Bipolar Disorder in Childhood and Adolescence

There has been a growing awareness that the onset of bipolar disorder (BD) is often in childhood or adolescence, even though the typical symptom picture of mood dysregulation in adolescence is in many ways dissimilar to the symptom picture in adults. We begin the chapter with a description of the early-onset form of the disorder and a discussion of the controversies surrounding the diagnosis of BD in younger populations. We present epidemiological findings, and discuss what we know about gender and racial/ethnic differences. The phenomenology of adolescent bipolar disorder and the range of functional impairments involved are addressed, with special attention to researchers’ attempts to define the core features of pediatric BD. We cover the research on the course and prognosis of the disorder, co-morbidity, genetics and neurobiology, and neuropsyhological investigations. Finally, we present research on psychosocial treatments, pharmacological treatments, and efforts at prevention.

Current models of etiology view bipolar disorder as a primarily genetic illness whose onset and course are influenced by environmental stressors. We examine what is known about the environmental and biological protective and risk factors whose complex interplay over different periods of development result in the expression of the disorder.

DIAGNOSIS

Quinn and Fristad (2004; see also Kowatch et al., 2005) acknowledged the difficulty of diagnosing early-onset BD and offered a comprehensive assessment approach including: 1) a timeline of the child’s development, from birth to present, showing all prior mood episodes; 2) a structured clinical interview, including comorbid conditions; 3) a family history genogram to ascertain familial loading; 4) depression and mania rating scales to assess symptom severity and track treatment outcome; 5) global rating scales using multiple informants; 6) use of mood logs. It is not clear, however, how frequently clinicians actually follow these recommendations in diagnosing the disorder.

The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM; American Psychiatric Association, 2000) spells out the criteria for diagnosing BD. Separate criteria sets define what constitutes a manic episode, a hypomanic episode, and a major depressive episode. Different combinations of these episodes are required to diagnose Bipolar I versus Bipolar II.

Manic episodes involve the experience of elated, expansive, or irritable mood (or any combination of these) plus at least three (four if the mood is only irritable) of the following symptoms: inflated self-esteem (or grandiosity); decreased need for sleep (e.g., feels rested after only three hours of sleep); more talkative than usual or pressure to keep talking; flight of ideas or subjective experience that thoughts are racing; distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli); increase in goal directed activity (e.g., uninhibited people-seeking) or psychomotor agitation; or excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., unrestrained buying sprees, sexual indiscretions, or foolish business investments in adults). These symptoms must be present for at least one week (or any duration if interrupted by hospitalization). The episode must cause marked impairment in social or occupational functioning, or necessitate hospitalization, or involve psychotic features.

Hypomanic episodes are defined by the same symptom set but the criteria specify that episode must last a minimum of four days rather than seven. The episode must represent an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic and must be noticeable to others, but it cannot cause severe impairment (otherwise it is classified as a manic episode).

Major depressive episodes require a distinct period of sadness or anhedonia lasting at least two weeks, accompanied by five of the following seven symptoms: appetite change or weight gain or loss, hypersomnia or insomnia, psychomotor agitation or retardation, fatigue or low energy, feelings of worthlessness or guilt, problems with concentration or indecisiveness, and suicidal ideation or attempt.

A mixed episode is said to occur when criteria sets are met for both a manic and a major depressive episode (except for duration) during at least a one-week period. With all four types of episodes, criteria specify that the symptoms are not due tothe direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other somatic treatment) or a general medical condition (e.g., hyperthyroidism).

Bipolar I is diagnosed when there is a current or past manic or mixed episode. Bipolar I can be used when there is a current manic episode and no history of any major depressive episode. In contrast, bipolar II requires the presence or history of a hypomanic episode and at least one major depressive episode (with no history of manic or mixed episodes). Cyclothymia involves hypomanicand depressive symptoms over a period of at least two years with no symptom-free periods of two months or longer.

In spite of the precision with which the DSM lays out criteria for diagnosing BD, the clinical presentation of the disorder in children and adolescents is widely debated. Areas of controversy include whether the diagnosis of BD in youth should require clearly demarcated mood episodes and, if so, of what duration, and whether specific hallmark symptoms (euphoria and grandiosity) should be required. The National Institute of Mental Health Research Roundtable on prepubertal BD (2001) agreed that pediatric BD can be described with “broad” or “narrow” phenotypes. The “narrow” phenotype is characterized by recurrent periods of major depression and mania or hypomania fitting the classic definitions of BD I and II respectively. The broad phenotype has been variously defined, but may involve chronic mood lability/instability rather than discrete mood episodes, and irritability with no euphoria or depression.

Even when children do have classic symptoms of mania or hypomania, the symptom presentation is colored by the developmental stage of the child. Moreover, a great proportion of children do not meet the duration criteria of four (hypomania) or seven (mania) days, and so are diagnosed as BD Not Otherwise Specified (NOS). Children with the “broad” phenotype constitute the majority of referrals to clinicians and are characterized by severe irritability, “affective storms,” mood lability, severe temper outbursts, depression, anxiety, hyperactivity, poor concentration, and impulsivity, all with or without clear mood episodicity. It is unclear whether broad phenotypes among children are true precursors to full bipolar I disorder in adulthood, although Birmaher et al. (2006) found that 25% of BD NOS children develop bipolar I or II disorder within an average of 22 months after their initial assessment.

Leibenluft, Charney, Towbin, Bhangoo, and Pine (2003) went one step further when they suggested classifying pediatric BD into “narrow,” “intermediate,” and “broad” phenotypes. The narrow phenotype includes those who meet the full DSM-IV criteria for mania or hypomania, including the duration criteria, and have the hallmark symptoms of elevated mood or grandiosity. The intermediate phenotype includes two subcategories: those with the hallmark symptom of elation but not meeting the duration criterion (i.e., symptoms lasting less than four days) and those meeting the duration criterion but with the less specific symptom of irritable mania or hypomania. (In the latter subcategory, elation is absent but the irritability must be episodic or periodic rather than chronic). The broad phenotype consists of nonepisodic symptoms of severe irritability and hyperarousal without elation or grandiosity.

Rich et al. (2007) suggested the term “severe mood dysregulation” for children in the broad phenotype category and developed a set of inclusion and exclusion criteria to further define the group. These are children who exhibit nonepisodic irritability accompanied by hyperarousal and hyperreactivity to negative emotional stimuli, without elation or grandiosity.

In summary, children and adolescents who are diagnosed as bipolar in the community often fail to meet strict DSM-IV criteria. Future diagnostic systems should attempt to capture the broader phenotypes that are being treated in clinicians’ offices, as these children – although not classically bipolar - often suffer from highly debilitating symptoms (Birmaher et al., 2006).

EPIDEMIOLOGY

Epidemiological studies have been hampered by the lack of consensus about how to define early-onset BD. Prevalence estimates vary depending on whether the narrow or broad phenotype is applied. Surveys that use strict DSM criteria reveal that the point prevalence of BD among youth is 1% or less. Kessler and Walters (1998) found that only a fraction of 1% of children and adolescents met DSM-III-R criteria for Bipolar I.

In the Oregon Adolescent Depression Project, Lewinsohn, Klein, and Seeley (1995) used DSM-III-R criteria to assess a cohort of 1,709 high school students. They reported the lifetime prevalence of Bipolar I, II and cyclothymia to be 0.99% in their sample. In addition to the adolescents that met strict criteria, they identified 97 “core positive” cases (5.7% of the sample) who experienced a distinct period of elevated, expansive, or irritable mood, with an average of 2.9 associated manic symptoms. Subjects in both groups were much more likely to report elevated or expansive than irritable mood, and relatively few subjects reported periods of irritable but not elevated mood. The most common manic symptom in both groups was increase in goal-directed activity. Other frequent symptoms included increased speech, inflated self-esteem, decreased need for sleep, and distractibility. Almost all symptoms were more frequent among the bipolar than core positive subjects. The authors also looked at the dimensional structure of the secondary (“B”) manic symptoms during the most recent episode across the two groups. Using principal-components analysis, the first component accounted for 38.2% of the variance and had relatively high and unique loadings on the following symptoms: decreased need for sleep, flight of ideas, distractibility, and poor judgment. This component reflects behavioral disorganization and impaired functioning; it correlated with total impairment ratings (social, family, and school). The second component accounted for an additional 14.6% of the variance and loaded on inflated self-esteem and increase in goal-directed activity. It appears to represent the grandiose-hyperactive part of the manic syndrome. (This dimension resembles the behavioral facilitation or behavioral engagement system that Depue and Iacono (1988) hypothesized to represent the core neurobehavioral disturbance in BD.) Lewinsohn’s study is limited by the reliance on self-report by adolescents, which may underestimate the frequency or severity of manic symptoms (Youngstrom, Findling, and Calabrese, 2004).

Lewinsohn et al. (2000) followed a subset of their sample of high school students into young adulthood (N = 1,507; mean age at entry was 16.6 years). In addition, all available first-degree relatives were interviewed. Using the K-SADS, they identified adolescents who met DSM-III-R criteria for BD (N = 17; mostly Bipolar II and cyclothymia), subsyndromal BD (SUB; N = 48), Major Depression (MDD; N = 275), disruptive behavior disorder (N = 49), and no disorder (N = 307). The BD and SUB groups were contrasted with each other and with the other diagnostic groups with respect to psychopathology during young adulthood. The BD group differed significantly from the SUB group only on total incidence of BD. Compared to the group with no disorders, the BD and SUB groups both showed significant impairment in psychosocial functioning and had higher mental health treatment utilization at age 24. About 1% of the MDD group “switched” to BD in young adulthood (a much lower rate of switching than found in clinical samples), and none of the SUB adolescents escalated to BD.

Although this study does not allow us to examine the continuity of BD from early childhood through adulthood, it gives clues about the relationship between “soft” signs of bipolar disorder in adolescence (SUB) and BD in early adulthood. Notably, evidence for the premise that SUB is a risk factor for future BD was supported by the significantly elevated rates of BD and MDD in the relatives of adolescents with SUB compared to the relatives of adolescents with no disorders. In addition, SUB was significantly elevated in the relatives of BD cases. The fact that SUB probands did not escalate to BD, however, suggests that soft signs of BD in adolescence may be a risk factor for future psychopathology, but not specifically BD. Alternatively, adolescent self-report is not the most reliable means of obtaining data on precursor states.

A more recent community epidemiologic survey of mental disorder in youth, the Great Smoky Mountains Study of Youth, focused on a sample of 4500 respondents in the age range 9 to 13 (Costello et al., 1996). None met criteria for Bipolar I and 0.1% met criteria for Bipolar II in the three months before the interview. In a small (n = 150) community sample of adolescents, 11.8% had a history of episodes lasting two days or longer in which they had four or more manic symptoms but did not meet criteria for Bipolar I, II, or cyclothymia (Carlson and Kashani, 1988).

Because of the complications surrounding the identification of cases of BD in youth, a useful approach in establishing prevalence is to work backward from the more clear-cut diagnosis of adult mania. Surveys of adults find that between 20% and 40% of those with a lifetime history of mania report that their first manic episode occurred during childhood or adolescence (e.g., Kessler, Rubinow, Holmes, Abelson, and Zhao, 1997; Lish, Dime-Meenan, Whybrow, Price, and Hirschfeld, 1994; Joyce, 1984). Given adult lifetime prevalence rates of BD in the range of 1 to 2%, it would appear that less than 1% of children and adolescents have manic symptoms that develop into adult BD. However, the cumulative lifetime prevalences of BD have increased in recent cohorts. A trend toward earlier age of onset of broadly defined BD with successively later years of birth has been reported (Rice et al., 1987). This is consistent with Kessler, Avenevoli, and Ries Merikangas (2001), who report that the lifetime prevalence as of age 18 in the recent National Comorbidity Survey (NCS) cohorts is 2.2%, which is 60 times higher than the prevalence in the oldest age cohorts of the NCS.

AGE OF ONSET

Goodwin and Jamison (1990), in a review of studies prior to 1990, describe the peak age of onset of BD as between 15 and 19 years old. In Lewinsohn et al.’s (1995) epidemiological study, the mean age of onset of the first affective episode for the 18 adolescents who met criteria for BD was 11.75 (SD = 2.96). This was significantly younger than the mean age of onset for the depressed, but not bipolar, adolescents in the sample. In the NCS-R, the mean age at onset was 18 (Merikangas et al., 2007).

Variation in age of onset may reflect underlying genetic heterogeneity in bipolar disorder, as it does in Alzheimer’s disease and breast cancer. Several studies have suggested that there may be three overlapping distributions of age of onset in bipolar disorder (Bellivier, Golmard, Henry, Leboyer, and Schurhoff, 2001; Bellivier et al., 2003; Lin et al., 2006). Most recently, Lin et al. (2006) assessed 211 bipolar disorder probands and their families as part of the NIMH Genetics Initiative for Bipolar Disorder. Using admixture analysis, they found three separate groups with different ages of onset. They assigned subjects to groups using cutoff points of less than age 21 for the first group, between 21 and 28 for the middle group, and greater than 28 for the third group. Earliest-onset subjects had higher risks of substance abuse, rapid cycling, and suicide attempts. Bipolar family members from a family with an earlier-onset proband were more likely than others to have an early onset (odds ratio=4.53, 95% CI=3.09–6.64).

Thus, it appears that age of onset may reflect underlying genetic heterogeneity and may aggregate within families. Age of onset may eventually be used to identify more homogenous subgroups of BD patients.

GENDER AND RACE/ETHNICITY

Although there are some findings on gender and ethnic differences in adult BD, reports of differences of this type in bipolar adolescents are sparse. Gender differences in depression have been found. Prepubertal boys have a slightly higher rate of depressed mood than girls, but in early adolescence, there is a dramatic increase in depression among girls but not boys (e.g., Hankin et al., 1998; Wichstrom, 1999). There are apparently no comparable gender differences in rates of mania. The COBY (Course and Outcome of Bipolar Youth) study, described in detail in a later section of this chapter, compared sex and race across the three diagnostic groups of Bipolar I, Bipolar II, and Bipolar NOS patients (Axelson et al., 2006). Racial differences were not in evidence across the three groups, but the proportion of males to females tended to differ across groups, with the lowest proportion of males (40%) in the Bipolar II group. This parallels the finding in adults that women are more likely to be diagnosed with Bipolar II, presumably because they report more depressive episodes than men (e.g., Schneck et al., 2004). Lewinsohn et al. (1995) noted few gender differences in their epidemiological sample and concluded that the prevalence, age of onset, phenomenology, and course of BD in adolescent males and females in a community setting was similar.

Patel, DelBello, and Strakowski (2006) examined ethnic differences in the symptom profiles of adolescents with bipolar disorder at their first psychiatric hospitalization. Compared with the white cohort, African-American youths were diagnosed more frequently as having psychotic features and had higher ratings for auditory hallucinations. It is worth remembering that racial and gender differences found in clinical samples can reflect many differences that are independent of differences in the etiology of the disorder, including differences in the willingness to undergo treatment, and, particularly for children and adolescents, differences in the reactions of others (e.g., parents or teachers) to the clinical symptoms (Hartung and Widiger, 1998).

PHENOMENOLOGY

Several research groups have used semistructured interviews to examine the cross-sectional presentation of BD in clinical samples of youth (Biederman, Faraone, Chu, and Wozniak,1999; Geller et al. 2000; Findling et al., 2001; Axelson et al., 2006). Geller and Luby (1997), in their review of child and adolescent bipolar disorder, provided a particularly helpful description of how symptoms like euphoria, grandiosity, and hypersexuality manifest differently across developmental stages (child, adolescent, adult). For example, a common presentation of grandiosity in bipolar children is to instruct their teachers about how the class should be taught or to insist that stealing may be wrong for other people but not for them. Common adolescent grandiose delusions are that they will achieve a prominent profession even though they are failing in school.

Kowatch et al. (2005) performed a meta-analysis of seven studies examining the phenomenology of mania among children and adolescents aged 5 to 18. The most common symptoms during manic episodes were increased energy, distractibility, and pressured speech. Approximately 80% of subjects showed irritability and grandiosity; 70% had the symptoms of elated mood, decreased need for sleep, or racing thoughts. Hypersexuality and psychosis were less common.

Core Features

There has been ongoing controversy about how best to characterize mania in early onset BD. The preeminent criterion for mania/hypomania (an elated, expansive, or irritable mood that clearly represents a change from the individual’s typical mood) contains the seeds of the dilemma(s). The first issue revolves around the affective nature of the mood (i.e., is elation required or is irritability enough to serve as a cardinal symptom of BD?); the second around the requirement that the mood syndrome is episodic and not an enduring characteristic of the individual.

Geller et al. (2001) felt that a method for differentiating BD from ADHD was needed because symptoms such as hyperactivity and distractibility are criteria for both disorders. They established a BD phenotype characterized by mania or hypomania with elation and/or grandiosity as one criterion for use in their longitudinal observation of a sample of early onset (prepubertal and early adolescent) BD subjects. Other researchers (e.g., Biederman, 1998) believe that severe, episodic irritability in the absence of elated mood can serve as a defining criterion for diagnosis of BD in children and adolescents (in keeping with DSM-IV). It is interesting that irritability has emerged consistently as a prominent symptom in clinical samples, and elated mood less so (although this could be an artifact of various research groups’ differing definitions of mania), whereas in the epidemiological sample previously described (Lewinsohn et al., 1995) subjects were more likely to endorse elevated than irritable mood. It may be that irritability is overrepresented in clinical samples and is one of the reasons these children are brought in for treatment. It is also possible that studies that use multiple informants will find more irritability than studies that rely on self-report only.

The requirement that mood syndromes be episodic is a particularly thorny one, especially for irritability and for euphoria (perhaps less so for depression, which more frequently presents as a discrete and extended mood state, even in children and adolescents). DSM-IV calls for four days duration to establish a hypomanic episode and seven days for mania. Carlson and Kelly (1998) noted that a substantial proportion of children and adolescents report manic-like symptoms that persist for only a few hours or days and do not meet criteria for BD. These youngsters often are quite impaired, but there is considerable uncertainty about what these symptoms mean diagnostically. With the sort of mood lability seen in children and adolescents, moods are sometimes changing hourly, or at least several times in a day. How many hours in a day must be mood-affected for the day to count toward the duration criteria? Must they be contiguous hours? And if an adolescent is irritable for two hours every morning, is that characteristic (because it happens every day) or uncharacteristic (because after the morning irritability, the child is able to maintain a more level mood)? The same issues arise for elevated, silly or giddy moods.

Attempts have been made to address some of these ambiguities, with promising results. Axelson et al. (2006) developed minimum criteria for a Bipolar NOS diagnosis that included these clarifications: mood and symptom duration of a minimum of four hours within a 24-hour period for a day to “count;” and a minimum of four days (not necessarily consecutive) meeting the mood, symptom, duration, and functional change criteria over the subject’s lifetime. Leibenluft et al. (2003), in work described earlier, offer an elegant approach for reconciling the complexities involved in early onset symptom pictures that may or may not include euphoria and grandiosity, may or may not meet duration criteria, and may or may not even appear to be episodic.

Irritability as a criterion for BD must be distinguished from irritability as a normal developmental phenomenon and as a common nonspecific psychiatric symptom. Leibenluft, Cohen, Gorrindo, Brook and Pine (2006) developed scales measuring episodic and chronic irritability and administered DSM-based structured interviews to 776 youths at three time points. They demonstrate that a child’s irritability is likely to remain consistent in terms of its longitudinal course (i.e., episodic versus chronic). Chronic irritability at time 1 (mean age 13.8) predicted ADHD at time 2 (mean age 16.2) and major depression at time 3 (mean age 22.1). Episodic irritability at time 1 predicted simple phobia and mania at time 2. Episodic and chronic irritability in adolescents appear to be stable, distinct concepts, suggesting that the work differentiating narrow phenotype BD from (nonepisodic) severe mood dysregulation is essential to furthering our understanding of BD in youth.

COURSE AND IMPACT ON FUNCTIONING

Numerous studies point to dysfunctions associated with early-onset BD, regardless of whether the narrow or broad phenotype is applied. Some of these negative outcomes include high rates of hospitalization, suicidal behavior, psychosis, reckless behavior, aggression, and substance abuse; psychiatric, medical, and educational service utilization; severe family conflicts; significant caregiver burden; and chronic psychosocial impairment (Biederman et al., 2003, 2004; Brent et al., 1988; Chang and Ketter, 2001; Craney and Geller, 2003; Findling et al., 2001; Geller et al., 2000; Geller, Tillman, Craney, and Bolhofner, 2004; Lewinsohn, Klein, and Seeley, 2000; McClellan, McCurry, Snell, and DuBose, 1999; Perlis et al. 2004; Strober et al. 1995; Wilens et al. 2004). Two recent studies of adults found that early age at onset was associated with a rapid cycling course in adulthood (Schneck et al., 2004; Coryell et al., 2003).

Long-term follow-up studies illustrate the low recovery rates and high relapse rates associated with the disorder. One of the earliest was a 5-year naturalistic prospective follow-up of 54 consecutive admissions of bipolar I adolescents (mean age at entry was 16.0 years) to a university inpatient service (Strober et al. 1995). These subjects received aggressive pharmacotherapy, as well as equally intensive psychoeducation, family therapy, and individual therapy. Only two of the 54 subjects (3.7%) failed to achieve criteria for recovery at any time through the 260 weeks. Time to recovery varied by index episode polarity, with subjects with a purely manic or mixed episode recovering in a median of 9 or 11 weeks respectively, whereas those with pure depression evidenced a median time to recovery of 26 weeks. Forty-four percent of those who recovered from their index episode had one or more relapses over the 5-year period. Comparing the results of this study with the findings on BD in adults (e.g., the NIMH Collaborative Study; Keller et al., 1986), it would appear that juveniles have a slower return to euthymia, but a lower relative risk of relapse, and longer time in remission than adult BD patients.

The COBY study (Axelson et al., 2006) was designed to extend the database on the cross-sectional presentation and longitudinal course of pediatric BD. Phenomenology (and family history) was examined as a function of Bipolar I, Bipolar II, or Bipolar NOS diagnosis. Most subjects (58.2%) met criteria for Bipolar I, with a few (6.8%) diagnosed as Bipolar II, and a substantial number (34.9%) diagnosed as Bipolar NOS, typically because they did not meet the episode duration criteria. The similarities among the three groups were perhaps more striking than the differences. Subjects with Bipolar I had more severe lifetime manic symptoms, greater functional impairment, and higher rates of hospitalization, psychosis, and suicide attempts than those diagnosed Bipolar NOS. The two groups were not different in age of onset, duration of illness, lifetime comorbidity, suicidal ideation, major depression, family history, and types of manic symptoms. The results suggest that all three diagnoses belong on a single continuum, with elevated mood as a common feature of youth with bipolar spectrum disorder.

This sample of children and adolescents (N = 263, mean age 13 years) was followed for two years (Birmaher et al., 2006). Approximately 70% of subjects recovered (defined as eight consecutive weeks with minimal to no symptoms) from their index episode and 50% of those had at least one recurrence. There were no differences in rates of recovery among the three diagnostic subgroups, although subjects with BD NOS took a significantly longer time to recover than the other two groups. During 60% of the weeks of follow-up, subjects had syndromal or subsyndromal symptoms, and 3% of the time, psychosis. Twenty percent of Bipolar II subjects converted to Bipolar I, and 25% of Bipolar NOS converted to Bipolar I or II.

A number of predictors of recovery emerged. Subjects with childhood onset were less likely than those with adolescent onset to recover. Children with lower SES, longer duration of BD symptoms, and a diagnosis of BD NOS were less likely to recover. Birmaher et al. provided an additional analysis in which they compared the bipolar I youth in their sample with bipolar I adults in a 20-year follow-up of subjects with baseline mood disorders (Judd et al., 2002). Youth spent significantly more time symptomatic and had more mixed/cycling episodes, mood symptom changes, and polarity switches than adults.

Geller et al. (2004) reported on a four-year naturalistic prospective outcome study of 86 subjects with an index episode of mania (defined by elated mood and/or grandiosity as one inclusion criterion) and a baseline age of 10.8 yrs. Follow-up assessments occurred every six months. Age of onset of the intake episode of mania was 7.4 years and episode duration was 79.2 consecutive weeks. Time to recovery was 60.2 weeks and the time to relapse after recovery was 40.4 weeks. Any BD diagnosis occurred during a mean of 67.1% of total follow-up weeks; subjects spent 56.9% of total weeks with mania or hypomania and 47.1% with depression. Two predictors of relapse emerged; baseline psychosis (associated with more time ill with mania or hypomania) and low maternal warmth, which predicted earlier relapse to mania or hypomania. In contrast, coming from an intact biological family predicted a shorter time to recovery.

In Judd et al.’s (2002) 20-year follow-up of adult subjects with baseline mood disorders, depressive episodes predominated, whereas the children in Geller’s sample spent more weeks with mania/hypomania than with depression. Methodological differences between the two studies may account for this difference, but it is also possible that mania or hypomania predominates during the prepubertal and early adolescent age range and depressive states may become more dominant with age (or that Judd et al. had more adult-onset patients).

Geller et al. (2004) and Birmaher et al. (2006) make a case for continuity between child- and adult-onset BD based on the similarity of mania symptom distribution between the two, the occurrence of both within the same families, the occurrence of maternal warmth and psychosis as predictors of outcome of both, and the fact that, across the life span and especially in youth, BD usually follows a changeable and sinuous course.

COMORBIDITY

Virtually every study of early-onset bipolar disorder has commented on the extensive comorbidities. Angold, Costello & Erkanli (1999) presented a meta-analysis of 21 community studies that used standardized psychiatric interviews with parents and children to generate diagnoses (DSM-III, III-R, or IV) and report rates of comorbidity between pairs of disorders. They concluded that comorbidity cannot be explained as artifact and is indeed a real phenomenon. Nonspecific symptoms like irritability blur the boundaries between diagnoses, calling for more work detailing the qualitative and quantitative aspects of individual symptoms in relation to different diagnoses. Nonetheless, studies find that comorbidity between disorders remains even after overlapping symptoms are removed from the criteria for the two diagnoses (Millberger, Biederman, Faraone, Murphy & Tsuang, 1995, ADHD and depression or GAD; Biederman, Faraone, Mick & Lelon, 1995, depression and ADHD or ODD). Angold et al. (1999) point to the importance of studying the development of patterns of symptomatology over time so that the developmental continuity of a single disease process is not obscured by current diagnostic categories.

The co-occurrence of BD and ADHD has been extensively studied by Biederman and colleagues. Biederman et al. (1996) contrasted 140 ADHD children (eligible subjects were 6 to 17 years of age) with and without BD at baseline and at four-year follow-up; 11% of ADHD children at baseline were diagnosed with BD and an additional 12% met criteria for BD after four years, rates significantly higher than those of controls at each assessment. Faraone, Biederman, Mennin, Wozniak & Spencer (1997) administered structured psychiatric interviews to the 822 first-degree relatives of the entire sample of 260 ADHD and control children. Comparing ADHD children with and without BD, they found that relatives of ADHD + BD children had a fivefold elevated risk for BD and an elevated risk for major depression with severe impairment. The authors concluded that comorbid ADHD + BD is familially distinct from other forms of ADHD and may be related to what others have termed childhood-onset BD (characterized by irritability rather than euphoria, a chronic rather than episodic course, and involving severe mood dysregulation leading to marked impairment).

A review of 17 studies that examined the co-occurrence of pediatric BD and ADHD in children, adolescents and, retrospectively, in adults (Singh, DelBello, Kowatch & Strakowski, 2006) led to similar conclusions: “…the literature most strongly suggests that ADHD symptoms represent a prodromal or early manifestation of pediatric-onset bipolar disorder in certain at-risk individuals” (p. 710). Thus, ADHD may be a developmentally specific phenotype of early-onset BD among children with a positive family history of BD. One prognostic question is whether these comorbid children grow up to become typical BD adults (i.e., those with pure mania) or atypical BD adults with dysphoric or mixed mania or rapid cycling.

The only prospective study of the rate, risk, and predictors of switching from ADHD to prepubertal and early adolescent Bipolar I (Tillman & Geller (2006) followed 81 ADHD subjects (mean age 9.7) and 94 healthy controls over six years. To be considered a “switcher”, a child had to meet criteria for a manic or mixed episode (with elated mood and/or grandiosity) of at least two weeks duration and impaired functioning. The cumulative risk of switching from ADHD to bipolar I through the 6-year follow-up was 28.5%, compared to a 2% switching rate for healthy controls.

A smaller body of literature documents the elevated risk for conduct disorder among children with mania. Reported comorbidity rates range from 42% in a sample of hospitalized adolescents with mania (Kutcher, Marton & Korenblum, 1989) to 69% in a clinical outpatient sample of children and adolescents (Kovacs & Pollock, 1995). In a review of the literature on the diagnostic dilemmas surrounding diagnosis of childhood mania, ADHD, and CD, Kim & Miklowitz (2002) concluded that reliable and accurate diagnoses can be made despite the symptom overlap among the three disorders. They concurred with Faraone et al. that children with BD and ADHD may have a distinct familial subtype of BD. However, they cite work by Carlson, Loney, Salisbury & Volpe (1998) that complicates the diagnostic picture by raising an alternative view: that the manic syndrome, at least as characterized by emotional lability, may be a part of the psychopathology of other disorders, and indeed has been recognized in children with schizophrenia, autism, and pervasive developmental disorders. This view suggests that manic symptoms sometimes represent “noise” that indicates the general severity of psychopathology, not specifically BD.

In summary, we must push beyond reporting rates of comorbidities to understanding what these co-occurring disorders represent. In order to do that, we will need universally accepted definitions of what childhood mania is, what comprises an episode, and longitudinal research that tracks the appearance and remission of different syndromes over different stages of development.

GENETICS AND NEUROBIOLOGY

BD is one of the most heritable of psychiatric illnesses, second only to autism. Family studies have shown that the relative risk to first-degree relatives of an individual with BD is about 7 (Satcher, 1999). Some degree of cofamiliality between unipolar and bipolar disorder is supported, suggesting partial overlap in the familial risk factors for the two disorders (Pennington, 2002). Similarly, in family studies of Bipolar I, Bipolar II, and cyclothymia, each disorder increases the risk in relatives for the other two disorders, but to a lesser extent than the risk found when both proband and relative have the same phenotype.

Lapalme, Hodgins, and LaRoche (1997) performed a meta-analysis of studies of the phenomenology of bipolar offspring. Seventeen studies were examined, 11 of which included a comparison group of offspring of parents with no mental disorder. Over half (52%) of the bipolar offspring met DSM-III or III-R criteria for a psychiatric disorder, compared to 29% of the controls. Furthermore, 5.4% of the bipolar offspring were diagnosed with BD, compared to 0% of the control group.

Twin studies further demonstrate the heritability of BD. Across studies, the average monozygotic concordance for BD is about 60%, whereas the average dizygotic concordance is about 12% (Kelsoe, 1997). Although genetic transmission is clearly significant, the fact that monozygotic concordance is less than 1.0 means that there must also be environmental influences on the development of BD. The mode of genetic transmission appears to be complex and likely involves multiple interacting genes (Satcher, 1999). Linkage studies have produced many initial “hits,” few of which have been replicated. Chromosomes 13 and 22 may be the most promising candidates for carrying genes that contribute to BD, although the variance contributed by each of these may be quite small. For a thorough review of the genetics of bipolar disorder literature, see Smoller & Finn (2003).

To understand what is different about the brain in BD, we need to understand what is disrupted in both the depressed and manic mood states. Some researchers have remarked on the frequent presentation of bipolar depression as atypical depression, while unipolar depression is more often associated with insomnia, anorexia, and psychomotor agitation (Kelley, 1987; Thase, 2007). Earlier studies suggested that bipolar and unipolar depression may be biologically as well as phenomenologically distinct. The symptoms of bipolar depression have been compared to animal models of mesolimbic dopamine depletion (Depue & Iacono, 1989; Swerdlow & Koob, 1987). The brain’s motivation system is organized in layers ranging from the brainstem through the limbic system to the cortical level. Depue and Iacono (1989) term this the “behavioral facilitation” system, whose function is to mobilize approach behaviors to seek rewards and to remove obstacles to rewards. They argue that most of the symptoms of mania can be viewed as exaggerated functioning of this system, whereas bipolar depression reflects reduced functioning. The behavioral facilitation system corresponds to the main projection sites of the mesolimbic and mesocortical dopamine pathways. Alterations in dopaminergic neurotransmission could either over- or underactivate this system, with opposite consequences for the level of goal-directed activity, and the manifestation of either mania or bipolar depression. This theory of BD is supported by studies of reward-seeking behaviors in animal models and by evidence of alterations in dopamine neurotransmission in BD.

The symptoms of unipolar depression have been linked to deficiencies in norepinephrine (Schildkraut, 1965) and serotonin (Prange, Wilson, Lynn, Alltop, & Stikeleather, 1974; Nemeroff, 1998). Animal studies have demonstrated that stress and loss can alter levels of norepinephrine and serotonin, as well as altering the function of the stress response system (Stone, 1975; Mineka, Gunnar, & Champoux, 1986; Sapolsky, 1994) Gold and Chrousos (1999) presented endocrinological data indicating that the hypersomnia, hyperphagia, lethargy, fatigue, and relative apathy of the atypical syndrome are associated with concomitant hypofunctioning of the stress response system, while melancholic features (sustained anxiety and dread for the future with physiological hyperarousal) involve sustained hyperactivity of the stress response system. These findings on the biological distinctions between unipolar (nonatypical or melancholic) and bipolar (atypical) depression suggest that unipolar depresson results from chronic stress (including loss) and that the opposite of unipolar depression is relief from chronic stress and the return of a normal capacity for pleasure. The opposite of bipolar depression is mania, an excessive pursuit and capacity for pleasure.

More recent research suggests that the distinction is not so straightforward. The concept of atypical depression emerged in the 1950’s to describe individuals with unusual depressive symptoms (hypersomnia and weight gain rather than insomnia and loss of appetite) who were shown to respond better to monoamine oxidase inhibitors than to tricyclic antidepressants. Recent authors, however, have challenged the validity of the subtype, noting that consistency across and within types of depression has been unimpressive and, in the post-MAOI era, no group of drugs has been clearly shown to have greater efficacy in atypical depression (Davidson, 2007). Furthermore, unipolar depression can present with atypical features. Tremblay et al. (2005) examined the symptoms of anhedonia and decreased motivation or drive (atypical depression) in major depression. Using fMRI to compare subjects with major depression and healthy controls before and after receiving dextroamphetamine to stimulate the brain reward system, they found that individuals with major depression had a hypersensitive response to the rewarding effects of the stimulant (i.e., more positive reinforcing effects from the drug). There were significant positive correlations between the degree of dextroamphetamine reward and the severity of anhedonia. It may be that the dopamine pathways comprising the brain reward system are implicated in a specific component of depression (anhedonia) which may be differently represented in atypical versus non-atypical depression. Mapping the correspondence between melancholic versus atypical and unipolar versus bipolar depression remains to be done. Understanding the biology of these differing mood presentations may shed light on phenomena such as mixed states, which are so common in child and adolescent bipolar disorder.

There are other neurotransmitter and neuroendocrine abnormalities in adult BD. Alterations in norepinephrine levels are correlated with mood cycles in BD and may play a causal role in the switch between cycles. There is evidence for low levels of GABA (the main cortical inhibitory neurotransmitter) in BD. The unaffected relatives of BD patients demonstrated sensitivity to the deleterious effects of tryptophan depletion (which lowers serotonin levels), suggesting that vulnerability to reduced tryptophan may represent an endophenotype for BD (Quintin, et al., 2001: Sobczak, et al., 2002). More recently, research in this area has moved from a focus on neurotransmitters and cell surface receptors to intracellular signaling pathways, or second messenger systems (the chemical cascade that occurs in the postsynaptic neuron after a neurotransmitter binds with a receptor). There is a growing consensus that the ability of medications such as lithium and valproic acid to treat multiple aspects of an illness as complex as BD arises from their major effects on intracellular signaling pathways, rather than on any single neurotransmitter system per se. Promising reports demonstrating neurotrophic and neuroprotective effects of mood stabilizers have emerged (Drevets, 2000; Moore, Bebchuk, Wilds, Chen, and Manji, 2000; Sassi, et al., 2002). (Findings on neurotransmitters and cellular signaling pathways in adults are reviewed in Howland and Thase, 1999; Miklowitz and Johnson, 2006; Manji et al., 2003).

Both structural and functional neuroimaging studies have produced useful clues to understanding the adult mood-disordered brain. The two main structural findings---white matter hyperintensities (WMH; focal areas of high intensity signal, possibly caused by abnormalities in myelin or microinfarcts) and cortical atrophy---both suggest a neurodegenerative process. These findings are not accounted for by medication and are correlated with the severity and chronicity of the disorder, cortisol levels, and age, leading to the hypothesis that the physiological changes associated with mood episodes cause neurodegeneration. Functional neuroimaging differences in adult BD include: 1) decreased frontal brain metabolism during a depressive episode (greater than that found in unipolar depression), 2) overall increases in brain metabolism with the switch to mania or hypomania, and 3) possible laterality differences in the frontal lobe metabolism between unipolar and bipolar disorder (left-hemisphere decreases in unipolar and right-hemisphere decreases in bipolar). These changes are probably more accurately conceptualized as state rather than trait markers (Pennington, 2002).

DelBello, Adler & Strakowski. (2006) provide a comprehensive overview of neuroimaging studies performed on children and adolescents from 1966 to 2005. Structural MRI studies suggest that severe prefrontal WMH occur in bipolar youth, similar to adults. Diffusion tensor imaging (DTI), a magnetic resonance technique that measures aspects of water diffusion, is used to assess subtler abnormalities in white matter tracts, like axonal disorganization. One study (Adler et al., 2006) reported that unmedicated first-episode bipolar adolescents, similar to bipolar adults, evidenced axonal disorganization. Since these indications were present at illness onset, they potentially represent an early biomarker of BD.

In addition to white matter abnormalities, structural MRI studies suggest abnormalities in the anterior cingulate, ventral prefrontal cortex, superior temporal gyral, amygdala, hippocampus, and putamen in bipolar youth. Some of these findings are similar to those reported in adults with BD. However, smaller amygdala volumes have been reported in bipolar youth (e.g., Chang, et al., 2005), whereas the amygdala tends to be enlarged in adults. This discrepancy may suggest age-specific structural MRI abnormalities.

Magnetic resonance spectroscopy (MRS, a non-invasive neuroimaging technique that provides in vivo measurement of the concentration of specific neurochemicals in localized brain regions) studies have found neurochemical abnormalities in second messenger metabolism, neuronal integrity, and possibly neurotransmission in the ventral and anterior cingulate prefrontal cortices and basal ganglia in bipolar children. Specifically, elevated prefrontal myo-inositol (a neurochemical involved in a second messenger pathway) has been reported in bipolar youth and may be an early, specific biomarker of BD in children and adolescents. Davanzo et al. (2003) were able to demonstrate a significant reduction in myo-inositol/creatine levels with acute lithium treatment in 11 manic children.

Studies of both adults and children with BD suggest involvement of two interconnected brain pathways: a ventral-limbic (amygdala) pathway thought to regulate mood, and a dorsal-subcortical pathway (including the thalamus and basal ganglia) that modulates cognitive processes. Several investigators have hypothesized that dysfunction within these pathways underlies the neurophysiology of BD (Strakowski, DelBello, and Adler, 2005; Chang et al., 2004). Perhaps decreased amygdala volumes in bipolar youth lead to increases in ventral prefrontal activation in an attempt to regulate mood. Dysfunction in the ventral-limbic pathways leads to mood dysregulation as well as to secondary abnormalities in the dorsal-subcortical pathway.

NEUROPSYCHOLOGY

Pediatric BD is associated with a number of neuropsychological deficits. Attempts have been made to clarify the nature of these deficits, and to determine whether deficits are specific to mood states or whether they remain after symptomatic recovery.

Central findings from several small studies suggest that pediatric BD involves impairment in attention (Dickstein, et al., 2004; Doyle, et al., 2005), set shifting (Dickstein, et al., 2004; Meyer, et al., 2004), visuospatial memory (Dickstein, et al., 2004; Olvera, Semrud-Clikeman, Pliszka and O’Donnell, 2004), processing speed and interference control (Doyle, et al., 2005), verbal memory (Doyle, et al., 2005; Meyer, et al., 2004; McClure, et al., 2005), and abstract problem solving or executive function (Doyle, et al., 2005; Murphy, et al., 1999). The Performance IQ scores of pediatric bipolar patients on the WISC were reported to be similar to those seen in schizophrenia spectrum disorders, and lower than those in ADHD, CD, ODD, and unipolar depression (McCarthy, et al., 2004; Meyer, et al., 2004).

Pavuluri et al. (2006) administered tests to assess attention, memory, visuospatial perception, and motor skills to pediatric BD patients who were medicated and euthymic, pediatric BD patients who were unmedicated and symptomatic, and healthy controls. Contrary to expectations, children with pediatric BD, regardless of medication and illness status, showed impairments in the domains of attention, executive functioning, working memory, and verbal learning compared to healthy individuals. Subjects with BD and ADHD performed worse on tasks assessing attention and executive function than patients with BD alone. Thus, there appear to be similar neurocognitive deficits in unmedicated acutely ill subjects and subjects who are medicated and clinically stable. However, this study used two separate cross-sectional groups of medicated and unmedicated patients. A design based on longitudinal follow-up of untreated patients through controlled treatment would be informative.

Rich et al. (2007) had children with severe mood dysregulation (broad phenotype; N=21), narrow-phenotype BD (N=35), and healthy comparison subjects (N=26) complete an attentional task that manipulated emotional demands (subjects were given verbal feedback regarding their response accuracy versus subjects won or lost money based on their performance) and induced frustration (on a portion of correct responses, subjects were informed that they were too slow and lost money). The researchers measured mood response, behavior, and brain activity in response to the task. Both patient groups reported more arousal than healthy subjects during frustration. When frustrated, narrow-phenotype children showed brain activity suggestive of impairment in executive attention. Regardless of emotional context, broad-phenotype subjects evidenced impairments in the initial stages of attention. The authors concluded that the pathophysiology of irritability may differ between severe mood dysregulation and narrow-phenotype BD.

TREATMENT

Treatment of adolescent bipolar disorder is based on pharmacotherapy and, where possible, psychotherapy. Here, we briefly review what is known about pharmacologic and psychosocial treatments. For a more comprehensive review, see Kowatch et al. (2005; practice guidelines for child psychiatrists).

Pharmacotherapy

In 2003, a group of 20 clinicians and Child and Adolescent Bipolar Foundation members met to develop a set of guidelines for the diagnosis and pharmacological treatment of pediatric BD (Kowatch, et al., 2005). The Assessment section of the guidelines provides a very useful adjunct to the DSM-IV criteria, providing suggestions for establishing symptom thresholds (i.e., how frequent or severe does a symptom have to be to count as present?) in making a diagnosis of childhood-onset patients. The guidelines also provide medication treatment algorithms for pediatric Bipolar I. For acute phase treatment of manic or mixed symptoms without psychosis, monotherapy with a mood stabilizer or atypical antipsychotic is the first step, with lithium or divalproex as the recommendation of the majority of the panel. A decision tree is provided to guide the clinician through succeeding stages of therapy, based on whether the patient responds to the initial treatment, partially responds, or shows no response. For children with acute manic or mixed symptoms with psychosis, the initial treatment should be a combination of a mood stabilizer and an atypical antipsychotic. Again, a decision tree provides guidance on how and when to augment with added medication(s).

There was insufficient evidence to develop a treatment algorithm for children with Bipolar I who are acutely depressed, but based on data on adults, lithium was recommended as a treatment option. Also covered are pharmacological treatment of comorbid disorders, maintenance/continuation treatment, and common side effects.

Randomized trials of various pharmacological agents have been undertaken, although a thorough review is beyond the scope of this chapter. (See Pavuluri, Birmaher, and Naylor, 2005 for a presentation of the published pharmacotherapy trials in pediatric bipolar disorder.) In the pharmacotherapy of adolescent mania, the best evidence is for lithium, divalproex, and atypical antipsychotics. Quetiapine (an atypical antipsychotic) appears to be effective alone or in conjunction with divalproex (Delbello, Schwiers, Rosenberg, & Strakowski, 2002; DelBello et al., 2006). A 61% rate of response was observed in an open-label trial of olanzapine (an atypical antipsychotic) for manic youths (Frazier et al., 2001). In a small sample of adolescents with bipolar depression, 84% responded to eight weeks of lamotrigine (a mood stabilizer/anticonvulsant) treatment, with decreases in depression, mania, and aggression (Chang, Saxena, and Howe, 2006).

Psychotherapy

Several psychosocial treatments for BD have been shown to be effective with adults. Effectiveness is generally measured as longer time to relapse, more time well, improved functioning and/or fewer or less severe symptoms/episodes. Included are Cognitive-Behavioral Therapy (CBT) (Lam, Hayward, Watkins, Wright, & Sham, 2005), Interpersonal and Social Rhythm Therapy [IPSRT; (Frank et al., 2005) an enhancement of Interpersonal Psychotherapy for Depression (Weissman, Markowitz, & Klerman, 2000) modified for BD], Family-Focused Therapy [FFT; (Miklowitz, George, Richards, Simoneau, & Suddath, 2003) an approach that involves the patient and his/her family and consists of psychoeducation about BD and training in communication and problem-solving skills], and group psychoeducation. The application of these approaches to pediatric BD is just beginning to receive attention.

Miklowitz, Biuckians, & Richards (2006) found in a small-scale open trial that adolescents with bipolar episodes who received FFT (family sessions consisting of education about BD, practice using four communication skills, and implementing family problem solving) and pharmacotherapy stabilized over 24 months in mania symptoms (Cohen’s d = 1.19), depressive symptoms (d = 0.87) and Child Behavior Checklist Problem Behavior scores (d= 0.99). This approach is now being examined in a 3-site randomized trial. In an open trial of FFT in combination with individual CBT, adjunctive to optimized pharmacotherapy, West, Henry, & Pavuluri (2007) observed improvements in symptoms (mania, aggression, psychosis, depression) and global functioning among bipolar children aged 5–17. These improvements were observed immediately following the 12-session treatment and at 1, 2, and 3 years. This child- and family-focused cognitive-behavioral therapy integrates principles of FFT and CBT and focuses on the specific problems of children and families coping with BD. It is based on a biological theory of excessive reactivity to stimuli in interaction with environmental stressors in eliciting symptomatic states.

Fristad, Gavazzi, & Mackinaw-Koons (2003) examined multifamily psychoeducation groups (MFPG) as adjunctive to pharmacotheraoy. Parents and children were provided with specific educational content, coached to practice communication skills, given workbooks containing materials presented in the sessions, and asked to complete family projects during the week. Parents in theMFPG’s reported a greater understanding of mood disorder, more positive family interactions, and increased use of appropriate psychosocial and medical services than waiting-list parents.

Feeny, Danielson, Schwartz, Youngstrom, and Findling (2006) developed a manualized, individually delivered cognitive behavioral intervention for adolescents with BD and tested it in an open trial, as an adjunct to pharmacotherapy. The treatment included skill-oriented training (problem-solving, social skills, relaxation, and relapse prevention) to improve mood symptoms and functioning. . Using existing data, baseline characteristics and outcome were compared to a matched group of eight adolescents with BD who did not receive any psychosocial intervention. They concluded that the treatment was associated with symptom improvement in adolescents with BD and warrants evaluation in randomized controlled trials.

Clearly, the development and validation of psychosocial treatments for pediatric BD is a priority. Given the disadvantages of polypharmacy for the younger age groups (for example, significant weight gain, rash, possibly increased suicide risk with antidepressants), the importance of developing effective psychosocial interventions is critical. Although all the psychosocial treatments tested to date have been adjuncts to pharmacotherapy, effective psychosocial agents could hopefully reduce the number of medications needed to stabilize patients with young-onset bipolar disorder.

PREVENTION

Researchers are now beginning to identify and study populations at high risk for developing BD, in particular offspring of parents with BD, as a means of identifying populations with whom preventative interventions would be cost-effective. Kindling theory (Post, 1992) postulates that mood disorders are created by an interplay between a susceptible genetic diathesis and environmental stressors, which over time lead to the crossing of a neurobiological threshold for a mood episode. With the onset of each successive episode of mania or depression, biological changes accrue, leading to more frequent and spontaneous episodes which may or may not be elicited by environmental stressors.

Chang, Steiner, and Ketter (2003) reviewed the research on numerous characteristics of bipolar offspring. Offspring of BD parents had elevated scores on the clinical scales of the Child Behavior Checklist (Dienes, Chang, Blasey, Adleman, and Steiner, 2002); tended toward temperaments that resulted in suboptimal reactions to psychosocial stressors, as measured from infancy to adolescence (Chang, Blasey, Ketter, and Steiner, 2003; Zahn-Waxler, Cummings, McKnew, and Radke-Yarrow, 1984; Gaensbauer, Harmon, Cytryn, and McKnew, 1984); and had poorer psychosocial functioning (Pellegrini et al., 1986).

Based on findings such as those reported above, bipolar offspring often appear to have subsyndromal and possibly prodromal forms of BD. Chang et al. (2003) investigated pharmacological interventions in this high-risk population. They reported clinical improvement after a 12-week open trial of divalproex in 78% of a cohort of 23 bipolar offspring with mood or behavior disorders. However, no placebo comparison was provided.

Findling et al. (2007) examined divalproex as monotherapy for children at risk for bipolar disorder (i.e., diagnosis of BD NOS or cyclothymia and a first-degree relative with bipolar disorder). in comparison with placebo ina randomized trial. No differences were observed over 5 years in time to medication discontinuation due to new mood episodes. Mood and psychosocial functioning ratings did not differ over time between the two groups, although both improved with time.

This study suggests that early pharmacological intervention may have no advantages over placebo in preventing the first onsets of bipolar disorder, although the issue has not been adequately examnined. Psychosocial prevention studies for at-risk youth will be an important direction for the next wave of research on early-onset BD.

CONCLUSIONS

The advances in our understanding of BD in adolescence are encouraging, yet challenges remain. We need to learn more about the youth who often receive a diagnosis of BD in the community, but who better fit the criteria for “severe emotion dysregulation.” What is their long-term outcome? Do the narrow versus broad phenotype children fall along the same continuum, or will neuropsychological and brain imaging studies reveal discontinuities? We need to articulate the multiple developmental pathways by which children arrive at a BD diagnosis in adolescence. In particular, how informative is age of onset, particularly pre- versus post- puberty, in illuminating course, prognosis, and treatment responsiveness? Is it possible to intervene with children at risk for developing BD, and forestall or eliminate the emergence of the disorder?

Further controlled studies of adjunctive psychotherapy approaches to adolescent BD are needed. It will be particularly important to examine which approaches work for which subgroups of this population, taking into account broad versus narrow phenotype and comorbid conditions. Early intervention may be a key to altering the deleterious course and functional impairments of BD over the lifespan.