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by mood lability. An undetermined proportion of these children are likely to have
BP disorder.
It is imperative to improve the diagnostic accuracy of BP disorder in youth.
Early-onset BP disorder has severe negative psychosocial and academic conse-
quences that can be potentially ameliorated by proper diagnosis and treatment
(Table 10.2). In addition to delay in proper treatment, BP youth who are mis-
diagnosed as simply ADHD or depressed often receive stimulant medication and/
or antidepressants that, without concomitant mood-stabilizer treatment, may
worsen the course of illness.
To identify BP disorder in youth, clinicians as well as researchers need to take
into account the following issues:
(1) As stated before, it appears that the manic/hypomanic symptoms in youth
frequently do not persist long enough to meet the time duration criteria required
by the DSM-IV for a manic and hypomanic episode (Klein et al., 1985; Geller
et al., 1995, 1998a, b; Wozniak et al., 1995; Geller and Luby, 1997; Axelson et al.,
1998; Biederman, 1998). These shorter periods of mania or hypomania can be
easily overlooked and patients can be misdiagnosed with unipolar depressions,
ADHD plus MDD, and personality disorders (e.g., borderline).
(2) Childhood-onset BP disorder is frequently manifested by mixed or very-
rapid-cycling episodes of very short duration instead of the classical DSM-
IV mixed and rapid-cycling DSM-IV classification (Akiskal et al., 1985; Klein
242 B. Birmaher and D. Axelson


et al., 1985; Bowring and Kovacs, 1992; Carlson and Weintraub, 1993;
Carlson, 1995; Geller et al., 1995, 1998a, b; 2000a, b; 2002a, b; Lewinsohn
et al., 1995, 2000; Weller et al., 1995; Wozniak et al., 1995; Axelson et al., 1998).
(3) Most children and adolescents with BP disorder have comorbidity with
ADHD and behavior-disruptive disorders (Bowring and Kovacs, 1992;
Carlson, 1995; Geller et al., 1995, 1998a, b, 2002a; Kovacs and Pollock, 1995;
Lewinsohn et al., 1995, 2000; Weller et al., 1995; Wozniak et al., 1995; Axelson
et al., 1998; Biederman, 1998). These comorbid conditions usually confound
the diagnosis of BP disorder in youth.
(4) It appears that early-onset BP disorder conveys a worse course and outcome
than BP disorder that started during adulthood (Geller et al., 2002a, b).
(5) The child™s emotional, cognitive, and behavioral developmental stages need to
be taken into consideration when assessing symptoms of BP disorder (e.g.,
fantasies versus grandiosity; Bowring and Kovacs, 1992; Carlson, 1995).
(6) Environmental factors (e.g., family conflicts, parental psychopathology, nega-
tive life events) may affect the clinical presentation and course of illness
(Geller et al., 2002b).
(7) Overdiagnosis of BP disorder in children and adolescents also has serious
consequences, as youth with other psychiatric conditions are unnecessarily
exposed to medications with significant risk for side-effects and do not receive
potentially therapeutic treatments for their actual disorder.



Longitudinal course
Lewinsohn et al. (1995) evaluated 1709 high-schoolers (ages 16.6 Æ 1.2 years old,
54% females, 91% Caucasian) with the K-SADS Present and Epidemiological ver-
sions and found 1% (18) with BP disorder (mainly BP-II and cyclothymia) and 5.7%
(97) with subsyndromal BP symptoms. These patients were reinterviewed 14 months
after intake and compared with 316 subjects with MDD and 845 normal controls.
The BP patients had the worse course, with a median duration for their index episode
of illness of 80 weeks. Also they had more functional impairment, psychosis, suicid-
ality, comorbid anxiety and disruptive disorders, and mental health utilization than
the other two groups (Fig. 10.3). The subjects with subsyndromal BP symptoms had
levels of impairment and comorbidity that were comparable to the BP group.
Strober et al. (1995) reported results from a 5-year naturalistic, prospective
follow-up of a small sample (n ¼ 54) of inpatient adolescents with BP-I disorder
utilizing semiannual assessments. Although the absolute likelihood of recovery
(! 8 weeks with < 2 symptoms) was high in the sample as a whole, 20% of the
sample had suicide attempts requiring medical attention and time to recovery
243 Bipolar disorder in children and adolescents


Suicide attempts Global assessment of function
90
50 87.5***
88
44.4
Percentage of subjects
45
86
40 83.6***
84
35
82
30
80
25
22.2* 78
20
76 74.9
15
74
10
72
5
70
0 1.2***
68
Bipolar MDD Never BP MDD NMI
mentally
ill

Fig. 10.3 Bipolar disorder in high-school students. MDD, major depressive disorder; BP, bipolar
disorder; NMI, never mentally ill. Asterisks, significant P-values less than 0.05.


varied significantly by polarity of the index episode. Recovery was most rapid in
subjects with pure mania (mean, 9 weeks) or mixed states (mean, 11 weeks) at
intake, followed by subjects who were cycling at the time of presentation (mean,
15 weeks). In contrast, a strikingly protracted time to recovery was observed in
subjects with pure depression at intake (mean, 26 weeks). Forty-four percent of the
subjects who recovered from their index episode had one or more relapse by
completion of the 5-year follow-up. Subjects with cycling or mixed episodes at
intake had the highest probability of recurrence (mixed/rapid cyclers: 60% versus
40% around week 60 after intake). If minor depression and hypomania were
included, the recurrence was approximately 60% for patients whose index episode
was mania or depression, 70% for mixed, and 80% for rapid cyclers.
Geller et al. (2002a) followed a group of 93 outpatients aged 10.9 Æ 2.7 years old
(57% prepubertal, 39% females, 89% Caucasian) every 6 months for 2 years. Most
of the sample (! 70%) had comorbid disorders with ADHD and/or oppositional
defiant disorder, psychosis (60%) and rapid cycling (77%). At intake the mean
duration of the index episode was 3.6 years. After 1 year, approximately 37% of the
sample showed recovery (no mania or hypomania and a Child-Global Assessment
Scale (C-GAS) ! 60 for 2 weeks) but the rates of relapse/recurrence were 38%.
After 2 years of follow-up, the proportions of subjects who recovered from mania
and who relapsed after recovery were 65.2% and 55.2%, respectively. The mean
time to recovery was 36 weeks. Relapse occurred after a mean of 28 weeks. Living
with an intact family improved the chance of recovery and low level of maternal
warmth increased the risk to relapse. Only 50% of the sample was treated with
antimanic medications and there were no demographic or clinical predictors of
relapse/recurrence.
Recently a multicenter pilot study (Birmaher, 2001) evaluated 73 outpatient
adolescents with BP-I (mean age 17.1 Æ 1.8 years, 75% female, 84% Caucasian)
244 B. Birmaher and D. Axelson


with the K-SADS Present and Epidemiological version and followed them every
4 months with the Longitudinal Interval Follow-up Evaluation (LIFE) for 4“224
weeks (mean 76 Æ 62 weeks). Approximately 68% of the subjects recovered (LIFE
psychiatric status rating ¼ 1“2 for 8 weeks) in 20“40 weeks. It took significantly
longer for the mixed (mean ¼ 58 weeks) BP patients to recover than those with
manic (mean ¼ 42 weeks) or depressive (mean ¼ 20 weeks) presentations. Despite
the high recovery rate, 59% of the patients had at least one recurrence, with mixed
BP patients having more recurrences and shorter periods before the onset of the
recurrent episode (mania ¼ 79 weeks, depression 30 weeks and mixed 26 weeks,
2 ¼ 6“8, df ¼ 2, P ¼ 0.03). During the follow-up time, almost all patients were on
psychotropic medication and 26% of the follow-up time patients received three
medications (e.g., mood stabilizer, antidepressants, and stimulants). Moreover,
70% had hospitalizations and the patient™s BP illness caused a severe family,
interpersonal, and economic burden.
In summary, the few longitudinal studies have helped to validate the diagnosis
of BP disorder in youth and have shown that this illness, in particular the mixed
and rapid-cycling subtypes, is protracted and causes significant psychosocial and
academic impairment.


Family history
Very few bottom-up (first-degree relatives of children and adolescents) and top-down
(offspring of BP children) studies have been published (DelBello and Geller, 2001).

Bottom-up studies
Strober et al. (1998) found that, compared with adolescents with schizophrenia,
youth with BP disorder have a high prevalence of first- (and second-) degree
relatives with BP disorder. Likewise, Faraone et al. (1997) found that children with
ongoing mood lability and severe temper outbursts diagnosed with ˜˜continuous™™
BP disorder had significantly more first-degree relatives with BP disorder than
children with only ADHD. These results suggest that these children (or at least
some) may indeed be suffering from BP disorder. The problem with this study,
however, is that children were not directly interviewed and the assessment was
only done with the K-SADS-Epidemiologic version (Orvashel et al., 1982) that
does not adequately evaluate BP disorder in children.

Top-down studies
Taking into account all the difficulties in diagnosing BP disorder in children
described above, it appears that, in comparison with offspring of parents with
non-BP disorders, and normal children, offspring of BP parents are five to seven
245 Bipolar disorder in children and adolescents


times more likely to develop BP disorder. However, offspring of BP parents are
also at risk of developing depression, anxiety, and disruptive disorders. The results
of these studies (Table 10.3) should be carefully examined because of the difficul-
ties in diagnosing children with BP disorder and due to the following methodo-
logical problems:
(1) small sample sizes with few young children
(2) lack of longitudinal follow-up
(3) inclusion of a heterogeneous group of parents (BP and unipolar)
(4) lack of controls
(5) retrospective assessments
(6) offspring assessments not conducted blind to parental diagnosis
(7) no direct assessment of offspring
(8) lack of analysis of developmental influences on psychopathology
(9) use of unspecified diagnostic criteria
(10) lack of standardized assessments of psychopathology and family history
(11) no assessments of parental comorbid psychiatric disorders
(12) no psychiatric assessment of the proband™s spouse
(13) no measurement of the effects of environmental stresses
(14) no evaluation of the presence of subsyndromal symptoms and whether
severe disruptive disorder symptoms are part of the clinical picture of BP
disorder during childhood
(15) lack of control for intrafamilial correlations
An ongoing study at the University of Pittsburgh Medical Center, USA, in a large
sample of children of BP and non-bipolar parents, taking into account the above
limitations, will help to clarify the initial symptoms of BP disorder in children. For
example, answers are being sought for questions such as: is the psychiatric symp-
tomatology in the offspring of BP parents the way that BP non-mood disorder
manifests in young children, prodromal symptoms of BP disorder, or the mani-
festations of other non-mood psychiatric disorders?


Treatment
There are no randomized controlled trials (RCT) for bipolar disorder in children
and adolescents. Open studies in samples of children and adolescents with more
typical DSM or Kraepelinian or DSM-type BP syndromes have suggested that
approximately 40“80% respond to lithium, valproate, and carbamazepine
(e.g., Geller and Luby, 1997; Kowatch et al., 2000) Despite the response and overall
tolerance to these medications, most of these patients usually require other
medications to control their mood (e.g., the atypical antipsychotics) or for the
management of their comorbid disorders (e.g., stimulants for ADHD). Patients
Table 10.3 High-risk studies (only those with offspring < 18 years old)

Family
BPD-off- Control Standardized Standardized history/blind
BPD spring: offspring interview: interview: interviews/
parents: sample size (parent™s offspring/direct parents/spouse psychosocial
Author sample size (ages) clinical status) Follow-up interviews diagnosis. a assessment

McKnew et al. (1979) 13 30 (5“15) N Once N/Y Y/N N/Y/N
(4 months
later)
Conners et al. (1979) 59 130 (ages ?) N N N/N Y/N N/N/N
unipolar
+ bipolar
Waters and
Marchenko-Bauer
(1980) 16 50 (> 15) N N Y/Y Y/Y N/N/N
Cytryn et al. (1982) 13 19 (5“13) 21 (˜˜normal™™?) N N/Y Y/N N/Y/N
Decina et al. (1983) 31 24 (7“14) 18 (˜˜normal™™ ?)N N/? N/N N/N/N
Kuyler et al. (1980) 49 49 (6“18) N N N/N Y/Y N/N/N
Zahn-Waxler et al. 7 (1“2.5 Once Lab
7 20 (˜˜normal™™?) Y N/N/N
(1984) years old) (2.5 years observation
old)
Kashani et al. (1985) 5 9 (7“17) 41 (unipolar) N Y/Y ?/Y N/Y/N
LaRoche et al. (1985) 22 39 (5“18) N N N/Y Y/N N/?/Y
Gershon et al. (1985) 20 29 (6“17) 37 (˜˜normal™™) N Y/Y Y/Y N/Y/N
Klein et al. (1985) 24 37 (15“21) 22 (psychiatric) N Y/ Y/Y N/Y/N
Pellegrini et al. (1986) 16 23 (7“18) 33 (˜˜normal™™?) N Y/Y YY ?/Y/Y
LaRoche et al. (1987) 21 37 (8“25) N Twice Y/Y Y/Y Y/N/Y
(3“7 years)
Hammen et al. Unipolar (22) q 6 months ‚
13 18 (8“16) Y/Y Y/Y N/N/Y
(1987, 1990) medical (14) 3 years
normal (36)
Nurnberger et al. (1988) 23 53 (15“25) 1“2 years 1“3 years Y/Y Y/Y N/?/N
Zahn-Waxler et al. 7 7 (5“6 12 (psychiatric Twice Y/Y Y/Y N/Y/N
(1988) years old) disorders)
Gregoroiu-Serbanecu
47 72 (10“17) 72 (˜˜normal™™?) N Y/Y N/Y Y/N/Y
et al. (1989)
Radke-Yarrow et al. Once (3 years Y/Y/N
2 44 (1.5“8) 80 (unipolar) N/Y Y/Y
(1992) later)
Todd et al. (1996) 60 50 (6“17) N N Y/Y Y/N Y/N/N
Chang et al. (2000) 37 60 N N Y/Y ?/N N/N/N

a
Not all the spouses were interviewed.
N, no; Y, yes; BPD, bipolar disorder.
248 B. Birmaher and D. Axelson


with mixed presentations and/or rapid cycles appear to have a poorer response
to the mood stabilizers. More recently, open studies have shown that BP children
and adolescents may respond to the atypical antipsychotics (e.g., Frazier et al.,

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