al., 1988). Current limited data suggest children with BD have a chronic course of the illness, characterized by continued morbidity, comorbidity and mood cyclicity (Geller et al., 2001; Geller et al., 2002). 

By adult standards, children with BD present with an atypical clinical picture, with irritability, mixed presentation and chronicity (Ballenger et al., 1982; Weller et al., 1995; Wozniak et al., 2001). While severe irritability can be a common characteristic in children with or without a psychiatric diagnosis, the irritability associated with mania has a much more hostile, vicious and attacking quality (Davis, 1979). In addition to a general level of irritability, children with mania also present with extremely impairing dysphoric, explosive episodes that generally occur daily with little or no precipitant. These explosions can last up to an hour or longer and may involve destruction of property such as kicking holes in walls and throwing and breaking household items. During these rages, children are hard to calm and often lash out physically at those around them. Swearing and hostile comments are also common. Parents almost universally say they "walk on eggshells" out of fear of these unpredictable outbursts (Wozniak et al., 2001).

Descriptions of euphoric moods are generally elicited by inquiring for giddy, goofy, hyperexcited, silly states with laughing fits. Parents often describe the child acting in an immature, clownish manner to the extent of alienating others. Grandiosity or flight of ideas can occur in the euphoric or irritable states. Parents also describe their children as having an extreme degree of grandiose defiance, refusing to comply with authority at home or at school. Children with BD often have comorbid oppositional defiant disorder (Wozniak et al., 2001). The defiant state has a grandiose quality that generates problems at home, in school, and in sports or other activities. Children will believe themselves to "know better" than adults around them and on this basis refuse to comply with what they see as petty or "stupid" demands put on them. These children are often labeled as having "an attitude problem" and inspire the anger of adults. 

Little is known about the variations between mania and depression in children and adolescents with BD. In our sample of children meeting criteria for mania, 86% have also had a depressive episode, and 90% have had the depressive episode overlap in time with the manic episode, representing a mixed state (Wozniak et al., 1995; Wozniak et al., 1993). This is usually described as children unpredictably switching in and out of depression, irritable mania with explosions and euphoric mania throughout the day, almost every day, with very little time spent in a regular age-appropriate mood state. Such a state has been referred to as 

 (Geller et al., 1995) and has been noted by a number of investigators (Findling and Calabrese, 2000; Wozniak et al., 1995). Because of the switching among these mood states, it is very difficult for some parents to agree that the child has had a full week of irritability or a full week of euphoria as required by some clinicians. On the other hand, parents describe periods of a mix of abnormal mood states spanning years with little normalcy. A better characterization, then, would be abnormal moods present almost every day, most of the days, for a majority of the time. 

Bipolar disorder generally has an insidious onset in children. In our sample, nearly one-quarter of parents could not identify an age of onset, but felt that the child had "always" had an abnormal mood, even by infant standards (Wozniak et al., 1995). Of the children with the abnormal mood states noted above, the average age of onset of the manic syndrome was 4.4 years with 70% described as beginning under age 5. 

Preschoolers with BD share many clinical characteristics of BD with their older counterparts. We recently described the clinical characteristics and functioning of 44 preschoolers (4 to 6 years of age) with BD and compared them to 29 school-aged children (7 to 9 years) with BD (Wilens et al., 2002). We found that preschoolers had similar rates of comorbid psychopathology of attention-deficit/hyperactivity disorder, disruptive disorders and anxiety disorders compared to school-aged youth. Preschoolers and school-aged children with BD typically manifest symptoms of mania and depression simultaneously (mixed states). Both preschoolers and school-aged children had substantial impairment in (pre)school, social and overall functioning. 

Whereas children under age 12 with BD have almost universal comorbidity with ADHD, there is a 57% rate of ADHD in adolescent-onset BD and a 13% rate of ADHD in adult-onset BD (Sachs et al., 2000; West et al., 1995; Wozniak et al., 1995). These aggregate findings have led to the conclusion that comorbidity with ADHD might be a marker for very-early-onset BD (Faraone et al., 1997). Bipolar disorder may also develop in youth with ADHD. In a well-characterized sample of boys with ADHD followed longitudinally, analysis of structured interview data revealed that at ascertainment, 11% of the sample met criteria for mania. Four years later at follow-up,  an additional 12% of the subjects had developed mania (Biederman et al., 1996a, 1996b).

Diagnostically, BD and ADHD share many symptoms. In one sample, however, 76% of children with mania still retained full or subthreshold diagnostic status even when subtracting the overlapping symptoms from the algorithm (Milberger et al., 1995). Studies that attempt to distinguish children with mania from children with ADHD note that children with mania generally have greater psychopathology and poorer functioning (Nieman and DeLong, 1987). Children with mania versus children with ADHD also have statistically significantly lower functioning, as well as statistically significantly higher scores on the Child Behavior Checklist (CBCL) subscales of aggression, psychosis and anxiety/depression (Biederman et al., 1995). The ADHD rating scales typically cannot distinguish children with mania and children with ADHD from each other. However, if an instrument such as the Mania Rating Scale (which asks questions specific to symptoms of mania) is used, children with mania can be identified (Fristad et al., 1992). In general, it is important to note that the ADHD criteria do not include a mood component. Thus, if the chief complaint or presenting symptom on examination is "severe moodiness," a mood disorder diagnosis should be considered (Wilens et al., in press).

In addition to ADHD, children with BD have high levels of comorbidity with conduct, anxiety and substance use disorders. Conduct disorder (CD) is a severe condition both from an individual as well as public health perspective, as it represents early antisocial behavior and many of these youngsters come to the attention of the criminal justice system. Various reports have documented an overlap between BD and CD, noting that the comorbid condition heralds a more complicated course. Family genetic work comparing rates of mania and antisocial disorders, as well as the combined condition in relatives of probands stratified by the presence or absence of these disorders, revealed high rates of conduct disorder or antisocial personality disorder (ASPD) in the relatives (Biederman et al., 1997). Further analysis demonstrated the presence of two types of CD/ASPD in the relatives of children with both CD and BD: CD/ASPD with mania ("dysphoric conduct disorder") and CD/ASPD without mania. The issue is clinically an important one: When an irritable and grandiose youngster with mania lies, steals or vandalizes, is it due to the disinhibition of the manic state or is it due to a coexisting antisocial personality? In such cases, if the mania is well-treated, would the conduct problems improve? The answers to these questions, not fully answered, could determine whether such a child should be treated in the mental health care system or enter the criminal justice system.

Juvenile-onset BD may be an important risk factor for substance use disorders (SUD) as well (West et al., 1996; Wilens et al., 2000; Wilens et al., 1999). We have shown that juvenile BD is a risk factor for early cigarette smoking (Wilens et al., 2000) and substance use (Wilens et al., 1999). Of interest, the highest risk for SUD is in individuals with adolescent-onset BD--who have as marked a risk for developing SUD as adolescents with CD (Wilens et al., 1999). It appears that the bulk of SUD in relationship to BD occurs secondary to mania--probably representing some form of self-medication phenomena; however, important family genetic contributions to SUD in this group cannot be ruled out. Of interest, in one controlled study by Geller and associates (1998), lithium (Eskalith, Lithobid) treatment decreased symptoms of both SUD and BD in adolescents, highlighting the importance of a careful clinical history for SUD in BD as well as BD in SUD adolescents--especially those with binge or remarkably excessive patterns of SUD. 

Few studies are available to guide empirically the treatment of BD in children and adolescents. A small literature has addressed the use of mood-stabilizing medications (valproic acid [Depakote], carbamazepine [Tegretol], lithium carbonate) in this patient population, however, much of this literature is limited by the lack of controlled clinical trials. Lithium, alone and in combination with other medications, is one of the original treatments for bipolar states in youth and continues to be an effective agent, albeit with a number of adverse effects and the need for aggressive monitoring (DeLong, 1978; DeLong and Aldershof, 1987; Kafantaris, 1995).

As part of a multisite study of divalproex sodium, Wagner and colleagues (2002) recently reported improvement in children with BD, replicating work by others (West et al., 1994). Biederman et al. (1998) systemically reviewed the clinical records of all pediatric referral patients with BD and showed that mood stabilizers were associated with significant improvement, albeit relatively slow, of the symptoms of BD. For both lithium and carbamazepine, higher doses and blood levels predicted greater clinical improvement. 

More recently, Kowatch et al. (2000), in an open study, showed significant improvement in BD symptoms with divalproex, lithium and carbamazepine. In this study, in which chlorpromazine (Thorazine) rescue was used, approximately 30% to 50% of youth improved. Similarly, Findling (2002) reported on preliminary findings from an ongoing 12-week study of lithium and valproate for youth with BD. Improvements not only in mania, but also in depressive features and overall functioning, were reported with this combination.

The advent of the atypical antipsychotics has provided an alternative treatment for this difficult-to-treat population. In a retrospective chart review study of 28 children and adolescents with BD treated with risperidone (Risperdal), 82% of subjects improved rapidly in manic and aggressive symptoms (Frazier et al., 1999). Furthermore, in an eight-week open study of olanzapine (Zyprexa) monotherapy in 23 children and adolescents, significant improvement was noted in both symptoms of mania and depression on doses ranging from 2.5 mg/day to 20 mg/day (Frazier et al., 2001). Both risperidone and olanzapine were well-tolerated. An interesting study by Delbello and colleagues (2002) showed that combined treatment of adolescents with BD with valproate plus quetiapine (Seroquel) resulted in a better outcome compared to valproate alone. Of note, more subjects in the combined group were reported to be "remitted" from their BD.

While the results associated with these studies of the atypical antipsychotic medications are promising, there is a continued need for additional short- and long-term controlled trials of mood-stabilizing medications of all classes. While well-tolerated, weight gain and the possible risk of tardive dyskinesia limit the utility of the atypical antipsychotic medications.

Because childhood-onset BD is a highly comorbid condition, in addition to being treated for BD, most subjects will require a combined pharmacotherapy approach (Wozniak and Biederman, 1996). For instance, when treating BD plus ADHD, studies suggest better outcome and tolerability when treating the BD first and then addressing the ADHD (Biederman et al., 1999). While serotonergic antidepressants are useful in the treatment of depression in BD, careful observation for manic activation is necessary (Biederman et al., 2000). In addition, individuals may require medications for treatment of symptoms of anxiety and obsessive-compulsive disorder that should also be sequenced after the treatment of mania. Because additional medications for ADHD, anxiety and depression may activate mania, these agents must be used cautiously, watching for exacerbation of mood instability.

This work was supported in part by grant RO1 DA12945 (TW).

Dr. Wilens is director of substance abuse services in the pediatric psychopharmacology unit at Massachusetts General Hospital and associate professor of psychiatry at Harvard Medical School.

Dr. Wozniak is assistant professor of psychiatry at Harvard Medical School.

Ballenger JC, Reus VI, Post RM (1982), The "atypical" picture of adolescent mania. Am J Psychiatry 139(5):602-606.
 

Biederman J, Faraone SV, Hatch M et al. (1997), Conduct disorder with and without mania in a referred sample of ADHD children. J Affect Disord 44(2-3):177-188.
 

Biederman J, Faraone S, Mick E et al. (1996a), Attention-deficit disorder and juvenile mania: an overlooked comorbidity? J Am Acad Child Adolesc Psychiatry 35(8):997-1008.
 

Biederman J, Faraone S, Milberger S et al. (1996b), A prospective 4-year follow-up study of attention-deficit hyperactivity and related disorders. Arch Gen Psychiatry 53(5):437-446.
 

Biederman J, Mick E, Bostic JQ et al. (1998), The naturalistic course of pharmacologic treatment of children with manic like symptoms: a systematic chart review. J Clin Psychiatry 59(11):628-637; quiz 638.
 

Biederman J, Mick E, Prince J et al. (1999), Systematic chart review of the pharmacologic treatment of comorbid attention deficit hyperactivity disorder in youth with bipolar disorder. J Child Adolesc Psychopharmacol 9(4):247-256.
 

Biederman J, Mick E, Spencer TJ et al. (2000), Therapeutic dilemmas in the pharmacotherapy of bipolar depression in the young. J Child Adolesc Psychopharmacol 10(3):185-192.
 

Biederman J, Wozniak J, Kiely K et al. (1995), CBCL clinical scales discriminate prepubertal children with structured interview-derived diagnosis of mania from those with ADHD. J Am Acad Child Adolesc Psychiatry 34(4):464-471.
 

Chang KD, Steiner H, Ketter TA (2000), Psychiatric phenomenology of child and adolescent bipolar offspring. J Am Acad Child Adolesc Psychiatry 39(4):453-460.
 

Davis RE (1979), Manic-depressive variant syndrome of childhood: a preliminary report. Am J Psychiatry 136(5):702-706.
 

Delbello MP, Schweirs ML, Rosenberg HL, Strakowski SM (2002), A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J am Acad Child Adoles Psychiatry 41(10):1216-1223.
 

DeLong GR (1978), Lithium carbonate treatment of select behavior disorders in children suggesting manic-depressive illness. J Pediatr 93(4):689-694.
 

DeLong GR, Aldershof AL (1987), Long-term experience with lithium treatment in childhood: correlation with clinical diagnosis. J Am Acad Child Adolesc Psychiatry 26(3):389-394.
 

Faedda GL, Baldessarini RJ, Suppes T et al. (1995), Pediatric-onset bipolar disorder: a neglected clinical and public health problem. Harv Rev Psychiatry 3(4):171-195.
 

Faraone SV, Biederman J, Wozniak J et al. (1997), Is comorbidity with ADHD a marker for juvenile-onset mania? J Am Acad Child Adolesc Psychiatry 36(8):1046-1055.
 

Findling RL (2002), Combination pharmacotherapy in pediatric bipolar disorders-mood stabilization. Presented at the 49th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. San Francisco; Oct. 22-27.
 

Findling RL, Calabrese JR (2000), Rapid-cycling bipolar disorder in children. Am J Psychiatry 157(9):1526-1527 [letter].
 

Frazier JA, Biederman J, Tohen M et al. (2001), A prospective open-label treatment trial of olanzapine monotherapy in children and adolescents with bipolar disorder. J Child Adolesc Psychopharmacol 11(3):239-250.
 

Frazier JA, Meyer MC, Biederman J et al. (1999), Risperidone treatment for juvenile bipolar disorder: a retrospective chart review. J Am Acad Child Adolesc Psychiatry 38(8):960-965.
 

Fristad MA, Weller EB, Weller RA (1992), The Mania Rating Scale: can it be used in children? A preliminary report. [Erratum appears J Am Acad Child Adolesc Psychiatry 1992; 31(5):1001.] J Am Acad Child Adolesc Psychiatry 31(2):252-257.
 

Geller B, Cooper TB, Sun K et al. (1998), 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 [see comment].
 

Geller B, Craney JL, Bolhofner K et al. (2001), One-year recovery and relapse rates of children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 158(2):303-305.
 

Geller B, Craney JL, Bolhofner K et al. (2002), Two-year prospective follow-up of children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 159(6):927-933 [see comment].
 

Geller B, Fox LW, Clark KA (1994), Rate and predictors of prepubertal bipolarity during follow-up of 6- to 12-year-old depressed children. J Am Acad Child Adolesc Psychiatry 33(4):461-468 [see comment].
 

Geller B, Luby J (1997), Child and adolescent bipolar disorder: a review of the past 10 years. [Erratum appears J Am Acad Child Adolesc Psychiatry 1997; 36(11):1642.] J Am Acad Child Adolesc Psychiatry 36(9):1168-1176 [see comments].
 

Geller B, Sun K, Zimerman B et al. (1995), Complex and rapid-cycling in bipolar children and adolescents: a preliminary study. J Affect Disord 34(4):259-268.
 

Kafantaris V (1995), Treatment of bipolar disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry 34(6):732-741.
 

Kowatch RA, Suppes T, Carmody TJ et al. (2000), Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 39(6):713-720.
 

Milberger S, Biederman J, Faraone SV et al. (1995), Attention deficit hyperactivity disorder and comorbid disorders: issues of overlapping symptoms. Am J Psychiatry 152(12):1793-1799.
 

Nieman GW, DeLong R (1987), Use of the personality inventory for children as an aid in differentiating children with mania from children with attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 26(3):381-388.
 

Sachs GS, Baldassano CF, Truman CJ, Guille C (2000), Comorbidity of attention deficit hyperactivity disorder with early- and late-onset bipolar disorder. Am J Psychiatry 157(3):466-468.
 

Strober M (1992), Relevance of early age-of-onset in genetic studies of bipolar affective disorder. J Am Acad Child Adolesc Psychiatry 31(4):606-610.
 

Strober M, Carlson G (1982), Predictors of bipolar illness in adolescents with major depression: a follow-up investigation. Adolesc Psychiatry 10:299-319.
 

Strober M, Morrell W, Burroughs J et al. (1988), A family study of bipolar I disorder in adolescence. Early onset of symptoms linked to increased familial loading and lithium resistance. J Affect Disord 15(3):255-268.
 

Wagner KD, Weller EB, Carlson GA et al. (2002), An open-label trial of divalproex in children and adolescents with bipolar disorder. J Am Acad Child Adoles Psychiatry 41(10):1224-1230.
 

Weller EB, Weller RA, Fristad MA (1995), Bipolar disorder in children: misdiagnosis, underdiagnosis, and future directions. J Am Acad Child Adolesc Psychiatry 34(6):709-714.
 

Weller RA, Weller EB, Tucker SG, Fristad MA (1986), Mania in prepubertal children: has it been underdiagnosed? J Affect Disord 11(2):151-154.
 

An increasing amount of systemic research has galvanized opinions regarding pediatric-onset bipolar disorder (BD). Although originally thought to be a rare condition, the number of pediatric-onset BD diagnoses is rising. This article summarizes current thinking regarding pediatric BD, including work focusing on presentation, psychiatric comorbidity and recent treatment data

Janet Wozniak, MD

Articles

The Clinical and Treatment Implications of Co-Occurring Mania and ADHD in Youths

Bipolar Disorder in Children and Adolescents: Diagnostic and Therapeutic Issues