Course and Outcome of Bipolar Disorder in Adolescents

Boris Birmaher, M.D.
Bibliography

Abstract
There are very few follow-up studies of bipolar adolescents. These studies have shown that this disorder is characterized by high rates of mixed and rapid cycling episodes, long time to recovery, high rates of chronicity, high rates of relapse, poor response to lithium, substance abuse, increased risk for suicide, and social, family, and academic impairment. However, further studies are still needed.

In this study, 3 centers: Brown University, Western Psychiatric Institute and Clinic (WPIC), and the University of California Los Angeles (UCLA) recruited 73 adolescents with BP-I and followed them for an average of 76.6 + 61.6 weeks (range: 4-224 weeks). At intake and every 4 months thereafter, patients were assessed with instrument to ascertain psychopathology, general functioning, health services utilization, treatment, and family burden. Despite the fact that approximately 70%-80% of the BP-I adolescents recovered, approximately 80% of each BP-I subgroup (mixed, manic, and depressed) experienced a recurrence of illness. Furthermore, most patients continued to have fair to poor social adjustment and there was substantial family and economic burden, indicating the need of continuous multimodal treatments for youth with this disorder. Paralleling results of the adult literature, patients with mixed BP had the poorest prognosis, with longer time to recuperate from the index episode and shorter time to relapse after the index episode remitted. Furthermore, patients with mixed BP disorder had the worse social adjustment, indicating the need of aggressive treatment for this population. Most of the follow-up time (approx. 96%) patients were treated with medications, in particular lithium or valproate. Importantly, despite our efforts to avoid polypharmacy treatment, approximately 40% of the time patients required at least 3 medications to control their symptoms.

Diagnosis and Follow-Up of a Prepubertal and Early Adolescent Bipolar Disorder Phenotype

Barbara Geller, M.D.
Bibliography

Abstract
Background: Findings from controlled, prospective study of subjects with a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP) will be presented. The contrast groups were attention deficit hyperactivity (ADHD) and community comparison (CC). There were 268 subjects (93 PEA-BP, 81 ADHD and 94 CC). Methods: The PEA-BP phenotype was defined by current DSM-IV mania or hypomania with elation and/or grandiosity as one criterion. The latter ensured that child mania was not diagnosed using only criteria that overlapped with those for ADHD (e.g., irritability, distractibility) and that subjects had at least one of the two cardinal features of mania (i.e., elated mood and/or grandiosity). PEA-BP and ADHD subjects were ascertained by consecutive new case methods to ensure generalizeabilty of the findings and CC were obtained from a random survey. A comprehensive assessment battery included the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) given separately to mothers about their children and to children about themselves by research nurses who were blind at baseline and who had established interrater reliability. Results: Findings supported the main study hypotheses. Discrete episodes of either mania or depression, with sudden onsets and clear offsets, similar to modal presentations in adults, were uncommon in PEA-BP and phenotypic similarity to severe, treatment resistant, continuously cycling adult-onset BP was frequent. PEA-BP subjects also had low recovery and high relapse rates that were unrelated to naturalistic anti-manic drug treatment. Psychosocial functioning was significantly worse in multiple domains in the PEA-BP compared to the ADHD and CC groups. Comment: Although it might seem intuitive that child-onset mania would be a less serious illness than late-teenage/adult-onset BP, this was clearly not the case. What remains to be answered is whether these child-onset mania subjects will go on to resemble modal late-teenage/adult-onset BP or continue to be chronic and mixed/cycling.
Key Words: child, adolescent, mania, diagnosis, follow-up, psychosocial, treatment.

Bipolar Disorder: A Developmental and Psychoendocrine Perspective

Ian M. Goodyer, M.D. F.Med.Sci.
Bibliography

Abstract
Bi-polar disorder in adolescence has a prevalence of around 1% compared with 2% in the adult population (Lewisohn et al 2000). The prevalence in childhood is unclear but clinical studies indicate that in this younger age group, major depression confers a higher than expected risk for bipolar disorder in late adolescence and early adult life (Geller et al 2000, 2001). It is well established that subjects with bipolar syndromes have a difficult and protracted illness with high recurrence rates in many cases and a consequent negative impact on general adjustment throughout life. Overall these findings indicate the importance of early identification of school aged subjects in the community at risk for subsequent bipolar syndromes, as well as more detailed attention to the management of current and apparent unipolar mood disordered cases. Public health prevention strategies may benefit from adopting a stratified high risk detection procedure which is a more efficient epidemiological approach to ascertaining those young people most liable for subsequent affective disorders (Goodyer et al 2000). Detection is the first step in prevention but is insufficient to determine the risk mechanisms and processes that result in disorder. For example the origins and implications of rapid mood cycling in the developing young person is one of many important questions that needs to be addressed in high risk and clinical studies. Whether elevated moods and depressed moods arise from the same neural, chemical and psychological processes remains unclear. Recent advances in psychological measurement of young people will be described that may help us determine what might govern the apparent loss of connection between the emotional and the thinking brain that leads to mood dysregulation and cognitive symptoms. In addition the potential role of the steroid hormone cortisol in episodic memory distortions leading to cognitive vulnerability consistent with unipolar and bi-polar depressions will be discussed.

References
Geller B., Zimmerman B., Williams M., et al (2001) Bipolar disorder at prospective folow up of adults who had prepubertal major depressive disorder. American Journal of Psychiatry, 158, 125-127.

Geller B., Craney J., Bolhofner K., et al (2000) One year recovery and relapse rates of children with a prepubertal and early adolescent bipolar disorder phenotype. American Journal of Psychiatry, 158, 303-305.

Lewinsohn PM., Klein DN., Seeley JR (2000) Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar disorders 2, 281-293.

Goodyer IM., Herbert J., Tamplin A et al., (2000) Recent life events, cortisol, dehydroepiandrosterone and the onset of major depression in high-risk adolescents. British Journal of Psychiatry, 177, 499-504.

Pharmacological Treatments of Children and Adolescents with Bipolar Disorders

Robert A. Kowatch, M.D.
Bibliography

Abstract
Pediatric bipolar disorders are now recognized as equally as prevalent in children and adolescents with an an estimated prevalence of 1% (Kashani JH, 1987; Lewinsohn, Klein, & Seeley, 1995) These disorders very difficult to treat pharmacologically and this may be because they are complicated in both their initial presentation and clinical course, and their overall response rate to mood stabilizers is fairly low, even by adult standards(B. Geller et al., 1998; Kowatch et al., 2000). These patients often have comorbid disorders that complicate their diagnosis and treatment response. These comorbid disorders include attention-deficit hyperactivity disorder (ADHD), anxiety disorders, and conduct disorders (Kovacs & Pollock, 1995; West, McElroy, Strakowski, Keck, & McConville, 1995; Wozniak et al., 1995). ADHD is the most common comorbid disorder among these patients with some groups finding comorbid rates as high as 98% (Wozniak et al., 1995) . Other cause of these patients’s treatment resistance may be because they often present with a mixed or “dysphoric” picture characterized by frequent short periods of intense mood lability and irritability rather than classic euphoric mania (Faedda et al., 1995).

We have recently completed two Stanley funded treatment studies in children and adolescents with bipolar disorders. In the first study, thirty-five outpatient subjects from our acute 8-week study (Kowatch et al., 2000) continued in open, prospective 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.

The objective of our second study was to determine the safety and efficacy of adjunctive treatment with Adderall vs. placebo in pediatric subjects with bipolar I or II disorder first treated with sodium divalproex. Thirty subjects, ages 7 to 15 years, with DSM-IV diagnoses of Bipolar I or II Disorder and ADHD were treated openly with divalproex for 6-8 weeks. Once euthymic, but still manifesting ADHD symptoms, they were randomized to Adderall or placebo in a double blind crossover design. The Young Mania Rating Scale was the primary outcome measure for manic symptoms. The Conner’s Parent and Teacher Rating Scales were the primary outcome measures for ADHD symptoms. Twenty-two of 23 subjects continued to suffer significant morbidity due to ADHD symptoms after their manic symptoms were treated with divalproex. Twenty-one of the original 30 subjects were deemed clinical responders to open treatment with divalproex monotherapy. No significant adverse events were reported. No subjects discontinued open treatment due to side effects.

Pediatric subjects with Bipolar Disorder I or II can obtain significant reductions in mania symptoms with divalproex monotherapy. We will present data on the efficacy of Adderall treatment from the double-blind phase of the study.

These studies were funded by a grant from the NAMI/Stanley Research Foundation.

References
Faedda, G. L., Baldessarini, R. J., Suppes, T., Tondo, L., Becker, I., & Lipschitz, D. S. (1995). Pediatric-onset bipolar disorder: A neglected clinical and public health problem. Harvard Rev Psychiatry, 3, 171-195.

Geller, B., Cooper, T. B., Sun, K., Zimerman, M. A., Frazier, J., Williams, M., & Heath, J. (1998). Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J. Am. Acad. Child Adolesc. Psychiatry, 37(2), 171-178.

Kashani JH, B. N., Helper E, et al. (1987). Psychiatric disorders in a community sample of adolescents. Am J Psychiatry, 144, 584-589.

Kovacs, M., & Pollock, M. (1995). Bipolar disorder and comorbid conduct disorder in childhood and adolescence. Journal of the American Academy of Child & Adolescent Psychiatry, 34(6), 715-723.

Kowatch, R. A., Suppes, T., Carmody, T. J., Bucci, J. P., Hume, J. H., Kromelis, M., Emslie, G. J., Weinberg, W. A., & Rush, A. J. (2000). Effect size of lithium, divalproex sodium and carbamazepine in children and adolescents with bipolar disorder. J Amer Acad Child Adol Psychiatry, 39(6), 713-720.

Lewinsohn, P. M., Klein, D. N., & Seeley, J. R. (1995). Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry, 34, 454-463.

West, S. A., McElroy, S. L., Strakowski, S. M., Keck, P. E., Jr., & McConville, B. J. (1995). Attention deficit hyperactivity disorder in adolescent mania. American Journal of Psychiatry, 152(2), 271-273.

Wozniak, J., Biederman, J., Kiely, K., Ablon, J. S., Faraone, S. V., Mundy, E., & Mennin, D. (1995). Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. J Am Acad Child Adolesc Psychiatry, 34(7), 867-876.

What Are the Risk Factors for an Early Development of Bipolar Disorder in Children?

Catrien G. Reichart, M.D.
Bibliography

Abstract
Among adults there is no difference in the prevalence of bipolar disorder between the US and the Netherlands. In the Dutch population a lifetime prevalence for bipolar disorder was found of 1.8% versus 1.6% in the US. In addition, among (older) adolescents bipolar disorder is also recognized both in the Netherlands and in the US. However, there appears to be a difference with respect to the occurrence of bipolar disorder among children. The prevalence of bipolar disorder among children seems to be much lower in the Netherlands than in the US. This suggests that in the US the illness tends to start earlier.

The question is how to explain this apparent difference. There is probably no difference in genetic loading for bipolar disorder as the prevalence among adults is about equal. Families in the US are probably also not more chaotic or distressing than in Europe. One possible explanation for the difference is that in the Netherlands bipolar disorder in (especially) children and adolescents is not recognized as such. However, both countries use similar diagnostic instruments. So there must be another explanation.

In the Netherlands we conducted a survey among the members of the Dutch Association for Manic Depressives and their Relatives (VMDB). The purpose of this survey was to obtain an indication of the prevalence of bipolar disorder and associated symptoms among a high risk group, i.e. the offspring of a parent with a bipolar disorder. Among 342 respondents we were able to identify 14 subjects with 'sub-threshold bipolar disorder' before the age of 20, while none of them fulfilled this criterion before the age of 12. These Dutch data suggest that bipolar disorder before puberty hardly exists in the Netherlands, even not among high risk children. In contrast, in a group of 198 children of a parent with a bipolar disorder, our US colleagues found 78 children with a bipolar disorder below the age of 20. This corresponds to a prevalence of about 39%. A huge difference with the 4% in the Dutch survey.

Another indication for a later start of bipolar disorder comes from the first results of our ongoing study in 140 high-risk children, mostly adolescents. In this study we did not find a higher rate of psychopathology than what has been found in the general population in the Netherlands. Only mood disorders were slightly more elevated (29% life time diagnoses and 14% current diagnoses).

Another explanation for the difference between the Netherlands and the US may be the much higher use of stimulants as well as antidepressants by US children. Our hypothesis is that in children who are genetically predetermined to develop bipolar disorder, the use of stimulants and related drugs such as antidepressants, brings this disorder to expression already before the age of 12.

If our hypothesis is true, one should be careful in prescribing these drugs to such children when they are hyperactive and one should also put more emphasis on psycho-social approaches. When one decides to prescribe a stimulant or antidepressant to such children, one should be aware of the possible development of a (hypo)manic episode as a first episode of bipolar disorder. Finally one should consider also the prescription of a mood stabilizer prior to or in combination with a stimulant or antidepressant.

Reference
Reichart CG, Nolen WA, Wals M, Hillegers MHJ. Bipolar disorder in children and adolescents: a clinical reality? Acta Neuropsychiatrica, 2000, 12: 132-135.

Panel Discussion

Discussant:  Martha Hellander
Bibliography
 

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