Current concepts in the validity, diagnosis and treatment of paediatric bipolar disorder

 
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International Journal of Neuropsychopharmacology (2003), 6, 293–300. Copyright f 2003 CINP
DOI : 10.1017/S1461145703003547

Current concepts in the validity, diagnosis and
treatment of paediatric bipolar disorder

Joseph Biederman, Eric Mick, Stephen V. Faraone, Thomas Spencer, Timothy E. Wilens
and Janet Wozniak
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston, MA, USA and Harvard Medical School, Boston,
MA, USA

Abstract

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Despite ongoing controversy, the view that paediatric bipolar disorder is rare or non-existent has been
increasingly challenged not only by case reports but also by systematic research. This research strongly
suggests that paediatric bipolar disorder may not be rare but that it may be difficult to diagnose. Since
children with bipolar disorder are likely to become adults with bipolar disorder, the recognition and
characterization of childhood-onset bipolar disorder may help identify a meaningful developmental
subtype of bipolar disorder worthy of further investigation. As recommended by Robins and Guze
[American Journal of Psychiatry (1970), 126, 983–987], a psychiatric disorder may be considered a valid
diagnostic entity if it can be shown to have differentiating features, evidence of familiality, specific treat-
ment responsivity and a unique course. The goal of this article is to review our work and the extant
literature within this framework to describe the evidence supporting bipolar disorder in children as a
valid clinical diagnosis.
Received 28 July 2002 ; Reviewed 29 October 2002 ; Revised 25 March 2003 ; Accepted 30 March 2003
Key words : Adolescents, ADHD, bipolar disorder, children, conduct disorder.

Introduction                                                               Historical overview

Despite continued debate and controversy over the                          Over the last two decades, the view that bipolar dis-
diagnosis of bipolar disorder in children (Biederman,                      order in children is extremely rare or non-existent has
1998; Klein et al., 1998), exhaustive reviews support                      been increasingly challenged by many case reports and
the existence of the disorder in youth (Faedda et al.,                     series. DeLong and Nieman (1983) described a series of
1995; Geller and Luby, 1997; Weller et al., 1995). Yet,                    children presenting with severe symptoms highly sug-
lingering concerns remain as to its validity. As rec-                      gestive of bipolar disorder and responsive to lithium
ommended by Robins and Guze (1970), a psychiatric                          carbonate. Carlson (1984) suggested that prepubertal
disorder may be considered a valid diagnostic entity if                    bipolar disorder may be characterized by severe irri-
it can be shown to have differentiating features, evi-                      tability, absence of episodes and high levels of hyper-
dence of familiality, specific treatment responsivity                       activity. Similarly, Akiskal et al. (1985) reported on the
and a unique course. Considering that the controversy                      case histories of a large group of adolescent relatives of
surrounding this disorder and diagnostic nihilism in-                      ‘classic ’ adult bipolar patients. They found that de-
hibits the study and treatment of these children, ap-                      spite frank symptoms of depression and bipolar dis-
plication of these criteria to this condition is sorely                    order, and frequent mental health contacts, none of
needed. The purpose of this review is to summarize                         these youth had been diagnosed with an affective
our programme of research and the research of others                       disorder. Weller et al. (1986) then reviewed over 200
within this framework in order to document what is                         articles published between the years of 1809 ad 1982
known regarding bipolar disorder in children.                              and identified 157 cases which would probably be
                                                                           considered manic by modern standards. However,
                                                                           48 % of those subjects retrospectively diagnosed as
Address for correspondence : Dr J. Biederman, Pediatric
                                                                           manic according to DSM-III criteria were not con-
Psychopharmacology Unit (ACC 725), Massachusetts General
Hospital, 15 Parkman Street, Boston, MA 02114-3139, USA.
                                                                           sidered so at the time of referral. Taken together, these
Tel.: 617-726-1731 Fax : 617-724-1540                                      reports suggested that paediatric bipolar disorder may
E-mail : biederman@helix.mgh.harvard.edu                                   not be rare, but difficult to diagnose.
294   J. Biederman et al.

Differentiating features                                     provide a valuable touchstone for evaluating the val-
                                                            idity of the diagnosis made in children, since bipolar
Atypical clinical presentation
                                                            disorder in adolescence has been more readily ac-
The atypicality (by adult standards) of the clinical        cepted (Ballenger et al., 1982; McGlashan, 1988). Far-
picture of childhood bipolar disorder has long been         aone et al. (1997b) compared the features of the mania
recognized (Davis, 1979; Weinberg and Brumback,             in children with the diagnosis, in adolescents with
1976). Notably, the literature consistently shows that      child-onset bipolar disorder, and in adolescents with
bipolar disorder in children is seldom characterized by     adolescent-onset bipolar disorder. With the exception
euphoric mood (Carlson, 1983, 1984). Rather, the most       of more euphoria among adolescents with adolescent-
common mood disturbance in manic children is severe         onset bipolar disorder, the frequencies of other symp-
irritability, with ‘affective storms ’, or prolonged and     toms of mania were strikingly similar between child
aggressive temper outbursts (Davis, 1979). The type of      and adolescent youth with bipolar disorder. As was

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irritability observed in manic children is very severe,     the case for children, the clinical presentation of bi-
persistent, and often violent (Wozniak et al., 1995a).      polar disorder among adolescents with childhood-
The outbursts often include threatening or attacking        onset was rarely biphasic ; it was usually chronic
behaviour towards family members, other children,           and mixed with a simultaneous onset of depression
adults and teachers. In between outbursts, these chil-      and mania (Faraone et al., 1997b). These results sug-
dren are described as persistently irritable or angry in    gested that despite atypicality the profile of manic
mood (Carlson, 1983, 1984; Geller and Luby, 1997).          features associated with childhood bipolar disorder
Thus, it is not surprising that these children frequently   may in fact represent a clinically meaningful manic
receive the diagnosis of conduct disorder. Aggressive       syndrome.
symptoms may be the primary reason for the high rate           While the adult course of paediatric bipolar dis-
of psychiatric hospitalization noted in manic children      order awaits data from longitudinal studies, the adult
(Wozniak et al., 1995a).                                    literature provides some interesting clues on the sub-
   In addition to the predominant abnormal mood in          ject. A review by McElroy et al. (1992) described
paediatric bipolar disorder, its natural course is also     ‘ mixed mania’, which affects 20–30 % of adults with
atypical compared with the natural course of adult          bipolar disorder. Subjects with mixed mania tend to
bipolar disorder. The course of paediatric bipolar dis-     have a chronic course, absence of discrete episodes,
order tends to be chronic and continuous rather than        onset of the disorder in childhood and adolescence, a
episodic and acute (Carlson, 1983, 1984; Feinstein and      high rate of suicide, poor response to treatment, and
Wolpert, 1973; McGlashan, 1988). For example, in a re-      an early history of neuropsychological deficits highly
cent review of the past 10 yr of research on paediatric     suggestive of attention deficit hyperactivity disorder
bipolar disorder, Geller and Luby (1997) concluded that     (ADHD). Thus, McElroy et al. (1992) identified a manic
childhood-onset bipolar disorder is a non-episodic,         syndrome in adults that shows the atypical features
chronic, rapid-cycling, mixed manic state. Such find-        of paediatric bipolar disorder. These findings suggest
ings have also been reported by Wozniak et al. (1995a)      that paediatric cases with bipolar disorder may de-
who found that the overwhelming majority of 43              velop into adults with mixed mania and thereby pro-
children from an outpatient psychopharmacology              vide further evidence that the atypical manic features
clinic who met diagnostic criteria for bipolar disorder     of children constitute a valid disorder.
on structured diagnostic interview, presented with
chronic, and mixed presentation. Carlson et al. (2000)
                                                            Comorbidity with ADHD
reported that early-onset manics were more likely to
have comorbid behaviour disorders in childhood and          A leading source of diagnostic confusion in childhood
to have fewer episodes of remission of a 2-yr period        bipolar disorder is its symptomatic overlap with
than were adult onset cases of bipolar disorder. Thus,      ADHD. Systematic studies of children and adolescents
paediatric bipolar disorder appears to present with an      show that rates of ADHD range from 60 to 90 % in
atypical picture characterized by predominantly irri-       paediatric patients with bipolar disorder (Borchardt
table mood, mania mixed with symptoms of major              and Bernstein, 1995; Geller et al., 1995; West et al.,
depression, and chronic as opposed to euphoric, bi-         1995; Wozniak et al., 1995a). Although the rates of
phasic, and episodic course.                                ADHD in samples of youth with bipolar disorder is
   Although the atypical features noted in children         universally high, the age at onset modifies the risk for
with manic-like symptoms raises the possibility of          comorbid ADHD. For example, while Wozniak (1995a)
misdiagnosis, adolescents with bipolar disorder may         found that 90 % of children with bipolar disorder also
Validity of bipolar disorder in children   295

had ADHD, West et al. (1995), reported that only 57 %          The potential for different rates of comorbidity
of adolescents with bipolar disorder were comorbid          with bipolar disorder in the combined-subtype, in-
with ADHD. Examining further developmental aspects          attentive-subtype and hyperactive impulsive-subtype
of paediatric bipolar disorder, Faraone et al. (1997 b)     of ADHD requires further research. Faraone et al.
found that adolescents with childhood-onset bipolar         (1998a) studied 301 ADHD children and adolescents
disorder had the same rates of comorbid ADHD as             consecutively referred to a paediatric psychopharma-
manic children (90 %) and that both these groups            cology clinic. Among these, 185 (61 %) were the com-
had higher rates of ADHD than adolescents with              bined type, 89 (30 %) the inattentive type and 27 (9 %)
adolescent-onset bipolar disorder (60 %). Furthermore,      the hyperactive/impulsive type. Bipolar disorder was
Sachs et al. (2000) reported that, among adults with        highest among combined-type youth (26.5 %) but was
bipolar disorder, a history of comorbid ADHD was            also elevated among hyperactive-impulsive (14.3 %)
only evident in those subjects with onset of bipolar        and inattentive (8.7 %) youth.

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disorder before age 19 yr. The mean onset of bipolar
disorder in those with a history of childhood ADHD
                                                            Comorbidity with conduct disorder (CD)
was 12.1 yr (Sachs et al., 2000). Similarly, Chang et al.
(2000) studied the offspring of patients with bipolar        Like ADHD, CD is also strongly associated with paedi-
disorder and found that 80 % of manic children had          atric bipolar disorder. This has been seen separately in
comorbid ADHD and that the onset of bipolar dis-            studies of children with CD, ADHD and bipolar dis-
order in adults with bipolar disorder and a history of      order. Wozniak et al. (1995a) reported that pre-
ADHD was 11.3 yr. These findings suggested that age          adolescent children satisfying structured interview
of onset of bipolar disorder, rather than chronological     criteria for bipolar disorder often had comorbid CD.
age at presentation, may be the critical developmental      Kovacs and Pollock (1995) reported a 69 % rate of CD
variable that identifies a highly virulent form of the       in a referred sample of manic youth and found that
disorder that is heavily comorbid with ADHD.                the presence of comorbid CD heralded a more com-
   One problem facing studies of ADHD and bipolar           plicated course of bipolar disorder. Similar findings
disorder is that these disorders share diagnostic cri-      were reported by Kutcher et al. (1989) who found that
teria. Of seven DSM-III-R criteria for a manic episode,     42 % of hospitalized youths with bipolar disorder
three are shared with the DSM-III-R criteria for            had comorbid CD. The Zurich longitudinal study,
ADHD : distractibility, motoric hyperactivity, and talk-    found that hypomanic cases had more disciplinary
ativeness. To avoid counting symptoms twice toward          difficulties at school and more thefts during their
the diagnosis of both ADHD and bipolar disorder, two        juvenile years than other children (Wicki and Angst,
different techniques of correcting for overlapping di-       1991). These reports are consistent with the well-
agnostic criteria have been used to evaluate the associ-    documented comorbidity between CD and major de-
ation between ADHD and paediatric bipolar disorder          pression (Angold and Costello, 1993) considering that
(Biederman et al., 1996).                                   juvenile depression often presages bipolar disorder
   In the subtraction method, overlapping symptoms          (Geller et al., 1994; Strober and Carlson, 1982).
are simply not counted when making the diagnosis. In           Biederman et al. (1997, 1999) investigated the over-
the proportion method, overlapping symptoms are             lap between bipolar disorder and CD in a consecutive
not counted but the diagnostic threshold is lowered to      sample of referred youth and in a sample of ADHD
require that the same proportion of symptoms from           subjects to clarify its prevalence and correlates. They
the reduced set is as that required for the original di-    found a striking similarity in the features of bipolar
agnosis (Milberger et al., 1995). Using these methods,      disorder regardless of comorbid CD. Additionally, the
Biederman et al. (1996) showed that 48 % of children        age at onset of bipolar disorder was similar in sub-
with bipolar disorder continued to meet criteria by         jects with or without comorbid CD. In both groups,
the subtraction method and 69 % by the proportion           mania presented with a predominantly irritable mood,
method. A total of 89 % of children with bipolar dis-       a chronic course, and was mixed with symptoms of
order maintained a full diagnosis of ADHD using the         major depression. Only two manic symptoms differed
subtraction method and 93 % maintained the ADHD             between these groups : ‘physical restlessness ’ and
diagnosis by the proportion method. Taken together          ‘poor judgement ’ were more common in the bipolar
these results suggest that the comorbidity between          disorder with CD group compared to the bipolar
ADHD and paediatric bipolar disorder is not a meth-         disorder-only group. Similarly, there were few differ-
odological artifact due to diagnostic criteria shared by    ences in the frequency of CD symptoms between CD
the two disorders.                                          youth with and without comorbid bipolar disorder.
296   J. Biederman et al.

Although children with CD and bipolar disorder had a        data from a longitudinal sample of boys with and
higher rate of ‘vandalizing ’ compared to CD-only sub-      without ADHD, Wozniak et al. (1999) identified paedi-
jects, this difference was not statistically significant.     atric bipolar disorder as an important antecedent
   Both the comorbid and non-comorbid subjects with         for, rather than consequence of, traumatic life events.
mania had high rates of major depression, anxiety           This temporal relationship between bipolar disorder
disorders, oppositional disorder, and psychosis than        and traumatic events could have important clinical
CD and ADHD children (Biederman et al., 1997, 1999).        and therapeutic implications. When traumatized chil-
In addition bipolar disorder comorbid with CD was           dren present with severe irritability and mood lability,
associated with poorer functioning and an increased         there may be a tendency by clinicians to attribute these
risk for psychiatric hospitalization (Biederman et al.,     symptoms to having experienced a trauma. Longi-
1997). Subjects with both CD and bipolar disorder also      tudinal research, however, suggests the opposite;
had a higher familial and personal risk for mood dis-       bipolar disorder may be an antecedent risk factor for

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orders than other CD subjects who had a higher per-         later trauma and not represent a reaction to the trauma
sonal risk for antisocial personality disorder (Faraone     (Wozniak et al., 1999).
et al., 1998b).
   Taken together, these studies suggest that subjects
                                                            Familial aggregation
who receive diagnoses of both CD and bipolar dis-
order may, in fact, have both disorders. While the          Although there are no twin or adoption studies of
resolution of this important issue awaits further re-       paediatric bipolar disorder, family studies strongly
search, the mere diagnosis of bipolar disorder in some      suggest that the paediatric onset form of the disorder
CD children offers important therapeutic possibilities       has a strong familial component (Faraone et al., 1997a ;
since delinquency and bipolar disorder require very         Strober, 1992; Strober et al., 1988 ; Todd et al., 1996;
different treatment strategies.                              Wozniak et al., 1995b). Strober (1992), Strober et al.
                                                            (1988) and Todd et al. (1993) proposed that paediatric
                                                            bipolar disorder might be a distinct subtype of bipolar
Paediatric bipolar disorder and trauma
                                                            disorder with a high familial loading. In examining the
Although it has been long suspected that bipolar dis-       comorbidity between bipolar disorder in children and
order in children may be the result of trauma and           ADHD or CD, we have reported on the familiality
associations between trauma and bipolar disorder            of bipolar disorder in families ascertained via child
have been reported in adults, there has been relatively     probands (Faraone et al., 1997a, 2001; Wozniak et al.,
limited systematic research of this issue. Kessler          1995b).
et al. (1995) found elevated lifetime rates of bipolar         We first examined the familiality of bipolar disorder
disorder among adult and adolescent subjects with           in children in a pilot sample of 16 families ascertained
post-traumatic stress disorder (PTSD). Helzer et al.        via a child proband with the disorder (Wozniak et al.,
(1987) reported a strong association between manic-         1995b). We compared the relatives of manic children
depressive illness and PTSD in adult subjects but did       to the relatives of ADHD children without bipolar
not determine if bipolar disorder was primary or sec-       disorder and to normal controls. Among the 46 first-
ondary to the trauma. This report further suggested         degree relatives of 16 children with bipolar disorder,
that behavioural problems including ‘stealing, lying,       13 % (n=6) met criteria for bipolar disorder with as-
truancy, vandalism, running away, fighting, misbe-           sociated impairment. This differed significantly from
haviour at school, early sexual experience, substance       both the ADHD (2 %; n=7) and normal control (3 %;
abuse, school expulsion or suspension, academic             n=7) groups. The relatives of ADHD and control
underachievement, and delinquency ’ prior to age            probands did not differ in their risk for bipolar dis-
15 yr predicted later PTSD (Helzer et al., 1987). Not       order. Almost identical findings were obtained in two
surprisingly, the authors concluded that ‘this associ-      independently defined family studies of ADHD pro-
ation may mean that persons with such behaviour in          bands with and without comorbid bipolar disorder
childhood had a greater likelihood of experiencing          (Faraone et al., 1998b, 2001). In a sample of boys with
trauma later on’.                                           ADHD and their relatives, we found an increased
   Since juvenile bipolar disorder is commonly associ-      family risk of bipolar disorder in children with bipolar
ated with extreme violence and severe behavioural           disorder (16 %) compared to relatives of non-manic
dysregulation (Wozniak et al., 1995a) as well as hyper-     children (3 %). Likewise, among families ascertained
sexuality, bipolar disorder in children could either be a   via girls with ADHD the rate of bipolar disorder
reaction to, or a risk factor for, trauma exposure. Using   in relatives of ADHD girls with comorbid bipolar
Validity of bipolar disorder in children   297

disorder was significantly greater (13 %) than either          follow up, only 29 % (the 45 % of the recovered 65 %
ADHD girls without bipolar disorder (5 %) or in the           that did not relapse) of the original sample would be
relatives of normal control girls (3 %) (Faraone et al.,      considered in remission, overall. In our study, the
2001).                                                        definition of remission that most closely replicates
   From these three studies, we estimate that the rate        what Geller et al. (2002) studied was syndromatic
of bipolar disorder in relatives of manic children was        remission that we estimated to be 27 % at 2 yr.
2.6–5.3 times higher than in non-manic children. Thus,           While the literature examining the long-term follow-
the evidence from these samples clearly indicates that        up of children with bipolar disorder is scant it docu-
the disorder may be highly familial.                          ments that the disorder is not transient. Even the most
                                                              optimistic definition of remission (syndromatic re-
                                                              mission), was attained by only 30 % of subjects over a
Longitudinal course
                                                              2-yr period. That less than 20 % of subjects attained

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Recently, Geller et al. (2002) reported on the 2-yr out-      functional remission or euthymia over the entire time-
come of a longitudinal sample of children with paedi-         period evaluated provides further evidence that paedi-
atric bipolar disorder. This study found that by the          atric bipolar disorder is a chronic mood disorder with
last follow-up period 65 % of subjects recovered from         a poor prognosis.
bipolar disorder but that 55 % relapsed after recovery.
However, since this study focused exclusively on full
                                                              Treatment response
syndromatic persistence of manic symptomatology, it
did not address the possibility of continued affective         In a series of controlled clinical trials Campbell and
instability in the form of sub-syndromal symptoms of          colleagues (Campbell et al., 1984, 1995; Cueva et al.,
the disorder and its associated impairments.                  1996) documented the efficacy of mood stabilizers
   We recently estimated the course of bipolar dis-           (lithium carbonate and carbamazepine) in the treat-
order in children with ADHD over a period covering            ment of aggressive CD children. However, these psy-
10 yr ( J. Biederman et al., unpublished observations)        chiatrically hospitalized CD youth were treated for
with different forms of persistence. As recently pro-          severe, uncontrollable and disorganized aggression
posed by Keck et al. (1998) the distinction between           and not necessarily for delinquency. Thus, it is poss-
different types of remission may clarify components of         ible that the therapeutic benefits observed in these
complex recovery processes. These investigators sug-          children with anti-manic treatments could have been
gested three levels of remission for psychiatric dis-         due to the anti-manic effects in treating aggressive
orders : syndromatic, symptomatic and functional.             manic children satisfying criteria for CD.
Syndromatic remission refers to the loss of full diag-            Biederman et al. (1998) systematically reviewed the
nostic status, symptomatic remission refers to the loss of    clinical records of all paediatrically referred patients
partial diagnostic status ; functional remission refers to    who, at initial intake satisfied diagnostic criteria for
the loss of partial diagnostic status plus functional re-     bipolar disorder based on a structured diagnostic in-
covery (full recovery). For bipolar disorder, another         terview with the mother. Mood stabilizers were fre-
critical dimension in assessing patterns of remission is      quently used in these children and their use was
the persistence of depressive symptomatology since            associated with significant improvement of manic-like
some subjects may remit from mania but may continue           symptoms that their psychiatrists had recorded in the
to manifest depression. Thus, Euthymia was defined by          medical record. In contrast, antidepressants, typical
failing to meet criteria for manic episode or for major       antipsychotics, and stimulants were not associated
depressive episode at follow-up.                              with improvement of manic-like symptoms. For both
   We found that the course of bipolar disorder was           lithium carbonate and carbamazepine higher and
chronic, protracted, and dysfunctional. Although 50 %         more therapeutic doses predicted greater decreases in
of bipolar youth remitted from the full syndrome of           the manic-like symptoms recorded by the treating
bipolar disorder at follow up (i.e. they no longer met        clinician in the medical record.
full diagnostic criteria), 80 % failed to attain functional       Although treatment with mood stabilizers was as-
remission or euthymia over a course of 10 yr. Our re-         sociated with a statistically significant decrease in
sults were in line with those of Geller et al. (2002) who     manic-like symptoms, this improvement was slow to
reported that 65 % of a sample of 89 subjects with            develop and was associated with frequent relapses.
prepubertal onset bipolar disorder had recovered by           Although somewhat discouraging, these findings
the 2-yr follow-up assessment, but that 55 % reported a       are consistent with outcome data from naturalistic
relapse during the same interval. Thus, at the 2-yr           follow-up studies of bipolar children and adults
298   J. Biederman et al.

(Strober et al., 1990, 1995). For example, the survival     once issues surrounding the validity of bipolar dis-
analysis from Biederman et al. (1998) indicated that        order in children are adequately addressed.
65 % of the children would improve if treated with
lithium carbonate for 2 yr. This finding is remarkably
                                                            Summary
consistent with results from DeLong and Aldershof
(1987) who reported a 66 % response rate for manic          The emerging literature indicates that bipolar disorder
children treated with lithium carbonate over a 10- to       can be identified in a substantial number of referred
70-month treatment period and with findings re-              children using systematic assessment methodology.
ported by Strober et al. (1995) showing that multiple       Thus, this disorder may not be as rare as previously
relapses were most often seen in subjects with mixed        considered. Children with bipolar disorder frequently
mania.                                                      demonstrate an atypical picture by adult standards
   More optimistic findings have resulted from in-           with a chronic course, severely irritable mood, and a

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vestigations of atypical neuroleptics in the treatment      mixed picture with depressive and manic symptoms
of juveniles with bipolar disorder. In a retrospective      co-occurring, and increased risk to relatives. Initial
chart review study of 28 youths with bipolar disorder,      clinical evidence suggests that atypical neuroleptics
82 % of subjects showed improvement in both manic           may play a unique therapeutic role in the management
and aggressive symptoms with risperidone treatment          of such youth. The high level of comorbidity with
(Frazier et al., 1999b). In contrast to the duration of     other disorders is common, further requiring the cau-
treatment required for improvement with mood stabil-        tious use of a combined pharmacotherapy approach.
izers, the average time to optimal response was 1.9¡        More research is needed to build a scientific foun-
1.0 months of therapy. Moreover, no serious adverse         dation for the notion that paediatric bipolar disorder
effects were observed. Similarly encouraging results         is a valid developmental subtype of bipolar disorder.
were reported by Frazier et al. (1999a) in an open trial    With this foundation and continued pilot research of
of olanzapine monotherapy. They found that treat-           promising psychopharmacological interventions, the
ment with olanzapine was associated with significant         field will be able to ethically conduct large-scale, ran-
improvements in both the Children’s Depression In-          domized clinical trials and, only then, will proven
ventory and the Young Mania Rating Scale in 23 manic        treatment options emerge.
children after 8 wk of monotherapy on doses ranging
from 2.5 to 20 mg/d.
   Similarly, Findling et al. (2000) recently reported      References
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