Despite ongoing controversy, the view that pediatric mania is rare or non-existent has been increasingly challenged not only by case reports but also by systematic research. This research strongly suggests that pediatric mania may not be rare but that it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include:

• - its pattern of comorbidity may be unique by adult standards, especially its overlap with ADHD, aggression and conduct disorder;

• - its overlap with substance use disorders;

• - its association with trauma and adversity;

• - its response to treatment is atypical by adult standards.

These issues will be reviewed in the presentation.

The appearance, the differential diagnosis and the prevalence of bipolar disorder in children and adolescents is discussed. Among adolescents bipolar disorder appears to have a similar prevalence in the US and The Netherlands. However, among children it is frequently diagnosed in the US and hardly in The Netherlands. It is concluded that bipolar disorder tends to start earlier in the US than in the Netherlands. It is hypothesized that this may be related to a higher use of stimulants and antidepressants by US children diagnosed as ADHD or depression, respectively.

Introduction: There are no definitively established acute or maintenance treatments for juvenile bipolar disorder.

Method: Two randomized, blind, maintenance clinical trials in children and adolescents with bipolar disorders are ongoing at the University Hospitals of Cleveland/Case Western Reserve University Stanley Clinical Research Center for bipolar disorder. The first is comparing the safety and effectiveness of lithium carbonate (Li+) to divalproex sodium (VPA) for up to 76 weeks in youths with stabilized bipolar illness (type 1 or 2). The second study is designed to compare the efficacy of VPA to placebo in the acute management of subsyndromal symptoms of bipolar disorder (‘cyclotaxia’) and the prevention of the full syndrome in children at risk. Both studies use the prospective life-chart method as an outcome measure.

Results: Sixty-six youths have received study medication as part of the trial that is comparing Li+ to VPA as a maintenance therapy. In addition, 32 youths have received blinded treatment as part of the ‘cyclotaxia’ prevention study. Combination Li+A/PA treatment appears generally well tolerated and seems to have robust anti-manic and antidepressant effects.

Discussion: Since the blind has not been broken on either of these clinical trials, conclusions about the maintenance effectiveness of either VPA or Li+ in youths with bipolar disorder type 1 or 2 cannot be made yet. Similarly, it is unclear whether VPA is superior to placebo in genetically high-risk youths with cyclotaxia. The final results of these trials should provide valuable information about the treatment of juvenile bipolar disorders.

Substantial evidence exists for a cohort effect (earlier onset and increased prevalence) for both unipolar and bipolar affective disorder in every generation born since World War II. This effect could be related to inherited mechanisms (e.g., bi-Hneal pedigrees or genetic anticipation) or to environmental/experiential effects on gene expression (e.g., stressor effects on the induction of transcription and growth factors, enzymes, hormones and their receptors, and signal transduction molecules) as documented in preclinical models of neonatal maternal separation.

This laboratory evidence is summarized and new clinical data on the impact of severe stressors on the unfolding course of bipolar illness are noted. The reported occurrence of childhood or adolescent physical or sexual abuse, compared to those who report their absence, is associated with: earlier bipolar illness onset; faster cycling (including ultradian) patterns; increased Axis I and II comorbidities; and increased time ill in a prospective year of follow-up. Selectively, physical abuse was associated with a reported pattern of increasingly severe mania and sexual abuse with increased numbers of serious suicide attempts.

In a retrospective survey of parents of children with an approximate average age of 13 who were diagnosed with bipolar illness (compared to those with other diagnoses and those with no diagnosis), a cluster of symptoms related to irritability and dyscontrol differentiated the bipolar children earliest. These symptoms included: temper tantrums, irritability, inattention, hyperactivity, impulsivity, poor frustration tolerance, and increased aggression.

Given the growing evidence that episodes of affective dysfunction can not only convey morbidity and mortality, but may also sensitize to further recurrence and thus change the course of illness, opportunities abound for early recognition and intervention in childhood onset bipolar illness. Such a successful endeavor would both allow a more normal psychobiological development and allow the possibility of preventing the unfolding of more full-blown bipolar illness altogether.

The purpose of this study was to determine psychopathology in a large sample of adolescent children (N = 140) of parents (N = 86) with bipolar disorders, using multiple sources of information (child, parent, teacher). The main aims of the study were: 1) to compare parent, teacher and self reported problem behavior ratings of children of bipolar parents with those of children from the general population, and 2) to determine the prevalence of DSM-IV diagnoses in offspring of bipolar parents, and 3) to examine the possible association between gender of the bipolar parent and psychopathology among the offspring.

We report the results of an acute-phase and continuation-phase study of the pharmacological treatment of children and adolescents with bipolar disorders. The acute phase study, with a duration of 6-8 weeks, aimed at developing effect sizes (ES) for lithium, divalproex sodium, and carbamazepine, in the acute phase treatment of Bipolar I or II children and adolescents during a mixed or manic episode. During the acute-phase of treatment, 42 outpatients with a mean age of 11.4 yr. (20 with Bipolar I Disorder and 22 with Bipolar II Disorder) were randomly assigned to 6-8 weeks of open treatment with either lithium, divalproex sodium, or carbamazepine. The primary efficacy measures were the weekly CGI Improvement scores and the Young Mania Rating Scale. Using a ≥ 50% change from baseline to exit in the Y-MRS scores to define response, the effect size for divalproex sodium was 1.63,1.06 for lithium, and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat sample, the response rates were: sodium divalproex 53%; lithium 38%; and carbamazepine 38% (x 2=0.85, 2 d.f., p=0.60). Thirty-five subjects continued in open, treatment for another 16-18 weeks, for a total of 24 weeks of prospective treatment. Overall, of the thirty-five continuation phase subjects, thirty (85%) were categorized as responders at the end of the continuation phase of treatment. Of these thirty-five subjects, 13 (37%) were only on a single mood stabilizer and no other psychotropic agents at the end of the continuation phase. Thirty-one percent of subjects in continuation were also treated with a stimulant medication in addition to mood stabilizers.