Prepubertal Bipolar Disorder, Research on Prepubertal Bipolar Disorder

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Roundtable on Prepubertal Bipolar Disorder

Research on prepubertal bipolar disorder

On April 27, 2000, the National Institute of Mental Health (NIMH) Developmental Psychopathology and Prevention Research Branch, in collaboration with the Child and Adolescent Treatment and Preventive Intervention Research Branch, convened a small roundtable meeting to discuss possible approaches to outstanding issues for research on prepubertal bipolar disorder.

The major questions were:

How early can bipolar disorder be diagnosed?
What is the predictive value of the early manifestations of bipolar illness in children (before puberty) in adolescents?
What is the risk/benefit ratio of treating children and adolescents with "prodromal" symptoms? Which treatments should be considered? For how long?
What is the potential impact of early treatment on course of illness?

Participants

Joseph Biederman, M.D., Boris Birmaher, M.D., Gabrielle Carlson, M.D., Kiki Chang, M.D., Barbara Geller, M.D., Kenneth Kendler, M.D., Robert Kowatch, M.D., David Kupfer, M.D., and Elizabeth Weller, M.D. NIMH participants were Wayne Fenton, M.D., Kimberly Hoagwood, Ph.D., Steven Hyman, M.D., Doreen Koretz, Ph.D., Ellen Leibenluft, M.D., Richard Nakamura, Ph.D., Editha Nottelmann, Ph.D., Ellen Stover, Ph.D., Benedetto Vitiello, M.D., and Gemma Weiblinger.

Meeting Summary

Open-ended discussion centered on two inter-related issues: (a) clinical assessment for treatment disposition and (b) definition of phenotype for resolving questions of nosology (the treatment questions remain to be addressed). Relevant to both is ascertainment (whether clinic-based, school-based, or community- or population-based) with specification of inclusion and exclusion criteria.

There was general agreement that a diagnosis of bipolar disorder, using DSM criteria, is possible in prepubertal children. Children seen in clinics fall into two categories: (1) those who clearly have a bipolar disorder (because they meet DSM-IV criteria for Bipolar I or II) and (2) those who may be bipolar, but do not fit the adult phenotype defined in DSM-IV. That is, some children meet full criteria for Bipolar-I or Bipolar-II, as currently defined; and children who do not meet full criteria, but suffer from mood disturbances and symptoms of bipolar disorder and are severely impaired, currently receive a diagnosis of "Bipolar-NOS." One estimate was that approximately 40% of children presenting at clinics with bipolar disorder are likely to be in the first category and approximately 60% in the second category.

Discussion resulted in agreement on two basic definitions:

a narrow phenotype that adheres strictly to Bipolar-I and Bipolar-II criteria; and
a broader phenotype that encompasses more heterogeneity, basically Bipolar-NOS, and includes children who do not quite meet criteria, but still are severely impaired by symptoms of mood instability.

Narrow phenotype: Consensus on the narrow phenotype was that it can be diagnosed with available psychiatric assessment instruments; e.g., the semi-structured K-SADS. For clear communication, however, it was suggested that it should be important to establish thresholds for boundaries between bipolar disorder subtypes (Bipolar-I, Bipolar-II, cyclothymia), as homogeneity is essential for biological and genetic research.

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Broader phenotype: Currently, severely impaired children with impairing mood disturbance, but not meeting full DSM-IV criteria for Bipolar I or II, are not included in research studies because of the perceived uncertainty of their diagnosis. Still, there is a need to study these children because of their significant impairment. They should be included in appropriate research protocols. In general, it was agreed that "Bipolar-NOS" could be used as a "working diagnosis" for advancing research on this broader phenotype, as long as the children are well described (with particular attention to symptoms of ADHD). As available diagnostic instruments may not generate a reliable and replicable diagnosis of Bipolar-NOS, it was recommended that careful assessment include all of the behaviors that are impairing, giving consideration when relevant to the frequency with which they occur as well as to severity; e.g.,

Aggressiveness, agitation, explosiveness
Irritability
Mood lability (fluctuation independent of input)
Thought disorder (paranoia, misinterpretation of social cues)
Communication disorder (pragmatic language disorder than can look like flight of ideas;: receptive and expressive language disorder than can interfere with the accurate performance and interpretation of structured interviews)
Cognitive ability/cognitive impairment (significantly low IQ, reading disabilities)

One approach suggested for building a communication platform was to operationalize in a more refined way dimensions of the various behavior problems seen in these children that may or may not meet specific criteria for disorders. This could be accomplished by collecting instruments for each dimension, preparatory to obtaining general agreement on the assessment of the various dimensions and developing a common battery for multi-informant assessments. Alternatively, it was suggested that these dimensions could be assessed with measures of individual choice and that the Child Behavior Checklist (CBCL), less likely to be affected by measurement and diagnostic differences, could then be used for calibration across sites.

With regard to comorbidity, it was recommended that assessment not rely strictly on DSM criteria to determine absence or presence of co-occurring disorders, as subthreshold clinical conditions may be important as well.

Once there is agreement on exclusion criteria (i.e., certain comorbidities [e.g., Pervasive Developmental Disorder] and/or physical disease) as well as inclusion criteria for the broader phenotype, it should be possible to address questions about etiological relationships among the disorders; e.g., whether Bipolar-NOS or subtypes of Bipolar-NOS are precursors of Bipolar-I and/or Bipolar II or have a different course. It was noted, for instance, that whereas classic manic-depressive course includes well periods, these children tend to have none. Moreover, it should be possible to identify and fully characterize children who have bipolar symptoms and are severely impaired and to follow them prospectively, with attention to developmental stages and transitions, in order to resolve whether they have a childhood-onset variant of bipolar disorder.

Validation studies also should take developmental manifestations into consideration. It was suggested that studies could go down in age range as far as four years of age. Reconstruction of the history of adults with early-onset bipolar illness may be useful as well. For example, in studies of offspring of bipolar parents, in which all of their children should be included, parents should be asked also about their own age at onset. In studies of both children who appear to have bipolar illness and children who may have bipolar illness, it was considered important that the children as well as their parents be interviewed with developmentally appropriate measures.

Diagnostic Instruments Currently Used in Studies of Bipolar Disorder in Children

Following the meeting, Dr. Geller, with assistance from Dr. Birmaher, assembled information about instruments currently in use in NIMH-funded studies of childhood-onset bipolar disorder. Their report can be found at http://www.nimh.nih.gov/bipolarchild.cfm. The most commonly used diagnostic instrument is the KSADS; in most cases the WASH-U-KSADS or with the addition of the WASH-U-KSADS mood disorders and rapid cycling sections. Ancillary instruments that are being used include the CBCL, Mania Rating Scale, KSADS mania rating scale, and CGAS. It appears that assessment of mood lability is a challenge at all age levels.

Questions to be Addressed (via e-mail, conference calls, further meetings)

Outstanding issues include the following:

Describing the course of Bipolar-I, Bipolar-II, cyclothymia, and Bipolar-NOS, with attention to possible developmental changes in symptom expression, with the goal of establishing the predictive validity of bipolar disorder in prepubertal children
Defining thresholds for and boundaries between Bipolar-I, Bipolar-II, and cyclothymia in prepubertal children
Defining occasions for combining versus separating Bipolar-I and Bipolar-II (For instance, in treatment studies of mania, where severity is an issue, combining manic with hypomanic patients may not be appropriate. However, combining should be appropriate when the focus of treatment is on decreasing number of cycles. Data from genetic studies suggest similarities as well as differences between Bipolar-I and Bipolar-II.)
Establishing inclusion and exclusion criteria for Bipolar-NOS (and identifying subtypes?)
Developing a common battery for the assessment of impairing behaviors in children who have and who may have bipolar disorder

According to the Robins and Guze model as expanded by Cantwell (1996), the stages for establishing the validity of disorders includes studies of:

Clinical phenomenology of the disorder: the core clinical picture and it common associated features, subtypes, and comorbidities;
Demographic factors (incidence, prevalence, morbidity risk, and life time expectancy) and documentation of age, gender, social class, ethnicity, and culture;
Biological factors correlated with a particular clinical picture (presence of damage and/or brain dysfunction, physical handicaps and disorders, neurological disorders) and laboratory studies in the areas of neurophysiology, neuroendocrinology, biochemistry, neuropharmacology, brain imaging, and neuropsychology;
Family environmental factors (e.g., discipline styles and other aspects of parent-child interaction);
Family genetics, including family aggregation, adoption, twin, linkage, segregation, gene mapping, etc.
Natural history of the disorder, including true prospective, true retrospective, catch up prospective and anterospective studies to explore continuities and discontinuities between childhood, adolescent, and adult disorders and the mechanism for these continuities and discontinuities;
Response to intervention.

Some of the work is ongoing. This model nevertheless can serve as a touchstone to set goals and mark progress.

Reference: Cantwell, D.P. (1996) Classification of child and adolescent psychopathology. Journal of Child Psychology and Psychiatry, 37, 3-12.

Contact:
Editha D. Nottelmann, Ph.D.
Chief, Mood, Anxiety, and Regulatory Disorders Program
Developmental Psychopathology and Prevention Research Branch
National Institute of Mental Health
6001 Executive Boulevard, Rm. 6200 MSC9617
Bethesda, MD 20892-9617
Tel. 301-443-5944
FAX 301-480-4415
e-mail: enottelm@nih.gov

Updated: October 02, 2000

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