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
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 ultradian rapid cycling (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.
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